Mechanistic Insights on Pd-Catalyzed Three-Component Reactions of Alkynols, Methyl Orthoformate, and Salicylaldehyde Derivatives. Application to the Synthesis of Steroid Chroman Ketals and Spiroketals with Antioxidant Activity.

Contrary to our previous report in which a Pd-catalyzed three-component reaction of a steroid alkynol, trimethyl orthoformate, and salicylaldehyde exclusively produced chroman ketals, the same reaction employing 2,5-dihydroxysalicylaldehyde led to a mixture of a chroman ketal and a spiroketal. Provided that both courses of the reaction imply a 4 + 2 inverse demand cycloaddition between an o-quinone methide and an enol ether, density functional theory calculations revealed that the chroman ketal/spiroketal selectivity is governed by both, the rate of the formation of the o-quinone methide and the isomerization of the initially produced exocyclic enol ether─that led to the spiroketal─to its endocyclic partner that produces the chroman ketal. Remarkably, Lewis catalysis is central to the observed reactivity, and the availability of plausible catalytic species controls the overall chemoselectivity. The methodology herein applied and scrutinized enriches the palette of reactions, leading to increased molecular complexity, as demonstrated in the obtained products, whose antioxidant activity and detailed NMR characterization are presented.

n-3 Polyunsaturated Fatty Acid Supplementation Affects Oxidative Stress Marker Levels in Patients with Type II Intestinal Failure: A Randomized Double Blind Trial.

Type II intestinal failure (IF-II) is a condition in which the gastrointestinal tract is compromised. Liver complications may occur because of the pathology and/or prolonged use of parenteral nutrition (PN); oxidative stress has been implicated as one of the causes. Lipid emulsions containing n-3 polyunsaturated fatty acids (PUFAs) have been proposed for the treatment. We aimed to evaluate the effect of 7-day n-3 PUFA supplementation on oxidative stress in IF-II patients receiving PN. This was a randomized, controlled, double-blinded, pilot trial of adult patients with IF-II, receiving either conventional PN (control) or PN enriched with n-3 PUFAs (intervention). Twenty patients were included (14 men, 49 ± 16.9 years), with the ANCOVA analysis the glucose (p = 0.003), and direct bilirubin (p = 0.001) levels reduced; whereas the high-density lipoprotein cholesterol (HDL-C) increased (p = 0.017). In the random-effect linear regression analysis, a reduction (p < 0.0001) in the malondialdehyde (MDA) level was found in the intervention group when the covariables age, HDL-C level, and alanine aminotransferase activity were considered. After 1 week of PN supplementation with n-3 PUFAs, the marker levels of some oxidative stress, blood lipids, and hepatic biomarkers improved in patients with IF-II.

An unexpected acid-catalyzed rearrangement of diacetoxy benzylidenespirostanes to spirochromene acetals and spiroindenes with radical scavenger activity.

23E-diacetoxybenzylidenespirostanes underwent rearrangement when treated with HCl in CH2Cl2/CH3OH. The course of the rearrangement depends on the substitution pattern in the phenyl ring. While compounds bearing an acetoxy group at the ortho position produced spirochromenes, the partners with no substituent at the ortho position led to spiroindenes. All the rearranged compounds exhibited moderate antioxidant activity.

Exposure to Sub-Lethal Doses of Permethrin Is Associated with Neurotoxicity: Changes in Bioenergetics, Redox Markers, Neuroinflammation and Morphology.

Permethrin (PERM) is a member of the class I family of synthetic pyrethroids. Human use has shown that it affects different systems, with wide health dysfunctions. Our aim was to determine bioenergetics, neuroinflammation and morphology changes, as redox markers after subacute exposure to PERM in rats. We used MDA determination, protein carbonyl assay, mitochondrial O2 consumption, expression of pro-inflammatory cytokines and a deep histopathological analysis of the hippocampus. PERM (150 mg/kg and 300 mg/kg body weight/day, o.v.) increased lipoperoxidation and carbonylated proteins in a dose-dependent manner in the brain regions. The activities of antioxidant enzymes glutathione peroxidase, reductase, S-transferase, catalase, and superoxide dismutase showed an increase in all the different brain areas, with dose-dependent effects in the cerebellum. Cytokine profiles (IL-1ß, IL-6 and TNF-α) increased in a dose-dependent manner in different brain tissues. Exposure to 150 mg/kg of permethrin induced degenerated and/or dead neurons in the rat hippocampus and induced mitochondrial uncoupling and reduction of oxidative phosphorylation and significantly decreased the respiratory parameters state 3-associated respiration in complex I and II. PERM exposure at low doses induces reactive oxygen species production and imbalance in the enzymatic antioxidant system, increases gene expression of pro-inflammatory interleukins, and could lead to cell damage mediated by mitochondrial functional impairment.

