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Antinuclear antibody (ANA)-positive immune thrombocytopenia (ITP) patients have an unsatisfactory prognosis due to the more severe conditions of these patients and poor response to first-line glucocorticoids (GCs). The current study intended to compare the efficacy and safety of AZA plus prednisone and prednisone alone as first-line treatment in ANA-positive ITP patients. Fifteen ANA-positive ITP patients receiving AZA plus prednisone (AZA + GC group) and eighteen ANA-positive ITP patients receiving prednisone alone (GC group) as first-line treatment were retrospectively enrolled. The complete response (CR) rate (60.0% versus 22.2%) (P = 0.038) was increased in the AZA + GC group versus the GC group, while the overall response rate (86.7% versus 55.6%) (P = 0.070) only showed an increasing trend that did not achieve statistical significance. In addition, multivariate analysis revealed that AZA + GC (versus GC) (odds ratio = 31.331, P = 0.018) was independently associated with a higher possibility of achieving CR. Additionally, accumulating relapse-free duration was prolonged in the AZA + GC group versus the GC group (median: 7.8 months versus 3.4 months) (P = 0.038). Additionally, the multivariate analysis suggested that AZA + GC (versus GC) (hazard ratio = 0.306, P = 0.007) was independently correlated with longer accumulating relapse-free duration. The incidence of adverse events did not differ between the two groups (all P > 0.05), and the common adverse events in the AZA + GC group were pneumonia (13.3%), anemia (13.3%), cough (13.3%), nausea (6.7%), and granulocytopenia (6.7%), which were all tolerable and manageable. First-line AZA plus prednisone realizes a better hematological response and relapse-free duration with acceptable adverse events compared to prednisone alone in ANA-positive ITP patients. [ABSTRACT FROM AUTHOR]

Our purpose was to investigate the effect of 3-deazaneplanocin A (DZNep) on human T-cell acute lymphoid leukemia (T-ALL) cells, and to explore the underlying molecular mechanisms. The human T-ALL cell line Molt4 was treated with DZNep, and cell proliferation was examined. The expression of Mps one binder kinase activator 1 gene (MOB1) mRNA and protein was determined by RT-PCR and Western blotting, respectively. The histone modification effect of DZNep on the lysine 9 of histone 3 associated with MOB1 promoters was examined with chromatin immunoprecipitation and quantitative PCR, and CpG methylation in MOB1 promoters was detected by bisulfite sequencing PCR. DZNep treatment inhibited the growth of Molt4 cells. The expressions of MOB1 genes were upregulated by DZNep treatment, and histone methylations in their promoters were significantly reduced. The results indicate that DZNep is a promising therapeutic compound for the treatment of human T-ALL. [ABSTRACT FROM AUTHOR]

Ixazomib is a selective, effective, and reversible inhibitor of 20S proteasome and is approved for the treatment of multiple myeloma. Ubiquitin-conjugating enzyme E2 (UBE2K) is involved in the synthesis of K48-linked ubiquitin chains and is the target of certain drugs used for the treatment of tumors. The purpose of this study was to investigate the relationship between ixazomib and UBE2K in myeloma cells. We used CCK-8 and Annexin V-FITC/propidium iodide kit to detect the effects of ixazomib on survival and apoptosis of RPMI-8226 and U-266 myeloma cell lines. Quantitative polymerase chain reaction and western blot were used to detect the change in gene and protein expression levels of myeloma cells treated with ixazomib. Furthermore, the regulatory effects of ixazomib on UBE2K and its downstream targets were investigated following the overexpression of UBE2K. In myeloma cells, ixazomib decreased cell survival and increased apoptosis in a dose-dependent manner. Ixazomib significantly increased the expression of HIST1H2BD, MNAT1, NEK3, and TARS2, while decreasing the expression of HSPA1B and UBE2K. In addition, ixazomib inhibited the proliferation of myeloma cells, blocked cell cycle, induced cell apoptosis, and increased the production of reactive oxygen species by inhibiting UBE2K expression. Lastly, ixazomib regulates mitosis- and apoptosis-related genes by lowering UBE2K expression. In summary, ixazomib leads to impaired proliferation of myeloma cells by targeting UBE2K. • Ixazomib inhibits the proliferation of myeloma cells by targeting UBE2K. • Ixazomib regulates the expression of mitosis- and apoptosis-related genes. • Ixazomib promotes the production of reactive oxygen species in myeloma cells. [ABSTRACT FROM AUTHOR]

