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RNA modifications in cellular metabolism:implications for metabolism-targeted therapy and immunotherapy

Signal Transduction and Targeted Therapy 2024年第4期9卷 1565-1594页

作者： Wei-Wei Liu Si-Qing Zheng Tian Li Yun-Fei Fei Chen Wang Shuang Zhang Fei Wang Guan-Min Jiang Hao Wang Department of laboratory Medicine The First Affliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina School of clinical Medicine Shandong UniversityJinanChina Core Unit of National clinical Research Center for laboratory Medicine HefeiChina Neurosurgical Department The First Affliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina Department of clinical laboratory The Fifth Affliated HospitalSun Yat-sen UniversityZhuhaiChina

Cellular metabolism is an intricate network satisfying bioenergetic and biosynthesis requirements of cells.Relevant studies have been constantly making inroads in our understanding of pathophysiology,and inspiring development of therapeutics.As a crucial component of epigenetics at post-transcription level,RNA modification significantly determines RNA fates,further affecting various biological processes and cellular phenotypes.To be noted,immunometabolism defines the metabolic alterations occur on immune cells in different stages and immunological contexts.In this review,we characterize the distribution features,modifying mechanisms and biological functions of 8 RNA modifications,including N6-methyladenosine(m6A),N6,2'-O-dimethyladenosine(m6Am),N1-methyladenosine(m1A),5-methylcytosine(m5C),N4-acetylcytosine(ac4C),N7-methylguanosine(m7G),Pseudouridine(V),adenosine-to-inosine(A-to-l)editing,which are relatively the most studied types.Then regulatory roles of these RNA modification on metabolism in diverse health and disease contexts are comprehensively described,categorized as glucose,lipid,amino acid,and mitochondrial metabolism.And we highlight the regulation of RNA modifications on immunometabolism,further influencing immune responses.Above all,we provide a thorough discussion about clinical implications of RNA modification in metabolism-targeted therapy and immunotherapy,progression of RNA modification-targeted agents,and its potential in RNAtargeted therapeutics.Eventually,we give legitimate perspectives for future researches in this field from methodological requirements,mechanistic insights,to therapeutic applications.

关键词： metabolism targeted alterations

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Fanconi anemia gene-associated germline predisposition in aplastic anemia and hematologic malignancies

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Frontiers of Medicine 2022年第3期16卷 459-466页

作者： Daijing Nie Jing Zhang Fang Wang Xvxin Li Lili Liu Wei Zhang Panxiang Cao Xue Chen Yang Zhang Jiaqi Chen Xiaoli Ma Xiaosu Zhou Qisheng Wu Ming Liu Mingyue Liu Wenjun Tian Hongxing Liu division of laboratory Medicine Hebei Yanda Lu Daopei HospitalLangfang 065201China Beijing Lu Daopei Institute of Hematology Beijing 100176China division of Pathology&laboratory Medicine Beijing Lu Daopei HospitalBeijing 100176China Department of clinical laboratory Medicine Shandong Provincial Hospital Affiliated to Shandong UniversityJinan 250021China

Whether Fanconi anemia(FA)heterozygotes are predisposed to bone marrow failure and hematologic neoplasm is a crucial but unsettled issue in cancer prevention and family consulting.We retrospectively analyzed rare possibly significant variations(PSVs)in the five most obligated FA genes,BRCA2,FANCA,FANCC,FANCD2,and FANCG,in 788 patients with aplastic anemia(AA)and hematologic malignancy.Sixty-eight variants were identified in 66 patients(8.38%).FANCA was the most frequently mutated gene(n=29),followed by BRCA2(n=20).Compared with that of the ExAC East Asian dataset,the overall frequency of rare PSVs was higher in our cohort(P=0.016).BRCA2 PSVs showed higher frequency in acute lymphocytic leukemia(P=0.038),and FANCA PSVs were significantly enriched in AA and AML subgroups(P=0.020;P=0.008).FA-PSV-positive MDS/AML patients had a higher tumor mutation burden,higher rate of cytogenetic abnormalities,less epigenetic regulation,and fewer spliceosome gene mutations than those of FA-PSV-negative MDS/AML patients(P=0.024,P=0.029,P=0.024,and P=0.013).The overall PSV enrichment in our cohort suggests that heterozygous mutations of FA genes contribute to hematopoietic failure and leukemogenesis.

