Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and...Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte hypertrophy.Methods:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass spectrometry.Cardiomyocytes were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 h.Cardiac hypertrophy-related indicators and NLRP3 inflammasome expression were evaluated.Subsequently,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying mechanism.Results:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene expression.Moreover,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated cardiomyocytes.Our further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col expression.Conclusion:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.展开更多
Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 g...Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 gene. This article presents a case of a 2-year-old female with progressive myoclonic epilepsy and psychomotor regression, with refractoriness to multiple anticonvulsants. The diagnosis was only made after the examination was carried out. Therefore, this article highlights the aspects of this rare disease and the importance of the exome for the diagnosis of rare conditions.展开更多
Distribution and activity of mitochondda are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphor...Distribution and activity of mitochondda are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5＇- triphosphate production is regulated by many control mechanism-firstly by oxygen, substrate level, adenosine-5＇-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by ＂second control mechanisms,＂ such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, aUosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5＇-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria similarly, decline of antioxidative enzyme activities （e.g. in the elderly） enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production.展开更多
In most eukaryotes,oxidative phosphorylation(OXPHOS)is the main energy production process and it involves both mitochondrial and nuclear genomes.The close interaction between the two genomes is critical for the coordi...In most eukaryotes,oxidative phosphorylation(OXPHOS)is the main energy production process and it involves both mitochondrial and nuclear genomes.The close interaction between the two genomes is critical for the coordinated function of the OXPHOS process.Some bivalves show doubly uniparental inheritance(DUI)of mitochondria,where two highly divergent mitochondrial genomes,one inherited through eggs(F-type)and the other through sperm(M-type),coexist in the same individual.However,it remains a puzzle how nuclear OXPHOS genes coordinate with two divergent mitochondrial genomes in DUI species.In this study,we compared transcription,polymorphism,and synonymous codon usage in the mitochondrial and nuclear OXPHOS genes of the DUI species Ruditapes philippinarum using sex-and tissue-specific transcriptomes.Mitochondrial and nuclear OXPHOS genes showed different transcription profiles.Strong co-transcription signal was observed within mitochondrial(separate for F-and M-type)and within nuclear OXPHOS genes but the signal was weak or absent between mitochondrial and nuclear OXPHOS genes,suggesting that the coordination between mitochondrial and nuclear OXPHOS subunits is not achieved transcriptionally.McDonald-Kreitman and frequency-spectrum based tests indicated that M-type OXPHOS genes deviated significantly from neutrality,and that F-type and M-type OXPHOS genes undergo different selection patterns.Codon usage analysis revealed that mutation bias and translational selection were the major factors affecting the codon usage bias in different OXPHOS genes,nevertheless,translational selection in mitochondrial OXPHOS genes appears to be less efficient than nuclear OXPHOS genes.Therefore,we speculate that the coordination between OXPHOS genes may involve post-transcriptional/translational regulation.展开更多
Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia.Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative p...Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia.Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative phosphorylation,in this study,effects of 10 kinds of Chinese herbal monomers on mitochondrial respiration and membrane potential of cerebral mitochondria isolated from hypoxia-exposed rats in vitro were investigated to screen anti-hypoxic drugs.Rats were exposed to a low-pressure environment of 405.35 mm Hg(54.04 kPa)for 3 days to establish high-altitude hypoxic models.Cerebral mitochondria were isolated and treated with different concentrations of Chinese herbal monomers(sinomenine,silymarin,glycyrrhizic acid,baicalin,quercetin,ginkgolide B,saffron,pipedne,ginsenoside Rgl and oxymatrine)for 5 minutes in vitro.Mitochondrial oxygen consumption and membrane potential were measured using a Clark oxygen electrode and the rhodamine 123 fluorescence analysis method,respectively.Hypoxic exposure significantly decreased the state 3 respiratory rate,respiratory control rate and mitochondrial membrane potential,and significantly increased the state 4 respiratory rate.Treatment with saffron ginsenoside Rgl and oxymatrine increased the respiratory control rate in cerebral mitochondria isolated from hypoxia-exposed rats in dose-dependent manners in vitro,while ginsenoside Rgl,piperine and oxymatrine significantly increased the mitochondrial membrane potential in cerebral mitochondria from hypoxia-exposed rats.The Chinese herbal monomers saffron,ginsenoside Rgl piperine and oxymatrine could thus improve cerebral mitochondrial disorders in oxidative phosphorylation induced by hypobaric hypoxia exposure in vitro.展开更多
Male infertility has become a global concern,accounting for 20-70%of infertility.Dysfunctional spermatogenesis is the most common cause of male infertility;thus,treating abnormal spermatogenesis may improve male infer...Male infertility has become a global concern,accounting for 20-70%of infertility.Dysfunctional spermatogenesis is the most common cause of male infertility;thus,treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community.Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways,such as mitochondrial oxidative phosphorylation(OXPHOS).Mitochondrial OXPHOS transmits electrons through the respiratory chain,synthesizes adenosine triphosphate(ATP),and produces reactive oxygen species(ROS).These mechanisms are vital for spermatogenesis,especially to maintain the normal function of testicular Sertoli cells and germ cells.The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply,oxidative stress,apoptosis,or ferroptosis,all inhibiting spermatogenesis and damaging the male reproductive system,leading to male infertility.This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells,which disrupts spermatogenesis and results in male infertility.In addition,we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders.However,relevant treatments have not been fully elucidated.Therefore,targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention.We believe this review will provide new and more accurate ideas for treating male infertility.展开更多
