Synergistic effects of combined treatment of 1,2-dichloroethane and high-dose ethanol on liver damage in mice and the related mechanisms.

Our previous studies have shown that the metabolism of 1,2-dichloroethane (1,2-DCE) mediated by CYP2E1 could result in oxidative damage in the liver of mice. In the current study, we further investigated the effects of combined treatment with 1,2-DCE and high dose ethanol on liver and the mechanisms since both of them can be metabolized by CYP2E1 in the liver. There are several novel findings in the current study. First, combined treatment of mice with 1,2-DCE and high-dose ethanol could synergistically upregulate both protein and mRNA levels of CYP2E1, which might aggravate liver damage through CYP2E1-mediated oxidative stress. Second, the combined treatment could also synergistically trigger NLRP3 inflammasome activation and inflammatory responses in the liver. Third, the combined treatment synergistically upregulated the antioxidant defence systems in response to oxidative stress, however the compensatory mechanisms of antioxidant defence systems appeared to be insufficient to protect liver damage in the mice. Finally, the upregulated CYP2E1 expression was confirmed by using its specific inhibitor to play the crucial roles in liver damage in the mice during the combined treatment.

The role of healthy lifestyles in preventing chronic disease among adults.

BACKGROUND: Although chronic diseases have become a public health dilemma in China, evidence regarding their relationship to a healthy lifestyle in the Chinese population remains limited. METHODS: Based on data obtained from a survey conducted by China's Centers for Disease Control and Prevention (CDC), odds ratios (OR) corresponding to 95% confidential intervals (CIs) related to healthy lifestyle factors were calculated using ordinal logistic regression. RESULTS: Most participants in our study presented 1 to 3 healthy lifestyle factors, and only 0.35% of men presented all 6 factors evaluated. Eighty-three percent of participants had at least one chronic disease. A decrease in chronic disease morbidity was followed by an increase in healthy lifestyle factors number. For the three chronic diseases (hypertension, diabetes, and/or dyslipidemia), a lack of physical activity represented 1.231 times (95% CI, 1.013-1.497) higher risk than being physically active. A body mass index (BMI) outside the range of 18.5-24.9 kg/m2 was associated with a higher risk of 1.361 times (95% CI, 1.139-1.625) compared to a BMI within 18.5-24.9 kg/m2. Comparing participants with healthy lifestyle factor ≤1, the OR for participants with 2, 3 and 4-6 healthy lifestyle factors were 0.675, and 0.425 (0.634 and 0.341 for men), respectively. CONCLUSIONS: Chronic diseases have become one of the leading health burdens in China, while healthy lifestyles have not kept pace. The inverse association between an increasing number of healthy lifestyle factors and chronic disease risk indicates an urgent public need to popularize a healthy lifestyle pattern.

The S100 calcium binding protein A11 promotes liver fibrogenesis by targeting TGF-ß signaling.

Liver fibrosis is a key transformation stage and also a reversible pathological process in various types of chronic liver diseases. However, the pathogenesis of liver fibrosis still remains elusive. Here, we report that the calcium binding protein A11 (S100A11) is consistently upregulated in the integrated data from GSE liver fibrosis and tree shrew liver proteomics. S100A11 is also experimentally activated in liver fibrosis in mouse, rat, tree shrew, and human with liver fibrosis. While overexpression of S100A11 in vivo and in vitro exacerbates liver fibrosis, the inhibition of S100A11 improves liver fibrosis. Mechanistically, S100A11 activates hepatic stellate cells (HSCs) and the fibrogenesis process via the regulation of the deacetylation of Smad3 in the TGF-ß signaling pathway. S100A11 physically interacts with SIRT6, a deacetylase of Smad2/3, which may competitively inhibit the interaction between SIRT6 and Smad2/3. The subsequent release and activation of Smad2/3 promote the activation of HSCs and fibrogenesis. Additionally, a significant elevation of S100A11 in serum is observed in clinical patients. Our study uncovers S100A11 as a novel profibrogenic factor in liver fibrosis, which may represent both a potential biomarker and a promising therapy target for treating liver fibrosis and fibrosis-related liver diseases.

A Facile, Protein-Derived Supramolecular Theranostic Strategy for Multimodal-Imaging-Guided Photodynamic and Photothermal Immunotherapy In Vivo.

