Background:Previous studies have not clarified the treatment of large pancreatic radiolucent stones(≥5 mm).The primary objective of this study was to assess the clinical features and therapeutic efficacy in patients ...Background:Previous studies have not clarified the treatment of large pancreatic radiolucent stones(≥5 mm).The primary objective of this study was to assess the clinical features and therapeutic efficacy in patients with chronic pancreatitis who have large radiolucent stones,and to propose a treatment strategy.Methods:This analysis examined the data of patients with large pancreatic ductal stones(≥5 mm)from March 2011 to June 2018.Patients with radiolucent stones were classified as the radiolucent stones group,while those with pancreatic radiopaque stones presented at the same time were randomly selected as controls in a 1:2 ratio.Data on demographics,disease courses and treatment details were retrieved,and stone clearance and pain relief during the follow-up were compared between the two groups.Results:A total of 52 patients with large radiolucent stones and 104 patients with large radiopaque stones were included in the study.Pancreatic extracorporeal shock wave lithotripsy(ESWL)was the ini-tial treatment for large radiopaque stone.Endoscopic retrograde cholangiopancreatography(ERCP)was the first-step treatment for all patients in the radiolucent stones group,of which one patient received medication after failed ERCP cannulation,and four who failed stone extraction were treated with ESWL following the placement of a nasopancreatic catheter.There was no significant difference in the complete stone clearance rate(75.0%vs.78.8%;P=0.553)between the two groups.Among the 51 patients in the large radiolucent stones group who were followed up for 5.8 years(range 2.1-12.6),complete pain relief was achieved in 42 patients(82.4%),with no significant difference compared with the radiopaque group(82.4%vs.76.4%;P=0.409).Conclusions:ERCP is an effective endotherapy for large radiolucent stone and should be considered the first-step treatment.When stone extraction failed during ERCP,ESWL is recommended following the placement of a nasopancreatic catheter.展开更多
A large multi-country outbreak of Oropouche virus(OROV),a segmented negative-sense RNA virus,is emerging in Latin America.By analyzing publicly available whole-genome sequences spanning 1955 to 2024,this study reveals...A large multi-country outbreak of Oropouche virus(OROV),a segmented negative-sense RNA virus,is emerging in Latin America.By analyzing publicly available whole-genome sequences spanning 1955 to 2024,this study reveals accelerated spatiotemporal evolution of OROV,cooperatively driven by genome mutagenesis and segment reassortment.The strains responsible for the 2023-2024 outbreak are universally reassortants,but form two divergent lineages,namely the Brazil and western Amazon basin lineages.This epidemic spreading is primarily fueled by localized transmission within countries and cross-border spread.Phylogenomic analysis further suggests that the S segment of the viral genome originated in Brazil around the 1740s,underwent diversification into five distinct clusters by the 1970s,and experienced rapid proliferation during 2020-2024.In contrast,the L segment originated in Peru around the 1630s and evolved into two independent clusters by the 1850s.Divergent evolutionary pressures have driven distinct patterns of amino acid changes in viral proteins between the Brazil and the western Amazon basin lineages.These mutations are predicted to alter the protein structures and bear functional consequences for viral fitness and transmission.These findings provide critical insights into the evolutionary dynamics of OROV and underscore the necessity of genome surveillance to track the transmission pathways and spatiotemporal evolution.展开更多
Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervica...Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervical cancer progression.Methods:The roles of m^(6)A RNA methylation and centromere protein K(CENPK)in cervical cancer were analyzed using bioinformatics analysis.Methylated RNA immunoprecipitation was adopted to detect m^(6)A modification of CENPK mRNA.Human cervical cancer clinical samples,cell lines,and xenografts were used for analyzing gene expression and function.Immunofluorescence staining and the tumorsphere formation,clonogenic,MTT,and EdU assays were performed to determine cell stemness,chemoresistance,migration,invasion,and proliferation in HeLa and SiHa cells,respectively.Western blot analysis,co-immunoprecipitation,chromatin immunoprecipitation,and luciferase reporter,cycloheximide chase,and cell fractionation assays were performed to elucidate the underlying mechanism.Results:Bioinformatics analysis of public cancer datasets revealed firm links between m^(6)A modification patterns and cervical cancer prognosis,especially through ZC3H13-mediated m^(6)A modification of CENPK mRNA.CENPK expression was elevated in cervical cancer,associated with cancer recurrence,and independently predicts poor patient prognosis[hazard ratio=1.413,95%confidence interval=1.078−1.853,P=0.012].Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo(P<0.001).We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK withβ-catenin,which promotedβ-catenin expression and nuclear translocation,facilitated p53 ubiquitination,and led to activation of Wnt/β-catenin signaling,but suppression of the p53 pathway.This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness,DNA damage repair pathways necessary for cisplatin/carboplatin resistance,epithelial-mesenchymal transition involved in metastasis,and DNA replication that drove tumor cell proliferation.Conclusions:CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.展开更多
Osteoarthritis(OA),characterized by cartilage degeneration,synovial inflammation,and subchondral bone remodeling,is among the most common musculoskeletal disorders globally in people over 60 years of age.The initiatio...Osteoarthritis(OA),characterized by cartilage degeneration,synovial inflammation,and subchondral bone remodeling,is among the most common musculoskeletal disorders globally in people over 60 years of age.The initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic process.Cartilage degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte metabolism.Therefore,maintaining mitochondrial homeostasis is an important strategy to mitigate OA.Mitophagy is a vital process for autophagosomes to target,engulf,and remove damaged and dysfunctional mitochondria,thereby maintaining mitochondrial homeostasis.Cumulative studies have revealed a strong association between mitophagy and OA,suggesting that the regulation of mitophagy may be a novel therapeutic direction for OA.By reviewing the literature on mitophagy and OA published in recent years,this paper elaborates the potential mechanism of mitophagy regulating OA,thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.展开更多
Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.Ho...Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.However,there are still unmet needs for treating chronic HEV infections.Herein,we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds.Upon screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities.Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection.Pyrazofurin selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains.Encouragingly,both drugs exhibited a sizeable therapeutic window against HEV.For instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients.Mechanistically,their anti-HEV mode of action depends on the blockage of pyrimidine synthesis.Notably,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral activity.In conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections.Based on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.展开更多
Objective:To analyse the genetic variability of EG95 sequences and provide guidance for EG95 vaccine application against Echinococcus granulosus(E. granulosus). Methods:We analysed EG95 polymorphism by collecting tota...Objective:To analyse the genetic variability of EG95 sequences and provide guidance for EG95 vaccine application against Echinococcus granulosus(E. granulosus). Methods:We analysed EG95 polymorphism by collecting total 97 different E. granulosus isolates from 12 different host species that originated from 10 different countries. Multiple sequence alignments and the homology were performed by Lasergene 1(DNASTAR Inc.,Madison,WI),and the phylogenetic analysis was performed by using MEGA5.1(CEMI,Tempe,AZ,USA). In addition,linear and conformational epitopes were analysed,including secondary structure,NXT/S glycosylation,fibronectin type ecoⅢ(Fnndary Ⅲ) domain and glycosylphosphatidylinositol anchor signal(GPIanchor). The s structure was predicted by PSIPRED method. Results:Our results indicated that most isolates overall shared 72.6-100% identity in EG95 gene sequence with the published standard EG95 sequence,X90928. However,EG95 gene indeed has polymorphism in different isolates. Phylogenetic analysis showed that different isolates could be divided into three subgroups. Subgroup 1 contained 87 isolates while Subgroup 2 and Subgroup 3 consisted of 3 and 7 isolates,respectively. Four sequences cloned from oncosphere shared a high identity with the parental sequence of the current vaccine,X90928,and they belonged to Subgroup 1. However,in comparison to X90928,several amino acid mutations occurred in most isolates besides oncosphere,which potentially altered the immunodominant linear epitopes,glycosylation sites and secondary structures in EG95 genes. All these variations might change their previous antigenicity and thereby affecting the efficacy of current EG95 vaccine. Conclusions:This study reveals the genetic variability of EG95 sequences in different E. granulosus isolates,and proposed that more vaccination trials would be needed to test the effectiveness of current EG95 vaccine against distinct isolates in different countries.展开更多
Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosi...Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.展开更多
The endoplasmic reticulum is a key site for protein production and quality control.More than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic reticulu...The endoplasmic reticulum is a key site for protein production and quality control.More than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic reticulum.However,during protein folding,unfolded and/or misfolded proteins are prone to occur,which may lead to endoplasmic reticulum stress.Organisms can monitor the quality of the proteins produced by endoplasmic reticulum quality control(ERQC)and endoplasmic reticulum-associated degradation(ERAD),which maintain endoplasmic reticulum protein homeostasis by degrading abnormally folded proteins.The underlying mechanisms of protein folding and ERAD in mammals have not yet been fully explored.Therefore,this paper reviews the process and function of protein folding and ERAD in mammalian cells,in order to help clinicians better understand the mechanism of ERAD and to provide a scientific reference for the treatment of diseases caused by abnormal ERAD.展开更多
Background:The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune diseases.The aim of this systematic review was to examine the evidence on the role of exercise training i...Background:The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune diseases.The aim of this systematic review was to examine the evidence on the role of exercise training in mitigating inflammation in adolescents and adults with autoimmune disease.Methods:PubMed,Web of Science,and Embase databases were systematically reviewed for related studies published between January 1,2003,and August 31,2023.All randomized and non-randomized controlled trials of exercise interventions with autoimmune disease study participants that evaluated inflammation-related biomarkers were included.The quality of evidence was assessed using the Tool for the assEssment of Study qualiTy and reporting in EXercise scale and Cochrane bias risk tool.Results:A total of 14,565 records were identified.After screening the titles,abstracts,and full texts,87 were eligible for the systematic review.These studies were conducted in 25 different countries and included a total of 2779 participants(patients with autoimmune disease,in exercise or control groups).Overall,the evidence suggests that inflammation-related markers such as C-reactive protein,interleukin 6,and tumor necrosis factor a were reduced by regular exercise interventions.Regular exercise interventions combined with multiple exercise modes were associated with greater benefits.Conclusion:Regular exercise training by patients with autoimmune disease exerts an anti-inflammatory influence.This systematic review provides support for the promotion and development of clinical exercise intervention programs for patients with autoimmune disease.Most patients with autoimmune disease can safely adopt moderate exercise training protocols,but changes in inflammation biomarkers will be modest at best.Acute exercise interventions are ineffective or even modestly but transiently pro-inflammatory.展开更多
BACKGROUND Primary sclerosing cholangitis(PSC)is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options.Recombinant adeno-associated virus(rAAV)provid...BACKGROUND Primary sclerosing cholangitis(PSC)is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options.Recombinant adeno-associated virus(rAAV)provides a promising platform for gene therapy on such kinds of diseases.A microRNA(miRNA)let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been evaluated.AIM To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8(rAAV8)on a xenobiotic-induced mouse model of sclerosing cholangitis.METHODS A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine(DDC)feeding for 2 wk or 6 wk.A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC feeding.Upon sacrifice,the liver and the serum were collected from each mouse.The hepatobiliary injuries,hepatic inflammation and fibrosis were evaluated.The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot.RESULTS rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 wk.The reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers,and prevent the proliferation of cholangiocytes and biliary fibrosis.Furthermore,inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1,which consequently inhibit of NF-κB-mediated hepatic inflammation.CONCLUSION Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis,which provides a possible clinical translation of PSC of human.展开更多