Metabolic reprogramming is a hallmark of cancer,with acute myeloid leukemia(AML)being no exception.Mitochondrial function,particularly its role in protecting tumor cells against chemotherapy,is of significant interest...Metabolic reprogramming is a hallmark of cancer,with acute myeloid leukemia(AML)being no exception.Mitochondrial function,particularly its role in protecting tumor cells against chemotherapy,is of significant interest in AML chemoresistance.In this study,we identified mitochondrial DNA content(mtDNAc),measured by quantitative PCR,as a simple and precise marker to stratify the metabolic states of AML patients.We show that patients with high mtDNAc are associated with increased mitochondrial metabolism and a higher dependency on oxidative phosphorylation(OXPHOS),often correlating with chemoresistance.Clinically,patients receiving cytarabine and an anthracycline-based regimen(7+3 regimen)experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence.展开更多
Osteoarthritis(OA)progresses due to the excessive generation of reactive oxygen and nitrogen species(ROS/RNS)and abnormal ATP energy metabolism related to the oxidative phosphorylation pathway in the mitochondria.High...Osteoarthritis(OA)progresses due to the excessive generation of reactive oxygen and nitrogen species(ROS/RNS)and abnormal ATP energy metabolism related to the oxidative phosphorylation pathway in the mitochondria.Highly active single-atom nanozymes(SAzymes)can help regulate the redox balance and have shown their potential in the treatment of inflammatory diseases.In this study,we innovatively utilised ligand-mediated strategies to chelate Pt^(4+)with modified g-C_(3)N_(4)byπ-πinteraction to prepare g-C_(3)N_(4)-loaded Pt single-atom(Pt SA/C_(3)N_(4))nanozymes that serve as superoxide dismutase(SOD)/catalase(CAT)mimics to scavenge ROS/RNS and regulate mitochondrial ATP production,ultimately delaying the progression of OA.Pt SA/C_(3)N_(4)exhibited a high loading of Pt single atoms(2.45 wt%),with an excellent photothermal conversion efficiency(54.71%),resulting in tunable catalytic activities under near-infrared light(NIR)irradiation.Interestingly,the Pt-N_(6) active centres in Pt SA/C_(3)N_(4)formed electron capture sites for electron holes,in which g-C_(3)N_(4)regulated the d-band centre of Pt,and the N-rich sites transferred electrons to Pt,leading to the enhanced adsorption of free radicals and thus higher SOD-and CAT-like activities compared with pure g-C_(3)N_(4)and g-C_(3)N_(4)-loaded Pt nanoparticles(Pt NPs/C_(3)N_(4)).Based on the use of H_(2)O_(2)-induced chondrocytes to simulate ROS-injured cartilage in vitro and an OA joint model in vivo,the results showed that Pt SA/C_(3)N_(4)could reduce oxidative stress-induced damage,protect mitochondrial function,inhibit inflammation progression,and rebuild the OA microenvironment,thereby delaying the progression of OA.In particular,under NIR light irradiation,Pt SA/C_(3)N_(4)could help reverse the oxidative stress-induced joint cartilage damage,bringing it closer to the state of the normal cartilage.Mechanistically,Pt SA/C_(3)N_(4)regulated the expression of mitochondrial respiratory chain complexes,mainly NDUFV2 of complex 1 and MT-ATP6 of ATP synthase,to reduce ROS/RNS and promote ATP production.This study provides novel insights into the design of artificial nanozymes for treating oxidative stress-induced inflammatory diseases.展开更多
Defects in the FAcilitates Chromatin Transcription(FACT)complex,a histone chaperone composed of SSRP1 and SUPT16H,are implicated in intellectual disability.Here,we reveal that the FACT complex promotes glycolysis and ...Defects in the FAcilitates Chromatin Transcription(FACT)complex,a histone chaperone composed of SSRP1 and SUPT16H,are implicated in intellectual disability.Here,we reveal that the FACT complex promotes glycolysis and sustains the correct cell fate of neural stem cells/neuroblasts in the Drosophila 3rd instar larval central brain.We show that the FACT complex binds to the promoter region of the estrogen-related receptor(ERR)gene and positively regulates ERR expression.ERR is known to act as an aerobic glycolytic switch by upregulating the enzymes required for glycolysis.Dysfunction of the FACT complex leads to the downregulation of ERR transcription,resulting in a decreased ratio of glycolysis to oxidative phosphorylation(G/O)in neuroblasts.Consequently,neuroblasts exhibit smaller cell sizes,lower proliferation potential,and altered cell fates.Overexpression of ERR or suppression of mitochondrial oxidative phosphorylation in neuroblasts increases the relative G/O ratio and rescues defective phenotypes caused by dysfunction of the FACT complex.Thus,the G/O ratio,mediated by the FACT complex,plays a crucial role in neuroblast cell fate maintenance.Our study may shed light on the mechanism by which mutations in the FACT complex lead to intellectual disability in humans.展开更多
Obesity-related glomerulopathy(ORG)is an independent risk factor for chronic kid-ney disease and even progression to end-stage renal disease.Efforts have been undertaken to elucidate the mechanisms underlying the deve...Obesity-related glomerulopathy(ORG)is an independent risk factor for chronic kid-ney disease and even progression to end-stage renal disease.Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG,but relatively little is known about cell-specific changes in gene expression.To define the transcriptomic landscape at single-cell resolution,we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing.We report for the first time that immune cells,including T cells and B cells,are decreased in ORG patients.Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells.This gene is related to inflammation and cell proliferation.Analysis of differential gene expression in glomerular cells(endothelial cells,mesangial cells,and podocytes)showed that these cell types were mainly enriched in genes related to oxidative phosphorylation,cell adhesion,thermogenesis,and inflammatory pathways(PI3K-Akt signaling,MAPK signaling).Furthermore,we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway.Moreover,an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients,with major interactions between parietal epithelial cells and podocytes.Altogether,our identification of molecular events,cell types,and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.展开更多
