Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells.

BACKGROUND AND PURPOSE: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic ß cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH: Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and ß-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS: Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with ß-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic ß-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.

Early tirofiban versus heparin for bridging dual antiplatelet therapy in patients undergoing coronary endarterectomy combined with coronary artery bypass grafting: a multicenter randomized controlled trial protocol (the THACE-CABG trial).

BACKGROUND: For complete revascularization, patients with diffuse coronary artery disease should have a coronary endarterectomy and a coronary artery bypass graft (CE-CABG). Sadly, CE can lead to a lack of endothelium, which raises the risk of thrombotic events. Even though daily dual antiplatelet therapies (DAPT) have been shown to reduce thrombotic events, the risk of perioperative thrombotic events is high during the high-risk period after CE-CABG, and there is no consistent protocol to bridge DAPT. This trial aims to compare safety and efficacy between tirofiban and heparin as DAPT bridging strategies after CE-CABG. METHODS: In phase I, 266 patients undergoing CE-CABG will be randomly assigned to tirofiban and heparin treatment groups to compare the two treatments in terms of the primary safety endpoint, chest tube drainage in the first 24 h. If the phase I trial shows tirofiban non-inferiority, phase II will commence, in which an additional 464 patients will be randomly assigned. All 730 patients will be studied to compare major cardiovascular and cerebrovascular events (MACCEs) between the groups in the first 30 days after surgery. DISCUSSION: Given the possible benefits of tirofiban administration after CE-CABG, this trial has the potential to advance the field of adult coronary heart surgery. TRIAL REGISTRATION: chictr.org.cn, ChiCTR2200055697. Registered 6 January 2022. https://www.chictr.org.cn/com/25/showproj.aspx?proj=149451 . Current version: 20,220,620.

Functional screening and rational design of compounds targeting GPR132 to treat diabetes.

Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.

Trends and hotspots in familial hypercholesterolemia: A bibliometric systematic review from 2002 to 2022.

BACKGROUND: We visually assessed the research hotspots of familial hypercholesterolemia (FH) using bibliometrics and knowledge mapping in light of the research state and development trend of FH. METHODS: We employed bibliometric tools, such as CiteSpace and the alluvial generator, to illustrate the scientific accomplishments on FH by extracting pertinent literature on FH from the Web of Science Core Collection database from January 1, 2002, to December 31, 2022. RESULTS: A total of 4402 papers in total were selected for study; 29.2% of all articles globally were from the USA, followed by the Netherlands and England. The University of Amsterdam, University of Oslo, and University of Western Australia are the 3 institutions with the most publications in this area. Gerald F. Watts, Raul D. Santos, and John J. P. Kastelein wrote the majority of the pieces that were published. The New England Journal of Medicine, Circulation, and Atherosclerosis were the journals with the greatest number of papers in this field. Prevalence and genetic analysis of FH, proprotein convertase subtilisin/kexin 9 inhibitors, and inclisiran are current research hotspots for the condition. Future research in this area will be focused on gene therapy. CONCLUSIONS: FH research has shown shows a trend of ascending followed by leveling off. The prevalence and diagnosis of FH, proprotein convertase subtilisin/kexin 9 inhibitors, inclisiran, and gene therapy are current research hotspots. This report may serve as a reference for current research trends.

Investigation of the transient heat transfer to a supersonic air jet impinging on a high-temperature plate based on a discrimination-experiment method.

A discrimination-experiment method is developed to investigate the transient heat transfer of air jet impingement by discretizing the solid domain into mutually adiabatic test cylinders. This method can not only reduce the influence of the transverse heat transfer of a solid domain on the heat transfer characteristics of the jet but can also simplify the two-dimensional or three-dimensional heat conduction problem into a one-dimensional problem. Moreover, the discrimination-experiment method eliminates the embedment of thermocouples into the solid domains, further improving the accuracy and reliability of the proposed method. The transient heat transfer characteristics of a supersonic air jet impinging on a high-temperature target (860°C) and the effects of thermo physical parameters, such as the density, specific heat capacity, thermal conductivity and nozzle-to-target distance (H/D = 3, 4, and 5) are analyzed in detail using the discrimination-experiment method. The results provide important guidance for the thermal design of supersonic air jet impingement.