BACKGROUND Hepatic fibrosis(HF)represents a pivotal stage in the progression and potential reversal of cirrhosis,underscoring the importance of early identification and therapeutic intervention to modulate disease tra...BACKGROUND Hepatic fibrosis(HF)represents a pivotal stage in the progression and potential reversal of cirrhosis,underscoring the importance of early identification and therapeutic intervention to modulate disease trajectory.AIM To explore the complex relationship between chronic hepatitis B(CHB)-related HF and gut microbiota to identify microbiota signatures significantly associated with HF progression in CHB patients using advanced machine learning algorithms.METHODS This study included patients diagnosed with CHB and classified them into HF and non-HF groups based on liver stiffness measurements.The HF group was further subdivided into four subgroups:F1,F2,F3,and F4.Data on clinical indicators were collected.Stool samples were collected for 16S rRNA sequencing to assess the gut microbiome.Microbiota diversity,relative abundance,and linear discriminant analysis effect size(LEfSe)were analyzed in different groups.Correlation analysis between clinical indicators and the relative abundance of gut microbiota was performed.The random forest and eXtreme gradient boosting algorithms were used to identify key differential gut microbiota.The Shapley additive explanations were used to evaluate microbiota importance.RESULTS Integrating the results from univariate analysis,LEfSe,and machine learning,we identified that the presence of Dorea in gut microbiota may be a key feature associated with CHB-related HF.Dorea possibly serves as a core differential feature of the gut microbiota that distinguishes HF from non-HF patients,and the presence of Dorea shows significant variations across different stages of HF(P<0.05).The relative abundance of Dorea significantly decreases with increasing HF severity(P=0.041).Moreover,the gut microbiota composition in patients with different stages of HF was found to correlate with several liver function indicators,such asγ-glutamyl transferase,alkaline phosphatase,total bilirubin,and the aspartate aminotransferase/alanine transaminase ratio(P<0.05).The associated pathways were predominantly enriched in biosynthesis,degradation/utilization/assimilation,generation of precursors,metabolites,and energy,among other categories.CONCLUSION HF affects the composition of the gut microbiota,indicating that the gut microbiota plays a crucial role in its pathophysiological processes.The abundance of Dorea varies significantly across various stages of HF,making it a potential microbial marker for identifying HF onset and progression.展开更多
Osteoarthritis(OA)is one of the most common degenerative joint diseases in the elderly,increasing in prevalence and posing a substantial socioeconomic challenge,while no disease-modifying treatments available.Better u...Osteoarthritis(OA)is one of the most common degenerative joint diseases in the elderly,increasing in prevalence and posing a substantial socioeconomic challenge,while no disease-modifying treatments available.Better understanding of the early molecular events will benefit the early-stage diagnosis and clinical therapy.Here,we observed the nucleus accumulation of ZBTB20,a member of ZBTB-protein family,in the chondrocytes of early-stage OA.Chondrocytes-specific depletion of Zbtb20 in adult mice attenuated DMM-induced OA progress,restored the balance of extracellular matrix anabolism and catabolism.The NF-κB signaling mediated disturbance of ECM maintenance by ZBTB20 requires its suppression of Pten and consequent PI3K-Akt signaling activation.Furthermore,the subcellular localization of ZBTB20 was modulated by the kinase LATS1.Independent approaches to modulating ZBTB20 via utilizing TRULI and DAPA can restore ECM homeostasis,improving the abnormal behavior and moderating cartilage degeneration.The compounds TRULI and DAPA modulating ZBTB20 may serve as anti-OA drugs.展开更多
Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by widespread inflammation,diffuse alveolar damage,and pulmonary edema,often leading to respiratory failure a...Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by widespread inflammation,diffuse alveolar damage,and pulmonary edema,often leading to respiratory failure and death.Despite significant advances in clinical care,ALI/ARDS remains the leading cause of death among intensive care unit patients.Sepsis is the primary risk factor for the development of ALI/ARDS,as excessive inflammatory responses contribute to organ injury and high mortality in critically ill patients.展开更多
TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulato...TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis.Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies.Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity.Here,we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network.In addition,we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases,which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.展开更多
A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota.An important next step is to elucidate a human-relevant&q...A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota.An important next step is to elucidate a human-relevant"map"of microbiota-host interactions that regulate the metabolic health of the host.An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity.Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions,including cancer,neurodegeneration,and aging.The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood.Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage.Changes in the composition and function of the gut microbiota,i.e.,dysbiosis,are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction.Many effects of the microbiota on the host are mediated by microbiota-derived metabolites.In this review,we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases.The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.展开更多
We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C-X3-C motif chemokine ligand 1(CX3 CL1) to induce microglia polarization. More impor...We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C-X3-C motif chemokine ligand 1(CX3 CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3 CL1(comprising amino acids 357–395 of CX3 CL1) disrupts the interaction between postsynaptic density-93 and CX3 CL1, reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke. However, the mechanism underlying these effects remains unclear. In the current study, we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points. The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion, whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion. We found that the peptide Tat-CX3 CL1(357–395 aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3 CL1. Furthermore, the a disintegrin and metalloprotease domain 17(ADAM17) inhibitor GW280264 x, which inhibits metalloprotease activity and prevents CX3 CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3 CL1 formation. Additionally, Tat-CX3 CL1(357–395 aa) attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31–34 days following surgery and immunofluorescence staining at 35 days after stroke, respectively. In conclusion, Tat-CX3 CL1(357–395 aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3 CL1(357–395 aa) is a potential therapeutic agent for ischemic stroke.展开更多
