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Heart failure is a group of complex clinical syndromes in the middle and late stages of cardiovascular diseases.Mitochondrial homeostasis imbalance is one of the pathological mechanisms in the occurrence and development of heart failure.This article revolved around the"yin-yang theory"in TCM and explained the pathological mechanism of heart failure through mitochondrial homeostasis.Heart failure is the syndrome of deficiency in nature and excess in superficiality fundamental.Its basic pathogenesis is"yang deficiency and yin excess".Based on the deficiency of heart yang qi and the stagnation of yin pathogens,the combination of deficiency and excess runs through the entire disease.Mitochondrial homeostasis imbalance is a manifestation of yin-yang imbalance at the cellular micro level,mainly manifested as inhibition of mitochondrial biosynthesis,mitochondrial dynamics imbalance,mitophagy disorder,etc.,which affects mitochondrial structure and function and leads to abnormal myocardial energy metabolism.Therefore,based on the"yin-yang theory",the basic treatment method is to"tonify deficiency and damage excess"to regulate mitochondrial biosynthesis,mitochondrial dynamics,and mitophagy,thereby maintaining mitochondrial homeostasis and improving myocardial energy metabolism,which is of great significance for the prevention and treatment of heart failure.
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Ginseng Radix et Rhizoma(GRR) has the function of replenishing vital energy and can lighten the body and prolong the life when taken for a long time, which is suitable for the development of anti-aging products, so this paper intends to sort out the progress of anti-aging research on GRR. After combing, the results of modern studies have shown that a variety of components in GRR have anti-aging effect, which can prolong the lifespan of aging animal models, as well as delay the aging of various systems. The anti-aging mechanisms mainly include anti-cellular senescence, anti-oxidative stress, inhibiting telomere shortening, maintaining mitochondrial homeostasis and so on. The anti-aging ingredients of GRR involved in the researches mainly include ginsenoside Rg1 and ginsenoside Rb1, in addition, ginsenoside Rg3, ginsenoside Rd, ginsenoside Rg2, ginsenoside Re, ginsenoside Rb2, oligosaccharides of GRR, polysaccharides of GRR, water extract of GRR, total saponins of Panax ginseng stems and leaves are also included. Therefore, under current background of population aging, the in-depth development of GRR and its transformation into anti-aging products are of great significance for delaying senility and improving the health conditions of aging population.
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BACKGROUND:Mitochondrial quality control is a complex process,which involves three aspects:mitochondrial biogenesis,mitochondrial dynamics change and mitochondrial autophagy,among which mitochondrial dynamics change is the intermediate link between mitochondrial biogenesis and mitochondrial autophagy.Mitochondria can improve their own quality control through dynamics change and then maintain their stable state. OBJECTIVE:To explore the molecular mechanism underlying the influence of exercise on mitochondrial dynamics,so as to provide theoretical basis for improving mitochondrial network homeostasis and promoting functional health. METHODS:Using the method of literature review,CNKI,Bailianyun Library,PubMed,Web of Science,EBCSO were searched for relevant literature with the keywords of"Exercise,Mitochondrial Steady State,Mitochondrial Quality Control,Mitochondrial Dynamics,Mitochondrial Fusion and Mitochondrial Division"in Chinese and English.The finally obtained literature was screened,read,and summarized. RESULTS AND CONCLUSION:Dynamin-related proteins 1/2 are responsible for mitochondrial fission,while mitofusins 1/2 and optic atrophy type 1 mediate the fusion of outer membrane and inner mitochondrial membranes respectively.Exercise training can improve the function of mitochondria by up-regulating the protein expression of mitofusins 1/2 and optic atrophy type 1 and down-regulating the protein expression level of dynamin-related protein 1,promoting mitochondrial fusion and inhibiting mitochondrial fission.The findings that a single acute exercise affects changes in mitochondrial dynamics are controversial.Furthermore,there is tissue variability in exercise-mediated changes in mitochondrial dynamics.
