Xuan Zhang

Multi-targeted protection of acetaminophen-induced hepatotoxicity in mice by tannic acid

Abstract Tannic acid (TA) is the polyphenol that has beneficial health effects against oxidative stress. However, the hepatoprotective effects of TA are still relatively unknown. In the present study, we evaluated the effects of TA on an acetaminophen (APAP)‐induced hepatotoxicity model, which was established by administration of 400 mg/kg of APAP. The levels of alanine transferase (ALT), aspartate transferase (AST), dendothelin‐1 (ET‐1), nitric oxide (NO) and malondialdehyde (MDA) in the APAP‐induced hepatotoxicity mice were significantly increased (up to ˜200%), while their levels were reduced by pretreatment with TA (25 and 50 mg/kg) (P < 0.05). The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH‐Px) in the APAP‐induced hepatotoxicity mice were significantly reduced (lower to ˜65%), while their activities were increased by pretreatment with TA (25 and 50 mg/kg) (P < 0.05). In addition, pretreatment with oral TA (25 and 50 mg/kg) for 3 days before the APAP administration dose‐dependently ameliorated changes in hepatic histopathology, suppressed overexpression of interleukin‐1&bgr; (IL‐1&bgr;), tumor necrosis factor‐&agr; (TNF‐&agr;), c‐fos, c‐jun, NF‐&kgr;B (p65) and caspase‐3 (all P < 0.05), downregulated bax and upregulated bcl‐2, nuclear factor erythroid 2‐related factor 2 (Nrf2) and heme oxygenase‐1 (HO‐1) (all P < 0.05) in the liver. These results indicate that TA exhibits significant hepatoprotective effects against APAP‐induced hepatotoxicity and suggest that the hepatoprotective mechanisms of TA may be related to anti‐oxidation, anti‐inflammation and anti‐apoptosis. HighlightsTannic acid inhibited oxidative stress induced by APAP.Tannic acid suppressed the inflammatory reactions induced by APAP.Tannic acid alleviated liver pathological damage and hepatocyte apoptosis induced by APAP.Tannic acid shows the protective effects on APAP‐induced hepatotoxicity.

Inhibition of myocardial hypertrophy by magnesium isoglycyrrhizinate through the TLR4/NF-κB signaling pathway in mice

ABSTRACT Magnesium isoglycyrrhizinate (MgIG) is a magnesium salt of the 18‐&agr; glycyrrhizic acid stereoisomer that has exhibited hepato‐protective effects and has anti‐inflammatory, antioxidant, and antiviral activities. Here, we have investigated the effects and potential mechanisms of action of MgIG, with respect to myocardial fibrosis induced by isoproterenol (ISO) in mice. Mice were administered MgIG for 14 days, with concurrent ISO dosing, and were sacrificed two weeks later. Lactate dehydrogenase (LDH) and creatine kinase (CK) concentrations were measured in the blood. Pathological changes in the myocardium were observed via light microscopy. In addition, the expression of the Bax and Bcl‐2 genes, and the basic fibroblast growth factor (bFGF) protein were measured via an immunohistochemical method. The RNA expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), c‐fos, and c‐jun mRNA were quantified by reverse transcription‐polymerase chain reaction (RT‐PCR) in the myocardial tissue. The protein expression of toll‐like receptor (TLR) 4, and nuclear factor kappa B (NF‐&kgr;B) (p65) were measured using Western blot assays. Compared with the control group, the ISO group showed significant increases in bFGF, Bax, Bcl‐2, TLR4, and NF‐&kgr;B (p65) expressions, as well as increased serum levels of LDH and CK. MgIG had a protective effect on ISO‐induced myocardial fibrosis, which might be ascribed, at least in part, to the inhibition of the TLR4/NF‐&kgr;B (p65) signaling pathway. Graphical abstract Figure. No Caption available. HighlightsMgIG ameliorates ISO‐induced myocardial hypertrophy.MgIG inhibits ISO‐induced proinflammatory cytokines release.MgIG inhibited the activation of TLR4/NF‐&kgr;B signals in ISO‐induced myocardial hypertrophy mice.

