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Ketogenic diet alleviates colitis by reduction of colonic group 3 innate lymphoid cells through altering gut microbiome

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Signal Transduction and Targeted Therapy 2021年第5期6卷 1573-1584页

作者： Cheng Kong Xuebing Yan Yongqiang Liu Linsheng Huang Yefei Zhu Jide He Renyuan Gao Matthew F.Kalady Ajay Goel Huanlong Qin Yanlei Ma Department of Gastrointestinal Surgery Shanghai Tenth People's HospitalTongji UniversityShanghaiChina Research Institute of Intestinal Diseases Tongji University School of MedicineShanghaiChina Department of Cancer Biology Lerner Research InstituteCleveland ClinicClevelandOHUSA Department of Oncology Affiliated Hospital of Yangzhou UniversityYangzhou UniversityYangzhouChina sDepartment of Coloreaal Surgery Digestive Disease and Surgery InstituteCleveland ClinicClevelandOHUSA Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute of City of Hope Comprehensive Cancer CenterDuarteCAUSA Department of Oncology Shanghai Medical CollegeFudan UniversityShanghaiChina Department of Colorectal Surgery Fudan University Shanghai Cancer CenterShanghaiChina

Accumulating evidence suggests that ketogenic diets(KDs)mediate the rise of circulating ketone bodies and exert a potential antiinflammatory effect;however,the consequences of this unique diet on colitis remain unknown.We performed a series of systematic studies using a dextran sulfate sodium(DSS)animal model of inflammatory colitis.Animals were fed with a KD,low-carbohydrate diet(LCD),or normal diet(ND).Germ-free mice were utilized in validation experiments.Colon tissues were analyzed by transcriptome sequencing,RT2 profiler PCR array,histopathology,and immunofluorescence.Serum samples were analyzed by metabolic assay kit.Fecal samples were analyzed by 16S rRNA gene sequencing,liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry.We observed that KD alleviated colitis by altering the gut microbiota and metabolites in a manner distinct from LCD.Quantitative diet experiments confirmed the unique impact of KD relative to LCD with a reproducible increase in Akkermansia,whereas the opposite was observed for Escherichia/Shigella.After colitis induction,the KD protected intestinal barrier function,and reduced the production of R0Ryt+CD3_group 3 innate lymphoid cells(ILC3s)and related inflammatory cytokines(IL-17a,IL-18,IL-22,Ccl4).Finally,fecal microbiota transplantation into germ-free mice revealed that the KD-mediated colitis inhibition and ILC3 regulation were dependent on the modification of gut microbiota.Taken together,our study presents a global view of microbiome-metabolomics changes that occur during KD colitis treatment,and identifies the regulation of gut microbiome and ILC3s as novel targets involving in IBD dietary therapy.

关键词： colitis lymphoid consequences

Utility of trans-vaginal ultrasound in diagnosis and follow-up of non-pregnant sexually active females with lower ureteric calculi

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Asian Journal of Urology 2020年第1期7卷 45-50页

作者： Siddharth Pandey Tanica Pandey Apul goel ajay Aggarwal Deepanshu Sharma Tushar Pandey Satya sankhwar Gaurav Garg Department of Urology King George’s Medical UniversityLucknowIndia Department of Radiology Raghav Pathlabs and ImagingHaldwaniIndia Department of Pathology Post Graduate Institute of Medical Education and ResearchChandigarhIndia

objective:To assess the utility of trans-vaginal ultrasonography in evaluation of non-pregnant sexually active female patients with lower ureteric calculi.Methods:A prospective study was done from January 2015 to December 2017 including non-pregnant sexually active females with suspected ureteric calculus.Trans-abdominal ultrasound was initially done in all patients.In those patients in whom trans-abdominal ultrasound was inconclusive or there was indirect evidence of lower ureteric calculus in form of ureteral dila-tion but no calculus was evident,trans-vaginal ultrasound was done.The patients with ureteric calculi detected on trans-vaginal ultrasound and kept on conservative management were also followed up with trans-vaginal ultrasound.Non-contrast computed tomography was done in patients with inconclusive trans-vaginal ultrasound.Results:As per the study protocol,156 out of the total 468 patients evaluated by trans-abdominal ultrasound were eligible for trans-vaginal ultrasound.Trans-vaginal ultrasound was done in 149 patients,as seven patients did not give consent.Seventy-nine patients were detected with a lower ureteric calculus on trans-vaginal ultrasound and 27 patients had gyne-cologic or other cause for their symptoms.Forty-three patients had an inconclusive trans-vaginal ultrasound of which 36 underwent non-contrast computed tomography,among them only one patient had a lower ureteric calculus.Stone free status could be easily demonstrated on follow-up trans-vaginal ultrasound.

