MicroNAR-194-5p hinders the activation of NLRP3 inflammasomes and alleviates neuroinflammation during intracerebral hemorrhage by blocking the interaction between TRAF6 and NLRP3.

The possible role of miR-194-5p in brain and neurodegenerative diseases has been reported, but its role in intracerebral hemorrhage (ICH) has not been studied. This study estimated the mechanism of miR-194-5p in ICH. ICH rat model was established by injecting collagenase type VII. miR-194-5p expression in brain tissue of ICH rats was overexpressed by injection of miR-194-5p agomir. Then neurological function score and brain water content were measured. The morphological changes of brain tissue and neuronal apoptosis were evaluated by histological staining. Levels of NLRP3 inflammasomes, IL-1ß and IL-18 were measured. The target relation between miR-194-5p and TRAF6 was verified and the binding of TRAF6 to NLRP3 was explored. miR-194-5p was decreased in ICH rats. After overexpression of miR-194-5p, the neuropathological injury in ICH rats was significantly reduced, and NLRP3-mediated inflammatory injury was inhibited. miR-194-5p targeted TRAF6. TRAF6 interacted with NLRP3 to promote the activation of NLRP3 inflammasomes. Overexpression of miR-194-5p reduced the interaction between TRAF6 and NLRP3, thereby alleviating the neuroinflammation. Collectively, overexpression of miR-194-5p reduced the TRAF6/NLRP3 interaction, thus inhibiting the activation of NLRP3 inflammasomes and reducing neuroinflammation during ICH. This study may shed new light on ICH treatment.

Antidepressant pathways of the Chinese herb jiaweisinisan through genetic ontology analysis.

Active compounds and corresponding targets of the traditional Chinese herb, jiaweisinisan, were obtained from systems pharmacological database and placed into ClueGO for gene ontology analysis. The targets of depression were obtained from the Online Mendelian Inheritance in Man, the Therapeutic Target Database, and the Pharmacogenomics Knowledge Base. Compound-target and target-pathway networks were constructed using Cytoscape, and then their topological parameters were analyzed. The targets of jiaweisinisan and depression were mapped to pathways, thereby constructing antidepressant pathways of jiaweisinisan. It was found that jiaweisinisan has 82 different active compounds and 306 relevant potential targets. Also, 107 unrepeatable targets related to depression were found. In all, 26 common targets were found to be the direct anti-depression targets of jiaweisinisan and 9 pathways of jiaweisinisan related to depression were divided into three modules (synaptic transmission, cell apoptosis, and immune-inflammatory). The jiaweisinisan formula was found to have synergistic antidepressant effects due to aspects of its herb composition and the active compounds therein, giving rise to potential targets and signaling pathways related to depression. Its antidepressant mechanisms were found to mainly involve the regulation of synaptic transmission, cell apoptosis, and immune-mediated inflammation.

[Study on mechanism of Guilu Erxianjiao in treatment of post-traumatic stress disorder based on network pharmacology].

The aim of this paper was to predict the multi-compound, multi-target and multi-pathway mechanism of Guilu Erxianjiao in treating post-traumatic stress disorder(PTSD) based on network pharmacology. Active compounds and corresponding targets of Guilu Erxianjiao were obtained from TCMSP, BATMAN-TCM, Chemistry and DrugBank database, and known therapeutic targets of PTSD were obtained from OMIM, TTD and DisGeNET Database. The protein interaction network of compound-disease was then built by combining with the STRING Database. Topological parameters of the network were analyzed by Cytoscape 3.6.0 to get key active compounds and their targets. The GO biological process analysis and KEGG pathway analysis of the key targets were conducted. Based on the results of KEGG, the "compound-target-pathway" network was built by Cytoscape 3.6.0 and the results were verified by SystemsDock online molecular docking tool. The prediction results showed that there were 67 active compounds and 420 targets for Guilu Erxianjiao, and 206 known PTSD-related therapeutic targets. Besides, 66 targets, 58 terms and 22 pathways were obtained from Cytoscape 3.6.0 topological parameters analysis, GO biological process analysis, and KEGG pathway analysis, respectively. Molecular docking results showed that both target with the maximum degree value and common targets of PTSD and Guilu Erxianjiao in the pathway can be effectively combined with their corresponding active compounds through molecular docking. The results suggested that Guilu Erxianjiao could exert anti-PTSD effect by regulating synaptic plasticity, anti-apoptotic, anti-inflammatory and promoting fear memory extinction through pathways such as LTP, PI3 K/Akt/mTOR, TNF, serotonergic synapse and dopaminergic synapse. This study provides a theoretical basis for further elucidating pharmacological mechanisms of Guilu Erxianjiao in treating PTSD.

