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Noncanonical pyroptosis pathway: a promising target of traditional Chinese medicine in the treatment of sepsis-related injury

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Integrative Medicine Discovery 2024年第20期8卷 1-4页

作者： Yan-Yan Cen Pan Wang Ting Zhu Ya-Lan Xiong Xi-Chun Pan Department of pharmacology College of PharmacyArmy Medical UniversityChongqing 400038China.

Sepsis is a life-threatening disease of organ failure caused by dysregulated host responses to infection and other infectious ***-organ injury is the leading cause of high mortality and septic shock during *** studies suggest that noncanonical pyroptosis,characterized mainly by the direct activation of caspase-11-gasdermin D-mediated pyroptosis by cytoplastic lipopolysaccharide,is closely related to sepsis-related organ ***,this review summarizes recent advances in the regulatory mechanisms and targeted natural products from traditional Chinese medicine of the noncanonical pyroptosis pathway in sepsis-related injury.

关键词： sepsis-related injury noncanonical pyroptosis caspase-11 gasdermin D

Investigating epithelial-neuronal signaling contribution in visceral pain through colon organoid-dorsal root ganglion neuron co-cultures

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Neural Regeneration Research 2024年第6期19卷 1199-1200页

作者： Francesco Margiotta Lorenzo Di Cesare Mannelli Antonino Morabito Carla Ghelardini Elena Lucarini Department of Neuroscience PsychologyDrug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology SectionUniversity of FlorenceFlorenceItaly Department of Neuroscience PsychologyDrug Research and Child Health-NEUROFARBAUniversity of FlorenceFlorenceItaly Meyer Children’s Hospital IRCCS FlorenceItaly

Abdominal pain is a common symptom associated with irritable bowel syndrome and inflammatory bowel diseases(IBDs),affecting about 20%of the global population(Grundy et al.,2019).Current pain therapies are poorly effective on visceral pain of intestinal origin and present several side effects,hence the need to identify novel molecular and cellular targets for drug development.

关键词： pain visceral colon

Narciclasine induces colon carcinoma cell apoptosis by inhibiting the IL-17A/Act1/TRAF6/NF-kB signaling pathway

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Genes & Diseases 2024年第5期11卷 428-441页

作者： Huiming Deng Qiang Liu Siman Yu Lifan Zhong Lianfang Gan Huiquan Gu Qianru Wang Ruxin Cheng Yong Liu Li Liu Ling Huang Ronghua Xu Department of Gastrointestinal Surgery Huazhong University of Science and Technology Union Shenzhen HospitalShenzhenGuangdong 518000China Research Center for Drug Safety Evaluation of Hainan Province HaikouHainan 571199China Department of pharmacology Hainan Medical UniversityHaikouHainan 571199China Department of Pathology Guangzhou Panyu Central HospitalGuangzhouGuangdong 511400China Hainan Province Key Laboratory for Drug Preclinical Study of pharmacology and Toxicology Research Hainan Medical UniversityHaikouHainan 571199China Hainan Center for Drug and Medical Device Evaluation and Service Hainan Medical Products AdministrationHaikouHainan 570216China

IL-17 A is a promoter of colorectal cancer initiation and *** is a polyhydroxy alkaloid compound isolated from Narcissus plants,which has potent anti-inflammatory and antitumor *** effects of narciclasine on colorectal tumors were evaluated,with a focus on IL-17 *** reduced the growth of HCT-116 and SW-480 colon cancer cells in vitro and in vivo in murine *** results of flow cytometry on JC-1 and Annexin V/PI revealed that narciclasine significantly reduced the mitochondrial membrane potential and induced apoptosis,findings confirmed by western blotting results of reduced Bcl2 and enhanced Bax expression,as well as accumulation of cleaved Caspase-3,Caspase-8,Caspase-9,and cytoplasmic *** narciclasine incubation,IL-17 A,Act1,and TRAF6 were down-regulated,while p-P65(Ser536)accumulated in the cytoplasm,a finding confirmed by laser scanning confocal ***17A substitution could partly reverse these narciclasine effects while they were elevated by IL17A ***,IL-17 A,Act1,and TRAF6 were significantly expressed to greater extents in human colorectal cancer compared to normal adjacent tissue specimens and were closely linked with a poor *** study provided evidence that narciclasine may be a useful therapeutic drug for colorectal cancer treatment through its actions in down-regulating the L-17A/Act1/TRAF6/NF-kB anti-apoptotic signaling pathway.

