Curcumin Prevents Renal Damage of l-NAME Induced Hypertension in by Reducing MMP-2 and MMP-9.

In the present study, we investigated whether curcumin administration would interfere with the main renal features of l-NAME-induced hypertension model. For this purpose, we conducted both in vitro and in vivo experiments to evaluate renal indicators of inflammation, oxidative stress, and metalloproteinases (MMPs) expression/activity. Hypertension was induced by l-NAME (70 mg/kg/day), and Wistar rats from both control and hypertensive groups were treated with curcumin (50 or 100 mg/kg/day; gavage) or vehicle for 14 days. Blood and kidneys were collected to determine serum creatinine levels, histological alterations, oxidative stress, MMPs expression and activity, and ED1 expression. l-NAME increased blood pressure, but both doses of curcumin treatment reduced these values. l-NAME treatment increased creatinine levels, glomeruli area, Bowman's space, kidney MMP-2 activity, as well as MMP-9 and ED1 expression, and reduced the number of glomeruli. Curcumin treatment prevented the increase in creatinine levels, MMP-2 activity, and reduced MMP-2, MMP-9, ED1, and superoxide levels, as well as increased superoxide dismutase activity and partially prevented glomeruli alterations. Moreover, curcumin directly inhibited MMP-2 activity in vitro. Thus, our main findings demonstrate that curcumin reduced l-NAME-induced hypertension and renal glomerular alterations, inhibited MMP-2 and MMP-9 expression/activity, and reduced oxidative stress and inflammatory processes, which may indirectly impact hypertension-induced renal outcomes.

Sarcoplasmic reticulum calcium ATPase (SERCA) proteolysis by matrix metalloproteinase-2 contributes to vascular dysfunction in early hypertension.

AIMS: Hypertension is associated with an increased activity of matrix metalloproteinase (MMP)-2 in the vasculature, which, in turn, proteolyzes extra- and intracellular proteins that lead to vascular dysfunction. The activity of sarcoplasmic reticulum calcium ATPase (SERCA) is decreased in the aortas of hypertensive rats. Increased activity of MMP-2 proteolyzed SERCA in rat heart during ischemia and reperfusion injury, thus impairing cardiac function. Therefore, we examined whether increased activity of MMP-2 in early hypertension contributes to proteolyze SERCA in the aortas, thus leading to maladaptive vascular remodeling and dysfunction. MAIN METHODS: Male Sprague-Dawley rats were submitted to two kidney-one clip (2K-1C) or Sham surgery and treated with doxycycline. Systolic blood pressure (SBP) was assessed by tail-cuff plethysmography. After 7 days, aortas were collected for zymography assays, Western blot to SERCA, ATPase activity assay, vascular reactivity, Ki-67 immunofluorescence and hematoxylin/eosin stain. KEY FINDINGS: SBP was increased in 2K-1C rats and doxycycline did not reduce it, but decreased MMP-2 activity and prevented SERCA proteolysis in aortas. Cross sectional area, media to lumen ratio and Ki-67 were all increased in the aortas of hypertensive rats and doxycycline decreased Ki-67. In 2K-1C rats, arterial relaxation to acetylcholine was impaired and doxycycline ameliorated it. SIGNIFICANCE: doxycycline reduced MMP-2 activity in aortas of 2K-1C rats and prevented proteolysis of SERCA and its dysfunction, thus ameliorating hypertension-induced vascular dysfunction.

Vascular injury associated with ethanol intake is driven by AT1 receptor and mitochondrial dysfunction.

