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Comprehensive prognostic and immune analysis of sterol Oacyltransferase 1 in patients with hepatocellular carcinoma

World Journal of Hepatology 2024年第3期16卷 439-451页

作者： Chang-Jiao Gan Yue Zheng Bin Yang Li-Min Cao Development Research Department National Medical Products Administration Institute of Executive DevelopmentBeijing 100071China School of Medicine Nankai University Affiliated Third Center HospitalTianjin 300070China Tianjin institute of Hepatobiliary disease The Third Central Hospital of TianjinTianjin 300170China Department of Science and Technology Tianjin Third Central HospitalTianjin 300170China

BACKGROUND Sterol O-acyltransferase 1(SOAT1)is an important target in the diagnosis and treatment of liver cancer.However,the prognostic value of SOAT1 in patients with hepatocellular carcinoma(HCC)is still not clear.AIM To investigate the correlation of SOAT1 expression with HCC,using RNA-seq and gene expression data of The Cancer Genome Atlas(TCGA)-liver hepatocellular carcinoma(LIHC)and pan-cancer.METHODS The correlation between SOAT1 expression and HCC was analyzed.Cox hazard regression models were conducted to investigate the prognostic value of SOAT1 in HCC.Overall survival and disease-specific survival were explored based on TCGA-LIHC data.Biological processes and functional pathways mediated by SOAT1 were characterized by gene ontology(GO)analysis and the Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis of differentially expressed genes.In addition,the protein-protein interaction network and co-expression analyses of SOAT1 in HCC were performed to better understand the regulatory mechanisms of SOAT1 in this malignancy.RESULTS SOAT1 and SOAT2 were highly expressed in unpaired samples,while only SOAT1 was highly expressed in paired samples.The area under the receiver operating characteristic curve of SOAT1 expression in tumor samples from LIHC patients compared with para-carcinoma tissues was 0.748,while the area under the curve of SOAT1 expression in tumor samples from LIHC patients compared with GTEx was 0.676.Patients with higher SOAT1 expression had lower survival rates.Results from GO/KEGG and gene set enrichment analyses suggested that the PI3K/AKT signaling pathway,the IL-18 signaling pathway,the calcium signaling pathway,secreted factors,the Wnt signaling pathway,the Jak/STAT signaling pathway,the MAPK family signaling pathway,and cell–cell communication were involved in such association.SOAT1 expression was positively associated with the abundance of macrophages,Th2 cells,T helper cells,CD56bright natural killer cells,and Th1 cells,and negatively linked to the abundance of Th17 cells,dendritic

关键词： Sterol O-acyltransferase 1 Hepatocellular carcinoma Prognostic Immune

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Bioactive components, pharmacological properties and underlying mechanism of Ganoderma lucidum spore oil: A review

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Chinese Herbal Medicines 2024年第3期16卷 375-391页

作者： Jianying Liu Binzhi Zhang Leqi Wang Shasha Li Qinqiang Long Xue Xiao Guangdong metabolic diseases Research Center of Integrated Chinese and Western Medicine (institute of Chinese Medicine) Guangdong Pharmaceutical University The Second Clinical College of Guangzhou University of Chinese Medicine Guangzhou Higher Education Mega Center NMPA Key Laboratory for Rapid Testing Technology of Drugs Guangdong Institute for Drug Control

Ganoderma lucidum is a Chinese medicinal fungus with a long history of use in healthcare and disease treatment.G.lucidum spores（GLS） are tiny germ cells released from the mushroom cap during the mature stage of growth.They contain all the genetic active substances of G.lucidum.G.lucidum spore oil（GLSO） is a lipid component extracted from broken-walled Ganoderma spores using supercritical CO2extraction technology.GLSO contains fatty acids,Ganoderma triterpenes,sterols and other bioactive compounds.Previous studies have demonstrated that GLSO has a wide range of pharmacological properties,including anti-tumor,anti-aging,neuroprotection,immunomodulation,hepatoprotection and modulation of metabolic diseases.This review summarizes the research progress of GLSO over the past two decades in terms of its bioactive components,extraction and processing techniques,pharmacological effects and safety evaluation.This provides a solid foundation for further research and application of GLSO.

