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Kynurenine (KYN), the most abundant metabolite of tryptophan, is classically associated with immune tolerance and tumor immune escape. In the last years, KYN is in the spotlight in other biological processes. Here, we showed that KYN inhibited tyrosinase expression and melanin content in primary human melanocyte and keratinocyte co-cultures. Furthermore, KYN decreased melanosome content in a 3D human skin reconstruction model. In these experiments, we used tyrosine + NH4 Cl to induce pigmentation. We compared the inhibitory effect of KYN on melanogenesis with the already known inhibitory effect promoted by IFN-γ. Since increased KYN production depends on the IFN-γ-inducible enzyme indoleamine-2,3-dioxygenase (IDO), we propose that part of the effect of IFN-γ on melanogenesis involves KYN production. From that, we tested if, during melanogenesis, changes in tryptophan metabolism would occur. For this purpose, we measured tryptophan, KYN and downstream products along with pigmentation. There were no significant changes in Trp metabolism, except for the high consumption of kynurenic acid. Our data identify the skin as a potential target for the action of KYN relevant for skin physiology and pigmentation. The results are discussed concerning the high production of KYN in skin inflammatory disorders and cancer.

Different models of reconstructed human epidermis (RHE) are currently validated to assess skin irritation in vitro and ultimately to the animal replacement of the Draize test. The development of a new RHE model is a challenge for many laboratories, representing a potential gain of autonomy and improvement of technological knowledge. The Organization for Economic Co-operation and Development (OECD) encourages the development of new models and, for this purpose, offers a thorough guideline on quality control parameters (OECD TG 439 performance standards). This work aimed to develop an RHE model (i.e. USP-RHE) for in vitro skin irritation assays, following the OECD TG 439. The developed model presents a well-differentiated epidermis similar to the Validated Reference Methods (VRM) and to native human epidermis. Quality parameters, i.e. optical density of negative control, tissue integrity and barrier function, were similar to VRM and in accordance with OECD TG 439. Moreover, the USP-RHE model was shown to have 85,7% of specificity (6/7), 100% of sensitivity (6/6) and 92,3% of accuracy (12/13) when compared to in vivo UN GHS classification. The within-laboratory reproducibility was 92.3% (12/13). Thus, we demonstrated that USP-RHE model attends to all OECD TG 439 performance standards and is ready to be used by private and public laboratories and companies for future validation studies.

Made available in DSpace on 2018-11-26T17:55:58Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-02-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) The Acid Black 210 dye is one of the most used black dyes by the leather industry. This compound contains three azo groups in its chemical structure, and has been quoted as a non-regulated dye with toxicological concern, since it could generate carcinogenic aromatic amines. The objective of this study was to perform the ecotoxicological risk assessment of this dye through testing its toxicity in vitro and in vivo with the Ames test, the Comet assay, the Daphnia similis test, and the zebrafish embryo acute toxicity test. Moreover, we evaluated the presence of this dye in environmental samples related with a tannery industry. All the tests performed were negative, with the exception of the Ames test with the Salmonella typhimurium TA98 strain, which resulted in a low mutagenic potency. Due to the low concentrations of the Acid Black 210 dye found in tannery effluents, and the high concentrations where any toxic activity is occasionally described, we concluded that this dye is safe from the ecotoxicological point of view in the areas evaluated and in the light of the current knowledge. (C) 2016 Elsevier Ireland Ltd. All rights reserved. Univ Sao Paulo, Lab Environm Toxicol, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto, SP, Brazil Univ Estadual Paulista, Inst Chem, BR-14800060 Araraquara, SP, Brazil Univ Sao Paulo, Sch Pharmaceut Sci, Skin Biol Lab, BR-05508000 Sao Paulo, SP, Brazil Univ Estadual Paulista, Inst Chem, BR-14800060 Araraquara, SP, Brazil FAPESP: 2008/10449-7 FAPESP: 2013/09317-7 FAPESP: 2013/06172-8 FAPESP: 2013/24340-5