Cytochalasin B(CB)was a depolymeriziner agent of F-aetin.Therefore a lot of plant cell motilities related to action,such as cytoplasmic streaming,pollen
Mitochondria are more than just the cellular powerhouse.They also play key roles in vital functions such as apoptosis,metabolism regulation,and other intracellular interactions.The mitochondrial DNA(mtDNA)encodes for ...Mitochondria are more than just the cellular powerhouse.They also play key roles in vital functions such as apoptosis,metabolism regulation,and other intracellular interactions.The mitochondrial DNA(mtDNA)encodes for 12 subunits of the oxidative phosphorylation(OXPHOS)system.Depletion of mtDNA in androgen-dependent prostate cancer(PCa)cell lines renders them androgen-independent and more aggressive.Paradoxically,pharmaceutical inhibition of OXPHOS is lethal for subsets of PCa cells,whereas others become dependent on androgen receptor(AR)signaling for survival.Given that the AR-mitochondria interaction is critical for early PCa,it is crucial to understand the details of this interaction.Technical hurdles have made mitochondria traditionally difficult to study,with many techniques used for isolation masking the properties of given individual mitochondria.Although the isolation of mitochondria enables us to study OXPHOS,we miss the context in which mitochondria interact with the rest of the cell.Both AR signaling and mtDNA affect apoptosis,metabolism regulation,cellular calcium storage and homeostasis,intracellular calcium signaling,and redox homeostasis.In this review,we will attempt to understand how the crosstalk between AR-mtDNA-OXPHOS is responsible for"life or death"decisions inside the cells.Our aim is to point toward potential vulnerabilities that can lead to the discovery of novel therapeutic targets.展开更多
Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness ...Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.展开更多
Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the an...Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the antitumor activity of CD8+T cells.Our study investigates the role of JAML+CD8+T cells in HCC.Methods:We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy.Flow cytometry was used to assess CD4+T cells differentiation and JAML expression in CD8+T cells infiltrating HCC.Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+(LDHA+)CD4+T cells and JAML+CD8+T cells.Subsequently,we evaluated the therapeutic effects of an agonistic anti-JAML antibody,both alone and combined with immunotherapy.Finally,RNA sequencing was conducted to identify potential regulatory mechanisms.Results:Immunotherapy significantly increased the percentage of CD8+T cells infiltrating HCC and induced histone modifications,such as H3K18 lactylation(H3K18la)in CD4+T cells.Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+T cells into Th1 cells.LDHA,an enzyme that converts pyruvate to lactate,plays a key role in this process.Correlation analysis revealed a strong positive relationship between LDHA+CD4+T cells and JAML+CD8+T cells in patients who responded to immunotherapy.Moreover,high JAML expression in CD8+T cells was associated with a more favorable prognosis.In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice,independent of the effects of anti-programmed cell death protein ligand-1 antibody(αPD-L1)-mediated immunotherapy.Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.Conclusions:Activation of JAML enhances CTL responses in HCC treatment,independent ofαPD-L1-mediated immunotherapy,providing a promising strategy for advanced HCC.展开更多
Chlorfenapyr poisoning is associated with high mortality due to the absence of evidence-based treatment strategies or specific antidotes.[1,2]Chlorfenapyr is a novel N-substituted halogenated pyrrole pro-insecticide.T...Chlorfenapyr poisoning is associated with high mortality due to the absence of evidence-based treatment strategies or specific antidotes.[1,2]Chlorfenapyr is a novel N-substituted halogenated pyrrole pro-insecticide.The active metabolite of tralopyril(a metabolite of chlorfenapyr)can uncouple oxidative phosphorylation and impair adenosine triphosphate(ATP)production.[3]Blood purification techniques,including hemoperfusion(HP),may facilitate tralopyril clearance.[4,5]Here,we present a case of severe chlorfenapyr poisoning that was treated with intensive HP.H owever,during follow-up,we unexpectedly found a ventricular aneurysm in the left ventricle that was not fully explained by coronary artery lesions.展开更多
Natural products play a crucial role in new drug development,but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action.In this study,we developed a new RP...Natural products play a crucial role in new drug development,but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action.In this study,we developed a new RPL19-TRAP^(KI)-seq method,combining CRISPR/Cas9 and TRAP technologies,to investigate these mechanisms.We identified and validated seven ribosomal large subunit surface proteins suitable for TRAP,selecting RPL19 for its high enrichment.We successfully established a stable cell line expressing EGFP-RPL19 using CRISPR knock-in and verified its efficiency and specificity in enriching ribosomes and translating mRNA.Integrated with next-generation sequencing,this method allows precise detection of translating mRNA.We validated RPL19-TRAP^(KI)-seq by investigating rapamycin,an mTOR inhibitor,yielding results consistent with previous reports.This optimized TRAP technology provides an accurate representation of translating mRNA,closely reflecting protein expression levels.Furthermore,we investigated SBF-1,a 23-oxa-analog of natural saponin OSW-1 with significant anti-tumor activity but an unclear mechanism.Using RPL19-TRAP^(KI)-seq,we found that SBF-1 exerts its cytotoxic effects on tumor cells by disturbing cellular oxidative phosphorylation.In conclusion,our method has been proven to be a promising tool that can reveal the mechanisms of small molecules with greater accuracy,setting the stage for future exploration of small molecules and advancing the fields of pharmacology and therapeutic development.展开更多
Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidati...Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.展开更多
