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1.
Expert Opin Drug Metab Toxicol ; 16(1): 11-30, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31903790

RESUMO

Introduction: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.


Assuntos
Desenvolvimento de Medicamentos , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Humanos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Receptores CCR4/antagonistas & inibidores , Receptores CCR4/metabolismo , Receptores CCR5/efeitos dos fármacos , Receptores CCR5/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Receptores de Quimiocinas/metabolismo
3.
Future Oncol ; 15(12): 1385-1395, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30880459

RESUMO

Despite the progress made in molecular and clinical research, patients with diffuse large B-cell lymphoma (DLBCL) still have a bad prognosis. Recently, chemokines/chemokine receptors have become the subject of interest in relation to DLBCL. Studies have demonstrated the important role of chemokines/chemokine receptors in the communication between DLBCL cells and tumor microenvironment. Studies have also reported the ability of chemokines/chemokine receptors in promoting the proliferation and invasion of DLBCL cells. Here, we summarize the data on mechanisms of DLBCL supporting the involvement of chemokine/chemokine receptor changes. We focus on the available evidence regarding chemokines/chemokine receptors as biomarkers and therapeutic targets for DLBCL.


Assuntos
Biomarcadores Tumorais/metabolismo , Quimiocinas/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Receptores de Quimiocinas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biópsia , Quimiocinas/antagonistas & inibidores , Progressão da Doença , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica/patologia , Prognóstico , Intervalo Livre de Progressão , Receptores de Quimiocinas/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos
4.
Arterioscler Thromb Vasc Biol ; 39(4): 583-592, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760014

RESUMO

With the incidence and impact of atherosclerotic cardiovascular disease and its clinical manifestations still rising, therapeutic options that target the causal mechanisms of this disorder are highly desired. Since the CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) has demonstrated that lowering inflammation can be beneficial, focusing on mechanisms underlying inflammation, for example, leukocyte recruitment, is feasible. Being key orchestrators of leukocyte trafficking, chemokines have not lost their attractiveness as therapeutic targets, despite the difficult road to drug approval thus far. Still, innovative therapeutic approaches are being developed, paving the road towards the first chemokine-based therapeutic against inflammation. In this overview, recent developments for chemokines and for the chemokine-like factor MIF (macrophage migration inhibitory factor) will be discussed.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Quimiocinas/antagonistas & inibidores , Terapia de Alvo Molecular , Anticorpos Monoclonais Humanizados/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Quimiocinas/fisiologia , Quimiotaxia de Leucócito , Ensaios Clínicos como Assunto , Previsões , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/fisiologia , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Fatores Inibidores da Migração de Macrófagos/fisiologia , Estudos Multicêntricos como Assunto , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/fisiologia , Terapias em Estudo/métodos , Pesquisa Médica Translacional
5.
Hypertension ; 73(2): 440-448, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30595125

RESUMO

Studies from our laboratory have revealed an important role for the maternal diet and the dietary protein source in the development of hypertension and renal injury in Dahl salt-sensitive (SS) rats. The current study sought to compare salt-induced hypertension, renal damage, and immune cell infiltration in the offspring of breeders fed either a casein- or gluten-based diet, with the hypothesis that offspring from gluten-fed breeders would fail to develop these SS phenotypes. When fed identical diets post-weaning, the F1 generation gluten offspring demonstrated lower mean arterial pressure (149.1±3.1 versus 162.5±5.8 mm Hg), albuminuria (166.2±34.6 versus 250.9±27.8 mg/day), and outer medullary protein casting (7.4±0.8% versus 13.1±1.3%) in response to high salt compared with the casein offspring (n=9-11). The gluten offspring also had fewer CD45+ leukocytes, CD11b/c+ monocytes/macrophages, CD3+ T cells, and CD45R+ B cells infiltrating the kidney. Analysis of the F2 generation gluten offspring also exhibited lower mean arterial pressure and renal damage compared with rats born from casein breeders (n=7-9), with no difference in renal immune cell infiltration. CMKLR1-receptor for the novel prohypertensive adipokine chemerin-was found via polymerase chain reaction array to be significantly upregulated (2.99-fold) in renal T cells isolated from F2 offspring of casein-fed versus gluten-fed parents. Furthermore, CMKLR1 inhibition via α-NETA (2-[α-naphthoyl] ethyltrimethylammonium iodide) treatment significantly attenuated renal immune cell infiltration, hypertension, and renal damage in SS rats fed high salt. Together, these data demonstrate the influence of the parental diet in determining the salt-induced hypertension, renal damage, and inflammatory phenotype of the offspring.


