Wip1 contributes to the adaptation of HepG2 human liver cancer cells to stress hormone-induced DNA damage.

Numerous studies have shown that the release of stress hormones resulting from repeated exposure to chronic psychological stress increases DNA damage and promotes tumorigenesis. However, the mechanisms that enable cancerous cells adapt to stress hormone-induced DNA damage and survive remain unclear. The present study aimed to investigate the impact of stress hormones on the survival of liver cancer cells and the underlying mechanism. HepG2 human liver cancer cells were treated with dexamethasone (DEX), epinephrine (EPI) and norepinephrine (NE) and subjected to the testing of DNA damage, cell survival and cell apoptosis by alkaline comet assay, CCK-8 viability assay and flow cytometry, respectively. The protein expression levels of DNA damage response factors were determined by western blotting analysis. The results revealed that treatment of HepG2 cells with DEX, EPI and NE induced DNA damage without affecting cell survival or inducing apoptosis. The protein levels of wild-type p53-induced phosphatase 1 (Wip1), a type 2C family serine/threonine phosphatase, were increased, and the dephosphorylation of DNA damage response factors, including phosphorylated (p-)ataxia-telangiectasia mutated and p-checkpoint kinase 2, occurred following treatment with DEX, EPI and NE. In addition, a cycloheximide chase assay was performed to explore the protein stability under treatment with stress hormones. Compared with vehicle-treated cells, Wip1 exhibited increased protein stability in stress hormone-treated HepG2 cells. Eventually, the depletion of Wip1 using small interfering RNA verified the role of Wip1 in the modulation of stress hormone-induced DNA damage. These findings suggest that cancerous cells likely adapt to stress hormone-induced DNA damage via Wip1 upregulation. The present study provides an insight into the underlying mechanism that links chronic psychological stress with tumor growth and progression.

Chronic stress promotes tumor immune evasion via the suppression of MHC-I expression and the upregulation of PD-L1.

Chronic stress induces cancer initiation and progression via regulation of diverse cancer risk factors including immune evasion. Our previous research demonstrated that ß-adrenergic blockade with propranolol almost completely reversed the accelerated tumor growth induced by chronic restraint stress, but the underlying mechanism of immune escape remains largely unknown. In the present study, a chronic restraint stress paradigm was applied to the H22 hepatocellular carcinoma (HCC) bearing mice to mimic the psychological stress. We observed that chronic restraint stress significantly promoted HCC growth and tumor escape from T cell surveillance. Chronic restraint stress reduced intratumor MHC-I expression and enhanced PD-L1 expression, whereas propranolol rectified the changes of MHC-I and PD-L1. Under chronic stress, the activated MAPK pathway suppressed MHC-I production by inactivating STAT1/IRF1 signaling pathway, and promoted PD-L1 translation by elevating eIF2α phosphorylation. These findings support the crucial role of ß-adrenergic signaling cascade in the tumor escape from T cell surveillance under chronic restraint stress.

Shumian Capsule Improves the Sleep Disorder and Mental Symptoms Through Melatonin Receptors in Sleep-Deprived Mice.

Healthy sleep is vital to maintaining the body's homeostasis. With the development of modern society, sleep disorder has gradually become one of the most epidemic health problems worldwide. Shumian capsule (SMC), a kind of traditional Chinese medicine (TCM) commonly used for insomnia, exhibits antidepressant and sedative effects in clinical practice. However, the underlying mechanisms have not been fully clarified. With the aid of a network pharmacology approach and function enrichment analysis, we identified the involvement of melatonin receptors in the antidepressant and sedative effects of SMC. In sleep-deprived mice, SMC treatment significantly alleviated insomnia and relevant mental alterations by improving both sleep latency and sleep duration. However, ramelteon, a selective melatonin receptor agonist that has been approved for the treatment of insomnia, only improved sleep latency. Additionally, SMC exhibited comparable effects on mental alterations with ramelteon as determined by an open-field test (OFT) and forced swimming test (FST). Mechanistically, we revealed that the melatonin receptor MT1 and MT2 signaling pathways involved the therapeutic effects of SMC. In addition to the single effect of traditional melatonin receptor agonists on treating sleep onset insomnia, SMC had therapeutic potential for various sleep disorders, such as sleep onset insomnia and sleep maintenance insomnia. Convergingly, our findings provide theoretical support for the clinical application of SMC.

Quantitative Association Between Serum/Dietary Magnesium and Cardiovascular Disease/Coronary Heart Disease Risk: A Dose-Response Meta-analysis of Prospective Cohort Studies.

BACKGROUND: The quantitative association between serum/dietary magnesium and cardiovascular disease (CVD) remains unclear. We conducted a dose-response meta-analysis to evaluate the quantitative association between serum/dietary magnesium and CVD, including coronary heart disease (CHD). METHODS: PubMed, China National Knowledge Infrastructure, and Web of Science were searched for publications. STATA 12.0 was used to analyze data. We used the random-effects model to reduce heterogeneity. RESULTS: Eighteen prospective cohort studies with 544,581 participants and 22,658 CVD cases were included. The follow-up duration was 1-28 years. The pooled relative risk (RR) of CVD for the relatively normal versus lowest serum and dietary magnesium level was 0.64 {[95% confidence interval (CI): 0.51-0.80] and 0.90 [95% CI: 0.84-0.96]}. The pooled RR of CHD for the relatively normal versus lowest serum and dietary magnesium level was 0.70 (95% CI: 0.57-0.85) and 0.86 (95% CI: 0.77-0.94). We noted a significant association between increasing serum magnesium levels (per 0.1-mg/dL increase) and risk of CVD (RR: 0.93, 95% CI: 0.88-0.97) and CHD (RR: 0.90, 95% CI: 0.84-0.96) and between dietary magnesium levels (per 100-mg/d increase) and risk of CVD (RR: 0.90, 95% CI: 0.83-0.96) and CHD (RR: 0.92, 95% CI: 0.82-0.98). Serum/dietary Mg level comparisons presented a 7%-10% decrease in CVD/CHD risk. The dose-response meta-analyses showed linear relationships between serum magnesium and CVD (Pnonlinearity = 0.833) or CHD (Pnonlinearity = 0.193) and dietary magnesium and CVD (Pnonlinearity = 0.463) or CHD (Pnonlinearity = 0.440). CONCLUSIONS: Increasing dietary magnesium or serum magnesium level is linearly and inversely associated with the risk of total CVD and CHD events.