Correction to: Dietary protein intake and subsequent risk of type 2 diabetes: a dose-response meta-analysis of prospective cohort studies.

The article Dietary protein intake and subsequent risk of type 2 diabetes: a dose-response meta-analysis of prospective cohort studies written by Jianhong Ye, Qixin Yu, Weihua Mai, Peiling Liang, Xiaoxia Liu, Yunnan Wang was originally published electronically on the publisher's internet portal (currently SpringerLink) on 30 March 2019 with open access. With the author(s)' decision to step back from Open Choice, the copyright of the article changed on 30 May 2019 to © Springer-Verlag Italia S.r.l., part of Springer Nature 2019 and the article is forthwith distributed under the terms of copyright.

Dietary protein intake and subsequent risk of type 2 diabetes: a dose-response meta-analysis of prospective cohort studies.

AIMS: Dietary proteins, including those obtained from animal and plant sources, have inconsistently been correlated with type 2 diabetes mellitus (T2DM) risk. Therefore, a meta-analysis was conducted to evaluate the association between dietary proteins and the risk of T2DM. METHODS: Prospective cohort studies published until November 2018 were systematically searched in PubMed, Embase, and the Cochrane library. The pooled relative risks (RRs) were calculated with 95% confidence intervals (CIs) using the random-effects model. RESULTS: Ten articles involving a total of 21 cohorts were included in the final meta-analysis. A total of 487,956 individuals were recruited in these studies and 38,350 T2DM cases were reported. Analysis of the pooled RRs indicated that high total protein intake was associated with an increased risk of T2DM (RR 1.10; P = 0.006), whereas moderate total protein intake was not significantly associated with T2DM risk (RR 1.00; P = 0.917). Moreover, a higher risk of T2DM was observed with high animal protein intake (RR 1.13; P = 0.013), whereas moderate animal protein intake had little or no effect on T2DM risk (RR 1.06; P = 0.058). Finally, high intake of plant protein did not affect T2DM risk (RR 0.93; P = 0.074), whereas moderate intake was associated with a reduced risk of T2DM (RR 0.94; P < 0.001). CONCLUSIONS: The results of this study indicate that high total protein and animal protein intakes are associated with an increased risk of T2DM, whereas moderate plant protein intake is associated with a decreased risk of T2DM.

Functional polymorphisms in NFκB1/IκBα predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese.

Lung inflammation is the major pathogenetic feature for both chronic obstructive pulmonary disease (COPD) and lung cancer. The nuclear factor-kappa B (NFκB) and its inhibitor (IκB) play crucial roles in inflammatory. Here, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in NFκB/IκB confer consistent risks for COPD and lung cancer. Four putative functional SNPs (NFκB1: -94del>insATTG; NFκB2: -2966G>A; IκBα: -826C>T, 2758G>A) were analyzed in southern and validated in eastern Chineses to test their associations with COPD risk in 1,511 COPD patients and 1,677 normal lung function controls, as well as lung cancer risk in 1,559 lung cancer cases and 1,679 cancer-free controls. We found that the -94ins ATTG variants (ins/del + ins/ins) in NFκB1 conferred an increased risk of COPD (OR 1.27, 95% CI 1.06-1.52) and promoted COPD progression by accelerating annual FEV1 decline (P = 0.015). The 2758AA variant in IκBα had an increased risk of lung cancer (OR 1.53, 95% CI 1.30-1.80) by decreasing IκBα expression due to the modulation of microRNA hsa-miR-449a but not hsa-miR-34b. Furthermore, both adverse genotypes exerted effect on increasing lung cancer risk in individuals with pre-existing COPD, while the -94del>insATTG did not in those without pre-existing COPD. However, no significant association with COPD or lung cancer was observed for -2966G>A and -826C>T. Our data suggested a common susceptible mechanism of inflammation in lung induced by genetic variants in NFκB1 (-94del>ins ATTG) or IκBα (2758G>A) to predict risk of COPD or lung cancer.

