Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur J Hum Genet ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001840

RESUMO

Ankylosing spondylitis (AS) is a common complex inflammatory disease; however, up to now distinct genes with monogenic pattern have not been reported for this disease. In the present study, we report a large Iranian family with several affected members with AS. DNAs of the three affected and two healthy cases were chosen for performing whole-exome sequencing (WES). After several filtering steps, candidate variants in the following genes were detected: RELN, DNMT1, TAF4ß, MUC16, DLG2, and FAM208. However, segregation analysis confirmed the association of only one variant, c.7456A>G; p.(Ser2486Gly) in the RELN gene with AS in this family. In addition, in silico predictions supported the probable pathogenicity of this variant. In this study, for the first time, we report a novel variant in the RELN gene, c.7456A>G; p.(Ser2486Gly), which completely co-segregates with AS. This association suggests potential insights into the pathophysiological bases of AS and it could broaden horizons toward new therapeutic strategies.

2.
Cytokine ; 128: 154997, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31978612

RESUMO

BACKGROUND: Ankylosing spondylitis (AS) is an auto-inflammatory debilitating disorder with a complex pathogenesis. The adenosinergic pathway is an immunologic regulating pathway with a potential role in AS pathophysiology. In the present study, we have aimed to investigate the influence of A2A adenosine receptor (A2AAR) activation on tumor necrosis factor-α (TNF-α) and interleukin-23 (IL-23) expression and secretion by monocyte-generated macrophages of AS patients. METHODS: Whole-blood separated monocytes were extracted from 14 AS patients and 14 healthy controls. Macrophages were differentiated by macrophage colony-stimulating factor (M-CSF), and surface markers were confirmed by flow cytometer. Cells were treated with CGS-21680 as a known agonist of A2AAR. Analysis of ADORA2A, TNFA, and IL23A gene expression was performed by SYBR green real-time PCR. The concentration of secreted cytokines was also measured by ELISA kits. RESULTS: Based on our analysis, CGS-21680 significantly decreased TNF-α secretion by monocyte-derived macrophages of AS patients. Moreover, A2AAR agonist increased the IL23A mRNA expression level in monocyte-derived macrophages of AS patients considerably. Whereas, CGS-21680 did not have any influence on macrophages of healthy individuals. CONCLUSION: According to our results, it appears that A2AAR activation can increase IL-23 secretion by monocyte-derived macrophages of AS patients. Although the TNF-α reducing effect of A2AAR agonists can be a potential target in AS treatment, robust increasing of IL-23 should be considered as the undesirable effect of these agents.

3.
Int J Rheum Dis ; 2019 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-31884692

RESUMO

BACKGROUND: Ankylosing spondylitis (AS) is a multifactorial rheumatic disease which mainly involves the axial skeleton. Macrophages and extracellular nucleotides have been shown to contribute to the inflammation process in autoimmune diseases. Membrane-bound purinergic P2 receptors might be involved in the modulation of immune cells in AS. Therefore, we aimed to analyze the messenger RNA (mRNA) expression of P2 receptors in the macrophages of AS patients and healthy controls. METHODS: Twenty-three AS patients and 23 age- and sex-matched healthy individuals were included in our study. Whole blood-separated monocytes of study participants were stimulated by macrophage colony-stimulating factor for 7 days and differentiated to macrophages. Monocyte and macrophage markers were analyzed by flow cytometry. SYBR green real-time polymerase chain reaction was used to measure the relative expression levels of P2RX1 , P2RX2 , P2RX3 , P2RX4 , P2RX5 , P2RX6 , P2RX7 , P2RY1 , P2RY2 , P2RY4 , P2RY6 , P2RY11 , P2RY12 , P2RY13 , P2RY14 , and PANX1 genes. RESULTS: P2RY13 and P2RY6 genes had the highest expression levels in macrophages among P2RY genes. P2RY1 mRNA expression was significantly down-regulated (-1.75 fold) and P2RY14 was up-regulated (2.6 fold) in macrophages of AS patients compared to healthy individuals. P2RX4 gene had the highest expression in monocyte-derived macrophages, followed by P2RX7 and P2RX1  genes. There was no significant difference in P2X receptor mRNA expression level between macrophages of AS patients and healthy individuals. CONCLUSIONS: Our results indicate that AS patients show altered expression levels of P2 receptor genes. Moreover, these changes might be associated with disease activity and patients' status.