BACKGROUND: Renin-angiotensin (Ang II)-aldosterone system (RAAS) is crucial for the cardiovascular risk associated with excessive ethanol consumption. Disturbs in mitochondria have been implicated in multiple cardiovascular diseases. However, if mitochondria dysfunction contributes to ethanol-induced vascular dysfunction is still unknown. We investigated whether ethanol leads to vascular dysfunction via RAAS activation, mitochondria dysfunction, and mitochondrial reactive oxygen species (mtROS). METHODS: Male C57/BL6J or mt-keima mice (6-8-weeks old) were treated with ethanol (20% vol./vol.) for 12 weeks with or without Losartan (10 mg/kg/day). RESULTS: Ethanol induced aortic hypercontractility in an endothelium-dependent manner. PGC1α (a marker of biogenesis), Mfn2, (an essential protein for mitochondria fusion), as well as Pink-1 and Parkin (markers of mitophagy), were reduced in aortas from ethanol-treated mice. Disturb in mitophagy flux was further confirmed in arteries from mt-keima mice. Additionally, ethanol increased mtROS and reduced SOD2 expression. Strikingly, losartan prevented vascular hypercontractility, mitochondrial dysfunction, mtROS, and restored SOD2 expression. Both MnTMPyP (SOD2 mimetic) and CCCP (a mitochondrial uncoupler) reverted ethanol-induced vascular dysfunction. Moreover, L-NAME (NOS inhibitor) and EUK 134 (superoxide dismutase/catalase mimetic) did not affect vascular response in ethanol group, suggesting that ethanol reduces aortic nitric oxide (NO) and H2O2 bioavailability. These responses were prevented by losartan. CONCLUSION: AT1 receptor modulates ethanol-induced vascular hypercontractility by promoting mitochondrial dysfunction, mtROS, and reduction of NO and H2O2 bioavailability. Our findings shed a new light in our understanding of ethanol-induced vascular toxicity and open perspectives of new therapeutic approaches for patients with disorder associated with abusive ethanol drinking.

Orchiectomy but not adjuvant-induced arthritis induces structural modifications in rat aortas.

PURPOSE: This study aimed to verify whether Adjuvant-Induced Arthritis (AIA) and/or Orchiectomy (ORX) modify the expression of the Nox1, Nox2 and Nox4 isoforms, the endothelial function or the structure of rat aortas. METHODS: Sixty-three Wistar rats were distributed into four groups: 1) Control; 2) ORX; 3) AIA; 4) Orchiectomy plus to Arthritis-induction (ORX/AIA). Thus, 21 days after the onset of AIA (by intradermal injection of Mycobacterium tuberculosis), the presence of Nox1, Nox2 and Nox4, the acetylcholine (ACh)-induced relaxation and the media layer thickness were assessed in the aorta taken from these animals. RESULTS: The Nox1, Nox2 and Nox4 were immunostained in intima, media and adventitia layers of aortas taken from all studied groups and AIA apparently increased this immunostaining. These modifications of Nox1, Nox2 or Nox4 expression, however, were not confirmed by Western blotting. In addition, neither AIA nor ORX changed the endothelial function, but ORX increased the media layer thickness in the studied aortas. CONCLUSION: The present study showed weak clues of increased expression of Nox1, Nox2 and Nox4 as a result of AIA, as well as of Nox1 reduction caused by ORX. In addition, the endothelial function was not modified in the aortas of these animals by both AIA and/or ORX. On the other hand, ORX increased significantly the aorta media layer thickness in the studied animals, which was apparently mitigated by AIA.

Dengue virus infection induces inflammation and oxidative stress on the heart.

OBJECTIVE: Dengue fever is one of the most important arboviral diseases in the world, and its severe forms are characterised by a broad spectrum of systemic and cardiovascular hallmarks. However, much remains to be elucidated regarding the pathogenesis triggered by Dengue virus (DENV) in the heart. Herein, we evaluated the cardiac outcomes unleashed by DENV infection and the possible mechanisms associated with these effects. METHODS: A model of an adapted DENV-3 strain was used to infect male BALB/c mice to assess haemodynamic measurements and the functional, electrophysiological, inflammatory and oxidative parameters in the heart. RESULTS: DENV-3 infection resulted in increased systemic inflammation and vascular permeability with consequent reduction of systolic blood pressure and increase in heart rate. These changes were accompanied by a decrease in the cardiac output and stroke volume, with a reduction trend in the left ventricular end-systolic and end-diastolic diameters and volumes. Also, there was a reduction trend in the calcium current density in the ventricular cardiomyocytes of DENV-3 infected mice. Indeed, DENV-3 infection led to leucocyte infiltration and production of inflammatory mediators in the heart, causing pericarditis and myocarditis. Moreover, increased reactive oxygen species generation and lipoperoxidation were also verified in the cardiac tissue of DENV-3 infected mice. CONCLUSIONS: DENV-3 infection induced a marked cardiac dysfunction, which may be associated with inflammation, oxidative stress and electrophysiological changes in the heart. These findings provide new cardiac insights into the mechanisms involved in the pathogenesis triggered by DENV, contributing to the research of new therapeutic targets for clinical practice.

