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Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer

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Genes & Diseases 2024年第3期11卷 338-350页

作者： Xin Xu Yuan Fang Somaira Nowsheen Ye-Xiong Li Zhenkun Lou Min Deng State Key Laboratory of Molecular Oncology and Department of Radiation Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of General Surgery Shanghai General HospitalShanghai Jiaotong University School of MedicineShanghai 200080China Department of General Surgery Zhongshan HospitalFudan UniversityShanghai 200032China Department of Dermatology University of California San DiegoSan DiegoCA 92093USA Department of Oncology Mayo ClinicRochesterMN 55905USA

The adenosine monophosphate(AMP)-activated protein kinase(AMPK)sits at a cen-tral node in the regulation of energy metabolism and tumor *** is best known to sense high cellular ADP or AMP levels,which indicate the depletion of energy *** studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic *** this study,we report that AMPK is also highly sensitive to extracellular matrix(ECM)*** found that AMPK is activated in cells when cultured under low ECM stiffness conditions and is functionally required for the metabolic switch induced by ECM *** regulation of AMPK requires the Hippo kinases but not LKB1/*** kinases directly phosphorylate AMPKa at Thr172 to activate AMPK at low ECM ***,we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma(PDAC)with high ECM stiffness and is associated with a poor survival *** activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC ***,these findings establish a novel model for AMPK regulation by the mechanical properties of ECMs and provide a rationale for simultaneously targeting the ECM stiffness-Hippo kinases-AMPK signaling and low glucose-LKB1-AMPK signaling pathways as an effective therapeutic strategy against PDAC.

关键词： AMPKactivity Cellularmetabolic switch ECM stiffness Hippokinase signaling Pancreaticductal adenocarcinoma

Oroxyloside protects against dextran sulfate sodium-induced colitis by inhibiting ER stress via PPARγ activation

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Chinese Journal of Natural Medicines 2024年第4期22卷 307-317页

作者： TAO Lei DOU Renjie CHEN Xueming CAO Yu DAI Zhen HU Ziyan MA Zhi GE Xiaoming ZHANG Ling WANG Xiaoping Nanjing institute for Food and Drug Control Nanjing 211198China State Key Laboratory of Natural Medicines School of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjing 211198China

Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), may result from immune system dysfunction, leading to the sustained overproduction of reactive oxygen species (ROS) and subsequent cellular oxidative stress damage. Recent studies have identified both peroxisome proliferator-activated receptor-γ (PPARγ) and endoplasmic reticulum (ER) stress as critical targets for the treatment of IBD. Oroxyloside (C22H20O11), derived from the root of Scutellaria baicalensis Georgi, has traditionally been used in treating inflammatory diseases. In this study, we investigated the molecular mechanisms by which oroxyloside mitigates dextran sulfate sodium (DSS)-induced colitis. We examined the effects of oroxyloside on ROS-mediated ER stress in colitis, including the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, and CHOP, which are associated with ER stress. The beneficial impact of oroxyloside was reversed by the PPARγ antagonist GW9662 (1 mg·kg^(−1), i.v.) in vivo. Furthermore, oroxyloside decreased pro-inflammatory cytokines and ROS production in both bone marrow-derived macrophages (BMDM) and the mouse macrophage cell line RAW 264.7. However, PPARγ siRNA transfection blocked the anti-inflammatory effect of oroxyloside and even abolished ROS generation and ER stress activation inhibited by oroxyloside in vitro. In conclusion, our study demonstrates that oroxyloside ameliorates DSS-induced colitis by inhibiting ER stress via PPARγ activation, suggesting that oroxyloside might be a promising effective agent for IBD.

