Protective Effect of Water-Soluble Acacetin Prodrug on APAP-Induced Acute Liver Injury Is Associated with Upregulation of PPARγ and Alleviation of ER Stress.

A water-soluble acacetin prodrug has been synthesized and reported by our group previously. Acetaminophen (APAP) overdose is a leading cause of acute liver injury. We found that subcutaneous injection of acacetin prodrug (5, 10, 20 mg/kg) decreased serum ALT, AST, and ALP, corrected the abnormal MDA and GSH in liver, and improved intrahepatic hemorrhage and destruction of liver structures in APAP (300 mg/kg)-treated mice.

Functional Potassium Channels in Macrophages.

Macrophages are the predominant component of innate immunity, which is an important protective barrier of our body. Macrophages are present in all organs and tissues of the body, their main functions include immune surveillance, bacterial killing, tissue remodeling and repair, and clearance of cell debris. In addition, macrophages can present antigens to T cells and facilitate inflammatory response by releasing cytokines.

The natural flavone acacetin protects against high-fat diet-induced lipid accumulation in the liver via the endoplasmic reticulum stress/ferroptosis pathway.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. To date, no medication has been approved to treat NAFLD. In this study, we evaluated the therapeutic effect of the natural flavone acacetin on high-fat diet (HFD)-induced NAFLD in mice and the underlying mechanisms.

K2P1 leak cation channels contribute to ventricular ectopic beats and sudden death under hypokalemia.

Hypokalemia causes ectopic heartbeats, but the mechanisms underlying such cardiac arrhythmias are not understood. In reduced serum K concentrations that occur under hypokalemia, K2P1 two-pore domain K channels change ion selectivity and switch to conduct inward leak cation currents, which cause aberrant depolarization of resting potential and induce spontaneous action potential of human cardiomyocytes. K2P1 is expressed in the human heart but not in mouse hearts.

Kir2.1 channel regulates macrophage polarization via the Ca2+/CaMK II/ERK/NF-κB signaling pathway.

Macrophage polarization plays a key role in the inflammatory response. Various ion channels expressed in macrophages have been documented, but very little is known about their roles in macrophage polarization. We found that knockdown or blockade of the Kir2.

Exosomal microRNAs: potential targets for the prevention and treatment of diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM), a condition in which myocardial dysfunction is caused by diabetes mellitus, has become an epidemic disorder in the world. DCM initially presents as diastolic relaxation dysfunction and will progress to heart failure in the absence of coronary artery disease, valvular disease, and other conventional cardiovascular risk factors such as hypertension and dyslipidemia. However, the underlying molecular mechanisms of DCM are poorly understood.

PPARα mediates night neon light-induced weight gain: role of lipid homeostasis.

Light pollution leads to high risk of obesity but the underlying mechanism is not known except for the influence of altered circadian rhythm. Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism, but its role in circadian-related obesity is not clear. Wild-type (WT) and null (KO) mice on a high-fat diet (HFD) were treated with neon light at night for 6 weeks.

Kir2 inward rectification-controlled precise and dynamic balances between Kir2 and HCN currents initiate pacemaking activity.

Spontaneous rhythmic action potential or pacemaking activity of pacemaker cells controls rhythmic signaling such as heartbeat. The mechanism underlying the origin of pacemaking activity is not well understood. In this study, we created human embryonic kidney (HEK) 293 cells that show pacemaking activity through heterologous expression of strong inward rectifier K subfamily 2 isoform 1 (Kir2.

Kir2.1 channels set two levels of resting membrane potential with inward rectification.

Strong inward rectifier K channels (Kir2.1) mediate background K currents primarily responsible for maintenance of resting membrane potential. Multiple types of cells exhibit two levels of resting membrane potential.

The Natural Flavone Acacetin Blocks Small Conductance Ca-Activated K Channels Stably Expressed in HEK 293 Cells.

The natural flavone acacetin inhibits several voltage-gated potassium currents in atrial myocytes, and has anti-atrial fibrillation (AF) effect in experimental AF models. The present study investigates whether acacetin inhibits the Ca-activated potassium (K) currents, including small conductance (SK1, SK2, and SK3), intermediate conductance (IK), and large-conductance (BK) channels stably expressed in HEK 293 cells. The effects of acacetin on these K channels were determined with a whole-cell patch voltage-clamp technique.

Kir2.1 and K2P1 channels reconstitute two levels of resting membrane potential in cardiomyocytes.

