Millerbentzen6990

Conclusion Together, our data suggest that impaired lipophagy, ER stress and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a novel form of hereditary liver disease with implications for the pathogenesis of non-alcoholic fatty liver disease. This article is protected by copyright. All rights reserved.OBJECTIVE Osteoclasts are responsible for bone destruction in rheumatoid arthritis (RA), and adipose-derived mesenchymal stromal cells (ADSCs) can inhibit experimental collagen-induced arthritis model. This study aims to determine whether ADSCs also suppresses osteoclastogenesis and bone erosion in collagen-induced arthritis(CIA). METHODS Osteoclasts were induced from bone-marrow-derived CD11b+ cells with Receptor Activator of Nuclear Factor-κ B Ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) stimulation, and assessed with tartrate-resistant acid phosphatase (TRAP) staining. For human cells, osteoclasts were produced from human CD14+ cells. ADSCs were generated and added to cultures with different ratios with CD11b+ cells. Transwell and antibody blockade experiments were performed to define the mechanism of action. NF-κB and RANKL expression were determined by western blotting and RT-qPCR. 2×106 ADSCs or fibroblast cells were adoptively transferred to DBA1/J mice on day 14 after immunization with type II collagen/ complete Freund's adjuvant (CII/CFA) while the onset and severity of the CIA were monitored. RESULTS ADSCs but not fibroblast cells completely suppressed osteoclastogenesis in vitro for human and mice. ADSCs injected after immunization and before of onset of CIA significantly suppressed disease development. Treatment with ADSCs dramatically decreased the levels of NF-κB p65/p50 in osteoclasts in vitro and P65/50 and RANKL expression by synovial tissues in vivo. CONCLUSION We have demonstrated that ADSCs can inhibit RANKL induced osteoclasts genesis via CD39 signals. Our findings also suggest that ADSCs can inhibit osteoclasts genesis without the involvement of regulatory T cells. ADSCs might represent a promising strategy for stem cell-based therapies for RA. Thus, manipulation of ADSCs may have therapeutic effects on RA and other bone erosion related diseases. This article is protected by copyright. All rights reserved.Hepatitis B virus (HBV) infection is ranked among the top health priorities worldwide. Accumulating evidence suggests that HBV infection and replication are closely associated with liver metabolism. The liver X receptors (LXRs), which belong to the superfamily of nuclear hormone receptors, are important physiological regulators of lipid and cholesterol metabolism. However, the association between the LXR pathway and HBV infection remains largely unclear. In this study, the antiviral activity of LXR agonists was investigated using multiple HBV cellular models. We observed that in HBV-infected primary human hepatocytes (PHHs), synthetic LXR agonists (T0901317, GW3965, and LXR-623), but not an LXR antagonist (SR9238), potently inhibited HBV replication and gene expression, as demonstrated by substantial reductions in viral RNA, DNA, and antigens production upon agonist treatment. However, covalently closed circular DNA (cccDNA) levels were not significantly reduced by the agonists. In addition, no rebound in viral replication was observed after treatment withdrawal, indicating a long-lasting inhibitory effect. These results suggest that LXR agonists decrease the transcriptional activity of cccDNA. In contrast, no significant anti-HBV effect was observed in HepG2-derived cell lines. Interestingly, LXR agonist treatment strongly reduced cholesterol 7α-hydroxylase 1 (CYP7A1) mRNA levels. Knockdown of CYP7A1 gene expression with siRNA inhibited HBV activity in PHHs, suggesting CYP7A1 as a potential factor contributing to the antiviral effects of LXR agonists. CONCLUSION We found that activation of the LXR pathway with synthetic LXR agonists could elicit potent anti-HBV activity in PHHs, possibly via sustained suppression of cccDNA transcription. Our work highlights the therapeutic potential of targeting LXR pathway for the treatment of chronic HBV infection. This article is protected by copyright. All rights reserved.BACKGROUND Allergic rhinoconjunctivitis is a public health problem. Allergen Immunotherapy is an effective and safe treatment, that modifies the natural course of allergic disease and induces long-term tolerance. OBJECTIVE To correlate basophil and antibody biomarkers of subcutaneous immunotherapy to clinical outcomes and cellular changes in target tissue. METHODS Adults suffering from allergic rhinoconjunctivitis due to grass pollen allergy were randomized to receive subcutaneous immunotherapy (n = 18) or to an open control group (n = 6). Patients reported daily symptom and medication scores and weekly rhinitis related quality of life scores during four pollen seasons. Biomarkers were measured every 3 months for three years treatment and every 6 months in the follow-up year. Nasal and cutaneous allergen challenge tests were performed annually. Leukocyte subsets were assessed in nasal mucosa biopsies at baseline and after treatment. RESULTS Subcutaneous immunotherapy led to a 447-fold decrease in basophil sensitivity during the first treatment year. This remained 100-fold lower than baseline during the 3 year-treatment period and 10-fold lower during the follow-up year (n = 18, P = .03). AR-A014418 chemical structure Decrease in basophil sensitivity after three weeks of treatment predicted long-term improvement in seasonal combined symptom and medication scores (ῥ=-0.69, P = .0027) during three years of treatment. AUC of IgE-blocking factor correlated to nasal allergen challenge (ῥ = 0.63, P = .0012) and SPT (ῥ = 0.45, P = .03). Plasma cell numbers in the nasal mucosa increased during treatment (P = .02). CONCLUSION Decrease in basophil sensitivity after three weeks of subcutaneous allergen immunotherapy predicted the clinical outcome of this treatment. © 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.