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1.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445367

RESUMO

Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)-an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO-control, AIA-untreated adjuvant-induced arthritis, AIA-BIL-adjuvant-induced arthritis administrated UCB, CO-BIL-control with administrated UCB. UCB was administered intraperitoneally 200 mg/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund's adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Bilirrubina/administração & dosagem , Adjuvante de Freund/efeitos adversos , Lipídeos/efeitos adversos , Mycobacterium/imunologia , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Bilirrubina/farmacologia , Proteína C-Reativa , Ceruloplasmina/metabolismo , Injeções Intraperitoneais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Resultado do Tratamento
2.
J Immunol ; 207(6): 1652-1661, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34426543

RESUMO

The IκB kinase (IKK) complex plays a vital role in regulating the NF-κB activation. Aberrant NF-κB activation is involved in various inflammatory diseases. Thus, targeting IKK activation is an ideal therapeutic strategy to cure and prevent inflammatory diseases related to NF-κB activation. In a previous study, we demonstrated that IKK-interacting protein (IKIP) inhibits the phosphorylation of IKKα/ß and the activation of NF-κB through disruption of the formation of IKK complex. In this study, we identified a 15-aa peptide derived from mouse IKIP (46-60 aa of IKIP), which specifically suppressed IKK activation and NF-κB targeted gene expression via disrupting the association of IKKß and NEMO. Importantly, administration of the peptide reduced LPS-induced acute inflammation and attenuated Zymosan-induced acute arthritis in mice. These findings suggest that this IKIP peptide may be a promising therapeutic reagent in the prevention and treatment of inflammatory diseases.


Assuntos
Quinase I-kappa B/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Peptídeos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Lipopolissacarídeos/efeitos adversos , Camundongos , Camundongos Knockout , Ligação Proteica , Transdução de Sinais/genética , Zimosan/efeitos adversos
3.
Front Immunol ; 12: 628065, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220796

RESUMO

Objective: Hypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/ß2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis. Methods: Complete Freund's adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the ß2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization. Results: On D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint. Conclusion and Significance: Our findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Artrite Experimental/prevenção & controle , Articulações/efeitos dos fármacos , Fentolamina/farmacologia , Receptores Adrenérgicos alfa/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Terbutalina/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Combinação de Medicamentos , Adjuvante de Freund , Articulações/diagnóstico por imagem , Articulações/metabolismo , Articulações/patologia , Masculino , Ratos Endogâmicos Lew , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais
4.
Biomed Pharmacother ; 139: 111635, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243601

RESUMO

This study aimed to evaluate the anti-inflammatory effect of Auraptene (AUR) and Umbelliprenin (UMB) in a rat model of rheumatoid arthritis (RA) induced by using complete Freund's adjuvant (CFA). Paw swelling of adjuvant arthritis rats measured at various times after CFA injection. Over 15 days of RA induction, mediator/cytokine-mediated processes involved in managing the regulation and resolving RA's inflammation were also quantified with ELISA. Histopathological changes were also assessed under a microscope 15 days after the CFA injection. AUR at all doses and UMB administration only at a 16 mM /kg administration dose significantly reduced CFA-induced paw edema level compared to the control group. UMB (64 and 32 mM) and AUR (64, 32, and 16 mM) could reduce the PGE2 (p < .0001-.01) and NO (p < .0001-.05) levels in the treatment groups compared to the negative control group. However, these compounds showed no significant effect on the TNF-α, IFN-γ, TGF-ß, IL-4, and IL-10 levels than the control group (p > .05). Unlike indomethacin and prednisolone, treatment of rats with AUR (16, 32, and 64 mM/kg) and UMB (16 and 32 mM/kg) reduced the level of IL-2 (p < .0001). In all treatment groups, the serum level of IL-17 was significantly reduced compared to the CFA group (p < .001-0.05). We suggested AUR and UMB could diminish inflammation by reducing the serum level of IL-17 and could be considered a proper alternative in the treatment of IL-17 related inflammatory diseases such as rheumatoid arthritis. Given that AUR and UMB apply their anti-inflammatory effects by changing distinct cytokine release/inhibition patterns, their potential application in diverse inflammatory diseases seems different.