Assuntos
Proteínas na Dieta/administração & dosagem , Hipertensão/etiologia , Fenômenos Fisiológicos da Nutrição Materna , Receptores de Quimiocinas/fisiologia , Animais , Caseínas/administração & dosagem , Feminino , Glutens/administração & dosagem , Rim/imunologia , Rim/patologia , Masculino , Ratos , Ratos Endogâmicos Dahl , Receptores de Quimiocinas/antagonistas & inibidores , Índice de Gravidade de Doença
6.
Curr Pharm Biotechnol ; 19(9): 715-727, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30332947

RESUMO

BACKGROUND: Vascular remodeling is an alteration in the structure of vessels in response to injury or hemodynamic changes. Disturbance of the structural and functional integrity of the endothelial cell layer can be observed in vascular remodeling associated with inflammation. Chemokines have been implicated in a wide range of diseases with prominent inflammatory components, and also in vascular remodeling. Among them, CC-chemokines are of great interest. They act through conventional CC-chemokine receptors (CCRs), widely expressed by leucocytes which are attracted to sites of chronic inflammation. However, many experimental data show that CCRs are expressed by vascular cells, suggesting a direct, leukocyte-independent effect on vascular remodeling. OBJECTIVE: Here, we discuss the role of CC-chemokines in atherosclerosis, angiogenesis, restenosis and renal dysfunction through direct activation of endothelial cells, endothelial progenitors, vascular smooth muscle cells, platelets, erythrocytes, mesangial cells and fibroblasts. RESULTS: The pathophysiological role of CC-chemokines has become more interesting since the discovery of the atypical chemokine receptor (ACKR) subfamily, that does not couple with G proteins and fails to transmit conventional intracellular signals. It has been demonstrated to be a chemokine scavenger or decoy receptor with a role in the regulation of acute inflammatory responses. CONCLUSION: At the vascular level, ACKRs are expressed by endothelial cells and endothelial lymphatic cells that seem to regulate angio- and lymph-angiogenesis. Pleiotropic effects of CC-chemokines on vascular wall cells and leukocytes increase their importance in vascular remodeling and suggest new drugs to counteract vascular dysfunction.


Assuntos
Quimiocinas CC/imunologia , Receptores de Quimiocinas/imunologia , Doenças Vasculares/imunologia , Remodelação Vascular/imunologia , Animais , Quimiocinas CC/antagonistas & inibidores , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Humanos , Inflamação , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/imunologia , Receptores de Quimiocinas/antagonistas & inibidores , Doenças Vasculares/tratamento farmacológico , Remodelação Vascular/efeitos dos fármacos
7.
J Pharmacol Exp Ther ; 367(3): 433-441, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30249618

RESUMO

Crossdesensitization between opioid and chemokine receptors and involvement of chemokines in pain modulation are well established. We investigated if coadministration of chemokine receptor antagonists (CRAs) with morphine would enhance the analgesic potency of morphine on incisional pain in rats. Animals underwent incisional surgery on the left hind paw and pain responses were evaluated using von Frey filaments at various time points postsurgery between 15 and 360 minutes and daily between 24 and 72 hours. Dose-response curves for morphine, maraviroc (a CCR5 antagonist), and AMD3100 (a CXCR4 antagonist) alone were established. While morphine significantly reduced pain in a time- and dose-dependent manner, maraviroc and AMD3100 had no effect by themselves. Coadministration of either maraviroc or AMD3100 with morphine significantly increased morphine's analgesic effect on incisional pain, shifting the dose-response curve to the left 2.3- and 1.8-fold, respectively. Coadministration of both CRAs with morphine significantly shifted further the morphine dose-response curve to the left 3.3-fold. The effect of treatments on mRNA levels in the draining popliteal lymph node for a panel of chemokines and cytokines showed that message for many of these mediators was upregulated by the incision, and the combination of morphine with the CRAs markedly downregulated them. The data show that combining morphine with CRAs potentiates morphine's analgesic effect on incisional pain. Thus, the same analgesic effect of morphine alone can be achieved with lower doses of morphine when combined with CRAs. Using morphine in lower doses could reduce unwanted side effects and possibly block development of tolerance and dependence.


Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Dor/tratamento farmacológico , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Regulação para Baixo/efeitos dos fármacos , Tolerância a Medicamentos/fisiologia , Masculino , Dor/metabolismo , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Receptores CXCR4/metabolismo
8.
J Crohns Colitis ; 12(suppl_2): S641-S652, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30137309

RESUMO

The principal targets for anti-chemokine therapy in inflammatory bowel disease (IBD) have been the receptors CCR9 and CXCR3 and their respective ligands CCL25 and CXCL10. More recently CCR6 and its ligand CCL20 have also received attention, the expression of the latter in enterocytes being manipulated through Smad7 signalling. These pathways, selected based on their fundamental role in regulating mucosal immunity, have led to the development of several therapeutic candidates that have been tested in early phase clinical trials with variable clinical efficacy. In this article, we appraise the status of chemokine-directed therapy in IBD, review recent developments, and nominate future areas for therapeutic focus.


Assuntos
Quimiocinas , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Receptores de Quimiocinas , Animais , Anticorpos Monoclonais/uso terapêutico , Quimiocina CCL20/imunologia , Quimiocina CCL20/metabolismo , Quimiocina CXCL10/antagonistas & inibidores , Quimiocina CXCL10/imunologia , Quimiocinas/antagonistas & inibidores , Quimiocinas/imunologia , Quimiocinas/metabolismo , Quimiocinas CC/imunologia , Humanos , Terapia de Alvo Molecular , Oligonucleotídeos/uso terapêutico , Receptores CCR/antagonistas & inibidores , Receptores CCR/imunologia , Receptores CCR6/imunologia , Receptores CXCR3/imunologia , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/imunologia , Proteína Smad7/antagonistas & inibidores , Sulfonamidas/uso terapêutico
9.
Toxicol Sci ; 166(1): 123-130, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30060248

RESUMO

CKA, a chemokine receptor antagonist intended for treating inflammatory conditions, produced dose-dependent hepatotoxicity in rats but advanced into the clinic where single doses of CKA up to 600 mg appeared safe in humans. Because existing toxicological platforms used during drug development are not perfectly predictive, a quantitative systems toxicology model investigated the hepatotoxic potential of CKA in humans and rats through in vitro assessments of CKA on mitochondrial respiration, oxidative stress, and bile acid transporters. DILIsym predicted that single doses of CKA caused serum ALT >3xULN in a subset of the simulated rat population, while single doses in a simulated human population did not produce serum ALT elevations. Species differences were largely attributed to differences in liver exposure, but increased sensitivity to inhibition of mitochondrial respiration in the rat also contributed. We conclude that mechanistic modeling can elucidate species differences in the hepatotoxic potential of drug candidates.


