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Biomedical subjects

Cesar G Fraga

Publications and source records attributed to Cesar G Fraga.

17 recordsLinked to original sources
PubMed2007

The interaction between the renin-angiotensin system and peroxisome proliferator activated receptors: a hypothesis including the participation of mitochondria in aging.

The objective of improving health is intimately associated with preventing and delaying age-related diseases. Nutritional and pharmacological approaches aimed at retarding aging are uncovering mechanisms, whose definitive roles in cell and tissue physiology need to be defined. In this article we hypothesize that peroxisome proliferator activated receptor (PPAR)-modulation is a pivotal process that underlies the association between mitochondria and the renin-angiotensin system (RAS) in aging. This hypothesis is based on several lines of evidence suggesting that: a) mitochondrial function and oxidant production are active participants in the aging process; b) PPARs, by regulating mitochondrial function and uncoupling proteins (UCP), seem to play a major role in the age-retarding effects of caloric restriction; c) RAS inhibition delays the deleterious effects of aging and also upregulates PPARs; and d) a number of physiological and molecular events that occur in experimental caloric restriction, and experimental and clinical RAS inhibition, involve changes in mitochondrial functions.

Aging↗
PubMed2006

Mitochondrial function and nitric oxide metabolism are modified by enalapril treatment in rat kidney.

The renal and cardiac benefits of renin-angiotensin system (RAS) inhibition in hypertension exceed those attributable to blood pressure reduction, and seem to involve mitochondrial function changes. To investigate whether mitochondrial changes associated with RAS inhibition are related to changes in nitric oxide (NO) metabolism, four groups of male Wistar rats were treated during 2 wk with a RAS inhibitor, enalapril (10 mg x kg(-1) x day(-1); Enal), or a NO synthase (NOS) inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) (1 mg x kg(-1) x day(-1)), or both (Enal+L-NAME), or were untreated (control). Blood pressure and body weight were lower in Enal than in control. Electron transfer through complexes I to III and cytochrome oxidase activity were significantly lower, and uncoupling protein-2 content was significantly higher in kidney mitochondria isolated from Enal than in those from control. All of these changes were prevented by L-NAME cotreatment and were accompanied by a higher production/bioavailability of kidney NO. L-NAME abolished mitochondrial NOS activity but failed to inhibit extra-mitochondrial kidney NOS, underscoring the relevance of mitochondrial NO in those effects of enalapril that were suppressed by L-NAME cotreatment. In Enal, kidney mitochondria H(2)O(2) production rate and MnSOD activity were significantly lower than in control, and these effects were not prevented by L-NAME cotreatment. These findings may clarify the role of NO in the interactions between RAS and mitochondrial metabolism and can help to unravel the mechanisms involved in renal protection by RAS inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Procyanidins protect Caco-2 cells from bile acid- and oxidant-induced damage.

Procyanidins can exert cytoprotective, anti-inflammatory, and anticarcinogenic actions in the gastrointestinal tract. Previous evidence has shown that procyanidins can interact with synthetic membranes and protect them from oxidation and disruption. Thus, in this study we investigated the capacity of a hexameric procyanidin fraction (Hex) isolated from cocoa to protect Caco-2 cells from deoxycholic (DOC)-induced cytotoxicity, cell oxidant increase, and loss of monolayer integrity. Hex interacted with the cell membranes without affecting their integrity, as evidenced by a Hex-mediated increase in the transepithelial electrical resistance, and inhibition of DOC-induced cytotoxicity. DOC induced an increase in cell oxidants, alterations in the paracellular transport, and redistribution of the protein ZO-1 from cell-cell contacts into the cytoplasm. Hex partially inhibited all these events at concentrations ranging from 2.5 to 20 microM. Similarly, Hex (5-10 microM) inhibited the increase in cell oxidants, and the loss of integrity of polarized Caco-2 cell monolayers induced by a lipophilic oxidant (2,2'-azobis (2,4-dimethylvaleronitrile). Results show that the assayed procyanidin fraction can interact with cell membranes and protect Caco-2 cells from DOC-induced cytotoxicity, oxidant generation, and loss of monolayer integrity. At the gastrointestinal tract, large procyanidins may exert beneficial effects in pathologies such us inflammatory diseases, alterations in intestinal barrier permeability, and cancer.

Azo Compounds↗
PubMed2006

Inhibition of angiotensin converting enzyme activity by flavanol-rich foods.

