Discovery of a new class of potent pyrrolo[3,4-c]quinoline-1,3-diones based inhibitors of human dihydroorotate dehydrogenase: Synthesis, pharmacological and toxicological evaluation.

Twenty N-substituted pyrrolo[3,4-c]quinoline-1,3-diones 3a-t were synthesized by a cyclization reaction of Pfitzinger's quinoline ester precursor with the selected aromatic, heteroaromatic and aliphatic amines. The structures of all derivatives were confirmed by IR, 1H NMR, 13C NMR and HRMS spectra, while their purity was determined using HPLC techniques. Almost all compounds were identified as a new class ofpotent inhibitors against hDHODH among which 3a and 3t were the most active ones with the same IC50 values of 0.11 µM, about seven times better than reference drug leflunomide. These two derivatives also exhibited very low cytotoxic effects toward healthy HaCaT cells and the optimal lipophilic properties with logP value of 1.12 and 2.07 respectively, obtained experimentally at physiological pH. We further evaluated the comparative differences in toxicological impact of the three most active compounds 3a, 3n and 3t and reference drug leflunomide. The rats were divided into five groups and were treated intraperitoneally, control group (group I) with a single dose of leflunomide (20 mg/kg) group II and the other three groups, III, IV and V were treated with 3a, 3n and 3t (20 mg/kg bw) separately. The investigation was performed in liver, kidney and blood by examining serum biochemical parameters and parameters of oxidative stress.

Thymus zygis, Valuable Antimicrobial (In Vitro and In Situ) and Antibiofilm Agent with Potential Antiproliferative Effects.

With the growing issues of food spoilage, microbial resistance, and high mortality caused by cancer, the aim of this study was to evaluate T. zygis essential oil (TZEO) as a potential solution for these challenges. Here, we first performed GC/MS analysis which showed that the tested TZEO belongs to the linalool chemotype since the abundance of linalool was found to be 38.0%. Antioxidant activity assays showed the superiority of TZEO in neutralizing the ABTS radical cation compared to the DPPH radical. The TZEO was able to neutralize 50% of ABTS•+ at the concentration of 53.03 ± 1.34 µg/mL. Antimicrobial assessment performed by employing disc diffusion and minimal inhibitory concentration assays revealed TZEO as a potent antimicrobial agent with the highest inhibition activity towards tested gram-negative strains. The most sensitive on the treatment with TZEO was Enterobacter aerogenes showing an MIC 50 value of 0.147 ± 0.006 mg/mL and a MIC 90 value of 0.158 ± 0.024 mg/mL. Additionally, an in situ analysis showed great effects of TZEO in inhibiting gram-negative E. coli, P. putida, and E. aerogenes growing on bananas and cucumbers. Treatment with the TZEO vapor phase in the concentration of 500 µg/mL was able to reduce the growth of these bacteria on the food models to the extent > 90%, except for E. coli growth on the cucumber, which was reduced to the extent of 83.87 ± 4.76%. Furthermore, a test on the antibiofilm activity of the tested essential oil revealed its biofilm prevention effects against Salmonella enterica which forms biofilms on plastic and stainless-steel surfaces. Performed tests on the TZEO effects towards cell viability showed no effects on the normal MRC-5 cell line. However, the results of MTT assay of TZEO effects on three cancer cell lines (MDA-MB-231, HCT-116, and K562) suggest that TZEO exerted the strongest effects on the inhibition of the viability of MDA-MB-231 cells, especially after long-term treatment in the highest concentration applied with reducing the viability of the cells to 57%. Additionally, results of NBT and Griess assays suggest that TZEO could be a convenient candidate for future testing for developing novel antitumor therapies.

Biological Activity of Cupressus sempervirens Essential Oil.

