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GRK2 inhibits Flt-1^(+)macrophage infiltration and its proangiogenic properties in rheumatoid arthritis

Acta Pharmaceutica Sinica B 2024年第1期14卷 241-255页

作者： Xuezhi Yang Yingjie Zhao Qi Wei Xuemin Zhu Luping Wang Wankang Zhang Xiaoyi Liu Jiajie Kuai Fengling Wang Wei Wei Institute of clinical pharmacology Anhui Medical UniversityKey Laboratory of Anti-Inflammatory and Immune MedicineAnhui Collaborative Innovation Center of Anti-Inflammatory and Immune MedicineMinistry of EducationHefei 230032China Department of clinical pharmacology the Second Affiliated Hospital of Anhui Medical UniversityHefei 230601China

Rheumatoid arthritis(RA)is an autoimmune disease with a complex ***-derived macrophages(MDMs)infiltration are associated with RA *** have reported the deletion of G-protein-coupled receptor kinase 2(GRK2)reprograms macrophages toward an anti-inflammatory phenotype by recovering G-protein-coupled receptor ***,as more GRK2-interacting proteins were discovered,the GRK2 interactome mechanisms in RA have been ***,in the collagen-induced arthritis mouse model,we performed genetic GRK2 deletion using GRK2^(f/f)Lyz2-Cre^(+/−)*** inflammation and M1 polarization were improved in GRK2^(f/f)Lyz2-Cre^(+/−)*** experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptorγ(PPARγ)as a new GRK2-interacting *** further confirmed that fms-related tyrosine kinase 1(Flt-1),which promoted macrophage migration to induce angiogenesis,was inhibited by GRK2-PPARγ***,excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγligand-binding domain and enhanced Flt-1 ***,the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology,Flt-1^(+)macrophages induced-synovial inflammation,and ***,we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular *** GRK2 activity is a viable strategy to inhibit MDMs infiltration,affording a distinct way to control joint inflammation and angiogenesis of RA.

关键词： GRK2 Monocyte-derived macrophages Rheumatoid arthritis PPARg Flt-1

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Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1677-1692页

作者： Dongsheng Bai Jiawei Zhao Runde Wang Jiaying Du Chen Zhou Chunyang Gu Yuxiang Wang Lulu Zhang Yue Zhao Na Lu State Key laboratory of Natural Medicines Jiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjing 210009China Department of clinical pharmacology School of PharmacyNanjing Medical UniversityNanjing 211166China

Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment,significantly curtailing the efficacy of these treatments and,in some cases,resulting in fatal *** identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis,the paucity of effective treatments for such damage is *** our study,we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells,thereby fortifying the integrity of the intestinal mucus *** enhanced barrier function serves to resist microbial invasion and sub-sequently reduces the inflammatory ***,this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy ***,*** up-regulates the expression of AUF1,leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet *** espe-cially significant finding is that *** activates the AhR pathway,thereby promoting the expression of *** summary,our results strongly indicate that *** enhances the intestinal mucus barrier,effec-tively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUFl pathway,consequently enhancing Muc2 mRNA stability.

关键词： Chemotherapy Mucositis Eubacterium coprostanoligenes MUC2 AUF1

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Ailanthone ameliorates pulmonary fibrosis by suppressing JUN-dependent MEOX1 activation

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3543-3560页

作者： Lixin Zhao Yuguang Zhu Hua Tao Xiying Chen Feng Yin Yingyi Zhang Jianfeng Qin Yongyin Huang Bikun Cai Yonghao Lin Jiaxiang Wu Yu Zhang Lu Liang Ao Shen Xi-Yong Yu The Fifth Affiliated Hospital Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target and Clinical PharmacologyNMPA&State Key LaboratorySchool of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China

