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We investigated the effect of asiatic acid (AA) on hemodynamic status, vascular function, oxidative stress markers, endothelial nitric oxide synthase (eNOS), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit expression in Nω-nitro- l-arginine methyl ester hydrochloride ( l-NAME)-induced hypertensive rats. Male Sprague-Dawley rats treated with l-NAME (40 mg/kg/day) in drinking water for 5 weeks showed significant increases in mean arterial pressure, heart rate, hindlimb vascular resistance, vascular dysfunction, superoxide anion (O2•−) production, and plasma malondialdehyde. Moreover, NO metabolite (NOx) levels were reduced, aortic eNOS expression was downregulated, and NADPH oxidase subunit p47phox was upregulated in hypertensive rats ( p < 0.05). Hypertensive rats that were administered AA (10 or 20 mg/kg/day) for the last 2 weeks of the study showed significant improvement in hemodynamic status and vascular function. The antihypertensive effects of AA were associated with elevated plasma NOx levels, together with upregulation of eNOS expression. Decreased vascular O2•− production, consistent with downregulation of p47phox expression, was also observed after AA treatment. Our results are therefore consistent with a model whereby AA reduces blood pressure by enhancing NO bioavailability. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background and Objective: Our recent study revealed the antihyperglycemic activity of an ethanolic extract of roselle calyxes (Hibiscus sabdariffa) in diabetic rats. The present study had, therefore, an objective to investigate the mechanism underlying this activity. Materials and Methods: Male Sprague Dawley rats were induced to be diabetes by intraperitoneal injection of 45 mg/kg streptozotocin (STZ). Normal rats as well as diabetic rats were administered with the ethanolic extract of H. sabdariffa calyxes (HS-EE) at 0.1 and 1.0 g/kg/day, respectively, for 6 weeks. Then, blood glucose and insulin levels, at basal and glucose-stimulated secretions, were measured. The pancreas was dissected to examine histologically. Results: HS-EE 1.0 g/kg/day significantly decreased the blood glucose level by 38 ± 12% in diabetic rats but not in normal rats. In normal rats, treatment with 1.0 g/kg HS-EE increased the basal insulin level significantly as compared with control normal rats (1.28 ± 0.25 and 0.55 ± 0.05 ng/ml, respectively). Interestingly, diabetic rats treated with 1.0 g/kg HS-EE also showed a significant increase in basal insulin level as compared with the control diabetic rats (0.30 ± 0.05 and 0.15 ± 0.01 ng/ml, respectively). Concerning microscopic histological examination, HS-EE 1.0 g/kg significantly increased the number of islets of Langerhans in both normal rats (1.2 ± 0.1 and 2.0 ± 0.1 islet number/10 low-power fields (LPF) for control and HS-EE treated group, respectively) and diabetic rats (1.0 ± 0.3 and 3.9 ± 0.6 islet number/10 LPF for control and HS-EE treated group, respectively). Conclusion: The antidiabetic activity of HS-EE may be partially mediated via the stimulating effect on insulin secretion. [ABSTRACT FROM AUTHOR]

Background: Phenethyl isothiocyanate (PEITC) is a cancer chemopreventive agent from cruciferous vegetables. Cholangiocarcinoma (CCA) is a chemo-resistant cancer with very poor prognosis. We evaluated the effects of PEITC on induction of apoptotic cell death in relation to cellular glutathione (GSH) and mitochondrial function of a CCA cell line, KKU-M214.Methods: Cytotoxic effects of PEITC on a CCA cell line, KKU-M214, and a reference cell line, Chang cells were evaluated. To delineate mechanisms of cell death, the following parameters were measured; GSH and superoxide levels as the oxidative status parameters, apoptosis related proteins levels using Western blotting. Cellular free calcium level and mitochondrial transmembrane potential were also measured.Results: PEITC induced apoptotic cell death of both KKU-M214 and Chang cells. After PEITC treatment, both cells showed decrease of Bcl-xl and increase of Bax