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PAID study design on the role of PKC activation in immune/inflammation-related depression:a randomised placebo-controlled trial protocol

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General Psychiatry 2021年第2期34卷 104-110页

作者： Xiaoyun Guo Ruizhi Mao Lvchun Cui Fan Wang Rubai Zhou Yun Wang Jia Huang Yuncheng Zhu Yamin Yao Guoqing Zhao Zezhi Li Jun Chen Jinhui Wang Yiru Fang Department of Psychiatry Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina Department of Psychology Shandong Provincial Hospital affiliated to Shandong First Medical UniversityJinanShandongChina Department of Neurology Renji HospitalShanghai Jiao Tong University School of MedicineShanghaiChina Clinical Research Center and division of mood disorders Shanghai Mental Health CenterShanghai Jiao Tong University School of MedicineShanghaiChina College of Life Sciences Chinese Academy of SciencesBeijingChina CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of ScienceShanghaiChina Shanghai Key Laboratory of Psychotic disorders ShanghaiChina

Background Inflammation that is mediated by microglia activation plays an important role in the pathogenesis of depression.Microglia activation can lead to an increase in the levels of proinflammatory cytokines,including TNF-α,which leads to neuronal apoptosis in the specific neural circuits of some brain regions,abnormal cognition and treatment-resistant depression(TRD).Protein kinase C(PKC)is a key regulator of the microglia activation process.We assume that the abnormality in PKC might result in abnormal microglia activation,neuronal apoptosis,significant changes in emotional and cognitive neural circuits,and TRD.In the current study,we plan to target at the PKC signal pathway to improve the TRD treatment outcome.Methods and analysis This is a 12-week,ongoing,randomised,placebo-controlled trial.Patients with TRD(N=180)were recruited from Shanghai Mental Health Center,Shanghai Jiao Tong University.Healthy control volunteers(N=60)were recruited by advertisement.Patients with TRD were randomly assigned to‘escitalopram+golimumab(TNF-αinhibitor)’,‘escitalopram+calcium tablet+vitamin D(PKC activator)’or‘escitalopram+placebo’groups.We define the primary outcome as changes in the 17-item Hamilton Depression Rating Scale(HAMD-17).The secondary outcome is defined as changes in anti-inflammatory effects,cognitive function and quality of life.Discussion This study might be the first randomised,placebo-controlled trial to target at the PKC signal pathway in patients with TRD.Our study might help to propose individualised treatment strategies for depression.Trial registration number The trial protocol is registered with ClinicalTrials.gov under protocol ID 81930033 and ClinicalTrials.gov ID NCT04156425.

关键词： placebo inflammation vitamin

Sphingosine-1-Phosphate Protects Against the Development of Cardiac Remodeling via Sphingosine Kinase 2 and the S1PR2/ERK Pathway

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Current Medical Science 2022年第4期42卷 702-710页

作者： Hui YAN Hu ZHAO Shao-wei YI Hang ZHUANG Dao-wen WANG Jian-gang JIANG Gui-fen SHEN Wuhan No.4 Hospital Wuhan Puai HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China division of Cardiology Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological DisordersTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Rheumatology and Immunology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Objective:Cardiac remodeling is a common pathological change in various cardiovascular diseases and can ultimately result in heart failure.Thus,there is an urgent need for more effective strategies to aid in cardiac protection.Our previous work found that sphingosine-1-phosphate(S1P)could ameliorate cardiac hypertrophy.In this study,we aimed to investigate whether S1P could prevent cardiac fibrosis and the associated mechanisms in cardiac remodeling.Methods:Eight-week-old male C57BL/6 mice were randomly divided into a sham,transverse aortic constriction(TAC)or a TAC+S1P treatment group.Results:We found that S1P treatment improved cardiac function in TAC mice and that the cardiac fibrosis ratio in the TAC+S1P group was significantly lower and was accompanied by a decrease inα-smooth muscle actin(α-SMA)and collagen type I(COL I)expression compared with the TAC group.We also found that one of the key S1P enzymes,sphingosine kinase 2(SphK2),which was mainly distributed in cytoblasts,was downregulated in the cardiac remodeling case and recovered after S1P treatment in vivo and in vitro.In addition,our in vitro results showed that S1P treatment activated extracellular regulated protein kinases(ERK)phosphorylation mainly through the S1P receptor 2(S1PR2)and spurred p-ERK transposition from the cytoplasm to cytoblast in H9c2 cells exposed to phenylephrine.Conclusion:These findings suggest that SphK2 and the S1PR2/ERK pathway may participate in the anti-remodeling effect of S1P on the heart.This work therefore uncovers a novel potential therapy for the prevention of cardiac remodeling.

