Ferulic acid inhibits H2O2-induced oxidative stress and inflammation in rat vascular smooth muscle cells via inhibition of the NADPH oxidase and NF-κB pathway

Ferulic acid (FA) is a dietary phenolic acid and has a wide range of therapeutic effects, including anti-aging, antitumor activity and antihypertensive effects. The aim of present study was to evaluate the inhibitory effects of FA on cell inflammation and oxidative stress against hydrogen peroxide (H₂O₂)-induced injury in rat vascular smooth muscle cells (VSMCs) in vitro. VSMCs were pretreated with FA 2 h before H₂O₂ incubation. The results suggested that FA inhibited H₂O₂-induced cell injury by reducing the MDA and increasing the SOD activity and GSH content. In rat VSMCs exposed to H₂O₂, FA increased the cell viability and restored the mitochondrial membrane depolarization. The level of ROS generation was reduced by pretreatment with FA through inhibiting the expression of NADPH oxidase and down-regulating MAPK and AKT pathways. We found that H₂O₂ stimulated the production of IL-6, IL-1β, TNF-α and NO, which could be reduced by pretreatment with FA through inhibiting the p-NF-κB as well as the iNOS expression. In conclusion, our results show that FA may serve as a novel drug in the treatment of these pathologies by inhibiting NADPH oxidase and NF-κB and subsequently decreasing VSMC oxidative stress and inflammation. These suggest that the inhibitory effect of FA on VSMC inflammation and oxidative stress is partially attributed to depressing NADPH and NF-κB expressions in VSMCs, decreasing the ROS production and reducing apoptosis of VSMCs.     

Effects of quercetin treatment on vascular function in deoxycorticosterone acetate-salt hypertensive rats. Comparative study with verapamil

This study analysed and compared the effects of chronic oral treatment with quercetin or verapamil on systolic blood pressure and vascular function in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Quercetin and verapamil inhibited the development of DOCA-salt-induced hypertension in a similar manner. DOCA-salt-hypertensive rats showed potassium depletion and oxidative stress, prevented only by concomitant quercetin administration. Quercetin and verapamil treatments reduced the endothelium-independent hyper-reactivity to KCl observed in the aorta of DOCA-salt-hypertensive rats, but only quercetin increased the contractile responses to angiotensin II, improved endothelial dysfunction and restored basal aortic Cu/Zn SOD expression, altered in DOCA-salt-treated rats. In conclusion, quercetin and verapamil show similar antihypertensive effects in mineralocorticoid hypertension, but quercetin was superior to verapamil in improving endothelial-dependent aortic dilatation, suggesting a better vascular protection in this volume expansion hypertension model.     

Quercetin stimulates mitochondrial apoptosis dependent on activation of endoplasmic reticulum stress in hepatic stellate cells

Context: Activation of hepatic stellate cells (HSCs) is a hallmark of liver fibrosis. Quercetin has benefits for liver fibrosis, but the mechanisms are unknown.

Objective: We investigated the quercetin effect on HSC survival and the role of endoplasmic reticulum stress (ERS).

Materials and methods: Rat HSCs and LO2 hepatocytes were treated with quercetin (0.5–120?μM) for 24?h. Quercetin (10–40?μM) effects on apoptosis for 24?h were analyzed by flow cytometry and TUNEL staining. Quercetin (10–40?μM) effects on the expression of Bcl-2, caspase-9, caspase-3, PARP-1, PERK, IRE1, ATF6, calnexin and CHOP for 24?h were analyzed by Western blot. Quercetin (10–40?μM) effects on mRNA expression of calnexin and CHOP for 24?h were analyzed by Real-time PCR.

Results: Quercetin at concentrations greater than 20?μM significantly inhibited HSC proliferation (IC₅₀ 27.2?μM), but did not affect hepatocyte growth until 80?μM (IC₅₀ 68.5?μM). Quercetin stimulated HSC apoptosis and the apoptotic rate reached 40% at a concentration of 40?μM (EC₅₀ 51.6?μM). Quercetin induced downregulation of Bcl-2 and upregulation of Bax, and increased cytochrome C in the cytoplasm in HSCs. The cleaved forms of caspase-9, caspase-3 and PARP-1 were also increased by quercetin. Furthermore, quercetin elevated mRNA and protein expression of calnexin and CHOP in HSCs but not in hepatocytes. Quercetin also increased phosphorylation of PERK and IRE1 and ATF6 cleavage. However, ERS inhibitor salubrinal significantly abrogated quercetin induction of HSC apoptosis.

