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Essential Hypertension and Oxidative Stress: Novel Future Perspectives.
Franco, C, Sciatti, E, Favero, G, Bonomini, F, Vizzardi, E, Rezzani, R
International journal of molecular sciences. 2022;23(22)
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High blood pressure is one of the main risk factors for cardiovascular disease and a significant contributor to the development of strokes, heart attacks, and heart and kidney failure leading to early disability and reduced life expectancy. Essential or primary hypotension makes up 95% of high blood pressure cases, which is abnormally elevated blood pressure that is not a result of any other medical condition. Essential hypertension arises from various factors such as diet, lifestyle, environmental and genetic influences. Despite many available medications, not all patients attain well-managed blood pressure levels. Unmanaged high blood pressure can, over time, lead to narrowing and stiffening of the blood vessels and ultimately to structural and functional changes in the blood tissues. In part, this is mediated by oxidative stress, changes in antioxidant capacity and chronic low-grade inflammation, which damage the blood vessels' endothelial tissue and result in vascular stiffness. Melatonin is one of the most potent antioxidants found in nature and has been studied in short-term trials for its blood pressure lowering, antioxidant and vascular protective effects. This small open-label randomised study sought to get a better understanding of the long-term use of melatonin. Initially, the study assessed endothelial tissue damage, oxidative status and vascular stiffness in patients with high blood pressure. Subsequently, some of the participants received a low-dose melatonin supplement (1 mg/day) for one year, whilst being monitored for clinical and structural vascular changes. The study included 23 patients and 14 in the final analysis. After one year, the results showed a significant improvement in arterial stiffness in the melatonin group (11) and an improvement in endothelial tissue function, though the latter was not at statistically significant levels. Improvement in arterial stiffness seemed to be linked to a reduction in total antioxidant capacity (TAC). These findings suggest that melatonin can contribute to restoring oxidative balance in blood plasma, which reflects improved arterial stiffness. The study also demonstrated that besides being a well-tolerated intervention, melatonin also has clinical benefits even when administered at lower doses than normal.
Abstract
Among cardiovascular diseases, hypertension is one of the main risk factors predisposing to fatal complications. Oxidative stress and chronic inflammation have been identified as potentially responsible for the development of endothelial damage and vascular stiffness, two of the primum movens of hypertension and cardiovascular diseases. Based on these data, we conducted an open-label randomized study, first, to evaluate the endothelial damage and vascular stiffness in hypertense patients; second, to test the effect of supplementation with a physiological antioxidant (melatonin 1 mg/day for 1 year) in patients with essential hypertension vs. hypertensive controls. Twenty-three patients of either gender were enrolled and randomized 1:1 in two groups (control and supplemented group). The plasmatic total antioxidant capacity (as a marker of oxidative stress), blood pressure, arterial stiffness, and peripheral endothelial function were evaluated at the beginning of the study and after 1 year in both groups. Our results showed that arterial stiffness improved significantly (p = 0.022) in supplemented patients. The endothelial function increased too, even if not significantly (p = 0.688), after 1 year of melatonin administration. Moreover, the supplemented group showed a significative reduction in TAC levels (p = 0.041) correlated with the improvement of arterial stiffness. These data suggest that melatonin may play an important role in reducing the serum levels of TAC and, consequently, in improving arterial stiffness.
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Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease.
Smith, GI, Shankaran, M, Yoshino, M, Schweitzer, GG, Chondronikola, M, Beals, JW, Okunade, AL, Patterson, BW, Nyangau, E, Field, T, et al
The Journal of clinical investigation. 2020;130(3):1453-1460
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Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity and is associated with multiorgan insulin resistance, dyslipidaemia and an increased risk of diabetes and coronary heart disease. The aims of this study were to (a) determine hepatic de novo lipogenesis (DNL) [the liver’s biochemical process of synthesising fatty acids] in 3 distinct cohorts, (b) determine the relationships among hepatic DNL and intrahepatic [within the liver] triglyceride (IHTG) content, and (c) determine the effect of moderate (10%) weight loss. This study is a cross-sectional study which included a total of 67 men and women (mean age: 39 ± 1 years; 14 men and 53 women). Results highlight the importance of DNL in the pathogenesis of hepatic steatosis [build up of fats in the liver] and suggest that increases in daily 24-hour plasma glucose and insulin concentrations are major drivers of increased DNL in individuals with obesity and NAFLD. Additionally, moderate (10%) weight loss caused a marked decrease in both hepatic DNL and IHTG content. Authors conclude that increases in circulating glucose and insulin promote hepatic DNL in individuals with NAFLD. Whereas an improvement in insulin sensitivity and a decrease in hepatic DNL, are potentially important contributors to the decline in IHTG content associated with moderate weight loss.
Abstract
BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.
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Effectiveness and safety of citicoline in mild vascular cognitive impairment: the IDEALE study.
Cotroneo, AM, Castagna, A, Putignano, S, Lacava, R, Fantò, F, Monteleone, F, Rocca, F, Malara, A, Gareri, P
Clinical interventions in aging. 2013;8:131-7
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The number of people aged 65 years and over with mild vascular cognitive impairment is continuing to increase. Vascular disease can reduce cerebral perfusion, causing oxidative stress and neurodegeneration. Citicoline [pharmaceutical] inhibits apoptosis associated with cerebral ischemia and in several models of neurodegeneration has been able to potentiate neuroplasticity. The aim of this study was to assess the effectiveness and safety of oral citicoline in elderly people with mild vascular cognitive impairment. A total of 349 patients were included in the study who were assigned to open-label treatment with oral citicoline 500 mg twice a day in a fasting state or to no treatment (controls). Results show that citicoline is effective and safe in the treatment of mild vascular cognitive impairment. The treated group showed improvement in MMSE (Mini-Mental State Examination) scores, with an increase of 0.5 points shown over the course of the study. Authors conclude that further studies are required in order to confirm the findings of this study, and to further assess the efficacy and safety of long-term administration of a dietary supplement such as Cytidine-5′-diphosphate choline.
