Improving salt tolerance and mitigating senescence in the presence of high salinity are crucial for sustaining agricultural productivity.Previous research has demonstrated that hydrogen peroxide(H_(2)O_(2)),specifical...Improving salt tolerance and mitigating senescence in the presence of high salinity are crucial for sustaining agricultural productivity.Previous research has demonstrated that hydrogen peroxide(H_(2)O_(2)),specifically H_(2)O_(2)derived from roots and mediated by the respiratory burst oxidase homolog(NADPH),plays a significant role in regulating ion and plant hormone homeostasis in glycophytic plants,such as Arabidopsis.However,the extent to which root-derived H_(2)O_(2)fulfils similar functions in halophytic plants remains uncertain.Therefore,our study aimed to explore the potential contribution of root-sourced H_(2)O_(2)in delaying leaf senescence induced by high salinity,utilizing seashore paspalum as a model halophytic plant.The application of the NADPH-oxidase inhibitor DPI,coupled with a series of leaf senescence analyses,we revealed that root-derived H_(2)O_(2)significantly retards salt-induced leaf senescence.Furthermore,through the application of hormone analysis,lipidomics,ionomics,Non-invasive Micro-test Technology(NMT),and transcriptomics,we established that NADPH-dependent H_(2)O_(2)induced by salt stress in the roots was indispensable for maintaining the balance of the aging hormone,jasmonic acid(JA),and sodium ion homeostasis within this halophytic plant.Finally,by utilizing AtrbohD Arabidopsis mutants and virus-induced gene silencing(VIGs)in Paspalum vaginatum,we demonstrated the pivotal role played by root-sourced H_(2)O_(2)in upholding JA homeostasis and regulating JA-triggered leaf senescence in P.vaginatum.This study offers novel insights into the mechanisms that govern plant leaf senescence and its response to salinity-induced stress.展开更多
The muscular system plays a critical role in the human body by governing skeletal movement,cardiovascular function,and the activities of digestive organs.Additionally,muscle tissues serve an endocrine function by secr...The muscular system plays a critical role in the human body by governing skeletal movement,cardiovascular function,and the activities of digestive organs.Additionally,muscle tissues serve an endocrine function by secreting myogenic cytokines,thereby regulating metabolism throughout the entire body.Maintaining muscle function requires iron homeostasis.Recent studies suggest that disruptions in iron metabolism and ferroptosis,a form of iron-dependent cell death,are essential contributors to the progression of a wide range of muscle diseases and disorders,including sarcopenia,cardiomyopathy,and amyotrophic lateral sclerosis.Thus,a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention.This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury,as well as associated muscle diseases and disorders.Moreover,we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders.Finally,we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.展开更多
Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was dimini...Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was diminished in the bone of aged and ovariectomized(OVX)mice,as well as in the serum of osteopenia and osteoporosis patients.In vitro loss-of-function and gain-offunction studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells.In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice.Mechanistically,NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1(Fn1).Moreover,we found that NELL2 activated the focal adhesion kinase(FAK)/AKT signaling pathway through Fn1/integrinβ1(ITGB1),leading to the promotion of osteogenesis and the inhibition of adipogenesis.Notably,administration of NELL2-AAV was found to ameliorate bone loss in OVX mice.These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis,suggesting its potential as a therapeutic target for managing osteoporosis.展开更多
Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is...Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.展开更多
Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and ...Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.展开更多
Microbes play a critical role in shaping immune development,with growing interest in how rhinovirus(RV)interacts with the host immune system,particularly in individuals with asthma and chronic obstructive pul-monary d...Microbes play a critical role in shaping immune development,with growing interest in how rhinovirus(RV)interacts with the host immune system,particularly in individuals with asthma and chronic obstructive pul-monary disease(COPD).Disruptions in microbial balance during RV infections can impair immune homeostasis and worsen disease outcomes.Recent studies emphasize RV-induced regulation of antiviral defenses,cytokine production,and immune tolerance.This review explores the interplay between RV,the immune system,and microbiota,highlighting the importance of these interactions in guiding effective therapies for respiratory in-fections.It advances existing literature by considering microbiota-mediated therapies as a novel approach to managing RV exacerbations in respiratory diseases like asthma and COPD.展开更多
Bone repair and regeneration is a complex spatiotemporal process recruiting a variety of cell types,which need to precisely mediated for effective healing post-damage.The concept of osteoimmunology emphasizes the exte...Bone repair and regeneration is a complex spatiotemporal process recruiting a variety of cell types,which need to precisely mediated for effective healing post-damage.The concept of osteoimmunology emphasizes the extensive and intricate crosstalk between the bone and the immune system.Despite the significant advancements in understanding osteoimmunology,the precise role of dendritic cells(DCs)in this field remains under investigation.As key antigen-presenting cells,DCs are critical in orchestrating adaptive immune responses and maintaining tissue homeostasis.Recent researches have further revealed the potential of DCs to influence the development or acceleration of inflammatory and autoimmune bone disease,as well as their interaction with skeletal cells in the context of bone repair and regeneration.展开更多
The Chinese seabass(Lateolabrax maculatus)is one of the most popular and valuable aquaculture species in China.Recently,the disease caused by Vibrio anguillarum has brought huge economic losses in the L.maculatus indu...The Chinese seabass(Lateolabrax maculatus)is one of the most popular and valuable aquaculture species in China.Recently,the disease caused by Vibrio anguillarum has brought huge economic losses in the L.maculatus industry.However,the immune response of L.maculatus after V.anguillarum infection remains unknown.In this study,the blood homeostasis,gut microbiota and transcriptomic profiling of L.maculatus after V.anguillarum infection were investigated.Our results indicated that the levels of superoxide dismutase(SOD),alanine aminotransferase(ALT)and total bilirubin(TBIL)increased,while the levels of blood glucose(BG),total protein(TP)and albumin(ALB)decreased after V.anguillarum infection.The analysis of the gut microbiota composition revealed that the dominant phyla was Firmicutes and Proteobacteria,and the relative abundance of genus Vibrio increased after V.anguillarum infection.Subsequently,the differentially expressed genes(DEGs)in the kidney and spleen after V.anguillarum infection were analyzed by transcriptome sequencing.The results indicated that immunity-related genes like TLR5,TLR8,TLR9,IL-1β,CCL3,IFNγ,CXCL11 and TNFαwere affected and the NOD-like receptor signaling pathway,cytokine-cytokine receptor interaction and Toll-like receptor signaling were activated.Thus,an effective immune and pro-flammatory response can help resist V.anguillarum infection.Our results provide a theoretical support for improving the disease resistance ability of L.maculatus.展开更多