Interval or continuous aerobic exercise performed 3 days a week increases endothelium-dependent relaxation in female rats fed with fructose

Abstract Aim: We investigated the effects of continuous or interval aerobic exercise training on vascular reactivity of female rats fed with fructose. Methods: Female Wistar rats (8-wk old) were divided into: sedentary (SD), continuous training (CTR), and interval training (ITR). Moderate intensity training protocols consisted of running 3 days/week for 7 weeks. CTR ran 40 min at 30%-40% of the maximal speed (MS) and TRI consisted of 7 sets of 1 min at 70% of MS followed by 3 min at 35% of MS. Animals were fed with standard chow and fructose (10%) in drinking water. Concentration-response curves to acetylcholine and phenylephrine, and oxidative stress biomarkers, were determined in the aorta. Body weight gain, visceral fat, and plasma triglycerides and glucose were also evaluated. Results: Endothelium-dependent relaxation was significantly increased by both exercise regimens (CTR: Emax = 85 ± 6% and ITR: Emax = 84 ± 1%) compared to sedentary rats (SD: Emax = 62 ± 5%). The contractile maximal response was not different but phenylephrine potency was increased in CTR (pEC50: 8.41 ± 0.19) and reduced in ITR (pEC50: 7.06 ± 0.11) compared to SD (pEC50: 7.77 ± 0.08). In addition, the generation of superoxide was lower in trained groups as compared with sedentary (about −28% in CTR and −22% in ITR). TBARS and nitrate/nitrite levels were not modified. Compared to the SD group, ITR gained 39% less body weight and CTR has 29% less visceral fat. Glucose and triglycerides were not modified. Conclusion: CTR and ITR, carried out 3 days/week, were efficient to improve endothelium-dependent relaxation and reduce superoxide generation in the aorta from female rats fed with fructose.

Melatonin decreases circulating Trypanosoma cruzi load with no effect on tissue parasite replication.

Cardiac damage during the acute phase of Chagas disease (CD) is associated with an increase in pro-inflammatory markers and oxidative stress. Melatonin (MEL) has emerged as a promising therapy for CD due to its antioxidant and immunomodulatory properties; however, the protective action of MEL in the cardiac tissue, as well as its direct action on the parasite cycle, is not fully understood. We investigated the effects of MEL on heart parasitism in mice infected with Trypanosoma cruzi and also its effects on the parasitic proliferation in vitro. Our in vivo study showed that MEL reduced circulating parasitemia load, but did not control tissue (heart, liver, and spleen) parasitism in mice. MEL did not prevent the redox imbalance in the left ventricle of infected mice. Our in vitro findings showed that MEL did not inhibit parasites replication within cells, but rather increased their release from cells. MEL did not control parasitism load in the heart or prevent the cardiac redox imbalance induced by acute T. cruzi infection. The hormone controlled the circulating parasitic load, but within cells MEL accelerated parasitic release, a response that can be harmful.

Ethanol consumption increases renal dysfunction and mortality in a mice model of sub-lethal sepsis.

