Exactly one hundred years ago,the world was emerging from the ravages of the Spanish flu pandemic that killed 30 million people.Today,we are also emerging from a similar pandemic caused by coronavirus disease(COVID-19...Exactly one hundred years ago,the world was emerging from the ravages of the Spanish flu pandemic that killed 30 million people.Today,we are also emerging from a similar pandemic caused by coronavirus disease(COVID-19).However,the world that survivors of the flu pandemic inherited was very different from the world that will be left after COVID-19 is finally over.Life,of course,has changed enormously in these last 100 years with the advent of air travel,cars,computers,and the internet.But not only healthy life has changed,but what has also changed is the reasons why we get ill and die.After the flu pandemic,the major killers were still infectious diseases and undernutrition.Nowadays,the main health problems are due to over-nutrition and non-communicable diseases such as obesity,Type 2 diabetes,cardiovascular diseases,cancer,and neurological diseases.展开更多
Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons.Abnormal myelin sheath is associated with many neurological diseases.Meningioma-expressed antigen 6(Mea6)/cutaneous T cell ly...Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons.Abnormal myelin sheath is associated with many neurological diseases.Meningioma-expressed antigen 6(Mea6)/cutaneous T cell lymphoma-associated antigen 5C(cTAGE5C)plays an important role in vesicle trafficking from the endoplasmic reticulum(ER)to Golgi,and conditional knockout(cKO)of Mea6 in the brain significantly affects neural development and brain function.However,whether the impaired brain function involves the development of oligodendrocytes and white matter beyond neurons remains unclear.In this study,by using different models of diffusion magnetic resonance imaging,we showed that cKO of Mea6 in oligodendrocytes leads to significant impairment of the gross and microstructure of the white matter,as well as a significant decrease of cholesterol and triglycerides in brains.Our lipidomic analysis of purified myelin sheath for the first time showed that Mea6 elimination in oligodendrocytes significantly altered the lipid composition in myelin lipidome,especially the proportion of very long chain fatty acids(VLCFAs).In particular,the levels of most VLCFA-containing phosphatidylcholines were substantially lower in the myelin sheath of the cKO mice.The reduction of VLCFAs is likely due to the downregulated expression of elongation of very long chain fatty acids(ELOVLs).Our study of an animal model with white matter malformation and the comprehensive lipid profiling would provide clues for future studies of the formation of myelin sheath,myelin lipids,and the pathogenesis of white matter diseases.展开更多
Dear Editor,Organisms have evolved mitochondrial stress response pathways to surveil mitochondrial function and activate repair programs upon detection of mitochondrial dysfunction[1].Failure to respond to mitochondri...Dear Editor,Organisms have evolved mitochondrial stress response pathways to surveil mitochondrial function and activate repair programs upon detection of mitochondrial dysfunction[1].Failure to respond to mitochondrial perturbation has been implicated in aging and age-related diseases[2,3].Mitochondrial perturbation in mammals primarily activates the integrated stress response(ISR).展开更多
Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and s...Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and the aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how the metabolic program in T cells is influenced by the aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring the metabolic programming of immune cells.展开更多
A multitude of bioactive compounds are produced by the gut microbiota,including metabolites with notable antimicrobial or immunomodulatory effects.Perhaps the most compelling of these compounds,however,are the ones wi...A multitude of bioactive compounds are produced by the gut microbiota,including metabolites with notable antimicrobial or immunomodulatory effects.Perhaps the most compelling of these compounds,however,are the ones with the potential to affect human mood and behavior.In an article published recently in Cell,McCurry et al.demonstrated that human gut bacteria are capable of producing neuroactive steroids,including a drug clinically approved by the United States Food and Drug Administration(FDA)for the treatment of postpartum depression.展开更多
