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1.
Life Sci ; 240: 117071, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31783051

RESUMO

AIMS: AML (Acute myeloid leukemia) is characterized as a heterogeneous cancer. Chemokines play fundamental roles in the onset, progression cellular, migration, survival and improvement of AML therapy outcomes. The CCR5 receptors together with their ligands have indirect effects on the progression of cancer. In the present study, we have decided to investigate the impact of chemotherapy on the expression of CCR5 and its related ligands (CCL5, CCL4 and CCL3). MAIN METHODS: In this study, peripheral blood and bone marrow specimens were collected prior and post the first stage of (7 + 3) chemotherapy from 25 AML-M4/M5 patients. The expression of CCR by Lymphocytes in peripheral blood was examined by flow cytometry and QRT-PCR. The serum levels of chemokines were measured by ELISA. KEY FINDINGS: There was not observed leukemic blast cells in peripheral blood smear at post first stage of chemotherapy. We found that the expression of CCR5 was attenuated in patients post the first stage of chemotherapy and the healthy control subjects. We have also observed that the serum levels of chemokines were elevated in AML patients prior to chemotherapy. Although in post-chemotherapy stage, only CCL3 was found to reach to the baseline level, CCL5 and CCL4 have not returned to the basal level and were significantly higher than healthy control subjects. SIGNIFICANCE: The current chemotherapy protocol was not able to completely inhibit CCL5 and CCL4. In conclusion, our findings in harmony with previous studies suggest that inhibition of chemokines along with chemotherapy in AML patients may aid therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiocina CCL3/efeitos dos fármacos , Quimiocina CCL4/efeitos dos fármacos , Quimiocina CCL5/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Monócitos/patologia , Receptores CCR5/efeitos dos fármacos , Adulto , Medula Óssea/metabolismo , Medula Óssea/patologia , Linhagem da Célula , Quimiocina CCL3/biossíntese , Quimiocina CCL4/biossíntese , Quimiocina CCL5/biossíntese , Quimiocinas/sangue , Progressão da Doença , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Contagem de Leucócitos , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Receptores CCR5/biossíntese
2.
Arthritis Rheumatol ; 71(5): 703-711, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30474934

RESUMO

OBJECTIVE: Ibudilast is a well-tolerated, orally available phosphodiesterase 4 (PDE4) inhibitor used to treat asthma and stroke. Since PDE4 inhibition suppresses inflammatory mediator production and cell proliferation in leukocytes, ibudilast may be a valuable therapy for the treatment of inflammatory autoimmune diseases such as rheumatoid arthritis (RA). This study was undertaken to assess the therapeutic potential of ibudilast by measuring its capacity to modulate inflammation in human leukocytes and RA synovial fibroblasts (RASFs) and in experimental arthritis. METHODS: Using standard curve quantitative polymerase chain reaction, the effect of ibudilast on gene expression in activated human leukocytes and RASFs was measured. Ibudilast was used to treat DBA/1 mice with collagen-induced arthritis, and an adoptive transfer model was used to assess its tolerogenic capacity. RESULTS: Ibudilast inhibited the expression of TNF, IL12A, and IL12B and the secretion of tumor necrosis factor (TNF) and interleukin-12 (IL-12)/23p40 from leukocytes, and reduced the expression of CCL5 and CCL3 in activated RASFs. Treatment of experimental arthritis with ibudilast resulted in a reduction in IL-17-producing cells and inhibition of disease progression. When combined with a TNF inhibitor, ibudilast caused marked suppression of active disease. Exposure of leukocytes from type II collagen-immunized DBA/1 mice to ibudilast in vitro attenuated their ability to adoptively transfer arthritis to DBA/1J-PrkdcSCID mice, providing evidence of an immunomodulatory effect. CONCLUSION: Our findings indicate that ibudilast reduces the expression and/or secretion of inflammatory mediators from activated human leukocytes and RASFs, inhibits Th17 cell responses in vivo, and improves established arthritis. Given the established safety profile of ibudilast in humans, its clinical evaluation in RA, either alone or in combination with a TNF inhibitor, should be considered.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Citocinas/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Piridinas/farmacologia , Transferência Adotiva , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CCL5/imunologia , Quimiocina CCL5/metabolismo , Quimiocinas/efeitos dos fármacos , Quimiocinas/imunologia , Quimiocinas/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Fibroblastos/imunologia , Fibroblastos/metabolismo , Humanos , Subunidade p35 da Interleucina-12/efeitos dos fármacos , Subunidade p35 da Interleucina-12/imunologia , Subunidade p35 da Interleucina-12/metabolismo , Subunidade p40 da Interleucina-12/efeitos dos fármacos , Subunidade p40 da Interleucina-12/imunologia , Subunidade p40 da Interleucina-12/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Membrana Sinovial/citologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
3.
Eur J Pharmacol ; 845: 91-98, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30287151