关键词： anti-aging anti-tumor bioactive components Ganoderma lucidum spore oil hepatoprotection immune regulation pharmacological properties

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Leucine regulates lipid metabolism in adipose tissue through adipokine-mTOR-SIRT1 signaling pathway and bile acid—microbe axis in a finishing pig model

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Animal Nutrition 2024年第1期16卷 158-173页

作者： Yunju Yin Saiming Gong Mengmeng Han Jingzun Wang Hanjing Shi Xianji Jiang Liu Guo Yehui Duan Qiuping Guo Qinghua Chen Fengna Li Key Laboratory of Agro-ecological Processes in Subtropical Region Institute of Subtropical AgricultureChinese Academy of SciencesHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessHunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production College of Animal Science and Technology Hunan Agricultural University College of Modern Agricultural Sciences University of Chinese Academy of Sciences College of Life Science and Engineering Northwest Minzu University

This study was conducted to explore the regulatory mechanism of leucine (Leu) on lipid metabolism of finishing pigs.Twenty-four Duroc×Landrace×Large cross pigs with an average body weight of68.33±0.97 kg were randomly allocated into 3 treatment groups with 8 replicates per group (1 pig per replicate).The dietary treatments were as follows:control group (CON),0.25%Leu group and 0.50%Leu group.The experimental period was 42 d.The results showed as follows.(1) Compared with the CON,0.25%and 0.50%Leu increased (P<0.01) the average daily gain (ADG),while the average backfat thickness (ABT) and the ratio of feed intake to body weight gain (F:G ratio) were decreased (P<0.05).(2)In the 0.25%Leu group,the relative mRNA expression levels of sterol regulatory element binding protein-1c (SREBP1c),recombinant fatty acid transport protein 1 (FATP1),chemerin and peroxisome proliferatoractivated receptor γ (PPARγ) were decreased but the level of fatty acid binding protein 4 (FABP4) and fatty acid translocase (FAT/CD36) were increased in backfat tissue.In the 0.25%Leu group,the protein levels of p-Rictor,p-Raptor,p-eIF4E-binding protein 1 (p-4EBP1),p-silent mating type information regulator 2homolog 1 (p-SIRT1) and acetylation ribosome s6 protein kinase 1 (Ac—S6K1) were increased (P<0.05).(3) Compared to the CON,the diversity of gut microbiota in the 0.25%Leu group was increased.Principal component analysis showed that the relative abundance of Bacteroidetes,Lactobacillus and Desulfovibrio was higher in the 0.25%Leu group than the CON,but the relative abundance of Firmicutes,Treponema and Shigella was lower than in the CON (P<0.05).(4) Four different metabolites were screened out from the serum of finishing pigs including allolithocholic acid (alloLCA),isolithocholic acid (isoLCA),ursodeoxycholic acid (UDCA) and hyodeoxycholic acid (HDCA),which correlate to various degrees with the above microorganisms.In conclusion,Leu could promote adipose tissue lipolysis of finishing pigs through the mTOR-SIRT1 signaling pathway,and S6K1 is a

关键词： Leu Lipid metabolism Gut microbiota Bile acid

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How do lateral septum projections to the ventral CA1 influence sociability?

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Neural Regeneration Research 2024年第8期19卷 1789-1801页

作者： Dan Wang Di Zhao Wentao Wang Fengai Hu Minghu Cui Jing Liu Fantao Meng Cuilan Liu Changyun Qiu Dunjiang Liu Zhicheng Xu Yameng Wang Yu Zhang Wei Li Chen Li Department of Rehabilitation Medicine Binzhou Medical University HospitalBinzhouShandong ProvinceChina Medical Research Center Binzhou Medical University HospitalBinzhouShandong ProvinceChina institute for metabolic&Neuropsychiatric Disorders Binzhou Medical University HospitalBinzhouShandong ProvinceChina Department of Psychology Binzhou Medical University HospitalBinzhouShandong ProvinceChina College of Nursing Binzhou Medical UniversityBinzhouShandong ProvinceChina

