Plant-based compositions and methods for modulating the inflammatory response following viral infection

Abstract

A polyphenol-rich composition is orally administered to alleviate signs or symptoms of post-viral syndrome, preferably post-COVID syndrome. The composition most typically comprises at least 50 wt% total catechins, at least 20 wt% total chlorogenic acids, and optionally up to 30 wt% total supplemental antioxidants. The composition may be formulated from unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or its extract, broccoli or its extract, and kale or its extract. In particular, such compositions have been effective in reducing inflammatory cytokines and interleukins, increasing NOHb, and reducing reactive oxygen species resulting from mitochondrial dysfunction, iNOS activity, and NOX2 activity in individuals infected with SARS-CoV2.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to the inventors' co-pending U.S. Provisional Patent Application No. 63 / 484,981, filed February 14, 2023, the entire contents of which are incorporated herein by reference.

[0002] The field of the invention is compositions and methods for nutritional supplements that alleviate symptoms or conditions following viral infection, particularly those associated with the SARS-CoV2 post-infection response. [Background technology]

[0003] This background discussion includes information that may be useful in understanding the present invention. No admission is made that any information provided herein is prior art or relevant to the invention(s) claimed herein, or that any publication specifically or implicitly referenced is prior art.

[0004] All publications and patent applications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In the event that a definition or use of a term in an incorporated reference contradicts or is contrary to the definition of that term provided herein, the definition of that term provided herein shall control and the definition of that term in the cited reference shall not apply.

[0005] During the COVID-19 pandemic, hundreds of millions of people worldwide have been infected, and long-term care for COVID-19 survivors has become a global burden. Viral exposure, even after complete resolution of the virus, can affect various internal organ systems as a complication of SARS-CoV2 infection. For example, adverse effects of infection have been reported in the immune, hematologic, respiratory, cardiovascular, digestive, hepatic, renal, musculoskeletal, and nervous systems. However, these persistent damaging effects persist even after infection with other viruses, such as influenza, rhinovirus (RV), respiratory syncytial virus (RSV), and Middle East respiratory syndrome (MERS).

[0006] In many infected individuals, complete resolution of symptoms occurs as a result of viral clearance. However, a significant number of individuals continue to experience postviral syndrome. It is generally believed that a variety of adverse effects are caused by an endothelial redox imbalance. Systemic imbalance is often distinguished by increased activity of ROS pathways (including phagocytic NADPH oxidase (NOX2), inducible nitric oxide synthase (iNOS), and mitochondrial pathways) and the associated suppression of NOHb. Together, these four conditions are often associated with the release of excessive proinflammatory cytokines and chemokines, resulting in the cellular oxidative stress and pathological dysregulation typically associated with viral injury. In more severe cases, high levels of pleiotropic proinflammatory cytokines (IL-6, IL-1, and TNF-α) have been shown to interact with their dense receptors, immune cells, and the vasculature, stimulating numerous processes involving further immune cell activation in response to changes in the vascular environment. The most common symptoms are fatigue and dyspnea, but also include cognitive and psychiatric disturbances and persistent pathological chronic subacute inflammation.

[0007] Endothelial imbalance can be caused by a variety of etiologies, including metabolic syndrome, cardiotoxicity, and other chronic conditions, as well as acute bacterial, viral, and environmental insults. However, there is limited evidence demonstrating that targeting ROS pathways can reduce systemic imbalance and stress. Unfortunately, this limited evidence does not consider individuals suffering from post-viral syndromes resulting from viral insults. For example, one study conducted on generally healthy subjects reported that a plant-based broad-spectrum antioxidant nutraceutical blend ("PB-Blend") significantly reduced real-time ROS measurements and simultaneously increased NOHb (Boris V. Nemzer et al., (2017): Oxidative Stress or Redox Signaling, DOI: 10.1080 / 10715762.2017.1390228). Although interesting, this study focused on the effect of the herbal blend on cellular metabolic indices (i.e., the internal ratio of NAD+ / NADH). This study in healthy individuals found that participants who ingested the blend exhibited only a 9.2-7.7% inhibition of mitochondrial and cellular ROS production, a 12.0-14.8% inhibition of nicotinamide dinucleotide phosphate oxidase system-dependent ROS production, a 9.5-44.5% inhibition of extracellular H2O2 production, and a 13.4-17.6% inhibition of TNF-α. Overall, the increase in bioavailable NO concentration was only about 1.7-2.3-fold.

[0008] In another study of healthy participants, researchers investigated the effects of a similar dietary antioxidant supplement on specific oxidative stress markers (OSM) (Boris V. Nemzer et al., (2014): Food Science & Nutrition, DOI: 10.1002 / fsn3.178). By monitoring OSM, the researchers measured ex vivo intracellular and extracellular ROS production, respiratory activity of blood cells, and mitochondrial-dependent ROS production and respiratory activity. This study also tracked the ability of healthy participants to modulate ex vivo cellular inflammatory responses induced by exogenous TNF-α, nitrosative stress, and changes in NOHb concentrations. Interestingly, administration of the antioxidant supplement resulted in only a 17% inhibition of mitochondrial and cellular ROS production, a 3.5-fold inhibition of extracellular NOX2-dependent ROS production, a near-complete inhibition of extracellular H2O2, and a significant increase in circulating NO levels.

[0009] Alternatively, in obese individuals, administration of an appropriate polyphenol-rich mixture increased participants' NOHb by 33–53% and reduced mitochondrial ROS by 54–75% (Boris V. Nemzer et al., (2021): A…Study on the Effects of a Plant-Based Dietary Supplement, DOI: 10.5539 / jfr.v10n2p21). While compelling, this study did not consider the effects of the polyphenol-rich mixture on additional ROS pathways in addition to the mitochondrial ROS pathway.

[0010] Thus, although various systems and methods for modulating immune responses are known in the art, all or nearly all of them have multiple drawbacks that make them disadvantageous, especially when combined with targeting three specific ROS pathways (i.e., the mitochondrial ROS pathway, the iNOS-dependent ROS pathway, and the NOX2-ROS pathway) in individuals suffering from post-viral infection syndrome. Thus, there remains a need for improved compositions and methods for alleviating signs or symptoms following viral infection, particularly those following SARS-CoV2 infection. Summary of the Invention

[0011] The present subject matter is directed to various compositions and methods for alleviating signs or symptoms of post-viral syndrome, particularly post-COVID syndrome, wherein oral administration of a polyphenol-rich composition, preferably comprising at least 50 wt. % total catechins and at least 20 wt. % total chlorogenic acids, modulates multiple different pathways that generate reactive oxygen species, thereby reducing inflammation, mitochondrial dysfunction, and / or oxidative-nitrosative stress.

[0012] In one aspect of the present subject matter, the inventors contemplate a method for alleviating a sign or symptom of post-viral syndrome (particularly post-COVID syndrome or post-viral fatigue syndrome), comprising orally administering a polyphenol-rich composition comprising primarily a plurality of chemically distinct catechins and a plurality of chemically distinct chlorogenic acids. Administration of the polyphenol-rich composition rapidly modifies a plurality of different pathways that most typically generate reactive oxygen species, thereby alleviating the sign or symptom of post-viral syndrome.