levels. While KKU-M214 cells released AIF, Chang cells released cytochrome c, with subsequent activation of caspase 3 and 9, upon PEITC treatment. PEITC induced superoxide formation in both cells, although it seemed not play a role in cell death. PEITC caused GSH redox stress in different ways in two cell types, because N-acetylcysteine (NAC) prevented redox stress in Chang but not in KKU-M214 cells. The loss of mitochondrial transmembrane potential was induced by PEITC concurrent with GSH stress, but was not a primary cause of cell death. The rapid increase of free calcium level in cytosol was associated with cell death in both cell lines. These events were prevented by NAC in Chang cells, but not in KKU-M214 cells.Conclusion: PEITC induced cell death KKU-M214 cells and Chang cells via increase of cellular calcium mobilization and activation of mitochondrial cell death pathway. The effects of PEITC on the redox stress was mediated via different ways in CCA and Chang cells because NAC could prevent redox stress in Chang cells, but not in KKU-M214 cells. The multiple effects of PEITC may be useful for the development of novel chemotherapy for CCA. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the cytoprotective effect of tetrahydrocurcumin, (THC) and curcumin (CUR) on cytotoxicity induced by doxorubicin and cadmium in Chang liver cells. Methods: Cytotoxicity was determined by sulforhodamine B assay. The expression of nuclear factorerythroid- 2-related factor 2 (Nrf2) Nrf2 regulated cytoprotecetive enzymes, glutamylcysteine ligase catalytic subunit (GCLC) and NADP (H): quinone oxidoreductase1 (NQO1) was determined by Western blot analysis. Nuclear translocation of Nrf-2 was analyzed by immunofluorescence method. The level of superoxide formation was assayed by chemiluminescence method. Results: Treatment with THC or CUR significantly induced GCLC and NQO1 expression and the nuclear translocation of Nrf2. Exposure to doxorubicin (DOX) or Cd for 24 h induced cell death of about 50%. However, pre-treatment with THC or CUR (1 or 6 µM) for 24 h significantly increased cell survival to 80 or 90%, respectively (p < 0.05). Similar pre-treatment with THC or CUR significantly protected against Cd-induced cell death by a level of 80 and 85%, respectively (p < 0.05). The cytoprotective effect of these compounds was associated with suppressed DOX- and Cd-induced superoxide formation and induction of GCLC and NQO1 expression. Conclusions: THC mediates its effects by activation of Nrf2 and its regulated enzymes, GCLC and NQO1. Induction of GCLC, NQO1 protein expression and suppression of superoxide are associated with the cytoprotective effect. [ABSTRACT FROM AUTHOR]

Phenformin (Phen), a potent activator of AMPK, is effective against some resistant cancers. This study evaluated the inhibition of proliferation, migration, invasion, and angiogenesis by Phen in aggressive cancer cells and investigated the underlying mechanism of the inhibition. Cholangiocarcinoma (CCA) KKU-156 and KKU-452 cells were used in this study. The results showed that Phen suppressed cell proliferation and induced apoptosis in both cells. Phen suppressed migration and invasion of cancer cells in wound healing and transwell chamber assays, respectively. The effects were associated with depletions of glutathione (GSH) and decreased glutathione redox ratio which represents cellular redox state. The redox stress was linked with the loss of mitochondrial transmembrane potential, as evaluated by JC-1 assay. The effect of Phen on angiogenesis was performed using HUVEC cultured cells. Phen alone did not affect tube formation of HUVEC cells. However, conditioned media from CCA cell cultures treated with Phen suppressed the tube-like structure formation. The antitumor effect of Phen was associated with AMPK activation and suppression of mTOR phosphorylation, HIF-1A, and VEGF protein expression. In conclusion, Phen inhibits cell proliferation, migration, invasion, and angiogenesis probably through AMPK-mTOR and HIF-1A-VEGF pathways. Phen may be repurposed as chemoprevention of cancer.

