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Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression

Signal Transduction and Targeted Therapy 2024年第8期9卷 3429-3448页

作者： Hao Peng Meng Yang Kun Feng Qingpeng Lv Yewei Zhang medical school Southeast UniversityNanjing 210009China Department of Ultrasound State Key Laboratory of Complex Severe and Rare DiseasesPeking Union Medical College HospitalChinese Academy of MedicalSciencesPeking Union Medical CollegeBeijing 100730China Hepatopancreatobiliary Center The Second Affiliated Hospital of Nanjing Medical UniversityNanjing 210009China

More than 90% of hepatocellular carcinoma(HCC)cases develop in the presence of fibrosis or cirrhosis,making the tumor microenvironment(TME)of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts(CAFs)and cancer stem cells(CSCs),which collectively regulate HCC ***,the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain *** study unveils a significant upregulation of Sema3C in fibrotic liver,HCC tissues,peripheral blood of HCC patients,as well as sorafenib-resistant tissues and cells,with its overexpression correlating with the acquisition of stemness properties in *** further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C,activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor ***,HCCcells-derived Sema3Cfacilitated extracellular matrix(ECM)contraction and collagen deposition in vivo,while also promoting the proliferation and activation of hepatic stellate cells(HSCs).Mechanistically,Sema3C interacted with NRP1 and ITGB1 in HSCs,activating downstream NF-kB signaling,thereby stimulating the release of IL-6 and upregulating HMGCR expression,consequently enhancing cholesterol synthesis in ***,CAF-secreted TGF-β1 activates AP1 signaling to augment Sema3C expression in HCC cells,establishing a positive feedback loop that accelerates HCC ***,blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in *** sum,our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CsCs and stroma during hepatocarcinogenesis,thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.

关键词： Sema hepatocellular thereby

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Genetic regulation of m^(6)A RNA methylation and its contribution in human complex diseases

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Science China(Life Sciences) 2024年第8期67卷 1591-1600页

作者： Kexuan Chen Jiuhong Nan Xushen Xiong The second Affiliated Hospital&Liangzhu Laboratory Zhejiang University School of MedicineHangzhou 311121China State Key Laboratory of Transvascular Implantation Devices The Second Affiliated HospitalZhejiang University School of MedicineHangzhou 311121China

N6-methyladenosine(m^(6)A)has been established as the most prevalent chemical modification in message RNA(mRNA),playing an essential role in determining the fate of RNA *** of m^(6)A has been revealed to lead to abnormal physiological conditions and cause various types of human *** studies have delineated the genetic regulatory maps for m^(6)A methylation by mapping the quantitative trait loci of m^(6)A(m^(6)A-QTLs),thereby building up the regulatory circuits linking genetic variants,m^(6)A,and human complex ***,we review the recent discoveries concerning the genetic regulatory maps of m^(6)A,describing the methodological and technical details of m^(6)A-QTL identification,and introducing the key findings of the cis-and trans-acting drivers of m^(6)*** further delve into the tissue-and ethnicity-specificity of m^(6)A-QTL,the association with other molecular phenotypes in light of genetic regulation,the regulators underlying m^(6)A genetics,and importantly,the functional roles of m^(6)A in mediating human complex ***,we discuss potential research avenues that can accelerate the translation of m^(6)A genetics studies toward the development of therapies for human genetic diseases.

关键词： m^(6)A disease genetics m^(6)A-QTL GWAS

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Relationship between dietary niacin intake and erectile dysfunction:a population-based study

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Asian Journal of Andrology 2024年第4期26卷 382-388页

作者： Wei-Long Lin Cheng Zheng Hao-Xu Wang Wei Zhang Ming-En Lin Department of Urology The First Affiliated Hospital of Shantou University Medical CollegeMedical College of Shantou UniversityShantou 515041China The second school of Clinical Medicine Southern Medical UniversityGuangzhou 510260China.