The aim of this study was to evaluate the antioxidant, antibiofilm, antimicrobial (in situ and in vitro), insecticidal, and antiproliferative activity of Cupressus sempervirens essential oil (CSEO) obtained from the plant leaf. The identification of the constituents contained in CSEO was also intended by using GC and GC/MS analysis. The chemical composition revealed that this sample was dominated by monoterpene hydrocarbons α-pinene, and δ-3-carene. Free radical scavenging ability, performed by using DPPH and ABTS assays, was evaluated as strong. Higher antibacterial efficacy was demonstrated for the agar diffusion method compared to the disk diffusion method. The antifungal activity of CSEO was moderate. When the minimum inhibitory concentrations of filamentous microscopic fungi were determined, we observed the efficacy depending on the concentration used, except for B. cinerea where the efficacy of lower concentration was more pronounced. The vapor phase effect was more pronounced at lower concentrations in most cases. Antibiofilm effect against Salmonella enterica was demonstrated. The relatively strong insecticidal activity was demonstrated with an LC50 value of 21.07% and an LC90 value of 78.21%, making CSEO potentially adequate in the control of agricultural insect pests. Results of cell viability testing showed no effects on the normal MRC-5 cell line, and antiproliferative effects towards MDA-MB-231, HCT-116, JEG-3, and K562 cells, whereas K562 cells were the most sensitive. Based on our results, CSEO could be a suitable alternative against different types of microorganisms as well as suitable for the control of biofilms. Due to its insecticidal properties, it could be used in the control of agricultural insect pests.

Green Synthesis of Silver Nanoparticles Using Salvia verticillata and Filipendula ulmaria Extracts: Optimization of Synthesis, Biological Activities, and Catalytic Properties.

The study's objective was to obtain silver nanoparticles (SVAgNP and FUAgNP) using aqueous extracts of Salvia verticillata and Filipendula ulmaria. The optimal conditions for nanoparticle synthesis were determined and obtained; nanoparticles were then characterized using UV-Vis, Fourier-transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), Dynamic Light Scattering (DLS), Scanning Electron Microscopy with Energy Dispersive Spectroscopy (SEM/EDS). SVAgNP and FUAgNP possessed a crystalline structure with 48.42% and 60.41% silver weight, respectively. The highest percentage of nanoparticles in the solution had a diameter between 40 and 70 nm. In DPPH˙ and ABTS˙+ methods, FUAgNP (IC50 15.82 and 59.85 µg/mL, respectively) demonstrated a higher antioxidant capacity than SVAgNP (IC50 73.47 and 79.49 µg/mL, respectively). Obtained nanoparticles also showed pronounced antibacterial activity (MIC ˂ 39.1 µg/mL for most of the tested bacteria), as well as high biocompatibility with the human fibroblast cell line MRC-5 and significant cytotoxicity on some cancer cell lines, especially on the human colon cancer HCT-116 cells (IC50 31.50 and 66.51 µg/mL for SVAgNP and FUAgNP, respectively). The nanoparticles demonstrated high catalytic effectiveness in degrading Congo red dye with NaBH4. The results showed a rapid and low-cost methodology for the synthesis of AgNPs using S. verticillata and F. ulmaria with promising biological potential.

Chemical Composition and Biological Activity of Tanacetum balsamita Essential Oils Obtained from Different Plant Organs.

