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Methane clathrate hydrate (MCH) is a promising energy resource, but controllable extraction of CH4from MCH remains a challenge. Gradually replacing CH4in MCH with CO2is an attractive scheme, as it is cost efficient and mitigates the environmentally harmful effects of CO2by sequestration. However, the practicable implementation of this method has not yet been achieved. In this study, using in situ neutron diffraction, we confirm that CH4in the 51262cages of bulk structure-I (sI) MCH can be substituted by gaseous CO2under high pressure and low temperature with a high substitution ratio (∼44%) while conserving the structure of the hydrate framework. First-principles calculations indicate that CO2binds more strongly to the 51262cages than methane does, and that the diffusion barrier for CH4is significantly lowered by an intermediate state in which one hydrate cage is doubly occupied by CH4and CO2. Therefore, exchange of CO2for CH4in MCH is not only energetically favorable but also kinetically feasible. Experimental and theoretical studies of CH4/CO2substitution elucidate a method to harness energy from these combustible ice resources. [ABSTRACT FROM AUTHOR]

Dysfunction of the intestinal barrier function occurs in hepatic injury, but the specific mechanisms responsible are largely unknown. Recently, NOD‐like receptor 3 (NLRP3) inflammasome functions in impairing endothelial barrier function. In this study, we test the hypothesis that TXNIP–NLRP3 axis repression prevents against intestinal barrier function disruption in nonalcoholic steatohepatitis (NASH). First, lipopolysaccharide (LPS)‐induced alterations in expression of ZO‐1 and occludin, myeloperoxidase (MPO) activity, reactive oxygen species (ROS) level, and transepithelial electric resistance (TEER) in intestinal epithelial cells (IECs) isolated from C57BL/6 wild‐type (WT) and TXNIP−/− mice were evaluated. The underlying regulatory mechanisms of TXNIP knockout in vivo were investigated with the detection of expressions of TXNIP, NLRP3 and ZO‐1, and occludin, the interaction of TXNIP–NLRP3, MPO activity, ROS level, permeability of intestinal mucosa, levels of inflammatory factors in serum, and LPS concentration. We identified that TXNIP knockout promoted ZO‐1 and occludin expression, yet reduced MPO activity, ROS level, and cell permeability in IECs, indicating restored the intestinal barrier function. However, LPS upregulated TXNIP and NLRP3 expression, as well as contributed to the interaction between TXNIP and NLRP3 in vitro. Furthermore, TXNIP was significantly upregulated in the intestinal mucosa of NASH mice and its knockout repaired the intestinal barrier disrupt, inhibited expression of inflammatory factors, and reduced LPS concentration as well as hepatic injury in vivo. Taken together, our findings demonstrated that inhibited the activation of the TXNIP–NLRP3 axis reduced MPO activity and oxidative stress and thus restoring the intestinal barrier function in NASH. TXNIP–NLRP3 axis may be a promising therapeutic strategy for the NASH treatment. Taken together, our findings demonstrated that inhibited activation of the TXNIP–NLRP3 axis reduced myeloperoxidase (MPO) activity and oxidative stress and thus restored the intestinal barrier function in nonalcoholic steatohepatitis (NASH). TXNIP–NLRP3 axis may be a promising therapeutic strategy for the NASH treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the effects of mothers against decapentaplegic homolog family member 4 (Smad4) deletion on inflammation and fibrogenesis in nonalcoholic steatohepatitis (NASH). METHODS: Biopsied liver samples from NASH patients and normal liver tissue samples from patients who had received liver resection for trauma were collected. Smad4Co/Co and wild‐type (WT) mice were used to construct the NASH model using a high‐fat diet (HFD) or methionine‐ and choline‐deficient diet (MCD). HE staining and TUNEL assay were used to observe the pathological changes and cell apoptosis, respectively. Quantitative real‐time polymerase chain reaction was used to detect the expression of inflammatory, fibrogenesis and apoptosis‐related genes, and immunohistochemistry to determine the protein expression of SMAD4, MCP‐1 and α‐SMA. RESULTS: SMAD4 protein expression significantly increased in NASH patients than in the control group. Compared with WT mice, HFD‐ and MCD‐fed Smad4Co/Co mice showed decreased hepatic steatosis, inflammation, liver cell apoptosis and nonalcoholic fatty liver activity score, reduced plasma glucose, triglyceride, free fatty acids, alanine aminotransferase and aspartate aminotransferase levels but increased adiponectin. Moreover, Smad4Co/Co decreased the expression of inflammatory markers (TNF‐α, MCP‐1, IFN‐γ), fibrogenetic markers (COL1A1, α‐SMA and TGF‐β1), lipogenic (Srebp1c, Fas and Acc) and proapoptotic genes (Bax and caspase‐3), but increased the expression of β‐oxidation (Ppar‐α, Cpt1 and Aco) and antiapoptotic genes (Bcl‐2). CONCLUSION: Smad4 deletion may inhibit lipogenesis, stimulate β‐oxidation, improve lipid metabolism and liver function, alleviate inflammation and fibrosis, and reduce cell apoptosis in NASH. [ABSTRACT FROM AUTHOR]

