Plasma homocysteine and oxidative stress in cardiovascular disease

Hyperhomocysteinemia (Hhcy) has been associated with pathological and stressful conditions and is a risk factor for cardiovascular disease (CVD). The aim of this study was to evaluate the correlation between plasma homocysteine (hcy) and lipid peroxidation in patient with CVD. This study was carried out on 40 patients with CVD as well as 15 healthy volunteers of comparable age and gender as control group. The patients were divided into 2 groups as follows: group I, included 20 patients with acute myocardial infarction and group II, included 20 patients with atherosclerotic coronary artery disease with no evidence of previous myocardial infarction. Plasma hcy, nitric oxide (NO) and malondialdhyde (MDA) [as index of lipid peroxidation] were measured in all groups. In addition serum total-cholesterol, HDL, LDL and triglycerides were evaluated. Results obtained showed that, there was a significant elevation in the levels of plasma hcy, NO and MDA in groups I and II as compared to control group. There was a strong positive correlation between plasma hcy and MDA (r = 0.59, p < 0.001). Also NO was positively correlated with both hcy (r = 0.49, p < 0.001) and MDA (r = 0.51, p < 0.001). Serum total cholesterol, LDL, and triglycerids were also significantly elevated while serum HDL was significantly decreased in groups I and II as compared to control group. It can be concluded that, hyperhomocysteinemia is a possible factor in free radical generation and therefore cardiovascular diseases.     

Cystathionine beta-synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment

Cystathionine beta-synthase (CBS) deficient homocystinuria is an inherited metabolic defect that if untreated typically results in mental retardation, thromboembolism and a range of connective tissue disturbances. A knockout mouse model has previously been used to investigate pathogenic mechanisms in classical homocystinuria (Watanabe et al., PNAS 92 (1995) 1585–1589). This mouse model exhibits a semi-lethal phenotype and the majority of mice do not survive the early neonatal period. We report here that the birth incidence of cbs (?/?) mice produced from heterozygous crosses is non-Mendelian and not significantly improved by treatment with either the Hcy lowering compound betaine or the cysteine donor N-acetylcysteine. Betaine treatment did improve survival of cbs (?/?) mice and restored fertility to female cbs (?/?) mice but did so without significantly lowering Hcy levels. Surviving cbs (?/?) mice failed to show any alteration in coagulation parameters compared to wild-type controls. Moribund cbs (?/?) mice exhibited severe liver injury and hepatic fibrosis while surviving cbs (?/?) mice although less severely affected, still exhibited a level of severe liver injury that is not found in the human disease. The hepatopathy observed in this model may offer an explanation for the failure of cbs (?/?) mice to respond to betaine or exhibit a hypercoagulative phenotype. We conclude that although this model provides useful data on the biochemical sequelae of classical homocystinuria, it does not successfully recapitulate a number of important features of the human disease and its use for studying mechanisms in homocystinuria should be treated with caution as the hepatopathy produces changes which could influence the results.     

Activation of NF-kappaB in lymphocytes and increase in serum immunoglobulin in hyperthyroidism: possible role of oxidative stress

This study evaluated oxidative stress, serum IgM and IgG, and nuclear factor (NF)-κB signaling in lymphocytes of hyperthyroidism patients. GSH content in lymphocytes was significantly lower and serum malondialdehyde, IgM and IgG levels were significantly higher in hyperthyroidism as compared to controls. In lymphocytes, the NF-κB signaling pathway was studied by western blot analysis of p65 and p-IκB. Density of p-IκB and p65 (in nuclear fraction) was significantly higher in hyperthyroidism as compared to controls. The density of p-IκB and p65 had significant positive correlation with serum malondialdehyde level and negative correlation with lymphocyte GSH level in hyperthyroid cases. The serum IgG and IgM levels were correlated significantly with density of p-IκB and p65. As immunoglobulin production is regulated by the NF-κB pathway, we conclude that the oxidative stress-induced activation of the NF-κB pathway might play a role in the rise of serum immunoglobulin level in hyperthyroidism.     

