Background Reproductive efficiency in goats is closely linked to the healthy development of follicles,with the proliferation of ovarian granulosa cells(GCs)playing a crucial role in this process.Sirtuin 3(SIRT3),an en...Background Reproductive efficiency in goats is closely linked to the healthy development of follicles,with the proliferation of ovarian granulosa cells(GCs)playing a crucial role in this process.Sirtuin 3(SIRT3),an enzyme that catalyzes post-translational modifications(PTMs)of proteins,is known to regulate a variety of mitochondrial metabolic pathways,thereby affecting cell fate.However,the specific effect of SIRT3 on the follicular development process remains unclear.Therefore,this study aimed to investigate the regulatory role of SIRT3 in the mitochondrial function and proliferation of goat GCs,as well as the underlying mechanisms involved.Results In this study,GCs from small follicles in goat ovaries presented increased proliferative potential and elevated SIRT3 expression levels compared with those from large follicles.In vitro,SIRT3 overexpression enhanced mitochondrial function,promoted proliferation and inhibited apoptosis in GCs.Correspondingly,the inhibition of SIRT3 led to the opposite effects.Notably,SIRT3 interacted with carnitine palmitoyl transferase 2(CPT2)and stabilized the CPT2 protein by mediating delactylation,which prolonged the half-life of CPT2 and prevented its degradation.Further investigation revealed that CPT2 overexpression enhanced fatty acidβ-oxidation and mitochondrial function in GCs.Additionally,CPT2 promoted the proliferation of GCs by increasing the protein levels ofβ-catenin and its downstream target,cyclin D1(CCND1).However,this effect was reversed by 3-TYP(a SIRT3 inhibitor).Conclusions SIRT3 stabilizes CPT2 protein expression through delactylation,thereby enhancing mitochondrial function and the proliferative capacity of GCs in goats.This study provides novel insights into the molecular mechanisms and regulatory pathways involved in mammalian follicular development.展开更多
BACKGROUND Spinal cord injury(SCI)often results in irreversible neurological deficits;therefore,effective treatment is urgently needed.Neural stem cells(NSCs)have excellent differentiation potential.However,the role o...BACKGROUND Spinal cord injury(SCI)often results in irreversible neurological deficits;therefore,effective treatment is urgently needed.Neural stem cells(NSCs)have excellent differentiation potential.However,the role of the long noncoding RNA X inactive-specific transcript(XIST)in NSCs and SCI remains unclear.AIM To explore the role of XIST in enhancing NSC function and its therapeutic potential in SCI.METHODS We used in vitro and in vivo models to examine the effects of XIST on NSCs.XIST was overexpressed in NSCs,and its impact on mitochondrial function,neuronal differentiation,and the insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2)/carnitine palmitoyl transferase 1A(CPT1A)pathway was assessed using a series of biochemical assays,quantitative PCR,and Seahorse XF24 analysis.A mouse model of SCI was used to evaluate the therapeutic effects of XIST in vivo.RESULTS Overexpression of XIST in NSCs significantly increased mitochondrial membrane potential,ATP production,and oxygen consumption rate.XIST also promoted NSC proliferation and neuronal differentiation while inhibiting astrocytic differentiation.Mechanistically,XIST regulated CPT1A expression post-transcriptionally by interacting with IGF2BP2.In vivo XIST-treated mice exhibited improved motor scores and reduced proinflammatory cytokine expression following SCI.CONCLUSIONThese findings suggested that XIST modulated mitochondrial function and neural differentiation in NSCs throughthe IGF2BP2/CPT1A pathway. While preliminary in vivo results are encouraging, further studies are needed todetermine the long-term therapeutic relevance and underlying mechanisms of XIST in SCI recovery.展开更多
Adiponectin receptor 1(Adipor1)deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice.Additional emerging evidence indicates tha...Adiponectin receptor 1(Adipor1)deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice.Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic(pTh17)and non-pathogenic(npTh17)cells,with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions.In the current study,we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and induced mitochondrial dysfunction in pTh17 cells.RNA sequencing demonstrated a significant increase in the expression levels of Fundc1,a gene related to mitochondrial function,in Adipor1-deficient CD4^(+)T cells.Fundc1 knockdown in Adipor1-deficient CD4^(+)T cells partially reversed the effects of Adipor1 deficiency on mitochondrial function and pTh17 differentiation.In conclusion,the current study demonstrated a novel role of Adipor1 in regulating mitochondrial function via Fundc1 to promote pTh17 cell differentiation,providing some insight into potential therapeutic targets for autoimmune and inflammatory diseases.展开更多
Background Weaning causes redox dyshomeostasis in piglets,which leads to hepatic oxidative damage.Microbederived antioxidants(MA)have great potential for anti-oxidat ion.This study aimed to investigate changes in hepa...Background Weaning causes redox dyshomeostasis in piglets,which leads to hepatic oxidative damage.Microbederived antioxidants(MA)have great potential for anti-oxidat ion.This study aimed to investigate changes in hepatic redox system,mitochondrial function and apoptosis after weaning,and effects of MA on growth performance and liver health in weaning piglets.Methods This study consisted of 2 experimets.In the both experiments,piglets were weaned at 21 days of age.In Exp.1,at 21(W0),22(W1),25(W4),28(W7),and 35(W14)days of age,6 piglets were slaughtered at each timepoint.In Exp.2,piglets were divided into 2 groups:one received MA gavage(MA)and the other received saline gavage(CON).At 25 days of age,6 piglets from each group were sacrificed.Results In Exp.1,weaning caused growth inhibition and liver developmental retardation from W0 to W4.The mRNA sequencing between W0 and W4 revealed that pathways related to"regulation of apoptotic process"and"reactive oxygen species metabolic process"were enriched.Further study showed that weaning led to higher hepatic content of reactive oxygen species(ROS),H_(2)O_(2) and O_(2)~-.Weaning enhanced mitochondrial fission and suppressed their fusion,activated mitophagy,thus triggering cell apoptosis.In Exp.2,MA improved growth performance of piglets with higher average daily gain(ADG)and average daily feed intake(ADFI).The hepatic ROS,as well as products of oxidative damage malonaldehyde(MDA)and 8-hydroxy-2'-deoxyguanosine(8-OHdG)in the MA group decreased significantly than that of the CON group.The MA elevated mitochondrial membrane potential,increased activity of mitochondrial respiratory chain complexes(MRC)ⅠandⅣ,enhanced mitochondrial fusion and reduced mitophagy thus decreasing cell apoptosis.Conclusions The present study showed that MA improved the growth performance of weaning piglets and reversed weaning-induced oxidative damage,mitochondrial dysfunction,and apoptosis.Our results suggested that MA had promising prospects for maintaining liver health in weaning piglets and provided a reference for studies of liver diseases in humans.展开更多