INTRODUCTION An effective coordination of immune and non-immune cells is essential for generating optimal regional immunity to combat tumorigenesis and infection at barrier tissues such as lung.Regional immune structu...INTRODUCTION An effective coordination of immune and non-immune cells is essential for generating optimal regional immunity to combat tumorigenesis and infection at barrier tissues such as lung.Regional immune structures such as inducible bronchus-associated lymphoid tissue(iBALT)and tertiary lymphoid structure(TLS)play essential roles in modulating lung local immune responses.While the identification of iBALTs or TLS is generally dependent on conventional histology,it remains poorly understood how immune cells are spatiotemporally coordinated in the lung at single-cell resolution to effectively eliminate malignant cells and invading pathogens.Recently studies have revealed the presence of dendritic cell(DC)-T immunity hubs in human lung with close association with tumor immunotherapy response[1],antiviral immunity[2],and inflammation resolution[3].展开更多
Myeloid-derived suppressor cells(MDSCs)play a protective role against neonatal inflammation during the early postnatal period.However,the mechanisms regulating neonatal MDSC function remain to be fully elucidated.In t...Myeloid-derived suppressor cells(MDSCs)play a protective role against neonatal inflammation during the early postnatal period.However,the mechanisms regulating neonatal MDSC function remain to be fully elucidated.In this study,we report that the bile acid receptor farnesoid X receptor(FXR)acts as a positive regulator of neonatal MDSC function.The FDA-approved FXR agonist obeticholic acid(OCA)protects against neonatal sepsis in an FXR-dependent manner.Genetic deficiency of FXR impairs the immunosuppressive and antibacterial functions of MDSCs,thereby exacerbating the severity of neonatal sepsis.Adoptive transfer of MDSCs alleviates sepsis in both Fxr^(−/−) and Fxr^(fl/fl)Mrp8-Cre^(+) pups.Mechanistic studies revealed that Hif1α,a well-established regulator of MDSCs,is a direct transcriptional target of FXR.In patients with neonatal sepsis,downregulation of FXR and HIF-1αin MDSCs was observed,which was inversely correlated with clinical parameters.These observations demonstrate the importance of FXR in neonatal MDSC function and its therapeutic potential in neonatal sepsis.展开更多
Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling a...Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.展开更多
The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors...The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors or memory populations.However,within the tumor microenvironment(TME),metabolic stress impairs CD8+T cell anti-tumor immunity,resulting in exhausted differentiation.Recent studies suggested that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy.In this review,we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions.Furthermore,we delved into the different metabolic switches that occur during T cell exhaustion,exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion,ultimately leading to a persistently exhausted state.Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.展开更多
基金supported by grants from the National Nat-ural Science Foundation of China(82270679 and 82370657)Shanghai Municipal Hospital Emerging Frontier Technology Joint Project(SHDC12021107)+1 种基金Shanghai Chenguang Program(20CG42)Shanghai New-Star Youth Doctor Program(HWRS2020087).
文摘Background:Previous studies have not clarified the treatment of large pancreatic radiolucent stones(≥5 mm).The primary objective of this study was to assess the clinical features and therapeutic efficacy in patients with chronic pancreatitis who have large radiolucent stones,and to propose a treatment strategy.Methods:This analysis examined the data of patients with large pancreatic ductal stones(≥5 mm)from March 2011 to June 2018.Patients with radiolucent stones were classified as the radiolucent stones group,while those with pancreatic radiopaque stones presented at the same time were randomly selected as controls in a 1:2 ratio.Data on demographics,disease courses and treatment details were retrieved,and stone clearance and pain relief during the follow-up were compared between the two groups.Results:A total of 52 patients with large radiolucent stones and 104 patients with large radiopaque stones were included in the study.Pancreatic extracorporeal shock wave lithotripsy(ESWL)was the ini-tial treatment for large radiopaque stone.Endoscopic retrograde cholangiopancreatography(ERCP)was the first-step treatment for all patients in the radiolucent stones group,of which one patient received medication after failed ERCP cannulation,and four who failed stone extraction were treated with ESWL following the placement of a nasopancreatic catheter.There was no significant difference in the complete stone clearance rate(75.0%vs.78.8%;P=0.553)between the two groups.Among the 51 patients in the large radiolucent stones group who were followed up for 5.8 years(range 2.1-12.6),complete pain relief was achieved in 42 patients(82.4%),with no significant difference compared with the radiopaque group(82.4%vs.76.4%;P=0.409).Conclusions:ERCP is an effective endotherapy for large radiolucent stone and should be considered the first-step treatment.When stone extraction failed during ERCP,ESWL is recommended following the placement of a nasopancreatic catheter.
基金supported by the National Natural Science Foundation of China,32270161,82302506.Research Grant of Jiangsu Commission of Health,ZD2021036The Starting Grant for Talents of Xuzhou Medical University,D2021007,D2021008,D2024017The Natural Science Foundation of the Jiangsu Higher Education Institutions of China(23KJD310005,23KJB310028,24KJD310005).
文摘A large multi-country outbreak of Oropouche virus(OROV),a segmented negative-sense RNA virus,is emerging in Latin America.By analyzing publicly available whole-genome sequences spanning 1955 to 2024,this study reveals accelerated spatiotemporal evolution of OROV,cooperatively driven by genome mutagenesis and segment reassortment.The strains responsible for the 2023-2024 outbreak are universally reassortants,but form two divergent lineages,namely the Brazil and western Amazon basin lineages.This epidemic spreading is primarily fueled by localized transmission within countries and cross-border spread.Phylogenomic analysis further suggests that the S segment of the viral genome originated in Brazil around the 1740s,underwent diversification into five distinct clusters by the 1970s,and experienced rapid proliferation during 2020-2024.In contrast,the L segment originated in Peru around the 1630s and evolved into two independent clusters by the 1850s.Divergent evolutionary pressures have driven distinct patterns of amino acid changes in viral proteins between the Brazil and the western Amazon basin lineages.These mutations are predicted to alter the protein structures and bear functional consequences for viral fitness and transmission.These findings provide critical insights into the evolutionary dynamics of OROV and underscore the necessity of genome surveillance to track the transmission pathways and spatiotemporal evolution.
基金the Joint Funds for the Innovation of Science and Technology Program of Fujian Province,China(2018Y9110)the Natural Science Foundation of Fujian Province,China,(2020J011126)the China Postdoctoral Science Foundation(2021T140468).
