Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In t...Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.展开更多
Inborn errors of metabolism(IEM)are rare disorders,most are liver-based with liver transplantation(LT)emerging as an effective cure in the pediatric population.LT has been shown to offer a cure or deter disease progre...Inborn errors of metabolism(IEM)are rare disorders,most are liver-based with liver transplantation(LT)emerging as an effective cure in the pediatric population.LT has been shown to offer a cure or deter disease progression and provide symptomatic improvement in patients with IEM.Each metabolic disorder is unique,with the missing enzyme or transporter protein causing substrate deficiency or toxic byproduct production.Knowledge about the distribution of deficient enzymes,the percentage of enzymes replaced by LT,and the extent of extrahepatic involvement helps anticipate and manage complications in the perioperative period.Most patients have multisystem involvement and can be on complex dietary regimens.Metabolic decompensation can be triggered due to the stress response to surgery,fasting and other unanticipated complications perioperatively.Thus,a multidisciplinary team’s input including those from metabolic specialists is essential to develop disease and patient-specific strategies for the perioperative management of these patients during LT.In this review,we outline the classification of IEM,indications for LT along with potential benefits,basic metabolic defects and their implications,details of extrahepatic involvement and perioperative management strategies for LT in children with some of the commonly presenting IEM,to assist anesthesiologists handling this cohort of patients.展开更多
Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chron...Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).展开更多
BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes...BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.展开更多
BACKGROUND An increasing number of studies have focused on the role of cellular metabolism in the development of colorectal cancer(CRC).However,no work is currently available to synthesize the field through bibliometr...BACKGROUND An increasing number of studies have focused on the role of cellular metabolism in the development of colorectal cancer(CRC).However,no work is currently available to synthesize the field through bibliometrics.AIM To analyze the development in the field of“glucose metabolism”(GM),“amino acid metabolism”(AM),“lipid metabolism”(LM),and“nucleotide metabolism”(NM)in CRC by visualization.METHODS Articles within the abovementioned areas of GM,AM,LM and NM in CRC,which were published from January 1,1991,to December 31,2022,are retrieved from the Web of Science Core Collection and analyzed by CiteSpace 6.2.R4 and VOSviewer 1.6.19.RESULTS The field of LM in CRC presented the largest number of annual publications and the fastest increase in the last decade compared with the other three fields.Meanwhile,China and the United States were two of the most prominent contri-butors in these four areas.In addition,Gang Wang,Wei Jia,Maria Notar-nicola,and Cornelia Ulrich ranked first in publication numbers,while Jing-Yuan Fang,Senji Hirasawa,Wei Jia,and Charles Fuchs were the most cited authors on average in these four fields,respectively.“Gut microbiota”and“epithelial-mesenchymal transition”emerged as the newest burst words in GM,“gut microbiota”was the latest outburst word in AM,“metastasis”,“tumor microenvironment”,“fatty acid metabolism”,and“metabolic reprogramming”were the up-to-date outbreaking words in LM,while“epithelial-mesenchymal transition”and“apoptosis”were the most recently occurring words in NM.CONCLUSION Research in“cellular metabolism in CRC”is all the rage at the moment,and researchers are particularly interested in exploring the mechanism to explain the metabolic alterations in CRC.Targeting metabolic vulnerability appears to be a promising direction in CRC therapy.展开更多
Metabolic reprogramming is a prominent cancer hallmark that enables uncontrolled growth,survival,and dissemination of tumor cells.Among the diverse metabolic alterations,dysregulation of arginine metabolism has garner...Metabolic reprogramming is a prominent cancer hallmark that enables uncontrolled growth,survival,and dissemination of tumor cells.Among the diverse metabolic alterations,dysregulation of arginine metabolism has garnered significant attention due to its profound impact on cancer cells and the tumor microenvironment(TME).Arginine,a semi-essential amino acid,has a central role in various cellular processes,including protein synthesis,nitric oxide(NO)production,and polyamine biosynthesis.In the context of cancer aberrant arginine metabolism fuels tumor cell growth and orchestrates a complex interplay between tumor and immune cells,ultimately facilitating immune evasion and tumor progression.展开更多
Diabetic osteoporosis(DOP)is a common complication in diabetes,driven by hyperglycemia-induced metabolic disturbances,chronic inflammation,and oxi-dative stress.This review describes the critical role of iron metaboli...Diabetic osteoporosis(DOP)is a common complication in diabetes,driven by hyperglycemia-induced metabolic disturbances,chronic inflammation,and oxi-dative stress.This review describes the critical role of iron metabolism dysregu-lation in DOP pathogenesis,focusing on ferroptosis,a novel iron-dependent cell death pathway characterized by lipid peroxidation and reactive oxygen species(ROS)overproduction.Diabetic conditions exacerbate iron overload,impairing osteoblast function and enhancing osteoclast activity,while triggering ferroptosis in bone cells.Ferroptosis not only accelerates osteoblast apoptosis but also amplifies osteoclast-mediated bone resorption,synergistically promoting bone loss.Furthermore,chronic inflammation and oxidative stress disrupt the balance between bone formation and resorption,with elevated pro-inflammatory cyto-kines(e.g.,tumor necrosis factor-α,interleukin-6)and ROS exacerbating cellular dysfunction.Therapeutic strategies targeting iron metabolism(e.g.,deferoxamine)and ferroptosis inhibition(e.g.,nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway activation,antioxidants like melatonin)demonstrate potential to mitigate DOP progression.Future research should prioritize personalized interventions,clinical trials of iron chelators and antioxidants,and mechanistic studies to refine therapeutic approaches.This review provides a comprehensive framework for understanding DOP pathogenesis and highlights innovative strategies to improve bone health in diabetic patients.展开更多
