Cardiovascular Protection by Metformin: Latest Advances in Basic and Clinical Research.

BACKGROUND: Metformin is among the most frequently prescribed antidiabetic drugs worldwide and remains the first-line therapy for type 2 diabetes due to its well-established glucose-lowering efficacy and favorable safety profile. SUMMARY: Studies over the past decades show that metformin also exerts many other beneficial effects independent of its glucose-lowering effect both in experimental models and human subjects. Among them, the most notable is its cardiovascular protective effect. In this review, we discuss the latest cutting-edge research findings on metformin's cardiovascular protection from both preclinical studies and randomized clinical trials. We focus on describing novel basic research discoveries reported in influential journals and discussing their implications in the context of latest clinical trial findings related to common cardiovascular and metabolic disorders, including atherosclerosis and dyslipidemia, myocardial injury, and heart failure. KEY MESSAGES: While substantial preclinical and clinical evidence suggests metformin as a potential cardiovascular protectant, large-scale randomized controlled trials are warranted to establish its clinical efficacy in treating patients with atherosclerotic cardiovascular disease and heart failure.

3H-1,2-dithiole-3-thione suppresses LPS-induced proinflammatory responses in macrophages: potential involvement of antioxidant induction, NF-κB, and Nrf2.

Previously, we reported that 3H-1,2-dithiole-3-thione (D3T), an Nrf2 activator, acted as a potential chemoprotectant against lipopolysaccharide (LPS)-induced mortality in mice. In view of the critical involvement of macrophages in the pathogenesis of LPS-induced endotoxemia, in the present study, we investigated the protective effects of D3T on LPS-induced proinflammatory responses in cultured murine RAW 264.7 macrophage cell line and primary peritoneal macrophages and the potential involvement of antioxidant induction, NF-κB, and Nrf2. We showed that treatment with D3T resulted in increased levels of a series of antioxidants in RAW 264.7 cells in a concentration-dependent manner. These included the reduced form of glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, and NADPH:quinone oxidoreductase 1. Catalase was also potently induced by D3T which, however, did not show a concentration dependency. Concurrent with the ability to induce the above cellular antioxidants, D3T pretreatment of RAW 264.7 cells also led to a concentration-dependent suppression of LPS-induced interleukin-1beta (IL-1ß) production and nitric oxide release. LPS-stimulated tumor necrosis factor-alpha (TNF-α) production was also suppressed by D3T, but to a much lesser extent. Using NF-κB reporter gene-expressing RAW 264.7 cells, we further showed that D3T pretreatment also suppressed LPS-induced NF-κB activation. To investigate the potential involvement of Nrf2, a chief regulator of cellular antioxidant genes, we used peritoneal macrophages isolated from Nrf2+/+ and Nrf2-/- mice. Our results showed that D3T pretreatment suppressed LPS-induced proinflammatory responses in Nrf2+/+ macrophages, and this inhibitory effect of D3T was completely lost in Nrf2-/- macrophages. Collectively, the results of the present study demonstrated that D3T acted as a potent suppressor of LPS-induced proinflammatory responses in macrophages. Antioxidant induction, NF-κB suppression, and Nrf2 activation appeared to contribute to the anti-proinflammatory activity of D3T in macrophages.

Nanoceria potently reduce superoxide fluxes from mitochondrial electron transport chain and plasma membrane NADPH oxidase in human macrophages.

Cerium oxide nanoparticles, also known as nanoceria, possess antioxidative and anti-inflammatory activities in animal models of inflammatory disorders, such as sepsis. However, it remains unclear how nanoceria affect cellular superoxide fluxes in macrophages, a critical type of cells involved in inflammatory disorders. Using human ML-1 cell-derived macrophages, we showed that nanoceria at 1-100 µg/ml potently reduced superoxide flux from the mitochondrial electron transport chain (METC) in a concentration-dependent manner. The inhibitory effects of nanoceria were also shown in succinate-driven mitochondria isolated from the macrophages. Furthermore, nanoceria markedly mitigated the total intracellular superoxide flux in the macrophages. These data suggest that nanoceria could readily cross the plasma membrane and enter the mitochondrial compartment, reducing intracellular superoxide fluxes in unstimulated macrophages. In macrophages undergoing respiratory burst, nanoceria also strongly reduced superoxide flux from the activated macrophage plasma membrane NADPH oxidase (NOX) in a concentration-dependent manner. Token together, the results of the present study demonstrate that nanoceria can effectively diminish superoxide fluxes from both METC and NOX in human macrophages, which may have important implications for nanoceria-mediated protection against inflammatory disease processes.

