Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability o...Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability or dysfunction may be the key stimulating factors to activate NLRP3 inflammasome,and sustained Ca^(2+)transfer can result in mitochondrial dysfunction.We focused on KCs to explore the damage to mitochondria by EA.After EA stimulation,cells produced an oxidative stress(OS)response with a significant increase in ROS release.Immunoprecipitation experiments and the addition of inhibitors revealed that the increase in the level of intracellular Ca^(2+)led to Ca^(2+)accumulation in the mitochondrial matrix via mitochondria-associated membranes(MAMs).This was accompanied by a significant release of m ROS,loss of MMP and ATP,and a significant increase in mitochondrial permeability transition pore opening,ultimately leading to mitochondrial instability.These findings confirmed the mechanism that EA induced mitochondrial Ca^(2+)imbalance in KCs via MAM,ultimately leading to mitochondrial dysfunction.Meanwhile,EA induced OS and the decrease of MMP and ATP in rat liver,and significant lesions were found in liver mitochondria.Swelling of the inner mitochondrial cristae and mitochondrial vacuolization occurred,with a marked increase in lipid droplets.展开更多
BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erl...BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.展开更多
Mitochondrial organelle transplantation (MOT) is an innovative strategy for the treatment of mitochondrial dysfunction such as cardiac ischemic reperfusion injuries, Parkinson’s diseases, brain and spinal cord injuri...Mitochondrial organelle transplantation (MOT) is an innovative strategy for the treatment of mitochondrial dysfunction such as cardiac ischemic reperfusion injuries, Parkinson’s diseases, brain and spinal cord injuries, and amyotrophic lateral sclerosis (ALS). However, one of the major challenges for widespread usage is a methodology for preservation of isolated mitochondria. Extracellular vesicles (EVs) are phospholipid bilayer-enclosed vesicles released from cells. EVs carry a cargo of proteins, nucleic acids, lipids, metabolites, and even organelles such as mitochondria. Purpose: To test if EVs enhance the stability of isolated mitochondria. Methods: We mixed isolated mitochondria of fibroblasts with EVs of mesenchymal stromal cells (imEVs) (9:1 in volume) and stored the mixture at 2°C - 6°C for different time periods. We measured morphology, mitochondrial membrane potential (MMP) and mitochondrial ATP content at 0, 2, 5 days. Key findings: After 2 days of storage, the mito-chondria without imEVs lost approximate 70% MMP (RFU: 1822 ± 68), compared to the fresh mitochondria (RFU: 5458 ± 52) (p 0.05). In agreement with MMP, mitochondria without imEVs lost significant mitochondrial ATP content (p 0.05), after 2 days of cold storage, compared to fresh mitochondria. Microscopy showed that imEVs promoted aggregation of isolated mitochondria. Summary: The preliminary data showed that imEVs enhanced the stability of isolated mitochondria in cold storage.展开更多
BACKGROUND Traditional treatments for pancreatic cancer(PC)are inadequate.Photodynamic therapy(PDT)is non-invasive,and proven safe to kill cancer cells,including PC.However,the mitochondrial concentration of the photo...BACKGROUND Traditional treatments for pancreatic cancer(PC)are inadequate.Photodynamic therapy(PDT)is non-invasive,and proven safe to kill cancer cells,including PC.However,the mitochondrial concentration of the photosensitizer,such as verteporfin,is key.AIM To investigate the distribution of fluorescence of verteporfin in PC cells treated with antitumor drugs,post-PDT.METHODS Workable survival rates of PC cells(AsPC-1,BxPC-3)were determined with chemotherapy[doxorubicin(DOX)and gemcitabine(GEM)]and non-chemotherapy[sirolimus(SRL)and cetuximab(CTX)]drugs in vitro,with or without verteporfin,as measured via MTT,flow