Post-translational modifications(PTMs)of proteins play a crucial role in living organisms,altering the properties and functions of proteins.There are over 450 known PTMs involved in various life activities.LSD1(lysine...Post-translational modifications(PTMs)of proteins play a crucial role in living organisms,altering the properties and functions of proteins.There are over 450 known PTMs involved in various life activities.LSD1(lysine-specific demethylase 1)is the first identified histone demethylase that can remove monomethylation or dimethylation modifications from histone H3 lysine K4(H3K4)and histone H3 lysine K9(H3K9).This ability of LSD1 allows it to inhibit or activate transcription.LSD1 has been found to abnormally express at the protein level in various tumors, making it relevant to multiple diseases. As a PTM enzyme, LSD1 itself undergoes various PTMs, including phosphorylation, acetylation, ubiquitination, methylation, SUMOylation, and S-nitrosylation, influencing its activity and function. Dysregulation of thesePTMs has been implicated in a wide range of diseases, including cancer, metabolic disorders,neurological disorders, cardiovascular diseases, and bone diseases. Understanding the speciesof PTMs and functions regulated by various PTMs of LSD1 provides insights into its involvementin diverse physiological and pathological processes. In this review, we discuss the structuralcharacteristics of LSD1 and amino acid residues that affect its enzyme activity. We also summarize the potential PTMs that occur on LSD1 and their involvement in cellular processes.Furthermore, we describe human diseases associated with abnormal expression of LSD1. Thiscomprehensive analysis sheds light on the intricate interplay between PTMs and the functionsof LSD1, highlighting their significance in health and diseases.展开更多
Background Alzheimer’s disease(AD)is associated with metabolic abnormalities linked to critical elements of neurodegeneration.We recently administered combined metabolic activators(CMA)to the AD rat model and observe...Background Alzheimer’s disease(AD)is associated with metabolic abnormalities linked to critical elements of neurodegeneration.We recently administered combined metabolic activators(CMA)to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals.CMA promotes mitochondrial fatty acid uptake from the cytosol,facilitates fatty acid oxidation in the mitochondria,and alleviates oxidative stress.Methods Here,we designed a randomised,double-blinded,placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients.One-dose CMA included 12.35 g L-serine(61.75%),1 g nicotinamide riboside(5%),2.55 g N-acetyl-L-cysteine(12.75%),and 3.73 g L-carnitine tartrate(18.65%).AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84.The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms.The secondary aim of this study was to evaluate the safety and tolerability of CMA.A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients.Results We showed a significant decrease of AD Assessment Scale-cognitive subscale(ADAS-Cog)score on day 84 vs day 0(P=0.00001,29%improvement)in the CMA group.Moreover,there was a significant decline(P=0.0073)in ADAS-Cog scores(improvement of cognitive functions)in the CMA compared to the placebo group in patients with higher ADAS-Cog scores.Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis.Moreover,the plasma levels of proteins and metabolites associated with NAD+and glutathione metabolism were significantly improved after CMA treatment.Conclusion Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics,metabolomics,proteomics and imaging analysis.展开更多
Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for om...Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for omics in LT.We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication.Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics.Significant molecules were identified and summarized based on omics,with a focus on post-transplant liver fibrosis,early allograft dysfunction,tumor recurrence,and graft failure.We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established.We also outlined the ideal workflow for omics in LT.In step with advances in technology,the quality of omics data can be guaranteed using an improved algorithm at a lower price.Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.展开更多
基金supported by the Basic Research of Medical Science and Technique Foundation of Henan Province,China(No.SBGJ202301004 to X.B.C.)the Key Project of the High Education from the Education Department of Henan Province,China(No.22ZX008 to Y.C.Z.)+4 种基金the Youth Supporting Program from Henan Province,China(No.2021HYTP060 to Y.C.Z.)the Youth Supporting Program from Zhengzhou University(No.JC202044046 to Y.C.Z.)the Science and Technology Project of Henan Province,China(No.232102311179 to Y.G.)the National Natural Science Foundation of China(No.U21A20416,82020108030 to H.M.L,82103997 to B.W.)the China Postdoctoral Science Foundation(No.2021M692950 to B.W.,2021M702942 to L.J.Z.).
