Garlic-derived exosome-like nanovesicles as a hepatoprotective agent alleviating acute liver failure by inhibiting CCR2/CCR5 signaling and inflammation.

Acute liver failure (ALF) is a life-threatening clinical syndrome mostly induced by viral infections or drug abuse. As a novel therapeutic adjuvant or delivery vehicle, plant-derived exosome-like nanovesicles (PELNVs) have been extensively studied in recent years. This study aimed to develop garlic-derived exosome-like nanovesicles (GaELNVs) in order to ameliorate liver injury induced by LPS/D-GalN in mice, inhibit inflammatory eruption and reduce inflammatory cells infiltration. The results showed that treatment with GaELNVs improved liver pathology and reduced the levels of soluble inflammatory mediators IL-6, IL-1ß and TNF-α in the serum of ALF mice. GaELNVs reversed the upregulation of Cleaved Caspase-9, Cleaved Caspase-3, p53 and Bax expression and decreased Bcl2 activation caused by D-GalN/LPS, and inhibited NF-κB p65 expression and translocation to the nucleus. Meanwhile, treatment with GaELNVs resulted significant reduction in NLRP3 activation and Caspase-1 maturation, as well as decrease in the release of the inflammatory mediator IL-18. Additionally, an upregulation of the expression of proteins related to energy metabolism and autophagy occurrence including Foxo3a, Sirt1, and LC3-II was detected in the liver. Oral administration of GaELNVs also led to significant alteration in the expression of F4/80 and CD11b in the liver. Furthermore, the detection of chemokines in mouse liver tissue revealed that GaELNVs exhibited minimal reduction in the expression of CCL2, CCL3, CCL5 and CCL8. The decreased expression of CCR2 and CCR5 in the liver suggests that GaELNVs have the ability to decrease the recruitment of monocytes from the circulation to the liver. A reduction in the infiltration of F4/80loCD11bhi monocyte-derived macrophages into the liver was also observed. This study provides novel evidence that GaELNVs can ameliorate inflammatory eruptions and hinder the migration of circulating monocytes to the liver, as well as decrease macrophage infiltration by inhibiting CCR2/CCR5 signaling. Consequently, GaELNVs hold promise as a novel therapeutic agent for clinical management of liver disease.

Association between circulating fatty acid metabolites and asthma risk: a two-sample bidirectional Mendelian randomization study.

BACKGROUND: Fatty acids are involved in a wide range of immunological responses in humans. Supplementation of polyunsaturated fatty acids has been reported to help alleviate symptoms and airway inflammation in asthma patients, whereas the effects of fatty acids on the actual risk of asthma remain controversial. This study comprehensively investigated the causal effects of serum fatty acids on asthma risk using two-sample bidirectional Mendelian Randomization (MR) analysis. METHODS: Genetic variants strongly associated with 123 circulating fatty acid metabolites were extracted as instrumental variables, and a large GWAS data of asthma was used to test effects of the metabolites on this outcome. The inverse-variance weighted method was used for primary MR analysis. The weighted median, MR-Egger regression, MR-PRESSO, and leave-one-out analyses were utilized to evaluate heterogeneity and pleiotropy. Potential confounders were adjusted by performing multivariable MR analyses. Reverse MR analysis was also conducted to estimate the causal effect of asthma on candidate fatty acid metabolites. Further, we performed colocalization analysis to examine the pleiotropy of variants within the fatty acid desaturase 1 (FADS1) locus between the significant metabolite traits and the risk of asthma. Cis-eQTL-MR and colocalization analysis were also performed to determine the association between RNA expression of FADS1 and asthma. RESULTS: Genetically instrumented higher average number of methylene groups was causally associated with a lower risk of asthma in primary MR analysis, while inversely, the higher ratio of bis-allylic groups to double bonds and the higher ratio of bis-allylic groups to total fatty acids, were associated with higher probabilities of asthma. Consistent results were obtained in multivariable MR when adjusted for potential confounders. However, these effects were completely eliminated after SNPs correlated with the FADS1 gene were excluded. The reverse MR also found no causal association. The colocalization analysis suggested that the three candidate metabolite traits and asthma likely share causal variants within the FADS1 locus. In addition, the cis-eQTL-MR and colocalization analyses demonstrated a causal association and shared causal variants between FADS1 expression and asthma. CONCLUSIONS: Our study supports a negative association between several PUFA traits and the risk of asthma. However, this association is largely attributed to the influence of FADS1 polymorphisms. The results of this MR study should be carefully interpreted given the pleiotropy of SNPs associated with FADS1.