cytometry,and laser confocal microscopy.Reduced cell proliferation was associated with GEM that was more enduring compared with DOX.Confocal laser microscopy allowed observation of GEM-and verteporfin-treated PC cells co-stained with 4’,6-diamidino-2-phenylindole and MitoTracker Green to differentiate living and dead cells and subcellular localization of verteporfin,respectively.RESULTS Cell survival significantly dropped upon exposure to either chemotherapy drug,but not to SRL or CTX.Both cell lines responded similarly to GEM.The intensity of fluorescence was associated with the concentration of verteporfin.Additional experiments using GEM showed that survival rates of the PC cells treated with 10μmol/L verteporfin(but not less)were significantly lower relative to nil verte-porfin.Living and dead stained cells treated with GEM were distinguishable.After GEM treatment,verteporfin was observed primarily in the mitochondria.CONCLUSION Verteporfin was observed in living cells.In GEM-treated human PC cells,verteporfin was particularly prevalent in the mitochondria.This study supports further study of PDT for the treatment of PC after neoadjuvant chemotherapy.展开更多
Background Vitamin A(VA)and its metabolite,retinoic acid(RA),are of great interest for their wide range of physiological functions.However,the regulatory contribution of VA to mitochondrial and muscle fiber compositio...Background Vitamin A(VA)and its metabolite,retinoic acid(RA),are of great interest for their wide range of physiological functions.However,the regulatory contribution of VA to mitochondrial and muscle fiber composition in sheep has not been reported.Method Lambs were injected with 0(control)or 7,500 IU VA palmitate into the biceps femoris muscle on d 2 after birth.At the age of 3 and 32 weeks,longissimus dorsi(LD)muscle samples were obtained to explore the effect of VA on myofiber type composition.In vitro,we investigated the effects of RA on myofiber type composition and intrinsic mechanisms.Results The proportion of type I myofiber was greatly increased in VA-treated sheep in LD muscle at harvest.VA greatly promoted mitochondrial biogenesis and function in LD muscle of sheep.Further exploration revealed that VA elevated PGC-1αmRNA and protein contents,and enhanced the level of p38 MAPK phosphorylation in LD muscle of sheep.In addition,the number of type I myofibers with RA treatment was significantly increased,and type IIx myofibers was significantly decreased in primary myoblasts.Consistent with in vivo experiment,RA significantly improved mitochondrial biogenesis and function in primary myoblasts of sheep.We then used si-PGC-1αto inhibit PGC-1αexpression and found that si-PGC-1αsignificantly abrogated RA-induced the formation of type I myofibers,mitochondrial biogenesis,MitoTracker staining intensity,UQCRC1 and ATP5A1 expression,SDH activity,and enhanced the level of type IIx muscle fibers.These data suggested that RA improved mitochondrial biogenesis and function by promoting PGC-1αexpression,and increased type I myofibers.In order to prove that the effect of RA on the level of PGC-1αis caused by p38 MAPK signaling,we inhibited the p38 MAPK signaling using a p38 MAPK inhibitor,which significantly reduced RA-induced PGC-1αand MyHC I levels.Conclusion VA promoted PGC-1αexpression through the p38 MAPK signaling pathway,improved mitochondrial biogenesis,and altered the composition of muscle fiber type.展开更多
BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mecha...BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.展开更多