Key Points: Outward and inward background currents across the cell membrane balance, determining resting membrane potential. Inward rectifier K channel subfamily 2 (Kir2) channels primarily maintain the resting membrane potential of cardiomyocytes. Human cardiomyocytes exhibit two levels of resting membrane potential at subphysiological extracellular K concentrations or pathological hypokalaemia, however, the underlying mechanism is unclear.

Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury.

The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats.

SKF-96365 blocks human ether-à-go-go-related gene potassium channels stably expressed in HEK 293 cells.

SKF-96365 is a TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in different systems, which was recently reported to induce QTc prolongation on ECG by inhibiting TRPC channels. The present study investigates whether the blockade of cardiac repolarization currents would be involved in the increase of QTc interval. Cardiac repolarization currents were recorded in HEK 293 cells stably expressing human ether-à-go-go-related gene potassium (hERG or hKv11.

Distinctive property and pharmacology of voltage-gated sodium current in rat atrial vs ventricular myocytes.

Background: Several mammalian species display distinct biophysical properties between atrial and ventricular voltage-gated sodium current (INa); however, the potential mechanism behind this phenomenon is unknown.

Objective: The purpose of this study was to investigate the potential molecular identities of the different INa in atrial and ventricular myocytes of rat hearts.

Methods: Whole-cell patch voltage-clamp and molecular biology techniques were used in the study.

SKF-96365 strongly inhibits voltage-gated sodium current in rat ventricular myocytes.

SKF-96365 (1-(beta-[3-(4-methoxy-phenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride) is a general TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in cardiovascular system. Recent reports showed that SKF-96365 induced a reduction in cardiac conduction. The present study investigates whether the reduced cardiac conduction caused by SKF-96365 is related to the blockade of voltage-gated sodium current (I Na) in rat ventricular myocytes using the whole-cell patch voltage-clamp technique.

TRPM7 channels regulate proliferation and adipogenesis in 3T3-L1 preadipocytes.

Transient receptor potential melastatin-7 (TRPM7) channels are involved in many cellular physiological and pathological processes. The present study was designed to investigate the expression of TRPM7 channels and the potential role in regulating cell proliferation and adipogenesis in 3T3-L1 preadipocytes with approaches of whole-cell patch voltage-clamp, molecular biology, cell proliferation, adipogenesis, etc. We found that a TRPM7-like current was recorded with Mg(2+) -free pipette solution in 3T3-L1 preadipocytes, and the current was inhibited by intercellular free Mg(2+) .

Pentamethylquercetin ameliorates fibrosis in diabetic Goto-Kakizaki rat kidneys and mesangial cells with suppression of TGF-β/Smads signaling.

Pentamethylquercetin (PMQ) has been shown to possess glucose-lowering properties, but its effect on renal fibrosis in diabetes is still unclear. This study was designed to investigate the effect of PMQ on renal fibrosis and the underlying mechanisms in spontaneous type II diabetic Goto-Kakizaki rats and mesangial cells in high glucose. We found that in Goto-Kakizaki rats, PMQ treatment attenuated glomerular volume, glycogen deposition, renal collagen and fibronectin accumulation, in addition to amelioration of diabetic symptoms, including reduction of urine volume and urine glucose levels.

Allitridi inhibits multiple cardiac potassium channels expressed in HEK 293 cells.

Allitridi (diallyl trisulfide) is an active compound (volatile oil) from garlic. The previous studies reported that allitridi had anti-arrhythmic effect. The potential ionic mechanisms are, however, not understood.

Evidence for functional expression of TRPM7 channels in human atrial myocytes.

Transient receptor potential melastatin-7 (TRPM7) channels have been recently reported in human atrial fibroblasts and are believed to mediate fibrogenesis in human atrial fibrillation. The present study investigates whether TRPM7 channels are expressed in human atrial myocytes using whole-cell patch voltage-clamp, RT-PCR and Western blotting analysis. It was found that a gradually activated TRPM7-like current was recorded with a K(+)- and Mg(2+)-free pipette solution in human atrial myocytes.

Effects of the natural flavone trimethylapigenin on cardiac potassium currents.

The natural flavones and polymethylflavone have been reported to have cardiovascular protective effects. In the present study, we determined whether quecertin, apigenin and their methylated compounds (3,7,3',4'-tetramethylquecertin, 3,5,7,3',4'-pentamethylquecertin, 7,4'-dimethylapigenin, and 5,7,4'-trimethylapigenin) would block the atrial specific potassium channel hKv1.5 using a whole-cell patch voltage-clamp technique.