HIF-1α suppresses myeloma progression by targeting Mcl-1.

HIF-1α is involved in the carcinogenesis and progression of multiple types of cancer. However, the precise role of HIF-1α is unclear in multiple myeloma. Through the qRT-PCR and CCK-8 assays, we demonstrated that silencing the expression of HIF-1α and Mcl-1, MM proliferation can be decreased and apoptosis can be induced. Next, using the GEO database, we found that Mcl-1 was increased in MMs. Mcl-1 overexpression counterbalanced the tumor suppressing effect of siHIF-1α on MM apoptosis. Additionally, HIF-1α acting as a transcription factor, could directly target the promoter region of Mcl-1 to promote Mcl-1 expression. Based on the experimental result, our findings strongly suggest that HIF-1α regulated the progression of MMs by directly targeting the Mcl-1.

PCSK9 E670G polymorphism increases risk of coronary artery disease in a Chinese Han population.

OBJECTIVE: Coronary artery disease (CAD) is the leading cause of morbidity and mortality in the world. The proprotein convertase subtilisin/kexin type 9 (PCSK9) E670G polymorphism has been reported to be associated with variability in levels of low density lipoprotein cholesterol, a risk factor for CAD. However, the relationship between PCSK9 E670G and CAD is still not fully elucidated. METHODS: A total of 225 patients and 189 control subjects were recruited in this study. DNA was extracted from peripheral blood samples and was genotyped by mass array method. In addition, we also conducted a meta-analysis of case-control studies to elucidate the relationship of CAD and polymorphism. RESULTS: The GG genotype of PCSK9 E670G was associated with a higher risk of CAD [odds ratio (OR) 2.994, 95% confidence interval (CI): 1.174-7.631], even adjusting for risk factors (OR 2.794, 95% CI: 1.215-7.460). Logistic regression analysis showed that the dominant genetic model increased the CAD risk (OR 2.313, 95% CI: 1.070-6.983) after adjusting the confounding factors. Meta-analysis results of 13 studies revealed that PCSK9 E670G polymorphism was correlated with CAD risk under different genetic models. CONCLUSION: Our results demonstrated that PCSK9 E670G genotype was associated with a high risk of CAD.

Immunosuppressive effect of arsenic trioxide on islet xenotransplantation prolongs xenograft survival in mice.

The role of arsenic trioxide (As2O3) in inhibiting immune rejection and prolonging islet allograft survival has been identified in islet allotransplantation. This study aims to explore the role of As2O3 in islet xenotransplantation and the action mechanism. The streptozotocin (STZ) was used in C57BL/6 mice to induce the type 1 diabetes mellitus (T1DM) for xenotransplantation models establishment. Donor islets were isolated by digesting. The flow cytometry (FCM) was used to analyze lymphocyte types. The blood sugar level was detected by using intraperitoneal glucose tolerance test (IPGTT). The serum level of cytokines was determined by the enzyme-linked immunosorbent assay (ELIZA). The cell proliferation was measured by MTT assay. The mRNA levels were quantified with qRT-PCR. As2O3 prolonged the survival of the recipient mice but had no influence on body weight. As2O3 protected the function of xenograft in insulin secretion and suppressed immune rejection of recipient. As2O3 inhibited proliferation of T lymphocyte and increased the proportion of Foxp3+ regulatory T cells in recipient mice. As2O3 inhibited activation and promoted clonal anergy of T lymphocyte. As2O3 decreased total number of B cells and reduced partial antibody levels in recipient mice. As2O3 and leflunomide showed a synergistic effect in suppressing islet xenotransplant rejection. As2O3 prolongs islet xenograft survival by inhibiting cellular immune response, and increasing Foxp3+ regulatory T cells, while decreasing partial antibody levels in serum.

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation.

Mesenchymal stem cell (MSC) differentiation is dramatically reduced after long-term in vitro culture, which limits their application. MSCs derived from induced pluripotent stem cells (iPSCs-MSCs) represent a novel source of MSCs. In this study, we investigated the therapeutic effect of iPSC-MSCs on diabetic mice. Streptozocin-induced diabetic mice transplanted with 400 islets alone or with 1×10(6) iPSC-MSCs were examined following rapamycin injection (0.1 mg/kg/day, i.p., from days 0 to 9) after transplantation. Our results showed that iPSC-MSCs combined with rapamycin significantly prolonged islet allograft survival in the diabetic mice; 50% of recipients exhibited long-term survival (>100 days). Histopathological analysis revealed that iPSC-MSCs combined with rapamycin preserved the graft effectively, inhibited inflammatory cell infiltration, and resulted in substantial release of insulin. Flow cytometry results showed that the proportion of CD4(+) and CD8(+) T cells was significantly reduced, and the number of T regulatory cells increased in the spleen and lymph nodes in the iPSC-MSCs combined with the rapamycin group compared with the rapamycin-alone group. Production of the Th1 proinflammatory cytokines interleukin-2 (IL-2) and interferon-γ was reduced, and secretion of the anti-inflammatory cytokines IL-10 and transforming growth factor-ß was enhanced compared with the rapamycin group, as determined using enzyme-linked immunosorbent assays. Transwell separation significantly weakened the immunosuppressive effects of iPSC-MSCs on the proliferation of Con A-treated splenic T cells, which indicated that the combined treatment exerted immunosuppressive effects through cell-cell contact and regulation of cytokine production. Taken together, these findings highlight the potential application of iPSC-MSCs in islet transplantation.