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A network based efficient drug repurposing strategy for targeting diabesity

Genes & Diseases 2023年第2期10卷 340-343页

作者： Subhajit Dutta Ted Natoli Deep Chanda Sindhuja Rajavelu Debojyoti De laboratory of cellular differentiation & metabolic disorder Department of BiotechnologyNational Institute of TechnologyDurgapurWest Bengal 713209India Cancer Program Broad Institute of MIT and HarvardCambridgeMA 02142USA

Type II diabetes and obesity are two of the most prevalent metabolic disorders effecting a huge population throughout the world. Research over the last decade has unequivocally established considerable molecular links between them and hence they are often described in conjugation as ‘diabesity’. The hallmarks of type II diabetes are primarily reduced insulin sensitivity, progressive insulin resistance and consequent hyperinsulinemia.1 Whereas, hyperinsulinemia promotes a plethora of fat synthesis from excess circulating carbohydrate and hyperactive fat storage mechanisms, ultimately inducing hepatic steatosis, myosteatosis and pancreatic steatosis.1 This in turn, aggravates the insulin sensitivity further, inflicting more insulin resistance and even more hyperinsulinemia. Needless to mention that the vicious process in turn, promotes uncontrolled weight gain1 and many secondary metabolic disorders. The prevalent anti-diabetic and anti-obesity medications comes with several limitations ranging from inefficiency to adverse side effects.2 Here, we report an efficient strategy of repositioning previously approved drugs with novel indication in the context of diabesity by investigating deregulated signalling axes affecting patients with both the disorders. Our approach relies extensively on deciphering the strength of gene association in various interactomes, as it is known that within networks, genes linked to similar disease phenotypes tend to be functionally similar3 and remain proximal to each other.4 Moreover, the potential drug targets associated to a disease pathway also cluster proximal to the disease pathways.

关键词： hence primarily network

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Endorepellin和neurexin互作促进神经上皮细胞自噬并维持正常神经管发育

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Science Bulletin 2024年第14期69卷 2260-2272页

作者：卢磊白梅竹郑煜芳王修坤陈仲中彭瑞 Richard H.Finnell 赵同金李承涛吴波雷云平李劲松王红艳 Shanghai Key laboratory of metabolic Remodeling and Health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Obstetrics&Gynecology Hospital State Key Laboratory of Genetic EngineeringFudan UniversityShanghai 200032China Key laboratory of Multi-Cell Systems Shanghai Key Laboratory of Molecular AndrologyCAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China Obstetrics&Gynecology Hospital The Institute of Obstetrics and GynecologyFudan UniversityShanghai 200090China Center for Precision Environmental Health Department of Molecular and Cellular BiologyBaylor College of MedicineHouston 77031USA Shanghai Medical College Fudan UniversityShanghai 200032China Prenatal Diagnosis Center of Shenzhen Maternity&Child Healthcare Hospital Shenzhen 518028China Children’s Hospital Fudan UniversityShanghai 201102China

Heparan sulfate proteoglycan 2(HSPG2)gene encodes the matrix protein Perlecan,and genetic inactivation of this gene creates mice that are embryonic lethal with severe neural tube defects(NTDs).We discovered rare genetic variants of HSPG2 in 10%cases compared to only 4%in controls among a cohort of 369 ***,a peptide cleaved from the domain V of Perlecan,is known to promote angiogenesis and autophagy in endothelial *** roles of enderepellin in neurodevelopment remain unclear so *** study revealed that endorepellin can migrate to the neuroepithelial cells and then be recognized and bind with the neuroepithelia receptor neurexin in *** the endocytic pathway,the interaction of endorepellin and neurexin physiologically triggers autophagy and appropriately modulates the differentiation of neural stem cells into neurons as a blocker,which is necessary for normal neural tube *** created knock-in(KI)mouse models with human-derived HSPG2 variants,using sperm-like stem cells that had been genetically edited by CRISPR/*** realized that any HSPG2 variants that affected the function of endorepellin were considered pathogenic causal variants for human NTDs given that the severe NTD phenotypes exhibited by these KI embryos occurred in a significantly higher response frequency compared to wildtype *** study provides a paradigm for effectively confirming pathogenic mutations in other genetic ***,we demonstrated that using autophagy inhibitors at a cellular level can repress neuronal ***,autophagy agonists may prevent NTDs resulting from failed autophagy maintenance and neuronal over-differentiation caused by deleterious endorepellin variants.