Assuntos
Ácidos Carboxílicos/toxicidade , Proteínas de Transporte/antagonistas & inibidores , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Indóis/toxicidade , Glicoproteínas de Membrana/antagonistas & inibidores , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Receptores de Quimiocinas/antagonistas & inibidores , Adulto , Animais , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Células Hep G2 , Humanos , Indóis/administração & dosagem , Indóis/farmacocinética , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Ratos Wistar , Especificidade da Espécie , Distribuição Tecidual
10.
Artigo em Inglês | MEDLINE | ID: mdl-29868513

RESUMO

Coxsackievirus B3 (CVB3) is the primary cause of viral myocarditis. An early and abundant neutrophil accumulation in the myocardium is a hallmark of early CVB3 infection. Yet the relative contribution of neutrophils to host susceptibility to CVB3 myocarditis remains largely unknown. Herein, peripheral neutrophil depletion was implemented in a BALB/c mouse model of acute CVB3 myocarditis using the specific 1A-8 (anti-Ly6G) or a RB6-8C5 (anti-Gr-1) mAb covering a wide range. Anti-Ly6G treatment led to systemic neutropenia throughout the disease, but did not alter virus replication, disease susceptibility and histopathological changes in the heart and pancreas of mice. In contrast, depletion of both neutrophils and monocytes/macrophages by anti-Gr-1 mAb prior to and after infection significantly promoted susceptibility of mice to CVB3 infection which was associated with exacerbated cardiac and pancreatic viral load. However, depletion of Gr1+ cells significantly suppressed acute myocarditis and pancreatic acini destruction at day 7 post infection via reducing Ly6Chigh monocyte population in the circulation. Additionally, cardiac interstitial fibrosis was not affected by neutrophil depletion, whereas Gr-1+ cells other than neutrophils increased cardiac fibrosis at day 21 p.i. by increasing cardiac expression of profibrotic cytokine TNF-α and TGF-ß. Thus, Neutrophil function is most likely not essential for CVB3 control and peripheral neutrophils play dispensable role in the pathogenesis of acute myocarditis and pancreatitis during CVB3 infection. Whereas Gr-1+ cells other than neutrophils play a major role in limiting viral replication while promoting myocardial and pancreatic inflammatory injury and fibrosis.


Assuntos
Antígenos Ly/imunologia , Infecções por Coxsackievirus/imunologia , Fibrose/induzido quimicamente , Miocardite/induzido quimicamente , Neutrófilos/imunologia , Receptores de Quimiocinas/imunologia , Replicação Viral/efeitos dos fármacos , Animais , Antígenos Ly/farmacologia , Infecções por Coxsackievirus/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose/patologia , Coração/virologia , Inflamação , Leucócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miocardite/patologia , Neutropenia , Pâncreas/patologia , Pâncreas/virologia , Receptores de Quimiocinas/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral
11.
Cytokine ; 110: 70-77, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29704821

RESUMO

Japanese encephalitis (JE) is a viral encephalitis disease caused by infection with the Japanese encephalitis virus (JEV). The virus can cross the blood-brain barrier and cause death or long-term sequela in infected humans or animals. In this study, we first investigated the distribution of JEV infection in brain and further analyzed the dynamic change in inflammation related genes, chemokines, as well as pathological characteristics. Results demonstrated that CCR2 and CCR5 antagonist could significantly inhibit the inflammation. The mice treated with CCR2 and CCR5 antagonists had a higher survival rate between 60% and 70%, respectively. In summary, our study thoroughly illustrated the characteristics of the dynamic change in inflammation related genes and chemokines induced by JEV infection. We further indicated that CCR5 and CCR2 are potential targets for treatment of JE.


Assuntos
Antagonistas dos Receptores CCR5/farmacologia , Quimiocinas/metabolismo , Encefalite Japonesa/tratamento farmacológico , Encefalite Japonesa/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Vírus da Encefalite Japonesa (Espécie)/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR2/antagonistas & inibidores , Receptores CCR5 , Células Vero
12.
J Biol Chem ; 293(8): 3003-3012, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-29279330