The aim of this study is to evaluate the chemical composition of Tanacetum balsamita L. essential oils (EOs) obtained from different plant organs, flowers (FEO), leaves (LEO), and stems (SEO), as well as to assess their biological properties. The results obtained by using GC and GC/MS analysis indicate that this plant belongs to the carvone chemotype. Moreover, we examined the oil's antimicrobial and antitumor potential. Antimicrobial effects were determined using minimum inhibitory concentrations assay and the vapor phase method. Obtained results indicate better antimicrobial activity of investigated EO samples compared to the commercially available antibiotics. On the treatment with FEO, Y. enterocolitica and H. influenzae showed high sensitivity, while treatment with LEO and SEO showed the highest effects against S. aureus. The vapor phase method, as an in situ antibacterial analysis, was performed using LEO. Obtained results showed that this EO has significant activity toward S. pneumoniae in the apple and carrot models, L. monocytogenes in the pear model, and Y. enterocolitica in the white radish model. The potential antitumor mechanisms of FEO, LEO, and SEO were determined by the means of cell viability, redox potential, and migratory capacity in the MDA-MB-231 and MDA-MB-468 cell lines. The results show that these EOs exert antiviability potential in a time- and dose-dependent manner. Moreover, treatments with these EOs decreased the levels of superoxide anion radical and increased the levels of nitric oxide in both tested cell lines. The results regarding total and reduced glutathione revealed, overall, an increase in the levels of total glutathione and a decrease in the levels of reduced glutathione, indicating strong antioxidative potential in tested cancer cells in response to the prooxidative effects of the tested EOs. The tested EOs also exerted a drop in migratory capacity, which indicates that they can be potentially used as chemotherapeutic agents.

GC, GC/MS Analysis, and Biological Effects of Essential Oils from Thymus mastchina and Elettaria cardamomum.

Spanish marjoram (Thymus mastichina) and cardamom (Elettaria cardamomum) are traditional aromatic plants with which several pharmacological properties have been associated. In this study, the volatile composition, antioxidative and antimigratory effects on human breast cancer (MDA-MB-468 cell line), antimicrobial activity, and antibiofilm effect were evaluated. Results obtained via treatment of human breast cancer cells generally indicated an inhibitory effect of both essential oils (EOs) on cell viability (after long-term treatment) and antioxidative potential, as well as the reduction of nitric oxide levels. Antimigratory effects were revealed, suggesting that these EOs could possess significant antimetastatic properties and stop tumor progression and growth. The antimicrobial activities of both EOs were determined using the disc diffusion method and minimal inhibition concentration, while antibiofilm activity was evaluated by means of mass spectrometry. The best antimicrobial effects of T. mastichina EO were found against the yeast Candida glabrata and the G+ bacterium Listeria monocytogenes using the disc diffusion and minimal inhibitory concentration methods. E. cardamomum EO was found to be most effective against Pseudomas fluorescens biofilm using both methods. Similarly, better effects of this oil were observed on G- compared to G+ bacterial strains. Our study confirms that T. mastichina and E. cardamomum EOs act to change the protein structure of older P. fluorescens biofilms. The results underline the potential use of these EOs in manufactured products, such as foodstuffs, cosmetics, and pharmaceuticals.

Chemical Composition, Antitumor Potential, and Impact on Redox Homeostasis of the Essential Oils of Orlaya grandiflora from Two Climate Localities.

It is well known that abiotic components can affect biosynthetic pathways in the production of certain volatile compounds. The aim of this study was to compare the chemical composition of essential oils obtained from Orlaya grandiflora (L.) Hoffm. collected from two localities in Serbia (continental climate, OG1) and Montenegro (Mediterranean climate, OG2) and to assess their antitumor potential on the human colon cancer HCT-116 and breast cancer MDA-MB-231 cell lines. EOs obtained by hydrodistillation were analyzed using GC-MS and GC-FID methods. The results indicate considerable differences in the chemical compositions of the two samples. Although in both samples the main class of volatiles observed was sesquiterpenes (47.5% for OG1 and 70.1% for OG2), the OG1 sample was characterized by a high amount of monoterpene hydrocarbons (29.3%), and sesquiterpene germacrene D (29.5%) as the most abundant compound. On the other hand, the OG2 sample contained a high quantity of oxygenated sesquiterpenes (20.6%), and ß-elemene (22.7%) was the major constituent. The possible antitumor mechanisms of these EOs in the HCT-116 and MDA-MB-231 cell lines were examined by means of cell viability, apoptosis, redox potential, and migratory capacity. The antiviability potential appeared to be dose dependent, since the results showed that both EOs decreased the viability of the tested cells. Stronger antitumor effects were shown in MDA-MB-231 cells after short-term treatment, especially at the highest applied concentration, where the percentage of viability was reduced by over 40%. All tested concentrations of EOs exhibited proapoptotic activity and elevated activity of caspase-3 in a dose- and time-dependent manner. The results also showed decreased concentrations of superoxide anion radical in the treated cells, which indicates their significant antioxidative role. Long-term treatments showed mild recovery effects on cell viability in both cell lines, probably caused by the balancing of redox homeostasis. Elevated levels of nitrites indicate high levels of nitric oxide (NO) production and suggest its higher bioavailability due to the antioxidative environment. The tested EOs also induced a drop in migratory capacity, especially after short-time treatments. Taken together, these results suggest considerable antitumor activity of both EOs, which could have potential therapeutic applications.