BCL2-interacting protein 3 (BNIP3) expression varies among cancers, and its role in myeloma cells remains unknown. We investigated the role of BNIP3 overexpression in myeloma cells, and particularly its effects on apoptosis and mitochondria. A BNIP3-overexpressing plasmid was transfected into the MM.1S and RPMI8226 myeloma cell lines. Transfected cell apoptosis rate and mitochondrial function were determined via flow cytometry and western blotting. We verified the signaling pathway underlying myeloma cell sensitivity to bortezomib (BTZ). Cell lines carrying the BNIP3-overexpressing plasmid exhibited higher rates of apoptosis and expression of Bax and Cleaved caspase 3 protein than the vector group, and less Bcl-2 protein expression than the control cells. Relative to the vector group, BNIP3-overexpressing strains contained more reactive oxygen species (ROS) and exhibited mitochondrial membrane potential (MMP) and dynamin-related protein 1 (Drp1) upregulation and mitofusin-1 (Mfn1) downregulation. BTZ supplementation increased BNIP3 expression. Relative to the BNIP3-OE group, the BNIP3-OE BTZ-treated group exhibited upregulated Bax and Cleaved caspase 3 protein expression, downregulated Bcl-2 protein expression, higher apoptosis rates, ROS levels, MMP, and Drp1 expression, and lower Mfn1 expression. BTZ treatment induced p38 MAPK (mitogen-activated protein kinase) signaling pathway activation in BNIP3-OE cells. Upon adding N-acetylcysteine (NAC) and the p38 MAPK inhibitor SB203580, the affected index levels returned to the baseline. BNIP3 overexpression induced apoptosis in myeloma cells and increased myeloma cell sensitivity to BTZ. These effects may be mediated by the ROS/p38 MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), a most common and highly prevalent joint disease, is closely associated with dysregulated expression and modification of RXRα. However, the role of RXRα in the pathophysiology of OA remains unknown. The present study aimed to investigate whether RXRα modulator, such as K-80003 can treat OA. Experimental OA was induced by intra-articular injection of monosodium iodoacetate (MIA) in the knee joint of rats. Articular cartilage degeneration was assessed using Safranin-O and fast green staining. Synovial inflammation was measured using hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay (ELISA). Expressions of MMP-13, ADAMTS-4 and ERα in joints were analyzed by immunofluorescence staining. Western blot, RT-PCR and co-Immunoprecipitation (co-IP) were used to assess the effects of K-80003 on RXRα-ERα interaction. Retinoid X receptor α (RXRα) modulator K‐80003 prevented the degeneration of articular cartilage, reduced synovial inflammation, and alleviated osteoarthritic pain in rats. Furthermore, K-80003 markedly inhibited IL-1β‐induced p65 nuclear translocation and IκBα degradation, and down-regulate the expression of HIF-2α, proteinases (MMP9, MMP13, ADAMTS-4) and pro-inflammatory factors (IL-6 and TNFα) in primary chondrocytes. Additionally, knockdown of ERα with siRNA blocked these effects of K-80003 in chondrocytes. In conclusion, RXRα modulators K-80003 suppresses inflammatory and catabolic responses in OA, suggesting that targeting RXRα‐ERα interaction by RXRα modulators might be a novel therapeutic approach for OA treatment. [ABSTRACT FROM AUTHOR]