Vitamin C for sepsis intervention: from redox biochemistry to clinical medicine.

Vitamin C, also known as ascorbic acid or ascorbate, is a water-soluble vitamin synthesized in plants as well as in animals except humans and several other animal species. Humans obtain vitamin C from dietary sources and via vitamin supplementation. Vitamin C possesses important biological functions, including serving as a cofactor for many enzymes, acting as an antioxidant and anti-inflammatory compound, and participating in regulating stem cell biology and epigenetics. The multifunctional nature of vitamin C contributes to its essentialness in maintaining and safeguarding physiological homeostasis, especially regulation of immunity and inflammatory responses. In this context, vitamin C has been investigated for its efficacy in treating diverse inflammatory disorders, including sepsis, one of the major causes of death globally and for which currently there is no cure. Accordingly, this Mini-Review surveys recent major research findings on the effectiveness of vitamin C and the underling molecular mechanisms in sepsis intervention in both experimental animal models and randomized controlled trials. To set a stage for discussing the effects and mechanisms of vitamin C in sepsis intervention, this Mini-Review begins with an overview of vitamin C redox biochemistry and its multifunctional properties.

NADPH-quinone oxidoreductase-1 mediates Benzo-[a]-pyrene-1,6-quinone-induced cytotoxicity and reactive oxygen species production in human EA.hy926 endothelial cells.

Numerous studies conducted in the past have reported deaths in the human population due to cardiovascular diseases (CVD) on exposure to air particulate matter (APM). BP-1,6-quinone (BP-1,6-Q) is one of the significant components of APM. However, the mechanism(s) by which it can exert its toxicity in endothelial cells is not yet completely understood. NAD(P)H: quinone oxidoreductase-1 (NQO1) is expressed highly in myocardium and vasculature tissues of the heart and plays a vital role in maintaining vascular homeostasis. This study, demonstrated that BP-1,6-Q diminishes NQO1 enzyme activity in a dose-dependent manner in human EA.hy926 endothelial cells. The decrease in the NQO1 enzyme causes potentiation in BP-1,6-Q-mediated toxicity in EA.hy926 endothelial cells. The enhancement of NQO1 in endothelial cells showed cytoprotection against BP-1,6-Q-induced cellular toxicity, lipid, and protein damage suggesting an essential role of NQO1 in cytoprotection against BP-1,6-Q toxicity. Using various biochemical assays and genetic approaches, results from this study further demonstrated that NQO1 also plays a crucial role in BP-1,6-Q-induced production of reactive oxygen species (ROS). These findings will contribute to elucidating BP-1,6-Q mediated toxicity and its role in the development of atherosclerosis.

Targeting glutathione with the triterpenoid CDDO-Im protects against benzo-a-pyrene-1,6-quinone-induced cytotoxicity in endothelial cells.

Epidemiological studies have exhibited a strong correlation between exposure to air pollution and deaths due to vascular diseases such as atherosclerosis. Benzo-a-pyrene-1,6-quinone (BP-1,6-Q) is one of the components of air pollution. This study was to examine the role of GSH in BP-1,6-Q mediated cytotoxicity in human EA.hy96 endothelial cells and demonstrated that induction of cellular glutathione by a potent triterpenoid, CDDO-Im (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole), protects cells against BP-1,6-Q induced protein and lipid damage. Incubation of EA.hy926 endothelial cells with BP-1,6-Q caused a significant increase in dose-dependent cytotoxicity as measured by LDH release assay and both apoptotic and necrotic cell deaths as measured by flow cytometric analysis. Incubation of EA.hy926 endothelial cells with BP-1,6-Q also caused a significant decrease in cellular GSH levels. The diminishment of cellular GSH by buthionine sulfoximine (BSO) potentiated BP-1,6-Q-induced toxicity significantly suggesting a critical involvement of GSH in BP-1,6-Q induced cellular toxicity. GSH-induction by CDDO-Im significantly protects cells against BP-1,6-Q induced protein and lipid damage as measured by protein carbonyl (PC) assay and thiobarbituric acid reactive substances (TBARS) assay, respectively. However, the co-treatment of cells with CDDO-Im and BSO reversed the cytoprotective effect of CDDO-Im on BP-1,6-Q-mediated lipid peroxidation and protein oxidation. These results suggest that induction of GSH by CDDO-Im might be the important cellular defense against BP-1,6-Q induced protein and lipid damage. These findings would contribute to better understand the action of BP-1,6-Q and may help to develop novel therapies to protect against BP-1,6-Q-induced atherogenesis.

