METTL3-mediated m6A modification of pri-miR-148a-3p affects prostate cancer progression by regulating TXNIP.

OBJECTIVE: Prostate cancer (PCa) severely affects men's health worldwide. The mechanism of methyltransferase-like 3 (METTL3) in affecting PCa development by regulating miR-148a-3p expression via N6-methyladenosine (m6A) modification was investigated. METHODS: METTL3, miR-148a-3p, and thioredoxin interacting protein (TXNIP) levels were determined using RT-qPCR and Western blotting. The m6A modification level of miR-148a-3p was observed by Me-RIP assay. Bioinformatics website predicted miR-148a-3p and TXNIP levels in PCa and their correlation, and the binding site between them was verified by dual-luciferase assay. The proliferation, migration, invasion, and apoptosis of PCa cells were examined by CCK-8 assay, Transwell assay, and flow cytometry. A transplanted tumor model was established in nude mice to observe the tumor growth ability, followed by determination of TXNIP levels in tumor tissues by immunohistochemistry. RESULTS: METTL3 interference restrained the proliferation, migration, and invasion and promoted apoptosis of PCa cells. METTL3 up-regulated miR-148a-3p by promoting the m6A modification of pri-miR-148a-3p in PCa cells. miR-148a-3p overexpression nullified the inhibitory actions of silencing METTL3 on PCa cell growth. miR-148a-3p facilitated PCa cell growth by silencing TXNIP. METTL3 interference inhibited tumor growth by down-regulating miR-148a-3p and up-regulating TXNIP. CONCLUSION: METTL3 promoted miR-148a-3p by mediating the m6A modification of pri-miR-148a-3p, thereby targeting TXNIP, interfering with METTL3 to inhibit the proliferation, migration and invasion of PCa cells, promote apoptosis, and inhibit tumor growth in nude mice.

Machine learning and integrative analysis identify the common pathogenesis of azoospermia complicated with COVID-19.

Background: Although more recent evidence has indicated COVID-19 is prone to azoospermia, the common molecular mechanism of its occurrence remains to be elucidated. The aim of the present study is to further investigate the mechanism of this complication. Methods: To discover the common differentially expressed genes (DEGs) and pathways of azoospermia and COVID-19, integrated weighted co-expression network (WGCNA), multiple machine learning analyses, and single-cell RNA-sequencing (scRNA-seq) were performed. Results: Therefore, we screened two key network modules in the obstructive azoospermia (OA) and non-obstructive azoospermia (NOA) samples. The differentially expressed genes were mainly related to the immune system and infectious virus diseases. We then used multiple machine learning methods to detect biomarkers that differentiated OA from NOA. Enrichment analysis showed that azoospermia patients and COVID-19 patients shared a common IL-17 signaling pathway. In addition, GLO1, GPR135, DYNLL2, and EPB41L3 were identified as significant hub genes in these two diseases. Screening of two different molecular subtypes revealed that azoospermia-related genes were associated with clinicopathological characteristics of age, hospital-free-days, ventilator-free-days, charlson score, and d-dimer of patients with COVID-19 (P < 0.05). Finally, we used the Xsum method to predict potential drugs and single-cell sequencing data to further characterize whether azoospermia-related genes could validate the biological patterns of impaired spermatogenesis in cryptozoospermia patients. Conclusion: Our study performs a comprehensive and integrated bioinformatics analysis of azoospermia and COVID-19. These hub genes and common pathways may provide new insights for further mechanism research.

Replication of the abnormal niacin response in first episode psychosis measured using laser Doppler flowmeter.

INTRODUCTION: Impaired sensitivity of the skin flush response to niacin is found in approximately 30% of patients with schizophrenia. Although the niacin response abnormality (NRA) may serve as a useful endophenotype for schizophrenia, few studies have directly replicated NRA in patients with first-episode psychosis (FEP). METHODS: In total, 204 patients with FEP, 16 with psychotic mood disorder (PMD), and 68 healthy controls (HC) were included. The log10 (EC50 ) values represent the concentration of methyl nicotinate required to elicit a half-maximal blood flow (MBF) response, and the MBF value was calculated. The NRA was defined as having log10 (EC50 ) molar value above the 90% and an MBF value below the 60% of those in the HC group. RESULTS: In total, 13.7% of the FEP, 12.5% of the PMD, and 7.4% of the HC group met the definition of NRA. Significant differences were found in the log10 (EC50 ) values between the FEP and HC groups (p = .014) and in the MBF between the FEP and PMD groups (p = .011). Patients with FEP and NRA had more severe negative symptoms than those with a normal niacin response. DISCUSSION: These data represent the NRA in patients with FEP, defining a small subgroup of patients with early-phase psychosis possessing a clinically significant phospholipid-signaling defect.

ECT-induced brain plasticity correlates with positive symptom improvement in schizophrenia by voxel-based morphometry analysis of grey matter.

BACKGROUND: Electroconvulsive therapy (ECT) is often considered as an augmentation of antipsychotic treatment for schizophrenia in drug-refractory cases. However, the mechanisms underlying the observed therapeutic effects are still not understood. OBJECTIVE: We aimed to investigate changes in whole brain grey matter volume (GMV) before and after modified ECT. GMV was determined using voxel-based morphometry (VBM) whole brain analysis. Correlations of brain structural changes with clinical improvement were also investigated. METHODS: Twenty-one schizophrenia patients treated with a full course of ECT combined with antipsychotics (ECT group) and 21 schizophrenia patients treated only with antipsychotics (Drug group) were observed in parallel. Magnetic resonance imaging scans were performed at baseline (T1) and follow-up (T2) for each patient. Data were compared to a healthy control group (HC group) of 23 persons who were only scanned at baseline. Demographic data were matched between the three groups. RESULTS: Significant interactions of group by time were found within four brain regions: the left parahippocampal gyrus/hippocampus, right parahippocampal gyrus/hippocampus, right temporal_pole_mid/superior temporal gyrus, and right insula. Post-hoc analysis revealed an increase of GMV across all four regions amongst ECT group, but a decrease of GMV within the Drug group. Furthermore, the ECT group showed a significant positive correlation of GMV change in the right parahippocampal gyrus/hippocampus with a reduction of positive subscore in the positive and negative syndrome scale. Both treatment groups did not differ significantly in terms of GMV from the HC group in these regions either at T1 or at T2. CONCLUSION: Our findings indicate that ECT may induce brain plasticity as indexed by grey matter volume change during the treatment of schizophrenia via distinct mechanics from those by antipsychotic medications. ECT may ameliorate the positive psychotic symptoms of patients suffering from schizophrenia by preferentially targeting limbic brain areas such as the parahippocampal gyrus/hippocampus.