[0013] Preferably, the alleviation of signs or symptoms of post-viral syndrome is associated with a partial or complete improvement in physical and / or mental function when compared to a subject not administered the composition.

[0014] In some embodiments, the plurality of chemically distinct catechins and the plurality of chemically distinct chlorogenic acids are present in one or more of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or its extract, and Brassica plant or its extract.For example, the polyphenol-rich composition may be prepared from at least one of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or its extract, broccoli or its extract, and kale or its extract.Alternatively, or in addition, the polyphenol-rich composition may be prepared from at least two of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or its extract, broccoli or its extract, and kale or its extract.Therefore, and from another perspective, the polyphenol-rich composition preferably comprises at least 50 wt% total catechins and at least 20 wt% total chlorogenic acids. In other embodiments, the polyphenol-rich composition may further comprise a total of up to 30 wt% of supplemental antioxidants. For example, at least one of the supplemental antioxidants may be selected from the group consisting of stilbenoids, curcumin, vitamin E, manganese, and coenzyme Q10. More generally, it is contemplated that a single dose of 10 to 150 mg of the polyphenol-rich composition (e.g., as a solid composition in a capsule) would be administered for a period of 1 day to 60 days, with administration for at least 7 days after a negative viral test.

[0015] After administration, relief of signs or symptoms of post-viral syndrome occurs, most typically within 30 minutes to 3 hours. It will be readily appreciated that the polyphenol-rich composition may be formulated as a capsule, tablet, gummy, chewable, dissolvable film, powder, or as an instant drink, juice drink, carbonated drink, or liquid concentrate.

[0016] Preferably, the post-viral syndrome is post-COVID syndrome or post-viral fatigue syndrome.

[0017] In another embodiment of the subject matter of the present invention, the symptom or condition is fatigue, mitochondrial dysfunction, endothelial dysfunction, immune dysfunction, oxidative stress, chronic subacute inflammation, neurological dysfunction, and / or cognitive dysfunction.For example, the intended pathways include mitochondrial reactive oxygen species generation, NOX2-dependent reactive oxygen species generation, and iNOS-dependent reactive oxygen species generation.Furthermore, administration of the polyphenol-rich composition may rapidly increase bioavailable NO and / or rapidly reduce inflammatory cytokines (e.g., circulating IL1-beta, IL8, IL10, and / or TNF-alpha).In some embodiments, the level of mitochondrial reactive oxygen species is reduced by at least 50%, iNOS activity is reduced by at least 55%, NOX2-dependent reactive oxygen species (ROS) generation is reduced by at least 40%, and / or circulating nitric oxide as measured by HbNO is increased by at least 30%.

[0018] Accordingly, the inventors contemplate a polyphenol-rich composition for treating a sign or symptom of post-viral syndrome, wherein the composition primarily comprises a plurality of chemically distinct catechins and a plurality of chemically distinct chlorogenic acids, wherein the composition, upon oral administration at a dose of 10-150 mg, rapidly modifies a plurality of different pathways that generate reactive oxygen species, thereby alleviating the sign or symptom of post-viral syndrome.

[0019] For example, the polyphenol-rich composition may comprise at least 50 wt% total catechins, at least 20 wt% total chlorogenic acids, and optionally up to 30 wt% total supplemental antioxidants. If desired, the polyphenol-rich composition may be prepared from at least one of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or extract thereof, broccoli or extract thereof, and kale or extract thereof. Among other suitable dosage forms, 10 to 150 mg of the polyphenol-rich composition may be prepared in solid form and formulated as a capsule or tablet for administration as a single daily dose for a period of 1 to 60 days. Administration may alleviate signs or symptoms of post-viral syndrome within 30 minutes to 3 hours. In other embodiments, the polyphenol-rich composition may be formulated as a capsule, tablet, gummy, chewable tablet, dissolvable film, or powder. Among other formulations, the polyphenol-rich composition may be formulated as an instant drink, juice drink, carbonated drink, or liquid concentrate.

[0020] As described above, intended post-viral syndromes include post-COVID syndrome and post-viral fatigue syndrome. For example, aching pain, sharp pain, fever, upper and / or lower respiratory tract dyspnea, shortness of breath, dyspnea, sore throat, fatigue, headache, abnormalities in chest imaging, and / or general malaise. Further intended symptoms or conditions may include mitochondrial dysfunction, endothelial dysfunction, immune dysfunction, oxidative stress, chronic subacute inflammation, neurological dysfunction, and / or cognitive impairment. Accordingly, observable markers of these ROS pathway modifications may be those related to inflammation (e.g., interleukins or inflammatory cytokines), mitochondrial function (e.g., mitochondrial reactive oxygen species (ROS)), and / or oxidative-nitrosative stress (e.g., due to iNOS activity, NOX2-dependent ROS generation, etc.).

[0021] Viewed from another aspect, the inventors contemplate the use of a polyphenol-rich composition in the manufacture of a medicament for the treatment of signs or symptoms of post-viral syndrome, wherein the composition primarily comprises a plurality of chemically distinct catechins and a plurality of chemically distinct chlorogenic acids, and wherein the composition is formulated for administration in a dose of 10 to 150 mg.

[0022] In other words, the inventors contemplate a polyphenol-rich composition for use as a therapeutic agent for treating post-viral syndrome, wherein the composition primarily comprises a plurality of chemically distinct catechins and a plurality of chemically distinct chlorogenic acids, wherein the composition is formulated for administration at a dose of 10 to 150 mg.

[0023] The polyphenol-rich composition rapidly modifies multiple different pathways that most typically generate reactive oxygen species.Therefore, the rapid modification of multiple different pathways can alleviate the aching pain, sharp pain, fever, upper and / or lower respiratory tract shortness of breath, sore throat, fatigue, and / or general malaise typically associated with post-viral infection syndrome.Symptoms or symptoms of post-viral infection syndrome can also include mitochondrial dysfunction, endothelial dysfunction, immune dysfunction, oxidative stress, chronic subacute inflammation, neurological dysfunction, and / or cognitive dysfunction.

[0024] In some embodiments, the pathways include mitochondrial reactive oxygen species generation, NOX2-dependent reactive oxygen species generation, and / or iNOS-dependent reactive oxygen species generation.

[0025] Preferably, the polyphenol-rich composition is provided in the form of plant material and / or its extract. For example, the plant material may be selected from the group consisting of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or its extract, broccoli or its extract, and kale or its extract. In some embodiments, the polyphenol-rich composition may comprise at least 50 wt% total of catechins, at least 20 wt% total of chlorogenic acids, and optionally up to 30 wt% total of supplemental antioxidants.

[0026] Therefore, administration of the polyphenol-rich composition can rapidly increase bioavailable NO, and / or rapidly reduce inflammatory cytokines and / or chemokines, and / or rapidly reduce circulating IL1-beta, IL8, IL10, and / or TNF-alpha.As a result, the level of mitochondrial reactive oxygen species is reduced by at least 50%; iNOS activity is reduced by at least 55%; wherein the NOX2-dependent ROS production is reduced by at least 40%; and / or circulating nitric oxide (NOHb) is increased by at least 30%.