The endocrine system is a fundamental type of long-range cell-cell communication that is important for maintaining metabolism,physiology,and other aspects of organismal homeostasis.Endocrine signaling is mediated by d...The endocrine system is a fundamental type of long-range cell-cell communication that is important for maintaining metabolism,physiology,and other aspects of organismal homeostasis.Endocrine signaling is mediated by diverse blood-borne ligands,also called hormones,including metabolites,lipids,steroids,peptides,and proteins.The size and structure of these hormones are fine-tuned to make them bioactive,responsive,and adaptable to meet the demands of changing environments.Why has nature selected such diverse ligand types to mediate communication in the endocrine system?What is the chemical,signaling,or physiologic logic of these ligands?What fundamental principles from our knowledge of endocrine communication can be applied as we continue as a field to uncover additional new circulating molecules that are claimed to mediate long-range cell and tissue crosstalk?This review provides a framework based on the biochemical logic behind this crosstalk with respect to their chemistry,temporal regulation in physiology,specificity,signaling actions,and evolutionary development.展开更多
The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application.A recent study published in Molecular Cell has ide...The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application.A recent study published in Molecular Cell has identified hyperoxidized perox-iredoxin 3(PRDX3)as a promising marker for ferroptosis,open-ing up new avenues for monitoring and targeting ferroptosis in disease treatment.展开更多
Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting(IF), a dietary patter...Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting(IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E(Apo E) knockout(Apo E-/-) mice, by enhancing intestinal flora production of indole-3-propionic acid(IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor(PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca2+. Importantly, IF alleviates myocardial and cerebral ischemia/reperfusion injury in Apo E-/-mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathways.展开更多
The balance between intestinal cholesterol absorption and cholesterol synthesis in the liver has remained a puzzling phenomenon for a long time because no study has been able to explain how the consumption of a choles...The balance between intestinal cholesterol absorption and cholesterol synthesis in the liver has remained a puzzling phenomenon for a long time because no study has been able to explain how the consumption of a cholesterol-rich diet impairs cholesterol synthesis in the liver.Recently,a group of researchers uncovered a hormone produced in the intestine without any known function,which they named cholesin,that suppresses sterol regulatory element-binding protein 2(SREBP-2),the master regulator of cholesterol synthesis in the liver.展开更多
Circadian rhythms are fundamental regulators of physiological processes, including immune function. Recent insights uncover that not only lymphocytes but also myeloid cells possess intrinsic circadian clocks that gove...Circadian rhythms are fundamental regulators of physiological processes, including immune function. Recent insights uncover that not only lymphocytes but also myeloid cells possess intrinsic circadian clocks that govern their behavior and function. Emerging evidence highlights how circadian regulation of metabolism critically shapes the inflammatory and tissue-repair functions of myeloid subsets. Furthermore, mitochondrial dynamics, a key metabolic feature, are under circadian control and influence antigen presentation and effector functions. Here, we review the interplay between circadian clocks, metabolism, and myeloid immunity, discussing their therapeutic opportunities for optimizing vaccination, infection management, and immunotherapy.展开更多
Diet interventions such as calorie restriction or time-restricted feeding offer potential for weight management,but long-term success is often hindered by poor adherence due to the rewarding effects of sugars.In this ...Diet interventions such as calorie restriction or time-restricted feeding offer potential for weight management,but long-term success is often hindered by poor adherence due to the rewarding effects of sugars.In this study,we demonstrate that sulfur amino acid restriction(SAAR)diets promote rapid fat loss without impairing appetite and physiological locomotion,outperforming diets with restricted branched-chain amino acids.Weekly cycling of SAAR diets preserves metabolic benefits,such as reduced fat mass and improved glucose sensitivity.Metabolic analysis and in vivo isotope tracing revealed a shift toward carbohydrate oxidation in white and brown adipose tissue(WAT and BAT),and liver during the SAAR diet refeeding state,leading to decreased de novo lipogenesis.Enhanced lipolysis and fatty acid oxidation were observed in the heart,brain,BAT,lungs,etc.The reintroduction of methionine or cystine negated these metabolic benefits.Further 13C and 2H tracing experiments indicated that cystine,rather than its derivatives like taurine or H2S,directly regulates adiposity.In a high-fat diet model,SAAR diet led to sustained fat mass reduction,regardless of the timing of intervention.Additionally,cystine levels correlated positively with body mass index(BMI)and total triglycerides in diabetic patients.Our findings highlight SAAR diet as a promising strategy for long-term weight control by modulating systemic glucose and lipid metabolism homeostasis.展开更多
