Label-free quantitative mass spectrometry analysis of the circadian proteome of Drosophila melanogaster lethal giant larvae mutants reveals potential therapeutic effects of melatonin.

Mutation in the Drosophila melanogaster lethal giant larvae (lgl), a tumor suppressor gene with a well-established role in cellular polarity, is known to results in massive cellular proliferation and neoplastic outgrowths. Although the tumorigenic properties of lgl mutant have been previously studied, however, little is known about its consequences on the proteome. In this study, mass spectrometry-based label-free quantitative proteomics was employed to investigate the changes in the head and intestinal tissues proteins of Drosophila melanogaster, due to lgl mutation and following treatment with melatonin. Additionally, to uncover the time-influenced variations in the proteome during tumorigenesis and melatonin treatment, the rhythmic expression of proteins was also investigated at 6-h intervals within 24-h clock. Together, the present study has identified 434 proteins of altered expressions (p < 0.05 and fold change ±1.5) in the tissues of flies in response to lgl mutation as well as posttreatment with melatonin. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed proteins revealed that lgl mutation had significantly affected the biological functions, including metabolism, and protein synthesis and degradation, in flies' tissues. Besides, melatonin had beneficially mitigated the deleterious effects of lgl mutation by reversing the alterations in protein expression closer to baseline levels. Further, changes in protein expression in the tissues due to lgl mutation and melatonin treatment were found rhythmically orchestrated. Together, these findings provide novel insight into the pathways involved in lgl-induced tumorigenesis as well as demonstrated the efficacy of melatonin as a potential anticancer agent. Data are available via ProteomeXchange with identifier PXD033191.

Application of Proteomics in Pancreatic Ductal Adenocarcinoma Biomarker Investigations: A Review.

Pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignancy with a poor prognosis is usually detected at the advanced stage of the disease. The only US Food and Drug Administration-approved biomarker that is available for PDAC, CA 19-9, is most useful in monitoring treatment response among PDAC patients rather than for early detection. Moreover, when CA 19-9 is solely used for diagnostic purposes, it has only a recorded sensitivity of 79% and specificity of 82% in symptomatic individuals. Therefore, there is an urgent need to identify reliable biomarkers for diagnosis (specifically for the early diagnosis), ascertain prognosis as well as to monitor treatment response and tumour recurrence of PDAC. In recent years, proteomic technologies are growing exponentially at an accelerated rate for a wide range of applications in cancer research. In this review, we discussed the current status of biomarker research for PDAC using various proteomic technologies. This review will explore the potential perspective for understanding and identifying the unique alterations in protein expressions that could prove beneficial in discovering new robust biomarkers to detect PDAC at an early stage, ascertain prognosis of patients with the disease in addition to monitoring treatment response and tumour recurrence of patients.

Melatonin improves cognitive behavior, oxidative stress, and metabolism in tumor-prone lethal giant larvae mutant of Drosophila melanogaster.

Mutant lethal giant larvae (lgl) flies (Drosophila melanogaster) are known to develop epithelial tumors with invasive characteristics. The present study has been conducted to investigate the influence of melatonin (0.025 mM) on behavioral responses of lgl mutant flies as well as on biochemical indices (redox homeostasis, carbohydrate and lipid metabolism, transaminases, and minerals) in hemolymph, and head and intestinal tissues. Behavioral abnormalities were quantitatively observed in lgl flies but were found normalized among melatonin-treated lgl flies. Significantly decreased levels of lipid peroxidation products and antioxidants involved in redox homeostasis were observed in hemolymph and tissues of lgl flies, but had restored close to normalcy in melatonin-treated flies. Carbohydrates including glucose, trehalose, and glycogen were decreased and increased in the hemolymph and tissues of lgl and melatonin-treated lgl flies, respectively. Key enzymes of carbohydrate metabolism showed a significant increment in their levels in lgl mutants but had restored close to wild-type baseline levels in melatonin-treated flies. Variables of lipid metabolism showed significantly inverse levels in hemolymph and tissues of lgl flies, while normalization of most of these variables was observed in melatonin-treated mutants. Lipase, chitinase, transaminases, and alkaline phosphatase showed an increment in their activities and minerals exhibited decrement in lgl flies; reversal of changes was observed under melatonin treatment. The impairment of cognition, disturbance of redox homeostasis and metabolic reprogramming in lgl flies, and restoration of normalcy in all these cellular and behavioral processes indicate that melatonin could act as oncostatic and cytoprotective agents in Drosophila.