Electrophilic Modulation of the Superoxide Anion Radical Scavenging Ability of Copper(II) Complexes with 4-Methyl Imidazole.

Three Cu(II) coordination compounds with 4-methyl imidazole were obtained, such as [Cu(C4H6N2)4(NO3)2], [Cu(C4H6N2)4Br2], and [Cu(C4H6N2)4Cl2]. Crystallographic studies confirmed their structural similarity with Cu(II) in the active site of endogenous copper-zinc superoxide dismutase (CuZn-SOD). The superoxide anion radical (O2•-) scavenging activity was evaluated by the non-enzymatic experimental assay and followed the trend [Cu(C4H6N2)4(NO3)2] > [Cu(C4H6N2)4Br2] > [Cu(C4H6N2)4Cl2]. The density functional theory and the hard and soft acids and bases principle showed the importance of the electron-deficient character of Cu(II) in the chemical reactivity of the coordination compounds; Cu(II) is the softest site in the molecule and it is preferred for the nucleophilic and radical attacks of the soft O2•-. A simple rule was obtained: "the electron-deficient character of Cu(II) is the key index for the O2•- scavenging activity and is modulated by the electron-releasing counteranion effect on the coordination compound".

S-allyl Cysteine, a Garlic Compound, Produces an Antidepressant-Like Effect and Exhibits Antioxidant Properties in Mice.

Depression is a psychiatric disorder, and oxidative stress is a significant mechanism of damage in this mood disorder. It is characterized by an enhancement of oxidative stress markers and low concentrations of endogenous antioxidants, or antioxidants enzymes. This suggests that antioxidants could have an antidepressant effect. S-allyl cysteine (SAC) is a compound with antioxidant action or free radical scavenger capacity. The purpose of the current research was to evaluate the antidepressant-like effect as well as the antioxidant role of SAC on a preclinical test, using the Porsolt forced swim test (FST). SAC (30, 70, 120, or 250 mg/kg, ip) was administered to male BALB/c mice daily for 17 days, followed by the FST at day 18. Oxidative stress markers (reactive oxygen species, superoxide production, lipid peroxidation, and antioxidant enzymes activities) were analyzed in the midbrain, prefrontal cortex, and hippocampus. SAC (120 mg/kg) attenuated the immobility scores (44%) in the FST, and protection was unrelated to changes in locomotor activity. This antidepressant-like effect was related to decreased oxidative stress, as indicated by lipid peroxidation and manganese-superoxide dismutase (Mn-SOD) activity in the hippocampus. SAC exerts an antidepressant-like effect that correlated, in part, with preventing oxidative damage in hippocampus.

Antimicrobial, Antioxidant Activities, and HPLC Determination of the Major Components of Verbena carolina (Verbenaceae).

Verbena carolina L. (Verbenaceae) is used as a decoction in Mexican folk medicine with applications against digestive problems and for dermatological infections. The present work firstly reported HPLC analysis, as well as the free radical scavenging capacity of the extracts and isolated compounds. Antimicrobial analyses of these substances against the bacteria Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Salmonella typhi and the fungi Candida albicans, Trichophyton mentagrophytes and T. rubrum were also tested, as well as the acute oral toxicity in mice of aqueous extracts. Major secondary metabolites in V. carolina extracts were isolated by conventional phytochemical methods which consisted of three terpenoids ((1), (3) and (4)) and four phenolic compounds ((2), (4)-(6)). Their contents were determined by HPLC in six different samples from different locations. The results indicated that ursolic acid (1), hispidulin (2), verbenaline (3), hastatoside (4), verbascoside (5), hispidulin 7-O-ß-d-glucuronopyranoside (6) and pectolinaringenin-7-O-α-d-glucuronopyranoside (7) were the main constituents and ranged from 0.17 to 3.37 mg/g of dried plant, with verbascoside being the most abundant and with a significant antioxidant activity in reactive oxygen species (ROS). Hispidulin was the only active compound against T. mentagrophytes and T. rubrum. The aqueous extract showed no significant toxicity (LD50: > 5000 mg/mL). To our knowledge, this is the first comprehensive report of the chemical characterization of V. carolina and also of the activity of its constituents towards reactive oxygen species and dermatophytes, and its safety for consumption.

