Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheime...Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.展开更多
Sirtuin 3(SIRT3),the main family member of mitochondrial deacetylase,targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as ...Sirtuin 3(SIRT3),the main family member of mitochondrial deacetylase,targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism,reactive oxygen species production and clearance,oxidative stress,and aging.Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis,thus leading to the defect in mitochondrial function and insufficient ATP production.Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis,dampening mitochondrial function.Mitochondrial dysfunction plays an important role in several diseases related to aging,such as cardiovascular disease,cancer and neurodegenerative diseases.Peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α)launches mitochondrial biogenesis through activating nuclear respiratory factors.These factors act on genes,transcribing and translating mitochondrial DNA to generate new mitochondria.PGC1αbuilds a bridge between SIRT3 and mitochondrial biogenesis.This review described the involvement of SIRT3 and mitochondrial dynamics,particularly mitochondrial biogenesis in agingrelated diseases,and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.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
In the context of non-alcoholic fatty liver disease (NAFLD), characterized by dysregulated lipid metabolism in hepatocytes, the quest for safe and effective therapeutics targeting lipid metabolism has gained paramount...In the context of non-alcoholic fatty liver disease (NAFLD), characterized by dysregulated lipid metabolism in hepatocytes, the quest for safe and effective therapeutics targeting lipid metabolism has gained paramount importance. Sanhuang Xiexin Tang (SXT) and Baihu Tang (BHT) have emerged as prominent candidates for treating metabolic disorders. SXT combined with BHT plus Cangzhu (SBC) has been used clinically for Weihuochisheng obese patients. This retrospective analysis focused on assessing the anti-obesity effects of SBC in Weihuochisheng obese patients. We observed significant reductions in body weight and hepatic lipid content among obese patients following SBC treatment. To gain further insights, we investigated the effects and underlying mechanisms of SBC in HFD-fed mice. The results demonstrated that SBC treatment mitigated body weight gain and hepatic lipid accumulation in HFD-fed mice. Pharmacological network analysis suggested that SBC may affect lipid metabolism, mitochondria, inflammation, and apoptosis—a hypothesis supported by the hepatic transcriptomic analysis in HFD-fed mice treated with SBC. Notably, SBC treatment was associated with enhanced hepatic mitochondrial biogenesis and the inhibition of the c-Jun N-terminal kinase (JNK)/nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK)/NF-κB pathways. In conclusion, SBC treatment alleviates NAFLD in both obese patients and mouse models by improving lipid metabolism, potentially through enhancing mitochondrial biogenesis. These effects, in turn, ameliorate inflammation in hepatocytes.展开更多
Mitochondria play an essential role in neural function,such as supporting normal energy metabolism,regulating reactive oxygen species,buffering physiological calcium loads,and maintaining the balance of morphology,sub...Mitochondria play an essential role in neural function,such as supporting normal energy metabolism,regulating reactive oxygen species,buffering physiological calcium loads,and maintaining the balance of morphology,subcellular distribution,and overall health through mitochondrial dynamics.Given the recent technological advances in the assessment of mitochondrial structure and functions,mitochondrial dysfunction has been regarded as the early and key pathophysiological mechanism of cognitive disorders such as Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,mild cognitive impairment,and postoperative cognitive dysfunction.This review will focus on the recent advances in mitochondrial medicine and research methodology in the field of cognitive sciences,from the perspectives of energy metabolism,oxidative stress,calcium homeostasis,and mitochondrial dynamics(including fission-fusion,transport,and mitophagy).展开更多
Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear. Mitochondrial dysfunction,
Objective:To explore the protective effect and underlying mechanism of Lycium barbarum polysaccharides(LBP)in a non-alcoholic fatty liver disease(NAFLD)cell model.Methods:Normal human hepatocyte LO2 cells were treated...Objective:To explore the protective effect and underlying mechanism of Lycium barbarum polysaccharides(LBP)in a non-alcoholic fatty liver disease(NAFLD)cell model.Methods:Normal human hepatocyte LO2 cells were treated with 1 mmol/L free fatty acids(FFA)mixture for 24 h to induce NAFLD cell model.Cells were divided into 5 groups,including control,model,low-,medium-and high dose LBP(30,100and 300μg/mL)groups.The monosaccharide components of LBP were analyzed with high performance liquid chromatography.Effects of LBP on cell viability and intracellular lipid accumulation were assessed by cell counting Kit-8 assay and oil red O staining,respectively.Triglyceride(TG),alanine