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Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with complex and diverse pathogenesis, and there is no effective treatment or specific drugs for its clinical treatment. In recent years, its incidence has been on the rise, and it has become the earnest expectation of medical researchers in China and abroad that related patients could be treated. AMP-activated protein kinase (AMPK) functions to regulate cellular energy homeostasis and mitochondrial homeostasis. When activated, it has a good intervention effect on NAFLD progression with lipid metabolism disorders and mitochondrial homeostasis disorders. For NAFLD, the activation of AMPK can inhibit the production of new lipogenesis in the liver, promote the oxidation of fatty acids in the liver, and enhance the mitochondrial function of adipose tissues. As a key target of metabolic diseases, AMPK can also improve apoptosis, liver fibrosis, autophagy, and inflammation. Traditional Chinese medicine (TCM) is good at treating diseases from multiple targets and multiple pathways and is also commonly used in the treatment of chronic liver disease in clinical practice. A large number of in vitro and in vivo experimental studies on NAFLD have shown that TCM monomers have good prospects for the treatment of NAFLD through the AMPK signaling pathway, including glycosides, phenols, alkaloids, flavonoids, quinones, terpenoids, and lignans, which are natural activators of AMPK. This study reviewed the research progress on TCM monomers in regulating the AMPK pathway to prevent and treat NAFLD, providing a broader perspective for TCM treatment of NAFLD.
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This study aims to explore the neuroprotective mechanism of ginsenoside Re(GS-Re) on drosophila model of Parkinson's disease(PD) induced by rotenone(Rot). To be specific, Rot was used to induce PD in drosophilas. Then the drosophilas were grouped and respectively treated(GS-Re: 0.1, 0.4, 1.6 mmol·L~(-1); L-dopa: 80 μmol·L~(-1)). Life span and crawling ability of drosophilas were determined. The brain antioxidant activity [content of catalase(CAT), malondialdehyde(MDA), reactive oxygen species(ROS), superoxide dismutase(SOD)], dopamine(DA) content, and mitochondrial function [content of adenosine triphosphate(ATP), NADH:ubiquinone oxidoreductase subunit B8(NDUFB8) Ⅰ activity, succinate dehydrogenase complex, subunit B(SDHB) Ⅱ activity] were detected by enzyme-linked immunosorbent assay(ELISA). The number of DA neurons in the brains of drosophilas was measured with the immunofluorescence method. The levels of NDUFB8 Ⅰ, SDHB Ⅱ, cytochrome C(Cyt C), nuclear factor-E2-related factor 2(Nrf2), heme oxygenase-1(HO-1), B-cell lymphoma/leukemia 2(Bcl-2)/Bcl-2-assaciated X protein(Bax), and cleaved caspase-3/caspase-3 in the brain were detected by Western blot. The results showed that model group [475 μmol·L~(-1) Rot(IC_(50))] demonstrated significantly low survival rate, obvious dyskinesia, small number of neurons and low DA content in the brain, high ROS level and MDA content, low content of SOD and CAT, significantly low ATP content, NDUFB8 Ⅰ activity, and SDHB Ⅱ activity, significantly low expression of NDUFB8 Ⅰ, SDHB Ⅱ, and Bcl-2/Bax, large amount of Cyt C released from mitochondria to cytoplasm, low nuclear transfer of Nrf2, and significantly high expression of cleaved caspase-3/caspase-3 compared with the control group. GS-Re(0.1, 0.4, and 1.6 mmol·L~(-1)) significantly improved the survival rate of PD drosophilas, alleviated the dyskinesia, increased DA content, reduced the loss of DA neurons, ROS level, and MDA content in brain, improved content of SOD and CAT and antioxidant activity in brain, maintained mitochondrial homeostasis(significantly increased ATP content and activity of NDUFB8 Ⅰ and SDHB Ⅱ, significantly up-regulated expression of NDUFB8 Ⅰ, SDHB Ⅱ, and Bcl-2/Bax), significantly reduced the expression of Cyt C, increased the nuclear transfer of Nrf2, and down-regulated the expression of cleaved caspase-3/caspase-3. In conclusion, GS-Re can significantly relieve the Rot-induced cerebral neurotoxicity in drosophilas. The mechanism may be that GS-Re activates Keap1-Nrf2-ARE signaling pathway by maintaining mitochondrial homeostasis, improves antioxidant capacity of brain neurons, then inhibits mitochondria-mediated caspase-3 signaling pathway, and the apoptosis of neuronal cells, thereby exerting the neuroprotective effect.