The treatment of microglial BV-2 cells with sodium arsenate（As（V）：0.1-400 μmol/L — 48 hr）induces a dose-dependent response.The neurotoxic effects of high concentrations of As（V）（100,200 and 400 μmol/L） are...The treatment of microglial BV-2 cells with sodium arsenate（As（V）：0.1-400 μmol/L — 48 hr）induces a dose-dependent response.The neurotoxic effects of high concentrations of As（V）（100,200 and 400 μmol/L） are characterized by increased levels of mitochondrial complexesⅠ,Ⅱ,and Ⅳ followed by increased superoxide anion generation.Moreover,As（V） triggers an apoptotic mode of cell death,demonstrated by an apoptotic SubG1 peak,associated with an alteration of plasma membrane integrity.There is also a decrease in transmembrane mitochondrial potential and mitochondrial adenosine triphosphate ATP.It is therefore tempting to speculate that As（V） triggers mitochondrial dysfunction,which may lead to defective oxidative phosphorylation subsequently causing mitochondrial oxidative damage,which in turn induces an apoptotic mode of cell death.展开更多
Cotyledon mitochondrion respiration and oxidative phosphorylation activity were studied in two groups of soybean seeds. One group was primed with polyethylene glycol (PEG) for different periods of time, and the other ...Cotyledon mitochondrion respiration and oxidative phosphorylation activity were studied in two groups of soybean seeds. One group was primed with polyethylene glycol (PEG) for different periods of time, and the other was unprimed (control), and both were then exposed to imbibition at low temperatures before their germination. The results indicated that when L-Malate (L-Mal) and á-Ketoglutarate (α-Kg) were used as substrates, the ADP-stimulated mitochondria respiration rates of control seeds were mark- edly higher than state Ⅲ respiration rates of primed seeds. However, the osmoconditioning pretreatment significantly enhanced the oxidative phosphorylation activity of cotyledon mitochondrion in 12 h. The oxidative phosphorylation activity of the mitochondrion of primed seeds was normal and the ADP/O value was consistent with the theoretical one. When reduced nicotinamide adenine dinu- cleotide (NADH) was used as the substrate, the mitochondria of control seeds still had oxidative phosphorylation activity, while ADP/O value was obviously lower than that of mitochondria of primed seeds. When Succinate (Succ) was used as the substrate, the oxidative phosphorylation activity of the primed seeds was normal after priming for 24 h. When different substrates were used, the emerging order of the oxidative phosphorylation activity of the primed seeds was NADH, α-Kg, Succ and in the last place L-Mal. The mechanism of soybean imbibitionl chilling injury and protective effect of PEG priming were discussed.展开更多
Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generat...Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.81960732 and 82060733)the Natural Science Foundation of Jiangxi Province(No.20224BAB206111)+2 种基金the Science and Technology Plan of Jiangxi Provincial Health Commission(No.202311141)the Open Project of Jiangxi Provincial Key Laboratory of Drug Design and Evaluation(No.JKLDE-KF-2101)the Open Project of Key Laboratory of Modern Preparation of TCM,Ministry of Education,Jiangxi University of Chinese Medicine(No.TCM-201911).
文摘Objective:Cymbopogon citratus(DC.)Stapf is a medicinal and edible herb that is widely used for the treatment of gastric,nervous and hypertensive disorders.In this study,we investigated the cardioprotective effects and mechanisms of the essential oil,the main active ingredient of Cymbopogon citratus,on isoproterenol(ISO)-induced cardiomyocyte hypertrophy.Methods:The compositions of Cymbopogon citratus essential oil(CCEO)were determined by gas chromatography-mass spectrometry.Cardiomyocytes were pretreated with 16.9µg/L CCEO for 1 h followed by 10µmol/L ISO for 24 h.Cardiac hypertrophy-related indicators and NLRP3 inflammasome expression were evaluated.Subsequently,transcriptome sequencing(RNA-seq)and target verification were used to further explore the underlying mechanism.Results:Our results showed that the CCEO mainly included citronellal(45.66%),geraniol(23.32%),and citronellol(10.37%).CCEO inhibited ISO-induced increases in cell surface area and protein content,as well as the upregulation of fetal gene expression.Moreover,CCEO inhibited ISO-induced NLRP3 inflammasome expression,as evidenced by decreased lactate dehydrogenase content and downregulated mRNA levels of NLRP3,ASC,CASP1,GSDMD,and IL-1β,as well as reduced protein levels of NLRP3,ASC,pro-caspase-1,caspase-1(p20),GSDMD-FL,GSDMD-N,and pro-IL-1β.The RNA-seq results showed that CCEO inhibited the increase in the mRNA levels of 26 oxidative phosphorylation complex subunits in ISO-treated cardiomyocytes.Our further experiments confirmed that CCEO suppressed ISO-induced upregulation of mt-Nd1,Sdhd,mt-Cytb,Uqcrq,and mt-Atp6 but had no obvious effects on mt-Col expression.Conclusion:CCEO inhibits ISO-induced cardiomyocyte hypertrophy through the suppression of NLRP3 inflammasome expression and the regulation of several oxidative phosphorylation complex subunits.
文摘Mitochondrial disorders are phenotypically varied, with serious clinical repercussions. Among them, there is the deficiency of combined oxidative phosphorylation of type 20, which occurs due to a defect in the VARS2 gene. This article presents a case of a 2-year-old female with progressive myoclonic epilepsy and psychomotor regression, with refractoriness to multiple anticonvulsants. The diagnosis was only made after the examination was carried out. Therefore, this article highlights the aspects of this rare disease and the importance of the exome for the diagnosis of rare conditions.
基金supported by grant NoMSM0021620849 given by the Ministry of Education,Youth and Sports of the Czech Republicby project PRVOUK-P26/LF1/4given by Charles University in Prague+1 种基金by grant No. SVV-2012-264514 from Charles University in Pragueby grant No.41310 given by the Grant Agency of Charles University in Prague,Czech Republic
文摘Distribution and activity of mitochondda are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5＇- triphosphate production is regulated by many control mechanism-firstly by oxygen, substrate level, adenosine-5＇-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by ＂second control mechanisms,＂ such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, aUosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5＇-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria similarly, decline of antioxidative enzyme activities （e.g. in the elderly） enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production.
基金supported by the China Scholarship Council,Italian Ministry of Education University and Research(MIUR)FIR2013 Programme(RBFR13T97A to F.G.)MIUR SIR Programme(RBSI14G0P5 to L.M.)Canziani Bequest to F.G.,and“Ricerca Fondamentale Orientata”(RFO)from the University of Bologna to F.G.and L.M.