Cucumis sativus Aqueous Fraction Inhibits Angiotensin II-Induced Inflammation and Oxidative Stress In Vitro.

Inflammation and oxidative stress play major roles in endothelial dysfunction, and are key factors in the progression of cardiovascular diseases. The aim of this study was to evaluate in vitro the effect of three subfractions (SFs) from the Cucumis sativus aqueous fraction to reduce inflammatory factors and oxidative stress induced by angiotensin II (Ang II) in human microvascular endothelial cells-1 (HMEC-1) cells. The cells were cultured with different concentrations of Ang II and 0.08 or 10 µg/mL of SF1, SF2, or SF3, or 10 µmol of losartan as a control. IL-6 (Interleukin 6) concentration was quantified. To identify the most effective SF combinations, HMEC-1 cells were cultured as described above in the presence of four combinations of SF1 and SF3. Then, the effects of the most effective combination on the expression of adhesion molecules, the production of reactive oxygen species (ROS), and the bioavailability of nitric oxide (NO) were evaluated. Finally, a mass spectrometry analysis was performed. Both SF1 and SF3 subfractions decreased the induction of IL-6 by Ang II, and C4 (SF1 and SF3, 10 µg/mL each) was the most effective combination to inhibit the production of IL-6. Additionally, C4 prevented the expression of adhesion molecules, reduced the production of ROS, and increased the bioavailability of NO. Glycine, arginine, asparagine, lysine, and aspartic acid were the main components of both subfractions. These results demonstrate that C4 has anti-inflammatory and antioxidant effects.

Synthesis and radical scavenger properties of novel spirochromenes derived from steroid sapogenins.

Tandem aldol condensation between steroid sapogenins and hydroxylated benzaldehydes afforded steroidal spirochromenes. Compounds that bear a phenolic hydroxyl group at position C-6', obtained by a reaction with 2,5-dihydroxybenzaldehyde, showed approximately 80% of maximal radical scavenging activity in the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay at 288 nM. In contrast, the starting steroid sapogenins and the spirochromenes without a phenolic group in the side chain proved to be inactive.

Hypoglycemic, antihyperglycemic, and antioxidant effects of the edible plant Anoda cristata.

ETHNOPHARMACOLOGICAL RELEVANCE: Some studies refer that the entire plant of Anoda cristata is consumed as food and medicine; in particular for treating diabetes, inflammation, fever, cough, and wounds. The aim of this study was to establish the preclinical efficacy of Anoda cristata as hypoglycemic and/or antihyperglycemic agent using well-known animal models. MATERIALS AND METHODS: The acute toxicity was analyzed by the Lorke method. Acute hypoglycemic as well as oral glucose and sucrose tolerance tests were used to determine the hypoglycemic and antihyperglycemic action of Anoda cristata. Several preparations of the plant, including a mucilage (M), an aqueous (T-AE), a free mucilage aqueous (FM-AE), and an organic (OE) extracts, were tested in healthy and NA-STZ-hyperglycemic mice. Glibenclamide (15mg/kg), acarbose (5mg/kg ) and metformin (200mg/kg) were used as positive controls. The major compounds acacetin (1) and diosmetin (2), isolated from an infusion of the plant applying chromatographic methods, were evaluated as hypoglycemic agents using the same assays. The FM-AE was tested also in rats with metabolic syndrome induced by a high-fructose fed. Finally some assays were performed to determine the antioxidant capacity of the FM-AE in vitro. RESULTS: The results demonstrated that the extracts and compounds from Anoda cristata were effective for reducing blood glucose levels in healthy and NA-STZ-hyperglycemic mice when compared with vehicle groups (p<0.05). The FM-AE exerted also positive effect over different biochemical parameters altered in rats with metabolic syndrome induced by a fructose diet. FM-AE has also antioxidant action effectively trapping ONOO(-) and ROO(•) radicals. The major flavonoids isolated from the plant, namely acacetin (1) and diosmetin (2), caused significant hypoglycemic effect and possessed antioxidant activity. CONCLUSION: Anoda cristata is effective to diminish glucose levels in vivo and to ameliorate different disorders related with the metabolic syndrome in rats. According to the results, the efficacy of Anoda cristata preparations could be due to the presence of active principles with different mode of actions at the molecular level, including α-glycosidases inhibitors, insulin secretagogues, glucose entrapment and radical trapping agents.