Subject(s)
Animals , Reactive Oxygen Species/metabolism , Antioxidants/pharmacology , Oxidative Stress , NF-E2-Related Factor 2/metabolism , Caspase 3/metabolism , Parkinson Disease/genetics , bcl-2-Associated X Protein/metabolism , Neuroprotective Agents/pharmacology , Kelch-Like ECH-Associated Protein 1/metabolism , Drosophila/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Apoptosis , Superoxide Dismutase/metabolism , Adenosine Triphosphate/pharmacologyABSTRACT
OBJECTIVE@#To summarize the role of chondrocyte mitochondrial homeostasis imbalance in the pathogenesis of osteoarthritis (OA) and analyze its application prospects.@*METHODS@#The recent literature at home and abroad was reviewed to summarize the mechanism of mitochondrial homeostasis imbalance, the relationship between mitochondrial homeostasis imbalance and the pathogenesis of OA, and the application prospect in the treatment of OA.@*RESULTS@#Recent studies have shown that mitochondrial homeostasis imbalance, which is caused by abnormal mitochondrial biogenesis, the imbalance of mitochondrial redox, the imbalance of mitochondrial dynamics, and damaged mitochondrial autophagy of chondrocytes, plays an important role in the pathogenesis of OA. Abnormal mitochondrial biogenesis can accelerate the catabolic reaction of OA chondrocytes and aggravate cartilage damage. The imbalance of mitochondrial redox can lead to the accumulation of reactive oxygen species (ROS), inhibit the synthesis of extracellular matrix, induce ferroptosis and eventually leads to cartilage degradation. The imbalance of mitochondrial dynamics can lead to mitochondrial DNA mutation, decreased adenosine triphosphate production, ROS accumulation, and accelerated apoptosis of chondrocytes. When mitochondrial autophagy is damaged, dysfunctional mitochondria cannot be cleared in time, leading to ROS accumulation, which leads to chondrocyte apoptosis. It has been found that substances such as puerarin, safflower yellow, and astaxanthin can inhibit the development of OA by regulating mitochondrial homeostasis, which proves the potential to be used in the treatment of OA.@*CONCLUSION@#The mitochondrial homeostasis imbalance in chondrocytes is one of the most important pathogeneses of OA, and further exploration of the mechanisms of mitochondrial homeostasis imbalance is of great significance for the prevention and treatment of OA.
Subject(s)
Humans , Reactive Oxygen Species/metabolism , Chondrocytes/metabolism , Osteoarthritis/metabolism , Homeostasis , Mitochondria/metabolism , Cartilage, Articular/metabolismABSTRACT
Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.