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

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. Using chemiluminescence and electron paramagnetic resonance (EPR) spin-trapping techniques, this study for the first time demonstrated the real-time formation of ROS in the redox activation of beta-lapachone from cancer cells mediated by mitochondria and NQO1 in melanoma B16-F10 and hepatocellular carcinoma HepG2 cancer cells. ES936, a highly selective NQO1 inhibitor, and rotenone, a selective inhibitor of mitochondrial electron transport chain (METC) complex I were found to significantly block beta-Lp meditated redox activation in B16-F10 cells. In HepG2 cells ES936 inhibited beta-Lp-mediated oxygen radical formation by ~80% while rotenone exerted no significant effect. These results revealed the differential contribution of METC and NQO1 to beta-lapachone-induced ROS formation and cancer cell killing. In melanoma B16-F10 cells that do not express high NQO1 activity, both NOQ1 and METC play a critical role in beta-Lp redox activation. In contrast, in hepatocellular carcinoma HepG2 cells expressing extremely high NQO1 activity, redox activation of beta-Lp is primarily mediated by NQO1 (METC plays a minor role). These findings will contribute to our understanding of how cancer cells are selectively killed by beta-lapachone and increase our ability to devise strategies to enhance the anticancer efficacy of this potentially novel drug while minimizing its possible adverse effects on normal cells.

Role of Peroxiredoxins in Protecting Against Cardiovascular and Related Disorders.

Peroxiredoxin (Prx) refers to a family of thiol-dependent peroxidases that decompose hydrogen peroxide, lipid hydroperoxides, as well as peroxynitrite, and protect against oxidative and inflammatory stress. There are six mammalian Prx isozymes (Prx1-6), classified as typical 2-Cys, atypical 2-Cys, or 1-Cys Prxs based on the mechanism and the number of cysteine residues involved during catalysis. In addition to their well-established peroxide-scavenging activity, some Prxs also participate in the regulation of various cell signaling pathways. Extensive animal studies employing primarily gene knockout models provide substantial evidence supporting a critical protective role of Prxs in various disease processes involving oxidative and inflammatory stress. This review surveys recent research findings, published primarily in influential journals, on the involvement of various Prx isozymes in protecting against cardiovascular injury and related disorders, including diabetes, metabolic syndromes, and sepsis, whose pathophysiology all intimately involves oxidative stress and inflammation.

Reactive oxygen species production by BP-1,6-quinone and its effects on the endothelial dysfunction: Involvement of the mitochondria.

Strong epidemiological evidence supports the association between increased air pollution and the risk of developing atherosclerotic cardiovascular diseases (CVDs). However, the mechanism remains unclear. As an environmental air pollutant and benzo-a-pyrene (BP) metabolite, BP-1,6-quinone (BP-1,6-Q) is present in the particulate phase of air pollution. This study was undertaken to examine the redox activity of BP-1,6-Q and mechanisms associated with it using EA.hy926 endothelial cells. BP-1,6-Q at 0.01-1 µM significantly stimulated the production of reactive oxygen species (ROS)·in intact cells and isolated mitochondria. Furthermore, BP-1,6-Q-induced ROS was altered by mitochondrial electron transport chain (METC) inhibitors of complex I (rotenone) and complex III (antimycin A), denoting the involvement of mitochondrial electron transport chain (METC) in BP-1,6-Q mediated ROS production. In METC deficient cells, interestingly, BP-1,6-Q-mediated ROS production was enhanced, suggesting that overproduction of ROS by BP-1,6-Q is not only produced from mitochondria but can also be from the cell outside of mitochondria (extramitochondrial). BP-1,6-Q also triggered endothelial-monocyte interaction and stimulated expression of vascular adhesion molecule-1 (VCAM-1). In conclusion, these results demonstrate that BP-1,6-Q can generate ROS within both mitochondria and outside of mitochondria, resulting in stimulation of adhesion of monocytes to endothelial cells, a key event in the pathogenesis of atherosclerosis.

3H-1,2-Dithiole-3-Thione as a Potentially Novel Therapeutic Compound for Sepsis Intervention.