Pulmonary fibrosis poses a significant health threat with very limited therapeutic options *** this study,we reported the enhanced expression of mesenchymal homobox 1(MEOX1)in pulmonary fibrosis patients,especially in their fibroblasts and endothelial cells,and confirmed MEOX1 as a central orchestrator in the activation of profibrotic *** high-throughput screening,we identified Ailanthone(AIL)from a natural compound library as the first small molecule capable of directly targeting and suppressing *** demonstrated the ability to inhibit both the activation of fibroblasts and endothelial-to-mesenchymal transition of endothelial cells when challenged by transforming growth factor-b1(TGF-b1).In an animal model of bleomycin-induced pulmonary fibrosis,AIL effectively mitigated the fibrotic process and restored respiratory ***,AIL acted as a suppressor of MEOX1 by disrupting the interaction between the transcription factor JUN and the promoter of MEOX1,thereby inhibiting MEOX1 expression and *** summary,our findings pinpointed MEOX1 as a cell-specific and clinically translatable target in ***,we demonstrated the potent anti-fibrotic effect of AIL in pulmonary fibrosis,specifically through the suppression of JUN-dependent MEOX1 activation.

关键词： Ailanthone MEOX1 Pulmonary fibrosis JUN TGF-b1 High-throughput screening Natural product

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Modern View on Potentials of Forensic Pharmaceutical and Pharmacological Expertise

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Journal of Forensic Science and Medicine 2024年第1期10卷 62-67页

作者： Elena M.Vazhnichaya Nataliia M.Deviatkina Department of pharmacology Clinical Pharmacology and PharmacyPoltava State Medical UniversityPoltavaUkraine

The great number of drugs and their variety have increased the potential of therapy but increased the risks of crimes related to the production,sale,and use of *** prosecution of such crimes requires pharmaceutical or pharmacological *** development of forensic pharmacy and forensic pharmacology is relevant and needs consideration of their modern *** purpose of the work is to analyze literature data on the scientific basis of forensic pharmaceutical and pharmacological expertise and their modern *** texts of articles,book chapters,and websites were studied using keywords relevant to the purpose of the *** is shown,that modern forensic pharmaceutical expertise is a separate type of expertise that focuses on the study of drugs and documents that regulate the production,distribution,and quality of *** uses the latest analytical methods of pharmacy.A pharmacologist analyzes body fluids and tissues and interprets the resulting data to help courts and investigators assess the role of a drug in the person’s behavior,illness,injury,or *** range of issues included in the pharmacological examination is fully within the competence of the forensic medical examination,which can be appointed in civil cases or criminal proceedings connected with harm to health or *** pharmacology is not the same as forensic toxicology or pharmacovigilance and requires a separate approach based on purely pharmacological knowledge.

关键词： Drug expertise forensic pharmacology forensic pharmacy

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Allosterically activating SHP2 by oleanolic acid inhibits STAT3-Th17 axis for ameliorating colitis

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2598-2612页

作者： Jinbo Hu Wen Liu Yi Zou Chenyang Jiao Jiazhen Zhu Qiang Xu Jianjun Zou Yang Sun Wenjie Guo State Key laboratory of Pharmaceutical Biotechnology Nanjing Drum Tower HospitalSchool of Life SciencesNanjing UniversityNanjing 210093China Department of clinical pharmacology Nanjing First HospitalNanjing Medical UniversityNanjing 210006China Jiangsu Key laboratory of New Drug Research and clinical Pharmacy Xuzhou Medical UniversityXuzhou 221004China

Src homology 2 domain-containing tyrosine phosphatase 2(SHP2)is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth,differentiation,and *** activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's ***,the identification of SHP2 activators and a complete understanding of their mechanism is *** used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open *** acid was identified as a suitable *** binding to R362,K364,and K366 in the active center of the PTP domain,oleanolic acid maintained the active open state of SHP2,which facilitated the binding between SHP2 and its *** oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rαand inhibiting the activation of ***,via the activation of SHP2 and subsequent attenuation of the STAT3-Th17 axis,oleanolic acid effectively mitigated colitis in *** protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor *** findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

关键词： Oleanolic acid SHP2 STAT3 Th17 Colitis Allosteric activator

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Anti-EGFR antibody monotherapy for colorectal cancer with severe hyperbilirubinemia: A case report

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World Journal of Gastrointestinal Oncology 2024年第2期16卷 557-562页

作者： Toshiaki Tsurui Yuya Hirasawa Yutaro Kubota Kiyoshi Yoshimura Takuya Tsunoda Department of Medical Oncology Showa UniversityTokyo 1428555Japan Department of clinical Immuno Oncology Clinical Research Institute of Clinical Pharmacology and TherapeuticsShowa UniversityTokyo 1578577Japan