4.
Pharmacol Rep ; 71(3): 393-398, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003148

RESUMO

BACKGROUND: To assess the therapeutic efficacy, safety and tolerability of Guluronic acid (G2013) in patients with ankylosing spondylitis (AS) patients. METHODS: This investigation was a 12-week randomized, placebo-controlled, phase I/II clinical trial involving 75 AS patients that were randomly divided into 3 groups: 25 as placebo, 25 Guluronic acid and 25 naproxen groups. Patients who had AS with active disease at baseline according to the modified New York criteria were considered for this trial. The primary consequence measure was the Appraisement of Spondyloarthritis International Society (ASAS) 20 response-rate at week 12. RESULTS: There were no statistically significant differences between groups at the entry. ASAS20 response at week 12 was achieved (60.8%) in patients receiving Guluronic acid compared with - (68.4% of) - patients in the naproxen group (p > 0.05) and (21.0%) of patients in the placebo group. In comparison with the placebo group from the baseline to week 12, patients who received Guluronic acid and naproxen showed significantly greater improvement in all secondary endpoints. Moreover, Guluronic acid decreased some inflammatory parameters more dramatically than naproxen and placebo group. Patients in the naproxen group had more incidence of gastrointestinal and others adverse events in comparison with Guluronic acid and placebo groups. CONCLUSION: The present research indicated that Guluronic acid and naproxen are similar in terms of efficacy. However, Guluronic acid had more notable safety characteristics identifying information than naproxen. Accordingly, it is proposed that Guluronic acid could be appropriate for management of AS. Clinical trial identifier; IRCT2016091813739N4.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Ácidos Hexurônicos/efeitos adversos , Ácidos Hexurônicos/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Adulto , Feminino , Humanos , Inflamação/tratamento farmacológico , Masculino , Naproxeno/uso terapêutico , Resultado do Tratamento
5.
PLoS Genet ; 15(4): e1008038, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946743

RESUMO

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1ß, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1ß, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1ß and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1ß function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.


Assuntos
Febre Familiar do Mediterrâneo/genética , Pirina/genética , Espondilite Anquilosante/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Febre Familiar do Mediterrâneo/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígeno HLA-B27/genética , Antígeno HLA-B51/genética , Humanos , Interleucina-1beta/sangue , Interleucina-23/sangue , Irã (Geográfico) , Masculino , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/imunologia , Turquia
6.
Int J Rheum Dis ; 22(6): 1107-1114, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30834699

RESUMO

AIM: Impaired regulation of immune tolerance results in autoimmune diseases, such as rheumatoid arthritis (RA). Survivin is an anti-apoptotic protein and can induce cellular mitosis. In the current study, we assessed the transcript level of total survivin (survivin-TS) and its three major variants and evaluated the expression level of important micro RNAs (miRNAs) involved in survivin expression regulation in RA patients. METHOD: Peripheral blood mononuclear cells (PBMCs) were isolated from 50 healthy controls and 50 RA-active patients. RNA extraction was performed and then single-strand complementary DNA was synthesized. Quantitative real-time polymerase chain reaction was used to assess the expression level of survivin-TS and its variants with effective miRNAs in PBMCs. RESULTS: Overexpression of survivin-2B (fold change = 1.57, P = 0.005), survivn-ΔEx3 (fold change = 1.93, P = 0.009) and downregulation of survivin-WT (fold change = 0.64, P = 0.0002) were found in PBMCs of patients, while messenger RNA (mRNA) expression of survivin-TS had no significant difference between RA patients and controls. Expression levels of miR-335-5p, miR-485-5p, miR-16-5p, miR-150-5p, miR-34a-5p, and miR-203a-3p were significantly increased in PBMCs from patients compared with healthy controls. In a correlation study, dysregulation of these miRNAs were not correlated with mRNA expression level of survivin. CONCLUSION: While survivin-TS was not differently expressed in RA patients, its variants had altered expression. Although miRNAs were aberrantly expressed in PBMCs from RA subjects, they did not regulate survivin-TS. miRNAs might be involved in RA pathogenesis, but not through controlling survivin.


