Shannonclayton6289

Both in vitro and in vivo studies indicate that LAMA2 inhibits osteogenesis and promotes adipogenesis. Mechanistically, we found that LAMA2 regulated osteogenesis and adipogenesis of MSCs by modulating the hedgehog signaling pathway. CONCLUSIONS The present work confirms that LAMA2 is a new molecular target for MSC-based bone regeneration.BACKGROUND Current therapies for multiple myeloma (MM) are associated with toxicity and resistance, highlighting the need for novel effective therapeutics. Berberine (BBR), a botanical alkaloid derived from several Berberis medicinal plants, has exhibited anti-tumor effects, including against multiple myeloma (MM); however, the molecular mechanism underlying the anti-MM effect has not been previously described. This study aimed to identify the target of berberine and related mechanisms involved in its therapeutic activity against MM. RESULTS Here, we demonstrated that BBR treatment killed MM cells in vitro and prolonged the survival of mice bearing MM xenografts in vivo. A screening approach integrating surface plasmon resonance (SPR) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified UHRF1 (ubiquitin-like with PHD and RING Finger domains 1) as a potential target of BBR. Combining molecular docking and SPR analysis, we confirmed UHRF1 as a BBR-binding protein and discovered that BBR binds UHRF1 in the tandem tudor domain and plant homeodomain (TTD-PHD domain). BBR treatment induced UHRF1 degradation via the ubiquitin-dependent proteasome system and reactivated p16INK4A and p73 in MM cells. Overexpression of UHRF1 promoted the MM cell proliferation and rendered MM cells more resistant to BBR, while silencing of UHRF1 with siRNA attenuated BBR-induced cytotoxicity. CONCLUSIONS In summary, our study has identified UHRF1 as a direct target of BBR and uncovered molecular mechanisms involved in the anti-MM activity of BBR. Targeting UHRF1 through BBR may be a novel therapeutic strategy against MM.BACKGROUND Despite attempts to improve universal health coverage (UHC) in low income countries like Nepal, most healthcare utilization is still financed by out-of-pocket (OOP) payments, with detrimental effects on the poorest and most in need. Evidence from high income countries shows that depression is associated with increased healthcare utilization, which may lead to increased OOP expenditures, placing greater stress on families. To inform policies for integrating mental healthcare into UHC in LMIC, we must understand healthcare utilization and OOP expenditure patterns in people with depression. We examined associations between symptoms of depression and frequency and type of healthcare utilization and OOP expenditure among adults in Chitwan District, Nepal. METHODS We analysed data from a population-based survey of 2040 adults in 2013, who completed the PHQ-9 screening tool for depression and answered questions about healthcare utilization. We examined associations between increasing PHQ-9 score and healtependent increases in healthcare utilization and OOP expenditure with increasing PHQ-9 scores. Future studies should evaluate whether provision of mental health services as an integrated component of UHC can improve overall health and reduce healthcare utilisation and expenditure, thereby alleviating financial pressures on families.BACKGROUND Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer's disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood. METHODS Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding. RESULTS We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE. CONCLUSION The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.BACKGROUND The treatment for brain metastases in small cell lung cancer (SCLC) is still controversial. The purpose of this study was to compare different brain radiotherapy treatments on SCLC patients with brain metastases. read more METHODS In this multi-center retrospective study, SCLC patients who had undergone whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for brain metastases from January 2012 to December 2018 were retrospectively screened. RESULTS A total of 263 eligible SCLC patients were included in this study, among whom, 73 were women and 190 were men. According to accepted brain radiotherapy, the remaining patients were divided into WBRT plus focal radiation boost (WBRT+boost), WBRT, and SRS groups. In pairwise comparisons of the overall survival (OS), WBRT+boost group led to longer survival than did WBRT both in all patients (17.9 vs 8.7 months; P  less then  0.001) and 140 matched patients (17.9 vs 11.7 months; P = 0.045). There were no significant differences in OS between WBRT+boost and SRS groups in all patients (17.9 vs 14.5 months; P = 0.432). Among 74 matched patients between WBRT+boost and SRS groups, however, patients who received WBRT+boost led to a longer survival than did SRS alone (21.8 vs 12.9 months; P = 0.040). In pairwise comparison of the intracranial progression-free survival time (iPFS), WBRT+boost group also showed survival advantages over WBRT (10.8 vs 6.5 months; P = 0.005) and SRS groups (10.8 vs 7.5 months; P = 0.032). CONCLUSION Due to the SCLC-derived multiple brain metastases and better survival time, focal radiation boost combined with adjuvant WBRT may be a preferred strategy for SCLC patients with brain metastases.