[0027] Various objects, features, aspects and advantages of the present subject matter will become more apparent from the following detailed description of preferred embodiments, taken in conjunction with the accompanying drawings, in which like numerals represent like components, and in which: [Brief explanation of the drawings]

[0028] [Figure 1] 1 is a graph depicting exemplary results regarding changes in cellular metabolic activity following administration of an exemplary mixture rich in vitamin C and polyphenols according to the present inventive subject matter. [Figure 2] 1 is a graph depicting exemplary results regarding changes in iNOS-dependent cellular metabolic activity following administration of an exemplary mixture rich in vitamin C and polyphenols according to the present inventive subject matter. [Figure 3]1 is a graph depicting exemplary results regarding changes in NOX2-dependent cellular metabolic activity following administration of an exemplary mixture rich in vitamin C and polyphenols according to the present inventive subject matter. [Figure 4] 1 is a graph depicting exemplary results regarding changes in circulating NOHb after administration of an exemplary mixture rich in vitamin C and polyphenols according to the present inventive subject matter. [Figure 5] Figure 5A is a graph showing exemplary results of changes in H2O2 production after administration of an exemplary mixture rich in vitamin C and polyphenols in accordance with the present inventive subject matter, where TNF-α levels mimic the effects of an acute viral infection. Figure 5B is a graph showing exemplary results of changes in H2O2 production after administration of an exemplary mixture rich in vitamin C and polyphenols in accordance with the present inventive subject matter, where TNF-α levels mimic the effects of a "cytokine storm." DETAILED DESCRIPTION OF THE INVENTION

[0029] The inventors have discovered that certain polyphenol-rich mixtures, particularly mixtures containing high concentrations of chemically distinct catechins and chemically distinct chlorogenic acids, can be used to modulate, particularly downregulate, several different pathways that generate reactive oxygen species, thereby alleviating the signs and / or symptoms of post-viral syndrome (particularly post-COVID syndrome). Furthermore, the compositions provided herein also exhibit a stimulatory effect on bioavailable nitric oxide.

[0030] Numerous previous studies have shown that viral infections can cause multiple complications in the inflammatory, cardiovascular, and immune systems. In particular, SARS-CoV2 infection is known to have long-term effects, including changes in the respiratory, circulatory, urinary, and nervous systems. These effects are caused, in part, by a rapid and significant increase in multiple ROS species, which are often associated with exacerbated immune responses and metabolic disorders. Furthermore, postviral syndromes are also associated with vascular dysfunction, likely due to low levels of bioavailable nitric oxide. In this context, we investigated whether a polyphenol-rich mixture could be used to suppress multiple pathways leading to ROS generation and increase bioavailable nitric oxide in subjects who have recovered from moderate COVID-19 infection. In particular, we focused on compositions that could modulate enzyme systems involved in the elevation of specific ROS, which, if uncontrolled, can cause metabolic dysfunction and oxidation-reduction (redox) imbalance.

[0031] In one exemplary application, the inventors prepared an herbal blend characterized by a relatively high polyphenol content (particularly chemically distinct catechins and chlorogenic acids). This exemplary blend had a total catechin content of greater than 50 wt% and a total chlorogenic acid content of greater than 20 wt%, and was substantially free of antioxidant vitamins C and E. This exemplary blend, containing unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry powder, broccoli powder, and kale powder, was packaged in 50 mg gelatin capsules for convenient oral administration. One or more such capsules are administered over a period of at least 14 days following a viral infection with the aim of achieving and / or sustaining relief of at least one sign or symptom of post-viral syndrome (particularly post-COVID syndrome).

[0032] While the above compositions are particularly preferred, it should be understood that many other compositions are also suitable for the uses described herein, so long as the polyphenol content in a dosage unit of such compositions is at least 50%, more preferably at least 60%, and most preferably at least 70% of the RDA. Viewed from another perspective, contemplated compositions provide a total amount of polyphenols of at least 20 mg, or at least 25 mg, or at least 30 mg, or at least 35 mg, or at least 40 mg per dosage unit. Typical dosage units contain polyphenol-rich compositions in the range of 25-500 mg, although smaller amounts (e.g., 10 mg, 20 mg) or larger amounts (e.g., 750 mg or 1,000 mg) are also considered suitable for the uses described herein, particularly when such dosage units contain additional active ingredients.

[0033] Further, it is contemplated that suitable compositions primarily comprise a plurality of chemically distinct catechins and chemically distinct chlorogenic acids. Preferably, the contemplated compositions comprise at least 20 wt. % total chlorogenic acids, at least 30 wt. % total chlorogenic acids, or at least 45 wt. % total chlorogenic acids. Accordingly, the nature of the particular components may vary, at least to some extent. However, while the source material for chlorogenic acids preferably includes coffee berries or coffee bean-derived materials (e.g., extracts of unroasted beans and / or whole coffee berries), other plant materials can also be used, including tea leaves, apples, pears, carrots, tomatoes, prunes, bay leaves, mustard, celery, chives, basil, rosemary, sage, oregano, collard greens, chicory, artichokes, burdock, eggplant, grapes, kiwi, honeysuckle, blueberries, sunflower seeds, zucchini, broccoli, cauliflower, yellow jasmine, asparagus, onions, spinach, peas, green peppers, okra, cabbage, and sweet potatoes. Most typically, such materials are subjected to one or more isolation steps to increase the concentration of chlorogenic acids. In further contemplated embodiments, the chlorogenic acids may be synthetic or semi-synthetic materials. Thus, contemplated chlorogenic acids include various esters of caffeic acid and quinic acid, as well as their various isomers, such as 5-O-caffeoylquinic acid (5-CQA), 4-O-caffeoylquinic acid (4-CQA), and 3-O-caffeoylquinic acid (3-CQA). Further contemplated chlorogenic acids include 3-Op-coumaroylquinic acid, 3-O-dimethoxycinnamoylquinic acid, 3-O-sinapoylquinic acid, 3,4-di-O-caffeoylquinic acid, 3,4-di-Op-coumaroylquinic acid, 3-O-caffeoyl-4-O-feruloylquinic acid, and their respective isomers at the 4- and 5-positions.

[0034] Similarly, with regard to suitable catechins, it is contemplated that the specific source of the catechins may vary. However, it is preferred that the contemplated compositions contain at least 50 wt. %, at least 60 wt. %, or at least 75 wt. Generally, however, it is preferred to obtain the catechins from one or more plant materials, with particularly preferred plant materials including tea leaves (fresh, fermented, or tea leaf extract), cherries, broccoli, kale, celery, broad beans, green beans, apples, blackberries, raspberries, apricots, black grapes, pears, strawberries, guavas, kale, and cacao. Most typically, such plant materials may be used in a raw, dried, fresh, or fermented state, or may be subjected to one or more isolation steps to enhance the concentration of catechins. In further contemplated embodiments, the catechins may also be synthetic or semi-synthetic. Thus, contemplated catechins include C((-)-catechin), EC((-)-epicatechin), ECG((-)-epicatechin gallate), EGC((-)-epigallocatechin), EGCG((-)-epigallocatechin gallate), GC((-)-gallocatechin), CG((-)-catechin gallate), and GCG((-)-gallocatechin gallate), and various isomers thereof.