Colorectal cancer(CRC)considerably affects global health,and its progression is intricately tied to interactions within the tumormicroenvironment.This review focuses on the intricate crosstalk between metabolic reprog...Colorectal cancer(CRC)considerably affects global health,and its progression is intricately tied to interactions within the tumormicroenvironment.This review focuses on the intricate crosstalk between metabolic reprogramming in CRC cells and the tumor immune microenvironment(TIME),thereby emphasizing the dual functionality of metabolic pathways in tumor growth and immune regulation.Furthermore,the review delves into key metabolic changes,including alterations in glucose,lipid,iron,and ammonia metabolism,and their profound effects on the immune landscape of CRC.Enhanced glycolysis and lipid metabolism facilitate tumor survival and proliferation,while establishing an immunosuppressive TIME that hinders effective immune responses.Moreover,the roles of iron and ammonia metabolism in immune evasion and tumor progression were explored,and these metabolic pathways presented as promising targets to improve CRC therapy.By conducting a comprehensive analysis of recent studies,this review provides insights into potential therapeutic targets within these metabolic interactions,with the aim of enhancing the efficacy of existing treatments and devising novel strategies for combating CRC.展开更多
Cantharidin (CTD), a natural compound used to treat multiple tumors in the clinic setting, has been limited due to acute kidney injury (AKI). However, the major cause of AKI and its underlying mechanism remain to be e...Cantharidin (CTD), a natural compound used to treat multiple tumors in the clinic setting, has been limited due to acute kidney injury (AKI). However, the major cause of AKI and its underlying mechanism remain to be elucidated. Serum creatinine (SCr) and blood urea nitrogen (BUN) were detected through pathological evaluation after CTD (1.5 mg/kg) oral gavage in mice in 3 days. Kidney lipidomics based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate lipids disorder after CTD exposure in mice. Then, spatial metabolomics based on matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to detect the kidney spatial distribution of lipids. Integrative analysis was performed to reveal the spatial lipid disorder mechanism and verify key lipids in vitro. The results showed that the levels of SCr and BUN were increased, and tubular necrosis was observed in mouse kidneys, resulting in acute tubular necrosis (ATN) in CTD-induced AKI. Then, lipidomics results revealed that after CTD exposure, 232 differential lipid metabolites and 11 pathways including glycerophospholipid (GP) and sphingolipid (SL) metabolism were disrupted. Spatial metabolomics revealed that 55 spatial differential lipid metabolites and nine metabolic pathways were disturbed. Subsequently, integrative analysis found that GP metabolism was stimulated in the renal cortex and medulla, whereas SL metabolism was inhibited in the renal cortex. Up-regulated lysophosphatidylcholine (LysoPC) (18:2(9Z,12Z)), LysoPC (16:0/0:0), glycerophosphocholine, and down-regulated sphingomyelin (SM) (d18:0/16:0), SM (d18:1/24:0), and SM (d42:1) were key differential lipids. Among them, LysoPC (16:0/0:0) was increased in the CTD group at 1.1196 μg/mL, which aggravated CTD-induced ATN in human kidney-2 (HK-2) cells. LysoPC acyltransferase was inhibited and choline phosphotransferase 1 (CEPT1) was activated after CTD intervention in mice and in HK-2 cells. CTD induces ATN, resulting in AKI, by activating GP metabolism and inhibiting SL metabolism in the renal cortex and medulla, LysoPC (16:0/0:0), LysoPC acyltransferase, and CEPT1 may be the therapeutic targets.展开更多
Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improv...Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improves DSS-induced impaired liver cholesterol metabolism.Here,we established the DSS-induced model and clarified that DSS exacerbated gut inflammation accompanied by disorders of liver cholesterol metabolism.Pu-erh tea reshaped gut microbes,limited gut oxidative stress and inflammation(nicotinamide adenine dinucleotide phosphate oxidase 2/reactive oxygen species/myeloid differentiation primary response protein 88/nuclear factor kappa-B,24.97%-52.89%),reduced gut bile acid reabsorption(up-regulation of farnesoid X receptor(FXR)/fibroblast growth factor 15,24.53%-55.91%),and promoted liver bile acid synthesis(up-regulation of peroxisome proliferator-activated receptor-α/cholesterol 7-alpha hydroxylase,34.65%-79.14%),thereby partly restoring liver cholesterol metabolism(regulated FXR/small heterodimer partner/sterol-regulatory element binding proteins,53.19%-95.40%).Altered bile acid metabolic profiles(increased chenodeoxycholic acid,ursodeoxycholic acid,lithocholic acid,etc.)may also improve liver cholesterol metabolism by altering gut and liver inflammation.Thus,gut microbial reshaping and altered bile acid metabolism may be key targets of Pu-erh tea for improving DSS-induced liver cholesterol metabolism disorders via the gut-gut microbe-bile acid-liver axis.展开更多
Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer,significantly hindering the long-term efficacy of novel cancer drugs.Accumulating evidence has shown that meta...Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer,significantly hindering the long-term efficacy of novel cancer drugs.Accumulating evidence has shown that metabolites derived from tumor cells regulate immune cell metabolism via tumor microenvironment crosstalk.However,as immunometabolic research has deepened,the leading role played by the intrinsic metabolic regulation of immune cells in the drug resistance of tumor cells has been discovered.Immune metabolites have been shown to cause immune resistance,target therapy resistance,and chemotherapy resistance,and drugs that target immune metabolism have great potential.To date,researchers have not fully explored the impact of immune-derived metabolites on tumor cells and their influence on the responsiveness to cancer drugs.In this review,we focus on the lactate,fatty acid,glucose,and nucleotide metabolic alterations that take place in T cells and macrophages and how these changes can impair anti-tumor immunity,ultimately promoting tumor cell survival and decreasing responsiveness to the corresponding therapeutic approaches.We present the current developments in drugs targeting immunometabolic pathways and propose constructive suggestions,such as precise delivery to immune cell targets to enhance efficacy and safety,offering novel perspectives for cancer drug development.展开更多
Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol ...Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.展开更多
Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzhei...Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.展开更多