Antiproliferative, antimigratory, and prooxidative potential of novel platinum(IV) complexes and resveratrol on breast cancer (MDA-MB-231) and choriocarcinoma (JEG-3) cell lines.

Platinum(IV) complexes offer the potential to overcome cisplatin resistance of cancer cells, with possible improved selectivity. Resveratrol, a natural polyphenol with anticancer and antioxidant capacity, could limit the possible side effects of chemotherapeutics on healthy cells. This study investigates the effects of platinum(IV) complexes containing some esters of the ethylenediamine-N,N'-di-S,S-(2,2'-dibenzyl)acetate acid (H2 -S,S-eddba), and resveratrol on proliferation, migration, and redox balance of breast cancer (MDA-MB-231), choriocarcinoma (JEG-3), and human lung fibroblast (MRC-5) cell line. According to IC50 values, all complexes exhibited a significantly stronger antiproliferative effect on tested cell lines compared to cisplatin. Due to reduced adverse effects on MRC-5 cells, the complex containing ethyl-substituent (10 µM) was selected for further examination with resveratrol (25 µM) cotreatment. Resveratrol enhanced the survival of MRC-5 cells while diminished the viability of both used cancer cell lines when applied combined with selected complex. Furthermore, cotreatment of these two compounds decreased the migratory potential of tested cancer cell lines. The examined platinum(IV) complex was able to induce oxidative stress in all tested cell lines. Resveratrol proved to be efficient in protecting MRC-5 cells from complex-induced oxidative damage, while it significantly amplified antiproliferative, antimigratory, and prooxidative effects of platinum(IV) complex on both examined cancer cell lines. These findings may be valuable in elucidating the mechanism of action of platinum(IV) drugs, which should be further investigated.

Evaluation of Toxic Effects of Novel Platinum (IV) Complexes in Female Rat Liver: Potential Protective Role of Resveratrol.

The use of cisplatin in chemotherapy may provoke a deteriorating impact in many vital organs, suggesting the need for more selective derivatives and effective protective cotreatments. This study assesses the effects of three novel Pt(IV) complexes containing ethyl-, propyl- and butyl-esters of the ethylenediamine-N, N'-di-S, S- (2,2'-dibenzyl) acetic acid on liver injury markers, redox parameters, and cell morphology of female rat liver tissue in comparison to cisplatin. In addition, the study evaluates the possible protective effects of resveratrol as well. The rats were divided into ten groups and were administered intraperitoneally with a single dose of cisplatin (7.5 mg/kg) or Pt(IV) complexes (10 mg/kg) and/or resveratrol (25 mg/kg). All treatments caused changes in body weight, food intake, and liver/bw ratio. Acute treatment with novel complexes decreased the levels of TB and TP while elevated the activity of ALT, AST, GGT, ALP which subsequently indicated on the liver damage. All three complexes significantly reduced the levels of LPO, O2.-, NO2- and activity of CAT, while increasing the activity of SOD, GSH-Px, GR, GST, and level of GSH, implying that these compounds could provoke redox balance disruption in liver cells. Moreover, according to the histopathological observations, the novel Pt(IV) complexes exerted stronger hepatotoxicity than cisplatin. Possible protective effects of resveratrol were not detected and even combined with examined compounds it abolished the activity of the antioxidative system of the liver cells causing more intense toxicity. Further investigation is required to elucidate the effects of Pt-based drugs and resveratrol in the estradiol-rich environment of female rats as well their influence on male rats' tissues.