Hyperglycemia is the dominant phenotype of diabetes and the main contributor of diabetic complications. Puerarin is widely used in cardiovascular diseases and diabetic vascular complications. However, little is known ...Hyperglycemia is the dominant phenotype of diabetes and the main contributor of diabetic complications. Puerarin is widely used in cardiovascular diseases and diabetic vascular complications. However, little is known about its direct effects on diabetes. The aim of our study is to investigate its antidiabetic effect in vivo and in vitro, and explore the underlying mechanism. We used type I diabetic mice induced by streptozotocin to observe the effects of puerarin on glucose metabolism. In addition, oxidative stress and hepatic mitochondrial respiratory activity were evaluated in type I diabetic mice. In vitro, glucose consumption in Hep G2 cells was assayed along with the q PCR detection of glucogenesis genes expression. Moreover, ATP production was examined and phosphorylation of AMPK was determined using Western blot. Finally, the molecular docking was performed to predict the potential interaction of puerarin with AMPK utilizing program Lib Dock of Discovery Studio 2018 software. The results showed that puerarin improved Hep G2 glucose consumption and upregulated the glucogenesis related genes expression. Also, puerarin lowered fasting and fed blood glucose with improvement of glucose tolerance in type I diabetic mice. Further mechanism investigation showed that puerarin suppressed oxidative stress and improved hepatic mitochondrial respiratory function with enhancing ATP production and activating phosphorylation of AMPK. Docking study showed that puerarin interacted with AMPK activate site and enhancing phosphorylation. Taken together, these findings indicated that puerarin exhibited the hypoglycemic effect through attenuating oxidative stress and improving mitochondrial function via AMPK regulation, which may serve as a potential therapeutic option for diabetes treatment.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 of...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
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
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
Focal ischemia due to reduction of cerebral blood flow(CBF),creates 2 zones of damage:the core area,which suffers severe damage,and penumbra area,which surrounds the core and suffers intermediate levels of injury.Obje...Focal ischemia due to reduction of cerebral blood flow(CBF),creates 2 zones of damage:the core area,which suffers severe damage,and penumbra area,which surrounds the core and suffers intermediate levels of injury.Objectives:A novel method is introduced,which evaluates mitochondrial function in the core and in the penumbra,during focal cerebral ischemia.Methods:Wistar rats underwent focal cerebral ischemia by middle cerebral artery occlusion(MCAO)for 60 minutes,followed by 60 minutes of reperfusion.Mitochondrial function was assessed by a unique Multi-Site—Multi-Parametric(MSMP)monitoring system,which measures mitochondrial NADH using fluorometric technique,and CBF using Laser Doppler Flowmetry(LDF).Results:At the onset of occlusion,CBF dropped and NADH increased significantly only in the right hemisphere.CBF levels were significantly lower and NADH significantly higher in the core than in the penumbra.After reperfusion,CBF and NADH recovered correspondingly to the intensity of ischemia.Conclusion:Application of the MSMP system can add significant information for the understanding of the cerebral metabolic state under ischemic conditions,with an emphasis on mitochondrial function.展开更多
Parkinson＇s disease （PD） is a progressive neurodegenerative disease, which is generally considered a multifactorial disorder that arises owing to a combination of genes and environmental factors. While most cases a...Parkinson＇s disease （PD） is a progressive neurodegenerative disease, which is generally considered a multifactorial disorder that arises owing to a combination of genes and environmental factors. While most cases are idiopathic, in about 10% of the patients a genetic cause can be detected, ascribable to mutations in more than a dozen genes. PD is characterized clinically by tremor, rigidity, reduced mo- tor activity （bradykinesia）, and postural instability and pathological- ly by loss of dopaminergic （DA） neurons in the substantia nigra pars compacta, loss of DA innervation in the striatum, and the presence of a-synuclein positive aggregates in the form of Lewy bodies. The symptomatic treatment of PD with levodopa, which aims at replac- ing dopamine, remains the gold standard, and no neuroprotective or disease-modifying therapy is available. During treatment, the disease continues to progress, and long-term use of levodopa has import- ant limitations including motor complications termed dyskinesias. Therefore, a pharmacological therapy able to prevent or halt the neu- rodegenerative process is urgently required.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
A metabolic switch favoring glycolysis over aerobic oxidative phosphorylation,termed the“Warburg effect”,is a hallmark of cancer cells[1].Hexokinase(HK)catalyzes the first and irreversible step of glycolysis,thereby...A metabolic switch favoring glycolysis over aerobic oxidative phosphorylation,termed the“Warburg effect”,is a hallmark of cancer cells[1].Hexokinase(HK)catalyzes the first and irreversible step of glycolysis,thereby limiting overall glycolytic activity.Mammals encode five HK family members:HK1-4 and HKDC1(HK domain containing 1).HKDC1 has an exceptionally low glucose affinity and,therefore,low hexokinase activity under physiological conditions[2],raising questions about its function.A recent study indicated that HKDC1 functions as a glucose sensor within the tumor microenvironment[3],and its dysregulated expression has been associated with chronic inflammation[4]and various cancers[5].展开更多
