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Rheumatoid arthritis disease is a chronic auto-immune inflammatory disease that mainly causes synovial joint inflammation and cartilage destruction. The tumor necrosis factor-α (TNF-α) is a pivotal cytokine that plays an important role in rheumatoid arthritis. The treatments focusing on a single cytokine inhibition are clinically able to produce meaningful responses in only about half of the treated patients due to multiple cytokines involved in this disease. In the present study, a bispecific tandem single-chain variable fragment was designed in order to suppress both human tumor necrosis factor-α and interleukin-23 (IL23) as a potential therapeutic drug candidate for this disease. To do so, at first, eight bispecific tandem single-chain variable fragment models were built against tumor necrosis factor-α and interleukin-23 cytokines with different domain orders by the homology modeling, and then 50 ns molecular dynamics simulation was performed for each one and then structural properties were exploited. The MD simulation results indicate the fact that the domains' order strongly affects tandem single-chain variable fragment properties, and in overall, the fragment VLAIL23+Linker+VHAIL23+linker+VLATNF+Linker +VHATNF +His6 (VL and VH are light and heavy chain variable fragments and AIL23 and ATNF are anti-interleukin 23 and anti-tumor necrosis factor-α, respectively, and His6 is the six histidine) not only separated antibody domains accurately but also had better stability and solvation free energy. Therefore, this structure can be considered as an effective potential drug for rheumatoid arthritis. It is expected that the findings of this research could shed a light on the treatment approaches of the rheumatoid arthritis disease. [ABSTRACT FROM AUTHOR]

Background and the purpose of the study: Recent studies have indicated the role of apoptosis and angiotensin in the pathogenesis of bleomycin induced-pulmonary fibrosis. Losartan, an angiotensin type 1 receptor (AT1R) antagonist, has ameliorated apoptosis and fibrosis from bleomycin. In this study, alterations in the expression of apoptosis-regulatory genes (bcl-2 and bax) were investigated in different cells of lung tissue of mice treated with bleomycin in the presence of losartan. Methods: Losartan (10 mg/kg, i.p.) was given to mice two days before administration of bleomycin (3 U/kg) and throughout the test period. After two weeks, lung tissues of mice were evaluated for fibrosis by biochemical measurement of collagen deposition and semiquantitative analysis of pathological changes of the lung. The expression of bcl-2 and bax was assessed by immunohistochemical assay using biotin-streptavidin staining method on paraffin-embedded lung tissues. Results and major conclusion: Pre-treatment with losartan significantly (P < 0.05) reduced the increase in lung collagen content and also inhibited the histological changes induced by bleomycin. Immunohistochemical studies showed that losartan significantly (P < 0.05) reduced the bax/bcl-2 expression ratio in the alveolar epithelial cells, lymphocytes, macrophages and interstitial myofibroblasts. Losartan also inhibited the bcl-2 upregulation which was educed by bleomycin in neutrophils. By reduction of bax/bcl-2 ratio as a determinant of susceptibility of a cell to apoptosis, losartan exerted protective effects on the alveolar epithelial cells that may be important in the amelioration of pulmonary fibrosis. These results may help to better understanding of the role of angiotensin II and apoptosis in pulmonary fibrosis. [ABSTRACT FROM AUTHOR]