关键词： Oroxyloside ER stress PPARγ Colitis

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Recent advances in cancer-associated fibroblast:Biomarkers,signaling pathways,and therapeutic opportunities

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Chinese Medical Journal 2024年第6期137卷 638-650页

作者： Donger Zhou Lei Zheng Department of Hepatobiliary-Pancreatic Surgery The Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310009China Sidney Kimmel Comprehensive cancer Center The Skip Viragh Pancreatic Cancer Center for Clinical Research and Careand The Bloomberg-Kimmel Institute for Immunotherapy at Johns Hopkins University School of MedicineBaltimoreMD 21287USA

Anti-cancer therapies usually focus on tumor cells,but non-tumor stromal components in the tumor microenvironment also play vital roles in tumor initiation and progression,which may be the prognostic factors and potential therapeutic ***-associated fibroblasts(CAFs)are the essential component in the tumor environment,exhibiting high heterogeneity in their cell origin and phenotype with diverse functions that influence tumor angiogenesis,immune systems,and ***-cell RNA sequencing and genetically engineered mouse models have increased our understanding of CAF diversity,and many subtypes have been ***,the precise functions of these subtypes need to be studied and *** of signaling pathways and epigenetic changes in CAFs facilitate understanding of the phenotypes of CAFs and the crosstalk between tumor cells and CAFs to provide potential therapeutic *** clinical trials,including phase III trials targeting CAFs,have been performed ***,few of these trials have generated promising results,which indicates that the complexity of CAFs in the tumor microenvironment remains largely unknown,and in-depth investigations of CAFs should be *** review summarizes the research on CAFs,focusing on the heterogeneity of their phenotypes and functions,specific signaling pathways,and the therapeutic strategies involving ***,we briefly discuss the current technologies commonly used in CAF studies and describe the challenges and future perspectives of CAF research.

关键词： cancer-associated fibroblasts Tumor microenvironment Anti-cancer therapy Targeted therapy

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clinical efficacy and identification of factors confer resistance to afatinib(tyrosine kinase inhibitor)in EGFR-overexpressing esophageal squamous cell carcinoma

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3130-3140页

作者： Yanni Wang Chang Liu Huan Chen Xi Jiao Yujiao Wang Yanshuo Cao Jian Li Xiaotian Zhang Yu Sun Na Zhuo Fengxiao Dong Mengting Gao Fengyuan Wang Liyuan Dong Jifang Gong Tianqi Sun Wei Zhu Henghui Zhang Lin Shen Zhihao Lu Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Department of Gastrointestinal OncologyPeking University Cancer Hospital and InstituteBeijingChina Genecast Biotechnology Co. LtdWuxiPR China State Key Laboratory of Holistic Integrative Management of Gastrointestinal cancers Beijing Key Laboratory of Carcinogenesis and Translational ResearchDepartment of Gastrointestinal OncologyPeking University Cancer Hospital and InstituteBeijingChina Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education) Department of PathologyPeking University Cancer Hospital and InstituteBeijingChina Precision Scientific(Beijing)Co. Ltd.BeijingChina Generulor Company Bio-X Lab ZhuhaiGuangdongChina Biomedical Innovation Center Beijing Shijitan HospitalCapital Medical UniversityBeijingChina Beijing Key Laboratory for Therapeutic cancer Vaccines Beijing Shijitan HospitalCapital Medical UniversityBeijingChina

Epidermal growth factor receptor(EGFR)is reportedly overexpressed in most esophageal squamous cell carcinoma(ESCC)patients,but anti-EGFR treatments offer limited survival *** preclinical data showed the promising antitumor activity of afatinib in EGFR-overexpressing *** proof-of-concept,phase II trial assessed the efficacy and safety of afatinib in pretreated metastatic ESCC patients(n=41)with EGFR overexpression(NCT03940976).The study met its primary endpoint,with a confirmed objective response rate(ORR)of 39%in 38 efficacy-evaluable patients and a median overall survival of 7.8 months,with a manageable toxicity *** analysis of pretreatment tumors revealed that neurotrophic receptor tyrosine kinase 2(NTRK2)was negatively associated with afatinib sensitivity and might serve as a predictive biomarker,irrespective of EGFR ***,knocking down or inhibiting NTRK2 sensitized ESCC cells to afatinib *** study provides novel findings on the molecular factors underlying afatinib resistance and indicates that afatinib has the potential to become an important treatment for metastatic ESCC patients.