Preventive Efficacy of Vanillic Acid on Regulation of Redox Homeostasis, Matrix Metalloproteinases and Cyclin D1 in Rats Bearing Endometrial Carcinoma.

Endometrial carcinoma is a malignant tumor of the female genital tract. This study has been performed to evaluate the chemopreventive efficacy of vanillic acid (a bio flavonoid) on endometrial carcinoma (EC) by assessing the levels of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), cytochrome P450, antioxidants-superoxide dismutase (SOD), catalase (CAT), glutathione peroxides (GPx), reduced glutathione (GSH), vitamins C and E, matrix metalloproteinases (MMP-2 and 9) and cell cycle check point protein (cyclin D1) in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induced carcinogenic rats. EC provoked by intravaginal detention of MNNG (150 mg/kg b.w. for 90 days), lead to enhancement of the levels of TBARS, LOOH, cytochrome P450, and decrement in the levels of antioxidants (SOD, CAT, GPx, GSH, vitamins C and E) and upregulated expression of MMP-2 and 9 and cyclin D1 (by western blot analysis). The treatment of vanillic acid (100 mg/kg b.w.) to MNNG treated rats (1) normalized the histopathological alterations, (2) reduced the levels of TBARS, LOOH and cytochrome P450 (3) increased the levels of antioxidants (SOD, CAT, GPx, GSH, vitamins C and E) in plasma and uterus and (4) down regulated the expression of MMP-2, 9 and cyclin D1. The effect of vanillic acid is more predominant in pre-treatment group than co-treated rats. Our results designate that vanillic acid inhibits the EC by elevating antioxidants and by regulating the levels of metalloproteinase and cell cycle check point protein.

Geraniol Inhibits Endometrial Carcinoma via Downregulating Oncogenes and Upregulating Tumour Suppressor Genes.

Endometrial carcinoma is the fourth most abundant cancer worldwide in women. Female Wistar rats were segregated into five groups: group I-control, group II-MNNG (N-methyl-N'-nitro-N-nitrosoguanidine-150 mg/kg) administered through intravaginal detention of cotton absorbent, group III-geraniol (GOH) only, group IV-GOH-pretreated (7 days before the start of MNNG administration); and group V-Co-administration of geraniol with MNNG. In this study, reverse transcriptase- PCR of K-ras, MAPK, PI3K, Wnt/ß-catenin genes, TGF-ß and expressions of PCNA, PTEN, progesterone receptor and E-cadherin by Western blotting were performed from endometrial cancer tissue and control tissues. The mRNA expressions of K-ras, MAPK, PI3K, Wnt/ß-catenin and TGF-ß were amplified in MNNG induced group. Oral administration of GOH (both pre and co-administration) reversed the mRNA expression towards normal. The reversibility is more predominant in pretreatment groups (p < 0.05). The expression of PCNA was upregulated and downregulation of PTEN, progesterone receptor and E-cadherin was noticed in MNNG induced rats. Pre and co-administration of GOH significantly reversed the expression pattern of proteins. GOH treatment is more effective in pretreatment groups (p < 0.05). These results provide powerful evidences that GOH could influence modulation of MAPK pathways and Wnt signalling pathways in the prevention of endometrial carcinoma in rats.

Chronotherapeutic effect of fisetin on expression of urea cycle enzymes and inflammatory markers in hyperammonaemic rats.

