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

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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 etiology.Monocyte-derived macrophages(MDMs)infiltration are associated with RA severity.We 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 signaling.However,as more GRK2-interacting proteins were discovered,the GRK2 interactome mechanisms in RA have been understudied.Thus,in the collagen-induced arthritis mouse model,we performed genetic GRK2 deletion using GRK2^(f/f)Lyz2-Cre^(+/−)mice.Synovial inflammation and M1 polarization were improved in GRK2^(f/f)Lyz2-Cre^(+/−)mice.Supporting experiments with RNA-seq and dual-luciferase reporter assays identified peroxisome proliferator-activated receptorγ(PPARγ)as a new GRK2-interacting protein.We further confirmed that fms-related tyrosine kinase 1(Flt-1),which promoted macrophage migration to induce angiogenesis,was inhibited by GRK2-PPARγsignaling.Mechanistically,excess GRK2 membrane recruitment in CIA MDMs reduced the activation of PPARγligand-binding domain and enhanced Flt-1 transcription.Furthermore,the treatment of mice with GRK2 activity inhibitor resulted in significantly diminished CIA pathology,Flt-1^(+)macrophages induced-synovial inflammation,and angiogenesis.Altogether,we anticipate to facilitate the elucidation of previously unappreciated details of GRK2-specific intracellular signaling.Targeting 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

Targeting KRAS in pancreatic cancer

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Oncology Research 2024年第5期32卷 799-805页

作者： SANDRA STICKLER BARBARA RATH GERHARD HAMILTON institute of pharmacology Medical University of ViennaViennaA-1090Austria

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies.The Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for therapy.However,the most common KRAS mutations in PDAC are G12D(44%),G12V(34%)and G12R(20%)that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer.KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of PDAC.Recently,the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development.The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(GEF)Son of Sevenless 1 that drives KRAS.These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

关键词： Pancreatic cancer PDAC KRAS SOS1 PROTAC

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 medicines.The prosecution of such crimes requires pharmaceutical or pharmacological expertise.The development of forensic pharmacy and forensic pharmacology is relevant and needs consideration of their modern capabilities.The purpose of the work is to analyze literature data on the scientific basis of forensic pharmaceutical and pharmacological expertise and their modern possibilities.The texts of articles,book chapters,and websites were studied using keywords relevant to the purpose of the review.It 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 medicines.It 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 death.The 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 death.Forensic 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

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 hepatocytes.The redefinition of NAFLD in 2023 marked a significant reposition in terminology,emphasizing a broader understanding of liver steatosis and its associated risks.MASLD is now recognized as a major risk factor for liver cirrhosis,hepatocellular carcinoma,and systemic complications such as cardiovascular diseases or systemic inflammation.Diagnostic challenges arise,particularly in identifying MASLD in lean individuals,necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools.Therapeutically,there is an urgent need for effective treatments targeting MASLD,with emerging pharmacological options focusing on,among others,carbohydrate and lipid metabolism.Additionally,understanding the roles of bile acid metabolism,the microbiome,and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches.There 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

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 life.It has been found that physical activity is a non-pharmacological intervention that improves the quality of life for those patients.Irisin 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 patients.In addition,experimental studies showed that exogenous irisin significantly decreased the inflammatory markers and the histological changes of the intestinal mucosa observed in experimental colitis.Furthermore,irisin produces changes in the diversity of the microbiota.Therefore,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

Effect of MDR1 gene polymorphism on progression of end-stage renal disease

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Acta Pharmacologica Sinica 2007年第4期28卷 579-583页

作者： Wei-xia ZHANG~2,Bing CHEN~2,Wen ZHANG~3,Nan CHEN~3,Zi-cheng YU~2,Wei-min CAI~(2,4)~2institute of clinical pharmacology and ~3Department of Nephrology,Ruijin Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200025,China institute of clinical pharmacology Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China Department of Nephrology Ruijin Hospital Shanghai Jiaotong University School of Medicine Shanghai China