aminotransferase(ALT),aspartate aminotransferase(AST),adenosine triphosphate(ATP)and oxidative stress indicators were evaluated.Energy balance and mitochondrial biogenesis related mRNA and proteins were determined by quantitative real-time polymerase chain reaction and Western blot,respectively.Results:Heteropolysaccharides with mannose and glucose are the main components of LBP.LBP treatment significantly decreased intracellular lipid accumulation as well as TG,ALT,AST and malondialdehyde levels(P<0.05 or P<0.01),increased the levels of superoxide dismutase,phospholipid hydroperoxide glutathione peroxidase,catalase,and ATP in NAFLD cell model(P<0.05).Meanwhile,the expression of uncoupling protein 2 was down-regulated and peroxisome proliferator-activated receptor gamma coactivator-1α/nuclear respiratory factor 1/mitochondrial transcription factor A pathway was up-regulated(P<0.05).Conclusion:LBP promotes mitochondrial biogenesis and improves energy balance in NAFLD cell model.展开更多
Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial...Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial biogenesis and quality control,disturbed mitochondrial trafficking,oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder.Unfortunately,conventional mitochondrial-targeted molecules,such as cysteamine,creatine,coenzyme Q10,or triheptanoin,yielded negative or inconclusive results.However,future therapeutic strategies,aiming to restore mitochondrial biogenesis,improving the fission/fusion balance,and improving mitochondrial trafficking,could prove useful tools in improving the phenotype of Huntington’s disease and,used in combination with genome-editing methods,could lead to a cure for the disease.展开更多
Cisplatin(CDDP)-induced ototoxicity is one of the common adverse effects of cisplatin chemotherapy.Thus far,effective approaches for attenuating hearing loss are unavailable in clinical practice.Mitochondrial biogenes...Cisplatin(CDDP)-induced ototoxicity is one of the common adverse effects of cisplatin chemotherapy.Thus far,effective approaches for attenuating hearing loss are unavailable in clinical practice.Mitochondrial biogenesis acts as a master element of mitochondrial health and is necessary for mitochondrial quality control.The current study examined whether mitochondrial biogenesis is involved in CDDP-induced ototoxicity.Herein,we showed that CDDP damaged mitochondrial function and caused death of House Ear Institute-Organ of Corti 1(HEI-OC1)cells by impairing mitochondrial biogenesis.Moreover,overexpression of peroxisome proliferatoractivated receptor-g coactivator-1a,a key factor in mitochondrial biogenesis,promoted mitochondrial biogenesis in HEI-OC1 cells and protected them against CDDP-induced cytotoxicity.These findings suggest that mitochondrial biogenesis is involved in the pathology of CDDP cytotoxicity of HEI-OC1 cells,and activation of peroxisome proliferator-activated receptor-g coactivator-1a can be considered a potential therapeutic strategy to attenuate CDDP-mediated ototoxicity.展开更多
Background:The survival of pancreatic cancer cells,particularly cancer stem cells which are responsible for tumor relapse,depends on mitochondrial function.Mitochondrial transcription factor A(TFAM)is critical for the...Background:The survival of pancreatic cancer cells,particularly cancer stem cells which are responsible for tumor relapse,depends on mitochondrial function.Mitochondrial transcription factor A(TFAM)is critical for the regulation of mitochondrial DNA and thus mitochondrial function.However,the possible involvement of TFAM in pancreatic cancer is unknown.Methods:Human samples were obtained from pancreatic cancers and their adjacent tissues;human pancreatic cell lines were cultured in RPMI1640 medium.TFAM expressions in pancreatic tissues and cultured cells were determined using immunohistochemistry,ELISA,and reverse transcription polymerase chain reaction(RT-PCR).The effect of TFAM on cell growth,migration,colony formation and apoptosis were evaluated.Mitochondrial biogenesis in pancreatic cancer and normal cells were examined.Results:The majority of pancreatic cancer tissues exhibited higher TFAM expression compared to the adjacent counterparts.Consistently,TFAM mRNA and protein levels were higher in pancreatic cancer cell lines than in immortalized normal pancreatic epithelial cells.There was no difference on TFAM level between gemcitabine-sensitive and resistant pancreatic cancer cells.Functional analysis demonstrated that TFAM overexpression activated pancreatic normal and tumor cells whereas TFAM inhibition effectively inhibited the growth of pancreatic cancer cells.TFAM inhibition enhanced gemcitabine’s cytotoxicity and suppressed growth,anchorage-independent colony formation and survival of gemcitabine-resistant pancreatic cancer cells.Mechanistic studies showed that TFAM inhibition resulted in remarkable mitochondrial dysfunction and energy crisis followed by oxidative stress.The basal mitochondrial biogenesis level correlated well with TFAM level in pancreatic cancer cells.Conclusions:TFAM played essential roles in pancreatic cancer via regulating mitochondrial functions which highlighted the therapeutic value of inhibiting TFAM to overcome gemcitabine resistance.展开更多