Brown adipose tissue(BAT)plays a key role in thermogenesis during acute cold exposure.However,it remains unclear how BAT is prepared to rapidly turn on thermogenic genes.Here,we show that damage-specific DNA binding p...Brown adipose tissue(BAT)plays a key role in thermogenesis during acute cold exposure.However,it remains unclear how BAT is prepared to rapidly turn on thermogenic genes.Here,we show that damage-specific DNA binding protein 1(DDB1)mediates the rapid transcription of thermogenic genes upon acute cold exposure.Adipose-or BAT-specific Ddb1 knockout mice show severely whitened BAT and significantly decreased expression of thermogenic genes.These mice develop hypothermia when subjected to acute cold exposure at 4℃ and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation.Mechanistically,DDB1 binds the promoters of Ucp1 and Ppargc1a and recruits positive transcriptional elongation factor b(P-TEFb)to release promoter-proximally paused RNA polymerase II(Pol II),thereby enabling rapid and synchronized transcription of thermogenic genes upon acute cold exposure.Our findings have thus provided a regulatory mechanism of how BAT is prepared to respond to acute cold challenge.展开更多
Nucleosomes are the fundamental unit of chromatin.Chromatin remodeler plays a crucial role in the regulation of gene expression in eukaryotes.It is involved in important physiological processes,such as development,imm...Nucleosomes are the fundamental unit of chromatin.Chromatin remodeler plays a crucial role in the regulation of gene expression in eukaryotes.It is involved in important physiological processes,such as development,immune response,and metabolic regulation.During gene expression regulation,chromatin remodelers slide nucleosomes along genomic DNA and play a major role in chromatin organization.Chd1 senses the extranucleosomal linker DNA and controls nucleosome spacing in cells.However,the mechanism of linker DNA sensing by Chd1 is not completely understood.Here,we report the cryo-electron microscope(cryoEM)structures of Chd1 engaging nucleosomes in different states.Chd1 induces two exit-DNA conformations,either fully wrapped or partially unwrapped states.Notably,in the unwrapped conformation,the exit DNA interacts with a positively charged loop of the motor,named the exit-DNA binding loop,and traps Chd1 in the closed state in the ATPase cycle,suggesting attenuation of its remodeling activity.Explored single-molecule fluorescence resonance energy transfer(smFRET)and biochemical data supported the regulation of Chd1 remodeling activity by the exit-DNA conformations,which is important for the linker DNA sensitivity.Mutants of the Chd1 exit-DNA binding loop compromised nucleosome organization in yeast cells.Together,our findings provide valuable insights into Chd1 regulation by exit DNA unwrapping.These results provide a new perspective for the study of cell development and metabolism.展开更多
Tumor immunotherapy has achieved breakthroughs in a variety of tumors. However, the systemic absence of T cells in tumors and immunosuppressive tumor microenvironment so far limits the efficacy of immunotherapy to a s...Tumor immunotherapy has achieved breakthroughs in a variety of tumors. However, the systemic absence of T cells in tumors and immunosuppressive tumor microenvironment so far limits the efficacy of immunotherapy to a small population of patients. Therefore, novel agents to increase T-cell tumor infiltration are urgently needed in the clinic. We recently found that inhibition of the ADP-ribosylation factor 1 (Arf1)-mediated lipid metabolism not only kills cancer stem cells (CSCs) but also elicits an anti-tumor immune response. In this study, we revealed a mechanism that targeting Arf1 promotes the infiltration of cytotoxic T lymphocytes (CTLs) into tumors through the C-C chemokine ligand 5 (CCL5)- C-C chemokine receptor type 5 (CCR5) pathway. We found that blockage of Arf1 induces the production of the unsaturated fatty acid (PE 18:1) that binds and sequestrates peroxisome proliferator- activated receptor-γ (PPARγ) from the PPARγ-nuclear factor-κB (NF-κB) cytoplasmic complex. The released NF-κB was then phospho-rylated and translocated into the nucleus to regulate the transcription of chemokine CCL5. CCL5 promoted infiltration of CTLs for tumor regression. Furthermore, the combination of the Arf1 inhibitor and programmed cell death protein 1 (PD-1) blockade induced an even stronger anti-tumor immunity. Therefore, targeting Arf1 represents a novel anti-tumor immune approach by provoking T-cell tumor infiltration and may provide a new strategy for tumor immunotherapy.展开更多