Aim:P-glycoprotein is localized at the apical brush-border membrane of the proxi-mal renal tubule and functions as extruding toxins and xenobiotics out of cells.The difference of P-glycoprotein’s function resulted from single nucleotide poly-morphisms in MDR1 (multidrug resistance gene encoding for P-gp) and may bethe cause of interindividual differences in susceptibility to end-stage renal dis-ease (ESRD).The purpose of this study is to compare the genotype frequency ofC3435T and G1199A polymorphisms in MDR1 between ESRD patients and healthycontrols in the Chinese population to determine whether the alteration of the P-gpfunction is associated with ESRD.Methods:Two hundred and eighty-four healthyChinese controls and 244 Chinese patients with ESRD were involved in this study.Allele specific PCR and polymerase chain reaction-restriction fragment lengthpolymorphism assay were used to determine the genotype MDR1 G1199A andC3435T,respectively.Results:The genotype distribution of 3435CC,3435CT,and 3435TT were 0.35,0.50,and 0.15,respectively,in the control group and 0.38,0.47,and 0.15 in the group with the ESRD patients.No variant allele 1199G>A wasfound in any of the patients.The value of serum creatinine for genotypes 3435CC,3435CT,and 3435TT in the ESRD patients were 753.8+276.0 μmol/L,849.6±342.2μmol/L,and 987.0±512.0 μmol/L,respectively.The difference between 3435TTand 3435CC reached statistical significance (PA variant allele.More studies are needed to clarifythe cause and interindividual differences in the susceptibility for the risk of ESRD.

关键词： end-stage renal disease multiple drug resistance gene 1 polymorphism

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Genes & Diseases 2024年第1期11卷 367-381页

作者： Yunchao Zhang Jiayu Tang Cheng Wang Qinxiu Zhang Anqi Zeng Linjiang Song School of Medical and Life Sciences Chengdu University of Traditional Chinese MedicineChengduSichuan 611137China institute of Translational pharmacology and clinical Application Sichuan Academy of Chinese Medical ScienceChengduSichuan 610041China School of Pharmacy Chengdu University of Traditional Chinese MedicineChengduSichuan 611137China

The incidence and mortality rates of cancer are increasing every year worldwide but the survival rate of cancer patients is still unsatisfactory.Therefore,it is necessary to further elucidate the molecular mechanisms involved in tumor development and drug resis-tance to improve cancer cure or survival rates.In recent years,autophagy has become a hot topic in the field of oncology research,which plays a double-edged role in tumorigenesis,pro-gression,and drug resistance.Meanwhile,long non-coding RNA(lncRNA)has also been shown to regulate autophagy,and the two-sided nature of autophagy determines the dual regulatory role of autophagy-related IncRNAs(ARlncRNAs).Therefore,ARlncRNAs can be effective ther-apeutic targets for various cancers.Furthermore,the high abundance and stability of ARlncR-NAs in tumor tissues make them promising biomarkers.In this review,we summarized the roles and mechanisms of ARlncRNAs in tumor cell proliferation,apoptosis,migration,invasion,drug resistance,angiogenesis,radiation resistance,and immune regulation.In addition,we described the clinical significance of these ARlncRNAs,including as biomarkers/therapeutic targets and their association with clinical drugs.

关键词： Apoptosis Autophagy Biomarker Cancer Drug resistance LncRNA

Expect the unexpected:Brown tumor of the mandible as the first manifestation of primary hyperparathyroidism

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World Journal of clinical Cases 2024年第7期12卷 1200-1204页

作者： Ana Majic Tengg Maja Cigrovski Berkovic Ivan Zajc Ivan Salaric Danko Müller Iva Markota Department of Endocrinology DiabetesMetabolic Diseases and Clinical PharmacologyClinical Hospital DubravaZagreb 10000Croatia Department for Sport and Exercise Medicine Faculty of Kinesiology University of ZagrebZagreb 10000Croatia Department of Oral Surgery Clinical Hospital DubravaZagreb 10000Croatia University of Zagreb School of Dental Medicine Zagreb 10000Croatia clinical Department of Pathology and Cytology Clinical Hospital DubravaZagreb 10000Croatia