关键词： Act1 Apoptosis Colonrectal cancer IL-17A Narciclasine NF-kB

Stepping up after spinal cord injury:negotiating an obstacle during walking

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Neural Regeneration Research 2025年第7期20卷 1919-1929页

作者： Alain Frigon Charly G.Lecomte Department of pharmacology-Physiology Faculty of Medicine and Health SciencesUniversitéde SherbrookeCentre de recherche du Centre Hospitalier Universitaire de SherbrookeSherbrookeQCCanada

Every day walking consists of frequent voluntary modifications in the gait pattern to negotiate *** spinal cord injury,stepping over an obstacle becomes *** over an obstacle requires sensorimotor transformations in several structures of the brain,including the parietal cortex,premotor cortex,and motor *** information and planning are transformed into motor commands,which are sent from the motor cortex to spinal neuronal circuits to alter limb trajectory,coordinate the limbs,and maintain *** spinal cord injury,bidirectional communication between the brain and spinal cord is disrupted and animals,including humans,fail to voluntarily modify limb trajectory to step over an ***,in this review,we discuss the neuromechanical control of stepping over an obstacle,why it fails after spinal cord injury,and how it recovers to a certain extent.

关键词： biomechanics locomotion neurophysiology obstacle negotiation spinal cord injury

Prefrontocortical Astrocytes Regulate Dominance Hierarchy in Male Mice

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Neuroscience Bulletin 2024年第3期40卷 415-417页

作者： Yong Tang Hai-Yan Yin Peter Illes School of Acupuncture and Tuina Chengdu University of Traditional Chinese MedicineChengdu 610075China International Joint Research Center on Purinergic Signaling Chengdu University of Traditional Chinese MedicineChengdu 610075China Rudolf Boehm Institute for pharmacology and Toxicology University of Leipzig04107 LeipzigGermany

Social hierarchy is a general self-organizational scheme in animal societies in which each member achieves a certain status of domination or subordination when getting access to resources,with profound consequences for survival,health,reproductive success,and multiple behaviors[1,2].The prefrontal cortex(PFC)was recognized as a central regulator of neuronal circuits determining the formation of social hierarchy;brain areas upstream of the PFC convey information about social status,and downstream brain regions execute dominance behavior[3].Social deficits have been suggested to be due to an elevation of excitatory/inhibitory(E/l)balance within the mouse dorsomedial(dm)PFC[4].A compensatory increase of inhibitory cell excitability partially rescued social deficits caused by such a disturbance of E/l balance.

关键词： consequences hierarchy determining

Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael S.Wolfe Computational Medicine Program and Department of pharmacology University of North Carolina–Chapel HillChapel HillNCUSA Department of Medicinal Chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface *** inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as ***,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-*** this review,we focus on recent studies of structural dynamic mechanisms ofγ-*** mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics *** an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental *** approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-*** addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is ***,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1951-1964页

作者： Longsheng Wang Jie Zhang Wenxin Zhang Mingming Zheng Hongjie Guo Xiaohui Pan Wen Li Bo Yang Ling Ding Zhejiang Province Key Laboratory of Anti-Cancer Drug Research Institute of Pharmacology and ToxicologyCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China The Innovation Institute for Artificial Intelligence in Medicine Zhejiang UniversityHangzhou 310018China Nanhu Brain-Computer Interface Institute Hangzhou 311100China

