Investigating the Impact of Sun/UV Protection and Ease of Skin Tanning on the Risk of Pseudoexfoliation Glaucoma: A Mendelian Randomization Study.

Purpose: To investigate the potential causal associations between the use of sun/ultraviolet (UV) protection and ease of skin tanning and the risk of pseudoexfoliation glaucoma (PXG) in European populations. Methods: Single nucleotide polymorphisms (SNPs) associated with the use of sun/UV protection and ease of skin tanning were selected from the UK Biobank genome-wide association study database consisting of 498,751 European participants. SNPs of PXG were obtained from the FinnGen study including 3424 PXG cases and 326,434 controls. Two-sample Mendelian randomization (MR) analyses were performed to assess the association between the use of sun/UV protection and ease of skin tanning and risk of PXG. Results: Inverse variance weighted regression of genetic susceptibility predicted that both use of sun/UV protection and ease of skin tanning were potentially positively associated with the decreased risk of PXG in the European ancestry (use of sun/UV protection: odds ratio [OR] = 0.47; 95% confidence interval [CI], 0.24-0.92; P = 0.028; ease of skin tanning: OR = 0.81; 95% CI, 0.67-0.97; P = 0.025). Conclusions: We found genetic evidence supporting a potential causal association between UV protection and a decreased risk of PXG in European population. Further research will help elucidate the underlying mechanisms and promote UV protection for eyes, especially in people with a high risk of PXG.

TIMELESS promotes the proliferation and migration of lung adenocarcinoma cells by activating EGFR through AMPK and SPHK1 regulation.

BACKGROUND: Lung adenocarcinoma (LUAD) has high morbidity and is prone to recurrence. TIMELESS (TIM), which regulates circadian rhythms in Drosophila, is highly expressed in various tumors. Its role in LUAD has gained attention, but the detailed function and mechanism have not been clarified completely at present. METHODS: Tumor samples from patients with LUAD patient data from public databases were used to confirm the relationship of TIM expression with lung cancer. LUAD cell lines were used and siRNA of TIM was adopted to knock down TIM expression in LUAD cells, and further cell proliferation, migration and colony formation were analyzed. By using Western blot and qPCR, we detected the influence of TIM on epidermal growth factor receptor (EGFR), sphingosine kinase 1 (SPHK1) and AMP-activated protein kinase (AMPK). With proteomics analysis, we comprehensively inspected the different changed proteins influenced by TIM and did global bioinformatic analysis. RESULTS: We found that TIM expression was elevated in LUAD and that this high expression was positively correlated with more advanced tumor pathological stages and shorter overall and disease-free survival. TIM knockdown inhibited EGFR activation and also AKT/mTOR phosphorylation. We also clarified that TIM regulated the activation of SPHK1 in LUAD cells. And with SPHK1 siRNA to knock down the expression level of SPHK1, we found that EGFR activation were inhibited greatly too. Quantitative proteomics techniques combined with bioinformatics analysis clarified the global molecular mechanisms regulated by TIM in LUAD. The results of proteomics suggested that mitochondrial translation elongation and termination were altered, which were closely related to the process of mitochondrial oxidative phosphorylation. We further confirmed that TIM knockdown reduced ATP content and promoted AMPK activation in LUAD cells. CONCLUSIONS: Our study revealed that siTIM could inhibit EGFR activation through activating AMPK and inhibiting SPHK1 expression, as well as influencing mitochondrial function and altering the ATP level; TIM's high expression in LUAD is an important factor and a potential key target in LUAD.

Influence of sleep disruption on inflammatory bowel disease and changes in circadian rhythm genes.

According to clinical investigations, sleep disruption (SD) can influence the immune system and cause inflammatory bowel disease (IBD). However, the detailed effects of sleep on IBD development and progression have not been clarified. Here, we used dextran sulfate sodium (DSS) to induce colitis in mice, and then interfered with SD (day-time 8:00 a.m. to 5:00 p.m.) to explore the influence of sleep on colitis by analyzing colon length, mouse body weight, disease activity index (DAI) score, pathology detection, and infiltration of inflammatory cells with LCA immunohistochemistry analysis. Next, we detected the mRNA levels of circadian genes and related inflammatory factors, including Bmal1, CLOCK, Cry1, Cry2, Per1, Per2, Timeless, Rev-erbα, TNF-α, IL-6, and IFN-γ. Additionally, we conducted a sleep survey in IBD patients and collected colon lesion sites to detect the mRNA levels of those eight circadian genes and three inflammatory factors. We found that SD promoted the body weight decrease, increased inflammation as shown with pathological staining of the DSS animal model, and increased expression of the clock gene Cry2 in DSS-induced colitis mice. In IBD patients with active disease, the mRNA level of circadian genes Bmal1, Cry1, Cry2, and Rev-erbα in inflammatory tissues decreased significantly compared with non-inflammatory tissues.