[0035] In another contemplated embodiment, the ratio of the chemically different catechins to the chemically different chlorogenic acids is preferably such that the amount of catechins is greater than that of chlorogenic acids.For example, suitable ratios of catechins to chlorogenic acids include 10:1, 10:2, 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, and 10:9, and in some embodiments, the catechins and chlorogenic acids are in approximately the same weight ratio.Similarly, in less preferred (but still contemplated) embodiments, the ratio of chlorogenic acids to catechins may be 10:1, 10:2, 10:3, 10:4, 10:5, 10:6, 10:7, 10:8, or 10:9.

[0036] Contemplated compositions may further comprise at least 2 wt. %, at least 5 wt. %, at least 10 wt. %, or at least 15 wt. % of supplemental antioxidants. If desired, contemplated compositions may comprise 2.5 wt. % to 7.5 wt. %, 10 wt. % to 20 wt. %, or 15 wt. % to 30 wt. As will be readily appreciated, suitable amounts of supplemental antioxidants also include up to 10 wt. %, up to 20 wt. %, up to 30 wt. %, or up to 40 wt. In some embodiments, preferred antioxidants include stilbenoids (such as resveratrol) or any derivatives, piceatannol, and / or trans-4-hydroxystilbene. Alternatively, or in addition, supplemental antioxidants may further include curcumin, coenzyme Q10, thiamine, riboflavin, nicotinic acid, folic acid, creatine, L-arginine, glutathione, alpha-lipoic acid, vitamin A, vitamin C, vitamin E, and / or minerals (including selenium), copper, zinc, and manganese. In some embodiments, supplemental antioxidants may be included alone or in combination with at least one other supplemental antioxidant of a different variant to provide 10% to 50% of the RDA. For example, contemplated compositions may contain curcumin and / or resveratrol in an amount of 10 wt% or less, or 8 wt% or less, or 6 wt% or less, or 4 wt% or less of the total wt%. In another aspect, the amount of curcumin and / or resveratrol in a single dosage unit is typically 10 mg or less, or 8 mg or less, or 6 mg or less, or 4 mg or less. When combined, supplemental antioxidants do not need to be present in equal amounts, and supplemental antioxidants present in some embodiments do not need to be present in other embodiments. Depending on the type of antioxidant pathway being targeted, supplemental antioxidants can be added and / or excluded.

[0037] It will be appreciated, therefore, that contemplated compositions may contain multiple different classes of antioxidants (typically with different mechanisms of action). For example, some antioxidants may act as direct redox agents, while others function as inhibitors of one or more ROS-generating enzymes; or still other antioxidants function as inhibitors of inflammatory mediators involved in downstream cellular ROS generation. Additionally, and particularly when the source of catechins and / or chlorogenic acids is a portion of the coffee plant or tea plant, it will be appreciated that contemplated compositions may also contain significant amounts of caffeine, typically less than 5% of the composition (e.g., 10 mg or less, or less than 5 mg per dosage unit).

[0038] Regardless of the type and amount of the components, it is generally contemplated that the polyphenol-rich composition will be administered to a subject with signs or symptoms of post-viral syndrome at a dosage of 10 mg to 500 mg at least once daily for at least two weeks. For example, a subject may take 50 mg once daily for two weeks. However, in other embodiments, the composition may be taken, for example, two or three times daily using dosage units of 10 mg, 25 mg, or 50 mg. It should be understood that the administration period may be less than two weeks or may be significantly longer. For example, a subject may take 10 mg once daily for 60 days, or 100 mg once daily for five days. Most typically, the resolution of signs and symptoms provides a guide to the subjective (dose) period. In some embodiments, the signs and / or symptoms disappear at least 15 minutes, at least 30 minutes, at least 1 hour, at least 1.5 hours, at least 3 hours, or at least 4 hours after administration. Among the signs and symptoms, signs and symptoms specifically intended include fatigue, malaise, headache, dyspnea, diarrhea, low levels of nitric oxide in the blood, redox imbalance / oxidative stress, aching pain, sharp pain, fever, upper and / or lower respiratory tract dyspnea, shortness of breath, sore throat, abnormalities on chest imaging, memory loss, "brain fog," and confusion.

[0039] As will be readily appreciated, contemplated compositions are preferably administered orally using capsules, although other administration methods and formulations are also considered suitable herein, including infusion or injection, as well as more conventional oral administration in liquid or solid forms commonly used in dietary supplements. Administerable forms include capsules, tablets, gummies, chewables, dissolvable films, powders, instant drinks, juice drinks, carbonated drinks, or liquid concentrates, among other options.

[0040] Without intending to be limited to any particular theory or hypothesis, it is contemplated that the compositions affect multiple enzyme systems in vivo, particularly the mitochondrial enzyme system, the NOX2 enzyme system, and the iNOS enzyme system, which are dysregulated after viral infection, as detailed below. Furthermore, contemplated compositions advantageously increase bioavailable nitric oxide (in the form of nitrosylated hemoglobin (NOHb)), which has also been found to be suppressed in subjects after viral infection. Therefore, contemplated compositions are considered particularly advantageous for alleviating or reducing the signs and / or symptoms of post-viral syndrome, particularly post-COVID syndrome. With regard to viral infection, SARS-CoV2 and its subvariants are particularly contemplated, but it should also be noted that other viruses are also considered suitable, including all viruses known to be associated with post-viral syndrome (e.g., influenza, MERS, Epstein-Barr virus, cytomegalovirus, human herpesvirus, enterovirus, rhinovirus, etc.).

[0041] Example We conducted a randomized, double-blind study of 28 individuals 18 to 24 days after moderate COVID-19 infection (CDC definitions of moderate disease and return-to-work criteria, as described at: www.cdc.gov / coronavirus / 2019-ncov / hcp / return-to-work.html). All subjects received a single dose of 50 mg of an exemplary polyphenol-rich mixture or 1,000 mg of vitamin C. Real-time intracellular ROS generation was measured using a portable electron spin resonance (ESR) spectrometer before and 30, 60, 120, and 180 minutes after administration to assess changes in bioavailable NO (measured as circulating NOHb), mitochondrial ROS generation, NOX2-dependent ROS generation, iNOS-dependent ROS generation, and TNFα-dependent ROS generation. Inflammatory, immune (hsCRP, plasma TNF-α levels), interleukin (IL-1, IL6, IL8, IL10), cytokine (IFN-γ, TNF-α, NF-kB), and immunoglobulin (IgA, IgM, IgG, IgE) profiles were also followed. Clinical cardiopulmonary exercise testing, blood O2 saturation, and respirometry tests were also performed, in addition to laboratory and cellular function tests. Unless otherwise indicated, tests were performed using methods and equipment described in WO2018 / 192635. Cytokine and interleukin concentrations were measured using standard commercially available test kits.

