Hypoxia-inducible factor 1α inhibits heat stress-induced pig intestinal epithelial cell apoptosis through eif2α/ATF4/CHOP signaling.

Unstoppable global warming and increased frequency of extreme heat leads to human and animals easier to suffer from heat stress (HS), with gastrointestinal abnormalities as one of the initial clinical symptoms. HS induces intestinal mucosal damage owing to intestinal hypoxia and hyperthermia. Hypoxia-inducible factor 1α (HIF-1α) activates numerous genes to mediate cell hypoxic responses; however, its role in HS-treated intestinal mucosa is unknown. This work aimed to explore HIF-1α function and regulatory mechanisms in HS-treated pig intestines. We assigned 10 pigs to control and moderate HS groups. Physical signs, stress, and antioxidant levels were detected, and the intestines were harvested after 72 h of HS treatment to study histological changes and HIF-1α, heat shock protein 90 (HSP90), and prolyl-4-hydroxylase 2 (PHD-2) expression. In addition, porcine intestinal columnar epithelial cells (IPEC-J2) underwent HS treatment (42 °C, 5 % O2) to further explore the functions and regulatory mechanism of HIF-1α. The results of histological examination revealed HS caused intestinal villi damage and increased apoptotic epithelial cell; the expression of HIF-1α and HSP90 increased while PHD-2 showed and opposite trend. Transcriptome sequencing analysis revealed that HS activated HIF-1 signaling. To further explore the role of HIF-1α on HS induced IPEC-J2 apoptosis, the HIF-1α was interfered and overexpression respectively, and the result confirmed that HIF-1α could inhibited cell apoptosis under HS. Furthermore, HS-induced apoptosis depends on eukaryotic initiation factor 2 alpha (eif2α)/activating transcription factor 4 (ATF4)/CCAAT-enhancer-binding protein homologous protein (CHOP) pathway, and HIF-1α can inhibit this pathway to alleviate IPEC-J2 cell apoptosis. In conclusion, this study suggests that HS can promote intestinal epithelial cell apoptosis and cause pig intestinal mucosal barrier damage; the HIF-1α can alleviate cell apoptosis by inhibiting eif2α/ATF4/CHOP signaling. These results indicate that HIF-1α plays a protective role in HS, and offers a potential target for HS prevention and mitigation.

Meta-analysis: Efficacy and safety of fibroblast growth factor 21 analogues for the treatment of non-alcoholic steatohepatitis and non-alcoholic steatohepatitis-related fibrosis.

BACKGROUND: Fibroblast growth factor 21 (FGF21) analogues have emerged as promising therapeutic targets for non-alcoholic steatohepatitis (NASH). However, the effects and safety of these analogues on NASH and NASH-related fibrosis remain unexplored. AIMS: To estimate the efficacy and safety of FGF21 analogues for treating NASH and NASH-related fibrosis. METHODS: PubMed, Embase, and the Cochrane Library were searched for relevant studies up to 11 October 2023. Primary outcomes were defined as the fibrosis improvement ≥1 stage without worsening of NASH and NASH resolution without worsening fibrosis. Secondary outcomes included biomarkers of fibrosis, liver injury, and metabolism. Treatment-related adverse events were also analysed. RESULTS: Nine studies, including 1054 patients with biopsy-proven NASH and stage F1-F4 fibrosis, were identified. Seven studies reported histological outcomes. The relative risk (RR) for obtaining fibrosis improvement ≥1 stage efficacy was 1.79 (95% CI 1.29-2.48, I2 = 37%, p < 0.001) with FGF21 analogues relative to placebo. Although no statistically significant difference was observed between FGF21 analogues in NASH resolution, sensitivity analyses and fragility index suggest that this result is unstable. The drugs improved hepatic fat fraction (HFF), along with other biomarkers of fibrosis, liver injury, and metabolism (MRE, LSM, Pro-C3, ELF, ALT, AST, TG, HDL-C, and LDL-C). Additionally, no significant difference in serious adverse event incidence rate was observed (RR = 1.26, 95% CI 0.82-1.94, I2 = 24%, p = 0.3). CONCLUSIONS: FGF21 analogues appear as promising agents for the treatment of NASH and NASH-related fibrosis, and they generally seem to be safe and well tolerated.

MC4R deficiency in pigs results in hyperphagia and ultimately hepatic steatosis without high-fat diet.

Melanocortin 4 receptor (MC4R)-deficient mice had been used for several years to study human nonalcoholic steatohepatitis (NASH). However, although liver pathologic and biochemical indicators have been examined, mice models do not always faithfully display the phenotype of the human disease. In this study, we investigated the MC4R knockout phenotype in miniature pigs. We found that pigs lacking MC4R exhibited hyperorexia, insulin resistance, hyperinsulinemia, disordered lipid metabolism and their livers accumulated significant amounts of fat. We have shown that deletion of MC4R results in hyperphagia and increased body fat, ultimately leading to hepatic steatosis without atherogenic diet.

Diet and gastric cancer: a casecontrol study in Fujian Province, China.

AIM:To explore the relationship between consumption of fish sauce, other dietary factors, living habits and the rish kf gastric cancer.METHODS:From May 1994 to July 1995, a population-based 1 2 case-control study was in Carried out inhigh-risk areas of gastric cancer, Changle and Fuqing cities, Fujian Province. Totally 272 cases and 544 age, gender-matched controls were included. Risk state analyses were made by ASRS package.RESULTS:Risk state single-factor analysis indicated that gastric cancer risk rose with high intake of fish sauce(OR =2.57), salted vegetables (OR =1.41), salted/fried fish and small shrimps (OR =1.57), low consumption of fresh vegetables (OR =1.95), fresh citrus fruits (OR =1.41), other fresh fruits (OR =1.31), green tea (OR =1.72), exposure to moldy foods (OR =2.32), irregular dinners (OR =5.47) and familial history of malignancy (OR =3.27).No significant relationship was observed between smoking, drinking, salt intake, use of refrigerator and gastric cancer rish. The results of rish state conditional Logistic regression showed that fish sauce, salted/dried fish and small shrimps, irregular dinners, familial history of malignancy were included in the best rish set. The summary ARS for the four factors was 75.49%.CONCLUSION:High intake of fish sauce, salted foods, moldy foods, irregular dinners and familial history of malignancy were possible risk factors for gastric cancer, whereas fresh vegetables and fruits.and green tea might have protective effects for gastric cancer.