Tangeretin is a polymethoxyflavone concentrated in citrus peels and has several biological activities. This study examined whether tangeretin improved reproductive dysfunction in N ω -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats received L-NAME to induce hypertension and reproductive dysfunction for 5 w and were treated with tangeretin (15 or 30 mg/kg) or sildenafil citrate (10 mg/kg) for the final two weeks. Mean arterial pressure (MAP), intracavernosal pressure (ICP) response to cavernous nerve stimulation, endothelial nitric oxide synthase (eNOS), Angiotensin II receptor type 1 (AT 1 R) and gp91 phox protein expressions and malondialdehyde (MDA) level in penile tissues were measured. Sperm concentrations and motility, seminiferous tubule morphology, serum testosterone, testicular eNOS and steroidogenic acute regulatory protein (StAR) expression were evaluated. Aortic superoxide generation, plasma and testicular MDA and plasma nitrate/nitrite levels were determined. Tangeretin reduced blood pressure and increased the maximum ICP/MAP associated with suppression of AT 1 R/gp91phox and upregulation of eNOS expression in hypertensive rats (P < 0.05). Furthermore, improvement of sperm quality relevant to increased testicular eNOS and StAR expression was found in tangeretin treated rats (P < 0.05). Changes in seminiferous tubule morphology in hypertensive rats were recovered by tangeretin (P < 0.05). It increased testosterone levels and reduced oxidative stress biomarkers and raised plasma nitrate/nitrite levels in L-NAME rats (P < 0.05). In conclusion, tangeretin improved maximum ICP/MAP and testicular dysfunction and morphology in rats treated with L-NAME. The molecular mechanisms are mediated by modulations of penile eNOS and AT 1 R/gp91 phox expressions and testicular eNOS and StAR expression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Oxidative stress plays a critical role in the pathophysiology of hypertension (HT) and the progression of atherosclerotic coronary artery disease (CAD). Genetic variations in superoxide dismutase (SOD), glutathione peroxidase 3 (GPX3), paraoxonase 1 (PON1) and glutathione S-transferase theta 1 (GSTT1) may modulate their gene functions, affecting protein functions. These changes could have an impact on the pathogenesis of HT and progression of CAD. The present study investigated the associations of individual and combined antioxidant-related gene polymorphisms with the incidence of HT and severity of CAD. Two study populations were enrolled. The HT-associated study comprised 735 control and 735 hypertensive subjects (mean age 59.3 ± 9.0 years), matched for age and sex. The CAD study, hospital-based subjects (mean age 62.1 ± 9.5 years), included 279 CAD patients and 165 non-CAD subjects. Gene polymorphisms were identified in genomic DNA using polymerase chain reaction (PCR)-based technique. Genetic variations were assessed for their associations with HT and severity of CAD. Antioxidant gene variants, SOD3 rs2536512-GG, GPX3 rs3828599-GG, PON1 rs705379-TT, and GSTT1 -/- and +/- , were independently associated with the incidence of HT. A combination of four HT-associated genotypes, as a genetic risk score (GRS), revealed an association of GRS 5 and GRS ≥ 6 with increased susceptibility to HT and CAD, and further with multivessel coronary atherosclerosis (multivessel CAD) compared with GRS 0-2 [respective ORs(95% CI) for GRS ≥ 6 = 2.37 (1.46-3.85), 3.26 (1.29-8.25), and 4.36 (1.36-14.0)]. Combined polymorphisms in these four antioxidant-related genes were associated with the incidences of HT and CAD, and with the severity of coronary atherosclerosis.

