The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anticancer agent possessing the ability to induce apoptosis in various cancer cells but not in non‑malignant cells. However, certain type of cancer cells are resistant to TRAIL‑induced apoptosis and some acquire resistance after the first treatment. So development of an agent that can reduce or avoid resistance in TRAIL‑induced apoptosis has garnered significant attention. The present study evaluated the anticancer potential of hispolon in TRAIL‑induced apoptosis and indicated hispolon can sensitize cancer cells to TRAIL. As the mechanism of action was examined, hispolon was found to activate caspase‑3, caspase‑8 and caspase‑9, while downregulating the expression of cell survival proteins such as cFLIP, Bcl‑2 and Bcl‑xL and upregulating the expression of Bax and truncated Bid. We also found hispolon induced death receptors in a non‑cell type‑specific manner. Upregulation of death receptors by hispolon was found to be p53-independent but linked to the induction of CAAT enhancer binding protein homologous protein (CHOP). Overall, hispolon was demonstrated to potentiate the apoptotic effects of TRAIL through downregulation of anti‑apoptotic proteins and upregulation of death receptors linked with CHOP and pERK elevation.
Triptolide, an active component extracted from the medicinal plant Tripterygium wilfordii Hook F., has been used to treat various diseases, including lupus, cancer, rheumatoid arthritis and nephritic syndrome. The present study investigated the effects of triptolide on multiple myeloma using western blotting and an electrophoretic mobility shift assay. Triptolide was found to suppress the inducible and constitutive activation of signal transducer and activator of transcription 3 (STAT3), which is closely associated with inflammation and tumorigenesis. Triptolide also inhibited the DNA binding of STAT3. This correlated with the downregulation of Src kinase and Janus kinase 1 and 2, and with the upregulation of protein tyrosine phosphatase non‑receptor type 6 (also known as SHP‑1). In addition, triptolide downregulated the expression of the STAT3‑regulated antiapoptotic (Bcl‑xL and myeloid cell leukemia‑1), proliferative (cyclin D1), and angiogenic (vascular endothelial growth factor) genes, suggesting that triptolide can induce apoptosis of tumor cells. These results suggest that triptolide may be a potential therapeutic anticancer agent for the prevention and treatment of multiple myeloma; thus further in‑depth investigations into its efficacy and toxicity are warranted.
The RING domain of MUL1 (RING MUL1 ) alone mediates ubiquitylation of the p53-transactivation domain (TAD p53 ). To elucidate the mechanism underlying the simultaneous recruitment of UBE2D2 and the substrate TAD p53 by RING MUL1 , we determined the complex structure of RING MUL1 :UBE2D2 and studied the interaction between RING MUL1 and TAD p53 in the presence of UBE2D2-UB thioester (UBE2D2~UB) mimetics. The RING MUL1 -binding induced the closed conformation of UBE2D2 S22R/C85S -UB K48R oxyester (UBE2D2 RS -UB R OE ), and strongly accelerated its hydrolysis, which was suppressed by the additional N77Amutation of UBE2D2. Interestingly, UBE2D2 S22R/N77A/C85S -UB K48R oxyester (UBE2D2 RAS -UB R OE ) already formed a closed conformation in the absence of RING MUL1 . Although TAD p53 exhibited weak binding for RING MUL1 or UBE2D2 alone, its binding affinity was enhanced and even further for RING MUL1 :UBE2D2 and RING MUL1 :UBE2D2 RAS -UB R OE , respectively. The recognition of TAD p53 by RING MUL1 as a complex with UBE2D2~UB is related to the multivalency of the binding events and underlies the ability of RING MUL1 to ubiquitylate the intrinsically disordered protein, TAD p53 .
Background and aims: The origin, niche, and function of human hepatic stem/progenitor cells (HHSPCs) have been longstanding areas of debate. We designed this study to elucidate the distribution of potential HHSPCs during the various stages of regeneration by the expression of known HHSPC markers. Methods: Immunostainings for c‐kit, cytokeratin (CK)19, and CD133 were performed in cases of massive hepatic necrosis (MHN) in various regenerating stages. Results: We identified c‐kit‐positive cells as single cells primarily in the stroma of portal tracts but rarely in the sinusoids. There were no differences in the numbers or distribution of c‐kit positive cells according to MHN regeneration stage. The number of CK19‐positive cells mostly in a ductular arrangement significantly increased along the interface, and single cells or small clusters of CK19‐positive cells were occasionally observed in the sinusoid in cases of MHN. CD133‐positive cells were located in ductular structures along the interface in cases of MHN, while no CD133‐positive cells were observed in the normal liver. Conclusion: The c‐kit‐ or CD133‐positive cells appear first at the limiting plate and are then organized into ductular structures or moved to the sinusoid as single cells or clusters during hepatic regeneration.
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