Hematoprotective effects and antioxidant properties of ß-glucan and vitamin C against acetaminophen-induced toxicity: an experimental study in rats.

Acetaminophen is widely used as an over-the-counter analgesic and antipyretic drug. The aim of the present study was to investigate the pro-oxidative effects of acetaminophen (300 mg/kg/day i.p.) and antioxidative effects of ß-glucan (4 mg/kg/day i.p.) and/or vitamin C (100 mg/kg/day i.p.) on the blood parameters of treated rats. After 3 days of treatment, hematological and parameters of redox status were measured. Exposure of rats to acetaminophen caused significant changes in some hematological parameters and the glutathione redox cycle, leading to an increased concentration of oxidative stress parameters and the formation of lipid peroxidation, while the activities of antioxidant enzymes were decreased. Administration of ß-glucan and/or vitamin C reduced lipid peroxidation and restored the levels of examined hematological and oxidative stress parameters and improved the activities of antioxidant enzymes. Obtained results demonstrated that acetaminophen has significant pro-oxidative effects and may disrupt redox balance in blood of rats, while the combination of ß-glucan and/or vitamin C amplified the antioxidant defense potential and exhibited a strong hematoprotective activity against acetaminophen-induced toxicity. Therefore, ß-glucan and vitamin C co-treatment may be a promising therapeutic option for the treatment of acute acetaminophen hematotoxicity.

Antiproliferative and antimigratory effects of 3-(4-substituted benzyl)-5- isopropyl-5-phenylhydantoin derivatives in human breast cancer cells.

In this study, a series of synthesized 3-(4-substituted benzyl)-5-isopropyl-5-phenylhydantoin derivatives as a potential antiproliferative and antimigratory agents were investigated. The possible antitumor mechanisms of investigated hydantoin derivatives were examined on human breast cancer cell line MDA-MB-231. The cells were treated with different concentrations of compounds (from 0.01 µM to 100 µM) during 24 h and 72 h. The proliferation index, nitric oxide production, apoptosis rate, and migration capacity were measured. The cell invasion potential was examined by measuring the level of MMP-9 and COX-2 gene expression. All tested compounds expressed antiproliferative activity and induced dose- and time-dependent increase in the level of nitrites. The investigated molecules significantly decreased cell survival rate, migration capacity and the expression levels of genes included in the process of tumor invasion. Obtained data suggest that the tested hydantoin derivatives express considerable antitumor activity by reducing cell division rate, elevating apoptosis level, and inhibiting the motility and invasiveness of breast cancer cells. The results obtained in this study indicate that investigated compounds express potential as a novel chemotherapeutic agents against breast cancer growth and progression.

Redox status, DNA and HSA binding study of naturally occurring naphthoquinone derivatives.

In the present work we modified the procedure for isolation of naphthoquinones α-methylbutyrylshikon ( 1 ), acetylshikonin ( 2 ) and ß-hydroxyisovalerylshikonin ( 3 ) from Onosma visianii Clem. We also investigated possible mechanisms of 1 , 2 and 3 as antitumor agents. Accordingly, we estimated concentrations of superoxide anion radical (O2 .-), nitrite (NO2 -) and glutathione in HCT-116 and MDA-MB-231 cell lines. Compounds 1 and 3 expressed significant prooxidative activity, while all tested compounds exhibited significant increase in nitrite levels. Also, all examined compounds significantly increased the concentration of oxidized glutathione (GSSG), suggesting significant prooxidative disbalance. The levels of reduced glutathione (GSH) were also elevated as a part of antioxidative cell response. The data indicate that induced oxidative imbalance could be one of the triggers for previously recorded decreased viability of HCT-116 and MDA-MB-231 cells exposed to tested naphthoquinone derivatives. Moreover, we examined interactions mode of compounds 1 , 2 and 3 with CT-DNA as one of the crucial targets of many molecules that express cytotoxic activity. The results obtained by UV-visible, fluorescence and molecular docking study revealed that 1 , 2 and 3 bound to CT-DNA through minor groove binding. Furthermore, the interactions between HSA and 1 , 2 and 3 were examined employing the same methods as for the CT-DNA interaction study. Based on the obtained results, it can be concluded that naphthoquinones 1 , 2 and 3 could be effectively transported by human serum albumin. As a conclusion, this study provides further insight of antitumor activity of selected naphthoquinones.

