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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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GRK2 mediated degradation of SAV1 initiates hyperplasia of fibroblast-like synoviocytes in rheumatoid arthritis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1222-1240页

作者： Paipai Guo Ji Jiang Rui Chu Feng He Mingli Ge Ruhong Fang Qiuyun Guan Huijuan Cheng Chunru Jiang Tiantian Su Zhenduo Zhu Hao Liu Wei Wei Shihao Zhang Qingtong Wang institute of Clinical Pharmacology Anhui Medical UniversityKey Laboratory of Anti-inflammatory and Immune MedicineMinistry of EducationCollaborative Innovation Center of Anti-inflammatory and Immune MedicinesHefei 230032China School of Pharmacy Bengbu Medical CollegeBengbu 233030China The Third Affiliated Hospital of Anhui Medical University(the First People’s Hospital of Hefei) Hefei 230061China

Hyperplasia and migration of fibroblast-like synoviocytes(FLSs)are the key drivers in the pathogenesis of rheumatoid arthritis(RA)and joint *** Yes-associated protein(YAP),which is a powerful transcription co-activator for proliferative genes,was observed in the nucleus of inflammatory FLSs with unknown upstream *** Gene Expression Omnibus database analysis,it was found that Salvador homolog-1(SAV1),the pivotal negative regulator of the Hippo-YAP pathway,was slightly downregulated in RA ***,SAV1 protein expression is extremely ***,it was revealed that SAV1 is phosphorylated,ubiquitinated,and degraded by interacting with an important serine-threonine kinase,G protein-coupled receptor(GPCR)kinase 2(GRK2),which was predominately upregulated by GPCR activation induced by ligands such as prostaglandin E2(PGE2)in *** process further contributes to the decreased phosphorylation,nuclear translocation,and transcriptional potency of YAP,and leads to aberrant FLSs *** depletion of GRK2 or inhibition of GRK2 by paroxetine rescued SAV1 expression and restored YAP phosphorylation and finally inhibited RA FLSs proliferation and ***,paroxetine treatment effectively reduced the abnormal proliferation of FLSs in a rat model of collagen-induced arthritis which was accompanied by a significant improvement in clinical ***,these results elucidate the significance of GRK2 regulation of Hippo-YAP signaling in FLSs proliferation and migration and the potential application of GRK2 inhibition in the treatment of FLSs-driven joint destruction in RA.

关键词： Rheumatoid arthritis Fibroblast-like synoviocytes G protein-coupled receptor kinase 2 Salvador homolog-1 Yes-associated protein

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Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease

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World Journal of Gastroenterology 2011年第37期17卷 4166-4173页

作者： Kara Bradford David Q Shih Department of Medicine Cedars Sinai Medical Center inflammatory bowel and immunobiology research institute Cedars-Sinai Medical Center

The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) *** reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate with therapeutic efficacy,whereas high 6-methylmercaptopurine(6-MMP) levels are associated with hepatotoxicity and *** to their complex metabolism,there is wide individual variation in patient response therein,both in achieving therapeutic drug levels as well as in developing adverse *** strategies to optimize 6-TGN while minimizing 6-MMP levels have been adopted to administer the thiopurine class of drugs to patients who otherwise would not tolerate these drugs due to *** this report,we will review different approaches to administer the thiopurine medications,including the administration of 6-mercaptopurine in those unsuccessfully treated with azathioprine;coadministration of thiopurine with allopurinol;co-administration of thiopurine with anti-tumor necrosis factor α;6-TGN administration;desensitization trials;and split dosing of 6-MP.

关键词： Azathioprine Drug levels inflammatory bowel disease 6-Mercaptopurine Thiopurine

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Glucagon-like peptide 1 receptor activation:anti-inflammatory effects in the brain

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Neural Regeneration research 2024年第8期19卷 1671-1677页

作者： Yolanda Diz-Chaves Zainab Maastor Carlos Spuch José Antonio Lamas Lucas C.González-Matías Federico Mallo Biomedical research Centre(CINBIO) Laboratory of EndocrinologyUniversity of VigoGalicia Sur Health Research InstituteVigoSpain Translational Neuroscience research Group Galicia Sur Health Research InstituteCIBERSAMHospitalÁlvaro CunqueiroSala InvestigaciónEstrada Clara CampoamorVigoSpain Biomedical research Centre(CINBIO) Laboratory of NeuroscienceUniversity of VigoGalicia Sur Health Research InstituteVigoSpain

