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Probiotic lactic acid bacteria (LAB) are a particular group of gram-positive bacteria that are usually involved in natural ferments and widely used in food manufacture industry. Most of them can produce exopolysaccharides (EPS), surface carbohydrate polymers with diverse biological functions. LAB EPS are potentially complementary and alternative medicines against cancer. EPS show anti-proliferative effects on a variety of tumor cells from intestine, liver, breast, etc. They modulate the development of tumors through various mechanisms including promoting apoptosis, inducing cell cycle arrest as well as anti-mutagenic, anti-oxidative, anti-angiogenesis and anti-inflammatory effects. Bacterial origin, existence form, chemical structure, purity et al. are important factors affecting the anticancer effects of EPS. The future challenge lies in elucidating the precise structure-function relationship of LAB EPS. Besides, more in vivo studies and further clinical trials are indispensable to confirm the anticancer effects., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The present study was designed to evaluate the effect of sodium copper chlorophyllin (SCC) in adenine-induced chronic kidney disease (CKD). CKD was induced in male Wistar rats by feeding 0.3% w/w adenine diet for 28 days. After induction, animals were treated with sodium copper chlorophyllin at dose 2.7, 5.4, and 10.8 mg/kg for the next 28 days. The biochemical and urines parameters like creatinine, blood urea nitrogen (BUN), albumin, total protein creatinine clearance, urea clearance, and glomerular filtration rate were assessed on days 0, 14, and 28. Plasma TGF-β1, COX-2, and IL-6 levels were assessed. Various oxidative stress parameters and TGF-β1 expression were determined in the kidney. Histopathology of the kidney was studied with different stains. Sodium copper chlorophyllin-treated animals showed a significant reduction in urine output and relative kidney weight. The treatment with sodium copper chlorophyllin significantly improved kidney function by normalizing biochemical and urine parameters. Treatment with SCC significantly reduced circulatory inflammatory mediators-TGF-β1, COX-2, and IL-6. Additionally, the treatment also significantly reduced oxidative stress and TGF-β1 expression in kidney tissues. Histopathology studies showed inhibition in the kidney damage due to the treatment of SCC. The sodium copper chlorophyllin treatment attenuated adenine-induced chronic kidney disease in rats.

Purple sweet potato anthocyanins are kinds of natural anthocyanin red pigments extracted from the root or stem of purple sweet potato. They are stable and have the functions of anti-oxidation, anti-mutation, anti-tumor, liver protection, hypoglycemia, and anti-inflammation, which confer them a good application prospect. Nevertheless, there is not a comprehensive review of purple sweet potato anthocyanins so far. The extraction, structural characterization, stability, functional activity, application in the food, cosmetics, medicine, and other industries of anthocyanins from purple sweet potato, together with their biotransformation in vitro or by gut microorganism are reviewed in this paper, which provides a reference for further development and utilization of anthocyanins.

The methanolic extracts from the peels of Citrus limon were found to show antimutagenic effects against 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the Ames test. From the methanolic extracts, four new coumarins (wakayamalimonol A-D) and a new furanocoumarin (wakayamalimonol E) were isolated together with fifteen known compounds. The absolute stereostructures of the new compounds were determined by chemical synthesis and the modified Mosher's method. Among the isolated constituents, coumarins, furanocoumarins, and limonoids showed antimutagenic effects in the Ames test. One of the major constituent, limonin, showed significant antimutagenic effects against mitomycinC and PhIP in the micronucleus test in vivo.

Malignant glioma is the most aggressive brain tumor. Hypoxic condition has been explored for killing cancer stem cells or drug-resistant tumor cells. This study investigated the effects of hypoxia on autophagic death and the possible mechanisms. Exposure of human malignant glioma U87-MG cells to cobalt chloride (CoCl2) increased cellular hypoxia-inducible factor-1α levels and concurrently decreased cell viability concentration- and time-dependently. In parallel, treatment with CoCl2 suppressed proliferation of human U87-MG cells. Autophagic cells and levels of LC3-II were concentration- and time-dependently induced in human U87-MG cells after exposure to CoCl2. However, pretreatment with 3-mehyladenine (3-MA) and chloroquine, inhibitors of cell autophagy, caused significant alleviations in CoCl2-induced cell autophagy. In contrast, exposure to rapamycin, an inducer of cell autophagy, synergistically induced hypoxia-induced autophagy of U87-MG cells. Administration of human U87-MG cells with CoCl2 triggered caspase-3 activation and cell apoptosis. Interestingly, pretreatment with 3-MA and chloroquine remarkably suppressed CoCl2-induced caspase-3 activation and cell apoptosis. Application of p53 small interference (si)RNA into human U87-MG cells downregulated levels of this protein and simultaneously lowered hypoxia- and 3-MA-induced alterations in cell autophagy, apoptosis, and death. The hypoxia-induced autophagy and apoptosis of DBTRG-05MG cells were significantly lowered by 3-MA pretreatment and p53 knockdown. Therefore, the present study shows that CoCl2 treatment can induce autophagy of human glioma cells and subsequent autophagic apoptosis via a p53-dependent pathway. Hypoxia-induced autophagic apoptosis may be applied as a therapeutic strategy for treatment of glioma patients.

Increased frequency of cells with chromosomal aberrations was revealed in 48-h cultures of peripheral blood lymphocytes isolated North Ossetia residents with impaired reproductive function. After 2-week treatment with antimutagenic drug Afobazole, the percentage of cells with chromosomal aberrations significantly decreased from 3.77±0.20 to 2.48±0.24% (p<0.001). Significant differences between chromosome damage levels before and after administration of the drug suggest that Afobazole could be recommended for protective purposes to this group of patients.

The scleroderma en coup de sabre is a variant of localized scleroderma that occurs preferentially in children. The disease progresses with a proliferative and inflammatory phase and later atrophy and residual deformity, which are treated with surgical techniques such as injectable fillers, transplanted or autologous fat grafting and resection of the lesion. Among the most widely used fillers is hyaluronic acid. However, there are limitations that motivate the search for alternatives, such as polymethylmethacrylate, a permanent filler that is biocompatible, non-toxic, non-mutagenic and immunologically inert. In order to illustrate its application, a case of scleroderma en coup de sabre in a 17-year-old patient, who was treated with polymethylmethacrylate with excellent aesthetic results, is reported.

