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Background & aimsThere is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH.MethodsMale C57BL/6 (control) or F11r(-/-) mice were fed a normal diet or a diet high in saturated fat, fructose, and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse-transcription polymerase chain reaction, and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S ribosomal RNA sequencing. We also analyzed biopsy specimens from proximal colons of 30 patients with nonalcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy.ResultsF11r(-/-) mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r(-/-) mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption, and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r(-/-) mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r(-/-) mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r(-/-) mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation.ConclusionsMice with defects in intestinal epithelial permeability develop more severe steatohepatitis after a HFCD than control mice, and colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to the development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH.

Dissipative solitons appear widely in physical systems with dissipative energy exchange, which have been regarded as an excellent platform for exploring nonlinear dynamics. The complex interactions among dispersion management and nonlinearity result in abundant asymmetric behaviors in diverse parameter spaces. Nevertheless, conventional detection methods impede direct and single-shot measurements of the transient polarization dynamics of dissipative solitons. Here, by using the division-of-amplitude method combined with dispersive Fourier transform techniques, we have experimentally observed the internal evolution of dissipative solitons in polarization space. By disturbing the cavity birefringence, we obtain asymmetrical spectra due to nonlinear phase evolution within numerous temporal roundtrips. The different phases across the lasing wavelengths result in wavelength-resolved symmetric breakage in polarization space, which is difficult to find in spectrum or pulse-shape measurements. The direct observation of hidden asymmetry in polarization space for dissipative soliton fiber lasers will facilitate theoretical modeling of mode-locked laser systems with complicated configurations, and it may also promote applications for polarization spectroscopy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Autophagy, oxidative stress and inflammatory reactions play an important role in non-alcoholic fatty liver disease. Curcumin has biological activities such as regulating autophagy, oxidative stress and inflammatory reaction. OBJECTIVE: To explore the effect and underlying mechanism of curcumin on experimental non-alcoholic fatty liver disease rats. METHODS: Non-alcoholic fatty liver model was established in rats fed 8-week high-fat diets. Forty healthy SPF male Sprague-Dawley rats were randomly divided into control group, model group, curcumin treatment group, and curcumin and 3-methyladenine (3-MA, an autophagic flux blocker) treatment group. AI the end of 8 weeks of high-fat diet, control and model groups were given PBS intragaslrically, curcumin treatment group given curcumin 500 mg/kg per day intragastrically, and curcumin+3-MA given curcumin 500 mg/kg per day intragastrically and 3-MA 2 mg/kg per day intraperitoneally. The interventions in each group were given for 8 continuous weeks. The biochemical parameters including serum alanine aminotransferase, aspartate aminotransferase, total triglyceride, total cholesterol, fasting blood glucose level were measured in rats. Oil red 0 staining was used to characterize the change of hepatic pathology. The ultrastructure of mitochondria was examined by transmission electron microscopy. The hepatic malondialdehyde level and superoxide dismutase activity were measured by thiobarbituric acid method and xanthine oxidase method, respectively. Western blot assay was performed to detect the expression level of autophagic molecular signals including P62, Beclin, LC3B and nuclear factor-κB. The experimental protocol was approved by the Animal Ethic Committee of Renmin Hospital of Wuhan University (approval No. 2018-541). RESULTS AND CONCLUSION: The serum alanine aminotransferase, aspartate aminotransferase, total triglyceride, and total cholesterol levels were significantly higher in the model group than the control group (P < 0.05). Compared with the model group, curcumin significantly decreased the levels of serum alanine aminotransferase, aspartate aminotransferase, total triglyceride, and total cholesterol (P < 0.05), but this effect was partly inhibited by 3-MA (P < 0.05). There was more cellular lipid deposition in the model group than the control group. Compared with the model group, curcumin significantly decreased cellular lipid deposition, but the decrease was partly inhibited by 3-MA. Compared with the control group, mitochondrial edema and cristae rupture (or even completely disappearing) were easily found in the model group. Curcumin significantly attenuated mitochondrial injury, which was partly inhibited by 3-MA. Hepatic superoxide dismutase activity in the model group was significantly lower than that in control group, and it significantly increased after curcumin treatment. The hepatic superoxide dismutase activity in the curcumin+3-MA group was higher than that in model group but lower than that in the curcumin group. Hepatic malondialdehyde level in the model group was higher than that in the control group, and it significantly decreased after curcumin treatment. Whereas the hepatic malondialdehydelevel in the curcumin+3-MA group was lower than that in model group but higher than that in the curcumin group. Compared with the control group, the model group showed significantly increased expressions of P62, nuclear factor-κB but decreased expressions of Beclin-1 and LC311/LC31 (all P < 0.05). Curcumin significantly decreased the expressions of P62 and nuclear factor-κB and increased the expressions of Beclin-1 and LC311/LC31; however, these changes were partly inhibited by 3-MA (all P < 0.05). Therefore, curcumin can effectively prevent hepatic steatosis in experimental non-alcoholic fatty liver disease rats by regulating inflammatory reaction and oxidative stress via activation of autophagy. [ABSTRACT FROM AUTHOR]

