Vascular Risk Factors and Alzheimer's Disease: Blood-Brain Barrier Disruption, Metabolic Syndromes, and Molecular Links.
He, JT, Zhao, X, Xu, L, Mao, CY
Journal of Alzheimer's disease : JAD. 2020;(1):39-58
Alzheimer's disease (AD) is a neurodegenerative disorder, marked by cortical and hippocampal deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles and cognitive impairment. Studies indicate a prominent link between cerebrovascular abnormalities and the onset and progression of AD, where blood-brain barrier (BBB) dysfunction and metabolic disorders play key risk factors. Pericyte degeneration, endothelial cell damage, astrocyte depolarization, diminished tight junction integrity, and basement membrane disarray trigger BBB damage. Subsequently, the altered expression of low-density lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate Aβ transport across the BBB. White matter lesions and microhemorrhages, dyslipidemia, altered brain insulin signaling, and insulin resistance contribute to tau and Aβ pathogenesis, and oxidative stress, mitochondrial damage, inflammation, and hypoperfusion serve as mechanistic links between pathophysiological features of AD and ischemia. Deregulated calcium homeostasis, voltage gated calcium channel functioning, and protein kinase C signaling are also common mechanisms for both AD pathogenesis and cerebrovascular abnormalities. Additionally, APOE polymorphic alleles that characterize impaired cerebrovascular integrity function as primary genetic determinants of AD. Overall, the current review enlightens key vascular risk factors for AD and underscores pathophysiologic relationship between AD and vascular dysfunction.
Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis.
Pizzocaro, A, Vena, W, Condorelli, R, Radicioni, A, Rastrelli, G, Pasquali, D, Selice, R, Ferlin, A, Foresta, C, Jannini, EA, et al
Journal of endocrinological investigation. 2020;(12):1675-1687
PURPOSE Low testosterone (T) in Klinefelter's syndrome (KS) can contribute to typical features of the syndrome such as reduced bone mineral density, obesity, metabolic disturbances and increased cardiovascular risk. The aim of the present study is to review and meta-analyze all available information regarding possible differences in metabolic and bone homeostasis profile between T treated (TRT) or untreated KS and age-matched controls. METHODS We conducted a random effect meta-analysis considering all the available data from observational or randomized controlled studies comparing TRT-treated and untreated KS and age-matched controls. Data were derived from an extensive MEDLINE, Embase, and Cochrane search. RESULTS Out of 799 retrieved articles, 21 observational and 22 interventional studies were included in the study. Retrieved trials included 1144 KS subjects and 1284 healthy controls. Not-treated KS patients showed worse metabolic profiles (including higher fasting glycemia and HOMA index as well as reduced HDL-cholesterol and higher LDL-cholesterol) and body composition (higher body mass index and waist circumference) and reduced bone mineral density (BMD) when compared to age-matched controls. TRT in hypogonadal KS subjects was able to improve body composition and BMD at spinal levels but it was ineffective in ameliorating lipid and glycemic profile. Accordingly, TRT-treated KS subjects still present worse metabolic parameters when compared to age-matched controls. CONCLUSION TRT outcomes observed in KS regarding BMD, body composition and glyco-metabolic control, are similar to those observed in male with hypogonadism not related to KS. Moreover, body composition and BMD are better in treated than untreated hypogonadal KS. Larger and longer randomized placebo-controlled trials are advisable to better confirm the present data, mainly derived from observational studies.
Effect of cinnamon supplementation on blood pressure and anthropometric parameters in patients with type 2 diabetes: A systematic review and meta-analysis of clinical trials.