Aim: Recommended initial treatment for mixed urinary incontinence involves behavioral therapy, and drug and pelvic floor muscle exercises. Our objective is to evaluate the outcome of these conservative treatments in our patients with mixed urinary incontinence., Methods: A retrospective review was conducted in patients with mixed urinary incontinence who were offered sequential conservative treatment modalities comprised of medication and physiotherapy. Outcome was defined as a score of 1 or less for questions 2 and 3 on the six-item Urodynamic Distress Inventory (UDI-6) and seven-item Incontinence Impact Questionnaire, in addition to clinical symptomatic improvement with no urgency, urge incontinence and voiding frequency of less than eight times per 24 h on a 3-day bladder diary after treatment. Treatment outcome of patients opting for medication plus physiotherapy (M + P) were analyzed against patients preferring medication only (M)., Results: Sixty-two mixed urinary incontinent patients received an initial treatment with conservative measures with mean follow-up of 14 months. A total of 61.2% (30/49) and 56.3% (9/13) subjects had improved symptoms in the M + P and M group, respectively. There was significant improvement in UDI-6 total score in the M + P group after conservative treatment, despite no significant difference when compared to the M group. Only 6.45% required subsequent anti-incontinence surgery after conservative treatment, amongst whom only half showed improvement after the surgery., Conclusion: Combined treatment with medication and physiotherapy is highly recommended for patients with mixed urinary incontinence. Conservative measures should still precede any surgical intervention. Further studies are needed to evaluate the long-term efficacy., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

Background/aims: Tyrosine-methionine-aspartate-aspartate (YMDD) mutations were the main limitation of lamivudine (LAM) for treating chronic hepatitis B (CHB). The aim of this study was to evaluate whether LAM combined with IFN-α offer advantage over lamivudine monotherapy for the occurrence of YMDD mutations in CHB using a meta-analysis., Methodology: We searched electronic databases and calculated the odds ratios (OR) with their 95% confidence intervals (CI) and pooled the results., Results: Our meta-analysis indicated that the difference of YMDD mutation rates between the combination therapy of IFN-α2b, IFN-α2a and Peg-IFN-α2a respectively plus LAM and LAM monotherapy (95% CI, 3.25-9.70, 95% CI, 5.77-17.51, 95% CI, 6.79-26.13, respectively). The rate of YMDD mutations in LAM monotherapy was increased when compared with combination and sequential combination group (95% CI, 6.79-22.16, and 95% CI, 2.69-7.75, respectively). The YMDD mutation rate in combination therapy was lower than that of LAM monotherapy in HBeAg positive patients (95% CI, 4.98-13.23)., Conclusions: Our present meta-analysis suggests that different types of IFN-a in combination with LAM can significantly reduce the rate of YMDD mutation compared to LAM monotherapy.

Natural plant extracts offer a promising hope in the prevention/treatment of cancer arising from genetic mutations. This study evaluated in vitro and in vivo mutagenic and antimutagenic effects of aqueous fraction of Myristica fragrans (AFMF) leaves on TA100 strain of Salmonella typhimurium and Mus musculus (Male Swiss albino mice), respectively. The antioxidant activity of AFMF against 2,2-diphenyl-1-picrylhydrazyl (DPPH), total phenolic and flavonoid contents were determined, followed by its phytochemical elucidation using the Ultra Performance Liquid Chromatography technique (UPLC). The mutagenicity of AFMF at 4, 20, 50, 100, 200, 500, and 1000 µg/well was <2.0 in S. typhimurium and the induced micronucleated polychromatic and normochromatic erythrocytes at 500, 1000, 2000, and 4000 mg/kg were not significantly different from the negative control (p≥0.05). The mutagenic activity of benzo[a]pyrene and cyclophosphamide was significantly suppressed above 50.0% throughout the tested concentrations. Fifty percent of the free radicals from DPPH were scavenged by AFMF at 0.11 mg/ml. Total phenolic and flavonoid contents of AFMF were 51.0 mg GAE/g and 27 mg QE/g, respectively. Rutin was elucidated by the UPLC technique, and thereby suspected to be the phytochemical responsible for the observed antimutagenic activity. Thus far, AFMF seems to contain a promising chemotherapeutic agent for the prevention of genetic damage that is crucial for cancer development.

Cisplatin is an effective antineoplastic drug. However, it provokes considerable collateral effects, including genotoxic and clastogenic activity. It has been reported that a diet rich in glutamine can help inhibit such collateral effects. We evaluated this activity in 40 Swiss mice, distributed into eight experimental groups: G1 - Control group (PBS 0.1 mL/10 g body weight); G2 - cisplatin group (cisplatin 6 mg/kg intraperitoneally); G3, G4, G5 - glutamine groups (glutamine at 150, 300, and 600 mg/kg, respectively; orally); G6, G7, G8 - Pre-treatment groups (glutamine at 150, 300, and 600 mg/kg, respectively; orally and cisplatin 6 mg/kg intraperitonially). For the micronucleus assay, samples of blood were collected (before the first use of the drugs at T0, then 24 (T1) and 48 (T2) hours after the first administration). For the comet assay, blood samples were collected only at T2. The damage reduction percentages for the micronucleus assay were 90.0, 47.3, and 37.3% at T1 and 46.0, 38.6, and 34.7% at T2, for G6, G7, and G8 groups, respectively. For the comet assay, the damage reduction percentages were 113.0, 117.4, and 115.0% for G6, G7, and G8, respectively. We conclude that glutamine is able to prevent genotoxic and clastogenic damages caused by cisplatin.

Alpha-blockers and antimuscarinics combination therapy has been commonly used for treatment of male lower urinary tract symptoms (LUTS). We conducted a meta-analysis aimed to access the relative efficacy and safety of combination therapy. We systematically searched Medline, Cochrane, and Embase for eligible studies. Fifteen randomized studies with 4556 patients were included. Overall, combination therapy significantly improved the urgency, voiding frequency, International Prostate Symptom Score (IPSS) total scores, and IPSS storage subscores. Addition of antimuscarinics had little effect on urinary function. The incidences of adverse events were acceptably low. Our meta-analysis demonstrated that the combination therapy was a safe, well-tolerated, and effective treatment for male LUTS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

As mutation causes many life-threatening diseases including cancer, a diet enriched with specific vegetables having potential to reduce mutagenesis possesses immense significance. In this study, 41 commonly used vegetables from diverse botanical taxa were evaluated and compared for their relative antimutagenic potential using standard assays [Escherichia coli RNA polymerase β (rpoB)-based Rif(S) → Rif(R) assay and Ames test] against known mutagens (UV, gamma radiation, 4-nitroquinoline-N-oxide and ethylmethanesulphonate). Significant differences in antimutagenicity were observed even among the cultivars within the same species, as well as at other phylogenetic levels such as genus or family. The effect of cooking in terms of boiling (aquathermal treatment), on the antimutagenicity of these vegetables, was also investigated. In majority of the cases, aquathermal treatment did not affect the antimutagenic potential. The antimutagenicity of these vegetables was not found to correlate well with their antioxidant properties.

