Dysfunction of drug transporters significantly affects therapeutic outcomes and drug efficacy in patients with liver injury.Clinical and experimental evidence demonstrates that liver injury involves complex inter-orga...Dysfunction of drug transporters significantly affects therapeutic outcomes and drug efficacy in patients with liver injury.Clinical and experimental evidence demonstrates that liver injury involves complex inter-organ interactions among the brain,eye,liver,intestine,and kidney.Recent advances in basic and clinical research have illuminated the physiologic and molecular mechanisms underlying transporter alterations in liver injury,particularly those associated with bilirubin,reactive oxygen species,ammonia,bile acid,and inflammatory factors.Notably,the influence of these transporter modifications on drug pharmacokinetics in liver injury patients remains inadequately understood.Additional research is necessary to fully comprehend these effects and their therapeutic implications.The documented alterations of transporters in distant organs across various liver diseases indicate that dosage modifications may be required when administering transporter-substrate drugs,including both traditional Chinese and Western medicines,to patients with liver dysfunction.This strategy helps maintain drug concentrations within therapeutic ranges while reducing adverse reactions.Furthermore,when utilizing transporter inducers or inhibitors clinically,consideration of their long-term effects on transporters and subsequent therapeutic impact is essential.Careful attention must be paid to avoid compromising the elimination of toxic metabolites and proteins when inhibiting these transporters.Similarly,prudent use of inducers or inducertype therapeutic drugs is necessary to prevent enhanced drug resistance.This review examines recent clinical and experimental findings regarding the inter-organ interaction of drug transporters in liver injury conditions and their clinical relevance.展开更多
Proline accumulation has been shown to occur in plants in response to various environmental stresses.Although proline metabolismrelated genes have been functionally characterized,the inter-organ transport of proline i...Proline accumulation has been shown to occur in plants in response to various environmental stresses.Although proline metabolismrelated genes have been functionally characterized,the inter-organ transport of proline in stressed plants remains unclear.In this study,free proline was detected with significant accumulations in the roots,stems,and leaves of watermelon drought-tolerant germplasm M08 and drought-susceptible line Y34 under drought stress.Expression profiling and enzyme activity measurements revealed that ClP5CS1 gene,rather than its paralog ClP5CS2,mainly contributes to the proline synthesis in leaves via the Glu pathway.Additionally,over-expression of the ClP5CS genes significantly enhanced the drought tolerance of transgenic Arabidopsis lines.Furthermore,we confirmed that proline is mainly synthesized in leaves and transported to roots in watermelon under drought stress.Transcriptome and expression analyses revealed that the genes involved in proline metabolism exhibited different expression levels.Specifically,ClP5CS1 was upregulated in leaves and roots,while ClP5CS2 was downregulated under drought stress.Also,415 and 362 differently expressed TFs were identified in roots and leaves,respectively,with the majority upregulated in the former.Ultimately,a model for proline metabolism was proposed.The findings of this study provided new insights into the biosynthesis,transport,and regulatory mechanism of drought-induced proline in plants.展开更多
Cancer cachexia is a multi-organ syndrome and closely related to changes in signal communication between organs,which is mediated by cancer cachexia factors.Cancer cachexia factors,being the general name of inflammato...Cancer cachexia is a multi-organ syndrome and closely related to changes in signal communication between organs,which is mediated by cancer cachexia factors.Cancer cachexia factors,being the general name of inflammatory factors,circulating proteins,metabolites,and microRNA secreted by tumor or host cells,play a role in secretory or other organs and mediate complex signal communication between organs during cancer cachexia.Cancer cachexia factors are also a potential target for the diagnosis and treatment.The pathogenesis of cachexia is unclear and no clear effective treatment is available.Thus,the treatment of cancer cachexia from the perspective of the tumor ecosystem rather than from the perspective of a single molecule and a single organ is urgently needed.From the point of signal communication between organs mediated by cancer cachexia factors,finding a deeper understanding of the pathogenesis,diagnosis,and treatment of cancer cachexia is of great significance to improve the level of diagnosis and treatment.This review begins with cancer cachexia factors released during the interaction between tumor and host cells,and provides a comprehensive summary of the pathogenesis,diagnosis,and treatment for cancer cachexia,along with a particular sight on multi-organ signal communication mediated by cancer cachexia factors.This summary aims to deepen medical community’s understanding of cancer cachexia and may conduce to the discovery of new diagnostic and therapeutic targets for cancer cachexia.展开更多
