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.

PRDM16 Upregulation Induced by MicroRNA-448 Inhibition Alleviates Atherosclerosis via the TGF-ß Signaling Pathway Inactivation.

The dysregulated expression of microRNAs (miRs) has been associated with pathological and physiological processes of atherosclerosis (AS). In addition, PR domain-containing 16 (PRDM16), a transcriptional mediator of brown fat cell identity and smooth muscle cell activities, may be involved in the hypercholesterolemia during development of AS. The bioinformatic analysis identified a regulatory miR-448 of PRDM16. Hence, the current study aimed to explore whether miR-448 influenced the activities of aortic smooth muscle cell (ASMCs) in AS. We validated that miR-448 was highly expressed in peripheral blood of patients with AS and aortic smooth muscle of AS model mice. Whereas, PRDM16 was downregulated in the aortic smooth muscle of AS model mice. PRDM16 overexpression was observed to inhibit oxidative stress injury and cell proliferation, and promote apoptosis of ASMCs. Mechanistic studies revealed that miR-448 targeted PRDM16 and negatively regulated the PRDM16 expression, while PRDM16 blocked the TGF-ß signaling pathway. Furthermore, Downregulated miR-448 alleviated oxidative stress injury, and attenuated ASMC cell proliferation, migration and enhanced cell apoptosis through upregulation of PRDM16. Taken together, silencing of miR-448 upregulates PRDM16 and inactivates the TGF-ß signaling pathway, thereby impeding development of AS by repressing the proliferation, migration and invasion of ASMCs.

Adenoviral ßARKct Cardiac Gene Transfer Ameliorates Postresuscitation Myocardial Injury in a Porcine Model of Cardiac Arrest.

OBJECTIVE: The aim of the study was to determine whether the inhibition of the G-protein-coupled receptor kinase 2 by adenoviral ßARKct cardiac gene transfer can ameliorate postresuscitation myocardial injury in pigs with cardiac arrest (CA) and explore the mechanism of myocardial protection. METHODS: Male landrace domestic pigs were randomized into the sham group (anesthetized and instrumented, but ventricular fibrillation was not induced) (n = 4), control group (ventricular fibrillation 8 min, n = 8), and ßARKct group (ventricular fibrillation 8 min, n = 8). Hemodynamic parameters were monitored continuously. Blood samples were collected at baseline, 30 min, 2 h, 4 h, and 6 h after the return of spontaneous circulation (ROSC). Left ventricular ejection fraction was assessed by echocardiography at baseline and 6 h after ROSC. These animals were euthanized, and the cardiac tissue was removed for analysis at 6 h after ROSC. RESULTS: Compared with those in the sham group, left ventricular +dp/dtmax, -dp/dtmax, cardiac output (CO), and ejection fraction (EF) in the control group and the ßARKct group were significantly decreased at 6 h after the restoration of spontaneous circulation. However, the ßARKct treatment produced better left ventricular +dp/dtmax, -dp/dtmax, CO, and EF after ROSC. The ßARKct treatment also produced lower serum cardiac troponin I, CK-MB, and lactate after ROSC. Furthermore, the adenoviral ßARKct gene transfer significantly increased ß1 adrenergic receptors, SERCA2a, RyR2 levels, and decreased GRK2 levels compared to control. CONCLUSIONS: The inhibition of GRK2 by adenoviral ßARKct cardiac gene transfer can ameliorate postresuscitation myocardial injury through beneficial effects on restoring the sarcoplasmic reticulum Ca-handling proteins expression and upregulating the ß1-adrenergic receptor level after cardiac arrest.

Allogenic chondrocyte/osteoblast-loaded ß-tricalcium phosphate bioceramic scaffolds for articular cartilage defect treatment.

The medical community has expressed significant interest in the treatment of cartilage defect. Successful repair of articular cartilage defects remains a challenge in clinics. Due to the huge advantages of 3D micro/nanomaterials, 3D artificial micro/nano scaffolds have been widely developed and explored in the tissue repair of articular joints. In this study, chondrocyte/osteoblast-loaded ß-tricalcium phosphate (ß-TCP) bioceramic scaffold and chondrocyte-loaded ß-TCP bioceramic scaffold were prepared by micromass stem cell culture and bioreactor-based cells-loaded scaffold culture for articular cartilage defect treatment. The results demonstrate chondrocyte and osteoblast can be successfully induced from allogeneic bone marrow stromal cells using micromass stem cell culture. Further, chondrocyte-loaded ß-TCP scaffold and osteoblast-loaded ß-TCP scaffold can be successfully prepared by bioreactor-based cells-loaded scaffold culture. Finally, the scaffolds are applied for Beagle articular cartilage defect treatment. The relative cartilage regeneration abilities on Beagle femoral trochleae were as follows: Chondrocyte/osteoblast-loaded ß-TCP bioceramic scaffold group > chondrocyte-loaded ß-TCP bioceramic scaffold group > ß-TCP bioceramic scaffold. Therefore, micromass stem cell culture and bioreactor-based cells-loaded scaffold culture can be applied to prepare chondrocyte/osteoblast-loaded ß-TCP bioceramic scaffold for articular cartilage defect treatment. It suggests allogenic chondrocyte/osteoblast-loaded ß-TCP bioceramic scaffold could be potentially used in the treatment of patients with cartilage defects.

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.

Association of Genetic Polymorphisms on VEGFA and VEGFR2 With Risk of Coronary Heart Disease.