关键词： sphingosine-l-phosphate cardiac remodeling sphingosine kinase 2 sphingosine-1-phosphate receptor extracellular regulated protein kinase

Nuclear miR-665 aggravates heart failure via suppressing phosphatase and tensin homolog transcription

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Science China(Life Sciences) 2020年第5期63卷 724-736页

作者： Jiahui Fan Xudong Zhang Xiang Nie Huaping Li Shuai Yuan Beibei Dai Jiabing Zhan Zheng Wen Jiangang Jiang Chen Chen Daowen Wang division of Cardiology Department of Internal MedicineTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological disorders Wuhan 430030China

Although numerous miRNAs have been discovered,their functions in the different subcellular organelles have remained obscure.In this study,we found that miR-665 was enriched in the nucleus of cardiomyocytes,and then investigated the underlying role of nuclear miR-665 in heart failure.RNA fluorescence in situ hybridization assays in human heart tissue sections and primary cardiomyocytes showed that miR-665 was localized in the nucleus of cardiomyocytes.Increased expression of nuclear miR-665 was observed not only in the cardiomyocytes isolated from the heart of mice treated in vivo by transverse aortic constriction(TAC),but also in phenylephrine(PE)-treated cultured cardiomyocytes in vitro.To further explore the role of miR-665 in heart failure,a type 9 recombinant adeno-associated virus(rAAV)system was employed to manipulate the expression of miR-665 in mice.Overexpression of miR-665 aggravated TAC-induced cardiac dysfunction,while down-expression of miR-665 showed opposite effects.Bioinformatic prediction and biological validation confirmed that the PTEN(phosphatase and tensin homolog)gene was one of the targets of miR-665 in the nucleus.Furthermore,restoring PTEN expression significantly eliminated the destructive effects of miR-665 over-expression in TAC-induced cardiac dysfunction.Our data showed that nuclear miR-665 aggravates heart failure via inhibiting PTEN expression,which provided a therapeutic approach for heart failure.

关键词： nucleus miR-665 heart failure phosphatase and tensin homolog

Potential contribution of increased soluble IL-2R to lymphopenia in COVID-19 patients

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Cellular & Molecular Immunology 2020年第8期17卷 878-880页

作者： Yaguang Zhang Xiaojing Wang Xuezhen Li Dong Xi Ruizhi Mao Xiaohui Wu Shipeng Cheng Xiaoyu Sun Chunyan Yi Zhiyang Ling Liyan Ma Qin Ning Yiru Fang Bing Sun Di Wu State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of Sciences320 Yueyang Road200031ShanghaiChina Department and Institute of Infectious Disease Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology430030WuhanChina Clinical Research Center and division of mood disorders Shanghai Mental Health CenterShanghai Jiao Tong University School of Medicine200030ShanghaiChina

Since the outbreak of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),more than 6 million cases are confirmed and over 300,000 cases are dead after infection.Dysfunction of immunity in COVID-19 patients has been considered as one of the fatal factors for patients,especially cytokine release syndrome and lymphopenia.1,2,3 The reduced number and increased exhaustion level of lymphocyte are associated with elevated inflammatory cytokines in COVID-19 patients.4,5 However,the mechanism of cytokine-induced lymphopenia in COVID-19 is very unclear.IL-2 is critical for the proliferation,differentiation,and function of T cells,including Tregs,CD4+,and CD8+effector cells.6 Here,we reported the negative relationship between the concentration of soluble IL-2 receptor(sIL-2R)and T-cell number in blood from COVID-19 patients.In vitro addition of recombinant CD25 could inhibit the proliferation and function of T cells from PBMC after stimulated with TCR signaling,which could be rescued by strong IL-2 signaling.Our data suggested the importance of IL-2 signaling in lymphopenia of COVID-19 patients.

