Endothelium Piezo1 deletion alleviates experimental varicose veins by attenuating perivenous inflammation.

Previous large-scale genetic studies have prioritized the causal genes piezo type mechanosensitive ion channel component 1 (PIEZO1) and castor zinc finger 1 (CASZ1) associated with varicose veins (VVs). This study aims to evaluate their roles in both clinical and experimental VVs. In this study, we investigated abundance of PIEZO1 and CASZ1 in both varicose and normal veins from the same patients. Yoda1 (a selective PIEZO1 agonist, 2.6 mg/kg/day) or vehicle was administered intraperitoneally for 3 weeks to evaluate the effect of PIEZO1 activation on experimental VVs. Subsequently, endothelial Piezo1 deletion mice (Piezo1iΔEC mice) were generated to explored the role of endothelial PIEZO1 on VVs. Laser speckle imaging, flow cytometry, cell tracing with Evans blue or rhodamine-6G, and histopathological staining were utilized to evaluate the pathophysiology of VVs. Our results showed that mRNA expression of PIEZO1, but not CASZ1, was abundant and increased in clinical VVs. The Piezo1tP1-td mice revealed endothelium-specific expression of PIEZO1 in mice veins. By establishing iliac vein ligation-induced VVs in mice, Yoda1 exacerbated experimental VVs with increased inflammatory cell infiltration. Subsequently, endothelial Piezo1 deletion (Piezo1iΔEC mice) alleviated experimental VVs and vascular remodeling by directly reducing vascular permeability and leukocyte-endothelium interactions compared to the control (Piezo1fl/fl mice). PIEZO1 is highly expressed in clinical VVs, meanwhile, activation or inhibition of PIEZO1 exerts a remarkable effect on experimental VVs. Furthermore, Piezo1 may constitute a potential therapeutic approach for the medical treatment of VVs.

PI3Kγ promotes neutrophil extracellular trap formation by noncanonical pyroptosis in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is one of the most life-threatening cardiovascular diseases; however, effective drug treatments are still lacking. The formation of neutrophil extracellular traps (NETs) has been shown to be a crucial trigger of AAA, and identifying upstream regulatory targets is thus key to discovering therapeutic agents for AAA. We revealed that phosphoinositide-3-kinase γ (PI3Kγ) acted as an upstream regulatory molecule and that PI3Kγ inhibition reduced NET formation and aortic wall inflammation, thereby markedly ameliorating AAA. However, the mechanism of NET formation regulated by PI3Kγ remains unclear. In this study, we showed that PI3Kγ deficiency inactivated the noncanonical pyroptosis pathway, which suppressed downstream NET formation. In addition, PI3Kγ regulation of noncanonical pyroptosis was dependent on cyclic AMP/protein kinase A signaling. These results clarify the molecular mechanism and crosstalk between PI3Kγ and NETosis in the development of AAA, potentially facilitating the discovery of therapeutic options for AAA.

Central GLP-1 contributes to improved cognitive function and brain glucose uptake after duodenum-jejunum bypass on obese and diabetic rats.

The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB), and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (Glp-1r) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including glucose transporter 1 (GLUT-1), GLUT-4, phospho-Akt substrate of 160kDa (pAS160), AS160, Rab10, Myosin-Va as well as the c-fos marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups whereas the Exe-9 and Glp-1r KD were opposite. Known to activate insulin-signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.NEW & NOTEWORTHY The improvement of cognitive function following bariatric surgery has been highlighted while its mechanisms remain elusive. The brain glucose uptake of patients was improved after RYGB, and the DJB and sham surgery performed on obese and diabetic Wistar rats revealed that the elevated central GLP-1 contributes to the dramatic improvement of cognitive function, brain glucose uptake, transport, glucose sensing, and neuronal activation.

Downregulation of circular RNA circDOCK7 identified from diabetic rats after sleeve gastrectomy contributes to hepatocyte apoptosis through regulating miR-139-3p and MCM3.