Over the course of several decades,robust research has firmly established the significance of mitochondrial pathology as a central contributor to the onset of skeletal muscle atrophy in individuals with diabetes.Howev...Over the course of several decades,robust research has firmly established the significance of mitochondrial pathology as a central contributor to the onset of skeletal muscle atrophy in individuals with diabetes.However,the specific intricacies governing this process remain elusive.Extensive evidence highlights that individuals with diabetes regularly confront the severe consequences of skeletal muscle degradation.Deciphering the sophisticated mechanisms at the core of this pathology requires a thorough and meticulous exploration into the nuanced factors intricately associated with mitochondrial dysfunction.展开更多
The endoplasmic reticulum(ER)is connected to mitochondria through mitochondria-associated ER membranes(MAMs).MAMs provide a framework for crosstalk between the ER and mitochondria,playing a crucial role in regulating ...The endoplasmic reticulum(ER)is connected to mitochondria through mitochondria-associated ER membranes(MAMs).MAMs provide a framework for crosstalk between the ER and mitochondria,playing a crucial role in regulating cellular calcium balance,lipid metabolism,and cell death.Dysregulation of MAMs is involved in the development of chronic liver disease(CLD).In CLD,changes in MAMs structure and function occur due to factors such as cellular stress,inflammation,and oxidative stress,leading to abnormal interactions between mitochondria and the ER,resulting in liver cell injury,fibrosis,and impaired liver function.Traditional Chinese medicine has shown some research progress in regulating MAMs signaling and treating CLD.This paper reviews the literature on the association between mitochondria and the ER,as well as the intervention of traditional Chinese medicine in regulating CLD.展开更多
AIM: lo investigate the mutation in D-loop region of mitochondrial DNA in gastric cancer and its influence on the changes of reactive oxygen species (ROS) and cell cycle. METHODS: The D-loop region was amplified by PC...AIM: lo investigate the mutation in D-loop region of mitochondrial DNA in gastric cancer and its influence on the changes of reactive oxygen species (ROS) and cell cycle. METHODS: The D-loop region was amplified by PCR and sequenced. Reactive oxygen species and cell cycle were detected by flow cytometry in 20 specimens from gastriccancer and adjacent normal tissues. According to the sequence results, gastric cancer tissue was divided into mutation group and control group. Reactive oxygen species, apoptosis and proliferation in the two groups were compared.RESULTS: Among the 20 gastric cancer specimens, 18 mutations were identified in 7 patients, the mutation rate being 35%. There were four microsatellite instabilities in the mutations. No mutation was found in the adjacent tissues. Reactive oxygen species, apoptosis, and proliferation in the mutation group were all significantly higher than those in control group.CONCLUSION: Mutation in D-loop region plays a role in the genesis and development of gastric cancer.展开更多
Attempts are being made to domesticate the grasscutter (Thryonomys swinderianus) for commercial production in Sub-Saharan Africa to cater for the protein needs of the people and to satisfy the craving for bushmeat, th...Attempts are being made to domesticate the grasscutter (Thryonomys swinderianus) for commercial production in Sub-Saharan Africa to cater for the protein needs of the people and to satisfy the craving for bushmeat, thereby reducing habitat destruction through hunting. The objective of this study was to determine the genetic diversity of grasscutter populations in Ghana. DNA was extracted from roots of hair samples collected from 84 grasscutters from three agro-ecological zones in Ghana, namely Guinea Savanna (n = 17), Forest (n = 22), and Coastal Savanna (n = 45). Mitochondrial D-loop was sequenced and the diversity was determined across the zones. Out of 26 haplotypes found, 15 were obtained from Guinea Savanna, 7 from Forest and 13 from Coastal Savanna. Haplotype diversities were 0.978, 0.853 and 0.875 respectively for Guinea Savanna, Forest and Coastal Savanna zones. Analysis of molecular variance (AMOVA) revealed significant differentiation between Forest and Savanna populations (FST = 0.14, p 0.05). Network analysis indicated two clusters, one of which consisted of only Savanna haplotypes. Population neutrality tests showed that Forest and Coastal Savanna populations had been stable while the Guinea Savanna zone population had undergone an expansion (Fu’s FS = ‐7.132,展开更多