Through the history of modern medicine, bioactive components in natural products have been either employed directly as medicines or used as prototypes for synthetic drug development. This brief Research Highlights paper considers 3H-1,2-dithiole-3-thione (D3T), a member of the 1,2-dithiole-3-thiones-compounds which may naturally occur in cruciferous vegetables. Among 1,2-dithiole-3-thiones, D3T is the most potent member with regard to the capacity of inducing tissue defenses against oxidative and inflammatory stress. Oxidative and inflammatory stress is a major pathophysiological process involved in numerous human disorders, including cancer, cardiovascular diseases, neurodegeneration, and sepsis, to name just a few. This article surveys recent major research findings on D3T as an inducer of tissue antioxidative and antiinflammatory defenses and as a potential therapeutic modality for sepsis intervention.

Graphene Quantum Dots Protect against Copper Redox-Mediated Free Radical Generation and Cardiac Cell Injury.

In this work, we investigated the effects of graphene quantum dots (GQDs) on copper redox-mediated free radical generation and cell injury. Using electron paramagnetic resonance (EPR) spectrometry in conjunction with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trap, we found that GQDs at a concentration as low as 1 µg/ml significantly inhibited Cu(II)/H2O2-mediated hydroxyl radical formation. GQDs also blocked Cu(II)-catalyzed nucleophilic addition of H2O to DMPO to form a DMPO-OH adduct in the absence of H2O2, suggesting a potential for GQDs to inhibit copper redox activity. Indeed, we observed that the presence of GQDs prevented H2O2-mediated reduction of Cu(II) to Cu(I) though GQDs themselves also caused the reduction of Cu(II) to Cu(I). To further investigate the effects of GQDs on copper redox activity, we employed the Cu(II)/hydroquinone system in which copper redox activity plays an essential role in the oxidation of hydroquinone to semiquinone radicals with consequent oxygen consumption. Using oxygen polarography as well as EPR spectrometry, we demonstrated that the presence of GQDs drastically blocked the oxygen consumption and semiquinone radical formation resulting from the reaction of Cu(II) and hydroquinone. These results suggested that GQDs suppressed free radical formation via inhibiting copper redox activity. Lastly, using cultured human cardiomyocytes, we demonstrated that the presence of GQDs also protected against Cu(II)/H2O2-mediated cardiac cell injury as indicated by morphological changes (e.g., cell shrinkage and degeneration). In conclusion, our work shows, for the first time, the potential for using GQDs to counteract copper redox-mediated biological damage.

Graphene Quantum Dots Potently Block Copper-Mediated Oxidative DNA Damage: Implications for Cancer Intervention.

Our early work suggested that graphene quantum dots (GQDs) block Cu(II)/Cu(I) redox cycle in biological systems. Here we report that GQDs could also potently protect against copper redox-mediated oxidative DNA damage. Using Cu(II)/hydrogen peroxide, Cu(II)/hydroquinone, and Cu(II)/ascorbic acid as three biologically relevant systems for inducing oxidative DNA damage, we demonstrated that GQDs protected against the above system-induced DNA strand breaks in ϕx-174 plasmid DNA in a concentration-dependent manner. Notably, a significant protection was observed with GQDs at 1 µg/ml, and a nearly complete protection was shown with 10 and 100 µg/ml of GQDs. Using electron paramagnetic resonance (EPR) spectrometry in conjunction with α-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN)-spin trapping, we showed that the above three systems generated hydroxyl radicals, as evidenced by the formation of a POBN-CH3 radical adduct in the presence of 0.5 M dimethyl sulfoxide (DMSO). Consistent with the protective effects of GQDs on DNA damage, the hydroxyl radical formation was markedly reduced in the presence of GQDs in a concentration dependent manner. A nearly complete blockage of the hydroxyl radical generation was seen with GQDs at 10 and 100 µg/ml. Taken together, our results showed that GQDs potently protected against oxidative DNA damage. Considering the critical role of copper in cancer development, our findings might have important implications for cancer intervention with GQD-based nanotech modality.

A Simple Bioluminescence Imaging Method for Studying Cancer Cell Growth and Metastasis after Subcutaneous Injection of Lewis Lung Carcinoma Cells in Syngeneic C57BL/6 Mice.