[0042] In particular, as detailed below, the baseline data collected revealed that the mitochondrial, NOX2, and iNOS enzyme systems are significantly involved in ROS generation 18-24 days after a positive PCR test for COVID-19. Surprisingly, administration of a single dose of the exemplary polyphenol-rich mixture described above exerted multifunctional effects on ROS species, significantly inhibiting (1)-(3) the following: (1) Inhibited mitochondrial ROS levels by up to 56%; (2) inhibited iNOS by up to 60%; and (3) inhibited NOX2-dependent ROS generation by up to 49%. Vitamin C also exhibited ROS mitigation activity, but more narrowly, selectively inhibiting NOX2-dependent ROS generation by 45%. Furthermore, circulating NOHb levels also increased significantly (33%) after administration of the exemplary polyphenol-rich mixture, whereas no such increase was observed after administration of vitamin C. The exemplary polyphenol-rich mixture and vitamin C demonstrated comparable potency in reducing H2O2 production induced by high doses of TNFα (200 ng / ml). Furthermore, the polyphenol-rich mixture's effect on redox imbalance rapidly and reliably improved plasma concentrations of selected interleukins (IL1 beta, IL8, IL10) and cytokines (TNFα) 3 hours after a single administration.

[0043] Test Design A preliminary, double-blind, randomized trial of a single dose of VDF product after moderate COVID-19 illness

[0044] Exam period 2 to 3 weeks.

[0045] Target audience composition Thirteen male and 15 female volunteers (see inclusion and exclusion criteria) were randomized into two parallel groups to receive either a single dose of 50 mg of the polyphenol-rich mixture or a single dose of 1000 mg vitamin C capsules.

[0046] Randomization Each male subject drew a slip of paper from the subject box bearing their number, followed immediately by a slip of paper from the treatment box bearing their treatment. In this way, each subject was randomly assigned to a treatment. A similar procedure was followed for the female subjects.

[0047] Double-blind The study sponsors prepared identically sized capsules containing the test material and placed them in bottles labeled "A" or "B." In the following description, Group A represents subjects who received 50 mg of an exemplary polyphenol-rich mixture (a mixture of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry powder, broccoli powder, and kale powder, containing at least 50 wt% total catechins and at least 20 wt% total chlorogenic acids); while Group B represents subjects who received 1,000 mg of vitamin C. The study sponsors implemented treatments according to the randomization procedure. The study sponsors did not receive the blinding "key" until all raw data collection was completed and delivery was completed. An independent statistical analysis of the raw data was performed by a third party, also blinded to the blinding "key."

[0048] Definition of moderate COVID-19 infection Confirmation of COVID-19 infection (positive early PCR test for COVID-19) and meeting CDC criteria for a moderate disease course: Individuals with any of the following symptoms and signs of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, myalgia, shortness of breath, dyspnea, or abnormalities on chest imaging) and evidence of lower respiratory tract disease by clinical evaluation or imaging and oxygen saturation (SpO2) ≥ 94% on room air at sea level.

[0049] Test eligibility criteria a, confirmed Covid-19 infection; b, negative Covid-19 rapid test on the day of the test; c, meets CDC criteria for returning to work (i.e., at least 10 days and up to 20 days have passed since the first symptoms appeared, at least 24 hours have passed since the last fever without the use of fever-reducing medication, and symptoms (e.g., cough, shortness of breath) have improved); d, otherwise medically stable population; e, BMI 24–30; and f, age 40–55 years.

[0050] Study Exclusion Criteria No vitamins / supplements taken in the 2 weeks prior to study participation. No therapeutic medications known to affect endothelial function. Commonly recognized contraindications to physical exercise; smokers, type 1 and type 2 diabetes; liver and kidney disorders; psychiatric disorders, other disorders of an acute or chronic nature (gastrointestinal, pulmonary, renal, cardiac, neurological, or psychiatric disorders), use of weight loss preparations or appetite suppressants, participation in a clinical trial within 30 days prior to the start of or during the study. Health status was confirmed by physical examination and clinical tests.

[0051] The assessment of oxidative nitrosative stress levels was performed using (i) total / cellular ROS (intracellular / extracellular ROS generation); (ii) mitochondria-dependent ROS generation (mitochondrial dysfunction); (iii) NOX2-dependent ROS generation (phagocytic / inflammatory NADPH oxidase), (iv) iNOS-dependent ROS generation (inducible / inflammatory iNOS dysfunction); and (v) Vitamin C cell depletion assay (vitamin C cell depletion); It included:

[0052] In addition, routine blood tests were performed, including hemograms, renal function tests (creatinine, urea), and liver function tests (ALT, AST, GGT, bilirubin, ALP).Metabolic status was assessed by fasting blood glucose (for metabolic syndrome assessment), plasma insulin (for metabolic syndrome assessment), insulin resistance index (for metabolic syndrome assessment), and HbA1c (for prediabetes / diabetes assessment).

[0053] Inflammatory / immune profiles were assessed by quantifying hsCRP, plasma TNF-α levels (as an early indicator of inflammation), interleukins (IL-1, IL-6, IL-8, IL-10), cytokines (IFN-γ, TNF-α, NF-kB titers), and immunoglobulin (IgA, IgM, IgG, IgE) profiles. A TNF-α hypersensitivity assay was performed to assess inflammatory resistance (robustness against a "cytokine storm").

[0054] Cellular metabolic activity (CMA) assays and extended cellular metabolic activity (eCMA) assays were used to track cellular, mitochondrial NADPH oxidase 1 or 2-dependent, peroxidase-dependent, and inducible nitric oxide synthase-dependent (iNOS-dependent) reactive oxygen species generation in real time. The cell membrane- and mitochondrial-permeable spin probe 1-hydroxy-3-methoxycarbonyl-2.2.5.5-tetramethylpyrrolidine (CMH, 1 mM) was dissolved in KHB buffer (20 mM; pH 7.4) and mixed with freshly drawn capillary blood for measurements of ROS generation and oxygen concentration (t = 36.6 °C, pO2 = 110 mm / Hg) under controlled temperatures (Nemzer et al., 2014). For extended CMA (eCMA) analysis, a portion of the sample was kept in an ice bath to obtain a 4 °C sample. This sample was mixed with: (a) NOX1 was mixed with superoxide dismutase (SOD, 50 mU / ml; eCMA-ENDO) to quantify the O2- released outside the cell; (b) mixed with catalase (50 mU / ml, eCMA-INFLA) for the purpose of analyzing peroxidase-dependent H2O2 production; (c) mixed with antimycin A (10 μM, eCMA-MITO) to assess mitochondria-dependent O2- / H2O2 production; (d) mixed with apocynin (10 μM, eCMA-PHAGO-NOX2) to detect phagocytic NADPH-dependent (NOX2-dependent) O2 production; and (e) To identify inducible nitric oxide-dependent (iNOS-dependent) O2- / ONOO- generation, blood samples were mixed with 1400W (0.1 μM, eCMA-iNOS). Addition of an oxygen label (NOX-15.1, 5 μM) to blood samples allowed for tracking of oxygen concentrations in cellular and mitochondrial NADPH oxidase-dependent oxygen consumption and peroxidase-dependent oxygen consumption. ESR signals were detected using a NOXYGEN system in conjunction with a portable VitaScreen ESR spectrometer. Calibration solutions containing standard concentrations of CP° (500 μM) or oxygen label (NOX-15.1, 100 μM) were filled into oxygen-permeable 50 μl PTX capillaries and used to calibrate the ESR signals. The oxygen label solution was deoxygenated using a perfusion of pure nitrogen (99.99%).

