Under the condition of chronic obesity, an increased level of free fatty acids along with low oxygen tension in the adipose tissue creates a pathophysiological adipose tissue microenvironment (ATenv) leading to the impairment of adipocyte function and insulin resistance. Here, we found the synergistic effect of hypoxia and lipid (HL) surge in fostering adipose tissue macrophages(ATMs) inflammation and its polarization. ATenv significantly increased miR-210-3p expression in ATMs which promotes NF-ĸB activation-dependent proinflammatory cytokines expressions along with the downregulation of anti-inflammatory cytokines expression. Interestingly, delivery of miR-210-3p mimic significantly increased the macrophage inflammation in absence of HL co-stimulation; while miR-210-3p inhibitor notably compromised HL-induced macrophage inflammation through increased production of SOCS1 (suppressor of cytokine signalling 1), a negative regulator of NF-ĸB inflammatory signalling pathway. Mechanistically, miR-210 directly binds to 3' UTR of SOCS1 mRNA and silenced its expression and thus preventing proteasomal degradation of NF-ĸB p65. Direct delivery of anti-miR-210-3p LNA in the ATenv markedly rescued mice from obesity-induced adipose tissue inflammation and insulin resistance. Thus, miR-210-3p inhibition in ATMs could serve as a novel therapeutic strategy for managing obesity-induced type 2 diabetes.
<p>Under the condition of chronic obesity, an increased level of free fatty acids along with low oxygen tension in the adipose tissue creates a pathophysiological adipose tissue microenvironment (AT<em>env</em>) leading to the impairment of adipocyte function and insulin resistance. Here, we found the synergistic effect of hypoxia and lipid (HL) surge in fostering adipose tissue macrophages(ATMs) inflammation and its polarization. AT<em>env </em>significantly increased <em>miR-210-3p</em> expression in ATMs which promotes NF-kB activation-dependent proinflammatory cytokines expressions along with the downregulation of anti-inflammatory cytokines expression. Interestingly, delivery of <em>miR-210-3p</em> mimic significantly increased the macrophage inflammation in absence of HL co-stimulation; while <em>miR-210-3p </em>inhibitor notably compromised HL-induced macrophage inflammation through increased production of SOCS1 (suppressor of cytokine signalling 1), a negative regulator of NF-kB inflammatory signalling pathway. Mechanistically, <em>miR-210</em> directly binds to 3′ UTR of <em>SOCS1</em> mRNA and silenced its expression and thus preventing proteasomal degradation of NF-kB p65. Direct delivery of anti-<em>miR-210-3p</em> LNA in the AT<em>env </em>markedly rescued mice from obesity-induced adipose tissue inflammation and insulin resistance. Thus, <em>miR-210-3p</em> inhibition in ATMs could serve as a novel therapeutic strategy for managing obesity-induced type 2 diabetes.</p>
Scrub typhus is a zoonotic bacterial disease caused by Orientia tsutsugamushi and accounts for up to 20% of common febrile illnesses and hospitalizations. The main obstacle to vaccine development is the lack of identification of relevant immunodominant antigens that stimulate broad-spectrum immune responses, including antibody, CD4 + T cells, and CD8 + T cells production. We examined the 56-kDa type-specific cell membrane surface protein (TSA56) and ScaA as candidates for developing vaccine and diagnostic assays using an in-silico approach. We predicted 35 linear and 29 conformational immunogenic B-cell epitopes and 51 non-overlapping strong binders of MHC class I and 27 for MHC class II T-cell epitopes in the conserved and variable regions of TSA56. We used this information to design effective multi-epitope vaccine constructs that are predicted to stimulate cross-protective immunity. Furthermore, the epitope-based vaccine constructs showed antigenic, non-allergenic, and interferon gamma-inducing properties, as predicted by online servers. We cloned the chimeric gene into a pET-15b plasmid vector and successfully expressed the histidine-tagged recombinant antigen in an Escherichia coli expression system. The findings the present study provide a platform for validations of the predicted epitopes and chimeric antigens for designing effective epitope-based vaccine candidates and serological diagnostic assays against scrub typhus.
Rotavirus A (RVA) was detected in the stool of a 12-month-old child with diarrhea, mild fever, and vomiting. A viral metagenomic approach identified a Wa-like genotype G3P[8] strain named RVA/Human-wt/IND/RM25112/2016.
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