Mitomycin C (MMC) is one of the most effective chemotherapeutic agents. However, during clinical use several side effects may occur. Recombinant human erythropoietin (rhEPO), a glycoprotein that regulates haematopoiesis, has been shown to exert an important cyto-protective effect in many tissues. The aim of this study was to explore whether rhEPO protects against MMC-induced genotoxicity in rat bone-marrow cells. Adult male Wistar rats were divided into six groups of 18 animals each: a control group, a 'rhEPO alone' group, an 'MMC alone' group and three 'rhEPO+MMC' groups (pre-, co- and post-treatment conditions). Our results show that MMC induced a noticeable genotoxic effect in rat bone-marrow cells. rhEPO reduced the effects of MMC significantly in every type of experiment conducted, such as the frequency of micronuclei, the percentage of chromosome aberrations and the level of DNA damage measured with the comet assay. The protective effect of rhEPO was more efficient when it was given 24h prior to MMC treatment., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Bamboo salt is a traditional Korean baked solar salt processed by packing the solar salt in bamboo joint cases and heating it several times to high temperatures. The antimutagenic activity and in vitro anticancer effects of bamboo salt on HepG2 human hepatoma cells were investigated and compared to those of other salt samples. Although solar salt and purified salt exhibited comutagenicity with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the Salmonella typhimurium TA100 strain, bamboo salt was associated with a lower degree of comutagenicity or antimutagenic activity. Bamboo salt baked nine times (9×) showed a greater increase in antimutagenic activity than salts baked once (1×) or three times (3×). At a concentration of 1%, the growth rate of HepG2 cells treated with 9× bamboo salt determined by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MIT) assay was reduced by 65%; this rate of inhibition was higher than that achieved with 1× baked bamboo salt (40%). Purified and solar salts had relatively lower inhibitory effects on growth rate (25% and 29%, respectively). Compared to the other salt samples, 9× bamboo salt significantly (p<0.05) induced apoptosis as determined by 4,6-diamidino-2-phenylindole (DAPI) staining and flow cytometry analysis. It also upregulated the expression of Bax, caspase-9 and caspase-3; and downregulated Bcl-2 expression. The bamboo salts, especially 9× bamboo salt, also significantly (p<0.05) downregulated the expression of inflammation-related NF-κB, iNOS, and COX-2, and upregulated the gene expression of IκB-α compared to the other salt sample.

Tagitinin C, a major sesquiterpenoid, was isolated from the leaves of Tithonia diversifolia. The high morbidity and mortality rate of hepatoma in Taiwan motivated our interest in the investigation of tagitinin C's mechanism against the human hepatocellular carcinoma. The methanolic extract of leaves of T. diversifolia (TDM) and tagitinin C were found to have cytotoxic activities against human hepatoma Hep-G2 cells in the MTT assay with IC(50) values of 40.0 ± 2.0 and 2.0 ± 0.1 μg/mL, respectively. This compound induced population increase in the sub-G(1) phase and S phase arrest. Treatment with tagitinin C isolated from TDM resulted in activation of both caspase 3 and caspase 8 which suggested that the antiproliferative effect of this compound was caspase-dependent apoptosis. Magnetic resonance techniques indicated that the tumorigenisity of xenografts derived from Hep-G2 cells was retarded by the delivery of tagitinin C (15 μg/mouse/day) relative to the control counterparts.

In this study, we evaluated the effects of whey protein on oxidative stress in rats that were subjected to oxidative stress induced by iron overload. Thirty male rats were assigned to 3 groups: the control group (regular [50 mg/kg diet] dose of iron+20% casein), iron overload group (high [2,000 mg/kg] dose of iron+20% casein, IO), and whey protein group (high dose of iron+10% casein+10% whey protein, IO+whey). After 6 wk, the IO group showed a reduction in the plasma total radical trapping antioxidant parameter and the activity of erythrocyte superoxide dismutase and an increase in lipid peroxidation (determined from the proportion of conjugated dienes). However, whey protein ameliorated the oxidative changes induced by iron overload. The concentration of erythrocyte glutathione was significantly higher in the IO+whey group than in the IO group. In addition, whey protein supplementation fully inhibited iron overload-induced DNA damage in leukocytes and colonocytes. A highly significant positive correlation was observed between plasma iron levels and DNA damage in leukocytes and colonocytes. These results show the antioxidative and antigenotoxic effects of whey protein in an in vivo model of iron overload-induced oxidative stress.

Cyclophosphamide (CP) is one of the most popular alkylating anticancer drugs that show a high therapeutic index, despite the widespread side effects and toxicity particularly in high-dose regimens and long-term use. Here, we evaluated and compared the efficacy of two different doses (50 and 100 mg/kg body weight, given orally for 30 consecutive days) of Egyptian sweet marjoram leaf powder (MLP) and marjoram leaf aqueous extract (MLE) in alleviating the genotoxicity, immunosuppression and other complications induced by CP in non-tumour-bearing albino rats. The present study showed (probably for the first time) that both MLP and MLE significantly alleviated (P < 0·05-0·001) most side effects and toxicity of CP-treated rats including the increase in chromosomal aberrations of bone marrow cells and serum malondialdehyde level, the decrease in the level of serum Ig, the delayed type of hypersensitivity response as also the weights and cellularity of lymphoid organs, and myelosuppression, leucopenia, macrocytic normochromic anaemia as well as thrombocytopenia by reactivating the non-enzymic (reduced glutathione) and enzymic (catalase, glutathione peroxidase, glutathione S-transferase, superoxide dismutase) antioxidant system and increasing the mitotic index of bone marrow cells. The modulatory effects of marjoram leaves shown in the present study were dose dependent in most cases and much higher in MLE (21-23 % for all parameters taken together). In addition, the doses used in the present study were considered safe. In conclusion, sweet marjoram leaves (especially in the form of a herbal tea) may be useful as an immunostimulant and in reducing genotoxicity in patients under chemotherapeutic interventions.

Aging is a well-recognized risk factor in the development of cardiovascular disease, which is the primary cause of death and disability in the elderly population. The normal process of aging is associated with progressive deterioration in structure and function of the heart and vasculature. These age-related changes likely act as both a catalyst and accelerator in the development of cardiovascular disease. Since the aging population is one of the fastest growing segments of the population, it is of vital importance that we have a thorough understanding of the physiological changes that occur with aging that contribute to the high incidence of cardiovascular disease in this population. This insight will allow for the development of more targeted therapies that can prevent and treat these conditions. One such anti-aging strategy that has received considerable attention as of late is calorie restriction. Calorie restriction has emerged as one of the most effective and reproducible interventions for extending lifespan, as well as protecting against obesity, metabolic disorders, and cardiovascular disease. Herein, we review the multiple beneficial effects that calorie restriction and resveratrol exert on the cardiovascular system with a particular focus on aging. Although calorie restriction and resveratrol have proven to be very effective in preventing and treating the development of cardiovascular disease in animal models, studies continue as to whether these profound beneficial effects can translate to humans to improve cardiovascular health.