文摘Background:Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis.In the current study,we determined the relevant players and role of N^(6)-methyladenine(m^(6)A)RNA methylation in cervical cancer progression.Methods:The roles of m^(6)A RNA methylation and centromere protein K(CENPK)in cervical cancer were analyzed using bioinformatics analysis.Methylated RNA immunoprecipitation was adopted to detect m^(6)A modification of CENPK mRNA.Human cervical cancer clinical samples,cell lines,and xenografts were used for analyzing gene expression and function.Immunofluorescence staining and the tumorsphere formation,clonogenic,MTT,and EdU assays were performed to determine cell stemness,chemoresistance,migration,invasion,and proliferation in HeLa and SiHa cells,respectively.Western blot analysis,co-immunoprecipitation,chromatin immunoprecipitation,and luciferase reporter,cycloheximide chase,and cell fractionation assays were performed to elucidate the underlying mechanism.Results:Bioinformatics analysis of public cancer datasets revealed firm links between m^(6)A modification patterns and cervical cancer prognosis,especially through ZC3H13-mediated m^(6)A modification of CENPK mRNA.CENPK expression was elevated in cervical cancer,associated with cancer recurrence,and independently predicts poor patient prognosis[hazard ratio=1.413,95%confidence interval=1.078−1.853,P=0.012].Silencing of CENPK prolonged the overall survival time of cervical cancer-bearing mice and improved the response of cervical cancer tumors to chemotherapy in vivo(P<0.001).We also showed that CENPK was directly bound to SOX6 and disrupted the interactions of CENPK withβ-catenin,which promotedβ-catenin expression and nuclear translocation,facilitated p53 ubiquitination,and led to activation of Wnt/β-catenin signaling,but suppression of the p53 pathway.This dysregulation ultimately enhanced the tumorigenic pathways required for cell stemness,DNA damage repair pathways necessary for cisplatin/carboplatin resistance,epithelial-mesenchymal transition involved in metastasis,and DNA replication that drove tumor cell proliferation.Conclusions:CENPK was shown to have an oncogenic role in cervical cancer and can thus serve as a prognostic indicator and novel target for cervical cancer treatment.
基金This work was supported by the National Natural Science Foundation of China(No.82071762)the Shanghai Key Lab of Human Performance(Shanghai University of Sport)(No.11DZ2261100)the 2021 Capacity Building of Shanghai Universities(No.21010503600),China。
文摘Osteoarthritis(OA),characterized by cartilage degeneration,synovial inflammation,and subchondral bone remodeling,is among the most common musculoskeletal disorders globally in people over 60 years of age.The initiation and progression of OA involves the abnormal metabolism of chondrocytes as an important pathogenic process.Cartilage degeneration features mitochondrial dysfunction as one of the important causative factors of abnormal chondrocyte metabolism.Therefore,maintaining mitochondrial homeostasis is an important strategy to mitigate OA.Mitophagy is a vital process for autophagosomes to target,engulf,and remove damaged and dysfunctional mitochondria,thereby maintaining mitochondrial homeostasis.Cumulative studies have revealed a strong association between mitophagy and OA,suggesting that the regulation of mitophagy may be a novel therapeutic direction for OA.By reviewing the literature on mitophagy and OA published in recent years,this paper elaborates the potential mechanism of mitophagy regulating OA,thus providing a theoretical basis for studies related to mitophagy to develop new treatment options for OA.
基金funded by the National Natural Science Foundation of China(32270161,32100117,32100118)the Natural Science Foundation of Jiangsu Province of China(BK20210899,BK20210900,BK20210901)+1 种基金Research Grant of Jiangsu Commission of Health,China(ZD2021036)the Starting Grant for Talents of Xuzhou Medical University(D2021007,D2021008).
文摘Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed patients.However,there are still unmet needs for treating chronic HEV infections.Herein,we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds.Upon screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities.Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection.Pyrazofurin selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains.Encouragingly,both drugs exhibited a sizeable therapeutic window against HEV.For instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients.Mechanistically,their anti-HEV mode of action depends on the blockage of pyrimidine synthesis.Notably,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral activity.In conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections.Based on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.
基金supported by the grants from the National Natural Science Foundation of China (No. 81501762)the Talents Scientific Research Foundation of Xuzhou Medical University (No. D2015004)+4 种基金the Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015B161)the Training Programs of Innovation and Entrepreneurship for College Students in Jiangsu Province (No. 201510313017Z)the Jiangsu Planned Projects for Postdoctoral Research Funds (No. 1501061A)the China Postdoctoral Science Foundation funded project (No. 2015M581864)the Jiangsu Qing Lan Project
文摘Objective:To analyse the genetic variability of EG95 sequences and provide guidance for EG95 vaccine application against Echinococcus granulosus(E. granulosus). Methods:We analysed EG95 polymorphism by collecting total 97 different E. granulosus isolates from 12 different host species that originated from 10 different countries. Multiple sequence alignments and the homology were performed by Lasergene 1(DNASTAR Inc.,Madison,WI),and the phylogenetic analysis was performed by using MEGA5.1(CEMI,Tempe,AZ,USA). In addition,linear and conformational epitopes were analysed,including secondary structure,NXT/S glycosylation,fibronectin type ecoⅢ(Fnndary Ⅲ) domain and glycosylphosphatidylinositol anchor signal(GPIanchor). The s structure was predicted by PSIPRED method. Results:Our results indicated that most isolates overall shared 72.6-100% identity in EG95 gene sequence with the published standard EG95 sequence,X90928. However,EG95 gene indeed has polymorphism in different isolates. Phylogenetic analysis showed that different isolates could be divided into three subgroups. Subgroup 1 contained 87 isolates while Subgroup 2 and Subgroup 3 consisted of 3 and 7 isolates,respectively. Four sequences cloned from oncosphere shared a high identity with the parental sequence of the current vaccine,X90928,and they belonged to Subgroup 1. However,in comparison to X90928,several amino acid mutations occurred in most isolates besides oncosphere,which potentially altered the immunodominant linear epitopes,glycosylation sites and secondary structures in EG95 genes. All these variations might change their previous antigenicity and thereby affecting the efficacy of current EG95 vaccine. Conclusions:This study reveals the genetic variability of EG95 sequences in different E. granulosus isolates,and proposed that more vaccination trials would be needed to test the effectiveness of current EG95 vaccine against distinct isolates in different countries.
