Many approaches to neurodegenerative diseases that focus on amyloid-βclearance and gene therapy have not been successful.Some therapeutic applications focus on enhancing neuronal cell survival during the pathogenesis...Many approaches to neurodegenerative diseases that focus on amyloid-βclearance and gene therapy have not been successful.Some therapeutic applications focus on enhancing neuronal cell survival during the pathogenesis of neurodegenerative diseases,including mitochondrial dysfunction.Plasma membrane(PM)redox enzymes are crucial in maintaining cellular physiology and redox homeostasis in response to mitochondrial dysfunction.Neurohormetic phytochemicals are known to induce the expression of detoxifying enzymes under stress conditions.In this study,mechanisms of neuroprotective effects of 4-hydroxycinnamic acid(HCA)were examined by analyzing cell survival,levels of abnormal proteins,and mitochondrial functions in two different neuronal cells.HCA protected two neuronal cells exhibited high expression of PM redox enzymes and the consequent increase in the NAD^(+)/NADH ratio.Cells cultured with HCA showed delayed apoptosis and decreased oxidative/nitrative damage accompanied by decreased ROS production in the mitochondria.HCA increased the mitochondrial complexes I and II activities and ATP production.Also,HCA increased mitochondrial fusion and decreased mitochondrial fission.Overall,HCA maintains redox homeostasis and energy metabolism under oxidative/metabolic stress conditions.These findings suggest that HCA could be a promising therapeutic approach for neurodegenerative diseases.展开更多
Objective:To investigate the effect of abnormal ovarian granulosa cell metabolism on in vitro fertilization and embryo transfer(IVF-ET)outcomes in obese polycystic ovary syndrome(PCOS)patients.Methods:Patients with PC...Objective:To investigate the effect of abnormal ovarian granulosa cell metabolism on in vitro fertilization and embryo transfer(IVF-ET)outcomes in obese polycystic ovary syndrome(PCOS)patients.Methods:Patients with PCOS who met the study criteria were screened according to the inclusion criteria.A total of 32 patients with obese PCOS were recruited into the study group,and 39 patients with non-obese PCOS were recruited into the control group.The general data(age,body mass index,and years of infertility),insulin resistance index(HOMA-IR),follicle-stimulating hormone(FSH),luteinizing hormone(LH),granulosa cell mitochondrial function,and IVF-ET outcome of patients in the study group and control group were retrospectively analyzed.Results:The differences in age and years of infertility between the study group and the control group were insignificant(P>0.05),and the body mass index(BMI)of the study group and control group was 30.5±1.24 kg/m2 and 22.3±1.12 kg/m2,respectively,in which the difference was statistically significant(P<0.05);the HOMA-IR of the study group was significantly higher than that of the control group(P<0.05);the reactive oxygen species(ROS)in the study group was significantly higher than that in the control group(P<0.05),and the ATP content in the study group was significantly lower than that in the control group(P<0.05);comparing the FSH and LH levels between the two groups,the difference was not statistically significant(P>0.05);the rate of IVF-ET failure was significantly higher in the study group than in the control group.Conclusion:PCOS is a complex endocrine disorder,and obesity is one of the independent risk factors for the development of PCOS.展开更多
Background:The objective of this experiment was to investigate the influence of dietary tributyrin on intestinal mucosa development,oxidative stress,mitochondrial function and AMPK-mTOR signaling pathway.Methods:Seven...Background:The objective of this experiment was to investigate the influence of dietary tributyrin on intestinal mucosa development,oxidative stress,mitochondrial function and AMPK-mTOR signaling pathway.Methods:Seventy-two pigs were divided into two treatments and received either a basal diet or the same diet supplemented with 750 mg/kg tributyrin.Each treatment has six replicates of six pigs.After 14 days,6 pigs from each treatment were selected and the jejunal samples were collected.Results:Results showed that supplemental tributyrin increased(P<0.05)villus height and villus height:crypt depth of weaned pigs.Pigs fed tributyrin had greater(P<0.05)RNA/DNA and protein/DNA ratios than pigs on the control group.The mRNA levels of sodium glucose transport protein-1 and glucose transporter-2 in the jejunum were upregulated(P<0.05)in pigs fed the tributyrin diet.Dietary tributyrin supplementation lowered(P<0.05)the malondialdehyde and hydrogen peroxide(H2O2)content in jejunum,enhanced(P<0.05)the mitochondrial function,as demonstrated by decreased(P<0.05)reactive oxygen species level and increased(P<0.05)mitochondrial membrane potential.Furthermore,tributyrin increased(P<0.05)mitochondrial DNA content and the mRNA abundance of genes related to mitochondrial functions,including peroxisomal proliferator-activated receptor-γcoactivator-1α,mitochondrial transcription factor A,nuclear respiratory factor-1 in the jejunum.Supplementation with tributyrin elevated(P<0.05)the phosphorylation level of AMPK and inhibited(P<0.05)the phosphorylation level of mTOR in jejunum compared with the control group.Conclusions:These findings suggest that dietary supplementation with tributyrin promotes intestinal mucosa growth,extenuates oxidative stress,improves mitochondrial function and modulates the AMPK-mTOR signal pathway of weaned pigs.展开更多
Mitochondrial dysfunction and endoplasmic reticulum stress(ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide(NO) is a multifunctional biomolecule with many varieties...Mitochondrial dysfunction and endoplasmic reticulum stress(ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide(NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca^(2+) flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstratedthe need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.展开更多