文摘In most eukaryotes,oxidative phosphorylation(OXPHOS)is the main energy production process and it involves both mitochondrial and nuclear genomes.The close interaction between the two genomes is critical for the coordinated function of the OXPHOS process.Some bivalves show doubly uniparental inheritance(DUI)of mitochondria,where two highly divergent mitochondrial genomes,one inherited through eggs(F-type)and the other through sperm(M-type),coexist in the same individual.However,it remains a puzzle how nuclear OXPHOS genes coordinate with two divergent mitochondrial genomes in DUI species.In this study,we compared transcription,polymorphism,and synonymous codon usage in the mitochondrial and nuclear OXPHOS genes of the DUI species Ruditapes philippinarum using sex-and tissue-specific transcriptomes.Mitochondrial and nuclear OXPHOS genes showed different transcription profiles.Strong co-transcription signal was observed within mitochondrial(separate for F-and M-type)and within nuclear OXPHOS genes but the signal was weak or absent between mitochondrial and nuclear OXPHOS genes,suggesting that the coordination between mitochondrial and nuclear OXPHOS subunits is not achieved transcriptionally.McDonald-Kreitman and frequency-spectrum based tests indicated that M-type OXPHOS genes deviated significantly from neutrality,and that F-type and M-type OXPHOS genes undergo different selection patterns.Codon usage analysis revealed that mutation bias and translational selection were the major factors affecting the codon usage bias in different OXPHOS genes,nevertheless,translational selection in mitochondrial OXPHOS genes appears to be less efficient than nuclear OXPHOS genes.Therefore,we speculate that the coordination between OXPHOS genes may involve post-transcriptional/translational regulation.
基金supported by the Natural Science Foundation of China,No.81171875
文摘Mitochondrial dysfunction is the key pathogenic mechanism of cerebral injury induced by high-altitude hypoxia.Some Chinese herbal monomers may exert anti-hypoxic effects through enhancing the efficiency of oxidative phosphorylation,in this study,effects of 10 kinds of Chinese herbal monomers on mitochondrial respiration and membrane potential of cerebral mitochondria isolated from hypoxia-exposed rats in vitro were investigated to screen anti-hypoxic drugs.Rats were exposed to a low-pressure environment of 405.35 mm Hg(54.04 kPa)for 3 days to establish high-altitude hypoxic models.Cerebral mitochondria were isolated and treated with different concentrations of Chinese herbal monomers(sinomenine,silymarin,glycyrrhizic acid,baicalin,quercetin,ginkgolide B,saffron,pipedne,ginsenoside Rgl and oxymatrine)for 5 minutes in vitro.Mitochondrial oxygen consumption and membrane potential were measured using a Clark oxygen electrode and the rhodamine 123 fluorescence analysis method,respectively.Hypoxic exposure significantly decreased the state 3 respiratory rate,respiratory control rate and mitochondrial membrane potential,and significantly increased the state 4 respiratory rate.Treatment with saffron ginsenoside Rgl and oxymatrine increased the respiratory control rate in cerebral mitochondria isolated from hypoxia-exposed rats in dose-dependent manners in vitro,while ginsenoside Rgl,piperine and oxymatrine significantly increased the mitochondrial membrane potential in cerebral mitochondria from hypoxia-exposed rats.The Chinese herbal monomers saffron,ginsenoside Rgl piperine and oxymatrine could thus improve cerebral mitochondrial disorders in oxidative phosphorylation induced by hypobaric hypoxia exposure in vitro.
基金supported by fundings from the Research Start-up Fund of Jining Medical University(Nos.600791001 and 600980001)Research Fund for Lin He’s Academician Workstation of New Medicine and Clinical Translation in Jining Medical University(No.JYHL2021MS13)the National Natural Science Foundation of China(No.81700055).
文摘Male infertility has become a global concern,accounting for 20-70%of infertility.Dysfunctional spermatogenesis is the most common cause of male infertility;thus,treating abnormal spermatogenesis may improve male infertility and has attracted the attention of the medical community.Mitochondria are essential organelles that maintain cell homeostasis and normal physiological functions in various ways,such as mitochondrial oxidative phosphorylation(OXPHOS).Mitochondrial OXPHOS transmits electrons through the respiratory chain,synthesizes adenosine triphosphate(ATP),and produces reactive oxygen species(ROS).These mechanisms are vital for spermatogenesis,especially to maintain the normal function of testicular Sertoli cells and germ cells.The disruption of mitochondrial OXPHOS caused by external factors can result in inadequate cellular energy supply,oxidative stress,apoptosis,or ferroptosis,all inhibiting spermatogenesis and damaging the male reproductive system,leading to male infertility.This article summarizes the latest pathological mechanism of mitochondrial OXPHOS disorder in testicular Sertoli cells and germ cells,which disrupts spermatogenesis and results in male infertility.In addition,we also briefly outline the current treatment of spermatogenic malfunction caused by mitochondrial OXPHOS disorders.However,relevant treatments have not been fully elucidated.Therefore,targeting mitochondrial OXPHOS disorders in Sertoli cells and germ cells is a research direction worthy of attention.We believe this review will provide new and more accurate ideas for treating male infertility.
基金supported by Fundação de AmparoàPesquisa do Estado de São Paulo(FAPESP,Grant#2013/08135-2,CNPq:465539/2014-9)D.A.P-M.Received a fellowship from FAPESP(Grant#2017/23117-1)+2 种基金I.W.received a fellowship from FAPESP(Grant#2015/09228-0)L.Q.and P.C.were funded by UKRI/MRC grant#MR/R007608/1.A.R.L-A.Received a research grant and fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq,Grant#303479/2018-3,#405918/2022-4)I.W and D.A.P-M were sponsored by the Abel Tasman Talent Program(ATTP)of the Graduate School of Medical Sciences of the University of Groningen/University Medical Center Groningen(UG/UMCG),The Netherlands.
