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Genes & Diseases 2024年第3期11卷 69-71页

作者： Jian Yang Lingxiao Wang Hui Sun Zhenxiang Zhao Yanchuan Ma Zhen Hu Liqin Zhai Yonggang Wang Translational Medicine Research Center Shanxi Medical UniversityTaiyuanShanxi030001China Department of Cell Biology and Genetics Shanxi Medical UniversityTaiyuanShanxi 030001China key laboratory of cellular physiology of the Ministry of Education Shanxi Medical UniversityTaiyuanShanxi 030001China Department of Colorectal Surgery The Fifth Clinical Medical College of Shanxi Medical UniversityTaiyuanShanxi 030012China Science&Technology Information and Strategy Research Center of shanxi TaiyuanShanxi 030006China Department of Pathology Shanxi Provincial People's HospitalTaiyuanShanxi 030012China Department of Anatomy College of Basic MedicineShanxi Medical UniversityTaiyuanShanxi 030001China

Esophageal squamous cell cancer(EScC)is one of the malignant tumors with high morbidity and mortality all over the world.^(1) In recent years,combined chemotherapy has gradually been the effective treatment method for EscC patients.Therefore,it is imperative to explore potential therapeutic targets for the treatment of EsCC.We previously reported a high-frequency amplification of pyrimidine metabolic pathway-related genes in EsCC tissues.

关键词： squamous esophageal cancer

Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology,cognition,and behavior in APP/PS1 mice

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Neural Regeneration Research 2025年第2期20卷 533-547页

作者： Yanli Zhang Tian Li Jie Miao Zhina Zhang Mingxuan Yang Zhuoran Wang Bo Yang Jiawei Zhang Haiting Li Qiang Su Junhong Guo Department of Neurology First Hospital of Shanxi Medical UniversityTaiyuanShanxi ProvinceChina Department of Neurology Sixth Hospital of Shanxi Medical University(General Hospital of Tisco)TaiyuanShanxi ProvinceChina Department of physiology Key Laboratory of Cellular PhysiologyMinistry of EducationShanxi Medical UniversityTaiyuanShanxi ProvinceChina Department of Hernia and Abdominal Wall Surgery Shanxi Bethune HospitalShanxi Academy of Medical SciencesTongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuanShanxi ProvinceChina Department of laboratory Medicine of Fenyang College Shanxi Medical UniversityFenyangShanxi ProvinceChina

In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.

关键词： Alzheimer’s disease amyloid-β APP/PS1 mice cerebrovascular endothelial cells cognitive deficits gamma-glutamyl transferase 5 neurovascular unit nuclear factor‐kappa B synaptic plasticity β-site APP cleaving enzyme 1

Herb pair of Huangqi-Danggui exerts anti-tumor immunity to breast cancer by upregulating PIK3R1

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Animal Models and Experimental Medicine 2024年第3期7卷 234-258页

作者： Hai-Xin Liu Li Lian Li-Li Hou Cai-Xia Liu Jin-Hong Ren Yuan-Biao Qiao Shi-Yuan Wen Qing-Shan Li College of Traditional Chinese Medicine and Food Engineering Shanxi University of Chinese MedicineTaiyuanChina shanxi key laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation College of Traditional Chinese Medicine and Food EngineeringShanxi University of Chinese MedicineTaiyuanChina College of Basic medical Sciences Shanxi Medical UniversityTaiyuanChina