This is a correction to:Mengqi Li,Xiaoyan Wei,Jinye Xiong,Jin-Wei Feng,Chen-Song Zhang,Sheng-Cai Lin,Hierarchical inhibition of mTORC1 by glucose starvation-triggered AXIN lysosomal translocation and by AMPK,Life Meta...This is a correction to:Mengqi Li,Xiaoyan Wei,Jinye Xiong,Jin-Wei Feng,Chen-Song Zhang,Sheng-Cai Lin,Hierarchical inhibition of mTORC1 by glucose starvation-triggered AXIN lysosomal translocation and by AMPK,Life Metabolism,Volume 2,Issue 3,June 2023,https://doi.org/10.1093/lifemeta/load005.展开更多
In response to contraction during exercise,skeletal muscle growth and metabolism are dynamically regulated by nerve action,blood flow,and metabolic feedback.α-Ketoglutarate(AKG),a bioactive intermediate in the tricar...In response to contraction during exercise,skeletal muscle growth and metabolism are dynamically regulated by nerve action,blood flow,and metabolic feedback.α-Ketoglutarate(AKG),a bioactive intermediate in the tricarboxylic acid cycle released during exercise,has been shown to promote skeletal muscle hypertrophy.However,the underlying mechanism of AKG in regulating skeletal muscle development and metabolism is still less known.2-Oxoglutarate receptor 1(OXGR1),the endogenous AKG receptor,is found to be distributed in the vascular smooth muscle(VSM)of skeletal muscles.OXGR1 knockout results in skeletal muscle atrophy,accompanied by decreased expression of myosin heavy chain I(MyHC I),capillary density,and endurance exercise capacity.Furthermore,the study found that dietary AKG supplementation increased mice endurance exercise distance,MyHC I/MyHC IIb ratio,arteriole,and capillary densities in skeletal muscle.Meanwhile,acute AKG administration gradually increased the blood flow in the lower limbs.Further,by using OXGR1 global knockout and OXGR1 VSM-specific(MYH11-Cre×OXGR1-FloxP)knockdown models,we found that OXGR1 in VSM is essential for AKG-induced improvement of skeletal muscle performances.According to the in vitro study,AKG expanded the cell area in VSM with a decreased intracellular pH by OXGR1.Our results demonstrated a novel role of AKG/OXGR1 in VSM of skeletal muscle to regulate blood flow and then enhance slow muscle fiber conversion and capillarization.These findings provide a theoretical basis for the AKG/OXGR1 signaling pathway to maintain human muscle function and improve meat production and livestock and poultry meat quality.展开更多
Breast cancer metastasis remains the leading cause of mortality in patients,yet its mechanisms are poorly understood.A recent Cell paper highlights the pivotal role of the proprotein convertase subtilisin/kexin type 9...Breast cancer metastasis remains the leading cause of mortality in patients,yet its mechanisms are poorly understood.A recent Cell paper highlights the pivotal role of the proprotein convertase subtilisin/kexin type 9(PCSK9)V474I germline variant in driving metastatic progression through suppression of the low-density lipoprotein receptor-related protein 1(LRP1)receptor,revealing novel therapeutic opportunities and genetic insights.展开更多
文摘Exactly one hundred years ago,the world was emerging from the ravages of the Spanish flu pandemic that killed 30 million people.Today,we are also emerging from a similar pandemic caused by coronavirus disease(COVID-19).However,the world that survivors of the flu pandemic inherited was very different from the world that will be left after COVID-19 is finally over.Life,of course,has changed enormously in these last 100 years with the advent of air travel,cars,computers,and the internet.But not only healthy life has changed,but what has also changed is the reasons why we get ill and die.After the flu pandemic,the major killers were still infectious diseases and undernutrition.Nowadays,the main health problems are due to over-nutrition and non-communicable diseases such as obesity,Type 2 diabetes,cardiovascular diseases,cancer,and neurological diseases.
基金This study was supported in part by grants from the National Natural Science Foundation of China(NSFC)(31921002,31730108,31730039,and 32061143026)Guangdong Province Key Field R&D Program(2018B030335001)+1 种基金Major Projects of the Ministry of Science and Technology(2021ZD0202300,2022ZD0211901,and 2019YFA0707103)the Strategic Priority Research Program and Innovation Program of the Chinese Academy of Sciences(XDB32020100,YJKYYQ20200052,and ZDBS-LY-SM028).