Adenosine(Ado)is significantly elevated in the tumor microenvironment(TME)compared to normal *** binds to adenosine receptors(AdoRs),suppressing tumor antigen presentation and immune cell activation,thereby inhibiting tumor adaptive *** downregulates major histocompatibility complex II(MHC II)and co-stimulatory factors on dendritic cells(DCs)and macrophages,inhibiting antigen *** suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor(TCR)binding and signal *** also inhibits chemokine secretion and KCa3.1 channel activity,impeding effector T cell trafficking and infiltration into the tumor ***,Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion,upregulating immune checkpoint proteins,and enhancing immune-suppressive cell *** Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other *** and clinical development of inhibitors targeting Ado generation or AdoRs is ***,this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity,as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

关键词： Adenosine Adenosine receptors Adenosine-generating enzymes Tumor microenvironment Immune suppression Immune escape Clinical treatment Targeting drugs

Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management

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Journal of Pharmaceutical Analysis 2024年第1期14卷 16-38页

作者： Nguyen Quang Thu Nguyen Tran Nam Tien Nguyen Thi Hai Yen Thuc-Huy Duong Nguyen Phuoc Long Huy Truong Nguyen Department of pharmacology and PharmacoGenomics Research Center Inje University College of MedicineBusan47392Republic of Korea Department of Chemistry University of EducationHo Chi Minh City700000Viet Nam Faculty of Pharmacy Ton Duc Thang UniversityHo Chi Minh City700000Viet Nam

The spread of tuberculosis(TB),especially multidrug-resistant TB and extensively drug-resistant TB,has strongly motivated the research and development of new anti-TB *** strategies to facilitate drug combinations,including pharmacokinetics-guided dose optimization and toxicology studies of first-and second-line anti-TB drugs have also been introduced and *** chromatography-mass spectrometry(LC-MS)has arguably become the gold standard in the analysis of both endo-and exo-genous *** technique has been applied successfully not only for therapeutic drug monitoring(TDM)but also for pharmacometabolomics *** improves the effectiveness of treatment,reduces adverse drug reactions,and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target *** on TDM,the dose would be optimized individually to achieve favorable *** is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs,aiding in the discovery of potential biomarkers for TB diagnostics,treatment monitoring,and outcome *** article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two ***,we discussed the advantages and disadvantages of this technique in practical *** pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was ***,we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies(pharmacometrics,drug and vaccine developments,machine learning/artificial intelligence,among others)to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients.

关键词： Tuberculosis Therapeutic drug monitoring LC-MS MIPD Pharmacometabolomics Precision medicine

Efficacy of intraovarian autologous platelet-rich plasma administration in women with low ovarian reserve: A systematic review and meta-analysis

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Asian pacific Journal of Reproduction 2024年第2期13卷 60-67页

作者： Yasmin Sabina Sa’diah Agung Dewanto Lukman A Chandra Department of Obstetrics and Gynecology Faculty of MedicinePublic Health and NursingUniversitas Gadjah MadaYogyakartaIndonesia Department of pharmacology and Therapy Faculty of MedicinePublic Health and NursingUniversitas Gadjah MadaYogyakartaIndonesia

Objective:To conduct a systematic examination and meta-analysis of the most reliable data from experimental studies evaluating the efficacy of autologous platelet-rich plasma(PRP)on low ovarian ***:A comprehensive search was performed utilizing pertinent search terms across electronic databases,including PubMed,Cochrane,and Google *** included studies that assigned infertile women with low ovarian reserve in experimental *** reserve parameters were measured before and after PRP injection into *** data of each study was retrieved and subsequently ***:Of 301 articles collected and reviewed,six studies were finally included in the *** PRP injection,infertile women showed a non-significant increase in anti-Mullerian hormone(AMH)level(MD=0.10;95%CI-0.04,0.23),a significant increase in antral follicular count(AFC)(MD=1.88;95%CI 0.47,3.29),and a non-significant reduction in follicle-stimulating hormone(FSH)level(MD=-0.22;95%CI-8.32,7.87).Conclusions:Autologous PRP may increase AFC,but not *** it is found beneficial in enhancing ovarian reserve(AFC),further research with strong evidence is still required.

关键词： Platelet-rich plasma Low ovarian reserve Ovarian rejuvenation