Rice bran hydrolysates contain highly nutritional proteins and beneficial phytochemicals. Sang-Yod rice bran hydrolysates (SRH) extracted from red pigmented rice is a rich source of nutrients and phenolic compounds. The present study evaluated the antihypertensive effect of SRH and its safety in Sprague-Dawley rats. Hypertension was induced in male rats by administration of L-NAME (50 mg/kg/day) in drinking water for three weeks, and the antihypertensive effect of SRH was evaluated. Treatment of SRH (250 or 500 mg/kg) significantly reduced arterial blood pressure and improved hemodynamic parameters. The antihypertensive effect was associated with decreased oxidative stress, suppressed p47 phox NADPH oxidase expression, increased nitric oxide bioavailability and decreased angiotensin II level and ACE activity. The SRH was shown to be safe after feeding male and female rats with a rodent diet containing 1.5% SRH for 90 days. Overall, these findings suggest that SRH is safe and may help to prevent hypertension.

Tangeretin is a citrus flavonoid that exerts several beneficial effects, including anti-inflammation, anti-oxidation and neuroprotection. In this study, the aim was to test the effect of tangeretin on Nω-Nitro-l-arginine methyl ester (l-NAME)-induced high blood pressure, and left ventricular dysfunction and remodeling in rats. Rats were divided into five groups (n = 8 per each group): a control group, an l-NAME group and three l-NAME groups treated with tangeretin (15 mg kg-1) or tangeretin (30 mg kg-1) or captopril (5 mg kg-1) for the final two weeks. After five weeks of experiment, l-NAME groups had high systolic blood pressures, and ventricular dysfunction and remodeling. Overexpression of angiotensin II type 1 receptor, phosphorylated-extracellular-regulated kinase 1/2 (pERK1/2), and phosphorylated-c-Jun N-terminal kinase (pJNK) protein but downregulation of endothelial nitric oxide synthase (eNOS) protein expression in ventricular tissues were observed in hypertensive rats while the protein expression of phosphorylated-mitogen activated protein kinase p38 did not differ among groups. The decrease in plasma NOx and increase in vascular superoxide generation, plasma malondialdehyde, angiotensin-converting enzyme activity and angiotensin II levels were found in hypertensive rats. These alterations were suppressed in hypertensive rats treated with tangeretin or captopril. In conclusion, tangeretin exhibits antihypertensive effects and alleviates ventricular dysfunction and remodeling in hypertensive rats. These effects are associated with the inhibition of renin angiotensin system activation and restoration of pERK1/2, pJNK, and eNOS protein expressions along with reduced oxidative stress and increased NO bioavailability.

Objective: Endothelial dysfunction associated with reduction in nitric oxide (NO) bioavailability plays an important role in development of hypertension. Consumption of a diet rich in antioxidants appears to lower the risk for hypertension. Virgin rice bran oil (VRBO) possesses antioxidant, anti-inflammatory, and hypocholesterolemic activities. However, to our knowledge, the antihypertensive effect of VRBO has not been investigated. The aim of this study was to examine the antihypertensive effect of VRBO in N ω -nitro-l-arginine methyl ester (L-NAME)-induced hypertensive rats and its underlying mechanisms., Methods: Hypertension was induced in rats by administration of L-NAME, after which VRBO, lisinopril (Lis), or VRBO + Lis was administered. Studies were then conducted on the hemodynamics of vascular responses to vasoactive substances, plasma angiotensin-converting enzyme (ACE), plasma nitrate/nitrite, oxidative stress, and inflammatory markers., Results: L-NAME administration induced hemodynamic changes including elevation of blood pressure, increased peripheral vascular resistance, and endothelial dysfunction. Reduction in plasma nitrate/nitrite, overproduction of vascular superoxide, and increases in plasma ACE, malondialdehyde, protein carbonyl, and plasma tumor necrosis factor-α were observed in L-NAME hypertensive rats. The changes were associated with a marked decrease in endothelial NO synthase expression, increased expression of gp91 phox