关键词： Neural tube defects Androgenetic haploid embryonic stem cells Basement membrane Neural stem cell Autophagy

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Cold-Induced Reprogramming of Subcutaneous White Adipose Tissue Assessed by Single-Cell and Single-Nucleus RNA Sequencing

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Research 2024年第1期2023卷 763-778页

作者： Qing Liu Qiaoyun Long Jiayu Zhao Wenjie Wu Zexin Lin Wei Sun Ping Gu Tuo Deng Kerry Martin Loomes Donghai Wu Alice P.S.Kong Jingying Zhou Alfred S.Cheng Hannah Xiaoyan Hui School of Biomedical Sciences The Chinese University of Hong KongHong KongChina Department of Pharmacology and Pharmacy The University of Hong KongHong KongChina Guangzhou Institute of Biomedicine and Health Chinese Academy of SciencesGuangzhouChina China-New Zealand Joint laboratory on Biomedicine and Health Chinese Academy of SciencesGuangzhouChina Department of Endocrinology Jinling HospitalNanjing UniversitySchool of MedicineNanjingChina National Clinical Research Center for metabolic Diseases and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina Key laboratory of Diabetes Immunology Ministry of Educationand Metabolic Syndrome Research CenterThe Second Xiangya Hospital of Central South UniversityChangshaChina Clinical Immunology Center The Second Xiangya Hospital of Central South UniversityChangshaChina School of Biological Sciences and Maurice Wilkins Centre University of AucklandAucklandNew Zealand Department of Medicine and Therapeutics The Chinese University of Hong KongHong KongChina Hong Kong Institute of Diabetes and Obesity The Chinese University of Hong KongPrince of Wales HospitalShatinHong KongChina Li Ka Shing Institute of Health Sciences The Chinese University of Hong KongPrince of Wales HospitalShatinHong KongChina

Adipose browning has demonstrated therapeutic potentials in several ***,by conducting transcriptomic profiling at the single-cell and single-nucleus resolution,we reconstituted the cellular atlas in mouse inguinal subcutaneous white adipose tissue(iWAT)at thermoneutrality or chronic cold *** major nonimmune cells within the iWAT,including adipose stem and progenitor cells(ASPCs),mature adipocytes,endothelial cells,Schwann cells,and smooth muscle cells,were recovered,allowing us to uncover an overall and detailed blueprint for transcriptomes and intercellular cross-talks and the dynamics during white adipose tissue brown *** findings also unravel the existence of subpopulations in mature adipocytes,ASPCs,and endothelial cells,as well as new insights on their interconversion and reprogramming in response to *** adipocyte subpopulation competent of major histocompatibility complex class Ⅱ(MHCⅡ)antigen presentation is ***,a subcluster of ASPC with CD74 expression was identified as the precursor of this MHCⅡ^(+)*** adipocytes are transdifferented from preexisting lipid generating adipocytes,which exhibit developmental trajectory from de novo differentiation of amphiregulin cells(Aregs).Two distinct immune-like endothelial subpopulations are present in iWAT and are responsive to *** data reveal fundamental changes during cold-evoked adipose browning.