Assuntos
Artrite/tratamento farmacológico , Cumarínicos/farmacologia , Adjuvante de Freund/farmacologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Substâncias Protetoras/farmacologia , Umbeliferonas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Artrite/metabolismo , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Citocinas/metabolismo , Edema/induzido quimicamente , Edema/tratamento farmacológico , Edema/metabolismo , Inflamação/metabolismo , Masculino , Ratos , Ratos Wistar
5.
J Med Chem ; 64(13): 8951-8970, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34138567

RESUMO

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound 50 afforded an optimum balance of PK profiles and potency. Oral administration of 50 attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, 50 demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinazolinonas/farmacologia , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite Experimental/induzido quimicamente , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Inflamação/induzido quimicamente , Camundongos , Camundongos Endogâmicos DBA , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinonas/administração & dosagem , Quinazolinonas/química , Relação Estrutura-Atividade
6.
Mol Immunol ; 135: 36-44, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857817

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease for which there are currently no effective therapies. Although mesenchymal stem cells (MSCs) can prevent arthritis through immunomodulatory mechanisms, there are several associated risks. Alternatively, MSC-derived small extracellular vesicles (sEVs) can mimic the effects of MSCs, while reducing the risk of adverse events. However, few studies have examined sEVs in the context of RA. Here, we evaluate the immunomodulatory effects of human umbilical cord MSC (hUCMSC)-derived sEVs on T lymphocytes in a collagen-induced arthritis (CIA) rat model to elucidate the possible mechanism of sEVs in RA treatment. We then compare these mechanisms to those of MSCs and methotrexate (MTX). METHODS: The arthritis index and synovial pathology were assessed. T lymphocyte proliferation and apoptosis, Th17 and Treg proportions, and interleukin (IL)-17, IL-10, and transforming growth factor (TGF)-ß expression were detected using flow cytometry. Retinoic acid receptor-related orphan receptor gamma t (RORγt) and forkhead box P3 (FOXP3), which are master transcriptional regulators of Th17 and Treg differentiation, were also assessed using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: sEV treatment ameliorated arthritis and inhibited synovial hyperplasia in a dose-dependent manner. These effects were mediated by inhibiting T lymphocyte proliferation and promoting their apoptosis, while decreasing Th17 cell proportion and increasing that of Treg cells in the spleen, resulting in decreased serum IL-17, and enhanced IL-10 and TGF-ß expression. Transcriptionally, sEVs decreased RORγt and increased FOXP3 expression in the spleen, and decreased RORγt and FOXP3 expression in the joints. In some aspects sEVs were more effective than MSCs and MTX in treating CIA. CONCLUSIONS: hUCMSC-derived sEVs ameliorate CIA via immunomodulatory T lymphocytes, and might serve as a new therapy for RA.


Assuntos
Artrite Experimental/terapia , Vesículas Extracelulares/metabolismo , Imunomodulação/imunologia , Células-Tronco Mesenquimais/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Artrite Experimental/induzido quimicamente , Células Cultivadas , Colágeno/toxicidade , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imunossupressores/farmacologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Metotrexato/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ratos , Ratos Wistar , Membrana Sinovial/patologia , Fator de Crescimento Transformador beta/metabolismo
7.
Front Immunol ; 12: 626310, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815378

RESUMO

Although B cells have been shown to contribute to the pathogenesis of rheumatoid arthritis (RA), the precise role of B cells in RA needs to be explored further. Our previous studies have revealed that adiponectin (AD) is expressed at high levels in inflamed synovial joint tissues, and its expression is closely correlated with progressive bone erosion in patients with RA. In this study, we investigated the possible role of AD in B cell proliferation and differentiation. We found that AD stimulation could induce B cell proliferation and differentiation in cell culture. Notably, local intraarticular injection of AD promoted B cell expansion in joint tissues and exacerbated arthritis in mice with collagen-induced arthritis (CIA). Mechanistically, AD induced the activation of PI3K/Akt1 and STAT3 and promoted the proliferation and differentiation of B cells. Moreover, STAT3 bound to the promoter of the Blimp-1 gene, upregulated Blimp-1 expression at the transcriptional level, and promoted B cell differentiation. Collectively, we observed that AD exacerbated CIA by enhancing B cell proliferation and differentiation mediated by the PI3K/Akt1/STAT3 axis.


Assuntos
Adiponectina/toxicidade , Artrite Experimental/enzimologia , Linfócitos B/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos B/enzimologia , Linfócitos B/imunologia , Colágeno Tipo II , Ativação Enzimática , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Fosfatidilinositol 3-Quinase/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Adiponectina/agonistas , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais
8.
PLoS One ; 16(4): e0250352, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33878143

