The peroxisome proliferator-activated receptor(PPARδ)agonists are reported to improve insulin sensitivity,reduce glucose levels,and alleviate dysfunctional lipid metabolism in animal models of type 2 diabetes mellitu...The peroxisome proliferator-activated receptor(PPARδ)agonists are reported to improve insulin sensitivity,reduce glucose levels,and alleviate dysfunctional lipid metabolism in animal models of type 2 diabetes mellitus.However,the underlying mechanisms remain incompletely understood.Metabolism plays an essential role in the biological system.Monitoring of metabolic changes in response to disease conditions or drug treatment is critical for better understanding of the pathophysiological mechanisms.In this study,metabolic profiling analysis by gas chromatography-mass spectrometry integrated with targeted analysis by liquid chro matography-mass spectrometry was carried out in plasma samples of db/db diabetic mice after six-week treatment of PPARδagonist GW501516.GW501516 treatment significantly altered levels of metabolites,such as branched-chain amino acids(BCAAs),BCAA metabolites(3-hydroxyisobutyric acid and 3-hydroxyisovaleric acid),long-chain fatty acids,uric acid and ketone bodies(3-hydroxybutyric acid and 2-hydroxybutyric acid)which are all associated with the impaired systemic insulin sensitivity.The pre sent results indicate the beneficial effect of PPARδagonist in alleviating insulin resistance of diabetic mice by favorably modulating metabolic profile,thus providing valuable information in understanding the therapeutic potential of PPARδagonists in correcting metabolic dysfunction in diabetes.展开更多
Indole-3-acetic acid(IAA)is an important plant hormone that requlates a variety of physiological processes in plants,and it is also produced by some microbes.However,the biosynthesis and roles of IAA in microorganisms...Indole-3-acetic acid(IAA)is an important plant hormone that requlates a variety of physiological processes in plants,and it is also produced by some microbes.However,the biosynthesis and roles of IAA in microorganisms,particularly in plant pathogens,remain to be determined.In this study,the plant pathogen Xanthomonas campestris pv.campestris(Xcc)strain XC1 was shown to produce IAA via an L-tryptophan(L-Trp)-dependent pathway.The intermediate metabolite indole-3-ethanol and Xcc1569 encoding aromatic amino acid aminotransferase were shown to be partially involved in the uncharacterized sub-pathway in an L-Trp-dependent IAA biosynthetic pathway.IAA positively regulated the viability of XC1,as indicated by its colony-forming units(CFUs),extracellular polysaccharide production,protease activity,and virulence on cabbage.IAA also negatively regulated reactive oxygen species(ROS)production in XC1.Furthermore,RNA-Seq revealed a gene cluster,ilvCGM-leuA,encoding the products responsible for branched-chain amino acid(BCAA)biosynthesis,which was negatively regulated by IAA.High-performance liquid chromatography(HPLC)analysis showed that IAA negatively regulated valine and leucine production.Deletion of ilvC significantly increased the CFUs and reduced the ROS levels of XC1.Exogenous BCAA addition to mutant strainΔilvC restored the CFU and ROS levels to those of wild-type strain XC1.These results revealed an IAA signaling cascade in XC1 that involved ilvCGM-leuA,BCAA production,ROS production,and colony formation.These IAA-regulated phenotypes contributed to the virulence of Xcc in host plants.Overall,these results explain IAA-mediated plant-Xcc interactions and underscore the potentially significant role of IAA in microbial physiology.展开更多
Alzheimer’s disease is an incurable chronic neurodegenerative disorder and the leading cause of dementia,imposing a growing economic burden upon society.The disease progression is associated with gradual deposition o...Alzheimer’s disease is an incurable chronic neurodegenerative disorder and the leading cause of dementia,imposing a growing economic burden upon society.The disease progression is associated with gradual deposition of amyloid plaques and the formation of neurofibrillary tangles within the brain parenchyma,yet severe dementia is the culminating phase of the enduring pathology.Converging evidence suggests that Alzheimer’s disease-related cognitive decline is the outcome of an extremely complex and persistent pathophysiological process.The disease is characterized by distinctive abnormalities apparent at systemic,histological,macromolecular,and biochemical levels.Moreover,besides the well-defined and self-evident characteristic profuse neurofibrillary tangles,dystrophic neurites,and amyloid-beta deposits,the Alzheimer’s disease-associated pathology includes neuroinflammation,substantial neuronal loss,apoptosis,extensive DNA damage,considerable mitochondrial malfunction,compromised energy metabolism,and chronic oxidative stress.Likewise,distinctive metabolic