Bile acids inhibit ferroptosis sensitivity through activating farnesoid X receptor in gastric cancer cells

BACKGROUND Gastric cancer(GC)is associated with high mortality rates.Bile acids(BAs)reflux is a well-known risk factor for GC,but the specific mechanism remains unclear.During GC development in both humans and animals,BAs serve as signaling molecules that induce metabolic reprogramming.This confers additional cancer phenotypes,including ferroptosis sensitivity.Ferroptosis is a novel mode of cell death characterized by lipid peroxidation that contributes universally to malignant progression.However,it is not fully defined if BAs can influence GC progression by modulating ferroptosis.AIM To reveal the mechanism of BAs regulation in ferroptosis of GC cells.METHODS In this study,we treated GC cells with various stimuli and evaluated the effect of BAs on the sensitivity to ferroptosis.We used gain and loss of function assays to examine the impacts of farnesoid X receptor(FXR)and BTB and CNC homology 1(BACH1)overexpression and knockdown to obtain further insights into the molecular mechanism involved.RESULTS Our data suggested that BAs could reverse erastin-induced ferroptosis in GC cells.This effect correlated with increased glutathione(GSH)concentrations,a reduced GSH to oxidized GSH ratio,and higher GSH peroxidase 4(GPX4)expression levels.Subsequently,we confirmed that BAs exerted these effects by activating FXR,which markedly increased the expression of GSH synthetase and GPX4.Notably,BACH1 was detected as an essential intermediate molecule in the promotion of GSH synthesis by BAs and FXR.Finally,our results suggested that FXR could significantly promote GC cell proliferation,which may be closely related to its anti-ferroptosis effect.CONCLUSION This study revealed for the first time that BAs could inhibit ferroptosis sensitivity through the FXR-BACH1-GSHGPX4 axis in GC cells.This work provided new insights into the mechanism associated with BA-mediated promotion of GC and may help identify potential therapeutic targets for GC patients with BAs reflux.

Novel subtype of obesity influencing the outcomes of sleeve gastrectomy:Familial aggregation of obesity

BACKGROUND Differences in the preoperative characteristics and weight loss outcomes after sleeve gastrectomy(SG)between patients with familial aggregation of obesity(FAO)and patients with sporadic obesity(SO)have not been elucidated.AIM To explore the impact of SG on weight loss and the alleviation of obesity-related comorbidities in individuals with FAO.METHODS A total of 193 patients with obesity who underwent SG were selected.Patients with FAO/SO were matched 1:1 by propensity score matching and were categorized into 4 groups based on the number of first-degree relatives with obesity(1 SO vs 1FAO,2SO vs 2FAO).The baseline characteristics,weight loss outcomes,prevalence of obesity-related comorbidities and incidence of major surgeryrelated complications were compared between groups.RESULTS We defined FAO as the presence of two or more first-degree relatives with obesity.Patients with FAO did not initially show significant differences in baseline data,short-term postoperative weight loss,or obesity-related comorbidities when compared to patients with SO preoperatively.However,distinctions between the two groups became evident at the two-year mark,with statistically significant differences in both percentage of total weight loss(P=0.006)and percentage of excess weight loss(P<0.001).The FAO group exhibited weaker remission of type 2 diabetes mellitus(T2DM)(P=0.031),hyperlipidemia(P=0.012),and non-alcoholic fatty liver disease(NAFLD)(P=0.003)as well as a lower incidence of acid reflux(P=0.038).CONCLUSION FAO patients is associated with decreased mid-to-long-term weight loss outcomes;the alleviation of T2DM,hyperlipidemia and NAFLD;and decreased incidence of acid reflux postoperatively.

Alterations in gut microbiota during remission and recurrence of diabetes after duodenal-jejunal bypass in rats

