RAE1 promotes nitrosamine-induced malignant transformation of human esophageal epithelial cells through PPARα-mediated lipid metabolism.

Esophageal cancer (EC) is the sixth cause of cancer-related deaths and still is a significant public health problem globally. Nitrosamines exposure represents a major health concern increasing EC risks. Exploring the mechanisms induced by nitrosamines may contribute to the prevention and early detection of EC. However, the mechanism of nitrosamine carcinogenesis remains unclear. Ribonucleic acid export 1 (RAE1), has an important role in mediating diverse cancer types, but, to date, there has been no study for any functional role of RAE1 in esophageal carcinogenesis. Here, we successfully verified the nitrosamine-induced malignant transformation cell (MNNG-M) by xenograft tumor model, based on which it was found that RAE1 was upregulation in the early stage of nitrosamine-induced esophageal carcinogenesis and EC tissues. RAE1 knockdown led to severe blockade in G2/M phase and significant inhibition of proliferation of MNNG-M cells, whereas RAE1 overexpression had the opposite effect. In addition, peroxisome proliferator-activated receptor-alpha (PPARα), was demonstrated as a downstream target gene of RAE1, and its down-regulation reduced lipid accumulation, resulting in causing cells accumulation in the G2/M phase. Mechanistically, we found that RAE1 regulates the lipid metabolism by maintaining the stability of PPARα mRNA. Taken together, our study reveals that RAE1 promotes malignant transformation of human esophageal epithelial cells (Het-1A) by regulating PPARα-mediated lipid metabolism to affect cell cycle progression, and offers a new explanation of the mechanisms underlying esophageal carcinogenesis.

The Impact of Preventive Strategies Adopted during Large Events on the COVID-19 Pandemic: A Case Study of the Tokyo Olympics to Provide Guidance for Future Large Events.

This study aimed to analyze the impact of hosting large events on the spread of pandemics, taking Tokyo Olympics 2020 as a case study. A risk assessment method for the whole organization process was established, which could be used to evaluate the effectiveness of various risk mitigation measures. Different scenarios for Games participants and Japanese residents during the Tokyo Olympics were designed based on the infection control protocols proposed by the Olympic Committee and local governments. A modified Wells-Riley model considering the influence of social distance, masking and vaccination, and an SIQRV model that introduced the effect of quarantine and vaccination strategies on the pandemic spread were developed in this study. Based on the two models, our predicted results of daily confirmed cases and cumulative cases were obtained and compared with reported data, where good agreement was achieved. The results show that the two core infection control strategies of the bubble scheme and frequent testing scheme curbed the spread of the COVID-19 pandemic during the Tokyo Olympics. Among Games participants, Japanese local staff accounted for more than 60% of the total in positive cases due to their large population and most relaxed travel restrictions. The surge in positive cases was mainly attributed to the high transmission rate of the Delta variant and the low level of immunization in Japan. Based on our simulation results, the risk management flaws for the Tokyo Olympics were identified and improvement measures were investigated. Moreover, a further analysis was carried out on the impact of different preventive measures with respect to minimizing the transmission of new variants with higher transmissibility. Overall, the findings in this study can help policymakers to design scientifically based and practical countermeasures to cope with pandemics during the hosting of large events.

Reduced plasma progranulin levels are associated with the severity of Parkinson's disease.

Blood levels of progranulin (PGRN) are suggested to be decreased in patients with Parkinson's disease (PD). However, the association between blood levels of progranulin and the severity of PD is not yet clear. A total of 55 PD patients and 55 normal control (NC) subjects were recruited in the present study. Hoehn and Yahr stages (H&Y) and Unified Parkinson's Disease Rating Scale scores (UPDRS) were examined to assess the severity of the disease. UPDRS motor section (UPDRS-III) was used to assess the motor function of the patients. Plasma levels of PGRN were tested by Elisa assays. Plasma PGRN levels are significantly decreased in PD patients (PD vs. NC: 333.8 ± 8.067 vs. 364.2 ± 10.11 ng/ml, p = 0.020). In the subgroup analysis, plasma PGRN levels decrease as H&Y score increases (H&Y = 1 vs. H&Y = 2: 363.5 ± 3.251 vs. 336.3 ± 7.403 ng/ml, p = 0.013; H&Y = 1 vs. H&Y = 3-5: 363.5 ± 3.251 vs. 218.1 ± 18.12 ng/ml, p < 0.001; H&Y = 2 vs. H&Y = 3-5: 336.3 ± 7.403 vs. 218.1 ± 18.12 ng/ml, p = 0.076). Plasma levels of progranulin are negatively correlated with the severity of PD, as reflected by UPDRS (γ=-0.754, p < 0.001), UPDRS-III (γ=-0.808, p < 0.001) and disease duration (γ=-0.633, p < 0.001). Circulating PGRN levels might be a potential indicator of the disease severity of PD.

MicroRNA-217/138-5p downregulation inhibits inflammatory response, oxidative stress and the induction of neuronal apoptosis in MPP+-induced SH-SY5Y cells.

Parkinson's disease (PD) is a common neurodegenerative disease. Various microRNAs (miRNAs) have been reported to play important roles in cell growth regulation and inflammatory reaction. However, the detailed roles of miR-217 and miR-138-5p in PD progression remain to be investigated. In the present study, we explored the effects and underlying mechanisms of miR-217 and miR-138-5p on the inflammatory response, oxidative stress and the induction of neuronal apoptosis in an in vitro PD cell line model induced by 1-methyl-4-phenylpyridinium (MPP+). The results of the biological software analysis and luciferase reporter assays demonstrated that sirtuin 1 (SIRT1) was a direct target of miR-217 and miR-138-5p. MiR-217 and miR-138-5p exhibited a negative regulatory effect on the expression of SIRT1 in SH-SY5Y cells. In addition, the expression levels of miR-217 and miR-138-5p were increased, and SIRT1 expression was decreased in SH-SY5Y cells following MPP+ treatment. Loss-of-function experiments indicated that treatment of the cells with inhibitors against miR-217 and miR-138-5p promoted cell viability and superoxide dismutase (SOD) activity, while the induction of cell apoptosis, lactate dehydrogenase (LDH) activity, and the reactive oxygen species (ROS) release were inhibited in MPP+-induced SH-SY5Y cells. Moreover, the expression levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were reduced in MPP+-induced SH-SY5Y cells. Treatment of the cells with the miR-217 and the miR-138-5p inhibitors significantly inhibited the ratio of phosphorylated (p)-p65/p65 expression levels in MPP+-induced SH-SY5Y cells. In summary, the present study demonstrated that the miR-217/miR-138-5p/SIRT1 axis was involved in the progression of PD by regulating the inflammatory response and the induction of oxidative stress and neuronal apoptosis. The data provide new diagnostic and therapeutic strategies for PD patients.