In recent years, considerable attention has been paid to exploring the complex gene regulatory networks involved in the development of the plant vascular system. Such information is crucial to our understanding of the...In recent years, considerable attention has been paid to exploring the complex gene regulatory networks involved in the development of the plant vascular system. Such information is crucial to our understanding of the molecular and cellular events which give rise to the integrated tissues of the xylem and phloem, leading to the formation of structurally continuous conduits that interconnect various organs of the plant. Vascular development begins in the embryo to form progenitor cells, and upon germination, these progenitor cells and their decedents in the shoot and root meristems will form phloem and xylem, and the cambium.展开更多
In this Special Issue, a focus is placed on the role of the xylem as an essential conduit for the long-distance delivery of water and mineral nutrients from the soil to the vegetative （above-ground） regions of the p...In this Special Issue, a focus is placed on the role of the xylem as an essential conduit for the long-distance delivery of water and mineral nutrients from the soil to the vegetative （above-ground） regions of the plant. Xylem cells destined to form tracheids or vessel members, which will make up the conduit for this water and mineral transport from the roots to the shoots, undergo apoptosis, a process of programmed cell death.展开更多
Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors.This predicts that some individuals should have consistently high,while others show con...Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors.This predicts that some individuals should have consistently high,while others show consistently low mitochondrial oxidative phosphorylation(OxPhos)capacity across organ systems.Here,we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans.Across up to 22 mouse tissues,neither mitochondrial OxPhos capacity nor mitochondrial DNA(mtDNA)density was correlated between tissues(median r=−0.01 to 0.16),indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues.Similarly,RNA sequencing(RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men(genotype-tissue expression[GTEx])showed only small to moderate coherence between some tissues,such as between brain regions(r=0.26),but not between brain–body tissue pairs(r=0.01).The mtDNA copy number(mtDNAcn)also lacked coherence across human tissues.Mechanistically,tissue-specific differences in mitochondrial gene expression were partially attributable to(i)tissue-specific activation of energy sensing pathways,including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α),the integrated stress response(ISR),and other molecular regulators of mitochondrial biology,and(ii)proliferative activity across tissues.Finally,we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes.These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.展开更多
Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure,it remains unexplored whether sleep disorder-caused hepatic damage contributes to the dev...Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure,it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease(CVD).Here,our findings revealed that sleep fragmentation(SF)displayed notable hepatic detrimental phenotypes,including steatosis and oxidative damage,along with significant abnormalities in cardiac structure and function.All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more,displaying memory properties.Mechanistically,persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)in the liver was the key initiator of SF-accelerated damage phenotypes.SF epigenetically controlled the acetylation of histone H3 lysine 27(H3K27ac)enrichment at the Nox4 promoter and markedly increased Nox4 expression in liver even after sleep recovery.Moreover,fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1(Sirt1)transcription after circadian misalignment.Accordingly,genetic manipulation of liver-specific Nox4 or Sirt1,along with pharmacological intervention targeting NOX4(GLX351322)or SIRT1(Resveratrol),could effectively erase the epigenetic modification of Nox4 by reducing the H3K27ac level and ameliorate the progression of liver pathology,thereby counteracting SF-evoked sustained CVD.Collectively,our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.展开更多