Angiotensin converting enzyme (ACE) activity was evaluated in the presence of flavanol-rich foods, i.e., wines, chocolates, and teas, and of purified flavonoids. All foods assayed inhibited ACE activity, red wines being more effective than white wine, and green tea more effective than black tea. The inhibition of ACE activity was associated with both phenolic and flavanol content in the foods. When isolated polyphenols were assayed, procyanidins (dimer and hexamer) and epigallocatechin significantly inhibited enzyme activity; similar concentrations of (+)-catechin, (-)-epicatechin, gallic acid, chlorogenic acid, caffeic acid, quercetin, kaempferol, and resveratrol were ineffective. When ACE activity was assayed in rat kidney membranes in the presence of chocolate extracts or purified procyanidins, it was observed that the inhibition depended on the chocolate content of flavanols and the number of flavanol units constituting the procyanidin. These experiments demonstrate that flavanols either isolated or present in foods could inhibit ACE activity. The occurrence of such inhibition in vivo needs to be determined, although is supported by the association between the consumption of flavanol-rich foods and reductions in blood pressure observed in several experimental models.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Cardioprotective effect of resveratrol via HO-1 expression involves p38 map kinase and PI-3-kinase signaling, but does not involve NFkappaB.

Recent studies have demonstrated that resveratrol (trans-3,4',5-trihydroxy stilbene), a phytoalexin found in the skin and seeds of grapes, can pharmacologically precondition (PC) the heart through a nitric oxide (NO)-dependent and adenosine receptors-mediated mechanism. Since NO can induce the expression of heme oxygenase-1 (HO-1), we examined if HO-1 induction has a direct role in resveratrol-preconditioning of the heart. Eight groups of rats were studied during 7 days: (i) control rats; (ii) rats receiving resveratrol (gavage, 2.5 mg/kg); (iii) rats injected tin protoporphyrin (SnPP), a HO-1 inhibitor, i.p. on days 1, 3 and 6; (iv) rats injected 202190 (SB), a p38MAPK inhibitor, i.p. for 7 days; (v) rats injected 294002 (LY), a Akt inhibitor, i.p. for 7days; (vi) rats receiving resveratrol and SnPP; (vii) rats receiving resveratrol and SB; and (viii) rats receiving resveratrol and LY. After the treatments, the rats were sacrificed, and the hearts isolated and subjected to 30 min global ischemia followed by 2 h of reperfusion. The results shown a significant cardioprotection with resveratrol as evidenced by superior post-ischemic ventricular recovery, reduced myocardial infarct size, and decreased number of apoptotic cardiomyocytes. SnPP treatment abolished the cardioprotective effect of resveratrol. Resveratrol induced the activation of nuclear factor kappa-beta(NFkappaB), the phosphorylation of p38MAP kinase beta and Akt, as well as the inhibition of p38 MAP kinase alpha; all these effects but the activation of NFkappaB, were completely reversed by treatment with SnPP. These results indicate that resveratrol generates cardioprotection by preconditioning the heart by HO-1-mediated mechanisms, which are regulated by p38MAP kinase and Akt survival signaling, but non-dependent on NFkappaB activation.

Animals↗
PubMed2005

Procyanidin structure defines the extent and specificity of angiotensin I converting enzyme inhibition.

Recent reports have shown a decrease in blood pressure associated with the consumption of flavanol-containing foods. However, the mechanism behind this effect is not yet known. Previously we demonstrated that the flavanol epicatechin and its related oligomers, the procyanidins, inhibit angiotensin I converting enzyme (ACE) activity in vitro. In this study, we further characterized epicatechin monomer, dimer, tetramer and hexamer ACE inhibitory effect, by performing fluorescence quenching and kinetic assays, using angiotensin I as substrate. Assessment of ACE activity in cultured human umbilical vein endothelial cells (HUVEC) indicated that the tetramer was the most active inhibitor decreasing the formation of angiotensin II by 52% (P<0.001). When ACE activity was measured using isolated rabbit lung ACE, dimer, tetramer and hexamer inhibited angiotensin II production at IC(50) values of 97.0, 4.4, and 8.2 microM, respectively. The quenching of ACE tryptophan fluorescence was assayed to evaluate the molecular interaction between ACE and procyanidins. The hexamer was the most active quencher decreasing ACE fluorescence by 56%, followed by the tetramer and the dimer, decreasing ACE fluorescence by 37% and 36%, respectively. ACE activity was evaluated in the presence of different concentrations of the ACE activator chloride ion (Cl(-)). Increased Cl(-) concentrations reduced IC(50) values for the dimer and tetramer. Finally, ACE inhibition was determined in the presence of different albumin concentrations. The presence of albumin did not reverse the ACE inhibition by dimer and tetramer, but decreased hexamer inhibition by 65%. In summary, the inhibitory effect of procyanidins on ACE and the extent of this inhibition were largely dependent on procyanidin structure. ACE inhibition by procyanidins in vivo might provide a mechanism to explain the benefits of flavonoid consumption on cardiovascular diseases.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2005