Background:According to traditional Chinese medicine(TCM),drugs supplementing the vital energy,Qi,can eliminate tumors by restoring host immunity.The objective of this study is to investigate the underlying immune mechanisms of anti-tumor activity associated with Qi-supplementing herbs,specifically the paired use of Huangqi and Danggui.Methods:Analysis of compatibility regularity was conducted to screen the combination of Qi-supplementing TCMs.Using the MTT assay and a transplanted tumor mice model,the anti-tumor effects of combination TCMs were investigated in vitro and in vivo.High content analysis and flow cytometry were then used to evaluate cellular immunity,followed by network pharmacology and molecular docking to dissect the significant active compounds and potential mechanisms.Finally,the anti-tumor activity and the mechanism of the active ingredients were verified by molecular experiments.Results:There is an optimal combination of Huangqi and Danggui that,administered as an aqueous extract,can activate immunity to suppress tumor and is more effective than each drug on its own in vitro and in vivo.Based on network pharmacology analysis,PIK3R1 is the core target for the anti-tumor immunity activity of combined Huangqi and Danggui.Molecular docking analysis shows 6 components of the combined Danggui and Huangqi extract(quercetin,jaranol,isorhamnetin,kaempferol,calycosin,and suchilactone)that bind to PIK3R1.Jaranol is the most important component against breast cancer.The suchilactone/jaranol combination and,especially,the suchilactone/kaempferol combination are key for immunity enhancement and the anti-tumor effects of the extract.Conclusions:The combination of Huangqi and Danggui can activate immunity to suppress breast cancer and is more effective than the individual drugs alone.

关键词： anti-tumor Danggui Huangqi immunity

Gut microbial-host-isozymes are new targets for diseases

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Science China(Life Sciences) 2024年第7期67卷 1525-1527页

作者： Zhiwei Zhang Kai Wang Changtao Jiang Department of physiology and Pathophysiology School of Basic Medical SciencesState Key Laboratory of Female Fertility PromotionCenter for Reproductive MedicinePeking UniversityBeijing 100191China Center for Obesity and Metabolic Disease Research School of Basic Medical SciencesState Key Laboratory of Vascular Homeostasis and RemodelingPeking UniversityBeijing 100191China

Gut microbiota can interact with the host through lots of media including small molecular metabolites and proteins(Cani,2019;Fan and Pedersen,2021;Krautkramer et al.,2021).Recently,a new interaction pattern was identified,i.e.,gut microbiota can mimic the function of the host by producing a variety of enzymes with functions homologous to host enzymes.

关键词： al. diseases pattern

Hepatic Zbtb18 (Zinc Finger and BTB Domain Containing 18) alleviates hepatic steatohepatitis via FXR (Farnesoid X Receptor)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 766-781页

作者： Lei Zhang Jiabing Chen Xiaoying Yang Chuangpeng Shen Jiawen Huang Dong Zhang Naihua Liu Chaonan Liu Yadi Zhong Yingjian Chen Kaijia Tang Jingyi Guo Tianqi Cui Siwei Duan Jiayu Li Shangyi Huang Huafeng Pan Huabing Zhang Xiaoqiang Tang Yongsheng Chang Yong Gao State key laboratory of Traditional Chinese Medicine Syndrome Science and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina key laboratory of Immune Microenvironment and Disease(Ministry of Education) Tianjin Key Laboratory of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical UniversityTianjinChina Jiangsu key laboratory of Immunity and Metabolism Department of Pathogen Biology and ImmunologyJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhouChina Department of Endocrinology The First Clinical CollegeGuangzhou University of Chinese MedicineGuangdongChina The Fourth Clinical medical College of Guangzhou university of Chinese Medicine ShenzhenChina Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor Nanjing University of Chinese MedicineNanjingChina Department of Biochemistry and Molecular Biology Metabolic Disease Research CenterSchool of Basic MedicineAnhui Medical UniversityHefeiChina key laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengduChina

A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease(NAFLD),coupled with hepatitis and insulin resistance.Yet the details of the underlying mechanisms are not fully understood.Here,we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of NAFLD.Hepatic Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation(FAO),and induced insulin resistance.Conversely,hepatic Zbtb18 overexpression alleviated hepato-steatosis,insulin resistance,and hyperglycemia in mice fed on a high-fat diet(HFD)or in diabetic mice.Notably,in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor(FXR)mediated FAO and Clathrin Heavy Chain(CLTC)protein hinders NLRP3 inflammasome activity.This key mechanism by which hepatocyte’s Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR’s deletion and forced expression in mice and cultured mouse primary hepatocytes(MPHs).Moreover,CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in macrophages.Altogether,Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression,which inhibits NLRP3 inflammasome’s activity alleviating inflammatory stress and insulin resistance,representing an attractive remedy for hepatic steatosis and fibrosis.