Hormones are important bioactive molecules that regulate the development,function,and homeostasis of tissues/organs via binding to hormone receptors(HRs)in target cells.Although human HRs are essential for both basic ...Hormones are important bioactive molecules that regulate the development,function,and homeostasis of tissues/organs via binding to hormone receptors(HRs)in target cells.Although human HRs are essential for both basic research and drug development,a comprehensive analysis of them is still lacking.Here,we present a systematic bioinformatic investigation of all known human HRs,characterizing their genomic distributions,biological functions,subcellular localizations,and expression patterns in various cell types and tissues/organs.We further explored the relationship between HR expression and aging,and identified HRs with aging-associated expression changes.In addition,a thorough analysis of HR-related diseases highlights the extensive involvement of HRs in various pathological conditions,particularly nervous system diseases and cancers.We constructed gender-specific cross-tissue/organ hormone-HR interaction networks,which provided valuable insights into hormone-mediated inter-organ communications.An interactive website was also developed to allow users to explore hormone-HR networks in different tissues/organs.These results revealed new features of human HRs and offered a comprehensive resource for human HR-related studies.展开更多
Brain diseases,mainly including acute brain injuries,neurodegenerative diseases,and mental disorders,have posed a significant threat to human health worldwide.Due to the limited regenerative capability and the existen...Brain diseases,mainly including acute brain injuries,neurodegenerative diseases,and mental disorders,have posed a significant threat to human health worldwide.Due to the limited regenerative capability and the existence of the blood–brain barrier,the brain was previously thought to be separated from the rest of the body.Currently,various cross-talks between the central nervous system and peripheral organs have been widely described,including the brain-gut axis,the brain-liver axis,the brain-skeletal muscle axis,and the brain-bone axis.Moreover,several lines of evidence indicate that leveraging systemic biology intervention approaches,including but not limited to lifestyle interventions,exercise,diet,blood administration,and peripheral immune responses,have demonstrated a significant influence on the progress and prognosis of brain diseases.The advancement of innovative proteomic and transcriptomic technologies has enriched our understanding of the nuanced interplay between peripheral organs and brain diseases.An array of novel or previously underappreciated blood-derived factors have been identified to play pivotal roles in mediating these communications.In this review,we provide a comprehensive summary of blood-to-brain communication following brain diseases.Special attention is given to the instrumental role of blood-derived signals,positing them as significant contributors to the complex process of brain diseases.The insights presented here aim to bridge the current knowledge gaps and inspire novel therapeutic strategies for brain diseases.展开更多
Exercise is an effective strategy to prevent and improve obesity and related metabolic diseases.Exercise increases the metabolic demand in the body.Although many of the metabolic health benefits of exercise depend on ...Exercise is an effective strategy to prevent and improve obesity and related metabolic diseases.Exercise increases the metabolic demand in the body.Although many of the metabolic health benefits of exercise depend on skeletal muscle adaptations,exercise exerts many of its metabolic effects through the liver,adipose tissue,and pancreas.Therefore,exercise is the physiological state in which inter-organ signaling is most important.By contrast,circadian rhythms in mammals are associated with the regulation of several physiological and biological functions,including body temperature,sleep-wake cycle,physical activity,hormone secretion,and metabolism,which are controlled by clock genes.Glucose and lipid tolerance reportedly exhibit diurnal variations,being lower in the evening than in the morning.Therefore,the effects of exercise on substrate metabolism at different times of the day may differ.In this review,the importance of exercise timing considerations will be outlined,incorporating a chrono-exercise perspective.展开更多
基金the National Natural Science Foundation of China(No.82173884).