文摘Lipid-rich myelin is a special structure formed by oligodendrocytes wrapping neuronal axons.Abnormal myelin sheath is associated with many neurological diseases.Meningioma-expressed antigen 6(Mea6)/cutaneous T cell lymphoma-associated antigen 5C(cTAGE5C)plays an important role in vesicle trafficking from the endoplasmic reticulum(ER)to Golgi,and conditional knockout(cKO)of Mea6 in the brain significantly affects neural development and brain function.However,whether the impaired brain function involves the development of oligodendrocytes and white matter beyond neurons remains unclear.In this study,by using different models of diffusion magnetic resonance imaging,we showed that cKO of Mea6 in oligodendrocytes leads to significant impairment of the gross and microstructure of the white matter,as well as a significant decrease of cholesterol and triglycerides in brains.Our lipidomic analysis of purified myelin sheath for the first time showed that Mea6 elimination in oligodendrocytes significantly altered the lipid composition in myelin lipidome,especially the proportion of very long chain fatty acids(VLCFAs).In particular,the levels of most VLCFA-containing phosphatidylcholines were substantially lower in the myelin sheath of the cKO mice.The reduction of VLCFAs is likely due to the downregulated expression of elongation of very long chain fatty acids(ELOVLs).Our study of an animal model with white matter malformation and the comprehensive lipid profiling would provide clues for future studies of the formation of myelin sheath,myelin lipids,and the pathogenesis of white matter diseases.
基金supported by the National Natural Science Foundation of China(32293212,92254305,and 31925012)the HHMI International Research Scholar Program(55008739)to Y.L.Y.L.was also supported by the Peking-Tsinghua Center for Life Sciences,Beijing Advanced Innovation Center for Genomics,and the Tencent Foundation through the XPLORER PRIZE.
文摘Dear Editor,Organisms have evolved mitochondrial stress response pathways to surveil mitochondrial function and activate repair programs upon detection of mitochondrial dysfunction[1].Failure to respond to mitochondrial perturbation has been implicated in aging and age-related diseases[2,3].Mitochondrial perturbation in mammals primarily activates the integrated stress response(ISR).
基金P.C.H.was supported in part by the Helmut Horten Foundation,the Anna Fuller Grant,the Cancer Research Institute Llyod J.OLD STAR Investigator award,the Melanoma Research Alliance Established Investigator Award,Ludwig Cancer Research,and the University of Lausanne.
文摘Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and the aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how the metabolic program in T cells is influenced by the aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring the metabolic programming of immune cells.
文摘A multitude of bioactive compounds are produced by the gut microbiota,including metabolites with notable antimicrobial or immunomodulatory effects.Perhaps the most compelling of these compounds,however,are the ones with the potential to affect human mood and behavior.In an article published recently in Cell,McCurry et al.demonstrated that human gut bacteria are capable of producing neuroactive steroids,including a drug clinically approved by the United States Food and Drug Administration(FDA)for the treatment of postpartum depression.
基金funded by NIH R01DK125260AHA 23IPA1042031(K.J.S.)NIH DK124265 and DK136526(J.Z.L.).
文摘The endocrine system is a fundamental type of long-range cell-cell communication that is important for maintaining metabolism,physiology,and other aspects of organismal homeostasis.Endocrine signaling is mediated by diverse blood-borne ligands,also called hormones,including metabolites,lipids,steroids,peptides,and proteins.The size and structure of these hormones are fine-tuned to make them bioactive,responsive,and adaptable to meet the demands of changing environments.Why has nature selected such diverse ligand types to mediate communication in the endocrine system?What is the chemical,signaling,or physiologic logic of these ligands?What fundamental principles from our knowledge of endocrine communication can be applied as we continue as a field to uncover additional new circulating molecules that are claimed to mediate long-range cell and tissue crosstalk?This review provides a framework based on the biochemical logic behind this crosstalk with respect to their chemistry,temporal regulation in physiology,specificity,signaling actions,and evolutionary development.
基金Research in the authors’laboratory has been supported by the University of Texas MD Anderson Cancer Center,National Institutes of Health grants R01CA181196,R01CA244144,R01CA247992,R01CA269646,and U54CA274220Cancer Prevention&Research Institute of Texas grant RP230072(to B.G.)Cancer Center Support(Core)Grant P30 CA016672 from The National Cancer Institute(to the University of Texas MD Anderson Cancer Center).