Social dysfunction is a risk factor for several neuropsychiatric illnesses.Previous studies have shown that the lateral septum(LS)-related pathway plays a critical role in mediating social behaviors.Howeve r,the role of the connections between the LS and its downstream brain regions in social behavio rs remains unclea r.In this study,we conducted a three-chamber test using electrophysiological and chemogenetic approaches in mice to determine how LS projections to ventral CA1(vCA1)influence sociability.Our res ults showed that gamma-aminobutyric acid(GABA)-e rgic neuro ns were activated following social experience,and that social behavio rs were enhanced by chemogenetic modulation of these neurons.Moreover,LS GABAergic neurons extended their functional neural connections via vCA1 glutamatergic pyramidal neurons,and regulating LSGABA→vCA1Gluneural projections affected social behaviors,which were impeded by suppressing LSprojecting vCA1 neuronal activity or inhibiting GABAAreceptors in vCA1.These findings support the hypothesis that LS inputs to the vCA1 can control social prefe rences and social novelty behaviors.These findings provide new insights rega rding the neural circuits that regulate sociability.

关键词： chemogenetics GABA receptor GABAergic neurons glutamatergic neurons lateral septum neural excitability neural projection social novelty social preference ventral CA1

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Retrospective study of the incidence, risk factors, treatment outcomes of bacterial infections at uncommon sites in cirrhotic patients

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World Journal of Hepatology 2024年第3期16卷 418-427页

作者： Sophie Schneitler Christina Schneider Markus Casper Frank Lammert Marcin Krawczyk Sören L Becker Matthias Christian Reichert institute of Medical Microbiology and Hygiene Saarland UniversityHomburg 66421Germany Department of Medicine II Saarland University Medical CenterHomburg 66421Germany Health Sciences Hannover Medical SchoolHannover 30625Germany Laboratory of metabolic Liver diseases Department of GeneralTransplant and Liver SurgeryCentre for Preclinical ResearchMedical University of WarsawWarsaw 02-097Poland

BACKGROUND Bacterial infections(BI)negatively affect the natural course of cirrhosis.The most frequent BI are urinary tract infections(UTI),pneumonia,and spontaneousbacterial peritonitis(SBP).AIM To assess the relevance of bacterial infections beyond the commonly recognized types in patients with cirrhosis and to investigate their relationship with other clinical variables.METHODS We retrospectively analyzed patients with cirrhosis and BI treated between 2015 and 2018 at our tertiary care center.BIs were classified as typical and atypical,and clinical as well as laboratory parameters were compared between the two groups.RESULTS In a cohort of 488 patients with cirrhosis,we identified 225 typical BI(95 UTI,73 SBP,72 pulmonary infections)and 74 atypical BIs,predominantly cholangitis and soft tissue infections(21 each),followed by intra-abdominal BIs(n=9),cholecystitis(n=6),head/throat BIs(n=6),osteoarticular BIs(n=5),and endocarditis(n=3).We did not observe differences concerning age,sex,or etiology of cirrhosis in patients with typical vs atypical BI.Atypical BIs were more common in patients with more advanced cirrhosis,as evidenced by Model of End Stage Liver disease(15.1±7.4 vs 12.9±5.1;P=0.005)and Child-Pugh scores(8.6±2.5 vs 8.0±2;P=0.05).CONCLUSION Atypical BIs in cirrhosis patients exhibit a distinct spectrum and are associated with more advanced stages of the disease.Hence,the work-up of cirrhosis patients with suspected BI requires detailed work-up to elucidate whether typical BI can be identified.

关键词： Bacterial infection Empirical antibiotic therapy End-stage liver disease Escherichia coli Multi-resistant pathogens

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Cold-Induced Reprogramming of Subcutaneous White Adipose Tissue Assessed by Single-Cell and Single-Nucleus RNA Sequencing

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Research 2024年第1期2023卷 763-778页