RESUMO

1,25-dihydroxyvitamin-D3 and its derivatives have shown anti-arthritic and chondroprotective effects in experimental animal models with prophylactic dosing. The purpose of this preliminary study was to test the efficacy and safety of calcipotriol, vitamin D analog, as a treatment for a fully-developed knee arthritis in Zymosan-induced arthritis (ZIA) model. Forty 5-month-old male Sprague-Dawley rats were randomized into three arthritis groups and a non-arthritic control group with no injections (10 rats/group). A day after Zymosan (0.1 mg) had been administrated into the right knee joints, the same knees were injected with calcipotriol (0.1 mg/kg), dexamethasone (0.1 mg/kg) or vehicle in a 100 µl volume. The left control knees were injected with saline (PBS) on two consecutive days. All injections, blood sampling and measurements were performed under general anesthesia on days 0, 1, 3 and 8. Internal organs and knees were harvested on day 8 and the histology of the whole knees was assessed blinded. Joints treated with calcipotriol showed a milder histological synovitis than those treated with vehicle (p = 0.041), but there was no statistically significant difference between the dexamethasone and vehicle groups. The clinical severity of arthritis did not differ between the arthritis groups measured by body temperature, swelling of the knee, thermal imaging, clinical scoring or cytokine levels on days 1, 3 and 8. Weight loss was bigger in rats treated with dexamethasone, propably due to loss of appetite,compared to other arthritis groups on days 2-3 (p<0.05). Study drugs did not influence serum calcium ion and glucose levels. Taken together, this preliminary study shows that a single intra-articular injection of calcipotriol reduces histological grade of synovitis a week after the local injection, but dexamethasone did not differ from the vehicle. Calcipotriol may have an early disease-modifying effect in the rat ZIA model without obvious side effects.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Calcitriol/análogos & derivados , Sinovite/tratamento farmacológico , Animais , Artrite Experimental/sangue , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Glicemia/metabolismo , Calcitriol/farmacologia , Cálcio/sangue , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Dexametasona/farmacologia , Esquema de Medicação , Membro Posterior , Injeções Intra-Articulares , Masculino , Ratos , Ratos Sprague-Dawley , Sinovite/sangue , Sinovite/induzido quimicamente , Sinovite/patologia , Resultado do Tratamento , Zimosan/administração & dosagem
9.
Nutrients ; 13(3)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805648

RESUMO

BACKGROUND: Polydatin is a stilbenoid with important antioxidant, anti-inflammatory, and immunomodulating properties. The aim of this study was to assess the anti-inflammatory preventive effect of polydatin in the mouse model of acute arthritis induced by calcium pyrophosphate (CPP) crystals. METHODS: Acute arthritis was induced by the injection of a suspension of sterile CPP crystals into the ankle joint of Balb/c mice. Animals were randomized to receive polydatin or colchicine (the control drug) according to a prophylactic and a therapeutic protocol. The primary outcome was the variation of ankle swelling obtained after crystal injection and treatment, while histological parameters such as leukocyte infiltration, IL-1ß and CXCL1 levels and tissue expression were considered as secondary outcomes. RESULTS: Prophylactic treatment with PD significantly diminished ankle swelling after 48 h from crystal injection. Secondary outcomes such as leukocyte infiltration, necrosis, edema, and synovitis were also decreased. PD caused a reduction in circulating levels of IL-1ß and CXCL1, as well as their tissue expression. By contrast, the therapeutic administration of PD did not have any beneficial effect. CONCLUSIONS: PD can effectively prevent acute inflammatory response to crystals in the mouse model of CPP crystal-induced arthritis. These results suggest that this bioactive compound might be used in the prevention of crystal-induced acute attacks in humans.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Experimental/prevenção & controle , Glucosídeos/farmacologia , Estilbenos/farmacologia , Doença Aguda , Animais , Artrite Experimental/induzido quimicamente , Pirofosfato de Cálcio , Quimiocina CXCL1/efeitos dos fármacos , Interleucina-1beta/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Tarso Animal/efeitos dos fármacos
10.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805383

RESUMO

There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). The aim of this study was to determine if prophylactic BBR use during the preclinical phase of collagen-induced arthritis would delay arthritic symptom onset, and to characterize the cellular mechanism underlying such an effect. DBA/1J mice were injected with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 18) to induce arthritis. Mice were then given i.p. injections of 1 mg/kg/day of BBR or PBS (vehicle with 0.01% DMSO) from days 0 to 28, were left untreated (CIA control), or were in a non-arthritic control group (n = 15 per group). Incidence of arthritis in BBR-treated mice was 50%, compared to 90% in both the CIA and PBS controls. Populations of B and T cells from the spleens and draining lymph nodes of mice were examined on day 14 (n = 5 per group) and day 28 (n = 10 per group). BBR-treated mice had significantly reduced populations of CD4+Th and CD4+CXCR5+ Tfh cells, and an increased proportion of Foxp3+ Treg at days 14 and 28, as well as reduced expression of co-stimulatory molecules CD28 and CD154 at both endpoints. The effect seen on T cell populations and co-stimulatory molecule expression in BBR-treated mice was not mirrored in CD19+ B cells. Additionally, BBR-treated mice experienced reduced anti-CII IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement for RA, and that its effect may be mediated specifically through T cell suppression. However, the cellular effector involved raises concern for BBR prophylactic use in the context of vaccine efficacy and other primary adaptive immune responses.