Background There is a growing focus on using various plant-derived agricultural by-products to increase the benefits of pig farming,but these feedstuffs are fibrous in nature.This study investigated the relationship b...Background There is a growing focus on using various plant-derived agricultural by-products to increase the benefits of pig farming,but these feedstuffs are fibrous in nature.This study investigated the relationship between dietary fiber physicochemical properties and feedstuff fermentation characteristics and their effects on nutrient utilization,energy metabolism,and gut microbiota in growing pigs.Methods Thirty-six growing barrows(47.2±1.5 kg)were randomly allotted to 6 dietary treatments with 2 apparent viscosity levels and 3β-glucan-to-arabinoxylan ratios.In the experiment,nutrient utilization,energy metabolism,fecal microbial community,and production and absorption of short-chain fatty acid(SCFA)of pigs were investigated.In vitro digestion and fermentation models were used to compare the fermentation characteristics of feedstuffs and ileal digesta in the pig’s hindgut.Results The production dynamics of SCFA and dry matter corrected gas production of different feedstuffs during in vitro fermentation were different and closely related to the physical properties and chemical structure of the fiber.In animal experiments,increasing the dietary apparent viscosity and theβ-glucan-to-arabinoxylan ratios both increased the apparent ileal digestibility(AID),apparent total tract digestibility(ATTD),and hindgut digestibility of fiber components while decreasing the AID and ATTD of dry matter and organic matter(P<0.05).In addition,increasing dietary apparent viscosity andβ-glucan-to-arabinoxylan ratios both increased gas exchange,heat production,and protein oxidation,and decreased energy deposition(P<0.05).The dietary apparent viscosity andβ-glucanto-arabinoxylan ratios had linear interaction effects on the digestible energy,metabolizable energy,retained energy(RE),and net energy(NE)of the diets(P<0.05).At the same time,the increase of dietary apparent viscosity andβ-glucan-to-arabinoxylan ratios both increased SCFA production and absorption(P<0.05).Increasing the dietary apparent viscosity andβ-glucan-to-arabinoxylan ratios increased the diversity and abundance of bacteria(P<0.05)and the relative abundance of beneficial bacteria.Furthermore,increasing the dietaryβ-glucan-to-arabinoxylan ratios led to a linear increase in SCFA production during the in vitro fermentation of ileal digesta(P<0.001).Finally,the prediction equations for RE and NE were established.Conclusion Dietary fiber physicochemical properties alter dietary fermentation patterns and regulate nutrient utilization,energy metabolism,and pig gut microbiota composition and metabolites.展开更多
Circadian rhythm is ubiquitous in nature.Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network,and regulate a variety of physiological and pathological processes,i...Circadian rhythm is ubiquitous in nature.Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network,and regulate a variety of physiological and pathological processes,including bone and cartilage metabolism.Deletion of the core clock gene Bmal1 leads to pathological bone alterations,while the phenotypes are not consistent.Studies have shown that multiple signaling pathways are involved in the process of Bmal1 regulating bone and cartilage metabolism,but the exact regulatory mechanisms remain unclear.This paper reviews the signaling pathways by which Bmal1 regulates bone/cartilage metabolism,the upstream regulatory factors that control Bmal1,and the current Bmal1 knockout mouse models for research.We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.展开更多
Understanding the metabolism of endogenous and exogenous substances in the human body is essential for elucidating disease mechanisms and evaluating the safety and efficacy of drug candidates during the drug developme...Understanding the metabolism of endogenous and exogenous substances in the human body is essential for elucidating disease mechanisms and evaluating the safety and efficacy of drug candidates during the drug development process.Recent advancements in artificial intelligence(AI),particularly in machine learning(ML)and deep learning(DL)techniques,have introduced innovative approaches to metabolism research,enabling more accurate predictions and insights.This paper emphasizes computational and AI-driven methodologies,highlighting how ML enhances predictive modeling for human metabolism at the molecular level and facilitates integration into genome-scale metabolic models(GEMs)at the omics level.Challenges still remain,including data heterogeneity and model interpretability.This work aims to provide valuable insights and references for researchers in drug discovery and development,ultimately contributing to the advancement of precision medicine.展开更多
Objective:Erianin has potential anticancer activities,especially against lung cancer.The specific mechanisms underlying the anticancer effects,including the molecular targets and signaling pathways in lung cancer,rema...Objective:Erianin has potential anticancer activities,especially against lung cancer.The specific mechanisms underlying the anticancer effects,including the molecular targets and signaling pathways in lung cancer,remain poorly understood and necessitate further investigation.Methods:Lung cancer cell viability was evaluated using the CCK-8 assay.Flow cytometry was used to examine the effects of erianin on apoptosis and cell cycle progression.m RNA sequencing and metabolomics analysis were utilized to explore erianin-induced biological changes.Potential targets were identified and validated through molecular docking and Western blot analysis.The roles of mammalian target of rapamycin(m TOR)and carbamoyl-phosphate synthetase/aspartate transcarbamylase/dihydroorotase(CAD)in erianin-induced growth inhibition were studied using gene overexpression/knockdown techniques with uridine and aspartate supplementation confirming pyrimidine metabolism involvement.Additionally,lung cancer-bearing nude mouse models were established to evaluate the anti-lung cancer effects of erianin in vivo.Results:Erianin significantly inhibits the proliferation of lung cancer cells,induces apoptosis,and causes G2/M phase cell cycle arrest.Integrative analysis of m RNA sequencing and metabolomics data demonstrated that erianin disrupts pyrimidine metabolism in lung cancer cells.Notably,uridine supplementation mitigated the inhibitory effects of erianin,establishing a connection between pyrimidine metabolism and anticancer activity.Network pharmacology analyses identified m TOR as a key target of erianin.Erianin inhibited m TOR phosphorylation,thereby blocking downstream effectors(S6K and CAD),which are essential regulators of pyrimidine metabolism.Conclusions:Erianin is a promising therapeutic candidate for lung cancer.Erianin likely inhibits lung cancer cell growth by disrupting pyrimidine metabolism by suppressing m TOR activation.展开更多