Interaction between oxidative stress and chemokines: possible pathogenic role in systemic lupus erythematosus and rheumatoid arthritis

Imbalance oxidative stress and chemokines are considered as a universal factors involved in the development of various clinical features seen in the patients with SLE and arthritis. To evaluate the interaction between oxidative stress and chemokines and their relationship with disease activity in SLE and RA patients, oxidative/anti-oxidant profiles and chemokines were assessed. Oxidant and anti-oxidant enzymes were measured in the plasma and the levels of chemokines; MCP-1/CCL2, RANTES/CCL5, MIP-1β/CCL-4 and IP-10/CXCL-10 were evaluated in the serum by an enzyme-linked immunosorbent assay (ELISA). A significant increase in the level of lipid peroxidation was found in SLE and RA patients and positively associated with disease activity. The activities of anti-oxidant enzymes: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and anti-oxidant molecule GSH were significantly reduced in both diseases. Strong positive associations were found between MDA with RANTES/CCL5 and MIP-1β/CCL4 than MCP-1/CCL-2 in SLE patients while a sturdy connotation was seen with MIP-1β/CCL4 and MCP-1/CCL-2 in RA patients. The anti-oxidant molecule GSH shows a negative association with serum levels of MCP-1/CCL-2, RANTES/CCL5 and IP-10/CXCL-10 in SLE patients and with MCP-1/CCL-2 and RANTES/CCL5 in RA patients. A low level of GSH and high level of RANTES/CCL5 were associated with lupus nephritis patients. These results indicates that excessive production of ROS disturbs redox status and can modulate the expression of inflammatory chemokines leading to inflammatory processes, exacerbating inflammation and affecting tissue damage in autoimmune diseases, as exemplified by their strong association with disease activity.     

Peculiarities of oxidative stress in the plasma of patients with familial hypercholesterolemia

Plasma level of lipid-standardized vitamin E is decreased, while the concentration of inflammatory transmitters C3a(desArg) and C5a(desArg) is elevated in heterozygous familial hypercholesterolemia caused by apoB,E-receptor deficiency. Leukocytes isolated from these patients exhibit enhanced spontaneous aggregation of superoxide anion generation and are resistant to activation with exogenous platelet activation factor (10⁻⁶ M). Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 2, pp. 213–216, February, 1998     

Urocortin 2 and urocortin 3 in endometriosis: evidence for a possible role in inflammatory response

Urocortin 2 (Ucn 2) and urocortin 3 (Ucn 3) are neuropeptides expressed by human endometrium. This study evaluated (i) the expression of Ucn 2 and Ucn 3 mRNA in endometriotic lesions and in endometrium of women with endometriosis; (ii) the effect of Ucn 2 and Ucn 3 on cytokines secretion from cultured endometrial stromal cells. Endometriotic tissue was collected from endometrioma (n=39); endometrial specimens were obtained from women with (n=39) and without (n=41) endometriosis throughout menstrual cycle. Tissue specimens were analysed for Ucn 2 and Ucn 3 mRNA expression and peptide localization; the effects of Ucn 2 or Ucn 3 on tumour necrosis factor (TNF-α) and interleukin (IL-4) secretion from cultured endometrial stromal cells was studied. Ucn 2 and Ucn 3 mRNA expression and localization were assessed by RT-PCR and by immuohistochemistry, respectively; cytokines secretion were measured by ELISA. Results showed that endometriotic tissue expressed both Ucn 2 and Ucn 3, with Ucn 3 expression higher in ectopic than in eutopic endometrium. Endometrial Ucn 2 mRNA expression in controls showed peak values at early proliferative phase, while in endometriotic patients low expression and no significant changes throughout menstrual cycle were observed. Endometrial Ucn 3 mRNA expression was highest in late secretory phase in controls, while in endometriotic patients low levels and no menstrual-cycle-related changes were found. When added to cultured endometrial cell cultures, Ucn 2 significantly increased TNF-α (P<0.01) and IL-4 (P<0.001), while Ucn 3 induced an increase of IL-4 secretion (P<0.01). In conclusion, endometriotic tissue expressed and localized Ucn 2 and Ucn 3; patients with endometriosis showed Ucn 2 and Ucn 3 mRNA expression in eutopic endometrium lower than in control group, with no endometrial cycle-related changes. Ucn 2 and Ucn 3-modulated TNF-α and IL-4 secretion from culture endometrial cells. These data suggest a possible involvement of Ucn 2 and Ucn 3 in the mechanisms of endometriosis.     

Intercellular communication in bronchial epithelial cells: review of evidence for a possible role in lung carcinogenesis

A challenging aspect of lung carcinogenesis is the elucidation of the mechanisms which permit initiated bronchial epithelial cells to attain a growth advantage over normal bronchial epithelial cells, and subsequently evolve into a malignant phenotype. In this review, the effects of interactions between normal and transformed cells, and the potential role of representative extrinsic factors on cell-cell communication are discussed. Evidence is presented to show how cell injury and the effects of serum and calcium may affect morphology and communication, and tumor development. A large number of autocrine-paracrine factors (e.g., TGF beta, TGF alpha) are released by bronchial epithelial cells. These factors may inhibit or promote the proliferation of normal and transformed bronchial epithelial cells, respectively. The ability of certain injurious and tumor promoting agents (e.g., formaldehyde, TPA) to select for the transformed phenotype may involve selective cell injury, the induction of terminal differentiation and an inhibition of gap junction communication among normal BE cells.     