In vivo imaging of cancer cell growth and invasion is instrumental in studying cancer cell behavior and in developing effective anticancer agents. In this ROS Protocols article, we report the experimental protocol and steps involving the implantation of luciferase-expressing Lewis lung carcinoma (LLC) cells in normal syngeneic C57BL/6 mice. Using the Berthold NightOwl LB981 in vivo imaging system, we observe the time-dependent growth and invasion of the lung cancer cells following subcutaneous injection of luciferase-expressing LLC cells. The three-dimensional image and counts of photon emission of the tumor mass are obtained to estimate the relative size of the tumor. Ex vivo imaging of the isolated lungs supplemented with D-luciferin and adenosine triphosphate (ATP) is obtained to determine lung metastasis of the LLC cells. The LLC cell load in entire mouse lungs is further determined by quantitative bioluminometry with a concurrently run standard curve of the number of LLC cells versus bioluminescence intensity. This in vivo imaging system in live mice, in combination with ex vivo imaging of isolated lungs as well as quantitative bioluminometry of target tissues, may provide important information on the in vivo cancer cell dynamics in immunocompetent syngeneic C57BL/6 mice and offer a valuable tool for studying experimental anticancer agents, including redox-modulating compounds, which are promising anticancer modalities.

In Vivo Bioluminescence Imaging of Nuclear Factor kappaB Activation: A Valuable Model for Studying Inflammatory and Oxidative Stress in Live Mice.

The nuclear factor kappaB (NF-κB) is a redox-sensitive transcription factor that plays a critical role in inflammation among other biological functions. This ROS Protocol article describes an in vivo bioluminescence imaging assay for assessing NF-κB activation using the commercially available transgenic mice carrying NF-κB response element-luciferase reporter gene (NF-κB-RE-Luc). Using the highly sensitive Berthold NightOwl LB981 in vivo bioluminescence imaging system, we are able to visualize the NF-κB activation in live mice under basal conditions, suggesting constitutive activation of NF-κB as a part of its fundamental biology. Treatment of mice with lipopolysaccharides (LPS) results in a drastic increase in bioluminescence, proving the validity of the model in assessing inflammatory stress. Treatment of mice with 3H-1,2-dithiole-3-thione (D3T), an activator of nuclear factor E-2 related factor 2 (Nrf2), led to a significant reduction in both basal and LPS-induced activation of NF-κB in the live mice, suggesting a value of this model in assessing drug efficacy in suppressing NF-κB activation and inflammatory stress. The protocols of this valuable model are detailed in this article along with a discussion of its potential use in studying disease conditions involving inflammatory and oxidative stress mechanisms and in assessing therapeutic modalities targeting the NF-κB signaling for disease intervention.

Nrf2 Signaling in Macrophages.

The nuclear factor E2-related factor 2 (Nrf2) is known as the chief regulator of cellular antioxidant defenses as well as a suppressor of inflammation. Macrophages act as major players in inflammatory responses. Because oxidative stress and inflammation are two intertwined processes, the anti-inflammatory activity of Nrf2 signaling is believed to result from its upregulation of cellular antioxidant defenses via the antioxidant response element-driven transcription. In a recent article published in Nature Communications (May 23, 2016; doi: 10.1038/ncomms11624), Kobayashi et al. reported that Nrf2 suppresses transcriptional upregulation of pro-inflammatory cytokines independent of its role in regulating cellular antioxidants and redox status. This study by Kobayashi et al. provides novel insights into the molecular basis of Nrf2 acting as a suppressor of inflammation.

A Highly Sensitive Chemiluminometric Assay for Real-Time Detection of Biological Hydrogen Peroxide Formation.

Hydrogen peroxide (H2O2) is a major reactive oxygen species (ROS) produced by various cellular sources, especially mitochondria. At high levels, H2O2 causes oxidative stress, leading to cell injury, whereas at low concentrations, this ROS acts as an important second messenger to participate in cellular redox signaling. Detection and measurement of the levels or rates of production of cellular H2O2 are instrumental in studying the biological effects of this major ROS. While a number of assays have been developed over the past decades for detecting and/or quantifying biological H2O2formation, none has been shown to be perfect. Perhaps there is no perfect assay for sensitively and accurately quantifying H2O2 as well as other ROS in cells, wherein numerous potential reactants are present to interfere with the reliable measurement of the specific ROS. In this context, each assay has its own advantages and intrinsic limitations. This article describes a highly sensitive assay for real-time detection of H2O2 formation in cultured cells and isolated mitochondria. This assay is based on the luminol/horseradish peroxidase-dependent chemiluminescence that is inhibitable by catalase. The article discusses the usefulness and shortcomings of this chemiluminometric assay in detecting biological H2O2 formation induced by beta-lapachone redox cycling with both cells and isolated mitochondria.