The polymorphisms and haplotypes of WWOX gene are associated with the risk of lung cancer in southern and eastern Chinese populations.

The WW domain-containing oxidoreductase (WWOX) gene is an identified tumor suppressor gene, of which several single nucleotide polymorphisms have been reported to contribute to cancer susceptibility. We hypothesized that genetic variations in WWOX are associated with lung cancer risk. In two independent case-control studies conducted in southern and eastern Chinese, we genotyped five tagSNPs of WWOX gene (rs10220974C > T, rs3764340C > G, rs12918952G > A, rs383362G > T, and rs12828G > A) in 1,559 lung cancer cases and 1,679 controls. Logistic regression analysis showed that two tagSNPs (rs3764340C > G; rs383362G > T) were significantly associated with lung cancer risk in dominant model (rs3764340C > G, GC/GG vs. CC: adjust OR = 1.35, 95% CI = 1.11-1.65; rs383362G > T, TG + TT vs. GG: adjust OR = 1.33, 95% CI = 1.14-1.55). The haplotype analysis further shown that the haplotype "G-T" was associated with the highest increased risk of lung cancer (OR = 2.20; 95% CI = 1.43-3.37). After combined these two loci, the number of the risk genotypes was associated with increased cancer risk in a dose-response manner (Ptrend = 3.16 × 10(-6) ). In addition, a gene-based association analysis by using VEGAS software suggested the WWOX as a susceptible gene for lung cancer (P = 0.009). However, for rs10220974C > T, rs12918952G > A, and rs12828G > A, no significant association was observed for lung cancer risk. Taken together, our data suggested that genetic variants in WWOX may be genetic biomarkers for susceptibility to lung cancer.

The polymorphism and haplotypes of PIN1 gene are associated with the risk of lung cancer in Southern and Eastern Chinese populations.

Peptidyl-prolyl cis/trans isomerase (PPIase), PIN1, has been found to be a critical catalyst that involves in multiple oncogenic signaling pathways. Recently, several putative functional polymorphisms of the PIN1 gene have been identified to be associated with cancer risk. In this study, we tested the hypothesis that two common polymorphisms, c.-842G>C (rs2233678) and c.-667C>T (rs2233679), in the PIN1 promoter are associated with risk of lung cancer. In two independent case-control studies of 1,559 lung cancer cases and 1,679 controls conducted in Southern and Eastern Chinese population, we found that compared with the most common c.-842GG genotype, the carriers of c.-842C variant genotypes (GC + CC) had a decreased risk of lung cancer (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.51-0.78, p = 1.13 × 10(-5) ). Although no association was observed between the c.-667C>T polymorphism and cancer risk, we found that the haplotype "C-C" had a greater protective effect (OR = 0.39, 95% CI = 0.23-0.67, p = 5.03 × 10(-4) ). The stratification analysis showed that the protective role of c.-842C variants was more pronounced in current smokers (p = 4.45 × 10(-5) ), especially in male smokers (p = 6.71 × 10(-6) ) and in those who smoked more than 20 pack-years (p = 2.30 × 10(-5) ) and the c.-842C variant genotypes interacted with smoking status (P(interaction) = 0.019) or pack-years smoked (P(interaction) = 0.008) on reducing cancer risk. Further functional assay revealed that the c.-842C variant allele had a lower transcription activity in luciferase assay and a lower DNA-binding ability with nuclear proteins, and low transcription activity in western blot assay. In conclusions, our data suggest that functional c.-842C variants and haplotype "C-C" in the PIN1 promoter contribute to decreased risk of lung cancer by diminishing the promoter activity, which may be susceptibility biomarkers for lung cancer.