Plasma homocysteine measurement: a study of pre-analytical variation factors for conditions for total plasma homocysteine concentration

An increase in homocysteine, a sulphur amino acid, is nowdays considered as a risk factor for cardiovascular diseases, and is independent of other risk factors. Reference range for total plasma homocysteine level in adults is usually 5-15 mmol/l. Hyperhomocysteinemia is defined as a fasting total plasma homocysteine level > 15 mmol/l. There may be also graded increased risks for subjects with homocysteinemia from 10 to 15 mmol/l. However, no threshold has been defined, partly because of the lack of standardization in pre-analytical and analytical steps. The aim of the present work was to evaluate three pre-analytical parameters on plasma homocysteine levels: i) the influence of three anticoagulants (EDTA, sodium citrate and lithium heparin); ii) the delay period of blood sample on ice before centrifugation; and iii) the advantages of strong acidic citrate at room temperature. The mean concentrations of total plasma homocysteine were different in function of the anticoagulant. These differences (EDTA minus lithium heparin or EDTA minus sodium citrate) were less than 10% however the used methods and could explain the good correlation between the results. However we recommend to keep the anticoagulant constant in the same study. When EDTA blood samples were immediately put on crushed ice, the maximum delay period before centrifugation could reach 4 hours. If ice is unavailable, strong acidic citrate at room temperature is a good alternative until for 4 hours.     

Invasive cytotrophoblasts manifest evidence of oxidative stress in preeclampsia

In preeclampsia, poor placental perfusion may result in maternal endothelial dysfunction, but the pathways involved are largely unknown. Candidate placental mediators include products of oxidative stress released into the maternal circulation. Xanthine oxidase has been implicated in postischemic-reperfusion injury via the generation of superoxide anion radicals (superoxide; O(2)(.-)) and hydrogen peroxide. We examined placentas and placental bed curettings and/or biopsies from preeclamptic control pregnant women to test the hypothesis that xanthine oxidase is a mediator of oxidative stress in placentas from women with preeclampsia. The expression of xanthine dehydrogenase/xanthine oxidase holoenzyme and the activity of xanthine oxidase, the isoform known to generate reactive oxygen species, were increased in a subpopulation of cytotrophoblasts of preeclamptic women. Additionally, the expression of superoxide dismutase, which would scavenge superoxide produced by xanthine oxidase, was reduced in the same cells. Furthermore, fluorescence immunostaining for nitrotyrosine, which was suggestive of superoxide-nitric oxide interactions to form peroxynitrite anion (ONOO(-)) in vivo, was increased in these cells and in villous vessels. Thus, our data indicate an increased capacity of placental cells to generate reactive oxygen species in preeclampsia.     

Protective role of dietary polyphenols in oxidative stress

The oxidative break down of the membrane polyunsaturated fatty acids is known to be accompanied by the formation of a complex mixture of lipidhydroperoxides and secondary products. These compounds are highly reactive and are capable of rapid reaction with cellular nucleophiles such as phospholipids and proteins, and it was found that these reaction products are candidates as impotant biomarkers to evaluate antioxidative activity of dietary antioxidants. The author has been involved in developing immunochemical detection methods for oxidative stress by application of polyclonal and monoclonal antibodies. From the hypothesis that endogenous antioxidants in plants must play an important role for antioxidative defense systems from oxidative stress, an intensive search for novel type of natural antioxidants has been carried out from numerous plant materials, including those used as foods, and we have isolated and identified a number of lipid-soluble and water-soluble dietary antioxidants from crop seeds, sesame seeds and some spices. In this paper, the recent progress of research on functions of dietary antioxidants is reviewed.     