Acrylamide is classified as a Class 2A carcinogen and mainly metabolized to produce hepatotoxicity.Phosphatidylcholine is thought to protect the liver from damage,but the protective role of phosphatidylcholine on acry...Acrylamide is classified as a Class 2A carcinogen and mainly metabolized to produce hepatotoxicity.Phosphatidylcholine is thought to protect the liver from damage,but the protective role of phosphatidylcholine on acrylamide-exposed metabolic disorders remains unclear.We investigated protective effect of phosphatidylcholine on the hepatic metabolism in rats exposed to acrylamide using metabolomics and molecular biology approaches.Overall,32 endogenous effect biomarkers and 4 exposure biomarkers were identified as differential signature metabolites responsible for acrylamide exposure and phosphatidylcholine protection.Acrylamide exposure interferes with glutathione metabolism by consuming antioxidant glutathione,cysteine and L-ascorbic acid,and disrupts lipid and carbohydrate metabolism through reducing carnitine content and increasing lipid peroxidation.The phosphatidylcholine treatment reduces the expression of cytochrome P4502E1,alleviates the oxidative stress and inflammation of the liver,and stabilizes the content of glutathione,and thus alleviates the disorder of glutathione.Meanwhile,phosphatidylcholine shifted acrylamide-induced phosphatidylcholine into lysophosphatidylcholine to storage from lysophosphatidylcholine to diacylglycerol,thereby maintaining metabolic homeostasis of glycerophospholipid.The results suggested that phosphatidylcholine supplementation alleviate the disorder of glutathione and lipid metabolism caused by acrylamide exposure,but not significantly change the levels of mercapturic acid adducts of acrylamide,providing the evidence for phosphatidylcholine protection against acrylamide-induced liver injury.展开更多
Soil salinity hampers plant performance.Elevated atmospheric CO_(2)(e[CO_(2)])could alleviate the detrimental effect of salinity on plants but whether abscisic acid(ABA)is involved in this process is unclear.To addres...Soil salinity hampers plant performance.Elevated atmospheric CO_(2)(e[CO_(2)])could alleviate the detrimental effect of salinity on plants but whether abscisic acid(ABA)is involved in this process is unclear.To address this issue,three tomato(Solanum lycopersicum)genotypes with varying endogenous ABA concentrations(wild-type AC,ABA-deficient mutant flacca and ABA-overproduction line SP5)were grown in pots under ambient(400μmol·mol^(-1))or elevated(800μmol·mol^(-1))CO_(2)with or without the addition of 100 mmol·L-1sodium chloride(NaCl).The results showed that e[CO_(2)]favored ion homeostasis by decreasing root-to-shoot delivery of Na^(+),which was mainly attributed to lowered transpiration rate rather than altered xylem-sap Na^(+)concentration.In AC and SP5,the low transpiration rate of e[CO_(2)]-plants under salinity was accompanied by enhanced endogenous ABA levels,which might play a role in upregulating the abundance of specific transcripts related to Na^(+)homeostasis(i.e.,SALT OVERLY SENSITIVE)under salt stress.In flacca,e[CO_(2)]-induced Na^(+)homeostasis was abolished,which could be ascribed to the low and unaltered ABA levels,albeit the ethylene biosynthesis was enhanced in flacca under salt stress,indicating an antagonistic relationship between ABA and ethylene.Furthermore,e[CO_(2)]inhibited ethylene biosynthesis under salt stress in all three genotypes.The results enrich our comprehension of the fundamental processes of e[CO_(2)]-conferred salt tolerance in tomato.展开更多
The SH2 domain-containing protein tyrosine phosphatase 2(SHP2,also known as PTP2C),encoded by PTPN11,is ubiquitously expressed and has context-specific effects.It promotes RAS/MAPK signaling downstream of receptor tyr...The SH2 domain-containing protein tyrosine phosphatase 2(SHP2,also known as PTP2C),encoded by PTPN11,is ubiquitously expressed and has context-specific effects.It promotes RAS/MAPK signaling downstream of receptor tyrosine kinases,cytokine receptors,and extracellular matrix proteins,and was shown in various lineages to modulate cell survival,proliferation,differentiation,and migration.Over the past decade,PTPN11 inactivation in chondrocytes was found to cause metachondromatosis,a rare disorder characterized by multiple enchondromas and osteochondroma-like lesions.Moreover,SHP2 inhibition was found to mitigate osteoarthritis pathogenesis in mice,and abundant but incomplete evidence suggests that SHP2 is crucial for cartilage development and adult homeostasis,during which its expression and activity are tightly regulated transcriptionally and posttranslationally,and by varying sets of functional partners.Fully uncovering SHP2 actions and regulation in chondrocytes is thus fundamental to understanding the mechanisms underlying both rare and common cartilage diseases and to designing effective disease treatments.We here review current knowledge,highlight recent discoveries and controversies,and propose new research directions to answer remaining questions.展开更多
Neurodegenerative diseases are prevalent conditions that greatly impact human health.These diseases are primarily characterized by the progressive loss and eventual death of neuronal function,although the precise mech...Neurodegenerative diseases are prevalent conditions that greatly impact human health.These diseases are primarily characterized by the progressive loss and eventual death of neuronal function,although the precise mechanisms underlying these processes remain incompletely understood.Iron is an essential trace element in the human body,playing a crucial role in various biological processes.The maintenance of iron homeostasis relies on the body's intricate and nuanced regulatory mechanisms.In recent years,considerable attention has been directed toward the relationship between dysregulated iron homeostasis and neurodegenerative diseases.The regulation of iron homeostasis within cells is crucial for maintaining proper nervous system function.Research has already revealed that disruptions in iron homeostasis may lead to ferroptosis and oxidative stress,which,in turn,can impact neuronal health and contribute to the development of neurodegenerative diseases.This article primarily explores the intimate relationship between iron homeostasis and neurodegenerative diseases,aiming to provide novel insights and strategies for treating these debilitating conditions.展开更多
Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Ret...Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.展开更多