Assuntos
Artrite Reumatoide/sangue , Leucócitos Mononucleares/metabolismo , MicroRNAs/sangue , RNA Mensageiro/sangue , Survivina/sangue , Adulto , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Mensageiro/genética , Survivina/genética
7.
J Cell Biochem ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30485530

RESUMO

BACKGROUND: Copy number variation (CNV) of DNA segments has been considered as an important component of genetic variation, affecting the quality and quantity of gene expression. Bone morphogenic protein 8A (BMP8A) has been reported to function in bone formation. With respect to the bone and joint complications in ankylosing spondylitis (AS), this investigation aimed to study the role of BMP8A gene CNV in impressing the gene expression as well as the disease risk. METHODS: A total of 900 individuals, including 450 patients with AS and 450 healthy controls were enrolled. The copy numbers of BMP8A gene were detected by TaqMan real-time polymerase chain reaction (PCR) method. BMP8A messenger RNA (mRNA) transcript level in peripheral blood mononuclear cells (PBMCs) was also measured by SYBR Green real-time gene expression PCR method. RESULTS: No significant association of BMP8A copy number was detected with the risk of AS. BMP8A mRNA expression level was significantly downregulated in patients compared with controls. mRNA expression level of BMP8A in both AS patients with and without syndesmophyte was significantly lower than the healthy control group. There was no correlation between the mRNA expression level of BMP8A and both demographic and clinical data of the patients. CONCLUSIONS: Although BMP8A gene expression was downregulated in patients with AS, its copy number could not affect the transcript level of BMP8A gene in PBMCs and was not associated with susceptibility to AS in Iranian population. BMP8a may take into account as an indicator of bone formation process in AS, but it seems that mechanisms other than CNV may regulate this protein.

8.
Immunopharmacol Immunotoxicol ; 40(5): 393-400, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30265175

RESUMO

Background: Ankylosing spondylitis (AS) is a common debilitating rheumatic disease in which the innate immune components especially the Interleukin (IL)-23/IL-17 axis related genes play important role in its pathogenesis. Nucleotide binding oligomerization domain-containing protein (NOD)2, as an innate receptor, is critical for IL-23 production in cells. Therefore, we aimed to stimulate NOD2 signaling and study its effects on cytokine production in peripheral blood mononuclear cells (PBMC) of these patients. Methods: PBMCs from 18 patients with active AS and 18 healthy individuals were separated by Ficoll-Hypaque density gradient centrifugation and cultured in the presence of muramyl dipeptide (MDP), as NOD2 ligand. Quantitative expression analysis of NOD1, NOD2, RIPK2, SLC15A4, NLRP1, NLRP3, IL23A, IL17A, IL1B, and TNFA genes was performed using Real-time polymerase chain reaction (PCR). Finally, protein changes of IL23A and IL17A expression were validated using enzyme linked immunosorbent assay (ELISA). Results: Apart from NOD1 that tend to be downregulated in the controls, all the selected genes showed overexpression in response to MDP in cells from the studied groups. Except RIPK2, all the genes had higher expression changes upon MDP stimulation in the AS population. Overexpression of IL23A and IL17A were confirmed at protein levels using ELISA. The strong positive correlation between NLRP3 and NOD2 was decreased after stimulation but new correlations between NLRP3 and IL1B, RIPK2 and SLC15A4 were observed after treatment. Conclusions: This study indicated that AS PBMCs were hyper-responsive to MDP stimulation. This observation implies an important role of NOD2 in the pathogenesis of inflammatory diseases including AS.


Assuntos
Acetilmuramil-Alanil-Isoglutamina/farmacologia , Leucócitos Mononucleares/imunologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Espondilite Anquilosante/imunologia , Acetilmuramil-Alanil-Isoglutamina/imunologia , Adulto , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/genética , Interleucina-17/genética , Interleucina-17/imunologia , Subunidade p19 da Interleucina-23/genética , Subunidade p19 da Interleucina-23/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Espondilite Anquilosante/sangue
9.
Avicenna J Med Biotechnol ; 10(3): 178-182, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30090213

