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1.
Life Sci ; 233: 116750, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31408659

RESUMO

AIM: Rheumatoid arthritis (RA) is the most widespread inflammatory arthropathy, which causes severe disability. It is highly important to ameliorate the side effects caused by different drugs used to treat RA. Therefore, this study assessed the potential role of ß-caryophyllene (BCP) in treating adjuvant-induced arthritis (AIA), increasing the efficacy of methotrexate (MTX) and/or leflunomide (LEF), and ameliorating their side effects. MATERIAL AND METHODS: AIA was induced in rats by injecting complete Freund's adjuvant. The rats were divided into different groups such as sham group; control group; monotherapy groups, including BCP (300 mg/kg), MTX (1 mg/kg), and LEF (10 mg/kg); and combined groups, including MTX + BCP, LEF + BCP, MTX + LEF, and MTX + LEF + BCP groups. KEY FINDINGS: Monotherapy with BCP or MTX or LEF as well as MTX + LEF significantly reduced paw thickness and arthritic index; the histopathological changes in hind paw joints were recovered; and oxidative stress and tumor necrosis factor-alpha (TNF-α) levels in arthritic rats were reduced. The co-administration of BCP and MTX and/or LEF significantly improved the therapeutic efficacy of MTX and/or LEF and significantly reduced the myelosuppressive and hepatotoxic effects of MTX and/or LEF. Taken together, BCP could be used with MTX and/or LEF for the treatment of RA to reduce the side effects of the drugs and increase their efficacy.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Artrite Experimental/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Imunossupressores/administração & dosagem , Leflunomida/administração & dosagem , Metotrexato/administração & dosagem , Sesquiterpenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Antimetabólitos Antineoplásicos/efeitos adversos , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Quimioterapia Combinada , Imunossupressores/efeitos adversos , Leflunomida/efeitos adversos , Masculino , Metotrexato/efeitos adversos , Ratos , Ratos Wistar , Sesquiterpenos/administração & dosagem
2.
Immunogenetics ; 71(7): 489-499, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31297569

RESUMO

Epigenetic modifications have been shown to be important for immune cell differentiation by regulating gene transcription. However, the role and mechanism of histone methylation in the development and differentiation of iNKT cells in rheumatoid arthritis (RA) mice have yet to be deciphered. The DBA/1 mouse RA model was established by using a modified GPI mixed peptide. We demonstrated that total peripheral blood, thymus, and spleen iNKT cells in RA mice decreased significantly, while iNKT1 in the thymus and spleen was increased significantly. PLZF protein and PLZF mRNA levels were significantly decreased in thymus DP T cells, while T-bet protein and mRNA were significantly increased in thymus iNKT cells. We found a marked accumulation in H3K27me3 around the promoter regions of the signature gene Zbtb16 in RA mice thymus DP T cells, and an accumulation of H3K4me3 around the promoters of the Tbx21 gene in iNKT cells. The expression levels of UTX in the thymus of RA mice were significantly reduced. The changes in the above indicators were particularly significant in the progressive phase of inflammation (11 days after modeling) and the peak phase of inflammation (14 days after modeling) in RA mice. Developmental and differentiation defects of iNKT cells in RA mice were associated with abnormal methylation levels (H3K27me3 and H3K4me3) in the promoters of key genes Zbtb16 (encoding PLZF) and Tbx21 (encoding T-bet). Decreased UTX of thymus histone demethylase levels resulted in the accumulation of H3K27me3 modification.


Assuntos
Artrite Reumatoide/patologia , Lisina/metabolismo , Células T Matadoras Naturais/patologia , Regiões Promotoras Genéticas , Timo/fisiologia , Animais , Artrite Experimental/patologia , Diferenciação Celular , Epigênese Genética , Regulação da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Metilação , Camundongos Endogâmicos DBA , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Baço/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
3.
Phytother Res ; 33(6): 1726-1735, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31155798

RESUMO

Rheumatoid arthritis (RA) is a complex chronic inflammatory disease that is associated with the aberrant activation of fibroblast-like synoviocytes (FLS). Kaempferitrin is a natural flavonoid glycoside that possesses anti-inflammatory bioactivity. However, the effect of kaempferitrin on RA has not yet been revealed. The aim of the present study was to investigate the effect of kaempferitrin on human RA-FLS MH7A cell line. We found that kaempferitrin inhibited proliferation and induced apoptosis of MH7A cells. Kaempferitrin decreased the levels of interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, matrix metalloproteinase (MMP)-1, and MMP-3 in MH7A cells. Moreover, kaempferitrin blocked the activation of nuclear factor-κB (NF-κB) and protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathways. Furthermore, treatment with kaempferitrin decreased paw thickness and arthritis scores, and reduced the serum levels of IL-1ß, IL-6, and TNF-α in a collagen-induced arthritis mouse model. In conclusion, kaempferitrin inhibited cell proliferation, induced cell apoptosis, and ameliorated inflammation of RA-FLS by suppressing the NF-κB and Akt/mTOR pathways.