RESUMO

Vitamin D has been suggested to harbor multiple biological activities, among them the potential of vitamin D in the protection of diabetic nephropathy (DN) has attracted special attention. Both animal studies and clinical trials have documented an inverse correlation between low vitamin D levels and DN risk, and supplementation with vitamin D or its active derivatives has been demonstrated to improve endothelial cell injury, reduce proteinuria, attenuate renal fibrosis, and resultantly retard DN progression. Vitamin D exerts its pharmacological effects primarily via vitamin D receptor, whose activation inhibits the renin-angiotensin system, a key culprit for DN under hyperglycemia. The anti-DN benefit of vitamin D can be enhanced when administrated in combination with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. Mechanistic studies reveal that pathways relevant to inflammation participate in the pathogenesis of DN, however, consumption of vitamin D-related products negatively regulates inflammatory response at multiple levels, indicated by inhibiting macrophage infiltration, nuclear factor-kappa B (NF-κB) activation, and production of such inflammatory mediators as transforming growth factor-ß(TGF-ß), monocyte chemoattractant protein 1(MCP-1), and regulated upon activation normal T cell expressed and secreted protein(RANTES). The robust anti-inflammatory property of vitamin D-related products allows them with a promising renoprotective therapeutic option for DN. This review summarizes new advances in our understanding of vitamin D-related products in the DN management.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Células Endoteliais/efeitos dos fármacos , Proteinúria/tratamento farmacológico , Receptores de Calcitriol/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Vitamina D/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Quimiocina CCL2/efeitos dos fármacos , Quimiocina CCL5/efeitos dos fármacos , Quimioterapia Combinada , Células Endoteliais/patologia , Humanos , NF-kappa B/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Vitamina D/farmacologia
4.
Clin Immunol ; 178: 10-19, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-26057130

RESUMO

Rheumatoid arthritis (RA) occurs two times more often in women than men. B cell depletion has been shown to be efficacious in treating RA. Our previous studies suggested that antigen presentation via B cells results in a sex-specific immune response in DR4 and DR4/DQ8 mice. Here we evaluated the mechanism of efficacy of the B cell depletion in treating arthritis-susceptible DQ8 mice. The data show that arthritic DQ8 mice treated with anti-CD20 antibody in therapeutic protocols show milder disease severity in females as compared to males, which is associated with decreased antibodies to citrullinated proteins and reduced levels of IL-23 and CCL5. Treatment led to significantly increased numbers of T regulatory and monocyte-derived suppressor F4/80+Gr1hi cells in females as compared to male DQ8 mice. Our observations suggest that therapeutic strategies that target B cells may benefit females while functions of DCs might be relatively more important for men than women.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Quimiocina CCL5/imunologia , Interleucina-23/imunologia , Células Supressoras Mieloides/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antirreumáticos/farmacologia , Artrite Experimental/genética , Artrite Reumatoide/genética , Linfócitos B/efeitos dos fármacos , Antígenos CD28/imunologia , Antígenos CD40/imunologia , Proliferação de Células , Quimiocina CCL5/efeitos dos fármacos , Quimiocinas/efeitos dos fármacos , Quimiocinas/imunologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Citometria de Fluxo , Cadeias beta de HLA-DQ/genética , Humanos , Interleucina-23/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/imunologia , Rituximab/farmacologia , Caracteres Sexuais , Linfócitos T Reguladores/efeitos dos fármacos
5.
J Am Heart Assoc ; 5(9)2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27633389

RESUMO

BACKGROUND: MKEY, a synthetic cyclic peptide inhibitor of CXCL4-CCL5 heterodimer formation, has been shown to protect against atherosclerosis and aortic aneurysm formation by mediating inflammation, but whether it modulates neuroinflammation and brain injury has not been studied. We therefore studied the role of MKEY in stroke-induced brain injury in mice. METHODS AND RESULTS: MKEY was injected into mice after stroke with 60 minutes of middle cerebral artery occlusion. Infarct volume and neurological deficit scores were measured. Protein levels of CCL5 and its receptor CCR5 were detected by Western blot and fluorescence-activated cell sorting (FACS), respectively. Numbers of microglia-derived macrophages (MiMΦs) and monocyte-derived MΦs (MoMΦs) in the brain, and their subsets, based on the surface markers CD45, CD11b, CCR2, CX3CR1, and Ly6C, were analyzed by FACS. MΦs and neutrophil infiltration in the ischemic brain were stained with CD68 and myeloperoxidase (MPO), respectively, and assessed by immunofluorescent confocal microscopy. The results showed that expressions of CCL5 and its receptor CCR5, were increased in the ischemic brain after stroke. MKEY injection significantly reduced infarct sizes and improved neurological deficit scores measured 72 hours after stroke. In addition, MKEY injection inhibited the number of MoMΦs, but not MiMΦs, in the ischemic brain. Furthermore, MKEY inhibited protein expression levels of Ly6C,CCR2, and CX3CR1 on MoMΦs. Lastly, the confocal study also suggests that the number of CD68-positive MΦs and MPO-positive neutrophils was inhibited by MKEY injection. CONCLUSIONS: MKEY injection protects against stroke-induced brain injury, probably by inhibiting MoMΦ-mediated neuroinflammation.


