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Nitric oxide (NO) is a simple structured and unstable free radical molecule, which participates in the regulation of many pathophysiological processes. It functions both as a second messenger and as an endogenous neurotransmitter. Diazeniumdiolates (NONOates) are a series of compounds containing the functional parent nuclear structure of [N(O)NO]—, which are the most widely studied NO donors. NONOates are unstable and easy to release NO in physiological conditions. The biomedical applications and drug development of NO donor have attracted the scientists' attention in recent years. In this review, recent advances in NONOates research are highlighted in terms of chemical structures, molecular characteristics, pharmacological effects, and biomedical application prospects. [ABSTRACT FROM AUTHOR]

USP15, a pivotal member of the deubiquitinase family, plays a crucial role in orchestrating numerous vital biological processes, including the regulation of NF-κB signaling pathway and deubiquitination of proto-oncogenes. In various cancers, USP15 has been validated to exhibit up-regulated expression, impacting the initiation and progression of cancer. However, its precise mechanism in bladder cancer remains elusive. Our study shed light on the significant overexpression of USP15 in bladder cancer cells compared to normal bladder cells, correlating with a poorer prognosis for bladder cancer patients. Strikingly, attenuation of USP15 expression greatly attenuated the proliferation, migration, and invasion of bladder cancer cells. Moreover, upregulation of USP15 was found to drive cancer progression through the activation of the NF-κB signaling pathway. Notably, USP15 directly deubiquitinates BRCC3, heightening its expression level, and subsequent overexpression of BRCC3 counteracted the antitumoral efficacy of USP15 downregulation. Overall, our findings elucidated the carcinogenic effects of USP15 in bladder cancer, primarily mediated by the excessive activation of the NF-κB signaling pathway, thereby promoting tumor development. These results underscore the potential of USP15 as a promising therapeutic target for bladder cancer in the future.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. The majority of patients with HCC are diagnosed with advanced-stage disease. Sorafenib is a frontline therapy drug approved by the Food and Drug Administration for advanced HCC. However, the poor aqueous solubility of sorafenib limits its applications. The present study aimed to overcome this limitation of sorafenib. Thus, bovine serum albumin (BSA)-based nanoparticles were developed to encapsulate hydrophobic sorafenib. The resultant sorafenib-loaded BSA nanoparticles (Sf-BSA-NPs) were thoroughly characterized for size distribution, encapsulation efficiency and morphology. Previous studies on HepG2 cells in vitro have demonstrated that Sf-BSA-NPs exhibit remarkable superiority to free sorafenib in cytocompatibility, cytotoxicity and proapoptotic effect. The results of the present study demonstrated that Sf-BSA-NPs were effective in improving aqueous solubility, and enhanced drug cytotoxicity, suggesting its therapeutic potential for HCC.

Aerobic glycolysis (the Warburg effect) promotes tumor metastasis; hence, drugs targeting its regulators are being developed. c-Myc, a critical transcription factor that regulates the Warburg effect, is involved in the tumorigenesis of many cancers, including pancreatic cancer (PC). However, the upstream regulating mechanisms of c-Myc in PC are unclear. Herein, we reported that E3 ubiquitin ligase RING-finger protein 6 (RNF6) was upregulated in PC tissues, and an elevated RNF6 level was closely associated with metastasis and poor prognosis in patients with PC. In functional experiments, RNF6 over-expression accelerated the metastatic ability of PC cells, whereas RNF6 knockdown impaired PC cell motility and invasiveness along with metastasis in an orthotopic mouse model. Furthermore, we found that RNF6 promoted PC cell metastasis by enhancing c-Myc-mediated aerobic glycolysis. Mechanistically, RNF6 increased the expression level of c-Myc by catalyzing the ubiquitination of Max-dimerization protein-1 (MAD1), a cellular antagonist of c-Myc. Lastly, RNF6 promoted the degradation of MAD1 via the ubiquitin-proteasome pathway, and this reduction in the MAD1 levels enabled c-Myc to promote the Warburg effect in PC. Our results demonstrate that RNF6 may be a novel biomarker in PC carcinogenesis, thereby indicating that targeting the RNF6/MAD1/c-Myc axis is a potential strategy for PC therapy., Competing Interests: None., (AJCR Copyright © 2021.)

Objective: To explore the role of eukaryotic translation elongation factor 1A1 (eEF1A1) in regulating the invasion and metastasis of hepatocellular carcinoma (HCC) cells and the possible mechanism., Methods: qRT-PCR and Western blotting were used to detect the mRNA and protein expression of eEF1A1 and NOB1 in different HCC cell lines and normal liver cells. The invasion and migration abilities of HCC cells with eEF1A1 knockdown or overexpression were examined using Transwell chamber assay and RTCA assay, and the changes in NOB1 mRNA and protein expressions in the cells were detected. The effects of increasing NOB1 expression in HCCLM3-sheEF1A1 cells and decreasing NOB1 expression in eEF1A1-overexpressing MHCC97h cells on eEF1A1 expression and cell invasion and migration abilities were analyzed using Western blotting, Transwell chamber assay and RTCA assay., Results: The expressions of eEF1A1 and NOB1 were significantly increased in positive correlation in HCC cells as compared with normal hepatocytes. Knockdown of eEF1A1 significantly decreased the invasion and migration of HCC cells and reduced the mRNA and protein expression of NOB1 ( P < 0.01). Overexpression of eEF1A1 significantly enhanced invasion and migration of HCC cells and increased NOB1 mRNA and protein expressions ( P < 0.01). Increasing NOB1 expression in HCCLM3-sheEF1A1 cells led to the restoration of NOB1 expression and cell invasion and migration abilities ( P < 0.01), whereas decreasing NOB1 in MHCC97h-eEF1A1 cells resulted in inhibition of NOB1 expression and cell invasion and migration ( P < 0.01)., Conclusions: eEF1A1 positively regulates the expression of NOB1 to promote the invasion and migration of HCC cells in vitro .

Background: The conventional method of bone mar row transplantation (BMT) requires a large quantity of bone marrow cells (BMC) transplanted by a single injection. However, the homing efficiency of BMC is low, because the emptying of available niches might be a continuous process after stem-cell death after irradiation. In this article, the death character of CD34 stem cells was directly detected, and a novel method of fractionated (Fr) BMT that aimed to better use each niche that was continuously emptied was developed., Methods: Apoptosis and necrosis were detected using trivariate fluorescence-activated cell sorting after labeling cells with phycoerythrin-CD34-fluorescein isothiocyanate-Annix V-7-aminoactinomycin D. Fr-BMT was conducted in a model of allogeneic BMT, where the total dosage of BMC was divided into four doses, and each dose was administrated for 4 consecutive days at 24-hr intervals after lethal irradiation., Results: CD34 cells underwent a continuous death process after lethal irradiation and presented three death peaks within a week. Fr-BMT decreased the BMC transplanted but increased the accumulatively homed BMC and enhanced the survival rates of recipients., Conclusions: Fr-BMT is able to enhance hematopoietic cell homing and engraftment, and this method might prove to be a solution to the previous clinical problem that a single unit of umbilical cord blood is not sufficient for engraftment in adults.