The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and ***-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues,including diffe rent brain ***-like peptide 1 activates several signaling pathways related to neuroprotection,like the support of cell growth/survival,enhancement promotion of synapse formation,autophagy,and inhibition of the secretion of proinflammatory cytokines,microglial activation,and apoptosis during neural *** glial cells,including astrocytes and microglia,maintain metabolic homeostasis and defe nse against pathogens in the central nervous *** brain insult,microglia are the first cells to respond,followed by reactive *** activated cells produce proinflammato ry mediators like cytokines or chemokines to react to the ***,under these circumstances,mic roglia can become chro nically inflammatory by losing their homeostatic molecular signature and,consequently,their functions during many *** processes promote the development of neurological disorders and influence their pathological evolution:like the formation of protein aggregates,the accumulation of abnormally modified cellular constituents,the formation and release by injured neurons or synapses of molecules that can dampen neural function,and,of critical impo rtance,the dysregulation of inflammato ry control *** glucagonlike peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies,restoring brain cell homeostasis under inflammatory conditions,modulating mic roglia activity,and decreasing the inflammato ry *** review summarizes recent advances linked to the anti-inflammato ry prope rties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis,Alzheimer’s disease,Parkins

关键词： astrocytes brain glucagon-like peptide 1 receptor inflammation microglia

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Immunomodulation of Proton-activated G Protein-coupled Receptors in Inflammation

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Current Medical Science 2024年第3期44卷 475-484页

作者： Min-shan LI Xiang-hong WANG Heng WANG Department of Otolaryngology-Head and Neck Surgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China institute of Allergy and Clinical Immunology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Hubei Clinical research Center for Nasal inflammatory Diseases Wuhan430030China

Proton-activated G protein-coupled receptors(GPCRs),initially discovered by Ludwig in 2003,are widely distributed in various *** receptors have been found to modulate the immune system in several inflammatory diseases,including inflammatory bowel disease,atopic dermatitis,and ***-activated GPCRs belong to the G protein-coupled receptor family and can detect alternations in extracellular *** detection triggers downstream signaling pathways within the cells,ultimately influencing the function of immune *** this review,we specifically focused on investigating the immune response of proton-activated GPCRs under inflammatory conditions.

关键词： proton-activated G protein-coupled receptors inflammation immunomodulation disease

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Insights on the use of biosimilars in the treatment of inflammatory bowel disease

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World Journal of Gastroenterology 2017年第11期23卷 1932-1943页

作者： Michael K Zheng David Q Shih Gary C Chen F.Widjaja Foundation Inflammatory Bowel and Immunobiology Research InstituteCedars-Sinai Medical Center Comprehensive Digestive institute of Nevada

Biologic therapy, such as those that target tumor necrosis factor(TNF) signaling, has proven to be an efficacious method of treatment for patients with inflammatory bowel disease(IBD) with regards to symptom management and mucosal healing. However, the rising prevalence of IBD worldwide and the everincreasing burden of biologic pharmaceuticals in the health care industry is alarming for insurance companies, clinicians, and patients. The impending patent expiry and the relatively high costs of biologics, particularly anti-TNF agents, have paved the way for biosimilar development for IBD. The United States Food and Drug Administration defines a biosimilar as a biological product that is highly similar to its reference medicinal product, with no clinically meaningful differences in terms of safety, purity, and potency. The hope with biosimilars is that their entry into the market will be able to drive competition between pharmaceutical companies to reduce prices like that of the generic market, and that access to appropriate biologic treatments for IBD patients is increased in the long-term. Yet, there are challenging issues such as indication extrapolation and interchangeability that are still being debated in the field of IBD and must be addressed in future issued guidance. This review will discuss the issues and implications concerning the use of biosimilar therapy for IBD.

关键词： Biosimilar Biologic inflammatory bowel disease Ulcerative colitis Crohn’s disease Indication extrapolation Interchangeability

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TPOL triggers apoptosis with mitochondrial injury through activating a ROS-dependent p53/p21/p27/Rb/Bax/Cyto C/caspase-mediated signaling

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中国病理生理杂志 2024年第8期40卷 1488-1496页

作者： CHENG Zongwei ZENG Boning XING Feiyue Department of immunobiology Institute of Tissue Transplantation and ImmunologyJinan UniversityGuangzhou 510632China

AIM:To explore the influence of ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate(TPOL)on cell apoptosis and its potential ***:HEK293T cells sensitive to TPOL were treated with different concentrations of TPOL with or without exposure to light radiation,before treatment with various inhibitors,N-acetyl-Lcysteine(NAC),pifithrin-αand *** viability was measured by CCK-8 *** V/propidium iodide staining was used to count the number of apoptotic ***-DA staining was used to detect reactive oxygen species(ROS)levels,and JC-1 staining was used to assess mitochondrial membrane potential by flow *** expression of apoptosis-related proteins and cell cycle-regulated molecules was measured by Western ***:TPOL enhanced the apoptosis of HEK293T cells in a dose-dependent manner(P<0.05),with a decrease in Bcl-2 and increases in Bax and cytochrome C(Cyto C),followed by up-regulation of activated caspase-9 and caspase-3,and the cleavage of PARP(P<0.05).The TPOL-enhanced cleavage of caspase-3 and PARP was rescued by Z-DVED-FMK(P<0.01).TPOL also led to a rapid increase in ROS,a reduction in mitochondrial membrane potential,and the release of Cyto C(P<0.01),all of which could be reversed by the ROS scavenger ***,the TPOL-caused alterations in p21,p27,Rb,and CDK2 were also recovered by the p53 inhibitor pifithrin-α(P<0.05).The TPOL-induced changes in Bax,Bcl-2,cleaved caspase-9,activated caspase-3,and cleaved PARP were subsequently rescued by pretreatment with pifithrin-α(P<0.05).CONCLUSION:TPOL can induce cellular apoptosis with ROS-mediated mitochondrial membrane damage through the activation of a ROS-dependent p53/p21/p27/Rb/Bax/Cyto C/caspase-mediated signal axis.

