50 results about "Mitochondrial homeostasis" patented technology

The invention discloses a medicine prepared from apoptotic fibroblast-derived vesicles and used for preventing and treating myocardial ischemia-reperfusion injury as well as a preparation method and application of the medicine, and relates to the technical field of biological medicines. The method comprises the following steps: digesting an in-vitro animal heart apex tissue to obtain a digested cell suspension; the myocardial fibroblasts are obtained; the method comprises the following steps: culturing myocardial fibroblasts in a DMEM (dulbecco's modified eagle medium) solution through apoptosis inducer H2O2 to obtain a culture solution; according to the method, apoptosis of fibroblasts is induced to generate specific extracellular vesicles, the surface of the extracellular vesicles carries CD22 as a marker, the content of the extracellular vesicles is enriched in miR-1246 and is taken by myocardial cells, expression of p53 is down-regulated, mitochondrial homeostasis is maintained, and the extracellular vesicles can be used for detecting apoptosis of the fibroblasts. The myocardial cell apoptosis is inhibited.

The invention discloses an application of Evaixin in prevention or treatment of mitochondrial abnormality diseases. The invention provides an application of an Avaixin oral liquid in preparation of a product for improving mitochondrial homeostasis imbalance. The mitochondrial homeostasis imbalance is caused by cardiovascular diseases. The invention proves that the Avaifuxin oral liquid has a potential protection effect on cardiovascular diseases, and plays a protection role by adjusting the dynamic balance of mitochondrial fusion and division processes. The invention is of great significance to further understanding the protective action mechanism of the Aiwei heart oral liquid on the mitochondrial homeostasis imbalance caused by cardiovascular diseases (hypertensive myocardial hypertrophy, myocardial fibrosis, ventricular remodeling, heart failure, myocardial infarction and myocardial ischemia-reperfusion injury) and improving the corresponding curative effect.

The invention discloses a metabolite for treating sarcopenia and application of the metabolite in a health-care product additive, and belongs to the technical field of biomedicine, and the application comprises application of indole-3-formaldehyde in preparation of a medicine for treating sarcopenia. The invention further discloses a health care product additive and a medicine for treating sarcopenia, wherein the medicine comprises indole-3-formaldehyde. According to the present invention, the indole-3-formaldehyde can be adopted as the health product additive or the effective component in the drug, can be used for treating sarcopenia, and can recover the skeletal muscle cell mitochondrial homeostasis so as to improve the muscle cell mitochondrial function index.

The invention provides a genetically engineered oriented electrostatic spinning fiber as well as a preparation method and application thereof, and belongs to the technical field of biomedical materials. Gene TSPAN9 is packaged in liposome through a micro-fluidic chip technology, then oriented electrostatic spinning fibers of a shell-core structure are prepared through an oriented micro-sol electrostatic spinning technology, and the liposome containing the TSPAN9 is protected on a core layer by hyaluronic acid; and the polylactic acid fibers are arranged in an oriented manner to form a shell layer. An in-vitro experiment shows that the oriented fiber closely simulates a fascia oriented arrangement structure, and the cell migration rate is remarkably improved through contact guidance; by slowly releasing lipidosome loaded with genes into cells and maintaining the mitochondrial steady state, mitochondrial respiration is effectively recovered, the active oxygen level is reduced, and the mitochondrial membrane potential function is maintained. In-vivo experiments show that the genetically engineered fiber can effectively inhibit inflammatory response and promote fascia tissue regeneration by promoting mitochondrial exocytosis to discharge damaged mitochondria.

The invention discloses a compound probiotic capable of increasing exercise tolerance and resisting exercise fatigue and application of the compound probiotic. The compound probiotic comprises lactobacillus plantarum SHY21-2 and lactobacillus fermentum SHY10, the preservation number of the lactobacillus plantarum is CCTCC NO: M 2020043, and the preservation number of the lactobacillus fermentum is CCTCC NO: M 2020042. The invention further discloses a preparation method of the compound probiotic capable of increasing exercise tolerance and resisting exercise fatigue. The invention discloses the compound probiotics capable of accurately regulating and controlling the mitochondrial homeostasis of the gastrocnemius muscle for the first time, and the compound probiotics can remarkably improve exercise tolerance and relieve exercise fatigue.

