| ObjectivesEmerging evidences have implied obesity as an independent risk factor for various types of cancer,since type 2 diabetes(T2D)is closely related to obesity,it is capable of favoring a suitable environment for tumor formation,progression and metastasis in several ways.Abnormality in endothelins(ETs)is a complication of both obesity and T2D,which leads to endothelial dysfunction(ED),causing vascular lesions,cardiovascular diseases and end-organ damages.Meanwhile,disrupted ET axis effects numerous signaling pathways that are involved in the occurrence and development of cancer,and ET-1 is the most clinically relevant.DNA damage can cause canceration,with its levels reflecting a potential risk of developing cancer.Bariatric surgeries provide significant remission for both obesity and T2D,among which sleeve gastrectomy(SG)has become the most performed procedure around the globe due to its simpler technique and fewer postoperative complications.Many clinical studies have shown that bariatric surgeries have an anti-cancer effect,but basic research about its specific mechanisms is still scarce.Therefore,by performing SG on Wistar rat model of obesity and T2D induced by high-fat diet(HFD)and intraperitoneal injection of streptozotocin(STZ),as well as assessing the transcriptional and translational alterations of ET-1 axis and quantifying DNA damage in lungs of these animal,an attempt was made to explore the effect of SG on ET-1 axis and DNA damage thereby elucidating the mechanism of SG in lowering the risk of lung cancer.Materials and MethodsAge-matched animals were randomly divided into 3 groups:one is the healthy Controls(C)that were fed with standard diet without taking any intervention,while the other two was given HFD and had i.p.injection of STZ to induce obesity and T2D,then sham(SH)surgeries and SGs(SG)were performed on those with fasting blood glucose(FBG)≥11.1mmol/L.Body weight,food intake,and FBG were measured before and at the 1st,2nd,4th,6th,8th,10th and 12th week after the surgery.Oral Glucose Tolerance Test(OGTT)was performed before and at the 4th,8th and 12th week after the surgery with its values being calculated by the area under the curve(AUC).Monthly after the operation,5 rats of each group were randomly euthanatized following the collection of serum and lungs were sampled and either stored under-80℃ or made into paraffin sections.Fasting serum insulin(FINS)were tested using enzyme-linked immunosorbent assay(ELISA)to measure the insulin resistance using formula:Homa-IR=FBG*FINS/22.5;Frozen lung samples were analyzed by polymerase chain reaction(PCR)and western blot(WB)to assess the expression of genes and proteins of ET-1 axis,and the sectioned lung samples were analyzed by immunohistochemistry using γ-H2AX as a marker of double-strand break(DSB)in cell nucleus which were further semi-quantified to evaluate the level of DNA damage to make a comparison on the risk of developing lung cancer among groups.ResultsA total of 15 rats in each group were included to the statistical analysis.Compared to SH group,the body weight,food intake,FBG,oral glucose tolerance and insulin sensitivity of SG group were significantly improved.In addition,the expression of genes and proteins of ET-1 axis in lungs of SG rats was normalized,along with the declined DNA damage level indicating a lower risk of developing lung cancer.ConclusionApart from reducing body weight and improving glycometabolism,SG reduces DNA damage in lungs of obese and diabetic rats.Besides,it also improves endothelial function and lowers the risk of lung cancer by ameliorating ET-1 axis. |
PDF Full Text Request