Jamali, N, Jalali, M, Saffari-Chaleshtori, J, Samare-Najaf, M, Samareh, A
Diabetes & metabolic syndrome. 2020;(2):119-125
BACKGROUND AND AIMS The present systematic review and meta-analysis was conducted to investigate the effect of cinnamon supplementation on blood pressure and anthropometric indices in patients with type 2 diabetes. METHODS PubMed, Embase, Scopus, Web of Science and Cochrane Library were systematically searched to find relevant records up to 22 August 2019. Standard mean difference (SMD) and 95% confidence interval (CI) were used to evaluate the effect of cinnamon supplementation on the outcomes of this study. In the case of heterogeneity, fixed and random effect models were used. The obtained data were analyzed by Stata 13. After excluding irrelevant records, 9 eligible articles were included. RESULTS This meta-analysis found a significant reduction in systolic blood pressure (SBP) (SMD: -0.532, 95% CI: [-1.032, -0.033], P = 0.037) and diastolic blood pressure (DBP) (SMD: -0.681, 95% CI: [-1.297, -0.065], P = 0.030) of patients with type 2 diabetes following cinnamon supplementation. Based on the results of the present study, cinnamon supplementation had no significant effect on the body weight (BW) (SMD: -0.309, 95% CI: [-0.793, 0.175], P = 0.211), body mass index (BMI) (SMD: -0.550, 95% CI: [-1.244, 0.144], P = 0.120). and waist circumference (WC) (SMD: -0.235, 95% CI: [-0.518, 0.047], P = 0.103). CONCLUSIONS Cinnamon supplementation significantly decreased SBP and DBP of patients with type 2 diabetes. Although cinnamon intake caused changes in anthropometric parameters, the observed changes were not statistically significant.
The effects of curcumin supplementation on oxidative stress, Sirtuin-1 and peroxisome proliferator activated receptor γ coactivator 1α gene expression in polycystic ovarian syndrome (PCOS) patients: A randomized placebo-controlled clinical trial.
Heshmati, J, Golab, F, Morvaridzadeh, M, Potter, E, Akbari-Fakhrabadi, M, Farsi, F, Tanbakooei, S, Shidfar, F
Diabetes & metabolic syndrome. 2020;(2):77-82
BACKGROUND & AIMS Curcumin is a biologically active phytochemical ingredient found in turmeric and has antioxidant pharmacologic actions that may benefit patients with polycystic ovarian syndrome (PCOS). The aim in this trial was to evaluate the efficacy of curcumin supplementation on oxidative stress enzymes, sirtuin-1 (SIRT1) and Peroxisome proliferator activated receptor γ coactivator 1α (PGC1α) gene expression in PCOS patients. METHODS Seventy-two patients with PCOS were recruited for this randomized, double-blinded, clinical trial. Thirty-six patients received curcumin, 1500 mg (three times per day), and 36 patients received placebo for 3 months. Gene expression of SIRT1, PGC1α and serum activity of glutathione peroxidase (Gpx) and superoxide dismutase (SOD) enzymes were evaluated at the beginning of trial and at 3-month follow-up. RESULTS Sixty-seven patients with PCOS completed the trial. Curcumin supplementation significantly increased gene expression of PGC1α (p = 0.011) and activity of the Gpx enzyme (p = 0.045). Curcumin also non-significantly increased gene expression of SIRT1 and activity of the SOD enzyme. CONCLUSIONS Curcumin seems to be an efficient reducer of oxidative stress related complications in patients with PCOS. Further studies on curcumin should strengthen our findings.
The Effect of Tildrakizumab on Cardiometabolic Risk Factors in Psoriasis by Metabolic Syndrome Status: Post Hoc Analysis of Two Phase 3 Trials (ReSURFACE 1 and ReSURFACE 2).
Menter, MA, Mehta, NN, Lebwohl, MG, Gottlieb, AB, Mendelsohn, AM, Rozzo, SJ, Leonardi, C
Journal of drugs in dermatology : JDD. 2020;(8):703-708
Background: Metabolic syndrome (MetS) is the most prevalent comorbidity in psoriasis and increases the risk of cardiovascular disease, diabetes, and mortality. Assessment of impacts of biologic therapies on cardiometabolic risk factors are relatively limited. This study evaluated the effect of tildrakizumab on cardiometabolic risk factors in patients with moderate to severe plaque psoriasis and stratified by MetS status. Methods: In this post hoc analysis of reSURFACE 1/2, tildrakizumab 100 and 200 mg were continuously administered to patients with moderate to severe plaque psoriasis at weeks 0 and 4, and every 12 weeks thereafter. Mean and mean percent changes from baseline were assessed for fasting serum glucose, low/high-density lipoprotein-cholesterol, total cholesterol, triglyceride levels, body weight, and blood pressure at week 64/52 for reSURFACE 1 and 2, respectively, in patients with and without MetS. Results: A total of 369 patients in reSURFACE 1 and 2 received continuous tildrakizumab 100 mg and 330 received tildrakizumab 200 mg; 21.4% and 20.3% in reSURFACE 1 and 2, respectively, had MetS. At week 64/52, mean changes in cardiometabolic risk factors from baseline did not significantly differ regardless of MetS status. Numerically larger mean decreases in fasting glucose, triglycerides, and systolic blood pressure following tildrakizumab 100 mg and in systolic and diastolic blood pressure following tildrakizumab 200 mg were observed in patients with MetS relative to those without MetS. Conclusions: Changes in cardiometabolic disease risk factors following tildrakizumab treatment were limited. Risk factors were not increased in patients with MetS vs without MetS. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.5337.