关键词： patients lympho immunity

Answer for questions of repeated measurements of variance analysis and distribution test of data—Authors’reply

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Frontiers of Medicine 2022年第4期16卷 661-665页

作者： Dao Wen Wang Li Ni Hualiang Jiang division of Cardiology Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological DisordersTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology ShanghaiTech UniversityShanghai 201210China

Thank the journal for sending us the Correspondence of Dr.Jie Wei for our article“Effects of Shuanghuanglian oral liquids on patients with COVID-19:a randomized,open-label,parallel-controlled,multicenter clinical trial”published in Frontiers of Medicine[1].We appreciate Dr.Jie Wei for agreeing with most of the conclusions in our paper and we address Dr.Jie Wei’s comments carefully as below.

关键词： journal comment carefully

Prevalence and risk factors for impaired renal function among Asian patients with nonalcoholic fatty liver disease

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 241-248页

作者： Chao Sun George Boon-Bee Goh Wan-Cheng Chow Wah-Kheong Chan Grace Lai-Hung Wong Wai-Kay Seto Yi-Hsiang Huang Han-Chieh Lin I-Cheng Lee Hye Won Lee Seung Up Kim Vincent Wai-Sun Wong Jian-Gao Fan Center for Fatty Liver Disease Department of GastroenterologyXinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai Key Lab of Pediatric Gastroenterology and NutritionShanghai 200092China Department of Gastroenterology&Hepatology Singapore General HospitalSingaporeSingapore Gastroenterology and Hepatology Unit Department of MedicineFaculty of MedicineUniversity of MalayaKuala LumpurMalaysia Department of Medicine and Therapeutics and State Key Laboratory of Digestive Disease The Chinese University of Hong KongHong KongChina Department of Medicine The University of Hong KongHong KongChina Institute of Clinical Medicine National Yang Ming Chiao Tung University School of MedicineTaipeiTaiwanChina division of Gastroenterology and Hepatology Taipei Veterans General HospitalTaipeiTaiwanChina Faculty of Medicine National Yang Ming Chiao Tung University School of MedicineTaipeiTaiwanChina Department of Internal Medicine Yonsei University College of MedicineSeoulKorea

Background:Nonalcoholic fatty liver disease(NAFLD)is associated with impaired renal function,and both diseases often occur alongside other metabolic disorders.However,the prevalence and risk factors for impaired renal function in patients with NAFLD remain unclear.The objective of this study was to identify the prevalence and risk factors for renal impairment in NAFLD patients.Methods:All adults aged 18-70 years with ultrasound-diagnosed NAFLD and transient elastography examination from eight Asian centers were enrolled in this prospective study.Liver fibrosis and cirrhosis were assessed by FibroScan-aspartate aminotransferase(FAST),Agile 3+and Agile 4 scores.Impaired renal function and chronic kidney disease(CKD)were defined by an estimated glomerular filtration rate(eGFR)with value of<90 mL/min/1.73 m^(2) and<60 mL/min/1.73 m^(2),respectively,as estimated by the CKD-Epidemiology Collaboration(CKD-EPI)equation.Results:Among 529 included NAFLD patients,the prevalence rates of impaired renal function and CKD were 37.4%and 4.9%,respectively.In multivariate analysis,a moderate-high risk of advanced liver fibrosis and cirrhosis according to Agile 3+and Agile 4 scores were independent risk factors for CKD(P<0.05).Furthermore,increased fasting plasma glucose(FPG)and blood pressure were significantly associated with impaired renal function after controlling for the other components of metabolic syndrome(P<0.05).Compared with patients with normoglycemia,those with prediabetes[FPG≥5.6 mmol/L or hemoglobin A1c(HbA1c)≥5.7%]were more likely to have impaired renal function(P<0.05).Conclusions:Agile 3+and Agile 4 are reliable for identifying NAFLD patients with high risk of CKD.Early glycemic control in the prediabetic stage might have a potential renoprotective role in these patients.

关键词： Nonalcoholic fatty liver disease Impaired renal function Agile 3+ Agile 4 Metabolic syndrome

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工程化干细胞的前沿生物医学策略（英文）

Science Bulletin 2024年第2期 248-279页

作者：王经琳张筱萱陈涵旭任昊桢周敏赵远锦 Department of Vascular Surgery Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University division of Hepatobiliary Surgery and Transplantation Surgery Department of General Surgery Nanjing Drum Tower Hospital School of Biological Science and Medical Engineering Southeast University Shenzhen Research Institute Southeast University

Stem cell therapy holds immense potential as a viable treatment for a widespread range of intractable disorders. As the safety of stem cell transplantation having been demonstrated in numerous clinical trials,various kinds of stem cells are currently utilized in medical applications. Despite the achievements, the therapeutic benefits of stem cells for diseases are limited, and the data of clinical researches are unstable.To optimize tthe effectiveness of stem cells, engineering approaches have been developed to enhance their inherent abilities and impart them with new functionalities, paving the way for the next generation of stem cell therapies. This review offers a detailed analysis of engineered stem cells, including their clinical applications and potential for future development. We begin by briefly introducing the recent advances in the production of stem cells(induced pluripotent stem cells(i PSCs), embryonic stem cells(ESCs), mesenchymal stem cells(MSCs) and hematopoietic stem cells(HSCs)). Furthermore, we present the latest developments of engineered strategies in stem cells, including engineered methods in molecular biology and biomaterial fields, and their application in biomedical research. Finally, we summarize the current obstacles and suggest future prospects for engineered stem cells in clinical translations and biomedical applications.

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Relationship between clinical remission of perianal fistulas in Crohn’s disease and serum adalimumab concentrations:A multicenter cross-sectional study

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World Journal of Gastroenterology 2022年第9期28卷 961-972页

作者： Laura Sirmai Anne-Laure Pelletier Nathalie Gault Camille Zallot Guillaume Bouguen Dominique Bouchard Pascale Roland Nicaise Marine Peyneau Sandrine Sironneau Marcelo De Carvalho Bittencourt Antoine Petitcollin Pedro Fernandez Xavier Roblin Laurent Siproudhis Laurent Abramowitz division of Hepato-Gastroenterology and Digestive Oncology Bichat Claude Bernard University HospitalParis 75018France division of Hepato-Gastroenterology Hospital Croix Saint SimonParis 75020France division of Epidemiology Biostatistics and Clinical ResearchUniversity Hospital Center BichatParis 75018France National Institute of Health and Medical Research CIC-EC1425 University Hospital Center BichatParis 75018France division of Gastroenterology Nancy Regional and University Hospital CenterNancy 54035France Imphy CIC 1414 Group and division of Gastroenterology and Hepatology University Hospital of RennesPontchaillouRennes 35033France division of Proctology Hospital BagatelleTalence 33400France division of Immunology University Hospital Center BichatParis 75018France Inflammation Microbiome and ImmunosurveillanceFaculty of PharmacyUniversitéParis-SaclayChâtenay-Malabry 92290France division of Radiology Bagatelle Hospital CenterTalence 33400France division of Immunology Nancy Regional and University Hospital CenterNancy 54000France University of Lorraine CNRS UMR 7365IMoPANancy 54000France Antoine Petitcol Department of Clinical and Biological Pharmacology and Pharmacovigilance Pharmacoepidemiology and Drug Information CenterRennes University HospitalRennes 35700France division of Radiology University Hospital Center BichatParis 75018France Orangerie Center Le Perreux-sur-Marne 94170France division of Gastroenterology CHU Saint EtienneSaint-Priest-en-Jarez 42270France division of Gastroenterology and Hepatology and Proctology University Hospital Center BichatParis 75018France Ramsay GDS Clinique Blomet Paris 75018France

BACKGROUND Crohn’s disease(CD)is complicated by perianal fistulas in approximately 20%of patients.Achieving permanent fistula closure remains a challenge for physicians.An association between serum anti-tumor necrosis factor-αconcentrations and clinical outcomes in patients with CD has been demonstrated;however,little information is available on serum adalimumab(ADA)concentrations and remission of perianal fistulas in such patients.AIM To study the relationship between serum ADA concentrations and clinical remission of CDassociated perianal fistulas.METHODS This cross-sectional study of patients with CD-associated perianal fistulas treated with ADA was performed at four French hospitals between December 2013 and March 2018.At the time of each serum ADA concentration measurement,we collected information about the patients and their fistulas.The primary study endpoint was clinical remission of fistulas defined as the absence of drainage(in accordance with Present’s criteria),with a PDAI≤4,absence of a seton and assessment of the overall evaluation as favorable by the proctologist at the relevant center.We also assessed fistula healing[defined as being in clinical and radiological(magnetic resonance imaging,MRI)remission]and adverse events.RESULTS The study cohort comprised 34 patients who underwent 56 evaluations(patients had between one and four evaluations).Fifteen patients had clinical remissions(44%),four of whom had healed fistulas on MRI.Serum ADA concentrations were significantly higher at evaluations in which clinical remission was identified than at evaluations in which it was not[14(10-16)vs 10(2-15)μg/mL,P=0.01].Serum ADA concentrations were comparable at the times of evaluation of patients with and without healed fistulas[11(7-14)vs 10(4-16)μg/mL,P=0.69].The adverse event rate did not differ between different serum ADA concentrations.CONCLUSION We found a significant association between high serum ADA concentrations and clinical remission of CD-associated perianal fistulas.

关键词： Crohn’s disease Clinical pharmacology Peri-anal disorders Adalimumab

Obesity is an important determinant of severity in newly defined metabolic dysfunction-associated fatty liver disease

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Hepatobiliary & Pancreatic Diseases International 2022年第3期21卷 241-247页

作者： Ji Hye Huh Kwang Joon Kim Seung Up Kim Bong-Soo Cha Byung-Wan Lee division of Endocrinology and Metabolism Department of Internal MedicineHallym University Sacred Heart HospitalAnyang 14068Korea division of Geriatrics Department of Internal MedicineYonsei University College of MedicineSeoul 03722Korea division of Endocrinology and Metabolism Department of Internal MedicineYonsei University College of MedicineSeoul 03722Korea Institute of Gastroenterology Department of Internal MedicineYonsei University College of MedicineSeoul 03722Korea

Background: The recently proposed definition of metabolic dysfunction-associated fatty liver disease(MAFLD) is based on the co-existence of hepatic steatosis with other metabolic disorders, including obesity and metabolic risk abnormalities such as hyperglycemia, high blood pressure and dyslipidemia. This study aimed to assess MAFLD severity according to the presence of metabolic abnormalities and obesity. Methods: Using transient elastography, hepatic steatosis and fibrosis severity were assessed by measuring the controlled attenuation parameter and liver stiffness measurement. A total of 1163 patients with MAFLD were categorized into the following four groups according to metabolic risk abnormalities and obesity presence: non-obese without metabolic risk abnormality group(Group 1;reference group);nonobese with metabolic risk abnormality group(Group 2);obese without metabolic risk abnormality group(Group 3);and obese with metabolic risk abnormality group(Group 4). A multiple logistic regression analysis was performed to determine severe hepatic steatosis and fibrosis risk in each group in both unadjusted and adjusted models. Results: In the adjusted model, the odds ratios(ORs) [95% confidence interval(CI)] for severe hepatic steatosis in Groups 2, 3, and 4 were 1.07(0.61-1.88), 2.43(1.44-4.08), and 4.07(2.56-6.48), respectively( P trend < 0.001). For liver fibrosis, compared with Group 1, Group 2 showed no significant increases in OR, whereas Groups 3 and 4(obese groups) showed significant increases(OR = 4.70, 95% CI: 1.24-17.82 and OR = 6.43, 95% CI: 1.88-22.02, respectively). Conclusions: Obesity, rather than metabolic abnormality, is the principal determinant of severe hepatic steatosis and fibrosis in patients with MAFLD.

关键词： Metabolic dysfunction-associated fatty liver disease Metabolically-healthy obesity Liver fibrosis