Assuntos
Apoptose/efeitos dos fármacos , Artrite Reumatoide/patologia , Proliferação de Células/efeitos dos fármacos , Inflamação/prevenção & controle , Quempferóis/farmacologia , Sinoviócitos/efeitos dos fármacos , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Experimental/prevenção & controle , Artrite Reumatoide/metabolismo , Artrite Reumatoide/prevenção & controle , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/fisiologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/metabolismo , Metaloproteinase 3 da Matriz , Camundongos , Camundongos Endogâmicos DBA , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sinoviócitos/patologia , Sinoviócitos/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
4.
Pharm Res ; 36(7): 97, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31076925

RESUMO

PURPOSE: The aim of this research was to design dexamethasone palmitate (DP) loaded sialic acid modified liposomes, with the eventual goal of using peripheral blood neutrophils (PBNs) that carried drug-loaded liposomes to improve the therapeutic capacity for rheumatoid arthritis (RA). METHODS: A sialic acid - cholesterol conjugate (SA-CH) was synthesized and anchored on the surface of liposomal dexamethasone palmitate (DP-SAL). The physicochemical characteristics and in vitro cytotoxicity of liposomes were evaluated. Flow cytometry and confocal laser scanning microscopy were utilized to investigate the accumulation of liposomes in PBNs. The adjuvant-induced arthritis was adopted to investigate the targeting ability and anti-inflammatory effect of DP loaded liposomes. RESULTS: Both DP-CL and DP-SAL existed an average size less than 200 nm with remarkably high encapsulation efficiencies more than 90%. In vitro and in vivo experiments manifested SA-modified liposomes provided a reinforced accumulation of DP in PBNs. As well, DP-SAL displayed a greater degree of accumulation in the joints and a stronger anti-inflammatory effect in terms of RA suppression. CONCLUSIONS: SA-modified liposomal DP was a promising candidate for RA-targeting treatment through the neutrophil-mediated drug delivery system.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Dexametasona/farmacocinética , Lipossomos/química , Ácido N-Acetilneuramínico/química , Neutrófilos/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/toxicidade , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Colesterol/química , Dexametasona/administração & dosagem , Dexametasona/toxicidade , Liberação Controlada de Fármacos , Articulações/efeitos dos fármacos , Articulações/patologia , Selectina L/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/patologia , Masculino , Neutrófilos/patologia , Palmitatos/química , Ratos Wistar , Distribuição Tecidual
5.
Cell Physiol Biochem ; 52(6): 1446-1462, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31088038

RESUMO

BACKGROUND/AIMS: Rheumatoid arthritis (RA) is characterized by a tumor-like expansion of the synovium and the subsequent destruction of adjacent articular cartilage and bone. Recent studies have shown that phosphatase and tension homolog deleted on chromosome 10 (PTEN) might contribute to the surviva of fibroblast-like synoviocytes (FLSs) and the production of pro-inflammatory cytokines in RA. The purpose of this study was to explore the functions and underlying mechanisms of PTEN in the proliferation and migration of FLSs. METHODS: FLSs were obtained from adjuvant-induced arthritis (AIA) and normal rats. The expression levels of PTEN, c-Myc, cyclin D1, PCNA, and MMP-9 were detected by quantitative-real-time-PCR and western blot assay. A BrdU proliferation assay, cell cycle analysis, and a wound-healing assay were used to study the role of PTEN in FLSs treated with PTEN inhibitor bpv, specific small interfering RNA targeting PTEN (PTEN-RNAi) or a PTEN over-expression vector (PTEN-GV141). Chromatin immunoprecipitation and methylation-special PCR assays were used to study the expression of PTEN mRNA in the presence of DNA methylation. RESULTS: PTEN expression was downregulated in AIA FLSs in comparison to normal rats. Moreover, inhibition of PTEN expression by bpv or PTEN-RNAi could promote the proliferation and migration of FLSs, and increase the expression of c-Myc, cyclin D1, PCNA, and MMP-9 in AIA FLSs, but had no effect on TIMP-1 expression.In addition, transfection of AIA FLSs with PTEN-GV141 reduced their proliferation and migration. Further study indicated that DNA methylation could regulate PTEN expression in AIA. CONCLUSION: Our findings suggest that PTEN might play a pivotal role in the proliferation and migration of FLSs through the activation of the AKT signaling pathway. Additionally, PTEN expression may be regulated by DNA methylation in the pathogenesis of AIA.


Assuntos
Artrite Experimental/metabolismo , Movimento Celular , Proliferação de Células , Fibroblastos/metabolismo , Regulação da Expressão Gênica , PTEN Fosfo-Hidrolase/biossíntese , Sinoviócitos/metabolismo , Animais , Artrite Experimental/genética , Artrite Experimental/patologia , Feminino , Fibroblastos/patologia , PTEN Fosfo-Hidrolase/genética , Ratos , Ratos Sprague-Dawley , Sinoviócitos/patologia
6.
Oxid Med Cell Longev ; 2019: 2484678, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049128

RESUMO

Due to atrophy, muscle weakness is a common occurrence in rheumatoid arthritis (RA). The majority of human studies are conducted on the vastus lateralis muscle-a muscle with mixed fiber type-but little comparative data between multiple muscles in either rodent or human models are available. The current study therefore assessed both muscle ultrastructure and selected redox indicators across various muscles in a model of collagen-induced rheumatoid arthritis in female Sprague-Dawley rats. Only three muscles, the gastrocnemius, extensor digitorum longus (EDL), and soleus, had lower muscle mass (38%, 27%, and 25% loss of muscle mass, respectively; all at least P < 0.01), while the vastus lateralis muscle mass was increased by 35% (P < 0.01) in RA animals when compared to non-RA controls. However, all four muscles exhibited signs of deterioration indicative of rheumatoid cachexia. Cross-sectional area was similarly reduced in gastrocnemius, EDL, and soleus (60%, 58%, and 64%, respectively; all P < 0.001), but vastus lateralis (22% smaller, P < 0.05) was less affected, while collagen deposition was significantly increased in muscles. This pathology was associated with significant increases in tissue levels of reactive oxygen species (ROS) in all muscles except the vastus lateralis, while only the gastrocnemius had significantly increased levels of lipid peroxidation (TBARS) and antioxidant activity (FRAP). Current data illustrates the differential responses of different skeletal muscles of the hindlimb to a chronic inflammatory challenge both in terms of redox changes and resistance to cachexia.


