Identification of circATG9A as a novel biomarker for renal cell carcinoma.

The incidence and mortality rates of renal cell carcinoma (RCC) have rapidly increased worldwide. To gain new insights into the regulatory role of circular RNAs (circRNAs) in RCC progression, we conducted RNA sequencing on three pairs of ccRCC and adjacent normal tissues. RT-PCR was utilized to analyze RNA expression. We investigated the effects of circATG9A on RCC cells through various assays including CCK-8, Transwell, wound healing, and colony formation assays. Furthermore, we employed FISH, RNA pull-down, luciferase reporter, and RIP assays to elucidate the mechanism by which circATG9A regulates RCC. Ultimately, we identified 118 differentially expressed circRNAs in RCC, including a novel circRNA, circATG9A, which was found to promote RCC progression both in vitro and in vivo. Moreover, mRNA sequencing, western blotting, and rescue experiments indicated that TRPM3 is the target of circATG9A in RCC progression. Bioinformatic analysis, RNA pull-down, FISH, and RIP assays suggested that circATG9A regulates TRPM3 expression by acting as a sponge for miR-497-5p. Finally, Western blotting revealed that circATG9A promotes the epithelial-mesenchymal transition (EMT) process through the Wnt/ß-catenin signaling pathway. Our findings demonstrate that circATG9A is a novel circRNA upregulated in RCC that plays a crucial role in the EMT process through the miR-497-5p/TRPM3/Wnt/ß-catenin axis. These results suggest that circATG9A could be a promising target for RCC prognosis and therapy.

TMAO promotes dementia progression by mediating the PI3K/Akt/mTOR pathway.

BACKGROUND: Dementia poses a serious threat to the daily and social abilities of patients, and trimethylamine-N-oxide (TMAO) is a metabolite of the gut microbiota involved in regulating the inflammatory response. However, the role of TMAO in dementia needs further investigation. This study aimed to investigate the effects and possible mechanisms of TMAO on dementia, which may provide ideas for the treatment of dementia. MATERIALS AND METHODS: Dementia mice were induced by D-galactose + AlCl3, and the changes in learning memory capacity, histopathology, inflammatory factors, and PI3K/Akt/mTOR in mice treated with TMAO were analyzed to determine the mechanism of TMAO action on dementia. In addition, the effect of TMAO+PI3K inhibitor treatment on mice was also analyzed to further determine the mechanism of TMAO effect on dementia. RESULTS: The results revealed that the dementia group had significantly higher TMAO levels and a significant hippocampal injury and inflammatory response. TMAO treatment promoted hippocampal injury and promoted the level of inflammatory cytokines. Further study of PI3K/Akt/mTOR signaling pathway showed that the expression of p-PI3K, p-Akt, and p-mTOR was significantly increased in the dementia group, and it was more obvious after TMAO treatment. And hippocampal injury, inflammatory response, and increase of p-PI3K, p-Akt, p-mTOR were reversed by TMAO+PI3K inhibitor. CONCLUSIONS: This study determined that TMAO promotes dementia through the PI3K/Akt/mTOR signaling pathway, suggesting that TMAO may be a potential target for dementia.

Associations of Substance Use Behaviors With Suicidal Ideation and Suicide Attempts Among US and Chinese Adolescents.