The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activator...The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activators of liver X receptors(LXRs),via sterol 27-hydroxylase,is regulated by the rate of flux of cholesterolto the inner mitochondrial membrane,via a complex of cholesterol trafficking proteins.Oxysterols are key signalling molecules,regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production,key features influencing the impact of these cells within atherosclerotic lesions.The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate,but may include steroidogenic acute regulatory protein and translocator protein.There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters(ABCA1,ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages.Thus,molecules which can sustain or improve mitochondrial structure,the function of the electron transport chain,or increase the activity of components of the protein complex involved in cholesterol transfer,may therefore have utility in limiting or regressing atheroma development,reducing the incidence of coronary heart disease and myocardial infarction.展开更多
OBJECTIVE Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens.Recent studies have shown that the imbalance of mitochondrial dynamics ...OBJECTIVE Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens.Recent studies have shown that the imbalance of mitochondrial dynamics was associated with the increased reactive oxygen species(ROS)production in endothelial cells,which is a significant contributor to the microvascular complications of diabetes.The present study was designed to determine the involvement of transcription factor FOXO1in diabetic wound healing and investigate underlying mechanisms.METHODS&RESULTS Impaired mitochondrial networks and increased phosphorylation of dynaminrelated protein-1(Drp1)at ser616,a protein required for mitochondrial fission,were observed in human umbilical vein endothelial cells(HUVECs)24 h after exposure to high concentrations of glucose.Inhibition of FOXO1 by si RNA or by FOXO1 selective inhibitor AS1842856 abrogated high glucos-induced alterations in mitochondrial networks and phosphorylation of Drp1.Treatment with AS1842856 or si RNA of FOXO1 could significantly increase the mitochondrial membrane potential and suppress the overproduction of ROS induced by high glucose.Addition of AS1842856 inhibited glucoseinduced apoptosis,ameliorated capillary tube formation in HUVECs.In vivo,AS1842856 dose-dependently rescued the delay of wound closure in diabetic mice,and5 mg·kg-1of AS1842856 treatment significantly increased the mean perfusion rate.CONCLUSION These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and function in endothelial cells,inhibition of FOXO1 rescued the delayed wound healing and improved wound angiogenesis in diabetic mice.展开更多
3′-Daidzein sulfonate sodium is a new synthetic water-soluble compound derived from daidzein(an active ingredient of the kudzu vine root). It has been shown to have a protective effect on cerebral ischemia/reperfusio...3′-Daidzein sulfonate sodium is a new synthetic water-soluble compound derived from daidzein(an active ingredient of the kudzu vine root). It has been shown to have a protective effect on cerebral ischemia/reperfusion injury in rats. We plan to study the mechanism of its protective effect. 3′-Daidzein sulfonate sodium was injected in rats after cerebral ischemia/reperfusion injury. Results showed that 3′-daidzein sulfonate sodium significantly reduced mitochondrial swelling, significantly elevated the mitochondrial membrane potential, increased mitochondrial superoxide dismutase and glutathione peroxidase activities, and decreased mitochondrial malondialdehyde levels. 3′-Daidzein sulfonate sodium improved the structural integrity of the blood-brain barrier and reduced blood-brain barrier permeability. These findings confirmed that 3′-daidzein sulfonate sodium has a protective effect on mitochondrial functions after cerebral ischemia/reperfusion injury, improves brain energy metabolism, and provides protection against blood-brain barrier damage.展开更多
Objective:The recent advent of flow cytometry(FCM),coupled with fluorescent dyes,has been successfully applied to assess mitochondrial function.The aim of this study was to investigate the feasibility and clinical sig...Objective:The recent advent of flow cytometry(FCM),coupled with fluorescent dyes,has been successfully applied to assess mitochondrial function.The aim of this study was to investigate the feasibility and clinical significance of detecting sperm mitochondrial function and to evaluate sperm mitochondrial function by using Rhodamine 123/propidium(Rh123/PI)dual fluorescent staining and FCM in asthenospermia and oligoasthenozoospermia.Methods:Twenty-five fertile men(with normal sperm parameters)and 230 infertile patients were examined.Fifty-five patients of the above 230 patients were selected for idiopathic infertility samples and were divided into two groups:asthenospermia(n=30)and oligoasthenozoospermia(n=25).Rh123/PI dual fluorescent staining and FCM were carried out to examine sperm mitochondrial function.Results:Significant differences were found between the normal and abnormal semen samples(P<0.05)when Rh123+/PI-,Rh123-/PI+and Rh123-/PI-sperm were examined by FCM,but there was no significant difference between the asthenospermia(P=0.469) and oligoasthenozoospermia group(P=0.950)when Rh123+/PI-and Rh123-/PI+sperm were then examined;however,a significant difference was found between the 2 groups(P=0.003)when Rh123-/PI-sperm were examined.There was no correlation between Rh123-/PI-sperm and semen parameters in the normal group,but there was a significant negative correlation between the sperm concentration and Rh123-/PI-sperm in asthenospermia and oligoasthenozoospermia patients(r=-0.509,-0.660;P=0.018,0.038).Conclusion:Rh123/PI dual fluorescent staining and FCM can provide reliable information to assess the quality of sperm and reveal differences in mitochondrial membrane potential in asthenospermia and oligoasthenozoospermia.展开更多