and vascular cell adhesion molecule-1, and activation of nuclear factor-κB in aortic tissues. Administration of either VRBO or Lis significantly mitigated all of these deleterious effects. The combination of VRBO and Lis was more effective than either treatment alone., Conclusions: The antihypertensive effect of VRBO may be mediated by restoration of hemodynamics, increased NO bioavailability, and alleviation of oxidative stress and inflammation. VRBO has an additive effect on antihypertensive medication., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Coronary stenosis is a consequence of atherosclerotic plaque progression that is associated with impaired fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor 1 (PAI-1) are fibrinolysis inhibitors whose levels are influenced by acquired conditions and by polymorphisms. This study therefore aimed to investigate the association of TAFI and PAI-1 gene polymorphisms with severity of coronary stenosis in subjects with stable coronary artery disease (CAD)., Materials and Methods: A total of 327 subjects suspected with CAD who underwent a coronary angiogram were recruited. Gensini score was applied to stratify the severity of coronary stenosis. Based on the Gensini score, the subjects were categorized into low-medium (<20) or high (≥20) groups. The study polymorphisms included TAFI Ala147Thr (505G/A), Thr325Ile (1040C/T), +1542C/G, +1583T/A and PAI-1 -675 4G/5G. Most polymorphisms were genotyped by allele-specific polymerase chain reaction, except for TAFI Thr325Ile that was genotyped by polymerase chain reaction-restriction fragment length polymorphism., Results: A significant increase in the Gensini score was found in TAFI 505A and +1583A allele carriers. Binary regression analysis revealed the independent association of the TAFI 505G/A and +1583T/A polymorphisms with a high Gensini score [adjusted OR = 1.67 (95% CI: 1.03, 2.73) and 1.69 (95% CI: 1.04, 2.76), respectively]. Neither the homozygous PAI-1 -675 4G/4G nor the heterozygous 4G/5G was associated with a high Gensini score., Conclusions: The results indicated the contribution of TAFI polymorphisms to atherosclerosis progression and severity of coronary stenosis in stable CAD., (Copyright © 2018. Published by Elsevier Ltd.)

Aims: Transcription factor Nrf2, which regulates the expression of cytoprotective and antioxidant enzymes, contributes to proliferation and resistance to chemotherapy in cancer. The inhibition of Nrf2 can sensitize cholangiocarcinoma (CCA) cells to the cytotoxicity of several chemotherapeutic agents. In this study, we investigated the mechanism of this chemosensitizing effect., Main Methods: KKU-100 cells were used in the study. Nrf2 expression was knocked down by siRNA and expression was validated by reverse transcription and polymerase chain reaction. Cytotoxicity was assessed by sulforhodamine B method. Intracellular reactive oxygen species (ROS) was examined by fluorescent dye, dichlorofluorescin diacetate method and mitochondrial transmembrane potential was assessed by JC1 dye assay., Key Findings: Cytotoxicity of cisplatin (Cis) in KKU-100 cells was enhanced by knockdown of Nrf2 expression. The enhanced cytotoxic effect was abolished by treatment with N-acetylcysteine, TEMPOL and MnTBAP. Cells with Nrf2 knockdown or Cis treatment increased production of ROS, and ROS was markedly enhanced by a combination of Nrf2 knockdown and Cis. The increased ROS formation was associated with a decrease in mitochondrial transmembrane potential (Δψ m ), where this decrease was prevented by antioxidant compounds. The loss of Δψ m and cell death were prevented by cyclosporine, an inhibitor of mitochondrial permeability transition pore (MPTP). Luteolin inhibited Nrf2 and markedly enhanced cytotoxicity in combination with Cis., Significance: Inhibition of Nrf2 is a feasible strategy in enhancing antitumor activity of chemotherapeutic agents and improving efficacy of chemotherapy in CCA., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Carthamus tinctorius L. (CT) is widely used in Asian countries as a beverage and in folk medicine. The effects of CT extract on hemodynamics, vascular remodeling, the renin-angiotensin system (RAS) and oxidative stress in