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
Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to ...Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to reveal the mechanism underlying such plasticity for intestinal health.Recent studies have found that metabolic pathways control stem cell fate in homeostasis,but the role of metabolism in the regeneration of ISCs after damage has not been clarified.Here,we find that in a human colorectal cancer dataset,miR-29a and b(miR-29a/b)are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy.We also show that these two microRNAs are required for intesti-nal stemness maintenance in mice,and their expression is induced in regenerated ISCs after irradiation injury,resulting in skewed ISC fate from differentiation towards self-renewal.This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation(FAO)and depression of oxidative phosphorylation,which in turn controls the balance between self-renewal and differentiation of ISCs.Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery.Finally,we filter the potential targets of miR-29a/b and identify Hnf4g,a transcription factor,that drives this metabolic reprogramming through regulating FAO-related enzymes.Our work discovers an impor-tant metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.展开更多
Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic intervention...Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic interventions demonstrated unsatisfactory therapeutic outcomes and potential systemic toxicity,resulting from the metabolic instability and limited targeting ability of inhibitors as well as complex tumor microenvironment.To address these limitations,here we developed a robust pyroelectric BaTiO_(3)@Au core–shell nanostructure(BTO@Au)to selectively and persistently block energy generation of tumor cells.Stimulated by near-infrared(NIR)laser,the Au shell could generate heat to activate the BaTiO_(3)core to produce reactive oxygen species(ROS)regardless of the constrained microenvironment,thus prominently inhibits mitochondrial oxidative phosphorylation(OXPHOS)and reduces ATP production to induce TNBC cell apoptosis.The therapeutic effects have been well demonstrated in vitro and in vivo,paving a new way for the development of metabolic interventions.展开更多
Peroxisome proliferator-activated receptorγ(PPARγ)is a transcriptional coactivator that binds to a diverse range of transcription factors.PPARγcoactivator 1(PGC-1)coactivators possess an extensive range of biologic...Peroxisome proliferator-activated receptorγ(PPARγ)is a transcriptional coactivator that binds to a diverse range of transcription factors.PPARγcoactivator 1(PGC-1)coactivators possess an extensive range of biological effects in different tissues,and play a key part in the regulation of the oxidative metabolism,consequently modulating the production of reactive oxygen species,autophagy,and mitochondrial biogenesis.Owing to these findings,a large body of studies,aiming to establish the role of PGC-1 in the neuromuscular system,has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases.Among these,some evidence has shown that various signaling pathways linked to PGC-1αare deregulated in muscular dystrophy,leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species(ROS)production.In the light of these results,any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies.PGC-1αis influenced by different patho-physiological/pharmacological stimuli.Natural products have been reported to display modulatory effects on PPARγactivation with fewer side effects in comparison to synthetic drugs.Taken together,this review summarizes the current knowledge on Duchenne muscular dystrophy,focusing on the potential effects of natural compounds,acting as regulators of PGC-1α.展开更多
MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a pr...MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer(NSCLC)resistance to the clinical MEK inhibitor trametinib.Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment,satisfying their energy demand and protecting them from apoptosis.As molecular events in this process,the pyruvate dehydrogenase complex(PDHc)and carnitine palmitoyl transferase IA(CPTIA),two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation.Importantly,the co-administration of trametinib and IACS-010759,a clinical mitochondrial complex I inhibitor that blocks OXPHOS,significantly impeded tumor growth and prolonged mouse survival.Overall,our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.展开更多
Swarming behavior facilitates pair formation,and therefore mating,in many eusocial termites.However,the physiological adjustments and morphological transformations of the flight muscles involved in flying and flightle...Swarming behavior facilitates pair formation,and therefore mating,in many eusocial termites.However,the physiological adjustments and morphological transformations of the flight muscles involved in flying and flightless insect forms are still unclear.Here,we found that the dispersal flight of the eusocial termite Reticulitermes chinensis Snyder led to a gradual decrease in adenosine triphosphate supply from oxidative phospho・rylation,as well as a reduction in the activities of critical mitochondrial respiratory enzymes from preflight to dealation.Correspondingly,using three-dimensional reconstruction and transmission electron microscopy(TEM),the flight muscles were found to be gradually deteriorated during this process.In particular,two tergo-pleural muscles(IItpm5 and IIItpm5)necessary to adjust the rotation of wings for wing shedding behavior were present only in flying alates.These findings suggest that flight muscle systems vary in function and morphology to facilitate the swarming flight procedure,which sheds light on the important role of swarming in successful extension and fecundity of eusocial termites.展开更多