文摘The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application.A recent study published in Molecular Cell has identified hyperoxidized perox-iredoxin 3(PRDX3)as a promising marker for ferroptosis,open-ing up new avenues for monitoring and targeting ferroptosis in disease treatment.
基金supported by the grants to J.G. from the National Basic Research Center of China (T2288101)the Shanghai Clinical Research Center for Interventional Medicine (19MC1910300)+7 种基金the Shanghai Municipal Key Clinical Specialty (shslczdzk01701)the State Key Clinical Specialty Construction Project (YW2021-002)the National Natural Science Foundation of China (81970298)the Clinical Research Special Fund of Zhongshan Hospital Fudan University (2020ZSLC57)2021 Clinical Research Navigation Project of Shanghai Medical College of Fudan Universitythe National Natural Science Foundation of China (82100355)the Shanghai Sailing Program (21YF1406000)the Shanghai Science and Technology Innovation Fund (22S31904900)
文摘Platelet hyperreactivity contributes significantly to thrombosis in acute myocardial infarction and stroke. While antiplatelet drugs are used, residual ischemic risk remains. Intermittent fasting(IF), a dietary pattern characterized by alternating periods of eating and fasting, has shown cardiovascular benefits, but its effect on platelet activation is unclear. This study demonstrates that IF inhibits platelet activation and thrombosis in both patients with coronary artery disease and apolipoprotein E(Apo E) knockout(Apo E-/-) mice, by enhancing intestinal flora production of indole-3-propionic acid(IPA). Mechanistically, elevated IPA in plasma directly attenuates platelet activation by binding to the platelet pregnane X receptor(PXR) and suppressing downstream signaling pathways, including Src/Lyn/Syk and LAT/PLCγ/PKC/Ca2+. Importantly, IF alleviates myocardial and cerebral ischemia/reperfusion injury in Apo E-/-mice. These findings suggest that IF mitigates platelet activation and thrombosis risk in coronary atherosclerosis by enhancing intestinal flora production of IPA, which subsequently activates the platelet PXR-related signaling pathways.
基金supported by a grant from the Natural Sciences and Engineering Research Council of Canada(RGPIN-2024-06088)and China Institute at the University of Alberta.
文摘The balance between intestinal cholesterol absorption and cholesterol synthesis in the liver has remained a puzzling phenomenon for a long time because no study has been able to explain how the consumption of a cholesterol-rich diet impairs cholesterol synthesis in the liver.Recently,a group of researchers uncovered a hormone produced in the intestine without any known function,which they named cholesin,that suppresses sterol regulatory element-binding protein 2(SREBP-2),the master regulator of cholesterol synthesis in the liver.
基金support of the CAMS Innovation Fund for Medical Sciences(CIFMS,2023-I2M-2-010,2024 RC310,and 2024-I2M-TS-033)the Suzhou Municipal Key Laboratory(SZS2023005)+1 种基金Y.X.is supported by the National Key Research and Development Program of China(2021YFA1100700)the CAMS Innovation Fund for Medical Sciences(2024-I2M-ZH-015).
文摘Circadian rhythms are fundamental regulators of physiological processes, including immune function. Recent insights uncover that not only lymphocytes but also myeloid cells possess intrinsic circadian clocks that govern their behavior and function. Emerging evidence highlights how circadian regulation of metabolism critically shapes the inflammatory and tissue-repair functions of myeloid subsets. Furthermore, mitochondrial dynamics, a key metabolic feature, are under circadian control and influence antigen presentation and effector functions. Here, we review the interplay between circadian clocks, metabolism, and myeloid immunity, discussing their therapeutic opportunities for optimizing vaccination, infection management, and immunotherapy.