the two-kidney, one clip (2K-1C) hypertensive rat model were investigated. Renovascular hypertension was induced in male Sprague-Dawley rats and were treated with CT extract (500mg/kg/day) or captopril (5mg/kg/day) or vehicle for four weeks. CT extract or captopril reduced blood pressure, hindlimb vascular resistance, and increased hindlimb blood flow in 2K-1C hypertensive rats (p<0.05). Increases in aortic wall thickness, cross-sectional area and collagen deposition in 2K-1C rats were alleviated with CT extract or captopril treatment (p<0.05). CT extract or captopril suppressed RAS activation, including elevated serum ACE activity, and plasma Ang II level and up-regulated aortic AT 1 R protein expression in 2K-1C rats (p<0.05). Furthermore, CT extract or captopril reduced vascular superoxide production, aortic NADPH oxidase subunit gp91 phox expression and increased plasma nitric oxide metabolite levels in 2K-1C rats (p<0.05). These findings suggest that CT extract ameliorated hemodynamic alteration and vascular remodeling in 2K-1C hypertensive rats. Possible mechanisms may involve RAS inhibitor effects and potent antioxidant activity., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Morbid obesity, the most significant risk factor for development of sev- eral respiratory diseases, is linked to decreased pulmonary function. The aim of this study was to determine the relationships between pulmonary function and plasma levels of homeostasis model assessment-insulin resistance (HOMA-IR), insulin, leptin, hs-CRP and fasting glucose. Values were measured in 39 Thai children and adolescents, divided into three groups according to lung function (forced expiratory volume in one second, FEV1); normal (Group A) FEV1 ≥ 80% (n = 19), obese normal (Group B) FEV1 ≥ 80% (n = 14) and obese (Group C) FEV1 < 80% (n = 6). Body mass index was highest in group C. Groups A and B were comparable for FEV1, forced vital capacity (FVC), maximal voluntary ventilation (MVV) and FEV1/FVC, whereas Group C exhibited significantly reduced FEV1, FVC and MVV but a normal FEV1/FVC ratio. All values except the FEV1/FVC ratio were significantly lower than in groups A and B. Group C had significantly higher levels of leptin, insulin, FG and HOMA-IR than Groups A and B (p < 0.001). There was a significant negative correlation between FEV1 and MVV with leptin, insulin and HOMA-IR, but not with high-sensitivity C-reactive protein (hs-CRP). We conclude that FEV1 is reduced in obese children and adolescents and inversely correlates with plasma leptin, insulin and HOMA-IR levels. We have shown that the most important factor in inducing a restrictive lung in these patients may be related to leptin status.

Hemoglobin E/β-thalassemia (HbE/β-thalassemia) is the most important type of thalassemia in northeastern Thailand. Serious complications of the disease are associated with iron overload and the consequences of oxidative damage to various organs, especially the cardiovascular system. Endothelial dysfunction is an important predictor for the long-term outcome of the disease. In this study, 19 patients with HbE/β-thalassemia (aged 12.9 ± 2.8 years) and 18 healthy controls (aged 11.8 ± 1.6 years) were enrolled and their oxidant and antioxidant status was determined. Their vascular endothelial function was assessed by ultrasonographic measurement of flow-mediated dilation (FMD) of the brachial artery. The thalassemia patients were found to have higher levels of oxidative stress (based on plasma levels of malondialdehyde and protein carbonyls) and significantly reduced antioxidant levels [based on levels of glutathione (GSH) in whole blood (p < 0.001)]. Thalassemia patients showed endothelial dysfunction as shown by their FMD response during reactive hyperemia (p < 0.001). The degree of impaired FMD response was correlated with the age, hemoglobin levels and serum free iron levels of subjects (p < 0.05). In conclusion, the FMD response was reduced in children with HbE/β-thalassemia and the degree of this reduction was correlated with the severity of anemia. FMD can be used for clinical evaluation of endothelial dysfunction, which could be an independent predictor of the cardiovascular events of thalassemia patients.

