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The present study reveals that lipotoxicity causes defective mitophagy and excessive mitochondrial reactive oxygen species accumulation. In turn, both events trigger NLRP3 inflammasome activation in fatty acid-overloaded primary hepatocytes. The novel insight advances the understanding of how fatty acids elicit lipotoxicity through oxidant stress and autophagy in mitochondria during progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis.
The authors investigated the effects and mechanism of IL-10 in renal ischemia-reperfusion injury (IRI). Compared to wild-type mice with IRI, IL-10 knockout (IL-10 KO) mice with IRI demonstrated decreased renal function, increased mRNA expressions of the pro-inflammatory cytokines, and increased expression of the pro-apoptosis factors. Our findings demonstrate that IL-10 suppresses the production of pro-inflammatory cytokines, renal dysfunction and the expression of pro-apoptosis factors after IRI.
Targeting splenic macrophages with immunosuppressive microRNA is a potential therapeutic strategy for sepsis. Interference of splenic macrophages by miR-146a-expressing plasmid and polyethyleneimine complex modulates the Toll-like receptor-related immunity, which results in the amelioration of excessive inflammation, multiple organ injury, and even death due to sepsis.
Doxorubicin inactivates the EGFR/Src/HMG-CR pathway, and decreases levels of both cholesterol and lipid rafts. Simvastatin enhances doxorubicin-induced cell death but cholesterol attenuates it. The anti-cancer effect of doxorubicin is attenuated in cholesterol-high diet-fed mice. Therefore, cholesterol control may be combined with treatment to enhance doxorubicin efficacy and reduce its side effects.
The authors show that fibroblast activation protein (FAP) induces the tumor promoting phenotype of fibroblasts through secretion of several cytokines. It activates tumor cells, recruits macrophages and polarizes them into the M2 phenotype. FAP may therefore be a valuable prognostic marker and specific target of anti-cancer therapy.
Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Here, the authors identified a previously unknown signaling circuit that contributes to tumor necrosis factor (TNF)-induced activation of FLS. The authors show that FOXO3 and its modulator PIK3IP1 are crucial for the TNF-driven interferon (IFN) response in RA-FLS.
The authors show that EBV-encoded oncoprotein LMP1 up-regulates cyclin-dependent kinase 1 (CDK1) and survivin expression in nasal NK/T-cell lymphoma (NNKTL). CDK1 and survivin inhibitors, including mithramycin, reduce the proliferation of NNKTL cells. Mithramycin further induces anti-tumor effects in an NNKTL xenograft mouse model. These results suggest that CDK1 and survivin may be potential therapeutic targets for NNKTL.
Systemic inflammation generates oxidized high-density lipoprotein (oxHDL) inducing endothelial malfunction mediated by the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). OxHDL interacts with LOX-1 and increases LOX-1 levels to the plasma membrane through the NOX-2/ROS/NF-κB pathway. Oxidative stress is able to induce LOX-1 expression in absence of oxHDL. Also, oxHDL induces TNF-α expression increase, which induces LOX-1 expression.
The role of neddylatin in inflammatory arthritis is not well understood. Here we reveal that NEDD8 and CULLIN-1 are significantly upregulated in the synovium of patients with RA. Neddylation activation is crucial for the pathobiology of collagen-induced arthritis. Mechanistically, TRAF6 neddylation at Lys124 is essential for IL-17A-induced NF-κB activation in synoviocytes.