Regular consumption of a flavanol-rich chocolate can improve oxidant stress in young soccer players.

The consumption of a diet rich in certain flavonoids, including the flavanol sub-class, has been associated with a reduced risk for vascular disease. We evaluated the effects of the regular consumption (14 d) of a flavanol-containing milk chocolate (FCMC) or cocoa butter chocolate (CBC) on variables related to vascular disease risk, oxidative stress and physical activity. Twenty-eight free-living, young (18-20 years old) male soccer players consumed daily 105 g of FCMC (168 mg of flavanols) or CBC (< 5 mg of flavanols), as part of their normal diet. The consumption of FCMC was significantly associated with a decrease in diastolic blood pressure (- 5 mm Hg), mean blood pressure (- 5 mm Hg), plasma cholesterol (-11%), LDL-cholesterol (-15%), malondialdehyde (- 12%), urate (- 11%) and lactate dehydrogenase (LDH) activity (- 11%), and an increase in vitamin E/cholesterol (+ 12%). No relevant changes in these variables were associated with CBC consumption. No changes in the plasma levels of (-)-epicatechin were observed following analysis of fasting blood samples. In conclusion, FCMC consumption was associated with changes in several variables often associated with cardiovascular health and oxidant stress. The presence of significant quantities of flavanols in FCMC is likely to have been one of the contributing factors to these results.

Adolescent↗
PubMed2004

The regular supplementation with an antioxidant mixture decreases oxidative stress in healthy humans. Gender effect.

BACKGROUND: Antioxidant consumption is claimed to be associated with improved antioxidant defenses and with the prevention of free radical-associated diseases. We evaluated if the regular supplementation with an antioxidant mixture modified oxidative stress parameters in healthy humans. METHODS: Malondialdehyde (MDA), vitamin E (alpha-tocopherol), beta-carotene, and ubiquinol-10 were determined in plasma by HPLC; plasma 2-thiobarbituric acid reactive substances (TBARS) were evaluated fluorometrically. The supplement contained 106 IU vitamin E, 10 mg beta-carotene, 60 mg coenzyme Q-10, and 40 microg selenium. RESULTS: After a 10-day wash out period, 16 healthy, free-living adults (31-48 years old; 9 women, 7 men) consumed the supplement daily during 30 days. At day 20, plasma concentration of vitamin E (alpha-tocopherol), beta-carotene, and ubiquinol-10 increased 45%, 66%, and 104%, respectively, over baseline values. Plasma MDA concentrations were reduced at days 20 (25%) and 30 (32%). Plasma TBARS concentrations decreased steadily during the treatment, reaching at day 30 an 11% decrease compared to baseline. Segregating by gender, both MDA and TBARS plasma concentrations were higher in men than in women at baseline. However, such differences disappeared after 30 days of supplementation. CONCLUSION: The observed modifications in variables associated with oxidative stress are indicative of an effective antioxidant action of the used mixture of lipid soluble compounds, and gender differences suggest that men should optimize their antioxidants defenses earlier in life than women.

Adult↗
PubMed2003

Inhibition of angiotensin converting enzyme (ACE) activity by flavan-3-ols and procyanidins.

It was determined that flavan-3-ols and procyanidins have an inhibitory effect on angiotensin I converting enzyme (ACE) activity, and the effect was dependent on the number of epicatechin units forming the procyanidin. The inhibition by flavan-3-ols and procyanidins was competitive with the two substrates assayed: N-hippuryl-L-histidyl-L-leucine (HHL) and N-[3-(2-furyl)acryloyl]-L-phenylalanylglycylglycine (FAPGG). Tetramer and hexamer fractions were the more potent inhibitors, showing Ki of 5.6 and 4.7 microM, respectively. As ACE is a membrane protein, the interaction of flavanols and procyanidins with the enzyme could be related to the number of hydroxyl groups on the procyanidins, which determine their capacity to be adsorbed on the membrane surface.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Enalapril and losartan attenuate mitochondrial dysfunction in aged rats.

