Background: Macrophage M1 polarization plays a pivotal role in inflammatory diseases. Progranulin (PGRN) has potential anti-inflammation action, however, the effect of PGRN on macrophage M1 polarization has been poorly studied. Our study aimed to investigate the effect of PGRN on lipopolysaccharide (LPS)-induced macrophage M1 polarization and clarify the underlying mechanisms. Methods: RAW264.7 cells were polarized to M1 macrophage by LPS with or without recombinant PGRN (rPGRN) and tumor necrosis factor alpha antibody (anti-TNF-α). A cell counting kit-8 assay (CCK-8), flow cytometry, Quantitative Real-Time PCR assay (q-PCR), Western blot assay and enzyme-linked immunosorbent assay (ELISA) were used to determine the effect of different treatments on cell proliferation, expression of surface phenotype marker and expressions and secretion of inflammatory cytokines. The activation of NF-κB/mitogen-activated protein kinase (MAPK) pathways and the nuclear translocation of NF-κB p65 were detected by Western blot and immunofluorescence respectively. THP-1 and primary bone marrow-derived monocytes (BMDMs) were also used to demonstrate effect of PGRN on expressions and secretion of inflammatory cytokines induced by LPS. Results: In RAW264.7 cells, rPGRN at concentrations below 80 ng/ml significantly promoted cell proliferation in dose dependent fashion. rPGRN significantly inhibited LPS-induced change of phenotype (CD86/CD206 ratio) and function (tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) expressions). LPS-stimulated secretion of TNF-α and activated phosphorylation of IKKα/β, IкBα, p65, JNK and p38 and the nucleus translocation of NF-кB p65 were also significantly downregulated by rPGRN. In addition, recombinant TNF-α (rTNF-α) significantly boosted TNF-α and iNOS expression vs the control group. Moreover, anti-TNF-α significantly inhibited LPS-induced TNF-α and iNOS expression. In THP-1 and BMDM cells, reversing effect of rPGRN on LPS-enhanced expressions of TNF-α and iNOS and secretion of TNF-α was further demonstrated.
The influence of Mg-1Ca-xwt.% Sr (x = 0.2, 0.5, 1.0, 2.0) alloys on the osteogenic differentiation and mineralization of pre-osteoblast MC3T3-E1 were studied through typical differentiation markers, such as intracellular alkaline phosphatase (ALP) activity, extracellular collagen secretion and calcium nodule formation. It was shown that Mg-1Ca alloys with different content of Sr promoted cell viability and enhanced the differentiation and mineralization levels of osteoblasts, and Mg-1Ca-2.0Sr alloy had the most remarkable and significant effect among all. To further investigate the underlying mechanisms, RT-PCR and Western Blotting assays were taken to analyze the mRNA expression level of osteogenesis-related genes and intracellular signaling pathways involved in osteogenesis, respectively. RT-PCR results showed that Mg-1Ca-2.0Sr alloy significantly up-regulated the expressions of the transcription factors of Runt-related transcription factor 2 (RUNX2) and Osterix (OSX), Integrin subunits, as well as alkaline phosphatase (ALP), Bone sialoprotein (BSP), Collagen I (COL I), Osteocalcin (OCN) and Osteopontin (OPN). Western Blotting results suggested that Mg-1Ca-2.0Sr alloy rapidly induced extracellular signal-regulated kinase (ERK) activation but showed no obvious effects on c-Jun N terminal kinase (JNK) and p38 kinase of MAPK. Taken together, our results demonstrated that Mg-1Ca-2.0Sr alloy had excellent biocompatibility and osteogenesis via the ERK pathway and is expected to be promising as orthopedic implants and bone repair materials.
Backgrounds. VitB6 deficiency has been associated with a number of adverse health effects. However, the effects of VitB6 in metabolic syndrome are poorly understood. Methods. VitB6 (50 mg/kg/day) was given to Apoe −/− mice with hkdigh-fat diet (HFD) for 8 weeks. Endothelial dysfunction, insulin resistance, and hepatic lipid contents were determined. Results. VitB6 administration remarkably increased acetylcholine-induced endothelium-dependent relaxation and decreased random blood glucose level in Apoe −/− mice fed with HFD. In addition, VitB6 improved the tolerance of glucose and insulin, normalized the histopathology of liver, and reduced hepatic lipid accumulation but did not affect the liver functions. Clinical and biochemical analysis indicated that the levels of VitB6 were decreased in patients with fatty liver. Conclusions. Vitamin B6 prevents endothelial dysfunction, insulin resistance, and hepatic lipid accumulation in Apoe −/− mice fed with HFD. Supplementation of VitB6 should be considered to prevent metabolic syndrome.
Long non-coding RNAs (lncRNAs) are involved in numerous biological functions and pathological processes. However, the clinical significance of lncRNAs and their functions in liver fibrosis remain largely unclear. Methods: The transcript of lncRNA SCARNA10 in serum and liver samples from patients with advanced hepatic fibrosis, liver tissues from two fibrosis mouse models, and cultured hepatic stellate cells (HSCs) was determined by real-time RT-PCR. The effects of lentivirus-mediated knockdown or over-expression of SCARNA10 in liver fibrosis were examined in vitro and in vivo . Moreover, the effects and mechanisms of down-regulation or over-expression of SCARNA10 on the expression of the genes involved in TGFβ pathway were determined. Results: It was found lncRNA ENSMUST00000158992, named as Scarna10, was remarkably up-regulated in mouse fibrotic livers according to the microarray data. We observed that the transcript of SCARNA10 was increased in the serum and liver from patients with advanced hepatic fibrosis. Furthermore, we found that SCARNA10 promoted liver fibrosis both in vitro and in vivo through inducing hepatocytes (HCs) apoptosis and HSCs activation. Mechanistically, RNA immunoprecipitation (RIP) assays demonstrated that SCARNA10 physically associated with polycomb repressive complex 2 (PRC2). Additionally, our results demonstrated that SCARNA10 functioned as a novel positive regulator of TGFβ signaling in hepatic fibrogenesis by inhibiting the binding of PRC2 to the promoters of the genes associated with ECM and TGFβ pathway, thus promoting the transcription of these genes. Conclusions: Our study identified a crucial role of SCARNA10 in liver fibrosis, providing a proof of this molecule as a potential diagnostic marker and a possible therapeutic target against liver fibrosis.
Background: Idebenone is an antioxidant and a coenzyme Q10 analog that has been used to treat neurodegeneration disease. Some studies show idebenone exerts anti-inflammatory effects. However, whether idebenone can be used to reduce the neuroinflammation in Parkinson’s disease (PD) has been little studied.Methods: The study investigated the potential anti-inflammatory effects of idebenone in vitro and in vivo, using cell models of Lipopolysaccharide (LPS)-simulated BV2 cells and animal models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD with or without idebenone. To verify how idebenone exerts its effects on the BV2 cell activation and PD model, we performed the mechanistic studies in vitro and in vivo.Results: In vitro study showed that pretreatment with idebenone could attenuate the production of pro-inflammatory factors in LPS-stimulated BV2 cells and promoted a phenotypic switch from the M1 state to the M2 state. Mechanistically, idebenone reduced the activation of the MAPK and NF-κB signaling pathway upon LPS stimulation. Furthermore, in vivo experiments confirmed that pretreatment with idebenone could ameliorate MPTP-induced neurodegeneration and modulate microglia phenotypes through inhibition of the MAPK and NF-κB signaling pathway in the SN.Conclusion: These results suggest that idebenone ameliorates the neurological deficits related to PD and this effect is partly mediated by inhibiting the neuroinflammation and modulating microglia phenotypes.
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