Theranostic systems that permit both diagnosis and treatment in vivo are highly appealing means by which to meet the demands of precision medicine. However, most such systems remain subject to issues related to complex molecular design and synthesis, potential toxicity, and possible photoactivity changes. Herein, a novel supramolecular theranostic strategy involving biomarker protein activation (BPA) and a host-guest strategy is proposed. To exemplify BPA, a facile "one-for-all" nanotheranostic agent for both albumin detection and cancer treatment is demonstrated, which utilizes a nanoparticulate heavy-atom-free BODIPY dye derivative (B4 NPs). The fluorescence and photoactivity of BODIPY dyes are completely suppressed by aggregation-induced self-quenching in the nanoparticulate state. However, a Balb/c nude mouse model is used to confirm that following the disassembly of injected B4 NPs, BODIPY specifically binds albumin in vivo, accompanied by significantly enhanced biocompatibility and photothermal conversion efficiency. More importantly, this supramolecular host-guest BPA strategy enables the resultant nanoplatform to act as a facile and efficient strategy for photodynamic and photothermal immunotherapy.

miR-669a-5p promotes adipogenic differentiation and induces browning in preadipocytes.

Obesity is a major global health issue that contributes to the occurrence of metabolic disorders. Based on this fact, understanding the underlying mechanisms and to uncover promising therapeutic approaches for obesity have attracted intense investigation. Brown adipose tissue (BAT) can help burns excess calories. Therefore, promoting White adipose tissue (WAT) browning and BAT activation is an attractive strategy for obesity treatment. MicroRNAs (miRNAs) are small, non-coding RNAs, which are involved in regulation of adipogenic processes and metabolic functions. Evidence is accumulating that miRNAs are important regulators for both brown adipocyte differentiation and white adipocyte browning. Here we report that the expression of miR-669a-5p increases during the adipogenic differentiation of 3T3-L1 and C3H10T1/2 adipocytes. miR-669a-5p supplementation promotes adipogenic differentiation and causes browning of 3T3-L1 and C3H10T1/2 cells. Moreover, the expression of miR-669a-5p is upregulated in iWAT of mice exposed to cold. These data demonstrate that miR-669a-5p plays a role in regulating adipocyte differentiation and fat browning.Abbreviations: Acadl: long-chain acyl-Coenzyme A dehydrogenase; Acadm: medium-chain acyl-Coenzyme A dehydrogenase; Acadvl: very long-chain acyl-Coenzyme A dehydrogenase, very long chain; Aco2: mitochondrial  aconitase 2; BAT: brown adipose tissue; Bmper: BMP-binding endothelial regulator; Cpt1-b:carnitine palmitoyltransferase 1b; Cpt2: carnitine palmitoyltransferase 2; Crat: carnitine acetyltransferase; Cs: citrate synthase; C2MC: Chromosome 2 miRNA cluster; DMEM: Dulbecco's modified Eagle medium; eWAT: epididymal white adipose tissue; ETC: electron transport chain; FAO: fatty acid oxidation; Fabp4:fatty acid binding protein 4; FBS: fetal bovine serum; Hadha: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; Hadhb: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta; HFD: high fat diet; Idh3a: isocitrate dehydrogenase 3 alpha; iWAT: inguinal subcutaneous white adipose tissue; Lpl: lipoprotein lipase; Mdh2: malate dehydrogenase 2; NBCS: NewBorn Calf Serum; mt-Nd1: mitochondrial NADH dehydrogenase 1; Ndufb8:ubiquinone oxidoreductase subunit B8; Nrf1: nuclear respiratory factor 1; Pgc1α: peroxisome proliferative activated receptor gamma coactivator 1 alpha; Pgc1b: peroxisome proliferative activated receptor, gamma, coactivator 1 beta; Pparγ: peroxisome proliferator activated receptor gamma; Prdm16: PR domain containing 16; Rgs4: regulator of G-protein signaling 4; Sdhb: succinate dehydrogenase complex, subunit B; Sdhc: succinate dehydrogenase complex, subunit C; Sdhd: succinate dehydrogenase complex, subunit D; Sh3d21: SH3 domain containing 21; Sfmbt2: Scm-like with four mbt domains 2; TG: triglyceride; TCA: tricarboxylic acid cycle; Tfam: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine, methyl ester; Ucp1: uncoupling protein 1; Uqcrc2: ubiquinol cytochrome c reductase core protein 2; WAT: White adipose tissue.