Chronic ethanol consumption and sepsis cause oxidative stress and renal dysfunction. This study aimed to examine whether chronic ethanol consumption sensitizes the mouse kidney to sub-lethal cecal ligation and puncture (SL-CLP) sepsis, leading to impairment of renal function by tissue oxidative and inflammatory damage. Male C57BL/6J mice were treated for 9 weeks with ethanol (20%, v/v) before SL-CLP was induced. Systolic blood pressure (SBP), survival rate, creatinine plasma, oxidative stress, and inflammatory parameters, inducible nitric oxide synthase (iNOS), cytokines, and metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) levels were evaluated. Chronic ethanol consumption increased SBP, plasma creatinine, O2.-, H2O2, lipid peroxidation, catalase activity, Nox4, IL-6, and TNF-α levels, and MMP-9/TIMP-1 ratio. SL-CLP decreased SBP, increased creatinine, lipid peroxidation, IL-6, TNF-α, nitrate/nitrite (NOx), and iNOS levels, and MMP-2/TIMP-2 ratio, and decreased catalase activity. SL-CLP mice previously treated with ethanol showed a similar decrease in SBP but higher mortality and creatinine levels than SL-CLP alone. These responses were mediated by increased O2-, lipid peroxidation, IL-6, TNF-α, NOx, iNOS, MMP-2, and MMP-9 levels, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios. Our findings demonstrated that previous oxidative stress and inflammatory damage caused by ethanol consumption sensitizes the kidney to SL-CLP injury, resulting in impaired kidney function and sepsis prognosis.

Chronic ethanol consumption compromises neutrophil function in acute pulmonary Aspergillus fumigatus infection.

Chronic ethanol consumption is a leading cause of mortality worldwide, with higher risks to develop pulmonary infections, including Aspergillus infections. Mechanisms underlying increased susceptibility to infections are poorly understood. Chronic ethanol consumption induced increased mortality rates, higher Aspergillus fumigatus burden and reduced neutrophil recruitment into the airways. Intravital microscopy showed decrease in leukocyte adhesion and rolling after ethanol consumption. Moreover, downregulated neutrophil activation and increased levels of serum CXCL1 in ethanol-fed mice induced internalization of CXCR2 receptor in circulating neutrophils. Bone marrow-derived neutrophils from ethanol-fed mice showed lower fungal clearance and defective reactive oxygen species production. Taken together, results showed that ethanol affects activation, recruitment, phagocytosis and killing functions of neutrophils, causing susceptibility to pulmonary A. fumigatus infection. This study establishes a new paradigm in innate immune response in chronic ethanol consumers.

Alcoholism is a chronic disease that has many damaging effects on the body. Over long periods, excessive alcohol intake weakens the immune system, putting consumers at increased risk of getting lung infections such as pneumonia. Some forms of pneumonia can be caused by the fungus Aspergillus fumigatus. This microbe does not tend to be a problem for healthy individuals, but it can be fatal for those with impaired immune systems. Here, Malacco et al. wanted to find out why excessive alcohol consumers are more prone to pneumonia. To test this, the researchers used two groups of mice that were either fed plain water or water containing ethanol. After 12 weeks, both groups were infected with Aspergillus fumigatus. The results showed that alcohol-fed mice were more susceptible to the infection caused by strong inflammation of the lungs. Normally, the immune system confronts a lung infection by activating a group of defense cells called neutrophils, which travel through the blood system to the infection site. Once in the right spot, neutrophils get to work by releasing toxins that kill the fungus. Malacco et al. discovered that after chronic alcohol consumption, neutrophils were less reactive to inflammatory signals and less likely to reach the lungs. They were also less effective in dealing with the infection. Neutrophil released fewer toxins and were thus less able to kill the microbial cells. These findings demonstrate for the first time how alcohol can affect immune cells during infection and pave the way for new possibilities to prevent fatal lung infections in excessive alcohol consumers. A next step would be to identify how alcohol acts on other processes in the body and to find a way to modulate or even revert the changes it causes.

Pyrrolidine dithiocarbamate reduces alloxan-induced kidney damage by decreasing nox4, inducible nitric oxide synthase, and metalloproteinase-2.