Assuntos
Artrite Experimental/metabolismo , Caquexia/metabolismo , Membro Posterior/metabolismo , Peroxidação de Lipídeos , Músculo Esquelético/metabolismo , Animais , Artrite Experimental/patologia , Caquexia/patologia , Feminino , Membro Posterior/patologia , Músculo Esquelético/patologia , Ratos , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
7.
Cell Biochem Funct ; 37(4): 208-215, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30941802

RESUMO

Abnormal hyperplasia of fibroblast-like synoviocytes (FLS) leads to the progression of rheumatoid arthritis (RA). This study aimed to investigate the role of miR-124a in the pathogenesis of RA. The viability and cell cycle of FLS in rheumatoid arthritis (RAFLS) were evaluated by Cell Counting Kit 8 and flow cytometry assay. The expression of PIK3CA, Akt, and NF-κB in RAFLS was examined by real-time PCR and Western blot analysis. The production of tumour necrosis factor (TNF)-α and interleukin (IL)-6 was detected by ELISA. The joint swelling and inflammation in collagen-induced arthritis (CIA) mice were examined by histological and immunohistochemical analysis. We found that miR-124a suppressed the viability and proliferation of RAFLS and increased the percentage of cells in the G1 phase. miR-124a suppressed PIK3CA 3'UTR luciferase reporter activity and decreased the expression of PIK3CA at mRNA and protein levels. Furthermore, miR-124a inhibited the expression of the key components of the PIK3/Akt/NF-κB signal pathway and inhibited the expression of pro-inflammatory factors TNF-α and IL-6. Local overexpression of miR-124a in the joints of CIA mice inhibited inflammation and promoted apoptosis in FLS by decreasing PIK3CA expression. In conclusion, miR-124a inhibits the proliferation and inflammation in RAFLS via targeting PIK3/NF-κB pathway. miR-124a is a promising therapeutic target for RA.


Assuntos
Artrite Reumatoide/patologia , Fibroblastos , Inflamação/genética , MicroRNAs/genética , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/genética , Sinoviócitos/metabolismo , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Proliferação de Células/genética , Colágeno , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Sinoviócitos/patologia
8.
Int J Mol Sci ; 20(8)2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-31003542

RESUMO

: To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pain, new dual inhibitors incorporating both a carbonic anhydrase (CA)-binding moiety and a cyclooxygenase inhibitor (NSAID) were tested in a rat model of rheumatoid arthritis induced by CFA intra-articular (i.a.) injection. A comparison between a repeated per os treatment and a single i.a. injection was performed. CFA (50 µL) was injected in the tibiotarsal joint, and the effect of per os repeated treatment (1 mg kg-1) or single i.a injection (1 mg ml-1, 50 µL) with NSAIDs-CAIs hybrid molecules, named 4 and 5, was evaluated. The molecules 4 and 5, which were administered daily for 14 days, significantly prevented CFA-induced hypersensitivity to mechanical noxious (Paw pressure test) and non-noxious stimuli (von Frey test), the postural unbalance related to spontaneous pain (Incapacitance test) and motor alterations (Beam balance test). Moreover, to study a possible localized activity, 4 and 5 were formulated in liposomes (lipo 4 and lipo 5, both 1 mg ml-1) and directly administered by a single i.a. injection seven days after CFA injection. Lipo 5 decreased the mechanical hypersensitivity to noxious and non-noxious stimuli and improved motor coordination. Oral and i.a. treatments did not rescue the joint, as shown by the histological analysis. This new class of potent molecules, which is able to inhibit at the same time CA and cyclooxygenase, shows high activity in a preclinical condition of rheumatoid arthritis, strongly suggesting a novel attractive pharmacodynamic profile.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Acetaminofen/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Experimental/genética , Artrite Experimental/patologia , Artrite Reumatoide/patologia , Inibidores da Anidrase Carbônica/administração & dosagem , Anidrases Carbônicas/genética , Modelos Animais de Doenças , Adjuvante de Freund/administração & dosagem , Humanos , Inflamação/genética , Inflamação/patologia , Injeções Intra-Articulares , Dor/genética , Dor/patologia , Manejo da Dor/métodos , Ratos
9.
Biomed Pharmacother ; 112: 108646, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970506

RESUMO

The present study reveals the anti-arthritic potential of traditionally used Parmotrema tinctorum (Pt) on experimental rats and purification of novel Isophthalic ester derivative. Arthritis was induced in rats using Freund's complete adjuvant (CFA) and subsequently treated with Pt extract (100 & 200 mg/kg.b.w). Assessment of antiarthritic activity was carried out using paw volume, arthritic score, haematological, biochemical, tissue antioxidant, histopathology and radiological analyses of ankle joints. The results revealed that continuous administration of Pt reduces the complication associated with arthritis by inhibiting the edema formation and arthritic score significantly (P < 0.05). The altered changes in biochemical parameters were brought back with an improvement in free radical scavenging ability after treatment with Pt significantly. Further purification of Pt using conventional column chromatography led to the isolation of four compounds and the structure of these isolated compounds were elucidated on the basis of spectral data's FT-IR, 1H NMR, 13C NMR, DEPT-NMR spectroscopy, COSY & HSQC-NMR spectroscopy and LC-MS. The spectral data revealed that the three compounds were found to be Methyl-γ-Orsellinate, Atranorin, and usnic acid (CI-III) along with a novel secondary metabolite, (C-IV)4-Hydroxy-5-methyl-isophthalicacid3-(3,4-dihydroxy-5-methyl-phenyl)ester (C16H14O7,318.1amu). The present study reveals that Parmotrema tinctorum reduces complications associated with arthritis and the compounds were isolated for the first time.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Adjuvante de Freund , Parmeliaceae/química , Ácidos Ftálicos/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Antioxidantes/metabolismo , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Feminino , Articulações do Pé/efeitos dos fármacos , Articulações do Pé/patologia , Estrutura Molecular , Ratos , Raios X
10.
Biomed Pharmacother ; 113: 108730, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30861411