文摘Metabolic reprogramming is a hallmark of cancer,with acute myeloid leukemia(AML)being no exception.Mitochondrial function,particularly its role in protecting tumor cells against chemotherapy,is of significant interest in AML chemoresistance.In this study,we identified mitochondrial DNA content(mtDNAc),measured by quantitative PCR,as a simple and precise marker to stratify the metabolic states of AML patients.We show that patients with high mtDNAc are associated with increased mitochondrial metabolism and a higher dependency on oxidative phosphorylation(OXPHOS),often correlating with chemoresistance.Clinically,patients receiving cytarabine and an anthracycline-based regimen(7+3 regimen)experienced inferior relapse-free survival and a higher overall rate of leukemia recurrence.
基金the support from the Guangxi Natural Science Foundation(No.2023GXNSFBA026020)Guangxi Scientific Research and Technological Development Foundation(Grant No.GuikeAB21220062)National Natural Science Foundation of China(Grant No.82160429,82360426,52301303,81960400).
文摘Osteoarthritis(OA)progresses due to the excessive generation of reactive oxygen and nitrogen species(ROS/RNS)and abnormal ATP energy metabolism related to the oxidative phosphorylation pathway in the mitochondria.Highly active single-atom nanozymes(SAzymes)can help regulate the redox balance and have shown their potential in the treatment of inflammatory diseases.In this study,we innovatively utilised ligand-mediated strategies to chelate Pt^(4+)with modified g-C_(3)N_(4)byπ-πinteraction to prepare g-C_(3)N_(4)-loaded Pt single-atom(Pt SA/C_(3)N_(4))nanozymes that serve as superoxide dismutase(SOD)/catalase(CAT)mimics to scavenge ROS/RNS and regulate mitochondrial ATP production,ultimately delaying the progression of OA.Pt SA/C_(3)N_(4)exhibited a high loading of Pt single atoms(2.45 wt%),with an excellent photothermal conversion efficiency(54.71%),resulting in tunable catalytic activities under near-infrared light(NIR)irradiation.Interestingly,the Pt-N_(6) active centres in Pt SA/C_(3)N_(4)formed electron capture sites for electron holes,in which g-C_(3)N_(4)regulated the d-band centre of Pt,and the N-rich sites transferred electrons to Pt,leading to the enhanced adsorption of free radicals and thus higher SOD-and CAT-like activities compared with pure g-C_(3)N_(4)and g-C_(3)N_(4)-loaded Pt nanoparticles(Pt NPs/C_(3)N_(4)).Based on the use of H_(2)O_(2)-induced chondrocytes to simulate ROS-injured cartilage in vitro and an OA joint model in vivo,the results showed that Pt SA/C_(3)N_(4)could reduce oxidative stress-induced damage,protect mitochondrial function,inhibit inflammation progression,and rebuild the OA microenvironment,thereby delaying the progression of OA.In particular,under NIR light irradiation,Pt SA/C_(3)N_(4)could help reverse the oxidative stress-induced joint cartilage damage,bringing it closer to the state of the normal cartilage.Mechanistically,Pt SA/C_(3)N_(4)regulated the expression of mitochondrial respiratory chain complexes,mainly NDUFV2 of complex 1 and MT-ATP6 of ATP synthase,to reduce ROS/RNS and promote ATP production.This study provides novel insights into the design of artificial nanozymes for treating oxidative stress-induced inflammatory diseases.
基金supported by grants from the National Key R&D Program of China(2018YFC1004904 and 2013CB945601).
文摘Defects in the FAcilitates Chromatin Transcription(FACT)complex,a histone chaperone composed of SSRP1 and SUPT16H,are implicated in intellectual disability.Here,we reveal that the FACT complex promotes glycolysis and sustains the correct cell fate of neural stem cells/neuroblasts in the Drosophila 3rd instar larval central brain.We show that the FACT complex binds to the promoter region of the estrogen-related receptor(ERR)gene and positively regulates ERR expression.ERR is known to act as an aerobic glycolytic switch by upregulating the enzymes required for glycolysis.Dysfunction of the FACT complex leads to the downregulation of ERR transcription,resulting in a decreased ratio of glycolysis to oxidative phosphorylation(G/O)in neuroblasts.Consequently,neuroblasts exhibit smaller cell sizes,lower proliferation potential,and altered cell fates.Overexpression of ERR or suppression of mitochondrial oxidative phosphorylation in neuroblasts increases the relative G/O ratio and rescues defective phenotypes caused by dysfunction of the FACT complex.Thus,the G/O ratio,mediated by the FACT complex,plays a crucial role in neuroblast cell fate maintenance.Our study may shed light on the mechanism by which mutations in the FACT complex lead to intellectual disability in humans.
基金supported by the Hunan Provincial Natural Science Foundation for Outstanding Youth(China)(No.2022JJ10093,2020JJ2020)the Scientific Research Fund of Hunan Provincial Health Commission(China)(No.B202303056777)+1 种基金the Major Research and Development Program of Hunan Province,China(No.2020SK2116)the Key Program of Hunan Provincial Health Commission(China)(No.202203052969).
文摘Obesity-related glomerulopathy(ORG)is an independent risk factor for chronic kid-ney disease and even progression to end-stage renal disease.Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG,but relatively little is known about cell-specific changes in gene expression.To define the transcriptomic landscape at single-cell resolution,we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing.We report for the first time that immune cells,including T cells and B cells,are decreased in ORG patients.Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells.This gene is related to inflammation and cell proliferation.Analysis of differential gene expression in glomerular cells(endothelial cells,mesangial cells,and podocytes)showed that these cell types were mainly enriched in genes related to oxidative phosphorylation,cell adhesion,thermogenesis,and inflammatory pathways(PI3K-Akt signaling,MAPK signaling).Furthermore,we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway.Moreover,an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients,with major interactions between parietal epithelial cells and podocytes.Altogether,our identification of molecular events,cell types,and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.
