5­Aza­dC suppresses melanoma progression by inhibiting GAS5 hypermethylation.

The in­depth study of melanoma pathogenesis has revealed that epigenetic modifications, particularly DNA methylation, is a universal inherent feature of the development and progression of melanoma. In the present study, the analysis of the tumor suppressor gene growth arrest­specific transcript 5 (GAS5) demonstrated that its expression was downregulated in melanoma, and its expression level had a certain negative association with its methylation modification level. The promoter of GAS5 presented with detectable CpG islands, and methylation­specific polymerase chain reaction analysis demonstrated that GAS5 was actually modified by methylation in melanoma tissues and cells; however, no methylation modification of GAS5 was detected in normal tissues. Following the treatment of melanoma cells with 5­Aza­2'­deoxycytidine (5­Aza­dC), GAS5 methylation was significantly reversed. The analysis of melanoma cell proliferation revealed that 5­Aza­dC inhibited A375 and SK­MEL­110 cell proliferation in a time­dependent manner. Further analysis of apoptosis demonstrated that 5­Aza­dC significantly increased the apoptosis level of the two cell lines. Moreover, migration analysis of melanoma cells revealed that 5­Aza­dC significantly reduced cell migration. Furthermore, 5­Aza­dC significantly decreased the invasive ability of the two cell lines. However, when the expression of GAS5 was silenced, the effects of 5­Aza­dC on cell proliferation, apoptosis, invasion and migration were not significant. Furthermore, the subcutaneous injection of A375 cells in nude mice successfully resulted in xenograft tumor formation. However, following an intraperitoneal injection of 5­Aza­dC, the volume and weight of xenograft tumors and Ki­67 expression were significantly reduced, and caspase­3 activity and GAS5 expression were enhanced; following the silencing of GAS5, the antitumor effect of 5­Aza­dC was significantly blocked. On the whole, the present study demonstrates that 5­Aza­dC inhibits the growth of melanoma, and its function may be related to the methylation modification of GAS5.

The Impact of COVID-19-Related Work Stress on the Mental Health of Primary Healthcare Workers: The Mediating Effects of Social Support and Resilience.

OBJECTIVE: The psychological condition of healthcare workers since the COVID-19 pandemic has attracted the attention of many studies. However, few have reported on psychosocial problems of primary healthcare workers in the COVID-19 pandemic. This study aimed to examine the mediating roles of social support and resilience in COVID-19-related work stress and symptoms of anxiety and depression. METHODS: A total of 840 primary healthcare workers in 17 community health centers in Guangzhou, China, were recruited from May to July 2021. Data on demographic characteristics, COVID-19-related work stress, social support, resilience, anxiety and depression were collected. A structural equation model was used for mediation analysis. RESULTS: More than half of participants reported mild or more severe (at least borderline abnormal) symptoms of anxiety (68.1%) and depression (55.6%). Social support and resilience mediate the association between COVID-19-related work stress and symptoms of anxiety and depression, respectively. Furthermore, the association between work stress and symptoms of anxiety and depression was also mediated by an accumulation of social support and resilience. The indirect effect of COVID-19-related work stress on anxiety and depression through resilience was much greater than other indirect effects. CONCLUSION: Anxiety and depression were prevalent among primary healthcare workers. This study highlights the psychological impact of the COVID-19-related psychosocial work environment on primary healthcare workers. There is an urgent need to improve working conditions for primary healthcare workers in the COVID-19 and to implement intervention strategies aimed at increasing individual resilience alongside the establishment of external supportive work environments.

A fusion protein composed of the DSL domain of Dll1 and RGD motif protects cryptic stem cells in irradiation injury.

Intestine is vulnerable to irradiation injury, which induces cell death and compromises regeneration of intestinal crypts. It is well accepted that cryptic stem cells, which are responsible for cryptic regeneration under physiological and pathological conditions, are controlled by multiple cell-intrinsic and environmental signals such as Notch signaling. Therefore, in the present study, we tested whether a soluble Notch ligand tethered to endothelial cells-mD1R-the Delta-Serrate-Lag2 (DSL) domain of mouse Notch ligand Delta-like1 fused with a RGD motif could protect cryptic cells from irradiation-induced intestinal injury. The result showed that administration of mD1R, which activated Notch signaling in intestinal cells, ameliorated loss of body weight and reduction of cryptic structures in intestine after total body irradiation (TBI) in mice. Histological staining showed that injection of mD1R after TBI promoted cryptic cell proliferation and reduced cell apoptosis in crypts. Immunofluorescence staining and reverse transcription (RT)-PCR showed that mD1R increased the level of Lgr5, Bmi1, Olfactomedin-4 (OLFM4), and IRIG1 in crypts, suggesting a protective effect on cryptic stem and progenitor cells after irradiation. Moreover, we found that administration of mD1R increased the number of Paneth cells and the mRNA level of Defa1, and the number Alcian Blue+ Goblet cells decreased first and then increased after irradiation, suggesting that mD1R promoted the maturation of the intestinal crypt after irradiation injury. Our data suggested that mD1R could serve as a therapeutic agent for the treatment of irradiation-induced intestinal injury.