Lung oxidative stress as related to exercise and altitude. Lipid peroxidation evidence in exhaled breath condensate: a possible predictor of acute mountain sickness

Lung oxidative stress (OS) was explored in resting and in exercising subjects exposed to moderate and high altitude. Exhaled breath condensate (EBC) was collected under field conditions in male high-competition mountain bikers performing a maximal cycloergometric exercise at 670 m and at 2,160 m, as well as, in male soldiers climbing up to 6,125 m in Northern Chile. Malondialdehyde concentration [MDA] was measured by high-performance liquid chromatography in EBC and in serum samples. Hydrogen peroxide concentration [H₂O₂] was analysed in EBC according to the spectrophotometric FOX₂ assay. [MDA] in EBC of bikers did not change while exercising at 670 m, but increased from 30.0±8.0 to 50.0±11.0 nmol l⁻¹ (P<0.05) at 2,160 m. Concomitantly, [MDA] in serum and [H₂O₂] in EBC remained constant. On the other hand, in mountaineering soldiers, [H₂O₂] in EBC under resting conditions increased from 0.30±0.12 μmol l⁻¹ at 670 m to 1.14±0.29 μmol l⁻¹ immediately on return from the mountain. Three days later, [H₂O₂] in EBC (0.93 ±0.23 μmol l⁻¹) continued to be elevated (P<0.05). [MDA] in EBC increased from 71±16 nmol l⁻¹ at 670 m to 128±26 nmol l⁻¹ at 3,000 m (P<0.05). Changes of [H₂O₂] in EBC while ascending from 670 m up to 3,000 m inversely correlated with concomitant variations in HbO2 saturation (r=−0.48, P<0.05). AMS score evaluated at 5,000 m directly correlated with changes of [MDA] in EBC occurring while the subjects moved from 670 to 3,000 m (r=0.51, P<0.05). Lung OS may constitute a pathogenic factor in AMS.     

Aldosterone-induced inflammation in the rat heart : role of oxidative stress

Heart failure and hypertension have each been linked to an induction of oxidative stress transduced by neurohormones, such as angiotensin II and catecholamines. Herein, we hypothesized that aldosterone (ALDO) likewise induces oxidative stress and accounts for a proinflammatory/fibrogenic phenotype that appears at vascular and nonvascular sites of injury found in both right and left ventricles in response to ALDO/salt treatment and that would be sustained with chronic treatment. Uninephrectomized rats received ALDO (0.75 micro g/hour) together with 1% dietary NaCl, for 3, 4, or 5 weeks. Other groups received this regimen in combination with an ALDO receptor antagonist, spironolactone (200 mg/kg p.o. daily), or an antioxidant, either pyrrolidine dithiocarbamate (PDTC) (200 mg/kg s.c. daily) or N-acetylcysteine (NAC) (200 mg/kg i.p. daily). Unoperated and untreated age- and gender-matched rats served as controls. We monitored spatial and temporal responses in molecular and cellular events using serial, coronal sections of right and left ventricles. Our studies included: assessment of systolic blood pressure; immunohistochemical detection of NADPH oxidase expression and activity; analysis of redox-sensitive nuclear factor-kappaB activation; in situ localization of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha mRNA expression; monitoring cell growth and infiltration of macrophages and T cells; and analysis of the appearance and quantity of fibrous tissue accumulation. At week 3 of ALDO/salt treatment and comparable to controls, there was no evidence of oxidative stress or pathological findings in the heart. However, at weeks 4 and 5 of treatment, increased gp91(phox) and 3-nitrotyrosine expression and persistent activation of RelA were found in endothelial cells and inflammatory cells that appeared in the perivascular space of intramural coronary arteries and at sites of lost cardiomyocytes in both ventricles. Coincident in time and space with these events was increased mRNA expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. Macrophages, lymphocytes, and proliferating endothelial and vascular smooth muscle cells and fibroblast-like cells were seen at each of these sites, together with an accumulation of fibrillar collagen, or fibrosis, as evidenced by a significant increase in ventricular collagen volume fraction. Co-treatment with spironolactone, PDTC, or NAC attenuated these molecular and cellular responses as well as the appearance of fibrosis at vascular and nonvascular sites of injury. Furthermore, elevated systolic blood pressure in ALDO-treated rats was partially suppressed by spironolactone or either antioxidant. Thus, chronic ALDO/salt treatment is accompanied by a time-dependent sustained activation of NADPH oxidase with 3-nitrotyrosine generation and nuclear factor-kappaB activation expressed by endothelial cells and inflammatory cells. This leads to a proinflammatory/fibrogenic phenotype involving vascular and nonvascular sites of injury found, respectively, in both normotensive and hypertensive right and left ventricles. Spionolactone, PDTC, and NAC each attenuated these responses suggesting ALDO/salt induction of oxidative/nitrosative stress is responsible for the appearance of this proinflammatory phenotype.     