Anti-Tumor Mechanisms of Novel 3-(4-Substituted Benzyl)-5-Isopropil-5- Phenylhydantoin Derivatives in Human Colon Cancer Cell Line.

BACKGROUND: Hydantoin and its newly synthesized derivatives have recently become a focus of interest due to their numerous biological activities and newly emerging beneficial effects in different pathological conditions, including cancer. OBJECTIVE: The aim of this study was to evaluate the possible anti-tumor mechanisms of a series of newly synthesized 3-(4-substituted benzyl)-5-isopropyl-5-phenylhydantoin derivatives in different aspects of cell physiology of human colon cancer cell line, HCT-116. METHODS: The increasing concentrations of derivatives (0.01µM up to 100µM) were applied to cells during 24h, 48h, and 72h after which the evaluation of proliferation, apoptosis, oxidative/anti-oxidative status, nitrite production, and migration/invasion potential of treated cells was performed. RESULTS: All tested compounds expressed the dose- and time-dependent anti-proliferative and pro-apoptotic activities against HCT-116 cells. The investigated derivatives induced a decrease in levels of oxidative stress parameters and an increase in levels of nitrite production by treated cells suggesting their significant antioxidative effects. The cell migration index and expression level of tumor invasion-promoting metalloproteinase- 9 (MMP-9) gene were significantly decreased after treatment with the tested hydantoin derivatives implicating their inhibitory role in colon cancer cell motility and invasion processes. The mRNA level of cyclooxygenase-2 (COX-2) gene as a pro-inflammatory gene related to colorectal carcinogenesis was reduced compared to values in the non-treated control cells indicating the significant anti-inflammatory/anti-tumor effects of these compounds. CONCLUSION: The obtained results show the significant anti-tumor potential of tested derivatives, especially 3- benzyl-5-isopropyl-5-phenylhydantoin and 3-(4-chlorobenzyl)-5-isopropyl-5-phenylhydantoin, suggesting their potential usage in the development of more effective chemotherapies.

Role of selenium and vitamin C in mitigating oxidative stress induced by fenitrothion in rat liver.

Excessive use of organophosphate insecticides, including fenitrothion (FNT) can cause detrimental consequences in non-target organisms. Selenium (Se) and vitamin C (Vit C) possess protective abilities against various toxic compounds due to their antioxidative properties. Accordingly, the aim of the present study was to examine the possible ameliorative effects of Se and Vit C in hepatotoxicity induced by FNT. For the purpose of this study, male Wistar albino rats were divided into control and groups treated with Se (0.5 mg/kg b.w, as Na2SeO3) and Vit C (100 mg/kg b.w), FNT (20 mg/kg b.w) and FNT in cotreatment with Se and Vit C for 30 days. The current data showed a reduction in absolute and relative liver weight after FNT administration. Increased activities of liver enzymes (AST, ALT, ALP, LDH and GGT) indicated liver damage. FNT alone caused significant alterations in biochemical parameters (glucose and total bilirubin). Elevation in LPO level along with decreased activities of antioxidant enzymes (SOD, CAT, GSH-Px) and GSH content reflected the presence of oxidative stress. Coadministration of FNT with Se and Vit C exhibited hepatoprotective role confirmed by reduction of oxidative stress levels and restoration in the values of examined parameters. Because of their beneficial effects, Se and Vit C may be used in reducing injuries caused by pesticides.