Renin-angiotensin system (RAS) inhibition can attenuate the effects of aging on renal function and structure; however, its effect on mitochondrial aging is unknown. To investigate whether an angiotensin-converting enzyme inhibitor (enalapril) or an angiotensin II receptor blocker (losartan) could mitigate age-associated changes in kidney mitochondria, male Wistar rats (14 mo old) received during 8 mo water containing either enalapril (10 mg/kg/day) (Enal), or losartan (30 mg/kg/day) (Los), or no additions (Old). Four-month-old untreated rats (Young) were also studied. In Old rats mitochondrial respiratory control, ADP/O, nitric oxide synthase activity, and uncoupling protein 2 levels were lower (46, 42, 27, and 76%, respectively), and Mn-SOD activity was higher (70%) than in Young, Enal, and Los rats. In Old rats mitochondrial hydrogen peroxide production was higher than in both Young (197%) and Enal or Los (40%) rats. In Old rats, kidney GSH/GSSG was lower than in both Young (80%) and Enal (57%) or Los (68%) rats. In Old rats electron microscopy showed effacement of microvilli in tubular epithelial cells, ill-defined mitochondrial cristae, lower mitochondrial numbers, and enhanced number of osmiophilic bodies relative to Young, Enal, or Los rats. In conclusion, enalapril and losartan can protect against both age-related mitochondrial dysfunction and ultrastructural alterations, underscoring the role of RAS in the aging process. An association with oxidative stress modulation is suggested.

Aging↗
PubMed2002

Iron toxicity and antioxidant nutrients.

Iron is an essential nutrient for the growth, development, and long-term survival of most organisms. High tissue iron concentrations have been associated with the development and progression of several pathological conditions, including certain cancers, liver and heart disease, diabetes, hormonal abnormalities, and immune system dysfunctions. In this review we discuss the relevance of iron toxicity on free radical-mediated tissue damage, and how iron interactions with nutrient antioxidants and other metals can affect the extent of oxidative damage to different biomolecules. It can be concluded that the ingestion of antioxidant rich foods may prevent or delay primary and secondary effects associated with iron overload-related diseases.

Animals↗
PubMed2002

Influence of flavan-3-ols and procyanidins on UVC-mediated formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine in isolated DNA.

The flavan-3-ols (-)-epicatechin (epicatechin) and (+)-catechin (catechin) and their related oligomers (procyanidins) isolated from cocoa were assayed for their capacity to inhibit the UVC-mediated formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (oxo(8)dG) in calf thymus DNA. The above-mentioned compounds inhibited oxo(8)dG production in a concentration- and time-dependent manner. After 30 min of irradiation (30 kJ/m(2)), 0.1, 1.0, 10, and 100 microM epicatechin inhibited oxo(8)dG formation by 20, 36, 64, and 74%, respectively. For the same dose of UVC, 0.1, 1.0, 10, and 100 microM catechin inhibited oxo(8)dG formation by 1, 23, 50, and 70%, respectively. Epicatechin was more efficient than catechin with respect to inhibiting oxo(8)dG formation (IC(50) 1.7 +/- 0.7 vs 4.0 +/- 0.7 microM). Monomer, tetramer, and hexamer fractions were equally effective in inhibiting oxo(8)dG formation when assayed at 10 microM monomer equivalent concentration. At similar concentrations (1-50 microM), the inhibition of the UVC-mediated oxo(8)dG formation by flavan-3-ols and procyanidins was in the range of that of alpha-tocopherol, Trolox, ascorbate, and glutathione. These results support the concept that flavan-3-ols and their related procyanidins can protect DNA from oxidation at concentrations that can be physiologically relevant. Both epimerism and degree of oligomerization are important determinants of the antioxidant activity of flavan-3-ols and procyanidins.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

Procyanidin dimer B2 [epicatechin-(4beta-8)-epicatechin] in human plasma after the consumption of a flavanol-rich cocoa.