Alzheimer's disease(AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved...Alzheimer's disease(AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.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
Triple-negative breast cancer(TNBC)cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria.On the other hand,dipeptidyl peptidase-IV(DPP-IV)inhibitors such as sitagliptin and vildagliptin and ...Triple-negative breast cancer(TNBC)cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria.On the other hand,dipeptidyl peptidase-IV(DPP-IV)inhibitors such as sitagliptin and vildagliptin and GLP-1 agonist exendin-4 are known to improve mitochondrial functions as well as biogenesis,but no study has evaluated the influence of these drugs on mitochondrial biogenesis on metastatic breast cancer cell line.We have recently reported anticancer effects of 5-aminoimidazole-4-carboxamide riboside on MDA-MB-231 cells via activation of AMP-dependent kinase(AMPK),which activates the downstream transcription factors PGC-1α,PGC-1β,or FOXO1 for mitochondrial biogenesis;above-mentioned incretin-based therapies are also known to activate AMPK.This study evaluated the effects of sitagliptin,vildagliptin,and exendin-4 on MDA-MB-231 cells and the underlying changes in mitochondrial biogenesis,were examined.Treatment with sitagliptin(100μM),vildagliptin(100μM),and exendin-4(10 nM)for 72 h to MDA-MB-231 cells led to a decrease in viability indicated by MTT assay,cell migration by scratch,and transwell migration assays,accompanied with marginal reduction in cell numbers along with the apoptotic appearance,the rate of apoptosis,and decreased lactate content in conditioned medium.These changes in the cancer phenotype were accompanied by an increase in the mitochondrial DNA to nuclear DNA ratio,increased MitoTracker green and red staining,and increased expression of transcription factors PGC-1α,NRF-1,NRF-2,TFAM,and HO-1.Pre-treatment of cells with these incretin-based drugs followed by 48 h treatment with 1μM doxorubicin increased doxorubicin sensitivity as observed by a decrease in viability by MTT assay.Thus,sitagliptin,vildagliptin,and exendin-4 exert their beneficial effects on TNBC cells via an increase in mitochondrial biogenesis that helps to switch Warburg metabolism into anti-Warburg effect.Therapeutic response was in the order of:sitagliptin>vildagliptin>exendin-4.展开更多
Energy restriction is defined as reducing nutrient intake without dragging the organism into malnutrition. Energy restriction is preferred because it is a non-genetic intervention that increases life expectancy. Nicot...Energy restriction is defined as reducing nutrient intake without dragging the organism into malnutrition. Energy restriction is preferred because it is a non-genetic intervention that increases life expectancy. Nicotinamide adenine dinucleotide(NAD~+)and adenosine monophosphate(AMP)levels, which are the indicators of intracellular energy deficiency, increase with energy restriction. The increase in NAD~+ level stimulates sirtuin(SIRT)enzymes, and the increase in AMP level stimulates AMP-activated protein kinase(AMPK). Various mechanisms are regulated by stimulating these enzymes. By Forkhead box O(FoxO)transcription factors, the ability of resistance to oxidative stress increases, and antioxidant genes, DNA repair, and autophagy genes are stimulated. Apoptosis is induced by stimulation of the p53 protein, and tumor growth is suppressed by the disruption of aging cells. The suppression of phosphoinositide 3-kinase(PI3K)-/-Akt, and therefore mTOR signal stimulates autophagy and mitophagia, and cleanses damaged cells and organelles. Mitochondrial biogenesis is stimulated, antioxidant capacity increases, and inflammatory response decreases. Adipose tissue and lipid metabolism are regulated by the regulation of fatty acid synthesis and oxidation. As a consequence, the effects of caloric restriction on cellular metabolism are regulated through the genetic pathways.展开更多
Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial ...Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.展开更多
Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease affecting both upper and lower motor neurons(MNs)with large unmet medical needs.Multiple pathological mechanisms are considered to contribut...Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease affecting both upper and lower motor neurons(MNs)with large unmet medical needs.Multiple pathological mechanisms are considered to contribute to the progression of ALS,including neuronal oxidative stress and mitochondrial dysfunction.Honokiol(HNK)has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke,Alzheimer’s disease and Parkinson’s disease.Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo.Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins(SOD1-G93A cells for short).Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione(GSH)synthesis and activating the nuclear factor erythroid 2-related factor 2(NRF2)-antioxidant response element(ARE)pathway.Also,honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells.Importantly,honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function.The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice.Overall,honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.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