基金supported by Jiangsu Provincial Medical Key Discipline,No.ZDXK202217(to CFL)Jiangsu Planned Projects for Postdoctoral Research Funds,No.1601056C(to SL).
文摘Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.
基金This work was supported by the National Natural Science Foundation of China(No.82071762)the Shanghai Key Lab of Human Performance(Shanghai University of Sport)(No.11DZ2261100)the 2021 Capacity Building of Shanghai Universities(No.21010503600),China。
文摘The endoplasmic reticulum is a key site for protein production and quality control.More than one-third of proteins are synthesized and folded into the correct three-dimensional conformation in the endoplasmic reticulum.However,during protein folding,unfolded and/or misfolded proteins are prone to occur,which may lead to endoplasmic reticulum stress.Organisms can monitor the quality of the proteins produced by endoplasmic reticulum quality control(ERQC)and endoplasmic reticulum-associated degradation(ERAD),which maintain endoplasmic reticulum protein homeostasis by degrading abnormally folded proteins.The underlying mechanisms of protein folding and ERAD in mammals have not yet been fully explored.Therefore,this paper reviews the process and function of protein folding and ERAD in mammalian cells,in order to help clinicians better understand the mechanism of ERAD and to provide a scientific reference for the treatment of diseases caused by abnormal ERAD.
基金supported by the National Natural Science Foundation of China(NO.31801003 for DX,NO.31701040 for BL)Shanghai Key Lab of Human Performance(Shanghai University of Sport)(NO.11DZ2261100)。
文摘Background:The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune diseases.The aim of this systematic review was to examine the evidence on the role of exercise training in mitigating inflammation in adolescents and adults with autoimmune disease.Methods:PubMed,Web of Science,and Embase databases were systematically reviewed for related studies published between January 1,2003,and August 31,2023.All randomized and non-randomized controlled trials of exercise interventions with autoimmune disease study participants that evaluated inflammation-related biomarkers were included.The quality of evidence was assessed using the Tool for the assEssment of Study qualiTy and reporting in EXercise scale and Cochrane bias risk tool.Results:A total of 14,565 records were identified.After screening the titles,abstracts,and full texts,87 were eligible for the systematic review.These studies were conducted in 25 different countries and included a total of 2779 participants(patients with autoimmune disease,in exercise or control groups).Overall,the evidence suggests that inflammation-related markers such as C-reactive protein,interleukin 6,and tumor necrosis factor a were reduced by regular exercise interventions.Regular exercise interventions combined with multiple exercise modes were associated with greater benefits.Conclusion:Regular exercise training by patients with autoimmune disease exerts an anti-inflammatory influence.This systematic review provides support for the promotion and development of clinical exercise intervention programs for patients with autoimmune disease.Most patients with autoimmune disease can safely adopt moderate exercise training protocols,but changes in inflammation biomarkers will be modest at best.Acute exercise interventions are ineffective or even modestly but transiently pro-inflammatory.
基金Supported by the National Natural Science Foundation of China,No.82172297Natural Science Foundation of Jiangsu Province of China,No.BK20211346 and No.BK20201011+1 种基金Natural Science Foundation of Jiangsu Higher Education Institutions of China,No.22KJA310007Xuzhou Science and Technology Project,No.KC22055.
文摘BACKGROUND Primary sclerosing cholangitis(PSC)is characterized by chronic inflammation and it predisposes to cholangiocarcinoma due to lack of effective treatment options.Recombinant adeno-associated virus(rAAV)provides a promising platform for gene therapy on such kinds of diseases.A microRNA(miRNA)let-7a has been reported to be associated with the progress of PSC but the potential therapeutic implication of inhibition of let-7a on PSC has not been evaluated.AIM To investigate the therapeutic effects of inhibition of a miRNA let-7a transferred by recombinant adeno-associated virus 8(rAAV8)on a xenobiotic-induced mouse model of sclerosing cholangitis.METHODS A xenobiotic-induced mouse model of sclerosing cholangitis was induced by 0.1% 3,5-Diethoxycarbonyl-1,4-Dihydrocollidine(DDC)feeding for 2 wk or 6 wk.A single dose of rAAV8-mediated anti-let-7a-5p sponges or scramble control was injected in vivo into mice onset of DDC feeding.Upon sacrifice,the liver and the serum were collected from each mouse.The hepatobiliary injuries,hepatic inflammation and fibrosis were evaluated.The targets of let-7a-5p and downstream molecule NF-κB were detected using Western blot.RESULTS rAAV8-mediated anti-let-7a-5p sponges can depress the expression of let-7a-5p in mice after DDC feeding for 2 wk or 6 wk.The reduced expression of let-7a-5p can alleviate hepato-biliary injuries indicated by serum markers,and prevent the proliferation of cholangiocytes and biliary fibrosis.Furthermore,inhibition of let-7a mediated by rAAV8 can increase the expression of potential target molecules such as suppressor of cytokine signaling 1 and Dectin1,which consequently inhibit of NF-κB-mediated hepatic inflammation.CONCLUSION Our study demonstrates that a rAAV8 vector designed for liver-specific inhibition of let-7a-5p can potently ameliorate symptoms in a xenobiotic-induced mouse model of sclerosing cholangitis,which provides a possible clinical translation of PSC of human.
基金Supported by the Zhejiang Provincial Natural Science Foundation,No.LZ22H270001.