BACKGROUND: Epidemiologic studies have linked flavonoid-rich foods with a reduced risk of cardiovascular mortality. Some cocoas are flavonoid-rich and contain the monomeric flavanols (-)-epicatechin and (+)-catechin and oligomeric procyanidins formed from these monomeric units. Both the monomers and the oligomers have shown potential in favorably influencing cardiovascular health in in vitro and preliminary clinical studies. Although previous investigations have shown increasing concentrations of (-)-epicatechin in human plasma after cocoa consumption, no information is available in the published literature regarding the presence of procyanidins in human plasma. OBJECTIVE: This study sought to determine whether procyanidins can be detected and quantified in human plasma after acute consumption of a flavanol-rich cocoa. DESIGN: Peripheral blood was obtained from 5 healthy adult subjects before (baseline, 0 h) and 0.5, 2, and 6 h after consumption of 0.375 g cocoa/kg body wt as a beverage. Plasma samples were analyzed for monomers and procyanidins with the use of reversed-phase HPLC with coulometric electrochemical array detection and liquid chromatography-tandem mass spectrometry. RESULTS: Procyanidin dimer, (-)-epicatechin, and (+)-catechin were detected in the plasma of human subjects as early as 0.5 h (16 +/- 5 nmol/L, 2.61 +/- 0.46 micro mol/L, and 0.13 +/- 0.03 micro mol/L, respectively) after acute cocoa consumption and reached maximal concentrations by 2 h (41 +/- 4 nmol/L, 5.92 +/- 0.60 micro mol/L, and 0.16 +/- 0.03 micro mol/L, respectively). CONCLUSION: Dimeric procyanidins can be detected in human plasma as early as 30 min after the consumption of a flavanol-rich food such as cocoa.

Adult↗
PubMedDate not supplied

Concerted action of the renin-angiotensin system, mitochondria, and antioxidant defenses in aging.

Angiotensin-converting enzyme inhibitors (ACEi) and AT-1 receptor blockers (ARB) are two types of drugs that inhibit the renin-angiotensin system (RAS), and can attenuate the progression to cardiac and/or renal functional impairment, secondary to diverse pathologies. Some of the beneficial effects of ACEi and ARB occur independently of the ability of these drugs to reduce arterial blood pressure. Both, in animals, and in humans, we observed an enhancement of antioxidant defenses that occurred after treatment with ACEi. Based on these results, we postulate that some of the beneficial health effects associated to RAS inhibition can be ascribed to the prevention of oxidant-mediated damage. Furthermore, considering that: (i). RAS inhibition attenuates certain age-associated degenerative changes; (ii). aging was postulated to result from the accumulation of oxidant-mediated damage; and (iii). mitochondria are a major source of oxidants, we studied potential associations among RAS inhibition, mitochondrial function and production of oxidants and nitric oxide, and aging. The results obtained suggest, that RAS inhibitors, i.e. enalapril and losartan, can protect against the effects of aging by attenuating oxidant damage to mitochondria, and in consequence, they preserve mitochondrial function. The mechanism(s) explaining such attenuation of oxidant damage can relay on a reduction of the ANG-II-dependent generation of superoxide and/or an increased detoxification of reactive nitrogen and oxygen species by recomposition of antioxidant defense levels.

Aging↗
PubMedDate not supplied

Relevance, essentiality and toxicity of trace elements in human health.

The metals Mn, Fe, Cu, and Zn, and the non-metal Se are considered "trace elements" (TE) because of their essentiality and very limited quantity in humans. The biological activities of Cu, Fe, Mn, and Se are strongly associated with the presence of unpaired electrons that allow their participation in redox reactions. In biological systems these metals are mostly bound to proteins, forming metalloproteins. Many of the metals in metalloproteins are part of enzymatic systems, have structural and storage functions, or use the protein to be transported to their target site in the organism. In humans Mn, Fe, Cu, Zn, and Se accomplish decisive functions to maintain human health. Deficiency in any of these TE leads to undesirable pathological conditions that can be prevented or reversed by adequate supplementation. In sufficiently nourished persons, supplementation should be carefully controlled, given the toxic effects ascribed to TE when present in quantities exceeding those required for accomplishing their biological functions. The dietary reference intakes provided by national regulatory agencies are guides to define intake, supplementation and toxicity of Mn, Fe, Cu, Zn, and Se, as well other elements considered micronutrients for humans.

Dietary Supplements↗