Background Oxidative stress contributes to adverse atrial remodeling in diabetes mellitus. This can be prevented by the PPAR-γ agonist pioglitazone through its anti-oxidant and anti-inflammatory effects. Purpose In this study, the molecular mechanisms underlying these effects were investigated. Methods Rabbits were randomly divided into control (C), diabetic (DM), and pioglitazone-treated DM (Pio) groups. Echocardiographic, hemodynamic, electrophysiological, intracellular Ca2+ properties were measured. Serum PPAR-γ levels, serum and tissue oxidative stress and inflammatory markers, mitochondrial morphology, reactive oxygen species (ROS) production rate, respiratory function, and mitochondrial membrane potential (MMP) levels were measured. Protein expression of pro-fibrotic marker transforming growth factor β1 (TGF-β1), and the mitochondrial proteins (PGC-1α, fission and fusion-related proteins) were measured. Results Compared with controls, the DM group demonstrated larger left atrial diameter and fibrosis area associated with a higher incidence of inducible AF. Lower serum PPAR-γ level was associated with lower PGC-1α, higher NF-κB and higher TGF-β1 expression. Mn-SOD protein was not different but lower mitochondrial fission- and fusion-related proteins were detected. Mitochondrial swelling, higher mitochondrial ROS, lower respiratory control rate, lower MMP and higher intracellular Ca2+ transients were observed. In the Pio group, reversal of structural remodeling and lower inducible AF incidence were associated with higher PPAR-γ and PGC-1α. NF-κB and TGF-β1 were lower and biogenesis, fission and fusion-related protein were higher. Mitochondrial structure and function, and intracellular Ca2+ transients were improved. In HL-1 cell line, transfected with PGC-1α siRNA blunted the effect of pioglitazone on Mn-SOD protein expression and MMP collapse in H2O2-treated cells. Conclusion Diabetes mellitus induces adverse atrial structural and electrophysiological remodeling, abnormal Ca2+ handling and mitochondrial damage and dysfunction. Pioglitazone prevented these abnormalities through the PPAR-γ/PGC-1α pathway. Acknowledgement/Funding National Natural Science Foundation of China (No 81570298, 81270245, 30900618 to T.L.)

Background Diabetes nephropathy (DN) is a serious diabetic problem that may progress to renal failure. The root of Curcuma longa L., often known as turmeric, provides various health benefits. Bisacurone is a bioactive terpenoid found in small amounts in turmeric that possesses anti-inflammatory and antioxidant properties. The present study focuses on the potential protective effects of bisacurone against DN via reducing renal inflammation, oxidative stress, and apoptosis. Methods Type 2 diabetes was created in rats by feeding them a high-fat/high-sugar diet for 8 weeks, followed by a low dose of streptozotocin and Bisacurone (50 and 100 μg/kg bisacurone) given for 4 weeks. Results In diabetic rats, bisacurone reduced hyperglycemia, protected against body weight (BW) loss, lowered renal markers, reduced lipid profile alterations and avoided histological abnormalities. Bisacurone treatment reduced oxidative stress by decreasing malondialdehyde (MDA) levels while enhancing antioxidant defenses through superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) levels. Furthermore, bisacurone treatment activated the renal Nrf2/Keap1 signaling pathway but attenuated the high levels of NFκB p65, TNF-α, IL-1β, IL-6, Cox2, and iNOS. Bisacurone also reduced Bax, caspase-3, caspase-9 and cytochrome c but increased Bcl-2 in the kidneys of diabetic rats. Conclusion In the present study, bisacurone reduces DN by reducing hyperglycemia, oxidative stress, inflammation, and apoptosis, while also increasing Nrf2/HO-1 signaling.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): National Natural Science Foundation of China Background Mitochondrial oxidative stress is an important mechanism of atrial remodeling and atrial fibrillation (AF) in the setting of diabetes. Currently, endoplasmic reticulum (ER) stress is regarded as the key link from homeostasis to dysfunction, and is a central feature of metabolic diseases such as type 2 diabetes. However, the molecular mechanisms underlying these processes have not been fully elucidated. Objective To explore the potential role of ER stress-mitochondrial oxidative stress in atrial remodeling and AF induction in diabetes. Methods  Mouse atrial cardiomyocytes (HL-1 cells) , type 2 diabetic rats and GRP75 conditional knockout mice were used as models systems. These findings were correlated with biomarker findings in human diabetic patients with confirmed atrial fibrillation. Results  In the diabetic rat atria, significant ER stress was observed. Treatment with tunicamycin (TM), an ER stress agonist, mass spectrometry (MS) demonstrated many known ER stress and calmodulin proteins, including Heat shock protein family A (Hsp70) member (Hspa) 5 (GRP78) and Hspa9 (GRP75) and in situ proximity ligation assay (PLA) indicated that TM led to increased protein expression of the IP3R1 (inositol 1,4,5-trisphosphate receptors 1)/GRP75 (glucose-regulated protein 75)/VDAC1 (voltage-dependent anion channel 1) complex in HL-1 cells. Silencing of GRP75 using siRNA in HL-1 cells and GRP75 conditional knockout in our mouse model led to impaired calcium transport from the ER to mitochondria, and alleviated mitochondrial oxidative stress and calcium overload. Moreover, GRP75 deficiency attenuates atrial remodeling and AF progression in Myh6-Cre+/Hspa9flox/flox + TM mice. Conclusions  The IP3R1/GRP75/VDAC1 complex mediates endoplasmic reticulum stress-mitochondrial oxidative stress plays an important role in diabetic atrial remodeling. Abstract Figure