关键词： evoked programming generating

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A cell transcriptomic profile p ovides insights into adipocytes of porcine mammary gland across development

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Journal of Animal Science and Biotechnology 2024年第1期15卷 182-200页

作者： Yongliang Fan Long Jin Zhiping He Tiantian Wei Tingting Luo Jiaman Zhang Can Liu Changjiu Dai Chao A Yan Liang Xuan Tao Xuebin Lv Yiren Gu Mingzhou Li State Key laboratory of Swine and Poultry Breeding Industry College of Animal Science and TechnologySichuan Agricultural UniversityChengdu 611130China Key laboratory of Qinghai‑Tibetan Plateau Animal Genetic Resource Reservation and Utilization Southwest Minzu UniversityChengdu 610041China Animal Breeding and Genetics Key laboratory of Sichuan Province Sichuan Animal Science AcademyChengdu 610000China

Background Studying the composition and developmental mechanisms in mammary gland is crucial for healthy growth of newborns. The mammary gland is inherently heterogeneous, and its physiological function dependents on the gene expression of multiple cell types. Most studies focused on epithelial cells, disregarding the role of neighboring *** Here, we constructed the largest transcriptomic dataset of porcine mammary gland cells thus far. The dataset captured 126,829 high-quality nuclei from physiological mammary glands across five developmental stages(d 90 of gestation, G90;d 0 after lactation, L0;d 20 after lactation, L20;2 d post natural involution, PI2;7 d post natural involution, PI7). Seven cell types were identified, including epithelial cells, adipocytes, endothelial cells, fibroblasts cells, immune cells, myoepithelial cells and precursor cells. Our data indicate that mammary glands at different developmental stages have distinct phenotypic and transcriptional signatures. During late gestation(G90), the differentiation and proliferation of adipocytes were inhibited. Meanwhile, partly epithelial cells were completely differentiated. Pseudo-time analysis showed that epithelial cells undergo three stages to achieve lactation, including cellular differentiation, hormone sensing, and metabolic activation. During lactation(L0 and L20), adipocytes area accounts for less than 0.5% of mammary glands. To maintain their own survival, the adipocyte exhibited a poorly differentiated state and a proliferative capacity. Epithelial cells initiate lactation upon hormonal stimulation. After fulfilling lactation mission, their undergo physiological death under high intensity lactation. Interestingly, the physiological dead cells seem to be actively cleared by immune cells via CCL21-ACKR4 pathway. This biological process may be an important mechanism for maintaining homeostasis of the mammary gland. During natural involution(PI2 and PI7), epithelial cell populatio

关键词： Adipocytes Cell–cell interaction Development Mammary gland snRNA-seq

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Transcriptional landscape of cotton roots in response to salt stress at single-cell resolution

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Plant Communications 2024年第2期5卷 46-66页

作者： Pengtao Li Qiankun Liu Yangyang Wei Chaozhu Xing Zhongping Xu Fang Ding Yuling Liu Quanwei Lu Nan Hu Tao Wang Xiangqian Zhu Shuang Cheng Zhaoguo Li Zilin Zhao Yanfang Li Jiangping Han Xiaoyan Cai Zhongli Zhou Kunbo Wang Baohong Zhang Fang Liu Shuangxia Jin Renhai Peng College of Biology and Food Engineering Anyang Institute of TechnologyAnyangHenan 455000China State Key laboratory of Cotton Biology Institute of Cotton ResearchChinese Academy of Agricultural SciencesAnyangHenan 455000China Research Base Anyang Institute of TechnologyState Key Laboratory of Cotton BiologyAnyang 455000HenanChina School of Life Sciences Zhengzhou UniversityZhengzhouHenan 450001China Hubei Hongshan laboratory National Key Laboratory of Crop Genetic ImprovementHuazhong Agricultural UniversityWuhanHubeiChina Hubei Key laboratory of Plant Pathology Huazhong Agricultural UniversityWuhanHubei 430070China Department of Biology East Carolina UniversityGreenvilleNC 27858USA