Assuntos
Encéfalo/efeitos dos fármacos , Quimiocina CCL5/efeitos dos fármacos , Infarto da Artéria Cerebral Média/metabolismo , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Fator Plaquetário 4/efeitos dos fármacos , Animais , Western Blotting , Encéfalo/citologia , Quimiocina CCL5/metabolismo , Dimerização , Citometria de Fluxo , Infarto da Artéria Cerebral Média/fisiopatologia , Macrófagos/citologia , Masculino , Camundongos , Microscopia Confocal , Microscopia de Fluorescência , Neutrófilos/citologia , Fator Plaquetário 4/metabolismo , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia
6.
Acta Odontol Scand ; 74(7): 550-557, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27546224

RESUMO

OBJECTIVE: Due to accumulation in the bone matrix and a half-life of at least 10 years, it is important to understand the cellular impact of bisphosphonates (BPs). This study assessed the effects of alendronate (ALN) on human primary osteoblasts. MATERIAL AND METHODS: Osteoblasts were incubated with ALN (5, 20 and 100 µM), and both cells and cell culture media were harvested after d 1, 3, 7 or 14. Proliferation was evaluated by 3H-thymidine incorporation and tetrazolium dye (MTT) colorimetric assay, and viability by the lactate dehydrogenase (LDH) activity in the medium. Differentiation was evaluated using protein Luminex multiplex assays and RT-PCR. RESULTS: ALN had no significant effects on cell viability. The lower concentrations enhanced the proliferation, whereas 100 µM diminished the proliferation. mRNA expression of osteocalcin (OC), alkaline phosphatase (ALP) and α-1 type 1 collagen were reduced, whereas ALN enhanced the expression of leptin mRNA and the secretion of interleukin-8 (IL-8) and regulated on activation normal T cell expressed and secreted (RANTES). CONCLUSIONS: ALN enhanced the secretion of immune factors from human osteoblasts. Combined with a lower rate of proliferation and a decline in differentiation, this indicates that higher dosages or accumulation may cause undesirable local changes in bone.


Assuntos
Alendronato/farmacologia , Conservadores da Densidade Óssea/farmacologia , Osteoblastos/efeitos dos fármacos , Alendronato/administração & dosagem , Fosfatase Alcalina/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Osso e Ossos/efeitos dos fármacos , Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL5/efeitos dos fármacos , Colágeno Tipo I/efeitos dos fármacos , Humanos , Interleucina-8/efeitos dos fármacos , L-Lactato Desidrogenase/efeitos dos fármacos , Leptina/análise , Osteocalcina/efeitos dos fármacos
7.
BMC Nephrol ; 17: 40, 2016 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-27044423

RESUMO

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, affecting close to a million people. Circulating galactose-deficient IgA (gd-IgA), present in patients with IgAN, form immune complex deposits in the glomerular mesangium causing local proliferation and matrix expansion. Intriguing though, individuals having gd-IgA deposits in the kidneys do not necessarily have signs of glomerular disease. Recurrence of IgAN only occurs in less than half of transplanted patients with IgAN, indicating that gd-IgA is not the only factor driving the disease. We hypothesize that, in addition to IgA complexes, patients with IgAN possess a subtype of mesangial cells highly susceptible to gd-IgA induced cell proliferation. METHODS: To test the hypothesis, we designed a technique to culture primary mesangial cells from renal biopsies obtained from IgAN patients and controls. The cell response to gd-IgA treatment was then measured both on gene and protein level and the proliferation rate of the cells in response to PDGF was investigated. RESULTS: When treated with gd-IgA, mesangial cells from patients with IgAN express and release more PDGF compared to controls. In addition, the mesangial cells from patients with IgAN were more responsive to treatment with PDGF resulting in an increased proliferation rate of the cells compared to control. Mesangial cells cultured from patients with IgAN expressed and released more IL-6 than controls and had a higher expression of matrix genes. Both mesangial cells derived from patients with IgAN and controls increased their expressed TGFß1 and CCL5 when treated with gd-IgA. CONCLUSION: We conclude that mesangial cells derived from IgAN patients have a mesangioproliferative phenotype with increased reactivity to IgA and that these cellular intrinsic properties may be important for the development of IgA nephropathy.


Assuntos
Complexo Antígeno-Anticorpo/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glomerulonefrite por IGA/imunologia , Imunoglobulina A/farmacologia , Fatores Imunológicos/farmacologia , Células Mesangiais/efeitos dos fármacos , Adulto , Idoso , Complexo Antígeno-Anticorpo/imunologia , Células Cultivadas , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CCL5/imunologia , Feminino , Galactose/metabolismo , Humanos , Imunoglobulina A/metabolismo , Interleucina-6/imunologia , Masculino , Células Mesangiais/imunologia , Fenótipo , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/imunologia , Adulto Jovem
8.
J Cereb Blood Flow Metab ; 35(12): 1957-65, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26126865

RESUMO

Pathologic conditions in the central nervous system, regardless of the underlying injury mechanism, show a certain level of blood-brain barrier (BBB) impairment. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation due to stroke, atherosclerosis, trauma, or brain infections. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators. The relationship between neuroinflammation and miRNA expression in brain endothelium remains unexplored. Previously, we showed the BBB-protective and anti-inflammatory effects of glycogen synthase kinase (GSK) 3ß inhibition in brain endothelium in in vitro and in vivo models of neuroinflammation. Using microarray screening, we identified miRNAs induced in primary human brain microvascular endothelial cells after exposure to the pro-inflammatory cytokine, tumor necrosis factor-α, with/out GSK3ß inhibition. Among the highly modified miRNAs, let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2 and CCL5. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across endothelium, diminished expression of pro-inflammatory cytokines, and increased BBB tightness, attenuating barrier 'leakiness' in neuroinflammation conditions. For the first time, we showed that miRNAs could be used as a therapeutic tool to prevent the BBB dysfunction in neuroinflammation.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Inflamação/patologia , MicroRNAs/farmacologia , Animais , Capilares/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/efeitos dos fármacos , Quimiocina CCL5/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Transfecção , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/toxicidade
9.
Respiration ; 89(6): 572-82, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25998443