dysfunction has been named a leading cause and a hallmark of Alzheimer’s disease that is apparent decades prior to disease manifestation.State-of-theart metabolomics studies demonstrate that altered branched-chain amino acids(BCAAs)metabolism accompanies Alzheimer’s disease development.Lower plasma valine levels are correlated with accelerated cognitive decline,and,conversely,an increase in valine concentration is associated with reduced risk of Alzheimer’s disease.Additionally,a clear BCAAs-related metabolic signature has been identified in subjects with obesity,diabetes,and atherosclerosis.Also,arginine metabolism is dramatically altered in Alzheimer’s disease human brains and animal models.Accordingly,a potential role of the urea cycle in the Alzheimer’s disease development has been hypothesized,and preclinical studies utilizing intervention in the urea cycle and/or BCAAs metabolism have demonstrated clinical potential.Continual failures to offer a competent treatment strategy directed against amyloid-beta or Tau proteins-related lesions,which could face all challenges of the multifaceted Alzheimer’s disease pathology,led to the hypothesis that hyperphosphorylated Tau and deposited amyloid-beta proteins are just hallmarks or epiphenomena,but not the ultimate causes of Alzheimer’s disease.Therefore,approaches targeting amyloid-beta or Tau are not adequate to cure the disease.Accordingly,the modern scientific vision of Alzheimer’s disease etiology and pathogenesis must reach beyond the hallmarks,and look for alternative strategies and areas of research.展开更多
Non-alcoholic fatty liver disease(NAFLD)is the steatosis of liver parenchyma unrelated to alcoholism,autoimmunity,and viral infection.It is also a metabolism-related syndrome,which has an unseparated relationship with...Non-alcoholic fatty liver disease(NAFLD)is the steatosis of liver parenchyma unrelated to alcoholism,autoimmunity,and viral infection.It is also a metabolism-related syndrome,which has an unseparated relationship with adipose tissue dysfunction and obesity.Hepatic encephalopathy(HE)is one of the severe complications of chronic liver disease and one of the end-stage syndromes of liver disease.Some researchers have suggested that NAFLD,like other forms of liver injury,may be related to the metabolic disorder of branched-chain amino acids(BCAAs),which have been approved to be associated with HE influencing ammonia and energy metabolism.However,several studies have revealed the relationship among amino acids in serum,HE,and chronic liver disease;there are few studies on the contents of amino acids in brain tissues of an animal model with NAFLD.In the present research,we established a NAFLD mouse model with C57 BL/6 mice and determined the contents of 13 amino acids in brain tissues of model mice by HPLC-FLD derivatization method using ortho-phthalaldehyde(OPA)to explore the relationship between the contents of amino acids in brain tissues and the progression of NAFLD.Moreover,the study showed that the changes of amino acid contents in the brain of the C57 BL/6 mice were associated with the advancement of NAFLD,and this change might be related to the mechanism of HE.展开更多
基金supported by Hong Kong Research Grants Council(No.C4024-16W)National Natural Science Foundation of China(No.91939302)Health and Medical Research Fund,Hong Kong Government(No.05161746)。
文摘The peroxisome proliferator-activated receptor(PPARδ)agonists are reported to improve insulin sensitivity,reduce glucose levels,and alleviate dysfunctional lipid metabolism in animal models of type 2 diabetes mellitus.However,the underlying mechanisms remain incompletely understood.Metabolism plays an essential role in the biological system.Monitoring of metabolic changes in response to disease conditions or drug treatment is critical for better understanding of the pathophysiological mechanisms.In this study,metabolic profiling analysis by gas chromatography-mass spectrometry integrated with targeted analysis by liquid chro matography-mass spectrometry was carried out in plasma samples of db/db diabetic mice after six-week treatment of PPARδagonist GW501516.GW501516 treatment significantly altered levels of metabolites,such as branched-chain amino acids(BCAAs),BCAA metabolites(3-hydroxyisobutyric acid and 3-hydroxyisovaleric acid),long-chain fatty acids,uric acid and ketone bodies(3-hydroxybutyric acid and 2-hydroxybutyric acid)which are all associated with the impaired systemic insulin sensitivity.The pre sent results indicate the beneficial effect of PPARδagonist in alleviating insulin resistance of diabetic mice by favorably modulating metabolic profile,thus providing valuable information in understanding the therapeutic potential of PPARδagonists in correcting metabolic dysfunction in diabetes.
基金supported by research grants from the National Natural Science Foundation of China(Nos.31972231 and 32172355 to HYW).