[0055] Inflammatory resistance was measured using an inflammatory resistance assay, which measures changes in extracellular H2O2 production by blood cells after (a) and (b) of the following, aimed at mimicking the conditions of a cytokine storm: (a) exposure to a final concentration of 40 ng / ml TNF-α (a concentration representative of elevated plasma TNF-α concentrations in human blood); Next, (b) exposed to 200 ng / ml (a five-fold higher dose of TNF-α and similar to the amount of TNF-α detectable in people with COVID-19);

[0056] Circulating levels of NOHb were measured using a bioavailable NO concentration assay; in this assay, heparinized venous blood samples were previously flash-frozen in liquid nitrogen and stored at -80°C; the samples were placed in finger-sized quartz sample dewars and analyzed for NOHb content at -196°C. To acquire ESR spectra at X-band 9.7 GHz, the NOXYSCAN SYSTEM ESR spectrometer, equipped with a specially designed cavity resonator, was operated with a 100 kHz magnetic field modulation using the following settings: Microwave power: 50 mW; magnetic field modulation width: 8 G; central magnetic field: 2.01 g; sweep width: 60 G; conversion time: 20 ms; time constant: 80 ms; number of scans: 60; total detection time: 600 s. The amount of detected NO· was determined from a calibration curve of the ESR signal intensity of red blood cells treated with known concentrations of nitrite (1–25 μM) and Na2S2O4 (20 mM).

[0057] To further explore the role of cytokines and interleukins in subjects' immune responses during the course of viral infection, we profiled inflammatory markers, including IL1β, IL6, IL8, IL10, IFNγ, and TNFα. Inflammatory markers were measured in plasma from samples taken before and after ingestion of a single dose of PB mixture or vitamin C using an electrochemiluminescence V-Plex immunoassay (MesoScale Discovery, Gaithersburg, MD, USA).

[0058] Chemicals used in spin probes 1-Hydroxy-3-methoxycarbonyl-2.2. 5.5-Tetramethylpyrrolidine (CMH, NOX-02.5-VIT), 1-hydroxy-4-phosphono-oxy-2.2.6,6-tetramethylpiperidine (PPH, NOX-03.2); For ESR: Krebs HEPES Puffer VIT (KHB-VIT, NOX-21.2-VIT) containing the metal chelators deferoxamine (DF, NOX-09.1) and diethyldithiocarbamate (DETC, NOX-10.1), heparin (100 U / ml), and Krebs-Hepes buffer (KHB, NOX-07.6); oxygen labeling (NOX-15.1); and eCMA working solutions: eCMA MITO (NOX-22.1-VIT), eCMA ENDO (NOX-23.1-VIT), eCMA-INFLA (NOX-24.1-VIT), eCMA-iNOS (NOX-26.1-VIT), and eCMA PHAGO NOX2 (NOX-25.1-VIT) were purchased from Noxygen Science Transfer & Diagnostics (Elzach, Germany). Unless otherwise specified, all other chemicals and reagents used were analytical grade and purchased from Sigma-Aldrich (St. Louis, MO, USA).

[0059] As can be seen in Figure 1, cellular metabolic activity was at a baseline above what is considered healthy levels, as indicated by the blue line. Administration of the exemplary polyphenol-rich mixture resulted in a significant and rapid decrease in cellular metabolic activity over a 3-hour period; on the other hand, administration of vitamin C resulted in a moderate (although not statistically significant) decrease in cellular activity over the same time frame.

[0060] As shown in Figure 2, with respect to iNOS-dependent cellular metabolic activity, administration of the exemplary polyphenol-rich mixture again rapidly and significantly reduced the deterioration of metabolic activity, while vitamin C had no significant effect over the same time frame. With respect to NOX2-dependent cellular metabolic activity, as shown in Figure 3, the exemplary polyphenol-rich mixture reduced cellular metabolic activity and maintained a reduced level of NOX2-dependent cellular metabolic activity compared to administration of vitamin C.

[0061] Furthermore, by measuring circulating nitrosylated hemoglobin (NOHb), the inventors demonstrated that the exemplary polyphenol-rich mixture also exerted beneficial effects on bioavailable nitric oxide. The results of the comparison of the exemplary polyphenol-rich mixture with vitamin C are shown in Figure 4.

[0062] Regarding TNF-α-induced H2O2 production, the inventors demonstrated that both the exemplary polyphenol-rich mixture and vitamin C were similarly able to suppress TNF-α-induced extracellular H2O2 production after mimicking TNF-α (40 ng / ml, similar to acute viral infection), as can be seen in Figure 5A. Similarly, at a higher concentration of TNF-α (200 ng / ml), which mimics a "cytokine storm," as can be seen in Figure 5B, the inhibitory potencies of both the exemplary polyphenol-rich mixture and vitamin C were also comparable. However, it should be noted that vitamin C was administered at a 20-fold higher dose than the exemplary polyphenol-rich mixture.

[0063] Further statistical analyses were performed using repeated measures analysis of variance (rm-ANOVA). Statistical rm-ANOVA tests require normally distributed data. Therefore, data were first examined for outliers within each variable of interest. Outliers were determined using Tukey's outlier approach (Q1 - 1.5 * (IQR)) and (Q3 + 1.5 * (IQR)); where Q1 is the first quartile and Q3 is the third quartile. Outliers beyond these boundaries were excluded from the analysis. Repeated measures analyses of variance (rm-ANOVAs) were performed with group as the between-subjects factor. In the case of interactions, a one-way analysis of variance was performed to determine the nature of the interaction in order to obtain appropriate estimates. Results are expressed as mean ± standard error of the mean (SEM). Statistical significance was determined at a level of p < 0.05.

[0064] Taken together, these results suggest that the exemplary polyphenol-rich mixture, when administered at least 50 mg, has great potential to increase bioavailable NOHb and regulate a wide range of enzyme systems related to mitochondrial ROS generation, iNOS-dependent ROS generation, and NOX2-dependent ROS generation. The exemplary polyphenol-rich mixture exhibits inherent antioxidant activity that can support against uncontrolled ROS generation in subjects with system imbalances caused by viral infection. In comparison, administration of 1,000 mg of vitamin C revealed narrow-spectrum antioxidant activity limited to inhibiting only NOX2-dependent ROS generation. Therefore, the exemplary polyphenol-rich mixture can be considered a novel alternative to or in combination with vitamin C, or as an alternative supplemental antioxidant for oxidative balance, immune support, and recovery, particularly for potential modulation of inflammatory responses to viral disorders that cause pathological feelings and discomfort.