作者： Qing Liu Qiaoyun Long Jiayu Zhao Wenjie Wu Zexin Lin Wei Sun Ping Gu Tuo Deng Kerry Martin Loomes Donghai Wu Alice P.S.Kong Jingying Zhou Alfred S.Cheng Hannah Xiaoyan Hui School of Biomedical Sciences The Chinese University of Hong KongHong KongChina Department of Pharmacology and Pharmacy The University of Hong KongHong KongChina Guangzhou institute of Biomedicine and Health Chinese Academy of SciencesGuangzhouChina China-New Zealand Joint Laboratory on Biomedicine and Health Chinese Academy of SciencesGuangzhouChina Department of Endocrinology Jinling HospitalNanjing UniversitySchool of MedicineNanjingChina National Clinical Research Center for metabolic diseases and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina Key Laboratory of Diabetes Immunology Ministry of Educationand Metabolic Syndrome Research CenterThe Second Xiangya Hospital of Central South UniversityChangshaChina Clinical Immunology Center The Second Xiangya Hospital of Central South UniversityChangshaChina School of Biological Sciences and Maurice Wilkins Centre University of AucklandAucklandNew Zealand Department of Medicine and Therapeutics The Chinese University of Hong KongHong KongChina Hong Kong institute of Diabetes and Obesity The Chinese University of Hong KongPrince of Wales HospitalShatinHong KongChina Li Ka Shing institute of Health Sciences The Chinese University of Hong KongPrince of Wales HospitalShatinHong KongChina

Adipose browning has demonstrated therapeutic potentials in several diseases.Here,by conducting transcriptomic profiling at the single-cell and single-nucleus resolution,we reconstituted the cellular atlas in mouse inguinal subcutaneous white adipose tissue(iWAT)at thermoneutrality or chronic cold condition.All major nonimmune cells within the iWAT,including adipose stem and progenitor cells(ASPCs),mature adipocytes,endothelial cells,Schwann cells,and smooth muscle cells,were recovered,allowing us to uncover an overall and detailed blueprint for transcriptomes and intercellular cross-talks and the dynamics during white adipose tissue brown remodeling.Our findings also unravel the existence of subpopulations in mature adipocytes,ASPCs,and endothelial cells,as well as new insights on their interconversion and reprogramming in response to cold.The adipocyte subpopulation competent of major histocompatibility complex class Ⅱ(MHCⅡ)antigen presentation is potentiated.Furthermore,a subcluster of ASPC with CD74 expression was identified as the precursor of this MHCⅡ^(+)adipocyte.Beige adipocytes are transdifferented from preexisting lipid generating adipocytes,which exhibit developmental trajectory from de novo differentiation of amphiregulin cells(Aregs).Two distinct immune-like endothelial subpopulations are present in iWAT and are responsive to cold.Our data reveal fundamental changes during cold-evoked adipose browning.

关键词： evoked programming generating

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Molecular mechanisms of DNA lesion and repair during antibody somatic hypermutation

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Science China Life Sciences 2024年

作者： Qian Hao Jinfeng Li Leng-Siew Yeap Shanghai institute of Immunology Department of Immunology and Microbiology State Key Laboratory of Oncogenes and Related Genes Shanghai Jiao Tong University School of Medicine Center for Immune-Related diseases at Shanghai institute of Immunology Department of Endocrinology and Metabolic Diseases Ruijin Hospital Shanghai Jiao Tong University School of Medicine

Antibody diversification is essential for an effective immune response, with somatic hypermutation(SHM) serving as a key molecular process in this adaptation. Activation-induced cytidine deaminase(AID) initiates SHM by inducing DNA lesions, which are ultimately resolved into point mutations, as well as small insertions and deletions(indels). These mutational outcomes contribute to antibody affinity maturation.The mechanisms responsible for generating point mutations and indels involve the base excision repair(BER) and mismatch repair(MMR)pathways, which are well coordinated to maintain genomic integrity while allowing for beneficial mutations to occur. In this regard,translesion synthesis(TLS) polymerases contribute to the diversity of mutational outcomes in antibody genes by enabling the bypass of DNA lesions. This review summarizes our current understanding of the distinct molecular mechanisms that generate point mutations and indels during SHM. Understanding these mechanisms is critical for elucidating the development of broadly neutralizing antibodies(bnAbs) and autoantibodies, and has implications for vaccine design and therapeutics.

