Caterina Carollo

Diabetes mellitus: oxidative stress and wine

SUMMARY This review focuses on the link between diabetes mellitus and oxidative stress and, in particular, on the role that moderate wine consumption may play in preventing diabetic complications and the onset of diabetes. With this aim, a search of PubMed was carried out for literature published up to March In diabetes mellitus, oxidative stress results both from exposure to hyperglycaemia through glycoxidation and sorbitol system activation, and from functional limitation of the hexose monophosphate shunt, leading to a decrease in glutathione synthesis. Oxidative stress alters the plasma lipoprotein profile (particularly low- density lipoproteins), the coagulative parameters (with an increased thrombotic risk), the endothelium (with a decrease in prostacyclin synthesis and an increase of thromboxane production) and the cell membranes (which undergo peroxidation). In diabetic patients, an altered oxidative pattern is present not only in the fasting state but also especially after food intake. In particular, food intake induces a decrease in the total radical-trapping antioxidant parameter (TRAP) and an elevation of hydroperoxides and thiobarbituric acid reactive substances (TBARS). Previously several clinical trials tried to improve the diabetic oxidative status using α-tocopherol, ascorbic acid and β-carotene supplementation. Some authors found, in normal subjects, a reduction of hydroperoxides postprandially when the meal included red wine. Other authors showed that the oxidative pattern present in type 2 diabetic patients was mitigated by red wine. These actions may reduce cardiovascular risk. Moreover, an inverse relationship was observed between alcohol consumption and the incidence of type 2 diabetes; this relationship was valid for a light to moderate intake and it seemed to depend on drinking regularly and to be independent of the type of alcoholic beverage. In conclusion, moderate and regular wine consumption could ameliorate the diabetic oxidative status. This lifestyle measure might contribute to preventing diabetic complications and the onset of diabetes.

Wine, Diet, and Arterial Hypertension

Hypertension is one of the leading causes of death in developed countries, and the number of prehypertensive patients is increasing. The beneficial effects of moderate wine consumption on cardiovascular diseases have been demonstrated, along with the healthy influence of a Mediterranean dietary pattern. The association of these 2 factors on hypertension and its complications is considered here. As wine polyphenols exert a vasorelaxing action, they might positively influence the hemodynamic situation of these patients. These effects could be enhanced by dietary constituents, such as garlic, onions, and olive oil, which are widely employed in Mediterranean cooking. By evaluating many studies performed in animal models and in humans, the authors conclude that moderate wine consumption, if associated with a healthy dietary pattern, such as the Mediterranean one, could help hypertensive patients to ameliorate their arterial pressure and quality of life by reducing cardiovascular morbidity and mortality rates.

Chronic renal failure: oxidative stress, endothelial dysfunction and wine

Atherosclerosis development is accelerated in chronic renal failure (CRF) and is the major cause of death in this clinical condition. An increased oxidative stress and an endothelial dysfunction, with their complex interrelationships, are relevant aspects of atherogenesis in CRF patients and might be targets for treatment. Many studies have underlined the cardiovascular protection provided by a moderate wine consumption. This beneficial effect is due to both alcohol and nonalcoholic components of wine including several phenolic molecules such as quercetin and resveratrol. Wine polyphenols have antioxidant properties and favorably influence endothelial function, in particular by stimulating nitric oxide-mediated vasodilation and inhibiting the endothelin-1 pathway. The possible advantage of a moderate wine consumption in CRF patients can be hypothesized and deserves clinical investigation.

Granulocyte integrins before and after activation in acute ischaemic stroke.

We examined in 19 subjects with acute ischaemic stroke (AIS) the PMN integrin pattern (CD11a, CD11b, CD11c, CD18), using indirect immunofluorescence and adopting a flow cytometer, at baseline and during activation, prolonged for 5 and 15 min, with 4-phorbol 12-myristate 13-acetate (PMA). At baseline, an increase in the expression of CD11c and CD18 and a decrease in the CD11b were evident in AIS subjects compared to normals. After activation, we found in normals a constant and significant increase of all PMN adhesive molecules, while in AIS subjects, we found an increase in CD11b and CD18, a decrease in CD11a and no variation in CD11c. While the basal upregulation of CD11c and CD18 may depend on the PMN spontaneous activation or on the increase of cytokines, the decrease of CD11b may be due to its self-consumption. After activation, the decrease in CD11a noted in AIS may be related to its cleavage or to an altered integrin phosphorylation/dephosphorylation balance.