AIM: To observe the alterations in gut microbiota in high-fat diet(HFD)-induced diabetes recurrence after duodenal-jejunal bypass(DJB) in rats. METHODS: We assigned HDF- and low-dose streptozotocin-induced diabetic rats into two major groups to receive DJB and sham operation respectively. When the DJB was completed, we used HFD to induce diabetes recurrence. Then, we grouped the DJB-operated rats by blood glucose level into the DJB-remission(DJB-RM) group and the DJB-recurrence(DJB-RC) group. At a sequence of time points after operations, we compared calorie content in the food intake(calorie intake), oral glucose tolerance test, homeostasis model assessment of insulin resistance(HOMA-IR), concentrations of glucagon-like peptide 1(GLP-1), serum insulin, total bile acids(TBAs) and lipopolysaccharide(LPS) and alterations in colonic microbiota.RESULTS: The relative abundance of Firmicutes in the control(58.06% ± 11.12%; P < 0.05 vs sham; P < 0.05 vs DJB-RC) and DJB-RM(55.58% ± 6.16%; P < 0.05 vs sham; P < 0.05 vs DJB-RC) groups was higher than that in the sham(29.04% ± 1.36%) and DJB-RC(27.44% ± 2.17%) groups; but the relative abundance of Bacteroidetes was lower(control group: 33.46% ± 10.52%, P < 0.05 vs sham 46.88% ± 2.34%, P < 0.05 vs DJB-RC 47.41% ± 5.67%. DJB-RM group: 34.63% ± 3.37%, P < 0.05 vs sham; P < 0.05 vs DJB-RC). Escherichia coli was higher in the sham(15.72% ± 1.67%, P < 0.05 vs control, P < 0.05 vs DJB-RM) and DJB-RC(16.42% ± 3.00%; P < 0.05 vs control; P < 0.05 vs DJB-RM) groups than in the control(3.58% ± 3.67%) and DJB-RM(4.15% ± 2.76%) groups. Improved HOMA-IR(2.82 ± 0.73, P < 0.05 vs DJB-RC 4.23 ± 0.72), increased TBAs(27803.17 ± 4673.42 ng/m L; P < 0.05 vs DJB-RC 18744.00 ± 3047.26 ng/m L) and decreased LPS(0.12 ± 0.04 ng/m L, P < 0.05 vs DJBRC 0.19 ± 0.03 ng/m L) were observed the in DJB-RM group; however, these improvements were reversed in the DJB-RC group, with the exception of GLP-1(DJB-RM vs DJB-RC P > 0.05). CONCLUSION: Alterations in gut microbiota may be responsible for the diabetes remission and recurrence after DJB, possibly by influencing serum LPS and TBAs.

Effects of sleeve gastrectomy with jejuno-jejunal or jejuno-ileal loop on glycolipid metabolism in diabetic rats

AIM To explore the effect of sleeve gastrectomy(SG) with jejuno-jejunal or jejuno-ileal loop on glycolipid metabolism in diabetic rats.METHODS Diabetic rats, which were induced by high-fat diet(HFD), nicotinamide and low-dose streptozotocin, underwent sham operations, SG, SG with jejuno-ileal loop(SG-JI) and SG with jejuno-jejunal loop(SG-JJ) followed by postoperative HFD. Then, at the time points of baseline and 2, 12 and 24 wk postoperatively, we determined and compared several variables, including the area under the curve for the results of oral glucose tolerance test(AUCOGTT), serum levels of triglyceride, cholesterol and ghrelin in fasting state, homeostasis model assessment of insulin resistance(HOMA-IR), body weight, calorie intake, glucagon-like peptide(GLP)-1 and insulin secretions after glucose gavage at dose of 1 g/kg.RESULTS At 2 wk postoperatively, rats that underwent SG, SGJJ and SG-JI, compared with sham-operated(SHAM)rats, demonstrated lower body weight, calorie intake and ghrelin(P < 0.05 vs SHAM), enhanced secretion of insulin and GLP-1 after glucose gavage(P < 0.05 vs SHAM), improved AUCOGTT, HOMA-IR, fasting serum triglyceride and cholesterol(AUCOGTT: 1616.9 ± 83.2, 837.4 ± 83.7, 874.9 ± 97.2 and 812.6 ± 81.9, P < 0.05 vs SHAM; HOMA-IR: 4.31 ± 0.54, 2.94 ± 0.22, 3.17 ± 0.37 and 3.41 ± 0.22, P < 0.05 vs SHAM; Triglyceride: 2.35 ± 0.17, 1.87 ± 0.23, 1.98 ± 0.30 and 2.04 ± 0.21 mmol/L, P < 0.05 vs SHAM; Cholesterol: 1.84 ± 0.21, 1.53 ± 0.20, 1.52 ± 0.20 and 1.46 ± 0.23 mmol/L). At 12 wk postoperatively, rats receiving SG-JJ and SG-JI had lower body weight, reduced levels of triglyceride and cholesterol and elevated level of GLP-1 compared to those receiving SG(P < 0.05 vs SG). At 24 wk after surgery, compared with SG, the advantage of SG-JJ and SG-JI for glucolipid metabolism was still evident(P < 0.05 vs SG). SG-JI had a better performance in lipid metabolism and GLP-1 secretion of rats than did SG-JJ.CONCLUSION SG combined with intestinal loop induces better glycolipid metabolism than simple SG, with the lipid metabolism being more improved with SG-JI compared to SG-JJ.