Identification of TIMELESS and RORA as key clock molecules of non-small cell lung cancer and the comprehensive analysis.

BACKGROUND: The incidence rate of non-small cell lung cancer (NSCLC) has been increasing worldwide, and the correlation of circadian rhythm disruption with a raised risk of cancer and worse prognosis has been shown by accumulating evidences recently. On the other hand, drug resistance and the impact of tumor heterogeneity have been inevitable in NSCLC therapy. These both lead to an urgent need to identify more useful prognostic and predictive markers for NSCLC diagnosis and treatment, especially on the aspect of circadian clock genes. METHODS: The expression of the main clock genes in cancer was probed with TIMER and Oncomine databases. The prognostic value of key clock genes was probed systematically with the Kaplan-Meier estimate and Cox regression on samples from TCGA database. RT-qPCR was performed on patient tissue samples to further validate the results from databases. The functional enrichment analysis was performed using the "ClusterProfiler" R package, and the correlation of key clock genes with tumor mutation burden, immune checkpoint, and immune infiltration levels were also assessed using multiple algorithms including TIDE, TIMER2.0, and XCELL. RESULTS: TIMELESS was significantly upregulated in lung tissue of clinical lung cancer patients as well as TCGA and Oncomine databases, while RORA was downregulated. Multivariate Cox regression analysis indicated that TIMELESS (P = 0.004, HR = 1.21 [1.06, 1.38]) and RORA (P = 0.047, HR = 0.868 [0.755, 0.998]) has a significant correlation with overall survival in NSCLC. Genes related to TIMELESS were enriched in the cell cycle and immune system, and the function of RORA was mainly focused on oncogenic signaling pathways or glycosylation and protein activation. Also, TIMELESS was positively correlated with tumor mutation burden while RORA was negatively correlated with it. TIMELESS and RORA were also significantly correlated with immune checkpoint and immune infiltration levels in NSCLC. Additionally, TIMELESS showed a significant positive relationship with lipid metabolism. CONCLUSIONS: TIMELESS and RORA were identified as key clock genes in NSCLC, and were independent prognostic factors for overall survival in NSCLC. The function of them were assessed in many aspects, indicating the strong potential of the two genes to serve as biomarkers for NSCLC progression and prognosis.

Antimetastatic Effects of Ganoderma lucidum Polysaccharide Peptide on B16-F10-luc-G5 Melanoma Mice With Sleep Fragmentation.

Ganoderma lucidum (Lingzhi) polysaccharide peptide (GL-pp) is a component of the globally acknowledged traditional Chinese medicine Ganoderma lucidum; Ganoderma lucidum is known for its sedative, hypnotic, immune regulatory, antitumor, and other pharmacological effects. In recent years, sleep disorders have been linked to many diseases and human body disorders, including cancer. Some experimental studies in mice found that sleep fragmentation could promote tumor development and progression. However, effects on GL-pp on tumor metastasis under circumstances of sleep disorders have rarely been studied. Thus, in this study, we used mice with sleep fragmentation (SF) bearing B16-F10-luc-G5 melanoma tumors to investigate the effect of SF on melanoma metastasis. Furthermore, we investigated the antitumor and antimetastatic effects of GL-pp (80 mg/kg) in mice suffering from SF and bearing B16-F10-luc-G5. Then, whole proteomics was used to analyze the differences in protein expression in the lung tissue between SF mice bearing B16-F10-luc-G5 with and without GL-pp administration. High-throughput pyrosequencing of 16S rRNA was also used to analyze the impact of GL-pp on the gut microbiota composition in SF mice bearing B16-F10-luc-G5. Last, the effects of GL-pp on macrophage polarization and TNF-α serum levels were detected. Collectively, we found that SF significantly facilitated the B16-F10-luc-G5 melanoma tumor metastasis in mice, while GL-pp significantly reduced B16-F10-luc-G5 melanoma tumor metastasis under the condition of SF, in which proteomics and gut microbiota had been changed greatly.