Mechanistic studies of cancer cell mitochondria- and NQO1-mediated redox activation of beta-lapachone, a potentially novel anticancer agent.

Unlabelled: Beta-lapachone (beta-Lp) derived from the Lapacho tree is a potentially novel anticancer agent currently under clinical trials. Previous studies suggested that redox activation of beta-Lp catalyzed by

Nad(p)h: quinone oxidoreductase 1 (NQO1) accounted for its killing of cancer cells. However, the exact mechanisms of this effect remain largely unknown.

Paraoxonases function as unique protectors against cardiovascular diseases and diabetes: Updated experimental and clinical data.

Paraoxonase (PON) refers to a family of three enzymes, namely PON1, PON2, and PON3. PON1 and PON3 are found in circulation bound to high-density lipoprotein, whereas PON2 is an intracellular protein. PON1 was first discovered as an enzyme to hydrolyze the organophosphate pesticide paraoxon, an activity that both PON2 and PON3 lack.

Early diurnal variation of serum leptin and adiponectin in nontreated obstructive sleep apnea disease: a prospective observational study.

Background: Obstructive sleep apnea (OSA) is a common disorder resulting in a myriad of adverse vascular risks, including altered inflammatory/anti-inflammatory adipokine balance. Recent studies are yet to agree on how this balance responds to the OSA severity. As it is customary in these studies to obtain a single blood sample in participants after completion of the nocturnal polysomnogram (PSG), we hypothesized that these adipokines' early ultradian pulsatility might contribute to the reported contradictory results.

Protective effects of extracts from Fructus rhodomyrti against oxidative DNA damage in vitro and in vivo.

Objective: To evaluate the potential protective effects of extracts from Fructus rhodomyrti (FR) against oxidative DNA damage using a cellular system and the antioxidant ability on potassium bromate- (KBrO3-) mediated oxidative stress in rats.

Methods: The effects of FR on DNA damage induced by hydrogen peroxide (H2O2) were evaluated by comet assay in primary spleen lymphocytes cultures. The effects of FR on the activities of SOD, CAT, and GPx and the levels of GSH, hydroperoxides, and 8-OHdG were determined in the plasma and tissues of rats treated with KBrO3.

Leptin's activity on the hydroxyl radical: a possible link to the oxidative stress-related endothelial vasodilation in patients with obstructive sleep apnea.

Purpose: Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity, whereas the underlying mechanism is still eluding, the thought participants are chronic intermittent hypoxia with consequent increase in the reactive oxygen species, leading to endothelial cell damage and dysfunction in these patients. As the hydroxyl radical (·OH) mediates the vascular smooth muscle relaxation, identification of its scavengers might reveal sentinel markers of decreased vascular responsiveness and worse long-term comorbid outcome. We therefore assessed leptin's scavenger effect on (∙)OH using the electronic paramagnetic resonance (EPR) method.

Genistein inhibits TNF-α-induced endothelial inflammation through the protein kinase pathway A and improves vascular inflammation in C57BL/6 mice.

Genistein, a soy isoflavone, has received wide attention for its potential to improve vascular function, but the mechanism of this effect is unclear. Here, we report that genistein at physiological concentrations (0.1 μM-5 μM) significantly inhibited TNF-α-induced adhesion of monocytes to human umbilical vein endothelial cells, a key event in the pathogenesis of atherosclerosis.

Protection against peroxynitrite-induced DNA damage by mesalamine: implications for anti-inflammation and anti-cancer activity.

Mesalamine (5-aminosalicylic acid, 5-ASA) is known to be the first-line medication for treatment of patients with ulcerative colitis. Studies have demonstrated that ulcerative colitis patients treated with 5-ASA have an overall decrease in the risk of developing colorectal carcinoma. However, the mechanisms underlying 5-ASA-mediated anti-inflammatory and anti-cancer effects are yet to be elucidated.

Oxidative stress and redox signaling mechanisms of alcoholic liver disease: updated experimental and clinical evidence.

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the United States and Europe. The spectrum of ALD ranges from fatty liver to alcoholic hepatitis and cirrhosis, which may eventually lead to hepatocellular carcinoma. In developed countries as well as developing nations, ALD is a major cause of end-stage liver disease that requires liver transplantation.

Role of leptin as antioxidant in obstructive sleep apnea: an in vitro study using electron paramagnetic resonance method.

