Polyunsaturated ecdysteroids for use in treatment

Abstract

Polyunsaturated ecdysteroids for use in treatment The present invention relates to polyunsaturated ecdysteroid compounds for use in hormonal, metabolic, inflammatory and oxidative stress related conditions, as well as pharmaceutical compositions comprising said compounds.

Description

[0001]Polyunsaturated ecdysteroids for use in treatment FIELD OF THE INVENTION The present invention relates to polyunsaturated ecdysteroid compounds for use in hormonal, metabolic, inflammatory and oxidative stress related conditions, as well as pharmaceutical compositions comprising said compounds. BACKGROUND OF THE INVENTION Oxidative stress has been described as an important factor in the onset and progression of many diseases, and it appears to be a common causative phenomenon in neurodegenerative disorders ^Deli, 2005; Cahlíková et al., 2011^, and plays an important role in obesity and inflammation. Obesity is a major risk factor for many non-communicable diseases e.g., metabolic, cardiovascular, musculoskeletal, Alzheimer's diseases, depression, dementia, obstructive sleep apnea and some types of cancer that are altogether responsible for over 70% of mortality worldwide ^Fitch et al., 2022^. Overweight and obesity affect almost 60% of adults and nearly one in three children in the WHO European Region. Early studies from several countries in the Region indicate that the prevalence of overweight and / or high mean body mass index has increased in children and adolescents during the COVID-19 pandemic ^WHO 2022^. In obesity, the average, healthy adipocytes are transformed into large dysfunctional ones with disturbance in the levels of the released adipokines; the levels of leptin and pro-inflammatory adipokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1β are elevated whereas adiponectin level is decreased ^Lustig et al., 2022^^Tun et al., 2020^. The increased levels of pro-inflammatory cytokines lead to a state of chronic low-grade inflammation and subsequently to a state of oxidative stress with increased reactive oxygen species. Both conditions potentiate each other and link obesity to many co-morbidities including type two diabetes mainly through insulin resistance in addition to other mechanisms ^Tun et al., 2020^. The increased levels of pro-inflammatory cytokines lead to a state of chronic low-grade inflammation and subsequently to a state of oxidative stress with increased reactive oxygen species. Both conditions potentiate each other and link obesity to many co-morbidities ^Tun et al., 2020^. Oxidative stress is also an important factor in degenerative disorders of the brain [Deli, 2005][Cahlíková et al., 2011]. Brain capillaries are expressing antioxidant enzymes like catalase, superoxide dismutase and the antioxidant tripeptide glutathione, which are part of the metabolic line of defense at the blood-brain barrier (BBB) [Pohl et al., 2018]. The reduction in the expression of these enzymes as a consequence of BBB damage contributes to the promotion of the oxidative stress and the appearance of reactive oxygen species (ROS) [Sweeney et al., 2019]. The knock-out of specific glutathione and cysteine transporters such as excitatory amino- acid carrier-1 (EAAC1) causes impaired neuronal glutathione metabolism, neurodegeneration, brain atrophy, behavioral changes, BBB damage and susceptibility to brain ischemia and oxidative stress [Aoyama et al., 2006][Choi et al., 2014]. Besides these observations, a disturbance in permeability, the activity of efflux and influx pumps at the BBB was observed in animal models of central nervous system (CNS) pathologies, which along with the oxidative stress provides further evidence that there is a direct causal relation between the BBB damage and the CNS disorders [Sweeney et al., 2019]. Oxidative stress has been also studied as an initiating factor in Parkinson’s disease, where the appearance of ROS has been correlated with the iron accumulation in the brain [Götz et al., 2004]. Iron levels increase with the severity of neuropathological changes in Parkinson's disease, presumably due to increased transport through the BBB in late stages of Parkinsonism. Iron overload may induce progressive degeneration of nigrostriatal neurons by facilitating the formation of ROS and cytotoxic protein aggregates [Götz et al., 2004]. In the past few years, the idea appeared that the protection of brain endothelial cells in neurodegenerative and other CNS diseases can be a novel and important therapeutic target [Sweeney et al., 2019]. The principle for this is that if a toxic substance is being produced in the body or ingested from the environment, it cannot reach the CNS if BBB prevents it from entering. During neurodegenerative diseases focal BBB breakdown leads to perivascular accumulation of blood-derived toxic products [Zlokovic, 2011][Kisler et al., 2017]. The brain vasculature is a complex network composed of arteries, arterioles, capillaries, venules and veins, which allow the vital distribution of nutrients and oxygen in the CNS [Daneman et al., 2015]. Brain endothelial cells form the functional basis of the BBB together with the surrounding pericytes and astrocytes [Daneman et al, 2015]. The specialized transporters of brain endothelial cells supply nutrients for the brain and keep the ionic homeostasis of the CNS [Deli, 2011]. Vascular disruption has also been found in coronavirus disease. Greene et al. have shown that BBB disruption is present both during acute infection and in patients with long COVID with cognitive impairment^Greene et al., 2024^. Ecdysteroids are polyhydroxylated steroidal hormones of four-ringed cholesterol or other sterols skeleton, typically with a polyhydroxylated cyclopentano-α-perhydrophenanthrene ring system, bearing 27-30 or 27-29 carbon atoms ^Arif et al., 2022^^Tarkowská et al., 2016^ with a long sterol alkyl side chain on C-17, and the presence of a 7-en-6-one chromophore group in ring B [Báthori et al., 2008]^Arif et al., 2022^^Tarkowská et al., 2016^. They are originally found in animals (zooecdysteroids), where they regulate insect molting and metamorphosis, and growth and development in arthropods and other invertebrates. Later it was discovered tobe present in many plants (phytoecdysteroids), where they protect them from insects, nematodes, andenvironmental stresses ^Arif et al., 2022^. Phytoecdysteroids are present at varying concentrations in different plant species including commonly consumed vegetables ^Tarkowská et al., 2016^. So far, over 500 different phytoecdysteroids have been identified in over 100 plants ^Arif et al., 2022^, with 20-hydroxyecdysone being the most common and abundant one ^Arif et al., 2022^^Tarkowská et al., 2016^. Phytoecdysteroids are reported to exert a wide variety of effects in mammals such as effects on protein, lipid, and carbohydrate metabolism. 20-Hydroxyecdysone (20E) is the most abundant phytoecdysteroid ^Csábi et al., 2015^. Its base-catalyzed autoxidation results in many oxidized derivatives including the rare natural ecdysteroid calonysterone (CAL) ^Bathori et al., 2008^. Earlier in vitro and in vivo studies confirmed the non-hormonal anabolic activities of 20-hydroxyecdysoneand other ecdysteroids ^Báthori et al., 2008^^Das et al., 2021^, in terms of stimulation of protein synthesis ^Gorelick-Feldman et al., 2008^^Gorelick-Feldman et al., 2010^, increased weight of the whole body and internal organs ^Syrov, 2000^, and improve skeletal muscle mass and fiber size ^Tóth et al., 2008^^Parr et al., 2014^. The observed anabolic effects encourage their use by sportsmen to enhance their physical performance ^Isenmann et al., 2019^. Obesity is a serious health and social problem in developed countries around the world. Drug therapy is often not possible or cannot be afforded due to poor patient compliance or therapeutic side effects. 20- Hydroxyecdysone (20E) is a worldwide used ‘green anabolic’ dietary supplement that also has beneficial effects in some animal models of metabolic diseases. The anti-obesity effect of 20E was previously demonstrated in C57BL / 6J mice ^Kizelsztein et al., 2009^ and rats ^Buniam et al., 2020^. Csábi et al. ^Csábi et al., 2015^ suggest that various ecdysteroid derivatives differ in their effect in murine skeletal muscle cells; a fact indicating that minor structural changes result in different biological effects. Marschall et al. conclude that there are conflicting reports on the effect of ecdysterone on liver and plasma fat concentrations in different rodent models of obesity, fatty liver and diabetes, and conclude that the effect depends on the rodent model used. The authors tested the hypothesis that ecdysterone has a lipid- lowering effect in genetically obese Zucker rats, and their study clearly showed that ecdysterone administration does not show a lipid-lowering effect in the liver and plasma of lean and obese Zucker rats. This result also suggest that the effect of the compounds is very sensitive to chemical structure ^Marschall et al., 2021^. Buniam J et al. concluded that 20E may be useful in the treatment or prevention of metabolic dysfunction associated fatty liver disease (MAFLD) by improving metabolism and dyslipidemia, and wanted to determine how 20E, as a dietary supplement, affects fat accumulation and lipogenesis in liver and adipose tissue in ovariectomized rats fed a high-fat and high-fructose diet (OHFFD). It was concluded that 20E, which among other beneficial effects reduced liver triglyceride content and visceral fat deposition, showed overall clear beneficial effects in OHFFD-induced MAFLD rats and may represent a promising option for the prevention or treatment of MAFLD ^Buniam J et al., 2023^. WO2009 / 114201 A2 relates to steroid ligands of natural and mutated nuclear receptors and their use in a nuclear receptor-based inducible gene expression system. The invention further relates to methods for modulating the expression of a gene of interest in a host cell using such ligands and corresponding gene switches, and to recombinant gene switch compositions comprising at least one gene switch; and at least one activating ligand, wherein the activating ligand is an ecdysone derivative; among which, among many other exemplary molecules, calonysterone is mentioned. However, there are no specific examples or justifications for these diseases and calonysterone. WO2020 / 231906 relates to nutritional supplements useful for enhancing endurance and recovery, and in certain embodiments for use in connection with human sports performance. Compositions according to the invention may be useful for reducing the likelihood of developing cardiovascular disease, triglyceride or LDL cholesterol levels, pain or inflammation, diabetes, chronic lung disease or irritable bowel syndrome, reducing symptoms of autoimmune disease or allergic conditions. The solution according to the invention teaches and utilizes plant extracts containing ecdysteroids, which include Rhaponticum extract, which may contain calonysterone among many other listed compounds. Specifically, however, the application does not describe the use of calonysterone for the uses disclosed in the present specification. In their preliminary publication, Vágvölgyi et al. ^Vágvölgyi et al., 2023^ from the inventors' research team tested six new ecdysteroid derivatives (an oxime and five oxime ethers) and investigated the modulation of oxidative stress in human brain endothelial cells; most of the compounds sensitized hCMEC / D3 brain microvascular endothelial cells to terc-butyl hydroperoxide (tBHP)-induced oxidative damage, which was assessed by impedance measurements. Tóth G. et al. [Tóth et al., 2023] describe ecdysteroid compounds with similar effects. Although the article refers to 14beta,15-dihydrocalcosterone, a structure very close to calonysterone, it has not been tested. The similar, albeit different compounds tested showed significant protective effects against oxidative stress or inflammation on blood-brain barrier endothelial cells at concentrations of 1 ^M. The present inventors aimed to investigate calonysterone as compared with 20-hydroxyecdysone in normal and obese male rats. Also, the inventors aimed to verify the presence or absence of the effects of these phytoecdysteroids on androgens, estrogens and corticoids. The inventors also investigated the effects of calonysterone and 20-hydroxyecdysone on body weight, blood glucose, antioxidant capacity, levels of adipokines, expression of cytokine (IL6) of low-grade inflammation, and epigenetic modification in a high-fat high-sugar diet (HFHSD) rat model. The effects of ecdysteroids in various CNS related pathologies and functions have been also studied from several aspects. They are suggested to have a regulatory role in the function of inhibitory neurotransmitters by acting on the modulatory site of GABAA receptors during tonic convulsion [Hanaya et al., 1997]. Ecdysones can couple with the cleaving enzyme of β-amyloid peptides and can hinder the amyloid protein aggregation [Chakraborty et al., 2017]. Ecdysterones or vitamin E inhibited the fibril formation and the neurotoxicity of aggregated β-amyloid fragments [Yang et al., 2003]. Ecdysterones protected mice against acute cerebral hypoxia and inhibited the production of lipid peroxides in brain tissue both in vivo and in vitro [Hu et al., 2012]. In another study ecdysterones reduced the content of oxidative stress markers, increased the activity of superoxide dismutase in hypoxia and protected against lipid oxidation following focal cerebral ischemia in rats [Cahlíková etal., 2011]. Ecdysterones also showed an antioxidant and free radical scavenging activity in various in vitro models[Cai et al., 2002][Hu et al., 2012]. The antioxidant and antiradical properties of 20E were also tested in vitamin- D deficient animal models showing positive results [Kuzmenko et al., 2001]. It is hypothesized, that the antioxidant action of 20E is mediated via the modification of the mitochondrial membrane through its lipid content by changing its cholesterol-phospholipid ratio [Zozulya et al., 2001]. Due to the low treatment effectivity and the high cost of current drug therapy in brain-related chronic diseases, researchers started to focus on the use of natural products , since the quality, efficacy and safety of herbal medicines is improving, along with lower research expenses [Di Paolo et al., 2019]. Certain ecdysteroids have been considered as adaptogenic, enhancing the physical performance; promoting vitality and increasing the resistance to stress and aging [Cahlíková et al., 2011][Hu et al., 2012][Csábi et al., 2019]. Information regarding their possible beneficial effects on the BBB and brain endothelial cells is limited and their effect is uncertain, taking into account in particular their high variability and very different effect even in case of minor structural changes. The present invention investigates the effects of 20E [Müller et al., 2017] and its metabolite calonysterone [Issaadi et al., 2019] and their synthetic derivatives for the first time on brain endothelial cell health, barrier integrity, and their possible protective and antioxidant effect on a human in vitro model of the BBB. These experiments are highly relevant in today’s accelerated search for a relief in neurodegenerative disease treatment. Due to the lack of effective treatment and the high health care system costs neurodegenerative diseases pose, new alternatives for their treatment are one of the main focuses in today’s drug research. As common etiopathogenetic markers, oxidative stress and neuroinflammation have been identified in these diseases as part of the aging process. During the recent years BBB disturbance has been taken into consideration, not only as a consequence of neurodegenerative damage but also as a cause [Sweeney et al., 2019]. The use of natural compounds in treating neurodegeneration has a long tradition and support. Many compounds, such as flavonoids, phenols, alkaloids, coumarins even phytosteroids have been tested for several targets with successful results. Especially the use of antioxidants has shown positive effects in in vivo studies [Martel et al., 2019]. Still, the knowledge about the effects of natural compounds on the BBB is still limited. However, the effects of natural and synthetic ecdysteroids on the BBB is largely unknown. Obesity-related health problems also impose a significant financial burden on society. The poor compliance of patients during drug therapy further increases the health damage. Above their many potential therapeutic benefits in multifactorial diseases such as diabetes, natural products and nature-originated therapies also have a strong trend to promote compliance that is of key importance in the success of a long-term treatment. The effects of calonysterone on obesity, and obesity-induced prediabetic / diabetic conditions have not been studied yet. During their studies, the object of the inventors was to test the effect of natural and synthetic ecdysteroids in respect of their effect on oxidative stress related metabolism, in particular on steroid hormones, on obesity, and on brain endothelial cells and on BBB integrity for the first time. Moreover, they have investigated the effects of calonysterone and 20-hydroxyecdysone on body weight, blood glucose, antioxidant capacity, levels of adipokines, expression of cytokine (IL6) of low-grade inflammation, and epigenetic modification in a HFHSD rat model. The inventors have explored effect of ecdysteroids on cell viability, barrier integrity and whether they have protective effects against inflammation or oxidative stress-causing compounds. The present inventor tested various phytoecdysteroids using a human brain endothelial cell line or cerebral microvascular endothelial cell line (hCMEC / D3). The results showed that all investigated compounds (20E and calonysterone) are promising molecules in BBB protection, mainly against oxidative stress. There is still a need for further the improved treatment of obesity by natural products; however, the effect of the vast number of phytoecdysteroids is very different and unpredictable. Moreover, their synthesis is difficult and sensitive. BRIEF DESCRIPTION OF THE INVENTION 1. The invention relates to a compound of formula I.a for use in the treatment of oxidative stress or in thetreatment of an oxidative stress disease, wherein, independently from each other, R1 is selected from the group consisting of H, OH, C1-4 alkyloxy (def), C1-22 alkyloxy, C1-22 acyloxy (def) and a halogen, R2 is selected from the group consisting of H, OH, C1-20 acyloxy, OR22, C1-4 alkyloxy, C1-20 acyloxy and a halogen, wherein R22 is selected from a formyl, C22-C2 alkylcarbonyl, C22-C3 alkenylcarbonyl or C22-C1 alkynylcarbonyl, preferably a C18-C2 alkylcarbonyl, C18-C3 alkenylcarbonyl, more preferably a C18-C8 alkylcarbonyl or a C6-C2 alkylcarbonyl; R3 is selected from the group consisting of H, OH, C1-20 acyloxy, OR23,C1-4 alkyloxy, C1-20 acyloxy and a halogen, wherein R22 is selected from a formyl, C22-C2 alkylcarbonyl, C22-C3 alkenylcarbonyl or C22-C1 alkynylcarbonyl, preferably a C18-C2 alkylcarbonyl, C18-C3 alkenylcarbonyl, more preferably a C18-C8 alkylcarbonyl or a C6-C2 alkylcarbonyl; or wherein R2 and R3 form acetonide , R4 is selected from H and CH3, R5 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen and the 14- 15 bond is a single bond, or R5 is nothing and the 14-15 bond is a double bond, R6 is H, R7 is selected from the group of moieties wherein, independently from each other, R10 is CH3, R11 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, R12 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, R13 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy or R13 is nothing and the 25-26 bond is a double bond halogen, wherein R11 and R12 may form acetonide, and moieties having the formula (2.1) wherein R15 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, preferably R15is selected from H, halogen, OH and CH3,preferably H, F and CH3,more preferably R15 is H, wherein preferably if the 14-15 bond is a single bond, then it is a 14^,15-bond (i.e. a 14^,15-dihydro variant), R8 is selected from H and CH3, R9 is selected from H and CH3. Preferably, if the 14-15 bond is a single bond, then it is a 14^,15-bond (i.e. a 14^,15-dihydro variant). Preferably R5 is H. More preferably the 14-15 bond is a double bond. Preferably: R1 is selected from H and OH; more preferably R1 is H. R5 is selected from H and OH, wherein preferably if R7 is H then the 14-15 bond is a double bond. In one or more preferred embodiments: R2 is selected from the group consisting of H, OH, C1-2 alkyloxy and C1-2 acyloxy, R3 is selected from the group consisting of H, OH, C1-2 alkyloxy and C1-2 acyloxy, or R2 and R3 form an acetonide. Preferably R2 is methyloxy or OH, more preferably OH. R3 is methyloxy or OH, more preferably OH. Preferably R5 is selected from H, methyloxy and OH, more preferably R5 is H. In one or more preferred embodiments: R11 is selected from the group consisting of H, OH, C1-2 alkyloxy and C1-2 acyloxy, R12 is selected from the group consisting of H, OH, C1-22 alkyloxy and C1-22 acyloxy, or R11 and R12 form an acetonide. Preferably R11 is methyloxy or OH, more preferably OH. R12 is methyloxy or OH, more preferably OH. Preferably, the compound for use of formula I.a is selected from a compound for use of formula I.b wherein the substituents are as defined for formula I.a). Preferably, independently from each other, R1 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably H, R2 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferablyOH, R3 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably OH, or R2 and R3 form acetonide, R4 is selected from H and CH3, preferably H, R5 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, wherein preferably if the 14-15 bond is a single bond, then it is a 14^,15-bond (i.e. a 14^,15-dihydro variant); or R5 is nothing and the 14-15 bond is a double bond, R6 is H, R7 is any moiety as defined above for formula I.a, R8 is selected from H and CH3, preferably CH3, R9 is selected from H and CH3, preferably CH3. More preferably the compound is a compound for use of formula I.c wherein the substituents are as defined for formula I.b, wherein preferably R5 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, wherein preferably if the 14-15 bond is a single bond, then it is a 14^,15-bond (i.e. a 14^,15-dihydro variant); preferably, wherein R7 is a moiety having the formula 1.2, (1.2) wherein the substituents are as defined for moiety 1.1, preferably whereinR10 is CH3, R11 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, preferably C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably OH, R12 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-22 alkyloxy, C1-22 acyloxy and a halogen, preferably C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably OH, R13 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, preferably C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably OH, wherein R11 and R12 may form acetonide, or R7 is a moiety having the formula 2.1, wherein the substituents are as defined for moiety 2.1, wherein R7 is a moiety having the formula 1.2 is preferred. In an aspect the invention relates to the compound of the invention, as defined as formula I.a for use in the treatment of a state of oxidative stress in a subject. In an aspect the invention relates to the compound of the invention, as defined as formula I.b for use in the treatment of a state of oxidative stress in a subject. In an aspect the invention relates to the compound of the invention, as defined as formula I.c for use in the treatment of a state of oxidative stress in a subject. Preferably, the invention relates to the compound of the invention for use in the treatment of an oxidative stress related damage (or damage caused by oxidative stress) in a subject, preferably in the treatment of and / or in a subject having an oxidative stress related metabolic disease as an oxidative stress disease. In particular, the compound is for use in or is used in the treatment of an oxidative stress related damage in the brain of a subject, preferably in the treatment of an oxidative stress related damage in the blood-brain barrier of a subject, preferably for use in and / or in a subject having a brain-related metabolic disease. In particular, the compound is for use in or is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet. In an aspect the invention relates to the compound of the invention for use in the treatment of chronic low-grade inflammation, preferably an oxidative stress related inflammation, preferably in normalizing IL-6 level in said patient. In particular, the oxidative stress is present in the adipose tissue of the subject. In particular, the oxidative stress is present in the central nervous system of the subject. In particular, the oxidative stress is present in the blood-brain barrier of the subject. In particular embodiments, the compound as defined in formula I.a, I.b or I.c is for use or is used in the treatment of an oxidative stress related metabolic disease as an oxidative stress disease. In particular embodiments, the compound is for use or is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet. Preferably the oxidative stress related damage is present in the adipose tissue of a subject. Preferably, the compound as defined in formula I.a, I.b or I.c is used in the treatment of a metabolic disease, preferably a metabolic disease due to or associated with high fat, high sugar diet, preferably for use in normalizing the level of an adipocytokine, said adipocytokine selected from an “offensive” adipocytokines, such as IL-6 and of “defensive” adipocytokines, such as adiponectin and leptin, for use in IL-6-induced inflammation or reduction of IL-6 level, for use in obesity or obesity-induced muscular dystrophy, preferably muscular dystrophy caused by high fat, high sugar diet, for use in the prevention of prevented the development of obesity-induced abnormal steroid hormone level, preferably in the prevention of prevented the development of obesity-induced high corticosterone levels, wherein preferably high corticosterone levels can induce low-grade inflammation in overweight, and / or in normalizing sex-hormone levels. In particular embodiments, the compound is used to prevent muscle loss or loss of muscle mass in a high-fat high-sugar diet, or to restore or regain muscle mass in a high-fat high-sugar diet. In the present invention, where appropriate, 25-26 may form a single bond or a double bond. Preferably, the compound as defined in formula I.a, I.b or I.c is used in the treatment of an oxidative-stress related damage of the blood-brain barrier. Preferably, the compound is used in the treatment of a harmful condition of the central nervous systemdue to a damage of the blood-brain barrier.In particular embodiments, the compound is used for use in increasing cell viability for endothelial cells of the blood-brain barrier, for use in protection of the blood-brain barrier, for use in increasing integrity of the blood-brain barrier, or preventing damage of the blood-brain barrier, preferably in increasing integrity of the blood-brain barrier damaged by oxidative stress, for use in reducing blood extravasation by protecting the blood-brain barrier, In a particular embodiment the compound of the invention is for use in post-covid syndrome. Preferably, the compound is used in the treatment of an oxidative-stress related damage of the blood- brain barrier. 