Background: Rheumatoid arthritis (RA) is characterized by in ammation mediated angiogenesis in synovial tissue, leading to apoptotic retardation and enhanced cell survival in synovial broblasts. Methotrexate (MTX) can reduce selective pro-in ammatory cytokines but unable to restore disrupted homeostasis between autophagy and apoptosis in fd-FLS.Objective: To evaluate the effect of black tea compound TF3 along with MTX upon uid derived (fd)-FLS to induce apoptosis and inhibit autophagy through ER stress-mediated pathways.Methods: FLS sourced from synovial uid (SF) of patients with RA (n=11) and osteoarthritis (OA) (n=10) were cultured following treatment with MTX/TF3 or in combination and underlying mechanisms were investigated. Extracellular in ammatory markers like CRP and cytokines (TNF-α, IL-6), angiogenic markers (VEGF, ANG-1) were quanti ed by ELISA. Cell viability of cultured fd-FLS was determined by MTT assay. fd-FLS treated with MTX/TF3 or combination of MTX(125nM) and TF3(10µM), followed by apoptosis measurement by ow cytometry. ER stress associated markers were quanti ed by RT-PCR (IRE1A and spliced-XBP-1) and immunoblotting (Grp78, Hsp70, CHOP, HIF1-α). Apoptotic (Bcl-2, Bax, and Caspases) and autophagic proteins (Beclin1, LC3b and p62) were quanti ed by immunoblot study.Results: MTX and TF3 both in single doses (IC 25 ) could down-regulate the levels of pro-in ammatory and angiogenic markers. Combination treatment modulated ER stress response and blocked the autophagmosomal proteins in fd-FLS and induced apoptosis.
Conclusion:Disruption in homeostasis between apoptosis and autophagy might be an underlying phenomenon in the progression of pathophysiology in fd-FLS. The combined administration of MTX and TF3 successfully balanced the homeostasis by inducing apoptosis.
Background: A comparative analysis of ow-mediated-vasodilation (FMD), vasoactive angiogenic, and brogenic mediators between treatment-naive and treated Systemic sclerosis (SSc) patients is an unmet need.Aim and Objective: 1) To assess the FMD and different pathogenic mediators in SSc patients [treatment naïve (Group-I, n=24) on vasodilator (Group-II, n=10), on vasodilator + immunosuppressive (Group-III, n=22)], and in healthy control (HC), n= 20]. To assess the proportion of circulating Endothelial cells in Group-I. Materials and method: FMD was measured in all the participants. Serum levels of NO, ET1, NO/ET1, sVCAM, sICAM, TGFβ, IL-6, VEGF were measured along with the gene expressions of eNOS, iNOS, ET-1, TGFβ. CEC was measured in Group-I and HC.Results: FMD was signi cantly decreased in all SSc patients though receiving treatment.Upregulation of serum NO and ET concentrations were noted post-treatment with an unaltered NO/ET1 ratio. NO was positively correlated with FMD (r= 0.6), and negatively with TGFβ (r=-0.5). ET-1 showed less correlation with TGFβ (r=-0.5) but no signi cant correlation with FMD. Circulating endothelial cell (CEC) was signi cantly higher in Group-I (3.2%) than HC (0.8%) (p = 0.002), and it showed a good correlation with NO (r=-0.7, p=0.0001) and NO/ET1 (r=-0.6,p=0.007). Conclusion: Endothelial dysfunction was seen in SSc patients irrespective of treatment which might be due to the unaltered NO/ET1. NO might be the major driving molecule in the vascular pathophysiology of SSc.
Background: A comparative analysis of flow-mediated-vasodilation (FMD), vasoactive angiogenic, and fibrogenic mediators between treatment-naive and treated Systemic sclerosis (SSc) patients is an unmet need.Aim and Objective: 1) To assess the FMD and different pathogenic mediators in SSc patients [treatment naïve (Group-I, n=24) on vasodilator (Group-II, n=10), on vasodilator + immunosuppressive (Group-III, n=22)], and in healthy control (HC), n= 20]. To assess the proportion of circulating Endothelial cells in Group-I.Materials and method: FMD was measured in all the participants. Serum levels of NO, ET1, NO/ET1, sVCAM, sICAM, TGFβ, IL-6, VEGF were measured along with the gene expressions of eNOS, iNOS, ET-1, TGFβ. CEC was measured in Group-I and HC. Results: FMD was significantly decreased in all SSc patients though receiving treatment.Upregulation of serum NO and ET concentrations were noted post-treatment with an unaltered NO/ET1 ratio. NO was positively correlated with FMD (r= 0.6), and negatively with TGFβ (r=-0.5). ET-1 showed less correlation with TGFβ (r=-0.5) but no significant correlation with FMD. Circulating endothelial cell (CEC) was significantly higher in Group-I (3.2%) than HC (0.8%) (p = 0.002), and it showed a good correlation with NO (r=-0.7, p=0.0001) and NO/ET1 (r=-0.6,p=0.007).Conclusion: Endothelial dysfunction was seen in SSc patients irrespective of treatment which might be due to the unaltered NO/ET1. NO might be the major driving molecule in the vascular pathophysiology of SSc.
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