Background: In this report, the isorhamnetin 3-o-robinobioside and its original extract, the ethyl acetate extract, from Nitraria retusa leaves, were evaluated for their ability to induce antioxidant and antigenotoxic effects in human chronic myelogenous leukemia cell line., Methods: Nitraria retusa products properties were carried out by firstly evaluating their effects against lipid peroxidation induced by H2O2, using the thiobarbituric acid reactive substances species (TBARS) assay, and proceeding to the assay of cellular antioxidant activity, then doing the comet assay., Results: The isorhamnetin 3-o-robinobioside showed a protective effect against lipid peroxidation induced by H2O2. The same natural compound and ethyl acetate extract inhibited oxidation induced by 2,2'-azobis (2-amidinopropane) dihydrochloride in human chronic myelogenous leukemia cells with respectively 50% inhibitory concentration values of 0.225 mg/ml and 0.31 mg/ml, reflecting a significant antioxidant potential. The same two products inhibited the genotoxicity induced by hydroxyl radicals in the same human cell line (by 77.77% at a concentration of 800 μg/ml and by 80.55% at a concentration of 1000 μg/ml respectively)., Conclusions: The isorhamnetin 3- o-robinobioside and its original extract, the ethyl acetate extract, from Nitraria retusa leaves, have a great antioxidant and antigenotoxic potential on human chronic myelogenous leukemia cell line K562.

Ethnopharmacological Relevance: Four species of Podocarpus are used in traditional medicine both in human and animal healthcare in South Africa. In vitro pharmacological screening of leaf and stem extracts of these species exhibited potent antimicrobial, anti-inflammatory, anti-tyrosinase, anthelmintic, acetylcholinesterase inhibitory and antioxidant activities., Aim of the Study: To investigate the mutagenicity, antimutagenicity and cytotoxicity effects of leaf and stem extract of South African Podocarpus species., Material and Methods: The mutagenicity and cytotoxic effects of extracts from four species of Podocarpus were tested using the Salmonella/microsome assay with and without metabolic activation, based on the plate-incorporation method and neutral red uptake (NRU) assay respectively. Five Salmonella typhimurium tester strains; TA98, TA100, TA102, TA1535 and TA1537 were used for mutagenicity testing. The relative cytotoxicity of the extracts was assessed by determining their NI(50) values (50% inhibition of NRU)., Results: The extracts did not show any mutagenic effects against all the tester strains with or without metabolic activation. All extracts demonstrated a strong antimutagenic effect on the mutations induced by 4NQO, decreasing its mutagenic effect in a dose-dependent manner. Strong cytotoxic effects were exhibited by petroleum ether extracts as compared to 80% ethanol extracts. When HepG2 cells were in contact with plant extracts in an increasing concentration, slopes of NRU decreased (highest-lowest %) following a concentration-dependent pattern. For 80% ethanol extracts, the most toxic extract in terms of percentage viability was leaves of Podocarpus falcatus whereby at 0.2 mg/ml, the viability of the cells was 38.9%. Stem extract of Podocarpus latifolius was the most toxic among PE extracts, giving a percentage viability of 46.4 at 0.1 mg/ml., Conclusion: Absence of mutagenicity does not indicate lack of toxicity, as was observed from these extracts. These findings will help in assessing the safety measures to be considered in the use of these species and also the need to determine the cytotoxic potential of these species against various forms of human cancer cells., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Epigenetics has been emphasized in the postgenome era to clarify obscure health risks of environmental toxicants including endocrine disrupting chemicals (EDCs). In addition, mixed exposure in real life can modify health consequences of the toxicants. Particularly, some nutritional and dietary materials modify individual susceptibility through changes in the epigenome. Therefore, we focused on some environmental toxicants that induce epigenetic alterations, and introduced chemopreventive materials to reverse the toxicants-induced epigenetic alterations. Methodologically, we used global and specific DNA methylation as epigenetic end points and searched epigenetic modulators in food. We reviewed various epigenetic end points induced by environmental toxicants including alcohol, asbestos, nanomaterials, benzene, EDCs, metals, and ionizing radiation. The epigenetic end points can be summarized into global hypomethylation and specific hypermethylation at diverse tumor suppress genes. Exposure timing, dose, sex, or organ specificity should be considered to use the epigenetic end points as biomarkers for exposure to the epimutagenic toxicants. Particularly, neonatal exposure to the epimutagens can influence their future adult health because of characteristics of the epimutagens, which disrupt epigenetic regulation in imprinting, organogenesis, development, etc. Considering interaction between epimutagenic toxicants and their reversers in food, we suggest that multiple exposures to them can alleviate or mask epigenetic toxicity in real life. Our present review provides useful information to find new end points of environmental toxicants and to prevention from environment-related diseases.

Up-to-date models of intrastromal corneal segments are reviewed. Different techniques of up-to-date models of intrastromal corneal segments implantation in keratoconus are described. Mechanical and laser techniques of forming of corneal tunnels are analyzed. Information about potential complications of intrastromal corneal segment implantation is given.

Despite clear results of observational studies linking a diet rich in fruits and vegetables to a decreased cancer risk, large interventional trials evaluating the impact of dietary micronutrient supplementation, mostly vitamins, could not show any beneficial effects. Today it has become clear that a single micronutrient, given in supernutritional doses, cannot match cancer preventive effects of whole fruits and vegetables. In this regard polyphenols came into focus, not only because of their antioxidant potential but also because of their ability to interact with molecular targets within the cells. Because polyphenols occur in many foods and beverages in high concentration and evidence for their anticancer activity is best for tissues they can come into direct contact with, field cancerization predestines upper aerodigestive tract epithelium for cancer chemoprevention by polyphenols. In this paper, we summarize cancer chemopreventive attempts with emphasis on head and neck carcinogenesis and discuss some methodological issues. We present data regarding antimutagenic effects of curcumin and epigallocatechin-3-gallate in human oropharyngeal mucosa cultures exposed to cigarette smoke condensate.

Neem (Azadirachta indica), a member of the Meliaceae family, is a fast growing tropical evergreen tree with a highly branched and stout, solid stem. Because of its tremendous therapeutic, domestic, agricultural and ethnomedicinal significance, and its proximity with human culture and civilization, neem has been called "the wonder tree" and "nature's drug store." All parts of this tree, particularly the leaves, bark, seed-oil and their purified products are widely used for treatment of cancer. Over 60 different types of biochemicals including terpenoids and steroids have been purified from this plant. Pre-clinical research work done during the last decade has fine-tuned our understanding of the anticancer properties of the crude and purified products from this plant. The anticancer properties of the plant have been studied largely in terms of its preventive, protective, tumor-suppressive, immunomodulatory and apoptotic effects against various types of cancer and their molecular mechanisms. This review aims at scanning scattered literature on "the anticancer biology of A. indica," related toxicity problems and future perspectives. The cogent data on the anticancer biology of products from A. indica deserve multi-institutional clinical trials as early as possible. The prospects of relatively cheaper cancer drugs could then be brighter, particularly for the under-privileged cancer patients of the world.