关键词： hepatic Hepatic impaired

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells(TCR-T cells)against hepatocellular carcinoma

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2215-2230页

作者： Wei Zhu Zhiming Zhang Jinzhang Chen Xiaolan Chen Lei Huang Xiaoyong Zhang Xuan Huang Na Ma Weikang Xu Xuan Yi Xinyu Lu Xin Fu Siwei Li Guoheng Mo Yiyue Wang Guosheng Yuan Mengya Zang Qi Li Xiaotao Jiang Yajing He Sha Wu Yukai He Yongyin Li Jinlin Hou State key laboratory of Organ Failure Research Guangdong Provincial Key Laboratory of Viral Hepatitis ResearchDepartment of Infectious DiseasesNanfang HospitalSouthern Medical UniversityGuangzhouChina Institute of cellular Medicine Newcastle University Medical SchoolNewcastleUK Department of Pathology The First People’s Hospital of FoshanFoshanChina Dermatology Hospital Southern Medical UniversityGuangzhouChina Department of Immunology School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina Microbiome Medicine Center Department of Laboratory MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina key laboratory of Proteomics of Guangdong Province Demonstration Center for Experimental Education of Basic Medical Sciences of ChinaGuangzhouChina medical College of Georgia Augusta University112015th StreetAugustaGAUSA

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma(HCC)are urgently needed.The common cytokine receptorγchain(γc)family cytokines such as IL-2,IL-7,IL-15 and IL-21 play fundamental roles in T cell development,differentiation and effector phases.This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy.The antitumor function of AFP-specific T cell receptor-engineered T cells(TCR-T)was augmented by exogenous IL-21 in vitro and in vivo.IL-21 enhanced proliferation capacity,promoted memory differentiation,downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation.A novel engineered IL-21 receptor was established,and TCR-T armed with the novel engineered IL-21 receptors(IL-21R-TCR-T)showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand.IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo.IL-21R-TCR-T exhibited a less differentiated,exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation.The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization.The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

关键词： hepatocellular TCR utilize

Oncogenic β-catenin-driven liver cancer is susceptible to methotrexate-mediated disruption of nucleotide synthesis

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Chinese medical Journal 2024年第2期137卷 181-189页

作者： Fangming Liu Yuting Wu Baohui Zhang Shuhui Yang Kezhuo Shang Jie Li Pengju Zhang Weiwei Deng Linlin Chen Liang Zheng Xiaochen Gai Hongbing Zhang Department of physiology State Key Laboratory of Common Mechanism Research for Major DiseasesHaihe Laboratory of Cell EcosystemInstitute of Basic Medical Sciences and School of Basic MedicineChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China Department of physiology Institute of Basic Medical Sciences and School of Basic MedicineGraduate School of Peking Union Medical CollegeChinese Academy of Medical SciencesBeijing100005China Department of physiology School of Life ScienceChina Medical UniversityShenyangLiaoning 110122China School of Life Sciences Westlake UniversityHangzhouZhejiang 310024China key laboratory of Pediatric Hematology and Oncology Ministry of HealthInstitute of Pediatric Translational MedicineShanghai Children’s Medical CenterShanghai Jiao Tong School of MedicineShanghai 200127China