文摘Post-translational modifications(PTMs)of proteins play a crucial role in living organisms,altering the properties and functions of proteins.There are over 450 known PTMs involved in various life activities.LSD1(lysine-specific demethylase 1)is the first identified histone demethylase that can remove monomethylation or dimethylation modifications from histone H3 lysine K4(H3K4)and histone H3 lysine K9(H3K9).This ability of LSD1 allows it to inhibit or activate transcription.LSD1 has been found to abnormally express at the protein level in various tumors, making it relevant to multiple diseases. As a PTM enzyme, LSD1 itself undergoes various PTMs, including phosphorylation, acetylation, ubiquitination, methylation, SUMOylation, and S-nitrosylation, influencing its activity and function. Dysregulation of thesePTMs has been implicated in a wide range of diseases, including cancer, metabolic disorders,neurological disorders, cardiovascular diseases, and bone diseases. Understanding the speciesof PTMs and functions regulated by various PTMs of LSD1 provides insights into its involvementin diverse physiological and pathological processes. In this review, we discuss the structuralcharacteristics of LSD1 and amino acid residues that affect its enzyme activity. We also summarize the potential PTMs that occur on LSD1 and their involvement in cellular processes.Furthermore, we describe human diseases associated with abnormal expression of LSD1. Thiscomprehensive analysis sheds light on the intricate interplay between PTMs and the functionsof LSD1, highlighting their significance in health and diseases.
基金funding provided by Royal Institute of Technology.This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation(72110).
文摘Background Alzheimer’s disease(AD)is associated with metabolic abnormalities linked to critical elements of neurodegeneration.We recently administered combined metabolic activators(CMA)to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals.CMA promotes mitochondrial fatty acid uptake from the cytosol,facilitates fatty acid oxidation in the mitochondria,and alleviates oxidative stress.Methods Here,we designed a randomised,double-blinded,placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients.One-dose CMA included 12.35 g L-serine(61.75%),1 g nicotinamide riboside(5%),2.55 g N-acetyl-L-cysteine(12.75%),and 3.73 g L-carnitine tartrate(18.65%).AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84.The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms.The secondary aim of this study was to evaluate the safety and tolerability of CMA.A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients.Results We showed a significant decrease of AD Assessment Scale-cognitive subscale(ADAS-Cog)score on day 84 vs day 0(P=0.00001,29%improvement)in the CMA group.Moreover,there was a significant decline(P=0.0073)in ADAS-Cog scores(improvement of cognitive functions)in the CMA compared to the placebo group in patients with higher ADAS-Cog scores.Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis.Moreover,the plasma levels of proteins and metabolites associated with NAD+and glutathione metabolism were significantly improved after CMA treatment.Conclusion Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics,metabolomics,proteomics and imaging analysis.
基金supported by Innovative Research Groups of National Natural Science Foundation of China(81721091)Major Program of National Natural Science Foundation of China(91542205)+8 种基金National S&T Major Project(2017ZX 10203205)National Natural Science Foundation of China(81902813)Zhejiang International Science and Technology Cooperation Project(2016C04003)Zhejiang Provincial Natural Science Foundation of China(LY18H030002)Zhejiang Medical Association(grant no.2019ZYC-A81)International Youth Exchange Programme by China Association for Science and Technology(2019),Tianqing Liver Diseases Research Fund(TQGB20200114)Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(2021KY145)Organ Transplantation Overseas Training for Youth Talents from Shulan Excellent Talent Project,CSCO(Chinese Society Of Clinical Oncology)-Bayer Tumor Research Funding(Y-bayer202001/zb-0003)Open Fund of Key laboratory of High-Incidence-Tumor Prevention&Treatment(Guangxi Medical University)belonged to Ministry of Education.
文摘Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for omics in LT.We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication.Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics.Significant molecules were identified and summarized based on omics,with a focus on post-transplant liver fibrosis,early allograft dysfunction,tumor recurrence,and graft failure.We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established.We also outlined the ideal workflow for omics in LT.In step with advances in technology,the quality of omics data can be guaranteed using an improved algorithm at a lower price.Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.