2. Preferably the invention relates to a compound of formula II.a for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease, wherein the substituents are as defined for formula I.a, or preferably for formula I.b or preferably I.c, wherein preferably R1 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, R2 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, R3 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, or R2 and R3 form an acetonide, R4is selected from H and CH3, R6 is H, and R7 is selected from the group of moieties (1.1) having the formula 1.1 or (1.2) having the formula (1.2) said substituents being defined for any one of formulae I.a, or preferably for formula I.b or preferably I.d above. Preferably,R10 is CH3, R11 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, R12 is selected from the group consisting of H, OH, C1-22 alkyloxy, C1-22 acyloxy and a halogen, R13 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, wherein R11 and R12 may form acetonide, and or R13 is nothing and the 25-26 bond is a double bond. Preferably R15 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, preferably R15 is selected from H, OH and CH3, preferably H and CH3, more preferably R15 is H, R8 is selected from H and CH3, preferably is CH3, R9 is selected from H and CH3, preferably is CH3. In particular embodiments, the compound is selected from a compound for use of formula II.b (II.b), wherein the substituents are as defined for formula I.b; or wherein the substituents are as defined for formula II.a; wherein preferably R7 is selected from the group of moieties having the formula 2.1 wherein R10 is CH3, R12 is selected from the group consisting of H, OH, C1-22 alkyloxy, C1-22 acyloxy, preferably H, OH and CH3, more preferably OH, R13 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 acyloxy, preferably H, OH and CH3, more preferably OH, R14 is selected from the group consisting of H, C1-3 alkyloxy, C1-3 acyloxy, preferably H, and CH3, more preferably H, or wherein R14 and R12 may form acetonide according to formula 2.2 (2.2), preferably any one of R10, R12, and R14 is selected from H, OH and CH3, R13 is selected from H and OH, or R11, R12, R13and R14is selected from moieties given for any of the formula (1.2, 2.1 and 2.2)preferably R10 is OH, wherein R15 is selected from the group consisting of H and CH3, more preferably R15 is H. In an aspect the invention relates to the compound of the invention for use in the treatment of a state of oxidative stress in a subject. Preferably the compound is a compound as defined in formula II.a or II.b, preferably II.b. In an aspect the invention relates to the compound of the invention for use in the treatment of an oxidative stress related damage (or damage caused by oxidative stress) in a subject, preferably in the treatment of and / or in a subject having an oxidative stress related metabolic disease as an oxidative stress disease. In particular, the compound is a compound as defined in formula II.a or II.b, preferably II.b, and the compound is for use in or is used in the treatment of an oxidative stress related damage in the brain of a subject, preferably in the treatment of an oxidative stress related damage in the blood-brain barrier of a subject, preferably for use in and / or in a subject having a brain-related metabolic disease. In particular, the compound is for use in or is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet. In an aspect the invention relates to the compound of the invention for use in the treatment of chronic low-grade inflammation, preferably an oxidative stress related inflammation, preferably in normalizing IL-6 level in said patient. In particular, the oxidative stress is present in the adipose tissue of the subject. In particular, the oxidative stress is present in the central nervous system of the subject. In particular, the oxidative stress is present in the blood-brain barrier of the subject. In particular embodiments, the compound is a compound as defined in formula II.a or II.b, preferably II.b for use or the compound is used in the treatment of an oxidative stress related metabolic disease as an oxidative stress disease. In particular embodiments, the compound is for use or is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet. Preferably the oxidative stress related damage is present in the adipose tissue of a subject. Preferably, the compound is used in the treatment of a metabolic disease, preferably a metabolic disease due to or associated with high fat, high sugar diet, preferably for use in normalizing the level of an adipocytokine, said adipocytokine selected from an “offensive” adipocytokines, such as IL-6 and of “defensive” adipocytokines, such as adiponectin and leptin, for use in IL-6-induced inflammation or reduction of IL-6 level, for use in obesity or obesity-induced muscular dystrophy, preferably muscular dystrophy caused by high fat, high sugar diet, for use in the prevention of prevented the development of obesity-induced abnormal steroid hormone level, preferably in the prevention of prevented the development of obesity-induced high corticosterone levels, wherein preferably high corticosterone levels can induce low-grade inflammation in overweight, and / or in normalizing sex-hormone levels. In particular embodiments, the compound is used to prevent muscle loss or loss of muscle mass in a high-fat high-sugar diet, orto restore or regain muscle mass in a high-fat high-sugar diet. Preferably, the compound is used in the treatment of an oxidative-stress related damage of the blood- brain barrier. Preferably, the compound is used in the treatment of a harmful condition of the central nervous system due to a damage of the blood-brain barrier. In particular embodiments, the compound is used for use in increasing cell viability for endothelial cells of the blood-brain barrier, for use in protection of the blood-brain barrier, for use in increasing integrity of the blood-brain barrier, or preventing damage of the blood-brain barrier, preferably in increasing integrity of the blood-brain barrier damaged by oxidative stress, for use in reducing blood extravasation by protecting the blood-brain barrier, In a particular embodiment the compound of the invention is for use in post-covid syndrome. Preferably, the compound is used in the treatment of an oxidative-stress related damage of the blood- brain barrier. 3. Preferably the invention relates to a compound of formula III.a for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease, (III.a)wherein each substituent is, independently, selected from substitutents as defined for formulae I.a, I.b., I.c, or, if applicable, for II.a and II.b, OR R1 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably H and OH, more preferably H, R2 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, R3 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, or R2 and R3 form an acetonide, R4 is selected from H and CH3, R5 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably H and OH, wherein preferably R5 is H and the 14-15 bond is a double bond, R6 is H, R8 is selected from H and CH3, preferably is CH3, R9 is selected from H and CH3, preferably is CH3. R10 is CH3, R11 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, R12 is selected from the group consisting of H, OH, methoxy, ethoxy, acetyloxy, formyloxy, C1-22 alkyloxy or C1-22 acyloxy, R13 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, or R11 and R12 may form acetonide, or R13 is nothing and the 25-26 bond is a double bond. In a preferred embodiment the invention relates to a compound of formula III.b for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease (III.b) wherein each substituent is, independently, selected from substitutents as defined for formulae III.a. (III.c) wherein each substituent is, independently, selected from substitutents as defined for formulae III.a or III.b, and R14 is selected from the group consisting of of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably H, and CH3, more preferably H, or wherein R14 and R12 form acetonide. In an aspect the invention relates to the compound of the invention, preferably the compound as defined in any of formulae III.a, III.b or III.c, is for use in the treatment of a state of oxidative stress in a subject. In an aspect the invention relates to the compound of the invention for use in the treatment of an oxidative stress related damage (or damage caused by oxidative stress) in a subject, preferably in the treatment of and / or in a subject having an oxidative stress related metabolic disease as an oxidative stress disease. In particular, the compound is for use in or is used in the treatment of an oxidative stress related damage in the brain of a subject, preferably in the treatment of an oxidative stress related damage in the blood-brain barrier of a subject, preferably for use in and / or in a subject having a brain-related metabolic disease. In particular, the compound is for use in or is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet. In an aspect the invention relates to the compound of the invention for use in the treatment of chronic low-grade inflammation, preferably an oxidative stress related inflammation, preferably in normalizing IL-6 level in said patient. In particular, the oxidative stress is present in the adipose tissue of the subject. In particular, the oxidative stress is present in the central nervous system of the subject. In particular, the oxidative stress is present in the blood-brain barrier of the subject. In particular embodiments, the compound as defined in any of formulae III.a, III.b or III.c, is for use or is used in the treatment of an oxidative stress related metabolic disease as an oxidative stress disease. In particular embodiments, the compound is for use or is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet. Preferably the oxidative stress related damage is present in the adipose tissue of a subject. Preferably, the compound is used in the treatment of a metabolic disease, preferably a metabolic disease due to or associated with high fat, high sugar diet, preferably for use in normalizing the level of an adipocytokine, said adipocytokine selected from an “offensive” adipocytokines, such as IL-6 and of “defensive” adipocytokines, such as adiponectin and leptin, for use in IL-6-induced inflammation or reduction of IL-6 level, for use in obesity or obesity-induced muscular dystrophy, preferably muscular dystrophy caused by high fat, high sugar diet, for use in the prevention of prevented the development of obesity-induced abnormal steroid hormone level, preferably in the prevention of prevented the development of obesity-induced high corticosterone levels, wherein preferably high corticosterone levels can induce low-grade inflammation in overweight, and / or in normalizing sex-hormone levels. In particular embodiments, the compound is used to prevent muscle loss or loss of muscle mass in a high-fat high-sugar diet, or to restore or regain muscle mass in a high-fat high-sugar diet. Preferably, the compound as defined in any of formulae III.a, III.b or III.c, is used in the treatment of an oxidative-stress related damage of the blood-brain barrier. Preferably, the compound is used in the treatment of a harmful condition of the central nervous system due to a damage of the blood-brain barrier. In particular embodiments, the compound is used for use in increasing cell viability for endothelial cells of the blood-brain barrier, for use in protection of the blood-brain barrier, for use in increasing integrity of the blood-brain barrier, or preventing damage of the blood-brain barrier, preferably in increasing integrity of the blood-brain barrier damaged by oxidative stress, for use in reducing blood extravasation by protecting the blood-brain barrier, In a particular embodiment the compound of the invention is for use in post-covid syndrome. Preferably, the compound is used in the treatment of an oxidative-stress related damage of the blood- brain barrier. Preferably the invention relates to a compound of formula IV.a, IV.b, IV.c or IV.d for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease, (IV.d), wherein in formula IV.a, IV.b, IV.c and IV.b said substituents are selected from the substituents as defined in any one of formulae III.a, III.b, III.c and III.b, respectively wherein R5 is hydrogen. Preferably, in any one of formulae III.a, III.b, III.c and III.b, independently from each other, R1 is selected from H and OH, more preferably H, R2 is selected from the group consisting of H and OH, preferably OH, R3 is selected from the group consisting of H and OH, preferably OH,or R2and R3form an acetonide,R4 is selected from H and CH3, preferably H, R6 is H, R8 is selected from H and CH3, preferably is CH3, R9 is selected from H and CH3, preferably is CH3. R10 is CH3, R11 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, R12 is selected from the group consisting of H, OH, methoxy, ethoxy, acetyloxy, formyloxy, C1-22 alkyloxy or C1-22 acyloxy, R13 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, or R11 and R12 form acetonide, or R13 is nothing and the 25-26 bond is a double bond. Preferably the compounds as defined in any of formulae III.a, III.b, III.c and III.b are for use in a disease as defined in paragraph 1, 2 or 3, preferably in paragraph 3. 5. Preferably, the invention relates to a compound of formula V for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease wherein R2 and R3 is as defined above, or R2 is selected from the group consisting of H and OH, preferably OH, R3 is selected from the group consisting of H and OH, preferably OH, or R2 and R3 form an acetonide, R4 is selected from H and CH3, preferably H, R13 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably R13 is OH. Preferably, the invention relates to a compound of formula VI for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease wherein any of the substituents is as defined above, OR preferably, R1 is selected from H and OH, more preferably H, R5 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably H and OH, wherein preferably R5 is H and the 14-15 bond is a double bond, R6 is H, R8 is selected from H and CH3, preferably is CH3, R9 is selected from H and CH3, preferably is CH3, R10 is CH3, R12 is selected from the group consisting of H, OH, methoxy, ethoxy, acetyloxy, formyloxy, C1-22 alkyloxy or C1-22 acyloxy, preferably R12 is OH. Preferably, the invention relates to a compound of formula VII for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease wherein any of the substituents is as defined above, OR preferably, R1 is selected from H and OH, more preferably H, R5 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably H and OH, wherein preferably R5 is H and the 14-15 bond is a double bond, R6 is H, R10 is CH3, R12 is selected from the group consisting of H, OH, methoxy, ethoxy, acetyloxy, formyloxy, C1-22 alkyloxy or C1-22 acyloxy, preferably R12 is OH. Preferably the compounds as defined in any of formulae V are for use in a disease as defined in paragraph 1, 2 or 3, preferably in paragraph 3. Preferably the compounds as defined in any of formulae VI are for use in a disease as defined in paragraph 1, 2 or 3, preferably in paragraph 3. Preferably the compounds as defined in any of formulae VII are for use in a disease as defined in paragraph 1, 2 or 3, preferably in paragraph 3. 6. Preferably, the invention relates to a compound of formula XI for use in the treatment of an oxidative- stress related damage of the blood-brain barrier, wherein the substituents are as defined for formula I.a, or preferably for formula I.b or preferably I.c, if applicable. Preferably, R1 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-22 alkyloxy, C1-22 acyloxy and ahalogen, R2 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, R3 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, or wherein R2 and R3 form acetonide, R5 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen and the 14- 15 bond is a single bond, or R5 is nothing and the 14-15 bond is a double bond, R6 is H, R7 is selected from the group of moieties having the formula 1.1 (1.1) wherein, independently from each other, R10 is CH3, R11 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, R12 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-22 alkyloxy, C1-22 acyloxy and a halogen, R13 is selected from the group consisting of H, OH, CH3, C1-4 alkyloxy, C1-20 acyloxy and a halogen, or R13 is nothing and the 25-26 bond is a double bond, wherein R11 and R12 may form acetonide, and moieties having the formula (2.1) wherein R15 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and ahalogen, preferably R15 is selected from H, OH and CH3, preferably H and CH3, more preferably R15 is H, wherein preferably if the 14-15 bond is a single bond, then it is a 14^,15-bond (i.e. a 14^,15-dihydro variant), R8 is selected from H and CH3, R9 is selected from H and CH3. Preferably, if the 14-15 bond is a single bond, then it is a 14^,15-bond (i.e. a 14^,15-dihydro variant). Preferably R5 is H. More preferably the 14-15 bond is a double bond. Preferably R7 is selected from the group of moieties having the formula 1. Preferably R1 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, R2 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, R3 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, or R2 and R3 form an acetonide, R4 is selected from H and CH3, R5 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably H and OH, wherein preferably R5 is H and the 14-15 bond is a double bond, R6 is H, and R7 is selected from the group of moieties having the formula 1.1 R11 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 acyloxy and a halogen, R12 is selected from the group consisting of H, OH, C1-22 alkyloxy, C1-22 acyloxy and a halogen, R13 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 acyloxy and a halogen, wherein R11 and R12 may form acetonide, or R13 is nothing and the 25-26 bond is a double bond, and moieties having the formula (2.1) wherein R15 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 acyloxy and a halogen, preferably R15 is selected from H, OH and CH3, preferably H and CH3, more preferably R15 is H, R11 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, R12 is selected from the group consisting of H, OH, C1-22 alkyloxy, C1-22 acyloxy and a halogen, R13 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, or R13 is nothing and the 25-26 bond is a double bond wherein R11 and R12 may form acetonide. Preferably R15 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, preferably R15 is selected from H, OH and CH3, preferably H and CH3, more preferably R15 is H, R8 is selected from H and CH3, preferably is CH3, R9 is selected from H and CH3, preferably is CH3. Preferably, the compound as defined in any of formulae XI or, preferably, XII, is used in the treatment of an oxidative-stress related damage of the blood-brain barrier. Preferably, the compound is used in the treatment of a harmful condition of the central nervous systemdue to a damage of the blood-brain barrier. In particular embodiments, the compound is used for use in increasing cell viability for endothelial cells of the blood-brain barrier, for use in protection of the blood-brain barrier, for use in increasing integrity of the blood-brain barrier, or preventing damage of the blood-brain barrier, preferably in increasing integrity of the blood-brain barrier damaged by oxidative stress, for use in reducing blood extravasation by protecting the blood-brain barrier, In a particular embodiment the compound of the invention is for use in post-covid syndrome. Preferably, the compound is used in the treatment of an oxidative-stress related damage of the blood- brain barrier. The invention also relates to compositions comprising any of the compounds for use according to the invention. Preferably the composition is a pharmaceutical composition comprising any of the compounds for use as defined in any of paragraphs 1, 2, 3, 4, 5 or 6 and a pharmaceutically acceptable excipient. Preferably the composition is a nutraceutical composition comprising any of the compounds for use as defined in any of paragraphs 1, 2, 3, 4, 5 or 6 and a nutraceutically acceptable excipient.. Preferably the pharmaceutical or nutraceutical composition is for or is suitable for enteral, e.g. oral or parenteral, e.g. intravenous, or topical administration into a patient. In a preferred embodiment the composition is for oral administration In case of oral preparation, solid dosage units, such as pills, tablets, etc. as given above, can be provided. In an embodiment in the composition the compound is in the form of a plant or animal extract. In an embodiment in the composition the compound is in the form of liposomes or vesicles like extracellular vesicles (EVs). Preferably, the compounds of the invention are present in unsolvated form. Preferably, the compounds of the invention are present in solvated form. Preferably, the compounds of the invention are present in aqueous solution. Preferably, the active ingredient is presented in a form as defined herein. The pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers. In an embodiment the pharmaceutical composition of the invention is an injectable composition. Injection liquids can be presented e.g. in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in the form of dry crystals or freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water or physiological salt solution, prior to use. In an embodiment the excipients comprise an antioxidant. The invention also relates to a method of treatment for treating a subject in need of such treatment. Preferably said subject having In a particular embodiment, the compound or the composition of the invention is used in the treatment of an oxidative stress related damage in the brain of a subject, preferably in the treatment of an oxidative stressrelated damage in the blood-brain barrier of a subject, preferably for use in and / or in a subject having a brain-related metabolic disease. In particular, the compound is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet. Preferebly, the subject is in need of treatment suffers in chronic low-grade inflammation, preferably an oxidative stress related inflammation. Preferably the subject is in need of normalizing IL-6 level in said patient. In a particular embodiment the oxidative stress is present in an organ selected from the group consisting of the adipose tissue of the subject, the central nervous system of the subject or the blood-brain barrier of the subject. In particular embodiments, the groups of compound used in specific condition are as disclosed hereinabove or herein. Preferably, an oxidative stress related metabolic disease is an oxidative stress disease. Preferably, the oxidative stress related damage due to a high-fat, high sugar diet. Preferably the compound or composition is used in normalizing the level of an adipocytokine, said adipocytokine selected from an “offensive” adipocytokines, such as IL-6 and of “defensive” adipocytokines, such as adiponectin and leptin, and / or in IL-6-induced inflammation or reduction of IL-6 level, and / or in obesity or obesity-induced muscular dystrophy, preferably muscular dystrophy caused by high fat, high sugar diet, and / or in the prevention of prevented the development of obesity-induced abnormal steroid hormone level, and / or in the prevention of prevented the development of obesity-induced high corticosterone levels, wherein preferably high corticosterone levels can induce low-grade inflammation in overweight, and / or in normalizing sex-hormone levels. In particular embodiments, the compound is used to prevent muscle loss or loss of muscle mass in a high-fat high-sugar diet, or to restore or regain muscle mass in a high-fat high-sugar diet. Preferably, the compound is used in the treatment of a harmful condition of the central nervous system due to a damage of the blood-brain barrier. In particular embodiments, the compound is used for use in increasing cell viability for endothelial cells of the blood-brain barrier, for use in protection of the blood-brain barrier, for use in increasing integrity of the blood-brain barrier, or preventing damage of the blood-brain barrier, preferably in increasing integrity of the blood-brain barrier damaged by oxidative stress, for use in reducing blood extravasation by protecting the blood-brain barrier, In a particular embodiment the compound of the invention is for use in post-covid syndrome. Preferably, the compound is used in the treatment of an oxidative-stress related damage of the blood- brain barrier. In an aspect the invention the compound is for use in or is used in the treatment of an oxidative stress related damage in the brain of a subject, preferably in the treatment of an oxidative stress related damage in theblood-brain barrier of a subject, preferably for use in and / or in a subject having a brain-related metabolic disease.In particular, the compound is for use in or is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet. In an aspect the invention relates to the compound of the invention for use in the treatment of chronic low-grade inflammation, preferably an oxidative stress related inflammation, preferably in normalizing IL-6 level in said patient. In particular, the oxidative stress is present in the adipose tissue of the subject. In particular, the oxidative stress is present in the central nervous system of the subject. In particular, the oxidative stress is present in the blood-brain barrier of the subject. In particular embodiments, the compound as defined in any of formulae III.a, III.b or III.c, is for use or is used in the treatment of an oxidative stress related metabolic disease as an oxidative stress disease. In particular embodiments, the compound is for use or is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet. Preferably the oxidative stress related damage is present in the adipose tissue of a subject. Preferably, the compound is used in the treatment of a metabolic disease, preferably a metabolic disease due to or associated with high fat, high sugar diet, preferably for use in normalizing the level of an adipocytokine, said adipocytokine selected from an “offensive” adipocytokines, such as IL-6 and of “defensive” adipocytokines, such as adiponectin and leptin, for use in IL-6-induced inflammation or reduction of IL-6 level, for use in obesity or obesity-induced muscular dystrophy, preferably muscular dystrophy caused by high fat, high sugar diet, for use in the prevention of prevented the development of obesity-induced abnormal steroid hormone level, preferably in the prevention of prevented the development of obesity-induced high corticosterone levels, wherein preferably high corticosterone levels can induce low-grade inflammation in overweight, and / or in normalizing sex-hormone levels. In particular embodiments, the compound is used to prevent muscle loss or loss of muscle mass in a high-fat high-sugar diet, or to restore or regain muscle mass in a high-fat high-sugar diet. Preferably, the compound as defined in any of formulae III.a, III.b or III.c, is used in the treatment of an oxidative-stress related damage of the blood-brain barrier. Preferably, the compound is used in the treatment of a harmful condition of the central nervous system due to a damage of the blood-brain barrier. In particular embodiments, the compound is used for use in increasing cell viability for endothelial cells of the blood-brain barrier, for use in protection of the blood-brain barrier,for use in increasing integrity of the blood-brain barrier, or preventing damage of the blood-brain barrier, preferably in increasing integrity of the blood-brain barrier damaged by oxidative stress, for use in reducing blood extravasation by protecting the blood-brain barrier, In a particular embodiment the compound of the invention is for use in post-covid syndrome. Preferably, the compound is used in the treatment of an oxidative-stress related damage of the blood- brain barrier. DEFINITIONS Oxidative stress (OS) is the state of a subject characterized by an imbalance between reactive oxygen species (ROS) and antioxidant defence capacity or the subject, i.e. an increased level of ROS, in particular superoxide anion radical (∙O2-), hydrogen peroxide (H2O2) and hydroxyl free radical (∙OH) in a highly preferred embodiment ∙OH. Oxidative stress, if persistent, is chronic oxidative stress. Chronic oxidative stress is understood herein as the presence of oxidative stress in the subject for a time period longer than in acute oxidative stress, i.e. for typically at least 5 days or at least 10 days or at least 15 days or for 1 week or for at least 2 weeks or for at least 3 weeks or, preferably, for at least 4 weeks or for at least 1 month or at least 2 months or at least 3 months or for at least for a half year or for at least a year. Oxidative stress disease or oxidative stress disorder (e.g. chronic oxidative stress disease or disorder) is a condition of a subject characterized by a chronic oxidative stress wherein in said subject any harmful effect or symptom of a chronic oxidative stress, e.g. cardiovascular problems, cancer, asthma and neurological disorder. Methods for assessment of oxidative stress are disclosed herein as well as known in the art. A “subject” as used herein is an individual of an animal species, including humans, preferably and in particular a vertebrate, more preferably a mammalian or avian species, in particular a mammalian species, highly preferably the individual is a primate, a hominid or a human. Preferably the animal has blood, e.g. a vertebrate; preferably the animal has a blood-brain barrier. A “patient” is a subject who is or intended to be under medical or veterinarian observation, supervision, diagnosis or treatment. “Therapy” may include prevention and / or treatment. A “treatment” of a subject refers to any process, action, therapy, or the like, wherein the subject or patient is under aid, in particular medical or veterinarian aid with the object of improving the subject’s or patient’s condition, either directly or indirectly. Improving the subject’s condition may include restoring or maintaining normal function of an organ or tissue, preferably at least partly restoring or maintaining health (medical or veterinarian treatment). Treatment typically refers to the administration of an effective amount of a compound or composition described herein. “Treating” or “treatment” of any disease or disorder refers, in some embodiments, to amelioration of at least one disease, disorder or condition or preferably reducing the development of the disease or disorder or at least one of the clinical symptoms or at least one physical parameter thereof. In a broader sense treatment includes both medical or veterinarian treatment and prevention (or prophylaxis) i.e. prevention of the onset of a disease as well, in a more limited sense prevention is not covered. More specifically, “prevention” of the development of a disease or condition refers to at least thereduction of likelihood of the risk of or susceptibility to acquiring a disease or disorder, or preferably causing at least one of the clinical symptoms of the disease or disorder not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease. Prevention may also relate to the treatment of a subject comprising administration of the compound of the invention with the aim of preventing the development of a condition or disease in said subject or preventing onset of said condition or disease or preventing exacerbation of the symptoms thereof. Preferably, prevention is a treatment of a subject exposed to, characterized by or having the status of oxidative stress, preferably chronic oxidative stress in order to prevent the development of an oxidative stress disease or disorder. Partial prevention, e.g. resulting in a less serious or alleviated form of the disease is preferably included in the meaning of this term. A “pharmaceutical composition” of the invention is a composition of matter which comprises at least one compound of the invention comprising an active agent and at least one further substance. Preferably the compound of the invention is present in an effective amount. Compositions may also comprise further biologically active substances useful e.g. in a combination therapy. Furthermore, the compositions may comprise biologically acceptable carriers, formulation agents, excipients etc. which may be known in the art, and which include any diluent, adjuvant, filler, excipient, stabilizer, or vehicle with which the agent is formulated for administration. The term “effective amount” qualifies the amount of a compound required to exert the effect of the active agent in a composition. A “therapeutically effective amount” is sufficient to relieve or prevent (or prevent worsening of) one or more of the symptoms or characteristic parameters of a condition, e.g. a disorder or disease. “Nutraceutical” refers to a foodstuff that provides health benefits in addition to its basic nutritional value. A nutraceutical has a physiological benefit or provide protection against physiological disorder or discomfort. A nutraceutical composition comprises a composition of the invention and at least an additional substance, e.g. a nutraceutical carrier or a food component. The term “dietary supplement” refers to a nutraceutical e.g. a nutraceutical composition intended to provide nutrients that may otherwise not be consumed in sufficient quantities. "Functional food" is also a nutraceutical e.g. a nutraceutical composition and refers to any modified food or food ingredient that may provide a benefit or provide protection against physiological disorder or discomfort; be-yond the traditional nutrients it contains. A “health claim” defines a health benefit for a nutraceutical and is subject to regulatory approval (analogous to an indication in case of a medicament) in accordance with a national or equivalent law. A “health claim” is to be as food labels and in food marketing. The term “alkyl” alone or in combinations means a straight or branched-chain saturated hydro-carbon group of a length as given by the number of carbon atom. In a broader sense the alkyl may comprise substituents, e.g. halogen substituents. In a narrower sense the alkyl does not comprise a substituent. In particular, “alkyl” includes both branched and straight chain alkyl groups. Typical alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, / er / -butyl. The terms “halogen” and ”halo” include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromoand iodo, respectively. The term “hydroxyalkyl” refers to an alkyl group substituted with one or more hydroxy groups such as, for example, hydroxymethyl and 2,3-dihydroxybutyl. The term “alkoxy” or “alkyloxy” includes both branched and straight chain alkyl groups attached to a terminal oxygen atom. Typical alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and tert-butoxy. As used herein, the term “alkanoyl” refers to a group which contains a double-bonded oxygen atom and an alkyl group having the formula R-C=O or R-(CO)-, wherein R represents an alkyl group that is linked to the carbon atom of the group by a single bond and the carbon atom may be linked by a single covalent bond to another moiety of the organic molecule. In organic chemistry, the alkanoyl group is usually derived from a carboxylic acid. An ”acetonide” is a cyclic ketal formed when a compound having a carbonyl group, preferably a ketone, e.g. an acetone or the like reacts with a diol (a molecule with two hydroxyl groups). It acts as a protecting group for diols in organic chemistry, shielding them from reactions that could otherwise affect them. The term "acetonide" is commonly used to describe this specific type of cyclic ketal. „Acetone” is understood herein as a ketone with short chain alkyls (a ketone is a molecule with a carbonyl group bonded to two alkyl groups). A „cyclic ketal” is a ring structure formed when a carbonyl group (C=O) reacts with two alcohol groups (R- OH) to create a cyclic ether with two oxygen atoms. The singular forms “a”, “an” and “the”, or at least “a”, “an”, include plural reference unless the context clearly dictates otherwise. The term “comprises” or “comprising” or “including” are to be construed here as having a non-exhaustive meaning and allow the addition or involvement of further features or method steps or components to anything which comprises the listed features or method steps or components. “Comprising” can be substituted by “including” if the practice of a given language variant so requires or can be limited to “consisting essentially of” if other members or components are not essential to reduce the invention to practice. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Animal experiment flowchart. HFHSD: high fat high sugar diet; SD: standard diet; n=18 in all groups, first day of week. Figure 2. The changes in body weight during the study. C: control (standard diet); HFHSD: high fat high sugar diet; 20E: 20-hydroxyecdysone; CAL: calonysterone treatments; ns: p>0.05; *: p <0.05; ***: p <0.001; compared to the control. ###: p <0.001 compared to the HFHSD group. Figure 3. Changes in testicle (A) and musculus levator ani (B) weight per 100g body weight. C: control (standard diet); HFHSD: high fat high sugar diet; 20E: 20-hydroxyecdysone; CAL: calonysterone treatments; ns: p>0.05; *: p <0.05 compared to the control. #: p <0.05; ##: p <0.01 compared to the HFHSD group. Figure 4. Changes in rat tibias anterior (A) and musculus solaneus (B) weight per 100g body weight. C: control (standard diet); HFHSD: high fat high sugar diet; 20E: 20-hydroxyecdysone; CAL: calonysteronetreatments; ns: p>0.05; ***: p <0.001 compared to the control. ##: p <0.01; ###: p <0.001 compared to theHFHSD group. Figure 5. Alterations of adrenergic receptor mRNA expression in testicular tissues (A) and testosterone (B) and estrogen level in the rat plasma (C). C: control (standard diet); HFHSD: high fat high sugar diet; 20E: 20- hydroxyecdysone; CAL: calonysterone treatments; ns: p>0.05; *: p <0.05; **: p <0.01 ***: p <0.001 compared to the control. #: p <0.05; ##: p <0.01 compared to the HFHSD group. Figure 6. Changes of plasma corticosterone levels in rats in different diet groups. C: control (standard diet); HFHSD: high fat high sugar diet; 20E: 20-hydroxyecdysone; CAL: calonysterone treatments; ns: p>0.05; *: p <0.05; **: p <0.01 ***: p <0.001 compared to the control. #: p <0.05; ##: p <0.01 compared to the HFHSD group. Figure 7. The animal experimental design.20E: 20-hydroxyecdysone; CAL: calonysterone, HFHSD: high fat high sugar diet; GTT: glucose tolerance test; SD: standard diet; n=6 in all groups. Figure 8. Changes in body weight during the study. C: control; HFHSD: high fat high sugar diet; 20E: 20- hydroxyecdysone; CAL: calonysterone; ns: p>0.05; *: p <0.05; **: p <0.01; compared to the control ##: p <0.01 compared to the HFHSD group. Figure 9. Effects of 20E and CAL on total antioxidant capacity (a) and the levels of superoxide dismutase (SOD, b) and catalase (CAT, c) in the liver after a control (C) and high fat high sugar diet (HFHSD). ns: p>0.05; *: p <0.05; **: p <0.01; ***: p <0.001 compared to the control (C) Figure 10. Changes of plasma concentration of leptin (a) and adiponectin (b) after control diet (C) and high fat high sugar diet (HFHSD) diet. ns>0.05, **: p <0.01; ***: p <0.001 compared to the control Figure 11. Effects of 20E and CAL on the levels of IL6 mRNA (a), protein (b) expression in the liver and the IL6 concentration in the plasma (c). HFHSD: high fat high sugar diet, C: control; ns>0.05, *: p <0.05; **: p <0.01 ***: p <0.001 compared to the control, # p <0.05; ## p <0.01, ### p <0.001 compared to the HFHSD group. Figure 12. Effects of 20E and CAL on the levels of global DNA methylation in the liver. HFHSD: high fat high sugar diet, C: control; ns>0.05, *: p < 0.05 Figure 13. Normalized cell index of hCMEC / D3 cells treated with different concentrations of 20E and calonysterone. a-c: 20E compound at 4 h, 6 h and 24 h timepoint, respectively. d-f: calonysterone at 4 h, 6 h and 24 h timepoint, respectively. Experiments were repeated at least twice, with a minimum of 4 technical parallels. Values are presented as mean ± SEM n=9-22. Figure 14. Normalized cell index of hCMEC / D3 cells treated with reactive oxygen species generating tBHP (350 µM) and in combination with the selected compounds. Calonysterone (Cal, 0,01 μM and 0,1 μM), and 20E (0,01 μM). a: at 4 hours treatment, b; at 6 hours treatment; c: at 24 hours treatment. Data were analyzed by one- way ANOVA followed by a Dunnett's multiple comparison test, *p<0.05, **p<0.01, ****p<0.0001, compared to the control and tBHP treated group. This treatment was repeated once, with at least an n=5 parallels. Values are presented as mean ± SEM, n=5-8. Figure 15. Effect of calonysterone treatment alone and in combination with the oxidative stressor tBHP (350 µM) on the barrier integrity of human brain endothelial cells. Transendothelial electrical resistance is shown as the % of the control. A) 30 min; B) 60 min. Values are presented as mean ± SEM, n=4. Here some treatments were repeated twice, with at least an n=4 parallels. Data were analyzed by one-way ANOVA followed byDunnett's multiple comparison test, *, p<0.05, compared to the control; and with t-test between tBHP andcombinations *, p<0.05. Figure 16. Effect of calonysterone treatment alone and in combination with the oxidative stressor tBHP (350 µM) on the barrier integrity of human brain endothelial cells. Cumulative clearance derived endothelial permeability coefficient (Pe) of fluorescent marker molecules FITC-dextran 10 kDa (FD10) and Evans-blue labelled albumin (EBA) is shown as the % of the control. A) FD10; B) EBA. Values are presented as mean ± SEM, n=3-7. Here some treatments were repeated twice, with at least an n=3 parallels. Data were analyzed by one- way ANOVA followed by Bonferroni multiple comparison test, a, p<0.05, compared to the control and b, p<0.05, compared to the tBHP treatment. Figure 17: hCMEC / D3 cells proteome untreated and treated with tBHP for 6 hours. a: volcano plot showing up- and downregulated genes. b: heatmap containing the up- and downregulated genes across the different comparisons. (genes up and downregulated are listed in Table 17b). c: Go enrichment of the genes that contribute to the biggest changes. Figure 18: hCMEC / D3 cells proteome on 20E (0.01 μM) + tBHP (350 μM) treatment for 6 hours versus the untreated group. a: volcano plot showing up- and downregulated genes. b: heatmap containing the up- and downregulated genes across the different comparisons (genes up and downregulated are listed in Table 18b). c: Go enrichment of the genes that contribute to the biggest changes. d:. Figure 19: hCMEC / D3 cells proteome on calonysterone (0.01 μM) + tBHP (350 μM) treatment for 6 hours versus the untreated group. a: volcano plot showing up- and downregulated genes. b: heatmap containing the up- and downregulated genes across the different comparisons (genes up and downregulated are listed in Table 19b). c: Go enrichment of the genes that contribute to the biggest changes. d:. Figure 20: a-b: Effects of different concentrations of compound 20E on brain endothelial cells during 24 hours treatment. c-d: Effects of different concentrations of compound calonysterone on brain endothelial cells during 24 hours treatment. e: The effect of selected concentrations of 20E and calonysterone upon treatment with tBHP and during 24 hours. DETAILED DESCRIPTION OF THE INVENTION Extensive studies have shown how oxidative stress is implicated in the pathophysiology of many diseases, among them obesity, inflammation and neurodegenerative diseases. Oxidative stress can cause cellular damage and subsequent cell death due to the oxidation of vital cellular components such as lipids, proteins, and DNA by ROS [Gilgun-Sherki et al., 2001]. The therapeutic use of most of the antioxidant compounds in brain diseases is limited since they are not able to cross the BBB. In addition, the possibility of protecting the damage of the BBB and their components from the oxidative stress has been studied from the pharmaceutical point of view [Freeman et al., 2012], but has not been studied in depth for natural products [Campos-Bedolla et al., 2014]. Obesity Obesity is complicated by several comorbid conditions, such as insulin resistance, type 2 diabetes, dyslipidemia, hypertension, cardiovascular disease, asthma, atherosclerosis, and nonalcoholic fatty liver disease. Over 65 % of people with obesity display metabolic-associated fatty liver disease (MAFLD), which can manifest as steatohepatitis, fibrosis, cirrhosis, or liver cancer [Lee et al., 2023^. Obesity is now one of the leading causes of preventable cancers and a preventable death, second only to smoking, and is poised to overtake it as theprimary cause in the next 20 years ^Jolissaint et al., 2023^. Obesity leads to many pathological consequencesincluding hypercoagulability, inflammation, endothelial dysfunction, and oxidative stress. In particular, obesity increases oxidative stress which in turn induces insulin resistance in many organs including the white adipose tissue, liver, and skeletal muscle. In the liver, the important organ for glucose and lipid metabolism, the increased drain of free fatty acids and proinflammatory cytokines through the portal vein and the excess of ectopic fat led to the accumulation of intermediate toxic lipid products that induce hepatic insulin resistance. This hepatic insulin resistance affects glucose metabolism through resistance to insulin- mediated suppression of gluconeogenesis resulting in increased hepatic glucose output and increase plasma glucose levels, as well as affects lipid metabolism through the enhancement of the de-novo liver lipogenesisresulting in further accumulation of the ectopic fat and hence to liver diseases ^Lustig et al., 2022^^Issaadi et al.,2017^. The possible contributors to oxidative stress in obesity include hyperglycemia, elevated tissue lipid levels, vitamin and mineral deficiencies, chronic inflammation, hyperleptinemia, increased muscle activity to carry excessive weight, endothelial dysfunction, impaired mitochondrial function, and it is also influenced by the type of diet ^Manna et al., 2015^. White adipose tissue (WAT) is not only an energy storage place in the body but also an important regulator of metabolic pathways including immunity and inflammation. Adipose tissue releases multiple pro-inflammatory and anti-inflammatory factors such as adipokines leptin, adiponectin, tumor necrosis factor alpha and cytokines such as IL-6 ^Buniam et al., 2020^. 20-hydroxyecdysone (20E; β-ecdysone; crustecdysone; ecdysterone; polypodine A; isoinokosterone; CAS 5289-74-7; IUPAC 2β,3β,14α,20R,22R,25-hexahydroxy-5β-cholest-7-en-6-one) is is a naturally occurring ecdysteroid hormone which controls the ecdysis (moulting) and metamorphosis of arthropods having the following formula 1: Calonysterone was first isolated and described in 1973 by Canonica L. et al. ^ Canonica L. et al., 1973^ and has the following formula 2: (IUPAC Name：(2S,3R,10R,13R,17S)-2,3,6-trihydroxy-10,13-dimethyl-17-[(2R,3R)-2,3,6-trihydroxy-6- methylheptan-2-yl]-1,2,3,4,11,12,16,17-octahydrocyclopenta[a]phenanthren-7-one, CAS No.: 51787-31-6). In their current studies, the present inventors have investigated the effects of CAL in an animal model with a high-fat and high-sugar diet (HFHSD). CAL fully prevented HFHSD-induced obesity and decreased the adipokines and inflammatory cytokine levels, and it has an antioxidant activity in the present model. This is the first in vivo study on this natural ecdysteroid, which may offer new alternatives for the treatment of metabolic diseases. More closely, calonysterone (CAL) and 20-hydroxyecdysterone (20E) prevented weight gain during the high-fat high-sugar diet. Six or thirteen weeks of HFHSD increased the blood glucose concentration compared to the control. Both 20E and CAL decreased the peak of the glucose concentration curve and shifted the time of peak to later (30 and 60 minutes). Surprisingly, after 12 weeks the 20E and CAL treatment did not stop the glucose level increasing effect of HFHSD diet in the present model. Some previous experiments with 20E were carried out in mouse model ^Kizelsztein et al., 2009^^Chen et al., 2017^ with shorter (4 weeks) diet-treatment period, higher dose ^Chen et al., 2017^ or used female rats ^Buniam et al., 2020^, in which the hormone level can influence the blood glucose concentration. Of note, the composition of the food of HFHSD may also be an important influencing factor. In the present study the animal feed contained 28% fat and 56% carbohydrates, in contrast with other studies ^Kizelsztein et al., 2009^^Buniam et al., 2020^ using 60% fat-derived calories and 21% carbohydrates. The present diet with 20E and CAL did not decrease the blood glucose levels after a long time used high sugar diet. There is now ample evidence indicating the importance of total antioxidant capacity (TAC) in plasma and tissues and its modification during oxidative stress development. It is well known that obesity is critically correlated with decreased antioxidant capacity, irrespective of age, metabolic and lifestyle variables, and therefore it could be hypothesized that lifestyle or pharmaceutical actions that modify redox state can be apotential therapeutic target for obesity-associated metabolic syndrome or related clinical conditions^Chrysohoou et al., 2007^. Earlier it was proven that the TAC seems to be the best biomarker to assess the antioxidant status of obese patients. Therefore, 20E and CAL have a protective effect on oxidative stress by reducing the TAC in obese rats. It is widely accepted that dietary antioxidant intake protects against oxidative damage and related clinical complications in many diseases. Superoxide dismutase(SOD) constitute a very important antioxidant defense against oxidative stress inthe body and 20E significantly increased SOD level. SOD form the front line of defense against reactive oxygen species (ROS)-mediated injury. These proteins catalyze the dismutation of superoxide anion radical (O2•–) into molecular oxygen and hydrogen peroxide (H2O2), and prevent superoxide-induced cellular damage [Younus, 2018]. Persistent hyperglycemia stimulates the production of ROS and weakens antioxidant defense, therefore the dietary or therapeutic protocols that increase SOD level (e.g., 20E intake) may have a protective effect. Upon the increase of adipose tissue, the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) was proven to be significantly diminished.20E and CAL increased the activity of these antioxidant enzymes and demonstrated a protective effect from the oxidative stress of liver tissues. Adipose tissue is not only a triglyceride-storage; studies in recent years have shown the role of white adipose tissue as a producer of certain substances with endocrine, paracrine, and autocrine action. These bioactive substances are denominated adipokines or adipocytokines, among which are found plasminogen activator inhibitor-1 (PAI-1), tumor necrosis factor-alpha (TNF-α), resistin, leptin, and adiponectin. These substances derive primarily from white adipose tissue and play a role in the homeostasis of various physiological processes ^Fernández-Sánchez et al., 2011^. Studies have observed that obesity causes high levels of leptin, which acts as a pro-inflammatory cytokine and amplifies the process of insulin resistance ^Kazmi et al., 2013^^Ekmen et al., 2016^. The levels of leptin in obese rats were high, which is consistent with hyperleptinemia, suggesting that a high-fat diet can induce leptin resistance in the special tissues. The dysregulated production of “offensive” adipocytokines, such as IL-6 and of “defensive” adipocytokines, such as adiponectin and leptin, is critically involved in the pathogenesis of obesity and metabolic syndrome ^Nguyen 2020^. Adiponectin, an adipokine secreted by adipocytes, is a well-known homeostatic factor for regulating glucose levels, lipid metabolism, and insulin sensitivity through its anti-inflammatory, anti-fibrotic, and antioxidant effects ^Furukawa et al., 2004^. Plasma adiponectin concentrations correlated inversely with systemic oxidative stress because the accumulated fat leads to dysregulated production of adipocytokines ^Nguyen 2020^. Its levels are decreased in various pathological states including insulin resistance, diabetes mellitus type 2, obesity, metabolic syndrome, or cardiovascular diseases. Many studies have shown the protective role of adiponectin in obesity-associated diseases and cancer ^Furukawa et al., 2004^. 20E and CAL normalized the level of these adipokines, and this allows the conclusion that said compounds protect from the pathological effects of leptin and adiponectin. Chronic low-grade inflammation has been well recognized as a key feature of obesity that is correlated with insulin resistance and type 2 diabetes. Among the adipose-secreted factors (adipokines), the inflammatory regulator interleukin-6 (IL-6) has emerged as one of the potential mediators that link obesity-derived chronic inflammation. Interleukin-6 (IL-6) is a pleiotropic cytokine that has both pro-inflammatory and anti-inflammatory effects depending on the context ^Wu et al., 2023^. Traditionally, IL-6 is considered a pro-inflammatory cytokine as it promotes neutrophilia and TH17 T cell differentiation while blocking regulatory T cell (T reg) differentiation, contributing to the pathophysiology of several inflammatory diseases. Together with obesity and type 2 diabetes, non-alcoholic fatty liver (NAFLD) is the most common liver disease that is observed in approximately 20-30% of the general population of Western countries ^Bedogni et al., 2005^. Adipose tissue contributes to up to 35% of circulating IL-6, the systemic effects of which have been best demonstrated in the liver, where a STAT3-SOCS-3 pathway mediates IL-6 impairment of insulin actions ^Kim et al., 2009^. Both ecdysteroids in the present study normalized the diet-induced increase in IL-6 levels in liver tissues and plasma. Pathophysiological changes (e.g., obesity), environmental factors, drugs and lifestyle can alter gene expression without affecting the DNA sequence, a phenomenon known as epigenetics. DNA methylation is an essential epigenetic mechanism, and its role in the pathogenesis of several diseases has been extensively studied. The process of DNA methylation consists of covalent binding of a methyl group to a cytosine residue in the DNA, where cytosines are followed by guanines (CpG sites). This chemical modification is mediated via a group of enzymes called DNA methyltransferases (DNMTs). DNA methylation, especially in the gene promoter regions, interferes with gene transcription. This effect is achieved by preventing transcription factors from accessing theDNA and recruiting transcription-repressive proteins ^Mahmoud et al., 2022^. There was no significant differencein the degree of methylation of the DNA in the liver of control and diet-induced obese rats, but the treatment with 20E and CAL significantly increased DNA methylation in the present study. This means that an increase in DNA methylation decreases the transcription rate of genes after ecdysteroid treatment. The present inventors presume that this plays a role in the bioactivity of 20E and CAL in the liver, for example in their antioxidant effects, and their ability to influence IL-6, leptin, or adiponectin levels. In a further set of experiments the inventors studied the anabolic effects of calonysterone as compared with 20-hydroxyecdysone in normal and obese animals and their effects on androgens, estrogens and corticoids. For this purpose again a high fat high sugar diet (HFHSD, 28% fat, 16% protein, 56% carbonhydrates) was provided to male rats and compared with the effect of standard diet from 5-6 weeks of age until the day of sacrifice, for 12 weeks. Animal handling is described in Example 2. The daily administration of phytoecdysteroid treatments for 12 weeks prevented the weight gain effect of the high-fat and high-sugar diet. Both ecdysteroids resulted in significantly reduced body weight in comparison with non-treated animals on both diets. Surprisingly, CAL performed better as a weight reducer than 20E. CAL was also effective in normalization of muscle weight even in animals on a high fat and sugar diet resulting in reduced testicular and musculus levator ani mass. Both phytoecdysteroids protected against skeletal muscle tissue atrophy. As to effects on steroid hormone household, both 20E and CAL increased the adrenergic receptor (Ar) mRNA expression in the testicular tissues whereas the plasma testosterone level changed inversely. The plasma estrogen level did not change after the treatments in the control group. In contrast, HFHSD increased the estrogen level but only the CAL protected against this effect. Corticosteroid levels reflect low level of inflammation; surprisingly the phytoecdysteroid treatments normalized corticosterone concentration during obesity. In summary, the newly synthesized derivative (CAL), like 20E, prevented obesity and obesity-induced muscular dystrophy caused by high fat and sugar diets. Both ecdysteroids prevented the development of obesity- induced high corticosterone levels which can induce low-grade inflammation in overweight. However, surprisingly, CAL was found to be significantly superior in preventing obesity-induced atrophy of the testis and musculus levator ani by protecting obese animals from elevated estrogen levels. In conclusion, the present inventors have demonstrated for the first time that calonysterone has a significant and favorable effect on diet-induced obesity, antioxidant capacity, adipokines, and inflammatory cytokine levels, reduces body mass whereas increases muscle mass, and normalizes steroid hormone levels in high fat high sugar diet. This study provides an experimental animal model to investigate the effects of phytoecdysteroids. These results open up new possibilities for the use of ecdysteroids and their derivatives in the prevention of obesity and the prevention of androgenic side effects. In previous studies antiradical properties of vitamin-D and ecdysterone were observed in an animal study using vitamin D-deficient mice [Kuzmenko et al., 2001][Wen et al., 2019]. They showed that treatment of β-ecdysone between 10-200 µM concentration efficiently protected nucleus pulposus cells against tBHP damage(100 µM). In another study, performed by Hu et al. [Hu et al., 2012], 20E was tested against many targets on oxidative stress, where treatment of cells with H2O2 caused neuronal injury, intracellular ROS production, mitochondrial membrane potential disturbance and an elevation of intracellular [Ca2+], all of which were markedly attenuated by 20E. The present invention supports the antioxidant activity of 20E and its derivatives for the scavenging activity of ROS produced by tBHP. The protection effect of the two compounds is apparent, and they were effective in rescuing the impedance of cell layers to the level of the control. In addition, to the mechanisms explored in previous studies, the high performance of these compounds could be due to their structure which exhibit small resonance systems that can capture the ROS and protect the cells. Since brain capillary endothelial cells serve as the functional basis of the blood-brain barrier and form the main interface between the blood and the brain, these compounds could interact directly with brain capillary endothelial cells in the body when consumed. Therefore, the present inventors investigated the direct effect of ecdysone hormones and their derivatives on cultured human brain endothelial cells. Effect of ecdysteroids on the cell viability Initially the present inventors have measured the cell viability to determine the most suitable concentration (0.01 – 10 μM) of each compound for the further experiments. It has been found that for the compounds tested there were concentrations increasing impedance reflecting to mild barrier tightening and all tested concentrations proved to be safe and not harmful for the cells. Several ecdyteroids were tested with an MTT assay on SHSY neuroblastoma cell line and found that the IC50 value for most of these compounds after 48 h treatment was above 40 µM, in one case 15 µM [Müller et al., 2017]. In another study, the effects of 20E were evaluated on HeLa cells with MTT test. This group found an IC50 at 60 µM after 24 hours treatment corresponding to the present invention, that up to 10 µM no toxic effect was observed [Peschel et al., 2011]. Wen et al. [Wen et al., 2019] showed that β-ecdysterone below 100 µM concentrations were not harmful for nucleus pulpous cells. The present inventors are thought to be the first to test cell viability for endothelial cells regarding the 20E and calonysterone. The impedance measured by the real time cell electronic sensing measurement correlates linearly with cell number, adherence, growth, and viability. A similar positive effect of both compounds has been observed at different concentrations, which is reflected in the increase in the cell index to above the control’s level. It can be concluded that this impedance increase is a basal brain endothelial cell protective effect, which strengthens the barrier integrity. In the last 20 years the need has appeared for suitable in vitro BBB models for rapid permeability screening of CNS drug candidates and to test their interaction with brain endothelial cells [Deli, 2011][Veszelka et al., 2011]. An ideal in vitro model of the BBB would express tight junctions, transporters and enzymes along with appropriate cellular morphology [Helms et al., 2016]. Summary for BBB measurements Several molting hormone analogs has been purified from a plant-originated food supplement and tested their effects on the hCMEC / D3 human brain endothelial cell line. For the present measurements a complex measurement method, ACEA’s xCellingence label-free cell electronic sensing system was used, which monitors viability and brain endothelial cell integrity in real time. The special 96-well E-plates with integrated goldelectrodes are sensitive indicators of intra- and intercellular changes.It has been observed that several compounds exhibit positive effects on the barrier integrity of brain endothelial cells. These beneficial concentrations of the compounds were used in protection assays against oxidative stress and inflammation successfully. Barrier integrity tests were performed with the ecdysteroid derivative performing the best in viability assays, where the present inventors saw a protective, barrier tightening effect after the simultaneous addition of the compound and tBHP. Further studies are needed to understand the molecular mechanism behind the benevolent effects of these ecdysteroids on brain endothelial cells. Barrier integrity - TEER In order to determine the tightness of the barrier, first a TEER measurement was used, which is recognized as the most sensitive method to assess barrier integrity of the BBB in in vitro models [Deli et al., 2005][Helms et al., 2016]. No previous studies have been carried out evaluating the tightness of the BBB for any ecdysteroid derivatives. In the present study, results show a contribution to BBB integrity protection against tBHP by calonysterone at 0.01 μM, 60 minutes after treatment. At 30 minutes calonysterone 0.1 μM+tBHP decrease is compensated by 60 minutes probably by the compound’s antioxidant potential. Barrier integrity - Permeability The BBB is a dynamic barrier where efflux pumps and solute carrier transporters act as the regulators of compound passage, while also have a role in the defense of the BBB [Abbott, 2013]. When this balance is disturbed, damage to brain cells can occur, which might lead to the appearance and progression of neurodegenerative diseases [Van