Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder for which no effective treatment is available. Studies have demonstrated that improving insulin resistance in type 2 diabetes mellitus (T2DM) can benefit patients with PD. In addition, a neuroprotective effect of glucagon-like peptide-1 (GLP-1) receptor agonists was demonstrated in experimental models of PD. In addition, there are some clinical trials to study the neuroprotective effect of GLP-1 analog on PD patients. Semaglutide is a long-acting, once-a-week injection treatment and the only available oral form of GLP-1 analog. In the present study, we treated the human neuroblastoma SH-SY5Y cell line with 6-hydroxydopamine (6-OHDA) as a PD in vitro model to explore the neuroprotective effects and potential mechanisms of semaglutide to protect against PD. Moreover, we compared the effect of semaglutide with liraglutide given at the same dose. We demonstrated that both semaglutide and liraglutide protect against 6-OHDA cytotoxicity by increasing autophagy flux and decreasing oxidative stress as well as mitochondrial dysfunction in SH-SY5Y cells. Moreover, by comparing the neuroprotective effects of semaglutide and liraglutide on PD cell models at the same dose, we found that semaglutide was superior to liraglutide for most parameters measured. Our results indicate that semaglutide, the new long-acting and only oral GLP-1 analog, may be represent a promising treatment for PD.

LncRNA GAS5 promotes epilepsy progression through the epigenetic repression of miR-219, in turn affecting CaMKIIγ/NMDAR pathway.

It has been widely reported that dysregulated long-chain noncoding RNAs (lncRNAs) are closely associated with epilepsy. This study aimed to probe the function of lncRNA growth arrest-specific 5 (GAS5), microRNA (miR)-219 and Calmodulin-dependent protein kinase II (CaMKII)γ/N-methyl-D-aspartate receptor (NMDAR) pathway in epilepsy. Epileptic cell and animal models were constructed using magnesium deficiency treatment and diazepam injection, respectively. GAS5 and miR-219 expressions in epileptic cell and animal models were determined using qRT-PCR assay. The protein levels of CaMKIIγ, NMDAR and apoptosis-related proteins levels were assessed by western blot. Cell counting kit-8 (CCK-8) assay was employed to determine cell proliferation. Besides, TNFα, IL-1ß, IL-6 and IL-8 levels were analyzed using enzyme-linked immunosorbent assay (ELISA). Furthermore, cell apoptosis was evaluated using TUNEL staining and flow cytometric analysis. Finally, the binding relationship between GAS5 and EZH2 was verified using RIP and ChIP assay. Our results revealed that GAS5 was markedly upregulated in epileptic cell and animal models, while miR-219 was down-regulated. GAS5 knockdown dramatically increased cell proliferation of epileptic cells, whereas suppressed inflammation and the apoptosis. Furthermore, our results showed that GAS5 epigenetically suppressed transcriptional miR-219 expression via binding to EZH2. miR-219 mimics significantly enhanced cell proliferation of epileptic cells, while inhibited inflammation and the apoptosis, which was neutralized by CaMKIIγ overexpression. Finally, miR-219 inhibition reversed the effects of GAS5 silence on epileptic cells, which was eliminated by CaMKIIγ inhibition. In conclusion, GAS5 affected inflammatory response and cell apoptosis of epilepsy via inhibiting miR-219 and further regulating CaMKIIγ/NMDAR pathway (See graphic summary in Supplementary Material).

Geniposide protection against Aß1-42 toxicity correlates with mTOR inhibition and enhancement of autophagy.

Overactivation of the PI3-K/Akt/mTOR signaling pathway and inhibition of autophagy in the brain are involved in Alzheimer's disease. The present paper's goal was to explore the potential mechanisms of geniposide to protect against Alzheimer's disease. We treated the human neuroblastoma SH-SY5Y cell line with Aß1-42 as an Alzheimer's disease in vitro model to explore the potential mechanisms of geniposide to protect against Alzheimer's disease. Further, SH-SY5Y cells damaged by Aß1-42 were treated with geniposide. Akt/mTOR-related proteins and autophagy-associated proteins were measured to reveal the molecular mechanisms by which geniposide protects against Aß1-42-induced toxicity. Results showed that Akt and mTOR's geniposide inhibited phosphorylation induced by Aß1-42, enhanced expression of the LC3II/LC3I ratio, and Atg7 and Beclin1 expression and inhibited expression of p62 induced by Aß1-42. Our results lead us to hypothesize that inhibition of the Akt/mTOR signaling pathway and autophagy enhancement are fundamental molecular mechanisms for geniposide to protect against Aß toxicity.