Inhibitory Effect of Cinobufagin on L-Type Ca2+ Currents, Contractility, and Ca2+ Homeostasis of Isolated Adult Rat Ventricular Myocytes

Cinobufagin (CBG), a major bioactive ingredient of the bufanolide steroid compounds of Chan Su, has been widely used to treat coronary heart disease. At present, the effect of CBG on the L-type Ca2+ current (I Ca-L) of ventricular myocytes remains undefined. The aim of the present study was to characterize the effect of CBG on intracellular Ca2+ ([Ca2+]i) handling and cell contractility in rat ventricular myocytes. CBG was investigated by determining its influence on I Ca-L, Ca2+ transient, and contractility in rat ventricular myocytes using the whole-cell patch-clamp technique and video-based edge-detection and dual-excitation fluorescence photomultiplier systems. The dose of CBG (10−8u2009M) decreased the maximal inhibition of CBG by 47.93%. CBG reduced I Ca-L in a concentration-dependent manner with an IC50 of 4 × 10−10u2009M, upshifted the current-voltage curve of I Ca-L, and shifted the activation and inactivation curves of I Ca-L leftward. Moreover, CBG diminished the amplitude of the cell shortening and Ca2+ transients with a decrease in the time to peak (Tp) and the time to 50% of the baseline (Tr). CBG inhibited L-type Ca2+ channels, and reduced [Ca2+]i and contractility in adult rat ventricular myocytes. These findings contribute to the understanding of the cardioprotective efficacy of CBG.

Effects of Tannic Acid, Green Tea and Red Wine on hERG Channels Expressed in HEK293 Cells.

Tannic acid presents in varying concentrations in plant foods, and in relatively high concentrations in green teas and red wines. Human ether-à-go-go-related gene (hERG) channels expressed in multiple tissues (e.g. heart, neurons, smooth muscle and cancer cells), and play important roles in modulating cardiac action potential repolarization and tumor cell biology. The present study investigated the effects of tannic acid, green teas and red wines on hERG currents. The effects of tannic acid, teas and red wines on hERG currents stably transfected in HEK293 cells were studied with a perforated patch clamp technique. In this study, we demonstrated that tannic acid inhibited hERG currents with an IC50 of 3.4 μM and ~100% inhibition at higher concentrations, and significantly shifted the voltage dependent activation to more positive potentials (Δ23.2 mV). Remarkably, a 100-fold dilution of multiple types of tea (green tea, oolong tea and black tea) or red wine inhibited hERG currents by ~90%, and significantly shifted the voltage dependent activation to more positive potentials (Δ30.8 mV and Δ26.0 mV, respectively). Green tea Lung Ching and red wine inhibited hERG currents, with IC50 of 0.04% and 0.19%, respectively. The effects of tannic acid, teas and red wine on hERG currents were irreversible. These results suggest tannic acid is a novel hERG channel blocker and consequently provide a new mechanistic evidence for understanding the effects of tannic acid. They also revealed the potential pharmacological basis of tea- and red wine-induced biology activities.

Magnesium isoglycyrrhizinate ameliorates doxorubicin‑induced acute cardiac and hepatic toxicity via anti‑oxidant and anti‑apoptotic mechanisms in mice

The present study investigated the effects and potential mechanisms of action of magnesium isoglycyrrhizinate (MgIG) in doxorubicin (DOX)-treated mice. Histopathological analysis and western blot analysis were conducted in the liver and heart tissues and biochemical analysis of the serum was performed. The results revealed that MgIG (10, 20 and 40 mg/kg/day) could protect the structure and functions of the liver and heart by inhibiting the activities of the myocardial enzymes creatine kinase (CK), CK-MB and lactate dehydrogenase and the hepatic-specific enzymes aspirate aminotransferase and alanine aminotransferase, increasing the activities of the antioxidants superoxide dismutase and glutathione peroxidase, and inhibiting cellular apoptosis induced by DOX (30 mg/kg). These results demonstrate that inhibiting lipid peroxidation and reducing myocardial and hepatocyte apoptosis may be one of the mechanisms by which MgIG exhibits hepatoprotective and cardioprotective effects in DOX-treated mice.

Protective effects of tannic acid on pressure overload-induced cardiac hypertrophy and underlying mechanisms in rats

The aim of this study was to examine the cardioprotective effects and latent mechanism of tannic acid (TA) on cardiac hypertrophy.

Characterization and structure-activity relationship of natural flavonoids as hERG K+ channel modulators

Objectives: Flavonoids are present in varying concentrations in plant foods and have been reported to have numerous pharmacological activities, such as anti‐cancer, antioxidant, anti‐inflammatory, hepatoprotective, and vasodilator effects. We found that quercetin, fisetin, and some related flavonoid derivatives could inhibit human ether‐à‐go‐go‐related gene (hERG) K+ channels. Key findings: In this study, we tested the effects of a series of flavonoids on the hERG K+ channel expressed in HEK293 cells. For the first time, we demonstrate that quercetin and fisetin (Fise) are potent hERG current blockers. The 50% inhibiting concentration (IC50) and maximum efficacy (Emax) of quercetin were 11.8 ± 0.9 &mgr;M and 82 ± 2%, while those of fisetin were 38.4 ± 6 &mgr;M and 100 ± 6%, respectively. Luteolin (Lute) was a less potent inhibitor of hERG current (48 ± 1% at 100 &mgr;M). Galangin, kaempferol, and isorhamnetin (100 &mgr;M) showed weaker activity on the hERG currents. Conclusion: These results suggest that quercetin, fisetin, and luteolin are potent hERG K+ channel inhibitors and reveal the structure‐activity relationship of natural flavonoids. HighlightsFlavonoid derivatives quercetin, fisetin, and luteolin are potent hERG K+ channel inhibitors.The present work reveal the structure‐activity relationship of natural flavonoids.The results also provide new mechanistic evidence for understanding the effects of these natural products.