Among the members of tumour necrosis factor family Fas ligand on binding to its receptor strongly induces apoptosis of tumour-infiltrating lymphocytes (TIL). Thus, FasL acts as an inhibitor of anti-tumour immune response. The present study demonstrates that retinoic acid morpholine amide (RAMA) significantly suppresses FasL expression in colon cancer cells in a dose- and time-dependent manner. The suppression of FasL mRNA and proteins was significant at a concentration of 30 μM after 48 h in CLT85 and HT26 colon cancer cells. There was around 2.6- and 3.2-fold decrease in FasL mRNA after incubation with 30 μM of RAMA in CLT85 cells and HT26 cells, respectively. The results from Western blot showed a decrease in FasL mRNA and protein expression in both CLT85 and HT26 cells after suppression of cyclooxygenase (COX)-2 and COX-1 by RNAi. However, when COX-2-specific silencer RNA (siCOX-2)- and siCOX-1-treated CLT85 and HT26 cells were exposed to RAMA, inhibition of FasL expression was further suppressed. The siCOX-2-treated CLT85 and HT26 cells on exposure to RAMA showed ∼87 and ∼54 % reduction in FasL mRNA, respectively. Co-culture of Jurkat T cells with RAMA-treated HT26 and CLT85 cells decreased the viability of Jurkat T cells by only 2 and 4.3 %, respectively, compared to 19.5 and 37.3 % in control HT26 and CLT85 cells. The results from real-time reverse transcription polymerase chain reaction (RT-PCR) and immunoblotting showed that suppression of EP1 prevented RAMA-induced FasL suppression in CLT85 cells at both the mRNA and protein levels. Thus, RAMA can be a potent therapeutic agent for the treatment of colon tumours. [ABSTRACT FROM AUTHOR]

Background: Repeated episodes of jaundice and pruritus are common in a group of autosomal recessive liver diseases known as benign recurrent intrahepatic cholestasis. Benign recurrent intrahepatic cholestasis (BRIC) is divided into two types, type 1 and type 2, and is caused by mutations in the ATP8B1 and ABCB11 genes. Here, we report a rare case of BRIC type 2 mutation., Case Presentation: A 45-year-old Chinese man had three frequent episodes of jaundice marked by extensive excoriation and severe pruritis, although he had no prior history of jaundice. Laboratory investigations showed no evidence of liver damage caused by viral, autoimmune, or acquired metabolic etiologies. The CT scan revealed an enlarged gallbladder with numerous punctate high-density shadows, while no wall thickening was observed. Endoscopic ultrasonography showed no evidence of dilation of the intrahepatic and extrahepatic bile duct, as well as the absence of gallstone., Diagnostic Evaluation: Immunohistochemical examinations of liver biopsy samples showed cytokeratin-7 positive hepatocytes, suggesting chronic intrahepatic cholestasis. The reticulin fiberstaining demonstrated that the portions of the hepatic plate in the center of the lobule were asymmetrically organized,and somewhat enlarged, with collapsed areas indicating intralobular inflammation. Moreover, there were areas of collapse that indicated the presence of intralobular inflammation. Whole exome sequencing revealed mutations in the ABCB11 gene; c.3084A>G, p.A1028A homozygous mutation (chr2-169789016), and c.2594C>T, p.A865V heterozygous mutation (chr2-169801131). Based on these findings, the final diagnosis of the patient was metabolism-related jaundice., Treatment: Apart from receiving tapering dosage of prednisone to lower bilirubin levels, the patient received no extra care., Conclusion: The comprehensive diagnosis of a middle-aged male patient with BRIC-2, which involved extensive radiological, hematological, and genetic investigations, informed a tailored tapering prednisone regimen, highlighting the importance of personalized medicine in managing atypical presentations of this rare cholestatic disorder.