We examined the effect of the NFκB inhibitor pyrrolidine-1-carbodithioic acid (PDTC) on inducible nitric oxide synthase (iNOS), matrix metalloproteinase-2 (MMP-2) activity, and oxidative and inflammatory kidney damage in alloxan-induced diabetes. Two weeks after diabetes induction (alloxan-130 mg/kg), control and diabetic rats received PDTC (100 mg/kg) or vehicle for 8 weeks. Body weight, glycemia, urea, and creatinine were measured. Kidney changes were measured in hematoxylin/eosin sections and ED1 by immunohistochemistry. Kidney thiobarbituric acid reactive substances (TBARS), superoxide anion (O2-), and nitrate/nitrite (NOx) levels, and catalase and superoxide dismutase (SOD) activities were analyzed. Also, kidney nox4 and iNOS expression, and NFkB nuclear translocation were measured by western blot, and MMP-2 by zymography. Glycemia and urea increased in alloxan rats, which were not modified by PDTC treatment. However, PDTC attenuated kidney structural alterations and macrophage infiltration in diabetic rats. While diabetes increased both TBARS and O2- levels, PDTC treatment reduced TBARS in diabetic and O2- in control kidneys. A decrease in NOx levels was found in diabetic kidneys, which was prevented by PDTC. Diabetes reduced catalase activity, and PDTC increased catalase and SOD activities in both control and diabetic kidneys. PDTC treatment reduced MMP-2 activity and iNOS and p65 NFκB nuclear expression found increased in diabetic kidneys. Our results show that the NFκB inhibitor PDTC reduces renal damage through reduction of Nox4, iNOS, macrophages, and MMP-2 in the alloxan-induced diabetic model. These findings suggest that PDTC inhibits alloxan kidney damage via antioxidative and anti-inflammatory mechanisms.

Cytokine modulation, oxidative stress and thymic dysfunctions: Role of age-related changes in the experimental Trypanosoma cruzi infection: Age-related thymic dysfunctions and Trypanosoma cruzi infection.

Aging is linked with a thymic oxidative damage and some infectious diseases such as Chagas' disease may aggravate this process. The aim of this study was to evaluate the production of distinct cytokines as well as the antioxidant/oxidant status of the thymus and thymocytes populations during Trypanosoma cruzi (T. cruzi) infection. Young (5 weeks old) and aged (18 weeks old) male Wistar rats were inoculated with blood trypomastigotes forms of the Y strain of T. cruzi. On the 16th day after T. cruzi infection, increased concentrations of transforming growth factor ß (TGF-ß), interleukin (IL)-12, IL-17 were detected in aged infected subjects as compared to young infected ones. Interestingly, a reduction in the production of tumor necrose factor (TNF)-α was observed in aged infected rats when compared to young infected subjects. Aged-infected rats presented increased O2- levels, compared to young counterparts. Significant raise in the generation of O2- in aged infected animals, as compared to uninfected counterparts was observed. Up-regulated expression of Nox2 in the thymus of young and aged infected animals was observed. An increased SOD2 expression was detected in the thymus of young animals infected with T. cruzi, when compared to uninfected young rats. Aged animals showed reduced thymus weight and the number of thymocytes. Decreased percentages of SPCD4+ and SPCD8+T cells were detected in aged and control groups when compared to young counterparts. In summary, this is the first data to directly examine the influence of aging on age-related dysfunctions during the acute phase of experimental Chagas disease. Concerning to oxidative stress, it is clear from our analysis that aged infected rats suffer a more intense oxidative damage when compared to young and infected ones. Age and infection triggered a dynamic interplay of cytokines, oxidative stress and thymic dysfunctions which led to impaired response from aged and infected rats. Such findings may have significant functional relevance in therapeutic strategies in order to reestablish the thymic immunological function which occurs in aged and T. cruzi infected subjects.

Benefits of Ascorbic Acid in Association with Low-Dose Benznidazole in Treatment of Chagas Disease.