Background Inverse associations have been observed between memory performance and blood concentrations of cadmium (Cd) and lead (Pb). Low antioxidant cell activity has also been linked to decline in memory due to aging. However, it has not yet been established whether the heavy metal-memory relationship is mediated by differences in antioxidant activity. Methods We examined Cd and Pb levels, as well as oxidative stress parameters, in blood samples from 125 older adults (age range 50–82 years). The Counting Span Test (CST) was used to evaluate working memory capacity (WMC). The Monte Carlo Method for Assessing Mediation (MCMAM) was used to analyze the mediation role of antioxidant activity in the heavy metals-memory association. Results High blood Cd (BCd) concentration alone, and in combination with elevated blood Pb (BPb) concentration, was associated with poor WMC (p ≤ 0.001) and low enzymatic antioxidant defenses (p ≥ 0.006). The variance in WMC accounted for by BCd or by BCd combine with BPb was 20.6% and 18.6%, respectively. The MCMAM revealed that the influence of BCd and BPb concentrations on WMC was mediated by low antioxidant capacity (confidence interval - CI: 0.072 to − 0.064 for BCd; CI: − 0.062 to − 0.045 for BPb). Conclusion These findings showed Pb and Cd blood concentration in older adults, even at levels below the current recommended threshold, was negatively associated with WMC and that this relationship may be partly mediated by low antioxidant defenses. Knowledge on the environmental factors that negatively influence brain and cognition during aging can help inform public policy strategies to prevent and control the adverse effects of environmental contaminant exposure during aging.

A receptor-independent (RI) four-dimensional structure-activity relationship (4D-QSAR) formalism was applied to a set of sixty-four β-N-biaryl ether sulfonamide hydroxamate derivatives, previously reported as potent inhibitors against matrix metalloproteinase subtype 9 (MMP-9). MMP-9 belongs to a group of enzymes related to the cleavage of several extracellular matrix components and has been associated to cancer invasiveness/metastasis. The best RI 4D-QSAR model was statistically significant (N=47; r(2) =0.91; q(2) =0.83; LSE=0.09; LOF=0.35; outliers=0). Leave-N-out (LNO) and y-randomization approaches indicated the QSAR model was robust and presented no chance correlation, respectively. Furthermore, it also had good external predictability (82 %) regarding the test set (N=17). In addition, the grid cell occupancy descriptors (GCOD) of the predicted bioactive conformation for the most potent inhibitor were successfully interpreted when docked into the MMP-9 active site. The 3D-pharmacophore findings were used to predict novel ligands and exploit the MMP-9 calculated binding affinity through molecular docking procedure.

The hair-dyeing ingredient, p-phenylenediamine (PPD), was previously reported to be mutagenic, possibly by inducing oxidative stress. However, the exact mechanism of PPD in inducing oxidative stress upon skin exposure during hair-dyeing in human keratinocytes remains unknown. The aim of our studies was therefore to investigate the toxicity of PPD and its by-products in human immortalized keratinocytes (HaCaT) after auto-oxidation and after reaction with hydrogen peroxide (H2O2). We found that the PPD half maximal effective cytotoxic concentration (EC50) to HaCaT is 39.37 and 35.63 μg/mL after 24 and 48 h, respectively, without addition of H2O2 to induce oxidation. When PPD (10 or 100 μg/mL) is combined with 10.5 μg/mL of H2O2, intracellular ROS production by HaCaT after 1 h was significantly increased and enhanced levels of DNA damage were observed after 4 h of exposure. After 24 h incubations, 20 μg/mL of PPD increased the level of DNA oxidation in HaCaT. Also, we found that the in vitro reaction between PPD and H2O2, even below the maximum allowance by cosmetic industries, released hydroxyl radicals which can damage DNA. Taken together, we conclude that PPD alone and when combined with H2O2 increases the formation of reactive oxygen species in human keratinocytes, leading to oxidative stress and subsequent DNA damage. These alterations suggest that the mechanism by which PPD exposure, alone or combined with H2O2, damages keratinocytes by the formation of the high reactive HO∙ radicals.