As a promising modality for cancer therapy, photodynamic therapy(PDT) still acquired limited success in clinical nowadays due to the extremely serious hypoxia and immunosuppression tumor microenvironment. To ameliorat...As a promising modality for cancer therapy, photodynamic therapy(PDT) still acquired limited success in clinical nowadays due to the extremely serious hypoxia and immunosuppression tumor microenvironment. To ameliorate such a situation, we rationally designed and prepared cascade two-stage re-oxygenation and immune re-sensitization BSA-MHI148@SRF nanoparticles via hydrophilic and hydrophobic self-assembly strategy by using near-infrared photodynamic dye MHI148 chemically modified bovine serum albumin(BSA-MHI148) and multi-kinase inhibitor Sorafenib(SRF) as a novel tumor oxygen and immune microenvironment regulation drug. Benefiting from the accumulation of SRF in tumors, BSA-MHI148@SRF nanoparticles dramatically enhanced the PDT efficacy by promoting cascade two-stage tumor re-oxygenation mechanisms:(i) SRF decreased tumor oxygen consumption via inhibiting mitochondria respiratory.(ii) SRF increased the oxygen supply via inducing tumor vessel normalization. Meanwhile, the immunosuppression micro-environment was also obviously reversed by two-stage immune re-sensitization as follows:(i) Enhanced immunogenic cell death(ICD) production amplified by BSA-MHI148@SRF induced reactive oxygen species(ROS) generation enhanced T cell infiltration and improve its tumor cell killing ability.(ii) BSA-MHI148@SRF amplified tumor vessel normalization by VEGF inhibition also obviously reversed the tumor immune-suppression microenvironment. Finally, the growth of solid tumors was significantly depressed by such well-designed BSAMHI148@SRF nanoparticles, which could be potential for clinical cancer therapy.展开更多
Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer.Although strategies to impede mitochondrial energy supply have been rapidly developed,the anticancer efficacy is still far from sa...Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer.Although strategies to impede mitochondrial energy supply have been rapidly developed,the anticancer efficacy is still far from satisfactory,mainly attributed to the hybrid metabolic pathways of mitochondrial oxidative phosphorylation(OXPHOS)and glycolysis.Herein,we construct a cancer cell membrane camouflaged nano-inhibitor,mTPPa-Sy nanoparticle(NP),which co-encapsulates OXPHOS inhibitor(mitochondrial-targeting photosensitizers:TPPa)and glycolysis inhibitor(syrosingopine(Sy))for synergistically blocking the two different energy pathways.The mTPPa-Sy NPs exhibit precision tumor-targeting due to the high affinity between the biomimic membrane and the homotypic cancer cells.Under laser irradiation,the mitochondrial-targeting TPPa,which is synthesized by conjugating pyropheophorbide a(PPa)with triphenylphosphin,produces excessive reactive oxygen species(ROS)and further disrupts the OXPHOS.Interestingly,OXPHOS inhibition reduces O_(2) consumption and improves ROS production,further constructing a closed-loop OXPHOS inhibition system.Moreover,TPPa-initiated OXPHOS inhibition in combination with the Sytriggered glycolysis inhibition results in lethal energy depletion,significantly suppressing tumor growth even after a single treatment.Our findings highlight the necessity and effectiveness of synergetic lethal energy depletion,providing a prospective strategy for efficient cancer therapy.展开更多
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supported by the National Natural Science Foundation of China(32372247)the National Key Research and Development Program of China(2023YFF1104501)to Huiyuan Guo.
文摘Intestinal stem cells(ISCs)initiate intestinal epithelial regeneration and tumorigenesis,and they experi-ence rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence.It is crucial to reveal the mechanism underlying such plasticity for intestinal health.Recent studies have found that metabolic pathways control stem cell fate in homeostasis,but the role of metabolism in the regeneration of ISCs after damage has not been clarified.Here,we find that in a human colorectal cancer dataset,miR-29a and b(miR-29a/b)are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy.We also show that these two microRNAs are required for intesti-nal stemness maintenance in mice,and their expression is induced in regenerated ISCs after irradiation injury,resulting in skewed ISC fate from differentiation towards self-renewal.This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation(FAO)and depression of oxidative phosphorylation,which in turn controls the balance between self-renewal and differentiation of ISCs.Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery.Finally,we filter the potential targets of miR-29a/b and identify Hnf4g,a transcription factor,that drives this metabolic reprogramming through regulating FAO-related enzymes.Our work discovers an impor-tant metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.