Mitochondrial function affected lipids metabolism.However,studies examining the nervous system have primarily focused on metabolism of glucose and have largely neglected to examine the metabolism of fatty acids.We inv...Mitochondrial function affected lipids metabolism.However,studies examining the nervous system have primarily focused on metabolism of glucose and have largely neglected to examine the metabolism of fatty acids.We investigated the effects of angiotensin-converting enzyme 2(ACE2)on mitochondrial function in DRG neuron lipid meta'bolism.The expression of long chain acyl-CoA synthetase(ACSL1-6)and genes related to mitochondrial function in DRGs of ACE2 knockout mice and Ad-ACE2-treated chronic constriction injury(CCI)rats were analyzed by q-PCR.Under the same condition,the lipid peroxide(LPO)content,fatty acid content.展开更多
Osteoporosis(OP)is a metabolic bone disease characterized by decreased bone mass,reduced bone density,and destruction of bone microstructures,which resulting in an increased brittleness and susceptibility to fractures...Osteoporosis(OP)is a metabolic bone disease characterized by decreased bone mass,reduced bone density,and destruction of bone microstructures,which resulting in an increased brittleness and susceptibility to fractures.The incidence of osteoporosis is associated with aging and some genetical and physiology abnormalities.With the accelerated growth of aged population in China,a large group of population has reduced bone density.The mid-aged and senior people are highly susceptible to osteoporosis.While some young people who have irregular dietary schedule and unhealthy life style might cause increased rate of osteoporosis.Signal transducers and activators of transcription 3(STAT3)is a transcription factor ubiquitously expressed in somatic and stem cells such as tumor cells,mesenchymal stem cells,osteoblasts,osteoclasts and osteocytes.STAT3 is involved in the regulation of cell proliferation differentiation,apoptosis,and other physiological functions.The results of relevant animal experiments and clinical trials showed that abnormal expression of STAT3 would affect normal bone development.展开更多
Aim: To study the mitochondrial function damage of sperm in-duced by reactive oxygen species (ROS) and the protection of melatonin (MLT) against the damage. Methods: Normal function spermatozoa were selected from seme...Aim: To study the mitochondrial function damage of sperm in-duced by reactive oxygen species (ROS) and the protection of melatonin (MLT) against the damage. Methods: Normal function spermatozoa were selected from semen samples by Percoll gradi-ent centrifugation technique. The ROS generated by the hypoxan-thine xanthine oxidase system was incubated with the normal sper-matozoa in the presence or absence of MLT (6 retool/L) for 30 and 60 minutes.展开更多
The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow.Mitochondria are directly affected by direct facto...The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow.Mitochondria are directly affected by direct factors such as ischemia,hypoxia,excitotoxicity,and toxicity of free hemoglobin and its degradation products,which trigger mitochondrial dysfunction.Dysfunctional mitochondria release large amounts of reactive oxygen species,inflammatory mediators,and apoptotic proteins that activate apoptotic pathways,further damaging cells.In response to this array of damage,cells have adopted multiple mitochondrial quality control mechanisms through evolution,including mitochondrial protein quality control,mitochondrial dynamics,mitophagy,mitochondrial biogenesis,and intercellular mitochondrial transfer,to maintain mitochondrial homeostasis under pathological conditions.Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage.This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage,particularly mitochondrial quality control mechanisms.It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.展开更多
DearEditor,Brain aging is associated with a decrease in cognitive function,which is often accompanied by defective changes in mitochondrial morphology and reduction in mitochondrial function(Faitg et al.,2021).The mai...DearEditor,Brain aging is associated with a decrease in cognitive function,which is often accompanied by defective changes in mitochondrial morphology and reduction in mitochondrial function(Faitg et al.,2021).The main function of mitochondria is to produce energy in the form of ATP,which is vital to fulfill high energy demand of neurons,mainly for synaptic processes(Lee et al.,2018).Mitochondrial dysfunction acts as a key factor for age-related cognitive decline(Grimm and Eckert,2017).展开更多
Mitochondria undergo morphological changes during spermatogenesis in some animals.The mechanism and role of mitochondrial morphology regulation,however,remain somewhat unclear.In this study,we analyzed the molecular c...Mitochondria undergo morphological changes during spermatogenesis in some animals.The mechanism and role of mitochondrial morphology regulation,however,remain somewhat unclear.In this study,we analyzed the molecular characteristics,expression dynamics and subcellular localization of optic atrophy protein 1(OPA1),a mitochondrial fusion and cristae maintenance-related protein,to reveal the possible regulatory mechanisms underlying mitochondrial morphology in Phascolosoma esculenta spermiogenesis.The full-length cDNA of the P.esculenta opa1 gene(Pe-opa1)is 3743 bp in length and encodes 975 amino acids.The Pe-OPA1 protein is highly conservative and includes a transmembrane domain,a GTPase domain,two helical bundle domains,and a lipid-interacting stalk.Gene and protein expression was higher in the coelomic fluid(a site of spermatid development)of male P.esculenta and increased first and then decreased from March to December.Moreover,their expression during the breeding stage was significantly higher than during the non-breeding stage,suggesting that Pe-OPA1 is involved in P.esculenta reproduction.The Pe-OPA1 protein was more abundant in components consisting of many spermatids than in components without,indicating that Pe-OPA1 mainly plays a role in the spermatid in coelomic fluid.Moreover,Pe-OPA1 was mainly detected in the spermatid mitochondria.Immunofluorescence experiments showed that the Pe-OPA1 are constitutively expressed and co-localized with mitochondria during spermiogenesis,suggesting its involvement in P.esculenta spermiogenesis.These results provide evidence for Pe-OPA1's involvement in the regulation of mitochondrial morphology during spermiogenesis.展开更多
BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against...BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.展开更多
Background During the transition period,the insufficient dry matter intake and a sharply increased in energy consumption to produce large quantities of milk,high yielding cows would enter a negative energy balance(NEB...Background During the transition period,the insufficient dry matter intake and a sharply increased in energy consumption to produce large quantities of milk,high yielding cows would enter a negative energy balance(NEB)that causes an increase in ketone bodies(KBs)and decrease in reproduction efficiency.The excess concentrations of circulating KBs,represented byβ-hydroxybutyric acid(BHBA),could lead to oxidative damage,which potentially cause injury to follicular granulosa cells(fGCs)and delayed follicular development.Sirtuin 3(Sirt3)regulates mitochondria reactive oxygen species(mitoROS)homeostasis in a beneficial manner;however,the molecular mechanisms underlying its involvement in the BHBA-induced injury of fGCs is poorly understood.The aim of this study was to explore the protection effects and underlying mechanisms of Sirt3 against BHBA overload-induced damage of fGCs.Results Our findings demonstrated that 2.4 mmol/L of BHBA stress increased the levels of mitoROS in bovine fGCs.Further investigations identified the subsequent mitochondrial dysfunction,including an increased abnormal rate of mitochondrial architecture,mitochondrial permeability transition pore(MPTP)opening,reductions in mitochondrial membrane potential(MMP)and Ca^(2+)release;these dysfunctions then triggered the caspase cascade reaction of apoptosis in fGCs.Notably,the overexpression of Sirt3 prior to treatment enhanced mitochondrial autophagy by increasing the expression levels of Beclin-1,thus preventing BHBA-induced mitochondrial oxidative stress and mitochondrial dysfunction in fGCs.Furthermore,our data suggested that the AMPK-mTOR-Beclin-1 pathway may be involved in the protective mechanism of Sirt3 against cellular injury triggered by BHBA stimulation.Conclusions These findings indicate that Sirt3 protects fGCs from BHBA-triggered injury by enhancing autophagy,attenuating oxidative stress and mitochondrial damage.This study provides new strategies to mitigate the fGCs injury caused by excessive BHBA stress in dairy cows with ketosis.展开更多
Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Ac...Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.展开更多
The aim of this study was to investigate whether punicalagin(PU)could prevent obesity-related cardiac dysfunction by promoting DNA demethy lation,and to explore its possible mechanism.C57BL/6J mice were fed with stand...The aim of this study was to investigate whether punicalagin(PU)could prevent obesity-related cardiac dysfunction by promoting DNA demethy lation,and to explore its possible mechanism.C57BL/6J mice were fed with standard diet,high-fat diet(HFD),HFD supplemented with resveratrol,low-dose PU(LPU)and high-dose PU(HPU)for 8 weeks.Compared with HFD group,body weight was significantly lower in PU treatment groups,number of cardionwocytes and the protein level of myosin heavy chain 7B were significantly higher in PU treatment groups.Levels of 5-hydroxymethylcytosine and 5-formylcytosine were significantly lower in HFD group than in other groups.Compared with the HFD group,the protein level of ten-eleven translocation enzyme(TET)2 was significantly higher in PU treatment groups,p-AMP-activated protein kinase(AMPK)was significantly higher in LPU group.Levels of total antioxidant capacity and the protein levels of complexesⅡ/Ⅲ/Ⅴ,oxoglutarate dehydrogenase,succinate dehydrogenase B and fumarate hdrolase were significantly lower in HFD group than PU treatment group.The ratio of(succinic acid+fumaric acid)/a-ketoglutarate was significantly higher in HFD group than other groups.In conclusion,PU up-regulated TETs enzyme activities and TET2 protein stability through alleviating mitochondrial dysfunction and activating AMPK,so as to promote DNA demethylation,thus preventing obesity-related cardiac dysfunction.展开更多
基金supported by the National Research Foundation of Korea(NRF)of the Korean Government(NRF-2021R1F1A1051212)by Logsynk Co.Ltd.(2-2021-1435-001).
文摘Many approaches to neurodegenerative diseases that focus on amyloid-βclearance and gene therapy have not been successful.Some therapeutic applications focus on enhancing neuronal cell survival during the pathogenesis of neurodegenerative diseases,including mitochondrial dysfunction.Plasma membrane(PM)redox enzymes are crucial in maintaining cellular physiology and redox homeostasis in response to mitochondrial dysfunction.Neurohormetic phytochemicals are known to induce the expression of detoxifying enzymes under stress conditions.In this study,mechanisms of neuroprotective effects of 4-hydroxycinnamic acid(HCA)were examined by analyzing cell survival,levels of abnormal proteins,and mitochondrial functions in two different neuronal cells.HCA protected two neuronal cells exhibited high expression of PM redox enzymes and the consequent increase in the NAD^(+)/NADH ratio.Cells cultured with HCA showed delayed apoptosis and decreased oxidative/nitrative damage accompanied by decreased ROS production in the mitochondria.HCA increased the mitochondrial complexes I and II activities and ATP production.Also,HCA increased mitochondrial fusion and decreased mitochondrial fission.Overall,HCA maintains redox homeostasis and energy metabolism under oxidative/metabolic stress conditions.These findings suggest that HCA could be a promising therapeutic approach for neurodegenerative diseases.
基金Baoding Science and Technology Program Project(Grant No.2241ZF120)Hebei Health Care Commission Scientific Research Funding Project(Grant No.20170827)+1 种基金Funding Project of Affiliated Hospital of Hebei University(Grant No.2016Q016)Funding Project of Affiliated Hospital of Hebei University(No.2022QC66).