Previous studies have reported a relationship between exposure to metals and polycyclic aromatic hydrocarbons(PAHs)and blood glucose levels,but whether the mechanisms are mediated by amino acids remains to be elucidat...Previous studies have reported a relationship between exposure to metals and polycyclic aromatic hydrocarbons(PAHs)and blood glucose levels,but whether the mechanisms are mediated by amino acids remains to be elucidated.We conducted a three-wave repeated measurement study involving 201 elderly individuals(aged≥50 years)from five communities in Beijing,China.We simultaneously measured eightmetals in both blood and urine,six monohydroxy PAHs in urine,and 23 amino acids in blood.Linear mixed-effects and sparse partial least squares models were used to evaluate the individual effects,and Bayesian kernel machine regression was employed to mixture effects.Mediation analysis was further used to explore whether amino acids mediators mediate the association.We observed significant associations of selenium and strontium with increased blood glucose.Additionally,blood copper,urinary nickel,as well as urinary 1+9 hydroxyphenanthrene,were associated with irregular blood glucose regulation.Moreover,we found that amino acids such as leucine,proline,and alanine may mediate the associations.This study is the first to investigate the effect of metals and PAHs on blood glucose homeostasis,while also exploring the mediating role of amino acids,offering new insights into the impact of metals and PAHs on blood glucose regulation.展开更多
The skeleton is innervated by different types of nerves and receives signaling from the nervous system to maintain homeostasis and facilitate regeneration or repair.Although the role of peripheral nerves and signals i...The skeleton is innervated by different types of nerves and receives signaling from the nervous system to maintain homeostasis and facilitate regeneration or repair.Although the role of peripheral nerves and signals in regulating bone homeostasis has been extensively investigated,the intimate relationship between the central nervous system and bone remains less understood,yet it has emerged as a hot topic in the bone field.In this review,we discussed clinical observations and animal studies that elucidate the connection between the nervous system and bone metabolism,either intact or after injury.First,we explored mechanistic studies linking specific brain nuclei with bone homeostasis,including the ventromedial hypothalamus,arcuate nucleus,paraventricular hypothalamic nucleus,amygdala,and locus coeruleus.We then focused on the characteristics of bone innervation and nerve subtypes,such as sensory,sympathetic,and parasympathetic nerves.Moreover,we summarized the molecular features and regulatory functions of these nerves.Finally,we included available translational approaches that utilize nerve function to improve bone homeostasis and promote bone regeneration.Therefore,considering the nervous system within the context of neuromusculoskeletal interactions can deepen our understanding of skeletal homeostasis and repair process,ultimately benefiting future clinical translation.展开更多
Polyamines(putrescine,spermidine,and spermine)are aliphatic compounds ubiquitous in prokaryotes and eukaryotes.Positively charged polyamines bind to negatively charged macromolecules,such as nucleic acids and acidic p...Polyamines(putrescine,spermidine,and spermine)are aliphatic compounds ubiquitous in prokaryotes and eukaryotes.Positively charged polyamines bind to negatively charged macromolecules,such as nucleic acids and acidic phospholipids,and are involved in physiological activities including cell proliferation,differentiation,apoptosis and gene regulation.Intracellular polyamine levels are regulated by biosynthesis,catabolism and transport.Polyamines in the body originate from two primary sources:dietary intake and intestinal microbial metabolism.These polyamines are then transported into the bloodstream,through which they are distributed to various tissues and organs to exert their biological functions.Polyamines synthesized by intestinal microorganisms serve dual critical roles.First,they are essential for maintaining polyamine concentrations within the digestive tract.Second,through transcriptional and post-transcriptional mechanisms,these microbial-derived polyamines modulate the expression of genes governing key processes in intestinal epithelial cells-including proliferation,migration,apoptosis,and cell-cell interactions.Collectively,these regulatory effects help maintain intestinal epithelial homeostasis and ensure the integrity of the gut barrier.In addition,polyamines interact with the gut microbiota to maintain intestinal homeostasis by promoting microbial growth,biofilm formation,swarming,and endocytosis vesicle production,etc.Supplementation with polyamines has been demonstrated to be important in regulating host intestinal microbial composition,enhancing nutrient absorption,and improving metabolism and immunity.In this review,we will focus on recent advances in the study of polyamine metabolism and transport in intestinal microbes and intestinal epithelial cells.We then summarize the scientific understanding of their roles in intestinal homeostasis,exploring the advances in cellular and molecular mechanisms of polyamines and their potential clinical applications,and providing a rationale for polyamine metabolism as an important target for the treatment of intestinal-based diseases.展开更多
The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive.Using conditional gene knockout mouse models,we demonstrated that loss of Beclin 1(B...The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive.Using conditional gene knockout mouse models,we demonstrated that loss of Beclin 1(Becn1),a major regulator of mammalian autophagy,exclusively in the megakaryocytic lineage disrupted autophagy in platelets but did not compromise megakaryopoiesis or the formation and function of platelets.Unexpectedly,conditional Becn1 deletion in male mice led to a remarkable increase in bone mass with improved bone quality,in association with a decrease in sex hormone binding globulin(SHBG)and an increase in free testosterone(FT).In vivo Becn1 overexpression in megakaryocytic lineage-specific cells reduced bone mass and quality,along with an increase in SHBG and a decrease in FT.Transplantation of wild-type bone marrow cells into megakaryocytic lineage Becn1-deficient male mice restored bone mass and normalized SHBG and FT.Furthermore,bilateral orchiectomy of Becn1^(f/f);Pf4-iCre mice,which are crippled with the production of testosterone,resulted in a reduction in bone mass and quality,whereas in vivo overexpression of SHBG,specifically in the liver of Becn1^(f/f);Pf4-iCre mice,decreased FT and reduced bone mass and quality.In addition,metformin treatment,which induces SHBG expression,reduced FT and normalized bone mass in Becn1^(f/f);Pf4-iCre mice.We thus concluded that Becn1 of the megakaryocytic lineage is dispensable locally for platelet hemostasis but limits bone mass by increasing SHBG,which in turn reduces the FT of male mice.Our findings highlight a mechanism by which Becn1 from megakaryocytic lineage cells distally balances bone growth.展开更多
