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High glucose microenvironment and human mesenchymal stem cell behavior

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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Site-specific incorporation of reduction-controlled guest amino acids into proteins for cucurbituril recognition

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Chinese Chemical Letters 2024年第5期35卷 193-196页

作者： Zhen Dai Linzhi Tan Yeyu Su Kerui Zhao Yushun Tian Yu Liu Tao Liu College of Chemistry State Key Laboratory of Elemento-Organic ChemistryNankai UniversityTianjin 300071China State Key Laboratory of Natural and Biomimetic Drugs Department of Molecular and Cellular PharmacologySchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China

Protein recognition using host-guest recognition approach is of great interest but has been limited mainly to the protein N-terminal ***,we site-specific incorporated two novel non-canonical amino acids containing supramolecular guest motifs into protein via an expanded genetic *** Staudinger reduction reactions,the encoded unnatural residues on protein becoming activated and can be specifically recognized by cucurbit[7]uril(CB[7])and cucurbit[8]uril(CB[8]).We demonstrated that enzyme containing guest amino acid incorporated near the active site can be reversibly regulated by CB[7]recognition,and CB[8]recognition induces protein *** amino acids will make useful addition to the supramolecular toolbox for protein targeting using molecular recognition approaches.

关键词： Protein recognition Host-guest recognition Non-canonical amino acids Staudinger reduction Expanded genetic code

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The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction

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molecular Plant 2024年第7期17卷 1129-1150页

作者： Paula Berman Luis Alejandro de Haro Ana-Rita Cavaco Sayantan Panda Younghui Dong Nikolay Kuzmich Gabriel Lichtenstein Yoav Peleg Hila Harat Adam Jozwiaki Jianghua Cai Uwe Heinig Sagit Meir Ilana Rogachev Asaph Aharoni Department of Plant and Environmental Sciences Weizmann Institute of ScienceRehovot 7610001Israel Life Sciences Core Facilities Weizmann Institute of ScienceRehovot 7610001Israel The Maurice and Vivienne Wohl Institute for Drug Discovery Weizmann Institute of ScienceRehovot 7610001Israel Present address:Department of Cell and Metabolic Biology Leibniz Institute of Plant BiochemistryWeinberg 306120 Halle(Saale)Germany Department of molecular&cellular pharmacology University of Miami Miler School of MedicineMiamiFL 33136USA Department of Botany and Plant Sciences University of California RiversideRiversideCA 92521USA Laboratory of Plant Hormones and Development Regulation of Chongqing School of Life SciencesChongqing UniversityChongqing 401331China

Mescaline,among the earliest identified natural hallucinogens,holds great potential in psychotherapy ***,despite the existence of a postulated biosynthetic pathway for more than half a century,the specific enzymes involved in this process are yet to be *** this study,we investigated the cactus Lophophora williamsii(Peyote),the largest known natural producer of the phenethylamine *** employed a multi-faceted approach,combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling,enzymatic assays,molecular modeling,and pathway engineering for pathway *** identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway,and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates,likely modulating mescaline levels in ***,we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells,providing novel insights into several challenges hindering complete heterologous mescaline *** together,our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline,safeguarding this valuable natural resource for future generations.

关键词： mescaline Lophophora williamsi Peyote biosynthetic pathway de novo genome sequencing mo-lecular modeling

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The clinical antiprotozoal drug nitazoxanide and its metabolite tizoxanide extend Caenorhabditis elegans lifespan and healthspan

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3266-3280页

作者： Wenfeng Li Shuming Chen Jing Lang Jing Luo Jiahui Chen Liping Zhang Zhijie Sun Deli Dong Department of pharmacology China Pharmaceutical UniversityNanjing 210009China

The drugs extending healthspan in clinic have always been *** is an FDA-approved clinical antiprotozoal *** is rapidly metabolized to tizoxanide after absorption in *** previous studies find that nitazoxanide and its metabolite tizoxanide induce mild mitochondrial uncoupling and activate cellular AMPK,oral nitazoxanide protects against experimental hyperlipidemia,hepatic steatosis,and ***,we demonstrate that both nitazoxanide and tizoxanide extend the lifespan and healthspan of Caenorhabditis elegans through Akt/AMPK/sir 2.1/daf16 ***,both nitazoxanide and tizoxanide improve high glucose-induced shortening of *** *** has been a clinical drug with a good safety profile,we suggest that it is a novel anti-aging drug.