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Gene-knockout by iSTOP enables rapid reproductive disease modeling and phenotyping in germ cells of the founder generation

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Science China(Life Sciences) 2024年第5期67卷 1035-1050页

作者： Yaling Wang Jingwen Chen Xueying Huang Bangguo Wu Peng Dai Feng Zhang Jinsong Li Lingbo Wang State Key Laboratory of Genetic Engineering Shanghai Key Laboratory of Metabolic Remodeling and HealthInstitute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China institute of Reproduction and Development Obstetrics and Gynecology HospitalFudan UniversityShanghai 200011China NHC Key Lab of Reproduction Regulation(Shanghai institute for Biomedical and Pharmaceutical Technologies) School of PharmacyFudan UniversityShanghai 200433China Shanghai Key Laboratoryof Maternal and Fetal Medicine Clinical and Translational Research Center of Shanghai First Maternity and Infant HospitalFrontier Science Center for Stem Cell ResearchSchoolof Life Sciences and TechnologyTongji UniversityShanghai 200092China State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China

Cytosine base editing achieves C·G-to-T·A substitutions and can convert four codons(CAA/CAG/CGA/TGG)into STOP-codons(induction of STOP-codons,iSTOP)to knock out genes with reduced mosaicism.iSTOP enables direct phenotyping in founders’somatic cells,but it remains unknown whether this works in founders’germ cells so as to rapidly reveal novel genes for fertility.Here,we initially establish that iSTOP in mouse zygotes enables functional characterization of known genes in founders’germ cells:Cfap43-iSTOP male founders manifest expected sperm features resembling human“multiple morphological abnormalities of the flagella”syndrome(i.e.,MMAF-like features),while oocytes of Zp3-iSTOP female founders have no zona pellucida.We further illustrate iSTOP’s utility for dissecting the functions of unknown genes with Ccdc183,observing MMAF-like features and male infertility in Ccdc183-iSTOP founders,phenotypes concordant with those of Ccdc183-KO offspring.We ultimately establish that CCDC183 is essential for sperm morphogenesis through regulating the assembly of outer dynein arms and participating in the intra-flagellar transport.Our study demonstrates iSTOP as an efficient tool for direct reproductive disease modeling and phenotyping in germ cells of the founder generation,and rapidly reveals the essentiality of Ccdc183 in fertility,thus providing a time-saving approach for validating genetic defects(like nonsense mutations)for human infertility.

关键词： disease modeling infertility multiple morphological abnormalities of the flagella(MMAF) induction of STOP-codons(iSTOP CRISPR-STOP) sperm motility

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RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

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Bone Research 2024年第1期12卷 165-179页

作者： Luis F.de Castro Jarred M.Whitlock Zachary Michel Kristen Pan Jocelyn Taylor Vivian Szymczuk Brendan Boyce Daniel Martin Vardit Kram Rebeca Galisteo Kamran Melikov Leonid V.Chernomordik Michael T.Collins Alison M.Boyce Skeletal Disorders and Mineral Homeostasis Section National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Section on Membrane Biology Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA metabolic Bone Disorders Unit National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA Department of Plastic and Reconstructive Surgery The Johns Hopkins Medical InstitutionsBaltimoreMDUSA Department of Pathology and Laboratory Medicine University of Rochester Medical CenterRochesterNYUSA NIDCR Genomics and Computational Biology Core National Institute of Dental and Craniofacial ResearchNational Institutes of HealthBethesdaMDUSA

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established treatments.Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment strategy.In this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical models.Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition.RNA sequencing of human and mouse tissue supported these findings.The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts.The results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within lesions.These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

关键词： dysplasia treatment finding

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The Wnt-dependent and Wnt-independent functions of BCL9 in development,tumorigenesis,and immunity:Implications in therapeutic opportunities

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Genes & diseases 2024年第2期11卷 701-710页

作者： Minjie Wu Heng Dong Chao Xu Mengqing Sun Haojin Gao Fangtian Bu Jianxiang Chen College of Pharmacy and Department of Hepatology Institute of Hepatology and Metabolic DiseasesThe Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhouZhejiang 311121China Laboratory of Cancer Genomics Division of Cellular and Molecular ResearchNational Cancer CentreSingapore 169610Singapore Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhouZhejiang 311121China

B-cell CLL/lymphoma 9(BCL9)is considered a key developmental regulator and a well-established oncogenic driver in multiple cancer types,mainly through potentiating the Wnt/β-catenin signaling.However,increasing evidences indicate that BCL9 also plays multiple Wnt-independent roles.Herein,we summarized the updates of the canonical and non-canonical functions of BCL9 in cellular,physiological,or pathological processes.Moreover,we also concluded that the targeted inhibitors disrupt the interaction ofβ-catenin with BCL9 reported recently.

关键词： BCL9 Development Immunity Multifaceted functions Therapeutic target Tumorigenesis

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