Hypoglycemic and antihyperglycemic effects of phytopreparations and limonoids from Swietenia humilis.

An aqueous extract from the seeds of Swietenia humilis (31.6-100mg/kg bw) lowered (p<0.05) blood glucose levels in normal and nicotinamide-streptozotocin (NA-STZ)-induced hyperglycemic mice. Furthermore, when administered to fructose-fed rats with metabolic syndrome, the decoction showed significant antihyperglycemic, hypoglycemic and hypolipidemic effects, as well as an augmentation of hepatic glycogen. Limonoids 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1), humulin B (2), methyl-2-hydroxy-3-ß-isobutyroxy-1-oxomeliac-8(30)-enate (3), methyl-2-hydroxy-3-ß-tigloyloxy-1-oxomeliac-8(30)-enate (4), humilinolide G (5), humilinolide C (6), methyl-2-hydroxy-3-ß-isobutyoyl-8α,30α-epoxy-1-oxo-meliacate (7), and humilinolide H (8), were isolated from a CH2Cl2-MeOH (1:1) extract of the seeds. Compounds 5 and 8 are analogs of compounds 6 and 7. The structure of 5 was unequivocally established by X-ray analysis. When tested in normal and NA-STZ-hyperglycemic mice, compounds 1, 2, and 4 (3.16-31.6 mg/kg bw) decreased glycemia during an oral glucose tolerance test. The present investigation sustains the contemporary popular uses of S. humilis seeds for treating metabolic disorders, including diabetes and dyslipidemia and demonstrates the potential of the mexicanolides as antihyperglycemic agents.

Characterization of N-diethylnitrosamine-initiated and ferric nitrilotriacetate-promoted renal cell carcinoma experimental model and effect of a tamarind seed extract against acute nephrotoxicity and carcinogenesis.

Renal cell carcinoma (RCC), the commonest malignancy in adult kidney, lacks of early signs, resulting often in metastasis at first diagnosis. N-Diethylnitrosamine (DEN)-initiated and ferric nitrilotriacetate (FeNTA)-promoted RCC may be a useful experimental model, but it is not well characterized. In this study, histological alterations and oxidative stress markers were analyzed at different times throughout RCC development, histological subtype was re-evaluated in the light of current classification, and a tamarind seed extract (TSE) effect was examined. Male Wistar rats experimental groups were control, TSE, DEN, DEN+FeNTA, and TSE+DEN+FeNTA. TSE was given 2 weeks before DEN administration (200 mg/kg) and throughout the experiment. Fourteen days after DEN treatment, two FeNTA doses (9 mg Fe/kg) for acute nephrotoxicity study, and increasing FeNTA doses (3-9 mg Fe/kg) twice a week for 16 weeks for carcinogenesis protocol, were administered. In acute study, necrosis and renal failure were observed and TSE ameliorated them. Throughout carcinogenesis protocol, preneoplastic lesions were observed since 1 month of FeNTA treatment, which were more evident at 2 months, when also renal cysts and RCC were already detected. RCC tumors were obtained without changes in renal function, and clear cell histological subtype was identified in all cases. 4-Hydroxy-2-nonenal and 3-nitro-L: -tyrosine levels increased progressively throughout protocol. TSE decreased both oxidative stress markers and, although there was no statistical difference, it delayed RCC progress and decreased its incidence (21 %). This study brings an insight of the time course events in this carcinogenesis model, identifies clear cell subtype and establishes TSE renoprotective effects.