The content of soluble sugars is a vital parameter that indicates the quality of fleshy fruits such as apple(Malus domestica Borkh.).Studying the patterns of accumulation of soluble sugars and regulatory mechanisms as...The content of soluble sugars is a vital parameter that indicates the quality of fleshy fruits such as apple(Malus domestica Borkh.).Studying the patterns of accumulation of soluble sugars and regulatory mechanisms associated with fruit development is crucial for breeding improved fruit varieties.Here,we report that MdCIbHLH1,a low temperature-induced b HLH transcription factor,inhibits the accumulation of soluble sugars by regulating sugar-metabolizing enzyme activities,photosynthetic performance,and the expression of sugar-related genes in developing apple fruits.MdCIbHLH1 inhibits MdFBP and MdPEPCK expression,thus blocking the conversion of acids to sugars in apple fruits.We also discovered that MdCIbHLH1 decreases the photosynthetic rate and carbohydrate accumulation in apple leaves.Our results suggest that soluble sugar accumulation in apple fruits is influenced by multiple factors,including metabolic status,photosynthesis,and carbohydrate allocation.MdCIbHLH1 is critically involved in controlling the accumulation of soluble sugars by coordinating carbohydrate synthesis and allocation,thus influencing sugar transport and its metabolism during the development of apple fruits.展开更多
Traditional Chinese medicine(TCM)has demonstrated unique advantages in the prevention and treatment of chronic diseases such as glycolipid metabolism disorder.However,its widespread application has been hindered by th...Traditional Chinese medicine(TCM)has demonstrated unique advantages in the prevention and treatment of chronic diseases such as glycolipid metabolism disorder.However,its widespread application has been hindered by the unclear biological essence of TCM syndromes and therapeutic mechanisms.As an emerging interdisciplinary field,phenomics integrates multi-dimensional data including genome,transcriptome,proteome,metabolome,and microbiome.When combined with TCM's holistic philosophy,it forms TCM phenomics,providing novel approaches to reveal the biological connotation of TCM syndromes and the mechanisms of herbal medicine.Taking glycolipid metabolism disorder as an example,this paper explores the application of TCM phenomics in glycolipid metabolism disorder.By analyzing molecular characteristics of related syndromes,TCM phenomics identifies differentially expressed genes,metabolites,and gut microbiota biomarkers to elucidate the dynamic evolution patterns of syndromes.Simultaneously,it deciphers the multi-target regulatory networks of herbal formulas,demonstrating their therapeutic effects through mechanisms including modulation of insulin signaling pathways,improvement of gut microbiota imbalance,and suppression of inflammatory responses.Current challenges include the subjective nature of syndrome diagnosis,insufficient standardization of animal models,and lack of integrated multi-omics analysis.Future research should employ machine learning,multimodal data integration,and cross-omics longitudinal studies to establish quantitative diagnostic systems for syndromes,promote the integration of precision medicine in TCM and western medicine,and accelerate the modernization of TCM.展开更多
Cold stimulation has been shown to regulate glucose,lipid,and amino acid metabolism,while also increasing heat production and energy expenditure in the body.Disordered energy metabolism is a key factor in the onset an...Cold stimulation has been shown to regulate glucose,lipid,and amino acid metabolism,while also increasing heat production and energy expenditure in the body.Disordered energy metabolism is a key factor in the onset and progression of chronic metabolic conditiones such as diabetes,obesity,and cardiovascular disease.Recent research has unveiled the myriad pathways through which cold stimulation affects human energy metabolism.This article provides an overview of how cold stimulation affects energy metabolism across the three major metabolic pathways.Furthermore,it explores the implications and potential therapeutic applications of cold stimulation in the prevention and treatment of various metabolic diseases.展开更多
基金supported by Shanghai Shenkang Center Demonstration Research Ward Construction,No.SHDC2022CRW010(to MF)Shanghai Shenkang Center Medical Enterprise Integration and Innovation Collaborative Special Project,No.SHDC2022CRT018(to MF)+4 种基金Shanghai Health System Key Supported Discipline-Rehabilitation Medicine,No.2023ZDFC0301(to JT)Science and Technology Development Project of Shanghai University of Traditional Chinese Medicine,No.23KFL009(to JT)Shanghai Postdoctoral Excellence Program,No.2022515(to CY)Yangfan Special Project of Shanghai Science and Technology Innovation Action Plan,No.23YF1447600(to CY)China Postdoctoral Science Foundation,No.2023M732338(to CY).
文摘Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.
文摘Inborn errors of metabolism(IEM)are rare disorders,most are liver-based with liver transplantation(LT)emerging as an effective cure in the pediatric population.LT has been shown to offer a cure or deter disease progression and provide symptomatic improvement in patients with IEM.Each metabolic disorder is unique,with the missing enzyme or transporter protein causing substrate deficiency or toxic byproduct production.Knowledge about the distribution of deficient enzymes,the percentage of enzymes replaced by LT,and the extent of extrahepatic involvement helps anticipate and manage complications in the perioperative period.Most patients have multisystem involvement and can be on complex dietary regimens.Metabolic decompensation can be triggered due to the stress response to surgery,fasting and other unanticipated complications perioperatively.Thus,a multidisciplinary team’s input including those from metabolic specialists is essential to develop disease and patient-specific strategies for the perioperative management of these patients during LT.In this review,we outline the classification of IEM,indications for LT along with potential benefits,basic metabolic defects and their implications,details of extrahepatic involvement and perioperative management strategies for LT in children with some of the commonly presenting IEM,to assist anesthesiologists handling this cohort of patients.