Mitochondria,the cellular powerhouses,are dynamic organelles whose quality control is essential for maintaining cellular homeostasis,particularly under stress conditions such as oxidative damage or metabolic imbalance...Mitochondria,the cellular powerhouses,are dynamic organelles whose quality control is essential for maintaining cellular homeostasis,particularly under stress conditions such as oxidative damage or metabolic imbalance[1].Among the mechanisms ensuring mitochondrial integrity,mitochondrial-derived vesicles(MDVs)have emerged as a critical pathway for shuttling damaged components to lysosomes or the extracellular space,distinct from the more widely studied mitophagy[2,3].展开更多
Activation of mitochondrial function and heat production in adipose tissue by the modification of dietary fat is a promising strategy against obesity.However,as an important source of lipids for ketogenic and daily di...Activation of mitochondrial function and heat production in adipose tissue by the modification of dietary fat is a promising strategy against obesity.However,as an important source of lipids for ketogenic and daily diets,the function of fats extracted from different adipose tissue sites was largely unknown.In this study,we illustrated the function of fats extracted from adipose tissues with different"beigeing"properties in the ketogenic diet and identified lipid profiles of fats that facilitate energy expenditure.We found that the anti-obesity effect of ketogenic diets was potentiated by using"beigeing"fat[porcine subcutaneous adipose tissue(SAT)]as a major energy-providing ingredient.Through lipidomic analyses,phosphatidylserine(PS)was identified as a functional lipid activating thermogenesis in adipose tissue.Moreover,in vivo studies showed that PS induces adipose tissue thermogenesis and alleviates diet-induced obesity in mice.Invitro studies showed that PS promotes UCP1 expression and lipolysis of adipocytes.Mechanistically,PS promoted mitochondrial function in adipocytes via the ADCY3-cAMP-PKA-PGClαpathway.In addition,PS-PGCla binding may affect the stability of the PGClαprotein,which further augments PS-induced thermogenesis.These results demonstrated the efficacy of dietary SAT fats in diminishing lipid accumulation and the underlying molecular mechanism of PS in enhancing UCP1 expression and mitochondrial function.Thus,our findings suggest that as dietary fat,"beigeing"fat provides more beneficial lipids that contribute to the improvement of mitochondrial function,including PS,which may become a novel,nonpharmacological therapy to increase energy expenditure and counteract obesity and its related diseases.展开更多
Diabetic cardiomyopathy(DCM)is a major cause of heart failure in diabetic patients.It progresses asymptomatically prior to the onset of severe cardiac symptoms[1];therefore,elucidating the underlying mechanisms of DCM...Diabetic cardiomyopathy(DCM)is a major cause of heart failure in diabetic patients.It progresses asymptomatically prior to the onset of severe cardiac symptoms[1];therefore,elucidating the underlying mechanisms of DCM is critical to providing early treatment options.This commentary elaborates on the findings of Jiang et al.[2],who investigated the role of adipokine hormone,Adipsin,as a cardioprotective factor in DCM.We provide an exposition and alternative treatment considerations,like Fisetin,and discuss the potential of investigating other cellular targets implicated in cardiac dysfunction,like the interleukin-1 receptor-associated kinaselike 2(Irak2)protein[3]and protein kinase R[4].展开更多
Artemisia argyi(A.argyi),a plant with a longstanding history as a raw material for traditional medicine and functional diets in Asia,has been used traditionally to bathe and soak feet for its disinfectant and itch-rel...Artemisia argyi(A.argyi),a plant with a longstanding history as a raw material for traditional medicine and functional diets in Asia,has been used traditionally to bathe and soak feet for its disinfectant and itch-relieving properties.Despite its widespread use,scientific evidence validating the antifungal efficacy of A.argyi water extract(AAWE)against dermatophytes,particularly Trichophyton rubrum,Trichophyton mentagrophytes,and Microsporum gypseum,remains limited.This study aimed to substantiate the scientific basis of the folkloric use of A.argyi by evaluating the antifungal effects and the underlying molecular mechanisms of its active subfraction against dermatophytes.The results indicated that AAWE exhibited excellent antifungal effects against the three aforementioned dermatophyte species.The subfraction AAWE6,isolated using D101 macroporous resin,emerged as the most potent subfraction.The minimum inhibitory concentrations(MICs)of AAWE6 against T.rubrum,M.gypseum,and T.mentagrophytes were 312.5,312.5,and 625μg·mL−1,respectively.Transmission electron microscopy(TEM)results and assays of enzymes linked to cell wall integrity and cell membrane function indicated that AAWE6 could penetrate the external protective barrier of T.rubrum,creating breaches(“small holes”),and disrupt the internal mitochondrial structure(“granary”).Furthermore,transcriptome data,quantitative real-time PCR(RT-qPCR),and biochemical assays corroborated the severe disruption of mitochondrial function,evidenced by inhibited tricarboxylic acid(TCA)cycle and energy metabolism.Additionally,chemical characterization and molecular docking analyses identified flavonoids,primarily eupatilin(131.16±4.52 mg·g^(−1))and jaceosidin(4.17±0.18 mg·g^(−1)),as the active components of AAWE6.In conclusion,the subfraction AAWE6 from A.argyi exerts antifungal effects against dermatophytes by disrupting mitochondrial morphology and function.This research validates the traditional use of A.argyi and provides scientific support for its antidermatophytic applications,as recognized in the Chinese patent(No.ZL202111161301.9).展开更多
Osteosarcoma is the most prevalent primarymalignant bone tumor,primarily affecting adolescents aged 15–25 years.It is characterized by a high recurrence rate,poor prognosis,and lack of important biomarkers.Significan...Osteosarcoma is the most prevalent primarymalignant bone tumor,primarily affecting adolescents aged 15–25 years.It is characterized by a high recurrence rate,poor prognosis,and lack of important biomarkers.Significant mitochondrial dysfunction in osteosarcoma cells has been widely reported by recent studies.Dysfunctional mitochondria occupy an important position in cellularmetabolic reprogramming,immune microenvironment regulation,and programmed cell death.Therefore,targeting mitochondrial dysfunction may represent a new mechanism to overcome therapeutic barriers in the treatment of osteosarcoma and provides crucial target molecules for further development of targeted therapies and immunotherapies.The present article summarizes the recent reports of mitochondrial dysfunction in osteosarcoma and links it to various programmed cell death mechanisms,aiming to provide the basis for further clinical practice.展开更多