Exfoliation of metal-organic frameworks into efficient single-layer metal-organic nanosheet electrocatalysts by the synergistic action of host-guest interactions and sonication.

Single-layer two-dimensional metal-organic framework (MOF) nanosheets combine the characteristic of highly ordered structures of MOFs and unique physical and chemical properties of two-dimensional (2D) materials, which is beneficial for developing high-performance electrocatalysts and studying the structure-property relationships. However, the instability of coordination bonds during exfoliation results in great difficulties in their preparation and characterization. This work takes advantage of the anisotropy of coordination bonds in three-dimensional (3D) pillared-layer MOFs and selectively breaks the interlayer bonding through substitution of the pillared ligands by capping solvent molecules synergized with sonication in a solvent over a relatively short time course (30 min), thus leading to single-layer metal-organic nanosheets, which retain the 2D layered structure of the original crystalline counterpart. The as-synthesized single-layer metal-organic nanosheets are efficient electrocatalysts for the oxygen evolution reaction (OER) with a turnover frequency as high as 0.144 s-1 and 0.294 s-1 at overpotentials of 400 mV and 500 mV in neutral electrolyte media, respectively, which are higher than other heterogeneous catalysts.

Involvement of CYP2E1 in the Course of Brain Edema Induced by Subacute Poisoning With 1,2-Dichloroethane in Mice.

This study was designed to explore the role of cytochrome P4502E1 (CYP2E1) expression in the course of brain edema induced by subacute poisoning with 1,2-dichloroethane (1,2-DCE). Mice were randomly divided into five groups: the control group, the 1,2-DCE poisoned group, and the low-, medium- and high-dose diallyl sulfide (DAS) intervention groups. The present study found that CYP2E1 expression levels in the brains of the 1,2-DCE-poisoned group were upregulated transcriptionally; in contrast, the levels were suppressed by DAS pretreatment in the intervention groups. In addition, the expression levels of both Nrf2 and HO-1 were also upregulated transcriptionally in the brains of the 1,2-DCE-poisoned group, while they were suppressed dose-dependently in the intervention groups. Moreover, compared with the control group, MDA levels and water contents in the brains of the 1,2-DCE-poisoned group increased, whereas NPSH levels and tight junction (TJ) protein levels decreased significantly. Conversely, compared with the 1,2-DCE- poisoned group, MDA levels and water contents in the brains of the intervention groups decreased, and NPSH levels and TJ protein levels increased significantly. Furthermore, pathological changes of brain edema observed in the 1,2-DCE-poisoned group were markedly improved in the intervention groups. Collectively, our results suggested that CYP2E1 expression could be transcriptionally upregulated in 1,2-DCE-poisoned mice, which might enhance 1,2-DCE metabolism in vivo, and induce oxidative damage and TJ disruption in the brain, ultimately leading to brain edema.

Involvement of the p38 MAPK signaling pathway in overexpression of matrix metalloproteinase-9 during the course of brain edema in 1,2-dichloroethane-intoxicated mice.

Accumulated data have revealed that subacute poisoning of 1,2-dichloroethane (1,2-DCE), an industrial solvent used in some countries can cause encephalopathy, in which brain edema is the main pathological change. However, the underlying mechanisms are unclear. In the present study, we hypothesized that the p38 MAPK (p38) signaling pathway could be activated in 1,2-DCE-intoxicated mice, which in turn stimulates transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), and then enhances the expression of proinflammatory factors, including matrix metalloproteinase-9 (MMP-9), finally leading to blood-brain barrier (BBB) disruption and brain edema formation. Our results revealed that brain water content and BBB permeability increased significantly in the intoxicated mice. Meanwhile, the levels of phosphorylated p38 (p-p38) and inhibitory κBα (p-IκB), as well as the expression levels of MMP-9, c-jun, c-fos, and p65, also increased markedly in the brains of intoxicated mice. Conversely, the protein levels of ZO-1, occludin and claudin-5 in these mice decreased markedly, but their JAM-1 protein levels increased dramatically. Our results revealed that p-p38 levels in the brains of intoxicated mice were suppressed by pretreatment with a p38 inhibitor. In response to suppressed p-p38 levels, the brain water contents and DNA binding activities of NF-κB and AP-1, as well as the expression levels of MMP-9, c-jun, c-fos, p65, p-IκB and JAM-1, decreased, whereas the protein levels of ZO-1, occludin and claudin-5 increased markedly. Taken together, our findings indicated that the p38 signaling pathway might be activated and involved in the course of brain edema in 1,2-DCE-intoxicated mice.