文摘Indole-3-acetic acid(IAA)is an important plant hormone that requlates a variety of physiological processes in plants,and it is also produced by some microbes.However,the biosynthesis and roles of IAA in microorganisms,particularly in plant pathogens,remain to be determined.In this study,the plant pathogen Xanthomonas campestris pv.campestris(Xcc)strain XC1 was shown to produce IAA via an L-tryptophan(L-Trp)-dependent pathway.The intermediate metabolite indole-3-ethanol and Xcc1569 encoding aromatic amino acid aminotransferase were shown to be partially involved in the uncharacterized sub-pathway in an L-Trp-dependent IAA biosynthetic pathway.IAA positively regulated the viability of XC1,as indicated by its colony-forming units(CFUs),extracellular polysaccharide production,protease activity,and virulence on cabbage.IAA also negatively regulated reactive oxygen species(ROS)production in XC1.Furthermore,RNA-Seq revealed a gene cluster,ilvCGM-leuA,encoding the products responsible for branched-chain amino acid(BCAA)biosynthesis,which was negatively regulated by IAA.High-performance liquid chromatography(HPLC)analysis showed that IAA negatively regulated valine and leucine production.Deletion of ilvC significantly increased the CFUs and reduced the ROS levels of XC1.Exogenous BCAA addition to mutant strainΔilvC restored the CFU and ROS levels to those of wild-type strain XC1.These results revealed an IAA signaling cascade in XC1 that involved ilvCGM-leuA,BCAA production,ROS production,and colony formation.These IAA-regulated phenotypes contributed to the virulence of Xcc in host plants.Overall,these results explain IAA-mediated plant-Xcc interactions and underscore the potentially significant role of IAA in microbial physiology.
基金supported by a Marie Curie CIG Grant 322113a Leir Foundation Grant+1 种基金a Ginzburg Family Foundation Granta Katz Foundation Grant to AOS
文摘Alzheimer’s disease is an incurable chronic neurodegenerative disorder and the leading cause of dementia,imposing a growing economic burden upon society.The disease progression is associated with gradual deposition of amyloid plaques and the formation of neurofibrillary tangles within the brain parenchyma,yet severe dementia is the culminating phase of the enduring pathology.Converging evidence suggests that Alzheimer’s disease-related cognitive decline is the outcome of an extremely complex and persistent pathophysiological process.The disease is characterized by distinctive abnormalities apparent at systemic,histological,macromolecular,and biochemical levels.Moreover,besides the well-defined and self-evident characteristic profuse neurofibrillary tangles,dystrophic neurites,and amyloid-beta deposits,the Alzheimer’s disease-associated pathology includes neuroinflammation,substantial neuronal loss,apoptosis,extensive DNA damage,considerable mitochondrial malfunction,compromised energy metabolism,and chronic oxidative stress.Likewise,distinctive metabolic dysfunction has been named a leading cause and a hallmark of Alzheimer’s disease that is apparent decades prior to disease manifestation.State-of-theart metabolomics studies demonstrate that altered branched-chain amino acids(BCAAs)metabolism accompanies Alzheimer’s disease development.Lower plasma valine levels are correlated with accelerated cognitive decline,and,conversely,an increase in valine concentration is associated with reduced risk of Alzheimer’s disease.Additionally,a clear BCAAs-related metabolic signature has been identified in subjects with obesity,diabetes,and atherosclerosis.Also,arginine metabolism is dramatically altered in Alzheimer’s disease human brains and animal models.Accordingly,a potential role of the urea cycle in the Alzheimer’s disease development has been hypothesized,and preclinical studies utilizing intervention in the urea cycle and/or BCAAs metabolism have demonstrated clinical potential.Continual failures to offer a competent treatment strategy directed against amyloid-beta or Tau proteins-related lesions,which could face all challenges of the multifaceted Alzheimer’s disease pathology,led to the hypothesis that hyperphosphorylated Tau and deposited amyloid-beta proteins are just hallmarks or epiphenomena,but not the ultimate causes of Alzheimer’s disease.Therefore,approaches targeting amyloid-beta or Tau are not adequate to cure the disease.Accordingly,the modern scientific vision of Alzheimer’s disease etiology and pathogenesis must reach beyond the hallmarks,and look for alternative strategies and areas of research.
基金National Natural Science Foundation of China(Grant No.81373870)。
文摘Non-alcoholic fatty liver disease(NAFLD)is the steatosis of liver parenchyma unrelated to alcoholism,autoimmunity,and viral infection.It is also a metabolism-related syndrome,which has an unseparated relationship with adipose tissue dysfunction and obesity.Hepatic encephalopathy(HE)is one of the severe complications of chronic liver disease and one of the end-stage syndromes of liver disease.Some researchers have suggested that NAFLD,like other forms of liver injury,may be related to the metabolic disorder of branched-chain amino acids(BCAAs),which have been approved to be associated with HE influencing ammonia and energy metabolism.However,several studies have revealed the relationship among amino acids in serum,HE,and chronic liver disease;there are few studies on the contents of amino acids in brain tissues of an animal model with NAFLD.In the present research,we established a NAFLD mouse model with C57 BL/6 mice and determined the contents of 13 amino acids in brain tissues of model mice by HPLC-FLD derivatization method using ortho-phthalaldehyde(OPA)to explore the relationship between the contents of amino acids in brain tissues and the progression of NAFLD.Moreover,the study showed that the changes of amino acid contents in the brain of the C57 BL/6 mice were associated with the advancement of NAFLD,and this change might be related to the mechanism of HE.