The acute phase of Chagas disease (CD) is characterized by high parasitic proliferation and intense inflammation, exacerbating the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive molecules are also increased by the metabolism of the nitroheterocyclic compounds benznidazole (BZ) and nifurtimox, the only drugs available for the treatment of CD. This oxidative environment, associated with the intracellular multiplication of Trypanosoma cruzi, leads to tissue destruction, triggering the pathogenic process. Both drugs have limited efficacy and serious side effects, which demonstrates the need to seek alternative therapies. Due to the difficulty in developing new drugs, reviewing therapeutic regimens appears advantageous, and the use of BZ in low doses associated with antioxidants, such as ascorbic acid (AA), would be a valid alternative to attenuate oxidative stress. In our in vivo studies, mice receiving the combination of 7.14 mg/kg of body weight/day AA and 10 mg/kg/day BZ10 (AA+BZ10) showed a reduction in parasitemia that was more effective than that with those receiving BZ or AA alone. The combined treatment was effective in decreasing intracellular ROS and lipid peroxidation in cardiac tissue. Histological and PCR analyzes showed that AA also reduced the cardiac parasitism. However, the greatest benefit was seen in AA+BZ10 group, since cardiac inflammation was significantly reduced. In addition, the combined therapy prevented the hepatic damage induced by the infection. Our findings suggest that AA combined with a low dose of BZ may improve the trypanocidal activity and attenuate the toxic effects of BZ. The decrease in oxidative damage and inflammation observed in mice treated with AA+BZ10 could result in increased cardioprotection.

Effects of melatonin on thymic and oxidative stress dysfunctions during Trypanosoma cruzi infection.

Although the exact etiology of Chagas disease is not completely elucidated, thymic atrophy and oxidative stress are believed to be important contributors to the pathogenesis during acute Trypanosoma cruzi (T. cruzi) infection. We hypothesized that exogenous melatonin, administered by gavage (5 mg/kg, p.o., gavage) to young (5 weeks old) and middle-aged (18 months old) male Wistar rats, would modulate thymic oxidative damage and reverse the age-related thymus regression during T. cruzi acute infection. Increased levels of superoxide anion (O2- ) were detected in the thymus of infected animals, and treatment with melatonin reverted this response. We found reduced TBARS levels as well as a significant increase in superoxide dismutase (SOD) activity in the thymus of all middle-aged melatonin-treated animals, infected or not with T. cruzi. Furthermore, melatonin increased the thymic expression of SOD1 and SOD2 in middle-aged control animals. Nox2 expression was not affected by melatonin treatment in young or middle-aged animals. Melatonin reverted the age-related thymic regression as revealed by the increase in thymus weight, total number of thymocytes, and reduction in age-related accumulation of double-negative thymocytes. This is the first report to directly examine the effects of melatonin treatment on the thymic antioxidant/oxidant status and thymic changes during T. cruzi infection. Our results revealed new antioxidant features that turn melatonin a potentially useful compound for the treatment of Chagas disease, a condition in which an excessive oxidative damage occurs.

Ageing is not associated with an altered immune response during Trypanosoma cruzi infection: Ageing and Trypanosoma cruzi infection.

The aims of this work were to evaluate the influence of ageing on the magnitude of the immune response in male Wistar rats infected with the Y strain of Trypanosoma cruzi (T. cruzi). Infected young animals displayed enhanced CD4+ T cells as compared to uninfected counterparts. Ageing also triggered a significant reduction in CD8+ T cells compared to young and uninfected groups. The percentage of spleen NKT cells was reduced for all groups, regardless of the infection status. Significant decreased B-cells was noted in aged controls and infected animals as compared to young counterparts. A significant decrease in MHC class II (RT1B) expression in all aged animals was observed, whether infected or not. The highest and significant levels of Thiobarbituric Acid Reactive Substances (TBARS) were noted in the aged and infected animals as compared to young-infected ones (16day). Consequently superoxide dismutase (SOD) activity was reduced for both control and infected aged animals. Significant elevation of 8-isoprostane levels was found in aged control and infected animals. Plasma glutathione (GSH) concentration was reduced in aged control animals, as well as, in the young infected animals. NO production was increased in both infected and uninfected aged animals compared to young infected and uninfected animals. Corticosterone levels were elevated in aged animals, whether infected or not. Thus, our results are inedited since the immune response is not worsened by the simple fact of animals being older. Ageing by itself triggered a damaged immune response as well as enhanced reactive oxygen species, when compared to young counterparts, but it did not contribute to impair the immune response of T. cruzi infected and aged rats.