关键词： Fanconi anemia aplastic anemia hematologic malignancy germline predisposition

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Cannabinoids drive Th17 cell differentiation in patients with rheumatic autoimmune diseases

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Cellular & Molecular Immunology 2021年第3期18卷 764-766页

作者： Konstantin Kotschenreuther Iris Waque Shuaifeng Yan Anja Meyer Thom Haak Julia von Tresckow Joanna Schiller Lydia Gloyer Mara Dittrich-Salamon David M.Kofler laboratory of Molecular Immunology and division of clinical Immunology and Rheumatology University of CologneCologneGermany DepartmentⅠof Internal Medicine University of CologneCologneGermany

The legalization of cannabinoids for medical use has reinforced their emerging role as a treatment of chronic pain in patients with cancer or rheumatic diseases.1,2 In addition to their role as pain relievers,evidence obtained from animal models suggests that cannabinoids have immunosuppressive properties.3 However,a definite immunosuppressive function of cannabinoids has not yet been confirmed in clinical trials.

关键词： rheumatic Th17 patients

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Morphological alterations and redox changes associated with hepatic warm ischemia-reperfusion injury

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World Journal of Hepatology 2017年第34期9卷 1261-1269页

作者： Rim Jawad Melroy D'souza Lisa Arodin Selenius Marita Wallenberg Lundgren Olof Danielsson Greg Nowak Mikael Bjornstedt Bengt Isaksson division of Pathology Department of Laboratory Medicine Karolinska Institutet Department of clinical Science Intervention and Technology (CLINTEC) Division of Surgery Karolinska Institutet Karolinska University Hospital Department of clinical Science Intervention and Technology (CLINTEC) Division of Transplantation Surgery Karolinska Institutet Karolinska University Hospital

AIM To study the effects of warm ischemia-reperfusion(I/R) injury on hepatic morphology at the ultrastructural level and to analyze the expression of the thioredoxin(TRX)and glutaredoxin(GRX) systems.METHODS Eleven patients undergoing liver resection were subjected to portal triad clamping(PTC). Liver biopsies were collected at three time points; first prior to PTC(baseline), 20 min after PTC(post-ischemia) and 20 min after reperfusion(post-reperfusion). Electron microscopy and morphometry were used to study and quantify ultrastructural changes, respectively. Additionally, gene expression analysis of TRX and GRX isoforms was performed by quantitative PCR. For further validation of redox protein status, immunogold staining was performed for the isoforms GRX1 and TRX1.RESULTS Post-ischemia, a significant loss of the liver sinusoidal endothelial cell(LSEC) lining was observed(P = 0.0003) accompanied by a decrease of hepatocyte microvilli in the space of Disse. Hepatocellular morphology was well preserved apart from the appearance of crystalline mitochondrial inclusions in 7 out of 11 patients. Postreperfusion biopsies had similar features as post-ischemia with the exception of signs of a reactivation of the LSECs. No changes in the expression of redox-regulatory genes could be observed at mR NA level of the isoforms of the TRX family but immunoelectron microscopy indicated a redistribution of TRX1 within the cell.CONCLUSION At the ultrastructural level, the major impact of hepatic warm I/R injury after PTC was borne by the LSECs with detachment and reactivation at ischemia and reperfusion, respectively. Hepatocytes morphology were well preserved. Crystalline inclusions in mitochondria were observed in the hepatocyte after ischemia.

关键词：肝的 ischemia-reperfusion 损害局部缺血灌注损害温暖 ischemia-reperfusion 损害 Glutaredoxins Thioredoxins 电子显微镜学氧化应力夹钳的门三个一组

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Graph-based network analysis in schizophrenia

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World Journal of Psychiatry 2012年第1期2卷 1-12页

作者： Sifis Micheloyannis Medical division Research Clinical Neurophysiological Laboratory (L. Widén Laboratory) University of Crete

Over the last few years, many studies have been published using modern network analysis of the brain. Researchers and practical doctors alike should understand this method and its results on the brain evaluation at rest, during activation and in brain disease. The studies are noninvasive and usually performed with elecroencephalographic, magnetoencephalographic, magnetic resonance imaging and diffusion tensor imaging brain recordings. Different tools for analysis have been developed, although the methods are in their early stages. The results of these analyses are of special value. Studies of these tools in schizophrenia are important because widespread and local network disturbances can be evaluated by assessing integration, segregation and several structural and functional properties. With the help of network analyses, the main findings in schizophrenia are lower optimum network organization, less efficiently wired networks, less local clustering, less hierarchical organization and signs of disconnection. There are only about twenty five relevant papers on the subject today. Only a few years of study of these methods have produced interesting results and it appears promising that the development of these methods will present important knowledge for both the preclinical signs of schizophrenia and the methods' therapeutic effects.