Conclusion: Quercetin activated ERS pathway in HSCs leading to apoptosis. We characterized an ERS-mediated mechanism for quercetin as a promising antifibrotic agent.     

Quercetin abrogates bisphenol A induced altered neurobehavioral response and oxidative stress in zebrafish by modulating brain antioxidant defence system

Bisphenol A (BPA), a well-recognized anthropogenic xenoestrogen, has been identified as a causative agent responsible for inducing carcinogenicity, cognitive impairment, neurotoxicity, oxidative stress, etc. However, BPA-induced neurotoxicity and its possible amelioration through natural compound intervention remain elusive. The current study was performed to elucidate the neurotoxic potential of BPA in zebrafish (Danio rerio) by waterborne exposure and its possible amelioration by quercetin co-supplementation. Protective effect of quercetin against BPA-induced altered neurobehavioral response, oxidative stress and neuromorphological changes were evaluated in zebrafish brain. The present findings reveal that BPA-induced altered neurobehavioral response was ameliorated by quercetin. Biochemical studies advocate the potential therapeutic efficacy of quercetin against BPA-induced oxidative stress in zebrafish brain. Quercetin also shows neuroprotection against BPA-induced augmented neuronal pyknosis in periventricular grey zone (PGZ) of zebrafish brain. These basic findings indicate that quercetin may act as an effective intervention against BPA-induced neurotoxicity in zebrafish through down-regulation of oxidative stress.     

Protective mechanism of quercetin and rutin on 2,2′-azobis(2-amidinopropane)dihydrochloride or Cu-induced oxidative stress in HepG2 cells

Protective effects of quercetin and rutin against oxidative stress were evaluated using in vitro and intracellular antioxidant assay. Quercetin showed higher peroxyl and hydroxyl radical-scavenging activity in a dose-dependent manner than did rutin in oxygen-radical absorbance capacity (ORAC). At 10 and 100 μM, quercetin had higher metal-chelating activity than rutin carrying rutinose at position C-3 and was also more efficient than rutin in reducing intracellular oxidative stress caused by peroxyl radicals and Cu²⁺. The protective activities of 10 and 100 μM quercetin against Cu²⁺-induced intracellular oxidation were 13.8% and 44.8%, respectively. Rutin showed no protective activity against Cu²⁺-induced oxidative stress. Quercetin showed significantly lower intracellular Cu²⁺-chelating activity than did 1,10-phenanthroline but offered greater protection from Cu²⁺-induced oxidative stress. Thus, quercetin may diffuse through the cell membrane more efficiently than rutin because quercetin does not carry rutinose, is hydrophilic, and reduces Cu²⁺-induced oxidative stress by scavenging radicals instead of chelating with metal ions.     

Mitochondrial division inhibitor (mdivi-1) inhibits proliferation and epithelial-mesenchymal transition via the NF-κB pathway in thyroid cancer cells

Excessively fragmented mitochondria have been reported in thyroid cancer (TC). Mitochondrial division inhibitor (mdivi-1), a putative inhibitor of dynamin-related protein 1 (Drp1), prevents mitochondrial fission and thereby restricts cell proliferation across several types of primary cancer. However, the role of mdivi-1 on TC has not been sufficiently studied. This research is intended to explore the therapeutic effect of mdivi-1 in TC cells. Results demonstrated that highly invasive TC cells displayed excessive mitochondrial fission with more fragmented mitochondria. Treatment with mdivi-1 inhibited mitochondrial fission in 8505C cells as indicated by transmission electron microscope (TEM). It also impaired the proliferation and increased apoptosis in 8505C and K1 cells as shown by plate cloning assay, cell viability assay, and apoptosis assay. Mdivi-1 treatment also attenuated migratory and invasive abilities in 8505C and K1 cells as shown by the transwell assay and the wound healing assay. And we noticed the same inhibition of mdivi-1 in cell migration and cell viability after the knockdown of Drp1 in 8505C cells. This demonstrated that mdivi-1 exerted an anti-tumor effect independently of Drp1 in 8505C cells. Moreover, mdivi-1 treatment reversed epithelial-mesenchymal transition (EMT) by inhibiting the NF-κB pathway in 8505C cells. The present findings demonstrate that mdivi-1 has a therapeutic role in thyroid carcinoma.     

Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression

Background and Purpose

Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity.

Experimental Approach

Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment.

Key Results

In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase.

Conclusions and Implications

Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy.     

Adenine attenuates the Ca<Superscript>2+</Superscript> contraction-signaling pathway via adenine receptor-mediated signaling in rat vascular smooth muscle cells

Our previous study demonstrated that adenine (6-amino-6H-purine) relaxed contracted rat aorta rings in an endothelial-independent manner. Although adenine receptors (AdeRs) are expressed in diverse tissues, aortic AdeR expression has not been ascertained. Thus, the aims of this study were to clarify the expression of AdeR in rat vascular smooth muscle cells (VSMCs) and to investigate the adenine-induced vasorelaxation mechanism(s). VSMCs were isolated from 8-week-old male Wistar-Kyoto rats and used in this study. Phosphorylation of myosin light chain (p-MLC) was measured by western blot. AdeR mRNA was detected by RT-PCR. Intracellular Ca²⁺ concentration ([Ca²⁺]_i) was measured by using Fura-2/AM. Vasorelaxant adenine (10–100 μM) significantly reduced p-MLC by angiotensin II (Ang II, 10 μM) in VSMCs (P < 0.05). We confirmed the expression of aortic AdeR mRNA and the activation of PKA in VSMCs through stimulation of AdeR by adenine by ELISA. Intracellular Ca²⁺ concentration ([Ca²⁺]_i) measurement demonstrated that adenine inhibits Ang II- and m-3M3FBS (PLC agonist)-induced [Ca²⁺]_i elevation. In AdeR-knockdown VSMCs, PKA activation and p-MLC reduction by adenine were completely abolished. These results firstly demonstrated that vasorelaxant adenine can suppress Ca²⁺ contraction signaling pathways via aortic AdeR/PKA activation in VSMCs.     

Concentration-dependent differential effects of quercetin on rat aortic smooth muscle cells

Quercetin is one of the most ubiquitous bioflavonoids in foods of plant origin. Although quercetin is generally considered to provide protection against oxidative injury and inflammation, recent studies have demonstrated that its cytoprotective effects occur within a narrow concentration range. We attempted to examine the concentration-dependent effect on proliferation and inflammation in the primary culture of rat aortic smooth muscle cells. We demonstrate that quercetin inhibited [3H]thymidine incorporation into rat aortic smooth muscle cells only at concentrations < or =50 microM in a concentration-dependent manner. Nevertheless, quercetin, at concentrations > or =100 microM, reduced cell viability; this was further characterized as being due to apoptosis, which occurred through the proteolytic activation of pro-caspase-3. Additionally, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) substantially increased in rat aortic smooth muscle cells exposed to 100 microM quercetin, results which differ from observations by others and ourselves of cells exposed to < or =50 microM quercetin. Unlike P-JNK and P-p38, the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/ERK2) was not significantly affected by the concentration-dependent effects of quercetin. Surprisingly, the adverse effects of higher concentrations of quercetin could be ameliorated by adding the antioxidants, catalase, and N-acetylcysteine (NAC). Furthermore, the electrophoretic mobility shift assay (EMSA) showed that rat aortic smooth muscle cells exposed to quercetin at concentrations of < or =50 microM caused concentration-dependent inhibition of nuclear factor kappa B (NF-kappaB) activity, whereas concentrations of > or =100 microM resulted in increased NF-kappaB binding activity. We demonstrate for the first time that quercetin at low concentrations has antiproliferative and antiinflammatory effects, but at concentrations of > or =100 microM, is likely to induce the opposite effects on rat aortic smooth muscle cells.     