Guanxinping Tablets Inhibit ET-1-Induced Proliferation and Migration of MOVAS by Suppressing Activated PI3K/Akt/NF-κB Signaling Cascade.

Background/Aim: Abnormal proliferation and migration of vascular smooth muscle cells is one of the main causes of atherosclerosis (AS). Therefore, the suppression of abnormal proliferation and migration of smooth muscle cells are the important means for the prevention and inhibition of AS. The clinical effects of Guanxinping (GXP) tablets and preliminary clinical research on the topic have proved that GXP can effectively treat coronary heart disease, but its underlying mechanism remains unclear. This study aimed to confirm the inhibitory effect of GXP on the abnormal proliferation of mouse aortic vascular smooth muscle (MOVAS) cells and to explore the underlying mechanism. Methods: MOVAS cells were divided into two major groups: physiological and pathological groups. In the physiological group, MOVAS cells were directly stimulated with GXP, whereas in the pathological group, the cells were stimulated by endothelin-1 (ET-1) before intervention by GXP. At the same time, atorvastatin calcium, which effectively inhibits the abnormal proliferation of MOVAS cells, was used in the negative control group. CCK8 assay, scratch test, ELISA, Western blotting, and immunofluorescence staining were performed to observe the proliferation and migration of MOVAS cells and the expression levels of related factors after drug intervention in each group. Results: In the physiological group, GXP had no significant effect on the proliferation and migration of MOVAS cells and the related factors. In the pathological group, a high dose of GXP reduced the abnormal proliferation and migration of MOVAS cells. Further, it reduced the expression levels of PI3K; inhibited the phosphorylation of Akt (protein kinase B); upregulated IκB-α levels; prevented nuclear factor kappa B (NF-κB) from entering the nucleus; downregulated the expression of interleukin 6 (IL6), IL-1ß, and iNOS; and upregulated the ratio of apoptosis-related factor Bax/Bcl-2. There was no significant difference between the high-dose GXP group and the atorvastatin calcium group (negative control group). Conclusion: Our findings revealed that GXP was able to inhibit the proliferation and migration of MOVAS cells by regulating the PI3K/Akt/NF-κB pathway.

Phototherapy for atopic dermatitis: Systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Phototherapies could represent an efficient option for the treatment of atopic dermatitis (AD), but the evidences available for clinical choices were contradictory. OBJECTIVE: This study aimed to evaluate the efficacy of different phototherapies on AD. METHODS: This systematic review and network meta-analysis included randomized controlled trials (RCTs) through searching keywords from PubMed, EMBASE, and the Cochrane library. We summarized different phototherapy types and scoring systems. Scoring Atopic Dermatitis (SCORAD) absolute score changes were estimated by mean differences (MDs) and standard deviations (SDs) and then included in the network meta-analysis. The effect sizes of comparison of different phototherapies were presented as MDs and 95% confidence intervals (CIs). Egger's test was used to evaluate publication bias. RESULTS: Eleven RCTs were included in the systematic review and 4 studies in the network meta-analysis. Based on the pooled estimates, medium-dose ultraviolet A1 (UVA1) cold light was superior to medium-dose UVA1 (MD 8.92; 95% CI: 5.60-12.24) but no significant difference between high-dose (UVA1) and medium-dose UVA1 cold light (MD 0.66; 95% CI: -5.57 to 6.90). Publication bias was not supported by Egger's test (P = .168). CONCLUSIONS: Due to possible long-term adverse effects of high-dose UVA1, medium-dose UVA1 cold light appears to be the superior form for AD.

An anion exchange pretreatment method for the determination of low-level uranium in the environmental water samples.