Ulcerative colitis (UC), a major type of inflammatory bowel disease, is also a chronic non-specific intestinal inflammation condition of unknown etiology. The pathogenesis of UC is closely associated with immune abnormalities, inflammatory damage and genetics. The present study aimed to explore the effects of microRNA (miR)-21-5p on the interleukin-6 (IL-6) receptor (IL6R)/signal transducer and activator of transcription (STAT3) signal pathway in UC, in order to identify a highly effective treatment for UC. A total of 45 patients with UC and 45 healthy controls were recruited for the present study. The expression levels of miR-21-5p and STAT3 in the sera of patients with UC and healthy controls were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). A UC rat model was established using dextran sulfate sodium. Following lipopolysaccharide (LPS) treatment, RAW264.7 cells were transfected with a miR-21-5p inhibitor. The levels of morphological damage and apoptosis of the colonic mucosal epithelial tissue were investigated using hematoxylin and eosin staining and a TUNEL staining assay, and then the colon macroscopic damage index and disease activity index were measured in rats. Western blot analysis was used to detect the protein expression levels of IL6R, STAT3, intracellular adhesion molecule 1 (ICAM-1), NF-κB, cleaved caspase-3, cleaved caspase-9 and Fas ligand (FasL). RT-qPCR detected the mRNA expression levels of miR-21-5p, IL6R, STAT3, ICAM-1, NF-κB, caspase-3, caspase-9 and FasL. An ELISA was performed to measure the levels of inflammatory cytokines. The viability and apoptosis levels of RAW264.7 cells were examined using MTT and flow cytometry assays. Additionally, STAT3 was investigated as a direct target of miR-21-5p in RAW264.7 cells using a dual-luciferase reporter assay. The results of the present study demonstrated that inflammation and apoptotic markers were revealed to be significantly downregulated following transfection with miR-21-5p inhibitors in RAW264.7 cells induced by LPS, and that cell viability was increased. Furthermore, STAT3 was confirmed to be a target of miR-21-5p in RAW264.7 cells. Collectively, these data demonstrated that miR-21-5p inhibition mediated the IL-6/STAT3 pathway in UC rats to decrease the levels of inflammation and apoptosis in RAW264.7 cells, and suggested that miR-21-5p may be an important therapy target in human UC. [ABSTRACT FROM AUTHOR]

Colon cancer is one of the most commonly diagnosed and deadly cancers worldwide. Further understanding of the biological mechanisms is important for exploring the molecular biomarkers and therapeutic targets of this disease. Dysregulation of long non-coding RNAs (lncRNAs) has been reported to be associated with the development and progression of various cancers. XIAP-AS1 is a novel lncRNA, which can regulate apoptosis in gastric cancer cells. However, the role of XIAP-AS1 in colorectal cancer (CRC) remains unclear. In this study, we found that XIAP-AS1 expression was significantly increased in CRC tissues and its expression showed a positive correlation with TNM stage and cumulative survival rate of CRC. To investigate whether XIAP-AS1 regulates the progression of CRC, we knocked down its expression in several CRC cell lines. CCK-8 assays showed that XIAP-AS1 knockdown remarkably suppressed CRC cell growth and arrested the cell cycle at the G0/G1 phase (flow cytometric analysis). Furthermore, XIAP-AS1 knockdown also remarkably blocked cell invasion of colon cancer cells by regulating the expression of EMT markers, such as E-cadherin, ZO-1, vimentin, and N-cadherin. Importantly, we found that XIAP-AS1 knockdown significantly reduced STAT3 phosphorylation. Overall, this study suggests that lncRNA XIAP-AS1 might serve as a potential oncogene for colon cancer. [ABSTRACT FROM AUTHOR]