RESUMO

Background: Ankylosing Spondylitis (AS) is a chronic autoinflammatory Spondyloarthropathy (SpA) which is characterized by sacroiliitis, which progresses to the axial skeleton. It seems that non-Human Leukocyte Antigen (HLA) and also HLA-B27 are associated with the susceptibility and pathogenesis of the disease. The recent Ge-nome-Wide Association Studies (GWASs) have reported intergenic rs6759298 to be associated with AS etiology. The aim of this study was investigation of the rs6759298 polymorphism in Iranian AS patients. In addition, probable correlations with clinical indices and manifestations were considered. Methods: This study included 403 patients with AS. The control group consisted of 506 healthy individuals who were matched for sex, age, and ethnicity with AS group. Genotyping of rs6759298 was determined using the Amplification-Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). Results: The GG genotype and G allele were found to be significantly more prevalent in the patient group in comparison to the control group [(p=2×10-6 and 7.44×10-9; OR (95% CI) =2.16 (1.56-2.98) and 1.73 (1.43-2.08)], respectively. Conclusion: No associations were found between patients with three genotypes and any disease manifestations or clinical indices. This investigation confirmed a highly significant association of rs6759298 with disease susceptibility, with no effect on disease progress or clinical presentations. Since rs6759298 belongs to the 2p15 gene desert, further studies would elucidate the exact role of this polymorphism in the pathogenesis of AS.

10.
Inflammopharmacology ; 26(3): 737-745, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29696564

RESUMO

BACKGROUND: Following the potent efficacy of ß-D-mannuronic acid (M2000) in phase I/II trial in ankylosing spondylitis patients, the present clinical trial was conducted to evaluate the efficacy, safety, and tolerability of this novel drug in rheumatoid arthritis (RA) patients who had inadequate response to conventional therapy. METHOD: The study was a 12-week randomized, controlled, phase I/II clinical trial with two treatment arms: M2000 and conventional treatment. Patients who had RA according to the modified American College of Rheumatology (ACR) criteria, with active disease at baseline also inadequate response to conventional therapy, were enrolled in this study. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety. RESULTS: There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000-treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P = 0.011). 10% of M2000-treated patients and 57.1% of conventional-treated patient's adverse events occurred during this study. CONCLUSION: Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Ácidos Hexurônicos/administração & dosagem , Administração Oral , Adulto , Idoso , Antirreumáticos/efeitos adversos , Quimioterapia Combinada , Feminino , Ácidos Hexurônicos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
11.
Clin Rheumatol ; 37(6): 1589-1595, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29524036

RESUMO

Macrophages play an important role in the ankylosing spondylitis (AS) auto-inflammatory responses and fibrocartilage destruction. Adenosine is a key modulator of inflammatory conditions. The various effects of adenosine are mediated by its interaction with adenosine receptors (AR). In this study, we investigated the mRNA expression of A1, A2A, A2B, and A3 adenosine receptors, ectonucleoside triphosphate diphosphohydrolase-1 (CD39), and ecto-5'-nucleotidase (CD73) in the monocyte-derived macrophages from AS patients in comparison to healthy controls. We also explored the correlation between analyzed gene expression and patients' clinical manifestations. Whole blood-separated monocytes from 23 healthy controls and 23 active AS patients were stimulated by macrophage colony-stimulating factor (M-CSF) for 7 days and differentiated to macrophages. Monocyte and macrophage markers were analyzed by flow cytometry. Analysis of adenosine receptors (ADORA1، ADORA2A، ADORA2B، ADORA3), CD39 and CD73 gene expression was performed by SYBR green real-time PCR. Our results demonstrated monocyte-derived macrophages from AS patients expressed increased level of A2AAR and reduced level of A1, A2BAR, and CD39 mRNA compared to healthy controls. We found an inverse correlation between A2AAR mRNA expression and Bath Ankylosing Spondylitis Functional Index (BASFI) score in AS patients. According to our results, altered expression level of adenosine-relying system would be involved in AS macrophage dysfunction and inflammation and correlated with functional status in AS patients.


Assuntos
5'-Nucleotidase/metabolismo , Apirase/metabolismo , Macrófagos/metabolismo , Receptores Purinérgicos P1/metabolismo , Espondilite Anquilosante/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Proteínas Ligadas por GPI/metabolismo , Humanos , Masculino , Adulto Jovem
12.
Inflammopharmacology ; 26(1): 57-65, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29063487