Amyotrophic lateral sclerosis(ALS)is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord.Currently,there is no cure or effective treatment for ALS a...Amyotrophic lateral sclerosis(ALS)is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord.Currently,there is no cure or effective treatment for ALS and the cause of disease is unknown in the majority of ALS cases.Neuronal mitochondria dysfunction is one of the earliest features of ALS.Mitochondria are highly dynamic organelles that undergo continuous fission,fusion,trafficking and turnover,all of which contribute to the maintenance of mitochondrial function.Abnormal mitochondrial dynamics have been repeatedly reported in ALS and increasing evidence suggests altered mitochondrial dynamics as possible pathomechanisms underlying mitochondrial dysfunction in ALS.Here,we provide an overview of mitochondrial dysfunction and dynamic abnormalities observed in ALS,and discuss the possibility of targeting mitochondrial dynamics as a novel therapeutic approach for ALS.展开更多
Objective: To evaluate the synergic effects of a novel oral supplement formulation, containing prebiotics,yeast b-glucans, minerals and silymarin(Silybum marianum), on lipid and glycidic metabolism, inflammatory and m...Objective: To evaluate the synergic effects of a novel oral supplement formulation, containing prebiotics,yeast b-glucans, minerals and silymarin(Silybum marianum), on lipid and glycidic metabolism, inflammatory and mitochondrial proteins of the liver, in control and high-fat diet-induced obese mice.Methods: After an acclimation period, 32 male C57 BL/6 mice were divided into the following groups:nonfat diet(NFD) vehicle, NFD supplemented, high-fat diet(HFD) vehicle and HFD supplemented. The vehicle and experimental formulation were administered orally by gavage once a day during the last four weeks of the diet(28 consecutive days). We then evaluated energy homeostasis, inflammation, and mitochondrial protein expression in these groups of mice.Results: After four weeks of supplementation, study groups experienced reduced glycemia, dyslipidemia,fat, and hepatic fibrosis levels. Additionally, proliferator-activated receptor-α, AMP-activated protein kinase-1α, peroxisome proliferator-activated receptor γ co-activator-1α, and mitochondrial transcription factor A expression levels were augmented;however, levels of inhibitor of nuclear factor-κB kinase subunit a and p65 nuclear factor-κB expression, and oxidative markers were reduced. Notably, the cortisol/C-reactive protein ratio, a well-characterized marker of the hypothalamic–pituitary–adrenal axis immune interface status, was found to be modulated by the supplement.Conclusion: We discovered that the novel supplement was able to modify different antioxidant, metabolic and inflammatory pathways, improving the energy homeostasis and inflammatory status, and consequently alleviated hepatic steatosis.展开更多
Increased cardiovascular fitness,VO_(2max),is associated with enhanced endurance capacity and a decreased rate of mortality.High intensity interval training(HIIT)is one of the best methods to increase VO_(2max)and end...Increased cardiovascular fitness,VO_(2max),is associated with enhanced endurance capacity and a decreased rate of mortality.High intensity interval training(HIIT)is one of the best methods to increase VO_(2max)and endurance capacity for top athletes and for the general public as well.Because of the high intensity of this type of training,the adaptive response is not restricted to Type I fibers,as found for moderate intensity exercise of long duration.Even with a short exercise duration,HIIT can induce activation of AMPK,PGC-1α,SIRT1 and ROS pathway as well as by the modulation of Ca^(2+)homeostasis,leading to enhanced mitochondrial biogenesis,and angiogenesis.The present review summarizes the current knowledge of the adaptive response of HIIT.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82171194 and 81974155(both to JL)the Shanghai Municipal Science and Technology Commission Medical Guide Project,No.16411969200(to WZ)Shanghai Municipal Science and Technology Commission Biomedical Science and Technology Project,No.22S31902600(to JL)。
文摘Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.
文摘Sirtuin 3(SIRT3),the main family member of mitochondrial deacetylase,targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism,reactive oxygen species production and clearance,oxidative stress,and aging.Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis,thus leading to the defect in mitochondrial function and insufficient ATP production.Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis,dampening mitochondrial function.Mitochondrial dysfunction plays an important role in several diseases related to aging,such as cardiovascular disease,cancer and neurodegenerative diseases.Peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α)launches mitochondrial biogenesis through activating nuclear respiratory factors.These factors act on genes,transcribing and translating mitochondrial DNA to generate new mitochondria.PGC1αbuilds a bridge between SIRT3 and mitochondrial biogenesis.This review described the involvement of SIRT3 and mitochondrial dynamics,particularly mitochondrial biogenesis in agingrelated diseases,and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.