关键词： esophageal squamous expressing

Biochemical consequences of glucocerebrosidase 1 mutations in Parkinson’s disease

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Neural Regeneration Research 2024年第4期19卷 725-727页

作者： Jeong Hyun Yoon Chiao-Yin Lee Anthony HV Schapira Department of clinical and Movement Neurosciences University College London Institute of Neurology Faculty of Medicine Imperial College London Aligning Science Across Parkinson's(ASAP)Collaborative Research Network

Parkinson’s disease(PD,OMIM#168600)is a common neurodegenerative disorder with a global prevalence of approximately 8.5 *** is characterized by four cardinal motor symptoms:bradykinesia,rigidity,resting tremor,and subsequently by postural *** usually involves non-motor symptoms such as rapid eye movement sleep disorder,dementia,anosmia,and autonomic *** gene glucocerebrosidase 1(GBA1),which encodes the lysosomal enzyme glucocerebrosidase(GCase)(IUBMB:EC 3.***.1.45),shows strong linkage with PD;variants of GBA1 are the commonest genetic association with PD(Sidransky et al.,2009).Several mechanisms may underlie the relationship between GBA1 mutations/variants and the molecular pathology of PD(Figure 1A and B).

关键词： cerebro consequences

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UniBind:a novel artificial intelligence-based prediction model for SARS-CoV-2 infectivity and variant evolution

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Signal Transduction and Targeted Therapy 2024年第1期9卷 14-15页

作者： Qihong Yan Jincun Zhao State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina

In a recent study published in Nature Medicine,Wang et *** an excellent framework called UniBind based on artificial intelligence(AI),which enables accurately predicting infectivity of SARS-CoV-2 variants and evolutionary trends of future viral variants.1 This computational method holds the possibility to not only serve as a valuable early-warning tool for monitoring potential pathogenic SARS-CoV-2 variants but also facilitate fundamental research on protein-protein interactions(PPIs).

关键词： artificial Bind prediction

Global research trends in postoperative ileus from 2011 to 2023:A scientometric study

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World Journal of Gastrointestinal Surgery 2024年第9期16卷 3020-3031页

作者： Yan Zhou Zi-Han Yin Ming-Sheng Sun Yang-Yang Wang Chen Yang Shu-Hao Li Fan-Rong Liang Fang Liu Acupuncture and Tuina School Chengdu University of Traditional Chinese MedicineChengdu 610075Sichuan ProvinceChina Department of Integrated Chinese and Western Medicine Sichuan Clinical Research Center for CancerSichuan Cancer Hospital&InstituteSichuan Cancer CenterAffiliated Cancer Hospital of University of Electronic Science and Technology of ChinaChengdu 610041Sichuan ProvinceChina

BACKGROUND Postoperative ileus(POI)is a common complication after abdominal surgery with high morbidity,which hinders patient recovery,prolongs hospitalization,and increases healthcare ***,POI has become a global public health *** triggering is *** and hormonal mechanisms are generally involved in POI *** studies have shown that beta adrenergic signaling of enteric glia is a POI ***,the status quo,trends,and frontiers of global research on POI remain *** To explore the current status,trends,and frontiers of POI research from 2011 to the present based on bibliometric *** Publications published on POI research from 2011 to 2023 were retrieved on June 1,2023,from the Web of Science Core *** 6.2.R2 and VOSviewer were used to conduct bibliometric *** In total,778 POI records published from 2011 to 2023 were *** the past few decades,the annual cumulative number of related articles has linearly increased,with China and the United States of America contributing *** publications were from 59 countries and *** and the University of Bonn were the top contributing country and institution,***&Motility was the most prolific *** Journal of Gastrointestinal Surgery had the highest number of *** Sven was the most productive *** keywords(e.g.,colon,prolonged ileus,acupuncture,paralytic ileus,pathophysiology,rectal cancer,gastrointestinal function,risk)and a series of reference citation bursts provided evidence for the research frontiers in recent *** This study demonstrates trends in the published literature on POI and provides new insights for *** emphasizes the importance of multidisciplinary cooperation in the development of this field.