RESUMO

Arthritis is a common chronic joint disorder, with general symptoms including stiffness and joint pain. ß-methylphenylalanine is a well-known non-proteogenic unnatural amino acid. This study analyzes the anti-arthritic activity of ß-methylphenylalanine in experimental rats. The experimental groups were as follows: group I, sham; group II, control; group III, 100 mg/kg of ß-methylphenylalanine; and group IV, 200 mg/kg of ß-methylphenylalanine. Lipid peroxidation, glutathione peroxidase (Gpx), reduced glutathione (GSH), superoxide dismutase (SOD), catalase, prostaglandin E2 (PGE2), matrix metalloproteinase-3 (MMP-3), ceruloplasmin, zinc, copper, mRNA, and protein expression of inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB) were determined. Supplementation with ß-methylphenylalanine significantly reduced lipid peroxidation, copper, PGE2 and MMP-3 levels, whereas GSH, Gpx, catalase, SOD and zinc levels were increased. Supplementation with ß-methylphenylalanine significantly reduced NF-κB mRNA expression by 26% and 47.8% in groups III and IV, respectively (P < 0.045), while iNOS mRNA expression was reduced by 14.3 and 47.6% in groups III and IV, respectively. NF-κB and iNOS protein expression increased by 160% and 120% respectively, in the control rats compared to the sham rats. However, supplementation with ß-methylphenylalanine significantly reduced NF-κB protein expression by 27% and 50% in groups III and IV, respectively, while iNOS protein expression was reduced by 22.7% and 45.4% in groups III and IV, respectively. Taken together, our data show that supplementation of ß-methylphenylalanine was effective against arthritis in a rat model.


Assuntos
Aminobutiratos/farmacologia , Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Aminobutiratos/administração & dosagem , Animais , Antirreumáticos/administração & dosagem , Artrite Experimental/patologia , Catalase/metabolismo , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Masculino , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/metabolismo , Ratos , Superóxido Dismutase/metabolismo , Zinco/metabolismo
11.
J Ethnopharmacol ; 237: 92-107, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-30872172

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The roots of Ribes orientale (Family Grossulariaceae) have long been used as a folk remedy to treat rheumatism and joints pain in Northern Areas of Pakistan. AIM OF THE STUDY: The purpose of study was to observe the preventive efficacy of roots of Ribes orientale (RO) aqueous ethanolic extract (30:70) and its aqueous and n-butanol fractions in treating rheumatoid arthritis and to determine its possible mechanism of action. MATERIAL AND METHODS: Arthritis was evaluated in vitro using heat induced bovine serum albumin and egg albumin denaturation and membrane stabilizing assays at 50-6400 µg/ml concentration of extract/fractions whereas, in vivo arthritis was evaluated at 50, 100, 200 mg/kg doses of extract/fractions in formaldehyde model by measuring rat paw volume/diameter. Moreover, highest effective dose (200 mg/kg) of extract/fractions was evaluated in Freünd complete adjuvant (FCA) model. Arthritis was induced in Sprague Dawley rats by immunization with 0.1 ml FCA in left footpad. RO extract/fractions at 200 mg/kg were orally administered from day 0, 30 min prior to adjuvant injection and sustained for 28 days. Paw volume/diameter, arthritic score, body weight, and hematological (WBC, RBC, ESR, Hb and Platelet count) and biochemical (AST, ALT, ALP, urea, creatinine, CRP and RF) parameters were observed. The mRNA expression levels of COX-2, IL-1ß, IL-6, NF-kB, TNF-α, IL-4 and IL-10 were measured by real time reverse transcription polymerase chain reaction (RT-PCR) whereas, PGE2 and TNF-α levels in serum samples were measured by Enzyme linked immunosorbent assay (ELISA). Furthermore, radiographs of hind paws and histological changes in ankle joint were analyzed in adjuvant injected rats. The anti-oxidant activity of plant extract and fractions was evaluated using DPPH and reducing power assays. In addition, phytochemistry, total phenolic and flavonoid contents, and HPLC analysis of most active fraction (aqueous fraction) were performed. RESULTS: Results showed that RO extract and fractions (notably aqueous fraction) significantly reduced protein denaturation and protected erythrocyte membrane in concentration dependent manner. Similarly, extract/fractions induced dose-dependent decrease in paw volume/diameter in the formaldehyde model. Plant extract and fractions significantly suppressed paw swelling and arthritic score, prevented cachexia and remarkably ameliorated hematological and biochemical changes. Furthermore, RO extract/fractions downregulated gene expression levels of PGE2, COX-2, IL-1ß, IL-6, NF-kB and TNF-α whereas, upregulated those of IL-4 and IL-10, compared with FCA control rats. The radiographic and histopathologic improvement in joint architecture was also observed in RO treated rats. Piroxicam, used as reference drug, also significantly suppressed arthritis. Additionally, plant exhibited notable anti-oxidant activity and phytochemical analysis revealed the presence of flavonoids and polyphenols. CONCLUSION: Results indicated that suppression of pro-inflammatory enzymes/cytokines, inhibition of protein denaturation, lysosomal membrane stabilizing abilities, and redox/free radical scavenging properties of RO extract and fractions support anti-arthritic and immunomodulatory property of Ribes orientale that might be due to its polyphenolic and flavonoid constituents. This suggests that Ribes orientale roots may be used as a therapeutic agent for treating human arthritis.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Ribes , Animais , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/patologia , Anti-Inflamatórios/farmacologia , Artrite Experimental/sangue , Artrite Experimental/imunologia , Artrite Experimental/patologia , Ciclo-Oxigenase 2/sangue , Citocinas/sangue , Eritrócitos/efeitos dos fármacos , Feminino , Humanos , Masculino , NF-kappa B/sangue , Fitoterapia , Extratos Vegetais/farmacologia , Raízes de Plantas , Ratos Sprague-Dawley
12.
J Ethnopharmacol ; 237: 20-27, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-30880257