基金supported by the Judith Jane Mason and Harold Stannett Williams Memorial Foundation National Medical Program(#Mason2210)to JX。
文摘Myalgic encephalomyelitis/chronic fatigue syndrome-an insidious disease:The recent COVID-19 pandemic has brought substantial attention to the overlapping symptoms between long COVID and myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS),a chronic and poorly understood neurological disorder(Shankar et al.,2024).
文摘BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.
基金National Natural Science Foundation of China,No.82173063 and No.81972220Wuxi Taihu Lake Talent Plan Supporting for Leading Talents in Medical and Health Profession+2 种基金Wuxi Medical Key Discipline,No.ZDXK2021002China Postdoctoral Science Foundation,No.2022M711370Postgraduate Research&Practice Innovation Program of Jiangsu Province,No.KYCX23_2573.
文摘BACKGROUND An increasing number of studies have focused on the role of cellular metabolism in the development of colorectal cancer(CRC).However,no work is currently available to synthesize the field through bibliometrics.AIM To analyze the development in the field of“glucose metabolism”(GM),“amino acid metabolism”(AM),“lipid metabolism”(LM),and“nucleotide metabolism”(NM)in CRC by visualization.METHODS Articles within the abovementioned areas of GM,AM,LM and NM in CRC,which were published from January 1,1991,to December 31,2022,are retrieved from the Web of Science Core Collection and analyzed by CiteSpace 6.2.R4 and VOSviewer 1.6.19.RESULTS The field of LM in CRC presented the largest number of annual publications and the fastest increase in the last decade compared with the other three fields.Meanwhile,China and the United States were two of the most prominent contri-butors in these four areas.In addition,Gang Wang,Wei Jia,Maria Notar-nicola,and Cornelia Ulrich ranked first in publication numbers,while Jing-Yuan Fang,Senji Hirasawa,Wei Jia,and Charles Fuchs were the most cited authors on average in these four fields,respectively.“Gut microbiota”and“epithelial-mesenchymal transition”emerged as the newest burst words in GM,“gut microbiota”was the latest outburst word in AM,“metastasis”,“tumor microenvironment”,“fatty acid metabolism”,and“metabolic reprogramming”were the up-to-date outbreaking words in LM,while“epithelial-mesenchymal transition”and“apoptosis”were the most recently occurring words in NM.CONCLUSION Research in“cellular metabolism in CRC”is all the rage at the moment,and researchers are particularly interested in exploring the mechanism to explain the metabolic alterations in CRC.Targeting metabolic vulnerability appears to be a promising direction in CRC therapy.
基金supported by grants from the National Key R&D Program of China(Grant no.2022YFC3401001)the National Natural Science Foundation of China(Grant nos.82025026,82230091,and 81872144)the Guangdong Basic and Applied Basic Research Foundation(Grant no.2023A1515140033).
文摘Metabolic reprogramming is a prominent cancer hallmark that enables uncontrolled growth,survival,and dissemination of tumor cells.Among the diverse metabolic alterations,dysregulation of arginine metabolism has garnered significant attention due to its profound impact on cancer cells and the tumor microenvironment(TME).Arginine,a semi-essential amino acid,has a central role in various cellular processes,including protein synthesis,nitric oxide(NO)production,and polyamine biosynthesis.In the context of cancer aberrant arginine metabolism fuels tumor cell growth and orchestrates a complex interplay between tumor and immune cells,ultimately facilitating immune evasion and tumor progression.
基金Supported by Henan Province Key Research and Development Program,No.231111311000Henan Provincial Science and Technology Research Project,No.232102310411+2 种基金Henan Province Medical Science and Technology Key Project,No.LHGJ20220566 and No.LHGJ20240365Henan Province Medical Education Research Project,No.WJLX2023079Zhengzhou Medical and Health Technology Innovation Guidance Program,No.2024YLZDJH022.
文摘Diabetic osteoporosis(DOP)is a common complication in diabetes,driven by hyperglycemia-induced metabolic disturbances,chronic inflammation,and oxi-dative stress.This review describes the critical role of iron metabolism dysregu-lation in DOP pathogenesis,focusing on ferroptosis,a novel iron-dependent cell death pathway characterized by lipid peroxidation and reactive oxygen species(ROS)overproduction.Diabetic conditions exacerbate iron overload,impairing osteoblast function and enhancing osteoclast activity,while triggering ferroptosis in bone cells.Ferroptosis not only accelerates osteoblast apoptosis but also amplifies osteoclast-mediated bone resorption,synergistically promoting bone loss.Furthermore,chronic inflammation and oxidative stress disrupt the balance between bone formation and resorption,with elevated pro-inflammatory cyto-kines(e.g.,tumor necrosis factor-α,interleukin-6)and ROS exacerbating cellular dysfunction.Therapeutic strategies targeting iron metabolism(e.g.,deferoxamine)and ferroptosis inhibition(e.g.,nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway activation,antioxidants like melatonin)demonstrate potential to mitigate DOP progression.Future research should prioritize personalized interventions,clinical trials of iron chelators and antioxidants,and mechanistic studies to refine therapeutic approaches.This review provides a comprehensive framework for understanding DOP pathogenesis and highlights innovative strategies to improve bone health in diabetic patients.
文摘Colorectal cancer(CRC)considerably affects global health,and its progression is intricately tied to interactions within the tumormicroenvironment.This review focuses on the intricate crosstalk between metabolic reprogramming in CRC cells and the tumor immune microenvironment(TIME),thereby emphasizing the dual functionality of metabolic pathways in tumor growth and immune regulation.Furthermore,the review delves into key metabolic changes,including alterations in glucose,lipid,iron,and ammonia metabolism,and their profound effects on the immune landscape of CRC.Enhanced glycolysis and lipid metabolism facilitate tumor survival and proliferation,while establishing an immunosuppressive TIME that hinders effective immune responses.Moreover,the roles of iron and ammonia metabolism in immune evasion and tumor progression were explored,and these metabolic pathways presented as promising targets to improve CRC therapy.By conducting a comprehensive analysis of recent studies,this review provides insights into potential therapeutic targets within these metabolic interactions,with the aim of enhancing the efficacy of existing treatments and devising novel strategies for combating CRC.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82260812 and 81803838)the Guizhou Provincial Science&Technology Program,China(Project Nos.:YQK[2023]038 and[2020]5007)+1 种基金the Beijing Natural Science Foundation,China(Grant No.:7254489)the Science and Technology Program of Zunyi city of Guizhou province of China(Project Nos.:(2022)420,[2021]-3,[2020]7,and(2022)419).