RESUMO

BACKGROUND: Nitrosative stress is involved in different airway diseases. Lipopolysaccharide (LPS) induces neutrophil-related cytokine release and nitrosative stress in human bronchial epithelial (BEAS-2B) cells alone or with human polymorphonuclear neutrophils (PMNs). Ambroxol protects against oxidative stress, and beclomethasone dipropionate is an anti-inflammatory drug. OBJECTIVES: We evaluated the ability of ambroxol and/or beclomethasone dipropionate to inhibit LPS-induced expression/release of RANTES, IL-8, inducible NO synthase (iNOS), myeloperoxidase (MPO) and 3-nitrotyrosine (3-NT: nitrosative stress biomarker) in BEAS-2B ± PMNs stimulated with LPS (1 µg/ml). METHODS: The effect of ambroxol and/or beclomethasone dipropionate on IL-8, RANTES and iNOS levels was assessed by Western blot analysis; IL-8, MPO and 3-NT levels were measured by ELISA. Cell viability was assessed by the trypan blue exclusion test. RESULTS: In BEAS-2B alone, LPS (at 12 h) increased RANTES/iNOS expression and IL-8 levels (p < 0.001). Ambroxol suppressed LPS-induced RANTES expression and IL-8 release (p < 0.001), whilst inhibiting iNOS expression (p < 0.05). Beclomethasone dipropionate had no effect on RANTES but halved iNOS expression and IL-8 release. Coculture of BEAS-2B with PMNs stimulated IL-8, MPO and 3-NT production (p < 0.001), potentiated by LPS (p < 0.001). Ambroxol and beclomethasone dipropionate inhibited LPS-stimulated IL-8, MPO and 3-NT release (p < 0.05). Ambroxol/beclomethasone dipropionate combination potentiated the inhibition of IL-8 and 3-NT production in BEAS-2B with PMNs (p < 0.05 and p < 0.01, respectively). Ambroxol and/or beclomethasone dipropionate inhibited nitrosative stress and the release of neutrophilic inflammatory products in vitro. CONCLUSION: The additive effect of ambroxol and beclomethasone dipropionate on IL-8 and 3-NT inhibition suggests new therapeutic options in the treatment of neutrophil-related respiratory diseases such as chronic obstructive pulmonary disease and respiratory infections.


Assuntos
Ambroxol/farmacologia , Beclometasona/farmacologia , Células Epiteliais/efeitos dos fármacos , Expectorantes/farmacologia , Glucocorticoides/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Brônquios/citologia , Linhagem Celular , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CCL5/metabolismo , Humanos , Interleucina-8/efeitos dos fármacos , Interleucina-8/metabolismo , Lipopolissacarídeos/toxicidade , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Nitrosação/efeitos dos fármacos , Peroxidase/efeitos dos fármacos , Peroxidase/metabolismo , Mucosa Respiratória/citologia , Tirosina/análogos & derivados , Tirosina/efeitos dos fármacos , Tirosina/metabolismo
11.
Int Forum Allergy Rhinol ; 5(3): 191-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25561293

RESUMO

BACKGROUND: The immunopathogenesis of chronic rhinosinusitis (CRS) is largely unknown, but it is thought that different inflammatory profiles are responsible for the different CRS subtypes. 25-Hydroxyvitamin-D (25-VD3) has been shown to alter inflammatory mediators in other disease processes and 25-VD3 deficiency is associated with CRS with nasal polyps (CRSwNP), but it is unknown if 25-VD3 levels impact local inflammation in CRS. This study investigated the correlation between plasma 25-VD3 and sinonasal mucus monocyte chemoattractant protein-1 (MCP-1), regulated upon activation normal T cell expressed and secreted (RANTES), and basic fibroblast growth factor (bFGF) levels in patients with CRS. METHODS: Study subjects undergoing endoscopic sinus surgery (ESS) for CRS were prospectively enrolled from January 2012 to August 2014. Control subjects included patients undergoing ESS for noninflammatory pathology. Blood and sinonasal mucus were collected at the time of ESS. Plasma 25-VD3 was measured by enzyme-linked immunosorbent assay (ELISA) and mucus levels of MCP-1, RANTES, and bFGF by cytometric bead array (CBA). RESULTS: A total of 57 patients were enrolled and categorized as CRS without nasal polyps (CRSsNP) (n = 31), CRSwNP (n = 14), and controls (n = 12). No significant correlation was found between MCP-1 and 25-VD3. There was a significant negative correlation between 25-VD3 and RANTES (r = -0.612; p = 0.026) and bFGF (r = -0.578; p = 0.039) in CRSwNP patients; however, there was no significant correlation in CRSsNP patients. CONCLUSION: This data suggests that 25-VD3 may play a role in regulation of RANTES and bFGF expression in CRSwNP. This may occur through regulation of NP fibroblasts or other immune cells. Further investigation is warranted to better elucidate the role of RANTES, bFGF, and 25-VD3 in CRSwNP.