Abstract
BACKGROUND The studio di intervento nel decadimento vascolare lieve (IDEALE study) was an open multicenter Italian study, the aim of which was to assess the effectiveness and safety of oral citicoline in elderly people with mild vascular cognitive impairment. METHODS The study was performed in 349 patients. The active or citicoline group was composed of 265 patients and included 122 men and 143 women of mean age 79.9 ± 7.8 years selected from six Italian regions. Inclusion criteria were age ≥ 65 years, Mini-Mental State Examination (MMSE) score ≥ 21, subjective memory complaints but no evidence of deficits on MMSE, and evidence of vascular lesions on neuroradiology. Those with probable Alzheimer's disease were excluded. The control group consisted of 84 patients, including 36 men and 48 women of mean age 78.9 ± 7.01 (range 67-90) years. Patients included in the study underwent brain computed tomography or magnetic resonance imaging, and plasma dosage of vitamin B12, folate, and thyroid hormones. Functional dependence was investigated by scores on the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales, mood was assessed by the Geriatric Depression Scale (GDS), and behavioral disorders using the Neuropsychiatric Inventory scale. Comorbidity was assessed using the Cumulative Illness Rating Scale. An assessment was made at baseline (T0), after 3 months (T1), and after 9 months (T2, ie, 6 months after T1). The main outcomes were an improvement in MMSE, ADL, and IADL scores in the study group compared with the control group. Side effects were also investigated. The study group was administered oral citicoline 500 mg twice a day throughout the study. RESULTS MMSE scores remained unchanged over time (22.4 ± 4 at T0; 22.7 ± 4 at T1; 22.9 ± 4 at T2), whereas a significant difference was found between the study and control groups, both in T1 and in T2. No differences were found in ADL and IADL scores between the two groups. A slight but not statistically significant difference was found in GDS score between the study and control groups (P = 0.06). No adverse events were recorded. CONCLUSION In this study, citicoline was effective and well tolerated in patients with mild vascular cognitive impairment. Citicoline activates biosynthesis of phospholipids in neuronal membranes, increases brain metabolism as well as norepinephrine and dopamine levels in the central nervous system, and has neuroprotective effects during hypoxia and ischemia. Therefore, citicoline may be recommended for patients with mild vascular cognitive impairment.
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Effects of dehydroepiandrosterone (DHEA) on cardiovascular risk factors in older women with frailty characteristics.
Boxer, RS, Kleppinger, A, Brindisi, J, Feinn, R, Burleson, JA, Kenny, AM
Age and ageing. 2010;39(4):451-8
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Older women have the highest incidence of cardiovascular disease. This is thought to be partly due to declining hormone levels and changes in body composition with age. Dehydroepiandrosterone (DHEA) is a hormone that is associated with improved body composition and sense of wellbeing, and naturally declines with age. The aim of this double-blind, randomised, placebo-controlled trial was to examine the effects of DHEA supplementation on cardiovascular risk factors in older frail women. 88 women with low DHEA levels and an average age of 76 completed the 6-month study. Participants received either 50mg/day DHEA or a placebo for 6 months, along with exercise in the form of either yoga or chair aerobics. All participants also received calcium and vitamin D3 supplementation. Whilst DHEA supplementation increased the levels of sex hormones studied, cardiovascular risk factors such as abdominal fat, blood pressure, cholesterol levels and fasting glucose levels did not change. The authors concluded that short-term DHEA supplementation in older women increases levels of oestrogen and testosterone, but these changes may not have any impact on cardiovascular disease risk.
Abstract
OBJECTIVE this analysis was to investigate the effects of dehydroepiandrosterone (DHEA) on cardiovascular risk factors in older women with frailty characteristics. DESIGN, SETTING AND PARTICIPANTS the study was a double-blind, randomised, placebo-controlled trial of 99 women (mean 76.6 +/- 6.0 year) with the low DHEA-S level and frailty. INTERVENTION participants received 50 mg/day DHEA or placebo for 6 months; all received calcium (1,000-1,200 mg/day diet) and supplement (combined) and cholecalciferol (1,000 IU/day). Women participated in 90-min twice weekly exercise regimens, either chair aerobics or yoga. MAIN OUTCOME MEASURES assessment of outcome variables included hormone levels (DHEA-S, oestradiol, oestrone, testosterone and sex hormone-binding globulin (SHBG)), lipid profiles (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides), body composition measured by dual energy absorptiometry, glucose levels and blood pressure (BP). RESULTS eighty-seven women (88%) completed 6 months of study; 88% were pre-frail demonstrating 1-2 frailty characteristics and 12% were frail with > or =3 characteristics. There were significant changes in all hormone levels including DHEA-S, oestradiol, oestrone and testosterone and a decline in SHBG levels in those taking DHEA supplements. In spite of changes in hormone levels, there were no significant changes in cardiovascular risk factors including lipid profiles, body or abdominal fat, fasting glucose or BP. CONCLUSION research to date has not shown consistent effects of DHEA on cardiovascular risk, and this study adds to the literature that short-term therapy with DHEA is safe for older women in relation to cardiovascular risk factors. This study is novel in that we recruited women with evidence of physical frailty.