基金supported by the National Natural Science Foundation of China(Nos.22007063 and 82002063)Shanxi Medical Key Science and Technology Project Plan of China(No.2020XM01)+4 种基金the National University of Singapore Start-up Grant(No.NUHSRO/2020/133/Startup/08)NUS School of Medicine Nanomedicine Translational Research Program(No.NUHSRO/2021/034/TRP/09/Nanomedicine)the Science Research Start-up Fund for Doctor of Shanxi Province(No.XD1809 and XD2011)the Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(No.2019L0414)Shanxi Province Science Foundation for Youths(No.201901D211316).
文摘Abnormal metabolism has become a potential target for highly malignant and invasive triple-negative breast cancer(TNBC)due to its relatively low response to traditional therapeutics.The existing metabolic interventions demonstrated unsatisfactory therapeutic outcomes and potential systemic toxicity,resulting from the metabolic instability and limited targeting ability of inhibitors as well as complex tumor microenvironment.To address these limitations,here we developed a robust pyroelectric BaTiO_(3)@Au core–shell nanostructure(BTO@Au)to selectively and persistently block energy generation of tumor cells.Stimulated by near-infrared(NIR)laser,the Au shell could generate heat to activate the BaTiO_(3)core to produce reactive oxygen species(ROS)regardless of the constrained microenvironment,thus prominently inhibits mitochondrial oxidative phosphorylation(OXPHOS)and reduces ATP production to induce TNBC cell apoptosis.The therapeutic effects have been well demonstrated in vitro and in vivo,paving a new way for the development of metabolic interventions.
基金supported by the crowd funding#Sport4Therapy to Giuseppe D’Antona(Italy)supported by Instituto de Salud CarlosⅢ,Grant Number:CIBEROBN CB12/03/30038
文摘Peroxisome proliferator-activated receptorγ(PPARγ)is a transcriptional coactivator that binds to a diverse range of transcription factors.PPARγcoactivator 1(PGC-1)coactivators possess an extensive range of biological effects in different tissues,and play a key part in the regulation of the oxidative metabolism,consequently modulating the production of reactive oxygen species,autophagy,and mitochondrial biogenesis.Owing to these findings,a large body of studies,aiming to establish the role of PGC-1 in the neuromuscular system,has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases.Among these,some evidence has shown that various signaling pathways linked to PGC-1αare deregulated in muscular dystrophy,leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species(ROS)production.In the light of these results,any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies.PGC-1αis influenced by different patho-physiological/pharmacological stimuli.Natural products have been reported to display modulatory effects on PPARγactivation with fewer side effects in comparison to synthetic drugs.Taken together,this review summarizes the current knowledge on Duchenne muscular dystrophy,focusing on the potential effects of natural compounds,acting as regulators of PGC-1α.
基金sponsored by the National Natural Science Foundation of China(82122045,82073073,81874207,and 81872418)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210802,China)+4 种基金MOE Key Laboratory of Biosystems Homeostasis&Protection(Zhejiang University,China)Science and Technology Commission of Shanghai Municipality(21S11902000,China)Jointed PI Program from Shanghai Changning Maternity and Infant Health Hospital(11300-412311-20033,China)ECNU Construction Fund of Innovation and Entrepreneurship Laboratory(44400-20201-532300/021,China)the ECNU multifunctional platform for innovation(011 and 004,China).
文摘MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer(NSCLC)resistance to the clinical MEK inhibitor trametinib.Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment,satisfying their energy demand and protecting them from apoptosis.As molecular events in this process,the pyruvate dehydrogenase complex(PDHc)and carnitine palmitoyl transferase IA(CPTIA),two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation.Importantly,the co-administration of trametinib and IACS-010759,a clinical mitochondrial complex I inhibitor that blocks OXPHOS,significantly impeded tumor growth and prolonged mouse survival.Overall,our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.
基金by the National Natural Science Foundation of China(31772516 and 31501634)was funded by the Key Foreign Cooperation Projects of the Bureau of International Cooperation of Chinese Academy of Sciences(152111KYSB20160067).
