Type 1 diabetes, its complications, and non-ischemic cardiomyopathy: a mendelian randomization study of European ancestry.

BACKGROUND: Type 1 diabetes (T1D) is a significant risk factor for a range of cardiovascular diseases. Nonetheless, the causal relationship between T1D and non-ischemic cardiomyopathy (NICM) remains to be elucidated. Furthermore, the mechanisms responsible for the progression from T1D to NICM have not been definitively characterized. OBJECTIVE: The aim of this study was to conduct a Mendelian randomization (MR) study to investigate the causal effects of T1D and its complications on the development of NICM. Additionally, this study aimed to conduct a mediation analysis to identify potential mediators within this correlation. METHODS: Genetic variants were used as instrumental variables for T1D. The summary data for T1D were obtained from two genome-wide association study datasets. The summary data for T1D with complications and NICM were obtained from the Finnish database. Two-sample MR, multivariable MR and mediation MR were conducted in this study. RESULTS: The study revealed a causal association between T1D, T1D with complications, and NICM (with odds ratios of 1.02, 95% CI 1.01-1.04, p = 1.17e-04 and 1.03, 95% CI 1.01-1.05, p = 3.15e-3). Even after adjusting for confounding factors such as body mass index and hypertension, T1D remained statistically significant (with odds ratio of 1.02, 95% CI 1.01-1.04, p = 1.35e-4). Mediation analysis indicated that monokine induced by gamma interferon may play a mediating role in the pathogenesis of T1D-NICM (mediation effect indicated by odds ratio of 1.005, 95% CI 1.001-1.01, p = 4.9e-2). CONCLUSION: The study demonstrates a causal relationship between T1D, its complications, and NICM. Additionally, monokine induced by gamma interferon may act as a potential mediator in the pathogenesis of T1D-NICM.

Acute left heart failure caused by Takayasu arteritis: a case report and literature review.

Takayasu arteritis is a rare disease. Coronary involvement may appear in patients with Takayasu arteritis. With delayed diagnosis and the difficulty of treatment, Takayasu arteritis patients complicated with coronary abnormalities usually have poor prognosis. We present a rare case of acute left heart failure caused by total occlusion of the left main coronary artery due to Takayasu arteritis. A 30-year-old Chinese woman presented at our hospital with recurrent chest tightness accompanied by dyspnoea. A series of modern imaging methods were used for diagnosis and evaluation of Takayasu arteritis, including invasive angiography, CT angiography, and vascular ultrasound. The patient received drugs therapy including glucocorticoids, immunosuppressants, and cardiovascular drugs, without a reperfusion therapy. Cardiac events, inflammatory marks, and cardiac function were observed during 2-year follow-up period. In this paper, we briefly disscuss the diagnosis and treatment for young women with cardiac complication caused by Takayasu arteritis.

Trimetazidine inhibits cardiac fibrosis by reducing reactive oxygen species and downregulating connective tissue growth factor in streptozotocin-induced diabetic rats.

Diabetes may affect myocardial fibrosis through oxidative stress. Trimetazidine (TMZ) is an anti-anginal agent. The present study aimed to determine the modulatory effect of TMZ on reactive oxygen species (ROS) and connective tissue growth factor (CTGF) expression and to evaluate the potential of TMZ to improve diastolic function in streptozotocin (STZ)-induced diabetic rats. After treating STZ-induced diabetic rats with TMZ for 16 weeks, a decrease in malondialdehyde levels, cardiac collagen volume fraction, left ventricular (LV) end-diastolic pressure and protein expression of collagen-I (Col I), Col III and CTGF compared with those in diabetic control rats was observed. In vitro, TMZ inhibited Col I, Col III and CTGF protein expression in cardiac fibroblasts treated with high glucose and decreased intracellular ROS generation and hydroxyproline content in the cell culture medium of cardiac fibroblasts. TMZ markedly improved cardiac fibrosis and diastolic function in diabetic rats. This effect was associated with a reduction in ROS production and CTGF expression in cardiac fibroblasts. The present study suggests that TMZ may be beneficial for protecting the hearts of diabetic patients.

Sodium Oleate-Based Nanoemulsion Enhances Oral Absorption of Chrysin through Inhibition of UGT-Mediated Metabolism.