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Objective:To investigate the effect of autophagy related gene Atg101 on white adipocyte senescence.Methods:An Atg101 knockdown model of 3T3-L1 mature adipocytes was constructed to probe the effect of Atg101 on autophagy-related proteins LC3 and p62 protein. The RNA-seq database of human subcutaneous adipose tissue was constructed and analyzed, and the co-expressed gene set was predicted based on the pearson correlation coefficient( R2>0.4, P<0.05) between FPKM values of Atg101 and other gene, followed by KEGG and Reactome enrichment analysis. Young mouse(8 weeks old) and old mouse(18 months old) models were established, and the expression levels of Atg101 in inguinal white adipose tissue and epididymal white adipose tissue were detected by quantitative real-time PCR(RT-qPCR) and Western blot. Furthermore, the differences in white adipocyte senescence-associated secretory phenotype(SASP), cell cycle and mitochondrial homeostasis-related genes were detected by RNA-seq, Western blot, and RT-qPCR to analyze the effects of Atg101 silencing on adipocyte senescence. Results:The autophagy-related protein LC3-Ⅱ expression was significantly decreased and p62 protein was induced after Atg101 was knockdowned in 3T3-L1 adipocytes, suggesting impaired cell autophagy. KEGG enrichment analysis revealed that Atg101 co-expressed gene set was mainly enriched in autophagy and senescence-related pathways; Reactome enrichment analysis revealed that this gene set was associated with multiple cell cycle signaling pathways. RT-qPCR and Western blot confirmed that both mRNA and protein levels of Atg101 were down-regulated in inguinal white adipose tissue of aging mice, and protein levels in epididymal white adipose tissue were also significantly reduced. Finally, it was further confirmed that SASP-related genes were induced after Atg101 knockdown in white adipocytes, and cell cycle-specific gene expression was restricted and cytokine-dependent protein kinase inhibitors p16 and p21 expressions were significantly increased, while mitochondrial homeostasis regulatory genes were also suppressed.Conclusions:Knockdown of Atg101 may regulate white adipocyte senescence by inhibiting autophagic activity, presenting impaired mitochondrial homeostasis.
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BACKGROUND: Myocardial fibrosis is an important topic in modern medical research, and its development is closely related to common heart diseases such as arrhythmia and chronic heart failure. Exercise intervention can significantly improve myocardial fibrosis, but there is no systematic and comprehensive understanding of the mechanism by which exercise improves myocardial fibrosis as well as the effects of different types of exercises on myocardial fibrosis. To date, it is still unclear about how exercise triggers the production of irisin against myocardial fibrosis. OBJECTIVE: To comprehensively review the exercise-induced production of irisin and its effect on myocardial fibrosis, and reveal its myocardial protection, so as to improve heart function and provide fundamental basis for preventing against common heart diseases, such as arrhythmia and chronic heart failure. METHODS: A search of ELSEVIER, Web of Science, CNKI, WanFanga, VIP and Taiwan Academic Literature Database was performed for articles regarding exercise, irisin, and myocardial fibrosis. The deadline for publication was August 2019. According to the inclusion and exclusion criteria, 58 articles were eligible for review. RESULTS AND CONCLUSION: Long-term and single exercise in human experiments has been shown to improve muscular and circulatory irisin levels, which has been better verified in animal experiments. A few experimental results indicate that long-term exercise has no significant effect on blood irisin levels, which may be due to different research subjects, exercise methods, exercise intensity, and exercise frequency. However, the specific mechanism is still unclear. Exercise can improve myocardial fibrosis by acting on myocardial mitochondrial stabilization, energy metabolism, oxidative stress and inflammatory response. The occurrence of myocardial fibrosis results from the regulation of neuroendocrine and oxidative stress and inflammatory responses. Irisin can influence the processes of oxidative stress and inflammation related to the mechanism of myocardial fibrosis, by inhibiting ROS/p38MAPK/NF-κB signaling pathway, endogenous reactive oxygen species and ROS-NLRP3 inflammation signaling pathway, and regulating the expression of uncoupling protein 2 and mitochondrial homeostasis. Therefore, exercise may improve myocardial fibrosis by upregulating the expression of irisin, thus providing myocardial protection.