Intact rat embryonic and placental tissues were found to have a characteristic ratio of cells with different degrees of DNA fragmentation. The genotoxic effect of cyclophosphamide was shown to be accompanied by a quantitative deviation from the control group established ratio of different cell types. A relationship was found between the abnormal ratio of different cell types in the embryonic and placental tissues and the occurrence of embryonic morphological abnormalities. The antimutagen afobazole (1, 10, and 100 mg/kg) was ascertained to be able to lower genotoxic effects in the embryonic and placental tissues and their related malformations. It is presumed that it is promising to use DNA damage index in the embryonic and placental cells as a biomarker of the course of embryogenesis and as a basis for devising an indicator test for rapid screening of potential teratogens.

Ilex paraguariensis dried and minced leaves are made into a brewed tea, prepared in a sui generis manner by large populations in South America, having evolved from a tea drunk by the Guarani ethnic group to a beverage that has a social and almost ritualistic role in some South American modern societies. It is used both as a source of caffeine, in lieu or in parallel with tea and coffee, but also as a therapeutic agent for its alleged pharmacological properties. Although with some exceptions, research on biomedical properties of this herb has had a late start and strongly lags behind the impressive amount of literature on green tea and coffee. However, in the past 15 years, there was a several-fold increase in the literature studying Ilex paraguariensis properties showing effects such as antioxidant properties in chemical models and ex vivo lipoprotein studies, vaso-dilating and lipid reduction properties, antimutagenic effects, controversial association with oropharyngeal cancer, anti-glycation effects and weight reduction properties. Lately, promising results from human intervention studies have surfaced and the literature offers several developments on this area. The aim of this review is to provide a concise summary of the research published in the past three years, with an emphasis on translational studies, inflammation and lipid metabolism. Ilex paraguariensis reduces LDL-cholesterol levels in humans with Ilex paraguariensis dyslipoproteinemia and the effect is synergic with that of statins. Plasma antioxidant capacity as well as expression of antioxidant enzymes is positively modulated by intervention with Ilex paraguariensis in human cohorts. A review on the evidence implicating Ilex paraguariensis heavy consumption with some neoplasias show data that are inconclusive but indicate that contamination with alkylating agents during the drying process of the leaves should be avoided. On the other hand, several new studies confirm the antimutagenic effects of Ilex paraguariensis in different models, from DNA double breaks in cell culture models to mice studies. Novel interesting work has emerged showing significant effect on weight reduction both in mice and in rat models. Some mechanisms involved are inhibition of pancreatic lipase, activation of AMPK and uncoupling of electron transport. Intervention studies in animals have provided strong evidence of anti-inflammatory effects of Ilex paraguariensis, notably protecting cigarette-induced lung inflammation acting on macrophage migration and inactivating matrix-metalloproteinase. Research on the effects of Ilex paraguariensis in health and disease has confirmed its antioxidant, anti-inflammatory, antimutagenic and lipid-lowering activities. Although we are still waiting for the double-blind, randomized prospective clinical trial, the evidence seems to provide support for beneficial effects of mate drinking on chronic diseases with inflammatory component and lipid metabolism disorders., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Medicinal plants represent an important resource in new drug research. Antioxidant properties of plants can help to scavenge reactive oxygen species. The objective of this work was to evaluate the genotoxic, antigenotoxic, tumoricidal, and apoptotic effect of some major phenols (apigenin, bisabolol, and protocatechuic acid) from two medicinal plants, Matricaria chamomilla and Uncaria tomentosa. The wing spot test of Drosophila melanogaster was used to evaluate the genotoxicity and antigenotoxicity of the three phenols. The human model of HL-60 leukemia cells was used for the assessment of the cytotoxic effect, growth, and cellular viability. The apoptotic effect was evaluated using a DNA fragmentation assay based on the formation of internucleosomal units. Protocatechuic acid (0.25 and 1 mM), apigenin (0.46 and 1.85 mM), and bisabolol (0.56 and 2.24 mM) did not exhibit any genotoxic effect. The three phenols showed an antigenotoxic effect against the hydrogen peroxide effect and also exhibited tumoricidal activity. Apigenin (2.24-35.96 mM) showed a lower 50% inhibitory concentration (0.75 and 3.87 mM for the trypan blue test and WST-8 colorimetric assay, respectively) than bisabolol and protocatechuic acid. These phenolics also induced apoptosis in HL-60 leukemia cells. This study suggests that the antioxidant activity of Chamomilla and Uncaria could be partially responsible of their beneficial activity.

Groundwater arsenic contamination has been a health hazard for West Bengal, India. Oxidative stress to DNA is recognized as an underlying mechanism of arsenic carcinogenicity. A phytochemical, curcumin, from turmeric appears to be potent antioxidant and antimutagenic agent. DNA damage prevention with curcumin could be an effective strategy to combat arsenic toxicity. This field trial in Chakdah block of West Bengal evaluated the role of curcumin against the genotoxic effects of arsenic. DNA damage in human lymphocytes was assessed by comet assay and fluorescence-activated DNA unwinding assay. Curcumin was analyzed in blood by high performance liquid chromatography (HPLC). Arsenic induced oxidative stress and elucidation of the antagonistic role of curcumin was done by observation on reactive oxygen species (ROS) generation, lipid peroxidation and protein carbonyl. Antioxidant enzymes like catalase, superoxide dismutase, glutathione reductase, glutathioneS-transferase, glutathione peroxidase and non-enzymatic glutathione were also analyzed. The blood samples of the endemic regions showed severe DNA damage with increased levels of ROS and lipid peroxidation. The antioxidants were found with depleted activity. Three months curcumin intervention reduced the DNA damage, retarded ROS generation and lipid peroxidation and raised the level of antioxidant activity. Thus curcumin may have some protective role against the DNA damage caused by arsenic.

Phytochemical investigation of the petroleum ether extract fraction of Polyalthia cerasoides seeds led to the isolation of two phytosterols (alpha-spinasterol and spinasterol) and a clerodane di-terpenoid. The structures of these compounds were elucidated using IR, (1)H-NMR, (13)C-NMR and Mass spectral analysis. Further, these compounds were tested for antiproliferative action against CACO-2 cell line and apoptotic action was determined by nuclear staining and DNA fragmentation analysis. The results showed that the compounds exhibited antiproliferative action at various concentrations with an IC(50) value of 28.6+/-4.34nM/ml, 57.7+/-6.81nM/ml and 60.0+/-7.10nM/ml for clerodane diterpenoid, spinasterol and alpha-Spinasterol respectively. Furthermore, the isolated compounds were screened for antimutagenic effect against methylmethane sulfonate (MMS) induced mutation. Phytosterols showed protective effect, whereas clerodane diterpenoid was less effective to MMS induced chromosomal aberrations. Our research contributes to the characterization of phytochemical constituents and to understand the ability of these compounds to antiproliferative and antimutagenic responses from the seed extracts.