Inhibition of transmembrane member 16A calcium-activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects.

Natural flavonoids are ubiquitous in dietary plants and vegetables and have been proposed to have antiviral, antioxidant, cardiovascular protective and anticancer effects. Transmembrane member 16A (TMEM16A)‐encoded Ca2+‐activated Cl− channels play a variety of physiological roles in many organs and tissues. Overexpression of TMEM16A is also believed to be associated with cancer progression. Therefore, inhibition of TMEM16A current may be a potential target for cancer therapy. In this study, we screened a broad spectrum of flavonoids for their inhibitory activities on TMEM16A currents.

Natural and synthetic flavonoids, novel blockers of the volume-regulated anion channels, inhibit endothelial cell proliferation

Natural flavonoids are ubiquitous in dietary plants and vegetables and have been proposed to have antiviral, antioxidant, cardiovascular protective, and anticancer effects. Volume-regulated anion channels (VRACs), which are essential for cell volume regulation, have been proposed to play a key role in cell proliferation and migration, apoptosis, transepithelial transport, and cancer development. In this study, we screened a group of 53 structurally related natural flavonoids and three synthetic flavonoids for their inhibitory activities on VRAC currents. A whole-cell patch technique was used to record VRAC currents in the human embryonic kidney (HEK) 293 and human umbilical vein endothelial (HUVEC) cells. The 5′-bromo-2-deoxyuridine (BrdU) assay technique was used to investigate cell proliferation. At 100xa0μM, 34 of 53 compounds significantly inhibited hypotonic extrasolution-induced VRAC currents by >u200950% in HEK293 cells. Among these compounds, luteolin, baicalein, eupatorin, galangin, quercetin, fisetin, karanjin, Dh-morin, genistein, irisolidone, and prunetin exhibited the highest efficacy for VRAC blockade (the mean inhibition >u200980%) with IC50s of 5–13xa0μM and Emaxs of about 87–99%. We also studied the effects of three synthetic flavonoids on VRAC currents in HEK293 cells. Flavoxate showed high inhibition efficacy toward VRAC currents (IC50u2009=u20092.3u2009±u20090.3xa0μM; Emaxu2009=u200991.8%u2009±u20092.7%). Finally, these flavonoids inhibited endogenous VRAC currents and cell proliferation in endothelial cells. This study demonstrates that natural and synthetic flavonoids are potent VRAC current inhibitors, and VRAC inhibition by flavonoids might be responsible for their anti-angiogenic effects.

Beyond voltage-gated ion channels: Voltage-operated membrane proteins and cellular processes

Voltage‐gated ion channels were believed to be the only voltage‐sensitive proteins in excitable (and some non‐excitable) cells for a long time. Emerging evidence indicates that the voltage‐operated model is shared by some other transmembrane proteins expressed in both excitable and non‐excitable cells. In this review, we summarize current knowledge about voltage‐operated proteins, which are not classic voltage‐gated ion channels as well as the voltage‐dependent processes in cells for which single voltage‐sensitive proteins have yet to be identified. Particularly, we will focus on the following. (1) Voltage‐sensitive phosphoinositide phosphatases (VSP) with four transmembrane segments homologous to the voltage sensor domain (VSD) of voltage‐gated ion channels; VSPs are the first family of proteins, other than the voltage‐gated ion channels, for which there is sufficient evidence for the existence of the VSD domain; (2) Voltage‐gated proton channels comprising of a single voltage‐sensing domain and lacking an identified pore domain; (3) G protein coupled receptors (GPCRs) that mediate the depolarization‐evoked potentiation of Ca2+ mobilization; (4) Plasma membrane (PM) depolarization‐induced but Ca2+‐independent exocytosis in neurons. (5) Voltage‐dependent metabolism of phosphatidylinositol 4,5‐bisphosphate (PtdIns[4,5]P2, PIP2) in the PM. These recent discoveries expand our understanding of voltage‐operated processes within cellular membranes.