Association Between Triglyceride-Glucose Index and 2-Year Adverse Cardiovascular and Cerebrovascular Events in Patients with Type 2 Diabetes Mellitus Who Underwent Off-Pump Coronary Artery Bypass Grafting.

BACKGROUND: Data on the relationship between the triglyceride glucose (TyG) index and prognosis after off-pump coronary artery bypass grafting (OPCABG) are limited. This retrospective observational cohort study evaluated the association of the TyG index with prognosis in patients with diabetes mellitus who underwent OPCABG. METHODS: The TyG index was calculated using the following equation: TyG index = ln (fasting triglyceride level [mg/dL] × fasting glucose level [mg/dL]/2). The primary outcomes included the occurrence of major adverse cardiovascular and cerebrovascular events (MACCEs), which were defined as all-cause death, nonfatal myocardial infarction, nonfatal stroke and symptomatic graft failure. The association between the TyG index and MACCEs was assessed by Cox proportional hazards regression analysis. RESULTS: A total of 1578 patients with diabetes who underwent OPCABG (mean age, 62.9 ± 8.0 years; men, 72.7%) were enrolled in this study. Over the follow-up of 2 years, 176 patients (11.2%) had at least 1 primary endpoint event. The follow-up incidence of the primary endpoint rose with increasing TyG index tertiles. The multivariate Cox proportional hazards regression analysis adjusted for multiple confounders revealed a hazard ratio for the primary endpoint of 2.133 (95% CI 1.347-3.377; P for trend = 0.001) when the highest and lowest TyG index tertiles were compared. CONCLUSION: The TyG index was significantly and positively associated with MACCEs, suggesting that the TyG index may be a valuable predictor of adverse cardiovascular and cerebrovascular outcomes after OPCABG in patients with T2DM.

Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism.

Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by ß cells. By screening the expression and functional characterization of olfactory receptors (ORs) in pancreatic islets, we identified Olfr109 as the receptor that detects insulin peptides. The engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signaling and promoted islet-resident macrophage proliferation through a ß cell-macrophage circuit and a ß-arrestin-1-mediated CCL2 pathway, as evidenced by ß-arrestin-1-/- mouse models. Systemic Olfr109 deficiency or deficiency induced by Pdx1-Cre+/-Olfr109fl/fl specifically alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and high-fat diet (HFD)-fed mice. We further determined the binding mode between insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic ß cells use Olfr109 to autonomously detect self-secreted insulin peptides, and this detection arrests insulin secretion and crosstalks with macrophages to increase intra-islet inflammation.

A bibliometric analysis on the progress of myocardial bridge from 1980 to 2022.

Introduction: Although the vast majority of patients with a myocardial bridge (MB) are asymptomatic, the anomaly was found to be associated with stable or unstable angina, vasospastic angina, acute coronary syndrome, and even malignant arrhythmias and sudden cardiac death in some cases. Methods: By retrieving the relevant literature on MB from 1 January 1980 to 31 July 2022 from the Web of Science Core Collection (WoSCC) database, we used the bibliometric tools, including CiteSpace, VOS viewer, and alluvial generator, to visualize the scientific achievements on MB. Results: A total of 630 articles were included. The number of published articles was in a fluctuating growth trend. These publications came from 37 contries, led by the USA and China. The leading country on MB was the United States, the leading position among institutions was Stanford University, and the most productive researcher on MB was Jennifer A. Tremmel. After analysis, the most common keywords were myocardial bridge, mortality, coronary angiography, descending coronary artery, and sudden death. Conclusion: Our findings can aid researchers in understanding the current state of MB research and in choosing fresh lines of inquiry for forthcoming investigations. Prevalence and prognosis, mechanism atherosclerosis, hemodynamic significance, and molecular autops will likely become the focus of future research. In addition, more studies and cooperations are still needed worldwide.

Heat transfer analysis of the forced air quenching with non-isothermal and non-uniform oxidation.