The study was conducted to investigate the regulatory mechanism of glutamine(Gln)on intestinal inflammation in an Escherichia coli lipopolysaccharide(E.coli LPS)-induced in vivo and in vitro models.Piglets(n=8)weaned ...The study was conducted to investigate the regulatory mechanism of glutamine(Gln)on intestinal inflammation in an Escherichia coli lipopolysaccharide(E.coli LPS)-induced in vivo and in vitro models.Piglets(n=8)weaned at 21 d of age were fed a basal diet(control and LPS groups)or 1%Gln diet(Gln t LPS group)ad libitum for 4 weeks.On d 22,24,26 and 28,piglets in the LPS and Gln t LPS groups were intraperitoneally injected with E.coli LPS.Intestinal porcine epithelial cells(IPEC-J2)(n=6)induced by LPS were used to assess related mechanisms and compound C was used to inhibit adenosine 50-monophosphate-activated protein kinase(AMPK)activity.Our current results showed that compared with the LPS treatment,the Gln t LPS treatment had better growth performance and greater villus height(P<0.05),and the Gln t LPS treatment reduced the rate of diarrhea by 6.4%(P<0.05);the Gln t LPS treatment decreased serum tumor necrosis factor(TNF-ɑ),interleukin-6(IL-6),Kt,cortisol and insulin levels,whereas increased(P<0.05)serum immunoglobulin M and epidermal growth factor levels;the Gln t LPS treatment increased(P<0.05)the expression of aquaporins and AMPK pathwayassociated targets in the jejunum and ileum of piglets,whereas decreased the expression of ion transporters(P<0.05).The in vitro results showed that 4 mmol/L Gln administration could inhibit(P<0.05)cell apoptosis and interleukin-1b(IL-1b),IL-6 and TNF-ɑsecretion in LPS-induced IPEC-J2 cells,promote(P<0.05)mitochondrial respiratory metabolism and increase(P<0.05)the number of mitochondria and mitochondrial membrane potential.The activity of AMPK was elevated by 70%to 300%in Gln-treated IPEC-J2 cells under LPS challenge or normal conditions.Our results indicate that pre-administration of Gln to piglets suppresses intestinal inflammation by modulating the crosstalk between AMPK activation and mitochondrial function.展开更多
AIM To comprehensively evaluate mitochondrial(dys)function in preclinical models of nonalcoholic steatohepatitis(NASH).METHODS We utilized two readily available mouse models of nonalcoholic fatty liver disease(NAFLD)w...AIM To comprehensively evaluate mitochondrial(dys)function in preclinical models of nonalcoholic steatohepatitis(NASH).METHODS We utilized two readily available mouse models of nonalcoholic fatty liver disease(NAFLD)with or without progressive fibrosis:Lep^(ob)/Lep^(ob)(ob/ob)and FATZO mice on high trans-fat,high fructose and high cholesterol(AMLN)diet.Presence of NASH was assessed using immunohistochemical and pathological techniques,and gene expression profiling.Morphological features of mitochondria were assessed via transmission electron microscopy and immunofluorescence,and function was assessed by measuring oxidative capacity in primary hepatocytes,and respiratory control and proton leak in isolated mitochondria.Oxidative stress was measured by assessing activity and/or expression levels of Nrf1,Sod1,Sod2,catalase and 8-OHdG.RESULTS When challenged with AMLN diet for 12 wk,ob/ob and FATZO mice developed steatohepatitis in the presence of obesity and hyperinsulinemia.NASH development was associated with hepatic mitochondrial abnormalities,similar to those previously observed in humans,including mitochondrial accumulation and increased proton leak.AMLN diet also resulted in increased numbers of fragmented mitochondria in both strains of mice.Despite similar mitochondrial phenotypes,we found that ob/ob mice developed more advanced hepatic fibrosis.Activity of superoxide dismutase(SOD)was increased in ob/ob AMLN mice,whereas FATZO mice displayed increased catalase activity,irrespective of diet.Furthermore,8-OHd G,a marker of oxidative DNA damage,was significantly increased in ob/ob AMLN mice compared to FATZO AMLN mice.Therefore,antioxidant capacity reflected as the ratio of catalase:SOD activity was similar between FATZO and C57 BL6 J control mice,but significantly perturbed in ob/ob mice.CONCLUSION Oxidative stress,and/or the capacity to compensate for increased oxidative stress,in the setting of mitochondrial dysfunction,is a key factor for development of hepatic injury and fibrosis in these mouse models.展开更多
Background and aim:Cholestasis-associated renal injury or cholemic nephropathy(CN)is a serious clinical problem.Previous studies mentioned that oxidative stress and mitochondrial impairment play a role in CN.There is ...Background and aim:Cholestasis-associated renal injury or cholemic nephropathy(CN)is a serious clinical problem.Previous studies mentioned that oxidative stress and mitochondrial impairment play a role in CN.There is no specific pharmacological intervention for CN.Metformin is an anti-diabetic drug administered for decades.On the other hand,novel pharmacological properties have emerged for this drug.The effect of metformin on oxidative stress parameters has been well-recognized in different experimental models.It has also been found that metformin positively affected mitochondrial function.The current study aimed to evaluate the effects of metformin in an animal model of CN.Methods:Rats underwent bile duct ligation(BDL)and were treated with metformin(250 and 500 mg/kg)for 14 consecutive days.Two weeks after the BDL operations,urine,serum,and kidney samples were collected and analyzed.Results:Markers of oxidative stress,including reactive oxygen species(ROS)formation,lipid peroxida-tion,protein carbonylation,depleted antioxidant capacity,and decreased glutathione(GSH)levels were detected in BDL animals.Moreover,mitochondrial indices,including adenosine triphosphate(ATP)level,dehydrogenase activity,mitochondrial membrane potential,and mitochondrial permeability,were impaired in the kidney of cholestatic rats.Renal histopathological alterations in cholestatic animals included tubular degeneration and interstitial inflammation,cast formation,and fibrosis.It was found that metformin significantly alleviated oxidative stress and improved mitochondrial indices in the kidney of cholestatic rats.Tissue histopathological alterations were also mitigated in metformin-treated groups.Conclusions:Metformin could be a candidate for managing CN.The nephroprotective role of metformin is primarily associated with its effects on oxidative stress parameters and mitochondrial function.展开更多
基金supported by the National Key Research and Development Program of China(2022YFD1300202)the Technology Innovation and Application Development Special Project of Chongqing(cstc2021jscx-gksbX0008).