文摘Cytochalasin B(CB)was a depolymeriziner agent of F-aetin.Therefore a lot of plant cell motilities related to action,such as cytoplasmic streaming,pollen
文摘Mitochondria are more than just the cellular powerhouse.They also play key roles in vital functions such as apoptosis,metabolism regulation,and other intracellular interactions.The mitochondrial DNA(mtDNA)encodes for 12 subunits of the oxidative phosphorylation(OXPHOS)system.Depletion of mtDNA in androgen-dependent prostate cancer(PCa)cell lines renders them androgen-independent and more aggressive.Paradoxically,pharmaceutical inhibition of OXPHOS is lethal for subsets of PCa cells,whereas others become dependent on androgen receptor(AR)signaling for survival.Given that the AR-mitochondria interaction is critical for early PCa,it is crucial to understand the details of this interaction.Technical hurdles have made mitochondria traditionally difficult to study,with many techniques used for isolation masking the properties of given individual mitochondria.Although the isolation of mitochondria enables us to study OXPHOS,we miss the context in which mitochondria interact with the rest of the cell.Both AR signaling and mtDNA affect apoptosis,metabolism regulation,cellular calcium storage and homeostasis,intracellular calcium signaling,and redox homeostasis.In this review,we will attempt to understand how the crosstalk between AR-mtDNA-OXPHOS is responsible for"life or death"decisions inside the cells.Our aim is to point toward potential vulnerabilities that can lead to the discovery of novel therapeutic targets.
基金supported by the National Natural Science Foundation of China,No.82202681(to JW)the Natural Science Foundation of Zhejiang Province,Nos.LZ22H090003(to QC),LR23H060001(to CL).
文摘Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.
基金funded by the Major Research Plan of the National Natural Science Foundation of China(No.92159202)the National Key Research and Development Program of China(No.2021YFA1100500)+1 种基金the Leading Innovation Team Project of Hangzhou Medical College(No.CXLJ202401)the Key Research and Development Plan of Zhejiang Provincial Department of Science and Technology(No.2024C03051)。
文摘Objective:Cytotoxic T lymphocytes(CTLs)play a crucial role in the therapeutic approach to hepatocellular carcinoma(HCC).Recent research has indicated that junctional adhesion molecule-like protein(JAML)enhances the antitumor activity of CD8+T cells.Our study investigates the role of JAML+CD8+T cells in HCC.Methods:We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy.Flow cytometry was used to assess CD4+T cells differentiation and JAML expression in CD8+T cells infiltrating HCC.Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+(LDHA+)CD4+T cells and JAML+CD8+T cells.Subsequently,we evaluated the therapeutic effects of an agonistic anti-JAML antibody,both alone and combined with immunotherapy.Finally,RNA sequencing was conducted to identify potential regulatory mechanisms.Results:Immunotherapy significantly increased the percentage of CD8+T cells infiltrating HCC and induced histone modifications,such as H3K18 lactylation(H3K18la)in CD4+T cells.Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+T cells into Th1 cells.LDHA,an enzyme that converts pyruvate to lactate,plays a key role in this process.Correlation analysis revealed a strong positive relationship between LDHA+CD4+T cells and JAML+CD8+T cells in patients who responded to immunotherapy.Moreover,high JAML expression in CD8+T cells was associated with a more favorable prognosis.In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice,independent of the effects of anti-programmed cell death protein ligand-1 antibody(αPD-L1)-mediated immunotherapy.Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.Conclusions:Activation of JAML enhances CTL responses in HCC treatment,independent ofαPD-L1-mediated immunotherapy,providing a promising strategy for advanced HCC.
基金supported by the National Key Research and Development Program of China(2023YFC3603100 and 2023YFC3603105)"Leading Goose"R&D Program of Zhejiang(2022C03076-4).
文摘Chlorfenapyr poisoning is associated with high mortality due to the absence of evidence-based treatment strategies or specific antidotes.[1,2]Chlorfenapyr is a novel N-substituted halogenated pyrrole pro-insecticide.The active metabolite of tralopyril(a metabolite of chlorfenapyr)can uncouple oxidative phosphorylation and impair adenosine triphosphate(ATP)production.[3]Blood purification techniques,including hemoperfusion(HP),may facilitate tralopyril clearance.[4,5]Here,we present a case of severe chlorfenapyr poisoning that was treated with intensive HP.H owever,during follow-up,we unexpectedly found a ventricular aneurysm in the left ventricle that was not fully explained by coronary artery lesions.
基金supported by the National Key Research and Development Program of China(No.2022YFC2804800 to W.J.)the National Natural Science Foundation of China(No.22494704.,22137002 to Y.D.,92253305 to W.J.and 31971111 to C.L.)+6 种基金the Science and Technology Commission of Shanghai Municipality(Grant 20JC1410900 to Y.D.)the University Innovation Research Group in Chongqing(No.CXQT21016 to Y.D.)the Chongqing Talent Program Project(No.CQYC20200302119 to Y.D.)High-Level Innovation Platform Cultivation Plan of Chongqing(to Y.D.)Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing(to Y.D.)Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(to W.J.)Chongqing Doctoral Express Entry Project(No.CSTB2022BSXM-JCX0044 to J.H.).