Vliet et al., 2007][Palmer, 2011][Zlokovic, 2011][Stanimirovic et al., 2012][Kakaroubas et al., 2019], therefore the need to find novel, brain endothelial cell protective molecules is relevant. In the present invention, the inventors tested two concentrations of calonysterone, due to its promising barrier enhancing effect alone and its role as a protecting agent against tBHP induced BBB permeability increase. First, the present inventors tested the permeability of a small molecular weight paracellular marker (FD10), where the inventors did not see an effect of the calonysterone treatment alone on the permeability compared to the control. This observation is similar to the observations during the TEER measurement where no increase in TEER was visible after the solo treatments. On the E-plate the inventors saw a short-term impedance increasing effect, which according to these latter observations might rather mean a proliferation inducing effect than a paracellular barrier integrity increasing one. On the other hand, when tBHP is added to the in vitro BBB model, a drastic increase in the paracellular permeability appears due to the production of ROS [Campos-Bedolla et al., 2014]. With the co-incubation of calonysterone and tBHP a marked reduction in the permeability increase is seen, which is comparable with the positive control, Edaravone’s effect for both concentrations. On the other hand, when the permeability was tested for the larger molecular weight marker dye (EBA), the results seems to be contradictory. In this case, the Calonysterone (0.1 μM) shows better protection than its lower concentration (0.01 μM). Here calonysterone in the lower concentration elevates permeability for EBA seven times higher as that of the control and does not exert a protective effect against tBHP, while the higher concentration does similarly to Edaravone. This result could suggest a different effect of calonysterone on the transcellular passage of EBA. 20E and its ecdysone derivatives have proved to be effective protectors of BBB in the present in vitromodel. First, the optimal concentration of the leading compounds was assessed, then compounds were used inprotection assays. It has been shown that the main mechanism for protection is based on the compounds’ antioxidant property which provided effective protection against an oxidative stressor. Besides this, protection against pro- inflammatory cytokines was observed as well, but further studies are needed to explore the possible specific pathways behind this phenomenon. In addition, promising results were observed on BBB integrity protection against ROS for the calonysterone. This molecule tested to be protective against reactive oxygen stress induced permeability increase of the BBB leading to the increase of TEER and decreased passage of both paracellular and transcellular marker molecules. Besides that, surprisingly, the proteomics results reveals that the presence of calonysterone has higher significant effect in protecting the brain endothelial cells against oxidative stress, compared to 20E. Together, these results show that calonysterone has a high potential as protective agent on the barrier integrity of the BBB, maybe not only as a preventive but also to rescue the damaged provoked by oxidative stress. Preparation of the ecdysteroid compounds of the invention 20-hydroxyecdysone (20E) 20-Hydroxyecdysone, originated from the roots extract of Cyanotis arachnoidea, was purchased from Shaanxi KingSci Biotechnology Co., Ltd. (Shanghai, People’s Republic of China) at 90% purity by means of HPLC- DAD and the extract was recrystallized two times from ethyl acetate−methanol (2:1, v / v) to reach a purity of 98.5% by means of HPLC-DAD. Calonysterone Calonysterone (CAL) can be prepared by base-catalyzed autoxidation of 20E as published before ^Csábi et al., 2015^. LC-MS can be used to monitor the composition of the fractions and to identify calonysterone and minor components generated alongside the starting material and the main product. Diacetonides of the compounds can be prepared from 20E and CAL by the method disclosed by Galyautdinov et al. ^Galyautdinov et al., 2006^ and Odinokov, V.N. et al. ^Odinokov, V.N. et al., 2003^. Other modifications of the ecdysteroids of the invention are also known in the art. In their review Savchenko, R.G. et al. ^Savchenko, R.G. 2022^ in their detailed review paper e.g. on semisynthetic method ^Savchenko, R.G.2022^ teach a number of method e.g. for O-acetylation and O-alkylation or etherification of ecdysteroids. Further methods include halogenation like fluorination of ecdysteroid OH groups. Chromatographic method for the preparation of natural ecdysteroids are also well-known in the art. Such methods are reviewed e.g. by Lafont R. et al. ^Lafont R. et al., 2021^. Compositions comprising the compounds of the invention Methods to formulate the compounds of the invention to pharmaceutical or nutraceutical compositions are known in the art. Preferably the pharmaceutical composition is for or is suitable for enteral, e.g. oral or parenteral, e.g. intravenous, or topical administration into a patient. Oral administration is preferred. Oral pharmaceutical compositions and nutraceutical compositions may be similar as to their formulations including the excipients used. Typically, nutraceutical compositions should better fit into the food matrix. As ecdysterons can be found in plants it may be convenient to formulate the compositions with plant extracts. The compounds of the invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water. In general, the solvated forms are considered equivalent to the unsolvated forms for the purpose of the invention. Nevertheless, embodiments of the compounds of the invention have typically several hydroxide groups and thus have a significant water solubility. For example for oral administration, the active ingredient may be presented in a form as follows. Said oral pharmaceutical compositions may be formulated e.g. as pills, tablets, tabs, coated tablets, film tablets, capsules, powders, granulates, sustained-release formulations, suspensions or drops. In general, preparation of a composition with a pharmaceutically acceptable carrier or excipient may be carried out as described in e.g. as a standard reference, Gennaro, A.R. et al., Remington: The Science and Practice of Pharmacy (20th Edition., Lippincott Williams & Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing). More specifically, oral lipid-based drug delivery systems can e.g. be prepared as described in the review paper Kalepu, S, Oral lipid-based drug delivery systems – an overview. Acta Pharmaceutica Sinica B, 20133(6) 361-372. Solubilization of oral and injectable formulation is taught e.g. in Strickley, R.G. Solubilizing Excipients in Oral and Injectable Formulations. Pharmaceutical Research, Vol.21, No.2, February 2004. The pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers. In case of oral preparation, solid dosage units, such as pills, tablets, etc. as given above, can be provided. Injection liquids can be presented e.g. in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in the form of dry crystals or freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water or physiological salt solution, prior to use. The compounds of the present invention are present in the pharmaceutical compositions in a purity appropriate for human or animal administration. Purification techniques include e.g. recrystallization as shown in the examples and / or chromatographic purification as well known in the art. According to a preferred variant of the invention, the ecdysteroid or its derivative or a plant or animal extract containing same is incorporated in the lipid phase of liposomes or vesicles like extracellular vesicles (EVs). Thus, the ecdysteroid or its derivative, or an extract containing it, is dissolved with the constituents of the lipid phase, before atomization, in an organic solution containing at least one amphiphilic lipid, such as soya bean lecithin, and optionally a lipophilic hydrophobic compound such as cholesterol or β-sitosterol. The organic solution can advantageously contain an antioxidant such as α-tocopherol. The lipid powder obtained is dispersed in a suitable aqueous medium, for example a phosphate-buffered saline (PBS) buffer solution, a glucose solution or a sodium chloride solution. A liposome suspension is thereby obtained. According to an advantageous embodiment, most especially in the case of a liposome composition, after the composition obtained has, where appropriate, been homogenized, the liposome compositions are gelled by mixing with a gel. A gelling procedure is also described U.S. Pat. No. US5609873A, especially in the examples. Lyposomes and vesicles can also be used in topical formulations of the invention. Below the invention is disclosed in more detail via examples. The examples serve the purposes ofillustration and teaching specific embodiments of the invention and are not to be considered as defining the scope of the invention. EXAMPLES EXAMPLE 1 - Androgen-estrogen balance in male rats with high-fat, high-sugar diet-induced obesity 1.1. Materials and methods 1.1.1. Preparation of phytoecdysteroids 20-hydroxyecdysone (20E) 20-Hydroxyecdysone, originated from the roots extract of Cyanotis arachnoidea, was purchased from Shaanxi KingSci Biotechnology Co., Ltd. (Shanghai, People’s Republic of China) at 90% purity by means of HPLC- DAD and the extract was recrystallized two times from ethyl acetate−methanol (2:1, v / v) to reach a purity of 98.5% by means of HPLC-DAD. Calonysterone Calonysterone (CAL) was prepared by base-catalyzed autoxidation of 20E as published before ^Csábi et al., 2015^. Briefly, 3 g of 20E was dissolved in 32 ml methanol, then 112 ml of water was added to the solution. Separately, 2.4 g NaOH was dissolved 24 ml water, then the two solutions were mixed, and stirred for 6 h at room temperature. Subsequently HCl was added and the solution was left further stirring overnight at room temperature. Finally, the pH was neutralized by NaOH solution and the reaction mixture was evaporated under reduced pressure at 40 °C. The purification of calonysterone was performed by a Combiflash Rf+ instrument (Teledyne ISCO, Lincoln, NE, USA) equipped with diode array and evaporative light scattering detection (DAD / ELSD), and commercially available prefilled RediSep columns (Teledyne ISCO, Lincoln, NE, USA). FLASH chromatography using C18 modified stationary phase using an aqueous mobile phase gradient containing 25 to 50 (v / v) % MeOH. Fractions were analyzed by TLC, and those containing pure calonysterone were combined and evaporated under reduced pressure at 40 °C. 1.1.2. Housing and handling of the animals The animals were treated in accordance with the European Communities Council Directive (2010 / 63 / EU) and the Hungarian Act for the Protection of Animals in Research (Article 32 of Act XXVIII). All experiments involving animal subjects were carried out with the approval of the National Scientific Ethical Committee on Animal Experimentation (registration number: IV / 717 / 2023). Sprague–Dawley rats (INNOVO Ltd., Gödöllő,Hungary) were kept at 22±3 °C; the relative humidity was 30–70% and the light / dark cycle was 12 / 12 h.The rats were divided into 2 groups and started to feed with a high fat high sugar diet (HFHSD, 28% fat, 16% protein, 56% carbonhydrates) (C1011, Altromin Spezialfutter GmbH & Co. KG, Lage, Germany) or standard diet (SD) (1314, AltrominSpezialfutter GmbH & Co. KG, Lage, Germany) from 5-6 weeks of age until the day of sacrifice, with tap water available ad libitum. The weight of the animals and food consumption were measured weekly. The animals were sacrificed under isoflurane anesthesia using a portable small animal anesthesia machine (R550, RWD, Shenzhen, China), the organs were removed, and wet weights were measured on an analytical balance (Kern ABJ-NM, Kern & Sohn GmbH, Balingen-Frommern, Germany). Blood samples were collected by cardiac puncture in a small animal operating room using sterile syringes, needles, and collecting tubes. Plasma samples along with liver tissue samples were stored at −80 °C until the analytical experiments. 1.1.3. In vivo studies Six-week-old Sprague-Dawley male rats (n = 36) were divided into six groups equally. Three groups of rats were fed with high-fat and high-sugar diet (HFHSD) to set as the obese group and the three normal control groups (C) were fed the standard commercial rat chow. The rats were treated with calonysterone (CAL) and 20-hydroxyecdysone (20E) (10 mg / kg) in methylcellulose daily, by oral gavages, or received no treatment as follows: Group 1: control HFHSD (no treated), Group 2: HFHSD + 20E treated, Group 3: HFHSD + CAL treated, Group 4: normal diet control (no treated, C), Group 5: normal diet control + 20E, Group 6: normal diet control + CAL. Rat feeding and treatments were continued for 12 weeks. The baseline data on the body weight and food intake of each animal were recorded. During the experiment, the amount of food consumed as well as the body weight of each animal was measured weekly. Following the end of the study animals were sacrificed and testicles tissues, musculus levator ani, musculus tibialis and anterior soleus and blood were collected for analysis. The experimental design is shown in Figure 1. 1.1.4. RT-PCR studies Tissue isolation. The testicles were collected and placed in RNAlater Solution (Sigma-Aldrich, Hungary), then stored at -75 °C until the extraction of total RNA. Total RNA preparation from tissue. Total cellular RNA was isolated by extraction with guanidinium thiocyanate-acid-phenol-chloroform according to the procedure of Chomczynski and Sacchi ^Chomczynski et al., 1987^. After precipitation with isopropanol, the RNA was washed with 75% ethanol and then resuspended in diethyl pyrocarbonate-treated water. RNA purity was controlled at an optical density of 260 / 280 nm with BioSpec Nano (Shimadzu, Japan); all samples exhibited an absorbance ratio in the range of 1.6-2.0. Real-time quantitative reverse transcription-PCR (RT-PCR). Reverse transcription and amplification of the PCR products were performed by using the TaqMan RNA-to-CT-Step One Kit (Thermo Fisher Scientific, Hungary) and an ABI StepOne Real-Time cycler. Reverse-transcriptase PCR amplifications were performed as follows: at 48 °C for 15 min and at 95 °C for 10 min, followed by 40 cycles at 95 °C for 15 sec and at 60 °C for 1 min. The generation of specific PCR products was confirmed by melting curve analysis. The following primers were used: assay ID Rn00560747_m1 for the Ar, and Rn00667869_m1 for β-actin as endogenous control (ThermoFisher Scientific). All samples were run in triplicate. The fluorescence intensities of the probes were plotted against PCRcycle number. The amplification cycle displaying the first significant increase in the fluorescence signal wasdefined as the threshold cycle (CT). 1.1.5. ELISA assays Following the manufacturers’ recommendations, plasma levels of testosterone (cat. no: ER1462, FineTest), estrogen (cat. no: ER0661, FineTest), and corticosterone (cat. no: ER0859, FineTest) were measured by rat ELISA Kits. 1.1.6 Statistical analysis Statistical analyses were performed with the Prism 4.0 software (Graphpad Software Inc. San Diego, CA, USA). All data were analyzed by one-way ANOVA, followed by Tukey’s multiple comparison test, and each is presented as the mean ±SEM. Significance was accepted at p<0.05. 1.2. Results 1.2.1. Effects of 20E and CAL on body weight The averages of body weight continuously increased during the study, and it was significantly higher in the obese groups compared to the control groups. The changes in the body weight between the first day and the last day of the study show a significant increase in the HFHSD group compared to the control. The daily administration of phytoecdysteroid treatments for 12 weeks prevented the weight gain effect of the high-fat and high-sugar diet. Figure 2 shows the changes in body weight during the study. Interestingly, CAL significantly decreased the body weight in the control normal diet group (Figure 2). 1.2.2. Effects of 20E and CAL on muscle mass Figures 3 and 4 illustrate changes in testicle and various muscles to show the effect of the diet. A high fat and sugar diet (HFHSD) resulted in reduced testicular and musculus levator ani mass, which 20E treatment could not prevent, whereas CAL administration normalized testicular and musculus levator ani weight (Figure 3). The investigated skeletal muscle tissues (tibialis anterior, musculus soleus) were atrophied by a high fat and sugar diet. Both 20E and CAL treated animals in HFHSD groups were protected against this effect of diet. The phytoecdysteroid treatments had no effects on the normal diet groups (Figure 4). 1.2.3. Effects of 20E and CAL on adrenergic receptor (Ar) mRNA expression and plasma hormone levels Figure 5 shows alterations of adrenergic receptor mRNA expression in testicular tissues, plasma testosterone level, as well as estrogen level in the rat plasma. The present inventors found significantly high adrenergic receptor (Ar) mRNA expression in the 20E pretreated normal diet group compared to the control and CAL treated animals. In the untreated HFHSD group were no significant changes in Ar mRNA expression compared to the control but the 20E and CAL increased the Ar mRNA expression in the testicular tissues (Figure 5A). The plasma testosterone level changed inversely with adrenergic receptor expression (Figure 5B). The plasma estrogen level did not change after the treatments in the control group. In contrast, HFHSD increased the estrogen level but only the CAL protected against this effect (Figure 5C). In addition to the effect on sex hormones, the effect of 20E and CAL treatment on glucocorticoids has been studied. In particular, plasma corticosterone levels were determined. Corticosterone is the primary glucocorticoid hormone in rats and its concentration is most easily measured in plasma ^Bekhbat et al., 2018^. There is scientific evidence that low levels of inflammation are present in the body during obesity ^Khanna et al., 2022^. This was demonstrated in the present animal model with elevated corticosterone levels (Figure 15). In control groups, treatment did not affect hormone levels. The significantly elevated corticosterone concentration during obesity was normalized by both 20E and CAL treatment. Different diets also affected plasma corticosterone levels in rats as shown on Figure 6. Plasma corticosterone level was higher in the CAL treated control group, but it was no significant changes, in contrast in obese rats the corticosterone concentration was significantly increased but the 20E and CAL normalized it (Figure 6). EXAMPLE 2 - Investigation of Calonysterone and 20-Hydroxyecdysone effects in high-fat, high-sugar diet- induced obesity rat model 2.1 Materials and methods 2.1.1. Preparation of phytoecdysteroids 20-hydroxyecdysone (20E) 20-Hydroxyecdysone, originated from the roots extract of Cyanotis arachnoidea, was purchased from Shaanxi KingSci Biotechnology Co., Ltd. (Shanghai, People’s Republic of China) at 90% purity by means of HPLC- DAD and the extract was recrystallized two times from ethyl acetate−methanol (2:1, v / v) to reach a purity of 98.5% by means of HPLC-DAD. Calonysterone Calonysterone (CAL) was prepared by base-catalyzed autoxidation of 20E as published before (8). Briefly, 3 g of 20E was dissolved in 32 ml methanol, then 112 ml of water was added to the solution. Separately, 2.4 g NaOH was dissolved 24 ml water, then the two solutions were mixed, and stirred for 6 h at room temperature. Subsequently HCl was added and the solution was left further stirring overnight at room temperature. Finally, the pH was neutralized by NaOH solution and the reaction mixture was evaporated under reduced pressure at 40 °C. The purification of calonysterone was performed by a Combiflash Rf+ instrument (Teledyne ISCO, Lincoln, NE, USA) equipped with diode array and evaporative light scattering detection (DAD / ELSD), and commercially available prefilled RediSep columns (Teledyne ISCO, Lincoln, NE, USA). FLASH chromatography using C18 modified stationary phase using an aqueous mobile phase gradient containing 25 to 50 (v / v) % MeOH. Fractions were analyzed by TLC, and those containing pure calonysterone were combined and evaporated under reduced pressure at 40 °C. 2.1.2. Housing and handling of the animals The animals were treated in accordance with the European Communities Council Directive (2010 / 63 / EU) and the Hungarian Act for the Protection of Animals in Research (Article 32 of Act XXVIII). All experiments involving animal subjects were carried out with the approval of the National Scientific Ethical Committee on Animal Experimentation (registration number: IV / 717 / 2023). Sprague–Dawley rats (INNOVO Ltd., Gödöllő, Hungary) were kept at 22±3 °C; the relative humidity was 30–70% and the light / dark cycle was 12 / 12 h. The rats were divided into 2 groups and started to feed with a high fat high sugar diet (HFHSD, 28% fat, 16% protein, 56% carbonhydrates) (C1011, Altromin Spezialfutter GmbH & Co. KG, Lage, Germany) or standard diet (SD) (1314, AltrominSpezialfutter GmbH & Co. KG, Lage, Germany) from 5-6 weeks of age until the day of sacrifice, with tap water available ad libitum. The weight of the animals and food consumption were measured weekly. The animals were sacrificed under isoflurane anesthesia using a portable small animal anesthesia machine (R550, RWD, Shenzhen, China), the organs were removed, and wet weights were measured on an analytical balance (Kern ABJ-NM, Kern & Sohn GmbH, Balingen-Frommern, Germany). Blood samples were collected by cardiac puncture in a small animal operating room using sterile syringes, needles, and collecting tubes. Plasma samples along with liver tissue samples were stored at −80 °C until the analytical experiments. In vivo studies Six weeks old Sprague-Dawley male rats (n = 24) were divided into four groups equally. Three groups of rats were fed with high-fat and high-sugar diet (HFHSD) to set as the obese group and the standard commercialrat chow was fed to the normal control group.The rats (n = 6 in each group) were treated with calonysterone (CAL) and 20-hydroxyecdysone (20E) (10 mg / kg) in methylcellulose daily, by oral gavages, or received no treatment as follows: Group 1: control HFHSD (no treated), Group 2: HFHSD + 20E treated, Group 3: HFHSD + CAL treated, Group 4: normal diet control (no treated). Rat feeding and treatments were continued for 12 weeks. The baseline data on the body weight and food intake of each animal were recorded. During the experiment, the amount of food consumed as well as the body weight of each animal was measured weekly. Plasma glucose during the glucose tolerance test (GTT) was measured at baseline, at weeks 6 and 12 of the experiment. Following the end of the study animals were sacrificed and liver tissues and blood were collected for analysis. The experimental design is shown in Figure 7. Glucose Tolerance Test Glucose tolerance test (GTT) was carried out at 0, 6, and 12 weeks of study. Glucose levels were measured with a Dcont®ETALON®Glucose Meter (77 Elektronika Ltd., HU). Animals have fasted for 16 h before glucose measurement. Fasting glucose levels were measured first at 8 a.m., then each rat was treated intraperitoneally with 2 mg / kg glucose in the form of a 25% solution. Blood glucose levels were determined 15, 30, 45, 60, 90, 120, and 240 min after the injection. The GTT was evaluated by the comparison of glucose level at each sampling time and the area under the curve of the plasma glucose concentration-time curve between the SD and HFHSD groups (28). 2.1.3. RT-PCR study Tissue isolation. The liver tissues were collected and placed in RNAlater Solution (Sigma-Aldrich, Hungary), then stored at -75 °C until the extraction of total RNA. Total RNA preparation from tissue. Total cellular RNA was isolated by extraction with guanidinium thiocyanate-acid-phenol-chloroform according to the procedure of Chomczynski and Sacchi [Chomczynski et al., 1987]. After precipitation with isopropanol, the RNA was washed with 75% ethanol and then resuspended in diethyl pyrocarbonate-treated water. RNA purity was controlled at an optical density of 260 / 280 nm with BioSpec Nano (Shimadzu, Japan); all samples exhibited an absorbance ratio in the range of 1.6-2.0. Real-time quantitative reverse transcription-PCR (RT-PCR). Reverse transcription and amplification of the PCR products were performed by using the TaqMan RNA-to-CT-Step One Kit (Thermo Fisher Scientific, Hungary) and an ABI StepOne Real-Time cycler. Reverse-transcriptase PCR amplifications were performed as follows: at 48 °C for 15 min and at 95 °C for 10 min, followed by 40 cycles at 95 °C for 15 sec and at 60 °C for 1 min. The generation of specific PCR products was confirmed by melting curve analysis. The following primers were used: assay ID Rn01410330_m1 for the IL6, and Rn00667869_m1 for β-actin as endogenous control (ThermoFisher Scientific). All samples were run in triplicate. The fluorescence intensities of the probes were plotted against PCR cycle number. The amplification cycle displaying the first significant increase in the fluorescence signal was defined as the threshold cycle (CT). 2.1.4. Western blot analysis Protein preparation from tissue. Liver tissues were homogenated with a solution of RIPA lysis and extraction buffer and protease inhibitors cocktail. Following protein extraction, the protein concentrations in the supernatant layer were measured with spectrophotometer, then stored at −80 ◦C until further use. 50 µg of protein per well was subjected to electrophoresis on 4-12% NuPAGE Bis-Tris Gel in XCell SureLockMini-Cell Units (ThermoFisher Scientific). Proteins were transferred from gels to nitrocellulose membranes, using the iBlot Gel Transfer System (ThermoFisher Scientific). Antibody binding was detected with the WesternBreeze Chromogenic Western blot immunodetection kit (ThermoFisher Scientific, Hungary). The blots were incubated on a shaker with IL6 (26kDa, 1:600, ThermoFisher Scientific), and ß-actin (42 kDa, 1:600, Bioss Antibody) polyclonal antibody in the blocking buffer. Images were captured with the EDAS290 imaging system (Kodak Ltd.), and the optical density of each immunoreactive band was determined with Kodak 1D Images analysis software. Optical densities were calculated as arbitrary units after local area background subtraction. 2.1.5. Colorimetric and ELISA assays Following the manufacturers’ recommendations, liver or plasma levels of superoxide dismutase (SOD, cat. no: MBS036924, MyBiosource, USA), catalase (CAT, cat. no: MBS458146, MyBiosource, USA), adiponectin (cat. no: ER0006, FineTest, China), leptin (ER0115, FineTest, China) and IL6 (cat. no: 900-M86, PeproTech, USA) were measured by rat ELISA Kits, and liver total antioxidant capacity (T-AOC) was measured by colorimetric assay Kit (cat. no: E-BC-K136-S, Elabscience, USA). All optical density values were measured using a SPECTROStar Nano microplate spectrophotometer (BMG Labtech, Germany). 2.1.5. Global DNA methylation in the liver The isolation of DNA from the liver tissues was made by GeneaidTM DNA Isolation Kit (Geneaid Biotech Ltd.), and the global DNA methylation was determined by Methylated DNA Quantification Kit (Abnova Ltd.). 2.1.6. Statistical analysis Statistical analyses were performed with the Prism 4.0 software (Graphpad Software Inc. San Diego, CA, USA). All data were analyzed by one-way ANOVA, followed by Newman-Keuls multiple comparison test, and each is presented as the mean ±SEM. Significance was accepted at p<0.05. 2.2. Results 2.2.1. Effects of 20E and CAL on body weight Throughout the experimental period, the body weights of all groups were monitored weekly. The averages of body weight continuously increased during the study, and it was significantly higher in the obese groups compared to the control group. The changes in the body weight between the first day and the last day of the study show a significant increase in the high fat high sugar diet (HFHSD) group compared to the control. The daily administration of phytoecdysteroid treatments for 12 weeks prevented the weight gain effect of the high-fat high-sugar diet. At the end of the experiment, the untreated obese rats showed the highest increase of changes in body weight compared to the control, 20E and CAL groups, i.e., the ecdysteroids fully prevented the HFHSD-induced obesity in the present model (Figure 8). 2.2.2. Effects of 20E and CAL on plasma glucose level Glucose tolerance tests were carried out in the 6th and 12th weeks of the experiment (Figure 7. HFHSD group had higher plasma glucose levels in all time points after glucose loading and significantly higher values for the AUC as compared to the control group. After six weeks of the HFHSD diet, the maximum glucose level was lower, but the values of AUC were similar after 20E and CAL treatment. The 20E and CAL administration to theHFHSD rats did not improve glucose tolerance as indicated by higher plasma glucose levels in all time points afterglucose loading on the 12th week. However, the course of the curves changed after the treatments, which may indicate different glucose sensitivity. (Data not shown.) 2.2.3. Effects of 20E and CAL on the liver antioxidant capacity Obese rats showed a significant reduction in the liver total antioxidant capacity compared to the control group. This reduction was prevented and significantly improved by phytoecdysteroid treatments compared to the control group (Fig 9a). 20E administration in the HFHSD rats significantly increased the levels of superoxide dismutase compared to the control (Fig 9b). The HFHSD significantly decreased, while the phytoecdysteroid (20E, CAL) treatments significantly increased the catalase levels compared to the control (Fig 9c). 2.2.4. Effects of 20E and CAL on leptin and adiponectin receptor concentration in plasma Changes of plasma concentration of leptin (a) and adiponectin (b) after control diet (C) and high fat high sugar diet (HFHSD) diet are shown on Figure 10. The plasma level of leptin significantly increased in the HFHSD group compared to the control group, and this was normalized by 20E and CAL treatment (Figure 10a). The plasma concentration of adiponectin significantly decreased after HFHS diet and both 20E and CAL normalized this (Fig 10b). 