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 grants from the National Key R&D Program of China(2017YFA0105803)the National Natural Science Foundation of China(82270886,82070811)+2 种基金the Science and Technology Plan Project of Guangzhou City(202007040003,202201020497)the 5010 Clinical Research Projects of Sun Yat-Sen University(2015015)the Dengfeng Plan High-level Hospital Construction Opening Project of Foshan Fourth People's Hospital(FSSYKF-2020011 and FSSYKF-2020009)。
文摘In the context of non-alcoholic fatty liver disease (NAFLD), characterized by dysregulated lipid metabolism in hepatocytes, the quest for safe and effective therapeutics targeting lipid metabolism has gained paramount importance. Sanhuang Xiexin Tang (SXT) and Baihu Tang (BHT) have emerged as prominent candidates for treating metabolic disorders. SXT combined with BHT plus Cangzhu (SBC) has been used clinically for Weihuochisheng obese patients. This retrospective analysis focused on assessing the anti-obesity effects of SBC in Weihuochisheng obese patients. We observed significant reductions in body weight and hepatic lipid content among obese patients following SBC treatment. To gain further insights, we investigated the effects and underlying mechanisms of SBC in HFD-fed mice. The results demonstrated that SBC treatment mitigated body weight gain and hepatic lipid accumulation in HFD-fed mice. Pharmacological network analysis suggested that SBC may affect lipid metabolism, mitochondria, inflammation, and apoptosis—a hypothesis supported by the hepatic transcriptomic analysis in HFD-fed mice treated with SBC. Notably, SBC treatment was associated with enhanced hepatic mitochondrial biogenesis and the inhibition of the c-Jun N-terminal kinase (JNK)/nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK)/NF-κB pathways. In conclusion, SBC treatment alleviates NAFLD in both obese patients and mouse models by improving lipid metabolism, potentially through enhancing mitochondrial biogenesis. These effects, in turn, ameliorate inflammation in hepatocytes.
基金supported by the National Natural Science Foundation of China,Nos.82271222(to ZL),81971012(to ZL),82071189(to XG),and 82201335(to YL)Key Clinical Projects of Peking University Third Hospital,No.BYSYZD2019027(to ZL)。
文摘Mitochondria play an essential role in neural function,such as supporting normal energy metabolism,regulating reactive oxygen species,buffering physiological calcium loads,and maintaining the balance of morphology,subcellular distribution,and overall health through mitochondrial dynamics.Given the recent technological advances in the assessment of mitochondrial structure and functions,mitochondrial dysfunction has been regarded as the early and key pathophysiological mechanism of cognitive disorders such as Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,mild cognitive impairment,and postoperative cognitive dysfunction.This review will focus on the recent advances in mitochondrial medicine and research methodology in the field of cognitive sciences,from the perspectives of energy metabolism,oxidative stress,calcium homeostasis,and mitochondrial dynamics(including fission-fusion,transport,and mitophagy).
文摘Insulin resistance is an important feature of type 2 diabetes and obesity. The underlying mechanisms of insulin resistance are still unclear. Mitochondrial dysfunction,
基金Supported by National Natural Science Foundation of China(No.81660537)Special Talents Start-up Project of Ningxia Medical University(No.XT2018009)Natural Science Foundation of Ningxia(No.2020AAC03163)。
文摘Objective:To explore the protective effect and underlying mechanism of Lycium barbarum polysaccharides(LBP)in a non-alcoholic fatty liver disease(NAFLD)cell model.Methods:Normal human hepatocyte LO2 cells were treated with 1 mmol/L free fatty acids(FFA)mixture for 24 h to induce NAFLD cell model.Cells were divided into 5 groups,including control,model,low-,medium-and high dose LBP(30,100and 300μg/mL)groups.The monosaccharide components of LBP were analyzed with high performance liquid chromatography.Effects of LBP on cell viability and intracellular lipid accumulation were assessed by cell counting Kit-8 assay and oil red O staining,respectively.Triglyceride(TG),alanine aminotransferase(ALT),aspartate aminotransferase(AST),adenosine triphosphate(ATP)and oxidative stress indicators were evaluated.Energy balance and mitochondrial biogenesis related mRNA and proteins were determined by quantitative real-time polymerase chain reaction and Western blot,respectively.Results:Heteropolysaccharides with mannose and glucose are the main components of LBP.LBP treatment significantly decreased intracellular lipid accumulation as well as TG,ALT,AST and malondialdehyde levels(P<0.05 or P<0.01),increased the levels of superoxide dismutase,phospholipid hydroperoxide glutathione peroxidase,catalase,and ATP in NAFLD cell model(P<0.05).Meanwhile,the expression of uncoupling protein 2 was down-regulated and peroxisome proliferator-activated receptor gamma coactivator-1α/nuclear respiratory factor 1/mitochondrial transcription factor A pathway was up-regulated(P<0.05).Conclusion:LBP promotes mitochondrial biogenesis and improves energy balance in NAFLD cell model.