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This study was designed to investigate the effect and mechanism of astragaloside IV (ASIV) on mitochondrial morphology and function of rat cardiomyocytes under hypoxia/reoxygenation injury. H9c2 cells were divided into control group, hypoxia/reoxygenation (H/R) group, and H/R + ASIV group. Cell viability and lactate dehydrogenase (LDH) leakage were measured by cell counting kit-8 (CCK-8) and LDH assay kit, respectively. Oxidative stress levels, such as superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA), were analyzed by commercial kits. Intracellular and mitochondrial reactive oxygen species (ROS) levels were detected by dihydroethidium (DHE) and MitoSOX. Changes of the mitochondrial membrane potential were detected using the fluorescent probe JC-1. Opening of mitochondrial permeability transition pore was examined via calcein acetoxymethyl ester (calcein-AM). Apoptosis was assessed using terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay kit. To detect protein expression of dynamin-related protein 1 (Drp1), mitofusin1 (Mfn1), Mfn2, Bax, B-cell lymphoma-2 (Bcl-2), and cleaved cysteine-aspartic protease (caspase)-3, Western blot analysis was carried out. Compared with the control group, ASIV (100 μmol·L-1) significantly improved H/R induced cell injury, LDH leakage, decrease of SOD activity, and GSH content, increase of MDA content and ROS content, loss of mitochondrial membrane potential, mitochondrial permeability transition pore opening, ROS production activation, mitochondrial fission/fusion imbalance, and cell apoptosis. In addition, the effect of ASIV against H/R injury was also verified on primary rat cardiomyocytes. The animal welfare and experimental process follow the rules of Animal Ethics Committee of Zhejiang Chinese Medical University. In conclusion, ASIV may play a protective role in mitochondria by regulating morphological dynamic stability and mitochondrial function, inhibiting excessive synthesis of ROS, improving the internal environment of oxidative stress, reducing cell apoptosis, and thereby protecting against cardiomyocytes’ hypoxia/reoxygenation injury.
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Septic cardiomyopathy is a common complication in severe sepsis and septic shock,mito‐chondrial function injury is one of the main aspects of its pathogenesis. The heart is a continuous power or‐gan,needs a lot of ATP to maintain normal systolic and diastolic function. Mitochondrial as the main ATP producing organelles,accounts for about one third of the myocardial volume,which being damaged will be harmful to the myocardial energy supply and cardiac function. This paper introduced the latest research pro‐gress of mitochondrial damage in septic cardiomyopathy,including mitochondrial NO production increase and oxidative stress,Ca2+ overload and mitochondrial membrane permeability increase,mitochondrial uncoupling and mitochondrial homeostasis,also discussed the potential treatments.
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Objective To investigated the different effect of moderate-intensity continuous training (MCT) and high-intensity interval exercise training (HIT) on ventricular remodeling and mitochondrial homeostasis after acute myocardial infarction (AMI).Methods The AMI rat model was achieved by ligating coronary artery.The AMI and sham operation rats were randomly (random number) divided into four groups:sham operation group (Sham),AMI control group (AMI),AMI MCT group (AMI + M),and AMI HIT group (AMI + H).Animals in the AMI + M and AMI + H groups underwent 4 weeks MCT and HIT respectively.Five weeks after AMI,hemodynamic changes,mitochondrial bioenergetics,and PINK1,Beclinl,Mfn2,Drp1,Tfam,COXⅣ,PGC-1α were detected.Results Comparing with AMI group,in AMI + M and AMI + H groups,Beclin1,PINK1,Mfn2 and PGC-1α expression elevated significantly (P <0.05 or P <0.01),whereas ROS generation and Drp1 expression showed dramatic decrease (P < 0.05 or P<0.01).In addition,in AMI + H group,±dp/dt max,mitochondrial membrane potential,ATP synthesis activity,Tfam and COXⅣ expression improved significantly (P < 0.05).Comparing with AMI + M group,in AMI + H group,± dp/dt max,PGC-1α,Tfam and COX Ⅳ expression improved significantly (P < 0.05).Conclusions HIT is superior to MCT for ameliorating ventricular remodeling and mitochondrial homeostasis after AMI.
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Mitochondrial dysfunction plays an important role in the process of PD, DJ-1 participates in regulating the function of mitochondria,which has an effect on the protection of mitochon-dria. DJ-1 mutations can lead to the decrease of the activity of mitochondrial complex Ⅰ, the decrease of mitochondrial mem-brane potential and then mitochondrial fragmention and mitoph-agy, and then further damage neurons and trigger PD. This re-view presents the role of DJ-1 in regulating the function of the mitochondria in the pathogenesis of Parkinson's disease(PD).