RESUMO

Chemokines are the principal regulators of leukocyte migration and are essential for initiation and maintenance of inflammation. Atypical chemokine receptor 2 (ACKR2) binds and scavenges proinflammatory CC-chemokines, regulates cutaneous T-cell positioning, and limits the spread of inflammation in vivo Altered ACKR2 function has been implicated in several inflammatory disorders, including psoriasis, a common and debilitating T-cell-driven disorder characterized by thick erythematous skin plaques. ACKR2 expression is abnormal in psoriatic skin, with decreased expression correlating with recruitment of T-cells into the epidermis and increased inflammation. However, the molecular mechanisms that govern ACKR2 expression are not known. Here, we identified specific psoriasis-associated microRNAs (miRs) that bind ACKR2, inhibit its expression, and are active in primary cultures of human cutaneous cells. Using both in silico and in vitro approaches, we show that miR-146b and miR-10b directly bind the ACKR2 3'-UTR and reduce expression of ACKR2 transcripts and protein in keratinocytes and lymphatic endothelial cells, respectively. Moreover, we demonstrate that ACKR2 expression is further down-regulated upon cell trauma, an important trigger for the development of new plaques in many psoriasis patients (the Koebner phenomenon). We found that tensile cell stress leads to rapid ACKR2 down-regulation and concurrent miR-146b up-regulation. Together, we provide, for the first time, evidence for epigenetic regulation of an atypical chemokine receptor. We propose a mechanism by which cell trauma and miRs coordinately exacerbate inflammation via down-regulation of ACKR2 expression and provide a putative mechanistic explanation for the Koebner phenomenon in psoriasis.


Assuntos
Regulação para Baixo , Regulação da Expressão Gênica , Queratinócitos/metabolismo , MicroRNAs/metabolismo , Interferência de RNA , Receptores de Quimiocinas/antagonistas & inibidores , Regiões 3' não Traduzidas , Células Cultivadas , Biologia Computacional , Células Endoteliais/citologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Epigênese Genética , Sistemas Especialistas , Genes Reporter , Células HEK293 , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Queratinócitos/citologia , Queratinócitos/imunologia , Queratinócitos/patologia , Especificidade de Órgãos , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Proteínas Recombinantes/metabolismo , Pele/imunologia , Pele/lesões , Pele/metabolismo , Pele/patologia , Resistência à Tração
13.
Pharmacol Rev ; 70(1): 174-196, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29279348

RESUMO

Chemerin, a chemoattractant protein and adipokine, has been identified as the endogenous ligand for a G protein-coupled receptor encoded by the gene CMKLR1 (also known as ChemR23), and as a consequence the receptor protein was renamed the chemerin receptor in 2013. Since then, chemerin has been identified as the endogenous ligand for a second G protein-coupled receptor, encoded by the gene GPR1 Therefore, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification recommends that the official name of the receptor protein for chemokine-like receptor 1 (CMKLR1) is chemerin receptor 1, and G protein-coupled receptor 1 is chemerin receptor 2 to follow the convention of naming the receptor protein after the endogenous ligand. Chemerin receptor 1 and chemerin receptor 2 can be abbreviated to Chemerin1 and Chemerin2, respectively. Chemerin requires C-terminal processing for activity, and human chemerin21-157 is reported to be the most active form, with peptide fragments derived from the C terminus biologically active at both receptors. Small-molecule antagonist, CCX832, selectively blocks CMKLR1, and resolvin E1 activation of CMKLR1 is discussed. Activation of both receptors by chemerin is via coupling to Gi/o, causing inhibition of adenylyl cyclase and increased Ca2+ flux. Receptors and ligand are widely expressed in humans, rats, and mice, and both receptors share ∼80% identity across these species. CMKLR1 knockout mice highlight the role of this receptor in inflammation and obesity, and similarly, GPR1 knockout mice exhibit glucose intolerance. In addition, the chemerin receptors have been implicated in cardiovascular disease, cancer, steroidogenesis, human immunodeficiency virus replication, and neurogenerative disease.