Aim: To investigate whether dicoumarol, a potent inhibitor of NAD(P)H quinone oxidoreductase-1 (NQO1), potentiates gemcitabine to induce cytotoxicity in cholangiocarcinoma cells (CCA) and the role of reactive oxygen generation in sensitizing the cells., Methods: Four human cell lines with different NQO1 activity were used; the human CCA cell lines, KKU-100, KKU-OCA17, KKU-M214, and Chang liver cells. NQO1 activity and mRNA expression were determined. The cells were pretreated with dicoumarol at relevant concentrations before treatment with gemcitabine. Cytotoxicity was determined by staining with fluorescent dyes. Oxidant formation was examined by assay of cellular glutathione levels and reactive oxygen species production by using dihydrofluorescein diacetate. Measurement of mitochondrial transmembrane potential was performed by using JC-1 fluorescent probe. Western blotting analysis was performed to determine levels of survival related proteins., Results: Dicoumarol markedly enhanced the cytotoxicity of gemcitabine in KKU-100 and KKU-OCA17, the high NQO1 activity and mRNA expressing cells, but not in the other cells with low NQO1 activity. Dicoumarol induced a marked decrease in cellular redox of glutathione in KKU-100 cells, in contrast to KKU-M214 cells. Dicoumarol at concentrations that inhibited NQO1 activity did not alter mitochondrial transmembrane potential and production of reactive oxygen species. Gemcitabine alone induced activation of NF-kappaB and Bcl-(XL) protein expression. However, gemcitabine and dicoumarol combination induced increased p53 and decreased Bcl-(XL) levels in KKU-100, but not in KKU-M214 cells., Conclusion: NQO1 may be important in sensitizing cells to anticancer drugs and inhibition of NQO1 may be a strategy for the treatment of CCA.

Objective: To evaluate the drug metabolizing enzyme CYP1A2 activity in pediatric hemoglobin E-beta-thalassemia patients, since CYP1A2 is responsible for the metabolism of a number of drugs. Alteration of its activity may have clinical consequences., Material and Method: Twenty-three hemoglobin E-beta thalassemia pediatric patients and 24 age-matched controls were recruited in the present study. Caffeine in the form of a soft drink was orally administered as a test probe for CYP1A2 activity. Plasma collected at pre-dose and 6 hr after intake was analyzed for the levels of caffeine and paraxanthine, its major metabolite to represent the activity of CYPIA2., Results: Biochemical markers, including blood glutathione and urinary lipid hydroperoxides indicated that patients were in an oxidant stress state. The plasma ratio of paraxanthine to caffeine was unchanged between patients and controls. Multiple regression analysis revealed that gender and the liver enzyme were the significant determinants of CYP1A2 activity (adjusted r2 = 0.48, p < 0.001). Male gender was associated with higher activity of CYP1A2 activity., Conclusion: The CYP1A2 activity is not apparently changed in thalassemia patients despite the presence of an oxidative stress state.

Tetracera loureiri is one of the most valued herbs in Thai traditional medicine. In this study, we describe its in vitro and in vivo antioxidant and hepatoprotective activities. The ethanol extract of T. loureiri possessed potent antioxidant and strong free radical scavenging properties assayed using ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH), respectively. The cytoprotective effects of T. loureiri were demonstrated in ethanolic extracts of freshly isolated rat hepatocytes against the chemical toxicants paracetamol and tertiary-butylhydroperoxide. The cells pretreated with the extract maintained the GSH/GSSG ratio and suppressed lipid peroxidation in a dose dependent manner. Pretreating rats with the ethanol extract orally, one hour prior to intraperitoneal injection of toxic doses of paracetamol, significantly prevented elevations of plasma ALT and AST. These results suggest that T. loureiri may be of potential therapeutic value in some liver disorders., (Copyright 2003 John Wiley & Sons, Ltd.)