Background:Tongyang Huoxue Decoction(TYHX)can modulate calcium homeostasis andmitochondrial quality management to safeguard sinus node function.Nonetheless,theprecise chemical process remains unclear.This study aimed ...Background:Tongyang Huoxue Decoction(TYHX)can modulate calcium homeostasis andmitochondrial quality management to safeguard sinus node function.Nonetheless,theprecise chemical process remains unclear.This study aimed to verify the upstreamregulatory influence of SERCA2a on the enhancement of calcium homeostasis andmitochondrial unfolded protein response(mtUPR)in sinus node cells(SANCs)by TYHX,while elucidating the protective mechanism of TYHX on SNC activity.Methods:In vitromodels of sh/ad-SERCA2a and si-β-tubulin were established,and TYHX was employed tointervene in each cell group.Various approaches were employed to detect functionsincluding mitochondrial membrane potential,mitochondrial respiration,oxidative stress,mitochondrial biosynthesis,and mitochondrial autophagy and UPR.In vivo confirmationthat TYHX suppresses apoptosis and inflammatory injury.Results:I/R injury led todiminished SANCs activity,compromised mitochondrial membrane potential,reducedmitochondrial respiratory function,and heightened oxidative stress.This further impededmitochondrial production,destabilized the proteome structure,triggered the mtUPR,andinhibited mitochondrial autophagy,thereby upsetting the dynamic equilibrium of themitochondrial quality control network.Furthermore,I/R injury intensified intracellularcalcium excess and worsened oxidative stress damage.Conversely,TYHX interventionmitigated intracellular calcium overload,augmented mitochondrial antioxidant capacity,stimulated mitochondrial autophagy,and decreased the mtUPR.Sh-SERCA2a counteractedthe regulatory influences of TYHX on calcium homeostasis,mitochondrial biogenesis,mtUPR,mitochondrial autophagy,and apoptosis.Conversely,ad-SERCA2a exerted minimalinfluence on the efficacy of TYHX.SERCA2a is a major target protein for TYHX todemonstrate its efficacy.When tubulin expression was minimal,there was no statisticallysignificant difference in the expression levels of mitochondrial autophagy,mitochondrialbiosynthesis,calcium homeostasis regulation,and mtUPR between the sh-SERCA2a andad-SERCA2a groups.This indicates that the normal expression of tubulin is essential forSERCA2a to enhance the efficiency of TYHX.Tubulin may serve as an upstream regulatorymolecule of SERCA2a.In vivo tests confirmed that TYHX may suppress apoptosis andmitigate cellular inflammatory damage.Conclusion:TYHX preserved intracellular calciumequilibrium,mitigated mitochondrial oxidative stress,sustained mitochondrial stability,enhanced mitochondrial biosynthesis,suppressed the mtUPR,facilitated mitochondrialautophagy,and inhibited apoptosis viaβ-tubulin-SERCA2a,thereby safeguarding sinus nodefunctionality from I/R injury.展开更多
Adult neurogenesis is a highly dynamic process that leads to the production of new neurons from a population of quiescent neural stem cells(NSCs).In response to specific endogenous and/or external stimuli,NSCs enter a...Adult neurogenesis is a highly dynamic process that leads to the production of new neurons from a population of quiescent neural stem cells(NSCs).In response to specific endogenous and/or external stimuli,NSCs enter a state of mitotic activation,initiating proliferation and differentiation pathways.Throughout this process,NSCs give rise to neural progenitors,which undergo multiple replicative and differentiative steps,each governed by precise molecular pathways that coordinate cellular changes and signals from the surrounding neurogenic niche.展开更多
Background Despite growing concerns about the adverse effects of antibiotics in farm animals,there has been little investigation of the effects of florfenicol in laying hens.This study examined the effect of florfenic...Background Despite growing concerns about the adverse effects of antibiotics in farm animals,there has been little investigation of the effects of florfenicol in laying hens.This study examined the effect of florfenicol on the intestinal homeostasis,immune system,and pathogen susceptibility of laying hens.Results The oral administration of florfenicol at field-relevant levels for 5 d resulted in a decrease in the gut microbiota genera Lactobacillus,Bacillus,and Bacteroides,indicating the development of intestinal dysbiosis.The dysbiosis led to decreased mRNA levels of key regulators peroxisome proliferator-activated receptor gamma(PPAR-γ)and hypoxia-inducible factor-1α(HIF-1α),compromising intestinal hypoxia.Intestinal homeostasis was also disrupted,with decreased expression of Occludin and Mucin 2(Muc2)genes combined with increased gut epithelial permeability.The breakdown in intestinal homeostasis and immune function provided a favorable environment for opportunistic bacteria like avian pathogenic Escherichia coli(APEC),culminating in systemic infection.Immunologically,florfenicol treatment resulted in increased proportion and absolute number of MRC1L-B^(+)monocytes/macrophages in the spleen,indicating an exacerbated infection.Furthermore,both the proportion and absolute number ofγδT cells in the lamina propria of the cecum decreased.Treatment with florfenicol reduced butyrate levels in the cecum.However,the administration of butyrate before and during florfenicol treatment restored factors associated with intestinal homeostasis,including PPAR-γ,Occludin,and Muc2,while partially restoring HIF-1α,normalized intestinal hypoxia and gut permeability,and reversed immune cell changes,suppressing APEC systemic infection.Conclusion The uncontrolled and widespread use of florfenicol can negatively affect intestinal health in chickens.Specifically,florfenicol was found to impair intestinal homeostasis and immune function in laying hens,including by reducing butyrate levels,thereby increasing their susceptibility to systemic APEC infection.The development of strategies for mitigating the adverse effects of florfenicol on gut health and pathogen susceptibility in laying hens is therefore essential.展开更多
基金supported by the Project funded by the Natural Science Foundation of Hainan Province(Grant No.322QN248)the National Natural Science Foundation of China(Grant Nos.32401488,32060409,32371782 and 32460358)+3 种基金the Innovational Fund for Scientific and Technological Personnel of Hainan Province(Grant No.KJRC 2023C21)the Hainan High-level Talents Project(Grant No.321RC475)Collaborative Innovation Center Project of Nanfan and High-Efficiency Tropical Agriculture in Hainan University(XTCX2022NYB08)Collaborative Innovation Center Project of Ecological Civilization in Hainan University(XTCX2022STC10).
文摘Improving salt tolerance and mitigating senescence in the presence of high salinity are crucial for sustaining agricultural productivity.Previous research has demonstrated that hydrogen peroxide(H_(2)O_(2)),specifically H_(2)O_(2)derived from roots and mediated by the respiratory burst oxidase homolog(NADPH),plays a significant role in regulating ion and plant hormone homeostasis in glycophytic plants,such as Arabidopsis.However,the extent to which root-derived H_(2)O_(2)fulfils similar functions in halophytic plants remains uncertain.Therefore,our study aimed to explore the potential contribution of root-sourced H_(2)O_(2)in delaying leaf senescence induced by high salinity,utilizing seashore paspalum as a model halophytic plant.The application of the NADPH-oxidase inhibitor DPI,coupled with a series of leaf senescence analyses,we revealed that root-derived H_(2)O_(2)significantly retards salt-induced leaf senescence.Furthermore,through the application of hormone analysis,lipidomics,ionomics,Non-invasive Micro-test Technology(NMT),and transcriptomics,we established that NADPH-dependent H_(2)O_(2)induced by salt stress in the roots was indispensable for maintaining the balance of the aging hormone,jasmonic acid(JA),and sodium ion homeostasis within this halophytic plant.Finally,by utilizing AtrbohD Arabidopsis mutants and virus-induced gene silencing(VIGs)in Paspalum vaginatum,we demonstrated the pivotal role played by root-sourced H_(2)O_(2)in upholding JA homeostasis and regulating JA-triggered leaf senescence in P.vaginatum.This study offers novel insights into the mechanisms that govern plant leaf senescence and its response to salinity-induced stress.
基金the National Natural Science Foundation of China(82471593 to J.M.32330047 and 31930057 to F.W.+2 种基金and 82071970 to Y.W.and 82072506 to Y.L.)the Science Fund for Distinguished Young Scholars of Hubei Province(2023AFA109 to Y.W.)Hubei Provincial Natural Science Foundation of China(2024AFB963 to Q.R.).