文摘[目的]研究庆阳驴养殖群体的遗传多样性与母系起源,了解其遗传信息,为保护庆阳驴种质资源、选育和遗传改良工作提供理论依据。[方法]随机选取133头庆阳驴,对其线粒体DNA(mitochondrial DNA,mtDNA)D-loop区序列进行PCR扩增、测序及比对,并探讨庆阳驴的遗传多样性与母系起源。[结果]在获得的520 bp D-loop碱基序列中,AT含量(57.3%)高于GC含量(42.8%),表现出碱基的偏倚性;检测到38个变异位点,包含8个碱基对的转换;其核苷酸多样性(Pi)、单倍型多样性(Hd)、平均核苷酸差异(K)分别为0.01591、0.895和8.274,与欧洲家驴和中国家驴研究的平均值相比较低,说明该驴品种核苷酸变异较为贫乏。庆阳驴mtDNA D-loop区存在35个单倍型,单倍型之间的遗传距离为0.002~0.042。系统进化结果显示,庆阳驴存在2个线粒体支系,表明其具有2个母系起源,且遗传距离表明,庆阳驴与克罗地亚家驴之间的遗传距离较近。[结论]本研究从分子水平初步揭示庆阳驴核苷酸变异比较贫乏,杂交程度高,mtDNA遗传多态性正逐步丧失,应加强庆阳驴品种的遗传资源保护工作。
基金supported by fund from the National Natural Science Foundation of China(32172322)。
文摘Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability or dysfunction may be the key stimulating factors to activate NLRP3 inflammasome,and sustained Ca^(2+)transfer can result in mitochondrial dysfunction.We focused on KCs to explore the damage to mitochondria by EA.After EA stimulation,cells produced an oxidative stress(OS)response with a significant increase in ROS release.Immunoprecipitation experiments and the addition of inhibitors revealed that the increase in the level of intracellular Ca^(2+)led to Ca^(2+)accumulation in the mitochondrial matrix via mitochondria-associated membranes(MAMs).This was accompanied by a significant release of m ROS,loss of MMP and ATP,and a significant increase in mitochondrial permeability transition pore opening,ultimately leading to mitochondrial instability.These findings confirmed the mechanism that EA induced mitochondrial Ca^(2+)imbalance in KCs via MAM,ultimately leading to mitochondrial dysfunction.Meanwhile,EA induced OS and the decrease of MMP and ATP in rat liver,and significant lesions were found in liver mitochondria.Swelling of the inner mitochondrial cristae and mitochondrial vacuolization occurred,with a marked increase in lipid droplets.
基金Supported by NIH/National Cancer Institute Grant,No.R01CA138441 and No.R01CA269452UW Madison Centene Pancreas Cancer Collaborative Award,No.21-8568.
文摘BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths.Increased activity of the epidermal growth factor receptor(EGFR)is often observed in pancreatic cancer,and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration.Nevertheless,erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes.We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential(Δψm),facilitate tumor cell uptake ofΔψm-sensitive agents,disrupt mitochondrial homeostasis,and subsequently trigger tumor cell death.Erlotinib has not been tested for this effect.AIM To determine whether erlotinib can elevateΔψm and increase tumor cell uptake ofΔψm-sensitive agents,subsequently triggering tumor cell death.METHODSΔψm-sensitive fluorescent dye was used to determine how erlotinib affectsΔψm in pancreatic adenocarcinoma(PDAC)cell lines.The viability of conventional and patient-derived primary PDAC cell lines in 2D-and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone(MitoQ),aΔψm-sensitive MitoQ.The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0.The preclinical efficacy of the twodrug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts.RESULTS Erlotinib elevatedΔψm in PDAC cells,facilitating tumor cell uptake and mitochondrial enrichment ofΔψm-sensitive agents.MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses,while erlotinib pretreatment potentiated low doses of MitoQ.SynergyFinder suggested that these drugs synergistically induced tumor cell lethality.Consistent with in vitro data,erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent.CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.