Antioxidative and haematoprotective activity of coenzyme Q10 and vitamin E against cadmium-induced oxidative stress in Wistar rats.

Cadmium (Cd) is a major environmental pollutant, which exerts adverse effects mainly by inducing oxidative stress. Coenzyme Q10 (CoQ10) and vitamin E (VE), naturally occurring antioxidants, improve health condition by inactivating free radicals and enhancing antioxidative defence. The aim of our study was to investigate the protective role of CoQ10 and/or VE pretreatment against Cd-induced haematotoxicity. Wistar albino rats were intramuscularly injected with CoQ10 (20 mg/kg b.w.) and/or VE (20 IU/kg b.w.) or with saline (control group). After 24 h, Cd was injected intraperitoneally (0.4 mg/kg b.w.) and 1 day after, animals were sacrificed. Acute Cd intoxication caused significant changes in haematological and biochemical parameters and altered the glutathione cycle, leading to the formation of lipid peroxidation, while the concentrations and activities of antioxidants (vitamins C and E, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) were decreased. CoQ10 and/or VE significantly maintained these values to near-normal levels, afforded additional protection by reducing lipid peroxidation and improved the levels of antioxidants in the blood. Plasma CoQ10 and VE levels negatively correlated with oxidative damage parameters while positively correlated with antioxidative defence parameters. Regarding their effects, CoQ10 and VE were in synergistic interaction. The present study suggested that CoQ10 and VE combination may be beneficial in protecting from Cd-induced haematotoxicity and may be used as a preventive against acute Cd intoxication of exposed people.

The ameliorating effects of selenium and vitamin C against fenitrothion-induced blood toxicity in Wistar rats.

Fenitrothion is widely used organophosphate pesticide in agriculture and health programs, but besides, it causes several toxic effects. The present study was designed to evaluate the possible protective effects of selenium (0.5mg/kg b.w.) and vitamin C (100mg/kg b.w) on altered haematological, biochemical and oxidative stress parameters in the blood of rats orally treated with fenitrothion (20mg/kg b.w) for 30days. Fenitrothion caused changes in body weight, food and water intake, and some haematological and biochemical parameters. Fenitrothion altered the glutathione redox status (GSH and GSSG) and decreased activity of antioxidant enzymes (GSH-Px, GST, SOD and CAT), leading to a lipid peroxidation. Selenium and vitamin C, by improving the activity of antioxidants, reduced oxidative stress and a lipid peroxidation, maintaining the values of examined parameters to optimal levels. Therefore, selenium and vitamin C could be useful in providing protection of exposed non-target organisms including people from fenitrothion.

Protective effects of quercetin and vitamin C against nicotine-induced toxicity in the blood of Wistar rats.

Nicotine is a potential inducer of oxidative stress, through which it can damage numerous biological molecules. The aim of our study was to investigate the prooxidative effects of nicotine and protective (additive or synergistic) effects of quercetin and vitamin C in the blood of experimental animals, to determine whether the combination of these antioxidants might be beneficial for clinical purposes. Wistar albino rats were receiving intraperitoneal nicotine injection (0.75 mg kg-1 per day) or saline (control group) or nicotine plus quercetin (40 mg kg-1 per day) and vitamin C (100 mg kg-1 per day) for three consecutive days. On day 4, we determined their blood lipid profile, liver enzymes, oxidative stress parameters, and antioxidative system parameters. Compared to untreated control, nicotine significantly increased total cholesterol, LDLcholesterol, triglycerides, liver enzymes (alanine transaminase, aspartate transaminase, and lactate dehydrogenase) and oxidative stress parameters (superoxide anion, hydrogen peroxide, and lipid peroxide) and decreased HDL-cholesterol, glutathione, and superoxide dismutase/catalase activity. Quercetin + vitamin C reversed these values significantly compared to the nicotine alone group. Our results confirm that nicotine has significant prooxidative effects that may disrupt the redox balance and show that the quercetin + vitamin C combination supports antioxidant defence mechanisms with strong haematoprotective activity against nicotine-induced toxicity. In practical terms, this means that a diet rich in vitamin C and quercetin could prevent nicotine-induced toxicity and could also be useful in the supportive care of people exposed to nicotine.