关键词： Schizophrenia Graph theory Small world networks Brain networks Brain connectivity

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The microbiome and autoimmunity: a paradigm from the gut–liver axis

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Cellular & Molecular Immunology 2018年第6期15卷 595-609页

作者： Bo Li Carlo Selmi Ruqi Tang ME Gershwin Xiong Ma division of Gastroenterology and Hepatology Key Laboratory of Gastroenterology and HepatologyMinistry of HealthState Key Laboratory for Oncogenes and Related GenesRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Institute of Digestive DiseaseShanghai 200001China division of Rheumatology and clinical Immunology Humanitas Research HospitalRozzanoItaly BIOMETRA Department University of Milan MilanItaly division of Rheumatology Department of MedicineAllergy and Clinical ImmunologyUniversity of California at DavisDavisCAUSA

Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experimental data in germ-free and gnotobiotic studies.Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown,as observed in rheumatic fever triggered by Streptococci via molecular mimicry,epitope spread and bystander effects.The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases,including rheumatoid arthritis,type 1 diabetes,multiple sclerosis and autoimmune liver disease.It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena.In fact,there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity,and microbial therapeutics is being investigated to prevent or halt autoimmune diseases.As a putative mechanism,it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens,giving rise to the differentiation of autoreactive Th17 cells and other T helper cells.This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity,with an emphasis on how dysbiosis may influence systemic autoimmunity.In particular,a gut–liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm,considering its anatomic and physiological connections.

关键词： autoimmunity autoimmune liver disease dysbiosis microbiome

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Fatal submucosal invasive gastric adenosquamous carcinoma detected at surveillance after gastric endoscopic submucosal dissection

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World Journal of Gastroenterology 2015年第14期21卷 4385-4390页

作者： Akinori Shirahige Haruhisa Suzuki Ichiro Oda Masau Sekiguchi Genki Mori Seiichiro Abe Satoru Nonaka Shigetaka Yoshinaga Shigeki Sekine Ryoji Kushima Yutaka Saito Takeo Fukagawa Hitoshi Katai Endoscopy division National Cancer Center Hospital Pathology division National Cancer Center Hospital Department of clinical laboratory Medicine and Diagnostic Pathology Shiga University of Medical Science Gastric Surgery division National Cancer Center Hospital

An 80-year-old man was under annual surveillance esophagogastroduodenoscopy after endoscopic submucosal dissection(ESD) for early gastric cancer(EGC).Two years after the initial ESD, a 0-Ⅱc type metachronous EGC lesion, 8 mm in size, without an ulcer scar, was found in the gastric antrum.The estimated tumor depth was up to the mucosa, and biopsy revealed well and poorly differentiated adenocarcinoma.ESD was performed for this lesion and en bloc resection with negative margins was achieved.Histopathological examination revealed an adenosquamous carcinoma 8 mm in size invading the deep submucosal layer(1600 μm), with lymphovascular invasion, consistent with the diagnosis of non-curative resection.Additional gastrectomy was recommended for this patient; however, two months after the ESD, preoperative computed tomography revealed multiple liver metastases, and the patient was considered as an unsuitable candidate for surgical resection.Systemic chemotherapy was therefore started; however, the patient died of gastric cancer 27 mo after the second ESD.Early gastric adenosquamous carcinoma localized to the mucosa and submucosa is extremely rare and its clinical behavior is not well known.The present report is very significant in that it underscores the distinct possibility of gastric adenosquamous carcinoma being very aggressive and fatal even when detected at an early cancer.

关键词： Early gastric cancer Endoscopic submucosal dissect

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clinical significance of lymph node metastasis in gastric cancer

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World Journal of Gastroenterology 2014年第14期20卷 3967-3975页

作者： Jing-Yu Deng Han Liang Gastric Oncology division Tianjin Medical University Cancer Hospital and City Key Laboratory of Tianjin Cancer CenterNational Clinical Center of Cancer

