Zinc-dependent histone deacetylases: Potential therapeutic targets for arterial hypertension.

The pathogenesis of hypertension caused by various genetic and environmental factors has not been elucidated. Clinical trials have evaluated various anti-hypertensive drugs with different therapeutic mechanisms. Due to the increasing prevalence of hypertension in the aging population and appearance of adverse effects, novel anti-hypertensive drugs need be developed. Histone deacetylases (HDACs), a group of enzymes which have recently attracted attention, are dysregulated in several cancers and cardiovascular diseases. Mammalian HDACs are categorized into four classes: class I HDAC (HDAC1, 2, 3, 8), class IIa HDAC (HDAC4, 5, 7, 9), class IIb HDAC (HDAC6, 10), and class IV HDAC (HDAC11) are zinc-dependent enzymes, while class III HDACs are nicotinamide adenine dinucleotide (NAD)-dependent enzymes. In this review, we focused on the pharmacological inhibitors of zinc-dependent HDACs used for controlling hypertension. We addressed the biological effects and underlying mechanisms of isoform-selective, class HDAC-selective, or pan-HDAC inhibitors on various hypertensive animal models (angiotensin II infusion mice, deoxycorticosterone acetate-salt-induced rats, spontaneously hypertensive rats, high-fat diet-treated mice, and nitric oxide (NO)-deficient mice) and HDAC5 deletion mice. We discuss the cardiovascular phenotypes of class I and IIa/b HDAC-deficient mice and potential adverse effects of HDAC inhibitors in preclinical studies. This review summarizes recent studies on synthetic or dietary HDAC inhibitors (sulforaphane, gallic acid, and curcumin) that alleviate hypertension by the regulating renin-angiotensin-aldosterone system, vascular hypertrophy, vasoconstriction, inflammation, or oxidative stress. Although the phenotypic analysis of hypertension in isoform HDAC deletion mice is required, few HDACs (HDAC3, HDAC4, and HDAC8) are promising therapeutic targets for treating hypertension.

The cytoprotective effect of Rumex Aquaticus Herba extract against hydrogen peroxide-induced oxidative stress in AGS cells.

The Rumex Aquaticus Herba extract containing quercetin-3-ß-D-glucuronopyranoside (ECQ) has been reported to exhibit various pharmacological activities, including anti-inflammatory and anti-oxidative effects. This plant has been traditionally used for the treatment of diarrhea, disinfestation, edema and jaundice, and as an antipyretic drug. The aim of the present study was to investigate the ability of ECQ to protect against oxidative damage and to determine its signaling mechanism in AGS cells. The protein expressions of heme oxygenase-1 (HO-1) and nuclear factor-erythroid 2 related factor 2 (Nrf2) were measured by Western blots. Cell viability was measured by MTT assay. Intracellular reactive oxygen species (ROS) levels were measured using 2',7'-dichlorofluorescein diacetate. Glutathione peroxidase levels were measured using kits. The protein expressions of HO-1 and its upstream mediator, Nrf2, increased after ECQ treatment. The HO-1 inhibitor, ZnPP, repressed the protective effect of ECQ on H2O2-induced cell damage. We found that LY294002, a specific PI3 K/Akt inhibitor, suppressed ECQ-induced HO-1 expression. ECQ significantly attenuated H2O2-induced cytotoxicity and ROS generation. Also, ECQ enhanced the antioxidant enzyme activities of glutathione peroxidase. These results suggest that ECQ exerts a cytoprotective effect against H2O2-induced oxidative stress by upregulation of Nrf2/HO-1 via the PI3 K/Akt pathway.

Upregulation of PBR mRNA expression in human neuroblastoma cells by flavonoids.

To investigate the putative mediation of peripheral benzodiazepine receptor (PBR) in the cytotoxicity of flavonoids, in this study, modulatory effects of several flavonoids on the lipid peroxide (LPO) production and PBR mRNA expression of human neuroblastoma cells were observed. Elevated levels of peroxidated products in cancer cells may activate pro-apoptotic and anti-proliferative signaling pathways. Treatment of 10(-6) M 4'-chlorodiazepam and PK 11195 ligands of the PBR for 6 days enhanced the generation of LPO of the human neuroblastoma cells. Several flavonoids, well-known cytotoxic substances, potentiated the enhancement of LPO production by PBR ligands. Treatment of 10(-6) M flavonoids for 6 days elevated the expression of PBR mRNA in cells. These findings indicate that the potential of flavonoids to induce apoptosis in cancer cells is strongly associated with their PBR-inducing properties, thereby providing a new mechanism by which polyphenolic compounds may exert their cancer-preventive and anti-neoplastic effects.

Anti-allergic effects of Lycopus lucidus on mast cell-mediated allergy model.

The current study characterizes the mechanism by which the aqueous extract of Lycopus lucidus Turcz. (Labiatae) (LAE) decreases mast cell-mediated immediate-type allergic reaction. The immediate-type allergic reaction is involved in many allergic diseases such as asthma and allergic rhinitis. LAE has been used as a traditional medicine in Korea and is known to have an anti-inflammatory effect. However, its specific mechanism of action is still unknown. LAE was anally administered to mice for high and fast absorption. LAE inhibited compound 48/80-induced systemic reactions in mice. LAE decreased the local allergic reaction, passive cutaneous anaphylaxis, activated by anti-dinitrophenyl (DNP) IgE antibody. LAE dose-dependently reduced histamine release from rat peritoneal mast cells activated by compound 48/80 or anti-DNP IgE. Furthermore, LAE decreased the secretion of TNF-alpha and IL-6 in phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187-stimulated human mast cells. The inhibitory effect of LAE on the pro-inflammatory cytokine was p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) dependent. LAE attenuated PMA plus A23187-induced degradation of IkappaBalpha and nuclear translocation of NF-kappaB, and specifically blocked activation of p38 MAPK, but not that of c-jun N-terminal kinase and extracellular signal-regulated kinase. Our findings provide evidence that LAE inhibits mast cell-derived immediate-type allergic reactions and involvement of pro-inflammatory cytokines, p38 MAPK, and NF-kappaB in these effects.