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Among the members of tumour necrosis factor family Fas ligand on binding to its receptor strongly induces apoptosis of tumour-infiltrating lymphocytes (TIL). Thus, FasL acts as an inhibitor of anti-tumour immune response. The present study demonstrates that retinoic acid morpholine amide (RAMA) significantly suppresses FasL expression in colon cancer cells in a dose- and time-dependent manner. The suppression of FasL mRNA and proteins was significant at a concentration of 30 μM after 48 h in CLT85 and HT26 colon cancer cells. There was around 2.6- and 3.2-fold decrease in FasL mRNA after incubation with 30 μM of RAMA in CLT85 cells and HT26 cells, respectively. The results from Western blot showed a decrease in FasL mRNA and protein expression in both CLT85 and HT26 cells after suppression of cyclooxygenase (COX)-2 and COX-1 by RNAi. However, when COX-2-specific silencer RNA (siCOX-2)- and siCOX-1-treated CLT85 and HT26 cells were exposed to RAMA, inhibition of FasL expression was further suppressed. The siCOX-2-treated CLT85 and HT26 cells on exposure to RAMA showed ∼87 and ∼54 % reduction in FasL mRNA, respectively. Co-culture of Jurkat T cells with RAMA-treated HT26 and CLT85 cells decreased the viability of Jurkat T cells by only 2 and 4.3 %, respectively, compared to 19.5 and 37.3 % in control HT26 and CLT85 cells. The results from real-time reverse transcription polymerase chain reaction (RT-PCR) and immunoblotting showed that suppression of EP1 prevented RAMA-induced FasL suppression in CLT85 cells at both the mRNA and protein levels. Thus, RAMA can be a potent therapeutic agent for the treatment of colon tumours.

Objective: Oxidative stress and inflammation play an important role in pathogenesis of alcohol-induced liver injury. The present study was designed to investigate the protective role of Lutein against alcohol-induced liver injury., Treatment: Wistar rats weighing 150-200 g were divided into 3 groups, control, EtOH treatment, Lutein followed by EtOH treatment. Ethanol-treated rats received EtOH [5 g/kg body weight] by gavage every 12 hours for a total of 3 doses. For Lutein pre-treatment, Lutein at a dose of 40 mg/kg was dissolved in the EtOH and gavaged 30 mins before EtOH treatment., Methods: Oxidative stress markers-(reactive oxygen species, lipid peroxidation, protein carbonyls and sulfhydryls content), liver markers (ALT, AST, ALP and LDH) were determined. Antioxidant enzyme activities and its master regulator Nrf-2 expression were analyzed. Further, inflammatory proteins NF-κB, COX-2, iNOS and inflammatory cytokines (TNF-α, MCP-1, IL-1β, IL-6) were analyzed., Results: The results showed significant decrease in oxidative stress markers and liver markers in the lutein pre-treatment. Lutein treatment down regulated inflammatory proteins and cytokines with concomitant up regulation in Nrf-2 levels and antioxidant enzymic activities., Conclusion: The present study showed that Lutein treatment exerted potent antioxidant and anti-inflammatory property and offered significant cytoprotection against alcohol-induced liver injury.