Urinary incontinence remains a common and distressing condition affecting many women and is known to have a significant effect on quality of life (QoL). Whilst conservative and behavioural therapy are important in the management of women with both stress incontinence and overactive bladder (OAB) ultimately many may benefit from pharmacological therapy. Antimuscarinic drugs are the commonly used agents in the treatment of OAB although often compliance and persistence are affected by adverse effects. Consequently many newer agents remain under investigation. In addition duloxetine has recently been introduced for the management of women with stress incontinence and may offer an alternative to surgery in selected cases. The aim of this review is to provide an overview of the current and new developments in the management of women with urinary incontinence as well as reviewing the role of oestrogen therapy in relation to lower urinary tract dysfunction., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Butea superba is a traditional tuberous Thai plant enriched with flavonoids that is used for treating erectile dysfunction. We investigated the mutagenic and antimutagenic potentials of a B. superba extract by using the pre-incubation method of the Ames test. Salmonella typhimurium strains TA 98 and TA 100 were applied as the tester strains in the presence and absence of an S9 mixture. Prior to the mutagenic and antimutagenic tests, the survival of the tester strains was measured by treating with the B. superba extract. The results show that the B. superba extract exhibited dose-dependent cytotoxic effects. Data from the Ames test revealed that the B. superba extract to be non-mutagenic in the presence and absence of the S9 mixture. In contrast, the B. superba extract showed antimutagenic potential towards either or both of the tested mutagens: 2-(2-furyl)-3-(5-nitro-2-furyl)-acrylamide (AF-2) and benzo(a)pyrene (B(a)P) in the respective presence and absence of the S9 mixture, respectively. The plant antimutagenic activity was confirmed by a rec assay. A further study by micronucleus test demonstrated that the B. superba extract at the maximum loading volume could induce acute micronucleus formation in the tested animals. The in vitro mutagenic and antimutagenic assays confirmed the safe consumption of B. superba products at low dose (not more than 781.25 microg/ml of the plant extract), but the in vivo genotoxic assay demonstrated the unsafe consumption at a high dose (300 mg/kg of the BW plant extract or 16 g/kg of the BW plant powder).

In the present investigation anti-tumour, anti-mutagenic and chemomodulatory potential of Chlorophytum borivilianum were evaluated. Chlorophytum borivilianum root extract had no toxic effect up to a dose of 800 mg/kg body weight/day. Significant increase (p<0.05 to p<0.001) in the activity of reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) and a significant decrease in the hepatic MDA level were observed at 100, 400, and 800 mg/kg body weight of Chlorophytum borivilianum root extract when compared with the control value. Skin papillomagenesis studies demonstrated a significant (p<0.001) decrease in cumulative numbers of papilloma, tumour incidence, tumour burden, tumour size and tumour weight and significant (p<0.01) increase in average latent period when the animals received Chlorophytum borivilianum root extract at a dose level of 800 mg/kg body weight/day orally in double distilled water at pre, peri and post initiation stages of carcinogenesis. A significant reduction in the frequency of chromosomal aberration and micronuclei was observed in the treated animals as compared to carcinogen controls. The present investigation suggests that Chlorophytum borivilianum has anti-tumour, anti-mutagenic and chemomodulatory effects.

Oxidative damage to biomolecules occurs by the accumulation of molecular damage due to free radicals and/or a diminution of antioxidant protection. The aim of this study was to evaluate the protection of organic and conventional purple grape juices in brain, liver, and plasma from adult Wistar rats (7 months old) against the oxidative damage provoked by carbon tetrachloride (CCl(4)). Adult rats were divided into three groups (control, conventional purple grape juice, and organic purple grape juice). Half of the rats received CCl(4), and the other half received the vehicle (vegetable oil). The chemical analytical determination showed that the highest levels of total phenolic, resveratrol, and catechins were seen in organic purple grape juices. Considering the treatment groups, it was observed that in all tissues (brain structures and liver) and plasma, CCl(4) treatment increased the lipid peroxidation (LP) levels. Both grape juices were capable to reduce LP levels in cerebral cortex and hippocampus; however, in the striatum and substantia nigra only the organic grape juice reduced LP level. CCl(4) caused an increase in catalase activity in cerebral cortex, hippocampus, and substantia nigra and in superoxide dismutase activity in substantia nigra. This increase was reduced by both juices in substantia nigra and hippocampus structures (P < .05). In the alkaline version of the comet assay performed on whole blood, it was observed that CCl(4) was capable of inducing mainly DNA damage class 4 and 3 frequencies, which was significantly reduced in groups that received both purple grape juices. This implies that both grape juices have an important antigenotoxic activity.

Silymarin, a polyphenolic flavonoid isolated from milk thistle (Silybum marianum), is being used clinically in Europe and Asia for the treatment of liver diseases. Silymarin has a strong antioxidative action capable of scavenging both free radicals and reactive oxygen species responsible for cancer. Silymarin, a powerful hepatoprotective and antioxidant, was chosen in the present study and was tested for its antimutagenic activity using an in vitro test, the Ames bacterial reverse mutation assay. The results indicated that silymarin showed a significant mutagenicity in frame shift mutant strains (TA97a and TA98) with metabolic activation. This compound also showed stronger antimutagenic effect against 2-aminofluorene and 4-nitroquinoline N-oxide induced mutation. When pre-, co- and post-treatment of silymarin was carried out, it showed stronger antimutagenic activity in the post-treatment with 2-aminofluorene and 4-nitroquinoline N-oxide in TA97a and TA98 strains., ((c) 2009 John Wiley & Sons, Ltd.)

This study explored the DNA protective (anti-mutagenic) effects of an oral, liquid, multi-phytonutrient dietary supplement containing a proprietary blend of fruits, vegetables and aloe vera concentrated components in addition to a proprietary catechin complex from green tea (VIBE Cardiac & Life, Eniva Nutraceuticals, Anoka, MN; herein described as "VIBE"). This study tested the hypothesis that VIBE would reduce DNA damage in skin cells exposed to UVR. Human epidermal cells, from the cell line A431NS, were treated with 0% (control), 0.125%, 0.5%, 1% and 2% VIBE, and then exposed to 240 J/m(2) UVR. The amount of DNA damage was assessed using the COMET assay. At each concentration tested, a significantly smaller amount of DNA damage was measured by the COMET assay for the VIBE treated cells compared to the control cells exposed to UVR without VIBE. The dose response curves showed a maximal response at 0.5% VIBE with a threefold reduction in COMET tail density compared to the control samples without VIBE (p < 0.001). Additional research is warranted in human clinical trials to further explore the results of this study which demonstrated the DNA protective and anti-mutagenic effects of VIBE for human skin cells exposed to UVR-induced DNA damage.