Studies about cervical carcinogenesis have demonstrated the increased expression of matrix-metalloproteinase (MMP) according to the grade of cervical intraepithelial lesions. Considering the importance of innovative techniques to introduce noninvasive and rapid diagnoses for patients, this study aimed to perform MMP-9 immunocytochemistry in cervical smears according to the cytopathological diagnoses, in order to monitor MMP activity in cervical smears. This cross-sectional study investigated the expression of MMP-9 in normal cervical smears, inflammatory cervical smears, squamous intraepithelial lesions, and cervical carcinoma. Cervical smears from 630 women were collected for cytopathological diagnoses and immunocytochemistry. Women with squamous intraepithelial lesions showed an increase in MMP-9 expression, with moderate to intense staining occurring with increasing cervical lesion grade. The prevalence of moderate to intense MMP-9 staining was 9% in normal cervical smears, 12% in cervical inflammation, 24% in low-grade squamous intraepithelial lesion (LSIL), 92% in high-grade squamous intraepithelial lesions (HSIL) and 100% in cervical carcinoma cases. In the specific case of LSIL, we found that association with MMP-9 is more evident when there is the simultaneous presence of an infectious agent. Thus, the expression of MMP-9 in cervical smears increases according to the grade of cervical lesion and LSIL in the presence of infectious agents showed higher MMP-9 expression than women with LSIL without infectious agents. Diagn. Cytopathol. 2014;42:827–833. © 2014 Wiley Periodicals, Inc.

Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent proteases involved in the extracellular matrix degradation. MMP-2 and MMP–9 are overexpressed in several human cancer types, including melanoma, thus the development of new compounds to inhibit MMPs' activity is desirable. Molecular dynamic simulation and molecular properties calculations were performed on a set of novel β-N-biaryl ether sulfonamide-based hydroxamates, reported as MMP-2 and MMP-9 inhibitors, for providing data to develop an exploratory analysis. Thermodynamic, electronic, and steric descriptors have significantly discriminated highly active from moderately and less active inhibitors of MMP-2 whereas apparent partition coefficient at pH 1.5 was also significant for the MMP-9 data set. Compound 47 was considered an outlier in all analysis, indicating the presence of a bulky substituent group in R3 is crucial to this set of inhibitors for the establishment of molecular interactions with the S1 subsite of both enzymes, but there is a limit. © 2012 Wiley Periodicals, Inc.

Summary Induction of apoptotic cell death in response to chemotherapy and other external stimuli has proved extremely difficult in melanoma, leading to tumor progression, metastasis formation and resistance to therapy. A promising approach for cancer chemotherapy is the inhibition of proteasomal activity, as the half-life of the majority of cellular proteins is under proteasomal control and inhibitors have been shown to induce cell death programs in a wide variety of tumor cell types. 4-Nerolidylcatechol (4-NC) is a potent antioxidant whose cytotoxic potential has already been demonstrated in melanoma tumor cell lines. Furthermore, 4-NC was able to induce the accumulation of ubiquitinated proteins, including classic targets of this process such as Mcl-1. As shown for other proteasomal inhibitors in melanoma, the cytotoxic action of 4-NC is time-dependent upon the pro-apoptotic protein Noxa, which is able to bind and neutralize Mcl-1. We demonstrate the role of 4-NC as a potent inducer of ROS and p53. The use of an artificial skin model containing melanoma also provided evidence that 4-NC prevented melanoma proliferation in a 3D model that more closely resembles normal human skin.

The antioxidant capacity of 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4-phenylthiazoles was evaluated. The values of antioxidant capacities of compounds 2d and 2e were found to be, respectively, 2,700 ± 150 and 3,135 ± 230 TE by the ORAC method, corresponding to a significant antioxidant capacity. recent publication, we reported the antioxidant capacity of phenylpyrazole using the ORAC method (14). In continua- tion of our research program, we report here the antioxidant evaluation of 2-(3,5-diaryl-4,5-dihydro-1H-pyrazol-1-yl)-4- phenylthiazoles, synthetic derivatives compounds of facile preparation (Scheme 1).