文摘Dysfunction of drug transporters significantly affects therapeutic outcomes and drug efficacy in patients with liver injury.Clinical and experimental evidence demonstrates that liver injury involves complex inter-organ interactions among the brain,eye,liver,intestine,and kidney.Recent advances in basic and clinical research have illuminated the physiologic and molecular mechanisms underlying transporter alterations in liver injury,particularly those associated with bilirubin,reactive oxygen species,ammonia,bile acid,and inflammatory factors.Notably,the influence of these transporter modifications on drug pharmacokinetics in liver injury patients remains inadequately understood.Additional research is necessary to fully comprehend these effects and their therapeutic implications.The documented alterations of transporters in distant organs across various liver diseases indicate that dosage modifications may be required when administering transporter-substrate drugs,including both traditional Chinese and Western medicines,to patients with liver dysfunction.This strategy helps maintain drug concentrations within therapeutic ranges while reducing adverse reactions.Furthermore,when utilizing transporter inducers or inhibitors clinically,consideration of their long-term effects on transporters and subsequent therapeutic impact is essential.Careful attention must be paid to avoid compromising the elimination of toxic metabolites and proteins when inhibiting these transporters.Similarly,prudent use of inducers or inducertype therapeutic drugs is necessary to prevent enhanced drug resistance.This review examines recent clinical and experimental findings regarding the inter-organ interaction of drug transporters in liver injury conditions and their clinical relevance.
基金support provided by the National Natural Science Foundation of China(Grant No.31701939)National Natural Science Foundation of Shaanxi province,China(Grant No.2019JQ-324)+1 种基金National Key R&D Program of China(Grant No.2018YFD0100704)the Modern Agro-industry Technology Research System of China(Grant No.CARS-25).
文摘Proline accumulation has been shown to occur in plants in response to various environmental stresses.Although proline metabolismrelated genes have been functionally characterized,the inter-organ transport of proline in stressed plants remains unclear.In this study,free proline was detected with significant accumulations in the roots,stems,and leaves of watermelon drought-tolerant germplasm M08 and drought-susceptible line Y34 under drought stress.Expression profiling and enzyme activity measurements revealed that ClP5CS1 gene,rather than its paralog ClP5CS2,mainly contributes to the proline synthesis in leaves via the Glu pathway.Additionally,over-expression of the ClP5CS genes significantly enhanced the drought tolerance of transgenic Arabidopsis lines.Furthermore,we confirmed that proline is mainly synthesized in leaves and transported to roots in watermelon under drought stress.Transcriptome and expression analyses revealed that the genes involved in proline metabolism exhibited different expression levels.Specifically,ClP5CS1 was upregulated in leaves and roots,while ClP5CS2 was downregulated under drought stress.Also,415 and 362 differently expressed TFs were identified in roots and leaves,respectively,with the majority upregulated in the former.Ultimately,a model for proline metabolism was proposed.The findings of this study provided new insights into the biosynthesis,transport,and regulatory mechanism of drought-induced proline in plants.
基金supported by the High-Level Talent Introduction Funds from the First Hospital of Lanzhou University.
文摘Cancer cachexia is a multi-organ syndrome and closely related to changes in signal communication between organs,which is mediated by cancer cachexia factors.Cancer cachexia factors,being the general name of inflammatory factors,circulating proteins,metabolites,and microRNA secreted by tumor or host cells,play a role in secretory or other organs and mediate complex signal communication between organs during cancer cachexia.Cancer cachexia factors are also a potential target for the diagnosis and treatment.The pathogenesis of cachexia is unclear and no clear effective treatment is available.Thus,the treatment of cancer cachexia from the perspective of the tumor ecosystem rather than from the perspective of a single molecule and a single organ is urgently needed.From the point of signal communication between organs mediated by cancer cachexia factors,finding a deeper understanding of the pathogenesis,diagnosis,and treatment of cancer cachexia is of great significance to improve the level of diagnosis and treatment.This review begins with cancer cachexia factors released during the interaction between tumor and host cells,and provides a comprehensive summary of the pathogenesis,diagnosis,and treatment for cancer cachexia,along with a particular sight on multi-organ signal communication mediated by cancer cachexia factors.This summary aims to deepen medical community’s understanding of cancer cachexia and may conduce to the discovery of new diagnostic and therapeutic targets for cancer cachexia.