Assuntos
Colecalciferol/farmacologia , Fator 2 de Crescimento de Fibroblastos/efeitos dos fármacos , Rinite/cirurgia , Vitaminas/farmacologia , Quimiocina CCL2/metabolismo , Quimiocina CCL5/efeitos dos fármacos , Colecalciferol/metabolismo , Doença Crônica , Endoscopia/métodos , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Muco/química , Pólipos Nasais/sangue , Pólipos Nasais/cirurgia , Rinite/sangue , Sinusite/sangue , Sinusite/cirurgia , Vitamina D/análogos & derivados , Vitamina D/metabolismo
12.
J Oral Pathol Med ; 44(3): 214-21, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25047680

RESUMO

BACKGROUND: Ellagic acid (EA) found in various fruits such as pomegranates, blackberries, raspberries, strawberries, and walnuts has different pharmacological functions including antioxidant, antitumor, antiallergic, anti-inflammatory, antibacterial, and antiviral activities. It is not known, however, if EA could enhance mucosal innate immunity. Our goal was to determine the effects of EA on the expression of innate immune mediators produced by oral epithelial cells. METHODS: Culture of primary human gingival epithelial cells (HGEs) was performed in duplicate, and after the primary HGEs had been treated with EA at a concentration ranging from 12.5 to 100 µM for 18 h the cells and supernatants were harvested. The expression of innate immune mediators including human ß-defensin 2 (hBD2), secretory leukocyte protease inhibitor (SLPI), and various cytokines and chemokines was measured at both transcriptional and translational levels by using quantitative real-time PCR, ELISA, and Luminex assay. RESULTS: In the presence of EA, the expression of hBD2-and SLPI mRNA was 3.7-folds and 2.6-folds greater than untreated controls, respectively, and consistent with their secreted protein levels. For cytokines and chemokines, increased expression of RANTES, IL-2, and IL-1ß was found in response to EA. In contrast, EA decreased the expression of IL-6, IL-8, and TNF-α. CONCLUSIONS: This study demonstrated that oral innate immunity is affected by EA found in fruits. Thus, it may play some roles in mucosal innate immunity. The potential of EA for modulating the innate immune mediators may lead to developing a new topical agent to treat and/or prevent immune-mediated oral diseases.


Assuntos
Ácido Elágico/farmacologia , Gengiva/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Técnicas de Cultura de Células , Células Cultivadas , Quimiocina CCL20/efeitos dos fármacos , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CXCL5/efeitos dos fármacos , Quimiocinas/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Gengiva/citologia , Humanos , Imunidade Inata/imunologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-2/análise , Interleucina-6/análise , Interleucina-8/efeitos dos fármacos , Fosfoproteínas/efeitos dos fármacos , Proteínas Ribossômicas/efeitos dos fármacos , Inibidor Secretado de Peptidases Leucocitárias/efeitos dos fármacos , Fator de Necrose Tumoral alfa/efeitos dos fármacos , beta-Defensinas/efeitos dos fármacos
13.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 34(10): 1231-7, 2014 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-25509268

RESUMO

OBJECTIVE: To investigate the effect of triptolide (TPL) on the renal tissue of diabetic rats and its possible mechanisms. METHODS: SD rats were randomly divided into the normal control group (as the normal group), the diabetic model group (the model group), the low dose TPL treatment group (the low dose TPL group, TPL 0.2 mg/kg by gastrogavage), the high dose TPL treatment group (the high dose TPL group, TPL 0.4 mg/kg by gastrogavage). Equal volume of normal saline was given to rats in the normal group and the model group. Five rats were randomly selected from each group at week 4, 8, and 12 of the experiment to detect body weight, kidney weight, 24 h urinary albumin (24 h UAL), plasma glucose (FBG), total cholesterol (TC), total triglyeride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell (WBC), and hemoglobin A1c (HbA1c). The mRNA and protein expression of regulated upon activation normal T-cell expressed and secreted (RANTES) in the renal tissue was assessed by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). The renal tissue was pathologically stained by HE, PAS, and Masson staining. The glomerular and renal tubular interstitial lesions were observed at each time point. The glomerular sclerosis index (GSI) was observed by PAS staining, and the renal interstitial filrosis index (RIFI) was calcutated. RESULTS: Compared with the same group at week 4, the expression of 24 h UAL, RANTES, GSI, and RIFI at week 12 significantly decreased in two TPL groups (P <0.01). Compared with the same group at week 8, the expression of 24 h UAL, RANTES, GSI, and RIFI at week 12 also significantly decreased in the two TPL groups (P <0. 05, P <0.01). Compared with the normal group, body weight and the kidney weight obviously decreased at week 4, 8, and 12 in the model group (P <0. 01); 24 h UAL, FBG, TG, TC, HbA1c, RANTES, GSI, and RIFI were obviously elevated (P <0.01). Compared with the model group, 24 h UAL, RANTES, GSI, and RIFI also decreased in the two TPL treatment groups (P <0.01). Compared with the low dose TPL group, they were attenuated in the high dose TPL group (P <0. 05, P <0. 01). CONCLUSION: TPL could not only inhibit the over-expression of RANTES, but also improve the glomerular sclerosis and renal interstitial fibrosis in the renal tissue of diabetic rats.