基金supported by grants from the National Science Foundation of China(32271354 to L.Y.)the National Key R&D Program of China(2022YFA1305200 to L.Y.)+3 种基金the Non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2021-RC350-008 to L.W.)the Talent Plan of Shanghai Branch-Chinese Academy of Sciences(CASSHB-QNPD-2023-011 to L.Y.)the State Key Laboratory Special Fund(2060204 to L.W.)the Beijing Natural Science Foundation(Z240014 to L.W.)。
文摘Diet interventions such as calorie restriction or time-restricted feeding offer potential for weight management,but long-term success is often hindered by poor adherence due to the rewarding effects of sugars.In this study,we demonstrate that sulfur amino acid restriction(SAAR)diets promote rapid fat loss without impairing appetite and physiological locomotion,outperforming diets with restricted branched-chain amino acids.Weekly cycling of SAAR diets preserves metabolic benefits,such as reduced fat mass and improved glucose sensitivity.Metabolic analysis and in vivo isotope tracing revealed a shift toward carbohydrate oxidation in white and brown adipose tissue(WAT and BAT),and liver during the SAAR diet refeeding state,leading to decreased de novo lipogenesis.Enhanced lipolysis and fatty acid oxidation were observed in the heart,brain,BAT,lungs,etc.The reintroduction of methionine or cystine negated these metabolic benefits.Further 13C and 2H tracing experiments indicated that cystine,rather than its derivatives like taurine or H2S,directly regulates adiposity.In a high-fat diet model,SAAR diet led to sustained fat mass reduction,regardless of the timing of intervention.Additionally,cystine levels correlated positively with body mass index(BMI)and total triglycerides in diabetic patients.Our findings highlight SAAR diet as a promising strategy for long-term weight control by modulating systemic glucose and lipid metabolism homeostasis.
基金This work was supported by the National Key R&D Program of China(2020YFA0803601)the National Natural Science Foundation of China(32125022 and 32101046)the China Postdoctoral Science Foundation(2019M661348 and 2020T130115).
文摘Brown adipose tissue(BAT)plays a key role in thermogenesis during acute cold exposure.However,it remains unclear how BAT is prepared to rapidly turn on thermogenic genes.Here,we show that damage-specific DNA binding protein 1(DDB1)mediates the rapid transcription of thermogenic genes upon acute cold exposure.Adipose-or BAT-specific Ddb1 knockout mice show severely whitened BAT and significantly decreased expression of thermogenic genes.These mice develop hypothermia when subjected to acute cold exposure at 4℃ and partial lipodystrophy on a high-fat diet due to deficiency in fatty acid oxidation.Mechanistically,DDB1 binds the promoters of Ucp1 and Ppargc1a and recruits positive transcriptional elongation factor b(P-TEFb)to release promoter-proximally paused RNA polymerase II(Pol II),thereby enabling rapid and synchronized transcription of thermogenic genes upon acute cold exposure.Our findings have thus provided a regulatory mechanism of how BAT is prepared to respond to acute cold challenge.
基金supported by the National Natural Science Foundation of China(20211310041)the Beijing Municipal Natural Science Foundation(7244333)+1 种基金the Beijing Hospitals Authority’s Ascent Plan(DFL20241201)the Natural Science Foundation of Henan Province(232300421039).
文摘Nucleosomes are the fundamental unit of chromatin.Chromatin remodeler plays a crucial role in the regulation of gene expression in eukaryotes.It is involved in important physiological processes,such as development,immune response,and metabolic regulation.During gene expression regulation,chromatin remodelers slide nucleosomes along genomic DNA and play a major role in chromatin organization.Chd1 senses the extranucleosomal linker DNA and controls nucleosome spacing in cells.However,the mechanism of linker DNA sensing by Chd1 is not completely understood.Here,we report the cryo-electron microscope(cryoEM)structures of Chd1 engaging nucleosomes in different states.Chd1 induces two exit-DNA conformations,either fully wrapped or partially unwrapped states.Notably,in the unwrapped conformation,the exit DNA interacts with a positively charged loop of the motor,named the exit-DNA binding loop,and traps Chd1 in the closed state in the ATPase cycle,suggesting attenuation of its remodeling activity.Explored single-molecule fluorescence resonance energy transfer(smFRET)and biochemical data supported the regulation of Chd1 remodeling activity by the exit-DNA conformations,which is important for the linker DNA sensitivity.Mutants of the Chd1 exit-DNA binding loop compromised nucleosome organization in yeast cells.Together,our findings provide valuable insights into Chd1 regulation by exit DNA unwrapping.These results provide a new perspective for the study of cell development and metabolism.
基金This work was financially supported by grants from the National Natural Science Foundation of China(NSFC:92057205 and 32150710518 to S.X.H.,and 82203511 to Y.W.)Greater Bay Area Institute of Precision Medicine(Guangzhou),Fudan University,China.
