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Targeting PKM2 signaling cascade with salvianic acid A normalizes tumor blood vessels to facilitate chemotherapeutic drug delivery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2077-2096页

作者： Cheng Qian Yueke Zhou Teng Zhang Guanglu Dong Mengyao Song Yu Tang Zhonghong Wei Suyun Yu Qiuhong Shen Wenxing Chen Jaesung P.Choi Juming Yan Chongjin Zhong Li Wan Jia Li Aiyun Wang Yin Lu Yang Zhao Jiangsu Key laboratory for pharmacology and Safety Evaluation of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China School of Medicine&Holistic Integrative Medicine Nanjing University of Chinese MedicineNanjing 210023China Centre for Inflammation Faculty of ScienceCentenary InstituteSchool of Life SciencesUniversity of Technology SydneySydney NSW 2050Australia Jiangsu Key laboratory of Immunity and Metabolism Department of Pathogenic Biology and ImmunologyNational Experimental Demonstration Center for Basic Medicine EducationXuzhou Laboratory of Infection and ImmunityXuzhou Medical UniversityXuzhou 221004China Department of General Surgery Jiangsu Province Hospital of Chinese MedicineAffiliated Hospital of Nanjing University of Chinese MedicineNanjing 210029China Macquarie Medical School Faculty of MedicineHuman Health SciencesMacquarie UniversitySydney NSW 2109Australia

Aberrant tumor blood vessels are prone to propel the malignant progression of tumors,and targeting abnormal metabolism of tumor endothelial cells emerges as a promising option to achieve vascular normalization and antagonize tumor ***,we demonstrated that salvianic acid A(SAA)played a pivotal role in contributing to vascular normalization in the tumor-bearing mice,thereby improving delivery and effectiveness of the chemotherapeutic *** was capable of inhibiting glycolysis and strengthening endothelial junctions in the human umbilical vein endothelial cells(HUVECs)exposed to ***,SAA was inclined to directly bind to the glycolytic enzyme PKM2,leading to a dramatic decrease in endothelial *** importantly,SAA improved the endothelial integrity via activating theβ-Catenin/Claudin-5 signaling axis in a PKM2-dependent *** findings suggest that SAA may serve as a potent agent for inducing tumor vascular normalization.

关键词： Salvianic acid A Tumor vascular normalization PKM2 β-Catenin Claudin-5 Endothelial glycolysis Tight junctions Doxorubicin

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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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Catalyst-free electrochemical dearomatization of pyridine derivatives

Green Synthesis and Catalysis

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Green Synthesis and Catalysis 2024年第2期5卷 136-139页

作者： Kui Wang Yingjun Tian Baoying Li Ling Wang Wei Gao Xiaofei Jia Ruiming Wang Yanping Zhu Jianbin Chen Chen Shandong Provincial Key laboratory of Molecular Engineering State Key Laboratory of Biobased Material and Green PapermakingSchool of Chemistry and Chemical EngineeringQilu University of Technology(Shandong Academy of Sciences)Jinan 250353China Key laboratory of Optic-electric Sensing and Analytical Chemistry for Life Science MOECollege of Chemistry and Molecular EngineeringQingdao University of Science and TechnologyQingdao 266042China State Key laboratory of biobased Material and Green Papermaking School of BioengineeringQilu University of Technology(Shandong Academy of Sciences)Jinan 250353China School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug EvaluationMinistry of EducationCollaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of ShandongYantai UniversityYantai 264005China

We demonstrated herein an electrochemical dearomatizative alkylation of Katritzky salts,wherein Katritzky salts were harnessed as both radical acceptors and donors.A wide range of privileged dihydropyridine scaffolds was constructed with good to excellent *** voltammetry(CV)and electron paramagnetic resonance(EPR)results confirmed the key intermediates-dihydropyridine radicals and gram-scale reaction highlighted the practical and sustainable feature of the newly developed protocol.

关键词： Dearomatization Electrosynthesis Katritzky salts Dihydropyridine

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Are we close to using Alzheimer blood biomarkers in clinical practice?