文摘Cantharidin (CTD), a natural compound used to treat multiple tumors in the clinic setting, has been limited due to acute kidney injury (AKI). However, the major cause of AKI and its underlying mechanism remain to be elucidated. Serum creatinine (SCr) and blood urea nitrogen (BUN) were detected through pathological evaluation after CTD (1.5 mg/kg) oral gavage in mice in 3 days. Kidney lipidomics based on ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to investigate lipids disorder after CTD exposure in mice. Then, spatial metabolomics based on matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) was used to detect the kidney spatial distribution of lipids. Integrative analysis was performed to reveal the spatial lipid disorder mechanism and verify key lipids in vitro. The results showed that the levels of SCr and BUN were increased, and tubular necrosis was observed in mouse kidneys, resulting in acute tubular necrosis (ATN) in CTD-induced AKI. Then, lipidomics results revealed that after CTD exposure, 232 differential lipid metabolites and 11 pathways including glycerophospholipid (GP) and sphingolipid (SL) metabolism were disrupted. Spatial metabolomics revealed that 55 spatial differential lipid metabolites and nine metabolic pathways were disturbed. Subsequently, integrative analysis found that GP metabolism was stimulated in the renal cortex and medulla, whereas SL metabolism was inhibited in the renal cortex. Up-regulated lysophosphatidylcholine (LysoPC) (18:2(9Z,12Z)), LysoPC (16:0/0:0), glycerophosphocholine, and down-regulated sphingomyelin (SM) (d18:0/16:0), SM (d18:1/24:0), and SM (d42:1) were key differential lipids. Among them, LysoPC (16:0/0:0) was increased in the CTD group at 1.1196 μg/mL, which aggravated CTD-induced ATN in human kidney-2 (HK-2) cells. LysoPC acyltransferase was inhibited and choline phosphotransferase 1 (CEPT1) was activated after CTD intervention in mice and in HK-2 cells. CTD induces ATN, resulting in AKI, by activating GP metabolism and inhibiting SL metabolism in the renal cortex and medulla, LysoPC (16:0/0:0), LysoPC acyltransferase, and CEPT1 may be the therapeutic targets.
基金supported by the National Natural Science Foundation of China funded project(32172627)Chongqing Modern Tea Technology System for Efficient Agriculture in Mountainous Areas 2022[8]the Germplasm Creation Research Program of Southwest University。
文摘Pu-erh tea has been shown to reduce gut inflammation in dextran sulfate sodium(DSS)-induced mice.Also,we found abnormal liver cholesterol metabolism in DSS-induced mice.However,it's not clear how Pu-erh tea improves DSS-induced impaired liver cholesterol metabolism.Here,we established the DSS-induced model and clarified that DSS exacerbated gut inflammation accompanied by disorders of liver cholesterol metabolism.Pu-erh tea reshaped gut microbes,limited gut oxidative stress and inflammation(nicotinamide adenine dinucleotide phosphate oxidase 2/reactive oxygen species/myeloid differentiation primary response protein 88/nuclear factor kappa-B,24.97%-52.89%),reduced gut bile acid reabsorption(up-regulation of farnesoid X receptor(FXR)/fibroblast growth factor 15,24.53%-55.91%),and promoted liver bile acid synthesis(up-regulation of peroxisome proliferator-activated receptor-α/cholesterol 7-alpha hydroxylase,34.65%-79.14%),thereby partly restoring liver cholesterol metabolism(regulated FXR/small heterodimer partner/sterol-regulatory element binding proteins,53.19%-95.40%).Altered bile acid metabolic profiles(increased chenodeoxycholic acid,ursodeoxycholic acid,lithocholic acid,etc.)may also improve liver cholesterol metabolism by altering gut and liver inflammation.Thus,gut microbial reshaping and altered bile acid metabolism may be key targets of Pu-erh tea for improving DSS-induced liver cholesterol metabolism disorders via the gut-gut microbe-bile acid-liver axis.
基金supported by the National Key Research and Development Program of China(No.2023YFC2508500)National Natural Science Foundation of China(No.82272951)National Natural Science Foundation of China(No.82272953)。
文摘Drug resistance continues to be the principal limiting factor in achieving a cure for patients with cancer,significantly hindering the long-term efficacy of novel cancer drugs.Accumulating evidence has shown that metabolites derived from tumor cells regulate immune cell metabolism via tumor microenvironment crosstalk.However,as immunometabolic research has deepened,the leading role played by the intrinsic metabolic regulation of immune cells in the drug resistance of tumor cells has been discovered.Immune metabolites have been shown to cause immune resistance,target therapy resistance,and chemotherapy resistance,and drugs that target immune metabolism have great potential.To date,researchers have not fully explored the impact of immune-derived metabolites on tumor cells and their influence on the responsiveness to cancer drugs.In this review,we focus on the lactate,fatty acid,glucose,and nucleotide metabolic alterations that take place in T cells and macrophages and how these changes can impair anti-tumor immunity,ultimately promoting tumor cell survival and decreasing responsiveness to the corresponding therapeutic approaches.We present the current developments in drugs targeting immunometabolic pathways and propose constructive suggestions,such as precise delivery to immune cell targets to enhance efficacy and safety,offering novel perspectives for cancer drug development.