The invention discloses application of eupatolide in preparation of a medicine for preventing and treating inflammatory bowel disease, application of eupatolide in preparation of a medicine for preventing and treating inflammatory bowel disease and application of a medicine preparation containing eupatolide in preparation of a medicine for preventing and treating inflammatory bowel disease, and researches that eupatolide (EPT) can be used for preparing the medicine for preventing and treating inflammatory bowel disease through targeting pyruvate kinase isoenzyme 2 (PKM2, Gene ID: 5135). The inflammatory response, glycolysis metabolism and mitochondrial homeostasis are synergistically regulated and controlled, so that the inhibition effect on the inflammatory bowel disease is exerted. Meanwhile, EPT has the advantages of being low in dosage, feasible in oral administration, free of obvious toxic and side effects and the like, and a solid experimental basis is provided for further developing EPT into candidate drugs for preventing and treating inflammatory bowel diseases.

The invention belongs to the technical field of medicines, and particularly relates to acetylated hawthorn polysaccharide as well as a preparation method and application thereof. The preparation method of the acetylated hawthorn polysaccharide comprises the following steps: adding fresh hawthorn fruits into a deep-eutectic solvent for homogenization, and extracting by adopting a physical method to obtain an extracting solution; carrying out alcohol precipitation and centrifugation on the extracting solution to prepare crude polysaccharide; and adding water into the crude polysaccharide, redissolving, deproteinizing, concentrating, dialyzing and freeze-drying to obtain the acetylated hawthorn polysaccharide. The method utilizes a physical method to cooperate with deep eutectic solvent extraction, is green and pollution-free, can realize efficient preparation and effective separation of acetylated hawthorn polysaccharide, has high acetylation degree, has in-vitro and in-vivo intestinal mitochondrial homeostasis regulation activity, has no toxic or side effect, is suitable for people with intestinal mitochondrial related diseases, and also has the functions of improving intestinal mitochondrial homeostasis regulation. And the composition is also suitable for preventing intestinal diseases of normal people.

The invention relates to hair-blacking essence and a preparation method thereof. Screening a symbiotic bacterium metabolism extract with small molecule peptide metabolism regulation capability; by combining low-concentration azelaic acid and zinc lactate components, scalp grease oxidation and abnormal proliferation of propionibacterium are inhibited; the expression of IL-10 anti-inflammatory factors is induced, the expression of TNF-alpha and IL-6 is reduced, and the hair follicle microinflammation state is reduced; a Wnt / beta-catenin pathway activator is used for inducing the melanin stem cells to be in a static state; the FGF-2 and the EGF are combined in a micro-dose manner to promote the amplification into precursor cells; mITF regulation peptides and a small amount of trace copper ions are supplemented to induce directional differentiation into mature melanocytes; a microcapsule carrier system with a three-layer structure; the penetration efficiency is improved; antioxidative peptide rich in reduced glutathione, NAD and a promoting factor are used, so that melanocytes are protected from oxidative damage; a coenzyme Q10 type mitochondrial homeostasis regulator is introduced, so that the energy metabolism is improved, the cell aging is delayed, the targeting property is strong, and the effect is accurate.

The application discloses a bZIP transcription factor mediating sensitivity change of Magnaporthe oryzae to mitochondrial respiratory inhibitors and high expression in mitochondrial dysfunction, and enhancing mtDNA replication in mitochondria PoATFS1 . PoATFS1 The overexpression transformant is sensitive to various respiratory inhibitors, and the knockout transformant is sensitive to various respiratory inhibitors. Meanwhile, PoATFS1 The mtDNA content in the overexpression transformant increases, and the mtDNA content in the knockout transformant decreases, which indicates that PoATFS1 The gene is involved in regulating mitochondrial homeostasis. The application provides a synergistic agent screening candidate target for restoring the sensitivity of resistant plant pathogens to respiratory inhibitors, and is favorable for the management of drug resistance of plant pathogens and the improvement of the activity of the existing respiratory inhibitors.