BACKGROUND: There has been growing interest in sodium copper chlorophyllin (Cu-Chl) as a food colourant and supplement owing to its beneficial biological activities. Studies have revealed that this green pigment inhibits experimental carcinogenesis and interacts with proteins and genotoxic agents. Health-related activities have also been associated with the prevention of lipid peroxidation. However, intestinal absorption of this pigment has been considered insignificant, raising questions of whether eventual biological properties are related to pre- or post-absorptive actions. In this study, intestinal absorption of Cu-Chl and its appearance in serum and organs were estimated by high-performance liquid chromatography analysis in rat feeding experiments. The effect of ingested Cu-Chl on lipid peroxidation was analysed by measuring thiobarbituric acid-reactive substances and antioxidant enzyme activities in hepatic and brain tissues of oxidative stress-induced rats. RESULTS: The two main components of commercial Cu-Chl, namely Cu-chlorin e6 and Cu-chlorin e4, showed different digestive behaviours, and only Cu-chlorin e4 was found in serum, liver and kidneys. Antioxidant activity in vivo could be observed in brain and seemed to be related to in situ protection but not to antioxidant enzyme modulation. CONCLUSION: As at least one of the major components of Cu-Chl is effectively absorbed, further pharmacokinetic studies are encouraged to access absorption rates and the role of ingested copper chlorophyllins in mammals. Copyright © 2009 Society of Chemical Industry

Background: We aimed to evaluate the ascorbic acid concentration in secondary aqueous humour (AH) from glaucomatous patients and to compare it with primary AH from primary open-angle glaucoma patients and non-glaucomatous patients. Methods: Primary AH samples were prospectively obtained from clinically uncontrolled primary open-angle glaucoma patients and senile cataract patients (controls) prior to trabeculectomy and cataract surgery. Secondary AH samples were obtained from eyes with previous intraocular surgery, prior to trabeculectomy or cataract surgery. AH (0.1 mL) was aspirated by inserting a 26-gauge needle into the anterior chamber just before surgery and then immediately stored at −80°C. The ascorbic acid concentration was determined in a masked fashion by high-pressure liquid chromatography. Results: A total of 18 patients with senile cataract, 16 glaucomatous patients with primary AH (no previous intraocular surgery) and 11 glaucomatous patients with secondary AH (previous intraocular surgery) were included. There was no difference in mean age between groups (P = 0.15). The mean ± standard deviation concentration of ascorbic acid in the secondary AH from glaucomatous patients (504 ± 213 µmol/L [95% confidence interval {CI}, 383–624]) was significantly lower than the concentration of ascorbic acid found in the primary aqueous of primary open-angle glaucoma (919 ± 427 µmol/L [95% CI, 709–1128]) and control patients (1049 ± 433 µmol/L [95% CI, 848–1249]; P