文摘Mitochondrial organelle transplantation (MOT) is an innovative strategy for the treatment of mitochondrial dysfunction such as cardiac ischemic reperfusion injuries, Parkinson’s diseases, brain and spinal cord injuries, and amyotrophic lateral sclerosis (ALS). However, one of the major challenges for widespread usage is a methodology for preservation of isolated mitochondria. Extracellular vesicles (EVs) are phospholipid bilayer-enclosed vesicles released from cells. EVs carry a cargo of proteins, nucleic acids, lipids, metabolites, and even organelles such as mitochondria. Purpose: To test if EVs enhance the stability of isolated mitochondria. Methods: We mixed isolated mitochondria of fibroblasts with EVs of mesenchymal stromal cells (imEVs) (9:1 in volume) and stored the mixture at 2°C - 6°C for different time periods. We measured morphology, mitochondrial membrane potential (MMP) and mitochondrial ATP content at 0, 2, 5 days. Key findings: After 2 days of storage, the mito-chondria without imEVs lost approximate 70% MMP (RFU: 1822 ± 68), compared to the fresh mitochondria (RFU: 5458 ± 52) (p 0.05). In agreement with MMP, mitochondria without imEVs lost significant mitochondrial ATP content (p 0.05), after 2 days of cold storage, compared to fresh mitochondria. Microscopy showed that imEVs promoted aggregation of isolated mitochondria. Summary: The preliminary data showed that imEVs enhanced the stability of isolated mitochondria in cold storage.
文摘BACKGROUND Traditional treatments for pancreatic cancer(PC)are inadequate.Photodynamic therapy(PDT)is non-invasive,and proven safe to kill cancer cells,including PC.However,the mitochondrial concentration of the photosensitizer,such as verteporfin,is key.AIM To investigate the distribution of fluorescence of verteporfin in PC cells treated with antitumor drugs,post-PDT.METHODS Workable survival rates of PC cells(AsPC-1,BxPC-3)were determined with chemotherapy[doxorubicin(DOX)and gemcitabine(GEM)]and non-chemotherapy[sirolimus(SRL)and cetuximab(CTX)]drugs in vitro,with or without verteporfin,as measured via MTT,flow cytometry,and laser confocal microscopy.Reduced cell proliferation was associated with GEM that was more enduring compared with DOX.Confocal laser microscopy allowed observation of GEM-and verteporfin-treated PC cells co-stained with 4’,6-diamidino-2-phenylindole and MitoTracker Green to differentiate living and dead cells and subcellular localization of verteporfin,respectively.RESULTS Cell survival significantly dropped upon exposure to either chemotherapy drug,but not to SRL or CTX.Both cell lines responded similarly to GEM.The intensity of fluorescence was associated with the concentration of verteporfin.Additional experiments using GEM showed that survival rates of the PC cells treated with 10μmol/L verteporfin(but not less)were significantly lower relative to nil verte-porfin.Living and dead stained cells treated with GEM were distinguishable.After GEM treatment,verteporfin was observed primarily in the mitochondria.CONCLUSION Verteporfin was observed in living cells.In GEM-treated human PC cells,verteporfin was particularly prevalent in the mitochondria.This study supports further study of PDT for the treatment of PC after neoadjuvant chemotherapy.
基金funded by the National Natural Science Foundation of China(31972559)the Distinguished and Excellent Young Scholar Cultivation Project of Shanxi Agricultural University(2022JQPYGC01).