In this paper, the heat transfer characteristics of the forced air quenching with non-isothermal and non-uniform oxidation are investigated. By introducing the variations of interfacial temperature and oxygen partial pressure, a three-layered non-isothermal high-temperature oxidation kinetic model is developed, in which a discrete-time modeling method is employed to solve the problem of integration of the transient terms, and a special interfacial grid treatment is used for considering the growth of each oxide layer and updating of the thermal properties. Moreover, a parameter identification method using the multi-objective genetic algorithm is proposed for the inverse solution of the oxidation parabolic parameters based on the measured scale thicknesses in oxidation experiment. A case study of the forced air quenching of a Q235 disk is presented to validate the availability of the developed formulas. Then the interfacial heat transfer characteristics are analyzed, while the numerical solutions with and without oxidation are both performed for in-depth comparison. Results indicate that the active quenching region is mainly centralized in the vicinity of stagnation region. The radial variation regularity of the temperature difference across the total oxide layer is mainly determined by the thermal conductivity and the scale thickness. The existence of the oxide scale actually produces a certain thermal resistance during the quenching process and the effects of the oxide scale increases with the radial coordinate due to the interfacial temperature distribution. The results obtained can provide theoretical derivation for precise control of the internal phase transformation during the forced air quenching process.

Outcomes of middle cardiac vein arterialization via internal mammary/thoracic artery anastomosis.

OBJECTIVE: Cardiac vein arterialization is seldom applied for treating right coronary artery disease. This study aimed to improve outcomes of cardiac vein arterialization in a porcine model using intramammary artery anastomosis. METHODS: A chronic, stenotic coronary artery model was established in 12 of 14 Chinese experimental miniature pigs of either sex, which were randomly divided into equal control (n =6) and experimental (n = 6) groups. In experimental animals, blood flow was reconstructed in the right coronary artery using intramammary artery. Arterialization involved dissection of right internal mammary artery from bifurcation to apex of thorax followed by end-to-side anastomosis of internal mammary artery and middle cardiac vein plus posterior descending branch of right coronary artery. Intraoperative heart rate was maintained at 110 beats/min. Graft flow assessment and echocardiography were performed when blood pressure and heart rate normalized. RESULTS: The experimental group had significantly higher mean endocardial and epicardial blood flow postoperatively than control group (mean endocardial blood flow: 0.37 vs. 0.14 ml/(g*min), p<0.001; mean epicardial blood flow: 0.29 vs. 0.22, p = 0.014). Transmural blood flow was also higher in experimental group than in control group (0.33 vs. 0.19, p<0.001); ejection fraction increased from 0.46% at baseline to 0.51% (p = 0.0038) at 6 hours postoperatively, and mean blood flow of internal mammary artery was 44.50, perfusion index 0.73 at postoperative 6 months, 43.33 and 0.80 at 3 months. CONCLUSION: Successful cardiac vein arterialization via intramammary artery in a porcine model suggests that this may be a viable method for reconstructing blood flow in chronic, severe coronary artery disease.

The application of intraoperative transit time flow measurement to accurately assess anastomotic quality in sequential vein grafting.

OBJECTIVES: Intraoperative transit time flow measurement (TTFM) is widely used to assess anastomotic quality in coronary artery bypass grafting (CABG). However, in sequential vein grafting, the flow characteristics collected by the conventional TTFM method are usually associated with total graft flow and might not accurately indicate the quality of every distal anastomosis in a sequential graft. The purpose of our study was to examine a new TTFM method that could assess the quality of each distal anastomosis in a sequential graft more reliably than the conventional TTFM approach. METHODS: Two TTFM methods were tested in 84 patients who underwent sequential saphenous off-pump CABG in Beijing An Zhen Hospital between April and August 2012. In the conventional TTFM method, normal blood flow in the sequential graft was maintained during the measurement, and the flow probe was placed a few centimetres above the anastomosis to be evaluated. In the new method, blood flow in the sequential graft was temporarily reduced during the measurement by placing an atraumatic bulldog clamp at the graft a few centimetres distal to the anastomosis to be evaluated, while the position of the flow probe remained the same as in the conventional method. This new TTFM method was named the flow reduction TTFM. Graft flow parameters measured by both methods were compared. RESULTS: Compared with the conventional TTFM, the flow reduction TTFM resulted in significantly lower mean graft blood flow (P < 0.05); in contrast, yielded significantly higher pulsatility index (P < 0.05). Diastolic filling was not significantly different between the two methods and was >50% in both cases. Interestingly, the flow reduction TTFM identified two defective middle distal anastomoses that the conventional TTFM failed to detect. Graft flows near the defective distal anastomoses were improved substantially after revision. CONCLUSIONS: In this study, we found that temporary reduction of graft flow during TTFM seemed to enhance the sensitivity of TTFM to less-than-critical anastomotic defects in a sequential graft and to improve the overall accuracy of the intraoperative assessment of anastomotic quality in sequential vein grafting.