Background: Adolescence has been described as a period of increased health risk-taking behaviors. Given the variety of cultural contexts, healthcare systems, and public health policies in different regions, the present study aimed to determine whether there are similar or different associations of substance use behaviors with suicidal ideation and suicide attempts among US and Chinese adolescents. Methods: This study included a total of 14,765 US adolescents from the 2017 National Youth Risk Behavior Surveillance System (YRBSS) and 24,345 Chinese adolescents from the 2017 School-based Chinese Adolescents Health Survey (SCAHS). Results: The proportions of suicidal ideation and suicide attempts were 17.4 and 5.7% among US adolescents, which were higher than those among Chinese adolescents (suicidal ideation: 13.7% and suicide attempts: 2.7%). Among Chinese adolescents, the most common substance use behavior was "alcohol use (55.4%)," followed by "cigarette use (11.6%)." Among US adolescents, the most popular substance was alcohol (ever used: 55.9%), followed by marijuana (ever used: 34.6%). Moreover, alcohol use was significantly related to suicidal ideation/suicide attempts only in Chinese adolescents [suicidal ideation: Adjusted odds ratio (AOR) = 1.88, 95% CI = 1.71~2.06; suicide attempts: AOR = 2.12, 95% CI = 1.71~2.63], and marijuana use was associated with suicidal ideation and suicide attempts only in the US adolescent group (suicidal ideation: AOR = 1.23, 95% CI = 1.06~1.44; suicide attempts: AOR = 1.51, 95% CI = 1.21~1.87). Moreover, although the associations of prescription pain medication use with suicide attempts were significant in both Chinese and US adolescent groups, the adjusted associations were stronger in Chinese adolescents than in US adolescents (Chinese adolescents: AOR = 3.97, 95% CI = 2.76~5.72; US adolescents: AOR = 1.76, 95% CI = 1.43~2.16; P < 0.05). Conclusions: The associations of alcohol use with suicidal ideation and suicide attempts were only significant in Chinese adolescents. Marijuana use was associated with suicidal ideation and suicide attempts only in the US adolescent group. Although the associations of prescription pain medication use with suicide attempts were significant in both Chinese and US adolescent groups, the adjusted associations were significantly stronger for Chinese adolescents. These findings might be related to the differences in cultural contexts, healthcare systems, and public health policies in the two different countries.

Overexpression of long noncoding RNA Malat1 ameliorates traumatic brain injury induced brain edema by inhibiting AQP4 and the NF-κB/IL-6 pathway.

Brain edema is a major traumatic brain injury (TBI)-related neurological complication. In the initiation stage of TBI, brain edema is characterized by astrocyte swelling (cytotoxic edema). We studied the impact of a long noncoding RNA, Malat1, on the TBI-induced astrocyte swelling and brain edema. Our results showed that Malat1 was downregulated in both the TBI rat model and the astrocyte fluid percussion injury (FPI) model, which concurred with brain edema and astrocyte swelling. Overexpression of Malat1 significantly inhibited rat brain edema, meanwhile reducing interleukin-6 (IL-6), nuclear factor-κB (NF-κB), and aquaporin 4 (AQP4) expression after TBI. In addition, overexpression of Malat1 ameliorated FPI-induced astrocyte swelling and reduced IL-6 release. Quantitative real-time polymerase chain reaction and Western blot analysis also corroborated the inhibitory effects of Malat1 on NF-κB and AQP4 expression after FPI. Our results highlighted the protective effects of Malat1 on the TBI-induced brain edema, which were mediated through regulating IL-6, NF-κB, and AQP4 expression. Our study could provide a novel approach for TBI treatment.

A study on role and mechanism of TLR4/NF-κB pathway in cognitive impairment induced by cerebral small vascular disease.