Coronary heart disease (CHD) is a cardiovascular disease which is contributed by abnormal neovascularization. VEGFA (vascular endothelial growth factor A) and VEGFR2 (vascular endothelial growth factor receptor 2) have been revealed to be involved in the pathological angiogenesis. This study was intended to confirm whether single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 were associated with CHD in a Chinese population, considering pathological features and living habits of CHD patients.Peripheral blood samples were collected from 810 CHD patients and 805 healthy individuals. Six tag SNPs within VEGFA and VEGFR2 were obtained from HapMap Database. Genotyping of SNPs was performed using SNapShot method (Applied Biosystems, Foster, CA). Odd ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated to evaluate the association between SNPs and CHD risk.Under the allelic model, 6 SNPs of VEGFA and VEGFR2 were remarkably associated with the susceptibility to CHD. Genotype CT of rs3025039, TT of rs2305948, and AA of rs1873077 were associated with a reduced risk of CHD when smoking, alcohol intake and diabetes were considered, while homozygote GG of rs1570360 might elevate the susceptibility to CHD (all P < 0.05) for patients who were addicted to smoking or those with hypertension. All of the combined effects of rs699947 (CC/CA) and rs2305948 (TT), rs3025039 (TT) and rs2305948 (TT), rs3025039 (CT) and rs1870377 (AA) had positive effects on the risk of CHD, respectively (all P < 0.05). By contrast, the synthetic effects of rs69947 (CA/AA) and rs1870377 (TA), rs699947 (CA) and rs7667298 (GG), rs699947 (AA) and rs7667298 (GG), rs1570360 (GG) and rs2305948 (TT), as well as rs1570360 (GG) and rs1870377 (AA) all exhibited adverse effects on the risk of CHD, respectively (all P < 0.05).Six polymorphisms in VEGFA and VEGFR2 may have substantial influence on the susceptibility to CHD in a Han Chinese population. Prospective cohort studies should be further designed to confirm the above conclusions.

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.

[Prognosis value of urine paraquat semi-quantitative in the patients with acute paraquat poisoning].

OBJECTIVE: To investigate the relationship between semi-quantification of urine paraquat and the severity of acute paraquat poisoning, and to evaluate the prognostic value of the test in patients with acute paraquat poisoning. METHODS: A total of 179 patients with acute paraquat poisoning were categorized into four groups according to their semi-quantification results of urine paraquat: +group (n = 36), ++group (n = 23), +++ group (n = 25), and ++++group (n = 95). The clinical features, severity of hepatic and renal injuries, respiratory failure, and clinical classification were compared between these four groups. Kaplan-Meier analysis was used to evaluate the survival rate. RESULTS: The 60-day mortality was 45.25% (81/179). The amount of ingestion increased significantly from +group to ++++group (P < 0.05). No patient in +group was found to have serious complications, while most patients in ++++group suffered organ dysfunction or even organ failure. The incidence of acute respiratory failure, renal failure, and hepatic failure in ++++group was significantly higher than that in +group, ++group, and +++group (P < 0.05). The urine paraquat concentration was positively correlated with the clinical severity of acute paraquat poisoning (Spearman correlation coefficient = 0.720, P < 0.01). Kaplan-Meier survival analysis showed that the mortality of ++++group (73.7%) was significantly higher than that of +++group (40%), ++group (4.3%), and +group (0%) (P < 0.05). CONCLUSION: The semi-quantification of urine paraquat is a promising test in evaluating the severity of acute paraquat poisoning. This test can be used to guide therapy and to predict the outcomes of patients suffering acute paraquat poisoning.

[The prognostic value of the Acute Kidney Injury Network criteria in patients with acute paraquat poisoning].

OBJECTIVE: To explore the prognostic value of the Acute Kidney Injury Network (AKIN) criteria in patients with acute paraquat (PQ) poisoning. METHODS: A retrospective study on 184 patients with acute PQ poisoning admitted to the Shandong Provincial Hospital from April 2010 to March 2013 was done. The clinical data and AKIN stage were compared between survivors and non-survivors, and multivariate analysis was done by Cox-proportional hazards regression model. Kaplan-Meier method was used to analyze survival rate of the patients in different stages of poisoning. RESULTS: The 60-day mortality was 42.93% (79/184). There were no significant differences between the survival and non-survival groups in respect of gender, simultaneous alcohol drinking, duration between ingestion and gastric lavage, duration between ingestion and first hemoperfusion, and number of hemoperfusion. Significant differences were found between two groups in age, quantity of ingestion, receiving hemoperfusion or not, AKIN stage, and initial laboratory data including white blood cell count, the percentage of neutrophil, blood glucose, blood urea nitrogen, creatinine, ß2-microglobulin (ß2-MG), serum K+, CO2, anion gap, and urinary concentration of PQ. The AKIN stage [odds ratio (OR)=3.242, 95% confidence interval (95%CI) 2.236-4.701, P=0.000], urinary concentrations of PQ (OR=1.773, 95%CI 1.008-3.116, P=0.047), the amount of ingestion (OR=1.003, 95%CI 1.000-1.006, P=0.040), and CO2 (OR=0.094, 95%CI 0.891-0.991, P=0.021) were independent prognostic factors for death among them. Kaplan-Meier survival analysis showed the survival rate of AKIN 3 group was significantly lower than that in AKIN 2 group (5.88% vs. 56.25%, χ2=16.149, P=0.000), AKIN 1 group (5.88% vs. 78.95%, χ2=62.444, P=0.000) and non-AKI group(5.88% vs. 100.0%, χ2=173.549, P=0.000). CONCLUSIONS: The AKIN staging is a reliable marker for mortality prediction in acute PQ poisoning patients. In cases without facilities to determine plasma PQ concentration, the staging of AKIN may be a simple and practical tool for assessing the severity of PQ poisoning.

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.