Background:Liver cancer is largely resistant to chemotherapy.This study aimed to identify the effective chemotherapeutics forβ-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1(CTNNB1),the most frequently altered proto-oncogene in hepatic neoplasms.Methods:Constitutiveβ-catenin-activated mouse embryonic fibroblasts(MEFs)were established by deleting exon 3(β-catenin^(Δ(ex3)/+)),the most common mutation site in CTNNB1 gene.A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibitedβ-catenin^(Δ(ex3)/+)but not for wild-type MEFs.Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis.The efficacy and selectivity of methotrexate(MTX)onβ-catenin-activated human liver cancer cells were determined in vitro.Immuno-deficient nude mice subcutaneously inoculated withβ-catenin wild-type or mutant liver cancer cells and hepatitis B virus(HBV);β-catenin^(lox(ex3)/+)mice were used,respectively,to evaluate the efficacy of MTX in the treatment ofβ-catenin mutant liver cancer.Results:MTX was identified and validated as a preferential agent against the proliferation and tumor formation ofβ-catenin-activated cells.Boosted nucleotide synthesis was the major metabolic aberration inβ-catenin-active cells,and this alteration was also the target of MTX.Moreover,MTX abrogated hepatocarcinogenesis of HBV;β-catenin^(lox(ex3)/+)mice,which stimulated concurrent Ctnnb1-activated mutation and HBV infection in liver cancer.Conclusion:MTX is a promising chemotherapeutic agent forβ-catenin hyperactive liver cancer.Since repurposing MTX has the advantages of lower risk,shorter timelines,and less investment in drug discovery and development,a clinical trial is warranted to test its efficacy in the treatment ofβ-catenin mutant liver cancer.

关键词： Liver cancer β-catenin Methotrexate Nucleotide synthesis Chemotherapy

Brain circuits for retching-like behavior

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National Science Review 2024年第1期11卷 145-160页

作者： Lifang Huo Zhimin Ye Meiling Liu Ziqing He Meizhu Huang Dapeng Li Qian Wu Qian Wang Xiaoqun Wang Peng Cao Ji Dong Congping Shang School of Basic medical Sciences Guangzhou National Laboratory The Fifth Afflliated Hospital Guangzhou Medical University Bioland laboratory (Guangzhou Regenerative Medicine and Health Guangdong laboratory) Department of Neurobiology School of Basic Medical Sciences Beijing Key Laboratory of Neural Regeneration and Repair Advanced Innovation Center for Human Brain Protection Capital Medical University State key laboratory of Cognitive Neuroscience and Learning IDG/McGovern Institute for Brain Research Beijing Normal University Changping Life Science laboratory National Institute of Biological Sciences

Nausea and vomiting are important defensive responses to cope with pathogens and toxins that invade the body. The nucleus of the solitary tract(NTS) is important for initiating these responses. However, the molecular heterogeneities and cellular diversities of the NTS occlude a better understanding of these defensive responses. Here, we constructed the single-nucleus transcriptomic atlas of NTS cells and found multiple populations of NTS neurons that may be involved in these defensive responses. Among these, we identified Calbindin1-positive(Calb1+) NTS neurons that are molecularly distinct from Tac1+neurons.These Calb1+neurons are critical for nausea and retching induced by cereulide; an emetic toxin secreted by Bacillus Cereus. Strikingly, we found that cereulide can directly modulate vagal sensory neurons that innervate Calb1+NTS neurons, a novel mechanism distinct from that for nausea and retching induced by Staphylococcal enterotoxin A. Together, our transcriptomic atlas of NTS neurons and the functional analyses revealed the neural mechanism for cereulide-induced retching-like behavior. These results demonstrate the molecular and cellular complexities in the brain that underlie defensive responses to the diversities of pathogens and toxins.