文摘Background Reproductive efficiency in goats is closely linked to the healthy development of follicles,with the proliferation of ovarian granulosa cells(GCs)playing a crucial role in this process.Sirtuin 3(SIRT3),an enzyme that catalyzes post-translational modifications(PTMs)of proteins,is known to regulate a variety of mitochondrial metabolic pathways,thereby affecting cell fate.However,the specific effect of SIRT3 on the follicular development process remains unclear.Therefore,this study aimed to investigate the regulatory role of SIRT3 in the mitochondrial function and proliferation of goat GCs,as well as the underlying mechanisms involved.Results In this study,GCs from small follicles in goat ovaries presented increased proliferative potential and elevated SIRT3 expression levels compared with those from large follicles.In vitro,SIRT3 overexpression enhanced mitochondrial function,promoted proliferation and inhibited apoptosis in GCs.Correspondingly,the inhibition of SIRT3 led to the opposite effects.Notably,SIRT3 interacted with carnitine palmitoyl transferase 2(CPT2)and stabilized the CPT2 protein by mediating delactylation,which prolonged the half-life of CPT2 and prevented its degradation.Further investigation revealed that CPT2 overexpression enhanced fatty acidβ-oxidation and mitochondrial function in GCs.Additionally,CPT2 promoted the proliferation of GCs by increasing the protein levels ofβ-catenin and its downstream target,cyclin D1(CCND1).However,this effect was reversed by 3-TYP(a SIRT3 inhibitor).Conclusions SIRT3 stabilizes CPT2 protein expression through delactylation,thereby enhancing mitochondrial function and the proliferative capacity of GCs in goats.This study provides novel insights into the molecular mechanisms and regulatory pathways involved in mammalian follicular development.
文摘BACKGROUND Spinal cord injury(SCI)often results in irreversible neurological deficits;therefore,effective treatment is urgently needed.Neural stem cells(NSCs)have excellent differentiation potential.However,the role of the long noncoding RNA X inactive-specific transcript(XIST)in NSCs and SCI remains unclear.AIM To explore the role of XIST in enhancing NSC function and its therapeutic potential in SCI.METHODS We used in vitro and in vivo models to examine the effects of XIST on NSCs.XIST was overexpressed in NSCs,and its impact on mitochondrial function,neuronal differentiation,and the insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2)/carnitine palmitoyl transferase 1A(CPT1A)pathway was assessed using a series of biochemical assays,quantitative PCR,and Seahorse XF24 analysis.A mouse model of SCI was used to evaluate the therapeutic effects of XIST in vivo.RESULTS Overexpression of XIST in NSCs significantly increased mitochondrial membrane potential,ATP production,and oxygen consumption rate.XIST also promoted NSC proliferation and neuronal differentiation while inhibiting astrocytic differentiation.Mechanistically,XIST regulated CPT1A expression post-transcriptionally by interacting with IGF2BP2.In vivo XIST-treated mice exhibited improved motor scores and reduced proinflammatory cytokine expression following SCI.CONCLUSIONThese findings suggested that XIST modulated mitochondrial function and neural differentiation in NSCs throughthe IGF2BP2/CPT1A pathway. While preliminary in vivo results are encouraging, further studies are needed todetermine the long-term therapeutic relevance and underlying mechanisms of XIST in SCI recovery.
基金the National Natural Science Foundation of China(Grant No.82071827)the Jiangsu Province Natural Science Foundation(Grant No.BK20210963).
文摘Adiponectin receptor 1(Adipor1)deficiency has been shown to inhibit Th17 cell differentiation and reduce joint inflammation and bone erosion in antigen-induced arthritis mice.Additional emerging evidence indicates that Th17 cells may differentiate into pathogenic(pTh17)and non-pathogenic(npTh17)cells,with the pTh17 cells playing a crucial role in numerous autoimmune and inflammatory conditions.In the current study,we found that Adipor1 deficiency inhibited pTh17 differentiation in vitro and induced mitochondrial dysfunction in pTh17 cells.RNA sequencing demonstrated a significant increase in the expression levels of Fundc1,a gene related to mitochondrial function,in Adipor1-deficient CD4^(+)T cells.Fundc1 knockdown in Adipor1-deficient CD4^(+)T cells partially reversed the effects of Adipor1 deficiency on mitochondrial function and pTh17 differentiation.In conclusion,the current study demonstrated a novel role of Adipor1 in regulating mitochondrial function via Fundc1 to promote pTh17 cell differentiation,providing some insight into potential therapeutic targets for autoimmune and inflammatory diseases.
基金supported by the National Natural Science Foundation of China(Gant no.32272903)。
文摘Background Weaning causes redox dyshomeostasis in piglets,which leads to hepatic oxidative damage.Microbederived antioxidants(MA)have great potential for anti-oxidat ion.This study aimed to investigate changes in hepatic redox system,mitochondrial function and apoptosis after weaning,and effects of MA on growth performance and liver health in weaning piglets.Methods This study consisted of 2 experimets.In the both experiments,piglets were weaned at 21 days of age.In Exp.1,at 21(W0),22(W1),25(W4),28(W7),and 35(W14)days of age,6 piglets were slaughtered at each timepoint.In Exp.2,piglets were divided into 2 groups:one received MA gavage(MA)and the other received saline gavage(CON).At 25 days of age,6 piglets from each group were sacrificed.Results In Exp.1,weaning caused growth inhibition and liver developmental retardation from W0 to W4.The mRNA sequencing between W0 and W4 revealed that pathways related to"regulation of apoptotic process"and"reactive oxygen species metabolic process"were enriched.Further study showed that weaning led to higher hepatic content of reactive oxygen species(ROS),H_(2)O_(2) and O_(2)~-.Weaning enhanced mitochondrial fission and suppressed their fusion,activated mitophagy,thus triggering cell apoptosis.In Exp.2,MA improved growth performance of piglets with higher average daily gain(ADG)and average daily feed intake(ADFI).The hepatic ROS,as well as products of oxidative damage malonaldehyde(MDA)and 8-hydroxy-2'-deoxyguanosine(8-OHdG)in the MA group decreased significantly than that of the CON group.The MA elevated mitochondrial membrane potential,increased activity of mitochondrial respiratory chain complexes(MRC)ⅠandⅣ,enhanced mitochondrial fusion and reduced mitophagy thus decreasing cell apoptosis.Conclusions The present study showed that MA improved the growth performance of weaning piglets and reversed weaning-induced oxidative damage,mitochondrial dysfunction,and apoptosis.Our results suggested that MA had promising prospects for maintaining liver health in weaning piglets and provided a reference for studies of liver diseases in humans.