关键词： Nitazoxanide Tizoxanide C.elegans Healthspan Lifespan AMPK Akt Mitochondrial uncoupling

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Na^(+)/K^(+)-ATPase:ion pump,signal transducer,or cytoprotective protein,and novel biological functions

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Neural Regeneration Research 2024年第12期19卷 2684-2697页

作者： Songqiang Huang Wanting Dong Xiaoqian Lin Jinsong Bian Department of pharmacology Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and DiseasesSchool of MedicineSouthern University of Science and TechnologyShenzhenGuangdong ProvinceChina Department of pharmacology School of Basic MedicineTongji Medical CollegeHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into ***,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell ***^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of *** re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological ***,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell *** recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's *** of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these *** this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell ***,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related *** potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.

关键词： antibody biological functions cellular communication electrochemical gradient ion balance ion channels Na^(+)/K^(+)-ATPase neurological diseases neurotransmitter release signal transduction

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Beyond natural targets: chemical synthesis reprograms the target specificity of rapamycin

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National Science Review 2022年第11期9卷 8-9页

作者： Ziyang Zhang Department of cellular and molecular pharmacology University of California

Natural products have served as a rich source of new drugs, either directly or as inspirations for pharmacophores [1].Under the constant pressure of evolution,natural products have exploited numerous biosynthetic mach... 详细信息

关键词： PRODUCTS

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From the dust:extracellular vesicles as regulators of development and neuroregeneration

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Neural Regeneration Research 2024年第5期19卷 933-934页

作者： Leon G.Coleman Jr The University of North Carolina at Chapel Hill School of MedicineDepartment of PharmacologyBowles Center for Alcohol StudiesChapel HillNCUSA

First impressions can have a lasting *** science,this can be especially problematic,because our lack of understanding often causes us to mislabel and thus ignore important biological *** this vein,extracellular vesicles(EVs)were once considered to be“cellular dust”.Similar to the previous concept of“junk DNA”to describe protein non-coding regions,EVs are far more than just cellular *** fact,EVs are emerging as key mediators of intracellular communication across nearly all biological *** includes peripheral immune responses(e.g.,arthropathies and sepsis),intra-organ communication(Seim et al.,2023),and a host of other physiological and pathological states(Figure 1A and B).

关键词： Figure extracellular

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Potassium and calcium channels in different nerve cells act as therapeutic targets in neurological disorders

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Neural Regeneration Research 2025年第5期20卷 1258-1276页

作者： Qing Qiu Mengting Yang Danfeng Gong Haiying Liang Tingting Chen Department of pharmacology School of PharmacyNantong UniversityNantongJiangsu ProvinceChina Jiangsu Province Key Laboratory of Inflammation and molecular Drug Target NantongJiangsu ProvinceChina Department of Pharmacy Longyan First Affiliated Hospital of Fujian Medical UniversityLongyanFujian ProvinceChina

The central nervous system, information integration center of the body, is mainly composed of neurons and glial cells. The neuron is one of the most basic and important structural and functional units of the central nervous system, with sensory stimulation and excitation conduction functions. Astrocytes and microglia belong to the glial cell family, which is the main source of cytokines and represents the main defense system of the central nervous system. Nerve cells undergo neurotransmission or gliotransmission, which regulates neuronal activity via the ion channels, receptors, or transporters expressed on nerve cell membranes. Ion channels, composed of large transmembrane proteins, play crucial roles in maintaining nerve cell homeostasis. These channels are also important for control of the membrane potential and in the secretion of neurotransmitters. A variety of cellular functions and life activities, including functional regulation of the central nervous system, the generation and conduction of nerve excitation, the occurrence of receptor potential, heart pulsation, smooth muscle peristalsis, skeletal muscle contraction, and hormone secretion, are closely related to ion channels associated with passive transmembrane transport. Two types of ion channels in the central nervous system, potassium channels and calcium channels, are closely related to various neurological disorders, including Alzheimer's disease, Parkinson's disease, and epilepsy. Accordingly, various drugs that can affect these ion channels have been explored deeply to provide new directions for the treatment of these neurological disorders. In this review, we focus on the functions of potassium and calcium ion channels in different nerve cells and their involvement in neurological disorders such as Parkinson's disease, Alzheimer's disease, depression, epilepsy, autism, and rare disorders. We also describe several clinical drugs that target potassium or calcium channels in nerve cells and could be u