RESUMO

OBJECTIVE: This study aimed at investigating the inhibitory effect of ß-D-mannuronic acid (M2000) on the Th17 circulating levels and IL-17 a related cytokine in rheumatoid arthritis (RA) patients. METHODS: The study included 27 patients with RA who had failed response to treatment. All patients were treated orally by M2000 at a dose of 500 mg twice daily for 12 weeks (Clinical trial identifier: IRCT2014011213739N2). The patients based on anti-tumor necrosis factor alpha (TNFα) blocker treatment were classified into two groups (conventional group and etanercept group). They were then allowed to continue their treatment excluding non-steroidal anti-inflammatory drugs (NSAIDs). The frequency of circulating Th17 cells and IL-17 serum level were determined before and 12 weeks after M2000 therapy and were compared to the healthy controls by using flow cytometry analysis and ELISA method, respectively. RESULTS: At baseline, higher circulating Th17 and IL-17 serum levels were significantly observed in both groups of RA patients than in the healthy controls (all P < 0.001). The frequency of Th17 cells significantly decreased in the conventional group as well as in the etanercept group after M2000 therapy but the level of reduction was higher in the conventional group compared to the etanercept group (P < 0.03 and P < 0.04, respectively). The IL-17 serum level significantly decreased in both groups after M2000 therapy (P < 0.01 and P < 0.02, respectively). Furthermore, the frequency of Th17 cells was positively correlated with Disease Activity Score (DAS28) (r = 0.34, P = 0.02). CONCLUSION: M2000 shows the inhibitory effect on the frequency of circulating Th17 cells as well as in the production of IL-17 in RA patients.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Ácidos Hexurônicos/uso terapêutico , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Adulto , Idoso , Artrite Reumatoide/metabolismo , Estudos de Casos e Controles , Citocinas/metabolismo , Etanercepte/uso terapêutico , Feminino , Humanos , Interleucina-17/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo
13.
Int Immunopharmacol ; 54: 112-117, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29127910

RESUMO

OBJECTIVE: To evaluate the efficacy, safety and tolerability of ß-d-mannuronic acid (M2000) in the treatment of ankylosing spondylitis (AS). METHODS: The study was a 12-week randomized, double-blind, placebo-controlled, phase I/II clinical trial with 3 treatment arms: placebo, ß-d-mannuronic acid and naproxen. Patients who had AS according to the modified New York criteria, with active disease at baseline were eligible for study. Primary outcome measure was the Assessment of SpondyloArthritis international Society (ASAS) 20 response rate at week 12. RESULTS: Of the 85 randomized patients, 27 were allocated to receive placebo, 28 naproxen, and 30 ß-d-mannuronic acid. There were no statistically significant differences between treatment groups at baseline. Of the patients receiving ß-d-mannuronic acid, 57.7% achieved an ASAS20 response at week 12, compared with 59% of the patients in the naproxen group (P>0.05) and 19% of the patients in the placebo group (P=0.007). In comparison with patients receiving placebo over the 12-week treatment period, those receiving ß-d-mannuronic acid and naproxen demonstrated statistically significantly greater improvement in all secondary endpoints. Interestingly, ß-d-mannuronic acid reduced some parameters associated with inflammation more effectively than naproxen and placebo. The incidence of gastrointestinal and other adverse events were higher on naproxen than on ß-d-mannuronic acid and placebo. CONCLUSION: The present study demonstrated similar efficacy, but with a more favorable safety profile for ß-d-mannuronic acid than naproxen and, therefore, suggest that ß-d-mannuronic acid is suitable for the management of AS. TRIAL REGISTRATION: Iranian registry of clinical trials; www.irct.ir; IRCT2013062213739N1.


Assuntos
Anti-Inflamatórios/uso terapêutico , Ácidos Hexurônicos/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Adulto , Antirreumáticos/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Irã (Geográfico) , Masculino , Naproxeno/uso terapêutico , Efeito Placebo , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
14.
Inflammopharmacology ; 26(2): 375-384, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28819782