BACKGROUND: Elevated blood ammonia leads to hyperammonaemia that affects vital central nervous system (CNS) functions. Fisetin, a naturally occurring flavonoid, exhibits therapeutic benefits, such as anti-cancer, anti-diabetic, anti-oxidant, anti-angiogenic, neuroprotective and neurotrophic effects. METHODS: In this study, the chronotherapeutic effect of fisetin on ammonium chloride (AC)-induced hyperammonaemic rats was investigated, to ascertain the time point at which the maximum drug effect is achieved. The anti-hyperammonaemic potential of fisetin (50mg/kg b.w. oral) was analysed when administered to AC treated (100mg/kg b.w. i.p.) rats at 06:00, 12:00, 18:00 and 00:00h. Amelioration of pathophysiological conditions by fisetin at different time points was measured by analysing the levels of expression of liver urea cycle enzymes (carbamoyl phosphate synthetase-I (CPS-I), ornithine transcarbamoylase (OTC) and argininosuccinate synthetase (ASS)), nuclear transcription factor kappaB (NF-κB p65), brain glutamine synthetase (GS) and inducible nitric oxide synthase (iNOS) by Western blot analysis. RESULTS: Fisetin increased the expression of CPS-I, OTC, ASS and GS and decreased iNOS and NF-κB p65 in hyperammonaemic rats. Fisetin administration at 00:00h showed more significant effects on the expression of liver and brain markers, compared with other time points. CONCLUSIONS: Fisetin could exhibit anti-hyperammonaemic effect owing to its anti-oxidant and cytoprotective influences. The temporal variation in the effect of fisetin could be due to the (i) chronopharmacological, chronopharmacokinetic properties of fisetin and (ii) modulations in the endogenous circadian rhythms of urea cycle enzymes, brain markers, redox enzymes and renal clearance during hyperammonaemia by fisetin. However, future studies in these lines are necessitated.

Role of Bacopa monnieri in the temporal regulation of oxidative stress in clock mutant (cryb) of Drosophila melanogaster.

Accruing evidences imply that circadian organization of biochemical, endocrinological, cellular and physiological processes contribute to wellness of organisms and in the development of pathologies such as malignancy, sleep and endocrine disorders. Oxidative stress is known to mediate a number of diseases and it is notable to comprehend the orchestration of circadian clock of a model organism of circadian biology, Drosophila melanogaster, under oxidative stress. We investigated the nexus between circadian clock and oxidative stress susceptibility by exposing D. melanogaster to hydrogen peroxide (H2O2) or rotenone; the reversibility of rhythms following exposure to Bacopa monnieri extract (ayurvedic medicine rich in antioxidants) was also investigated. Abolishment of 24h rhythms in physiological response (negative geotaxis), oxidative stress markers (protein carbonyl and thiobarbituric acid reactive substances) and antioxidants (superoxide dismutase, catalase, glutathione-S-transferase and reduced glutathione) were observed under oxidative stress. Furthermore, abolishment of per mRNA rhythm in H2O2 treated wild type flies and augmented susceptibility to oxidative stress in clock mutant (cry(b)) flies connotes the role of circadian clock in reactive oxygen species (ROS) homeostasis. Significant reversibility of rhythms was noted following B. monnieri treatment in wild type flies than cry(b) flies. Our experimental approach revealed a relationship involving oxidative stress and circadian clock in fruit fly and the utility of Drosophila model in screening putative antioxidative phytomedicines prior to their use in mammalian systems.

Effect of melatonin on antioxidant status and circadian activity rhythm during hepatocarcinogenesis in mice.

AIM: Alteration of circadian systems can cause cancer and affects its development and response to therapeutics. The present study investigates whether cancer can disrupt circadian locomotor rhythms and evaluated the influence of melatonin (MLT) and oxaliplatin on the levels of antioxidants and circadian locomotor activity rhythms in N-nitrosodiethylamine (NDEA)-induced liver tumor in Indian field mouse (Mus booduga). MATERIALS AND METHODS: Effects of NDEA, NDEA, and MLT, as well as NDEA and oxaliplatin, on levels of mice liver marker enzymes and antioxidants and their circadian locomotor activity rhythm were assessed. RESULTS: Treatment of mice with NDEA caused significant alteration of their liver marker enzymes [aspartate transaminase and alanine transaminase; P<0.05 Duncan's multiple range test (DMRT) test] antioxidant levels (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase; P<0.05, DMRT test] and circadian locomotor activity rhythm, which were abrogated when the animals were also given MLT or the anticancer drug, oxaliplatin. CONCLUSION: Our study demonstrated that the circadian clock was disturbed by hepatocarcinogenesis and the effects could be reversed by the chronobiotic, MLT.