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Neural Regeneration Research 2024年第12期19卷 2583-2585页

作者： Bruno P.Imbimbo Simone Lista Camillo Imbimbo Robert Nisticò Department of Research&Development Chiesi FarmaceuticiParmaItaly i+HeALTH Strategic Research Group Department of Health SciencesMiguel de Cervantes European University(UEMC)ValladolidSpain Department of Brain and Behavioral Sciences University of PaviaPaviaItaly School of Pharmacy University of Rome“Tor Vergata”RomeItaly laboratory of pharmacology of Synaptic Plasticity EBRI Rita Levi-Montalcini FoundationRomeItaly

Alzheimer's disease(AD) is a progressive neurodegenerative disease histologically characterized by the presence of extraneuronal plaques,mainly formed by the 42-aminoacid isoform of amyloid-(Aβ_(1-42)),and by intraneuronal neurofibrillary to ngles,mainly formed by the tau protein and its hyperphosphorylated isoforms(p-tau).AD is the most common cause of dementia,with an estimated lifetime risk of about 1 in 10 for men and 1 in 5 for women.

关键词： Alzheimer tau Aβ

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Phosphatidic acid-enabled MKL1 contributes to liver regeneration:Translational implication in liver failure

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Acta Pharmaceutica Sinica B 2024年第1期14卷 256-272页

作者： Jiawen Zhou Xinyue Sun Xuelian Chen Huimin Liu Xiulian Miao Yan Guo Zhiwen Fan Jie Li Yong Xu Zilong Li State Key laboratory of Natural Medicines Department of PharmacologyChina Pharmaceutical UniversityNanjing 211198China Institute of biomedical Research Liaocheng UniversityLiaocheng 252200China Department of Pathology Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210008China Department of Infectious Diseases Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical SchoolNanjing 210008China Institute of Viruses and Infectious Diseases Nanjing UniversityNanjing 210008China

Liver regeneration following injury aids the restoration of liver mass and the recovery of liver *** the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver *** report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure *** with MKL1 deletion exhibited defective regenerative response in the *** analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative ***2 mediated phosphorylation primed MKL1 for its interaction with *** interest,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver ***,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely correlated with liver injury in liver failure *** conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver *** for small-molecule compounds boosting MKL1 activity may be considered as a reasonable approach to treat acute liver failure.

关键词： Liver failure Liver regeneration Transcription regulation Transcription factor Hepatocytes Phosphatidic acid Phospholipase d2 Translational medicine

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Activation of glutamatergic neurons in the somatosensory cortex promotes remyelination in ischemic vascular dementia

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Fundamental Research 2024年第1期4卷 188-198页

作者： Yi-Ting Zhou Da-Dao An Yi-Xin Xu Ying Zhou Qing-Qing Li Hai-Bin Dai Xiang-Nan Zhang Yi Wang Min Lou Zhong Chen Wei-Wei Hu Department of pharmacology and Department of Pharmacy of the Second Affiliated Hospital NHC and CAMS Key Laboratory of Medical NeurobiologySchool of Basic Medical SciencesCollege of Pharmaceutical SciencesZhejiang University School of MedicineHangzhou 310058China Department of Pharmacy Sir Run Run Shaw HospitalHangzhou 310012China Key laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province School of Pharmaceutical SciencesZhejiang Chinese Medical UniversityHangzhou 310053China Department of Neurology the Second Affiliated Hospital of Zhejiang UniversitySchool of MedicineHangzhou 310003China

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia,however no effective treatments are ***,based on magnetic resonance imaging studies of patients with white matter damage,we found that this damage is associated with disorganized cortical *** a mouse model,optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell(OPC)proliferation,remyelination in the corpus callosum,and recovery of cognitive ability after cerebral *** therapeutic effect of such stimulation was restricted to the upper layers of the cortex,but also spanned a wide time window after ***,enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic ***,skin stroking,an easier method to translate into clinical practice,activated the somatosensory cortex,thereby promoting OPC proliferation,remyelination and cognitive recovery following cerebral *** summary,we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral *** should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