RESUMO

Ankylosing spondylitis (AS) is a debilitating chronic inflammatory disease with genetic predisposition, which is characterized by the involvement of spine and sacroiliac joints. Due to the relatively unsuccessful treatments, we designed ß-D-mannuronic (M2000) with the beneficial effects in various experimental models as a novel non-steroidal anti-inflammatory drug (NSAID). The aims of our present study were: first, to compare the therapeutic effects of M2000, as a novel designed NSAID, with naproxen and placebo in Iranian patients with AS during 12 weeks; second, to evaluate the effect of M2000 on gene expression of cyclooxygenase enzyme (COX-1/COX-2), a key enzyme in the initiation of inflammatory pathways in AS patients; and third, to assess the activity of COX-1 and COX-2 enzymes in the presence/absence of M2000 at the different doses in the murine macrophage, J774 cell line. This was a sub-study of phase II, randomized, placebo-controlled trial with three treatment arms: M2000, naproxen, and placebo. The outcome measures were the mean changes from baseline to week 12. The gene expression was assessed by real-time PCR. The COX-1 and COX-2 activities were evaluated by ELISA in J774 cell line induced by LPS and arachidonic acid (AA). Our findings demonstrated that M2000 had beneficial therapeutic effects on pain, stiffness, and inflammation, whereas no adverse effects were observed following the use of M2000 after 12 weeks. The analysis of gene expression showed that M2000 could effectively reduce the expression levels of COX-1 and COX-2 in comparison with untreated patients. In addition, the enzymatic activities in the presence of M2000 were significantly less than LPS- and AA-treated groups. Our results indicate that M2000, as a novel designed NSAID with immunosuppressive properties, can be considered as one of the therapeutic options for the treatment of inflammatory diseases without adverse events. Clinical trial identifier IRCT2013062213739N1/ http://www.IRCT.ir .


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica/efeitos dos fármacos , Ácidos Hexurônicos/uso terapêutico , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Espondilite Anquilosante/tratamento farmacológico , Adulto , Animais , Linhagem Celular , Feminino , Humanos , Imunossupressores/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Irã (Geográfico) , Macrófagos/metabolismo , Masculino , Camundongos , Monócitos/metabolismo , Espondilite Anquilosante/metabolismo
15.
Iran J Allergy Asthma Immunol ; 16(5): 433-442, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29149783

RESUMO

The aim of this study was to investigate the effect of ß-D-mannuronic acid (M2000) on hematological parameters in patients with active rheumatoid arthritis. This study was conducted on 25 patients with active rheumatoid arthritis (RA) (identifier: IRCT2014011213739N2). M2000 was administered orally for anemic and non-anemic RA patients at a dose of 500 mg twice daily for 12 weeks. The patients were permitted to continue the conventional treatments excluding NSAIDs. Blood samples were collected at baseline, 4 and 12 weeks after drug administration and were tested for hematological parameters. Moreover, serum levels of TNF-α and IL-6 were analysed before and after M2000 therapy compared to healthy controls using enzyme linked immunosorbent assay method. We found a significant increase in the count of red blood cells and also hemoglobin (Hb) concentration (0.9 g/dL) in anemic patients after 12 weeks of M2000 therapy (p<0.02 and p<0.01, respectively). Furthermore, our results showed an improvement in Hb level (0.45 g/dL) even in non-anemic patients who were treated by M2000 (p<0.04). The leukocytosis in RA patients, significantly decreased in both anemic and non-anemic patients after 12 weeks of M2000 therapy (p<0.02 and p<0.03, respectively). The percent of neutrophils significantly increased in anemic patients (p<0.01) while in non-anemic patients it significantly decreased after 12 weeks of M2000 therapy (p<0.01). The serum levels of IL-6 and TNF-α significantly decreased after 12 weeks of M2000 therapy (p<0.01 and p<0.04, respectively). M2000 improves hematological parameters in RA patients by its potent inhibitory effect on serum levels of TNF-α and IL-6.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Ácidos Hexurônicos/uso terapêutico , Imunossupressores/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Reumatoide/imunologia , Biomarcadores , Citocinas/sangue , Citocinas/metabolismo , Índices de Eritrócitos/efeitos dos fármacos , Feminino , Ácidos Hexurônicos/farmacologia , Humanos , Imunossupressores/imunologia , Imunossupressores/farmacologia , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
16.
Arthritis Res Ther ; 19(1): 168, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28728599