Assuntos
Quimiocina CCL5/efeitos dos fármacos , Nefropatias Diabéticas/tratamento farmacológico , Diterpenos/farmacologia , Imunossupressores/farmacologia , Fenantrenos/farmacologia , Animais , Quimiocina CCL5/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/metabolismo , Compostos de Epóxi/farmacologia , Hemoglobina A Glicada/metabolismo , Rim/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Glomérulos Renais/metabolismo , Túbulos Renais/metabolismo , RNA Mensageiro/genética , Ratos
14.
Age (Dordr) ; 36(3): 9645, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24691968

RESUMO

Cancer is an age-associated disease. Although the mechanisms of age-associated increase in cancer incidence are not completely understood, it is believed that the tumor stromal environment significantly influences epithelial malignancy. Fibroblasts are a major cell type in the stroma and, under normal conditions, fibroblasts reside in the quiescent state. Cellular quiescence is a reversible process where cells enter into the proliferative cycle and then exit back to quiescence. We have shown previously that quiescent fibroblasts lose their proliferative capacity as they age, and we defined this mode of cellular aging as chronological life span. Using conditioned media and co-culture experiments, results from this study show that normal human fibroblasts (NHFs) nearing the end of their chronological life span stimulate the proliferation of MB231 and MCF7 human breast epithelial cancer cells. Chemokine C-C motif ligand 5 (CCL5) expression was found to be approximately 8-fold higher in old compared to that in young quiescent NHFs, which correlated with an increase in the ERK1/2-cyclin D1 pro-proliferative pathway in MB231 cells. Conditioned media treated with anti-CCL5 antibody suppressed the activation of the ERK1/2-cyclin D1 pathway and proliferation of MB231 cells. Hydroxytyrosol, a dietary polyphenol and an active ingredient of olive, inhibited CCL5 expression in aging quiescent NHFs. This inhibition was associated with NHFs inability to activate the ERK1/2-cyclin D1 pathway and enhance proliferation of MB231 cells. These results show that fibroblasts nearing the end of their chronological life span promote proliferation of human breast epithelial cancer cells and dietary polyphenols inhibit this process.


Assuntos
Envelhecimento/genética , Neoplasias da Mama/patologia , Quimiocina CCL5/genética , Regulação Neoplásica da Expressão Gênica , Álcool Feniletílico/análogos & derivados , RNA Neoplásico/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Antioxidantes/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proliferação de Células , Quimiocina CCL5/biossíntese , Quimiocina CCL5/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Recém-Nascido , Álcool Feniletílico/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Células Tumorais Cultivadas
15.
J Clin Periodontol ; 41(3): 295-302, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24433307

RESUMO

AIM: We hypothesized that platelet inactivation induced by drugs might interfere with periodontal repair in experimental periodontitis by suppressing the release of biological mediators from platelets at the site of injury. MATERIAL AND METHODS: Sixty rats were randomly assigned to six groups (n = 10) and ligatures were placed around lower first molars of three groups. The other three groups were used as negative controls. Ligatures were removed after 10 days of periodontitis induction and all groups were submitted to treatment with aspirin (Asp) (30 mg/kg), clopidogrel (Clop) (75 mg/kg) or NaCl 0.9% intra-gastrically once daily for 3 days. Periodontal tissue was assessed by the measurement of CXCL12, CXCL4, CCL5 and platelet-derived growth factor (PDGF) by enzyme-linked immunosorbent assay; histomorphometrical analysis of polymorphonuclear (PMN) infiltration, attachment loss, bone loss and osteoclast numbers and quantification of blood vessels by imunnohistochemistry. RESULTS: During periodontal repair and treatment with NaCl 0.9%, CCL5 was decreased and CXCL12 increased when compared with negative control groups. Asp and Clop did not affect CCL5 expression, decreased CXCL12 but only Clop decreased CXCL4 and PDGF content compared with saline-treated animals. Clop increased blood vessel number, reduced PMN count and decreased attachment and bone loss, also decreased osteoclast number in animals submitted or not to periodontal repair. CONCLUSION: Systemic administration of Clop for 3 days improved the repair process associated with experimental periodontal disease, suggesting that it may have therapeutic value under situations where tissues undergo a transition from inflammation to repair.


Assuntos
Periodontite/tratamento farmacológico , Periodonto/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/uso terapêutico , Ticlopidina/análogos & derivados , Perda do Osso Alveolar/tratamento farmacológico , Animais , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Contagem de Células , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CXCL12/efeitos dos fármacos , Clopidogrel , Infusões Parenterais , Masculino , Microvasos/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Osteoclastos/efeitos dos fármacos , Perda da Inserção Periodontal/tratamento farmacológico , Inibidores da Agregação de Plaquetas/administração & dosagem , Fator Plaquetário 4/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio , Ticlopidina/administração & dosagem , Ticlopidina/uso terapêutico
16.
Int J Clin Exp Pathol ; 6(4): 678-85, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23573314