Assuntos
Artrite Experimental/prevenção & controle , Berberina/farmacologia , Linfócitos T/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/imunologia , Artrite Reumatoide/prevenção & controle , Linfócitos B , Berberina/uso terapêutico , Colágeno Tipo II/toxicidade , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos DBA , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Linfócitos T/imunologia
11.
Eur J Pharmacol ; 899: 174044, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33745959

RESUMO

The nuclear factor erythroid 2-related factor (Nrf2) signaling pathway has recently emerged as a novel therapeutic target in treating various diseases. Therefore, the present study aimed to assess the protective role of the Nrf2 activator, dimethyl fumarate (DMF) in the complete Freund's adjuvant (CFA)- induced arthritis model. DMF (25, 50, and 100 mg/kg) and dexamethasone (2 mg/kg) were orally administered for 14 days. Pain-related tests, paw volume, and arthritic scores were measured weekly. Serum TNF-α, IL-1ß, cyclic citrullinated peptide (CCP), C-reactive protein (CRP), and rheumatoid factor (RF) levels were estimated. Nitrite, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione (GSH), catalase (CAT), and myeloperoxidase (MPO) levels were also evaluated. NF-κB, Nrf2, HO-1, and COX-2 levels were estimated in the joint tissue. DMF treatment exerted anti-arthritic activity by enhancing the nociceptive threshold, improving arthritis scores, and reducing paw edema. Also, DMF suppressed changes in oxidative stress markers and inflammatory mediators and enhanced Nrf2 and HO-1 levels in CFA-injected rats. These findings indicate that the anti-arthritic activity of DMF may be mediated by the activation of the Nrf2/HO-1 pathway, which reduced oxidative damage and inflammation.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/prevenção & controle , Fumarato de Dimetilo/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Articulações/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/enzimologia , Artrite Experimental/patologia , Citocinas/metabolismo , Feminino , Adjuvante de Freund , Mediadores da Inflamação/metabolismo , Articulações/enzimologia , Articulações/patologia , Estresse Oxidativo/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Ratos Wistar , Transdução de Sinais
12.
Int J Mol Sci ; 22(3)2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33572654

RESUMO

Altered sialylation patterns play a role in chronic autoimmune diseases such as rheumatoid arthritis (RA). Recent studies have shown the pro-inflammatory activities of immunoglobulins (Igs) with desialylated sugar moieties. The role of neuraminidases (NEUs), enzymes which are responsible for the cleavage of terminal sialic acids (SA) from sialoglycoconjugates, is not fully understood in RA. We investigated the impact of zanamivir, an inhibitor of the influenza virus neuraminidase, and mammalian NEU2/3 on clinical outcomes in experimental arthritides studies. The severity of arthritis was monitored and IgG titers were measured by ELISA. (2,6)-linked SA was determined on IgG by ELISA and on cell surfaces by flow cytometry. Zanamivir at a dose of 100 mg/kg (zana-100) significantly ameliorated collagen-induced arthritis (CIA), whereas zana-100 was ineffective in serum transfer-induced arthritis. Systemic zana-100 treatment reduced the number of splenic CD138+/TACI+ plasma cells and CD19+ B cells, which was associated with lower IgG levels and an increased sialylation status of IgG compared to controls. Our data reveal the contribution of NEU2/3 in CIA. Zanamivir down-modulated the T and B cell-dependent humoral immune response and induced an anti-inflammatory milieu by inhibiting sialic acid degradation. We suggest that neuraminidases might represent a promising therapeutic target for RA and possibly also for other antibody-mediated autoimmune diseases.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inibidores Enzimáticos/administração & dosagem , Neuraminidase/antagonistas & inibidores , Zanamivir/administração & dosagem , Animais , Artrite Experimental/induzido quimicamente , Colágeno/efeitos adversos , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos C57BL , Orthomyxoviridae/enzimologia , Ácidos Siálicos/metabolismo
13.
Life Sci ; 273: 119260, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33636171