基金supported by the National Natural Science Foundation of China (No. 81770847)the Drug Innovation Major Project (No. 2018ZX09711001-003-005)+1 种基金the CAMS Innovation Fund for Medical Sciences (CIFMS)(Nos. 2017-I2M-1-010and 2016-I2M-3-007)National Key Research and Development Plan (No. 2016YFC1000905)。
文摘Hyperglycemia is the dominant phenotype of diabetes and the main contributor of diabetic complications. Puerarin is widely used in cardiovascular diseases and diabetic vascular complications. However, little is known about its direct effects on diabetes. The aim of our study is to investigate its antidiabetic effect in vivo and in vitro, and explore the underlying mechanism. We used type I diabetic mice induced by streptozotocin to observe the effects of puerarin on glucose metabolism. In addition, oxidative stress and hepatic mitochondrial respiratory activity were evaluated in type I diabetic mice. In vitro, glucose consumption in Hep G2 cells was assayed along with the q PCR detection of glucogenesis genes expression. Moreover, ATP production was examined and phosphorylation of AMPK was determined using Western blot. Finally, the molecular docking was performed to predict the potential interaction of puerarin with AMPK utilizing program Lib Dock of Discovery Studio 2018 software. The results showed that puerarin improved Hep G2 glucose consumption and upregulated the glucogenesis related genes expression. Also, puerarin lowered fasting and fed blood glucose with improvement of glucose tolerance in type I diabetic mice. Further mechanism investigation showed that puerarin suppressed oxidative stress and improved hepatic mitochondrial respiratory function with enhancing ATP production and activating phosphorylation of AMPK. Docking study showed that puerarin interacted with AMPK activate site and enhancing phosphorylation. Taken together, these findings indicated that puerarin exhibited the hypoglycemic effect through attenuating oxidative stress and improving mitochondrial function via AMPK regulation, which may serve as a potential therapeutic option for diabetes treatment.
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 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.
文摘Focal ischemia due to reduction of cerebral blood flow(CBF),creates 2 zones of damage:the core area,which suffers severe damage,and penumbra area,which surrounds the core and suffers intermediate levels of injury.Objectives:A novel method is introduced,which evaluates mitochondrial function in the core and in the penumbra,during focal cerebral ischemia.Methods:Wistar rats underwent focal cerebral ischemia by middle cerebral artery occlusion(MCAO)for 60 minutes,followed by 60 minutes of reperfusion.Mitochondrial function was assessed by a unique Multi-Site—Multi-Parametric(MSMP)monitoring system,which measures mitochondrial NADH using fluorometric technique,and CBF using Laser Doppler Flowmetry(LDF).Results:At the onset of occlusion,CBF dropped and NADH increased significantly only in the right hemisphere.CBF levels were significantly lower and NADH significantly higher in the core than in the penumbra.After reperfusion,CBF and NADH recovered correspondingly to the intensity of ischemia.Conclusion:Application of the MSMP system can add significant information for the understanding of the cerebral metabolic state under ischemic conditions,with an emphasis on mitochondrial function.
基金supported by the Ministry of Health and Department of Educational Assistance,University and Research of the Autonomous Province of Bolzano
文摘Parkinson＇s disease （PD） is a progressive neurodegenerative disease, which is generally considered a multifactorial disorder that arises owing to a combination of genes and environmental factors. While most cases are idiopathic, in about 10% of the patients a genetic cause can be detected, ascribable to mutations in more than a dozen genes. PD is characterized clinically by tremor, rigidity, reduced mo- tor activity （bradykinesia）, and postural instability and pathological- ly by loss of dopaminergic （DA） neurons in the substantia nigra pars compacta, loss of DA innervation in the striatum, and the presence of a-synuclein positive aggregates in the form of Lewy bodies. The symptomatic treatment of PD with levodopa, which aims at replac- ing dopamine, remains the gold standard, and no neuroprotective or disease-modifying therapy is available. During treatment, the disease continues to progress, and long-term use of levodopa has import- ant limitations including motor complications termed dyskinesias. Therefore, a pharmacological therapy able to prevent or halt the neu- rodegenerative process is urgently required.
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supported by the German Research Foundation(DFG)through the individual grant SO1141/10-1,the Research Unit FOR5042“miTarget-The Microbiome as a Target in Inflammatory Bowel Diseases”(project P5)the Excellence Cluster EXS2167“Precision Medicine in Chronic Inflammation”,an intramural grant of the medical faculty of Kiel University(grant no K126408)Felix Sommer and ZMB Young Scientist Award 2021,category doctoral students(grant no F384430)to Lea Järke.
文摘A metabolic switch favoring glycolysis over aerobic oxidative phosphorylation,termed the“Warburg effect”,is a hallmark of cancer cells[1].Hexokinase(HK)catalyzes the first and irreversible step of glycolysis,thereby limiting overall glycolytic activity.Mammals encode five HK family members:HK1-4 and HKDC1(HK domain containing 1).HKDC1 has an exceptionally low glucose affinity and,therefore,low hexokinase activity under physiological conditions[2],raising questions about its function.A recent study indicated that HKDC1 functions as a glucose sensor within the tumor microenvironment[3],and its dysregulated expression has been associated with chronic inflammation[4]and various cancers[5].
基金supported by the National Key Research and Development Program of China(2022YFE0210100)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0480000)+6 种基金the National Natural Science Foundation projects of China(32371007,32025010,32488301,92254301,92357302,92157202,32241002,32261160376,and 32370782)the Major Project of Guangzhou National Laboratory(GZNL2024A03006)the Key Research Program,CAS(ZDBS-ZRKJZ-TLC003,YSBR-075 and 188GJHZ2024048GC)Guangdong Province Science and Technology Program(2023B0303000023,2023B1111050005,2023B1212060050,2023B1212120009,2024B1515040020,and 2024A1515030120)Guangzhou Science and Technology Program(202206060002 and 2025A04J5485)Health@InnoHK funding support from the Innovation Technology Commission of the Hong Kong SAR,and Major Research Project(GIBHMRP25-01)Basic Research Project of Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences.