文摘Swarming behavior facilitates pair formation,and therefore mating,in many eusocial termites.However,the physiological adjustments and morphological transformations of the flight muscles involved in flying and flightless insect forms are still unclear.Here,we found that the dispersal flight of the eusocial termite Reticulitermes chinensis Snyder led to a gradual decrease in adenosine triphosphate supply from oxidative phospho・rylation,as well as a reduction in the activities of critical mitochondrial respiratory enzymes from preflight to dealation.Correspondingly,using three-dimensional reconstruction and transmission electron microscopy(TEM),the flight muscles were found to be gradually deteriorated during this process.In particular,two tergo-pleural muscles(IItpm5 and IIItpm5)necessary to adjust the rotation of wings for wing shedding behavior were present only in flying alates.These findings suggest that flight muscle systems vary in function and morphology to facilitate the swarming flight procedure,which sheds light on the important role of swarming in successful extension and fecundity of eusocial termites.
基金supported by the National Natural Science Foundation of China(82003697 and 21977081)the Zhejiang Provincial Natural Science of Foundation of China(LZ19H180001)+2 种基金Wenzhou Medical University(KYYW201901,China)Wenzhou Science and Technology Plan Project(Grant No.Y2020827,China)Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province(Grant No:2018E10008,China).
文摘As a promising modality for cancer therapy, photodynamic therapy(PDT) still acquired limited success in clinical nowadays due to the extremely serious hypoxia and immunosuppression tumor microenvironment. To ameliorate such a situation, we rationally designed and prepared cascade two-stage re-oxygenation and immune re-sensitization BSA-MHI148@SRF nanoparticles via hydrophilic and hydrophobic self-assembly strategy by using near-infrared photodynamic dye MHI148 chemically modified bovine serum albumin(BSA-MHI148) and multi-kinase inhibitor Sorafenib(SRF) as a novel tumor oxygen and immune microenvironment regulation drug. Benefiting from the accumulation of SRF in tumors, BSA-MHI148@SRF nanoparticles dramatically enhanced the PDT efficacy by promoting cascade two-stage tumor re-oxygenation mechanisms:(i) SRF decreased tumor oxygen consumption via inhibiting mitochondria respiratory.(ii) SRF increased the oxygen supply via inducing tumor vessel normalization. Meanwhile, the immunosuppression micro-environment was also obviously reversed by two-stage immune re-sensitization as follows:(i) Enhanced immunogenic cell death(ICD) production amplified by BSA-MHI148@SRF induced reactive oxygen species(ROS) generation enhanced T cell infiltration and improve its tumor cell killing ability.(ii) BSA-MHI148@SRF amplified tumor vessel normalization by VEGF inhibition also obviously reversed the tumor immune-suppression microenvironment. Finally, the growth of solid tumors was significantly depressed by such well-designed BSAMHI148@SRF nanoparticles, which could be potential for clinical cancer therapy.
基金This work was financially supported by National Natural Science Foundation of China(No.81773656)Liaoning Revitalization Talents Program(No.XLYC1808017)+1 种基金Shenyang Youth Science and Technology Innovation Talents Program(No.RC190454)National Postdoctoral Foundation of China(No.2021M693868).
文摘Mitochondrial bioenergy plays a vital role in the occurrence and development of cancer.Although strategies to impede mitochondrial energy supply have been rapidly developed,the anticancer efficacy is still far from satisfactory,mainly attributed to the hybrid metabolic pathways of mitochondrial oxidative phosphorylation(OXPHOS)and glycolysis.Herein,we construct a cancer cell membrane camouflaged nano-inhibitor,mTPPa-Sy nanoparticle(NP),which co-encapsulates OXPHOS inhibitor(mitochondrial-targeting photosensitizers:TPPa)and glycolysis inhibitor(syrosingopine(Sy))for synergistically blocking the two different energy pathways.The mTPPa-Sy NPs exhibit precision tumor-targeting due to the high affinity between the biomimic membrane and the homotypic cancer cells.Under laser irradiation,the mitochondrial-targeting TPPa,which is synthesized by conjugating pyropheophorbide a(PPa)with triphenylphosphin,produces excessive reactive oxygen species(ROS)and further disrupts the OXPHOS.Interestingly,OXPHOS inhibition reduces O_(2) consumption and improves ROS production,further constructing a closed-loop OXPHOS inhibition system.Moreover,TPPa-initiated OXPHOS inhibition in combination with the Sytriggered glycolysis inhibition results in lethal energy depletion,significantly suppressing tumor growth even after a single treatment.Our findings highlight the necessity and effectiveness of synergetic lethal energy depletion,providing a prospective strategy for efficient cancer therapy.