The extract enriched in total oligomer flavonoids (TOF), and the aqueous, methanol, and ethyl acetate extracts of Acacia salicina were investigated for their polyphenolic compound content, antioxidative activity in the nitro blue tetrazolium/riboflavin assay system, antibacterial activity against Gram-positive and Gram-negative bacterial reference strains, antigenotoxic activity tested with the Ames assay, and cytotoxic activity against the K562 human chronic myelogenous leukemia cell line and L1210 leukemia murine cells. TOF extract was effective at inhibiting nitro blue tetrazolium reduction by superoxide radical in a nonenzymatic O(2)(*-)-generating system. Significant activity against bacterial reference strains Staphylococcus aureus, Enterococcus faecalis, Salmonella enteritidis, and Salmonella typhimurium was shown with all the tested extracts. These extracts significantly decreased the genotoxicity induced by sodium azide and 4-nitro-o-phenylenediamine. A pronounced cytotoxic effect on both leukemia cell lines was detected in TOF, methanolic and ethyl acetate extracts. The antioxidant, antimicrobial, antigenotoxic, and cytotoxic activities exhibited by A. salicina depended on the chemical composition of the tested extracts.

Alterations that could lead to the cancer development may also be related to an adverse development of offspring in experimental animals. Some functional foods, which contain the polysaccharide beta-glucan, have been described as being effective in the prevention of clastogenic damage. Based on that finding, the aim of the present study was to determine the efficacy of this sugar polymer in the mutagenic and teratogenic damage control. Two sets of females, pregnant and non-pregnant, were evaluated. The results indicated that beta-glucan was effective in preventing clastogenic damage in pregnant as well as non-pregnant females. In addition, pregnant females were more susceptible to mutagenic damage. However, teratogenic effects were not prevented effectively, although there was a trend toward a reduction in level of malformations. Despite beta-glucan did not prevent malformations, it increased fetal viability and reduced number of post-implantation losses and resorption, thereby enhancing reproductive performance in females.

Background: Chronic renal hypoxia is suspected to play a pathogenic role in the genesis of diabetic nephropathy (DN). Cobalt enhances the activity of the hypoxia-inducible factor (HIF), a key factor in the defence against hypoxia. Its long-term effect on DN is evaluated., Methods: Cobalt chloride was given to hypertensive, type 2 diabetic rats with nephropathy (SHR/NDmcr-cp). Treatment was initiated at the age of 13 weeks and continued for 26 weeks., Results: Cobalt did not correct hypertension and metabolic abnormalities (obesity, hyperglycaemia and hyperlipidaemia) but reduced proteinuria as well as histological kidney injury. Cobalt upregulated renal HIF-1alpha and HIF-2alpha expression and increased the expression of HIF-regulated genes, including erythropoietin, vascular endothelial growth factor and heme oxygenase-1. The renal expression of transforming growth factor (TGF)-beta and connective tissue growth factor (CTGF) was significantly reduced by cobalt. The renal expression of NADPH oxidase, a marker of oxidative stress, and the renal content of pentosidine, a marker of advanced glycation, were also significantly reduced by cobalt., Conclusions: Cobalt achieved renal protection independently of metabolic status and blood pressure. Its effect was attributed to the upregulation of HIF and HIF-regulated genes and to a mitigated advanced glycation and oxidative stress.

The polysaccharides beta-glucans occur as a principal component of the cellular walls. Some microorganisms, such as yeast and mushrooms, and also cereals such as oats and barley, are of economic interest because they contain large amounts of beta-glucans. These substances stimulate the immune system, modulating humoral and cellular immunity, and thereby have beneficial effect in fighting infections (bacterial, viral, fungal and parasitic). beta-Glucans also exhibit hypocholesterolemic and anticoagulant properties. Recently, they have been demonstrated to be anti-cytotoxic, antimutagenic and anti-tumorogenic, making them promising candidate as pharmacological promoters of health.

Hypobaric hypoxia, characteristic of high altitude is known to increase the formation of reactive oxygen and nitrogen species (RONS), and decrease effectiveness of antioxidant enzymes. RONS are involved and may even play a causative role in high altitude related ailments. Brain is highly susceptible to hypoxic stress and is involved in physiological responses that follow. Exposure of rats to hypobaric hypoxia (7619 m) resulted in increased oxidation of lipids and proteins due to increased RONS and decreased reduced to oxidized glutathione (GSH/GSSG) ratio. Further, there was a significant increase in superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) levels. Increase in heme oxygenase 1 (HO-1) and heat shock protein 70 (HSP70) was also noticed along with metallothionein (MT) II and III. Administration of cobalt appreciably attenuated the RONS generation, oxidation of lipids and proteins and maintained GSH/GSSH ratio similar to that of control cells via induction of HO-1 and MT offering efficient neuroprotection. It can be concluded that cobalt reduces hypoxia oxidative stress by maintaining higher cellular HO-1 and MT levels via hypoxia inducible factor 1alpha (HIF-1alpha) signaling mechanisms. These findings provide a basis for possible use of cobalt for prevention of hypoxia-induced oxidative stress.

The aim of this study was to investigate the antimutagenic effects of Spirulina (SP) on male and female mice by the dominant lethal test using cyclophosphamide (CP) as a mutagen. Animals of both sex were given SP orally at 0, 200, 400 or 800 mg/kg body weight (b.w.) for 2 weeks prior to starting the CP treatment. CP was i.p. injected daily for 5 days at 40 mg/kg b.w. For the male-dominant lethal test, each male was caged with untreated females per week for 3 weeks. For the female-dominant lethal test the above doses and schedule treatments were used and treated females were caged for one week with untreated males (1-2). On days 13-15 after breeding was |started all the females were evaluated for incidence of pregnancy, total corpora lutea, total implants and pre- and post-implant losses. In the male-dominant lethal test, the CP induced pre- and post-implant losses in untreated females were inhibited at all SP doses. In the female-dominant lethal test only post-implantation losses were prevented at the same doses. Semen examination of a separate group of mice showed that SP improved its quality. Our results illustrate protective effects of SP in relation to CP-induced genetic damage to germ cells.

Diet-related mutagenesis plays an etiologic role in chronic diseases, including cardiovascular disease and cancer. Many dietary mutagens are DNA reactive, leading to distinct spectra of base-pair substitution mutations and structural chromosome changes. Examples include aflatoxin B1, ochratoxin A, ptaquiloside, various pyrrolizidine alkaloids, heterocyclic amines including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and polycyclic aromatic hydrocarbons such as benzo[a]pyrene. However, endogenously or exogenously formed reactive species, inhibitors of topoisomerase II enzymes (e.g., flavonoids), of DNA repair (e.g., caffeine), or of the mitotic spindle (possibly acrylamide), also cause mutations, including structural chromosome changes and copy number variants. Genomic instability also results from inadequate nutrient intake (e.g., folate and selenium). Antimutagens include vitamin C, carotenoids, chlorophyllin, dietary fibers, and plant polyphenols acting through various mechanisms. Polymorphisms in genes for nutrient uptake, metabolism, and excretion will affect dietary intake in determining individual risk of disease development. Human studies utilizing nutrigenomic/nutrigenetic technologies will be essential to quantifying and overcoming diet-related mutagenesis.