Phacoemulsification has been successfully employed in humans and animals for lens extraction. This ultrasonic extracapsular surgical technique induces hydroxyl radical formation in the anterior chamber, which accumulates despite irrigation and aspiration. In this paper we determined the total antioxidant status of aqueous humor after phacoemulsification by measuring aqueous humor ascorbic acid levels. Mixed-breed dogs (n = 11; weighing about 10 kg) with normal eyes as determined by slit-lamp biomicroscopy, applanation tonometry, and indirect ophthalmoscopy had phacoemulsification performed in one eye with the other eye used as a control. Samples of aqueous humor were obtained by anterior chamber paracentesis before surgery and at days 1, 2, 3, 7, and 15 after surgery. Total aqueous humor antioxidant status was inferred from the capacity of aqueous humor to inhibit free radical generation by 2,2-azobis (2-amidopropane) chlorine. Ascorbic acid concentrations were measured by high-pressure liquid chromatography with UV detection. Protein content was determined with the biuret reagent. Statistical analysis was performed by anova followed by the paired t-test. Total antioxidant capacity was reduced from 48 to 27 min during the first 24 h with a gradual increase thereafter, remaining statistically lower than the control eye until 7 days postoperatively. Reduced levels of ascorbic acid followed this reduction in antioxidant capacity (from 211 to 99 microm after 24 h), remaining lower than the control eye until 15 days postoperatively. Protein concentration in aqueous humor increased from 0.62 mg/mL to 30.8 mg/mL 24 h after surgery, remaining statistically lower than the control eye until 15 days postoperatively. Paracentesis alone did not significantly alter the parameters measured. These results indicate that after phacoemulsification, the aqueous humor ascorbic acid levels and antioxidant defenses in aqueous humor are reduced, indirectly corroborating free radical production in the anterior chamber as a result of phacoemulsification. The inflammatory process consequent to the surgical procedure demonstrated by increased protein content in aqueous humor can also contribute to free radical production and ascorbic acid consumption.

Due to its antioxidant and photoprotective properties, Pothomorphe umbellata is a promising candidate for use in cosmetic and pharmaceutical formulations. These properties arise from the presence of 4-nerolidylcathecol (4-NC), a polyphenolic compound isolated from P. umbellata roots. This study investigates its photostability properties, as well as the chemical and the in vitro sun protection factor (SPF) of P. umbellata root extract in a gel formulation. A high performance liquid chromatography method was used to evaluate the chemical stability using 4-NC as marker at 5, 25 and 45 degrees C for 103 days. The photostability and the sun protection factor were analyzed by ultraviolet (UV) spectophotometry using samples irradiated with UVB lamp. No significant difference of the 4-NC concentration was found in formulations stored at 5 and 25 degrees C. All samples stored at 45 degrees C, however, showed degradation of gel structure. After 2h of UVB exposure, there was no change in the absorption profile of 4-NC. The sun protection factor of P. umbellata root extract gel to final concentration of 0.1% 4-NC was not expressive (SPF=3.35+/-0.02), suggesting the predominance of its antioxidant activity.

The scientific establishment has been discussing the relationship between aging and oxidative stress for quite some time now. While we are still far from a general agreement about this subject, there is an impressive amount of data collected that can be used to draw a compelling picture of the events that take place during the human aging process and their correlation with the oxidant status of the organism. In this review, we bring forth the results of some key studies that can help to elucidate the aging-oxidative stress puzzle, as well as to explain which are the fundamental events in this interplay and why their causal relationships remain so elusive. We also put forward here data on the systemic oxidative stress status of a group of 503 healthy human subjects. The data consist of the plasma levels of TBARS and of the nutritional antioxidants, alpha-tocopherol, beta-carotene and ascorbic acid, and of the activity of the antioxidant enzymes, Cu, Zn-superoxide dismutase, catalase and glutathione peroxidase, of red blood cells. The data indicate that a moderate situation of oxidative stress gradually develops during human aging.

Antioxidants such as vitamins E and C are known to play a significant role in ameliorating or preventing oxidative damage to the skin. However, to provide a satisfactory protection they must first permeate the skin, which serves as a permeation barrier. In this study we evaluated the influence of three different formulations (gel, gel–emulsion and emulsion) on the percutaneous absorption of 4-nerolidylcathecol, an antioxidant compound isolated from Pothomorphe umbellata root extracts. Also, the absorption of the isolated 4-nerolidylcathecol was compared with its absorption when dried P. umbellata root ethanolic extract was incorporated into a gel formulation. The ‘lag time method’ was employed for the analysis of the in vitro permeation data. All formulations showed satisfactory percutaneous penetration with the 4-nerolidylcathecol–gel presenting a higher rate of penetration leading to higher dry drug levels in the tissue.