Sildenafil treatment prevents glomerular hypertension and hyperfiltration in rats with renal ablation.

BACKGROUND: Sildenafil treatment ameliorates progressive renal injury resulting from extensive renal ablation; however, modifications induced by sildenafil in the glomerular hemodynamic pathophysiology of the remnant kidney have not been investigated. AIM: To determine the effects of sildenafil in the glomerular microcirculation and their relation to histological damage in the renal ablation model. METHODS: Micropuncture studies were performed 60 days after 5/6 nephrectomy in rats that received no treatment, sildenafil (5 mg/kg/day) and reserpine, hydralazine and hydrochlorothiazide to maintain the blood pressure within normal levels. Sham-operated rats untreated and treated with sildenafil served as controls. RESULTS: As expected, renal ablation induced systemic and glomerular hypertension, hyperfiltration, proteinuria, glomerulosclerosis and tubulointerstitial inflammatory damage in the remnant kidney. Sildenafil treatment prevented single-nephron hyperfiltration and hypertension, suppressed renal arteriolar remodeling, ameliorated systemic hypertension and proteinuria, increased urinary excretion of cGMP and NO(2)(-)/NO(3)(-), decreased oxidative stress and improved histological damage in the remnant kidney. Normalization blood pressure with reserpine, hydralazine and hydrochlorothiazide did not modify glomerular hemodynamics, proteinuria or histological changes induced by renal ablation. CONCLUSIONS: Beneficial effects of sildenafil in the remnant kidney are associated with a reduction in the arteriolar remodeling, renal inflammatory changes and prevention of changes in the glomerular microcirculation.

Antidepressant-like effect of a Ginkgo biloba extract (EGb761) in the mouse forced swimming test: role of oxidative stress.

EGb761 is a well-defined mixture of active compounds extracted from Ginkgo biloba leaves. This extract is used clinically due to its neuroprotective effects, exerted probably via its potent antioxidant or free radical scavenger action. Previous studies suggest that oxidative stress, via free radical production, may play an important role in depression and animal models for depression-like behavior. Preclinical studies have suggested that antioxidants may have antidepressants properties. The aim of this study was to investigate the antidepressant-like of EGb761 due to its antioxidant role against oxidative stress induced in the forced swimming test, the most widely used preclinical model for assessing antidepressant-like behavior. Male BALB/c mice were pretreated with EGb761 (10mg/kg, ip) daily for 17 days followed by the forced swimming test and spontaneous locomotor activity. Animals were sacrificed to evaluate lipid peroxidation, different antioxidant enzyme activities, serotonin and dopamine content in midbrain, hippocampus and prefrontal cortex. EGb761 significantly decreased the immobility time (39%) in the forced swimming test. This antidepressant-like effect of EGb761 was associated with a reduction in lipid peroxidation and superoxide radical production (indicated by a downregulation of Mn-superoxide dismutase activity), both of which are indicators of oxidative stress. The protective effect of EGb761 is not related to excitatory or inhibitory effects in locomotor activity, and was also associated with the modulation of serotonergic and dopaminergic neurotransmission. It is suggested that EGb761 produces an antidepressant-like effect, and that an antioxidant effect against oxidative stress may be partly responsible for its observed neuroprotective effects.

S-Allylcysteine, a garlic compound, protects against oxidative stress in 1-methyl-4-phenylpyridinium-induced parkinsonism in mice.

