Analysis of m6A modulator-mediated methylation modification patterns and the tumor microenvironment in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. In the development and progression of LUAD, epigenetic aberration plays a crucial role. However, the function of RNA N6-methyladenosine (m6A) modifications in the LUAD progression is unknown. The m6A regulator modification patterns in 955 LUAD samples were analyzed comprehensively. Patterns were systematically correlated with the tumor microenvironment (TME) cell-infiltration characteristics. Using principal component analysis algorithms, the m6Ascore was generated to quantify m6A modification patterns in individual tumors. Then, their values for predicting prognoses and therapeutic response in LUAD patients were assessed. Three distinct m6A modification patterns in LUAD were identified. Among them, the prognosis of m6Acluster C was the best, while the prognosis of m6Acluster A was the worst. Interestingly, the characterization of TME cell infiltration and biological behavior differed among the three patterns. To evaluate m6A modification patterns within individual tumors, an m6Ascore signature was constructed. The results showed that the high m6Ascore group was associated with a better prognosis; tumor somatic mutations and tumor microenvironment differed significantly between the high- and low- m6Ascore groups. Furthermore, in the cohort with anti-CTLA-4 treatment alone, patients with a high m6Ascore had higher ICI scores, which indicated significant therapeutic advantage and clinical benefits.

Integrated analysis of RNA-binding proteins in thyroid cancer.

Recently, the incidence of thyroid cancer (THCA) has been on the rise. RNA binding proteins (RBPs) and their abnormal expression are closely related to the emergence and pathogenesis of tumor diseases. In this study, we obtained gene expression data and corresponding clinical information from the TCGA database. A total of 162 aberrantly expressed RBPs were obtained, comprising 92 up-regulated and 70 down-regulated RBPs. Then, we performed a functional enrichment analysis and constructed a PPI network. Through univariate Cox regression analysis of key genes and found that NOLC1 (p = 0.036), RPS27L (p = 0.011), TDRD9 (p = 0.016), TDRD6 (p = 0.002), IFIT2 (p = 0.037), and IFIT3 (p = 0.02) were significantly related to the prognosis. Through the online website Kaplan-Meier plotter and multivariate Cox analysis, we identified 2 RBP-coding genes (RPS27L and IFIT3) to construct a predictive model in the entire TCGA dataset and then validate in two subsets. In-depth analysis revealed that the data gave by this model, the patient's high-risk score is very closely related to the overall survival rate difference (p = 0.038). Further, we investigated the correlation between the model and the clinic, and the results indicated that the high-risk was in the male group (p = 0.011) and the T3-4 group (p = 0.046) was associated with a poor prognosis. On the whole, the conclusions of our research this time can make it possible to find more insights into the research on the pathogenesis of THCA, this could be beneficial for individualized treatment and medical decision making.

microRNA-9 and -29a regulate the progression of diabetic peripheral neuropathy via ISL1-mediated sonic hedgehog signaling pathway.

In this study, we tested the hypothesis that overexpression of miR-9 and miR-29a may contribute to DPN development and progression. We performed a meta-analysis of miR expression profile studies in human diabetes mellitus (DM) and the data suggested that miR-9 and miR-29a were highly expressed in patients with DM, which was further verified in serum samples collected from 30 patients diagnosed as DM. Besides, ISL1 was confirmed to be a target gene of miR-9 and miR-29a. Lentivirus-mediated forced expression of insulin gene enhancer binding protein-1 (ISL1) activated the sonic hedgehog (SHH) signaling pathway, increased motor nerve conduction velocity and threshold of nociception, and modulated expression of neurotrophic factors in sciatic nerves in rats with DM developed by intraperitoneal injection of 0.45% streptozotocin, suggesting that ISL1 could delay DM progression and promote neural regeneration and repair after sciatic nerve damage. However, lentivirus-mediated forced expression of miR-9 or miR-29a exacerbated DM and antagonized the beneficial effect of ISL1 on DPN. Collectively, this study revealed potential roles of miR-9 and miR-29a as contributors to DPN development through the SHH signaling pathway by binding to ISL1. Additionally, the results provided an experimental basis for the targeted intervention treatment of miR-9 and miR-29a.

Long intergenic noncoding RNA p21 suppresses the apoptosis of hippocampus neurons in streptozotocin-diabetic mice by sponging microRNA-221 through upregulation of FOS.

Diabetes is associated with neurological complications, and accumulated evidence shows that biological pathways in diabetes are targeted by noncoding RNA transcripts. In this study, the role of long intergenic noncoding RNA (lincRNA) p21/microRNA-221 (miR-221)/fructooligosaccharide (FOS) axis was investigated in the mice with diabetes treatment. The streptozotocin-induced diabetic mouse model was established. The learning ability and the pathological changes in mice were analyzed. After that, the interaction among miR-221, lincRNA p21, and FOS was explored and verified. The subcellular location of lincRNA p21 was identified. Finally, the cell cycle and apoptosis of the hippocampus neurons were measured. In the diabetic mice, the levels of blood glucose were higher and the leaning abilities were inhibited. miR-221 was highly expressed in the diabetic mice whereas lincRNA p21 and FOS were poorly expressed. miR-221 could bind with both lincRNA p21 and FOS. miR-221 silencing or lincRNA p21 overexpression in the diabetes mice reduced the cell apoptosis rate, and the expression of Bax and cleaved Caspase-3, whereas increase the Bcl-2 expression. Overexpression of lincRNA p21 promotes FOS expression by binding to miR-221, thereby, inhibiting hippocampal neuron apoptosis in diabetic mice. This may offer potential targets for diabetes.

Rapamycin inhibits activation of AMPK-mTOR signaling pathway-induced Alzheimer's disease lesion in hippocampus of rats with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is strongly correlated with Alzheimer's disease (AD). Rapamycin has important uses in oncology, cardiology and transplantation medicine. This study aims to investigate effects of rapamycin on AD in hippocampus of T2DM rat by AMPK/mTOR signaling pathway. METHODS: Morris water maze test was applied to evaluate the learning and memory abilities. The fasting plasma glucose (FBG), glycosylated haemoglobin, total cholesterol, triglyceride and serum insulin level were measured. RT-qPCR and Western blot analysis were performed to test expression of AMPK and mTOR. Immunohistochemistry was used to detect the Aß deposition and immunoblotting to test the total tau, p-tau and Aß precursor APP expressions. RESULTS: After treated with rapamycin, T2DM rats and rats with T2DM and AD showed increased learning-memory ability, and decreased levels of FBG, glycosylated hemoglobin, total cholesterol, triglyceride and serum insulin, decreased expression of APP and p-tau, increased AMPK mRNA expression and p-AMPK and decreased Aß deposition, mTOR mRNA expression and p-mTOR. CONCLUSION: The study demonstrated that rapamycin reduces the risk of AD in T2DM rats and inhibits activation of AMPK-mTOR signaling pathway, thereby improving AD lesion in hippocampus of T2DM rats.