关键词： Chronic cerebral hypoperfusion Optogenetic stimulation Oligodendrocyte progenitor cellIschemic vascular dementia Glutamatergic neuron Remyelination

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Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis

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Cellular & Molecular Immunology 2024年第3期21卷 227-244页

作者： Kang-Gu Lee Bong-Ki Hong Saseong Lee Naeun Lee Seung-Whan Kim Donghyun Kim Wan-Uk Kim Center for Integrative Rheumatoid Transcriptomics and Dynamics The Catholic University of KoreaSeoul 06591Republic of Korea Department of biomedicine&Health Sciences The Catholic University of KoreaSeoul 06591Republic of Korea Department of pharmacology Asan Medical CenterUniversity of Ulsan College of MedicineSeoul 05505Republic of Korea bio-Medical Institute of Technology University of UlsanSeoul 05505Republic of Korea Department of Microbiology and Immunology Seoul National University College of MedicineSeoul 03080Republic of Korea Institute of Infectious Diseases Seoul National University College of MedicineSeoul 03080Republic of Korea Division of Rheumatology Department of Internal MedicineThe Catholic University of KoreaSeoul 06591Republic of Korea

Transcriptional coactivators regulate the rate of gene expression in the *** receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but its role in innate immunity and inflammatory diseases remains ***,we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory ***,nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC,forming cytoplasmic ***,NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3,promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1βand active *** note,Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3^(R258W) gain-of-function mutation in *** ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases,folic-induced acute tubular necrosis and crystal-induced arthritis,in *** with these findings,NCOA6 was highly expressed in macrophages derived from gout patients,and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling ***,NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases,including gout.

关键词： Nuclear receptor coactivator 6 Nuclear-to-cytoplasmic translocation NLRP3 inflammasome NACHT domain Gouty arthritis

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Exploring a novel class tryptophan hydroxylase 1 inhibitor derived from Sambucus williamsii Hance for the osteoporosis treatment

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Acupuncture and Herbal Medicine 2024年第1期4卷 102-112页

作者： Yu-Xin Zhu Zi-Ling Tang Lu Lu Zuo-Cheng Qiu Dabo Pan Yang Yu Hui-Hui Xiao Man-Sau Wong State Key laboratory of Chinese Medicine and Molecular pharmacology(Incubation) The Hong Kong Polytechnic University Shenzhen Research InstituteShenzhenChina Guangzhou Key laboratory of Formula-Pattern of Traditional Chinese Medicine School of Traditional Chinese MedicineJinan UniversityGuangzhouChina Guangdong Provincial Key laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research College of PharmacyJinan UniversityGuangzhouChina Department of Food Science and Nutrition The Hong Kong Polytechnic UniversityHong KongChina Research Center for Chinese Medicine Innovation The Hong Kong Polytechnic UniversityHong KongChina

Objective:Gut-derived serotonin strongly inhibits bone formation by inhibiting osteoblast *** previous study demonstrated that the lignan-rich fraction prepared from Sambucus willimasii Hance,a folk herbal medicine used to treat bone fractures and joint diseases in China,exerted bone-protective effects,and its actions were modulated by suppressing the synthesis of gut-derived serotonin via the inhibition of intestinal tryptophan hydroxylase 1(TPH-1).However,there is no direct evidence for the action of lignans on *** study aimed to verify the direct action of lignans on the TPH-1 and its influence on serotonin synthesis and bone ***:Molecular docking and surface plasmon resonance were performed to determine the affinities of lignans to *** cell viability and the protein activity and expression of TPH-1 were measured in RBL2H3 *** serum serotonin level and bone mineral density upon lignan treatment in ovariectomized mice were ***:The lignans showed high binding scores and binding affinities to TPH-1,inhibited the activity and protein expression of TPH-1,suppressed the serum serotonin levels in ovariectomized mice as well as promoted bone mineral ***:This is the first study to report that lignans are novel TPH-1 inhibitors and that these lignans could be potential agents for the management of serotonin-related diseases,including osteoporosis.