OBJECTIVE: To investigate the role and potential mechanism of Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway in cognitive impairment induced by cerebral small vascular disease (CSVD), so as to provide a reference for the clinical treatment of CSVD-induced cognitive impairment. METHODS: Mice with TLR4 gene knockout (n = 20) and those with wild-type TLR4 gene (n = 40) aged 8-10 weeks old were divided into blank control group (Control group, n = 20), wild-type + CSVD group (WT + CSVD group, n = 20) and TLR4 gene knockout + CSVD group (TLR4 KO + CSVD group, n = 20). Allogeneic thrombosis (particle diameter: 50-70 mm) was injected to the mouse's external carotid artery to create a model of learning and memory dysfunction. Step-down test and Y-type maze test were utilized to examine the learning and memory abilities of the mice. Reverse transcription-polymerase chain reaction (RT-PCR) and immunoblotting techniques were adopted to measure the levels of apoptosis-related genes [B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (Bax), C-caspase-3 and T-caspase-3] in the brain tissues of mice. Terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method was applied to detect the apoptosis of neuronal cells in the brain tissues. Meanwhile, the levels of oxidative stress markers, including superoxide dismutase (SOD), gp91 and malondialdehyde (MDA), were measured. Finally, the expression level of TLR4/NF-κB pathway was detected. RESULTS: The latency in the step-down test in the WT + CSVD group was remarkably longer than that in the Control group, and the number of errors was evidently larger than that in the Control group (p < 0.05). At the same time, in the WT + CSVD group, the expression levels of pro-apoptotic genes Bax and C-caspase-3 were up-regulated markedly, while the expression level of anti-apoptotic gene Bcl-2 declined notably (p < 0.05). TUNEL results showed that the number of apoptotic cells in the brain tissues in the WT + CSVD group was about 12 times that in the Control group (p < 0.05). Meanwhile, the SOD expression level was lowered, and the MDA expression level was elevated in the brain tissues in the WT + CSVD group. In addition, the TLR4/NF-κB pathway was prominently activated in the mice in the WT + CSVD group (p < 0.05). After TLR4 gene knockout, the cognitive functions of the mice were improved markedly, and the apoptosis of neuronal cells and oxidative stress in the brain tissues were suppressed significantly in the meantime. Moreover, the activation of the TLR4/NF-κB signaling pathway was also inhibited. CONCLUSION: The TLR4/NF-κB pathway is involved in the occurrence and development of CSVD-induced cognitive impairment through regulating oxidative stress and cell apoptosis.

Long Noncoding RNA EBF3-AS Promotes Neuron Apoptosis in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia; its pathophysiological mechanism remains unclear. Long noncoding RNAs (lncRNAs) play key roles in AD. lncRNA EBF3-AS has been found dysregulated in AD, which is abundantly expressed in the brain. The aim of this study was to investigate the role of EBF3-AS in AD. Results showed that the expressions of lncRNA EBF3-AS and EBF3 (early B cell factor 3) were upregulated in hippocampus of APP/PS1 mice (AD model mice). EBF3-AS knockdown by siRNA inhibited the apoptosis induced by Aß25-35 and okadaic acid (OA) in SH-SY5Y. The expression of EBF3 was downregulated in Aß25-35- and OA-treated SH-SY5Y, which was reversed by EBF3-AS knockdown. EBF3 knockdown can reverse the Aß25-35-induced apoptosis in SH-SY5Y. These results revealed that lncRNA EBF3-AS promoted neuron apoptosis in AD, and involved in regulating EBF3 expression. EBF3-AS may be a new therapeutic target for treatment of AD.

The relationship between polymorphisms of XRCC5 genes with astrocytoma prognosis in the Han Chinese population.

BACKGROUND: Gliomas are highly malignant with a poor prognosis. Studies have reported that DNA repair genes influence risk for glioma, but its relationship with prognosis is unclear. In this study, we want to explore the relationship between DNA repair genes (XRCC3, XRCC4 and XRCC5) and prognosis of astrocytoma in the Chinese Han population. MATERIALS AND METHODS: 160 astrocytoma cases were recruited in our study. Survival probabilities were estimated by using Kaplan-Meier analysis, and significant differences were analyzed by using the log-rank test. Cox proportional hazards models were used to analyze the associations between genotypes with astrocytoma survival. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable models. All tests were two-sided and p < 0.05 was considered to be significant. RESULTS: The SNP (rs9288516) in XRCC5 (HR: 1.69, 95%CI: 1.04 - 2.77, p = 0.049), surgical approach (HR: 0.61, 95%CI: 0.43 - 0.88, p = 0.003) and chemotherapy (HR: 0.71, 95%CI: 0.50 - 0.99, p = 0.029) were associated with astrocytoma prognosis. Further, the "A/A" genotype of rs9288516 in XRCC5 (HR: 1.67, 95%CI: 1.02 - 2.72, p = 0.042) had significantly outcomes after adjusting for potential confounders, patients with poor tumor differentiation and the coexistence of the unfavorable genotypes. CONCLUSION: These results suggest that polymorphisms of XRCC5 play an important role in astrocytoma prognosis in the Chinese Han population which could be used in the determination of astrocytoma prognosis in clinical researches.