The invention belongs to the field of biological medicine, particularly discloses pharmaceutical application of a Dio3 inhibitor screened based on a thyroid hormone disorder algorithm in sepsis cardiomyopathy, and discloses that the core pathological mechanism of SIC is thyroid hormone signal axis disorder caused by Dio3 abnormal up-regulation, further mitochondrial autophagy key protein is inhibited, and the application of the Dio3 inhibitor in sepsis cardiomyopathy is developed for the first time. And myocardial mitochondrial homeostasis imbalance and functional cardiac dysfunction are caused. Through single intraperitoneal injection (25mg / kg) of a compound PBENZ-DBRMD (specific Dio3 inhibitor) within 12 hours after sepsis occurs, heart function indexes (EF% / FS%) can be remarkably recovered, and mitochondrial autophagy disorder can be reversed. Meanwhile, serum transT3 (rT3) is provided as an SIC early diagnosis marker (rT3 is strongly negatively correlated with EF%). The scheme provides a new targeted intervention strategy for SIC, and has the characteristics of simplicity and convenience in operation and definite curative effect.

The present invention is focused on extending the lifespan and the healthy period of life (healthspan), delaying the development of chronic diseases and dysfunctions, which is a growing need of aging societies. Among the strategies to promote and extend healthspan, nutrition and food ingredients play a central role. The present invention is related to standardized delphinidin-rich maqui berry composition comprising different amounts and combination of delphinidins, which represent a potent class of antioxidant anthocyanins as agent for reducing progressive loss of skeletal muscle, increasing muscle mass and anti-aging agent or geroprotective agent, and thereby, enhancing the healthspan and preserving locomotive functions for longer periods of life. Such effect was measured as climbing ability during life time in an animal model (Drosophila melanogaster), Experimental assays demonstrated that delphinidin-rich standardized maqui berry extracts upregulate the expression of antioxidant enzymes and mitochondrial homeostasis-related proteins, which determine contractile muscle function. Such delphinidin-rich standardized maqui berry composition is useful as antioxidant supplement for adults and elderly.

The invention discloses application of PINK1 / Parkin in cognitive impairment by adjusting mitochondria, and relates to the technical field of biological medicine, and the technical key points are as follows: the PINK1 / Parkin can mediate the autophagy mechanism of the mitochondria, inhibit excessive mitochondrial autophagy generated by the cognitive impairment caused by aluminum exposure, maintain the steady state balance of the mitochondria in the body of a patient, and inhibit the mitochondrial autophagy caused by aluminum exposure. The excessive formation of ROS is inhibited, and the progress of cognitive impairment of a patient is slowed down.

The invention relates to the technical field of biology, in particular to application of lactobacillus plantarum SCS7 and an acellular extract of the lactobacillus plantarum SCS7 in preparation of a medicine for relieving aflatoxin B1 induced liver injury. The cell-free extract of the lactobacillus plantarum SCS7 is applied to preparation of a medicine for relieving aflatoxin B1 induced liver injury. Aflatoxin B1 causes liver injury and disorder of intestinal flora. Meanwhile, the lactobacillus plantarum SCS7 cell-free extract recovers the mitochondrial function damaged by aflatoxin B1 by inhibiting over-activated mitochondrial autophagy, so that the mitochondrial homeostasis is balanced, meanwhile, the composition of intestinal flora and the abundance of dominant flora are adjusted, and the content of short-chain fatty acid is increased to maintain the intestinal flora homeostasis. The research possibly enriches the protective effect and mechanism of lactobacillus plantarum on liver injury caused by various factors, and the lactobacillus plantarum has wide application prospects.

The invention discloses an application of PINK1 in regulation and control of ER positive breast cancer tamoxifen drug resistance. The invention relates to application of PINK1 as a biomarker in evaluating the tamoxifen resistance of ER positive breast cancer cells. The drug resistance is evaluated by detecting the expression level of PINK1 in a sample and combining mitochondrial autophagy activity. The expression level of the PINK1 comprises an mRNA level and / or a protein level. According to the invention, the drug resistance formation process is systematically analyzed from the perspective of quality control of an organelle of mitochondrial autophagy, and through public database analysis and experimental verification, the overall up-regulation of the mitochondrial autophagy pathway in drug-resistant cells is clearly revealed, and the drug-resistant phenotype is promoted by maintaining the mitochondrial steady state, thereby opening up a new direction for understanding the drug-resistant mechanism.