Uranium in environmental water is usually at trace or ultra-trace levels with high concentrations of background ions so that the detection of uranium often couples with pretreatment processes to lower the detection limit, and improve the selectivity and accuracy of instruments. A simple, green, effective and efficient anion exchange pretreatment method was proposed to favor the determination of low-level uranium in natural environmental water samples. To determine the applicability and obtain the optimum operating parameters, the effects of coprecipitation, pH, contact time, uranium concentration, background ions, eluent and the flow speed on the uranium recovery were investigated. The experimental results showed that the proper addition of saturated Na2CO3 solution for pH adjustment did not lead to uranium loss in natural water samples, and the optimum pH value for adsorption was determined from 6 to 8. The adsorption speed was improved a lot with the employment of a novel silica-supported anion exchange resin, which also showed good linear dependence in the concentration range from <0.5 µg/L to 1000 µg/L with high tolerance limits towards common background ions. The optimum eluent was determined as 1 M HNO3, and the optimum flow speeds for adsorption and desorption were about 4.0 and 1.0 mL/min, respectively. Based on these results, a pretreatment process was finally established, which realized the quantitative recovery of uranium from six different natural water samples with the chemical yields exceeding 95% and the enrichment factors about 100 times.

Metabolism and Toxicity of Emodin: Genome-Wide Association Studies Reveal Hepatocyte Nuclear Factor 4α Regulates UGT2B7 and Emodin Glucuronidation.

Emodin is the main toxic component in Chinese medicinal herbs such as rhubarb. Our previous studies demonstrated that genetic polymorphisms of UDP-glucuronosyltransferase 2B7 (UGT2B7) had an effect on the glucuronidation and detoxification of emodin. This study aimed to reveal the transcriptional regulation mechanism of UGT2B7 on emodin glucuronidation and its effect on toxicity. Emodin glucuronic activity and genome and transcriptome data were obtained from 36 clinical human kidney tissues. The genome-wide association studies (GWAS) identified that four single nucleotide polymorphisms (SNPs) (rs6093966, rs2868094, rs2071197, and rs6073433), which were located on the hepatocyte nuclear factor 4α (HNF4A) gene, were significantly associated with the emodin glucuronidation (p < 0.05). Notably, rs2071197 was significantly associated with the gene expression of HNF4A and UGT2B7 and the glucuronidation of emodin. The gene expression of HNF4A showed a high correlation with UGT2B7 (R2 = 0.721, p = 5.83 × 10-11). The luciferase activity was increased 7.68-fold in 293T cells and 2.03-fold in HepG2 cells, confirming a significant transcriptional activation of UGT2B7 promoter by HNF4A. The knockdown of HNF4A in HepG2 cells (36.6%) led to a significant decrease of UGT2B7 (19.8%) and higher cytotoxicity (p < 0.05). The overexpression of HNF4A in HepG2 cells (31.2%) led to a significant increase of UGT2B7 (24.4%) and improved cell viability (p < 0.05). Besides, HNF4A and UGT2B7 were both decreased in HepG2 cells and rats after treatment with emodin. In conclusion, emodin used long term or in high doses could inhibit the expression of HNF4A, thereby reducing the expression of UGT2B7 and causing hepatotoxicity.

Superconductivity in the PbO-type structure alpha-FeSe.

The recent discovery of superconductivity with relatively high transition temperature (Tc) in the layered iron-based quaternary oxypnictides La[O(1-x)F(x)] FeAs by Kamihara et al. [Kamihara Y, Watanabe T, Hirano M, Hosono H (2008) Iron-based layered superconductor La[O1-xFx] FeAs (x = 0.05-0.12) with Tc = 26 K. J Am Chem Soc 130:3296-3297.] was a real surprise and has generated tremendous interest. Although superconductivity exists in alloy that contains the element Fe, LaOMPn (with M = Fe, Ni; and Pn = P and As) is the first system where Fe plays the key role to the occurrence of superconductivity. LaOMPn has a layered crystal structure with an Fe-based plane. It is quite natural to search whether there exists other Fe based planar compounds that exhibit superconductivity. Here, we report the observation of superconductivity with zero-resistance transition temperature at 8 K in the PbO-type alpha-FeSe compound. A key observation is that the clean superconducting phase exists only in those samples prepared with intentional Se deficiency. FeSe, compared with LaOFeAs, is less toxic and much easier to handle. What is truly striking is that this compound has the same, perhaps simpler, planar crystal sublattice as the layered oxypnictides. Therefore, this result provides an opportunity to better understand the underlying mechanism of superconductivity in this class of unconventional superconductors.