文摘Objective:To investigate the effect of abnormal ovarian granulosa cell metabolism on in vitro fertilization and embryo transfer(IVF-ET)outcomes in obese polycystic ovary syndrome(PCOS)patients.Methods:Patients with PCOS who met the study criteria were screened according to the inclusion criteria.A total of 32 patients with obese PCOS were recruited into the study group,and 39 patients with non-obese PCOS were recruited into the control group.The general data(age,body mass index,and years of infertility),insulin resistance index(HOMA-IR),follicle-stimulating hormone(FSH),luteinizing hormone(LH),granulosa cell mitochondrial function,and IVF-ET outcome of patients in the study group and control group were retrospectively analyzed.Results:The differences in age and years of infertility between the study group and the control group were insignificant(P>0.05),and the body mass index(BMI)of the study group and control group was 30.5±1.24 kg/m2 and 22.3±1.12 kg/m2,respectively,in which the difference was statistically significant(P<0.05);the HOMA-IR of the study group was significantly higher than that of the control group(P<0.05);the reactive oxygen species(ROS)in the study group was significantly higher than that in the control group(P<0.05),and the ATP content in the study group was significantly lower than that in the control group(P<0.05);comparing the FSH and LH levels between the two groups,the difference was not statistically significant(P>0.05);the rate of IVF-ET failure was significantly higher in the study group than in the control group.Conclusion:PCOS is a complex endocrine disorder,and obesity is one of the independent risk factors for the development of PCOS.
基金National Natural Science Foundation of China(31872387)Zhejiang Provincial Natural Science Foundation(Sodium butyrate promotes restoration of intestinal barrier induced by oxidative stress in piglets through AMPK mediated mitophagy)and Zhejiang Provincal Key R&D Project(2019C02051).
文摘Background:The objective of this experiment was to investigate the influence of dietary tributyrin on intestinal mucosa development,oxidative stress,mitochondrial function and AMPK-mTOR signaling pathway.Methods:Seventy-two pigs were divided into two treatments and received either a basal diet or the same diet supplemented with 750 mg/kg tributyrin.Each treatment has six replicates of six pigs.After 14 days,6 pigs from each treatment were selected and the jejunal samples were collected.Results:Results showed that supplemental tributyrin increased(P<0.05)villus height and villus height:crypt depth of weaned pigs.Pigs fed tributyrin had greater(P<0.05)RNA/DNA and protein/DNA ratios than pigs on the control group.The mRNA levels of sodium glucose transport protein-1 and glucose transporter-2 in the jejunum were upregulated(P<0.05)in pigs fed the tributyrin diet.Dietary tributyrin supplementation lowered(P<0.05)the malondialdehyde and hydrogen peroxide(H2O2)content in jejunum,enhanced(P<0.05)the mitochondrial function,as demonstrated by decreased(P<0.05)reactive oxygen species level and increased(P<0.05)mitochondrial membrane potential.Furthermore,tributyrin increased(P<0.05)mitochondrial DNA content and the mRNA abundance of genes related to mitochondrial functions,including peroxisomal proliferator-activated receptor-γcoactivator-1α,mitochondrial transcription factor A,nuclear respiratory factor-1 in the jejunum.Supplementation with tributyrin elevated(P<0.05)the phosphorylation level of AMPK and inhibited(P<0.05)the phosphorylation level of mTOR in jejunum compared with the control group.Conclusions:These findings suggest that dietary supplementation with tributyrin promotes intestinal mucosa growth,extenuates oxidative stress,improves mitochondrial function and modulates the AMPK-mTOR signal pathway of weaned pigs.
基金Supported by Ministerio de Ciencia E Innovación-Bernat Soria-Innpacto Proyect,No.IPT-2011-1615-900000Instituto de Salud Carlos III,Gobierno de Espana-Bernat Soria,No.TERCEL RD06/0010/0025+1 种基金Consejeria de Salud Junta de Andalucia-Francisco Javier Bedoya Bergua,No.PI-0105-2010Consejeria de Economia Innovación Ciencia y Empleo-Junta de Andalucia-Francisco Javier Bedoya,No.CTS-7127/2011.
文摘Mitochondrial dysfunction and endoplasmic reticulum stress(ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide(NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca^(2+) flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstratedthe need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.
文摘The aim of this review is to explore the role of mitochondria in regulating macrophage sterol homeostasis and inflammatory responses within the aetiology of atherosclerosis.Macrophage generation of oxysterol activators of liver X receptors(LXRs),via sterol 27-hydroxylase,is regulated by the rate of flux of cholesterolto the inner mitochondrial membrane,via a complex of cholesterol trafficking proteins.Oxysterols are key signalling molecules,regulating the transcriptional activity of LXRs which coordinate macrophage sterol metabolism and cytokine production,key features influencing the impact of these cells within atherosclerotic lesions.The precise identity of the complex of proteins mediating mitochondrial cholesterol trafficking in macrophages remains a matter of debate,but may include steroidogenic acute regulatory protein and translocator protein.There is clear evidence that targeting either of these proteins enhances removal of cholesterol via LXRα-dependent induction of ATP binding cassette transporters(ABCA1,ABCG1) and limits the production of inflammatory cytokines; interventions which influence mitochondrial structure and bioenergetics also impact on removal of cholesterol from macrophages.Thus,molecules which can sustain or improve mitochondrial structure,the function of the electron transport chain,or increase the activity of components of the protein complex involved in cholesterol transfer,may therefore have utility in limiting or regressing atheroma development,reducing the incidence of coronary heart disease and myocardial infarction.