BACKGROUND Hyperbilirubinemia with hepatic metastases is a common complication and a poor prognostic factor for colorectal cancer(CRC).Effective drainage is often im-possible before initiating systemic chemotherapy,owing to the liver’s diffuse metastatic ***,an appropriate chemotherapeutic approach for the treatment of hyperbilirubinemia is currently *** SUMMARY The patient,a man in his 50s,presented with progressive fatigue and severe *** tomography revealed multiple hepatic masses with thick-ened walls in the sigmoid colon,which was pathologically confirmed as a well-differentiated *** RAS or BRAF mutations were *** Eastern Cooperative Oncology Group(ECOG)performance status(PS)score was *** drainage was impossible due to the absence of a dilated bile duct,and panitumumab monotherapy was promptly ***,the bilirubin level decreased and then normalized,and the patient’s PS improved to zero ECOG score after four cycles of therapy without significant adverse *** Anti-EGFR antibody monotherapy is a safe and effective treatment for RAS wild-type CRC and hepatic metastases with severe hyperbilirubinemia.

关键词： Colorectal neoplasms Panitumumab Chemotherapy Hyperbilirubinemia Jaundice Case report

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Interaction between inflammatory bowel disease,physical activity,and myokines:Assessment of serum irisin levels

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World Journal of Gastroenterology 2024年第22期30卷 2923-2926页

作者： Marwan SM Al-Nimer Department of Therapeutics and clinical pharmacology College of MedicineUniversity of DiyalaBaqubah 32001Iraq

Inflammatory bowel disease(IBD),including Crohn’s disease and ulcerative colitis,showed a wide spectrum of intestinal and extra-intestinal manifestations,which rendered the patients physically inactive and impaired their quality of *** has been found that physical activity is a non-pharmacological intervention that improves the quality of life for those *** is one member of the myokines secreted by muscle contraction during exercise and could be used as an antiinflammatory biomarker in assessing the physical activity of IBD *** addition,experimental studies showed that exogenous irisin significantly decreased the inflammatory markers and the histological changes of the intestinal mucosa observed in experimental ***,irisin produces changes in the diversity of the ***,endogenous or exogenous irisin,via its anti-inflammatory effects,will improve the health of IBD patients and will limit the barriers to physical activity in patients with IBD.

关键词： Irisin Inflammatory bowel disease Physical activity Myokines Prognostic marker

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Elafibranor:A promising treatment for alcoholic liver disease,metabolic-associated fatty liver disease,and cholestatic liver disease

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World Journal of Gastroenterology 2024年第40期30卷 4393-4398页

作者： Hang Zhang Xuan Dong Lei Zhu Fu-Shan Tang Department of clinical Pharmacy Key Laboratory of Basic Pharmacology of Guizhou Province and School of PharmacyZunyi Medical UniversityZunyi 563006Guizhou ProvinceChina Key laboratory of Basic pharmacology of Ministry of Education and Joint International Research laboratory of Ethnomedicine of Ministry of Education Zunyi Medical UniversityZunyi 563006Guizhou ProvinceChina Key laboratory of clinical Pharmacy in Zunyi City Zunyi Medical UniversityZunyi 563006Guizhou ProvinceChina

Liver diseases pose a significant threat to human *** effective therapeutic agents exist for some liver diseases,there remains a critical need for advancements in research to address the gaps in treatment options and improve patient *** article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease(ALD),as reported by Koizumi et al in the World Journal of *** summarize the impact and mechanisms of Elafibranor on ALD,metabolic-associated fatty liver disease,and cholestatic liver disease based on current *** also explore its potential as a dual agonist of PPARα/δ,which is undergoing Phase III clinical trials for metabolic-associated *** goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application.