关键词： Lignan Osteoporosis Sambucus williamsii Hance Serotonin TPH-1 inhibitor

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Topological reorganization and functional alteration of distinct genomic components in gallbladder cancer

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Frontiers of Medicine 2024年第1期18卷 109-127页

作者： Guoqiang Li Peng Pu Mengqiao Pan Xiaoling Weng Shimei Qiu Yiming Li Sk Jahir Abbas Lu Zou Ke Liu Zheng Wang Ziyu Shao Lin Jiang Wenguang Wu Yun Liu Rong Shao Fatao Liu Yingbin Liu Department of Biliary-Pancreatic Surgery Renji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200127China State Key laboratory of Oncogenes and Related Genes Shanghai Cancer InstituteShanghai200127China Shanghai Key laboratory of Biliary Tract Disease Shanghai200082China Department of Health Science and Engineering University of Shanghai for Science and TechnologyShanghai200082China Shanghai Tenth People’s Hospital of Tongji University Shanghai200072China Department of General Surgery Xinhua HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200082China Department of pharmacology Shanghai Jiao Tong University School of MedicineShanghai200025China

Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human ***,knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely ***,by taking advantage of in situ Hi-C,RNA-sequencing,and chromatin immunoprecipitation sequencing(ChIP-seq),we investigated structural reorganization and functional changes in chromosomal compartments,topologically associated domains(TADs),and CCCTC binding factor(CTCF)-mediated loops in gallbladder cancer(GBC)tissues and cell *** observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression *** inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal ***,the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial–mesenchymal transition activation were enriched in cancer compared with their control ***-specific enhancer–promoter loops,which contain multiple transcription factor binding motifs,acted as a central element to regulate aberrant gene *** of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene ***,our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.

关键词： 3D genome cancer TADs loop gene regulation

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Agmatine ameliorates diabetes type 2-induced nephropathy in rats

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Asian Pacific Journal of Tropical biomedicine 2024年第1期14卷 8-16页

作者： Fatemah O.Kamel Ohoud Shagroud Mai AAlim A.Sattar Ahmad Gamal S Abd El-Aziz Abdulhadi S.Burzangi Duaa Bakhshwin Maha Jamal Shahid Karim Department of Clinical pharmacology Faculty of MedicineKing Abdulaziz UniversityJeddah 21589Saudi Arabia Department of Anatomy Faculty of MedicineKing Abdulaziz UniversityJeddah 21589Saudi Arabia

Objective:To assess the nephroprotective potential of agmatine in a rat model of streptozotocin-induced diabetic ***:A single dose of streptozotocin(40 mg/kg)coupled with a fructose diet induced diabetes in Wistar ***(40 and 80 mg/kg)was administered to rats for 12 *** body weight and fasting blood glucose were measured *** level,urine output,total protein,albumin,blood urea nitrogen,creatinine,and cystatin-C were also determined at the end of the ***,superoxide dismutase,glutathione,interleukin-1β,interleukin-6,and tumor necrosis factor-alpha were evaluated in kidney *** study was also performed using hematoxylin and eosin ***:Agmatine at both doses significantly increased final body weight,and lowered fasting blood glucose,urine output,insulin,total protein,albumin,blood urea nitrogen,creatinine,and cystatin-C levels compared with the diabetic group(P<0.05).Inflammatory markers and antioxidant effect were significantly improved in agmatine-treated ***,the histopathological changes in renal structure were ameliorated by agmatine ***:Agmatine alleviates diabetic nephropathy by improving renal functions and reducing inflammation and oxidative *** molecular mechanisms of its nephroprotective actions need to be investigated in future study.

关键词： Agmatine Type 2 diabetes Nephropathy Oxidative stress Nephroprotection

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