RESUMO

BACKGROUND: This study aimed to compare efficacy and safety of test-adalimumab (CinnoRA®, CinnaGen, Iran) to the innovator product (Humira®, AbbVie, USA) in adult patients with active rheumatoid arthritis (RA). METHODS: In this randomized, double-blind, active-controlled, non-inferiority trial, a total of 136 patients with active RA were randomized to receive 40 mg subcutaneous injections of either CinnoRA® or Humira® every other week, while receiving methotrexate (15 mg/week), folic acid (1 mg/day), and prednisolone (7.5 mg/day) over a period of 24 weeks. Physical examinations, vital sign evaluations, and laboratory tests were conducted in patients at baseline and at 12-week and 24-week visits. The primary endpoint in this study was the proportion of patients achieving moderate and good disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR)-based European League Against Rheumatism (EULAR) response. The secondary endpoints were the proportion of patients achieving American College of Rheumatology (ACR) criteria for 20% (ACR20), 50% (ACR50), and 70% (ACR70) responses along with the disability index of health assessment questionnaire (HAQ), and safety. RESULTS: Patients who were randomized to CinnoRA® or Humira® arms had comparable demographic information, laboratory results, and disease characteristics at baseline. The proportion of patients achieving good and moderate EULAR responses in the CinnoRA® group was non-inferior to the Humira® group at 12 and 24 weeks based on both intention-to-treat (ITT) and per-protocol (PP) populations (all p values >0.05). No significant difference was noted in the proportion of patients attaining ACR20, ACR50, and ACR70 responses in the CinnoRA® and Humira® groups (all p values >0.05). Further, the difference in HAQ scores and safety outcome measures between treatment arms was not statistically significant. CONCLUSION: CinnoRA® was shown to be non-inferior to Humira® in terms of efficacy at week 24 with a comparable safety profile to the reference product. TRIAL REGISTRATION: IRCT.ir, IRCT2015030321315N1 . Registered on 5 April 2015.


Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
17.
Curr Clin Pharmacol ; 12(2): 127-130, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28578645

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) and migraine are both common disorders which are caused by a faulty immune system and autonomic nervous system dysfunction, respectively. Although current treatment outlook has shown a great improvement in these two diseases, however many side effects have been reported. CASE REPORT: We reported a case of 43-years-female that has suffered from rheumatoid arthritis for 3 years with a 6 years history of migraine. She had used different types of medication for both rheumatoid arthritis and migraine but during these 6 years no improvement had been observed and even migraine progression in this patient became worse. She was admitted to the hospital for 12 weeks follow-up to evaluate the effect of ß-D-mannuronic acid (M2000) on her RA disease. MATERIALS AND METHODS: During 12 weeks of M2000 therapy, the signs and symptoms of migraine along with RA indices including Disease Activity Score (DAS28), simple disease activity index (SDAI) and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (anti-CCP) and blood determinants were measured. RESULTS AND DISCUSSION: The patient achieved a strong clinical improvement after 12 weeks of M2000 therapy in DAS28, SDAI and laboratory parameters. Moreover, M2000 showed a significant effect on the severity and the duration of migraine pain as well as times of migraine attack. In the present case, both rheumatoid arthritis and migraine as two different inflammatory diseases were diagnosed. Therefore, reducing the inflammation could be a valuable target to decrease the signs and symptoms of migraine and rheumatoid arthritis and help to the treatment process. CONCLUSION: M2000 as a novel designed non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive property is able to treat migraine in addition to its potent efficacy on treatment of rheumatoid arthritis.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Ácidos Hexurônicos/uso terapêutico , Transtornos de Enxaqueca/tratamento farmacológico , Adulto , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Reumatoide/complicações , Feminino , Ácidos Hexurônicos/farmacologia , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Transtornos de Enxaqueca/complicações , Índice de Gravidade de Doença , Resultado do Tratamento
18.
Mod Rheumatol ; 27(5): 862-867, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27846758

RESUMO

OBJECTIVE: Interleukin (IL)-23/IL-17 pathway involves in the pathogenesis of ankylosing spondylitis (AS). The exact mechanism implicated in overexpression of IL-23 and activation of the IL-23/IL-17 axis is not clear. The aim of the study was to clarify whether macrophages of AS patients undergo unfolded protein response (UPR) and secret increased IL-23. METHODS: Peripheral blood monocyte isolated from 10 HLA-B27+ patients and five HLA-B27+ normal subjects were differentiated to macrophages by macrophage-colony stimulating factor (M-CSF) for seven days. Flow cytometry was used to detect monocyte purity and expression of macrophage markers. Analysis of mRNA expression for HLA-B and B27, UPR-associated proteins (BiP, CHOP, MDG1, and XBP1) and IL-23 was performed by RT-qPCR. RESULTS: RT-qPCR data showed a significant overexpression of HLA-B27, UPR genes (BiP, CHOP, and XBP1), and IL-23 in M-CSF-derived macrophages from AS patients compared to healthy controls. Increased expression of MDG1 was not significant. CONCLUSIONS: Our data suggest that UPR activation occurs in M-CSF-derived macrophages of AS patients and is accompanied by overexpression of HLA-B27. UPR appears to be associated with overproduction of IL-23 in AS macrophages.