Semaglutide-mediated protection against Aß correlated with enhancement of autophagy and inhibition of apotosis.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue with an extended half-life of approximately 1 week has being come into clinic trial to treat parkingson's disease but little is known about its effect to prevent against Alzheimer's disease (AD). The goal of the present study was to explore the potential mechanisms of semaglutide to protect against AD. METHODS: We treated SH-SY5Y cell line with Aß25-35 as an AD model. Further, SH-SY5Y cells damaged by Aß25-35 were treated by semaglutide. Autophagy-related proteins and apoptosis-related proteins were measured to explore molecular mechanisms for semaglutide to protect against Aß25-35. RESULTS: Semaglutide enhanced autophagy by increasing the expression of LC3II, Atg7, Beclin-1 and P62 which were inhibited by Aß25-35. Further we showed that semaglutide inhibited apoptosis by inhibiting the expression of Bax induced by Aß25-35 and increasing the expression of Bcl2 inhibited by Aß25-35. CONCLUSION: Our results provide a clue for the hypothesis that autophagy enhancement and apoptosis inhibition may be involved in the effect of semaglutide to protect against Aß 25-35.

Sodium Ferulate Protects against Angiotensin II-Induced Cardiac Hypertrophy in Mice by Regulating the MAPK/ERK and JNK Pathways.

Background and Objective. It has been reported that sodium ferulate (SF) has hematopoietic function against anemia and immune regulation, inflammatory reaction inhibition, inhibition of tumor cell proliferation, cardiovascular and cerebrovascular protection, and other functions. Thus, this study aimed to investigate the effects of SF on angiotensin II- (AngII-) induced cardiac hypertrophy in mice through the MAPK/ERK and JNK signaling pathways. Methods. Seventy-two male C57BL/6J mice were selected and divided into 6 groups: control group, PBS group, model group (AngII), model + low-dose SF group (AngII + 10 mg/kg SF), model + high-dose SF group (AngII + 40 mg/kg SF), and model + high-dose SF + agonist group (AngII + 40 mg/kg SCU + 10 mg/kg TBHQ). After 7 d/14 d/28 days of treatments, the changes of blood pressure and heart rates of mice were compared. The morphology of myocardial tissue and the apoptosis rate of myocardial cells were observed. The mRNA and protein expressions of atrial natriuretic peptide (ANP), transforming growth factor-ß (TGF-ß), collagen III (Col III), and MAPK/ERK and JNK pathway-related proteins were detected after 28 days of treatments. Results. SF improved the mice's cardiac abnormality and decreased the apoptosis rate of myocardial cells in a time- and dose-dependent manner (all P < 0.05). MAPK/ERK pathway activator inhibited the protective effect of SF in myocardial tissue of mice (P < 0.05). SF could inhibit the expression of p-ERK, p-p38MAPK, and p-JNK and regulate the expressions of ANP, TGF-ß, and Col III (all P < 0.05). Conclusion. Our findings provide evidence that SF could protect against AngII-induced cardiac hypertrophy in mice by downregulating the MAPK/ERK and JNK pathways.

Complete mitochondrial genome sequence of the heart failure model of cardiomyopathic Syrian hamster (Mesocricetus auratus).

In this study we sequenced the complete mitochondrial genome sequencing of a heart failure model of cardiomyopathic Syrian hamster (Mesocricetus auratus) for the first time. The total length of the mitogenome was 16,267 bp. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region.

Association of AT1R polymorphism with hypertension risk: An update meta-analysis based on 28,952 subjects.

BACKGROUND: Previous studies have shown that angiotensin II AT1 receptor gene (AT1R) polymorphisms are associated with the risk for hypertension. However, the results remain controversial. In the present study, we performed a meta-analysis to systematically summarize the association between AT1R genetic polymorphisms and the risk for hypertension. METHODS: We searched the literature in PubMed, EMBASE, ISI Web of Science, Wanfang, and Chinese National Knowledge Infrastructure databases (CNKI) to find case-control studies on the associations of AT1R genetic polymorphisms with the risk for hypertension. The meta-analysis was performed by using RevMan 5.0 software. The association of hypertension risk with AT1R genetic polymorphism was estimated by pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Fifty-six studies involving 28,952 subjects were included in the present meta-analysis. Our results suggest that the polymorphism (A1166C) of AT1R gene is associated with a statistically increased hypertension risk, not only in Asian populations but also in Caucasian populations. We did not find any association in African populations. CONCLUSIONS: This meta-analysis suggests that A1166C polymorphism in the AT1R gene is associated with the risk of hypertension in Asian and Caucasian populations.

Prognostic significance of TBX2 expression in non-small cell lung cancer.

T-box2 (TBX2) expression has been reported to be related to aggressive tumor features. However, the role of TBX2 in non-small-cell lung cancer (NSCLC) tumorigenesis has never been elucidated. So we aimed at investigating the potential role of TBX2 in NSCLC. TBX2 expression was evaluated by qRT-PCR and Western blotting in 50 paired fresh lung cancer tissues as well as immunohistochemistry on 212 paraffin-embedded sections. We showed that the expression level of TBX2 was significantly increased in NSCLC as compared with the adjacent noncancerous tissue. Positive expression level of TBX2 was associated with histological type, lymph node metastasis and distant metastasis. Kaplan-Meier survival curves showed that positive expression level of TBX2 was associated with poor overall survival (OS) and progression-free survival of NSCLC patients. Results showed that TBX2 positivity was an independent prognostic factor for OS (HR 1.87, 95% CI 1.004-3.153, p = 0.012). On the basis of these results, we suggested that TBX2 protein expression may be an unfavorable independent prognostic parameter for NSCLC.