Existing research on the precise link between dietary niacin intake and erectile dysfunction(ED)is ***,this study aimed to investigate the potential association between dietary niacin intake and the risk of *** logistic regression and restricted cubic splines(RCSs)were used to examine the relationship between dietary niacin intake and *** interaction analysis was performed to assess the impact of different subgroups on the study *** addition,1:1 propensity score matching(PSM)was employed to adjust for potential confounding factors,ensuring the reliability of the *** analyzed data were collected from the 2001–2004 National Health and Nutrition Examination Survey(NHANES)in the *** study encompassed 3184 adults,among whom 863 participants were identified as having *** adjustments for potential confounders,the findings revealed that higher niacin intake,specifically in the highest tertile,was associated with a decreased risk of ED compared to that in the lowest tertile,showing an odds ratio(OR)of 0.56(95%confidence interval[CI]:0.37–0.85).Analysis of dose–response curves illustrated a negative correlation between dietary niacin intake and the risk of *** and interaction analyses fortified the consistency of these ***,PSM corroborated the validity of the *** study suggests an inverse association between dietary niacin intake and the risk of ***,establishing a cause-and-effect relationship remains elusive,and defining the safe threshold of niacin intake to prevent ED requires further investigation.

关键词： dietary niacin erectile dysfunction National Health and Nutrition Examination Survey propensity score matching

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Engineered extracellular vesicles for targeted reprogramming of cancer-associated fibroblasts to potentiate therapy of pancreatic cancer

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3077-3096页

作者： Pengcheng Zhou Xuanlong Du Weilu Jia Kun Feng Yewei Zhang Department of General Surgery Affiliated Hospital of Nantong UniversityNantongChina school of Medicine Southeast UniversityNanjingChina Nanjing medical University NanjingChina Hepatobiliary and Pancreatic Center The Second Affiliated Hospital of Nanjing Medical UniversityNanjingChina

Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for *** tumor microenvironment(TME)in pancreatic cancer,distinguished by fibrosis and the existence of cancer-associated fibroblasts(CAFs),exerts a pivotal influence on both tumor advancement and resistance to *** advancements in the field of engineered extracellular vesicles(EVs)offer novel avenues for targeted therapy in pancreatic *** study aimed to develop engineered EVs for the targeted reprogramming of CAFs and modulating the TME in pancreatic *** obtained from bone marrow mesenchymal stem cells(BMSCs)were loaded with miR-138-5p and the anti-fibrotic agent pirfenidone(PFD)and subjected to surface modification with integrinα5-targeting peptides(named IEVs-PFD/138)to reprogram CAFs and suppress their pro-tumorigenic ***α5-targeting peptide modification enhanced the CAF-targeting ability of ***-138-5p directly inhibited the formation of the FERMT2-TGFBR1 complex,inhibiting TGF-βsignaling pathway *** addition,miR-138-5p inhibited proline-mediated collagen synthesis by directly targeting the FERMT2-PYCR1 *** combination of miR-138-5p and PFD in EVs synergistically promoted CAF reprogramming and suppressed the pro-cancer effects of *** experiments using the orthotopic stroma-rich and patient-derived xenograft mouse models yielded promising *** particular,IEVs-PFD/138 effectively reprogrammed CAFs and remodeled TME,which resulted in decreased tumor pressure,enhanced gemcitabine perfusion,tumor hypoxia amelioration,and greater sensitivity of cancer cells to ***,the strategy developed in this study can improve chemotherapy *** IEVs-PFD/138 as a targeted therapeutic agent to modulate CAFs and the TME represents a promising therapeutic approach for pancreatic cancer.

关键词： inhibited targeted chemotherapy

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M^(6)A modification in cardiovascular disease:With a focus on programmed cell death

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Genes & Diseases 2024年第5期11卷 272-284页

作者： Wen Li Yao Liu Ruiyan Xu Yuan Zong Lu He Jun Hu Guohua Li Institute of Cardiovascular Disease Key Laboratory for Arteriosclerology of Hunan ProvinceHunan International Scientific and Technological Cooperation Base of Arteriosclerotic DiseaseDepartment of PathophysiologyMOE Key Lab of Rare Pediatric DiseasesHengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China Department of Cardiovascular Medicine The Second Affiliated HospitalHengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China Department of Obstetrics and Gynecology The First Affiliated HospitalHengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China Department of Cardiovascular Surgery The Second Affiliated HospitalHengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China

N^(6)-methyladenosine(m^(6)A)methylation is one of the most predominant internal RNA modifications in eukaryotes and has become a hot spot in the field of epigenetics in recent *** diseases(CVDs)are a leading cause of death *** evidence demonstrates that RNA modifications,such as the m^(6)A modification,are associated with the development and progression of many diseases,including *** increasing body of studies has indicated that programmed cell death(PCD)plays a vital role in ***,the molecular mechanisms underlying m^(6)A modification and PCD in CVDs remain poorly ***,elaborating on the highly complex connections between the m^(6)A mechanisms and different PCD signaling pathways and clarifying the exact molecular mechanism of m^(6)A modification mediating PCD have significant meaning in developing new strategies for the prevention and therapy of *** is great potential for clinical application.