Sleeve gastrectomy (SG) is the most widely used bariatric procedures globally, which could improve glucose and lipid metabolism dramatically. Circular RNAs (circRNAs) are being increasingly implicated in numerous pathophysiological processes. However, for diabetes mellitus (DM), the expression and function of circRNAs remain largely undetermined, in particular, whether circRNAs mediate the amelioration of DM observed after SG. Using a diabetic rat model, we subjected liver tissue from SG and sham-operated rats to RNA sequencing. Amongst the 103 differentially regulated circRNAs identified in diabetic rats after SG, we focused on circDOCK7, a highly expressed circRNA derived from the back-splicing of the DOCK7 gene. Silencing of circDOCK7 significantly inhibited cellular proliferation and induction of apoptosis in insulin-resistant rat hepatocytes. Further analysis indicated circDOCK7 harbored binding sites for miR-139-3p and regulated the expression of minichromosome maintenance 3 (MCM3) through sequestration of miR-139-3p. Our findings therefore demonstrate a novel regulatory pathway involving circDOCK7 that regulates cellular proliferation and apoptosis through increasing the expression of MCM3. Overall, our study establishes a list of specific circRNAs expressed in diabetic rat liver after SG including circDOCK7 which serve as potential biomarkers and treatment targets for DM patients.

Sleeve Gastrectomy Ameliorates Diabetes-Related Spleen Damage by Improving Oxidative Stress Status in Diabetic Obese Rats.

PURPOSE: Oxidative stress and inflammation are important pathogenic mediators in diabetes-related organ damage. Accumulating evidence suggests that immunodeficiency in diabetes is associated with diabetes-induced spleen damage. Sleeve gastrectomy (SG) has been proved to improve diabetes and its multiple associated complications. However, the ameliorative role of SG against spleen damage in diabetes has not been investigated. MATERIALS AND METHODS: Animal model of diabetic obese rats induced by high-fat diet (HFD) combined with streptozotocin (STZ) was treated with sham operation, caloric restriction, and SG. Metabolic parameters were measured, and the morphological and histopathological changes, status of oxidative stress, and levels of inflammatory factors were evaluated. RESULTS: SG reduced body weight and improved glucose tolerance and insulin sensitivity in diabetic obese rats. SG significantly reversed splenic atrophy and alleviated abnormalities of white and red pulp. Additionally, SG also reversed the increased splenocyte apoptosis (P < 0.001). Meanwhile, indicators of oxidative stress including reactive oxygen species (ROS), nitric oxide (NO), malondialdehyde (MDA), and protein carbonylation were reduced, and the activity and expression of antioxidant enzymes including SOD and CAT were improved after SG. The mRNA expression of inflammatory factors in SG groups such as TNF-α (P < 0.001), IL-6 (P < 0.001), MCP-1 (P < 0.01), and ICAM-1 (P < 0.001) was also significantly reduced. CONCLUSION: SG ameliorates diabetes-related splenic injury by restoring the balance between oxidative stress process and antioxidant defense systems as well as reducing inflammation in the spleen. These findings indicate that SG is an appropriate therapeutic strategy for diabetes-related spleen damage.

Cystic Pancreatic Neuroendocrine Tumors Represent a Distinct Clinical Entity with Less Aggressive Biological Behaviors.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) uncommonly present as cystic lesions. There is a gap in knowledge of their clinicopathological characteristics and biological behaviors. Previous reported studies remained inconsistent and controversial. The purpose of this study is to investigate the clinicopathological features of cystic pNET and determine if it represents a distinct clinical entity by comparing its characteristics with those of solid pNETs. METHODS: Patients with pNETs who underwent surgical resections from January 2014 to April 2019 at Qilu Hospital of Shandong University were reviewed retrospectively. Demographics, clinical characteristics, surgical data, and oncological as well as histological characteristics of cystic pNETs and their solid counterparts were collected and analyzed. RESULTS: A total of 122 patients were included in this study, and 10.7% (13/122) patients were cystic. There is no significant difference between cystic pNETs and solid pNETs in age (43.6 ± 15.8 versus 50.9 ± 14.5 y, P = 0.093) and sex distribution (P = 0.085). Cystic pNETs are more likely to be asymptomatic (61.5% versus 23.9%, P = 0.008) and nonfunctional (92.3% versus 52.7%, P = 0.006) than solid pNETs. However, the tumor size (4.8 ± 4.5 versus 2.8 ± 1.9 cm, P = 0.124), proportion of multiple endocrine neoplasia type 1 (92.3% versus 98.2%, P = 0.289), and tumor location (P = 0.154) are similar in both groups. Compared with solid pNETs, cystic pNETs have a lower Ki-67 index and incidence of liver metastasis, but the difference is not significant. CONCLUSIONS: Cystic pNETs are more likely to be nonfunctional and indolent and seem to exhibit less aggressive biological behaviors than solid pNETs. Conservative approach should be considered for certain selected patients.