RESUMO

AIMS: Investigate the involvement of 15-hydroxyeicosatetraenoic acid (15-HETE), an anti-inflammatory molecule, on the beneficial effects of exercise therapy for osteoarthritis (OA). MAIN METHODS: 15-HETE (10 µM, twice a week) and monosodium iodoacetate (MIA) (1 mg) were injected into rat knee joints. Treadmill exercise was applied on OA rat. Primary rat chondrocytes were treated with 15-HETE, LY294002 and interleukin (IL)-1ß. Rats undergo a 1 hour single session treadmill exercise once. 15-HETE levels in the knee joint were evaluated using ELISA after a single session of treadmill exercise on healthy and OA rats. Matrix metalloproteinase (MMP)3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-5, p-Akt, Akt, and collagen type 2 (COL2) expression were evaluated using RT-PCR and western blotting. OA degree was evaluated using X-ray, scored by Osteoarthritis Research Society International (OARSI) and Mankin scores. COL2 and MMP-13 expression in articular was evaluated using immunohistochemistry. KEY FINDINGS: Medium intensity exercise alleviated OA. 15-HETE levels after exercise was increased. 15-HETE inhibited IL-1ß-induced inflammation in primary chondrocytes and increased p-Akt levels. LY294002 blocked the effect of 15-HETE in vitro. Finally, 15-HETE alleviated cartilage damage, inhibited MMP-13 expression, and increased COL2 expression in joint cartilage tissue. SIGNIFICANCE: Treadmill exercise alleviates OA and increases 15-HETE levels in the knee joint, which suppresses inflammation in chondrocytes via PI3k-Akt signalling in vitro and in vivo.


Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/prevenção & controle , Ácidos Hidroxieicosatetraenoicos/farmacologia , Inflamação/tratamento farmacológico , Osteoartrite/prevenção & controle , Condicionamento Físico Animal , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Ácido Iodoacético/toxicidade , Masculino , NF-kappa B/metabolismo , Osteoartrite/induzido quimicamente , Osteoartrite/patologia , Ratos , Ratos Sprague-Dawley
14.
Int J Med Sci ; 18(4): 861-872, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33456343

RESUMO

Osteoarthritis (OA) is a common joint disease characterized by degradation and inflammation of cartilage extracellular matrix. We aimed to evaluate the protective effect of Caragana sinica root (CSR) on interleukin (IL)-1ß-stimulated rat chondrocytes and a monosodium iodoacetate (MIA)-induced model of OA. In vitro, cell viability of CSR-treated chondrocytes was measured by MTT assay. The mRNA expression of Matrix metallopeptidases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) and extracellular matrix (ECM) were analyzed by quantitative real-time PCR (qRT-PCR). Moreover, the protein expression of MAPK (phosphorylation of EKR, JNK, p38), inhibitory kappa B (IκBα) and nuclear factor-kappa B (NF-κB p65) was detected by western blot analysis. In vivo, the production of nitric oxide (NO) was detected by Griess reagent, while those of inflammatory mediators, MMPs and ECM were detected by ELISA. The degree of OA was evaluated by histopathological analyses, Osteoarthritis Research Society International (OARSI) score and micro-CT analysis. CSR significantly inhibited the expression of MMPs, ADAMTSs and the degradation of ECM in IL-1ß-stimulated chondrocytes. Furthermore, CSR significantly suppressed IL-1ß-stimulated of MAPKs, NF-κB signaling pathway. In vivo, CSR and Indomethacin inhibited the production of inflammatory mediators, MMPs and degradation of ECM in MIA-induced model of OA. In addition, CSR improved the severity of OA. Taken together, these results suggest CSR is a potential therapeutic active agent in the treatment of OA.


Assuntos
Artrite Experimental/tratamento farmacológico , Caragana/química , NF-kappa B/metabolismo , Osteoartrite/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/imunologia , Artrite Experimental/patologia , Células Cultivadas , Condrócitos , Humanos , Mediadores da Inflamação/metabolismo , Ácido Iodoacético/administração & dosagem , Ácido Iodoacético/toxicidade , Masculino , Osteoartrite/induzido quimicamente , Osteoartrite/imunologia , Osteoartrite/patologia , Extratos Vegetais/isolamento & purificação , Raízes de Plantas/química , Cultura Primária de Células , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
15.
J Ethnopharmacol ; 271: 113883, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33508366