Naringenin (citrus flavonone) induces growth inhibition, cell cycle arrest and apoptosis in human hepatocellular carcinoma cells.

Search for new substances with antiproliferative activity and apoptosis inducing potential towards HepG2 cells is important since HCC is notoriously resistant to conventional chemotherapy. Dietary phytochemicals with significant anti-proliferative and apoptosis inducing potential are considered as agents promising for cancer therapy. Naringenin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong cytotoxic activity in numerous types of cancer cells. However, the detailed molecular mechanisms of its antiproliferative effects and apoptosis induction are still unclear. In this study, we investigated antiproliferative and apoptosis-inducing effect of naringenin in human hepatocellular carcinoma HepG2 cells. Naringenin was shown to inhibit the proliferation of HepG2 cells resulted partly from an accumulation of cells in the G0/G1 and G2/M phase of the cell cycle. Naringenin induced a rapid accumulation of p53, which might account for the naringenin-induced G0/G1 and G2/M phase arrests in Hep G2 cells. In addition, naringenin have been shown to induce apoptosis as evidenced by nuclei damage and increased proportion of apoptotic cells detected by flow cytometry analysis. Naringenin triggered the mitochondrial-mediated apoptosis pathway as shown by an increased ratio of Bax/Bcl-2, subsequent release of cytochrome C, and sequential activation of caspase-3. Our results showed that naringenin had inhibitory effect on the growth of HepG2 cell line through inhibition of cell proliferation and apoptosis induction. The elucidation of the drug targets of naringenin on inhibition of tumor cells growth should enable further development of naringenin for liver cancer therapy.

Inhibitory effect of naringenin (citrus flavonone) on N-nitrosodiethylamine induced hepatocarcinogenesis in rats.

We evaluated the effects of naringenin on N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats. Administration of NDEA induced hepatocellular carcinoma (HCC), as evidenced by changes in histopathological architecture, increased activity of cytochrome P450, decreased activity of glutathione S-transferase (GST) as well as decreased antioxidant status, enhanced lipid peroxidation and increased liver marker enzymes. Pre- and post-treatment with naringenin effectively suppressed NDEA-initiated hepatocarcinoma and the associated preneoplastic lesions by modulating xenobiotic-metabolizing enzymes (XMEs), alleviating lipid peroxidation (through both free radical scavenging and the enhanced antioxidant status), and decreased levels of liver marker enzymes. These results indicate that naringenin prevents lipid peroxidation and hepatic cell damage and also protects the antioxidant system in N-nitrosdithylamine-induced hepatocarcinogenesis.

Attenuation of NDEA-induced hepatocarcinogenesis by naringenin in rats.

Chemoprevention is one of the most promising and realistic approaches in the prevention of cancer. Several bioactive compounds present in fruits and vegetables have revealed their cancer curative potential on hepatocellular carcinoma. Naringenin is one such naturally occurring flavonoid widely found in citrus fruits. In this study, we examined the molecular mechanisms by which naringenin inhibited NDEA-induced hepatocellular carcinoma in rats by analysing the expression patterns of proliferating cell nuclear antigen, Bcl-2, NF-κB, VEGF and MMP-2/9. Enhanced cell proliferation and apoptotic evasion in NDEA-induced hepatocarcinogenesis was associated with imbalance in pro-apoptotic and anti-apoptotic proteins together with upregulation of proliferating cell nuclear antigen (PCNA) and downregulation of caspase-3. Administration of pretreatment and posttreatment of naringenin decreased the expression of PCNA and Bcl-2 and increased the expression of Bax and caspase-3, indicating antiproliferative and apoptotic effects, respectively. Administration of NDEA increased the tumour expression of NF-κB, COX-2, VEGF, MMP-2 and MMP-9 that was correlated with more aggressive lesions and tumour growth. Downregulation of NF-κB, VEGF and MMPs by naringenin seen in the present study were correlated with the inhibition of liver tumour induced by NDEA. Our results suggest that naringenin could act as a legitimate agent by inhibiting cancer processes.