Sleeve gastrectomy ameliorates alveolar structures and surfactant protein expression in lungs of obese and diabetic rats.

BACKGROUND: Bariatric surgeries have been shown to be effective in reversing damaged pulmonary function in individuals suffering from obesity and type 2 diabetes mellitus, whereas its underlying mechanisms remain largely unknown. METHODS: Sleeve gastrectomy (SG) was performed on obese and diabetic Wistar rats, and their pulmonary function and lung tissues were compared to sham-operated (SH) obese and diabetic rats, and age-matched healthy controls (C) to explore the improvements in microstructures and expression of surfactant protein (SP)-A and -C at postoperative 4th, 8th, and 12th week. RESULT: Apart from the profound metabolic changes and improvement in pulmonary function, lung volume was restored along with an improved diffusion capacity noted by thinned capillary basement membrane and decreased harmonic mean length of diffusion barrier in SG rats. The digital slices of light microscope showed the general changes brought on by the SG, including normalized basic structures, ameliorated inflammatory status, as well as reduced lipid deposition, where the hydroxyproline (HYP), triglyceride (TG) assays, and electron microscope further suggested that the improvement in alveolar structures lies in reduced collagen fibers, lipids and septal tissues, increased capillary blood, and normalized alveolar type 2 (AT2) cells. Besides, disrupted SP-A and SP-C expression were also normalized after SG. CONCLUSION: The improvement of lung function after SG is related to the ameliorated alveolar structures, and surface protein expression induced by weight loss and improved glucose metabolism.

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 4th, 8th, and 12th weeks. The risk was also evaluated using nuclear phosphorylation of H2A 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.

Sleeve Gastrectomy Attenuates Diabetic Nephropathy by Upregulating Nephrin Expressions in Diabetic Obese Rats.

PURPOSE: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and sleeve gastrectomy (SG) is considered to be an effective strategy to improve pre-existing DN. However, the mechanism remains unknown. MATERIALS AND METHODS: Animal model of DN was induced by high-fat diet (HFD) and streptozotocin (STZ). SG or sham surgery was performed and rats were sacrificed at 4, 8, and 12 weeks after surgery. The basic parameters (blood glucose, body weight, kidney weight), indicators of renal function including serum creatinine (Scr), blood urea nitrogen (BUN), urine microalbumin, urine creatinine (Ucr), microalbumin creatinine ratio (UACR), ultrastructural changes of glomerulus, and the expression of nephrin gene and protein in glomerular podocytes were compared among groups. RESULTS: Blood glucose and body weight of SG rats were significantly lower than those of the sham-operated rats, and renal function of SG groups were also significantly improved within the postoperative period of 12 weeks. The results of periodic acid-Schiff staining (PAS) and transmission electron microscopy (TEM) showed that glomerular hypertrophy and accumulation of extracellular matrix proteins were significantly alleviated after SG, and the thickness of basement membrane and the fusion or effacement of foot processes were also significantly improved. The mRNA and protein expression of nephrin in SG groups was significantly higher than that in the sham group. CONCLUSION: These results suggest that SG attenuates DN by upregulating the expression of nephrin and improving the ultrastructure of glomerular filtration membrane. This study indicates that SG can be used as an available therapeutic intervention for DN.