文摘Background Vitamin A(VA)and its metabolite,retinoic acid(RA),are of great interest for their wide range of physiological functions.However,the regulatory contribution of VA to mitochondrial and muscle fiber composition in sheep has not been reported.Method Lambs were injected with 0(control)or 7,500 IU VA palmitate into the biceps femoris muscle on d 2 after birth.At the age of 3 and 32 weeks,longissimus dorsi(LD)muscle samples were obtained to explore the effect of VA on myofiber type composition.In vitro,we investigated the effects of RA on myofiber type composition and intrinsic mechanisms.Results The proportion of type I myofiber was greatly increased in VA-treated sheep in LD muscle at harvest.VA greatly promoted mitochondrial biogenesis and function in LD muscle of sheep.Further exploration revealed that VA elevated PGC-1αmRNA and protein contents,and enhanced the level of p38 MAPK phosphorylation in LD muscle of sheep.In addition,the number of type I myofibers with RA treatment was significantly increased,and type IIx myofibers was significantly decreased in primary myoblasts.Consistent with in vivo experiment,RA significantly improved mitochondrial biogenesis and function in primary myoblasts of sheep.We then used si-PGC-1αto inhibit PGC-1αexpression and found that si-PGC-1αsignificantly abrogated RA-induced the formation of type I myofibers,mitochondrial biogenesis,MitoTracker staining intensity,UQCRC1 and ATP5A1 expression,SDH activity,and enhanced the level of type IIx muscle fibers.These data suggested that RA improved mitochondrial biogenesis and function by promoting PGC-1αexpression,and increased type I myofibers.In order to prove that the effect of RA on the level of PGC-1αis caused by p38 MAPK signaling,we inhibited the p38 MAPK signaling using a p38 MAPK inhibitor,which significantly reduced RA-induced PGC-1αand MyHC I levels.Conclusion VA promoted PGC-1αexpression through the p38 MAPK signaling pathway,improved mitochondrial biogenesis,and altered the composition of muscle fiber type.
基金the Domestic First-class Construction Disciplines of the Hunan University of Chinese MedicinePostgraduate Research Innovation Program of Hunan Province,No.CX20220771Clinical MedTech Innovation Project of Hunan Province,No.2021SK51415.
文摘BACKGROUND Immune dysregulation and metabolic derangement have been recognized as key factors that contribute to the progression of hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF).However,the mechanisms underlying immune and metabolic derangement in patients with advanced HBV-ACLF are unclear.AIM To identify the bioenergetic alterations in the liver of patients with HBV-ACLF causing hepatic immune dysregulation and metabolic disorders.METHODS Liver samples were collected from 16 healthy donors(HDs)and 17 advanced HBV-ACLF patients who were eligible for liver transplantation.The mitochondrial ultrastructure,metabolic characteristics,and immune microenvironment of the liver were assessed.More focus was given to organic acid metabolism as well as the function and subpopulations of macrophages in patients with HBV-ACLF.RESULTS Compared with HDs,there was extensive hepatocyte necrosis,immune cell infiltration,and ductular reaction in patients with ACLF.In patients,the liver suffered severe hypoxia,as evidenced by increased expression of hypoxia-inducible factor-1α.Swollen mitochondria and cristae were observed in the liver of patients.The number,length,width,and area of mitochondria were adaptively increased in hepatocytes.Targeted metabolomics analysis revealed that mitochondrial oxidative phosphorylation decreased,while anaerobic glycolysis was enhanced in patients with HBV-ACLF.These findings suggested that,to a greater extent,hepa-tocytes used the extra-mitochondrial glycolytic pathway as an energy source.Patients with HBV-ACLF had elevated levels of chemokine C-C motif ligand 2 in the liver homogenate,which stimulates peripheral monocyte infiltration into the liver.Characterization and functional analysis of macrophage subsets revealed that patients with ACLF had a high abundance of CD68^(+)HLA-DR^(+)macrophages and elevated levels of both interleukin-1βand transforming growth factor-β1 in their livers.The abundance of CD206^(+)CD163^(+)macrophages and expression of interleukin-10 decreased.The correlation analysis revealed that hepatic organic acid metabolites were closely associated with macrophage-derived cytokines/chemokines.CONCLUSION The results indicated that bioenergetic alteration driven by hypoxia and mitochondrial dysfunction affects hepatic immune and metabolic remodeling,leading to advanced HBV-ACLF.These findings highlight a new therapeutic target for improving the treatment of HBV-ACLF.
基金the Foundation of State Key Laboratory of Component-based Chinese Medicine,No.CBCM2023107National Natural Science Foundation of China,No.81901853Specially Funded Scientific Research Project of the Fourth Affiliated Hospital of Harbin Medical University,No.HYDSYTB202126.