基金supported by the National Natural Science Foundation of China,No.82072110Suzhou Municipal Science and Technology Bureau,No.SKJY2021046+1 种基金Shanghai Key Lab of Forensic Medicine&Key Lab of Forensic Science,Ministry of Justice,China(Academy of Forensic Science),No.KF202201a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)(all to TW).
文摘Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.
基金financially supported by the National Natural Science Foundation of China,No.823 74552 (to WP)the Science and Technology Innovation Program of Hunan Province,No.2022RC1220 (to WP)+1 种基金the Natural Science Foundation of Hunan Province of China,Nos.2020JJ4803 (to WP),2022JJ40723 (to MY)the Scientific Research Launch Project for New Employees of the Second Xiangya Hospital of Central South University (to MY)
文摘Alzheimer’s disease not only affects the brain,but also induces metabolic dysfunction in peripheral organs and alters the gut microbiota.The aim of this study was to investigate systemic changes that occur in Alzheimer’s disease,in particular the association between changes in peripheral organ metabolism,changes in gut microbial composition,and Alzheimer’s disease development.To do this,we analyzed peripheral organ metabolism and the gut microbiota in amyloid precursor protein-presenilin 1(APP/PS1)transgenic and control mice at 3,6,9,and 12 months of age.Twelve-month-old APP/PS1 mice exhibited cognitive impairment,Alzheimer’s disease-related brain changes,distinctive metabolic disturbances in peripheral organs and fecal samples(as detected by untargeted metabolomics sequencing),and substantial changes in gut microbial composition compared with younger APP/PS1 mice.Notably,a strong correlation emerged between the gut microbiota and kidney metabolism in APP/PS1 mice.These findings suggest that alterations in peripheral organ metabolism and the gut microbiota are closely related to Alzheimer’s disease development,indicating potential new directions for therapeutic strategies.
基金supported by the National Key Research and Development Program(No.2021YFD1300201)Jilin Provincial Department of Science and Technology Innovation Platform and Talent Special Project(No.20230508090RC).
文摘Background There is a growing focus on using various plant-derived agricultural by-products to increase the benefits of pig farming,but these feedstuffs are fibrous in nature.This study investigated the relationship between dietary fiber physicochemical properties and feedstuff fermentation characteristics and their effects on nutrient utilization,energy metabolism,and gut microbiota in growing pigs.Methods Thirty-six growing barrows(47.2±1.5 kg)were randomly allotted to 6 dietary treatments with 2 apparent viscosity levels and 3β-glucan-to-arabinoxylan ratios.In the experiment,nutrient utilization,energy metabolism,fecal microbial community,and production and absorption of short-chain fatty acid(SCFA)of pigs were investigated.In vitro digestion and fermentation models were used to compare the fermentation characteristics of feedstuffs and ileal digesta in the pig’s hindgut.Results The production dynamics of SCFA and dry matter corrected gas production of different feedstuffs during in vitro fermentation were different and closely related to the physical properties and chemical structure of the fiber.In animal experiments,increasing the dietary apparent viscosity and theβ-glucan-to-arabinoxylan ratios both increased the apparent ileal digestibility(AID),apparent total tract digestibility(ATTD),and hindgut digestibility of fiber components while decreasing the AID and ATTD of dry matter and organic matter(P<0.05).In addition,increasing dietary apparent viscosity andβ-glucan-to-arabinoxylan ratios both increased gas exchange,heat production,and protein oxidation,and decreased energy deposition(P<0.05).The dietary apparent viscosity andβ-glucanto-arabinoxylan ratios had linear interaction effects on the digestible energy,metabolizable energy,retained energy(RE),and net energy(NE)of the diets(P<0.05).At the same time,the increase of dietary apparent viscosity andβ-glucan-to-arabinoxylan ratios both increased SCFA production and absorption(P<0.05).Increasing the dietary apparent viscosity andβ-glucan-to-arabinoxylan ratios increased the diversity and abundance of bacteria(P<0.05)and the relative abundance of beneficial bacteria.Furthermore,increasing the dietaryβ-glucan-to-arabinoxylan ratios led to a linear increase in SCFA production during the in vitro fermentation of ileal digesta(P<0.001).Finally,the prediction equations for RE and NE were established.Conclusion Dietary fiber physicochemical properties alter dietary fermentation patterns and regulate nutrient utilization,energy metabolism,and pig gut microbiota composition and metabolites.
基金National Natural Science Foundation of China(82171003 and 82171002)Research and Develop Program of West China Hospital of Stomatology Sichuan University(NO.LCYJ-2022-YY-1)。
文摘Circadian rhythm is ubiquitous in nature.Circadian clock genes such as Bmal1 and Clock form a multi-level transcription-translation feedback network,and regulate a variety of physiological and pathological processes,including bone and cartilage metabolism.Deletion of the core clock gene Bmal1 leads to pathological bone alterations,while the phenotypes are not consistent.Studies have shown that multiple signaling pathways are involved in the process of Bmal1 regulating bone and cartilage metabolism,but the exact regulatory mechanisms remain unclear.This paper reviews the signaling pathways by which Bmal1 regulates bone/cartilage metabolism,the upstream regulatory factors that control Bmal1,and the current Bmal1 knockout mouse models for research.We hope to provide new insights for the prevention and treatment of bone/cartilage diseases related to circadian rhythms.
基金supported in part by the National Natural Science Foundation of China(Grant Nos.:82425104 and 82173690)the National Key R&D Program of China(Grant Nos:2022YFC3400501 and 2022YFC3400504)the Shanghai Rising-Star Program,China(Grant No:23QA1402800).
文摘Understanding the metabolism of endogenous and exogenous substances in the human body is essential for elucidating disease mechanisms and evaluating the safety and efficacy of drug candidates during the drug development process.Recent advancements in artificial intelligence(AI),particularly in machine learning(ML)and deep learning(DL)techniques,have introduced innovative approaches to metabolism research,enabling more accurate predictions and insights.This paper emphasizes computational and AI-driven methodologies,highlighting how ML enhances predictive modeling for human metabolism at the molecular level and facilitates integration into genome-scale metabolic models(GEMs)at the omics level.Challenges still remain,including data heterogeneity and model interpretability.This work aims to provide valuable insights and references for researchers in drug discovery and development,ultimately contributing to the advancement of precision medicine.