Renal protective effect of hesperidin on gentamicin-induced acute nephrotoxicity in male Wistar albino rats.

OBJECTIVES: The aim of the study was to investigate the renoprotective effect of hesperidin (HDN), a citrus flavanoid with anti-oxidant properties against gentamicin (GEN)-induced nephrotoxicity in male Wistar albino rats. METHODS: Urea, uric acid, creatinine, thiobarbituric acid reactive substances (TBARS), nitric oxide (NO), total cholesterol, free fatty acids, and triglyceride levels were measured in the serum. Further, glutathione (GSH), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities were determined in the erythrocytes. Morphological changes in renal tissues were examined using light microscopy. RESULTS: Acute renal injury was evidenced by: (1) increased serum urea, uric acid, creatinine, TBARS, and NO, (2) decreased SOD, GPx, and GSH levels, and (3) necrosis in proximal tubules and glomerular atrophy. HDN supplementation to GEN-induced rats significantly decreased serum urea, uric acid, creatinine, TBARS, NO generation, but SOD, GPx activities, and GSH content increased when compared with GEN alone. Moreover, HDN supplementation resulted in complete reversal of GEN-induced tubular necrosis, and an increase in total cholesterol, free fatty acids, and triglycerides to normal levels. DISCUSSION: Our results suggested that HDN acts as a potent scavenger of free radicals in the kidney to prevent the toxic effects of GEN both at the biochemical and histopathological levels.

Circadian disruption accelerates liver carcinogenesis in mice.

BACKGROUND: The circadian timing system rhythmically controls behavior, physiology, cellular proliferation and xenobiotic metabolism over the 24-h period. The suprachiasmatic nuclei in the hypothalamus coordinate the molecular clocks in most mammalian cells through an array of circadian physiological rhythms including rest-activity, body temperature, feeding patterns and hormonal secretions. As a result, shift work that involves circadian disruption is probably carcinogenic in humans. In experimental models, chronic jet-lag (CJL) suppresses rest-activity and body temperature rhythms and accelerates growth of two transplantable tumors in mice. CJL also suppresses or significantly alters the expression rhythms of clock genes in liver and tumors. Circadian clock disruption from CJL downregulates p53 and upregulates c-Myc, thus favoring cellular proliferation. Here, we investigate the role of CJL as a tumor promoter in mice exposed to the hepatic carcinogen, diethylnitrosamine (DEN). METHODS: In experiment 1 (Exp 1), the dose-dependent carcinogenicity of chronic intraperitoneal (i.p.) administration of DEN was explored in mice. In Exp 2, mice received DEN at 10 mg/kg/day (cumulative dose: 243 mg/kg), then were randomized to remain in a photoperiodic regimen where 12 h of light alternates with 12 h of darkness (LD 12:12) or to be submitted to CJL (8-h advance of light onset every 2 days). Rest-activity and body temperature were monitored. Serum liver enzymes were determined repeatedly. Mice were sacrificed and examined for neoplastic lesions at 10 months. RESULTS: In Exp 1, DEN produced liver cancers in all the mice receiving 10 mg/kg/day. In Exp 2, mice on CJL had increased mean plasma levels of aspartate aminotransferase and more liver tumors as compared to LD mice at approximately 10 months (p = 0.005 and 0.028, respectively). The mean diameter of the largest liver tumor was twice as large in CJL vs LD mice (8.5 vs 4.4 mm, p = 0.027). In LD, a single histologic tumor type per liver was observed. In CJL, up to four different types were associated in the same liver (hepatocellular- or cholangio-carcinomas, sarcomas or mixed tumors). DEN itself markedly disrupted the circadian rhythms in rest-activity and body temperature in all the mice. DEN-induced disruption was prolonged for >or= 3 months by CJL exposure. CONCLUSIONS: The association of circadian disruption with chronic DEN exposure suggests that circadian clocks actively control the mechanisms of liver carcinogenesis in mice. Persistent circadian coordination may further be critical for slowing down and/or reverting cancer development after carcinogen exposure.