Diabetes recurrence after metabolic surgeries correlates with re-impaired insulin sensitivity rather than beta-cell function

AIM To investigate factors causing diabetes recurrence after sleeve gastrectomy(SG)and duodenal-jejunal bypass(DJB).METHODS SG and DJB were performed on rats with diabetes induced by high-fat diet(HFD)and streptozotocin(STZ).HFD was used to induce diabetes recurrence at 4 wk postoperatively.Body weight,oral glucose tolerance test,homeostatic model assessment of insulin resistance(HOMA-IR),insulin signaling[IR,insulin receptor substrate(IRS 1,IRS2,phosphatidylinositol3-kinase and AKT in liver and skeletal muscle],oral glucose stimulated insulin secretion,beta-cell morphology(mass,apoptosis and insulin secretion),glucagon-like peptide(GLP)-1,PYY and ghrelin were compared among SG rats with common low-fat diet(SG-LFD),SG with HFD(SG-HFD),DJB rats with LFD(DJB-LFD),DJB with HFD(DJB-HFD)and shamoperation with LFD(Sham)at targeted postoperative times.RESULTS SG and DJB resulted in significant improvement in glucose tolerance,lower HOMA-IR,up-regulated hepatic and muscular insulin signaling,higher levels of oral glucose-stimulated insulin secretion,bigger betacell mass,higher immunofluorescence intensity of insulin,fewer transferase-mediated d UTP-biotin 3’nick end-labeling(TUNEL)-positive beta cells and higher postprandial GLP-1 and PYY levels than in the Sham group.The improvement in glucose tolerance was reversed at 12 wk postoperatively.Compared with the SG-LFD and DJB-LFD groups,the SG-HFD and DJB-HFD groups showed higher HOMA-IR,down-regulated hepatic and muscular insulin signaling,and more TUNEL-positive beta cells.No significant difference was detected between HFD and LFD groups for body weight,glucose-stimulated insulin secretion,betacell mass,immunofluorescence intensity of insulin,and postprandial GLP-1 and PYY levels.Fasting serum ghrelin decreased in SG groups,and there was no difference between HFD-SG and LFD-SG groups.CONCLUSION HFD reverses the improvement in glucose homeostasis after SG and DJB.Diabetes recurrence may correlate with re-impaired insulin sensitivity,but not with alterations of beta-cell function and body weight.

Effects of sleeve gastrectomy plus trunk vagotomy compared with sleeve gastrectomy on glucose metabolism in diabetic rats

AIM To investigate the effects of sleeve gastrectomy plus trunk vagotomy(SGTV) compared with sleeve gastrectomy(SG) in a diabetic rat model.METHODS SGTV, SG, TV and Sham operations were performed on rats with diabetes induced by high-fat diet and streptozotocin. Body weight, food intake, oral glucose tolerance test, homeostasis model assessment of insulin resistance(HOMA-IR), hepatic insulin signaling(IR, IRS1, IRS2, PI3 K and AKT), oral glucose stimulatedinsulin secretion, GLP-1 and ghrelin were compared at various postoperative times.RESULTS Both SG and SGTV resulted in better glucose tolerance, lower HOMA-IR, up-regulated hepatic insulin signaling, higher levels of oral glucose-stimulated insulin secretion, higher postprandial GLP-1 and lower fasting ghrelin levels than the TV and Sham groups. No significant differences were observed between the SG and SGTV groups. In addition, no significant differences were found between the TV and Sham groups in terms of glucose tolerance, HOMA-IR, hepatic insulin signaling, oral glucose-stimulated insulin secretion, postprandial GLP-1 and fasting ghrelin levels. No differences in body weight and food intake were noted between the four groups.CONCLUSION SGTV is feasible for diabetes control and is independent of weight loss. However, SGTV did not result in a better improvement in diabetes than SG alone.