Assuntos
Receptores de Quimiocinas/agonistas , Receptores de Quimiocinas/antagonistas & inibidores , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Humanos , Receptores de Quimiocinas/química , Receptores de Quimiocinas/metabolismo , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/metabolismo , Terminologia como Assunto
14.
Br J Dermatol ; 178(2): 492-501, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28845522

RESUMO

BACKGROUND: Adipose tissue is now appreciated as the pivotal regulator of metabolic and endocrine functions. Subcutaneous (SC) fat, in contrast to visceral fat, may protect against metabolic syndrome and systemic inflammation. We demonstrated that chronic as well as acute ultraviolet (UV) irradiation to the skin induces loss of underlying SC fat. UV-irradiated SC fat may produce chemokines or cytokines that modulate lipid homeostasis and secretion of adipokines. OBJECTIVES: To elucidate UV-induced specific adipochemokines implicated in UV-induced modulation of SC fat. METHODS: Primary cultured adipocytes were treated with conditioned medium from UV- or sham-irradiated skin cells. Young and older healthy participants provided SC fat from sun-exposed and sun-protected skin. Sun-protected skin from other participants was irradiated with UV. Differentially expressed adipochemokines were screened by cytokine array, and confirmed in vitro and in vivo. The functions of select adipochemokines involved in lipid metabolism were examined via short interfering RNA-mediated knockdown of cognate receptors. RESULTS: Specific adipochemokines, including C-X-C motif chemokine (CXCL) family members such as CXCL5/ENA-78, and C-C motif chemokine (CCL) family members such as CCL20/MIP-3α and CCL5/RANTES, were greatly induced in SC fat by UV exposure. They could impair triglyceride synthesis via downregulation of lipogenic enzymes and sterol regulatory element-binding protein-1 through their respective cognate receptors, CXC chemokine receptor type (CXC-R)2, C-C chemokine receptor type (CCR)-6, and CCR-5. In addition, UV irradiation induced infiltration of adipose tissue macrophages responsible for the secretion of several chemokines into SC fat. CONCLUSIONS: These UV-induced adipochemokines may be implicated in the reduction of lipogenesis in SC fat, leading to impairment of fat homeostasis and associated comorbidities such as obesity.


Assuntos
Adipócitos/metabolismo , Adipocinas/efeitos da radiação , Quimiocinas/efeitos da radiação , Gordura Subcutânea/metabolismo , Raios Ultravioleta , Adipocinas/biossíntese , Adulto , Idoso , Quimiocina CCL20/efeitos da radiação , Quimiocina CCL5/efeitos da radiação , Quimiocina CXCL5/efeitos da radiação , Quimiocinas/biossíntese , Feminino , Técnicas de Silenciamento de Genes , Humanos , Lipogênese/efeitos da radiação , Macrófagos/efeitos da radiação , Masculino , Interferência de RNA/efeitos da radiação , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/efeitos da radiação , Triglicerídeos/biossíntese , Regulação para Cima/efeitos da radiação
15.
MAbs ; 10(1): 104-117, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28952876

RESUMO

C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a-C5aR1 receptor are well defined, whereas C5a-C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that neutralizes C5a and C5adesArg binding to the C5aR1 and C5aR2 receptors, without affecting complement-mediated bacterial cell killing. Unlike other anti-C5a mAbs described, this antibody has been shown to inhibit the effects of C5a by blocking C5a binding to both C5aR1 and C5aR2 receptors. The crystal structure of the antibody in complex with human C5a reveals a discontinuous epitope of 22 amino acids. This is the first time the epitope for an antibody that blocks C5aR1 and C5aR2 receptors has been described, and this work provides a basis for molecular studies aimed at further understanding the C5a-C5aR2 receptor interaction. MEDI7814 has therapeutic potential for the treatment of acute inflammatory conditions in which both C5a receptors may mediate inflammation, such as sepsis or renal ischemia-reperfusion injury.


Assuntos
Anticorpos Monoclonais/farmacologia , Afinidade de Anticorpos , Complemento C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptores de Quimiocinas/antagonistas & inibidores , Anticorpos Monoclonais/química , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Sítios de Ligação de Anticorpos , Complemento C5a/química , Complemento C5a/imunologia , Complemento C5a/metabolismo , Mapeamento de Epitopos/métodos , Epitopos , Células HEK293 , Humanos , Ligação Proteica , Conformação Proteica , Engenharia de Proteínas , Receptor da Anafilatoxina C5a/química , Receptor da Anafilatoxina C5a/imunologia , Receptor da Anafilatoxina C5a/metabolismo , Receptores de Quimiocinas/química , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Relação Estrutura-Atividade
16.
Biochem Biophys Res Commun ; 493(4): 1510-1517, 2017 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-28986258