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Copaifera species folkloric names are "copaíbas, copaibeiras, copaívas or oil stick", which are widely used in Brazilian folk medicine. Among all ethnopharmacological applications described for Copaifera spp oleoresins, their anti-inflammatory effect stands out. However, the knowledge of anti-inflammatory and antinociceptive properties of Copaifera pubiflora Benth is scarce. AIM OF THE STUDY: To investigate the cytotoxic, anti-inflammatory, and antinociceptive activities of C. pubiflora oleoresin (CPO), and its major compound ent-hardwickiic acid (HA). MATERIAL AND METHODS: The phosphatase assay was used to evaluate the cytotoxicity of CPO and HA in three different cell lines. CPO and HA doses of 1, 3, and 10 mg/kg were employed in the biological assays. The assessment of motor activity was performed using open-field and rotarod tests. Anti-inflammatory activity of CPO and HA was assessed through luciferase assay, measurement of INF-γ, IL-1ß, IL-6, IL-10, and TNF-α in a multi-spot system with the immortalized cell line THP-1, zymosan-induced arthritis, and carrageenan-induced paw edema. Acetic acid-induced abdominal writhing and formalin tests were undertaken to evaluate the antinociceptive potential of CPO and HA. In addition, the evaluation using carrageenan was performed to investigate the effect of CPO in pain intensity to a mechanical stimulus (mechanical hyperalgesia), using the von Frey filaments. A tail-flick test was used to evaluate possible central CPO and HA actions. RESULTS: In the cytotoxicity evaluation, CPO and HA were not cytotoxic to the cell lines tested. CPO and HA (10 mg/kg) did not affect animals' locomotor capacity in both open-field and rotarod tests. In the luciferase assay, CPO and HA significantly reduced luciferase activity (p < 0.05). This reduction indicates a decrease in NF-κB activity. HA and CPO decreased INF-γ, IL-1ß, IL-6, IL-10, and TNF-α at 24 and 72 h in the multi-spot system. In zymosan-induced arthritis, CPO and HA decreased the number of neutrophils in the joint of arthritic mice and the number of total leukocytes (p < 0.05). In experimental arthritis HA significantly decreased joint swelling (p < 0.05). CPO and HA also increased the mechanical threshold during experimental arthritis. HA and CPO significantly inhibited the carrageenan-induced paw edema, being the doses of 10 mg/kg the most effective, registering maximum inhibitions of 58 ± 8% and 76 ± 6% respectively, p < 0.05. CPO and HA reduced the nociceptive behavior in both phases of formalin at all tested doses. The highest doses tested displayed inhibitions of 87 ± 1% and 72 ± 4%, respectively, p < 0.001, in the first phase, and 87 ± 1% and 81 ± 2%, respectively, p < 0.001, in the second phase. Oral treatment of CPO and HA (1, 3, 10 mg/kg) significantly reduced the nociceptive response in acetic acid-induced abdominal writhings, and the 10 mg/kg dose was the most effective with maximum inhibitions of 86 ± 2% and 82 ± 1%, respectively, p < 0.001. Both HA and CPO significantly decreased the intensity of mechanical inflammatory hyper-nociception on carrageenan-induced hyperalgesia at all tested doses, and 10 mg/kg was the most effective dose with maximum inhibitions of 73 ± 5% and 74 ± 7%, respectively, p < 0.05.CPO increased the tail-flick latencies in mice, and concomitant administration of naloxone partially reduced its effect. CONCLUSIONS: CPO and HA may inhibit the production of inflammatory cytokines by suppressing the NF-κB signaling pathway, resulting in anti-inflammatory and antinociceptive activities.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Diterpenos/uso terapêutico , Edema/tratamento farmacológico , Fabaceae/química , Extratos Vegetais/uso terapêutico , Ácido Acético/toxicidade , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Brasil , Carragenina/toxicidade , Linhagem Celular , Citocinas/metabolismo , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Edema/induzido quimicamente , Formaldeído/toxicidade , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Locomoção/efeitos dos fármacos , Medicina Tradicional , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Zimosan/toxicidade
16.
BMC Complement Med Ther ; 21(1): 39, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33478498

RESUMO

BACKGROUND: Curcumin, a natural polyphenolic substance, has been known for more than two millennia as having strong anti-inflammatory activity towards multiple ailments, including arthritis. The main drawback of curcumin is its poor solubility in water, which leads to low intestinal absorption and minimal bioavailability. In this study, we aimed to compare the anti-arthritic in vivo effect of different curcumin preparations - basic curcumin extract, micellar curcumin, curcumin mixture with piperine, and microencapsulated curcumin. METHODS: Arthritis was induced in Wistar rats by complete Freund's adjuvant, and the severity of arthritis was evaluated daily using the arthritis score system. Curcumin preparations were given to animals per os daily for 20 consecutive days, starting at 6th day after arthritis induction. To determine the inflammatory background, pro-inflammatory cytokines were determined using the ELISA test. In addition, hematologic test, weight change, and limb swelling were tracked. RESULTS: Our results indicate that curcumin had a rather weak effect on arthritis progression in the Wistar rat model, microencapsulated curcumin effectively prevented the progression of arthritis - the disease stabilized after 10 days of supplementation. It also reduced the levels of immune cells (neutrophils and leukocytes), as well as pro-inflammatory cytokines - TNFα, IL-1, and IL-6, which levels were close to arthritis-free control. Other formulations of curcumin had lower or no effect on arthritis progression. CONCLUSION: Our study shows that the same concentrations of curcumin had a distinctly expressed positive anti-inflammatory effect depending on the form of its delivery. Specifically, we found that microencapsulated curcumin had the most promising effect for treatment.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Artrite Experimental/tratamento farmacológico , Curcumina/administração & dosagem , Curcumina/química , Composição de Medicamentos/métodos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/genética , Artrite Experimental/imunologia , Citocinas/imunologia , Feminino , Adjuvante de Freund/efeitos adversos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Ratos , Ratos Wistar
17.
Acta Biochim Pol ; 68(1): 71-76, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33480230