NADPH Oxidase Plays a Role on Ethanol-Induced Hypertension and Reactive Oxygen Species Generation in the Vasculature.

AIMS: Investigate the role of NADPH oxidase on ethanol-induced hypertension and vascular oxidative stress. METHODS: Male Wistar rats were treated with ethanol (20% v/v). RESULTS: Apocynin (10 mg/kg/day, i.p.) prevented ethanol-induced hypertension. The increased contractility of endothelium-intact and endothelium-denuded aortic rings from ethanol-treated rats to phenylephrine was prevented by apocynin. Ethanol consumption increased superoxide anion (O2 (-)) generation and lipid peroxidation and apocynin prevented these responses. The decrease on plasma and vascular nitrate/nitrite (NOx) levels induced by ethanol was not prevented by apocynin. Treatment with ethanol did not affect aortic levels of hydrogen peroxide (H2O2) or reduced glutathione (GSH). Ethanol did not alter the activities of xanthine oxidase (XO), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Ethanol increased the expression of Nox1, PKCδ, nNOS, SAPK/JNK and SOD2 in the rat aorta and apocynin prevented these responses. No difference on aortic expression of Nox2, Nox4, p47phox, Nox organizer 1 (Noxo1), eNOS and iNOS was detected after treatment with ethanol. Ethanol treatment did not alter the phosphorylation of SAPK/JNK, p38MAPK, c-Src, Rac1 or PKCδ. CONCLUSIONS: The major new finding of our study is that the increased vascular generation of reactive oxygen species (ROS) induced by ethanol is related to increased vascular Nox1/NADPH oxidase expression. This mechanism is involved in vascular dysfunction and hypertension induced by ethanol. Additionally, we conclude that ethanol consumption induces the expression of different proteins that regulate vascular contraction and growth and that NADPH oxidase-derived ROS play a role in such response. SHORT SUMMARY: The key findings of our study are that ethanol-induced hypertension is mediated by NADPH oxidase. Moreover, increased vascular Nox1 expression is related to the generation of reactive oxygen species (ROS) by ethanol. Finally, ROS induced by ethanol increase the expression of the regulatory vascular proteins.

Interleukin-17, oxidative stress, and inflammation: role of melatonin during Trypanosoma cruzi infection.

Although the exact etiology of Chagas' disease remains unknown, the inflammatory process and oxidative stress are believed to be the main contributors to the dysfunction and pathogenesis during chronic Trypanosoma cruzi infection. Our hypothesis is that melatonin administered for 2 months daily could modulate the oxidative stress and the inflammatory response during the chronic infection. Flow cytometric analysis of macrophages and antigen-presenting cells (APC), expression of RT1B as well as LFA-1 and MCP-1 in CD4(+) and CD8(+) T cells and levels of interleukin-17A were assessed. The oxidative stress was evaluated through lipid peroxidation (LPO) analysis on the plasma of thiobarbituric acid-reactive substances (TBARS) and nitric oxide production. Decreased concentrations of nitrite and TBARS were found in infected and melatonin-treated animals, as well as a rising trend in the production of IL-17A as compared to infected and untreated counterparts. A significant decrease was found in the percentages of CD4(+) and CD8(+) T lymphocytes MCP-1 producers for infected and melatonin-treated rats. Reduced percentage of CD8(+) T cells producing LFA-1 was observed in control and melatonin-treated animals as compared to untreated rats. The cellular response of peritoneal APC cells and macrophages significantly dropped in infected and treated animals. As an endpoint, the use of antioxidant compounds such as melatonin emerges as a new and promising approach to control the oxidative stress during the chronic Chagas' disease partially mediated through the abrogation of LPO and the prevention of the inflammatory response and can be used for further investigation on treatment trials for other infectious diseases.