关键词： Apoptosis Autophagy Cardiovascular diseases Ferroptosis N^(6)-methyladenosine Programmed cell death Pyroptosis

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A combined nanotherapeutic approach targeting farnesoid X receptor,ferroptosis,and fibrosis for nonalcoholic steatohepatitis treatment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2228-2246页

作者： Jiangtao Fu Pingping Zhang Zhiguo Sun Guodong Lu Qi Cao Yiting Chen Wenbin Wu Jiabao Zhang Chunlin Zhuang Chunquan Sheng Jiajun Xu Ying Lu Pei Wang The Center for Basic Research and Innovation of Medicine and Pharmacy(MOE) School of PharmacyNaval Medical UniversityShanghai 200433China National Demonstration Center for Experimental Pharmaceutical Education Naval Medical University/Second Military Medical UniversityShanghai 200433China Department of Diving and Hyperbaric Medicine Naval Special Medical CenterNaval Medical UniversityShanghai 200433China

Obeticholic acid(OCA),a farnesoid X receptor(FXR)agonist with favorable effects on fatty and glucose metabolism,has been considered the leading candidate drug for nonalcoholic steatohepatitis(NASH)***,its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major ***,a newly recognized form of cell death characterized by uncontrolled lipid peroxidation,is involved in the progression of *** oxide(NO)is a versatile biological molecule that can degrade extracellular *** this study,we developed a PEGylated thiolated hollow mesoporous silica nanoparticles(MSN)loaded with OCA,as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol(ONL@MSN).Biochemical analyses,histology,multiplexed flow cytometry,bulk-tissue RNA sequencing,and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle(ONL@MSN)in a mouse NASH *** with the OCA-loaded nanoparticles(O@MSN),ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ***@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis,inhibition of immune response/lipid peroxidation,and correction of microbiota *** findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR,ferroptosis,and fibrosis.

关键词： Nonalcoholic steatohepatitis Nanotherapy Farnesoid X receptor Ferroptosis Fibrosis Obeticholic acid S-Nitrosothiol Liproxstatin-1

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Potential clinical application of microRNAs in bladder cancer

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Journal of Biomedical Research 2024年第4期38卷 289-306页

作者： Pei Wang Xiaowei Wei Xiaojun Qu Yefei Zhu Laboratory Medicine Center the Second Affiliated Hospital of Nanjing Medical UniversityNanjingJiangsu 210011China school of Biological Science and medical Engineering Southeast UniversityNanjingJiangsu 210096China

Bladder cancer(BC)is the tenth most prevalent malignancy globally,presenting significant clinical and societal challenges because of its high incidence,rapid progression,and frequent ***,cystoscopy and urine cytology serve as the established diagnostic methods for ***,their efficacy is limited by their invasive nature and low ***,the development of highly specific biomarkers and effective noninvasive detection strategies is imperative for achieving a precise and timely diagnosis of BC,as well as for facilitating an optimal tumor treatment and an improved ***(miRNAs),short noncoding RNA molecules spanning around 20–25 nucleotides,are implicated in the regulation of diverse carcinogenic *** altered miRNAs form robust functional regulatory networks that exert a notable influence on the tumorigenesis and progression of *** into aberrant miRNAs derived from blood,urine,or extracellular vesicles indicate their potential roles as diagnostic biomarkers and prognostic indicators in BC,enabling miRNAs to monitor the progression and predict the recurrence of the ***,the investigation centered on miRNA as a potential therapeutic agent presents a novel approach for the treatment of *** review comprehensively analyzes biological roles of miRNAs in tumorigenesis and progression,and systematically summarizes their potential as diagnostic and prognostic biomarkers,as well as therapeutic targets for ***,we evaluate the progress made in laboratory techniques within this field and discuss the prospects.