S-Allylcysteine (SAC), the most abundant organosulfur compound in aged garlic extract, has multifunctional activity via different mechanisms and neuroprotective effects that are exerted probably via its antioxidant or free radical scavenger action. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse has been the most widely used model for assessing neuroprotective agents for Parkinson's disease. 1-Methyl-4-phenylpyridinium (MPP(+)) is the stable metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and it causes nigrostriatal dopaminergic neurotoxicity. Previous studies suggest that oxidative stress, via free radical production, is involved in MPP(+)-induced neurotoxicity. Here, we report on the neuroprotective effect of SAC against oxidative stress induced by MPP(+) in the striatum of C57BL/6J mice. Mice were pretreated with SAC (125 mg/kg ip) daily for 17 days, followed by administration of MPP(+) (0.72 mg/kg icv), and were sacrificed 24 h later to evaluate lipid peroxidation, different antioxidant enzyme activities, spontaneous locomotor activity and dopamine (DA) content. MPP(+) administration resulted in a significant decrease in DA levels in the striatum. Mice receiving SAC (125 mg/kg ip) had significantly attenuated MPP(+)-induced loss of striatal DA levels (32%). The neuroprotective effect of SAC against MPP(+) neurotoxicity was associated with blocked (100% of protection) of lipid peroxidation and reduction of superoxide radical production - indicated by an up-regulation of Cu-Zn-superoxide dismutase activity - both of which are indices of oxidative stress. Behavioral analyses showed that SAC improved MPP(+)-induced impairment of locomotion (35%). These findings suggest that in mice, SAC attenuates MPP(+)-induced neurotoxicity in the striatum and that an antioxidant effect against oxidative stress may be partly responsible for its observed neuroprotective effects.

Hypochlorous acid scavenging activities of thioallyl compounds from garlic.

The hypochlorous acid (HOCl) scavenging capacities of 10 garlic compounds containing modifications in the thioallyl group (-S-CH2CH ═ CH2) were determined by a catalase protection assay, and the corresponding structure-activity relationships using molecular descriptors were calculated. This scavenging activity was enhanced by increasing the number of S atoms or by the alanyl group (-CH2CH-NH2-COOH) and decreased in the absence of the C ═ C bond or in the presence of a sulfoxide group in the thioallyl group. Interestingly, S-allylcysteine and its corresponding sulfoxide (alliin) showed the highest and lowest HOCl-scavenging capacities, respectively. Quantitative modeling by multiple regression analysis and partial least-squares projections showed that the topological descriptor polar surface area and two electronic properties, namely, highest occupied molecular orbital and total energy, contributed mainly to variations in the HOCl scavenging activity of thioallyl compounds. These observations provide new insights on the antioxidant mechanism of garlic derivatives in processes involving HOCl production.

Sulforaphane protects against cisplatin-induced nephrotoxicity.

Cisplatin (cis-diamminedichloroplatinum II, CDDP) is a chemotherapeutic agent that induces nephrotoxicity associated with oxidative/nitrosative stress. Sulforaphane (SFN) is an isothiocyanate produced by the enzymatic action of myrosinase on glucorophanin, a glucosinolate contained in cruciferous vegetables. SFN is able to induce cytoprotective enzymes through the transcription factor Nrf2. The purpose of this study was to evaluate whether SFN induces a cytoprotective effect on the CDDP-induced nephrotoxicity. Preincubation of LLC-PK1 cells with 0.5-5 microM SFN by 24 h was able to prevent, in a concentration-dependent way, CDDP-induced cell death. Immunofluorescent staining confirmed the nuclear translocation of Nrf2 after treatment with SFN. In the in vivo studies, CDDP was given to Wistar rats as a sole i.p. injection at a dose of 7.5 mg/kg. SFN (500 microg/kg i.v.) was given two times (24 h before and 24 after CDDP-injection). Animals were killed three days after CDDP-injection. SFN attenuated CDDP-induced renal dysfunction, structural damage, oxidative/nitrosative stress, glutathione depletion, enhanced urinary hydrogen peroxide excretion and the decrease in antioxidant enzymes (catalase, glutathione peroxidase and glutathione-S-transferase). The renoprotective effect of SFN on CDDP-induced nephrotoxicity was associated with the attenuation in oxidative/nitrosative stress and the preservation of antioxidant enzymes.

Targeting oxidative/nitrergic stress ameliorates motor impairment, and attenuates synaptic mitochondrial dysfunction and lipid peroxidation in two models of Huntington's disease.