文摘Over the course of several decades,robust research has firmly established the significance of mitochondrial pathology as a central contributor to the onset of skeletal muscle atrophy in individuals with diabetes.However,the specific intricacies governing this process remain elusive.Extensive evidence highlights that individuals with diabetes regularly confront the severe consequences of skeletal muscle degradation.Deciphering the sophisticated mechanisms at the core of this pathology requires a thorough and meticulous exploration into the nuanced factors intricately associated with mitochondrial dysfunction.
基金Supported by the National Natural Science Foundation of China,No.82204755,and No.81960751the Guangxi Natural Science Foundation Youth Project,No.2023GXNSFBA026274+1 种基金the Guangxi University of Traditional Chinese Medicine School-level Project Youth Fund,No.2022QN008Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine Research Project,No.2022MS008 and No.2022QJ001.
文摘The endoplasmic reticulum(ER)is connected to mitochondria through mitochondria-associated ER membranes(MAMs).MAMs provide a framework for crosstalk between the ER and mitochondria,playing a crucial role in regulating cellular calcium balance,lipid metabolism,and cell death.Dysregulation of MAMs is involved in the development of chronic liver disease(CLD).In CLD,changes in MAMs structure and function occur due to factors such as cellular stress,inflammation,and oxidative stress,leading to abnormal interactions between mitochondria and the ER,resulting in liver cell injury,fibrosis,and impaired liver function.Traditional Chinese medicine has shown some research progress in regulating MAMs signaling and treating CLD.This paper reviews the literature on the association between mitochondria and the ER,as well as the intervention of traditional Chinese medicine in regulating CLD.
文摘AIM: lo investigate the mutation in D-loop region of mitochondrial DNA in gastric cancer and its influence on the changes of reactive oxygen species (ROS) and cell cycle. METHODS: The D-loop region was amplified by PCR and sequenced. Reactive oxygen species and cell cycle were detected by flow cytometry in 20 specimens from gastriccancer and adjacent normal tissues. According to the sequence results, gastric cancer tissue was divided into mutation group and control group. Reactive oxygen species, apoptosis and proliferation in the two groups were compared.RESULTS: Among the 20 gastric cancer specimens, 18 mutations were identified in 7 patients, the mutation rate being 35%. There were four microsatellite instabilities in the mutations. No mutation was found in the adjacent tissues. Reactive oxygen species, apoptosis, and proliferation in the mutation group were all significantly higher than those in control group.CONCLUSION: Mutation in D-loop region plays a role in the genesis and development of gastric cancer.
文摘Attempts are being made to domesticate the grasscutter (Thryonomys swinderianus) for commercial production in Sub-Saharan Africa to cater for the protein needs of the people and to satisfy the craving for bushmeat, thereby reducing habitat destruction through hunting. The objective of this study was to determine the genetic diversity of grasscutter populations in Ghana. DNA was extracted from roots of hair samples collected from 84 grasscutters from three agro-ecological zones in Ghana, namely Guinea Savanna (n = 17), Forest (n = 22), and Coastal Savanna (n = 45). Mitochondrial D-loop was sequenced and the diversity was determined across the zones. Out of 26 haplotypes found, 15 were obtained from Guinea Savanna, 7 from Forest and 13 from Coastal Savanna. Haplotype diversities were 0.978, 0.853 and 0.875 respectively for Guinea Savanna, Forest and Coastal Savanna zones. Analysis of molecular variance (AMOVA) revealed significant differentiation between Forest and Savanna populations (FST = 0.14, p 0.05). Network analysis indicated two clusters, one of which consisted of only Savanna haplotypes. Population neutrality tests showed that Forest and Coastal Savanna populations had been stable while the Guinea Savanna zone population had undergone an expansion (Fu’s FS = ‐7.132,