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The whole plant of Glycine tabacina (Labill.) Benth has been used as a traditional herbal medicine to treat rheumatism, ostealgia and nephritis in China. It is also one of the sources of the renowned native herbal medicine 'I-Tiao-Gung' in Taiwan. AIM OF THE STUDY: This study aimed to investigate the anti-arthritic effect of ethanol extract of G. tabacina (GTE) in a collagen-induced arthritis (CIA) rat model. MATERIALS AND METHODS: The chemical profile of GTE was analyzed by HPLC-UV. The CIA was induced in male Wistar rats by intradermal injection of bovine type II collagen at tail root, back and ankle joints. The rats were orally administrated daily with GTE (1.11, 2.22 and 4.44 g dry weight of herb powder per kg body weight) from day 0 and continued for 30 days. Swelling volume and thickness of paw, arthritis index, X-radiographs and histopathological changes were examined to assess the severity of arthritis. Furthermore, the levels of pro-inflammatory cytokines, such as interleukin1ß (IL-1ß), IL-6 and tumor necrosis factor α (TNF-α), total superoxide dismutase (T-SOD) activity and malonaldehyde (MDA) level were measured to preliminarily explore the possible mechanisms. RESULTS: Oral administration of GTE significantly ameliorated the arthritic symptoms in CIA rat model, as indicated by the effects on paws swelling and arthritis index. X-radiographic analysis and histopathological examinations demonstrated that GTE effectively protected the bone and cartilage of joints from erosion, lesion and deformation. The efficacy of GTE treatment on CIA was comparable to that of indomethacin (positive drug). Besides, the overproduction of IL-1ß, IL-6 and TNF-α was remarkably inhibited in the serum of all GTE treatment groups. The restoration of serum T-SOD activity and MDA level proved that GTE administration alleviated the oxidative stress in CIA rats. CONCLUSIONS: GTE exhibited strong anti-CIA activity through inhibiting pro-inflammatory cytokines and oxidation in rats, suggesting its potential preventive and therapeutic effects on rheumatoid arthritis (RA).


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Fabaceae , Extratos Vegetais/uso terapêutico , Animais , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/patologia , Anti-Inflamatórios/farmacologia , Artrite Experimental/imunologia , Artrite Experimental/patologia , Citocinas/sangue , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/patologia , Masculino , Malondialdeído/sangue , Oxirredução , Fitoterapia , Extratos Vegetais/farmacologia , Ratos Wistar , Superóxido Dismutase/sangue
13.
J Ethnopharmacol ; 236: 183-195, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30849505

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Paullinia pinnata L. (Sapindaceae) is an African woody vine, traditionally used for the treatment of itch and pain-related conditions such as rheumatoid arthritis. AIM: This work evaluates, in vitro and in vivo, the anti-inflammatory and analgesic effects of aqueous (AEPP) and methanol (MEPP) extracts from Paullinia pinnata leaves. METHODS: AEPP and MEPP (100, 200 and 300 mg/kg/day) were administered orally in monoarthritic rats induced by a unilateral injection of 50 µl of Complete Freund's Adjuvant (CFA) in the ankle joint. During the 14 days of treatment, pain and inflammation were evaluated alternatively in both ankle and paw of the CFA-injected leg. Malondialdehyde (MDA) and glutathione (GSH) levels were assessed in serum and spinal cord. Histology of soft tissue of the ankle was also analyzed. For in vitro studies, AEPP and MEPP (10, 30 and 100 µg/ml) were evaluated against nitric oxide (NO) production by macrophages that were either non-stimulated or stimulated with LPS, 8-Br-AMPc and the mixture of both substances after 8 h exposure. These extracts were also evaluated on TNF-α and IL-1ß production in cells stimulated with LPS for 8 h. Finally, the ability of the extracts to bind to neuroactive receptors was evaluated in vitro using competitive binding assays with >45 molecular targets. RESULTS: AEPP and MEPP significantly reduced by 20-98% (p < 0.001) the inflammation and pain sensation in both the ankle and paw. AEPP significantly increased glutathione levels (p < 0.05) in serum. Both extracts reduced MDA production in serum and spinal cord (p < 0.001), and significantly improved tissue reorganization in treated arthritic rats. P. pinnata extracts did not affect NO production in non-stimulated macrophages but significantly reduced it by 47-88% in stimulated macrophages. AEPP and MEPP also significantly inhibited TNF-α (35-68%) and IL-1ß (31-36%) production in LPS stimulated macrophages. No cytotoxic effect of plant extracts was observed. MEPP showed concentration-dependent affinity for Sigma 2 receptors with an IC50 of 50 µg/ml. CONCLUSION: These results demonstrate the analgesic and anti-inflammatory effects of P. pinnata extracts on monoarthritis and further support its traditional use for pain and inflammation. These activities are at least partly due to the ability of these extracts to inhibit the production of NO, TNF-α, IL-1ß and to likely modulate Sigma 2 receptors.


