Cainknight5859

Non-alcoholic fatty liver disease (NAFLD) is a serious global public health concern. Nevertheless, there are no specific medications for treating the associated abnormal accumulation of hepatic lipids such as cholesterol and triglycerides. While seminal findings suggest a link between hepatic cholesterol accumulation and NAFLD progression, the molecular bases of these associations are not well understood. Here, we experimentally demonstrate that hepatic Niemann-Pick C1-Like 1 (NPC1L1), a cholesterol re-absorber from bile to the liver, can cause steatosis, an early stage of NAFLD using genetically engineered L1-Tg mice characterized by hepatic expression of NPC1L1 under the control of ApoE promoter. Contrary to wild-type mice that have little expression of hepatic Npc1l1, the livers of L1-Tg mice fed a high-fat diet became steatotic within only a few weeks. Moreover, hepatic NPC1L1-mediated steatosis was not only prevented, but completely rescued, by orally administered ezetimibe, a well-used lipid-lowering drug on the global market, even under high-fat diet feedings. These results indicate that hepatic NPC1L1 is an NAFLD-exacerbating factor amendable to therapeutic intervention and would extend our understanding of the vital role of cholesterol uptake from bile in the development of NAFLD. Furthermore, administration of a TLR4 inhibitor also prevented the hepatic NPC1L1-mediated steatosis formation, suggesting a latent link between physiological roles of hepatic NPC1L1 and regulation of innate immune system. Our results revealed that hepatic NPC1L1 is a novel NAFLD risk factor contributing to steatosis formation that is rescued by ezetimibe; additionally, our findings uncover feasible opportunities for repositioning drugs to treat NAFLD in the near future. © 2019 The Authors.Dengue virus (DENV), a member of Flaviviridae family, has become neurovirulent in humans after rapid geographical expansion. Host proteasomal machinery contains both ubiquitin ligases as well as deubiquitinases (DUBs), known to influence key cellular and biological functions. MicroRNA-mediated modulations of DUBs in case of DENV infections have not been explored yet. DENV propagation, MiRNA overexpression, miRNA knockdown, transfection, RT-PCR, luciferase assay, and western blotting have been used in this study to establish the interaction of miR-590 and USP42. DENV infection in human microglial cells resulted in downregulation of host DUB-USP42 in a dose-dependent manner and DENV-NS5 gene alone was found to be sufficient for this downregulation. miR-590 was upregulated upon NS5 overexpression in a dose-dependent manner. Downregulation of USP42 was observed with miR-590 overexpression. The specificity of this regulation was confirmed by miR-590 mimic and anti-miR transfections in microglial cells. miR-590 overexpression and knockdown affected the expression level of TRAF6 in indirect manner in microglial cells. read more The luciferase assay demonstrated the direct regulatory interaction between miR-590 and 3'UTR of USP42. These findings establish that DENV-NS5 protein can potentially modulate the host deubiquitinase protein USP42 expression via altering cellular miR-590 levels in human microglial cells. © 2019 The Authors.Alarmins and damage-associated molecular patterns (DAMPs) are powerful inflammatory mediators, capable of initiating and maintaining sterile inflammation during acute or chronic tissue injury. Recent evidence suggests that alarmins/DAMPs may also trigger tissue regeneration and repair, suggesting a potential contribution to tissue fibrogenesis. High mobility group B1 (HMGB1), a bona fide alarmin/DAMP, may be released passively by necrotic cells or actively secreted by innate immune cells. Macrophages can release large amounts of HMGB1 and play a key role in wound healing and regeneration processes. Here, we hypothesized that macrophages may be a key source of HMGB1 and thereby contribute to wound healing and fibrogenesis. Surprisingly, cell-specific deletion approaches, demonstrated that macrophage-derived HMGB1 is not involved in tissue fibrogenesis in multiple organs with different underlying pathologies. Compared to control HMGB1Flox mice, mice with macrophage-specific HMGB1 deletion (HMGB1ΔMac) do not display any modification of fibrogenesis in the liver after CCL4 or thioacetamide treatment and bile duct ligation; in the kidney following unilateral ureter obstruction; and in the heart after transverse aortic constriction. Of note, even under thermoneutral housing, known to exacerbate inflammation and fibrosis features, HMGB1ΔMac mice do not show impairment of fibrogenesis. In conclusion, our study clearly establishes that macrophage-derived HMGB1 does not contribute to tissue repair and fibrogenesis. © 2018 The Authors.Alpha-1-acid glycoprotein (AGP) is a major acute-phase protein. Biosynthesis of AGP increases markedly during inflammation and infection, similar to nitric oxide (NO) biosynthesis. AGP variant A (AGP) contains a reduced cysteine (Cys149). Previously, we reported that S-nitrosated AGP (SNO-AGP) synthesized by reaction with a NO donor, possessed very strong broad-spectrum antimicrobial activity (IC50 = 10-9-10-6 M). In this study, using a cecal ligation and puncture animal model, we confirmed that AGP can be endogenously S-nitrosated during infection. Furthermore, we examined the antibacterial property of SNO-AGP against multidrug-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa to investigate the involvement of SNO-AGP in the host defense system. Our results showed that SNO-AGP could inhibit multidrug efflux pump, AcrAB-TolC, a major contributor to bacterial multidrug resistance. In addition, SNO-AGP decreased biofilm formation and ATP level in bacteria, indicating that SNO-AGP can revert drug resistance. It was also noteworthy that SNO-AGP showed synergistic effects with the existing antibiotics (oxacillin, imipenem, norfloxacin, erythromycin, and tetracycline). In conclusion, SNO-AGP participated in the host defense system and has potential as a novel agent for single or combination antimicrobial therapy. © 2018 The Authors.