2.2.5. Effects of 20E and CAL on pro-inflammatory cytokines IL6 mRNA and protein expressions in the liver and plasma The effects of 20E and CAL on pro-inflammatory cytokine IL6 were also studied at various levels, including mRNA and protein expression in the liver as well as on plasma IL6 level. IL6 mRNA and protein expression significantly increased in liver tissues of obese rats and both 20E and CAL efficiently counteracted this effect of HFHSD (Fig 11a-b). HFHSD significantly increased the plasma IL6 level that was dramatically decreased after phytoecdysteroid treatment, especially after treatment with 20E that decreased IL6 level significantly below that of the control group (Fig 11c). 2.2.6. Effects of 20E and CAL on the levels of global DNA methylation in the liver Administration of phytoecdysteroid in obese rats significantly increased the levels of global DNA methylation in the liver compared to the control (Fig 12). EXAMPLE 3 – Effect of Ecdysone derivatives on the blood-brain barrier 3.1. Material and Methods 3.1.1. Materials All reagents were purchased from Sigma-Aldrich Ltd. Hungary, unless otherwise indicated. 3.1.2. Blood-brain barrier cell culture model: hCMEC / D3 human brain endothelial cell line The human hCMEC / D3 brain endothelial cell line [Weksler et al., 2005] was purchased from Merck Millipore. The cultures under passage number 35 were kept in Petri dishes coated with rat tail collagen and grown in a cell culture incubator at 37 °C with 5% CO2. The basal medium used was the MCDB 131 (Pan Biotech) supplemented with 5 % fetal bovine serum (FBS), GlutaMAX (100 ×, Life Technologies, USA), lipid supplement(100 ×, Life Technologies, USA), 10 µg / ml ascorbic acid, 550 nM hydrocortisone, 37.5 µg / ml heparin, 1 ng / mlbasic fibroblast growth factor (bFGF, Roche, USA), 5 µg / ml insulin-5 µg / ml transferrin- 5 ng / ml selenium (ITS) supplement (100 ×, PanBiotech, Germany), 10 mM HEPES and gentamycin (50 µg / ml). Medium change was performed every two or three days. When cells reached a confluence of 90 % they were passaged to rat tail collagen-coated 96-well plates for the viability assays (E-plate, ACEA Biosciences, USA). Before each experiment the medium was supplemented with 10 mM LiCl for 24 h to improve BBB properties (Veszelka et al., 2018). 3.1.3. Cell viability assay: impedance measurement Impedance measurement correlates linearly with cell number, adherence, growth and viability [Walter et al., 2016]. Kinetics of the viability of brain endothelial cells after treatment was monitored by a real time impedance measurement machine (RTCA-SP, ACEA Biosciences, San Diego, CA, USA). The hCMEC / D3 cells were seeded at a cell number of 5×103 / well onto the 96-well E-plate (ACEA Biosciences) with golden electrodes at the bottom of the wells, and were kept in the CO2 incubator at 37 ºC for 5-6 days. Medium change was performed every second day. Cells were treated with the target compounds at the stable plateau growth phase with 0.01, 0.03, 1, 3, 30, 10 µM concentrations of 20E and Calonysterone. Triton X-100 detergent was used to determine 100% toxicity. Effects of the treatment were followed for 24 h. 3.1.4. Treatments Preparation of stock solutions All compounds were received in powder form. The stock solutions were prepared by diluting the compounds in DMSO at a final concentration of 10 mM. Compounds were stored at -20 °C. Aliquots were always freshly thawed and used directly for experiment. Concentrations applied in the cell culture The compounds were tested in the cell culture, by preparing a sub-stock of 100 µM in cell culture medium, from the 10mM. From this sub-stock a serial dilution was made: 10 µM, 3 µM, 1 µM, 0.3 µM, 0.1 µM, 0.03 µM and 0.01 µM. For further tests the most effective concentration of each compound was selected: 20 E – 0.01 µM; Calonysterone – 0.1 µM and 0.01 µM. Tert-Butyl hydroperoxide (tBHP) treatment Tert-Butyl hydroperoxide is an oxidative compound that can induce cell death via apoptosis or necrosis. tBHP generates tert-butoxyl radicals via iron-dependent reactions, resulting in lipid peroxidation, depletion of intracellular glutathione followed by modification of protein thiols resulting in the loss of cell viability [Martin et al., 2001][Zhao et al., 2017]. First several concentrations were tested to determine an approx.50 % cell viability loss. Concentrations from 1-1000 µM were tested. The present inventors found that treatment with 350 µM tBHP was effective in reducing cell viability. Therefore, this concentration was combined with the selected concentrations of the compounds to test potential protective effects. 3.1.5. BBB integrity assays TEER measurement To test the barrier integrity hCMEC / D3 cells were cultivated on cell culture inserts (Transwell clear PET, 24-well format, surface: 0.33 cm2) to model the BBB in a two-compartment system. This model was used to investigate the most effective ecdysteroid metabolite, calonysterone alone, and in protection against tBHP. Cellswere passaged as described previously and seeded to the top compartment of the culture inserts at a density of1.5 × 104cells / insert. Cells received fresh culture medium every second day. To follow the development of the barrier properties of the monolayers, TEER was measured before every medium change with an EVOM voltohmmeter (World Precision Instruments Inc., USA) combined with chamber electrodes designed for 24-well inserts. TEER should be expressed relative to the surface of the inserts (Ω × cm2) and the TEER of cell-free inserts (70 Ω × cm2) should be subtracted from the measured values. TEER before and after calonysterone treatment was measured in the same buffer used for the permeability measurements. Culture plates were placed onto a heating pad set to 37 °C to minimize the temperature-derived fluctuations in the TEER values. Permeability assay Brain endothelial cells were cultured on cell culture inserts positioned into 24-well plates. The permeability experiment here was performed as follows: treatments were added to the inserts first in the appropriate buffer, then permeability marker dyes in a 40 × dilution were added. The buffer was Ringer Hepes solution, which was supplemented with 1 % bovine serum albumin (BSA), ITS (200 ×), 1.5 µM hydrocortisone, 37.5 µg / ml heparin, 1 ng / ml bFGF, 5 µg / ml ascorbic acid and lipid supplement (100 ×). Before the experiment new 24-well plates were prepared with 900 µl of the experimental buffer in the wells and pre-warmed at 37 °C. To start the experiment, inserts were moved to these multiwell plates, and in the apical chambers culture medium was replaced with the treatment solutions. The seven treatment groups received: only buffer (control group), calonysterone 0.01 µM or 0.01 µM together with tBHP (350 µM), calonysterone 0.1 µM or 0.1 µM together with tBHP (350 µM); tBHP (350 µM) alone and edaravone (10 µM) together with tBHP (350 µM). When treatments were added, 5 µl concentrated dye solution was pipetted to the apical chamber with a final concentration of 10 µg / ml for FITC-dextran (FD10, Mw: 10 kDa) and 167.5 µg / ml Evans blue which binds stochiometrically to the 1 % BSA (EBA, mw: 67 kDa). After 30 and 60 minutes the inserts were transferred to new wells containing fresh buffer in the bottom compartments. Incubations were performed at 37 °C in a CO2 incubator on a shaking platform (100 rpm). At the end of the permeability assay samples from the compartments were taken and the amount of tracers was determined by a spectrofluorometer (Horiba Jobin Yvon Fluorolog 3, Kyoto, Japan). Excitation and emission wavelengths were the following: 582 nm / 662 nm (EBA); 490 nm / 516 nm (FD10). The clearance at each timepoint from the top compartment to the bottom was calculated with the following formula [Hülper et al., 2013]: After this the average volume cleared was plotted vs. time, and permeability × surface area product value for endothelial monolayer (PSe) was calculated by the following formula: PSe divided by the surface area generated the endothelial permeability coefficient (Pe; in cm / s), which is used at the data presentation. Statistics Data are presented as means ± SD. Statistical significance between treatment groups was determined using one-way ANOVA followed by Dunnett’s or Bonferroni multiple comparison post-tests (GraphPad Prism 5.0; GraphPad Software, USA). The number of parallel samples was minimum four. Changes were consideredstatistically significant at p < 0.05. Results Evaluation of the effect of compounds 20E and Calonysterone on brain endothelial cells Effects of 20E, and its metabolite calonysterone were tested on hCMEC / D3 cell integrity and viability using the real-time cell electronic sensing method with impedance measurement. Normalized cell index of hCMEC / D3 cells treated with different concentrations of 20E and calonysterone is shown at various timepoints (4h, 6h and 24h). First, a 0.01-10 µM concentration range was tested for all compounds (Figure 20a-d). The present inventors observed no effect on cell viability or integrity for 20E and calonysterone. On the contrary, the inventors observed that impedance was increased for both compounds after 4h and 6h treatment (Figure 20a,b and 20d,e), and maintained up to 24h (Figure 20c, f). At these beneficial concentrations, there is no toxicity through time up to 24 hours. Interestingly, both series of compounds showed a similar behavior after treatment characterized by a slight decrease at the first hour, which is a probable effect of the medium change, followed by an increase in impedance and a sustained elevated cell index up to 24 hours (Figure 13). Particularly, calonysterone and 20E showed a beneficial effect on the cells for a longer time, with a sustained promotion of cell index close to the untreated control (Figure 13). Evaluation of the role of 20E and Calonysterone in the protection against oxidative stress at the chosen concentrations on brain endothelial cells For the evaluation of the role of the compounds in protecting against reactive oxygen species, cells were treated with tBHP (350 µM) alone and in combination with the compounds at the chosen concentrations. Due to its structure, the tBHP produces high amounts of ROS which causes damage to the cells [Kučera et al., 2014]. The optimal concentration of tBHP was evaluated as well, and a concentration which does not decrease cell index below ~50 % was chosen in the protection assay. Figure 14 shows normalized cell indices of hCMEC / D3 cells treated with reactive oxygen species generating tBHP (350 µM) and in combination with the selected compounds, including CAL and 20E, at various timepoints (4 h, 6 h and 24 h). On the E-plate the inventors observed that there was a significant rescue effect for all compounds (Figure 14). The addition of tBHP causes a pronounced decrease in cell viability during the first hour followed by a maximum of 30 % recovery until cells stabilize (Figure 20e). All compounds effectively protected against the tBHP damage (Figure 20e). The inventors have selected 0.01 μM for 20E since it showed an increased cell index, keeping a constant effect for 24h (Figure 20a-b). For calonysterone, the concentrations of 0.01 μM and 0.1 μM were selected for further tests (Figure 20c-d). Calonysterone (Cal, 0,01 μM and 0,1 μM), and 20E (0,01 μM). a: at 4hours treatment, b; at 6hours treatment; c: at 24hours treatment. Effects of calonysterone treatment on the barrier integrity of brain endothelial cellsTransendothelial electrical resistance measurement Due to the beneficial effects measured at the impedance measurements, the inventors decided to investigate the effect of calonysterone on barrier integrity. First TEER measurement was performed, which is determining the barrier’s permeability for ions [Yeste et al., 2018]. TEER is commonly expressed as resistance multiplied by the area of the culture surface where the endothelial monolayer is kept (Ω × cm2). The measurement was performed during the permeability study, at 30 and 60 minutes. Edaravone is used as positive control [Tóth et al., 2014] Figure 15 shows the effect of calonysterone treatment alone and in combination with the oxidative stressor tBHP (350 µM) on the barrier integrity of human brain endothelial cells. Transendothelial electrical resistance is shown as the % of the control. At the beginning of the experiment hCMEC / D3 cells show a uniform background TEER of 22 Ω × cm2, which indicates, that this cell line does not form a tight barrier as primary cultures do [Weksler et al., 2005][Weksler et al., 2013]. After 30 minutes of treatment tBHP already exerts a significant TEER decreasing effect compared to the control (Figure 15A). Edaravone + tBHP treatment significantly elevates TEER compared to the tBHP alone. Calonysterone (0.1 µM) with tBHP combination shows a decreased TEER after 30 mins compared to the control, which is later compensated (Figure 15A and 15B). Regarding the TEER after 60 minutes, a clear trend its observed (Figure 15B). First, the reduction of resistance in the group of tBHP alone is even more significant compared to the control. The inventors can observe a positive rescuing effect in the case of the combination treatment with calonysterone (0.01 μM) and Edaravone. These findings with the calonysterone corroborate the results gained on the E-plate measurements. Permeability measurement During the treatment with compounds, TEER measurement and the permeability assay using fluorescent marker molecules was going parallel. The inventors treated the cells with two concentrations of calonysterone alone and in combination with tBHP and tested the passage of two fluorescent marker molecules, FITC-dextran 10 kDa (FD10) and EBA. Here Edaravone treatment was used as a positive control for an antioxidant molecule. Figure 16 illustrates the effect of calonysterone treatment alone and in combination with the oxidative stressor tBHP (350 µM) on the barrier integrity of human brain endothelial cells. Cumulative clearance derived endothelial permeability coefficient (Pe) of fluorescent marker molecules FITC-dextran 10 kDa (FD10) and Evans- blue labelled albumin (EBA) is shown as the % of the control. Baseline permeability values were 4.52 ±0.64 cm / s for FD10 and 1.41 ±0.24 cm / s for EBA, which is similar to previous results [Weksler et al., 2005][Walter et al., 2016]. tBHP exerts a significant permeability elevation to 400 % of the control’s level in the case of the paracellular permeability marker FD10, and above 1000 % of the level of the control in the case of the transcellular permeability marker EBA. For FD10 all two concentrations of calonysterone in combination with tBHP decrease the permeability elevation effect of tBHP at least to its half, comparable manner to Edaravone, showing a protective effect for the paracellular pathway (Figure 16A). Interestingly in the case of EBA permeability, the calonysterone alone (0.01 μM) treatment increased the passage of the dye to the bottom compartment to 700 % to the control’s level and also its effect in the combination with tBHP was not protective for this permeability route. The higher calonysterone concentration (0.1 μM) did notchange EBA permeability in the solo treatment and rescued the elevated permeability phenotype in the case ofcombination with tBHP very well, just as Edaravone did. In general, the results show that low concentrations of calonysterone treatment rescue the barrier integrity, increasing the effect of the oxidative stressor tBHP on the present human brain endothelial cell line model. The effect observed is the truest for both concentrations in the case of the FD10 paracellular marker, while calonysterone 0.1 μM shows protection in EBA permeability. Effect of 20E and Calonysterone in the protection against oxidative stress at the proteomic level The present inventors have performed proteomics on cells treated for 6 hours with tBHP and the compounds, having as reference the untreated cells and cells treated with tBHP. Figure 17 presents the data obtained on hCMEC / D3 cells proteome untreated and treated with tBHP for 6 hours, including a volcano plot showing up- and downregulated genes (Figure 17a) and a heatmap containing the up- and downregulated genes across the different comparisons (Figure 17b). A “Go enrichment” of the genes that contribute to the biggest changes (Figure 17c) has also been added. The following table (Table 17b) describes the genes up and downregulated. Table 17b – Genes up and downregulated due to 6 h tBPH treatment in hCMEC / D3 cells proteome symbol Iog10_base_mean log2FC padj significance HMOX1 -0.09 0.771 1.2519E-05 Up regulated MRPL45 -0.86 -0.659 0.00865041 Down regulated ETHE1 0.13 -0.752 3.8603E-06 Down regulated PMPCB -0.75 -0.986 6.0439E-08 Down regulated METTL7A -0.45 -1.105 9.4273E-09 Down regulated AD 11 -0.56 -1.262 3.4654E-08 Down regulated In order to observe differential expression in the different groups, the inventors have defined a Log2 Fold Change (Log2FC) as 0.58 as a minimum, indicating that the differences observed are at least 1.5x bigger than the control group and with a minimal p-value of 0.05. The inventors observed changes in the cell proteome when comparing the tBHP group with the untreated group (Figure 17). A total of 5 proteins were found downregulated and 1 protein upregulated (Figure 17 a,b). From those, PMPCB, which is the catalytic subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursor proteins, and ETHE1, a sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix, were responsible for the biggest changes in Go enriched pathways (Figure 17c). The heat map of Figure 17b shows that the genes upregulated in the untreated group were downregulated upon the treatment with tBHP. Since PMPCB and ETHE1 are related to the mitochondrial membrane, their downregulation can indicate mitochondrial damage. On Tables 4 to 6 the inventors describe the different pathways that significantly change at biological, cellular and molecular level upon treatment with tBHP. Figure 18 presents the data obtained on hCMEC / D3 cells proteome on 20E (0.01 μM) + tBHP (350 μM) treatment for 6 hours versus the untreated group. Again, a volcano plot shows up- and downregulated genes (Figure 18a) and heatmap containing the up- and downregulated genes across the different comparisons is also shown (Figure 18b). Additionally a “Go enrichment” of the genes that contribute to the biggest changes are shown on Figure 18c. The following table describes the genes up and downregulated in the hCMEC / D3 cells proteome on (Table 18b) upon 6 h 20E (0.01 μM) + tBHP (350 μM) treatment. Table 18b symbol Iog10_base_mean log2FC Padj significance COL1A2 0.29 1.286 0.0223426 Up regulated HMOX1 -0.09 0.756 3.2747E-05 Up regulated TMOD2 0.16 0.737 0.0044694 Up regulated HBA2 0.5 0.675 0.00414611 Up regulated HBA1 0.5 0.675 0.00414611 Up regulated IL18 -0.15 -0.768 0.00849801 Down regulated PMPCB -0.75 -0.936 2.6406E-07 Down regulated METTL7A -0.45 -1.067 3.5007E-08 Down regulated ADI1 -0.56 -1.128 3.0194E-07 Down regulated In more detail, to understand the protective effect of 20E upon oxidative stress, the cells were kept under 20E (0.01 μM) + tBHP (350 μM) treatment for 6 hours. The inventors have then compared the proteome of this condition with the untreated. Applying the same log2FC and p-value criteria as with the tBHP and untreated group, the inventors could observe that 5 proteins were upregulated and 4 proteins downregulated (Figure 18a-b). The proteins HBA1, HBA2, HMOX1, IL18 and COL1A2 contributed significantly for the Go enrichment pathways changes (Figure 18c). The changes in the up- and down-regulated genes can be observedin the heatmap across the different comparisons (Figure 18b). On Tables 4b to 7 the inventors describe thedifferent pathways that significantly change at biological, cellular and molecular level upon treatment with tBHP. Figure 19 presents the data obtained on hCMEC / D3 cells proteome on calonysterone (0.01 μM) + tBHP (350 μM) treatment for 6 hours versus the untreated group. Again, a volcano plot shows up- and downregulated genes (Figure 19a) and heatmap containing the up- and downregulated genes across the different comparisons is also shown (Figure 19b). Additionally a “Go enrichment” of the genes that contribute to the biggest changes are shown on Figure 19c. The following table describes the genes up and downregulated in the hCMEC / D3 cells proteome on (Table 19b) upon 6 h calonysterone (0.01 μM) + tBHP (350 μM) treatment. Table 19bsymbol Iog10 base mean log2FC padj significance ITIH4 -0.7 1.295 0.0148605 Up regulated AHSG 0.69 1.186 0.01009153 Up regulated SERPINF2 0.09 1.18 0.01182859 Up regulated AFP 0.11 1.177 0.02005137 Up regulated A1BG -0.12 1.175 0.0159017 Up regulated ITIH2 0.16 1.144 0.01564233 Up regulated SASS6 -0.13 1.138 0.02004772 Up regulated ALB 0.76 1.123 0.01647179 Up regulated LTF 0.62 1.028 0.02312235 Up regulated GC 0.25 1.017 0.03240049 Up regulated SERPINF1 -0.41 0.885 0.03675652 Up regulated A2M 0.33 0.881 0.02744284 Up regulated PZP 0.02 0.88 0.03035582 Up regulated C3 -0.29 0.866 0.01669125 Up regulated ORMDL2 -0.91 0.743 0.00788551 Up regulated HBA2 0.5 0.599 0.00544123 Up regulated HBA1 0.5 0.599 0.00544123 Up regulated HTATIP2 -0.47 0.583 0.00381451 Up regulated MRPS9 -0.26 -0.582 0.00166092 Down regulated ETHE1 0.13 -0.711 6.9394E-06 Down regulated GHITM -0.84 -0.782 0.00083223 Down regulated PMPCB -0.75 -1.012 4.5106E-08 Down regulated METTL7A -0.45 -1.281 1.6276E-09 Down regulated ADI1 -0.56 -1.309 2.2663E-08 Down regulated To understand the protective effect of calonysterone upon oxidative stress, the cells were kept under calonysterone (0.01 μM) + tBHP (350 μM) treatment for 6 hours. The present inventors have then compared the proteome of this condition with the untreated. Applying the same log2FC and p-value criteria as with the tBHP and untreated group, the inventors could observe higher changes that was not observed in the treatment with 20E (Figure 19). The inventors have observed 18 up-regulated proteins and 6 down-regulated proteins (Figure 19a-b). C3, A2M, SERPINF2, AHSG, HBA1, HBA2, LTF, ITH4, SERPINF1, ALB, PZP, AFP, A1BG, PMPCB are the proteins influencing the biggest changes on the proteome (Figure 19c). The alterations in gene expression, both upregulation and downregulation, are visually depicted in the heatmap for various comparisons (Figure 19d).Additionally, supplementary figures 8-10 provide a detailed description of the pathways that undergo significantchanges at the biological, cellular, and molecular levels following treatment with tBHP. EXAMPLE 4 – Industrial-scale preparation of calonysterone and related ecdysteroid derivatives The cost-effective and scalable isolation of a large amount of Calonysterone produced by the autooxidation reaction of 20-hydrodyecdysone can be carried out using centrifugal partition chromatography. The scalable CPC isolation method of Calonysterone has not been previously published before. LC-MS was used to monitor the composition of the fractions and to identify the 2-3 minor components generated alongside the starting material and the main product. A methodological difficulty in the separation was the large amount of sodium chloride, which accounts for about half of the weight of the final product. Biphasic solvent systems were developed that are able to dissolve salt without any decrease in resolution, thus avoiding a preliminary, costly and time-consuming desalting step. The following systems were used to experimentally perform the separation on a laboratory-scale CPC in ascending mode on a 250 ml rotor with a 1 g of injected sample: • Methyl-isobutyl-ketone / Aceton / H2O 3 / 4 / 3 (v / v / v) • EtOAc / MeOH / H2O 4 / 2 / 4 (v / v / v) • EtOAc / MeOH / H2O 4 / 1,5 / 4 (v / v / v) • Methyl-ethyl-ketone / EtOAc / H2O 5 / 1 / 4 (v / v / v) • Methyl-isobutyl-ketone / MeOH / H2O 1 / 1 / 1 (v / v / v) The present results show that over 90% purity can be obtained of calonysterone with good yield using all systems, with only differences in sample solubility and solvent system stability. The EtOAc / MeOH / H2O 4 / 2 / 4 (v / v / v) solvent system was chosen for scale-up in ascending mode. This means an injected sample of 8 g on a 2100 ml rotor (pilot scale rCPC®) with a short, 20 minutes long method. By these novel, scalable methods 10g of purified Calonysterone can be obtained per hour. Scalability of rCPC assures that by using the industrial-size instrument, iCPC®, at least a 100g per hour of productivity is achievable. This is therefore the first method to produce calonysterone on an industrial scale. The same instruments and methods are appropriate to the industrial-scale fractionation and purification of other oxidized minor ecdysteroids present in large amounts in commercially available extracts of Cyanotis arachnoidea worldwide marketed as food supplements. Tables Table 1 - hCMEC / D3 cells proteome untreated and treated with tBHP for 6 hours: table describing the genes up and downregulated symbol Iog10_base_mean log2FC padj significance HMOX1 -0.09 0.771 1.2519E-05 Up regulated MRPL45 -0.86 -0.659 0.00865041 Down regulated ETHE1 0.13 -0.752 3.8603E-06 Down regulated PMPCB -0.75 -0.986 6.0439E-08 Down regulated METTL7A -0.45 -1.105 9.4273E-09 Down regulated ADI1 -0.56 -1.262 3.4654E-08 Down regulated Table 2 - hCMEC / D3 cells proteome on 20E (0.01 μM) + tBHP (350 μM) treatment for 6 hours versus the untreated group: table describing the genes up and downregulated symbol Iogl0_base_mean log2FCPadj significance COL1A2 0.29 1.286 0.0223426 Up regulated HMOX1 -0.09 0.756 3.2747E-05 Up regulated TMOD2 0.16 0.737 0.0044694 Up regulated HBA2 0.5 0.675 0.00414611 Up regulated HBA1 0.5 0.675 0.00414611 Up regulated IL18 -0.15 -0.768 0.00849801 Down regulated PMPCB -0.75 -0.936 2.6406E-07 Down regulated METTL7A -0.45 -1.067 3.5007 E-08 Down regulated ADI1 -0.56 -1.128 3.0194E-07 Down regulated Table 3 - hCMEC / D3 cells proteome on calonysterone (0.01 μM) + tBHP (350 μM) treatment for 6 hours versus the untreated group: table describing the genes up and downregulated symbol Iog10 base mean log2FC padj significance ITIH4 -0.7 1.295 0.0148605 Up regulated AHSG 0.69 1.186 0.01009153 Up regulated SERPINF2 0.09 1.18 0.01182859 Up regulated AFP 0.11 1.177 0.02005137 Up regulated A1BG -0.12 1.175 0.0159017 Up regulated ITIH2 0.16 1.144 0.01564233 Up regulated SASS6 -0.13 1.138 0.02004772 Up regulated ALB 0.76 1.123 0.01647179 Up regulated LTF 0.62 1.028 0.02312235 Up regulated GC 0.25 1.017 0.03240049 Up regulated SERPINF1 -0.41 0.885 0.03675652 Up regulated A2M 0.33 0.881 0.02744284 Up regulated PZP 0.02 0.88 0.03035582 Up regulated C3 -0.29 0.866 0.01669125 Up regulated ORMDL2 -0.91 0.743 0.00788551 Up regulated HBA2 0.5 0.599 0.00544123 Up regulated HBA1 0.5 0.599 0.00544123 Up regulated HTATIP2 -0.47 0.583 0.00381451 Up regulated MRPS9 -0.26 -0.582 0.00166092 Down regulated ETHE1 0.13 -0.711 6.9394E-06 Down requlated GHITM -0.84 -0.782 0.00083223 Down regulated PMPCB -0.75 -1.012 4.5106E-08 Down regulated METTL7A -0.45 -1.281 1.6276E-09 Down regulated ADI1 -0.56 -1.309 2.2663E-08 Down regulated Table 4: biological process enrichment table from the up- and downregulated genes of the tBHP and untreat cells comparison. GO term p_adj fold enrichment symbols G0:0006851 mitochondrial calcium ion transmembrane transport 0.08562215 62.7 PMPCB G0:0009404 toxin metabolic process 0.08562215 62.7 ETHE1 G0:0034982 mitochondrial protein processing 0.08562215 120.807692 PMPCB Table 5: Cell component enrichment table from the up- and downregulated genes of the tBHP and untreat cells comparison. GO term p_adj fold enrichment symbols G0:0005759 mitochondrial matrix 0.08562215 8.28144989 PMPCB, ETHE1 Table 6: Molecular function enrichment table from the up- and downregulated genes of the tBHP and untreat cells comparison. GO term p_adj fold enrichment symbols G0:0016701 oxidoreductase activity, acting on single 0.08562215 55.9553571 ETHE1 donors with incorporation of molecular oxygen G0:0016702 oxidoreductase activity, acting on single 0.08562215 58.037037 ETHE1 donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen Table 7: biological process enrichment table from the up- and downregulated genes of the 20E (0.01 μM) + tBHP (350 μM) and untreat cells comparison. GO term p adj fold enrichment symbols GO: 0015671 oxygen transport 0.00873721 119.6190476 HBA2, HBA1 GO: 0042033 chemokine biosynthetic process 0.00873721 112.125 IL18, HMOX1 GO: 0050755 chemokine metabolic process 0.00873721 112.125 IL18, HMOX1 GO: 0051187 cofactor catabolic process 0.00873721 47.92307692 HMOX1, HBA2, HBA1 GO: 0015669 gas transport 0.00941017 94.37593985 HBA2, HBA1 GO: 0051291 protein heterooligomerization 0.00941017 23.89922481 COL1A2, HBA2, HBA1 GO: 0042542 response to hydrogen peroxide 0.00998996 21.05821918 HMOX1, HBA2, HBA1 GO: 0042744 hydrogen peroxide catabolic process 0.01919451 55.91964286 HBA2, HBA1 GO: 0015701 bicarbonate transport 0.02933582 42.53741497 HBA2, HBA1 GO: 0000302 response to reactive oxygen species 0.02941399 13.06681034 HMOX1, HBA2, HBA1 GO: 0097237 cellular response to toxic substance 0.03506019 12.09 HMOX1, HBA2, HBA1 GO: 0017001 antibiotic catabolic process 0.0381641 30.72413793 HBA2, HBA1 hydrogen peroxide metabolic GO: 0042743 process 0.0381641 31.26817043 HBA2, HBA1 GO: 0046677 response to antibiotic 0.05925481 9.096036585 HMOX1, HBA2, HBA1 INDUSTRIAL APPLICATION Nowadays, many people refrain from drug therapy but are happy to use naturally derived nutritional supplements. 20-hydroxyecdysone is known to have beneficial effects (e.g. muscle mass and muscle strength gains), which is why it is used as a dietary supplement in many countries, but not for obesity prevention or antioxidant effects. Surprisingly, the present inventors have found calonysterone has better effects than that of 20-hydroxyecdysone on weight loss, antioxidant activity, adipokines and inflammatory cytokine levels, which can improve the damage to health caused by obesity. Furthermore, 20E and calonysterone affect favorably brain endothelial barrier tightness and viability exert protective effects on brain endothelial cells in reactive oxygen stress, and improve BBB barrier integrity and alleviate reactive oxygen species induced BBB integrity changes. In the past 20 years, the “green wave” of returning to the natural formulations, and the apparent safety of these products have been playing an important role in this trend. The ecdysone-type compounds were first discovered few decades ago as hormones in insects, but later it was realized that these molecules are also produced in plants. 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Claims

CLAIMS 1. A compound of formula I.a for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease,wherein, independently from each other, R1 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-22 alkyloxy, C1-22 acyloxy and a halogen, R2 is selected from the group consisting of H, OH, C1-20 acyloxy, OR22, C1-4 alkyloxy, C1-20 acyloxy and a halogen, wherein R22 is selected from a formyl, C22-C2 alkylcarbonyl, C22-C3 alkenylcarbonyl or C22-C1 alkynylcarbonyl, preferably a C18-C2 alkylcarbonyl, C18-C3 alkenylcarbonyl, more preferably a C18-C8 alkylcarbonyl or a C6-C2 alkylcarbonyl; R3 is selected from the group consisting of H, OH, C1-20 acyloxy, OR23,C1-4 alkyloxy, C1-20 acyloxy and a halogen, wherein R22 is selected from a formyl, C22-C2 alkylcarbonyl, C22-C3 alkenylcarbonyl or C22-C1 alkynylcarbonyl, preferably a C18-C2 alkylcarbonyl, C18-C3 alkenylcarbonyl, more preferably a C18-C8 alkylcarbonyl or a C6-C2 alkylcarbonyl; or wherein R2 and R3 form acetonide, R4 is selected from H and CH3, R5 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen and the 14- 15 bond is a single bond, or R5 is nothing and the 14-15 bond is a double bond, R6 is H, R7 is selected from the group of moieties(1.1)wherein, independently from each other, R10 is CH3, R11 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, R12 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, R13 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy or R13 is nothing and the 25-26 bond is a double bond halogen, wherein R11 and R12 may form acetonide, and moieties having the formula (2.1)wherein R15 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, preferably R15 is selected from H, halogen, OH and CH3, preferably H, F and CH3, more preferably R15 is H, wherein preferably if the 14-15 bond is a single bond, then it is a 14^,15-bond (i.e. a 14^,15-dihydro variant), R8 is selected from H and CH3, R9 is selected from H and CH3.