24-hour rhythms in oxidative stress during hepatocarcinogenesis in rats: effect of melatonin or alpha-ketoglutarate.

To compare the effects of alpha-ketoglutarate (alpha-KG) and melatonin on 24-h rhythmicity of oxidative stress in N-nitrosodiethylamine (NDEA)-injected Wistar male rats, melatonin (5 mg/kg i.p.) or alpha-KG (2 g/kg through an intragastric tube) was given daily for 20 weeks. In blood collected at 6 time points during a 24-h period, serum activity of aspartate transaminase (AST) and alanine transaminase (ALT) and the levels of alpha-fetoprotein (alpha-FP) were measured as markers of liver function. To assess lipid peroxidation and the antioxidant status, plasma levels of thiobarbituric acid reactive substances (TBARS) and of reduced glutathione (GSH) were measured, together with the activity of erythrocyte superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST). NDEA augmented mesor and amplitude of rhythms in AST and ALT activity and plasma alpha-FP levels and mesor values of plasma TBARS, while decreasing mesor values of plasma GSH and erythrocyte SOD, CAT, GPx and GST. Acrophases were delayed by NDEA in all cases except for alpha-FP rhythm, which became phase-advanced. Co-administration of melatonin or alpha-KG partially counteracted the effects of NDEA. Melatonin decreased mesor of plasma TBARS and augmented mesor of SOD activity. The results indicate that melatonin and alpha-KG are effective in protecting from NDEA-induced perturbation of 24-h rhythms in oxidative stress. Melatonin augmented antioxidant defense in rats.

Prevention of N-nitrosodiethylamine-induced hepatocarcinogenesis by S-allylcysteine.

Chemopreventive effect of S-allylcysteine (constituent of garlic) on N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis was evaluated in Wistar rats. Significantly decreased lipid peroxidation products (thiobarbituric acid reactive substances-TBARS and lipid hydroperoxides) with increased level of reduced glutathione, increased activities of glutathione S-transferase, and glutathione peroxidase were observed in liver of NDEA-treated rats when compared with control rats. The activities of superoxide dismutase and catalase were significantly decreased in tumor tissue when compared with control. Administration of S-allylcysteine (SAC) showed the inhibition of tumor incidence, modulated the lipid peroxidation, and increased the reduced glutathione, glutathione-dependent enzymes, superoxide dismutase, and catalase in NDEA-induced carcinogenesis. From our results, we speculate that S-allylcysteine mediates its chemopreventive effects by modulating lipid peroxidation, GST stimulation, and by increasing the antioxidants. Hence SAC prevents cells from loss of oxidative capacity in NDEA-induced hepatocarcinogenesis.

Prevention by melatonin of hepatocarcinogenesis in rats injected with N-nitrosodiethylamine.

N-nitrosodiethylamine (NDEA) is a potent carcinogenic agent that induces liver cancer. To evaluate the chemopreventive function of melatonin in this experimental model, Wistar male rats received a single i.p. injection of NDEA or vehicle followed by weekly s.c. injections of carbon tetrachloride or vehicle for 6 weeks. Melatonin (5 mg/kg body weight) or its vehicle (0.5 mL saline) was given i.p. on a daily basis 2 hr before lights off for 20 wk. At the end of this period the rats were killed and liver and blood samples were taken for histological and biochemical studies. As markers for liver function, the activity of aspartate transaminase (AST) and alanine transaminase (ALT) and the levels of alpha-fetoprotein were measured in serum. To assess lipid peroxidation and the antioxidant status in liver and blood, the levels of thiobarbituric acid reactive substances (TBARS) and of reduced glutathione (GSH) were measured. The activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST) was assessed in liver and erythrocyte fraction of NDEA-treated rats. NDEA administration inhibited body weight, macro- and microscopically detectable liver tumors and increased levels of plasma AST, ALT and alpha-fetoprotein. NDEA treatment decreased liver TBARS levels and CAT and SOD activities and increased liver GSH levels and GST and GPx activities. Plasma TBARS were augmented, while plasma GSH levels and the activities of erythrocyte CAT, SOD, GST and GPx decreased, in NDEA-treated rats. Melatonin administration significantly curtailed tumor development and counteracted all the biochemical effects.