文摘Tumor immunotherapy has achieved breakthroughs in a variety of tumors. However, the systemic absence of T cells in tumors and immunosuppressive tumor microenvironment so far limits the efficacy of immunotherapy to a small population of patients. Therefore, novel agents to increase T-cell tumor infiltration are urgently needed in the clinic. We recently found that inhibition of the ADP-ribosylation factor 1 (Arf1)-mediated lipid metabolism not only kills cancer stem cells (CSCs) but also elicits an anti-tumor immune response. In this study, we revealed a mechanism that targeting Arf1 promotes the infiltration of cytotoxic T lymphocytes (CTLs) into tumors through the C-C chemokine ligand 5 (CCL5)- C-C chemokine receptor type 5 (CCR5) pathway. We found that blockage of Arf1 induces the production of the unsaturated fatty acid (PE 18:1) that binds and sequestrates peroxisome proliferator- activated receptor-γ (PPARγ) from the PPARγ-nuclear factor-κB (NF-κB) cytoplasmic complex. The released NF-κB was then phospho-rylated and translocated into the nucleus to regulate the transcription of chemokine CCL5. CCL5 promoted infiltration of CTLs for tumor regression. Furthermore, the combination of the Arf1 inhibitor and programmed cell death protein 1 (PD-1) blockade induced an even stronger anti-tumor immunity. Therefore, targeting Arf1 represents a novel anti-tumor immune approach by provoking T-cell tumor infiltration and may provide a new strategy for tumor immunotherapy.
文摘This is a correction to:Mengqi Li,Xiaoyan Wei,Jinye Xiong,Jin-Wei Feng,Chen-Song Zhang,Sheng-Cai Lin,Hierarchical inhibition of mTORC1 by glucose starvation-triggered AXIN lysosomal translocation and by AMPK,Life Metabolism,Volume 2,Issue 3,June 2023,https://doi.org/10.1093/lifemeta/load005.
基金This work was supported by the Major Program of the National Natural Science Foundation of China(31790411 to Q.J.)The Local Innovative and Research Teams Project of Guangdong Province(2019BT02N630 to G.S.)+1 种基金Guangdong Laboratory for Lingnan Modern Agricultural Project(NZ2021028)National Natural Science Foundation of China(31972636 to S.W.).
文摘In response to contraction during exercise,skeletal muscle growth and metabolism are dynamically regulated by nerve action,blood flow,and metabolic feedback.α-Ketoglutarate(AKG),a bioactive intermediate in the tricarboxylic acid cycle released during exercise,has been shown to promote skeletal muscle hypertrophy.However,the underlying mechanism of AKG in regulating skeletal muscle development and metabolism is still less known.2-Oxoglutarate receptor 1(OXGR1),the endogenous AKG receptor,is found to be distributed in the vascular smooth muscle(VSM)of skeletal muscles.OXGR1 knockout results in skeletal muscle atrophy,accompanied by decreased expression of myosin heavy chain I(MyHC I),capillary density,and endurance exercise capacity.Furthermore,the study found that dietary AKG supplementation increased mice endurance exercise distance,MyHC I/MyHC IIb ratio,arteriole,and capillary densities in skeletal muscle.Meanwhile,acute AKG administration gradually increased the blood flow in the lower limbs.Further,by using OXGR1 global knockout and OXGR1 VSM-specific(MYH11-Cre×OXGR1-FloxP)knockdown models,we found that OXGR1 in VSM is essential for AKG-induced improvement of skeletal muscle performances.According to the in vitro study,AKG expanded the cell area in VSM with a decreased intracellular pH by OXGR1.Our results demonstrated a novel role of AKG/OXGR1 in VSM of skeletal muscle to regulate blood flow and then enhance slow muscle fiber conversion and capillarization.These findings provide a theoretical basis for the AKG/OXGR1 signaling pathway to maintain human muscle function and improve meat production and livestock and poultry meat quality.
文摘Breast cancer metastasis remains the leading cause of mortality in patients,yet its mechanisms are poorly understood.A recent Cell paper highlights the pivotal role of the proprotein convertase subtilisin/kexin type 9(PCSK9)V474I germline variant in driving metastatic progression through suppression of the low-density lipoprotein receptor-related protein 1(LRP1)receptor,revealing novel therapeutic opportunities and genetic insights.