Gastric cancer,one of the most common malignancies in the world,frequently reveals lymph node,peritoneum,and liver metastases.Most of gastric cancer patients present with lymph node metastasis when they were initially diagnosed or underwent surgical resection,which results in poor prognosis.Both the depth of tumor invasion and lymph node involvement are considered as the most important prognostic predictors of gastric cancer.Although extended lymphadenectomy was not considered a survival benefit procedure and was reported to be associated with high mortality and morbidity in two randomized controlled European trials,it showed significant superiority in terms of lower locoregional recurrence and disease related deaths compared to limited lymphadenectomy in a 15-year followup study.Almost all clinical investigators have reached a consensus that the predictive efficiency of the number of metastatic lymph nodes is far better than the extent of lymph node metastasis for the prognosis of gastric cancer worldwide,but other nodal metastatic classifications of gastric cancer have been proposed as alternatives to the number of metastatic lymph nodes for improving the predictive efficiency for patient prognosis.It is still controversial over whether the ratio between metastatic and examined lymph nodes is superior to the number of metastatic lymph nodes in prognostic evaluation of gastric cancer.Besides,the negative lymph node count has been increasingly recognized to be an important factor significantly associated with prognosis of gastric cancer.

关键词： Stomach Neoplasm Lymph node Metastasis Prognosis

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Ghrelin receptor gene polymorphisms are associated with female metabolic syndrome in Chinese population

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Chinese Medical Journal 2008年第17期121卷 1666-1669页

作者： LI Wei-ju ZHEN Yi-song SUN Kai XUE Hao SONG Xiao-dong WANG Yi-bo FAN Xiao-han HAN Yun-feng HUI Ru-tai Hypertension division Fuwai Hospital and Cardiovascular Institute Key laboratory of clinical Cardiovascular Genetics Ministry of Education Sino-German laboratory for Molecular Medicine

Background The ghrelin plays an important role in the regulation of food intake and energy homeostasis. Therefore, the ghrelin receptor gene （GHSR） is an excellent candidate for studying metabolic syndrome. This study aimed to investigate whether polymorphisms in ghrelin receptor gene are associated with metabolic syndrome in Chinese population. Methods Subjects consisted of 698 patients aged 41 to 80 years, diagnosed as metabolic syndrome by International Diabetes Federation （IDF） 2005 criteria, and 762 age- and gender-matched controls. Three variants within the GHSR were selected and genotyped using polymerase chain reaction （PCR） and restriction fragment length polymorphism （RFLP）. Odds ratios were estimated using a case-control study design by controlling confounding factors. Results The NA genotype （rs2922126） in the promoter was associated with metabolic syndrome （OR 1.41, 95%C/ 1.03-1.94）, increased waist circumference （OR 1.75, 95%C/1.26-2.42）, and increased fast blood glucose （OR 1.49, 95%CI 1.07-2.06） in women. The NA genotype （rs509030） in the intron was associated with lower plasma high density lipoprotein in women （OR 1.37, 95%C/1.02-1.84）. Conclusion The polymorphisms within GHSR might be a genetic risk factor for metabolic syndrome in women.

关键词： metabolic syndrome polymorphism ghrelin receptor

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PCSK9 and triglyceride-rich lipoprotein metabolism

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The Journal of Biomedical Research 2015年第6期29卷 429-436页

作者： Irena Druce Hussein Abujrad Teik Chye Ooi clinical Research laboratory Division of Endocrinology and MetabolismDepartment of MedicineUniversity of Ottawa Chronic Disease Program Ottawa Hospital Research InstituteThe Ottawa Hospital

Pro-protein convertase subtilisin-kexin 9 （PCSK9） is known to affect low-density lipoprotein （LDL） metabolism, but there are indications from several lines of research that it may also influence the metabolism of other lipopro- teins, especially triglyceride-rich lipoproteins （TRL）. This review summarizes the current data on this possible role of PCSK9. A link between PCSK9 and TRL has been suggested through the demonstration of （1） a correlation between plasma PCSK9 and triglyceride （TG） levels in health and disease, （2） a correlation between plasma PCSK9 and markers of carbohydrate metabolism, which is closely related to TG metabolism, （3） an effect of TG-lowering fibrate therapy on plasma PCSK9 levels, （4） an effect of PCSK9 on postprandial lipemia, （5） an effect of PCSK9 on adipose tissue biology, （6） an effect of PCSK9 on apolipoprotein B production from the liver and intestines, （7） an effect of PCSK9 on receptors other than low density lipoprotein receptor （LDLR） that are involved in TRL metabolism, and （8） an effect of anti-PCSK9 therapy on serum TG levels. The underlying mechanisms are unclear but starting to emerge.

关键词： hyperlipidemia hypercholesterolemia molecular biology

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