文摘The muscular system plays a critical role in the human body by governing skeletal movement,cardiovascular function,and the activities of digestive organs.Additionally,muscle tissues serve an endocrine function by secreting myogenic cytokines,thereby regulating metabolism throughout the entire body.Maintaining muscle function requires iron homeostasis.Recent studies suggest that disruptions in iron metabolism and ferroptosis,a form of iron-dependent cell death,are essential contributors to the progression of a wide range of muscle diseases and disorders,including sarcopenia,cardiomyopathy,and amyotrophic lateral sclerosis.Thus,a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention.This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury,as well as associated muscle diseases and disorders.Moreover,we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders.Finally,we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
基金supported by grants from National Natural Science Foundation of China(82272444,81972031,81972033)China Postdoctoral Science Foundation(2022M722382)Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-032A)。
文摘Neural EGFL-like 2(NELL2)is a secreted protein known for its regulatory functions in the nervous and reproductive systems,yet its role in bone biology remains unexplored.In this study,we observed that NELL2 was diminished in the bone of aged and ovariectomized(OVX)mice,as well as in the serum of osteopenia and osteoporosis patients.In vitro loss-of-function and gain-offunction studies revealed that NELL2 facilitated osteoblast differentiation and impeded adipocyte differentiation from stromal progenitor cells.In vivo studies further demonstrated that the deletion of NELL2 in preosteoblasts resulted in decreased cancellous bone mass in mice.Mechanistically,NELL2 interacted with the FNI-type domain located at the C-terminus of Fibronectin 1(Fn1).Moreover,we found that NELL2 activated the focal adhesion kinase(FAK)/AKT signaling pathway through Fn1/integrinβ1(ITGB1),leading to the promotion of osteogenesis and the inhibition of adipogenesis.Notably,administration of NELL2-AAV was found to ameliorate bone loss in OVX mice.These findings underscore the significant role of NELL2 in osteoblast differentiation and bone homeostasis,suggesting its potential as a therapeutic target for managing osteoporosis.
基金supported by the Notional Natural Science Foundation of Chino,No.82160690Colloborotive Innovation Center of Chinese Ministry of Education,No.2020-39Science and Technology Foundation of Guizhou Province,No.ZK[2021]-014(all to FZ)。
文摘Copper,one of the most prolific transition metals in the body,is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations.Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins,including copper transporters(CTR1 and CTR2),the two copper ion transporters the Cu-transporting ATPase 1(ATP7A)and Cu-transporting beta(ATP7B),and the three copper chaperones ATOX1,CCS,and COX17.Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue.Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins,including ceruloplasmin and metallothionein,is involved in the pathogenesis of neurodegenerative disorders.However,the exact mechanisms underlying these processes are not known.Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress.Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction.Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation,with elevated levels activating several critical inflammatory pathways.Additionally,copper can bind aberrantly to several neuronal proteins,including alphasynuclein,tau,superoxide dismutase 1,and huntingtin,thereby inducing neurotoxicity and ultimately cell death.This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases,with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis.By synthesizing the current findings on the functions of copper in oxidative stress,neuroinflammation,mitochondrial dysfunction,and protein misfolding,we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders,such as Wilson's disease,Menkes'disease,Alzheimer's disease,Parkinson's disease,amyotrophic lateral sclerosis,Huntington's disease,and multiple sclerosis.Potential clinically significant therapeutic targets,including superoxide dismutase 1,D-penicillamine,and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline,along with their associated therapeutic agents,are further discussed.Ultimately,we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.
基金financially supported by the National Natural Science Foundation of China(3226058782060598)+4 种基金the Scientific Research Program of Guizhou Provincial Department of Education(QJJ[2023]019)the Science&Technology Program of Guizhou Province(QKHPTRC-CXTD[2022]014)the Excellent Youth Talents of Zunyi Medical University(17zy-006)the Innovation and Entrepreneurship Training Program for College Students of China(202210661140)the Innovation and Entrepreneurship Training Program for College Students of Zunyi Medical University(ZYDC2021110).
文摘Ochratoxin A(OTA),a secondary fungal metabolite known for its nephrotoxic effects,is widespread in various foods and animal feeds.Our recent investigation suggests a correlation between OTA-induced nephrotoxicity and sigma-1 receptor(Sig-1R)-mediated mitochondrial apoptosis in human proximal tubule epithelial-originated kidney-2(HK-2)cells.However,the involvement of Sig-1R in OTA-induced nephrotoxicity,encompassing other forms of regulated cell death like ferroptosis,remains unexplored.In this research,cell viability,apoptotic rate,cholesterol levels,mitochondrial glutathione(mGSH)levels,reactive oxygen species(ROS)levels,and protein expressions in HK-2 cells treated with OTA and/or blarcamesine hydrochloride(Anavex 2-73)were evaluated.The results suggest that OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,subsequently promoting sterol regulatory element-binding protein 2,3-hydroxy-3-methylglutaryl-CoA reductase,GRAM domain-containing protein 1B,steroidogenic acute regulatory protein,mitochondrial,78 kDa glucose-regulated protein,CCAAT/enhancer-binding protein homologous protein,cyclophilin D,cleaved-caspase-3,B-cell lymphoma-2-associated X protein,and long-chain fatty acid-CoA ligase 4,inhibiting tumor necrosis factor receptor-associated protein 1,mitochondrial 2-oxoglutarate/malate carrier protein,B-cell lymphoma-2-like protein 1,and glutathione peroxidase 4,reducing mGSH levels,and increasing total cholesterol,mitochondrial cholesterol,and ROS levels.In conclusion,OTA induces mitochondrial apoptosis and ferroptosis by inhibiting Sig-1R,thereby disrupting redox and cholesterol homeostasis in vitro.The regulation of cholesterol homeostasis by Sig-1R and its involvement in OTA-induced mitochondrial apoptosis and ferroptosis are reported here for the first time.
文摘Microbes play a critical role in shaping immune development,with growing interest in how rhinovirus(RV)interacts with the host immune system,particularly in individuals with asthma and chronic obstructive pul-monary disease(COPD).Disruptions in microbial balance during RV infections can impair immune homeostasis and worsen disease outcomes.Recent studies emphasize RV-induced regulation of antiviral defenses,cytokine production,and immune tolerance.This review explores the interplay between RV,the immune system,and microbiota,highlighting the importance of these interactions in guiding effective therapies for respiratory in-fections.It advances existing literature by considering microbiota-mediated therapies as a novel approach to managing RV exacerbations in respiratory diseases like asthma and COPD.
基金supported by the“Pioneer and Leading Goose+X”research and development program of Zhejiang Province Science and Technology Department(2024C03193)the National Natural Science Foundation of China(No.82271026)Start-up Fund of Stomatology Hospital,School of Stomatology,Zhejiang University School of Medicine(2023PDF017).
文摘Bone repair and regeneration is a complex spatiotemporal process recruiting a variety of cell types,which need to precisely mediated for effective healing post-damage.The concept of osteoimmunology emphasizes the extensive and intricate crosstalk between the bone and the immune system.Despite the significant advancements in understanding osteoimmunology,the precise role of dendritic cells(DCs)in this field remains under investigation.As key antigen-presenting cells,DCs are critical in orchestrating adaptive immune responses and maintaining tissue homeostasis.Recent researches have further revealed the potential of DCs to influence the development or acceleration of inflammatory and autoimmune bone disease,as well as their interaction with skeletal cells in the context of bone repair and regeneration.