Epicardial unipolar radiofrequency ablation for left ventricular aneurysm related ventricular arrhythmia.

We report a case of a 62-year-old Chinese man with typical triple-vessel lesions and apical left ventricular aneurysm accompanied with ventricular tachycardia. Off-pump coronary artery bypass (OPCAB) grafting was performed in combination with epicardial unipolar radiofrequency ablation and linear closure of left ventricular aneurysm. The patient recovered well without postoperative complications. Holter monitoring showed no recurrence of the ventricular arrhythmia and the attack frequency of arrhythmia decreased significantly. The patient has been angina-free for 25 months since the operation and shows increasing exercise tolerance. Thus, left ventricular aneurysm plication combined with epicardial unipolar radiofrequency ablation during OPCAB may be beneficial for patients with ventricular aneurysm and preoperative malignant ventricular arrhythmia.

Intratracheal antitumor necrosis factor-α antibody attenuates lung tissue damage following cardiopulmonary bypass.

The aim of this study is to investigate the protective effect and underlying mechanism of antitumor necrosis factor-α antibody (TNF-α Ab) on lung tissue injury after cardiopulmonary bypass (CPB). Twenty-eight healthy New Zealand white rabbits were randomly divided into four groups. Group I received only an open chest operation. Groups II-IV all received CPB. Furthermore, groups III and IV received post-CPB endotracheal intubation with phosphate buffered saline or TNF-α Ab (2400 pg/kg), respectively. Perioperative blood neutrophil count, TNF-α level, and malondialdehyde (MDA) levels were determined in both the right and left atriums. Lung water content, TNF-α messenger RNA, protein, apoptosis in situ, and pathomorphological changes were also measured. The results show that TNF-α Ab can significantly inhibit leukocyte accumulation, reduce secretion of TNF-α and MDA, decrease lung tissue apoptosis, and attenuate post-CPB pathomorphological changes. TNF-α Ab administration, however, cannot suppress the expression of TNF-α, suggesting that the protective effects of TNF-α Ab originate from inhibiting the numerous biological functions of TNF-α. Intratracheal TNF-α Ab administration demonstrates a notable protective effect against lung injury after CPB.

Epicardial radiofrequency ablation for left ventricular aneurysm related ventricular arrhythmias during off-pump coronary artery bypass surgery.

BACKGROUND: Left ventricular aneurysm (LVA) is one of the serious complications after acute myocardial infarction. We attempted to evaluate the preliminary efficacy of LVA repair combined with epicardial radiofrequency ablation for ventricular arrhythmia during off-pump coronary artery bypass grafting (OPCAB). METHODS: From June 2009 to April 2011, 31 patients with LVA had angina symptoms and ventricular arrhythmia. In all patients, circular and cross-shaped radiofrequency epicardial ablations were performed using unipolar ablation pen along the border between the aneurysm wall and normal cardiac tissue and in the central zone of the aneurysms, followed by a linear placation of ventricular aneurysms on beating heart. RESULTS: All the patients showed complete recovery. The average number of grafted vessels was 2.7 ± 1.3. Intraoperative examinations revealed that the ventricular arrhythmia was effectively controlled by radiofrequency ablation. All cases had been followed up for one year. Holter monitoring revealed a significant reduction in ventricular arrhythmias (P < 0.05). Echocardiography showed significant increase in left ventricular ejection fraction (P < 0.05) and decrease in left ventricular end-diastolic diameter (P < 0.05). CONCLUSIONS: For patients with ventricular aneurysm and preoperative malignant arrhythmia, aneurysm repair plus epicardial radiofrequency ablation in OPCAB was found to be an effective and feasible therapeutic technique. However, medium- to long-term therapeutic efficacy of this method remains to be determined by future studies and observations.