关键词： ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate reactive oxygen species mitochondria apoptosis

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Aging-induced memory loss due to decreased N1-acetyl-5-methoxykynuramine,a melatonin metabolite,in the hippocampus:a potential prophylactic agent for dementia

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Neural Regeneration research 2025年第6期20卷 1705-1706页

作者： Kazuki Watanabe Atsuhiko Hattori Department of immunobiology Institute of Development Aging and CancerTohoku UniversitySendaiMiyagiJapan Department of Sport and Wellness College of Sport and WellnessRikkyo UniversityNiizaSaitamaJapan

Melatonin(N-acetyl-5-methoxytryptamine)is known as the hormone of darkness because it is synthesized at night and involved in regulating the circadian *** hormone is primarily synthesized by the vertebrate pineal gland,but is ubiquitous among invertebrates,unicellular organisms,plants,and even cyanobacteria(Hattori and Suzuki,2024).Melatonin is well-conserved evolutionarily and possesses several physiological functions,such as immune response,bone and glucose metabolism,and memory formation besides regulating the circadian rhythm.

关键词： metabolism primarily agent

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Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1690-1704页

作者： Shu-Chang Nie Yan-Hua Jing Lu Lu Si-Si Ren Guang Ji Han-Chen Xu institute of Digestive Diseases Longhua HospitalChina-Canada Center of Research for Digestive DiseasesShanghai University of Traditional Chinese MedicineShanghai 200032China Shanghai Frontiers Science Center of Disease and Syndrome Biology of inflammatory Cancer Transformation Shanghai 200032China State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine(Shanghai University of Traditional Chinese Medicine) Shanghai 200032China

Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of *** create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer ***,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor *** this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC *** study provides ideas and methods to enhance survival rates in patients with CRC.

关键词： Myeloid-derived suppressor cells Tumor microenvironment Colorectal cancer Therapy Immunosuppression

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Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8^(+)T Cell Immunity against Tumor

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research 2024年第3期2023卷 433-444页

作者： Anze Yu Jinfei Fu Zheng Yin Hui Yan Xiang Xiao Dawei Zou Xiaolong Zhang Xiongbing Zu Xian C.Li Wenhao Chen immunobiology and Transplant Science Center Department of SurgeryHouston Methodist Research Institute and Institute for Academic MedicineHouston Methodist HospitalHoustonTXUSA Department of Urology First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdongChina Systems Medicine and Bioengineering Department Houston Methodist Neal Cancer CenterHoustonTXUSA Department of Radiology Houston Methodist HospitalWeill Cornell MedicineHoustonTXUSA Department of Urology Xiangya HospitalCentral South UniversityChangshaHunanChina Department of Surgery Weill Cornell MedicineCornell UniversityNew YorkNYUSA.

T-cell-based immunotherapy is gaining momentum in cancer treatment;however,our comprehension of the transcriptional regulation governing T cell antitumor activity remains *** objective of this study was to explore the function of interferon regulatory factor 4(IRF4)in antitumor CD8^(+)T cells using the TRAMP-C1 prostate cancer and B16F10 melanoma *** achieve this,we generated an Irf4^(GFP-DTR) mouse strain and discovered that CD8^(+)tumor-infiltrating lymphocytes(TILs)expressing high levels of *** exhibited a more differentiated PD-1high cell *** administering diphtheria toxin to tumor-bearing Irf4^(GFP-DTR) mice,we partially depleted ***^(+)TILs and observed an accelerated tumor *** specifically explore the function of IRF4 in antitumor CD8^(+)T cells,we conducted 3 adoptive cell therapy(ACT)***,depleting ***^(+)CD8^(+)TILs derived from ACT significantly accelerated tumor growth,emphasizing their crucial role in controlling tumor ***,deleting the Irf4 gene in antitumor CD8^(+)T cells used for ACT led to a reduction in the frequency and effector differentiation of CD8^(+)TILs,completely abolishing the antitumor effects of ***,we performed a temporal deletion of the Irf4 gene in antitumor CD8^(+)T cells during ACT,starting from 20 days after tumor implantation,which significantly compromised tumor ***,sustained expression of IRF4 is essential for maintaining CD8^(+)T cell immunity in the melanoma model,and these findings carry noteworthy implications for the advancement of more potent immunotherapies for solid tumors.

关键词： sustained immunity implantation

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