In this study, we reproduced two toxic models resembling some motor/kinetic deficits of Huntington's disease induced by bilateral intrastriatal injections of either quinolinic acid (QUIN, 120 nmol/microl per side) or 3-nitropropionic acid (3-NP, 250 nmol/microl per side) to rats. Motor skills (including total distance walked/traveled and total horizontal and vertical activities) were evaluated in a box-field system at 1 and 7 days post-lesion. In order to investigate whether these alterations were associated with the oxidative/nitrergic stress evoked by the nitrogen reactive species peroxynitrite (ONOO(-)) in the striatum, some rats were pretreated with the ONOO(-) decomposition catalyst iron porphyrinate (Fe(TPPS), 10 mg/kg, i.p.) 120 min prior to toxins infusion. With the aim to further characterize some possible mechanisms by which motor tasks were affected and/or preserved, biochemical analysis of peroxidative damage to lipids and mitochondrial dysfunction were both assessed in synaptic membranes isolated from the striata of QUIN-, 3-NP- and/or Fe(TPPS)-treated animals. Our results show that targeting oxidative/nitrergic stress by Fe(TPPS) in these toxic models results in amelioration of motor deficits linked to inhibition of peroxidative damage and recovery of mitochondrial function in synaptic membranes. Based on these findings, we hypothesize that the protection exerted by Fe(TPPS) on the biochemical markers analyzed reflects the possible preservation of the functional status of the nerve tissue by limiting the deleterious actions of ONOO(-), further accounting for partial recovery of integrative motor functions.

Treatment with pyrrolidine dithiocarbamate improves proteinuria, oxidative stress, and glomerular hypertension in overload proteinuria.

We evaluated whether the blockade of the proinflammatory transcription factor NF-kappaB would modify the oxidative stress, inflammation, and structural and hemodynamic alterations found in the kidney as a result of massive proteinuria. Twenty male Sprague-Dawley rats were injected with 2 g of BSA intraperitoneally daily for 2 wk. Ten of them received in addition the inhibitor of NF-kappaB activation pyrrolidine dithiocarbamate (PDTC; 200 mg.kg(-1).day(-1) sc) and the rest received vehicle. Seven rats that received intraperitoneal saline were used as controls. Glomerular hemodynamics were studied after 14 days. Markers of oxidative stress (NF-kappaB subunit p65+ cells, 3-nitrotyrosine, and 4-hydroxynonenal), inflammation (cortical CD68+ cells and NOS-II), and afferent arteriole damage were assessed by immunohistochemistry and morphometry. Activity of antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase was evaluated in renal cortex and medulla. Albumin overload induced massive proteinuria, oxidative stress with reduced activity of antioxidant enzymes, NF-kappaB activation, inflammatory cell infiltration, a significant presence of proteinaceous casts, systemic and glomerular hypertension, as well as arteriolar remodeling. Treatment with PDTC prevented or improved all of these findings. In this model of nephrotic syndrome, we demonstrate a key role for oxidative stress and inflammation in causing systemic and glomerular hypertension and proteinuria. Oxidative stress and inflammation may have a key role in accelerating renal injury associated with intense proteinuria.

Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions.

Ketone bodies play a key role in mammalian energy metabolism during the suckling period. Normally ketone bodies' blood concentration during adulthood is very low, although it can rise during starvation, an exogenous infusion or a ketogenic diet. Whenever ketone bodies' levels increase, their oxidation in the brain rises. For this reason they have been used as protective molecules against refractory epilepsy and in experimental models of ischemia and excitotoxicity. The mechanisms underlying the protective effect of these compounds are not completely understood. Here, we studied a possible antioxidant capacity of ketone bodies and whether it contributes to the protection against oxidative damage induced during hypoglycemia. We report for the first time the scavenging capacity of the ketone bodies, acetoacetate (AcAc) and both the physiological and non-physiological isomers of beta-hydroxybutyrate (D- and L-BHB, respectively), for diverse reactive oxygen species (ROS). Hydroxyl radicals (.OH) were effectively scavenged by D- and L-BHB. In addition, the three ketone bodies were able to reduce cell death and ROS production induced by the glycolysis inhibitor, iodoacetate (IOA), while only D-BHB and AcAc prevented neuronal ATP decline. Finally, in an in vivo model of insulin-induced hypoglycemia, the administration of D- or L-BHB, but not of AcAc, was able to prevent the hypoglycemia-induced increase in lipid peroxidation in the rat hippocampus. Our data suggest that the antioxidant capacity contributes to protection of ketone bodies against oxidative damage in in vitro and in vivo models associated with free radical production and energy impairment.