Disruption of Intracellular ATP Generation and Tight Junction Protein Expression during the Course of Brain Edema Induced by Subacute Poisoning of 1,2-Dichloroethane.

The aim of this study was to explore changes in intracellular ATP generation and tight junction protein expression during the course of brain edema induced by subacute poisoning of 1,2-dichloroethane (1,2-DCE). Mice were exposed to 1.2 g/m3 1,2-DCE for 3.5 h per day for 1, 2, or 3 days, namely group A, B, and C. Na+-K+-ATPase and Ca2+-ATPase activity, ATP and lactic acid content, intracellular free Ca2+ concentration and ZO-1 and occludin expression in the brain were measured. Results of present study disclosed that Ca2+-ATPase activities in group B and C, and Na+/K+-ATPase activity in group C decreased, whereas intracellular free Ca2+ concentrations in group B and C increased significantly compared with control. Moreover, ATP content decreased, whereas lactic acid content increased significantly in group C compared with control. On the other hand, expressions of ZO-1 and occludin at both the protein and gene levels in group B and C decreased significantly compared with control. In conclusion, findings from this study suggest that calcium overload and depressed expression of tight junction associated proteins, such as ZO-1 and occludin might play an important role in the early phase of brain edema formation induced by subacute poisoning of 1,2-DCE.

[Roles of CYP2E1 in liver damage induced by 1,2-dichloroethane].

OBJECTIVE: To explore the expression of CYP2E1 in the liver of mice and its effects on liver injury induced by 1,2-dichloroethane (1, 2-DCE). METHODS: (1) Thirty-two female mice were randomly divided into four groups, which were control group, low dose group, medium dose group and high dose group. Mice were exposed to 1,2-DCE through respiratory for 4 h per day for 10 days. At the end of exposure, the mice were sacrificed, their blood and liver were collected rapidly. Pathological analysis was examined. Activity of ALT and AST in serum and activity of CYP2E1 in liver were mice were randomly divided into six groups, ie simple control group, corn oil control group, inhibitor control group, simple poisonous group, low and high dose diallyl sulfide (DAS) intervention groups. Mice were treated orally with DAS in corn oil 4 hours before 1, 2-DCE exposure. The examination indicators were as aforementioned. RESULTS: (1) Compared to control group, activity of ALT in serum of mice in the high dose group and expression of CYP2E1 in the liver of mice in medium and high dose group increased significantly. In addition, the histological observation suggested obvious liver damage in medium and high dose group. (2) CYP2E1 protein expression and activity in liver and ALT in serum decreased significantly in DAS-intervention groups compared to simple poisonous group. Along with the changes of CYP2E1 and ALT, pathological changes of liver damage was better. CONCLUSION: Our results suggested that expression of CYP2E1 and oxidative damage in the liver could be induced by 1,2-DCE exposure, and CYP2E1 inhibitors can reduce the hepatic tissue damage caused by DCE.

Roles of aquaporins and matrix metalloproteinases in mouse brain edema formation induced by subacute exposure to 1,2-dichloroethane.

The aim of this study was to explore the effects of 1,2-dichloroethane (1,2-DCE) on expression of aquaporins (AQPs) and matrix metalloproteinases (MMPs) in the process of brain edema formation. Two parts were included in this study, establishment of animal model of brain edema, and mechanism of brain edema induced by subacute exposure to 1,2-DCE. In part one, mice were exposed to 0, 1.1, 1.2 or 1.3g/m(3) 1,2-DCE, 3.5h per day for 3days. Pathological analysis and water content detection in the brain were examined. In part two, mice were exposed to 1.2g/m(3) 1,2-DCE, 3.5h per day for 1, 2 or 3days, named group D, E and F, respectively. Expression of AQP4, MMP2 and MMP9 in the brain was determined by immunochemical staining, western blot and real time PCR. According to the results of part one, the 1.2g/m(3) dose was chosen for part two, a follow-up time-course study. In part two, protein expression of MMP2 and MMP9 in group F, and AQP4 in group E and F significantly increased compared to the control. Similarly, mRNA levels of AQP4 in group F, and MMP9 in group E and F significantly increased. Our results suggested that exposure to 1,2-DCE might up-regulate the expression of AQP4 protein and MMP9 mRNA at the early phase of brain edema, and AQP4 may play an important role in the brain edema formation.