Sleeve gastrectomy ameliorates endothelial function and prevents lung cancer by normalizing endothelin-1 axis in obese and diabetic rats

BACKGROUND Previous evidence has implied that obesity is an independent risk factor for developing cancer.Being closely related to obesity,type 2 diabetes mellitus provides a suitable environment for the formation and metastasis of tumors through multiple pathways.Although bariatric surgeries are effective in preventing and lowering the risk of various types of cancer,the underlying mechanisms of this effect are not clearly elucidated.AIM To uncover the role and effect of sleeve gastrectomy(SG)in preventing lung cancer in obese and diabetic rats.METHODS SG was performed on obese and diabetic Wistar rats,and the postoperative transcriptional and translational alterations of the endothelin-1(ET-1)axis in the lungs were compared to sham-operated obese and diabetic rats and age-matched healthy controls to assess the improvements in endothelial function and risk of developing lung cancer at the postoperative 4 th,8 th,and 12 th weeks.The risk wasalso evaluated using nuclear phosphorylation of H2 A histone family member X as a marker of DNA damage(double-strand break).RESULTS Compared to obese and diabetic sham-operated rats,SG brought a significant reduction to body weight,food intake,and fasting blood glucose while improving oral glucose tolerance and insulin sensitivity.In addition,ameliorated levels of gene and protein expression in the ET-1 axis as well as reduced DNA damage indicated improved endothelial function and a lower risk of developing lung cancer after the surgery.CONCLUSION Apart from eliminating metabolic disorders,SG improves endothelial function and plays a protective role in preventing lung cancer via normalized ET-1 axis and reduced DNA damage.

Effect of oligofructose on resistance to postoperative high-fat diet-induced damage of metabolism in diabetic rats after sleeve gastrectomy

BACKGROUND Sleeve gastrectomy(SG) can induce prominent remission of type 2 diabetes mellitus.However,the long-term remission rate of diabetes usually decreases over time.Oligofructose has been verified to modulate host metabolism.The aim of this study was to explore the protective effect of oligofructose on high-fat diet(HFD)-induced metabolic dysfunction after SG.AIM To study the effect and mechanism of oligofructose on diabetic remission in diabetic rats after SG.METHODS SG and SHAM operation were performed on diabetes rats induced with an HFD,nicotinamide,and low-dose streptozotocin.Then the rats in the SHAM and SG groups were continuously provided with the HFD,and the rats in sleeve gastrectomy-oligofructose group were provided with a specific HFD containing10% oligofructose.Body weight,calorie intake,oral glucose tolerance test,homeostasis model assessment of insulin resistance,lipid profile,serum insulin,glucagon-like peptide 1(GLP-1),total bile acids,lipopolysaccharide(LPS),and colonic microbiota levels were determined and compared at the designated time points.All statistical analyses were performed using Statistic Package for Social Science version 19.0(IBM,United States),and the statistically significant difference was considered at P <0.05.RESULTS At 2 wk after surgery,rats that underwent SG exhibited improved indexes of glucose and lipid metabolism.Compared with the SG group,the rats from SGoligofructose group exhibited better parameters of glucose and lipid metabolism,lower body weight(526.86±21.51 vs 469.25±21.84,P <0.001),calorie intake(152.14±9.48 vs 129.63±8.99,P <0.001),homeostasis model assessment of insulin resistance(4.32±0.57 vs 3.46±0.52,P <0.05),and LPS levels(0.19±0.01 vs 0.16±0.01,P <0.05),and higher levels of insulin(1.17±0.17 vs 1.58±0.16,P <0.001) and GLP-1(12.39±1.67 vs 14.94±1.86,P <0.001),and relative abundances of Bifidobacterium(0.0034±0.0014 vs 0.0343±0.0064,P <0.001),Lactobacillus(0.0161±0.0037 vs 0.0357±0.0047,P <0.001),and Akkermansia muciniphila(0.0050±0.0024 vs 0.0507±0.0100,P <0.001) at the end of the study.However,no difference in total bile acids levels was observed between the two groups.CONCLUSION Oligofructose partially prevents HFD-induced glucose and lipid metabolism damage after SG,which may be due to the changes of calorie intake,insulin,GLP-1,LPS,and the gut microbiota in rats.