Assuntos
Analgésicos/farmacologia , Anti-Inflamatórios/farmacologia , Artralgia/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Medicina Tradicional Africana/métodos , Paullinia/química , Extratos Vegetais/farmacologia , Analgésicos/isolamento & purificação , Analgésicos/uso terapêutico , Animais , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/imunologia , Articulação do Tornozelo/patologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/uso terapêutico , Artralgia/etiologia , Artralgia/patologia , Artrite Experimental/complicações , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Avaliação Pré-Clínica de Medicamentos , Feminino , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Masculino , Metanol/química , Óxido Nítrico/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Ratos , Ratos Wistar , Resultado do Tratamento , Água/química
14.
Phytomedicine ; 58: 152825, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30831463

RESUMO

BACKGROUND: The seeds of Vitex negundo, with rich lignans metabolites, have been widely used as a traditional Chinese medicine and Ayurvedic herbal medicine for the treatment of rheumatism and joint inflammation. The total lignans of Vitex negundo seeds (TOV) were suggested to play an important role in the treatment of arthritis. PURPOSE: The aim of the study was designed to investigate the anti-arthritic effects of TOV on collagen-induced arthritis (CIA) in rats as well as its possible mechanisms. METHODS: TOV was prepared by combined macroporous resin and polyamide column chromatography, and constituents of TOV were analyzed by HPLC. CIA model in rats was established by immunization with chicken type II collagen and then the rats were intragastrically administrated with TOV for 30 days. Rat arthritis was evaluated by measurements of hind paw edema, arthritis index score, weight growth and indices of thymus and spleen, and by histological examination. Levels of serum MMP-2, MMP-3, MMP-9, IL-1ß, IL-6, IL-8, IL-10, IL-17A and TNF-α were also examined. In addition, the expression of COX-2, iNOS and IκB, p-IκB in synovial tissues was evaluated by western blotting. The analgesic and anti-inflammatory effects of TOV were also evaluated in acetic acid-induced writhing and xylene-induced ear edema in mice, respectively. In addition, acute toxicity test was employed to preliminarily assess the safety of TOV. RESULTS: TOV significantly inhibited the paw edema and decreased the arthritis index, with no influence on the body weight and the indices of thymus and spleen of CIA rats. Meanwhile, TOV dose-dependently reduced the infiltration of inflammatory cells, synovial hyperplasia and attenuated cartilage damage. Additionally, the serum levels of IL-1ß, IL-6, IL-8, IL-17A, TNF-α, MMP-3 and MMP-9 were markedly decreased, while the level of serum IL-10 was increased in TOV-treated rats. The significant reduction of the expression of COX-2, iNOS and p-IκB and the notable increase of IκB in synovial tissues were also observed in TOV-treated animals. TOV also significantly inhibited acetic acid-induced writhing and decreased xylene-induced ear edema in mice. Finally, the maximal tolerable dose (MTD) of TOV was determined to be 16.0 g/kg. CONCLUSION: These results suggest that TOV has significant anti-arthritic effects on collagen-induced arthritis in rats, which may be attributed to the inhibition of the levels of IL-1ß, IL-6, IL-8, IL-17A, TNF-α, MMP-3 and MMP-9, and the increase of IL-10 in serum as well as down-regulation of the protein expression of COX-2 and iNOS in synovial tissues via suppressing the phosphorylation and degradation of IκB. Due to its high efficacy and safety, TOV can be regarded as a promising drug candidate for rheumatoid arthritis treatment.


Assuntos
Artrite Experimental/tratamento farmacológico , Edema/tratamento farmacológico , Lignanas/farmacologia , Medicina Tradicional Chinesa , Vitex/química , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Galinhas , Colágeno Tipo II/efeitos adversos , Ciclo-Oxigenase 2/metabolismo , Citocinas/sangue , Edema/patologia , Feminino , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Sementes/química , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia
15.
Phytomedicine ; 58: 152876, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30851579