The invention belongs to the technical field of pharmacy, and particularly relates to application of spermidine in sepsis treatment. Experiments prove that spermidine can regulate mitochondrial biogenesis and inhibit mitochondrial excessive autophagy to remarkably improve mitochondrial quality, maintain mitochondrial homeostasis and relieve myocardial dysfunction and heart structure damage. In addition, spermidine can inhibit oxidative stress caused by excessive inflammatory response so as to recover normal functions of mitochondria. The spermidine has a potential treatment effect on sepsis and has a good clinical application prospect in treating sepsis and related diseases caused by excessive autophagy.

The invention provides application of an environmental response type anti-oxidation system to regulation and control of mitochondrial homeostasis and heart regeneration. The present invention relates to a reduced glutathione-modified polydopamine melanin nanoparticle, and particularly provides a reduced glutathione-modified polydopamine melanin nanoparticle, a method for promoting transformation of M1 macrophages to M2 macrophages by using the reduced glutathione-modified polydopamine melanin nanoparticle, a method for promoting damage repair of target cells, and a pharmaceutical composition.

The invention belongs to the technical field of biological medicines, and particularly relates to a polyphenol-protein self-assembly material as well as a preparation method and application thereof. According to the invention, polyphenol-protein self-assembly materials (NE APs) are effectively formed by utilizing a plurality of physical interactions between EGCG (epigallocatechin gallate) and a growth factor NRG-1. The NRG-1 can be continuously released from the NE APs, and the EGCG protects the NRG-1 from oxidative stress and maintains the biological activity of the NRG-1 related to stem cell recruitment, migration and angiogenesis. In addition, the NE APs utilize EGCG to clear ROS, maintain mitochondrial homeostasis and promote osteogenic differentiation ability, and meanwhile, through TNF / NF-kappa B / JAK-STAT signal pathways, immunoreaction is synergistically regulated. In-vivo experiments show that NE APs accelerates repair of inflammatory bone defects by enhancing stem cell recruitment, angiogenesis and immunoregulation, and has good practical application value.

The invention discloses an application of dapam nitrile and a medicine. The invention relates to the field of medicines, in particular to application of dapam nitrile in preparation of medicines for treating and / or preventing metabolism-related fatty liver diseases and the medicines for treating and / or preventing the metabolism-related fatty liver diseases, and active ingredients of the medicines comprise dapam nitrile and further comprise pharmaceutically acceptable excipients, carriers and / or diluents. The dapam-susulonitrile can target NLRP3 inflammasomes, maintain the mitochondrial homeostasis in liver cells, reduce lipid deposition of the liver cells and the liver and improve glucose metabolism and lipid metabolism.

A method for treating a disease associated with cell autophagy functional deficiency and / or lysosomal functional deficiency, such as neurodegenerative diseases, by inhibiting KEAP1 activity and / or enhancing the expression of nuclear erythroid 2-related factor 2 (NRF2) and / or the downstream genes thereof. The expression of NRF2 and / or the downstream genes thereof is enhanced with a KEAP1 inhibitor, a KEAP1 gene knockdown, and / or an NRF2 activator. The method and product can increase the acidic environment in the lysosomes of neurons, increase the enzymatic activity of cathepsins, decrease the abnormal storage of proteins, protect mitochondrial homeostasis in neurons, and increase the capability of mitochondria to generate ATP.

The invention discloses a zwitterionic active compound modified by a mitochondrial targeting group as well as a preparation method and application of the zwitterionic active compound, and belongs to the technical field of precise nutrition and medicines. The preparation method comprises the following steps: synthesizing a negatively charged anionic active compound through an electrophilic addition reaction between an active compound and NaHSO3; and synthesizing the active compound modified by the mitochondrial targeting group through electrostatic coupling between the anionic active compound and the cationic mitochondrial targeting molecule. The preparation method is simple and efficient, meanwhile, the obtained product can retain the original functional activity of the active compound to the maximum extent, and meanwhile accurate positioning and efficient enrichment of the active compound in mitochondria are promoted; the active compound can effectively relieve mitochondrial homeostasis under oxidative stress and has a wide application prospect.