关键词： Postoperative ileus Scientometric analysis VOSviewer CiteSpace Visualization Trends

Burden of six major types of digestive system cancers globally and in China

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中华医学杂志(英文版) 2024年第16期137卷 1957-1964页

作者： Zhou Yueyang Song Kai Chen Yuqing Zhang Yuelun Dai Min Wu Dong Chen Hongda Center for Prevention and Early Intervention National Infrastructures for Translational Medicine Institute of Clinical Medicine Peking Union Medical College Hospital Chinese Academy of Medical Science and Peking Union Medical College Beijing China Department of Gastroenterology Peking Union Medical College Hospital Chinese Academy of Medical Science and Peking Union Medical College Beijing China Department of cancer Epidemiology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China Department of Gastroenterology People’s Hospital of Xizang Autonomous Region Lhasa Xizang autonomous region China

Background: Digestive system cancers constitute a significant number of cancer cases, but their burden is not uniform. As Global cancer Observatory (GLOBOCAN) 2022 has recently updated its estimates of cancer burden, we aimed to investigate the burden of six major digestive system cancers both worldwide and in China, along with geographical and temporal variations in cancer-specific incidence and ***: We extracted data on primary cancers of the esophagus, stomach, colorectum, liver, pancreas, and gallbladder from the GLOBOCAN database for 2022. Age-standardized incidence and mortality rates were calculated and stratified by sex, country, region, and human development index (HDI). We used the 2022 revision of the World Population Prospects (United Nations) to obtain demographic data for various age groups in China from 1988 to 2012 and used the joinpoint model and the average annual percentage change (AAPC) to analyze cancer incidence trends in ***: In 2022, the estimated global incidence of digestive system cancers reached 4,905,882, with an estimated 3,324,774 cancer-related deaths. Colorectal cancer was most prevalent in terms of incidence and mortality. There was a significant correlation between the burden of gastrointestinal cancers and country HDI. From 1988 to 2012, the incidence of esophageal, gastric, and liver cancers declined in China, whereas colorectal and pancreatic cancer incidences continued to increase. By 2050, colorectal and liver cancers are projected to remain the leading cancer types in China in terms of incidence and mortality, ***: Digestive system cancers remain a significant public health challenge globally and in China. Although progress has been made in the prevention and control of some cancers, the burden of digestive system cancers persists. The implementation of tertiary prevention strategies must be intensified to reduce the incidence and mortality of digestive system cancers, mitigating t

关键词： Digestive system cancer Incidence Mortality GLOBOCAN 2022 China Global Esophagus cancer Stomach cancer Colorectal cancer

Emerging trends in early-onset gastric cancer

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中华医学杂志(英文版) 2024年第18期137卷 2024 Aug 15页

作者： Wang Xinlin Gao Xianchun Yu Jun Zhang Xiaotian Nie Yongzhan State Key Laboratory of Holistic Integrative Management of Gastrointestinal cancers Xi’an Shaanxi China National clinical Research Center for Digestive Diseases Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi’an Shaanxi China Beijing Key Laboratory of Carcinogenesis and Translational Research Department of Gastrointestinal Oncology Peking University Cancer Hospital &amp institute Beijing China

The incidence of early-onset gastric cancer (EOGC) is consistently increasing, and its etiology is notably complex. This increase may be attributed to distinctive factors that differ from those associated with late-onset gastric cancer (LOGC), including genetic predispositions, dietary factors, gastric microbiota dysbiosis, and screening of high-risk cases. These factors collectively contribute to the onset of cancer. EOGC significantly differs from LOGC in terms of clinicopathological and molecular characteristics. Moreover, multiple differences in prognosis and clinical management also exist. This study aimed to systematically review the latest research advancements in the epidemiological characteristics, etiological factors, clinicopathological and molecular features, prognosis, and treatment modalities of EOGC.

关键词： Early-onset gastric cancer Epidemiology Etiology Clinicopathological features Molecular signaling Prognosis clinical management