Assuntos
Interleucina-23/metabolismo , Macrófagos , Espondilite Anquilosante , Adulto , Apoptose , Feminino , Antígeno HLA-B27/metabolismo , Humanos , Interleucina-17/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/metabolismo , Resposta a Proteínas não Dobradas/fisiologia
19.
Iran J Immunol ; 13(3): 197-203, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27671511

RESUMO

BACKGROUND: Periodontitis and rheumatoid arthritis (RA) share a number of clinical and pathologic features, one of which is the presence of the tumor necrosis factor alpha (TNF-α)-induced bone resorption that is involved in the pathogenesis of both. OBJECTIVES: To investigate the effect of TNF-α blockade on periodontal conditions in patients with active RA. METHOD: The periodontal statuses of 36 patients (26 females, 10 males) diagnosed with active RA were evaluated both before and after anti-TNF-α therapy. Gingival index, bleeding on probing (BOP), probing pocket depth (PPD), oral hygiene index (OHI), and levels of TNF-α in gingival crevicular fluid (GCF) were measured at the baseline and 6 weeks after the treatment. Wilcoxon signed ranked test was used for statistical analyses. RESULTS: Based on OHI (p=0.860), the level of plaque control did not change during the study period, but there was a significant reduction in gingival inflammation based on the mean BOP (p=0.049) and GI (p=0.036) before and after 6 weeks of anti-TNF-α therapy. The mean PPD index did not significantly differ at the baseline and 6 weeks after treatment (p=0.126). CONCLUSION: Anti-TNF-α therapy might have a desirable effect on periodontal conditions and might reduce TNF-α level in GCF of patients with RA.


Assuntos
Artrite Reumatoide/terapia , Reabsorção Óssea/terapia , Líquido do Sulco Gengival/imunologia , Imunoterapia/métodos , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Artrite Reumatoide/imunologia , Reabsorção Óssea/imunologia , Feminino , Gengiva/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Índice Periodontal , Fator de Necrose Tumoral alfa/imunologia
20.
Rheumatol Int ; 35(4): 677-84, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25216713

RESUMO

The Leeds Behçet's disease quality-of-life (BD-QoL) questionnaire is a specific and valid measure which is applied in English-speaking patients. We conducted Persian adaptation of BD-QoL questionnaire. Between June and December 2012, 220 Iranian patients fulfilling International Study Group criteria for the diagnosis of BD attending the rheumatology clinics at Tehran University of Medical Sciences were enrolled. Bilingual translators undertook the forward translation and cross-cultural adaptation of the BD-QoL questionnaire. Back-translation was conducted, and this version was sent to the designer of the questionnaire and revised accordingly. SF-36 health survey, Iranian Behçet's disease dynamic activity measure (IBDDAM), and Behçet's Disease Current Activity Form (BDCAF) were other administered measures. The Varimax rotation method with Kaiser normalization defined 5 factors with eigenvalues greater than 1.0. Studied cases were comprised of 118 males (53.6 %) and 102 females (46.4 %). Mean age of the patients was 38.3 ± 11.3 years (range 16-73). The mean BD-QoL score was 10.3 ± 8.8. Test-retest reliability was high, and two time points were significantly correlated (Spearman's correlation coefficient of 0.75-0.84). Cronbach's α coefficient of 0.949 demonstrated the excellent internal consistency. These factors cumulatively explained 58.74 % of total variance. The ratio of first to second eigenvalue was 7.08, which underlined the undimensionality. The results revealed adapted BD-QoL scores had significant correlation with IBDDAM (correlation coefficient = 0.19, P value = 0.005) and BDCAF (correlation coefficient = 0.21, P value = 0.002). Conversely, no significant correlation between BD-QoL and SF-36 results was detected (P value = 0.078). The Persian version of BD-QoL was shown to be unidimensional, highly reliable, and adequate construct validity.


Assuntos
Síndrome de Behçet/psicologia , Qualidade de Vida/psicologia , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Síndrome de Behçet/diagnóstico , Feminino , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Traduções , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA