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

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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Structural basis for polyuridine tract recognition by SARS-CoV-2 Nsp15

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Protein & Cell 2024年第7期15卷 547-552页

作者： Fumiaki Ito Hanjing Yang Z.Hong Zhou Xiaojiang S.Chen molecular and Computational biology Department of Biological SciencesUniversity of Southern CaliforniaLos AngelesCA 90089United States Department of Microbiology Immunology and Molecular GeneticsUniversity of CaliforniaLos AngelesCA 90095United States California NanoSystems Institute University of CaliforniaLos AngelesCA90095United States Genetic Molecular and Cellular Biology ProgramKeck School of MedicineUniversity of Southern CaliforniaLos AngelesCA 90089United States Norris Comprehensive Cancer Center University of Southern CaliforniaLos AngelesCA 90089United States Center of Excellence in NanoBiophysics University of Southern CaliforniaLos AngelesCA 90089United States

Dear Editor,Coronaviruses have evolved a wide array of tactics to evade host antiviral *** host cells detect invading foreign nucleic acids including viral genome and viral replication intermediates,they activate interferon(IFN)signaling via cytoplasmic pattern recognition receptors(Kang et al.,2002;Kato et al.,2006).Remarkable stealth activities exhibited by coronaviruses are facilitated by a series of non-structural proteins(Nsps),such as Nsp15(Deng and Baker,2018;Deng et al.,2019;Hackbart et al.,2020),which is a uridine-specific endoribonuclease that mediates evasion of host detection of viral double-stranded RNA(dsRNA)(Bhardwaj et al.,2004;Deng et al.,2017;Frazier et al.,2021;Ivanov et al.,2004).Nsp15 targets a polyuridine[poly(U)]tract on the coronavirus negative strand RNA(Hackbart et al.,2020).Nsp15 limits the abundance and length of poly(U)within the negative strand RNA 5ʹ-extension by trimming down the initially synthesized poly(U)lead sequence to the optimal length that can suppress dsRNA formation but still serves as a template for poly(A)tail of the positive strand genome of the coronaviruses(Hofmann and Brian,1991).

关键词： p15 interferon template

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Emerging roles and therapeutic potentials of sphingolipids in pathophysiology:emphasis on fatty acyl heterogeneity

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Journal of Genetics and Genomics 2024年第3期51卷 268-278页

作者： Jinming Mu Sin Man Lam Guanghou Shui State Key Laboratory of molecular Developmental biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100101China Lipidall Technologies Company Limited ChangzhouJiangsu 213000China

Sphingolipids not only exert structural roles in cellular membranes,but also act as signaling molecules in various physiological and pathological processes.A myriad of studies have shown that abnormal levels of sphingolipids and their metabolic enzymes are associated with a variety of human ***,blood sphingolipids can also be used as biomarkers for disease *** review summarizes the biosynthesis,metabolism,and pathological roles of sphingolipids,with emphasis on the biosynthesis of ceramide,the precursor for the biosynthesis of complex sphingolipids with different fatty acyl *** possibility of using sphingolipids for disease prediction,diagnosis,and treatment is also *** endogenous ceramides and complex sphingolipids along with their specific fatty acyl chain to promote future drug development will also be discussed.

关键词： Sphingolipids Ceramide Therapeutic targets Microdomain Biomarker

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Si-Wu-Tang attenuates liver fibrosis via regulating lncRNA H19-dependent pathways involving cytoskeleton remodeling and ECM deposition

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Chinese Journal of Natural Medicines 2024年第1期22卷 31-46页

作者： QU Jiaorong XUE Xiaoyong WANG Zhixing MA Zhi JIA Kexin LI Fanghong ZHANG Yinhao WU Ruiyu ZHOU Fei ZHAO Piwen LI Xiaojiaoyang School of Life Sciences Beijing University of Chinese MedicineBeijing 100029China School of Chinese Materia Medica Beijing University of Chinese MedicineBeijing 100029China State Key Laboratory of Medical molecular biology Department of Molecular Biology and BiochemistryInstitute of Basic Medical SciencesChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100005China

Liver fibrosis is a dynamic wound-healing response characterized by the agglutination of the extracellular matrix(ECM).Si-Wu-Tang(SWT),a traditional Chinese medicine(TCM)formula,is known for treating gynecological diseases and liver *** previous studies demonstrated that long non-coding RNA H19(H19)was markedly upregulated in fibrotic livers while its deficiency markedly reversed ***,the mechanisms by which SWT influences H19 remain ***,we established a bile duct ligation(BDL)-induced liver fibrosis model to evaluate the hepatoprotective effects of SWT on various cells in the *** results showed that SWT markedly improved ECM deposition and bile duct reactions in the ***,SWT relieved liver fibrosis by regulating the transcription of genes involved in the cytoskeleton remodeling,primarily in hepatic stellate cells(HSCs),and influencing cytoskeleton-related angiogenesis and hepatocellular *** modulation collectively led to reduced ECM *** extensive bioinformatics analyses,we determined that H19 acted as a miRNA sponge and mainly inhibited miR-200,miR-211,and let7b,thereby regulating the above cellular regulatory ***,SWT reversed H19-related miRNAs and signaling pathways,diminishing ECM deposition and liver ***,these protective effects of SWT were diminished with the overexpression of H19 in *** conclusion,our study elucidates the underlying mechanisms of SWT from the perspective of H19-related signal networks and proposes a potential SWT-based therapeutic strategy for the treatment of liver fibrosis.

关键词： Liver fibrosis LncRNA H19 Si-Wu-Tang miRNAs Cytoskeleton ECM deposition

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Self-assembled amphiphilic NIR-Ⅱ emissive nano-micelles for imaging-guided photothermal therapy of colorectal cancer

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Science China Chemistry 2024年第8期67卷 2767-2774页

作者： Axin He Fangfang Xia Da Han Qinglai Yang Weihong Tan Institute of molecular Medicine(IMM) Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200240China Center for molecular Imaging Probe Hunan Province Key Laboratory of Cancer Cellular and Molecular PathologyCancer Research InstituteHengyang Medical SchoolUniversity of South ChinaHengyang 421001China The Key Laboratory of Zhejiang Province for Aptamers and Theranostics Zhejiang Cancer Hospital Hangzhou Institute of Medicine(HIM)Chinese Academy of SciencesHangzhou 310022China molecular Science and Biomedicine Laboratory(MBL) State Key Laboratory of Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringCollege of BiologyAptamer Engineering Center of Hunan ProvinceHunan UniversityChangsha 410082China

Colorectal cancer(CRC) is one of the major causes of cancer-related mortality worldwide. Most near-infrared(NIR) agents used in clinical CRC treatment are at NIR-I(700–900 nm) window, which has limitations on deep tissue, and fluorescent probes in the second NIR(1,000–1,700 nm) allow high-resolution bioimaging with deep tissue penetration. However, existing NIR-II fluorophores used in clinical are still rare. Herein, based on shielding-donor-acceptor-donor-shielding(S-D-A-D-S) scaffold, we developed an organic small-molecule fluorophore IR-BTGP with NIR-II emission for imaging-guided photothermal therapy(PTT) in CRC mice model. Amphiphilic IR-BTGP can be self-assembled into spherical nano-micelles, which presents reliable water solubility and photothermal conversion efficiency(30.2%). In vitro experiments indicate that cancer cells treated with IRBTGP were significantly killed upon 808 nm light irradiation. Furthermore, in vivo NIR-II fluorescence imaging confirms that IR-BTGP accumulates in the tumor region. Remarkably, a significant tumor inhibition rate(78.5%) was observed in tumorbearing mice when treated with IR-BTGP plus 808 nm irradiation. Therefore, this work shows that IR-BTGP holds great promise as an NIR-II fluorescence imaging-guided PTT platform for CRC in the future.

关键词： photothermal therapy(PTT) second near-infrared(NIR-Ⅱ)imaging organic molecule

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High glucose microenvironment and human mesenchymal stem cell behavior

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World Journal of Stem Cells 2024年第3期16卷 237-244页

作者： Muhammad Abdul Mateen Nouralsalhin Alaagib Khawaja Husnain Haider Basic Sciences Sulaiman AlRajhi UniversityAlQaseem 52736Saudi Arabia cellular and molecular Pharmacology Sulaiman AlRajhi Medical SchoolAl Bukairiyah 51941Saudi Arabia

High glucose(HG)culture conditions in vitro and persistent exposure to hyperglycemia in diabetes patients are detrimental to stem cells,analogous to any other cell type in our *** interferes with diverse signaling pathways,*** target of rapamycin(mTOR)-phosphoinositide 3-kinase(PI3K)-Akt signaling,to impact physiological cellular functions,leading to low cell survival and higher cell apoptosis *** elucidating the underlying mechanism responsible for the apoptosis of adipose tissue-derived mesenchymal stem cells(MSCs),a recent study has shown that HG culture conditions dysregulate mTORPI3K-Akt signaling in addition to mitochondrial malfunctioning due to defective mitochondrial membrane potential(MtMP)that lowers ATP *** organelle-level dysfunction energy-starves the cells and increases oxidative stress and ultrastructural *** of the mitochondrial electron transport chain produces an altered mitochondrial NAD+/NADH redox state as evidenced by a low NAD+/NADH ratio that primarily contributes to the reduced cell survival in *** previous studies have also reported altered mitochondrial membrane polarity(causing hyperpolarization)and reduced mitochondrial cell mass,leading to perturbed mitochondrial *** hostile microenvironment created by HG exposure creates structural and functional changes in the mitochondria,altering their bioenergetics and reducing their capacity to produce *** are significant data,as MSCs are extensively studied for tissue regeneration and restoring their normal functioning in cell-based ***,MSCs from hyperglycemic donors should be cautiously used in clinical settings for cell-based therapy due to concerns of their poor sur-vival rates and increased rates of post engraftment *** hypergly-cemia alters the bioenergetics of donor MSCs,rectifying the loss of MtMP may be an excellent target for future research to restore the normal functioning of MSCs i

关键词： Adipose tissue Apoptosis Bioenergetics Cell survival Cell therapy Hyperglycemia Mitochondria Mesenchymal stem cells Stem cells

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CD9 role in proliferation, rejuvenation, and therapeutic applications

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Genes & Diseases 2024年第3期11卷 95-97页

作者： Sai Priyanka Kodam Neda Baghban Mujib Ullah Institutefor Immunityand Transplantation Stem Cell Biology and Regenerative MedicineSchool of MedicineMolecular Medicine Department of MedicineStanford UniversityPaloAltoCA94304USA

The CD9 gene,also known as the Tspan29 gene,codes for a protein called CD9,which is a member of the tetraspanin family of transmembrane proteins.^(1) The CD9 protein is involved in various cellular processes,including cell proliferation,differentiation,adhesion,and migration.^(1,2) CD9 has also been found to play a role in the regulation of stem cell proliferation and differentiation.

关键词： migration. therapeutic CD9

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GreenPhos,a universal method for in-depth measurement of plant phosphoproteomes with high quantitative reproducibility

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molecular Plant 2024年第1期17卷 199-213页

作者： Xiaoxiao Duan Yuanya Zhang Xiahe Huang Xiao Ma Hui Gao Yan Wang Zhen Xiao Chengcheng Huang Zhongshu Wang Bolong Li Wenqiang Yang Yingchun Wang State Key Laboratory of molecular Developmental biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBejing 100101China University of Chinese Academy of Sciences Bejing 100049China Key Laboratory of Photobiology Instute of BotanyChinese Academy of SciencesBejing 100093China

Protein phosphorylation regulates a variety of important cellular and physiological processes in ***-depth profiling of plant phosphoproteomes has been more technically challenging than that of animal *** is largely due to the need to improve protein extraction efficiency from plant cells,which have a dense cell wall,and to minimize sample loss resulting from the stringent sample clean-up steps required for the removal of a large amount of biomolecules interfering with phosphopeptide purification and mass spectrometry *** this end,we developed a method with a streamlined workflow for highly efficient purification of phosphopeptides from tissues of various green organisms including Arabidopsis,rice,tomato,and Chlamydomonas reinhardtii,enabling in-depth identification with high quantitative reproducibility of about 11000 phosphosites,the greatest depth achieved so far with single liquid chromatography-mass spectrometry(LC-MS)runs operated in a data-dependent acquisition(DDA)*** mainstay features of the method are the minimal sample loss achieved through elimination of sample clean-up before protease digestion and of desalting before phosphopeptide enrichment and hence the dramatic increases of time-and *** method,named GreenPhos,combined with single-shot LC-MS,enabled in-depth quantitative identification of Arabidopsis phosphoproteins,including differentially phosphorylated spliceosomal proteins,at multiple time points during salt stress and a number of kinase substrate *** is expected to serve as a universal method for purification of plant phosphopeptides,which,if samples are further fractionated and analyzed by multiple LC-MS runs,could enable measurement of plant phosphoproteomes with an unprecedented depth using a given mass spectrometry technology.