文摘Mitochondria,the cellular powerhouses,are dynamic organelles whose quality control is essential for maintaining cellular homeostasis,particularly under stress conditions such as oxidative damage or metabolic imbalance[1].Among the mechanisms ensuring mitochondrial integrity,mitochondrial-derived vesicles(MDVs)have emerged as a critical pathway for shuttling damaged components to lysosomes or the extracellular space,distinct from the more widely studied mitophagy[2,3].
基金supported by the National Natural Science Foundation of China(32272887 and 31722053)the National Key R&D Program of China(2018YFA0800403)to T.S.
文摘Activation of mitochondrial function and heat production in adipose tissue by the modification of dietary fat is a promising strategy against obesity.However,as an important source of lipids for ketogenic and daily diets,the function of fats extracted from different adipose tissue sites was largely unknown.In this study,we illustrated the function of fats extracted from adipose tissues with different"beigeing"properties in the ketogenic diet and identified lipid profiles of fats that facilitate energy expenditure.We found that the anti-obesity effect of ketogenic diets was potentiated by using"beigeing"fat[porcine subcutaneous adipose tissue(SAT)]as a major energy-providing ingredient.Through lipidomic analyses,phosphatidylserine(PS)was identified as a functional lipid activating thermogenesis in adipose tissue.Moreover,in vivo studies showed that PS induces adipose tissue thermogenesis and alleviates diet-induced obesity in mice.Invitro studies showed that PS promotes UCP1 expression and lipolysis of adipocytes.Mechanistically,PS promoted mitochondrial function in adipocytes via the ADCY3-cAMP-PKA-PGClαpathway.In addition,PS-PGCla binding may affect the stability of the PGClαprotein,which further augments PS-induced thermogenesis.These results demonstrated the efficacy of dietary SAT fats in diminishing lipid accumulation and the underlying molecular mechanism of PS in enhancing UCP1 expression and mitochondrial function.Thus,our findings suggest that as dietary fat,"beigeing"fat provides more beneficial lipids that contribute to the improvement of mitochondrial function,including PS,which may become a novel,nonpharmacological therapy to increase energy expenditure and counteract obesity and its related diseases.
基金supported by the Office of Naval Research Grant(N00014-22-1-2184)。
文摘Diabetic cardiomyopathy(DCM)is a major cause of heart failure in diabetic patients.It progresses asymptomatically prior to the onset of severe cardiac symptoms[1];therefore,elucidating the underlying mechanisms of DCM is critical to providing early treatment options.This commentary elaborates on the findings of Jiang et al.[2],who investigated the role of adipokine hormone,Adipsin,as a cardioprotective factor in DCM.We provide an exposition and alternative treatment considerations,like Fisetin,and discuss the potential of investigating other cellular targets implicated in cardiac dysfunction,like the interleukin-1 receptor-associated kinaselike 2(Irak2)protein[3]and protein kinase R[4].
基金This work was supported by the National Natural Science Foundation of China(No.32270391)the Natural Science Foundation of Hubei Province(Nos.2023AFA032 and 2022CFB391)+1 种基金the Young Qihuang Scholars of the State Administration of Traditional Chinese Medicine,Hubei Province Administration of Traditional Chinese Medicine Research Project(No.ZY2023Z023)the Earmarked Fund for CARS-21 and Key Project at Central Government Level:the Ability Establishment of Sustainable Use for Valuable Chinese Medicine Resources(No.2060302).
文摘Artemisia argyi(A.argyi),a plant with a longstanding history as a raw material for traditional medicine and functional diets in Asia,has been used traditionally to bathe and soak feet for its disinfectant and itch-relieving properties.Despite its widespread use,scientific evidence validating the antifungal efficacy of A.argyi water extract(AAWE)against dermatophytes,particularly Trichophyton rubrum,Trichophyton mentagrophytes,and Microsporum gypseum,remains limited.This study aimed to substantiate the scientific basis of the folkloric use of A.argyi by evaluating the antifungal effects and the underlying molecular mechanisms of its active subfraction against dermatophytes.The results indicated that AAWE exhibited excellent antifungal effects against the three aforementioned dermatophyte species.The subfraction AAWE6,isolated using D101 macroporous resin,emerged as the most potent subfraction.The minimum inhibitory concentrations(MICs)of AAWE6 against T.rubrum,M.gypseum,and T.mentagrophytes were 312.5,312.5,and 625μg·mL−1,respectively.Transmission electron microscopy(TEM)results and assays of enzymes linked to cell wall integrity and cell membrane function indicated that AAWE6 could penetrate the external protective barrier of T.rubrum,creating breaches(“small holes”),and disrupt the internal mitochondrial structure(“granary”).Furthermore,transcriptome data,quantitative real-time PCR(RT-qPCR),and biochemical assays corroborated the severe disruption of mitochondrial function,evidenced by inhibited tricarboxylic acid(TCA)cycle and energy metabolism.Additionally,chemical characterization and molecular docking analyses identified flavonoids,primarily eupatilin(131.16±4.52 mg·g^(−1))and jaceosidin(4.17±0.18 mg·g^(−1)),as the active components of AAWE6.In conclusion,the subfraction AAWE6 from A.argyi exerts antifungal effects against dermatophytes by disrupting mitochondrial morphology and function.This research validates the traditional use of A.argyi and provides scientific support for its antidermatophytic applications,as recognized in the Chinese patent(No.ZL202111161301.9).
基金supported by the Guangxi Natural Science Foundation(No.2023JJA140880).
文摘Osteosarcoma is the most prevalent primarymalignant bone tumor,primarily affecting adolescents aged 15–25 years.It is characterized by a high recurrence rate,poor prognosis,and lack of important biomarkers.Significant mitochondrial dysfunction in osteosarcoma cells has been widely reported by recent studies.Dysfunctional mitochondria occupy an important position in cellularmetabolic reprogramming,immune microenvironment regulation,and programmed cell death.Therefore,targeting mitochondrial dysfunction may represent a new mechanism to overcome therapeutic barriers in the treatment of osteosarcoma and provides crucial target molecules for further development of targeted therapies and immunotherapies.The present article summarizes the recent reports of mitochondrial dysfunction in osteosarcoma and links it to various programmed cell death mechanisms,aiming to provide the basis for further clinical practice.