Polymorphonuclear Integrins, Membrane Fluidity, and Cytosolic Ca2+ Content After Activation in Essential Hypertension

The purpose of this research was to obtain further information about the role of polymorphonuclear leukocytes in essential hypertension. These cells could be involved in the pathogenesis of organ injury. Thirty subjects (14 men and 16 women) with essential hypertension were enrolled. In these subjects we determined, at baseline and after in vitro activation with 4-phorbol 12-myristate 13-acetate and N-formyl-methionyl-leucyl-phenylalanine, the polymorphonuclear leukocyte membrane fluidity, obtained by labeling the cells with 1-[4-(trimethylamino)phenyl]-6-phenyl-1,3,5-hexatriene, cytosolic Ca2+ concentration, obtained by marking the cells with Fura 2-AM, and integrin pattern (CD11a, CD11b, CD11c, and CD18), by using the indirect immunofluorescence with a flow cytometer. At baseline there was no difference in membrane fluidity between normal subjects and hypertensives, whereas hypertensives showed an increase in cytosolic Ca2+ content and an increase of the phenotypical expression of CD11a, CD11b, and CD18. In normal subjects and in hypertensives, after activation, no variation was found in membrane fluidity and cytosolic Ca2+ content. In normal subjects, after activation, we observed a significant increase of the expression of all adhesion molecules, whereas in hypertensives we found an increase of the expression of CD11b, CD11c, and CD18 but also a decrease of CD11a. The behavior of the polymorphonuclear leukocyte integrin profile may have several explanations, and in particular, the trend of CD11a after chemotactic activation may be related to its cleavage or to an altered integrin phosphorylation/dephosphorylation balance hypothetically present in this clinical condition.

Nitric oxide metabolites and oxidative stress in mild essential hypertension

Many papers have showed non univocal data about oxidative stress status and nitric oxide metabolites in essential hypertension. Considering this preamble we examined the total antioxidant status (TAS), the lipid peroxidation (LP), expressed as thiobarbituric acid-reactive substances (TBARS), the stable end products of nitric oxide (NOx) and LP/NOx ratio in 25 subjects with untreated mild essential hypertension. The obtained data show a significant increase in TBARS (p < 0.001) and NOx (p < 0.001) in hypertensives and no variation in TAS and in TBARS/NOx ratio. None of these parameters was statistically related to the metabolic parameters or to the blood pressure values. The high level of lipid peroxidation observed in this group of hypertensives suggests the timely and specific employment of antihypertensive and antioxidant agents while the NOx increase seems to confirm the inflammatory status accompanying this clinical condition.

Elastase, myeloperoxidase, nitric oxide metabolites and oxidative status in subjects with clinical stable chronic renal failure on conservative treatment

We evaluated, in a group of 41 CRF undialyzed subjects (29 men and 12 women, mean age 64.1 +/- 11.3 years), some parameters that reflect leukocyte activation (elastase, myeloperoxidase - MPO), plasma NO metabolites (NO(x)) and the oxidative status (lipid peroxidation expressed as thiobarbituric acid-reactive substances (TBARS) and total antioxidant status (TAS). Elastase was determined, on plasma separated from fasting venous blood, as elastase/alpha1-proteinase inhibitor complex. MPO was evaluated employing the Myeloperoxidase ELISA kit. The NO production was evaluated by a micromethod. The oxidation of polyunsaturated fatty acids was evaluated in plasma by detection of the thiobarbituric acid-reactive substances (TBARS). Total antioxidant status was measured by spectrophotometry. We found a significant increase of elastase, TBARS and NO(x), without any significant variation of MPO and TAS. In this group of CRF subjects, no statistical correlation was found between these examined parameters, creatinine level, creatinine clearance, leukocyte count and hemoglobin level. These findings need to be underlined if we consider that chronic renal failure is an inflammatory condition and this research furtherly supports literature data regarding the role of activated leukocytes in the development of the vascular complications. These observations explain why the examination of leukocyte count and function could become a tool to verify the clinical outcome in these patients.