基金received funding from the Natural Science Foundation of Shandong Province(No.ZR2023MC141)the Innovation and Entrepreneurship Training Program for College Students(No.202210435003)financial support was also provided by the‘First Class Fishery Discipline’Program and the Special Talent Program‘One Thing One Decision(Yishi Yiyi)’in Shandong Province,China。
文摘The Chinese seabass(Lateolabrax maculatus)is one of the most popular and valuable aquaculture species in China.Recently,the disease caused by Vibrio anguillarum has brought huge economic losses in the L.maculatus industry.However,the immune response of L.maculatus after V.anguillarum infection remains unknown.In this study,the blood homeostasis,gut microbiota and transcriptomic profiling of L.maculatus after V.anguillarum infection were investigated.Our results indicated that the levels of superoxide dismutase(SOD),alanine aminotransferase(ALT)and total bilirubin(TBIL)increased,while the levels of blood glucose(BG),total protein(TP)and albumin(ALB)decreased after V.anguillarum infection.The analysis of the gut microbiota composition revealed that the dominant phyla was Firmicutes and Proteobacteria,and the relative abundance of genus Vibrio increased after V.anguillarum infection.Subsequently,the differentially expressed genes(DEGs)in the kidney and spleen after V.anguillarum infection were analyzed by transcriptome sequencing.The results indicated that immunity-related genes like TLR5,TLR8,TLR9,IL-1β,CCL3,IFNγ,CXCL11 and TNFαwere affected and the NOD-like receptor signaling pathway,cytokine-cytokine receptor interaction and Toll-like receptor signaling were activated.Thus,an effective immune and pro-flammatory response can help resist V.anguillarum infection.Our results provide a theoretical support for improving the disease resistance ability of L.maculatus.
基金supported by the National Natural Science Foundation of China(21976156)。
文摘Acrylamide is classified as a Class 2A carcinogen and mainly metabolized to produce hepatotoxicity.Phosphatidylcholine is thought to protect the liver from damage,but the protective role of phosphatidylcholine on acrylamide-exposed metabolic disorders remains unclear.We investigated protective effect of phosphatidylcholine on the hepatic metabolism in rats exposed to acrylamide using metabolomics and molecular biology approaches.Overall,32 endogenous effect biomarkers and 4 exposure biomarkers were identified as differential signature metabolites responsible for acrylamide exposure and phosphatidylcholine protection.Acrylamide exposure interferes with glutathione metabolism by consuming antioxidant glutathione,cysteine and L-ascorbic acid,and disrupts lipid and carbohydrate metabolism through reducing carnitine content and increasing lipid peroxidation.The phosphatidylcholine treatment reduces the expression of cytochrome P4502E1,alleviates the oxidative stress and inflammation of the liver,and stabilizes the content of glutathione,and thus alleviates the disorder of glutathione.Meanwhile,phosphatidylcholine shifted acrylamide-induced phosphatidylcholine into lysophosphatidylcholine to storage from lysophosphatidylcholine to diacylglycerol,thereby maintaining metabolic homeostasis of glycerophospholipid.The results suggested that phosphatidylcholine supplementation alleviate the disorder of glutathione and lipid metabolism caused by acrylamide exposure,but not significantly change the levels of mercapturic acid adducts of acrylamide,providing the evidence for phosphatidylcholine protection against acrylamide-induced liver injury.
基金supported by the Chinese Scholarship Council(CSC).
文摘Soil salinity hampers plant performance.Elevated atmospheric CO_(2)(e[CO_(2)])could alleviate the detrimental effect of salinity on plants but whether abscisic acid(ABA)is involved in this process is unclear.To address this issue,three tomato(Solanum lycopersicum)genotypes with varying endogenous ABA concentrations(wild-type AC,ABA-deficient mutant flacca and ABA-overproduction line SP5)were grown in pots under ambient(400μmol·mol^(-1))or elevated(800μmol·mol^(-1))CO_(2)with or without the addition of 100 mmol·L-1sodium chloride(NaCl).The results showed that e[CO_(2)]favored ion homeostasis by decreasing root-to-shoot delivery of Na^(+),which was mainly attributed to lowered transpiration rate rather than altered xylem-sap Na^(+)concentration.In AC and SP5,the low transpiration rate of e[CO_(2)]-plants under salinity was accompanied by enhanced endogenous ABA levels,which might play a role in upregulating the abundance of specific transcripts related to Na^(+)homeostasis(i.e.,SALT OVERLY SENSITIVE)under salt stress.In flacca,e[CO_(2)]-induced Na^(+)homeostasis was abolished,which could be ascribed to the low and unaltered ABA levels,albeit the ethylene biosynthesis was enhanced in flacca under salt stress,indicating an antagonistic relationship between ABA and ethylene.Furthermore,e[CO_(2)]inhibited ethylene biosynthesis under salt stress in all three genotypes.The results enrich our comprehension of the fundamental processes of e[CO_(2)]-conferred salt tolerance in tomato.
基金NIH and NIAMS Grants R21 AR081642(W.Y.),R01 AR066746(W.Y.),R01 AR080062(V.L.)and R01 AR83245(V.L.)supported by the Rhode Island Hospital Orthopaedic Foundation(W.Y.).
文摘The SH2 domain-containing protein tyrosine phosphatase 2(SHP2,also known as PTP2C),encoded by PTPN11,is ubiquitously expressed and has context-specific effects.It promotes RAS/MAPK signaling downstream of receptor tyrosine kinases,cytokine receptors,and extracellular matrix proteins,and was shown in various lineages to modulate cell survival,proliferation,differentiation,and migration.Over the past decade,PTPN11 inactivation in chondrocytes was found to cause metachondromatosis,a rare disorder characterized by multiple enchondromas and osteochondroma-like lesions.Moreover,SHP2 inhibition was found to mitigate osteoarthritis pathogenesis in mice,and abundant but incomplete evidence suggests that SHP2 is crucial for cartilage development and adult homeostasis,during which its expression and activity are tightly regulated transcriptionally and posttranslationally,and by varying sets of functional partners.Fully uncovering SHP2 actions and regulation in chondrocytes is thus fundamental to understanding the mechanisms underlying both rare and common cartilage diseases and to designing effective disease treatments.We here review current knowledge,highlight recent discoveries and controversies,and propose new research directions to answer remaining questions.