RESUMO

PURPOSE: To develop a novel intraarticular injection of diclofenac for the treatment of arthritis. METHOD: Diclofenac loaded nanoparticles were prepared by a nanoprecipitation technique using Eudragit L 100 as the polymer and polyvinyl alcohol as the surfactant. The nanoparticles were evaluated for particle size, zeta potential, scanning electron microscopy, drug release, encapsulation efficiency, and loading efficiency studies. The optimized nanoparticulate formulation was developed for intra articular injection. Intraarticulate injection was evaluated for pH, appearance, viscosity, osmolarity and syringability studies. The optimized injection formulation was tested in an arthritic model consisting of 25 rabbits. RESULT: Nanoprecipitation method was found to be suitable for diclofenac nanoparticles. The shape of the prepared nanoparticles was found to be spherical and devoid of any cracks and crevices. The average particle size of a diclofenac nanoparticle was found to range from 87±0.47 to 103±0.26 nm. The zeta potential of the prepared nanoparticles was found to be in the range of 0.598±0.34 to 0.826±0.25 mV. The encapsulation efficiency was found to be between 73.45% to 99.03%, while the drug loading was observed between 10.34 to 35.32%. The percentage drug release at 12 hours was found to range from 73.45% to 99.03%. CONCLUSION: The developed intraarticular injection was found to be within the physically and chemically accepted limits. Animals treated with the intra articular injection of diclofenac showed a significant reduction in swelling as compares to the other groups.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Experimental/tratamento farmacológico , Diclofenaco/administração & dosagem , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Injeções Intra-Articulares/métodos , Nanopartículas/química , Animais , Artrite Experimental/induzido quimicamente , Precipitação Química , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Feminino , Masculino , Tamanho da Partícula , Ácidos Polimetacrílicos/química , Álcool de Polivinil/química , Coelhos , Soroalbumina Bovina/administração & dosagem , Soroalbumina Bovina/efeitos adversos , Resultado do Tratamento
18.
J Ethnopharmacol ; 271: 113837, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33460755

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Saposhnikovia divaricata (SD), a Chinese crude drug, has long been recognized for therapeutic effect to rheumatoid arthritis (RA). At present, the mechanisms of SD treatment in RA have not been fully understood especially on the perspective of metabolomics. AIM OF THE STUDY: To study the pharmacodynamic effects of Saposhnikovia divaricata decoction on CIA rats, and explore the therapeutic mechanism by metabolomics methods. MATERIALS AND METHODS: Wistar rats were randomly divided into normal group, CIA model group, dexamethasone group and SD decoction groups (10 g crude drug/kg, 5 g crude drug/kg and 2.5 g crude drug/kg of SDD). Body weight, arthritis scores, serum cytokine levels and histopathological parameters of rats were assessed. A metabolomics method based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOFMS) was established to collect the metabolic profiles of rats and explore the metabolic changes that occurred after SDD treatment. RESULTS: SDD showed its protective effect on the affected joints, especially in the middle dosage group of SDD. Eighteen and 13 potential biomarkers for the SDD treatment of CIA rats were identified in the plasma and urine, respectively. SDD could regulate the disturbed metabolic pathways including tryptophan metabolism, glycerophospholipid catabolism, primary bile acid biosynthesis and fatty acid metabolism. CONCLUSIONS: In summary, SDD treatment could effectively alleviate symptoms of RA and regulate metabolic disorders in CIA rats.