Chlorogenic acid is a natural potent antioxidant. It can be used in cosmetics formulations, but for this purpose its photochemical stability should be determined to ensure that the compound will not be degraded after UV radiation exposure. To evaluate this possibility, the concentration of a chlorogenic acid solution was determined by HPLC before and after UVA and UVB irradiation.The results indicate that chlorogenic acid is not degraded under UVA or UVB irradiation.

The in vivo protective effects of methanol extracts of eight South American medicinal plants traditionally used as antiinflammatory were determined by means of spontaneous lipid peroxidation of liver tissue in rats. The production of TBARS was reduced in a dose dependent manner for A. macrocarpa (IC50 = 132 mg/kg), A. urundeuva (IC50 = 176 mg/kg), C. reticulata (IC50 = 561mg/kg) and S. obtusifolium (IC50 = 918 mg/kg). The extracts of P. peltata and U. tomentosa were only effective at a high concentration (300 mg/kg), although these values were not significant. The lyophilized latex of C. lechleri decreased the production of TBARS at a 200 mg/kg dose, although pro-oxidant effects were observed at lower doses (50 mg/kg). The extract of H. pallida was pro-oxidant at lower concentrations (50 mg/kg).

1. Lindane (25-60 mg/kg) at 24 h after dosage induced a dose-dependent increase in oxygen consumption by perfused rat livers, an effect not observed at early times (2-6 h) after administration. About 60% of the increase in liver oxygen uptake is suppressed by the antioxidant, desferrioxamine, indicating enhanced free radical activity induced by the insecticide. 2. The hepatic content of total GSH equivalents (GSH + 2GSSG) decreased 4 h after lindane treatment (60 mg/kg), together with significant diminution in net and fractional rates of sinusoidal GSH efflux, that returned to control values 24 h after treatment. 3. These data indicate that lindane resulted in marked changes in hepatic oxidative capacity and glutathione metabolism, which condition the production of oxidative stress in the liver at different times of intoxication.

1. Lindane administered to untreated rats or rats pretreated with phenobarbital (PB) or 3-methylcholanthrene (MC) increased liver lipid peroxidation, of the same magnitude in all groups. 2. PB pretreatment produced a 50% increase in lipid peroxidation (TBAR) by liver homogenates and microsomes, an effect accompanied by increases in cytochrome P-450, NADPH-cytochrome P-450 reductase, NADPH oxidase and microsomal superoxide anion production, MC pretreatment resulted in increases in liver cytochrome P-450 and NADPH oxidase only. 3. Pretreatment of rats with PB, but not MC or lindane, gave increases in glutathione peroxidase and reductase. 4. Pretreatment with PB, but not MC, increased liver GSH. Lindane decreased liver GSH to the same extent as PB plus lindane. 5. Biliary GSH, GSSG and bile flow were decreased by lindane to similar extents in all groups. 6. Lindane induced periportal necrosis with haemorrhagic foci in all groups. 7. Data presented indicate that the early lipid peroxidative response of liver to lindane was unchanged by PB- or MC-stimulated hepatic microsomal enzyme induction.

Exposure to UV radiation up-regulates the synthesis of matrix metalloproteinases (MMPs), a group of matrix-degrading enzymes. MMPs are regarded as promising therapeutic targets and the development of effective inhibitors is an important research focus. The plant Pothomorphe umbellata has been shown to exert a potent antioxidant activity on the skin and to delay the onset and reduce the incidence of UVB-induced chronic skin damage. The aim of the present study was to determine the effect of P. umbellata ethanolic root extract on MMP-2 and MMP-9. The in vitro inhibition of MMP-2 and MMP-9 was measured by gelatin zymography in the presence of different concentrations of P. umbellata extract, as well as in the presence of its isolated active principle 4-nerolidylcatechol (4-NC). The inhibitory effect of the P. umbellata extract was stronger than that of 4-NC. Gelatin zymography and histological analysis revealed that P. umbellata was able to inhibit constitutive MMP-9 activity in vivo in mice sacrificed 2 h after UVB irradiation. The intensity of the MMP-2 band was unchanged. Our data contribute to the elucidation of the mechanism of prevention of photoaging by P. umbellata and may provide a rational basis for the use of this plant in prophylaxis against and treatment of skin cancer.