Prooxidative effects of aspartame on antioxidant defense status in erythrocytes of rats.

Since aspartame (L-aspartyl-L-phenylalanine methyl ester, ASP) is one of the most widely used artificial sweeteners, the aim of the present study was to investigate its effects on serum glucose and lipid levels as well as its effects on oxidative/antioxidative status in erythrocytes of rats. The experiment included two groups of animals: the control group was administered with water only, while the experimental group was orally administered with ASP (40 mg/kg b.w.) daily, for a period of six weeks. When compared with the control group, the group administrated with ASP indicated higher values of serum glucose, cholesterol and triglycerides. Significantly increased concentrations of superoxide anion (O2 .-), hydrogen peroxide (H2O2), peroxynitrite (?N??-) and lipid peroxides (LPO) were recorded in the erythrocytes of ASP treated group in comparison to the control group. In the course of chronic ASP administration, the following was observed: the concentration of reduced glutathione (GSH) and the activity of catalase (CAT) increased. Thus, these findings suggest that long-term consumption of ASP leads to hyperglycemia and hyperlipidemia, as well as to oxidative stress in erythrocytes.

Protective effects of oestradiol against cadmium-induced changes in blood parameters and oxidative damage in rats.

The aim of this study was to investigate the protective effects of oestradiol (E2, 4 mg kg-1 b.w. i.p.) against cadmium-induced (Cd, 2 mg kg-1 b.w. i.p.) blood changes in rats. Cadmium induced a significant decline in haemoglobin, haematocrit, and total erythrocyte, lymphocyte, and thrombocyte count, whereas total leukocytes and granulocytes increased. A significant increase was also observed in serum cholesterol, triglycerides, glucose, AST, and ALT activities, whereas total protein and albumin levels dropped significantly. Administration of E2 in combination with Cd alleviated most of these adverse effects. In terms of oxidative stress, Cd significantly increased oxygen-free radicals (O2 •- and H2O2) in neutrophils and lipid peroxidation in erythrocytes, whereas E2 treatment reversed these changes to control values. Acute Cd poisoning significantly lowered antioxidant enzyme (SOD and CAT) activity and the level of non-enzymatic antioxidants (GSH and vitamin E), while increasing in GSSG. Treatments with E2 reversed Cd-induced effects on the antioxidant defences and significantly lowered Cd-induced oxidative damage in erythrocytes. This study suggests that exogenous E2 effectively restores redox balance in rat erythrocytes and counters adverse haematological and biochemical effects of Cd poisoning. It also improves the antioxidant capacity of erythrocytes, acting in synergy with endogenous antioxidants.

Lipid peroxidative damage on Cisplatin exposure and alterations in antioxidant defense system in rat kidneys: a possible protective effect of selenium.

Cisplatin (Cis-diamminedichloroplatinum II, CP) is an important chemotherapeutic agent, useful in the treatment of several cancers, but with several side effects such as nephrotoxicity. The present study investigated the possible protective effect of selenium (Se) against CP-induced oxidative stress in the rat kidneys. Male Wistar albino rats were injected with a single dose of cisplatin (7 mg CP/kg b.m., i.p.) and selenium (6 mg Se/kg b.m, as Na(2)SeO(3), i.p.), alone or in combination. The obtained results showed that CP increased lipid peroxidation (LPO) and decreased reduced glutathione (GSH) concentrations, suggesting the CP-induced oxidative stress, while Se treatment reversed this change to control values. Acute intoxication of rats with CP was followed by statistically significant decreased activity of antioxidant defense enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and glutathione-S-transferase (GST). Treatment with Se reversed CP-induced alterations of antioxidant defense enzyme activities and significantly prevented the CP-induced kidney damage.