Assuntos
Anti-Inflamatórios/farmacologia , Apiaceae/química , Artrite Experimental/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Animais , Articulação do Tornozelo/metabolismo , Articulação do Tornozelo/patologia , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Biomarcadores/sangue , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Colágeno/toxicidade , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Masculino , Espectrometria de Massas , Ratos Wistar , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos
19.
J Ethnopharmacol ; 271: 113849, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33485983

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea laniceps Hand.-Mazz. (Compositae) is a representative "snow lotus" herb well known in Chinese folk medicine to treat inflammation-related diseases such as arthritis. S. laniceps (SL) shows anti-inflammatory and analgesic potencies and contains various constituents potentially with cyclooxygenase-2 (COX-2) selective inhibition. The herb is a valuable source of natural alternatives to synthetic COX-2 selective nonsteroidal anti-inflammatory drugs, a common medication for rheumatoid arthritis (RA) and osteoarthritis (OA) reported with serious cardiovascular side effects. AIM OF THE STUDY: Based on an innovative drug screening platform, this study aimed to discover safe, effective COX-2 selective inhibitors from SL. MATERIALS AND METHODS: An enzyme-anchored nanomagnetic fishing assay was developed to separate COX-2 ligands from SL. Cell and animal models of cardiomyocytes, lipopolysaccharide-stimulated macrophages, rat adjuvant-induced arthritis, and anterior cruciate ligament transection-induced OA rats, were adopted to screen the single/combined ligands regarding toxicity and bioactivity levels. Molecular docking was employed to unravel binding mechanisms of the ligands towards COX-1 and COX-2. RESULTS: Four COX-2 selective compounds were separated from SL using optimized COX-2-functionalized magnetic nanoparticles. All the four ligands were proved with evidently lower cardiotoxicity both in vitro and in vivo than celecoxib, a known COX-2 selective inhibitor. Two ligands, scopoletin and syringin, exhibited potent anti-arthritic activities in rat models of RA and OA by alleviating clinical statuses, immune responses, and joint pathological features; their optimum combination ratio was discovered with stronger remedial effects on rat OA than single administrations. The COX-1/2 binding modes of the two phytochemicals contributed to explain their cardiac safety and therapeutic performances. CONCLUSIONS: The screened chemicals are promising to be developed as COX-2 selective inhibitors as part of treating RA and OA. The hybrid strategy for discovering therapeutic agents from SL is shown here to be efficient; it should be equally valuable for finding other active chemicals in other natural sources.


Assuntos
Inibidores de Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Descoberta de Drogas/métodos , Medicamentos de Ervas Chinesas/farmacologia , Nanopartículas Magnéticas de Óxido de Ferro/química , Nanoconjugados/química , Saussurea/química , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Celecoxib/efeitos adversos , Linhagem Celular , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Medicamentos de Ervas Chinesas/efeitos adversos , Medicamentos de Ervas Chinesas/química , Glucosídeos/efeitos adversos , Glucosídeos/farmacologia , Articulações/diagnóstico por imagem , Articulações/patologia , Ligantes , Simulação de Acoplamento Molecular , Células Musculares/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Osteoartrite/etiologia , Fenilpropionatos/efeitos adversos , Fenilpropionatos/farmacologia , Componentes Aéreos da Planta/química , Ratos Sprague-Dawley , Escopoletina/efeitos adversos , Escopoletina/farmacologia , Remodelação Ventricular/efeitos dos fármacos
20.
Nutrients ; 13(2)2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499113

RESUMO

: Oleuropein (OL), an olive tree secoiridoid and its peracetylated derivate (Per-OL) have exhibited several beneficial effects on LPS-stimulated macrophages and murine experimental systemic lupus erythematosus (SLE). This study was designed to evaluate dietary Per-OL in comparison with OL supplementation effects on collagen-induced arthritis (CIA) murine model. Three-weeks-old DBA-1/J male mice were fed from weaning with a standard commercial diet or experimental enriched-diets in 0.05 % (w/w) OL, 0.05% and 0.025% Per-OL. After six weeks of pre-treatment, arthritis was induced by bovine collagen type II by tail base injection (day 0) and on day 21, mice received a booster injection. Mice were sacrificed 42 days after the first immunization. Both Per-OL and OL diets significantly prevented histological damage and arthritic score development, although no statistically significant differences were observed between both compounds. Also, serum collagen oligomeric matrix protein (COMP), metalloprotease (MMP)-3 and pro-inflammatory cytokines levels were ameliorated in paws from secoiridoids fed animals. Mitogen-activated protein kinases (MAPK)s and nuclear transcription factor-kappa-B (NF-κB) activations were drastically down-regulated whereas nuclear factor E2-related factor 2 (Nrf2) and heme-oxygenase-1 (HO-1) protein expressions were up-regulated in those mice fed with OL and Per-OL diets. We conclude that both Per-OL and its parent compound, OL, supplements might provide a basis for developing a new dietary strategy for the prevention of rheumatoid arthritis.


Assuntos
Artrite Experimental/dietoterapia , Inflamassomos/efeitos dos fármacos , Glucosídeos Iridoides/farmacologia , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Heme Oxigenase-1/metabolismo , Inflamassomos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
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