The invention relates to a cartilage organ with a mitochondrial homeostasis maintaining function as well as a preparation method and application of the cartilage organ. The preparation method comprises the following steps: preparing a DNA (deoxyribonucleic acid)-silk fibroin hybrid hydrogel solution containing MnO2 nanoparticles and Melatonin; the DNA-silk fibroin hybrid hydrogel solution is mixed with bone marrow mesenchymal stem cells, and a DNA-silk fibroin hybrid hydrogel solution loaded with BMSCs is obtained; a cartilage organ precursor is formed through DLP biological 3D printing; and culturing the cartilage organ precursor in a culture medium to obtain the cartilage organ with the function of maintaining the mitochondrial homeostasis. According to the functionalized cartilage organoid, the culture efficiency of the organoid can be improved, and the stable state of cell mitochondria can be better maintained, so that the activity of cartilage cells is improved, cartilage regeneration and repair are promoted, and alternative materials are provided for preparing medicaments or medical instruments for repairing cartilage defects.

The invention discloses application of dimethyl fumarate in preparation of a medicine for preventing and / or treating skeletal muscle atrophy, and belongs to the field of medicine. It is proved for the first time that DMF can effectively relieve related symptoms of skeletal muscle atrophy caused by cancer cachexia, and a new thought is provided for treatment of skeletal muscle atrophy. The DMF can relieve skeletal muscle atrophy by reducing mitochondrial damage and improving mitochondrial homeostasis imbalance, and the potential mechanism of the DMF is possibly related to the regulation of HIF1alpha, mTOR and other pathways. In addition, DMF can improve cancer cachexia skeletal muscle atrophy and does not inhibit tumor growth, which indicates that DMF directly acts on skeletal muscle instead of tumor. Due to the common end characteristic of mitochondrial homeostasis imbalance and the like in amyotrophy caused by different causes (such as aging and drug toxicity), the adjusting effect of DMF on homeostasis in skeletal muscle can be expanded to be used for preventing and treating other types of amyotrophy, including amyotrophy caused by aging, glucocorticoid, chemotherapy drugs and the like. The invention provides an application basis for preventing and treating skeletal muscle atrophy by DMF.

The invention belongs to the technical field of biological medicines, and particularly discloses a polypeptide for protecting lung vascular endothelial cells and relieving lung injury and application of the polypeptide. The polypeptide is Humanin-G (HNG), and the amino acid sequence of the polypeptide is MAPRGFSCLLLLTGEIDLPVKRRA. The polypeptide is targeted to mitochondria of pulmonary vascular endothelial cells, provides protection from energy supply and cell survival roots, and has profound significance in improving functions of the pulmonary vascular endothelial cells and reducing the death rate of sepsis-induced acute lung injury (ALI). Researches show that when the polypeptide is used in the acute injury stage, lung inflammation of a model animal can be relieved by 25%-50%, the lung injury HE score can be reduced by about 50%, pulmonary edema can be relieved by about 30%, mitochondrial functions can be recovered by about 70%, the ATP yield can be increased by 30%, and the effect is excellent. Therefore, the invention provides a brand new strategy for maintaining the mitochondrial homeostasis by using the polypeptide so as to relieve lung injury.

The application belongs to the technical field of biological medicine, and particularly relates to a kind of polyphenol-protein self-assembly material and its preparation method and application.The application effectively forms polyphenol-protein self-assembly material (NE APs) by using multiple physical interactions between EGCG and growth factor NRG-1.NRG-1 can be continuously released from NE APs, and EGCG protects NRG-1 from oxidative stress, maintains its biological activity related to stem cell recruitment, migration and angiogenesis.In addition, NE APs utilize the ability of EGCG to scavenge ROS, maintain mitochondrial homeostasis and promote osteogenic differentiation, while synergistically regulating immune response through TNF / NF-κB / JAK-STAT signaling pathways.In vivo experiments show that NE APs accelerate the repair of inflammatory bone defects by enhancing stem cell recruitment, angiogenesis and immune regulation, and have good practical application value.

This invention discloses the application of OXR1 as a target in the preparation of drugs for treating osteoclast-related bone diseases. This invention reveals for the first time the crucial role of OXR1 in osteoclast differentiation: OXR1 directly binds to the KEAP1 protein, promoting the interaction between KEAP1 and p62, thereby mediating mitophagy, clearing excess reactive oxygen species generated during osteoclast differentiation, and maintaining mitochondrial homeostasis. Inhibiting OXR1 expression or function can effectively block osteoclast differentiation and reduce bone loss. Based on this, this invention provides two intervention strategies targeting OXR1: one is gene therapy using adeno-associated viruses carrying shRNA targeting OXR1; the other is screening and validating the novel use of the FDA-approved drug velpatasvir as an OXR1 inhibitor. In vitro and in vivo experiments confirmed that both significantly inhibit osteoclast activity and improve the osteoporotic phenotype in ovariectomized mice.