Oxygen and Oxygen Toxicity: The Birth of Concepts.

Molecular dioxygen (O2) is an essential element of aerobic life, yet incomplete reduction or excitation of O2 during aerobic metabolisms generates diverse oxygen-containing reactive species, commonly known as reactive oxygen species (ROS). On the one hand, ROS pose a serious threat to aerobic organisms via inducing oxidative damage to cellular constituents. On the other hand, these reactive species, when their generation is under homeostatic control, also play important physiological roles (e.g., constituting an important component of immunity and participating in redox signaling). This article defines oxygen and the key facts about oxygen, and discusses the relationship between oxygen and the emergence of early animals on Earth. The article then describes the discovery of oxygen by three historical figures and examines the birth of the concepts of oxygen toxicity and the underlying free radical mechanisms. The article ends with a brief introduction to the emerging field of ROS-mediated redox signaling and physiological responses.

Nrf2 Deficiency Promotes Melanoma Growth and Lung Metastasis.

The role of Nrf2, a key regulator of antioxidant and cytoprotective genes, in tumorigenesis remains controversial. Here we showed that Nrf2 deficiency led to increased local tumor growth in mice following subcutaneous injection of B16-F10 melanoma cells, as indicated by increased proportion of animals with locally palpable tumor mass and time-dependent increases in tumor volume at the injection site. In vivo bioluminescence imaging also revealed increased growth of melanoma in Nrf2-null mice as compared with wild-type mice. By using a highly sensitive bioluminometric assay, we further found that Nrf2 deficiency resulted in a remarkable increase in lung metastasis of B16-F10 melanoma cells as compared with wild-type mice. Taken together, the results of this short communication for the first time demonstrated that Nrf2 deficiency promoted melanoma growth and lung metastasis following subcutaneous inoculation of B16-F10 cells in mice.

Comparative study of oxidative stress biomarkers in urine of cooks exposed to three types of cooking-related particles.

OBJECTIVES: To evaluate how exposure to deep-frying oils, repeated frying oil (RFO) and restaurant waste oil (RWO) affects emission of polycyclic aromatic hydrocarbons (PAHs) and oxidative stress in male restaurant workers. METHODS: The study participants included 236 male restaurant workers in 12 restaurants in Shenzhen. Airborne particulate PAHs were measured over 12h on each of two consecutive work days. Urinary 1-hydroxypyrene (1-OHP) measurements were used to indicate cooking oil fumes (COF) exposure, and urinary malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were adopted as oxidative stress markers. RESULTS: The production and emission rates of ultrafine particles (UFPs) and PM2.5 were higher in the exposed groups than in the control group. The concentrations of summed PAHs were in the order of RFO-frying group>RWO-frying group>deep-frying group>unexposed control group. Urinary 1-OHP was found to be a significant predictor of elevated urinary MDA and 8-OHdG concentrations (all, P<0.05). UFPs were a significant predictor of elevated urinary 8-OHdG for restaurant workers (P<0.05). The RFO- and RWO-frying groups had higher mean urinary concentrations of 1-OHP, MDA and 8-OHdG than the control group (P<0.05). RFO exposure was found to be a significant risk factor for elevated urinary 8-OHdG and RWO exposure was found to be a significant risk factor for elevated urinary MDA (both, P<0.001). CONCLUSIONS: Concentrations of urinary 1-OHP, MDA and 8-OHdG reflect occupational exposure to PAHs from COFs and oxidative stress in restaurants workers. Exposure to RFO may cause increased oxidative DNA damage, and exposure to RWO might cause increased lipid peroxidation.

Doxorubicin Redox Biology: Redox Cycling, Topoisomerase Inhibition, and Oxidative Stress.

Doxorubicin (also called Adriamycin) is effective in treating a wide range of human cancers and currently considered as one of the most important drugs in cancer chemotherapeutics. The clinical use of doxorubicin is, however, associated with dosage-dependent cardiotoxicity and development of heart failure, which diminish the therapeutic index of this widely used anticancer drug. This article first surveys key research findings on doxorubicin redox biology that may impact its cardiotoxicity as well as anticancer activity. It then discusses emerging concepts, especially the topoisomerase IIb-p53-mitochondrion axis that may lead to the development of mechanistically based novel strategies to protect against cardiotoxicity and enhance the effectiveness of doxorubicin therapy.