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Qi Kong,1 Ling-ling Qian,1 Lei Zhang,1 Huan-huan Liu,1,2 Fan Yang,1 Xiao-lu Zhang,1 Chao Wang,1 Xiao-xi Zhao,1 Ku-lin Li,1 Ru-xing Wang1,2 1Department of Cardiology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, People’s Republic of China; 2Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, People’s Republic of ChinaCorrespondence: Ru-xing Wang; Ku-lin Li, Department of Cardiology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214023, People’s Republic of China, Email ruxingw@aliyun.com; liyantong2002@126.comPurpose: The aim of this study was to investigate the effects and mechanisms of SGLT2 inhibitor empagliflozin on diabetic coronary function.Methods: A rat diabetic model was established by injection of streptozotocin. Rats in the treated group were administered empagliflozin by gavage and rat coronary vascular tensions were measured after eight weeks. Large conductance calcium activated K+ channel currents were recorded using a patch clamp technique, while human coronary artery smooth muscle cells were used to explore the underlying mechanisms.Results: After incubation with empagliflozin (10, 30, 100, 300, 1000 μmol/L), the Δ relaxation % of rat coronary arteries were 2.459 ± 1.304, 3.251 ± 1.119, 6.946 ± 3.407, 28.36 ± 11.47, 86.90 ± 3.868, respectively. Without and with empagliflozin in the bath solution, BK channel opening probabilities at a membrane potential of +60 mV were 0.0458 ± 0.0517 and 0.3413 ± 0.2047, respectively (p < 0.05, n = 4 cells). After incubation with iberiotoxin, the Δ tensions of rat coronary arteries in the control (Ctrl), untreated (DM), low empagliflozin (10 mg/kg/d)-treated (DM+L-EMPA) and high empagliflozin (30mg/kg/d)-treated (DM+H-EMPA) group were 103.20 ± 5.85, 40.37 ± 22.12, 99.47 ±

Fan Yang,1,&ast; Huan-Huan Liu,2,&ast; Lei Zhang,1,&ast; Xiao-Lu Zhang,1 Jie Zhang,1 Feng Li,1 Ning Zhao,2 Zhi-Yuan Zhang,1 Qi Kong,1 Xiao-Yu Liu,1 Ying Wu,1 Zhi-Ming Yu,1 Ling-Ling Qian,1 Ru-Xing Wang1,2 1Department of Cardiology, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, 214023, People’s Republic of China; 2Wuxi School of Medicine, Jiangnan University, Wuxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling-Ling Qian; Ru-Xing Wang, Department of Cardiology, the Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, 214023, People’s Republic of China, Tel +0086-510-85351593, Email qianlingling@njmu.edu.cn; ruxingw@aliyun.comPurpose: Diabetes mellitus is an independent risk factor for atrial fibrillation (AF), which may be related to accumulation of advanced glycation end products (AGEs). However, the mechanisms involved are not completely clear. Abnormality of gap junction proteins, especially connexin 43 (Cx43) and connexin 40 (Cx40) in atrial myocytes, is an important cause of increased susceptibility of AF. The aim of our work is to investigate the mechanism of dysregulated Cx43 and Cx40 in atrial myocytes of diabetic rats.Methods: We established a type 1 diabetic rat model by intraperitoneal injection of streptozotocin. HL-1 cells and primary rat atrial myocytes were treated with AGEs in vitro. Using Western blotting, immunofluorescence staining, immunohistochemistry, and lucifer yellow diffusion measurements, we investigated dysregulation of Cx43 and Cx40 and its mechanism in atrial myocytes of diabetic rats.Results: Accumulation of AGEs was found in diabetic rats. The expression of Cx43 and Cx40 was reduced in the atrium of diabetic rats, accompanied by the decrease of phosphorylated Adenosine 5’-monophosphate-activated protein kinase (p-AMPK). Similar results were found in cultured HL-1 cells and primary rat atrial myocytes, suggesting