基金The project supported by National Natural Science Foundation of China(81373405,30901803)Beijing Higher Education Young Elite Teacher Project(YETP0053)
文摘OBJECTIVE Refractory wounds in diabetic patients constitute a serious complication that often leads to amputation with limited treatment regimens.Recent studies have shown that the imbalance of mitochondrial dynamics was associated with the increased reactive oxygen species(ROS)production in endothelial cells,which is a significant contributor to the microvascular complications of diabetes.The present study was designed to determine the involvement of transcription factor FOXO1in diabetic wound healing and investigate underlying mechanisms.METHODS&RESULTS Impaired mitochondrial networks and increased phosphorylation of dynaminrelated protein-1(Drp1)at ser616,a protein required for mitochondrial fission,were observed in human umbilical vein endothelial cells(HUVECs)24 h after exposure to high concentrations of glucose.Inhibition of FOXO1 by si RNA or by FOXO1 selective inhibitor AS1842856 abrogated high glucos-induced alterations in mitochondrial networks and phosphorylation of Drp1.Treatment with AS1842856 or si RNA of FOXO1 could significantly increase the mitochondrial membrane potential and suppress the overproduction of ROS induced by high glucose.Addition of AS1842856 inhibited glucoseinduced apoptosis,ameliorated capillary tube formation in HUVECs.In vivo,AS1842856 dose-dependently rescued the delay of wound closure in diabetic mice,and5 mg·kg-1of AS1842856 treatment significantly increased the mean perfusion rate.CONCLUSION These findings suggested that FOXO1 is critical to preserve mitochondrial quantity and function in endothelial cells,inhibition of FOXO1 rescued the delayed wound healing and improved wound angiogenesis in diabetic mice.
基金supported by the National Natural Science Foundation of China,No.81160399,81560583the Science and Technology Landing Project of China,No.KJLD13085the Science and Technology Project of the Education Department of Jiangxi Province of China,No.GJJ12560
文摘3′-Daidzein sulfonate sodium is a new synthetic water-soluble compound derived from daidzein(an active ingredient of the kudzu vine root). It has been shown to have a protective effect on cerebral ischemia/reperfusion injury in rats. We plan to study the mechanism of its protective effect. 3′-Daidzein sulfonate sodium was injected in rats after cerebral ischemia/reperfusion injury. Results showed that 3′-daidzein sulfonate sodium significantly reduced mitochondrial swelling, significantly elevated the mitochondrial membrane potential, increased mitochondrial superoxide dismutase and glutathione peroxidase activities, and decreased mitochondrial malondialdehyde levels. 3′-Daidzein sulfonate sodium improved the structural integrity of the blood-brain barrier and reduced blood-brain barrier permeability. These findings confirmed that 3′-daidzein sulfonate sodium has a protective effect on mitochondrial functions after cerebral ischemia/reperfusion injury, improves brain energy metabolism, and provides protection against blood-brain barrier damage.
基金supported by the program of The Project Supported by Natural Science Basic Research Plan in Shaanxi Province of China(No.SJ08-ZD05)
文摘Objective:The recent advent of flow cytometry(FCM),coupled with fluorescent dyes,has been successfully applied to assess mitochondrial function.The aim of this study was to investigate the feasibility and clinical significance of detecting sperm mitochondrial function and to evaluate sperm mitochondrial function by using Rhodamine 123/propidium(Rh123/PI)dual fluorescent staining and FCM in asthenospermia and oligoasthenozoospermia.Methods:Twenty-five fertile men(with normal sperm parameters)and 230 infertile patients were examined.Fifty-five patients of the above 230 patients were selected for idiopathic infertility samples and were divided into two groups:asthenospermia(n=30)and oligoasthenozoospermia(n=25).Rh123/PI dual fluorescent staining and FCM were carried out to examine sperm mitochondrial function.Results:Significant differences were found between the normal and abnormal semen samples(P<0.05)when Rh123+/PI-,Rh123-/PI+and Rh123-/PI-sperm were examined by FCM,but there was no significant difference between the asthenospermia(P=0.469) and oligoasthenozoospermia group(P=0.950)when Rh123+/PI-and Rh123-/PI+sperm were then examined;however,a significant difference was found between the 2 groups(P=0.003)when Rh123-/PI-sperm were examined.There was no correlation between Rh123-/PI-sperm and semen parameters in the normal group,but there was a significant negative correlation between the sperm concentration and Rh123-/PI-sperm in asthenospermia and oligoasthenozoospermia patients(r=-0.509,-0.660;P=0.018,0.038).Conclusion:Rh123/PI dual fluorescent staining and FCM can provide reliable information to assess the quality of sperm and reveal differences in mitochondrial membrane potential in asthenospermia and oligoasthenozoospermia.
文摘Mitochondrial function affected lipids metabolism.However,studies examining the nervous system have primarily focused on metabolism of glucose and have largely neglected to examine the metabolism of fatty acids.We investigated the effects of angiotensin-converting enzyme 2(ACE2)on mitochondrial function in DRG neuron lipid meta'bolism.The expression of long chain acyl-CoA synthetase(ACSL1-6)and genes related to mitochondrial function in DRGs of ACE2 knockout mice and Ad-ACE2-treated chronic constriction injury(CCI)rats were analyzed by q-PCR.Under the same condition,the lipid peroxide(LPO)content,fatty acid content.
文摘Osteoporosis(OP)is a metabolic bone disease characterized by decreased bone mass,reduced bone density,and destruction of bone microstructures,which resulting in an increased brittleness and susceptibility to fractures.The incidence of osteoporosis is associated with aging and some genetical and physiology abnormalities.With the accelerated growth of aged population in China,a large group of population has reduced bone density.The mid-aged and senior people are highly susceptible to osteoporosis.While some young people who have irregular dietary schedule and unhealthy life style might cause increased rate of osteoporosis.Signal transducers and activators of transcription 3(STAT3)is a transcription factor ubiquitously expressed in somatic and stem cells such as tumor cells,mesenchymal stem cells,osteoblasts,osteoclasts and osteocytes.STAT3 is involved in the regulation of cell proliferation differentiation,apoptosis,and other physiological functions.The results of relevant animal experiments and clinical trials showed that abnormal expression of STAT3 would affect normal bone development.
