Barbeebenson2027

05). Differentiation of healthy donor monocytes in SSc patient-derived plasma conferred the immunophenotype of SSc patient macrophages (n=13, p less then 0.05). selleck compound Transwell experiments demonstrated that co-culture of SSc macrophages with SSc fibroblasts induced fibroblast activation (n=3, p less then 0.05). CONCLUSION These data demonstrate the activation profile of SSc macrophages is pro-fibrotic. SSc macrophages are activated under basal conditions, and release mediators and express surface markers associated with both alternative and inflammatory macrophage activation. These results also suggest that activation of SSc MØs arises from soluble factors in local microenvironments. These studies implicate macrophages as likely drivers of fibrosis in SSc and suggest therapeutic targeting of these cells may be beneficial in ameliorating disease in SSc patients. This article is protected by copyright. All rights reserved.OBJECTIVE The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is closely linked to the pathophysiology of a wide range of inflammatory diseases. We aimed to identify small molecules that directly bind to NLRP3 to develop pharmacological interventions for NLRP3-related diseases. METHODS A structure-based virtual screening analysis was performed with approximately 62,800 compounds to select efficient NLRP3 inhibitors. The production of caspase-1(p10) and IL-1β was measured by immunoblotting and ELISA to examine NLRP3 inflammasome activation. Two gouty arthritis models and an air pouch inflammation model induced by MSU crystal injection were used for in vivo experiments. Primary synovial fluid cells from gout patients were used to determine human relevance. RESULTS β-Carotene (provitamin A) suppressed the NLRP3 inflammasome activation induced by various activators including MSU crystals, in mouse bone marrow-derived primary macrophages (p less then 0.05). Surface plasmon resonance analysis demonstrated the direct binding of β-carotene to the pyrin domain (PYD) of NLRP3 (KD =3.41E-06). Molecular modeling and mutation assays revealed the interaction mode between β-carotene and the NLRP3 PYD. Inflammatory symptoms induced by MSU crystals were attenuated by oral administration of β-carotene in gouty arthritis mouse models (p less then 0.05), correlating with its suppressive effects on the NLRP3 inflammasome in inflamed tissues. Furthermore, β-carotene reduced IL-1β secretion from human synovial fluid cells isolated from gout patients (p less then 0.05), showing its inhibitory efficacy in human patient cells. CONCLUSION Our results present β-carotene as a selective and direct inhibitor of NLRP3 and the binding to NLRP3 PYD as a novel pharmacological strategy to combat NLRP3 inflammasome-driven diseases, including gouty arthritis. This article is protected by copyright. All rights reserved.The Bacillus subtilis US191 strain producing highly thermostable β-mannanase was previously selected as potential probiotic candidate for application as feed supplement in poultry industry. Initially, the level of extracellular β-mannanase production by this strain was 1.48 U ml-1 . To improve this enzyme titer, the present study was undertaken to optimize the fermentation conditions through experimental designs and valorization of agro-industrial byproducts. Using the Plackett-Burman design, in submerged fermentation, a set of 14 culture variables was evaluated in terms of their effects on β-mannanase production. Locust bean gum (LBG), soymeal, temperature, and inoculum size were subsequently optimized by response surface methodology using Box-Behnken design. Under optimized conditions (1 g L-1 LBG, 8 g L-1 soymeal, temperature of 30°C and inoculum size of 1010  CFU ml-1 ), a 2.59-fold enhancement in β-mannanase titer was achieved. Next, to decrease the enzyme production cost, the effect of partial substitution of LBG (1 g L-1 ) by agro-industrial byproducts was investigated, and a Taguchi design was applied. This allowed the attaining of a β-mannanase production level of 8.75 U ml-1 in presence of 0.25 g L-1 LBG, 5 g L-1 of coffee residue powder, 5 g L-1 of date seeds powder, and 5 g L-1 of prickly pear seeds powder as mannans sources. Overall, a 5.91-fold improvement in β-mannanase production by B. subtilis US191 was achieved. © 2020 American Institute of Chemical Engineers.As glucocorticoids and immunosuppressive drugs are non-specific therapeutic agents that cause many adverse reactions, the development of biologicals aiming to control specific molecular targets is anticipated for the treatment of systemic lupus erythematosus (SLE). The antibody targeting B cell-activating factor belonging to the tumor necrosis factor family (BAFF) belimumab was the first biological approved for SLE. At present, many biologicals, such as anifrolumab (anti-type I interferon receptor antibody) and ustekinumab (antibody against interleukin 12/23 [p40]), are in clinical trials. Thus, successful treatments with biologicals targeting "bridging cytokines" produced by dendritic cells, which form a bridge between the innate and acquired immune/autoimmune systems, is of particular interest. Moreover, a phase IIb clinical trial of baricitinib, a low-molecular-weight compound targeting Janus kinase 1/2, in patients with SLE revealed that baricitinib was significantly more effective for relieving arthritis and skin manifestations than placebo, and the trial met the primary endpoint. In the future, it is expected that drugs with better efficacy and safety profiles will be used to apply therapeutic strategies, such as precision medicine, in which different molecular target drugs are used for patients classified by their conditions, and to set a therapeutic goal of the discontinuation of glucocorticoids. © 2020 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.BACKGROUND Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). While rapid progression (RP) has been proposed as a non-negligible pattern of response to ICIs, its definition and related factors remain unclear. This study aimed to develop a clinical definition of RP and to identify related factors. METHODS We retrospectively evaluated Chinese patients who had received an ICI as second-line or later treatment for locally advanced or metastatic NSCLC at a single center. We defined RP as radiological progression at the first response assessment ( less then 2 months after starting the ICI), as well as confirmation of progressive disease or cancer-related death occurring at less then 3 months. The clinical outcomes were compared for patients with RP or non-RP to identify prognostic factors. RESULTS The study evaluated 74 eligible patients with detailed records regarding their ICI therapy, including 25 patients (33.8%) who had experienced RP. Relative to patients with non-RP, patients with RP had significantly shorter median progression-free survival (1.