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Link between mutations in ACVRL1 and PLA2G4A genes and chronic intestinal ulcers:A case report and review of literature

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World Journal of Gastrointestinal Surgery 2024年第3期16卷 932-943页

作者： Yong-Jing Tang Jian Zhang Jie Wang Ren-Dong Tian Wei-Wei Zhong Ben-Sheng Yao Bing-Yu Hou Ying-Hua Chen Wei He Yi-Huai He department of infectious diseases The Affiliated Hospital of Zunyi Medical UniversityZunyi 563000Guizhou ProvinceChina department of Gastroenterology Dafang County People's HospitalBijie 551600Guizhou ProvinceChina department of Internal Medicine Puchang BranchMedical CommunitySuiyang County People's HospitalZunyi 563300Guizhou ProvinceChina department of infectious diseases Jingmen Central HospitalJingmen 448000Hubei ProvinceChina department of infectious diseases Dafang County People's HospitalBijie 551600Guizhou ProvinceChina

BACKGROUND Genetic factors of chronic intestinal ulcers are increasingly garnering *** present a case of chronic intestinal ulcers and bleeding associated with mu-tations of the activin A receptor type II-like 1(ACVRL1)and phospholipase A2 group IVA(PLA2G4A)genes and review the available relevant *** SUMMARY A 20-year-old man was admitted to our center with a 6-year history of recurrent abdominal pain,diarrhea,and dark *** the onset 6 years ago,the patient had received treatment at a local hospital for abdominal pain persisting for 7 d,under the diagnosis of diffuse peritonitis,acute gangrenous appendicitis with perforation,adhesive intestinal obstruction,and pelvic *** surgical treat-ment included exploratory laparotomy,appendectomy,intestinal adhesiolysis,and pelvic abscess *** patient’s condition improved and he was ***,the recurrent episodes of abdominal pain and passage of black stools started again one year after *** the basis of these features and results of subsequent colonoscopy,the clinical diagnosis was established as in-flammatory bowel disease(IBD).Accordingly,aminosalicylic acid,immunotherapy,and related symptomatic treatment were administered,but the symptoms of the patient did not improve *** investigations revealed mutations in the ACVRL1 and PLA2G4A ***1 and PLA2G4A are involved in angiogenesis and coagulation,*** suggests that the chronic intestinal ulcers and bleeding in this case may be linked to mutations in the ACVRL1 and PLA2G4A *** Kangfuxin liquid was administered to promote healing of the intestinal mucosa and effectively manage clinical *** Mutations in the ACVRL1 and PLA2G4A genes may be one of the causes of chronic intestinal ulcers and bleeding in *** administered Kangfuxin liquid may have therapeutic potential.

关键词： Intestinal ulcers Crohn’s disease Ulcerative colitis Activin A receptor type II-like 1 Phospholipase A2 group 4A Case report

Minimizing the ratio of ionizable lipid in lipid nanoparticles for in vivo base editing

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National Science Review 2024年第6期11卷 285-293页

作者： Qiubing Chen Xuebin Wang Yizhou Zhang Ming Tian Junyi Duan Ying Zhang Hao Yin departments of Urology and Laboratory Medicine Frontier Science Center for Immunology and Metabolism Medical Research InstituteZhongnan Hospital of Wuhan UniversityWuhan University State Key Laboratory of Virology Tai Kang Center for Life and Medical Sciences Tai Kang Medical SchoolWuhan University department of Rheumatology and Immunology Zhongnan Hospital of Wuhan UniversityWuhan University Wuhan Research center for infectious diseases and Cancer Chinese Academy of Medical Sciences RNA Institute Wuhan University

Lipid nanoparticles(LNPs) have gained clinical approval as carriers for both siRNA and mRNA. Among the crucial components of LNPs, ionizable lipids play a pivotal role in determining the efficiency of RNA delivery. In this study, we synthesized a series of ionizable lipids, denoted as HTO, with a higher count of hydroxyl groups compared to SM-102. Remarkably, LNPs based on HTO12 lipid demonstrated comparable mRNA delivery efficiency and biosafety to those based on SM-102. However, the former reduced the ratio of ionizable lipid/total lipids to mRNA in LNPs by 2.5 times compared to SM-102. The HTO12 LNP efficiently encapsulated adenine base editor mRNA and sgRNA targeting Pcsk9, leading to substantial gene editing within the liver of mice and effective reduction of the target protein. Our study underscores that ionizable lipids with multiple hydroxyl groups may facilitate an improved lipid-to-mRNA ratio to minimize the dosage of ionizable lipids for in vivo delivery.

关键词： ionizable lipid lipid nanoparticle mRNA delivery base editor delivery Pcsk9

Estrogen receptorα-mediated signaling inhibits type Ⅰ interferon response to promote breast carcinogenesis

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Journal of Molecular Cell Biology 2023年第7期15卷 59-72页

作者： Li-Bo Cao Zi-Lun Ruan Yu-Lin Yang Nian-Chao Zhang Chuan Gao Cheguo Cai Jing Zhang Ming-Ming Hu Hong-Bing Shu department of infectious diseases Medical Research InstituteZhongnan Hospital of Wuhan UniversityCollege of Life SciencesWuhan UniversityWuhan 430072China Frontier Science center for Immunology and Metabolism Taikang Center for Life and Medical SciencesWuhan UniversityWuhan 430072China Research Unit of Innate Immune and Inflammatory diseases Chinese Academy of Medical SciencesWuhan 430072China

Estrogen receptorα(ERα)is an important driver and therapeutic target in∼70%of breast *** ERαdrives breast carcinogenesis is not fully *** this study,we show that ERαis a negative regulator of type I interferon(IFN)*** of ERαby its natural ligand estradiol inhibits IFN-β-induced transcription of downstream IFN-stimulated genes(ISGs),whereas ERαdeficiency or the stimulation with its antagonist fulvestrant has opposite ***,ERαinduces the expression of the histone 2A variant H2A.Z to restrict the engagement of the IFN-stimulated gene factor 3(ISGF3)complex to the promoters of ISGs and also interacts with STAT2 to disrupt the assembly of the ISGF3 *** two events mutually lead to the inhibition of ISG transcription induced by type I *** a xenograft mouse model,fulvestrant enhances the ability of IFN-βto suppress ERα^(+)breast tumor ***,clinical data analysis reveals that ERα^(+)breast cancer patients with higher levels of ISGs exhibit higher long-term survival *** together,our findings suggest that ERαinhibits type I IFN response via two distinct mechanisms to promote breast carcinogenesis.

关键词： estrogen receptor type I interferon breast cancer

Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern

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Hepatobiliary & Pancreatic diseases International 2016年第4期15卷 371-377页

作者： Feng Gao Heng-Kai Zhu Yang-Bo Zhu Qiao-Nan Shan Qi Ling Xu-Yong Wei Hai-Yang Xie Lin Zhou Xiao Xu Shu-Sen Zheng Division of Hepatobiliary and Pancreatic Surgery Department of Surgery First Affiliated Hospital Zhejiang University School of Medicine Collaborative Innovation center for Diagnosis and Treatment of infectious diseases Zhejiang University Key Lab of Combined Multi-Organ Transplantation Ministry of Public Health First Affiliated Hospital Zhejiang University School of Medicine

BACKGROUND： Four tumor markers for hepatocellular carcinoma（HCC）, alpha-fetoprotein（AFP）, glypican-3（GPC3）, vascular endothelial growth factor（VEGF） and des-gammacarboxy prothrombin（DCP）, are closely associated with tumor invasion and patient＇s survival. This study estimated the predictability of preoperative tumor marker levels along with pathological parameters on HCC recurrence after ***： A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups： patients with macroscopic vascular invasion（Ma VI ＋） and those without Ma VI（Ma VI-）. The predictive value of tumor markers and clinical parameters were evaluated by univariate and multivariate ***： In all patients, tumor size（〉8 cm） and Ma VI were closely related to HCC recurrence after hepatectomy. For Ma VI＋ patients, VEGF（〉900 pg/m L） was a significant predictor for recurrence（RR=2.421; 95% CI： 1.272-4.606; P=0.007）. The 1- and 2-year tumor-free survival rates for Ma VI＋ patients with VEGF ≤900 pg/m L versus for those with VEGF 〉900 pg/m L were 51.5% and 17.6% versus 19.0% and 4.8%（P〈0.001）. For Ma VI- patients, DCP 〉445 m Au/m L and tumor size 〉8 cm were two independent risk factors for tumor recurrence（RR=2.307, 95% CI： 1.132-4.703, P=0.021; RR=3.150, 95% CI： 1.392-7.127, P=0.006; respectively）. The 1- and 2-year tumor-free survival rates for the patients with DCP ≤445 m Au/m L and those with DCP 〉445 m Au/m L were 90.4% and 70.7% versus 73.2% and 50.5% respectively（P=0.048）. The 1-and 2-year tumor-free survival rates for the patients with tumor size ≤8 cm and 〉8 cm were 83.2% and 62.1% versus 50.0% and 30.0%, respectively（P=0.003）.CONCLUSIONS： The Ma VI＋ patients with VEGF ≤900 pg/m L had a relatively high tumor-free survival than those with VEGF 〉900 pg/m L. In the Ma VI- patients, DCP 〉445 m Au/m L and tumor size 〉8

关键词： tumor markers hepatocellular carcinoma recurrence vascular invasion prediction

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Advanced Glycation End Products Promote Differentiation of CD4^+ T Helper Cells toward Pro-inflammatory Response

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Journal of Huazhong university of Science and Technology(Medical Sciences) 2014年第1期34卷 10-17页

作者：韩晓群龚作炯徐三清李汛王立坤伍仕敏吴建红杨华芬 department of infectious diseases Renmin Hospital of Wuhan University department of Pediatrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology department of infectious diseases Wuhan Medical Treatment Center

This study investigated the effect of advanced glycation end products（AGEs） on differentiation of na ve CD4＋T cells and the role of the receptor of AGEs（RAGE） and peroxisome proliferator-activated receptors（PPARs） activity in the process in order to gain insight into the mechanism of immunological disorders in diabetes. AGEs were prepared by the reaction of bovine serum albumin（BSA） with glucose. Human na ve CD4＋T cells, enriched from blood of healthy adult volunteers with negative selection assay, were cultured in vitro and treated with various agents including AGEs, BSA, high glucose, PGJ2 and PD68235 for indicated time. In short hairpin（sh） RNA knock-down experiment, na ve CD4＋T cells were transduced with media containing shRNA-lentivirus generated from lentiviral packaging cell line, Lent-XTM293 T cells. Surface and intracellular cytokine stainings were used for examination of CD4＋T cell phenotypes, and real-time PCR and Western blotting for detection of transcription factor mRNA and protein expression, respectively. The suppressive function of regulatory T（Treg） cells was determined by a [3H]-thymidine incorporation assay. The results showed that AGEs induced higher pro-inflammatory Th1/Th17 cells differentiated from na ve CD4＋T cells than the controls, whereas did not affect anti-inflammatory Treg cells. However, AGEs eliminated suppressive function of Treg cells. In addition, AGEs increased RAGE mRNA expression in na ve CD4＋T cells, and RAGE knock-down by shRNA eliminated the effect of AGEs on the differentiation of CD4＋T cells and the reduction of suppressive function of Treg cells. Furthermore, AGEs inhibited the mRNA expression of PPARγ, not PPARα; PPARγ agonist, PGJ2, inhibited the effect of AGEs on na ve CD4＋T cell differentiation and reversed the AGE-reduced suppressive function of Treg cells; on the other hand, PPARγ antagonist, PD68235, attenuated the blocking effect of RAGE shRNA on the role of AGEs. It was concluded that AGEs may promote CD4＋T cells

关键词： diabetes advanced glycation end products CD4T cell subsets pro-inflammatory re-sponse

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Liver diseases in COVID-19:Etiology,treatment and prognosis

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World Journal of Gastroenterology 2020年第19期26卷 2286-2293页

作者： Jian Wu Shu Song Hong-Cui Cao Lan-Juan Li State Key Laboratory for the Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310003Zhejiang ProvinceChina department of Laboratory Medicine The Third People’s Hospital of Yancheng CityYancheng 224001Jiangsu ProvinceChina department of Pathology Shanghai Public Health Clinical CenterFudan UniversityShanghai 201508China Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic-chemical Injury diseases Hangzhou 310003Zhejiang ProvinceChina

In December 2019,a novel coronavirus named severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)was identified in Wuhan,China causing coronavirus disease-2019(COVID-19).Numerous studies have shown varying degrees of liver damage in patients infected with ***,in previous case studies of COVID-19,the exact cause of liver injury has not been clearly elucidated,nor is there clear evidence of the interaction between liver injury and *** study will analyze the causes of liver injury in COVID-19 and the influence of liver-related complications on the treatment and prognosis of COVID-19.

关键词： SARS-CoV-2 COVID-19 Liver injury Etiology Treatment Prognosis

Mitochondrial DNA-triggered innate immune response:mechanisms and diseases

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Cellular & Molecular Immunology 2023年第12期20卷 1403-1412页

作者： Ming-Ming Hu Hong-Bing Shu department of infectious diseases Medical Research InstituteZhongnan Hospital of Wuhan UniversityFrontier Science Center for Immunology and MetabolismTaikang Center for Life and Medical SciencesCollege of Life SciencesWuhan UniversityResearch Unit of Innate Immune and Inflammatory DiseasesChinese Academy of Medical SciencesWuhan430072China Research Unit of Innate Immune and Inflammatory diseases Chinese Academy of Medical SciencesWuhan430072China

Various cellular stress conditions trigger mitochondrial DNA(mtDNA)release from mitochondria into the *** released mtDNA is sensed by the cGAS-MITA/STING pathway,resulting in the induced expression of type I interferon and other effector *** processes contribute to the innate immune response to viral infection and other stress *** deregulation of these processes causes autoimmune diseases,inflammatory metabolic disorders and ***,the cGAS-MITA/STING pathway is a potential target for intervention in infectious,inflammatory and autoimmune diseases as well as *** this review,we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway,the effects of the pathway under various physiological and pathological conditions,and advances in the development of drugs that target cGAS and MITA/STING.

关键词： Mitostress Virus Innate immunity Disease MITA/STING

Small-molecule anti-COVID-19 drugs and a focus on China's homegrown mindeudesivir(WV116)

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Frontiers of Medicine 2023年第6期17卷 1068-1079页

作者： Qiuyu Cao Yi Ding Yu Xu Mian Li Ruizhi Zheng Zhujun Cao Weiqing Wang Yufang Bi Guang Ning Yiping Xu Ren Zhao department of Endocrine and Metabolic diseases Shanghai Institute of Endocrine and Metabolic DiseasesRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai National Clinical Research center for Metabolic diseases State Key Laboratory of Medical GenomicsKey Laboratory for Endocrine and Metabolic Diseases of the National Health CommissionShanghai National Center for Translational MedicineRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China department of infectious Disease Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Clinical Trials center Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China department of General Surgery Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China

The coronavirus disease 2019(COVID-19)pandemic has stimulated tremendous efforts to develop therapeutic agents that target severe acute respiratory syndrome coronavirus 2 to control viral *** far,a few small-molecule antiviral drugs,including nirmatrelvir-ritonavir(Paxlovid),remdesivir,and molnupiravir have been marketed for the treatment of ***-ritonavir has been recommended by the World Health Organization as an early treatment for outpatients with mild-to-moderate ***,the existing treatment options have limitations,and effective treatment strategies that are cost-effective and convenient for tackling COVID-19 are still *** date,four domestically developed oral anti-COVID-19 drugs have been granted conditional market approval in *** drugs include azvudine,simnotrelvir-ritonavir(Xiannuoxin),leritrelvir,and mindeudesivir(VV11).Preclinical and clinical studies have explored the efficacy and tolerability of mindeudesivir and supported its early use in mild-to-moderate COVID-19 cases at high risk for *** this review,we discuss the most recent findings regarding the pharmacological mechanism and therapeutic effects focusing on mindeudesivir and other small-molecule antiviral agents for *** findings will expand our understanding and highlight the potential widespread application of China's homegrown anti-COVID-19 drugs.

关键词： COVID-19 antiviral drugs mindeudesivir

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Identification of Persister Drug Combination Clinafloxacin+Cefuroxime+Gentamicin That Eradicates Persistent Pseudomonas aeruginosa Infection in a Murine Cystic Fibrosis Model

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infectious Microbes & diseases 2023年第1期5卷 21-28页

作者： Yuting Yuan Rebecca Yee Naina Gour Xinzhong Dong Jie Feng Wanliang Shi Ying Zhang department of Molecular Microbiology and Immunology Johns Hopkins Bloomberg School of Public HealthBaltimoreMarylandUSA The Solomon H.Snyder department of Neuroscience and the center for Sensory Biology Johns Hopkins University School of MedicineBaltimoreMarylandUSA State Key Laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina Research Units of infectious Disease and Microecology Chinese Academy of Medical SciencesHangzhouZhejiangChina Jinan Microecological Biomedicine Shandong Laboratory JinanShandongChina

Pseudomonas aeruginosa can cause persistent infections,such as biofilm infections,in cystic fibrosis patients,which are difficult to cure due to non-growing persister bacteria that are not effectively killed by the current *** antibiotic activity against growing *** is well documented,their activity against non-growing stationary phase cultures is less ***,we evaluated six major classes of antibiotics,including cell wall and cell membrane inhibitors,protein synthesis inhibitors,DNA synthesis inhibitors,RNA synthesis inhibitors,sulfa drugs and nitrofurantoin,for their activity against growing and non-growing *** foundthat cell wall and cell membrane inhibitors(cefuroxime and colistin),DNA synthesis inhibitors(clinafloxacin)and sulfa drugs(sulfamethoxazole)had good activity against stationary-phase bacteria,while protein synthesis inhibitors(gentamicin),RNA synthesis inhibitor(rifampin)and nitrofurantoin showed relatively poor *** was the only drug able to completely eradicate stationary-phase bacteria within four *** cefuroxime+gentamicin+clinafloxacin combination was able to kill all bacteria from a biofilm within two days,whereas the clinically used drug combination cefuroxime+gentamicin/colistin only partially killed the *** amurine persistent cystic fibrosis lung infectionmodel,only the cefuroxime+gentamicin+clinafloxacin drug combination eradicated all bacteria from the lungs,whereas clinafloxacin alone,cefuroxime+clinafloxacin or the currently recommended drug combination cefuroxime+gentamicin failed to do *** complete eradication is a property of the clinafloxacin combination,as the otherwise identical levofloxacin combination did not clear the bacterial loads from the *** findings offer new therapeutic options for more effective treatment of persistent *** infections,with possible implications for treating other persistent infections.

关键词： Pseudomonas aeruginosa persisters stationary-phase bacteria biofilm clinafloxacin cystic fibrosis