Propolis has been reported to display a broad spectrum of biological activities such as anticancer, antioxidant, anti-inflammatory, antibiotic and antifungal properties, among others. There is great interest not only in the determination of the chemical composition of propolis but also in the understanding of the mechanisms related to its therapeutic actions. In this respect, the aim of the present investigation was to study the influence of both simultaneous (6, 12 and 24 mg/kg b. w.) and subacute (12 mg/kg b. w.) treatment with a crude hydroalcoholic extract of propolis on the frequency of chromosome aberrations induced by the chemotherapeutic agent doxorubicin (DXR) in Wistar rat bone marrow cells. HPLC analysis of the crude extract allowed the quantification of the phenolic compounds: caffeic acid, P-coumaric acid, aromadendrin 4'-methyl ether, 3-prenyl- P-coumaric acid (drupanin), isosakuranetin, kaempferide, 3,5-diprenyl- P-coumaric acid (artepellin C), baccharin and 2,2-dimethyl-6-carboxyethenyl-2 H-1-benzopyran. A total of 100 metaphase cells/animal were analyzed for chromosome aberration frequency and 1000 cells/animal were counted to obtain the mitotic index. The results showed that the dose of 12 mg propolis/kg b. w., administered either as a single dose or as subacute treatment, caused a statistically significant decrease in the frequency of chromosome damage induced by DXR compared to the group treated only with DXR. This reduction might be, in part, due to the presence of phenolic compounds in the studied propolis, which are able to capture free radicals produced by chemotherapeutic agents such as DXR.

The hepatopulmonary syndrome (HPS) occurs when intrapulmonary dilatation causes hypoxemia in cirrhosis. The free radicals may play a significant contributory role in the progression of HPS, and flavonoid agents could protect against deleterious effects of free radicals. The flavonoid quercetin was evaluated in an experimental model of biliary cirrhosis induced by bile duct ligation (BDL) in rats. Quercetin was administered at 50mg/kg for 14 days to cirrhotic and non-cirrhotic rats. Bone marrow was extracted from animals to analyze micronuclei. Lung, liver and blood were extracted to detect DNA damage using the comet assay. The results showed that the micronuclei and DNA damages to lung and liver were increased in BDL rats. Quercetin caused no damage to the DNA while decreasing the occurrence of micronucleated cells in bone marrow as well as DNA damage to lung and liver in cirrhotic rats. Quercetin showed antimutagenic activity against hydroperoxides as evaluated by the oxidative stress sensitive bacterial strains TA102 Salmonella typhimurium and IC203 Escherichia coli, suggesting protection by free radical scavenging. In Saccharomyces cerevisie yeast strains lacking mitochondrial or cytosolic superoxide dismutase, these results indicate that quercetin protects cells by induction of antioxidant enzymes. The present study is the first report of genotoxic/antigenotoxic effects of quercetin in a model of animal cirrhosis. In this model, quercetin was not able to induce genotoxicity and, conversely, it increased the genomic stability in the cirrhotic rats, suggesting beneficial effects, probably by its antioxidant properties.

Diabetes is a metabolic disorder characterized by elevated blood glucose levels. Although conventional treatments such as insulin and other drugs reduce blood glucose, there is still a therapeutic need for effective orally administered drugs. Trace elements like vanadium and tungstate have been successfully demonstrated to reduce blood glucose in experimental diabetes with minimal chronic complications. We investigated the anti-hyperglycemic effects of cobalt in streptozotocin-diabetic rats. Normal and diabetic rats were provided with drinking water containing 3.5 mM cobalt chloride for three weeks followed by 4 mM for four weeks. Body weights and fluid consumption were monitored on a daily basis, while food intake was recorded twice every week. Prior to termination, an oral glucose tolerance test was performed on the animals. Diabetic rats lost significant body weight (357 +/- 2 gm) compared to controls (482 +/- 3 gm). Body weight was further reduced by cobalt treatment (290 +/- 2 gm). Although it was difficult to establish a dosing regimen without weight loss, food and fluid consumption in cobalt-treated diabetic rats improved significantly compared to untreated diabetics. Plasma glucose levels were significantly reduced with reference to diabetic controls (29.3 +/- 0.9 mM) by the fourth week to a lower but still hyperglycemic level (13.6 +/- 3.4 mM). Cobalt-treated diabetic rats demonstrated an enhanced ability to clear a glucose load compared to untreated diabetics. Cobalt treatment neither affected the feeding and drinking patterns nor plasma glucose in normoglycemic animals although body weights decreased compared to untreated controls. We conclude that chronic cobalt treatment decreases plasma glucose levels in STZ-diabetic rats and improves tolerance to glucose.

Chlorophyllin (CHL) is a potent antimutagen in vitro, an effective anti-carcinogen in several animal models, and significantly reduced urinary biomarkers of aflatoxin B(1) (AFB(1)) exposure in a human population. Here we report an expanded analysis of CHL chemoprevention using the potent environmental hydrocarbon dibenzo[a,l]pyrene (DBP). A dose-dose matrix design employed over 12 000 rainbow trout to evaluate the interrelationships among dietary carcinogen dose, anti-carcinogen dose, carcinogen-DNA adduct levels at exposure and eventual tumor outcome in two target organs. Included was an evaluation of the pharmaceutical CHL preparation (Derifil), used previously in a study of individuals chronically exposed to AFB(1). CHL was pre-, co- and post-fed at doses of 0-6000 p.p.m. and co-fed with DBP at doses of 0-371.5 p.p.m. for 4 weeks. This protocol generated a total of 21 dose-dose treatment groups, each evaluated with three or more replicates of 100 animals. The DBP-only treatment produced dose-responsive increases in liver and stomach DBP-DNA adducts, whereas increasing CHL co-treatment doses produced successive inhibition in liver (49-83%) and stomach (47-75%) adduct levels at each DBP dose examined. The remaining 8711 trout were necropsied, 10 months later. DBP treatment alone produced a logit incidence versus log [DBP] dose-response curve in stomach that was linear; CHL co-treatment provided dose-dependent tumor inhibition which ranged from 30 to 68% and was predictable from the adduct response. The Derifil CHL preparation was also found to effectively reduce DNA adduction and final tumor incidence in stomach (as well as liver), with a potency compatible with its total chlorin content. Liver tumor incidence in the DBP-only groups appeared to plateau near 60%. At DBP doses of