RESUMO

Fibrosis or scarring of the liver parenchyma is a mainstay of chronic liver diseases and is associated with increased morbidity and mortality. Since complete scarring of the liver develops over several decades, therapeutic intervention with the aim of ameliorating fibrosis is of great clinical interest. In a recent study, we could identify the chemokine receptor antagonist Met-CCL5 as a potential compound to inhibit fibrosis progression and accelerate its regression. In the current study we characterized immune changes during fibrosis regression associated with the treatment with the CCL5 (RANTES) chemokine receptor antagonist Met-CCL5 in an established mouse model of chronic liver damage. Met-CCL5 or PBS was given after fibrosis induction (8 weeks of CCl(4)) and mice were sacrificed three and seven days after peak fibrosis. Mouse livers were analyzed for immune cell infiltration and cytokine gene expression. The results show that overall monocyte recruitment was not affected by Met-CCL5, but there was a significant shift to a pro-inflammatory Gr1+ monocyte population in the livers of mice treated with Met-CCL5. These monocytes were mostly iNOS +, a phenomenon which was also evident when analyzing the overall gene expression profiles in the livers. Since a shift in monocyte subpopulations has recently been identified to contribute to fibrosis regression, our results help explaining the efficacy of CCL5 chemokine antagonism as a novel treatment option for fibrotic liver diseases.


Assuntos
Quimiocina CCL5/antagonistas & inibidores , Cirrose Hepática/patologia , Cirrose Hepática/prevenção & controle , Monócitos/efeitos dos fármacos , Monócitos/patologia , Receptores CCR/antagonistas & inibidores , Animais , Tetracloreto de Carbono/efeitos adversos , Contagem de Células , Quimiocina CCL5/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores CCR/efeitos dos fármacos
17.
J Periodontol ; 84(8): 1048-57, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23030238

RESUMO

BACKGROUND: Possible synergism between female sex hormones and vitamin D on periodontitis pathology has not been assessed. Here, the authors investigate effects of estrogen, progesterone, and vitamin D on periodontitis in a population-based sample and use cell studies to explore mechanistic explanations of the population-based findings. METHODS: The epidemiologic analysis uses cross-sectional data from the continuous National Health and Nutrition Examination Survey 2001 to 2004. The cross sections include 1,230 women aged 40 to 85 years who received a periodontal examination, responded to questions regarding hormone replacement therapy (HRT), and provided a blood sample for serum vitamin D assessments. For mechanistic cell culture studies, human monocytes were cultured with or without lipopolysaccharide (LPS), estradiol, progesterone, and/or 1,25-dihydroxyvitamin D3; and transcriptional activity of interleukin (IL)-6, IL-1ß, B lymphocyte chemoattractant (BLC), and regulated on activation normal T-cell expressed and secreted (RANTES) was assessed. RESULTS: HRT use (versus none) was associated with higher attachment levels and more teeth only among participants who were vitamin D sufficient (>20 ng/mL). The odds ratio for having moderate/severe periodontitis among users of HRT versus participants who did not use HRT was 0.69 among participants who were vitamin D sufficient and 1.19 in participants who were vitamin D deficient. LPS-induced IL-6, IL-1ß, and BLC expression was attenuated in human monocytes treated with estrogen and progesterone. Downregulation of IL-6 expression by estrogen and progesterone was potentiated when vitamin D was included. LPS-induced IL-6 and RANTES expression was decreased, and BLC expression was totally reversed, by vitamin D treatment. CONCLUSIONS: The association between HRT and clinical periodontal measures was strongest among women with high vitamin D levels. This association is plausibly mediated via an anti-inflammatory transcriptional mechanism.


Assuntos
Terapia de Reposição Hormonal , Periodontite/classificação , Vitamina D/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/efeitos dos fármacos , Calcitriol/uso terapêutico , Linhagem Celular , Quimiocina CCL5/efeitos dos fármacos , Fatores Quimiotáticos/análise , Estudos de Coortes , Estudos Transversais , Escherichia coli , Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios , Feminino , Humanos , Interleucina-1beta/efeitos dos fármacos , Interleucina-6/análise , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Perda da Inserção Periodontal/classificação , Vigilância da População , Progesterona/uso terapêutico , Linfócitos T/efeitos dos fármacos , Perda de Dente/classificação , Vitamina D/sangue
18.
J Laryngol Otol ; 126(5): 495-502, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22559798

RESUMO

BACKGROUND: Little is known about the effects of macrolides on the cytokines and chemokines that modulate the function of eosinophils in nasal polyposis. METHODS: Twenty-two non-allergic and 18 allergic patients with nasal polyps were administered clarithromycin 500 mg/day (single oral dose) for eight weeks. We measured the nasal secretion levels of the T helper 2 (also known as Th2) cytokines interleukin 4, 5 and 6, the 'regulated on activation, normal T cell expressed and secreted' (also known as RANTES) chemokine, and the eosinophilic cationic protein, before and after treatment. RESULTS: After clarithromycin treatment, we found reduced levels of the 'regulated on activation, normal T cell expressed and secreted' chemokine in samples from both non-allergic and allergic patients (p < 0.05). Clarithromycin treatment decreased the levels of eosinophilic cationic protein only in non-allergic patients (p < 0.05), and decreased the level of interleukin 6 only in allergic patients (p < 0.05). Decreased levels of the 'regulated on activation, normal T cell expressed and secreted' chemokine were associated with a reduction in polyp size both in non-allergic and allergic patients. CONCLUSION: Clarithromycin has a strong anti-inflammatory effect in nasal polyposis, but has different immunomodulatory effects in allergic and non-allergic nasal polyposis patients.