Lei Zhang,1,&ast; Huan-Huan Liu,2,&ast; Feng Li,1 Fan Yang,1 Ling-Ling Qian,1 Ru-Xing Wang1 1Department of Cardiology, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, People’s Republic of China; 2Wuxi School of Medicine, Jiangnan University, Wuxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ru-Xing Wang, Tel +86-510-85351593, Fax +86-510-85350555, Email ruxingw@aliyun.comAbstract: Diabetes is a significant risk factor for arrhythmias. However, the pathophysiology of diabetes-related arrhythmias still needs to be elucidated, presumably associated with structural and electrical remodeling. There is growing evidence that inflammation and arrhythmias are intimately associated, which has spurred significant interest in exploring the regulatory links in diabetes. Recent research findings have revealed a vital role for the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, and facilitated the occurrence of arrhythmias in diabetes, including NLRP3 inflammasome activation by multiple stressors and its downstream cytokines, interleukin-1β (IL-1β) and interleukin-18 (IL-18). This narrative review aims to summarize the complex interaction between NLRP3 inflammasomes signaling and diabetes-related arrhythmias. Articles regarding the role of NLRP3 inflammasome in diabetes-related arrhythmias and relevant mechanisms were selected. Relevant articles were selected from PubMed. The search terms were “NLRP3 inflammasome” and “diabetes” and “arrhythmia”. Important references from selected articles were also retrieved. The role of NLRP3 inflammasome signaling in diabetes-induced arrhythmias may provide a new option for the prevention and treatment diabetes-related arrhythmias.Keywords: NLRP3, inflammasome, diabetes, arrhythmia

Six structurally related flavonoids including two flavones apigenin and luteolin, one isoflavone genistein, and three flavonols, galangin, kaempferol and quercetin, are affected differently as radical scavengers by presence of Ca(II). Except for apigenin showing no reaction with Ca(II), other flavonoids all coordinate with Ca(II) to form 1 : 2 Ca(II)-flavonoid complexes confirmed by UV-vis and mass spectra. Coordination with Ca(II) for luteolin with the 3′, 4′-catechol group and for flavonols with 3-hydroxyl and 4-carbonyl significantly enhance the DPPH• scavenging efficiencies shown by stopped-flow spectra. Addition of Ca(II) shows no effect on radical scavenging rate of Genistein, as an isomer of apigenin, although both containing the same 4-carbonyl and 5-hydroxyl as a potential chelating group as confirmed by mass spectra and cyclic voltammetry. The two structure elements, 3′, 4′-catechol and the combination of 3-hydroxyl and 4-carbonyl, are identified as important factors for Ca(II) enhancement of radical scavenging of flavonoids. Coordination of Ca(II) to kaempferol forming a 1 : 2 Ca(II)-kaempferol complex at 3,4 site shows the most significant enhancement in radical scavenging efficiency by a factor of 4.4 compared to other investigated flavonoids.

Tyrosinase, widely distributed in nature, is a copper-containing polyphenol oxidase involved in the formation of melanin. Flavonoids are most often considered as tyrosinase inhibitors but have also been confirmed to be tyrosinase substrates. Four structure-related flavonoids including flavones (apigenin and luteolin) and flavonols (kaempferol and quercetin) are found to promote not inhibit browning induced by tyrosinase catalyzed oxidation both in model systems and in mushrooms under aerobic conditions. A comparison with enzymatic oxidation and autooxidation of flavonoids alone has helped to clarify why flavonoids function as a substrate rather than an inhibitor. Flavonoids almost do not affect the kinetics of melanin formation from enzymatic oxidation ofl-dopa in excess. In addition, a new brown complex formed during the reaction of flavonoid quinone and dopaquinone is suggested to enhance the browning effects by competing with isomerization and autooxidation. Structure-activity relationships of the four flavonoids in melanin formation leading to browning induced by autooxidation and enzymatic oxidation confirm the enzymatic nature of the browning.