Increasing soil salinization has led to severe reductions in plant yield and quality,and investigating the mo-lecular mechanism of salt stress response is therefore an urgent *** this study,we systematically analyzed the response of cotton roots to salt stress using single-cell transcriptomics technology;56281 high-quality cells were obtained from 5-day-old lateral root tips of Gossypium arboreum under natural growth conditions and different salt *** cell types with an array of novel marker genes were identified and confirmed by in situ RNA hybridization,and pseudotime analysis of some specific cell types revealed their potential differentiation *** changes in cell numbers under salt stress were observed for outer epidermal and inner endodermal cells,which were significantly enriched in response to stress,amide biosynthetic process,glutathione metabolism,and glycolysis/*** of differentially expressed genes identified in multiple comparisons revealed other functional ag-gregations concentrated on plant-type primary cell wall biogenesis,defense response,phenylpropanoid biosynthesis,and metabolic *** candidate differentially expressed genes encoding transcrip-tion factors or associated with plant hormones also responsive to salt stress were identified,and the func-tion of Ga03G2153,annotated as auxin-responsive GH3.6,was confirmed by virus-induced gene *** GaGH3.6-silenced plants showed a severe stress-susceptible phenotype,and physiological and biochemical measurements indicated that they suffered more significant oxidative *** results suggest that GaGH3.6 might participate in cotton salt tolerance by regulating redox *** thus construct a transcriptional atlas of salt-stressed cotton roots at single-cell resolution,enabling us to explore cellular heterogeneity and differentiation trajectories and providing valuable insights into the mo-lecular mechanisms that underlie plan

关键词： cotton salt stress scRNA-seq root cell types virus-induced gene silencing

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Protein acylation:mechanisms,biological functions and therapeutic targets

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Signal Transduction and Targeted Therapy 2023年第1期8卷 220-249页

作者： Shuang Shang Jing Liu Fang Hua CAMS Key laboratory of Molecular Mechanism and Target Discovery of metabolic disorder and Tumorigenesis State Key Laboratory of Bioactive Substance and Function of Natural MedicinesInstitute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical College100050 BeijingP.R.China

metabolic reprogramming is involved in the pathogenesis of not only cancers but also neurodegenerative diseases,cardiovascular diseases,and infectious *** the progress of metabonomics and proteomics,metabolites have been found to affect protein acylations through providing acyl groups or changing the activities of acyltransferases or ***,protein acylation is involved in key cellular processes relevant to physiology and diseases,such as protein stability,protein subcellular localization,enzyme activity,transcriptional activity,protein–protein interactions and protein–DNA ***,we summarize the functional diversity and mechanisms of eight kinds of nonhistone protein acylations in the physiological processes and progression of several *** also highlight the recent progress in the development of inhibitors for acyltransferase,deacylase,and acylation reader proteins for their potential applications in drug discovery.

关键词： diseases cardiovascular mechanisms

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A zebrafish tufm mutant model for the COXPD4 syndrome of aberrant mitochondrial function

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Journal of Genetics and Genomics 2024年第9期51卷 922-933页

作者： Ting Li Tursunjan Aziz Guangyuan Li Lin Zhang Jihua Yao Shunji Jia School of Life Sciences Fudan UniversityShanghai 200438China State Key laboratory of Membrane Biology Tsinghua-Peking Center for Life SciencesSchool of Life SciencesTsinghua UniversityBeijing 100084China State Key laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China

Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular *** in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4(COXPD4),a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain(MRC)*** development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical *** this study,we construct a zebrafish tufm−/−mutant that closely resembles the COXPD4 syndrome,exhibiting compromised mitochondrial protein translation,dysfunctional mitochondria with oxidative phosphorylation defects,and significant metabolic suppression of the tricarboxylic acid *** this COXPD4 zebrafish model,we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing *** data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.