基金supported in part by the National Natural Science Foundation of China,No.82371153(to YS)the Natural Science Foundation of Shandong Province,Nos.ZR2021MH378,ZR2022QH073(to LC)+1 种基金the Shandong Society of Geriatric Science and Technology Project,No.LKJGG2021Z020(to YS)the Yantai Science and Technology Innovation Development Project,Nos.2022YD009,2023YD050。
文摘Neurodegenerative diseases are prevalent conditions that greatly impact human health.These diseases are primarily characterized by the progressive loss and eventual death of neuronal function,although the precise mechanisms underlying these processes remain incompletely understood.Iron is an essential trace element in the human body,playing a crucial role in various biological processes.The maintenance of iron homeostasis relies on the body's intricate and nuanced regulatory mechanisms.In recent years,considerable attention has been directed toward the relationship between dysregulated iron homeostasis and neurodegenerative diseases.The regulation of iron homeostasis within cells is crucial for maintaining proper nervous system function.Research has already revealed that disruptions in iron homeostasis may lead to ferroptosis and oxidative stress,which,in turn,can impact neuronal health and contribute to the development of neurodegenerative diseases.This article primarily explores the intimate relationship between iron homeostasis and neurodegenerative diseases,aiming to provide novel insights and strategies for treating these debilitating conditions.
文摘Calcium (Ca^(2+)) is a key intracellular messenger involved in a variety of cellular functions.Intracellular Ca^(2+)dysregulation drives neuron cell death in multiple degenerative diseases and traumatic conditions.Retinal ganglion cell(RGC) degeneration occurs in blinding diseases such as glaucoma and other optic neuropathies.
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project(No.2023ZD0513200)the National Natural Science Foundation of China(Nos.82404278 and 82404365)China Postdoctoral Science Foundation(Nos.2023M730317 and 2023T160066).
文摘Previous studies have reported a relationship between exposure to metals and polycyclic aromatic hydrocarbons(PAHs)and blood glucose levels,but whether the mechanisms are mediated by amino acids remains to be elucidated.We conducted a three-wave repeated measurement study involving 201 elderly individuals(aged≥50 years)from five communities in Beijing,China.We simultaneously measured eightmetals in both blood and urine,six monohydroxy PAHs in urine,and 23 amino acids in blood.Linear mixed-effects and sparse partial least squares models were used to evaluate the individual effects,and Bayesian kernel machine regression was employed to mixture effects.Mediation analysis was further used to explore whether amino acids mediators mediate the association.We observed significant associations of selenium and strontium with increased blood glucose.Additionally,blood copper,urinary nickel,as well as urinary 1+9 hydroxyphenanthrene,were associated with irregular blood glucose regulation.Moreover,we found that amino acids such as leucine,proline,and alanine may mediate the associations.This study is the first to investigate the effect of metals and PAHs on blood glucose homeostasis,while also exploring the mediating role of amino acids,offering new insights into the impact of metals and PAHs on blood glucose regulation.
基金supported by the Health&Medical Research Fund(18190481)the General Research Fund(14120520).
文摘The skeleton is innervated by different types of nerves and receives signaling from the nervous system to maintain homeostasis and facilitate regeneration or repair.Although the role of peripheral nerves and signals in regulating bone homeostasis has been extensively investigated,the intimate relationship between the central nervous system and bone remains less understood,yet it has emerged as a hot topic in the bone field.In this review,we discussed clinical observations and animal studies that elucidate the connection between the nervous system and bone metabolism,either intact or after injury.First,we explored mechanistic studies linking specific brain nuclei with bone homeostasis,including the ventromedial hypothalamus,arcuate nucleus,paraventricular hypothalamic nucleus,amygdala,and locus coeruleus.We then focused on the characteristics of bone innervation and nerve subtypes,such as sensory,sympathetic,and parasympathetic nerves.Moreover,we summarized the molecular features and regulatory functions of these nerves.Finally,we included available translational approaches that utilize nerve function to improve bone homeostasis and promote bone regeneration.Therefore,considering the nervous system within the context of neuromusculoskeletal interactions can deepen our understanding of skeletal homeostasis and repair process,ultimately benefiting future clinical translation.
基金supported by projects from the Xinjiang Production and Construction Corps Major Science and Technology"Revealing the List and Taking Command"Project(2023AB078)the Ministry of Science and Technology High-end Foreign Expert Project(G2023014066L)the Xinjiang Production and Construction Corps Agricultural Science and Technology Innovation Engineering Special Project(NCG202232).
文摘Polyamines(putrescine,spermidine,and spermine)are aliphatic compounds ubiquitous in prokaryotes and eukaryotes.Positively charged polyamines bind to negatively charged macromolecules,such as nucleic acids and acidic phospholipids,and are involved in physiological activities including cell proliferation,differentiation,apoptosis and gene regulation.Intracellular polyamine levels are regulated by biosynthesis,catabolism and transport.Polyamines in the body originate from two primary sources:dietary intake and intestinal microbial metabolism.These polyamines are then transported into the bloodstream,through which they are distributed to various tissues and organs to exert their biological functions.Polyamines synthesized by intestinal microorganisms serve dual critical roles.First,they are essential for maintaining polyamine concentrations within the digestive tract.Second,through transcriptional and post-transcriptional mechanisms,these microbial-derived polyamines modulate the expression of genes governing key processes in intestinal epithelial cells-including proliferation,migration,apoptosis,and cell-cell interactions.Collectively,these regulatory effects help maintain intestinal epithelial homeostasis and ensure the integrity of the gut barrier.In addition,polyamines interact with the gut microbiota to maintain intestinal homeostasis by promoting microbial growth,biofilm formation,swarming,and endocytosis vesicle production,etc.Supplementation with polyamines has been demonstrated to be important in regulating host intestinal microbial composition,enhancing nutrient absorption,and improving metabolism and immunity.In this review,we will focus on recent advances in the study of polyamine metabolism and transport in intestinal microbes and intestinal epithelial cells.We then summarize the scientific understanding of their roles in intestinal homeostasis,exploring the advances in cellular and molecular mechanisms of polyamines and their potential clinical applications,and providing a rationale for polyamine metabolism as an important target for the treatment of intestinal-based diseases.
基金supported in part by grants from the National Natural Science Foundation of China(No.81673093,No.82170227,No.91649113,No.82470165,No.82000121,No.31771640)the Jiangsu Science and Technology Department(No.SBK20200191)+1 种基金the State Key Laboratory of Radiation Medicine and Protection of Soochow University(No.GZC00201)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘The crosstalk between megakaryocytic lineage cells and the skeletal system has just begun to be explored but remains largely elusive.Using conditional gene knockout mouse models,we demonstrated that loss of Beclin 1(Becn1),a major regulator of mammalian autophagy,exclusively in the megakaryocytic lineage disrupted autophagy in platelets but did not compromise megakaryopoiesis or the formation and function of platelets.Unexpectedly,conditional Becn1 deletion in male mice led to a remarkable increase in bone mass with improved bone quality,in association with a decrease in sex hormone binding globulin(SHBG)and an increase in free testosterone(FT).In vivo Becn1 overexpression in megakaryocytic lineage-specific cells reduced bone mass and quality,along with an increase in SHBG and a decrease in FT.Transplantation of wild-type bone marrow cells into megakaryocytic lineage Becn1-deficient male mice restored bone mass and normalized SHBG and FT.Furthermore,bilateral orchiectomy of Becn1^(f/f);Pf4-iCre mice,which are crippled with the production of testosterone,resulted in a reduction in bone mass and quality,whereas in vivo overexpression of SHBG,specifically in the liver of Becn1^(f/f);Pf4-iCre mice,decreased FT and reduced bone mass and quality.In addition,metformin treatment,which induces SHBG expression,reduced FT and normalized bone mass in Becn1^(f/f);Pf4-iCre mice.We thus concluded that Becn1 of the megakaryocytic lineage is dispensable locally for platelet hemostasis but limits bone mass by increasing SHBG,which in turn reduces the FT of male mice.Our findings highlight a mechanism by which Becn1 from megakaryocytic lineage cells distally balances bone growth.