Quercetin induces rapid eNOS phosphorylation and vasodilation by an Akt-independent and PKA-dependent mechanism

Consumption of the flavonoid quercetin exerts beneficial effects on many chronic diseases. The mechanisms involved in the vasorelaxant effect of quercetin remain uncertain. In the present study, we examined the role of quercetin in vasodilation and rapid endothelial nitric oxide synthase (eNOS) activity in endothelial cells. Quercetin induced a rapid, dose-dependent phosphorylation of eNOS at serine 1179. PKA, Akt and ERK1/2 were all quickly phosphorylated in the process too, but not AMPK and CaMK II. The specific kinase inhibitors for Akt or ERK1/2 could not abolish the quercetin-induced eNOS phosphorylation at Ser1179, which, however, was significantly abolished by H89, an inhibitor of PKA. Concomitantly, intracellular cAMP production was quickly increased by quercetin stimulation and an adenylate cyclase activator, forskolin, also induced eNOS phosphorylation at Ser1179. Quercetin enhanced nitric oxide (NO) production, which was abolished by an eNOS inhibitor, L-NAME or H89. Quercetin exerted a vasodilatory effect on rings with an intact endothelium but not on endothelium-deprived rings, and also inhibited vascular contractility induced by angiotensin II or phenylephrine in rat aortic rings. We conclude that quercetin quickly phosphorylates eNOS at Ser1179 via an Akt-independent, cAMP/PKA-mediated pathway to enhance the production of NO and to promote vasodilation.     

Effect of quercetin on lipopolysaccharide induced-sickness behavior and oxidative stress in rats

Objectives:

Gram-negative infections and control infusion of recombinant cytokines in human have been shown to induce sickness behavior characterized by fever, prolong sleep, decreased food and water intake, reduced mobility, depression, and anxiety. Therefore, the present study was undertaken to investigate the effect of bioflavonoid quercetin in lipopolysaccharide (LPS)-induced sickness behavior.

Materials and Methods:

Wistar albino rats were divided into six groups (n=6). Three groups received vehicle and two doses of quercetin (2 and 25 mg/kg, i.p.) respectively for 2 weeks before being challenged with LPS (1 mg/kg, i.p). One group received vehicle for 2 weeks and was challenged with saline on day 15. The per se effect of quercetin (2 and 25 mg/kg, i.p.) was also seen after 2 weeks of dosing. LPS-induced sickness behavior in rats was quantified by measuring time in social exploration, anxiety, food and water consumption, and weight loss. Levels of cytokines (TNF-α, IL-1β, and IL-6) and oxidative stress in rat brain were also analyzed.

Results:

Quercetin (2 and 25 mg/kg) administration significantly (P<0.05) attenuated LPS-induced sickness behavior by modulating cytokines production as well inhibiting LPS-induced oxidative stress.

Conclusions:

Adequate intake of dietary flavonoids (like quercetin) may help promote recovery from sickness behavior.     

Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells

Dietary polyphenols have been correlated with a reduced risk of developing cancer. Quercetin (a natural polyphenolic compound) induced apoptosis in many human cancer cell lines, including breast cancer MCF-7 cells. However, the involvement of possible signaling pathways and the roles of quercetin in apoptosis are still undefined. The purpose of this study was to investigate the effects of quercetin on the induction of the apoptotic pathway in human breast cancer MCF-7 cells. When MCF-7 cells were treated with quercetin for 24 and 48 h and at various doses (10–175 μM), cell viability decreased significantly in time- and dose-dependent manners. Exposure of MCF-7 cells to 10–175 μM quercetin resulted in an approximate 90.25% decrease in viable cells. To explicate the mechanism underlying the antiproliferative effect of quercetin, cell cycle distribution and apoptosis in MCF-7 cells was investigated after exposure to 150 μM quercetin for 6–48 h. Quercetin caused a remarkable increase in the number of S phase (14.56% to 61.35%) and sub-G1 phase cells (0.1% to 8.32%) in a dose- and time-dependent manner. Quercetin caused S phase arrest by decreasing the protein expression of CDK2, cyclins A and B while increasing the p53 and p57 proteins. Following incubation with quercetin for 48 h, MCF-7 cells showed apoptotic cell death by the decreased levels of Bcl-2 protein and ΔΨ _m and increased activations of caspase-6, -8 and -9. Moreover, quercetin increased the AIF protein released from mitochondria to nuclei and the GADD153 protein translocation from endoplasmic reticulum to the nuclei. These data suggested that quercetin may induce apoptosis by direct activation of the caspase cascade through the mitochondrial pathway in MCF-7 cells.     