基金Huxiang Young Talent Support Program(2020RC3052)Natural Science Foundation of China(31902168,31872371)+4 种基金Hunan Key Research and Development Plan(2020NK2059)State Key Laboratory of Animal Nutrition(2004DA125184F1907)Special Funds for Construction of Innovative Provinces in Hunan Province(2019RS3022)Guangxi Key Research and Development Plan(Guike AB19259012)Guangxi Guilin Science and Technology Planning Project(2020010901).
文摘The study was conducted to investigate the regulatory mechanism of glutamine(Gln)on intestinal inflammation in an Escherichia coli lipopolysaccharide(E.coli LPS)-induced in vivo and in vitro models.Piglets(n=8)weaned at 21 d of age were fed a basal diet(control and LPS groups)or 1%Gln diet(Gln t LPS group)ad libitum for 4 weeks.On d 22,24,26 and 28,piglets in the LPS and Gln t LPS groups were intraperitoneally injected with E.coli LPS.Intestinal porcine epithelial cells(IPEC-J2)(n=6)induced by LPS were used to assess related mechanisms and compound C was used to inhibit adenosine 50-monophosphate-activated protein kinase(AMPK)activity.Our current results showed that compared with the LPS treatment,the Gln t LPS treatment had better growth performance and greater villus height(P<0.05),and the Gln t LPS treatment reduced the rate of diarrhea by 6.4%(P<0.05);the Gln t LPS treatment decreased serum tumor necrosis factor(TNF-ɑ),interleukin-6(IL-6),Kt,cortisol and insulin levels,whereas increased(P<0.05)serum immunoglobulin M and epidermal growth factor levels;the Gln t LPS treatment increased(P<0.05)the expression of aquaporins and AMPK pathwayassociated targets in the jejunum and ileum of piglets,whereas decreased the expression of ion transporters(P<0.05).The in vitro results showed that 4 mmol/L Gln administration could inhibit(P<0.05)cell apoptosis and interleukin-1b(IL-1b),IL-6 and TNF-ɑsecretion in LPS-induced IPEC-J2 cells,promote(P<0.05)mitochondrial respiratory metabolism and increase(P<0.05)the number of mitochondria and mitochondrial membrane potential.The activity of AMPK was elevated by 70%to 300%in Gln-treated IPEC-J2 cells under LPS challenge or normal conditions.Our results indicate that pre-administration of Gln to piglets suppresses intestinal inflammation by modulating the crosstalk between AMPK activation and mitochondrial function.
文摘AIM To comprehensively evaluate mitochondrial(dys)function in preclinical models of nonalcoholic steatohepatitis(NASH).METHODS We utilized two readily available mouse models of nonalcoholic fatty liver disease(NAFLD)with or without progressive fibrosis:Lep^(ob)/Lep^(ob)(ob/ob)and FATZO mice on high trans-fat,high fructose and high cholesterol(AMLN)diet.Presence of NASH was assessed using immunohistochemical and pathological techniques,and gene expression profiling.Morphological features of mitochondria were assessed via transmission electron microscopy and immunofluorescence,and function was assessed by measuring oxidative capacity in primary hepatocytes,and respiratory control and proton leak in isolated mitochondria.Oxidative stress was measured by assessing activity and/or expression levels of Nrf1,Sod1,Sod2,catalase and 8-OHdG.RESULTS When challenged with AMLN diet for 12 wk,ob/ob and FATZO mice developed steatohepatitis in the presence of obesity and hyperinsulinemia.NASH development was associated with hepatic mitochondrial abnormalities,similar to those previously observed in humans,including mitochondrial accumulation and increased proton leak.AMLN diet also resulted in increased numbers of fragmented mitochondria in both strains of mice.Despite similar mitochondrial phenotypes,we found that ob/ob mice developed more advanced hepatic fibrosis.Activity of superoxide dismutase(SOD)was increased in ob/ob AMLN mice,whereas FATZO mice displayed increased catalase activity,irrespective of diet.Furthermore,8-OHd G,a marker of oxidative DNA damage,was significantly increased in ob/ob AMLN mice compared to FATZO AMLN mice.Therefore,antioxidant capacity reflected as the ratio of catalase:SOD activity was similar between FATZO and C57 BL6 J control mice,but significantly perturbed in ob/ob mice.CONCLUSION Oxidative stress,and/or the capacity to compensate for increased oxidative stress,in the setting of mitochondrial dysfunction,is a key factor for development of hepatic injury and fibrosis in these mouse models.
基金This work was financially supported by the Vice-Chancellor of Research Affairs of Shiraz University of Medical Sciences,Shiraz,Iran(Grant No.19444).
文摘Background and aim:Cholestasis-associated renal injury or cholemic nephropathy(CN)is a serious clinical problem.Previous studies mentioned that oxidative stress and mitochondrial impairment play a role in CN.There is no specific pharmacological intervention for CN.Metformin is an anti-diabetic drug administered for decades.On the other hand,novel pharmacological properties have emerged for this drug.The effect of metformin on oxidative stress parameters has been well-recognized in different experimental models.It has also been found that metformin positively affected mitochondrial function.The current study aimed to evaluate the effects of metformin in an animal model of CN.Methods:Rats underwent bile duct ligation(BDL)and were treated with metformin(250 and 500 mg/kg)for 14 consecutive days.Two weeks after the BDL operations,urine,serum,and kidney samples were collected and analyzed.Results:Markers of oxidative stress,including reactive oxygen species(ROS)formation,lipid peroxida-tion,protein carbonylation,depleted antioxidant capacity,and decreased glutathione(GSH)levels were detected in BDL animals.Moreover,mitochondrial indices,including adenosine triphosphate(ATP)level,dehydrogenase activity,mitochondrial membrane potential,and mitochondrial permeability,were impaired in the kidney of cholestatic rats.Renal histopathological alterations in cholestatic animals included tubular degeneration and interstitial inflammation,cast formation,and fibrosis.It was found that metformin significantly alleviated oxidative stress and improved mitochondrial indices in the kidney of cholestatic rats.Tissue histopathological alterations were also mitigated in metformin-treated groups.Conclusions:Metformin could be a candidate for managing CN.The nephroprotective role of metformin is primarily associated with its effects on oxidative stress parameters and mitochondrial function.