文摘BACKGROUND Hepatic fibrosis(HF)represents a pivotal stage in the progression and potential reversal of cirrhosis,underscoring the importance of early identification and therapeutic intervention to modulate disease trajectory.AIM To explore the complex relationship between chronic hepatitis B(CHB)-related HF and gut microbiota to identify microbiota signatures significantly associated with HF progression in CHB patients using advanced machine learning algorithms.METHODS This study included patients diagnosed with CHB and classified them into HF and non-HF groups based on liver stiffness measurements.The HF group was further subdivided into four subgroups:F1,F2,F3,and F4.Data on clinical indicators were collected.Stool samples were collected for 16S rRNA sequencing to assess the gut microbiome.Microbiota diversity,relative abundance,and linear discriminant analysis effect size(LEfSe)were analyzed in different groups.Correlation analysis between clinical indicators and the relative abundance of gut microbiota was performed.The random forest and eXtreme gradient boosting algorithms were used to identify key differential gut microbiota.The Shapley additive explanations were used to evaluate microbiota importance.RESULTS Integrating the results from univariate analysis,LEfSe,and machine learning,we identified that the presence of Dorea in gut microbiota may be a key feature associated with CHB-related HF.Dorea possibly serves as a core differential feature of the gut microbiota that distinguishes HF from non-HF patients,and the presence of Dorea shows significant variations across different stages of HF(P<0.05).The relative abundance of Dorea significantly decreases with increasing HF severity(P=0.041).Moreover,the gut microbiota composition in patients with different stages of HF was found to correlate with several liver function indicators,such asγ-glutamyl transferase,alkaline phosphatase,total bilirubin,and the aspartate aminotransferase/alanine transaminase ratio(P<0.05).The associated pathways were predominantly enriched in biosynthesis,degradation/utilization/assimilation,generation of precursors,metabolites,and energy,among other categories.CONCLUSION HF affects the composition of the gut microbiota,indicating that the gut microbiota plays a crucial role in its pathophysiological processes.The abundance of Dorea varies significantly across various stages of HF,making it a potential microbial marker for identifying HF onset and progression.
基金supported by grants from the National Natural Science Foundation of China(82002351,82394442,82130070,82272442)funded by the Innovation Capability Support Program of Shaanxi Province(2024SF-LCZX-16)+2 种基金the Shaanxi Province Health Scientific Research Innovation Ability Promotion Plan(2024PT-12)the Independent Exploration and Innovation Project of Xi’an Jiaotong University(xzy012023121)the project of Xi’an Postdoctoral Innovation Base.
文摘Osteoarthritis(OA)is one of the most common degenerative joint diseases in the elderly,increasing in prevalence and posing a substantial socioeconomic challenge,while no disease-modifying treatments available.Better understanding of the early molecular events will benefit the early-stage diagnosis and clinical therapy.Here,we observed the nucleus accumulation of ZBTB20,a member of ZBTB-protein family,in the chondrocytes of early-stage OA.Chondrocytes-specific depletion of Zbtb20 in adult mice attenuated DMM-induced OA progress,restored the balance of extracellular matrix anabolism and catabolism.The NF-κB signaling mediated disturbance of ECM maintenance by ZBTB20 requires its suppression of Pten and consequent PI3K-Akt signaling activation.Furthermore,the subcellular localization of ZBTB20 was modulated by the kinase LATS1.Independent approaches to modulating ZBTB20 via utilizing TRULI and DAPA can restore ECM homeostasis,improving the abnormal behavior and moderating cartilage degeneration.The compounds TRULI and DAPA modulating ZBTB20 may serve as anti-OA drugs.
基金supported by National Natural Science Foundation of China(82471792,82270004,81870061,82202382,31770945)Beijing Municipal Natural Science Foundation(7242135)Zhejiang Provincial Natural Science Foundation(LY20H010003).
文摘Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS)is a severe clinical disorder characterized by widespread inflammation,diffuse alveolar damage,and pulmonary edema,often leading to respiratory failure and death.Despite significant advances in clinical care,ALI/ARDS remains the leading cause of death among intensive care unit patients.Sepsis is the primary risk factor for the development of ALI/ARDS,as excessive inflammatory responses contribute to organ injury and high mortality in critically ill patients.
基金We thank Dr.Bingjing Wang for helpful discussion.This work was supported by grants from the National Natural Science Foundation of China(81788101,81922032)CAMS Innovation Fund for Medical Sciences(2016-12M-1-003).
文摘TET2,a member of ten-eleven translocation(TET)family as a-ketoglutarate-and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine(5mC),has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis.Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies.Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity.Here,we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network.In addition,we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases,which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.
基金Supported by The National Natural Science Foundation of China,No.81770853 and No.81970730.
文摘A significant breakthrough in the field of obesity research was the demonstration that an obese phenotype could be manipulated by modulating the gut microbiota.An important next step is to elucidate a human-relevant"map"of microbiota-host interactions that regulate the metabolic health of the host.An improved understanding of this crosstalk is a prerequisite for optimizing therapeutic strategies to combat obesity.Intestinal mucosal barrier dysfunction is an important contributor to metabolic diseases and has also been found to be involved in a variety of other chronic inflammatory conditions,including cancer,neurodegeneration,and aging.The mechanistic basis for intestinal barrier dysfunction accompanying metabolic disorders remains poorly understood.Understanding the molecular and cellular modulators of intestinal barrier function will help devise improved strategies to counteract the detrimental systemic consequences of gut barrier breakage.Changes in the composition and function of the gut microbiota,i.e.,dysbiosis,are thought to drive obesity-related pathogenesis and may be one of the most important drivers of mucosal barrier dysfunction.Many effects of the microbiota on the host are mediated by microbiota-derived metabolites.In this review,we focus on several relatively well-studied microbial metabolites that can influence intestinal mucosal homeostasis and discuss how they might affect metabolic diseases.The design and use of microbes and their metabolites that are locally active in the gut without systemic side effects are promising novel and safe therapeutic modalities for metabolic diseases.