Quercetin attenuates airway inflammation and mucus production induced by cigarette smoke in rats

Mucus hypersecretion is a feature of many chronic airway diseases induced by cigarette smoke (CS), and evidence suggests that the antioxidant and anti-inflammatory flavonoid quercetin may protect against CS-induced respiratory pathology. In this study, the ability of quercetin to protect against CS-induced mucin expression was examined in vivo and in vitro. Quercetin or 0.2% Tween aqueous solution was administered intraperitoneally to rats,which were then exposed to CS for 28 days. Cell counts and pro-inflammatory cytokine levels were measured in bronchoalveolar lavage fluid (BALF). Lung tissue was examined for total glutathione (GSH) and total antioxidant capacity (T-AOC), histopathological lesions, goblet cell hyperplasia, epidermal growth factor receptor (EGFR) phosphorylation and NF-κB pathway activation. To complement these in vitro studies, human airway epithelial NCI-H292 cells were pretreated with quercetin and then exposed to cigarette smoke extract (CSE). Cell lysates were examined for Muc5ac expression, EGFR phosphorylation and NF-κB pathway activation. In vivo, quercetin pretreatment suppressed CS-induced goblet cell hyperplasia, inflammation, oxidative stress, EGFR phosphorylation and NF-κB pathway activation in rat lung. In vitro, quercetin pretreatment attenuated the CSE-induced Muc5ac expression, NF-κB activation and EGFR phosphorylation. Our results suggest that quercetin attenuates CS-induced mucin protein synthesis in rat lung, possibly by inhibiting oxidative stress and inflammation via a mechanism involving NF-κB pathway activation and EGFR phosphorylation. These findings suggest that quercetin has a potential for treating chronic airway diseases.     

槲皮素及其衍生物治疗慢性肾脏病的作用机制研究进展

慢性肾脏病一直以来是世界范围内的公共卫生问题,一旦错过早期干预期,进入终末期肾脏病只能行肾脏替代治疗来维持生存。槲皮素是一种植物类黄酮,槲皮素及其衍生物具有抗氧化、抗炎、抗菌、抗凋亡、抗纤维化等作用。槲皮素及其衍生物槲皮素3-O-葡萄糖苷酸、二氢槲皮素能够抑制氧化应激、抑制炎症反应、抑制纤维化、抑制细胞凋亡、调节肠道菌群、预防造影剂肾病,在保护肾脏方面发挥重要作用。对槲皮素及其衍生物治疗慢性肾脏病的作用机制进行综述,希望为临床用药提供参考。     

Protective effect of quercetin in gentamicin-induced oxidative stress in vitro and in vivo in blood cells. Effect on gentamicin antimicrobial activity

We have evaluated the effect of gentamicin and gentamicin plus quercetin on ROS production, endogenous antioxidant defenses (SOD and CAT) and lipid peroxidation in vitro on human leukocytes and in vivo on whole rat blood. Gentamicin generated ROS production in human leukocytes, produced a dual effect on both enzymes dosage-dependent and generated an increase in lipid peroxidation. Quercetin, in leukocytes stimulated by gentamicin, showed more inhibitory capacity in ROS production than the reference inhibitor (vitamin C) in mononuclear cells and a similar protective behavior at this inhibitor in polymorphonuclear cells. Quercetin, in both cellular systems, tend to level SOD and CAT activities, reaching basal values and could prevent lipidic peroxidation induced by gentamicin. The results in Wistar rats confirmed that therapeutic doses of gentamicin can induce oxidative stress in whole blood and that the gentamicin treatment plus quercetin can suppress ROS generation, collaborate with SOD and CAT and diminish lipid peroxidation. Finally, flavonoid and antibiotic association was evaluated on the antimicrobial activity in S. aureus and E. coli, showing that changes were not generated in the antibacterial activity of gentamicin against E. coli strains, while for strains of S. aureus a beneficial effect observes. Therefore, we have demonstrated that gentamicin could induce oxidative stress in human leukocytes and in whole blood of Wistar rats at therapeutic doses and that quercetin may to produce a protective effect on this oxidative stress generated without substantially modifying the antibacterial activity of gentamicin against E. coli strains, and it contributes to this activity against S. aureus strains.     