文摘Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial biogenesis and quality control,disturbed mitochondrial trafficking,oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder.Unfortunately,conventional mitochondrial-targeted molecules,such as cysteamine,creatine,coenzyme Q10,or triheptanoin,yielded negative or inconclusive results.However,future therapeutic strategies,aiming to restore mitochondrial biogenesis,improving the fission/fusion balance,and improving mitochondrial trafficking,could prove useful tools in improving the phenotype of Huntington’s disease and,used in combination with genome-editing methods,could lead to a cure for the disease.
基金supported by the Project funded by China Postdoctoral Science Foundation(No.2018M640863 to JP)the National Natural Science Foundation of China(No.81771018,81570935,81570916,and 81873699 to HX and YZ)+1 种基金the Guangdong Natural Science Foundation of China(No.2015A030313084 and 2017A030313585 to HX)Yixian Research Launch Project of China(No.YXQH201807 to HX).
文摘Cisplatin(CDDP)-induced ototoxicity is one of the common adverse effects of cisplatin chemotherapy.Thus far,effective approaches for attenuating hearing loss are unavailable in clinical practice.Mitochondrial biogenesis acts as a master element of mitochondrial health and is necessary for mitochondrial quality control.The current study examined whether mitochondrial biogenesis is involved in CDDP-induced ototoxicity.Herein,we showed that CDDP damaged mitochondrial function and caused death of House Ear Institute-Organ of Corti 1(HEI-OC1)cells by impairing mitochondrial biogenesis.Moreover,overexpression of peroxisome proliferatoractivated receptor-g coactivator-1a,a key factor in mitochondrial biogenesis,promoted mitochondrial biogenesis in HEI-OC1 cells and protected them against CDDP-induced cytotoxicity.These findings suggest that mitochondrial biogenesis is involved in the pathology of CDDP cytotoxicity of HEI-OC1 cells,and activation of peroxisome proliferator-activated receptor-g coactivator-1a can be considered a potential therapeutic strategy to attenuate CDDP-mediated ototoxicity.
基金This work was supported by the grant from Science and Technology Project of Hubei Provincial Department of Education(B2020139).
文摘Background:The survival of pancreatic cancer cells,particularly cancer stem cells which are responsible for tumor relapse,depends on mitochondrial function.Mitochondrial transcription factor A(TFAM)is critical for the regulation of mitochondrial DNA and thus mitochondrial function.However,the possible involvement of TFAM in pancreatic cancer is unknown.Methods:Human samples were obtained from pancreatic cancers and their adjacent tissues;human pancreatic cell lines were cultured in RPMI1640 medium.TFAM expressions in pancreatic tissues and cultured cells were determined using immunohistochemistry,ELISA,and reverse transcription polymerase chain reaction(RT-PCR).The effect of TFAM on cell growth,migration,colony formation and apoptosis were evaluated.Mitochondrial biogenesis in pancreatic cancer and normal cells were examined.Results:The majority of pancreatic cancer tissues exhibited higher TFAM expression compared to the adjacent counterparts.Consistently,TFAM mRNA and protein levels were higher in pancreatic cancer cell lines than in immortalized normal pancreatic epithelial cells.There was no difference on TFAM level between gemcitabine-sensitive and resistant pancreatic cancer cells.Functional analysis demonstrated that TFAM overexpression activated pancreatic normal and tumor cells whereas TFAM inhibition effectively inhibited the growth of pancreatic cancer cells.TFAM inhibition enhanced gemcitabine’s cytotoxicity and suppressed growth,anchorage-independent colony formation and survival of gemcitabine-resistant pancreatic cancer cells.Mechanistic studies showed that TFAM inhibition resulted in remarkable mitochondrial dysfunction and energy crisis followed by oxidative stress.The basal mitochondrial biogenesis level correlated well with TFAM level in pancreatic cancer cells.Conclusions:TFAM played essential roles in pancreatic cancer via regulating mitochondrial functions which highlighted the therapeutic value of inhibiting TFAM to overcome gemcitabine resistance.
文摘Alzheimer's disease(AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.
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.
基金The work was supported by the Council of Scientific and Industrial Research-Junior Research Fellowship to Ms.Pooja Jaiswal(File No.09/301(0137)/2019-EMR-I)Ms.Versha Tripathi(09/301(0138)/2019-EMR-I)+1 种基金We also acknowledge the India-Belarus joint project(DST/INT/BLR/P-24/2019)funded by the Department of Science and TechnologyNew Delhi and the research grant from Devi Ahilya University,Indore(Dev/Seedmoney2.0/2020-21/655)sanctioned to Dr.Hamendra Singh Parmar.