Beyond Body Weight-Loss: Dietary Strategies Targeting Intrahepatic Fat in NAFLD.
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease in industrialized countries. It is regarded as the hepatic manifestation of the metabolic syndrome (MetS) resulting from insulin resistance. Moreover, insulin resistance impairs glycogen synthesis, postprandially diverting a substantial amount of carbohydrates to the liver and storing them there as fat. NAFLD has far-reaching metabolic consequences involving glucose and lipoprotein metabolism disorders and risk of cardiovascular disease, the leading cause of death worldwide. No pharmaceutical options are currently approved for the treatment of NAFLD. Exercise training and dietary interventions remain the cornerstone of NAFLD treatment. Current international guidelines state that the primary goal of nutritional therapy is to reduce energy intake to achieve a 7%-10% reduction in body weight. Meal replacement therapy (formula diets) results in more pronounced weight loss compared to conventional calorie-restricted diets. However, studies have shown that body mass index (BMI) or weight reduction is not obligatory for decreasing hepatic fat content or to restore normal liver function. Recent studies have achieved significant reductions in liver fat with eucaloric diets and without weight loss through macronutrient modifications. Based on this evidence, an integrative nutritional therapeutic concept was formulated that combines the most effective nutrition approaches termed "liver-fasting." It involves the temporary use of a low calorie diet (total meal replacement with a specific high-protein, high-soluble fiber, lower-carbohydrate formula), followed by stepwise food reintroduction that implements a Mediterranean style low-carb diet as basic nutrition.
Adjunctive acetazolamide therapy for the treatment of Bartter syndrome.
Mazaheri, M, Assadi, F, Sadeghi-Bojd, S
International urology and nephrology. 2020;(1):121-128
PURPOSE Bartter syndrome is a rare hereditary salt-losing tubulopathy caused by mutations of several genes in the thick ascending limb of Henle's loop, characterized by polyuria, hypokalemic metabolic alkalosis, growth retardation and normal blood pressure. Cyclooxygenase inhibitors, potassium-sparing diuretics and angiotensin-converting enzyme inhibitors are currently used to treat electrolyte derangements, but with poor response. Whether treatment with acetazolamide, a carbonic-anhydrase inhibitor, would result in better clinical outcomes is unknown. METHODS We randomly assigned children with Bartter syndrome in a 1:1 ratio to either receive indomethacin, enalapril, and spironolactone or indomethacin, enalapril, and spironolactone plus acetazolamide once daily in the morning for 4 weeks. After 2 days of washout, participants crossed over to receive the alternative intervention for 4 weeks. The present study examines the serum bicarbonate lowering effect of acetazolamide as an adjunctive therapy in children with Batter syndrome. RESULTS Of the 43 patients screened for eligibility, 22 (51%), between the ages 6 and 42 months, were randomized to intervention. Baseline characteristics were similar between the two groups. Addition of acetazolamide for a period of 4 weeks significantly reduced serum bicarbonate and increased serum potassium levels, parallel with a reduction in serum aldosterone and plasma renin concentration. The 24-h urine volume, sodium, potassium, and chloride decreased significantly. CONCLUSION Our data define a new physiologic and therapeutic role of acetazolamide for the management of children with Bartter syndrome.
What about glucocorticoids in primary Sjögren's syndrome?