Quercetin sensitizes human glioblastoma cells to temozolomide in vitro via inhibition of Hsp27

Aim： Quercetin is an effective Hsp27 inhibitor and has been reported to facilitate tumor cell apoptosis. The aim of this study was to investigate whether quercetin could sensitize human glioblastoma cells to temozolomide （TMZ） in vitro.
Methods： Both U251 and U87 human glioblastoma cells were treated with quercetin and/or TMZ for 48 h. Cell viability was detected using the MTT assay. Cell apoptosis was analyzed with caspase-3 activity kits and flow cytometry. Hsp27 expression and phosphorylation were examined using Western blot analysis. RNA interference using Hsp27 siRNA oligos was performed to knock down the gene expression of Hsp27.
Results： TMZ （200 or 400 μmol/L） alone effectively inhibited the viability of U251 and U87 cells. When combined with quercetin （30 μmol/L）, TMZ （100 μmol/L） significantly inhibited the cell viability, and the inhibition of TMZ （200 and 400 μmol/L） was enhanced. TMZ or quercetin anole did not affect caspase-3 activity and cell apoptosis, while TMZ combined with quercetin significantly increased caspase-3 activity and induced cell apoptosis. TMZ anole significantly increased Hsp27 phosphorylation in U251 and U87 cells, while quercetin or Hsp27 siRNA oligos combined with TMZ attenuated TMZ-induced Hsp27 phosphorylation and significantly inhibited Hsp27 expression.
Conclusion： Combined treatment with TMZ and quercetin efficiently suppressed human glioblastoma cell survival in vitro.     

The dietary antioxidants resveratrol and quercetin protect cells from exogenous pro-oxidative damage.

In the colorectal epithelium oxidative stress is observed endogenously in premalignant adenoma cells or induced by nutritional factors like fatty acid hydroperoxides (LOOH). Bioactive phenols like resveratrol and quercetin can quench reactive oxygen species and protect from pro-oxidative damage. Our study used colorectal adenoma and carcinoma cell lines to assess antioxidant protective effects of resveratrol and quercetin. It demonstrated that both compounds efficiently protect from oxidative stress induced by LOOH. Effective concentrations (10 microM resveratrol and 1 microM quercetin) can easily be reached in the intestinal lumen after consumption of plant foods or food supplements. Both compounds prevent LOOH-induced formation of intracellular H2O2, stimulation of cyclooxygenase-2 and vascular endothelial growth factor. For reduction of endogenous H2O2 levels in colorectal tumor cells higher antioxidant-concentrations are needed in all cell lines. Quercetin (10 microM) alone even increased H2O2 in LT97 adenoma cells and stimulated VEGF production. Resveratrol and quercetin also induced 10-30% and 40-60% cell loss respectively by apoptosis. In summary, this indicates that resveratrol and quercetin have little protective capacity in absence of exogenous stress. They are however highly efficient in protecting against nutrition induced oxidative stress damage suggesting that this constitutes the major part of their tumor protective activity.     

Nicorandil ameliorates mitochondrial dysfunction in doxorubicin-induced heart failure in rats: Possible mechanism of cardioprotection

Despite of its known cardiotoxicity, doxorubicin is still a highly effective anti-neoplastic agent in the treatment of several cancers. In the present study, the cardioprotective effect of nicorandil was investigated on hemodynamic alterations and mitochondrial dysfunction induced by cumulative administration of doxorubicin in rats. Doxorubicin was injected i.p. over 2 weeks to obtain a cumulative dose of 18 mg/kg. Nicorandil (3 mg/kg/day) was given orally with or without doxorubicin treatment. Heart rate and aortic blood flow were recorded 24 h after receiving the last dose of doxorubicin. Rats were then sacrificed and hearts were rapidly excised for estimation of caspase-3 activity, phosphocreatine and adenine nucleotides contents in addition to cytochrome c, Bcl2, Bax and caspase 3 expression. Moreover, mitochondrial oxidative phosphorylation capacity, creatine kinase activity and oxidative stress markers were measured together with the examination of DNA fragmentation and ultrastructural changes. Nicorandil was effective in alleviating the decrement of heart rate and aortic blood flow and the state of mitochondrial oxidative stress induced by doxorubicin cardiotoxicity. Nicorandil also preserved phosphocreatine and adenine nucleotides contents by restoring mitochondrial oxidative phosphorylation capacity and creatine kinase activity. Moreover, nicorandil provided a significant cardioprotection via inhibition of apoptotic signaling pathway, DNA fragmentation and mitochondrial ultrastructural changes. Interestingly, nicorandil did not interfere with cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. In conclusion, nicorandil was effective against the development of doxorubicin-induced heart failure in rats as indicated by improvement of hemodynamic perturbations, mitochondrial dysfunction and ultrastructural changes without affecting its antitumor activity.