[0065] It should also be understood that in some embodiments, numbers expressing amounts of ingredients, properties (such as concentrations), reaction conditions, and the like, used to describe and claim particular embodiments of the present invention may, in some instances, be modified by the term "about." Accordingly, in some embodiments, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties to be obtained in a particular embodiment. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each different value within the range. Unless otherwise indicated herein, each individual value is incorporated herein as if it were individually recited.

[0066] As used herein, the term "administering" a pharmaceutical composition or agent refers to both direct and indirect administration of the pharmaceutical composition or agent, where direct administration of the pharmaceutical composition or agent is typically performed by a medical professional (e.g., a doctor, a nurse, etc.), and indirect administration includes providing or making available the pharmaceutical composition or agent to a medical professional for direct administration (e.g., by injection, infusion, oral delivery, topical delivery, etc.). Furthermore, it should be noted that the terms "prognosing" or "predicting" with respect to a condition, susceptibility to developing a disease, or response to an intended treatment is intended to encompass the act of predicting or forecasting (but not treatment or diagnosis of) the condition, susceptibility, and / or response, including the rate of progression, improvement, and / or duration of the condition in a subject.

[0067] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "etc.") provided herein with respect to specific embodiments is intended merely to clarify the invention and does not limit the scope of the invention as claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0068] As used throughout this specification and the claims that follow, the meanings of "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Also, as used herein, the meaning of "in" includes "in" and "on," unless the context clearly dictates otherwise. Furthermore, the term "coupled to," as used herein, is intended to include both direct coupling (where two coupled elements are in contact with each other) and indirect coupling (where at least one additional element is located between the two elements), unless the context clearly dictates otherwise. Thus, the terms "coupled to" and "coupled with" are used synonymously.

[0069] Those skilled in the art will recognize that many more modifications beyond those described above are possible without departing from the inventive concepts herein. Accordingly, nothing limits the subject matter of the present invention except as set forth in the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms "comprises" and "comprising" should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced element, component, or step may be present with, used in, or combined with other elements, components, or steps not expressly referenced. When the specification or claims refer to at least one member selected from the group consisting of A, B, C, ..., and N, the sentence should be interpreted as requiring only one member of that group (i.e., not A+N, B+N, etc.).

Claims

1. 1. A method for alleviating a sign or symptom of post-viral syndrome comprising: the method comprising orally administering a polyphenol-rich composition comprising primarily a plurality of chemically distinct catechins and a plurality of chemically distinct chlorogenic acids; wherein administration of the polyphenol-rich composition rapidly modifies multiple different pathways that generate reactive oxygen species, thereby alleviating the signs or symptoms of the post-viral syndrome. method.

2. 10. The method of claim 1, wherein alleviating the signs or symptoms of post-viral syndrome is associated with a partial or complete improvement in physical and / or mental function compared to a subject not administered the composition.

3. 10. The method of claim 1, wherein the plurality of chemically distinct catechins and the plurality of chemically distinct chlorogenic acids are present in one or more of an extract of unroasted coffee beans, an extract of green tea, an extract of turmeric, a tart cherry or an extract thereof, and a plant of the Brassicaceae family or an extract thereof.

4. 10. The method of claim 1, wherein the polyphenol-rich composition is prepared from at least one of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or extract thereof, broccoli or extract thereof, and kale or extract thereof.

5. 10. The method of claim 1, wherein the polyphenol-rich composition is prepared from at least two of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or extract thereof, broccoli or extract thereof, and kale or extract thereof.

6. 10. The method of claim 1, wherein the polyphenol-rich composition comprises at least 50 wt% total catechins and at least 20 wt% total chlorogenic acids.

7. 10. The method of claim 1, wherein the polyphenol-rich composition further comprises a supplemental antioxidant in a total amount of up to 30 wt%.

8. 8. The method of claim 7, wherein at least one of the supplemental antioxidants is selected from the group consisting of stilbenoids, curcumin, vitamin E, manganese, and coenzyme Q10.

9. 10. The method of claim 1, wherein 10 to 150 mg of the polyphenol-rich composition is administered in a single dose daily for a period of 1 to 60 days.

10. 10. The method of claim 1, wherein said alleviating a sign or symptom of post-viral syndrome occurs within 30 minutes to 3 hours after administration.

11. 10. The method of claim 1, wherein the polyphenol-rich composition is formulated into a capsule, tablet, gummy, chewable, dissolvable film, or powder.

12. 10. The method of claim 1, wherein the polyphenol-rich composition is formulated into an instant beverage, a juice beverage, a carbonated beverage, or a liquid concentrate.

13. 10. The method of claim 1, wherein the post-viral syndrome is post-COVID syndrome or post-viral fatigue syndrome.

14. 10. The method of claim 1, wherein the polyphenol-rich composition is administered for at least seven days after a negative viral test.

15. 10. The method of claim 1, wherein the symptom or condition is fatigue, mitochondrial dysfunction, endothelial dysfunction, immune dysfunction, oxidative stress, chronic subacute inflammation, neurological dysfunction, and / or cognitive dysfunction.

16. 10. The method of claim 1, wherein one of the pathways is mitochondrial reactive oxygen species production.

17. 2. The method of claim 1, wherein one of the pathways is NOX2-dependent reactive oxygen species generation.

18. 2. The method of claim 1, wherein one of the pathways is iNOS-dependent reactive oxygen species generation.

19. 2. The method of claim 1, wherein administration of the polyphenol-rich composition rapidly increases bioavailable NO and / or wherein administration of the polyphenol-rich composition rapidly reduces inflammatory cytokines.

20. 10. The method of claim 1, wherein administration of the polyphenol-rich composition rapidly reduces circulating IL1-beta, IL8, IL10, and / or TNF-alpha.

21. 10. The method of any one of the preceding claims, wherein mitochondrial reactive oxygen species levels are reduced by at least 50%, iNOS activity is reduced by at least 55%, wherein the NOX2-dependent ROS production is reduced by at least 40%, and / or wherein the circulating nitric oxide, as measured as NOHb, is increased by at least 30%.

22. 1. A polyphenol-rich composition for treating a sign or symptom of post-viral syndrome, comprising: wherein the composition primarily comprises a plurality of chemically distinct catechins and a plurality of chemically distinct chlorogenic acids; and wherein said composition, when administered orally at a dose of 10-150 mg, rapidly modifies multiple different pathways that generate reactive oxygen species, thereby alleviating the signs or symptoms of said post-viral syndrome. composition.

23. 23. The polyphenol-rich composition of claim 22, comprising at least 50 wt. % total catechins, at least 20 wt. % total chlorogenic acids, and optionally up to 30 wt. % total supplemental antioxidants.

24. 23. The polyphenol-rich composition of claim 22, prepared from at least one of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or extract thereof, broccoli or extract thereof, and kale or extract thereof.

25. 23. The polyphenol-rich composition of claim 22, wherein the polyphenol-rich composition is administered daily in a single dose of 10-150 mg per day for a period of 1 to 60 days.