关键词： plant phosphoproteomics phosphopeptides LC–MS Arabidopsis salt stress

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Emerging role of cellular senescence in normal lung development and perinatal lung injury

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Chinese Medical Journal Pulmonary and Critical Care Medicine 2024年第1期2卷 10-16页

作者： Phyllis A.Dennery Hongwei Yao Department of molecular biology Cell Biology&BiochemistryDivision of Biology and MedicineBrown UniversityProvidenceRI 02912USA Department of Pediatrics Warren Alpert Medical School of Brown UniversityProvidenceRI 02903USA

cellular senescence is a status of irreversible growth arrest,which can be triggered by the p53/p21cip1 and p16INK4/Rb pathways via intrinsic and external *** cells are typically enlarged and flattened,and characterized by numerous molecular *** latter consists of increased surfaceome,increased resid-ual lysosomal activity at pH 6.0(manifested by increased activity of senescence-associated beta-galactosidase[SA-𝛽-gal]),senescence-associated mitochondrial dysfunction,cytoplasmic chromatin fragment,nuclear lamin b1 exclusion,telomere-associated foci,and the senescence-associated secretory *** features vary depending on the stressor leading to senescence and the type of *** senescence plays pivotal roles in organismal aging and in the pathogenesis of aging-related ***,senescence can also both promote and inhibit wound healing *** recently report that senescence as a programmed pro-cess contributes to normal lung *** senescence is also observed in Down Syndrome,as well as in premature infants with bronchopulmonary dysplasia and in a hyperoxia-induced rodent model of this ***,this senescence results in neonatal lung *** this review,we briefly discuss the molecular features of *** then focus on the emerging role of senescence in normal lung development and in the pathogenesis of bronchopulmonary dysplasia as well as putative signaling pathways driving ***,we discuss potential therapeutic approaches targeting senescent cells to prevent perinatal lung diseases.

关键词： Senescence Normal lung development Bronchopulmonary dysplasia Down syndrome Senolytics

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A multi-platform analysis of human gingival crevicular fluid reveals ferroptosis as a relevant regulated cell death mechanism during the clinical progression of periodontitis

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International Journal of Oral Science 2024年第2期16卷 265-279页

作者： Alfredo Torres M.Angélica Michea Ákos Végvári Marion Arce Valentina Pérez Marcela Alcota Alicia Morales Rolando Vernal Mauricio Budini Roman A.Zubarev Fermín E.González Laboratory of Experimental Immunology&Cancer Faculty of DentistryUniversity of ChileSantiagoChile Department of Conservative Dentistry Faculty of DentistryUniversity of ChileSantiagoChile Division of Chemistry I Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden Periodontal biology Laboratory Faculty of DentistryUniversidad de ChileSantiagoChile Laboratory of cellular and molecular Pathology Institute for Research in Dental SciencesFaculty of DentistryUniversity of ChileSantiagoChile

Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases,yet its association with progressive periodontitis remains *** investigate the involvement and significance of ferroptosis in periodontitis progression,we assessed sixteen periodontitis-diagnosed *** progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid(GCF)collection was performed for further *** metrics,proteomic data,in silico methods,and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with *** western blot analyses validated key ***,a single-cell RNA sequencing(scRNA-seq)dataset(GSE164241)for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis *** progression was identified as occurring at a faster rate than traditionally *** samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic *** addition,specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins,including SNCA,CA1,HBB,SLC4A1,and ANK1 was strongly associated with the clinical progression status of ***,we found specific proteins-drivers or suppressors-associated with ferroptosis(SNCA,FTH1,HSPB1,CD44,and GCLC),revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of ***,the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to *** analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients,which offer new insights into the molecular mechanisms of progressive periodontal *** findings may le

关键词： finding progression faster

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