文摘Aim: To study the mitochondrial function damage of sperm in-duced by reactive oxygen species (ROS) and the protection of melatonin (MLT) against the damage. Methods: Normal function spermatozoa were selected from semen samples by Percoll gradi-ent centrifugation technique. The ROS generated by the hypoxan-thine xanthine oxidase system was incubated with the normal sper-matozoa in the presence or absence of MLT (6 retool/L) for 30 and 60 minutes.
基金supported by the National Natural Science Foundation of China,Nos.82130037(to CH),81971122(to CH),82171323(to WL)the Natural Science Foundation of Jiangsu Province of China,No.BK20201113(to WL)。
文摘The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow.Mitochondria are directly affected by direct factors such as ischemia,hypoxia,excitotoxicity,and toxicity of free hemoglobin and its degradation products,which trigger mitochondrial dysfunction.Dysfunctional mitochondria release large amounts of reactive oxygen species,inflammatory mediators,and apoptotic proteins that activate apoptotic pathways,further damaging cells.In response to this array of damage,cells have adopted multiple mitochondrial quality control mechanisms through evolution,including mitochondrial protein quality control,mitochondrial dynamics,mitophagy,mitochondrial biogenesis,and intercellular mitochondrial transfer,to maintain mitochondrial homeostasis under pathological conditions.Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage.This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage,particularly mitochondrial quality control mechanisms.It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.
基金supported by the National Natural Science Foundation of China (Grant Nos.82125009,U19A2034,31871082,91849101,32121002,82071185,32100794 and 92149303)the National Key R&D Program of China (2020YFA0509300,2021YFA0804900)+4 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB39000000)CAS Project for Young Scientists in Basic Research (YSBR-013)Collaborative Innovation Program of Hefei Science Center,CAS (2022HSC-CIP003)the Fundamental Research Funds for the Central Universities (YD2070002011,WK2070000168)Institute of Health and Medicine,Hefei Comprehensive National Science Center (QYZD20220003).
文摘DearEditor,Brain aging is associated with a decrease in cognitive function,which is often accompanied by defective changes in mitochondrial morphology and reduction in mitochondrial function(Faitg et al.,2021).The main function of mitochondria is to produce energy in the form of ATP,which is vital to fulfill high energy demand of neurons,mainly for synaptic processes(Lee et al.,2018).Mitochondrial dysfunction acts as a key factor for age-related cognitive decline(Grimm and Eckert,2017).
基金the Ningbo Science and Technology Plan Projects(Nos.2019B10016,2016C10004)the Major Science and Technology Projects in Zhejiang Province(No.2011C12013)+1 种基金the Natural Science Foundation of Zhejiang Province(No.LY18C190007)the Collaborative Innovation Center for Zhejiang Marine High-efficiency and Healthy Aquaculture,the K.C.Wong Magna Fund in Ningbo University。
文摘Mitochondria undergo morphological changes during spermatogenesis in some animals.The mechanism and role of mitochondrial morphology regulation,however,remain somewhat unclear.In this study,we analyzed the molecular characteristics,expression dynamics and subcellular localization of optic atrophy protein 1(OPA1),a mitochondrial fusion and cristae maintenance-related protein,to reveal the possible regulatory mechanisms underlying mitochondrial morphology in Phascolosoma esculenta spermiogenesis.The full-length cDNA of the P.esculenta opa1 gene(Pe-opa1)is 3743 bp in length and encodes 975 amino acids.The Pe-OPA1 protein is highly conservative and includes a transmembrane domain,a GTPase domain,two helical bundle domains,and a lipid-interacting stalk.Gene and protein expression was higher in the coelomic fluid(a site of spermatid development)of male P.esculenta and increased first and then decreased from March to December.Moreover,their expression during the breeding stage was significantly higher than during the non-breeding stage,suggesting that Pe-OPA1 is involved in P.esculenta reproduction.The Pe-OPA1 protein was more abundant in components consisting of many spermatids than in components without,indicating that Pe-OPA1 mainly plays a role in the spermatid in coelomic fluid.Moreover,Pe-OPA1 was mainly detected in the spermatid mitochondria.Immunofluorescence experiments showed that the Pe-OPA1 are constitutively expressed and co-localized with mitochondria during spermiogenesis,suggesting its involvement in P.esculenta spermiogenesis.These results provide evidence for Pe-OPA1's involvement in the regulation of mitochondrial morphology during spermiogenesis.
文摘BACKGROUND Leukemia stem cells(LSCs)are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia(AML),as they are protected by the bone marrow microenvironment(BMM)against conventional therapies.Gossypol acetic acid(GAA),which is extracted from the seeds of cotton plants,exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.AIM To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.METHODS In this study,LSCs were magnetically sorted from AML cell lines and the CD34+CD38-population was obtained.The expression of leucine-rich pentatricopeptide repeat-containing protein(LRPPRC)and forkhead box M1(FOXM1)was evaluated in LSCs,and the effects of GAA on malignancies and mitochondrial RESULTS LRPPRC was found to be upregulated,and GAA inhibited cell proliferation by degrading LRPPRC.GAA induced LRPPRC degradation and inhibited the activation of interleukin 6(IL-6)/janus kinase(JAK)1/signal transducer and activator of transcription(STAT)3 signaling,enhancing chemosensitivity in LSCs against conventional chemotherapies,including L-Asparaginase,Dexamethasone,and cytarabine.GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC.Furthermore,GAA induced reactive oxygen species accumulation,disturbed mitochondrial homeostasis,and caused mitochondrial dysfunction.By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC,GAA resulted in the elimination of LSCs.Meanwhile,GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.CONCLUSION Taken together,the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.