关键词： Elafibranor Peroxisome proliferator activated receptor Liver fibrosis Alcoholic liver disease Metabolic-associated fatty liver disease Metabolic-associated steatohepatitis Cholestatic liver disease Primary biliary cholangitis Liver diseases

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Formulation,characterization and in vivo and in vitro evaluation of aloe-emodin-loaded solid dispersions for dissolution enhancement

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Journal of Traditional Chinese Medicine 2024年第1期44卷 54-62页

作者： LI Xiuyan LUO Yuting WANG Jinhui DU Zhimin Key laboratory of Basic and Application Research of Beiyao Heilongjiang University of Chinese MedicineMinistry of EducationHarbin 150040China College of Pharmacy Harbin Medical UniversityHarbin 150081China Institute of clinical pharmacology the Second Affliated Hospital of Harbin Medical University(University Key aboratory of Drug ResearchHeilongjiang Province)Harbin 150086China Department of clinical pharmacology College of Pharmacy Harbin Medical UniversityHarbin 150081China State Key laboratory of Quality Research in Chinese Medicines Macao University of Science and TechnologyMacao 999078China

OBJECTIVE:To prepare aloe-emodin solid dispersion(AE-SD)and determine the metabolic process of AE and AE-SD in ***:AE-SD was prepared via solvent evaporation or solvent melting using PEG-6000 and PVP-K30 as *** analysis,X-ray diffraction spectroscopy,differential scanning calorimetry,Fourier transform infrared spectroscopy and scanning electron microscopy were used to identify the physical state of *** prescriptions were screened via the dissolution degree determination *** Phoenix software,AE suspension and AE-SD were subjected to a pharmacokinetic comparison study analyzing the alteration of behavior in vivo after AE was prepared as a solid *** toxicity was assessed in mice,and the physiological toxicity was used as the determination criterion for ***:AE-SD showed that AE existed in the carrier in an amorphous *** with polyethylene glycol,polyvinylpyrrolidone(PVP)inhibited AE crystallization,causing the drug to transform from a dense crystalline state to an amorphous form and increasing the degree of drug ***,it was more suitable as a carrier material for *** addition of poloxamer(POL)was more beneficial to the stability of solid dispersions and could reduce the amount of *** dissolution test confirmed that the optimal ratio of AE to the composite vector AE-PVP-POL was 1:2:2,and its dissolution effect was also *** on the pharmacokinetic comparison,the drug absorption was faster and quickly reached the peak of blood drug concentration in AE-SD compared to AE,the Cmax of AE-SD was greater than that of AE,and t1/2 and mean residence time of AE-SD were less than *** results showed that the drug metabolism in AE-SD was better,and the residence time was *** toxicology study showed that both AE and AE-SD had no ***:This paper established that the solubility of the drug could be increased after preparing a solid dispersion,

关键词： aloe-emodin solid dispersion solvent evaporation drug liberation pharmacokinetics

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Metabolic dysfunction-associated steatotic liver disease:Navigating terminological evolution,diagnostic frontiers and therapeutic horizon-an editorial exploration

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World Journal of Gastroenterology 2024年第18期30卷 2387-2390页

作者： Aleksandra Boldys Lukasz Buldak Department of Internal Medicine and clinical pharmacology School of Medicine in KatowiceMedical University of SilesiaKatowice 40-752Poland

Metabolic dysfunction-associated steatotic liver disease(MASLD),once known as non-alcoholic fatty liver disease(NAFLD),represents a spectrum of liver disorders characterized by lipid accumulation within *** redefinition of NAFLD in 2023 marked a significant reposition in terminology,emphasizing a broader understanding of liver steatosis and its associated *** is now recognized as a major risk factor for liver cirrhosis,hepatocellular carcinoma,and systemic complications such as cardiovascular diseases or systemic *** challenges arise,particularly in identifying MASLD in lean individuals,necessitating updated diagnostic protocols and investing in non-invasive diagnostic ***,there is an urgent need for effective treatments targeting MASLD,with emerging pharmacological options focusing on,among others,carbohydrate and lipid ***,understanding the roles of bile acid metabolism,the microbiome,and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic *** is a strong need to emphasize the importance of collaborative efforts in understanding,diagnosing,and managing MASLD to improve physicians’approaches and patient outcomes.

关键词： Metabolic dysfunction-associated steatotic liver disease Diagnostics Pathophysiology of metabolic dysfunction-associated steatotic liver disease Therapy of metabolic dysfunction-associated steatotic liver disease Therapeutic innovations

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