文摘Triple-negative breast cancer(TNBC)cell line MDA-MB-231 is known for Warburg metabolism and defects in mitochondria.On the other hand,dipeptidyl peptidase-IV(DPP-IV)inhibitors such as sitagliptin and vildagliptin and GLP-1 agonist exendin-4 are known to improve mitochondrial functions as well as biogenesis,but no study has evaluated the influence of these drugs on mitochondrial biogenesis on metastatic breast cancer cell line.We have recently reported anticancer effects of 5-aminoimidazole-4-carboxamide riboside on MDA-MB-231 cells via activation of AMP-dependent kinase(AMPK),which activates the downstream transcription factors PGC-1α,PGC-1β,or FOXO1 for mitochondrial biogenesis;above-mentioned incretin-based therapies are also known to activate AMPK.This study evaluated the effects of sitagliptin,vildagliptin,and exendin-4 on MDA-MB-231 cells and the underlying changes in mitochondrial biogenesis,were examined.Treatment with sitagliptin(100μM),vildagliptin(100μM),and exendin-4(10 nM)for 72 h to MDA-MB-231 cells led to a decrease in viability indicated by MTT assay,cell migration by scratch,and transwell migration assays,accompanied with marginal reduction in cell numbers along with the apoptotic appearance,the rate of apoptosis,and decreased lactate content in conditioned medium.These changes in the cancer phenotype were accompanied by an increase in the mitochondrial DNA to nuclear DNA ratio,increased MitoTracker green and red staining,and increased expression of transcription factors PGC-1α,NRF-1,NRF-2,TFAM,and HO-1.Pre-treatment of cells with these incretin-based drugs followed by 48 h treatment with 1μM doxorubicin increased doxorubicin sensitivity as observed by a decrease in viability by MTT assay.Thus,sitagliptin,vildagliptin,and exendin-4 exert their beneficial effects on TNBC cells via an increase in mitochondrial biogenesis that helps to switch Warburg metabolism into anti-Warburg effect.Therapeutic response was in the order of:sitagliptin>vildagliptin>exendin-4.
文摘Energy restriction is defined as reducing nutrient intake without dragging the organism into malnutrition. Energy restriction is preferred because it is a non-genetic intervention that increases life expectancy. Nicotinamide adenine dinucleotide(NAD~+)and adenosine monophosphate(AMP)levels, which are the indicators of intracellular energy deficiency, increase with energy restriction. The increase in NAD~+ level stimulates sirtuin(SIRT)enzymes, and the increase in AMP level stimulates AMP-activated protein kinase(AMPK). Various mechanisms are regulated by stimulating these enzymes. By Forkhead box O(FoxO)transcription factors, the ability of resistance to oxidative stress increases, and antioxidant genes, DNA repair, and autophagy genes are stimulated. Apoptosis is induced by stimulation of the p53 protein, and tumor growth is suppressed by the disruption of aging cells. The suppression of phosphoinositide 3-kinase(PI3K)-/-Akt, and therefore mTOR signal stimulates autophagy and mitophagia, and cleanses damaged cells and organelles. Mitochondrial biogenesis is stimulated, antioxidant capacity increases, and inflammatory response decreases. Adipose tissue and lipid metabolism are regulated by the regulation of fatty acid synthesis and oxidation. As a consequence, the effects of caloric restriction on cellular metabolism are regulated through the genetic pathways.
基金supported by the European Regional Development Fund-Project MAGNET (No. CZ.02.1.01/0.0/0.0/15_003/0000492)。
文摘Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogeneses that manifest distinct molecular mechanisms and clinical manifestations with abnormal protein dynamics and impaired bioenergetics. Mitochondrial dysfunction is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. The prevalence and incidence of these diseases is on the rise with the increasing global population and average lifespan. Although many therapeutic approaches have been tested, there are currently no effective treatment routes for the prevention or cure of these diseases. We present the current status of our knowledge and understanding of the involvement of mitochondrial dysfunction in these diseases and highlight recent advances in novel therapeutic strategies targeting neuronal bioenergetics as potential approach for treating these diseases.