关键词： Tufm Mitochondria COXPD4 Disease model Zebrafish

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Promising use of metformin in treating neurological disorders:biomarker-guided therapies

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Neural Regeneration Research 2024年第5期19卷 1045-1055页

作者： Allison Loan Charvi Syal Margarita Lui Ling He Jing Wang Regenerative Medicine Program Ottawa Hospital Research InstituteOttawaONCanada Department of Biology Faculty of ScienceUniversity of OttawaOttawaONCanada Department of Pediatrics and Medicine Johns Hopkins Medical SchoolBaltimoreMDUSA Department of cellular and Molecular Medicine Faculty of MedicineUniversity of OttawaOttawaONCanada University of Ottawa Brain and Mind Research Institute OttawaONCanada

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available *** most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy ***,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological *** that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological *** molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted *** this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.

关键词： Alzheimer’s disease Huntington’s disease metformin mitochondrial perturbation multiple sclerosis neural degenerative diseases Parkinson’s disease stroke targeted therapy

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Tanshinone IIA ameliorates energy metabolism dysfunction of pulmonary fibrosis using 13C metabolic flux analysis

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Journal of Pharmaceutical Analysis 2024年第2期14卷 244-258页

作者： Baixi Shan Haoyan Zhou Congying Guo Xiaolu Liu Mingyu Wu Rao Zhai Jun Chen State Key laboratory of Natural Medicines China Pharmaceutical UniversityNanjing210009China Department of Pharmacognosy School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing210009China

Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic target anti-PF. The well-documented against PF properties of Tanshinone IIA (Tan IIA) have been primarily attributed to its antioxidant and anti-inflammatory potency. Emerging evidence suggests that Tan IIA may target energy metabolism pathways, including glycolysis and tricarboxylic acid (TCA) cycle. However, the detailed and advanced mechanisms underlying the anti-PF activities remain obscure. In this study, we applied [U-13C]-glucose metabolic flux analysis (MFA) to examine metabolism flux disruption and modulation nodes of Tan IIA in PF. We identified that Tan IIA inhibited the glycolysis and TCA flux, thereby suppressing the production of transforming growth factor-β1 (TGF-β1)-dependent extracellular matrix and the differentiation and proliferation of myofibroblasts in vitro. We further revealed that Tan IIA inhibited the expression of key metabolic enzyme hexokinase 2 (HK2) by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α) pathway activities, which decreased the accumulation of abnormal metabolites. Notably, we demonstrated that Tan IIA inhibited ATP citrate lyase (ACLY) activity, which reduced the collagen synthesis pathway caused by cytosol citrate consumption. Further, these results were validated in a mouse model of bleomycin-induced PF. This study was novel in exploring the mechanism of the occurrence and development of Tan IIA in treating PF using 13C-MFA technology. It provided a novel understanding of the mechanism of Tan IIA against PF from the perspective of metabolic reprogramming.

关键词： Pulmonary fibrosis Tanshinone IIA 13C-metabolic flux analysis metabolic reprogramming

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Recent development and gene therapy for glycogen storage disease type Ia

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Liver Research 2017年第3期1卷 174-180页

作者： Janice Y.Chou Goo-Young Kim Jun-Ho Cho Section on cellular differentiation Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaMDUSA

Glycogen storage disease type Ia(GSD-Ia)is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase-α(G6Pase-αor G6PC)that is expressed primarily in the liver,kidney,and intestine.G6Pase-αcatalyzes the hydrolysis of glucose-6-phosphate(G6P)to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis,and is a key enzyme for endogenous glucose *** active site of G6Pase-αis inside the endoplasmic reticulum(ER)*** catalysis,the substrate G6P must be translocated from the cytoplasm into the ER lumen by a G6P transporter(G6PT).The functional coupling of G6Pase-αand G6PT maintains interprandial glucose *** therapies for GSD-Ia are available,but cannot prevent the long-term complication of hepatocellular adenoma that may undergo malignant transformation to hepatocellular *** models of GSD-Ia are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches,including gene therapy.

关键词： Glycogen storage disease type Ia(GSD-Ia) Glucose-6-phosphatase-α(G6Pase-αor G6PC) Gene therapy Hepatocellular adenoma Recombinant adeno-associated virus vector

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