基金supported by the National Natural Science Foundation of China(32102549)the National Key R&D Program of Ningxia(2021BEF02023)+2 种基金the earmarked fund for CARS(CARS-36)the Agricultural Science and Technology Innovation Program(ASTIP-IAS06)the National Key R&D Program of Gansu(21YF5NJ196)。
文摘Background During the transition period,the insufficient dry matter intake and a sharply increased in energy consumption to produce large quantities of milk,high yielding cows would enter a negative energy balance(NEB)that causes an increase in ketone bodies(KBs)and decrease in reproduction efficiency.The excess concentrations of circulating KBs,represented byβ-hydroxybutyric acid(BHBA),could lead to oxidative damage,which potentially cause injury to follicular granulosa cells(fGCs)and delayed follicular development.Sirtuin 3(Sirt3)regulates mitochondria reactive oxygen species(mitoROS)homeostasis in a beneficial manner;however,the molecular mechanisms underlying its involvement in the BHBA-induced injury of fGCs is poorly understood.The aim of this study was to explore the protection effects and underlying mechanisms of Sirt3 against BHBA overload-induced damage of fGCs.Results Our findings demonstrated that 2.4 mmol/L of BHBA stress increased the levels of mitoROS in bovine fGCs.Further investigations identified the subsequent mitochondrial dysfunction,including an increased abnormal rate of mitochondrial architecture,mitochondrial permeability transition pore(MPTP)opening,reductions in mitochondrial membrane potential(MMP)and Ca^(2+)release;these dysfunctions then triggered the caspase cascade reaction of apoptosis in fGCs.Notably,the overexpression of Sirt3 prior to treatment enhanced mitochondrial autophagy by increasing the expression levels of Beclin-1,thus preventing BHBA-induced mitochondrial oxidative stress and mitochondrial dysfunction in fGCs.Furthermore,our data suggested that the AMPK-mTOR-Beclin-1 pathway may be involved in the protective mechanism of Sirt3 against cellular injury triggered by BHBA stimulation.Conclusions These findings indicate that Sirt3 protects fGCs from BHBA-triggered injury by enhancing autophagy,attenuating oxidative stress and mitochondrial damage.This study provides new strategies to mitigate the fGCs injury caused by excessive BHBA stress in dairy cows with ketosis.
基金the financial support from the National Natural Science Foundation of China(Nos.91853106,81870420 and 82070590)the Program for Guangdong Introducing Innovative and Enterpre-neurial Teams(No.2016ZT06Y337,China)+3 种基金The Fundamental Research Funds for the Central Universities(No.19ykzd25,China)National Key Research and Development Program(No.2017YFE0109900,China)Special Topics of General Projects of Guangzhou Science and Technology Plan of China(201904010075)CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-074,China)。
文摘Nonalcoholic fatty liver disease(NAFLD),especially nonalcoholic steatohepatitis(NASH),is a common hepatic manifestation of metabolic syndrome.However,there are no effective therapy to treat this devastating disease.Accumulating evidence suggests that the generation of elastin-derived peptides(EDPs)and the inhibition of adiponectin receptors(Adipo R)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis.We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix(ECM)and ameliorated liver fibrosis.However,the degradation of the ECM lead to the generation of EDPs,which could further alter liver homeostasis negatively.Thus,in this study,we successfully combined AdipoR1/2 agonist JT003 with V14,which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation.We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other.These effects are induced by the enhancement of the mitochondrial antioxidant capacity,mitophagy,and mitochondrial biogenesis via AMPK pathway.Furthermore,specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress,increased mitophagy and mitochondrial biogenesis.These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.
基金supported by the Natural Science Foundation of Shandong Province (ZR2020QH294 and ZR2021QH342)。
文摘The aim of this study was to investigate whether punicalagin(PU)could prevent obesity-related cardiac dysfunction by promoting DNA demethy lation,and to explore its possible mechanism.C57BL/6J mice were fed with standard diet,high-fat diet(HFD),HFD supplemented with resveratrol,low-dose PU(LPU)and high-dose PU(HPU)for 8 weeks.Compared with HFD group,body weight was significantly lower in PU treatment groups,number of cardionwocytes and the protein level of myosin heavy chain 7B were significantly higher in PU treatment groups.Levels of 5-hydroxymethylcytosine and 5-formylcytosine were significantly lower in HFD group than in other groups.Compared with the HFD group,the protein level of ten-eleven translocation enzyme(TET)2 was significantly higher in PU treatment groups,p-AMP-activated protein kinase(AMPK)was significantly higher in LPU group.Levels of total antioxidant capacity and the protein levels of complexesⅡ/Ⅲ/Ⅴ,oxoglutarate dehydrogenase,succinate dehydrogenase B and fumarate hdrolase were significantly lower in HFD group than PU treatment group.The ratio of(succinic acid+fumaric acid)/a-ketoglutarate was significantly higher in HFD group than other groups.In conclusion,PU up-regulated TETs enzyme activities and TET2 protein stability through alleviating mitochondrial dysfunction and activating AMPK,so as to promote DNA demethylation,thus preventing obesity-related cardiac dysfunction.