Priori, R, Mastromanno, L, Izzo, R
Clinical and experimental rheumatology. 2020;(4):237-244
Glucocorticoids (GCs) are involved in several physiological processes such as metabolism, water and electrolyte balance, growth, cardiovascular and cognitive functions, reproduction. Furthermore, they exert different effects on innate and adaptive immune cells. Due to their anti-inflammatory and immunosuppressive functions, these drugs are largely used for the treatment of inflammatory and autoimmune diseases. In comparison to other autoimmune rheumatic diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), to date no reliable evidence is available for the use of systemic GCs in Sjögren's syndrome (SS), which is still based on case reports, case studies, retrospective or prospective studies and a small number of randomised controlled trials (RCTs). Despite this gap in our knowledge, GCs are commonly used in SS for glandular, joint, cutaneous, lung, haematological, renal, neurological involvement. More recently, some sets of recommendations for the management of SS have provided a few pieces of advice regarding the use of GCs in this condition. Future studies should not neglect the role of GCs, as this traditional therapeutic weapon can still have a role in the management of SS. Accordingly, this review will address and discuss the use of systemic GCs in isolated or primary SS.
A state of the art review on the novel mediator asprosin in the metabolic syndrome.
Luís, C, Fernandes, R, Soares, R, von Hafe, P
Porto biomedical journal. 2020;(6):e108
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Metabolic syndrome is a complex and heterogeneous pathology characterized by a cluster of biochemical, clinical, and metabolic factors that came together in raising the risk of cardiovascular diseases, type 2 diabetes mellitus, and all-cause mortality. Some of these features are well defined in this syndrome like: obesity, inflammation, hypertension, insulin resistance, atherosclerotic dyslipidemias, endothelial dysfunction, and inflammation. This circuit is intermediated by a complex network of hormones, cytokines, transcription factors, and adipokines, among others. Some like leptin, adiponectin, Plasminogen activator inhibitor-1, interleukin-6, Tumor necrosis factor, and their influence on the metabolic syndrome are well described in the literature and new players are described continuously. One novel player was described in 2016 by Romere et al as a fasting-induced glycogenic protein hormone named asprosin. In order to perform a state-of-the-art, nonsystematic review of asprosin, a study of the available literature was carried out in the main database (Pubmed) and the results were studied and correlated to better understand the mechanism of action of this hormone. Asprosin is not only associated with the metabolic syndrome features like glucose and lipid metabolism, insulin resistance, obesity and inflammation but also in other pathologies metabolic syndrome related like diabetic retinopathy, polycystic ovary syndrome and anorexia nervosa. A limited number of pathways were already unveiled although much more research is needed to better understand the therapeutical potential of asprosin in the metabolic syndrome.
Influences of Resistance versus Aerobic Exercise on Physiological and Physical Fitness Changes in Previously Inactive Men with Obesity: A Prospective, Single-Blinded Randomized Controlled Trial.
Kim, B, Kim, S
Diabetes, metabolic syndrome and obesity : targets and therapy. 2020;:267-276
PURPOSE The purpose of this study was to comparatively investigate changes in physiological and physical fitness in previously inactive men with obesity in response to aerobic exercise (AE) or resistance exercise (RE). METHODS A total of 27 inactive men with obesity, aged 34-60 years, attended a 90-min AE or RE program 3 days/week for 12 weeks. The subjects underwent assessments of energy intake (by a 3-day weighted dietary record), body weight (by a digital scale), body composition (by whole-body dual-energy X-ray absorptiometry), VO2max (by a cycling ergometer), muscle strength (by a Biodex System 3 dynamometer) and blood analysis. RESULTS There were no significant interactions (P = 0.100~0.730) among energy intake variables. RE led to decreased fat mass (-4.39%, P < 0.05) and improved cardiorespiratory capacity (+11.66%, P < 0.05), as well as increases in lean mass (+2.12%, P < 0.01) and muscle strength variables (+8.41~+11.00%, P < 0.01 for all), without significant weight change. Although AE induced decreases in fat mass (-5.91%, P < 0.05) and weight (-2.28%, P < 0.05) and improved cardiorespiratory capacity (+19.07%, P < 0.01), lean mass and muscle strength variables remained unchanged. RE showed a stronger positive influence than AE on lean mass (P = 0.003) and muscle strength variables (P = 0.001~0.015), and RE and AE had similar influences on weight, fat mass, cardiorespiratory capacity and blood markers. CONCLUSION It may be an efficient exercise regimen to perform RE first and then utilize AE to maintain the changes that occur in response to RE.