Hyperparathyroidism(HPT)is a condition in which one or more parathyroid glands produce increased levels of parathyroid hormone(PTH),causing disturbances in calcium homeostasis.Most commonly HPT presents with asymptomatic hypercalcemia but the clinical spectrum may include disturbances reflecting the combined effects of increased PTH secretion and hypercalcemia.Brown tumors are rare,benign,tumor-like bone lesions,occurring in 1.5%to 4.5%of patients with HPT,as a complication of an uncontrolled disease pathway,and are nowadays rarely seen in clinical practice.The tumor can appear either as a solitary or multifocal lesion and usually presents as an asymptomatic swelling or a painful exophytic mass.Furthermore,it can cause a pathological fracture or skeletal pain and be radiologically described as a lytic bone lesion.The diagnosis of a brown tumor in HPT is typically confirmed by assessing the levels of serum calcium,phosphorus,and PTH.Although when present,brown tumor is quite pathognomonic for HPT,the histologic finding often suggests a giant cell tumor,while clinical presentation might suggest other more frequent pathologies such as metastatic tumors.Treatment of brown tumors frequently focuses on managing the underlying HPT,which can often lead to regression and resolution of the lesion,without the need for surgical intervention.However,in refractory cases or when dealing with large symptomatic lesions,surgical treatment may be necessary.

关键词： Brown tumor Hyperparathyroidism Lytic bone lesions Giant cell tumor

Proteomics analysis of coronary atherosclerotic heart disease with different Traditional Chinese Medicine syndrome types before and after percutaneous coronary intervention

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Journal of Traditional Chinese Medicine 2024年第3期44卷 554-563页

作者： WANG Zhibo LI Ying WANG Daoping MA Bo MIAO Lan REN Junguo LIU Jinghua LIU Jianxun Beijing Key Laboratory of pharmacology of Chinese Materia Region Institute of Basic Medical SciencesXiyuan HospitalChina Academy of Chinese Medical SciencesNational Clinical Research Center of Cardiovascular Disease of Traditional Chinese Medicine the National Key Facility for Crop Gene Resources and Genetic Improvement Institute of Crop ScienceChinese Academy of Agricultural Science Department of Cardiology Beijing Anzhen HospitalCapital Medical University

OBJECTIVE: To investigate the underlying protein molecular mechanisms of "Qi stagnation and blood stasis syndrome"(QS) and "Qi deficiency and blood stasis syndrome"(QD), as two subtypes of coronary artery disease(CAD) in Traditional Chinese Medicine(TCM),following percutaneous coronary intervention(PCI).METHODS: In this study, a total of 227 CAD patients with QS and 211 CAD patients with QD were enrolled; all participants underwent PCI. Label-free quantification proteomics were employed to analyze the changes in serum in two subtypes of CAD patients before and 6 months after PCI, aiming to elucidate the intervention mechanism of PCI in treating CAD characterized by two different TCM syndromes.RESULTS: Biochemical analysis revealed significant changes in tumor necrosis factor-α, high density lipoprotein cholesterol, blood stasis clinical symptoms observation, and Gensini levels in both patient groups post-PCI; Proteomic analysis identified 79 and 95 differentially expressed proteins in the QS and QD patient groups, respectively, compared to their control groups.complement C8 alpha chain, complement factor H,apolipoprotein H, apolipoprotein B, plasminogen,carbonic anhydrase 2, and complement factor Ⅰ were altered in both comparison groups. Furthermore,enrichment analysis demonstrated that cell adhesion and connectivity-related processes underwent changes in QS patients post-PCI, whereas lipid metabolism-related pathways, including the peroxisome proliferator-activated receptor signaling pathway and extracellular matrix receptor interaction, underwent changes in the QD group.The protein-protein interaction network analysis further enriched 52 node proteins, including apolipoprotein B,lipoprotein(a), complement C5, apolipoprotein A4,complement C8 alpha chain, complement C8 beta chain,complement C8 gamma chain, apolipoprotein H,apolipoprotein A-Ⅱ, albumin, complement C4-B,apolipoprotein C3, among others. The functional network of these proteins is posited to contribute to the pathophysiology of CAD characterized by TC

关键词： Traditional Chinese Medicine syndrome coronary atherosclerotic heart disease peptide mapping percutaneous coronary intervention proteomics