Centrally Administered Cortistation-14 Induces Antidepressant-Like Effects in Mice via Mediating Ghrelin and GABAA Receptor Signaling Pathway

Cortistatin-14 (CST-14), a recently discovered cyclic neuropeptide, can bind to all five cloned somatostatin receptors (SSTRs) and ghrelin receptor to exert its biological activities and co-exists with GABA within the cortex and hippocampus. However, the role of CST-14 in the control of depression processes is not still clarified. Here, we tested the behavioral effects of CST-14 in the in a variety of classical rodent models of depression [forced swimming test (FST), tail suspension test (TST) and novelty-suppressed feeding test]. In the models of depression, CST-14 produced antidepressant-like effects, and does not altered locomotor activity levels. And, we found that CST-14 mRNA and BDNF mRNA were significantly decreased in the hippocampus and cortex after mice exposed to stress. Further data show that i.c.v. administration of CST-14 produce rapid antidepressant effects, and does not altered locomotor activity levels. Then these antidepressant-like effects were significantly reversed by [D-Lys3]GHRP-6 (ghrelin receptor antagonist), but not c-SOM (SSTRs antagonist). Meanwhile, the effects of some neurotransmitter blockers indicates that only GABAA system, but not CRF1 receptor, α/β-adrenergic receptor, is involved in the antidepressant effect of CST-14. The effects of the mTOR inhibitor (rapamycin), the PI3K inhibitor (LY294002) and the p-ERK1/2 inhibitor (U0126) suggesting that the ERK/mTOR or PI3K/Akt/mTOR signaling pathway is not involved in the antidepressant effects of CST-14. Interestingly, intranasal administration of CST-14 led to reducing depressive-like behavior, and near-infrared fluorescent experiments showed the real-time in vivo bio-distribution in brain after intranasal infusion of Cy7.5-CST-14. Taken all together, the results of present study point to a role for CST-14 in the modulation of depression processes via the ghrelin and GABAA receptor, and suggest cortistation may represent a novel strategy for the treatment of depression disorders.Highlights:-CST-14 and BDNF mRNA are decreased in hippocampus and cortex once mice exposed to stress.-i.c.v. or intranasal administration of CST-14 produce rapid antidepressant effects.-NIR fluorescence imaging detected the brain uptake and distribution after intranasal CST-14.-Antidepressant effects of CST-14 were only related to ghrelin and GABAA system.-Co-injection of CST-14 and NPS produce antidepressant effect, and do not impair memory

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488–47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10−13), ALDH2/MYL2 (rs671, P = 3.40 × 10−11; rs12229654, P = 4.56 × 10−9), ITIH4 (rs2535633, P = 1.77 × 10−10) and NT5C2 (rs11191580, P = 3.83 × 10−8) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10−8) and an additional 14 at P < 1.0 × 10−3 with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity

Efficient Production of Human Norovirus-Specific IgY in Egg Yolks by Vaccination of Hens with a Recombinant Vesicular Stomatitis Virus Expressing VP1 Protein

Human norovirus (HuNoV) is responsible for more than 95% of outbreaks of acute nonbacterial gastroenteritis worldwide. Despite major efforts, there are no vaccines or effective therapeutic interventions against this virus. Chicken immunoglobulin Y (IgY)-based passive immunization has been shown to be an effective strategy to prevent and treat many enteric viral diseases. Here, we developed a highly efficient bioreactor to generate high titers of HuNoV-specific IgY in chicken yolks using a recombinant vesicular stomatitis virus expressing HuNoV capsid protein (rVSV-VP1) as an antigen. We first demonstrated that HuNoV VP1 protein was highly expressed in chicken cells infected by rVSV-VP1. Subsequently, we found that White Leghorn hens immunized intramuscularly with rVSV-VP1 triggered a high level of HuNoV-specific yolk IgY antibodies. The purified yolk IgY was efficiently recognized by HuNoV virus-like particles (VLPs). Importantly, HuNoV-specific IgY efficiently blocked the binding of HuNoV VLPs to all three types (A, B, and O) of histo-blood group antigens (HBGAs), the attachment factors for HuNoV. In addition, the receptor blocking activity of IgY remained stable at temperature below 70 &#176;C and at pH ranging from 4 to 9. Thus, immunization of hens with VSV-VP1 could be a cost-effective and practical strategy for large-scale production of anti-HuNoV IgY antibodies for potential use as prophylactic and therapeutic treatment against HuNoV infection