文摘In recent years, considerable attention has been paid to exploring the complex gene regulatory networks involved in the development of the plant vascular system. Such information is crucial to our understanding of the molecular and cellular events which give rise to the integrated tissues of the xylem and phloem, leading to the formation of structurally continuous conduits that interconnect various organs of the plant. Vascular development begins in the embryo to form progenitor cells, and upon germination, these progenitor cells and their decedents in the shoot and root meristems will form phloem and xylem, and the cambium.
文摘In this Special Issue, a focus is placed on the role of the xylem as an essential conduit for the long-distance delivery of water and mineral nutrients from the soil to the vegetative （above-ground） regions of the plant. Xylem cells destined to form tracheids or vessel members, which will make up the conduit for this water and mineral transport from the roots to the shoots, undergo apoptosis, a process of programmed cell death.
基金supported by the NIH grants(R35GM119793,R01AG066828,and R01AG086764)Baszucki Group to M.P.
文摘Energy transformation capacity is generally assumed to be a coherent individual trait driven by genetic and environmental factors.This predicts that some individuals should have consistently high,while others show consistently low mitochondrial oxidative phosphorylation(OxPhos)capacity across organ systems.Here,we test this assumption using multi-tissue molecular and enzymatic assays in mice and humans.Across up to 22 mouse tissues,neither mitochondrial OxPhos capacity nor mitochondrial DNA(mtDNA)density was correlated between tissues(median r=−0.01 to 0.16),indicating that animals with high mitochondrial content or capacity in one tissue may have low content or capacity in other tissues.Similarly,RNA sequencing(RNAseq)-based indices of mitochondrial expression across 45 tissues from 948 women and men(genotype-tissue expression[GTEx])showed only small to moderate coherence between some tissues,such as between brain regions(r=0.26),but not between brain–body tissue pairs(r=0.01).The mtDNA copy number(mtDNAcn)also lacked coherence across human tissues.Mechanistically,tissue-specific differences in mitochondrial gene expression were partially attributable to(i)tissue-specific activation of energy sensing pathways,including the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α),the integrated stress response(ISR),and other molecular regulators of mitochondrial biology,and(ii)proliferative activity across tissues.Finally,we identify subgroups of individuals with distinct mitochondrial distribution strategies that map onto distinct clinical phenotypes.These data raise the possibility that tissue-specific energy sensing pathways may contribute to idiosyncratic mitochondrial distribution patterns among individuals.
基金supported by National Natural Science Foundation of China(No.82272601)Young Taishan Scholars Program(No.TSQN202306013,China)Natural Science Foundation of Shandong Province(No.ZR2021MH330,China).
文摘Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure,it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease(CVD).Here,our findings revealed that sleep fragmentation(SF)displayed notable hepatic detrimental phenotypes,including steatosis and oxidative damage,along with significant abnormalities in cardiac structure and function.All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more,displaying memory properties.Mechanistically,persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)in the liver was the key initiator of SF-accelerated damage phenotypes.SF epigenetically controlled the acetylation of histone H3 lysine 27(H3K27ac)enrichment at the Nox4 promoter and markedly increased Nox4 expression in liver even after sleep recovery.Moreover,fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1(Sirt1)transcription after circadian misalignment.Accordingly,genetic manipulation of liver-specific Nox4 or Sirt1,along with pharmacological intervention targeting NOX4(GLX351322)or SIRT1(Resveratrol),could effectively erase the epigenetic modification of Nox4 by reducing the H3K27ac level and ameliorate the progression of liver pathology,thereby counteracting SF-evoked sustained CVD.Collectively,our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.