Introduction: As in obstructive sleep apnea (OSA), the chronic cycles of hypoxia and reoxygenation are thought to be conducive of oxidative stress (OS) with generation of reactive oxygen species, identifying effective mechanisms of protection against oxidant-mediated tissue damage becomes of outmost importance. Leptin's role had been recently extended into that of participant to OS; while its exact role in this process is yet to be defined, elevated leptin levels correlate significantly with several indices of OSA disease severity such as nocturnal hypoxemia, possibly acting as a counteractive mechanism against the chronic intermittent hypoxia-related OS and serving as a marker of future risk of atherosclerotic disease. We therefore investigated leptin's antioxidant mechanism on superoxide (O (2) (-•) ) anions using spectrophotometry and electron paramagnetic resonance (EPR).

EPR studies on hydroxyl radical-scavenging activities of pravastatin and fluvastatin.

Statins are known clinically by their cholesterol reduction properties through the inhibition of HMG-CoA reductase. There is mounting evidence suggesting a protective role of statins in certain types of cancer, cardiac, and vascular disease through a mechanism that extends beyond their lipid lowering ability. The root mechanism of damage likely involves the inflammatory cascade, specifically compounds known as reactive oxygen species such as the hydroxyl radical.

Genistein induces pancreatic beta-cell proliferation through activation of multiple signaling pathways and prevents insulin-deficient diabetes in mice.

Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic beta-cell function are very limited. In the present study, we investigated the effect of genistein on beta-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice.

Potent inhibition of peroxynitrite-induced DNA strand breakage and hydroxyl radical formation by dimethyl sulfoxide at very low concentrations.

Dimethyl sulfoxide (DMSO) is frequently used as a solvent for many water-insoluble drugs in biological studies at concentrations often up to 1%. However, little is known about its effects on oxidatively generated DNA damage at very low concentrations (0.005-0.

The neuroprotective effect of intranasally applied leptin against hypoxic neuronal injury.

Hypoxia may result from hypoperfusion, as seen in the cardio-respiratory arrest. Subsequent to the acute neuronal damage, the delayed neuronal death ensues, and further neurons die within hours or days thereafter. An effective neuroprotective therapeutic agent should counteract one or, ideally, all well-established neuronal death pathways, i.

Malathion, lindane, and piperonyl butoxide, individually or in combined mixtures, induce immunotoxicity via apoptosis in murine splenocytes in vitro.

Lindane, malathion, and piperonyl butoxide were cultured singly or as mixtures with murine splenocytes to evaluate changes in cell death and caused cytotoxicity in a concentration- and time-dependent manner. Pesticide mixture studies were then performed based on minimum cytotoxicity concentrations ( View Article and Find Full Text PDF

Inhibition of peroxynitrite-mediated DNA strand cleavage and hydroxyl radical formation by aspirin at pharmacologically relevant concentrations: implications for cancer intervention.

Epidemiological studies have suggested that the long-term use of aspirin is associated with a decreased incidence of human malignancies, especially colorectal cancer. Since accumulating evidence indicates that peroxynitrite is critically involved in multistage carcinogenesis, this study was undertaken to investigate the ability of aspirin to inhibit peroxynitrite-mediated DNA damage. Peroxynitrite and its generator 3-morpholinosydnonimine (SIN-1) were used to cause DNA strand breaks in phiX-174 plasmid DNA.

Ethyl pyruvate inhibits peroxynitrite-induced DNA damage and hydroxyl radical generation: implications for neuroprotection.

Ethyl pyruvate (EP) has recently been reported to afford protection against neurodegenerative disorders. However, the mechanism underlying EP-mediated neuroprotection remains to be elucidated. Because peroxynitrite has been extensively implicated in the pathogenesis of various forms of neurodegenerative disorders via its cytotoxic effects, this study was undertaken to investigate whether the neuroprotective effect of EP is associated with inhibition of peroxynitrite-induced DNA strand breaks, a critical event leading to peroxynitrite elicited cytotoxicity.

Cruciferous nutraceutical 3H-1,2-dithiole-3-thione protects human primary astrocytes against neurocytotoxicity elicited by MPTP, MPP(+), 6-OHDA, HNE and acrolein.