Assuntos
Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Citocinas/metabolismo , Muco/efeitos dos fármacos , Mucosa Nasal/efeitos dos fármacos , Pólipos Nasais/tratamento farmacológico , Rinite Alérgica Perene/tratamento farmacológico , Adulto , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Quimiocina CCL5/efeitos dos fármacos , Quimiocina CCL5/metabolismo , Claritromicina/administração & dosagem , Claritromicina/farmacologia , Citocinas/efeitos dos fármacos , Proteína Catiônica de Eosinófilo/efeitos dos fármacos , Proteína Catiônica de Eosinófilo/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Muco/química , Mucosa Nasal/metabolismo , Pólipos Nasais/metabolismo , Pólipos Nasais/patologia , Estudos Prospectivos , Rinite Alérgica Perene/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Células Th2/metabolismo , Resultado do Tratamento , Adulto Jovem
19.
J Med Dent Sci ; 57(4): 193-201, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23896774

RESUMO

Airway smooth muscle cells (ASMCs) have been reported to express Toll-like receptors (TLRs) and take part in the pathogenesis of asthma exacerbation. Though TLRs were found to activate epidermal growth factor receptor (EGFR) in airway epithelial cells, little is known about the association of TLR ligands with EGFR signaling pathways in ASMCs. Using primary cultured ASMCs from Brown Norway rats, TLR4, eotaxin, and RANTES mRNA were examined by real-time quantitative RT-PCR after stimulation with the TLR4 ligand, lipopolysaccharides (LPS). The concentration of RANTES protein in culture supernatant was measured by ELISA. The effect of EGFR signaling inhibitors on RANTES expression was examined as well. Phosphorylation of EGFR after stimulation was examined by Western Blotting. Rat ASMCs expressed TLR4 and eotaxin, and LPS upregulated RANTES production. The EGFR tyrosine kinase inhibitor AG1478, the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the matrix metalloproteinase (MMP) inhibitor GM6001 inhibited RANTES expression induced by LPS. LPS phosphorylated EGFR. TLR4 activation can induce RANTES expression via EGFR transactivation and PI3K/Akt pathway in rat ASMCs. MMP-induced EGFR proligand cleavage and ligand binding to EGFR seem to be involved in this pathway. These findings may be critical in the pathogenesis of asthma exacerbation by airway infection.


Assuntos
Quimiocina CCL11/efeitos dos fármacos , Quimiocina CCL5/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Miócitos de Músculo Liso/efeitos dos fármacos , Receptor 4 Toll-Like/efeitos dos fármacos , Traqueia/efeitos dos fármacos , Animais , Asma/fisiopatologia , Técnicas de Cultura de Células , Células Cultivadas , Quimiocina CCL5/antagonistas & inibidores , Cromonas/farmacologia , Dipeptídeos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/efeitos dos fármacos , Masculino , Inibidores de Metaloproteinases de Matriz/farmacologia , Morfolinas/farmacologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Quinazolinas/farmacologia , Ratos Endogâmicos BN , Transdução de Sinais/efeitos dos fármacos , Traqueia/citologia , Ativação Transcricional/efeitos dos fármacos , Tirfostinas/farmacologia
20.
Mod Rheumatol ; 19(4): 372-8, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19458908

RESUMO

This study was performed to analyze the effect of etanercept, the soluble tumor necrosis factor-alpha (TNF-alpha) receptor, on the serum levels of several chemokines including monocyte chemotactic protein-1 (MCP-1), regulated upon activation normal T expressed and presumably secreted (RANTES), and granzyme B in rheumatoid arthritis (RA) patients. Twenty-eight patients with RA were administered etanercept once or twice a week for more than 6 months. Clinical and laboratory parameters were measured and serum levels of MCP-1, RANTES, and granzyme B were determined using enzyme-linked immunosorbent assay (ELISA) kits at baseline and at 3 and 6 months after the initial treatment. In addition, the levels of MCP-1, RANTES, and granzyme B produced by cultured synovial cells stimulated with TNF-alpha were measured. A significant decrease in serum MCP-1 levels was observed at 3 and 6 months after initial treatment with etanercept. Serum RANTES and granzyme B levels did not show significant changes. TNF-alpha induced MCP-1, RANTES, and granzyme B production in cultured synovial cells from RA patients. Serum MCP-1 levels were significantly correlated with the disease activity scores of 28 joints combined with CRP (DAS28-CRP), indicating the role of MCP-1 in the pathogenesis of rheumatoid inflammation. This study demonstrated that a reduction of MCP-1 production in RA patients was a newly determined effect of etanercept. Another cascade not associated with TNF-alpha may induce granzyme B and RANTES production in RA patients.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Quimiocina CCL2/efeitos dos fármacos , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Idoso , Artrite Reumatoide/sangue , Artrite Reumatoide/fisiopatologia , Proteína C-Reativa/análise , Células Cultivadas , Quimiocina CCL2/sangue , Quimiocina CCL5/sangue , Quimiocina CCL5/efeitos dos fármacos , Etanercepte , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Granzimas/sangue , Granzimas/efeitos dos fármacos , Humanos , Masculino , Índice de Gravidade de Doença , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Fator de Necrose Tumoral alfa/farmacologia
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