Oral bioavailability of flavonoids (and many phenolic drugs) is severely limited by extensive first-pass glucuronidation. Here we aimed to determine the modulatory effects of commonly used pharmaceutical excipients (PEs) on UDP-glucuronosyltransferase (UGT) activities and to evaluate the potential of nanoemulsions containing a UGT-inhibitory PE for oral absorption enhancement of chrysin, a model flavonoid. The effects of PEs on glucuronidation were determined using tissue (liver and intestine) microsomes, expressed UGT1A1 enzyme, and UGT1A1-overexpressing HeLa cells. Nanoemulsions were prepared using a modified emulsification technique and subsequently characterized by particle size, zeta-potential, morphology, and in vitro drug release. Pharmacokinetic studies were performed with rats to assess the effects of nanoemulsions on the metabolism and pharmacokinetics of chrysin. Of 21 PEs, five (i.e., Brij 35, Brij 58, labrasol, sodium oleate, and Tween 20) significantly inhibited chrysin glucuronidation. Of note, sodium oleate was the most potent inhibitor of glucuronidation. Eight PEs including Tween 80 had no effects on glucuronidation of chrysin. The chrysin nanoemulsions prepared with sodium oleate (named SO-NE) were spherical or near-spherical (particle size, 83.2 nm; zeta-potential, -43.7 mV; entrapment efficiency, 89.5%). The reference nanoemulsions prepared with Tween 80 (T80-NE) were highly similar to SO-NE in terms of particle size, zeta-potential, and drug release. It was demonstrated in pharmacokinetic studies that SO-NE led to a 4.3-fold increase in systemic exposure of chrysin and a 3.5-fold increase in Cmax value, whereas T80-NE did not cause any changes in chrysin pharmacokinetics. In conclusion, sodium oleate-based nanoemulsions greatly enhanced oral absorption of chrysin. Oral absorption enhancement of chrysin was attained through targeted inhibition of first-pass glucuronidation by sodium oleate.

Efflux Transport Characterization of Resveratrol Glucuronides in UDP-Glucuronosyltransferase 1A1 Transfected HeLa Cells: Application of a Cellular Pharmacokinetic Model to Decipher the Contribution of Multidrug Resistance-Associated Protein 4.

Resveratrol undergoes extensive metabolism to form biologically active glucuronides in humans. However, the transport mechanisms for resveratrol glucuronides are not fully established. Here, we aimed to characterize the efflux transport of resveratrol glucuronides using UGT1A1-overexpressing HeLa cells (HeLa1A1 cells), and to determine the contribution of multidrug resistance-associated protein (MRP) 4 to cellular excretion of the glucuronides. Two glucuronide isomers [i.e., resveratrol 3-O-glucuronide (R3G) and resveratrol 4'-O-glucuronide (R4'G)] were excreted into the extracellular compartment after incubation of resveratrol (1-100 µM) with HeLa1A1 cells. The excretion rate was linearly related to the level of intracellular glucuronide, indicating that glucuronide efflux was a nonsaturable process. MK-571 (a dual inhibitor of UGT1A1 and MRPs) significantly decreased the excretion rates of R3G and R4'G while increasing their intracellular levels. Likewise, short-hairpin RNA (shRNA)-mediated silencing of MRP4 caused a significant reduction in glucuronide excretion but an elevation in glucuronide accumulation. Furthermore, ß-glucuronidase expressed in the cells catalyzed the hydrolysis of the glucuronides back to the parent compound. A cellular pharmacokinetic model integrating resveratrol transport/metabolism with glucuronide hydrolysis/excretion was well fitted to the experimental data, allowing derivation of the efflux rate constant values in the absence or presence of shRNA targeting MRP4. It was found that a large percentage of glucuronide excretion (43%-46%) was attributed to MRP4. In conclusion, MRP4 participated in cellular excretion of R3G and R4'G. Integration of mechanistic pharmacokinetic modeling with transporter knockdown was a useful method to derive the contribution percentage of an exporter to overall glucuronide excretion.

Characterization of chrysin glucuronidation in UGT1A1-overexpressing HeLa cells: elucidating the transporters responsible for efflux of glucuronide.

Active transport of glucuronide out of cells is a critical process in elimination of drugs via the glucuronidation pathway. Here, HeLa cells were stably transfected with UGT1A1 and the contributions of BCRP and MRP family transporters to the cellular efflux of chrysin glucuronide (CG) were determined. The cDNA of UGT1A1 was introduced into HeLa cells using the lentiviral transfection method. The modified cells were functional in generation of the glucuronide from chrysin. Ko143 at 10-20 µM (a dual inhibitor of BCRP and UGT1A1) caused a marked decrease (51.3%-59.7%, P < 0.01) in the excretion rate and efflux clearance of CG. Likewise, MK-571 at 5-20 µM (an inhibitor of MRPs but an activator of UGT1A1) resulted in a significant reduction in the excretion rate (18.2%-64.0%, P < 0.01) and efflux clearance (37.0%-90.2%, P < 0.001). By contrast, dipyridamole and leukotriene C4 showed no inhibitory effects on CG excretion. The chemical inhibition indicated that excretion of CG was contributed by the MRP family transporters, whereas the role of BCRP was unclear. Furthermore, short hairpin RNA-mediated silencing of a target transporter led to a marked reduction in the excretion rate of CG (38.6% for BCRP, 39.3% for MRP1, 36.4% for MRP3, and 28.7% for MRP4; P < 0.01). Transporter silencing also led to substantial decreases in the efflux clearance (44.7% for BCRP, 60.4% for MRP1, 36.7% for MRP3, and 28.7% for MRP4; P < 0.01). The gene silencing results suggested that BCRP, MRP1, MRP3, and MRP4 were significant contributors to excretion of CG.