关键词： vomiting nausea nucleus of the solitary tract Calbindin1 neural circuits

Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1677-1692页

作者： Dongsheng Bai Jiawei Zhao Runde Wang Jiaying Du Chen Zhou Chunyang Gu Yuxiang Wang Lulu Zhang Yue Zhao Na Lu State key laboratory of Natural Medicines Jiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjing 210009China Department of Clinical Pharmacology School of PharmacyNanjing Medical UniversityNanjing 211166China

Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment,significantly curtailing the efficacy of these treatments and,in some cases,resulting in fatal conse-quences.Despite identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis,the paucity of effective treatments for such damage is evident.In our study,we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells,thereby fortifying the integrity of the intestinal mucus barrier.This enhanced barrier function serves to resist microbial invasion and sub-sequently reduces the inflammatory response.Importantly,this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy drugs.Mechanistically,E.copr up-regulates the expression of AUF1,leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet cells.An espe-cially significant finding is that E.copr activates the AhR pathway,thereby promoting the expression of AUF1.In summary,our results strongly indicate that E.copr enhances the intestinal mucus barrier,effec-tively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUFl pathway,consequently enhancing Muc2 mRNA stability.

关键词： Chemotherapy Mucositis Eubacterium coprostanoligenes MUC2 AUF1

Dynamic changes in butyrate levels regulate satellite cell homeostasis by preventing spontaneous activation during aging

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Science China(Life Sciences) 2024年第4期67卷 745-764页

作者： Shujie Chen Liujing Huang Bingdong Liu Huimin Duan Ze Li Yifan Liu Hu Li Xiang Fu Jingchao Lin Yinlan Xu Li Liu Dan Wan Yulong Yin Liwei Xie Department of Endocrinology and Metabolism Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China State key laboratory of Applied Microbiology Southern China Guangdong Provincial Key Laboratory of Microbial Culture Collection and ApplicationGuangdong Open Laboratory of Applied MicrobiologyInstitute of MicrobiologyGuangdong Academy of SciencesGuangzhou 510070China School of Public Health Xinxiang Medical UniversityXinxiang 453003China Department of Infectious Diseases Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China Metabo-Profile Biotechnology(Shanghai)Co.Ltd. Shanghai 201315China Institute of Aging Research Guangdong Provincial Key Laboratory of Medical Molecular DiagnosticsSchool of Medical TechnologyGuangdong Medical UniversityDongguan 524023China Department of Rehabilitation Medicine Nanfang HospitalSouthern Medical UniversityGuangzhou 510000China laboratory of Animal Nutritional physiology and Metabolic Process Key Laboratory of Agro-ecological Processes in Subtropical RegionInstitute of Subtropical AgricultureChinese Academy of SciencesChangsha 410125China Bioland laboratory Guangzhou Regenerative Medicine and Health Guangdong LaboratoryGuangzhou 510005China

The gut microbiota plays a pivotal role in systemic metabolic processes and in particular functions,such as developing and preserving the skeletal muscle system.However,the interplay between gut microbiota/metabolites and the regulation of satellite cell(SC)homeostasis,particularly during aging,remains elusive.We propose that gut microbiota and its metabolites modulate SC physiology and homeostasis throughout skeletal muscle development,regeneration,and aging process.Our investigation reveals that microbial dysbiosis manipulated by either antibiotic treatment or fecal microbiota transplantation from aged to adult mice,leads to the activation of SCs or a significant reduction in the total number.Furthermore,employing multi-omics(e.g.,RNA-seq,16S r RNA gene sequencing,and metabolomics)and bioinformatic analysis,we demonstrate that the reduced butyrate levels,alongside the gut microbial dysbiosis,could be the primary factor contributing to the reduction in the number of SCs and subsequent impairments during skeletal muscle aging.Meanwhile,butyrate supplementation can mitigate the antibiotics-induced SC activation irrespective of gut microbiota,potentially by inhibiting the proliferation and differentiation of SCs/myoblasts.The butyrate effect is likely facilitated through the monocarboxylate transporter 1(Mct1),a lactate transporter enriched on membranes of SCs and myoblasts.As a result,butyrate could serve as an alternative strategy to enhance SC homeostasis and function during skeletal muscle aging.Our findings shed light on the potential application of microbial metabolites in maintaining SC homeostasis and preventing skeletal muscle aging.

关键词： gut microbiota aging satellite cells butyrate Slc16a1(Mct1)