The present inventive technology is directed the novel therapeutic application of muropeptides as class of novel ATP synthase agonists. In particular, the invention includes systems, methods and compositions for the use of muropeptides as novel ATP synthase agonists, and their use as a therapeutic agents to treat diseases and conditions that involve abnormal ATP synthase and mitochondrial activities.

The invention discloses a method for relieving aniline liver injury by activating FXR with melatonin, and belongs to the technical field of biomedicines.The method comprises the steps that S1, an effective dose of melatonin is applied to an aniline-exposed individual or animal model; and S2, verifying the activation effect of the melatonin on FXR (farnesoid receptor) by detecting the expression or activity level of the FXR in the intestinal tract. In the invention, an intestinal FXR-mitochondrial cross-organ regulation network is disclosed, by specifically targeting intestinal FXR and RIPK1 / MLKL phosphorylation pathway, the stable state of mitochondria can be effectively regulated, the ultrastructure and gene time sequence map of the mitochondria are ingeniously integrated, the dynamic change of the mitochondria is deeply analyzed from the microscopic level, the mechanism deficiency of the traditional research is made up, and the research on the mitochondria is facilitated. Meanwhile, it is clear that 20 mg / kg is the optimal dosage of the melatonin, the ALT / AST level is remarkably reduced, the fuzzy dilemma of the traditional clinical medication dosage is broken through, a melatonin and antibiotic synergistic treatment scheme is further developed, the treatment effect is greatly improved, and intestinal microenvironment factors are fully considered.

The invention provides an application of procyanidine B2 or a red rice extract in treatment of skin light injury. The proanthocyanidin B2 or the red rice extract containing the proanthocyanidin B2 is combined with a key subunit NDUFA7 in NADH: ubiquinone oxidoreductase (compound I) in mitochondria to stabilize the positioning of the proanthocyanidin B2 or the red rice extract containing the proanthocyanidin B2 in the compound I and improve the activity of NADH dehydrogenase, so that the stable state of the mitochondria is maintained, the generation of ROS is reduced, the PERK-Nrf2 axis of the targeted mitochondria activates antioxidant response, and the mitochondrial activity of the mitochondria is improved. On the other hand, the excessive stress of NF-kappa B and p53-POMC axes is reduced, and the effect of repairing skin light damage is achieved by synergistically promoting cell survival and steady state maintenance through multiple channels.

The invention relates to application of an OGN overexpression vector in preparation of a medicine for preventing reperfusion myocardial injury, and belongs to the technical field of biological medicine. Aiming at the problem that an existing mitochondrial targeting strategy is insufficient in multi-target cooperation in MI / RI prevention, the invention provides application of an OGN overexpression vector in preparation of drugs for preventing reperfusion myocardial injury, and the OGN overexpression vector is a recombinant adeno-associated virus vector and contains a nucleotide sequence for coding OGN. According to the invention, three-dimensional mitochondrial steady state regulation of myocardial ischemia reperfusion injury is realized for the first time, and myocardial energy metabolism is remarkably improved and cell death is reduced by enhancing mitochondrial respiratory chain activity, stabilizing membrane potential and inhibiting ROS outbreak, so that heart failure caused by MI / RI is effectively reversed. Experimental data confirm that AAV-mediated OGN overexpression has a protective effect on cardiac functions and has remarkable clinical transformation potential.

The invention relates to the technical field of nano-selenium materials, in particular to a nano-selenium material based on glutathione driving and a preparation method and application thereof.The nano-selenium material is prepared from glutathione and sodium selenite through a one-pot hydrothermal method, the preparation method is simple and easy to implement, and the nano-selenium material is suitable for industrial production. The prepared GSH-Se nanoparticles comprise a nano-selenium core and a glutathione modified shell, and a solution of the GSH-Se nanoparticles has excellent colloidal stability and broad-spectrum free radical scavenging characteristics. Meanwhile, the GSH-Se nanoparticles provided by the invention have the effects of improving Parkinson's disease, promoting mitochondrial homeostasis, relieving neuroinflammation, improving dopaminergic neuron function and motor behavior disorder and the like, and have great clinical application value.