Thioredoxin as a biomarker for oxidative stress in patients with rheumatoid arthritis

There is no doubt that oxidative stress occurs in patients with rheumatoid arthritis (RA) and play an important role in both inflammation and destruction of RA joints. Thioredoxin (TRX) is a ubiquitous redox-active protein and is known to be induced in several cells against oxidative stress and to be secreted extracellularly. To clarify whether plasma thioredoxin levels could be a marker for oxidative stress in patients with RA, we measured plasma TRX levels in patients with RA using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) and investigated its relationship to TRX concentrations in the inflammatory joints.We have found that the plasma TRX levels of RA patients were significantly higher than those of normal subjects (86.8 +/-54.1 ng/ml versus 38.6 +/-18.5 ng/ml, P<0.0001). The plasma levels were correlated with the disease activity of RA and also with serum C-reactive protein (CRP) values (P<0.01). The concentration of TRX in synovial fluid (SF) from RA was 353.3 +/- 220.1 ng/ml (mean +/- S.D.) which was significantly higher than that in SF from osteoarthritis patients (70.6 +/- 31.0 ng/ml, P<0.0001). The SF TRX concentration was significantly correlated with the number of leukocytes infiltrating in SF and with the serum CRP levels. The serum TRX levels were significantly positively correlated with the SF TRX concentrations in RA patients (P<0.05). By the histological examination for synovial tissue of RA patients, TRX was shown to be present on the surface of synovial lining layer as well as in the leukocytes.Moreover, urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage by endogenously generated oxygen radicals, was significantly higher in RA patients than in healthy subjects (11.55 +/- 4.71 versus 7.76 +/- 2.26 ng/mg creatinine, P<0.0001). Plasma TRX levels were significantly correlated with urinary excretion of 8-OHdG (P<0.005). We concluded that plasma TRX level is a new biomarker for the disease activity of RA and may reflect higher levels of oxidative stress in RA patients.     

Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria

Few studies have looked at optimal or acceptable serum phenylalanine levels in later life in patients with phenylketonuria (PKU). This study examined the oxidative stress status of adolescents and adults with PKU. Forty PKU patients aged over fifteen years were enrolled, and were compared with thirty age-matched controls. Oxidative stress markers, anti-oxidant enzyme activities in erythrocytes, and blood anti-oxidant levels were examined. Nitric oxide (NO) production was also examined as a measure of oxidative stress. Plasma thiobarbituric acid reactive species and serum malondialdehyde-modified LDL levels were significantly higher in PKU patients than control subjects, and correlated significantly with serum phenylalanine level (P<0.01). Plasma total anti-oxidant reactivity levels were significantly lower in the patient group, and correlated negatively with phenylalanine level (P<0.001). Erythrocyte superoxide dismutase and catalase activities were higher and correlated significantly with phenylalanine level (P<0.01). Glutathione peroxidase activity was lower and correlated negatively with phenylalanine level (P<0.001). The oxidative stress score calculated from these six parameters was significantly higher in patients with serum phenylalanine of 700-800 μmol/l. Plasma anti-oxidant substances, beta-carotene, and coenzyme Q(10) were also lower (P<0.001), although the decreases did not correlate significantly with the phenylalanine level. Serum nitrite/nitrate levels, as stable NO products, were higher together with low serum asymmetric dimethylarginine, as an endogenous NO inhibitor. Oxidative stress status is closely linked with serum phenylalanine levels. Phenylalanine level in should be maintained PKU below 700-800 μmol/l even in adult patients.     

Dubowitz syndrome: possible evidence for a clinical subtype

Clinico-genetic analysis of 21 personal observations and review of the literature confirmed the existence of a wide phenotypic spectrum of Dubowitz syndrome. It is shown that in spite of marked microcephaly, severe mental deficiency is rare in Dubowitz syndrome and about half of the patients are mentally normal. A "new" clinical subtype is defined, which also includes anorectal anomalies and premature craniosynostosis. All three families with this form are natives of a small area of Byelorussia, suggesting an autosomal or X-linked recessive mode of inheritance of this subtype. The data obtained confirm autosomal recessive inheritance of Dubowitz syndrome.     

Pseudomonas aeruginosa-induced lung injury: role of oxidative stress.