2. The compound for use according to claim 1, wherein R1 is selected from H and OH; more preferably R1 is H. R2 is selected from the group consisting of H, OH, C1-2 alkyloxy and C1-2 acyloxy, R3 is selected from the group consisting of H, OH, C1-2 alkyloxy and C1-2 acyloxy, or R2 and R3 form an acetonide, R4 is selected from H and CH3, R4 is selected from H and CH3, R5 is selected from H, methyloxy and OH, wherein preferably if R5 is H then the 14-15 bond is a double bond. R11 is selected from the group consisting of H, OH, C1-2 alkyloxy and C1-2 acyloxy, R12 is selected from the group consisting of H, OH, C1-22 alkyloxy and C1-22 acyloxy, or R11 and R12 form an acetonide.

3. The compound for use according to claim 1 or 2, wherein formula I.a is selected from a compound for use of formula I.bwherein the substituents are as defined for formula I.a). Preferably, independently from each other, R1 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably H, R2 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably OH, R3 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably OH, or R2 and R3 form acetonide, R4 is selected from H and CH3, preferably H, R5 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, wherein preferably if the 14-15 bond is a single bond, then it is a 14^,15-bond (i.e. a 14^,15-dihydro variant); or R5 is nothing and the 14-15 bond is a double bond, R6 is H, R7 is any moiety as defined above for formula I.a, R8 is selected from H and CH3, preferably CH3, R9 is selected from H and CH3, preferably CH3. The compound for use according to any of claims 1 to 3, wherein the compound is a compound for use of formula I.cwhereinR5 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-2 or C2-3 acyloxy, wherein if the 14-15 bond is a single bond, then it is a 14^,15-bond R7 is a moiety having the formula 1.2,(1.2) wherein R10 is CH3, R11 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, preferably C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably OH, R12 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-22 alkyloxy, C1-22 acyloxy and a halogen, preferably C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably OH, R13 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, preferably C1-2 alkyloxy, C1-2 or C2-3 acyloxy, highly preferably OH, wherein R11 and R12 may form acetonide, wherein the further substituents are as defined for formula I.a or I.b or formula 1.1, respectively.