Astrocytes possess important roles in maintaining normal brain function and providing trophic support to the neurons. They also suffer a range of toxic insults, being a chief target of prooxidants such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridinium (MPP(+)), 6-hydroxydopamine (6-OHDA), 4-hydroxy-2-nonenal (HNE), and acrolein. Recently, we have observed that the cellular antioxidants and phase 2 enzymes can be upregulated by 3H-1,2-dithiole-3-thione (D3T), a nutraceutical found in cruciferous vegetables, against many prooxidants in human neuroblastoma cell lines (SH-SY5Y).

Cruciferous dithiolethione-mediated coordinated induction of total cellular and mitochondrial antioxidants and phase 2 enzymes in human primary cardiomyocytes: cytoprotection against oxidative/electrophilic stress and doxorubicin toxicity.

3H-1,2-dithiole-3-thione (D3T), a cruciferous organosulfur compound, induces cytoprotective enzymes in animal cardiovascular cells. However, it remains unknown if D3T also upregulates antioxidants and phase 2 enzymes in human cardiomyocytes, and protects against cell injury induced by oxidative/electrophilic species as well as doxorubicin. In this study, we found that D3T (10-50 muM) potently induced a series of antioxidants and phase 2 enzymes in primary cultured human cardiomyocytes, including superoxide dismutase (SOD), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx) glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), aldose reductase (AR), and heme oxygenase (HO).

Alpha-lipoic acid potently inhibits peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation: implications for the neuroprotective effects of alpha-lipoic acid.

Alpha-lipoic acid (LA) has recently been reported to afford protection against neurodegenerative disorders in humans and experimental animals. However, the mechanisms underlying LA-mediated neuroprotection remain an enigma. Because peroxynitrite has been extensively implicated in the pathogenesis of various forms of neurodegenerative disorders, this study was undertaken to investigate the effects of LA in peroxynitrite-induced DNA strand breaks, a critical event leading to peroxynitrite-elicited cytotoxicity.

Upregulation of cellular glutathione by 3H-1,2-dithiole-3-thione as a possible treatment strategy for protecting against acrolein-induced neurocytotoxicity.

Acrolein, an unsaturated aldehydic product of lipid peroxidation, has been implicated in the pathogenesis of various neurodegenerative disorders including Parkinson's disease. However, protection against acrolein toxicity in neuronal cells via chemical upregulation of cellular aldehyde-detoxification factors has not been investigated. In this study, we have investigated the induction of glutathione (GSH), GSH S-transferase (GST), and aldose reductase (AR) by the unique nutraceutical compound 3H-1,2-dithiole-3-thione (D3T); and the protective effects of the D3T-mediated cellular defenses on acrolein-mediated toxicity in human neuroblastoma SH-SY5Y cells.

Carcinogenic chromium(VI)-induced protein oxidation and lipid peroxidation: implications in DNA-protein crosslinking.

Hexavalent chromium [Cr(VI)] compounds are Group-I human carcinogens. Cr(VI)-induced DNA-protein crosslinks (DPCs) have been implicated in the mutagenic and carcinogenic effects of Cr(VI). Although multiple mechanisms have been suggested for Cr(VI)-induced DNA-protein crosslinking, the mechanism of formation of DNA-protein crosslinks is not well understood.

Potent induction of total cellular and mitochondrial antioxidants and phase 2 enzymes by cruciferous sulforaphane in rat aortic smooth muscle cells: cytoprotection against oxidative and electrophilic stress.

Sulforaphane, a cruciferous isothiocyanate compound, upregulates cytoprotective genes in liver, but its effects on antioxidants and phase 2 defenses in vascular cells are unknown. Here we report that incubation of rat aortic smooth muscle A10 cells with sulforaphane (0.25-5 microM) resulted in concentration-dependent induction of a spectrum of important cellular antioxidants and phase 2 enzymes, including superoxide dismutase (SOD), catalase, the reduced form of glutathione (GSH), glutathione peroxidase, glutathione reductase (GR), glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase 1 (NQO1).

Nuclear factor E2-related factor 2-dependent myocardiac cytoprotection against oxidative and electrophilic stress.

Nuclear factor E2-related factor 2 (Nrf2) is a critical regulator of cytoprotective gene expression. However, the role of this transcription factor in myocardiac cytoprotection against oxidative and electrophilic stress remains unknown. This study was undertaken to investigate if Nrf2 signaling could control the constitutive and inducible expression of antioxidants and phase 2 enzymes in primary cardiomyocytes as well as the susceptibility of these cells to oxidative and electrophilic injury.