Pseudomonas aeruginosa is a Gram-negative pathogen that can cause lung injury in immunocompromised patients, primarily by inducing a release of host-derived mediators responsible for the influx of phagocytes to the lung. These phagocytes exert their antimicrobial actions by releasing toxic metabolites, including reactive oxygen species and proteases, which can also cause cell injury. This study was carried out to assess the pulmonary oxidant-antioxidant status of male adult Sprague-Dawley rats infected with different numbers of P. aeruginosa (10(4)-10(7)cfu/animal). Intratracheal instillation of P. aeruginosa resulted in lung injury, as evidenced by increases in wet lung weight and decreases in the lung activities of angiotensin converting enzyme and alkaline phosphatase, enzymes localized primarily in pulmonary endothelial and alveolar type II epithelial cells, respectively. The P. aeruginosa -induced lung injury was directly related to the infiltration of neutrophils, as indicated by increases in myeloperoxidase activity. The challenge of animals with P. aeruginosa resulted in increases in lipid peroxidation and decreases in glutathione content, which were associated with the indices of lung injury and neutrophil infiltration. Such a challenge also resulted in weakening the antioxidant defence system, as evidenced by decreases in superoxide dismutase, catalase and glutathione peroxidase activities. These data suggest that changes in the pulmonary oxidant-antioxidant status may play an important role in the P. aeruginosa -induced lung injury.     

The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome

BACKGROUND: Oxidative stress and hyperhomocysteinaemia are risk factors for cardiovascular diseases. The aim of this study was to assess the effects of rosiglitazone and metformin on cardiovascular disease risk factors such as insulin resistance, oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome (PCOS). METHODS: Fifty lean patients (BMI <25 kg/m2) with PCOS and 35 healthy subjects were included this study. Serum homocysteine, sex steroids, fasting insulin, fasting glucose and lipid levels were measured. Total antioxidant status (TAS; combines concentrations of individual antioxidants) and malonyldialdehyde concentration (MDA) were determined. Insulin resistance was evaluated by using the homeostasis model insulin resistance index (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Area under the curve insulin (AUCI) and the insulin sensitivity index (ISI). Patients were divided into two groups. One group was treated with metformin (n = 25) and the other received rosiglitazone (n = 25) for 12 weeks. All measurements were repeated at the end of 12 weeks. RESULTS: Compared with healthy women, those with PCOS had significantly elevated serum MDA, homocysteine, HOMA-IR, AUCI and lipoprotein a levels, and significantly decreased serum TAS, QUICKI and ISI. Serum free testosterone levels showed a significant positive correlation with MDA, AUCI and HOMA-IR, and a negative correlation with TAS, ISI and QUICKI in PCOS patients. HOMA-IR and AUCI significantly decreased, while QUICKI and ISI significantly increased after treatment in both groups. Serum TAS level increased and serum MDA level decreased after the rosiglitazone treatment, but these parameters did not change after the metformin treatment. Serum homocysteine and lipid levels did not change in either group, while serum androgen levels and LH/FSH ratio significantly decreased after the treatment period in only the rosiglitazone-treated group. CONCLUSION: Elevated insulin resistance, oxidative stress and plasma homocysteine levels and changes in serum lipid profile (risk factors for cardiovascular disease) were observed in lean PCOS patients. Rosiglitazone seemed to decrease elevated oxidative stress when compared with metformin treatment in lean PCOS patients.     

Experimental depression induces renal oxidative stress in rats

Depression has been associated to inflammatory and oxidative events. Previous report has shown renal oxidative stress in patients with depression. In order to analyze if depressive status is related to renal oxidative and inflammatory events, Sprague Dawley rats were submitted to forced swimming test (FST) and the renal oxidative metabolism, monocyte-macrophage infiltration and Angiotensin II (Ang II) expression were determined. Rats were submitted to FST daily (30 min) for 15 days. Motor activity was analyzed before FST. Kidney sections were homogenized to measure nitric oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH) and catalase activity by enzymatic and biochemical methods. Renal frozen sections were studied for superoxide anion (O₂-), monocyte/macrophage infiltration and Ang II expression by histochemical and immunofluorescence methods. In addition, three groups of FST rats were treated with losartan, sertraline or water for 18 days with further renal O₂-analysis. In the FST group, struggle time, motor activity, food intake and body weight gain were found decreased. Increased number of glomerular, interstitial and tubular O₂-positive cells was observed in FST rats. High renal content of nitrite/nitrate (NO), MDA and decreased amount of GSH were found in FST rats. Values of renal ED-1 or Ang II positive cells in FST rats remained similar to controls; however, AT1 receptor blocking (losartan) and sertraline reduced both depressive-like behavior and renal O₂-expression. These data suggests that depression-like behavior in rats is involved in kidney oxidative stress probably mediated by AT1 receptors.