Screening and study enrolment in the Randomized Evaluation of Normal vs. Augmented Level (RENAL) Replacement Therapy Trial

Background and Objectives: Aspects of trial design, screening and study efficiency can affect recruitment and the findings of the trial itself. A clear understanding of the screening and study inclusion process will assist clinicians in interpreting trial results. Design: Prospective observational data collection on all patients screened for possible inclusion in a randomized controlled trial of normal vs. augmented renal replacement therapy in critically ill patients (the RENAL Trial). Setting: 35 hospitals in Australia and New Zealand. Participants: All patients screened for the RENAL Trial. Results: We screened 4,551 patients. Of these patients, 767 were ineligible because of lack of inclusion criteria and 2,085 because of exclusion criteria. Of the remaining 1,699, 1,508 (88.7%) were enrolled. The three most common exclusion criteria which prevented recruitment of potentially eligible patients were that the patient had end-stage kidney failure and was already on chronic dialysis (484; 23.2%), the patient’s body weight was either <60 or >120 kg (456; 21.8%), and the fact that the patient had already received renal replacement therapy during the index admission. Important modifiable impediments to recruitment were inability to obtain consent in 191 cases, unavailability of research staff in 124 cases, physician objection in 89 cases, and inability to deliver the trial protocol in 78 cases. Conclusion: The RENAL Trial’s enrolment efficiency was high and compared favourably with previous large intensive care units trials and with that of trials in patients with acute renal failure. The high rate of enrolment suggests that the results can be applied with confidence to most patients with de novo acute renal failure. The loss of close to 1.5% of patients due to consent issues highlights a common problem in critical care trials. The low rate of physician objection suggests clinical equipoise.

Nitric oxide metabolites, leukocyte activation markers and oxidative status in dialyzed subjects.

Aims: Our purpose was to evaluate, in a group of 42 end-stage renal disease patients who regularly undergo hemodialysis, some indexes of leukocyte activation, nitric oxide metabolites (NOx) and other parameters that reflect the oxidative stress before and after a standard hemodialysis session. Methods: Elastase and myeloperoxidase (MPO) were determined by means of ELISA. The NO production was evaluated by a micromethod which measures the concentration of NOx. The oxidation of polyunsaturated fatty acids was evaluated in plasma by detection of thiobarbituric acid-reactive substances (TBARS). Total antioxidant status (TAS) was obtained using spectrophotometry. Results: At baseline, we observed an increase of elastase, NOx, TBARS and TAS, without any variation of MPO. After the dialysis session, we found an increase in elastase and MPO, a decrease in NOx and TAS and no variation in TBARS. No modification occurred after subdividing the patients in two subgroups. Conclusions: Our data confirm the involvement of leukocytes and oxidative stress in hemodialysis patients.

Nitric oxide metabolites (nitrite and nitrate) in several clinical condition

We determined the concentration of nitric oxide metabolites (NO2-+NO3-), expressed as NOx, in several clinical conditions. Regarding this, we have examined 25 subjects with arterial hypertension, 41 subjects with chronic kidney disease in conservative treatment, 106 subjects with metabolic syndrome subdivided according to the presence (n = 43) or not (n = 63) of diabetes mellitus, 48 subjects with obstructive sleep apnea syndrome (OSAS), 14 women with systemic sclerosis complicated with Raynauds phenomenon, 42 dialyzed subjects and 105 young subjects with acute myocardial infarction (AMI). In subjects with arterial hypertension, chronic kidney disease, metabolic syndrome, systemic sclerosis, as well as, in dialyzed and AMI subjects, we found at baseline a NOx increase. In dyalized subjects after a standard dialysis session, we observed a decrease in NOx. The increase in NOx in juvenile AMI was significantly influenced by cigarette smoking and less by cardiovascular risk factors and the extent of coronary lesions; at 3 and 12 months later than the initial event, we observed a decrease of NOx that remains significantly higher than the control group. In subjects with OSAS no difference in NOx was noted in comparison with normal controls, although their subdivision according to the apnea/hypopnea index operates a clear distinction regarding NOx concentration.