In this work we evaluated the influence of topical application of P. umbellata root extract gel, containing 0.1% of 4-nerolidylcathecol, on the antioxidant network in UV-induced oxidative damage in hairless mouse skin. The UV-irradiation had no influence on ascorbic acid levels or on the antioxidant enzyme (superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase) activities, but topical P. umbellata treatment protected α-tocopherol from being depleted after UV-irradiation. α-Tocopherol concentration decreased significantly (≈40%, P 0.05). These data demonstrate that P. umbellata may be successfully used as a topical photoprotective agent.

The i.p. administration of 60 mg kg-1 body weight of lindane, the gamma-isomer of hexachlorocyclohexane, to fed rats led to an enhancement of hepatic lipid peroxidation after 24 h of treatment. This was evidenced by significant increases in the hepatic production and biliary release of thiobarbituric acid reactive substances, and in the biliary release of glutathione disulphide. Under these conditions, the content of cytochrome P450 was enhanced concomitantly with increases in the total microsomal oxygen uptake, superoxide radical generation and (+)-catechin (cyanid-3-ol) sensitive respiration. The glutathione status of hepatocytes was altered by lindane as the content and biliary release of glutathione disulphide was drastically augmented, leading to a decrease in the cellular and biliary GSH/GSSG ratios. It is suggested that lindane treatment leads to an induced oxidative capacity, which, in turn, alters the glutathione status of the liver tissue.

1. Lindane (60 mg/kg) administered orally to rats increased liver cytochrome P-450 content and superoxide radical (O2-.) generation 24 h after treatment, while formation of thiobarbituric acid reactants and NADPH/ADP-supported microsomal chemiluminescence were significantly increased 4 h after treatment. 2. Hepatic superoxide dismutase (SOD) and catalase decreased 6 h after lindane treatment and SOD/O2-. ratio progressively decreased during 4 to 24 h after lindane treatment. 3. Morphological evidence of hepatic cell injury after lindane treatment was seen at all times studied, and appeared to increase with time. 4. Lindane administration results in time-dependent oxidative stress in liver which involves an early component (4-6 h) related to the reductive metabolism of lindane, and a late component (24 h) associated with the induction of cytochrome P-450; the biochemical changes correlated with the observed morphological lesions.

Background Phenolic compounds combine antioxidant and hypocholesterolemic activities and, consequently, are expected to prevent or minimize cardiometabolic risk. Methods To evaluate the effect of an aqueous extract (AQ) and non-esterified phenolic fraction (NEPF) from rosemary on oxidative stress in diet-induced hypercholesterolemia, 48 male 4-week old Wistar rats were divided into 6 groups: 1 chow diet group (C) and 5 hypercholesterolemic diet groups, with 1 receiving water (HC), 2 receiving AQ at concentrations of 7 and 140 mg/kg body weight (AQ70 and AQ140, respectively), and 2 receiving NEPF at concentrations of 7 and 14 mg/kg body weight (NEPF7 and NEPF14, respectively) by gavage for 4 weeks. Results In vitro, both AQ and NEPF had remarkable antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH●) assay, which was similar to BHT. In vivo, the group that received AQ at 70 mg/kg body weight had lower serum total cholesterol (−39.8%), non-HDL-c (−44.4%) and thiobarbituric acid reactive substance (TBARS) levels (−37.7%) compared with the HC group. NEPF (7 and 14 mg/kg) reduced the tissue TBARS levels and increased the activity of tissular antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase). Neither AQ nor NEPF was able to ameliorate the alterations in the hypercholesterolemic diet-induced fatty acid composition in the liver. Conclusions These data suggest that phenolic compounds from rosemary ameliorate the antioxidant defense in different tissues and attenuate oxidative stress in diet-induced hypercholesterolemic rats, whereas the serum lipid profile was improved only in rats that received the aqueous extract.