文摘Natural products play a crucial role in new drug development,but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action.In this study,we developed a new RPL19-TRAP^(KI)-seq method,combining CRISPR/Cas9 and TRAP technologies,to investigate these mechanisms.We identified and validated seven ribosomal large subunit surface proteins suitable for TRAP,selecting RPL19 for its high enrichment.We successfully established a stable cell line expressing EGFP-RPL19 using CRISPR knock-in and verified its efficiency and specificity in enriching ribosomes and translating mRNA.Integrated with next-generation sequencing,this method allows precise detection of translating mRNA.We validated RPL19-TRAP^(KI)-seq by investigating rapamycin,an mTOR inhibitor,yielding results consistent with previous reports.This optimized TRAP technology provides an accurate representation of translating mRNA,closely reflecting protein expression levels.Furthermore,we investigated SBF-1,a 23-oxa-analog of natural saponin OSW-1 with significant anti-tumor activity but an unclear mechanism.Using RPL19-TRAP^(KI)-seq,we found that SBF-1 exerts its cytotoxic effects on tumor cells by disturbing cellular oxidative phosphorylation.In conclusion,our method has been proven to be a promising tool that can reveal the mechanisms of small molecules with greater accuracy,setting the stage for future exploration of small molecules and advancing the fields of pharmacology and therapeutic development.
文摘Spermatozoa are highly specialized cells. Adenosine triphosphate （ATP）, which provides the energy for supporting the key functions of the spermatozoa, is formed by 2 metabolic pathways, namely glycolysis and oxidative phosphorylation （OXPHOS）. It is produced in the mitochondria through OXPHOS as well as in the head and principal piece of the flagellum through glycolysis. However, there is a great discrepancy as to which method of ATP production is primarily utilized by the spermatozoa for successful fertilization. Mitochondrial respiration is considered to be a more efficient metabolic process for ATP synthesis in comparison to glycolysis. However, studies have shown that the diffusion potential of ATP from the mitochondria to the distal end of the flagellum is not sufficient to support sperm motility, suggesting that glycolysis in the tail region is the preferred pathway for energy production. It is suggested by many investigators that although glycolysis forms the major source of ATP along the flagellum, energy required for sperm motility is mainly produced during mitochondrial respiration. Nevertheless, some studies have shown that when glycolysis is inhibited, proper functioning and motility of spermatozoa remains intact although it is unclear whether such motility can be sustained for prolonged periods of time, or is sufficiently vigorous to achieve optimal fertilization. The purpose of this article is to provide an overview of mammalian sperm energy metabolism and identify the preferred metabolic pathway for ATP generation which forms the basis of energy Droduction in human spermatozoa during fertilization.
基金supported by grants from the University of Bourgogne(Dijon,France)the University of Monastir(Monastir,Tunisia)
文摘The treatment of microglial BV-2 cells with sodium arsenate（As（V）：0.1-400 μmol/L — 48 hr）induces a dose-dependent response.The neurotoxic effects of high concentrations of As（V）（100,200 and 400 μmol/L） are characterized by increased levels of mitochondrial complexesⅠ,Ⅱ,and Ⅳ followed by increased superoxide anion generation.Moreover,As（V） triggers an apoptotic mode of cell death,demonstrated by an apoptotic SubG1 peak,associated with an alteration of plasma membrane integrity.There is also a decrease in transmembrane mitochondrial potential and mitochondrial adenosine triphosphate ATP.It is therefore tempting to speculate that As（V） triggers mitochondrial dysfunction,which may lead to defective oxidative phosphorylation subsequently causing mitochondrial oxidative damage,which in turn induces an apoptotic mode of cell death.
基金the National Natural Science Foundation of China (Grant No.30170100)
文摘Cotyledon mitochondrion respiration and oxidative phosphorylation activity were studied in two groups of soybean seeds. One group was primed with polyethylene glycol (PEG) for different periods of time, and the other was unprimed (control), and both were then exposed to imbibition at low temperatures before their germination. The results indicated that when L-Malate (L-Mal) and á-Ketoglutarate (α-Kg) were used as substrates, the ADP-stimulated mitochondria respiration rates of control seeds were mark- edly higher than state Ⅲ respiration rates of primed seeds. However, the osmoconditioning pretreatment significantly enhanced the oxidative phosphorylation activity of cotyledon mitochondrion in 12 h. The oxidative phosphorylation activity of the mitochondrion of primed seeds was normal and the ADP/O value was consistent with the theoretical one. When reduced nicotinamide adenine dinu- cleotide (NADH) was used as the substrate, the mitochondria of control seeds still had oxidative phosphorylation activity, while ADP/O value was obviously lower than that of mitochondria of primed seeds. When Succinate (Succ) was used as the substrate, the oxidative phosphorylation activity of the primed seeds was normal after priming for 24 h. When different substrates were used, the emerging order of the oxidative phosphorylation activity of the primed seeds was NADH, α-Kg, Succ and in the last place L-Mal. The mechanism of soybean imbibitionl chilling injury and protective effect of PEG priming were discussed.
基金supported by NIH Grant Al-15614 (to CAD)the Ministerio de Ciencia e Innovacion (PID2020-120267BRI00AEI/10.13039/501100011033)(to RLV)。
文摘Metabolism is a fundamental process by which biochemicals are broken down to produce energy(catabolism) or used to build macromolecules(anabolism). Metabolism has received renewed attention as a mechanism that generates molecules that modulate multiple cellular responses. This was first identified in cancer cells as the Warburg effect, but it is also present in immunocompetent cells. Studies have revealed a bidirectional influence of cellular metabolism and immune cell function, highlighting the significance of metabolic reprogramming in immune cell activation and effector functions. Metabolic processes such as glycolysis, oxidative phosphorylation, and fatty acid oxidation have been shown to undergo dynamic changes during immune cell response, facilitating the energetic and biosynthetic demands. This review aims to provide a better understanding of the metabolic reprogramming that occurs in different immune cells upon activation, with a special focus on central nervous system disorders. Understanding the metabolic changes of the immune response not only provides insights into the fundamental mechanisms that regulate immune cell function but also opens new approaches for therapeutic strategies aimed at manipulating the immune system.