26. 23. The polyphenol-rich composition of claim 22, wherein the alleviation of the signs or symptoms of post-viral syndrome occurs within 30 minutes to 3 hours after administration.

27. 23. The method of claim 22, wherein the polyphenol-rich composition is formulated into a capsule, tablet, gummy, chewable, dissolvable film, or powder.

28. 23. The polyphenol-rich composition of claim 22, formulated into an instant beverage, juice beverage, carbonated beverage, or liquid concentrate.

29. 23. The polyphenol-rich composition of claim 22, wherein the post-viral syndrome is post-COVID syndrome or post-viral fatigue syndrome.

30. 30. The polyphenol-rich composition of claim 29, wherein the symptoms or signs are aching pain, sharp pain, fever, upper and / or lower respiratory tract shortness of breath, difficulty breathing, sore throat, fatigue, headache, abnormalities on chest imaging, and / or general malaise.

31. 23. The polyphenol-rich composition of claim 22, wherein the symptom or condition is mitochondrial dysfunction, endothelial dysfunction, immune dysfunction, oxidative stress, chronic subacute inflammation, neurological dysfunction, and / or cognitive dysfunction.

32. 23. The polyphenol-rich composition of claim 22, comprising: wherein one of the pathways is mitochondrial reactive oxygen species production; wherein one of the pathways is NOX2-dependent reactive oxygen species generation; and / or wherein one of the pathways is iNOS-dependent reactive oxygen species generation; composition.

33. 23. The polyphenol-rich composition of claim 22, comprising: wherein administration of the polyphenol-rich composition rapidly increases bioavailable NO; and / or wherein administration of the polyphenol-rich composition rapidly reduces inflammatory cytokines; composition.

34. 34. A polyphenol-rich composition according to any one of claims 22 to 33, comprising: whereby mitochondrial reactive oxygen species levels are reduced by at least 50%, reduce iNOS activity by at least 55%; wherein said NOX2-dependent ROS production is reduced by at least 40%; and / or wherein said circulating nitric oxide, as measured as NOHb, is increased by at least 30%. composition.

35. 1. Use of a polyphenol-rich composition in the manufacture of a medicament for the treatment of a symptom or condition of post-viral syndrome; wherein the composition primarily comprises a plurality of chemically distinct catechins and a plurality of chemically distinct chlorogenic acids; and wherein the composition is formulated for administration at a dose of 10-150 mg. Uses of the composition.

36. 36. The use of claim 35, wherein the polyphenol-rich composition rapidly modulates multiple different pathways that generate reactive oxygen species.

37. 37. The use of claim 36, wherein the rapid modulation of multiple different pathways relieves aching pain, sharp pain, fever, upper and / or lower respiratory tract shortness of breath, sore throat, fatigue, and / or general malaise typically associated with post-viral syndrome.

38. 36. The use of claim 35, wherein the symptoms or conditions of the post-viral syndrome further include mitochondrial dysfunction, endothelial dysfunction, immune dysfunction, oxidative stress, chronic subacute inflammation, neurological dysfunction, and / or cognitive dysfunction.

39. 36. The use of claim 35, wherein the polyphenol-rich composition is provided in the form of plant material and / or extracts thereof.

40. 40. The use of claim 39, wherein the plant material is selected from the group consisting of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or extract thereof, broccoli or extract thereof, and kale or extract thereof.

41. 36. The use of claim 35, wherein the polyphenol-rich composition comprises at least 50 wt. % total catechins, at least 20 wt. % total chlorogenic acids, and optionally up to 30 wt. % total supplemental antioxidants.

42. 36. The use of claim 35, wherein one of the pathways is mitochondrial production of reactive oxygen species.

43. 36. The use of claim 35, wherein one of the pathways is NOX2-dependent reactive oxygen species generation.

44. 36. The use of claim 35, wherein one of the pathways is iNOS-dependent reactive oxygen species generation.

45. 36. The use of claim 35, wherein administration of the polyphenol-rich composition rapidly increases bioavailable NO; and / or Rapidly reducing inflammatory cytokines and / or chemokines; and / or rapidly reducing circulating IL1-beta, IL8, IL10, and / or TNF-alpha; Uses of the composition.

46. 36. The use of claim 35, wherein said mitochondrial reactive oxygen species levels are reduced by at least 50% and iNOS activity is reduced by at least 55%, and wherein said NOX2-dependent ROS generation is reduced by at least 40%; and / or wherein the circulating nitric oxide, as measured as NOHb, is increased by at least 30%. Uses of the composition.

47. A polyphenol-rich composition for use as a therapeutic agent in the treatment of post-viral syndrome, wherein the composition comprises primarily a plurality of chemically distinct catechins and a plurality of chemically distinct chlorogenic acids, and wherein the composition is formulated for administration at a dose of 10 to 150 mg.

48. 48. The polyphenol-rich composition of claim 47, wherein the composition rapidly modulates multiple different pathways that generate reactive oxygen species.

49. 49. The polyphenol-rich composition of claim 48, wherein the rapid modulation of multiple different pathways relieves aching pain, sharp pain, fever, upper and / or lower respiratory tract shortness of breath, sore throat, fatigue, and / or general malaise typically associated with post-viral syndrome.

49. 48. The polyphenol-rich composition of claim 47, wherein the signs or symptoms of the post-viral syndrome further comprise mitochondrial dysfunction, endothelial dysfunction, immune dysfunction, oxidative stress, chronic subacute inflammation, neurological dysfunction, and / or cognitive dysfunction.

50. 48. The polyphenol-rich composition of claim 47, provided in the form of plant material and / or extracts thereof.

51. 51. The polyphenol-rich composition of claim 50, wherein the plant material is selected from the group consisting of unroasted coffee bean extract, green tea extract, turmeric extract, tart cherry or extract thereof, broccoli or extract thereof, and kale or extract thereof.

52. 48. The polyphenol-rich composition of claim 47, wherein the polyphenol-rich composition comprises at least 50 wt.% total catechins, at least 20 wt.% total chlorogenic acids, and optionally up to 30 wt.% total supplemental antioxidants.

53. 48. The polyphenol-rich composition of claim 47, wherein one of said pathways is mitochondrial reactive oxygen species production.

54. 48. The polyphenol-rich composition of claim 47, wherein one of said pathways is NOX2-dependent reactive oxygen species generation.

55. 48. The polyphenol-rich composition of claim 47, wherein one of said pathways is iNOS-dependent reactive oxygen species generation.

56. 48. The polyphenol-rich composition of claim 47, comprising: wherein administering the polyphenol-rich composition comprises: Rapidly increases bioavailable NO; and / or Rapidly reducing inflammatory cytokines and / or chemokines; and / or rapidly reducing circulating IL1-beta, IL8, IL10, and / or TNF-alpha; composition.

57. 48. The polyphenol-rich composition of claim 47, comprising: wherein the level of mitochondrial reactive oxygen species is reduced by at least 50%; reduce iNOS activity by at least 55%; wherein said NOX2-dependent ROS production is reduced by at least 40%, and / or wherein said circulating nitric oxide, as measured as NOHb, is increased by at least 30%. composition.

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