基金supported by the grants from National Natural Science Foundation of China(Nos.82073835 and 81872855)National Key R&D Program of China(No.2019YFC1708901)+2 种基金CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1028)Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study(BZ0150,China)Disciplines construction project(201920200802,China)。
文摘Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease affecting both upper and lower motor neurons(MNs)with large unmet medical needs.Multiple pathological mechanisms are considered to contribute to the progression of ALS,including neuronal oxidative stress and mitochondrial dysfunction.Honokiol(HNK)has been reported to exert therapeutic effects in several neurologic disease models including ischemia stroke,Alzheimer’s disease and Parkinson’s disease.Here we found that honokiol also exhibited protective effects in ALS disease models both in vitro and in vivo.Honokiol improved the viability of NSC-34 motor neuron-like cells that expressed the mutant G93A SOD1 proteins(SOD1-G93A cells for short).Mechanistical studies revealed that honokiol alleviated cellular oxidative stress by enhancing glutathione(GSH)synthesis and activating the nuclear factor erythroid 2-related factor 2(NRF2)-antioxidant response element(ARE)pathway.Also,honokiol improved both mitochondrial function and morphology via fine-tuning mitochondrial dynamics in SOD1-G93A cells.Importantly,honokiol extended the lifespan of the SOD1-G93A transgenic mice and improved the motor function.The improvement of antioxidant capacity and mitochondrial function was further confirmed in the spinal cord and gastrocnemius muscle in mice.Overall,honokiol showed promising preclinical potential as a multiple target drug for ALS treatment.
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by grants from National Institutes of Health(R03AG044680,R21NS085747 and R01NS089604)Alzheimer’s Association(2014-NIRG-301299).
文摘Amyotrophic lateral sclerosis(ALS)is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord.Currently,there is no cure or effective treatment for ALS and the cause of disease is unknown in the majority of ALS cases.Neuronal mitochondria dysfunction is one of the earliest features of ALS.Mitochondria are highly dynamic organelles that undergo continuous fission,fusion,trafficking and turnover,all of which contribute to the maintenance of mitochondrial function.Abnormal mitochondrial dynamics have been repeatedly reported in ALS and increasing evidence suggests altered mitochondrial dynamics as possible pathomechanisms underlying mitochondrial dysfunction in ALS.Here,we provide an overview of mitochondrial dysfunction and dynamic abnormalities observed in ALS,and discuss the possibility of targeting mitochondrial dynamics as a novel therapeutic approach for ALS.
基金financed in part by the Coordenacao de Aperfeicoamento de Pessoal de Nível Superior,Brasil (CAPES),Finance Code 001. With a PNPD fellow from Graduate Program in Anesthesiology,Surgical Sciences,and Perioperative Medicine,FMUSP,and Efeom Nutricao SA。
文摘Objective: To evaluate the synergic effects of a novel oral supplement formulation, containing prebiotics,yeast b-glucans, minerals and silymarin(Silybum marianum), on lipid and glycidic metabolism, inflammatory and mitochondrial proteins of the liver, in control and high-fat diet-induced obese mice.Methods: After an acclimation period, 32 male C57 BL/6 mice were divided into the following groups:nonfat diet(NFD) vehicle, NFD supplemented, high-fat diet(HFD) vehicle and HFD supplemented. The vehicle and experimental formulation were administered orally by gavage once a day during the last four weeks of the diet(28 consecutive days). We then evaluated energy homeostasis, inflammation, and mitochondrial protein expression in these groups of mice.Results: After four weeks of supplementation, study groups experienced reduced glycemia, dyslipidemia,fat, and hepatic fibrosis levels. Additionally, proliferator-activated receptor-α, AMP-activated protein kinase-1α, peroxisome proliferator-activated receptor γ co-activator-1α, and mitochondrial transcription factor A expression levels were augmented;however, levels of inhibitor of nuclear factor-κB kinase subunit a and p65 nuclear factor-κB expression, and oxidative markers were reduced. Notably, the cortisol/C-reactive protein ratio, a well-characterized marker of the hypothalamic–pituitary–adrenal axis immune interface status, was found to be modulated by the supplement.Conclusion: We discovered that the novel supplement was able to modify different antioxidant, metabolic and inflammatory pathways, improving the energy homeostasis and inflammatory status, and consequently alleviated hepatic steatosis.
文摘Increased cardiovascular fitness,VO_(2max),is associated with enhanced endurance capacity and a decreased rate of mortality.High intensity interval training(HIIT)is one of the best methods to increase VO_(2max)and endurance capacity for top athletes and for the general public as well.Because of the high intensity of this type of training,the adaptive response is not restricted to Type I fibers,as found for moderate intensity exercise of long duration.Even with a short exercise duration,HIIT can induce activation of AMPK,PGC-1α,SIRT1 and ROS pathway as well as by the modulation of Ca^(2+)homeostasis,leading to enhanced mitochondrial biogenesis,and angiogenesis.The present review summarizes the current knowledge of the adaptive response of HIIT.