关键词： bladder cancer microRNAs biomarker diagnosis detection method

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Norepinephrine-Astrocyte Signaling Regulates Cortical State Homeostasis

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Neuroscience Bulletin 2024年第7期40卷 1021-1024页

作者： Yulan Li Lixuan Li Yibei Wang Xinyi Li Zhong Chen Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou 310053China Department of Neurology Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310009China

Cortical states such as high and low arousal during wakefulness or rapid eye movement(REM)and non-REM(NREM)phases of sleep are fundamental biological processes that are highly conserved across *** intricate balance or... 详细信息

关键词： homeostasis NREM stasis

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Bayesian network-based survival prediction model for patients having undergone post-transjugular intrahepatic portosystemic shunt for portal hypertension

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World Journal of Gastroenterology 2024年第13期30卷 1859-1870页

作者： Rong Chen Ling Luo Yun-Zhi Zhang Zhen Liu An-Lin Liu Yi-Wen Zhang Department of Infectious Diseases Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China

BACKGROUND Portal hypertension(PHT),primarily induced by cirrhosis,manifests severe symptoms impacting patient *** transjugular intrahepatic portosystemic shunt(TIPS)is a critical intervention for managing PHT,it carries risks like hepatic encephalopathy,thus affecting patient survival *** our knowledge,existing prognostic models for post-TIPS survival in patients with PHT fail to account for the interplay among and collective impact of various prognostic factors on ***,the development of an innovative modeling approach is essential to address this *** To develop and validate a Bayesian network(BN)-based survival prediction model for patients with cirrhosis-induced PHT having undergone *** The clinical data of 393 patients with cirrhosis-induced PHT who underwent TIPS surgery at the second Affiliated Hospital of Chongqing medical University between January 2015 and May 2022 were retrospectively *** were selected using Cox and least absolute shrinkage and selection operator regression methods,and a BN-based model was established and evaluated to predict survival in patients having undergone TIPS surgery for *** Variable selection revealed the following as key factors impacting survival:age,ascites,hypertension,indications for TIPS,postoperative portal vein pressure(post-PVP),aspartate aminotransferase,alkaline phosphatase,total bilirubin,prealbumin,the Child-Pugh grade,and the model for end-stage liver disease(MELD)*** on the above-mentioned variables,a BN-based 2-year survival prognostic prediction model was constructed,which identified the following factors to be directly linked to the survival time:age,ascites,indications for TIPS,concurrent hypertension,post-PVP,the Child-Pugh grade,and the MELD *** Bayesian information criterion was 3589.04,and 10-fold cross-validation indicated an average log-likelihood loss of 5.55 with a standard deviation of *** model’s acc

关键词： Bayesian network Cirrhosis Portal hypertension Transjugular intrahepatic portosystemic shunt Survival prediction model

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Comparative studies between humans and golden Syrian hamsters via thromboelastography

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Animal Models and Experimental Medicine 2024年第4期7卷 570-577页

作者： Ze Yang Lili Xie Jingjing Ba Simin Zan Letong Zhang Xinyi Zhang Yang Yu school of Laboratory Animal&Shandong Laboratory Animal Center Shandong First Medical University&Shandong Academy of Medical SciencesJinanChina The second Affiliated Hospital of Shandong First medical University TaianChina

Background:Thromboelastography(TEG)is a widely utilized clinical testing method for real-time monitoring of platelet function and the thrombosis *** metab-olism disorders are crucial risk factors for *** lipid metabolism charac-teristics of hamsters resemble those of humans more closely than mice and rats,and their relatively large blood volume makes them suitable for studying the mechanisms of thrombosis related to plasma lipid *** blood samples from golden Syrian hamsters and healthy humans were obtained following standard clinical *** was employed to evaluate coagulation factor function,fibrinogen(Fib)function,platelet function,and the fibrinolytic ***:The whole blood from hamster or healthy human was isolated following the clinical procedure,and TEG was employed to evaluate the coagulation factor func-tion,Fib function,platelet function,and fibrinolytic *** analysis used ACLTOP750 automatic coagulation analysis *** routine testing used XN-2000 automatic blood ***:TEG parameters revealed that hamsters exhibited stronger coagulation fac-tor function than humans(reaction time[R],p=0.0117),with stronger Fib function(alpha angle,p<0.0001;K-time[K],p<0.0001).Platelet function did not differ signifi-cantly(maximum amplitude[MA],p=0.077).Hamsters displayed higher coagulation status than humans(coagulation index[CI],p=0.0023),and the rate of blood clot dissolution in hamsters differed from that in humans(percentage lysis 30 min after MA,p=0.02).Coagulation analysis parameters indicated that prothrombin time(PT)and activated partial thromboplastin time(APTT)were faster in hamsters than in hu-mans(PT,p=0.0014;APTT,p=0.03),whereas the Fib content was significantly lower in hamsters than in humans(p<0.0001).No significant difference was observed in thrombin time(p=0.1949).Conclusions:In summary,TEG could be used to evaluate thrombosis and bleeding parameters in whole blood samples

关键词： platelet function Syrian hamster thromboelastography(TEG) thrombosis

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