基金supported by the National Natural Science Foundation of China(82104207)Natural Science Foundation of Zhejiang Province(LQ22H280001)。
文摘Objective:Erianin has potential anticancer activities,especially against lung cancer.The specific mechanisms underlying the anticancer effects,including the molecular targets and signaling pathways in lung cancer,remain poorly understood and necessitate further investigation.Methods:Lung cancer cell viability was evaluated using the CCK-8 assay.Flow cytometry was used to examine the effects of erianin on apoptosis and cell cycle progression.m RNA sequencing and metabolomics analysis were utilized to explore erianin-induced biological changes.Potential targets were identified and validated through molecular docking and Western blot analysis.The roles of mammalian target of rapamycin(m TOR)and carbamoyl-phosphate synthetase/aspartate transcarbamylase/dihydroorotase(CAD)in erianin-induced growth inhibition were studied using gene overexpression/knockdown techniques with uridine and aspartate supplementation confirming pyrimidine metabolism involvement.Additionally,lung cancer-bearing nude mouse models were established to evaluate the anti-lung cancer effects of erianin in vivo.Results:Erianin significantly inhibits the proliferation of lung cancer cells,induces apoptosis,and causes G2/M phase cell cycle arrest.Integrative analysis of m RNA sequencing and metabolomics data demonstrated that erianin disrupts pyrimidine metabolism in lung cancer cells.Notably,uridine supplementation mitigated the inhibitory effects of erianin,establishing a connection between pyrimidine metabolism and anticancer activity.Network pharmacology analyses identified m TOR as a key target of erianin.Erianin inhibited m TOR phosphorylation,thereby blocking downstream effectors(S6K and CAD),which are essential regulators of pyrimidine metabolism.Conclusions:Erianin is a promising therapeutic candidate for lung cancer.Erianin likely inhibits lung cancer cell growth by disrupting pyrimidine metabolism by suppressing m TOR activation.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.32122080,31972375)Shandong Province(Grant No.ZR2020YQ25)。
文摘The content of soluble sugars is a vital parameter that indicates the quality of fleshy fruits such as apple(Malus domestica Borkh.).Studying the patterns of accumulation of soluble sugars and regulatory mechanisms associated with fruit development is crucial for breeding improved fruit varieties.Here,we report that MdCIbHLH1,a low temperature-induced b HLH transcription factor,inhibits the accumulation of soluble sugars by regulating sugar-metabolizing enzyme activities,photosynthetic performance,and the expression of sugar-related genes in developing apple fruits.MdCIbHLH1 inhibits MdFBP and MdPEPCK expression,thus blocking the conversion of acids to sugars in apple fruits.We also discovered that MdCIbHLH1 decreases the photosynthetic rate and carbohydrate accumulation in apple leaves.Our results suggest that soluble sugar accumulation in apple fruits is influenced by multiple factors,including metabolic status,photosynthesis,and carbohydrate allocation.MdCIbHLH1 is critically involved in controlling the accumulation of soluble sugars by coordinating carbohydrate synthesis and allocation,thus influencing sugar transport and its metabolism during the development of apple fruits.
基金National Natural Science Foundation of China(82474323)High Level Chinese Medical Hospital Promotion Project(HLCMHPP20230CZ40907)China Academy of Chinese Medical Sciences Outstanding Young Scientific and Technological Talents Program(ZZ13-YQ-026).
文摘Traditional Chinese medicine(TCM)has demonstrated unique advantages in the prevention and treatment of chronic diseases such as glycolipid metabolism disorder.However,its widespread application has been hindered by the unclear biological essence of TCM syndromes and therapeutic mechanisms.As an emerging interdisciplinary field,phenomics integrates multi-dimensional data including genome,transcriptome,proteome,metabolome,and microbiome.When combined with TCM's holistic philosophy,it forms TCM phenomics,providing novel approaches to reveal the biological connotation of TCM syndromes and the mechanisms of herbal medicine.Taking glycolipid metabolism disorder as an example,this paper explores the application of TCM phenomics in glycolipid metabolism disorder.By analyzing molecular characteristics of related syndromes,TCM phenomics identifies differentially expressed genes,metabolites,and gut microbiota biomarkers to elucidate the dynamic evolution patterns of syndromes.Simultaneously,it deciphers the multi-target regulatory networks of herbal formulas,demonstrating their therapeutic effects through mechanisms including modulation of insulin signaling pathways,improvement of gut microbiota imbalance,and suppression of inflammatory responses.Current challenges include the subjective nature of syndrome diagnosis,insufficient standardization of animal models,and lack of integrated multi-omics analysis.Future research should employ machine learning,multimodal data integration,and cross-omics longitudinal studies to establish quantitative diagnostic systems for syndromes,promote the integration of precision medicine in TCM and western medicine,and accelerate the modernization of TCM.
基金The research was supported by the National Natural Science Foundation of China(No.82170262,to Fang S H)Heilongjiang Province Applied Technology Research and Development Plan(GA20C009,to E M Y)The Natural Science Foundation of Heilongjiang Province(TD2020H001,to Yu B).
文摘Cold stimulation has been shown to regulate glucose,lipid,and amino acid metabolism,while also increasing heat production and energy expenditure in the body.Disordered energy metabolism is a key factor in the onset and progression of chronic metabolic conditiones such as diabetes,obesity,and cardiovascular disease.Recent research has unveiled the myriad pathways through which cold stimulation affects human energy metabolism.This article provides an overview of how cold stimulation affects energy metabolism across the three major metabolic pathways.Furthermore,it explores the implications and potential therapeutic applications of cold stimulation in the prevention and treatment of various metabolic diseases.