5. The compound for use according to claim 1, wherein formula I.a is selected from a compound for use of formula II.a for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease,wherein the substituents are as defined for formula I.a, or preferably for formula I.b or preferably I.c, wherein preferably R1 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 or C2-3 acyloxy and a halogen,R2 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, R3 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, or R2 and R3 form an acetonide, R4 is selected from H and CH3, R6 is H, and R7 is selected from the group of moieties(1.2) having the formula (1.2) said substituents being defined for any one of formulae I.a, or preferably for formula I.b or preferably I.d above. Preferably. R10 is CH3, R11 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, R12 is selected from the group consisting of H, OH, C1-22 alkyloxy, C1-22 acyloxy and a halogen, R13 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, wherein R11 and R12 may form acetonide, and or R13 is nothing and the 25-26 bond is a double bond. Preferably R15 is selected from the group consisting of H, OH, C1-2 alkyloxy, C1-3 or C2-3 acyloxy and a halogen, preferably R15 is selected from H, OH and CH3, preferably H and CH3, more preferably R15 is H, R8 is selected from H and CH3, preferably is CH3, R9 is selected from H and CH3, preferably is CH3.The compound for use according to claim 1, wherein formula II.a is selected from a compound for use of formula II.b(II.b), wherein the substituents are as defined for formula I.b; or wherein the substituents are as defined for formula II.a; wherein preferably R7 is selected from the group of moieties having the formula 2.1wherein R10 is CH3, R12 is selected from the group consisting of H, OH, C1-22 alkyloxy, C1-22 acyloxy, preferably H, OH and CH3, more preferably OH, R13 is selected from the group consisting of H, OH, C1-3 alkyloxy, C1-3 acyloxy, preferably H, OH and CH3, more preferably OH, R14 is selected from the group consisting of H, C1-3 alkyloxy, C1-3 acyloxy, preferably H, and CH3, more preferably H, or wherein R14 and R12 may form acetonide according to formula 2.2(2.2), preferably any one of R10, R12, and R14 is selected from H, OH and CH3, R13 is selected from H and OH or R11, R12, R13 and R14 is selected from moieties given for any of the formula (1.2, 2.1 and 2.2) preferably R10 is OH, wherein R15 is selected from the group consisting of H and CH3, more preferably R15 is H.

7. The compound for use according to any of the previous claims wherein said compound is a compound of formula III.a for use in the treatment of oxidative stress or in the treatment of an oxidative stress disease,(III.a) wherein each substituent is, independently, selected from substitutents as defined for formulae I.a, I.b., I.c, or, if applicable, for II.a and II.b, OR R1 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably H and OH, more preferably H, R2 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, R3 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, or R2 and R3 form an acetonide,R4 is selected from H and CH3, R5 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably H and OH, wherein preferably R5 is H and the 14-15 bond is a double bond, R6 is H, R8 is selected from H and CH3, preferably is CH3, R9 is selected from H and CH3, preferably is CH3. R10 is CH3, R11 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, R12 is selected from the group consisting of H, OH, methoxy, ethoxy, acetyloxy, formyloxy, C1-22 alkyloxy or C1-22 acyloxy, R13 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, or R11 and R12 may form acetonide, or R13 is nothing and the 25-26 bond is a double bond.

8. The compound for use according to claim 7, wherein said compound is a compound of formula III.b(III.b) wherein each substituent is, independently, selected from substitutents as defined for formulae III.a, and R14 is selected from the group consisting of of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, preferably H, and CH3, more preferably H, or wherein R14 and R12 form acetonide.The compound for use according to claim 7, wherein said compound is a compound selected from the group consisting of formula IV.a, IV.b, IV.c and IV.d,(IV.d), wherein in formula IV.a, IV.b, IV.c and IV.b said substituents are, independently from each other: R1 is selected from H and OH, more preferably H, R2 is selected from the group consisting of H and OH, preferably OH, R3 is selected from the group consisting of H and OH, preferably OH, or R2 and R3 form an acetonide, R4 is selected from H and CH3, preferably H, R6 is H, R8 is selected from H and CH3, preferably is CH3, R9 is selected from H and CH3, preferably is CH3. R10 is CH3, R11 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, R12 is selected from the group consisting of H, OH, methoxy, ethoxy, acetyloxy, formyloxy, C1-22 alkyloxy or C1-22 acyloxy, R13 is selected from the group consisting of H, OH, methoxy, ethoxy or acetyloxy, formyloxy, or R11 and R12 form acetonide, or R13 is nothing and the 25-26 bond is a double bond.

10. The compound for use according to any of claims 1 to 9, for use in the treatment of an oxidative stress related damage in a subject, and / or in a subject having an oxidative stress related metabolic disease as an oxidative stress disease.

11. The compound for use according to any of claims 1 to 10, wherein the compound is for use in or is used in the treatment of an oxidative stress related damage in the brain of a subject, preferably in the treatment of an oxidative stress related damage in the blood-brain barrier of a subject, preferably for use in and / or in a subject having a brain-related metabolic disease, wherein preferably the compound is a compound as defined in formula II.a or II.b, preferably II.b.

12. The compound for use according to any of claims 1 to 10, wherein the compound is for use in or is used in the treatment of an oxidative stress related damage due to a high-fat, high sugar diet wherein preferably the compound is a compound as defined in formula II.a or II.b, preferably II.b.

13. The compound for use according to any of claims 1 to 10, wherein the compound is for use in the treatment of chronic low-grade inflammation, preferably an oxidative stress related inflammation, preferably in normalizing IL-6 level in said patient wherein preferably the compound is a compound as defined in formula II.a or II.b, preferably II.b.

14. The compound for use according to any of claims 1 to 10, wherein the compound is for use in the treatment of an oxidative-stress related damage of the blood- brain barrier, preferably, the compound is used in the treatment of a harmful condition of the central nervous system due to a damage of the blood-brain barrier wherein preferably the compound is a compound as defined in formula II.a or II.b, preferably II.b.

15. A compound of formula XI for use in the treatment of an oxidative-stress related damage of the blood- brain barrier,OR preferably,wherein the substituents are as defined for formula I.a, or preferably for formula I.b or preferably I.c, if applicable, and wherein R7 is selected from the group of moieties(1.1) wherein, independently from each other, R10 is CH3, R11 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-22 alkyloxy, C1-22 acyloxy and a halogen, R13 is selected from the group consisting of H, OH, CH3, C1-4 alkyloxy, C1-20 acyloxy and a halogen, or R13 is nothing and the 25-26 bond is a double bond, wherein R11 and R12 may form acetonide, and moieties having the formula (2.1)wherein R15 is selected from the group consisting of H, OH, C1-4 alkyloxy, C1-20 acyloxy and a halogen, preferably R15 is selected from H, OH and CH3, preferably H and CH3, more preferably R15 is H,wherein preferably if the 14-15 bond is a single bond, then it is a 14^,15-bond (i.e. a 14^,15-dihydro variant), R8 is selected from H and CH3, R9 is selected from H and CH3.

16. A composition for use in a condition as defined in any of claims 1 to 15, said composition comprising a compound for use according to any of claim 1 to 14 or 15, and one or more physiologically tolerable excipient, wherein the one or more excipients comprise an antioxidant.

17. The composition according to claim 16, wherein the composition is a pharmaceutical composition comprising any of the compounds for use as defined in any of claims 1 to 16 and a pharmaceutically acceptable excipient.

18. The composition according to claim 16, wherein the composition is a nutraceutical composition comprising any of the compounds for use as defined in any of claims 1 to 16 and a nutraceutically acceptable excipient.

19. The composition according to any of claims 16 to 17 wherein said composition is for or is suitable for enteral, e.g. oral or parenteral, e.g. intravenous, or topical administration into a patient. In a preferred embodiment the composition is for oral administration, preferably, in case of oral preparation, solid dosage units, such as pills, tablets, etc. as given above, can be provided.

20. The composition according to any of claims 16 to 19, wherein the compounds of the invention are present in unsolvated form, and / or the compounds of the invention are present in solvated form, and / or the compounds of the invention are present in aqueous solution, and / or the active ingredient is presented in a plant extract.

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