基金supported by the Chinese Academy of Sciences for Young Scientists in Basic Research Project(YSBR-073)Beijing Municipal Science&Technology Commission(Z231100007223010)+2 种基金National Key Research and Development Program of China(2023YFC3402202)Strategic Priority Research Program of Chinese Academy of Sciences(XDA0460203)the National Natural Science Foundation of China(91940304)。
文摘Hormones are important bioactive molecules that regulate the development,function,and homeostasis of tissues/organs via binding to hormone receptors(HRs)in target cells.Although human HRs are essential for both basic research and drug development,a comprehensive analysis of them is still lacking.Here,we present a systematic bioinformatic investigation of all known human HRs,characterizing their genomic distributions,biological functions,subcellular localizations,and expression patterns in various cell types and tissues/organs.We further explored the relationship between HR expression and aging,and identified HRs with aging-associated expression changes.In addition,a thorough analysis of HR-related diseases highlights the extensive involvement of HRs in various pathological conditions,particularly nervous system diseases and cancers.We constructed gender-specific cross-tissue/organ hormone-HR interaction networks,which provided valuable insights into hormone-mediated inter-organ communications.An interactive website was also developed to allow users to explore hormone-HR networks in different tissues/organs.These results revealed new features of human HRs and offered a comprehensive resource for human HR-related studies.
基金supported by the National Natural Science Foundation of China(82071466,82371470,82071468,and 82201618)the“Sail Plan”Key Medical Specialty(ZYLX202139)+2 种基金the“Mission”Talent Project of Beijing Municipal Administration of Hospitals(SML20150802)the Beijing Municipal Science and Technology Project(Z181100001918026)the Project for Innovation and Development of Beijing Municipal Geriatric Medical Research Center(11000023T000002036320)。
文摘Brain diseases,mainly including acute brain injuries,neurodegenerative diseases,and mental disorders,have posed a significant threat to human health worldwide.Due to the limited regenerative capability and the existence of the blood–brain barrier,the brain was previously thought to be separated from the rest of the body.Currently,various cross-talks between the central nervous system and peripheral organs have been widely described,including the brain-gut axis,the brain-liver axis,the brain-skeletal muscle axis,and the brain-bone axis.Moreover,several lines of evidence indicate that leveraging systemic biology intervention approaches,including but not limited to lifestyle interventions,exercise,diet,blood administration,and peripheral immune responses,have demonstrated a significant influence on the progress and prognosis of brain diseases.The advancement of innovative proteomic and transcriptomic technologies has enriched our understanding of the nuanced interplay between peripheral organs and brain diseases.An array of novel or previously underappreciated blood-derived factors have been identified to play pivotal roles in mediating these communications.In this review,we provide a comprehensive summary of blood-to-brain communication following brain diseases.Special attention is given to the instrumental role of blood-derived signals,positing them as significant contributors to the complex process of brain diseases.The insights presented here aim to bridge the current knowledge gaps and inspire novel therapeutic strategies for brain diseases.
基金supported by the Japan Society for the Promotion of Science(KAKENHI grant numbers 20K19689 and 18K17940 to H.-K.K.and 19H01089 to S.S.)and the JST-Mirai Program(grant number JMPJM120D5)to S.S.
文摘Exercise is an effective strategy to prevent and improve obesity and related metabolic diseases.Exercise increases the metabolic demand in the body.Although many of the metabolic health benefits of exercise depend on skeletal muscle adaptations,exercise exerts many of its metabolic effects through the liver,adipose tissue,and pancreas.Therefore,exercise is the physiological state in which inter-organ signaling is most important.By contrast,circadian rhythms in mammals are associated with the regulation of several physiological and biological functions,including body temperature,sleep-wake cycle,physical activity,hormone secretion,and metabolism,which are controlled by clock genes.Glucose and lipid tolerance reportedly exhibit diurnal variations,being lower in the evening than in the morning.Therefore,the effects of exercise on substrate metabolism at different times of the day may differ.In this review,the importance of exercise timing considerations will be outlined,incorporating a chrono-exercise perspective.