关键词： astrocytes calcium channels central nervous system extracellular ion concentration microglia neurological disorders neurons potassium channels

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Targeting NRP1 axis as a strategy for treating energy metabolism impairment induced by SARS-CoV-2 spike

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Science China Life Sciences 2024年

作者： Lihui Zhang Wanting Hu Jingxuan Li Yuehan Li Feng Liu Wenyi Xiao Ning Jiang Zhiyong Xiao Lu Han Wenxia Zhou Beijing Institute of pharmacology & Toxicology State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology & Toxicology School of Chinese Materia Medica Tianjin University of Traditional Chinese Medicine

Dear Editor,Free spike protein of SARS-CoV-2 alone can cause abnormal energy metabolism(Table S1 in Supporting Information), and limited research suggested a potential correlation between spike-induced mitochondrial damage and the ACE2 receptor(Lei et al., 2021; Yang et al., 2023). In order to further explore the mechanisms involved, we observed that the wild-type S1 protein of SARS-CoV-2 exerts a more potent inhibitory effect on host cell ATP compared to the wild-type S protein, S2protein, the Omicron variant S1 protein and HCoV-NL63 S1protein in HLMVEC and 293T cell lines(Figure 1A and B),indicating the importance of exploring the mechanism by which the S1 protein causes ATP decrease. Meanwhile, the S1protein did not lead to significant changes in cellular lactate levels, indicating that its primary mechanism involves impairing oxidative phosphorylation and mitochondrial damage(Figure 1C and D).

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Presepsin as a biomarker of bacterial translocation and an indicator for the prescription of probiotics in cirrhosis

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World Journal of Hepatology 2024年第5期16卷 822-831页

作者： Irina Efremova Roman Maslennikov Elena Poluektova Oleg Medvedev Anna Kudryavtseva George Krasnov Maria Fedorova Filipp Romanikhin Maria Zharkova Oxana Zolnikova Gyunay Bagieva Vladimir Ivashkin Department of Internal Medicine Gastroenterology and HepatologySechenov UniversityMoscow 119435Russia Department of Scientific Scientific Community for the Promotion of the Clinical Study of the Human MicrobiomeMoscow 119435Russia Department of pharmacology Lomonosov Moscow State UniversityMoscow 119192Russia Department of Post-Genomic Research Laboratory Engelhardt Institute of Molecular BiologyRussian Academy of SciencesMoscow 119991Russia

BACKGROUND The gut–liver axis and bacterial translocation are important in cirrhosis,but there is no available universal biomarker of cellular bacterial translocation,for which presepsin may be a *** To evaluate the relationship of the blood presepsin levels with the state of the gut microbiota in cirrhosis in the absence of obvious *** This study included 48 patients with Child–Pugh cirrhosis classes B and C and 15 healthy *** fecal microbiome was assessed using 16S rRNA gene *** levels of presepsin were measured.A total of 22 patients received a probiotic(Saccharomyces boulardii)for 3 *** Presepsin levels were higher in patients with cirrhosis than in healthy individuals[342(91-2875)vs 120(102-141)pg/mL;P=0.048].Patients with elevated presepsin levels accounted for 56.3%of all included *** had lower levels of serum albumin and higher levels of serum total bilirubin and overall severity of cirrhosis as assessed using the Child–Pugh *** with elevated presepsin levels had an increased abundance of the main taxa responsible for bacterial translocation,namely Bacilli and Proteobacteria(including the main class Gammaproteobacteria and the minor taxa Xanthobacteraceae and Stenotrophomonas),and a low abundance of bacteria from the family Lachnospiraceae(including the minor genus Fusicatenibacter),which produce short-chain fatty acids that have a positive effect on intestinal barrier *** presepsin level directly correlated with the relative abundance of Bacilli,Proteobacteria,and inversely correlated with the abundance of Lachnospiraceae and *** 3 months of taking the probiotic,the severity of cirrhosis on the Child–Pugh scale decreased significantly only in the group with elevated presepsin levels[from 9(8-11)to 7(6-9);P=0.004],while there were no significant changes in the group with normal presepsin levels[from 8(7-8)to 7(6-8);P=0.123].A high level of presepsin

关键词： Dysbiosis Gut Intestinal permeability Leaky gut Gut-liver axis Liver Microbiota

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