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune diseased state, characterized by hyperplasia of the synovial membrane, degradation of cartilage, and bone erosion of diarthrodial joints. Kadsura heteroclita (Roxb) Craib (Schizandraceae), a traditional Tujia ethnomedicine called Xue Tong in China, has been long used for the prevention and treatment of rheumatic and arthritic diseases, especially in the southern China. This study aimed to evaluate anti-arthritic effects of the ethanol extract of Kadsura heteroclita stems (KHS) on complete Freund's adjuvant (CFA)-induced arthritis (AIA) in rats, as well as to explore the underlying mechanisms of anti-arthritis. METHODS: AIA was established in male Sprague-Dawley (SD) rats as described previously, and animals were daily treated by gavage with KHS ethanol extract (200, 400, or 800 mg/kg) or vehicle (0.3% CMCNa) throughout the 30-day experiment. The incidence and severity of arthritis were evaluated using clinical parameters. At the end of experiments, tissue swelling and bone destruction of the hind paws were assessed by computed tomography (CT) and histopathological analyses. Serum levels of tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), IL-6, and IL-17A and IL-17F were measured by ELISA, and protein expression of matrix metalloproteinases-1 (MMP-1), MMP-3 and tissue inhibitor of MMP-1 (TIMP-1) were detected by Western blot. RESULTS: Treatment with KHS dose-dependently inhibited paw swelling and reduced arthritis scores of AIA rats. CT images displayed that KHS remarkably protected AIA rats from tissue swelling and bone erosion of joints. Histopathological analyses revealed that KHS markedly reduced inflammatory cell infiltration, synovial proliferation, and the formation of pannus in the ankle joints of AIA rats. KHS was found to significantly suppress the production of TNF-α, IL-1 ß, IL-6, IL-17A and IL-17F, inhibited the protein expression of MMP-1 and MMP-3, and elevated the protein expressions of TIMP-1. CONCLUSION: KHS demonstrates potential anti-arthritic effects via inhibiting pivotal mediators of inflammation and cartilage destruction. This study strongly supports identification and isolation of active fractions of KHS which would be a potential candidate for further investigation as a new anti-arthritic botanical drug.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Kadsura/química , Animais , Antirreumáticos/administração & dosagem , Antirreumáticos/química , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Edema/tratamento farmacológico , Adjuvante de Freund/toxicidade , Interleucinas/sangue , Masculino , Caules de Planta/química , Ratos Sprague-Dawley , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Necrose Tumoral alfa/sangue
16.
EBioMedicine ; 41: 538-555, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30824383

RESUMO

BACKGROUND: Osteoblasts participating in the inflammation regulation gradually obtain concerns. However, its role in joint inflammation of rheumatoid arthritis (RA) is largely unknown. Here, we investigated the role of osteoblastic pleckstrin homology domain-containing family O member 1 (PLEKHO1), a negative regulator of osteogenic lineage activity, in regulating joint inflammation in RA. METHODS: The level of osteoblastic PLEKHO1 in RA patients and collagen-induced arthritis (CIA) mice was examined. The role of osteoblastic PLEKHO1 in joint inflammation was evaluated by a CIA model and a K/BxN serum-transfer arthritis (STA) model which were induced in osteoblast-specific Plekho1 conditional knockout mice and mice expressing high Plekho1 exclusively in osteoblasts, respectively. The effect of osteoblastic PLEKHO1 inhibition was explored in a CIA mice model and a non-human primate arthritis model. The mechanism of osteoblastic PLEKHO1 in regulating joint inflammation were performed by a series of in vitro studies. RESULTS: PLEKHO1 was highly expressed in osteoblasts from RA patients and CIA mice. Osteoblastic Plekho1 deletion ameliorated joint inflammation, whereas overexpressing Plekho1 only within osteoblasts exacerbated local inflammation in CIA mice and STA mice. PLEKHO1 was required for TRAF2-mediated RIP1 ubiquitination to activate NF-κB for inducing inflammatory cytokines production in osteoblasts. Moreover, osteoblastic PLEKHO1 inhibition diminished joint inflammation and promoted bone formation in CIA mice and non-human primate arthritis model. CONCLUSIONS: These data strongly suggest that the highly expressed PLEKHO1 in osteoblasts contributes to joint inflammation in RA. Targeting osteoblastic PLEKHO1 may exert dual therapeutic action of alleviating joint inflammation and promoting bone formation in RA.


Assuntos
Artrite Experimental/patologia , Artrite Reumatoide/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Articulações/metabolismo , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Proteínas Ativadoras de GTPase/metabolismo , Haplorrinos , Humanos , Inflamação/patologia , Inflamação/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Articulações/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo
17.
Arch Immunol Ther Exp (Warsz) ; 67(3): 153-160, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30874838

RESUMO

Rheumatoid arthritis (RA) is a common autoimmune disease which impacts a large number of patients worldwide, and new drugs are required for lower the disease burden. Theaflavin-3, 3'-digallate (TFDG) is polyphenol exhibiting inhibition on inflammatory factors. This study aimed to explore the attenuation of TFDG on RA. The collagen-induced arthritis (CIA) mouse model was established and administered with TFDG. The arthritis score and incidence was recorded to assess the amelioration of TFDG on arthritis. Histopathological change of the mouse joint tissues was evaluated by haemotoxylin and eosin staining. The expression of pro-inflammatory mediators including interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6 was quantified by ELISA. The activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways in the synovium were determined by Western blotting. In comparison with the control, administration of TFDG significantly reduced arthritis score and incidence in the CIA mouse model. TFDG significantly suppressed the expression of IL-1ß, TNF-α, and IL-6, as well as the levels of MMP-1, MMP-2, and MMP-3 in the synovium. TFDG also showed remarkable inhibition on the activation of NF-κB and the phosphorylation of P38, JNK2, and ERK. This study puts up evidence that TFDG exerts protection on RA via inhibiting the activation of NF-κB- and MAPK-signaling pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Biflavonoides/farmacologia , Catequina/farmacologia , Ácido Gálico/análogos & derivados , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Biflavonoides/uso terapêutico , Catequina/uso terapêutico , Colágeno/administração & dosagem , Colágeno/imunologia , Avaliação Pré-Clínica de Medicamentos , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Humanos , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Articulações/efeitos dos fármacos , Articulações/imunologia , Articulações/patologia , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/imunologia , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
18.
J Pharm Pharmacol ; 71(6): 971-981, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30784067