基金supported by the National Natural Science Foundation of China,Nos. 82071304 (to QXZ), 81671149 (to QXZ),and 81971179 (to XML)the Natural Science Foundation of Jiangsu Province,Nos. BK20191463 (to XML) and BK20161167 (to QXZ)。
文摘We previously reported that postsynaptic density-93 mediates neuron-microglia crosstalk by interacting with amino acids 357–395 of C-X3-C motif chemokine ligand 1(CX3 CL1) to induce microglia polarization. More importantly, the peptide Tat-CX3 CL1(comprising amino acids 357–395 of CX3 CL1) disrupts the interaction between postsynaptic density-93 and CX3 CL1, reducing neurological impairment and exerting a protective effect in the context of acute ischemic stroke. However, the mechanism underlying these effects remains unclear. In the current study, we found that the pro-inflammatory M1 phenotype increased and the anti-inflammatory M2 phenotype decreased at different time points. The M1 phenotype increased at 6 hours after stroke and peaked at 24 hours after perfusion, whereas the M2 phenotype decreased at 6 and 24 hours following reperfusion. We found that the peptide Tat-CX3 CL1(357–395 aa) facilitates microglial polarization from M1 to M2 by reducing the production of soluble CX3 CL1. Furthermore, the a disintegrin and metalloprotease domain 17(ADAM17) inhibitor GW280264 x, which inhibits metalloprotease activity and prevents CX3 CL1 from being sheared into its soluble form, facilitated microglial polarization from M1 to M2 by inhibiting soluble CX3 CL1 formation. Additionally, Tat-CX3 CL1(357–395 aa) attenuated long-term cognitive deficits and improved white matter integrity as determined by the Morris water maze test at 31–34 days following surgery and immunofluorescence staining at 35 days after stroke, respectively. In conclusion, Tat-CX3 CL1(357–395 aa) facilitates functional recovery after ischemic stroke by promoting microglial polarization from M1 to M2. Therefore, the Tat-CX3 CL1(357–395 aa) is a potential therapeutic agent for ischemic stroke.
基金supported by Grants from the National Key R&D Program of China(2023YFA1801400)National Natural Science Foundation of China(92374115 and 82388201).
文摘INTRODUCTION An effective coordination of immune and non-immune cells is essential for generating optimal regional immunity to combat tumorigenesis and infection at barrier tissues such as lung.Regional immune structures such as inducible bronchus-associated lymphoid tissue(iBALT)and tertiary lymphoid structure(TLS)play essential roles in modulating lung local immune responses.While the identification of iBALTs or TLS is generally dependent on conventional histology,it remains poorly understood how immune cells are spatiotemporally coordinated in the lung at single-cell resolution to effectively eliminate malignant cells and invading pathogens.Recently studies have revealed the presence of dendritic cell(DC)-T immunity hubs in human lung with close association with tumor immunotherapy response[1],antiviral immunity[2],and inflammation resolution[3].
基金supported by the following grants:National Natural Science Foundation of China(No.82430055,81925018,and 82130049 to J.Z.,82001691 to J.H.,and 82488301,82225015,and 82171284 to Q.L.)supported by grants to J.H.+2 种基金the China Postdoctoral Science Foundation(2020M672582)the Science and Technology Planning Project of Guangzhou(No.2024A03J1237)the New Cornerstone Science Foundation through the XPLORER PRIZE(to Q.L.).
文摘Myeloid-derived suppressor cells(MDSCs)play a protective role against neonatal inflammation during the early postnatal period.However,the mechanisms regulating neonatal MDSC function remain to be fully elucidated.In this study,we report that the bile acid receptor farnesoid X receptor(FXR)acts as a positive regulator of neonatal MDSC function.The FDA-approved FXR agonist obeticholic acid(OCA)protects against neonatal sepsis in an FXR-dependent manner.Genetic deficiency of FXR impairs the immunosuppressive and antibacterial functions of MDSCs,thereby exacerbating the severity of neonatal sepsis.Adoptive transfer of MDSCs alleviates sepsis in both Fxr^(−/−) and Fxr^(fl/fl)Mrp8-Cre^(+) pups.Mechanistic studies revealed that Hif1α,a well-established regulator of MDSCs,is a direct transcriptional target of FXR.In patients with neonatal sepsis,downregulation of FXR and HIF-1αin MDSCs was observed,which was inversely correlated with clinical parameters.These observations demonstrate the importance of FXR in neonatal MDSC function and its therapeutic potential in neonatal sepsis.
基金This study was supported by grants from the National Institutes of Health(AI64639 and GM84459)the core facilities of MD Anderson Cancer Center are supported by the NIH/NCI Cancer Center Support Grant(CCSG)P30CA016672.
文摘Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections.We show that TNF receptor-associated factor 2(TRAF2)maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections.This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase(NIK)and degradation of the proapoptotic factor Bim.NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105.Interestingly,while NIK is required for Tpl2-ERK signaling under normal conditions,uncontrolled NIK activation due to loss of its negative regulator,TRAF2,causes constitutive degradation of p105 and Tpl2,leading to severe defects in ERK activation and effector/memory CD8 T cell survival.Thus,TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.
基金National Natural Science Foundation of China(Nos.81788101,82271775,and 81972875)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(Nos.2021-I2M-1-021,2021-I2M-1-061,and 2022-I2M-1-047)+1 种基金Haihe Laboratory of Cell Ecosystem Innovation Fund(No.22HHXBSS00009)Natural Science Foundation Outstanding Youth Fund of Jiangsu Province(Nos.BK20220049 and BK20211505)
文摘The efficacy of adaptive immune responses in cancer treatment relies heavily on the state of the T cells.Upon antigen exposure,T cells undergo metabolic reprogramming,leading to the development of functional effectors or memory populations.However,within the tumor microenvironment(TME),metabolic stress impairs CD8+T cell anti-tumor immunity,resulting in exhausted differentiation.Recent studies suggested that targeting T cell metabolism could offer promising therapeutic opportunities to enhance T cell immunotherapy.In this review,we provide a comprehensive summary of the intrinsic and extrinsic factors necessary for metabolic reprogramming during the development of effector and memory T cells in response to acute and chronic inflammatory conditions.Furthermore,we delved into the different metabolic switches that occur during T cell exhaustion,exploring how prolonged metabolic stress within the TME triggers alterations in cellular metabolism and the epigenetic landscape that contribute to T cell exhaustion,ultimately leading to a persistently exhausted state.Understanding the intricate relationship between T cell metabolism and cancer immunotherapy can lead to the development of novel approaches to improve the efficacy of T cell-based treatments against cancer.