关键词： Trans-abdominal ultrasound Trans-vaginal ultrasound Lower ureteric calculus Ureteric colic Ureter

Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3085-3102页

作者： Ningna Weng Siyuan Qin Jiayang Liu Xing Huang Jingwen Jiang Li Zhou Zhe Zhang Na Xie Kui Wang Ping Jin Maochao Luo Liyuan Peng Edouard C.Nice Ajay Goel Suxia Han Canhua Huang Qing Zhu Department of Abdominal Oncology West China Hospital of Sichuan UniversityChengdu 610041China State Key Laboratory of Biotherapy and Cancer Center West China HospitalWest China School of Basic Medical Sciences&Forensic MedicineSichuan UniversityCollaborative Innovation Center for BiotherapyChengdu 610041China Department of Pancreatic Surgery West China Hospital of Sichuan UniversityChengdu 610041China Department of Biochemistry and Molecular Biology Monash UniversityClaytonVIC 3800Australia Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute of City of HopeBiomedical Research CenterMonroviaCA 91016USA Department of Oncology the First Affiliated HospitalXi’an Jiaotong UniversityXi’an 710061China

Pancreatic ductal adenocarcinoma(PDAC)is characterized by the highest mortality among carcinomas.The pathogenesis of PDAC requires elevated autophagy,inhibition of which using hydroxychloroquine has shown promise.However,current realization is impeded by its suboptimal use and unpredictable toxicity.Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach.Here,using a patient-derived organoid model,we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents,through which econazole(ECON),an antifungal compound,emerged as the top candidate.Further testing in cell-line and xenograft models of PDAC validated this activity,which occurred as a direct consequence of dysfunctional autophagy.More specifically,ECON boosted autophagy initiation but blocked lysosome biogenesis.RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3(ATF3).Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1(ID-1)led to inactivation of the AKT/mammalian target of rapamycin(m TOR)pathway,thus giving rise to autophagosome accumulation in PDAC cells.The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis.Furthermore,ECON,as an autophagy inhibitor,exhibited synergistic effects with trametinib on PDAC.This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

关键词： Econazole Autophagy PDAC ATF3 AKT Organoid Trametinib Therapy

Cancer-associated histone mutation H2BG53D disrupts DNA–histone octamer interaction and promotes oncogenic phenotypes

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Signal Transduction and Targeted Therapy 2020年第1期5卷 2230-2233页

作者： Yi Ching Esther Wan Tsz Chui Sophia Leung Dongbo Ding Xulun Sun Jiaxian Liu Lina Zhu Tze Zhen Evangeline Kang Du Yang Yuchen Zhang Jitian Zhang Chengmin Qian Michael Shing Yan Huen Qing Li Maggie Zi Ying Chow Zongli Zheng Junhong Han Ajay Goel Xin Wang Toyotaka Ishibashi Kui Ming Chan Department of Biomedical Sciences City University of Hong KongHong KongChina Key Laboratory of Biochip Technology Biotech and Health CentreShenzhen Research Institute of City University of Hong KongShenzhenChina Division of Life Science Hong Kong University of Science and TechnologyHong KongChina State Key Laboratory of Protein and Plant Gene Research School of Life Sciences and Peking-Tsinghua Center for Life SciencesPeking UniversityPekingChina School of Biomedical Sciences The University of Hong KongHong KongChina Ming Wai Lau Centre for Reparative Medicine Karolinska InstitutetHong KongChina State Key Laboratory of Biotherapy and Cancer Center West China HospitalWest China Medical SchoolSichuan UniversitySichuanChina Department of Molecular Diagnostics and Experimental Therapeutics Beckman Research Institute at City of Hope Comprehensive Cancer CenterDuarteCAUSA

Dear Editor,Recent studies from us and others have deciphered the clinical relevance of a variety of oncohistones1 in different diseases.The H3K27M and H3K36M mutant histones exert dominant-negative effects on methylation levels of histone H3K27 and H3K36 on wildtype histone protein in pediatric brain cancers2–4 and chondroblastoma,5,6 respectively.In contrast to H3K27M and H3K36M that act in trans to cause global reduction of methylation at the respective residues,the H3G34 mutations,including H3G34V/R and H3G34W/L found in pediatric high-grade glioma and giant cell tumor of the bone,affect the H3K36 methylation in cis and alter the H3K36 methylation on the nucleosome containing the H3G34 mutation(s).

关键词： Cancer clinical pediatric