Role for TLR2 in NK Cell-Mediated Control of Murine Cytomegalovirus In Vivo

Natural killer (NK) cells are essential for the early control of murine cytomegalovirus (MCMV) infection. Here, we demonstrate that toll-like receptor 2 (TLR2) plays a role in the NK cell-mediated control of MCMV. TLR2 knockout (KO) mice had elevated levels of MCMV in the spleen and liver on day 4 postinfection compared to C57BL/6 mice. In vivo depletion of NK cells with anti-NK1.1 antibodies, however, eliminated the differences in viral titers between the two groups, suggesting that the effect of TLR2 on MCMV clearance on day 4 was NK cell mediated. The defect in early antiviral control was associated with a decreased NK cell population in the spleen and liver and reduced amounts of interleukin-18 and α/β interferon secreted in the TLR2 KO mice. Our studies suggest that in addition to the reported involvement of TLR9 and TLR3, TLR2 is also involved in innate immune responses to MCMV infection

Association Between Joint Physical Activity and Dietary Quality and Lower Risk of Depression Symptoms in US Adults: Cross-sectional NHANES Study

BackgroundDepression escalating public health concern and the modest efficacy of currently available treatments have prompted efforts to identify modifiable risk factors associated with depression symptoms. Physical inactivity, poor nutrition, or other lifestyle behaviors are among the potentially modifiable risk factors most consistently linked with depression. Past evidence regarding the single effect of physical activity (PA) or dietary quality (DQ) on reducing the risk of depression symptoms has been well-documented. However, the association of the joint effect of PA and DQ on depression symptoms has never been investigated in a representative sample of adults. ObjectiveThis study investigates the association between PA and depression symptoms and between DQ and depression symptoms, and their combined effects on US adults. MethodsData were obtained from the National Health and Nutrition Examination Survey (NHANES) 2007 to 2018 cycles. The primary exposures were DQ and PA, measured using the Healthy Eating Index (HEI)-2015 and the metabolic equivalent (MET) minutes per week reported in questionnaires, respectively. Depression symptoms were defined as a 9-item Patient Health Questionnaire (PHQ-9) score of ≥10. We created 4 lifestyle categories: healthy diet and active individuals, unhealthy diet but active individuals, healthy diet but inactive individuals, and unhealthy diet and inactive individuals. Participants were considered to have a healthy diet if they fell within the 60th percentile of the HEI-2015 or to be active if they met the current guidelines for PA. A survey-multivariable logistic regression approach was used to model adjust the variables relevant to the associations, and an age-adjusted prevalence for depression symptoms was calculated following the NHANES guidelines. ResultsIn total, 19,295 participants represented a weighted number of 932.5 million adults aged 20 to 80 years in the noninstitutionalized US population. The total age-adjusted prevalence of depression symptoms among all respondents was 7.08% (1507/19,295). Of the respondents, 81.97% (15,816/19,295) met the PA recommendation and 26.79% (5170/19,295) scored at or above the 60th percentile on the HEI-2015. Depression symptoms were inversely associated with a higher level of PA (adjusted odds ratio [AOR] 0.819, 95% CI 0.716-0.938) and healthy DQ (AOR 0.809, 95% CI 0.701-0.931), respectively. A healthy diet combined with recommended PA was associated with a significantly lower risk of depression symptoms (AOR 0.658, 95% CI 0.538-0.803) than those who consumed an unhealthy diet but were physically active (AOR 0.890, 95% CI 0.765-1.038) or consumed a healthy diet but were physically inactive (AOR 1.077, 95% CI 0.817-1.406). ConclusionsOur findings indicate that people with a healthy diet and recommended PA have a lower risk of depression symptoms than those with an unhealthy diet and a low level of PA. A healthy dietary habit and regular PA are potential precautions against depression