RESUMO

OBJECTIVES: The creation of a new valid preclinical model of articular pain by the intra-articular (i.a.) injection of mucilages for the screening of new treatments against arthritis. METHODS: A single intra-articular injection (20 µl) of mucilages (from Althaea officinalis roots and Linum usitatissimun seeds) or vegetal components (Amorphophallus konjac gum powder and ß-glucan, used as reference standard) were assessed in the rat. The pathology progression was monitored by behavioural measurements (paw pressure test, von Frey test, incapacitance test and beam balance test) and compared to that induced by the i.a. injections of monoiodioacetate (MIA) and Complete Freund's Adjuvant (CFA), well-recognized models of osteoarthritis and rheumatoid arthritis, respectively. KEY FINDINGS: Among all, the mucilage of L. usitatissimun showed the best pro-algic profile inducing a painful long-lasting condition. Hypersensitivity was characterized as a mixed form of inflammatory and neuropathic pain by the responsiveness to ibuprofen (100 mg/kg, p.o.) and pregabalin (30 mg/kg, p.o.). The histological evaluation of joint showed a damage that represents both MIA and CFA features. CONCLUSIONS: In conclusion, a single i.a. injection of L. usitatissimun mucilage can represent a valid model to assess articular pain in the rat for the screening of new treatments against arthritis.


Assuntos
Artrite Experimental/patologia , Artrite Reumatoide/patologia , Osteoartrite/patologia , Mucilagem Vegetal/toxicidade , Althaea/química , Analgésicos/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Linho/química , Adjuvante de Freund/toxicidade , Ibuprofeno/farmacologia , Injeções Intra-Articulares , Masculino , Neuralgia/tratamento farmacológico , Neuralgia/etiologia , Osteoartrite/tratamento farmacológico , Dor/tratamento farmacológico , Dor/etiologia , Mucilagem Vegetal/administração & dosagem , Pregabalina/farmacologia , Ratos , Ratos Sprague-Dawley
19.
Eur J Pharmacol ; 852: 179-188, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30796904

RESUMO

Berberine (BBR) is a traditional folk medicine with excellent anti-inflammatory properties. This study aimed to investigate the anti-arthritic effects of BBR in adjuvant arthritis (AA) in rats and its regulatory role in the polarization of macrophages. Rats were immunized with Complete Freund's Adjuvant (CFA), and then BBR (40, 80, 160 mg/kg) was administered orally for 14 days. BBR significantly reduced paw swelling and arthritis global assessment as well as alleviated joint destruction and inflammatory cell infiltration. The index of the thymus and thymocyte proliferation were significantly reduced by BBR. Moreover, BBR treatment restrained the phagocytic function of macrophages and restored the balance of M1/M2 by reducing the levels of M1 cytokines (tumour necrosis factor-α, interleukin-1ß, and interleukin-6), increasing the levels of M2 cytokines (interleukin-10 and transforming growth factor-ß1), increasing the expression of arginase 1(Arg1) (M2 marker) and decreasing the expression of inducible nitric oxide synthase (iNOS) (M1 marker). BBR also downregulated the ratio of Th17/Treg cells. Further research on the adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/nuclear factor κB (NF-κB) pathway found that BBR upregulated the activity of AMPK, while it downregulated the expression of phospho-RelA (p-p65), phospho-NF-kappa-B inhibitor alpha (p-IκBα) and cyclooxygenase (COX)-2. Therefore, our findings suggest BBR has significantly therapeutic effects in AA rats by regulating the polarization of macrophages through the AMPK/NF-кB pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Artrite Experimental/tratamento farmacológico , Berberina/farmacologia , Fatores Imunológicos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , NF-kappa B/metabolismo , Animais , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/patologia , Arginase/metabolismo , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Berberina/uso terapêutico , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Citocinas/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Fagocitose/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/citologia , Células Th17/efeitos dos fármacos , Tomografia Computadorizada por Raios X
20.
Artigo em Inglês | MEDLINE | ID: mdl-30727927

RESUMO

BACKGROUND: Production of tumor necrosis factor (TNF)-α by inflammatory cells in lesions is the hallmark of the pathogenesis of rheumatoid arthritis (RA). Regulation of inflammatory responses in knee joints of patients with RA is critical for improving severe symptoms. Flavonoids have inhibitory effects on the acute and chronic inflammatory responses caused by TNF-α. The flavonoid quercetin (QUER) is one of the most prominent dietary antioxidants. OBJECTIVE: The present study investigated the preventive and therapeutic effects of QUER on inflammatory responses in collagen-induced arthritis (CIA) in mice. METHODS: Mice with CIA, a mouse model for RA, were treated with QUER orally three times a week either from the second immunization with collagen (day 21) or day 28 when symptoms of CIA had developed midway. RESULTS: In both cases, inflammation-related clinical scores of knee joints were significantly reduced by treatment with QUER. Histological analyses showed that the representative characteristics of RA, such as damage to interchondral joints, infiltration of inflammatory cells, and pannus formation, were significantly reduced by QUER treatment. Oral administration of QUER significantly decreases lipopolysaccharide (LPS)-induced TNF-α production in a dose-dependent manner. Expression of TNF- α mRNA in knee joints was decreased in QUER-treated mice, compared with those of CIA controls. CONCLUSION: These results suggest that oral administration of QUER might effectively improve symptoms of RA.


Assuntos
Antioxidantes/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Quercetina/uso terapêutico , Animais , Antioxidantes/farmacologia , Artrite Experimental/patologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Quercetina/farmacologia
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