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with an estimated 5 year survival rate of approximately 5% of all stages combined. High potential of PDAC metastasis is a leading cause for high mortality and poor prognosis. The majority of patients present with distant metastasis at diagnosis. Fractalkine (FKN) is recognized as a chemokine and a specific ligand of CX3CR1. It has been reported that FKN/CX3CR1 system was upregulated in many types of solid tumors. However, role of FKN/CX3CR1 in PDAC development remains unclear. In the current investigation, we found that FKN and CX3CR1 expression was significantly increased in PDAC tissues, especially in the metastatic samples, and was highly-correlated with severity of PDAC. Ectopic expression of FKN promoted the proliferation and migration of PDAC, while knockdown of CX3CR1 reversed the function of FKN. In addition, PDAC cells with FKN-deficiency showed impaired proliferation and migration activity. The underlying mechanism is that FKN/CX3CR1 activated JAK/STAT signaling, which in turn regulated cell growth. Consistently, in vivo tumorigenesis assay validated the regulatory role of FKN/CX3CR1 in PDAC growth. Our investigation helped understanding the pathogenesis of PDAC occurrence, and demonstrated critical role of FKN/CX3CR1 in PDAC development.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Quimiocina CX3CL1/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de Quimiocinas/metabolismo , Animais , Receptor 1 de Quimiocina CX3C , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/secundário , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CX3CL1/antagonistas & inibidores , Quimiocina CX3CL1/genética , Técnicas de Silenciamento de Genes , Humanos , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/genética , Interferência de RNA , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
17.
Biol Res ; 50(1): 26, 2017 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-28870240

RESUMO

BACKGROUND: CCL2 was up-regulated in neurons and involved in microglia activation and neurological decline in mice suffering from hepatic encephalopathy (HE). However, no data exist concerning the effect of neuron-derived CCL2 on microglia activation in vitro. METHODS: The rats were pretreated with CCL2 receptor inhibitors (INCB or C021, 1 mg/kg/day i.p.) for 3 days prior to thioacetamide (TAA) administration (300 mg/kg/day i.p.) for inducing HE model. At 8 h following the last injection (and every 4 h after), the grade of encephalopathy was assessed. Blood and whole brains were collected at coma for measuring CCL2 and Iba1 expression. In vitro, primary neurons were stimulated with TNF-α, and then the medium were collected for addition to microglia cultures with or without INCB or C021 pretreatment. The effect of the medium on microglia proliferation and activation was evaluated after 24 h. RESULTS: CCL2 expression and microglia activation were elevated in the cerebral cortex of rats received TAA alone. CCL2 receptors inhibition improved neurological score and reduced cortical microglia activation. In vitro, TNF-α treatment induced CCL2 release by neurons. Medium from TNF-α stimulated neurons caused microglia proliferation and M1 markers expression, including iNOS, COX2, IL-6 and IL-1ß, which could be suppressed by INCB or C021 pretreatment. The medium could also facilitate p65 nuclear translocation and IκBα phosphorylation, and NF-κB inhibition reduced the increased IL-6 and IL-1ß expression induced by the medium. CONCLUSION: Neuron-derived CCL2 contributed to microglia activation and neurological decline in HE. Blocking CCL2 or inhibiting microglia excessive activation may be potential strategies for HE.