[Antidepressants: use, adherence and awareness among medical students]. / Antidepressivos: uso, adesão e conhecimento entre estudantes de medicina.

This study assessed the degree of adherence and drug-related awareness and opinions regarding the importance of guidance with respect to treatment among medical students who use antidepressants. It is a cross-sectional descriptive study, carried out in a public Medical School in the state of Sao Paulo, Brazil. Of the 289 students interviewed, 33 (11.4%) use or had already used antidepressants, with fluoxetine being the most prescribed. The nurse was not cited as being responsible for guidance on the antidepressant. Although most students had received guidance on antidepressants, they did not heed guidance and still had doubts regarding their use. There was a statistically significant association regarding the consumption of other drugs in addition to antidepressants and the existence of side effects, as well as regarding an increase of the dosage without medical consultation and the existence of such side effects. Actions are necessary to acknowledge the importance of the teaching of psychopharmacology in the training of the medical professional and for greater harmony between theory and practice.

Hypertension and chronic ethanol consumption: What do we know after a century of study?

The influences of life habits on the cardiovascular system may have important implications for public health, as cardiovascular diseases are among the leading causes of shorter life expectancy worldwide. A link between excessive ethyl alcohol (ethanol) consumption and arterial hypertension was first suggested early last century. Since then, this proposition has received considerable attention. Support for the concept of ethanol as a cause of hypertension derives from several epidemiologic studies demonstrating that in the general population, increased blood pressure is significantly correlated with ethanol consumption. Although the link between ethanol consumption and hypertension is well established, the mechanism through which ethanol increases blood pressure remains elusive. Possible mechanisms underlying ethanol-induced hypertension were proposed based on clinical and experimental observations. These mechanisms include an increase in sympathetic nervous system activity, stimulation of the renin-angiotensin-aldosterone system, an increase of intracellular Ca(2+) in vascular smooth muscle, increased oxidative stress and endothelial dysfunction. The present report reviews the relationship between ethanol intake and hypertension and highlights some mechanisms underlying this response. These issues are of interest for the public health, as ethanol consumption contributes to blood pressure elevation in the population.

Antidepressivos: uso, adesão e conhecimento entre estudantes de medicina / Antidepressants: use, adherence and awareness among medical students

Este estudo avaliou em estudantes de medicina que usam antidepressivos, o grau de adesão e conhecimento relacionados ao medicamento e a opinião sobre a importância da orientação no tratamento. Trata-se de estudo transversal e descritivo, realizado em uma Faculdade de Medicina pública paulista. Dos 289 alunos entrevistados, 33 (11,4%) utilizam ou já utilizaram antidepressivos, sendo a fluoxetina o mais prescrito. O enfermeiro não foi citado como responsável pela orientação sobre o antidepressivo. Embora a maioria dos estudantes tenha recebido orientações sobre antidepressivo, a maioria não aderia ao mesmo havendo, ainda, dúvidas quanto ao seu uso. Houve associação estatisticamente significativa quanto ao consumo de outros medicamentos além do antidepressivo e presença de efeitos colaterais e quanto ao aumento da dose sem consulta médica e presença dos referidos efeitos. São necessárias ações para valorização do ensino da psicofarmacologia na formação do profissional de medicina e para maior articulação entre teoria e prática profissional.

This study assessed the degree of adherence and drug-related awareness and opinions regarding the importance of guidance with respect to treatment among medical students who use antidepressants. It is a cross-sectional descriptive study, carried out in a public Medical School in the state of Sao Paulo, Brazil. Of the 289 students interviewed, 33 (11.4%) use or had already used antidepressants, with fluoxetine being the most prescribed. The nurse was not cited as being responsible for guidance on the antidepressant. Although most students had received guidance on antidepressants, they did not heed guidance and still had doubts regarding their use. There was a statistically significant association regarding the consumption of other drugs in addition to antidepressants and the existence of side effects, as well as regarding an increase of the dosage without medical consultation and the existence of such side effects. Actions are necessary to acknowledge the importance of the teaching of psychopharmacology in the training of the medical professional and for greater harmony between theory and practice.