基金supported by Academic inheritance and communication project of China Academyof Chinese Medical Sciences(CI2022E012XB)High Level Chinese Medical Hospital Promotion Project(HLCMHPP2023053)Beijing Traditional Chinese Medicine Inheritance“New 3+3”Project Zhi-Ming Liu’s(Ru-Xiu Liu)Inheritance Workstation(2023-SZ-G-02).
文摘Background:Tongyang Huoxue Decoction(TYHX)can modulate calcium homeostasis andmitochondrial quality management to safeguard sinus node function.Nonetheless,theprecise chemical process remains unclear.This study aimed to verify the upstreamregulatory influence of SERCA2a on the enhancement of calcium homeostasis andmitochondrial unfolded protein response(mtUPR)in sinus node cells(SANCs)by TYHX,while elucidating the protective mechanism of TYHX on SNC activity.Methods:In vitromodels of sh/ad-SERCA2a and si-β-tubulin were established,and TYHX was employed tointervene in each cell group.Various approaches were employed to detect functionsincluding mitochondrial membrane potential,mitochondrial respiration,oxidative stress,mitochondrial biosynthesis,and mitochondrial autophagy and UPR.In vivo confirmationthat TYHX suppresses apoptosis and inflammatory injury.Results:I/R injury led todiminished SANCs activity,compromised mitochondrial membrane potential,reducedmitochondrial respiratory function,and heightened oxidative stress.This further impededmitochondrial production,destabilized the proteome structure,triggered the mtUPR,andinhibited mitochondrial autophagy,thereby upsetting the dynamic equilibrium of themitochondrial quality control network.Furthermore,I/R injury intensified intracellularcalcium excess and worsened oxidative stress damage.Conversely,TYHX interventionmitigated intracellular calcium overload,augmented mitochondrial antioxidant capacity,stimulated mitochondrial autophagy,and decreased the mtUPR.Sh-SERCA2a counteractedthe regulatory influences of TYHX on calcium homeostasis,mitochondrial biogenesis,mtUPR,mitochondrial autophagy,and apoptosis.Conversely,ad-SERCA2a exerted minimalinfluence on the efficacy of TYHX.SERCA2a is a major target protein for TYHX todemonstrate its efficacy.When tubulin expression was minimal,there was no statisticallysignificant difference in the expression levels of mitochondrial autophagy,mitochondrialbiosynthesis,calcium homeostasis regulation,and mtUPR between the sh-SERCA2a andad-SERCA2a groups.This indicates that the normal expression of tubulin is essential forSERCA2a to enhance the efficiency of TYHX.Tubulin may serve as an upstream regulatorymolecule of SERCA2a.In vivo tests confirmed that TYHX may suppress apoptosis andmitigate cellular inflammatory damage.Conclusion:TYHX preserved intracellular calciumequilibrium,mitigated mitochondrial oxidative stress,sustained mitochondrial stability,enhanced mitochondrial biosynthesis,suppressed the mtUPR,facilitated mitochondrialautophagy,and inhibited apoptosis viaβ-tubulin-SERCA2a,thereby safeguarding sinus nodefunctionality from I/R injury.
文摘Adult neurogenesis is a highly dynamic process that leads to the production of new neurons from a population of quiescent neural stem cells(NSCs).In response to specific endogenous and/or external stimuli,NSCs enter a state of mitotic activation,initiating proliferation and differentiation pathways.Throughout this process,NSCs give rise to neural progenitors,which undergo multiple replicative and differentiative steps,each governed by precise molecular pathways that coordinate cellular changes and signals from the surrounding neurogenic niche.
基金supported by a the National Research Foundation(NRF),funded by the Ministry of Science and ICT(RS-2023-00218476,RS-2024-00454619)the Cooperative Research Program for Agriculture Science and Technology Development(RS-2022-RD010165)+1 种基金the Ministry of Health&Welfare,Republic of Korea(RS-2022-KH128577)the BK21 FOUR Program of the Department of Agricultural Biotechnology,Seoul National University,Seoul,Korea.
文摘Background Despite growing concerns about the adverse effects of antibiotics in farm animals,there has been little investigation of the effects of florfenicol in laying hens.This study examined the effect of florfenicol on the intestinal homeostasis,immune system,and pathogen susceptibility of laying hens.Results The oral administration of florfenicol at field-relevant levels for 5 d resulted in a decrease in the gut microbiota genera Lactobacillus,Bacillus,and Bacteroides,indicating the development of intestinal dysbiosis.The dysbiosis led to decreased mRNA levels of key regulators peroxisome proliferator-activated receptor gamma(PPAR-γ)and hypoxia-inducible factor-1α(HIF-1α),compromising intestinal hypoxia.Intestinal homeostasis was also disrupted,with decreased expression of Occludin and Mucin 2(Muc2)genes combined with increased gut epithelial permeability.The breakdown in intestinal homeostasis and immune function provided a favorable environment for opportunistic bacteria like avian pathogenic Escherichia coli(APEC),culminating in systemic infection.Immunologically,florfenicol treatment resulted in increased proportion and absolute number of MRC1L-B^(+)monocytes/macrophages in the spleen,indicating an exacerbated infection.Furthermore,both the proportion and absolute number ofγδT cells in the lamina propria of the cecum decreased.Treatment with florfenicol reduced butyrate levels in the cecum.However,the administration of butyrate before and during florfenicol treatment restored factors associated with intestinal homeostasis,including PPAR-γ,Occludin,and Muc2,while partially restoring HIF-1α,normalized intestinal hypoxia and gut permeability,and reversed immune cell changes,suppressing APEC systemic infection.Conclusion The uncontrolled and widespread use of florfenicol can negatively affect intestinal health in chickens.Specifically,florfenicol was found to impair intestinal homeostasis and immune function in laying hens,including by reducing butyrate levels,thereby increasing their susceptibility to systemic APEC infection.The development of strategies for mitigating the adverse effects of florfenicol on gut health and pathogen susceptibility in laying hens is therefore essential.