Assuntos
Quimiocina CCL2/metabolismo , Encefalopatia Hepática/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Quimiocina CCL2/antagonistas & inibidores , Meios de Cultura/farmacologia , Modelos Animais de Doenças , Expressão Gênica , Encefalopatia Hepática/induzido quimicamente , Encefalopatia Hepática/terapia , Interleucina-6/metabolismo , Microglia/efeitos dos fármacos , Doenças do Sistema Nervoso , Ratos , Tioacetamida
18.
DNA Cell Biol ; 36(9): 801-811, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28777668

RESUMO

Therapeutic control of tumors is challenging as they tend to alter their biological functions and microenvironment. In a CT26/HER2 tumor model, HER2 DNA vaccines and even anti-PD-L1 Abs failed to display antitumor therapeutic activity while inducing Ag-specific cytotoxic T lymphocyte (CTL) activity. To clarify this contradictory finding, we selected tumor cells (CT26/HER2-1) from one tumor-bearing animal in the therapeutic model. CT26/HER2-1 cells behaved similar to wild-type CT26/HER2 cells in their HER2 expression, immune cell stimulation for IFN-γ production, and antitumor immune sensitivity. A similar finding was obtained with additional CT26/HER2-2, -3, -4, -5, and -6 cells from the therapeutic model, suggesting that a lack of antitumor therapeutic activity of HER2 DNA vaccines might be ascribed to a factor in the tumor microenvironment, but not to an alteration in tumor cell functions. When tumor-bearing mice were depleted of myeloid-derived suppressor cells (MDSCs) by anti-Gr-1 Ab treatment, they displayed HER2 vaccine-mediated antitumor activity, suggesting a role of MDSCs in blocking antitumor activity. Moreover, when tumor-bearing mice were treated with gemcitabine, they displayed HER2 vaccine-mediated antitumor activity, suggesting that cytotoxic drug treatment makes tumor cells susceptible to lysis by CTLs. Thus, these studies show that therapeutic control of HER2 DNA vaccines can be achieved by anti-Gr-1 Ab treatment through MDSC depletion and by gemcitabine treatment through sensitization of tumor cells to CTL-mediated killing in this model. These findings may have implications for achieving therapeutic control of CTL-resistant tumors in cancer therapy.


Assuntos
Vacinas Anticâncer/farmacologia , Desoxicitidina/análogos & derivados , Receptor ErbB-2/genética , Microambiente Tumoral/efeitos dos fármacos , Vacinas de DNA/farmacologia , Animais , Anticorpos/farmacologia , Antígeno B7-H1/metabolismo , Desoxicitidina/farmacologia , Feminino , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Receptores de Quimiocinas/antagonistas & inibidores , Linfócitos T Citotóxicos/efeitos dos fármacos
19.
Curr Pharm Des ; 23(25): 3689-3698, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28625137

RESUMO

BACKGROUND: Chemerin is an adipokine that induces insulin resistance by the mechanism of inflammation in adipose tissue but these are still unclear. A high level of chemerin in humans is considered as a marker of inflammation in insulin resistance and obesity as well as in type 2 diabetes mellitus. Despite the role of chemerin in insulin resistance progression, chemerin as one of the novel adipokines is proposed to be involved in high cancer risk and mortality. AIM: The aim of this paper was to review the role of CMKLR-1 receptor and the potential therapeutic target in the management of chemerin induced type 2 diabetes mellitus and cancer. PATHOPHYSIOLOGY: Increased chemerin secretion activates an inflammatory response. The inflammatory response will increase the oxidative stress in adipose tissue and consequently results in an insulin-resistant state. The occurrence of inflammation, oxidative stress and insulin resistance leads to the progression of cancers. CONCLUSION: Chemerin is one of the markers that may involve in development of both cancer and insulin resistance. Chemokine like receptor- 1 (CMKLR-1) receptor that regulates chemerin levels exhibits a potential therapeutic target for insulin resistance, type 2 diabetes and cancer treatment.


Assuntos
Antineoplásicos/administração & dosagem , Diabetes Mellitus Tipo 2/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Hipoglicemiantes/administração & dosagem , Neoplasias/metabolismo , Receptores de Quimiocinas/metabolismo , Animais , Antineoplásicos/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/tratamento farmacológico , Gerenciamento Clínico , Sistemas de Liberação de Medicamentos/métodos , Humanos , Hipoglicemiantes/metabolismo , Resistência à Insulina/fisiologia , Neoplasias/tratamento farmacológico , Receptores de Quimiocinas/antagonistas & inibidores
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