Melatonin treatment improves the antioxidant status and decreases lipid content in brain and liver of rats.

This study examines the effect of a daily administration of melatonin for 45 days at two doses (0.5 and 1.0 mg/kg body wt.) on antioxidant status, lipid peroxidation and lipid profile in the brain and liver in rats. Both doses of melatonin caused a significant decrease in lipid peroxidation and the levels of cholesterol, phospholipids, triglycerides and free fatty acids in the examined tissues. Concomitantly, the treatment with melatonin augmented the activity of the brain and liver antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase as well as increased glutathione levels. These results offer a support to the hypothesis that melatonin in pharmacological amounts effectively reduces oxidative stress and acts as an antihyperlipidemic agent.

Influence of monosodium glutamate on circadian rhythms of lipid peroxidation products and antioxidants in rats.

Monosodium glutamate (MSG) was administrated subcutaneously for 60 days to Wistar rats and 24h rhythms of thiobarbituric acid reactive substances (TBARS) and antioxidants such as reduced glutathione, superoxide dismutase and catalase were studied. MSG treatment was found to advance TBARS and to delay the acrophases of GSH and catalase. Amplitude and mesor values of these rhythms were found to be altered during MSG treatment. As glutamate levels in brain were found to be significantly increased (in MSG), we hypothesize that increased glutamate levels in brain could alter these biochemical rhythms probaly by modulating the transmission in several areas/nuclei in brain.

Temporal patterns of lipid peroxidation product formation and antioxidants activity in oral cancer patients.

The aim of this study was to assess the temporal patterns of (the formation of) thiobarbituric acid reactive substances and the activities of antioxidant enzymes in the erythrocytes of ten healthy adult subjects and ten oral cancer patients of comparable age. The levels of thiobarbituric acid reactive substances and the activities of antioxidant enzymes were assayed at 6-hour intervals using colorimetric methods. The Cosinorwin computer software program was used to analyse the characteristics of biochemical rhythms, such as acrophase, amplitude, and mesor (rhythms: acrophase, amplitude, mesor, etc.). There is a phase delay in erythrocyte thiobarbituric acid reactive substance levels and enzymatic antioxidant activities in oral cancer patients as compared to healthy subjects. The desynchronisation of thiobarbituric acid reactive substance production and enzymatic antioxidant rhythms reflected an alteration of circadian clock function in oral cancer patients and may require specific measures for chronotherapy.

S-allylcysteine inhibits circulatory lipid peroxidation and promotes antioxidants in N-nitrosodiethylamine-induced carcinogenesis.

Effects of S-allylcysteine (SAC), an organosulfur compound of garlic, on circulatory lipid peroxidation and antioxidant levels were evaluated in N-nitrosodiethylamine (NEDA)-induced hepatocarcinogenesis in Wistar rats. Significantly elevated thiobarbituric acid reactive substances in the circulation of rats bearing carcinoma indicated the higher levels of lipid peroxidation which was accompanied by significantly decreased levels of antioxidants (beta-carotene, ascorbic acid, alpha-tocopherol, reduced glutathione, glutathione peroxidase, superoxide dismutase and catalase) when compared with controls. Lipid peroxidation has been implicated as a major cause in cancer development. SAC-administered rats showed the inhibition of tumor incidence and lipid peroxidation with simultaneous elevation in antioxidants. We suggest that SAC exerts its chemopreventive effects by decreasing lipid peroxidation and enhancing the levels of antioxidants in NDEA carcinogenesis by reducing the formation of free radicals.