Acute assessment of subjective appetite and implicated hormones after a hypnosis-induced hallucinated meal: a randomized cross-over pilot trial.

The use of hypnosis can generate hallucinatory phenomena, which ranged from vivid/auditory imagery to fully developed "hallucinations" in selected people. The aim of this pilot trial was investigating the acute effects of a hypnosis-induced hallucinated breakfast (HB) compared to those of a real breakfast (RB) on subjective appetite and appetite-regulating hormones in highly hypnotizable individuals. Eight healthy post-menopausal women were recruited to consume two meals: the HB and the RB in a randomized crossover design. Participants underwent appetite sensations measurements (before meal and each 30-min until 270-min) and blood sample collection (at 0, 20, 60, 90, 180-min). A 3-day food-record was filled after each meal. The adjusted repeated measures ANCOVA did not show any meal×time interactions on subjective appetite postprandially. As expected, significantly higher glucose (p < 0.001), insulin (p < 0.001), and lower free fatty acid (p < 0.001) concentrations were found after the RB, but not following HB. Furthermore, RB significantly increased postprandial levels of glucagon-like-peptide-1 and peptide-YY at 20, 60, 90 and 180-min, whereas acylated-ghrelin and leptin levels did not differ. Postprandial neuropeptide-Y and orexin-A values significantly increased at different time-points after RB, but not following HB, while α-melanocyte-stimulating hormone levels enhanced after HB only. Energy intakes were significantly lower after HB on the test-day only (HB = 1146.6 ± 343.8 vs RB = 1634.7 ± 274.2 kcal/d; p = 0.003). Appetite sensation might be modulated by fully developed meal "hallucination" induced by hypnosis, likely affecting brain-peptides implicated in the appetite regulation. However, further studies are needed to verify these results obtained in a highly selected group of individuals. NCT03934580.

Effects of resveratrol on bone health in type 2 diabetic patients. A double-blind randomized-controlled trial.

OBJECTIVES: Patients with type 2 diabetes (T2DM) are at increased fracture risk. Resveratrol has shown beneficial effects on bone health in few studies. The aim of this trial was to investigate the effects of resveratrol on bone mineral density (BMD) and on calcium metabolism biomarkers in T2DM patients. METHODS: In this double-blind randomized placebo-controlled trial 192 T2DM outpatients were randomized to receive resveratrol 500 mg/day (Resv500 arm), resveratrol 40 mg/day (Resv40 arm) or placebo for 6 months. BMD, bone mineral content (BMC), serum calcium, phosphorus, alkaline phosphatase, and 25-hydroxy vitamin D were measured at baseline and after 6 months. RESULTS: At follow-up, calcium concentrations increased in all patients, while within-group variations in alkaline phosphatase were higher in both resveratrol arms, and 25-hydroxy vitamin D increased in the Resv500 arm only, without between-group differences. Whole-body BMD significantly decreased in the placebo group, while whole-body BMC decreased in both the placebo and Resv40 arms. No significant changes in BMD and BMC values occurred in the Resv500 arm. The adjusted mean differences of change from baseline were significantly different in the Resv500 arm vs placebo for whole-body BMD (0.01 vs -0.03 g/cm2, p = 0.001), whole-body BMC (4.04 vs -58.8 g, p < 0.001), whole-body T-score (0.15 vs -0.26), and serum phosphorus (0.07 vs -0.01 µmol/L, p = 0.002). In subgroup analyses, in Resv500 treated-patients BMD values increased to higher levels in those with lower calcium and 25-hydroxy vitamin D values, and in alcohol drinkers. CONCLUSIONS: Supplementation with 500 mg resveratrol prevented bone density loss in patients with T2DM, in particular, in those with unfavorable conditions at baseline.

Impact of sirtuin-1 expression on H3K56 acetylation and oxidative stress: a double-blind randomized controlled trial with resveratrol supplementation.

AIMS: Sirtuin-1 (SIRT-1) down-regulation in type 2 diabetes mellitus (T2DM) has been associated with epigenetic markers of oxidative stress. We herein aim to evaluate whether an increase in SIRT-1 expression affects histone 3 acetylation at the 56 lysine residue (H3K56ac) in T2DM patients randomly selected to receive either resveratrol (40 mg or 500 mg) or a placebo for 6 months. The primary outcome is changes in the H3K56ac level by variation in SIRT-1 expression and the secondary outcome is the evidence of association between SIRT-1 level, antioxidant markers (TAS), and metabolic variables. METHODS AND RESULTS: At baseline, peripheral blood mononuclear cell H3K56ac values among the SIRT-1 tertiles did not differ. At trial end, SIRT-1 levels were significantly higher in patients receiving 500 mg resveratrol. At follow-up, patients were divided into tertiles of delta (trial end minus baseline) SIRT-1 value. Significant reductions in H3K56ac and body fat percentage were found in the highest tertile as were increased TAS levels. A multiple logistic regression model showed that the highest delta SIRT-1 tertile was inversely associated with variations in H3K56ac (OR = 0.66; 95% CI 0.44-0.99), TAS (OR = 1.01; 95% CI 1.00-1.02), and body fat percentage (OR = 0.75; 95% CI 0.58-0.96). CONCLUSIONS: We provide new knowledge on H3K56ac and SIRT-1 association in T2DM. These data suggest that boosting SIRT-1 expression/activation may impact redox homeostasis in these patients. ClinicalTrials.gov Identifier NCT02244879.

Dual therapy targeting the endocannabinoid system prevents experimental diabetic nephropathy.

BACKGROUND: The endocannabinoid system has been implicated in the pathogenesis of diabetic nephropathy (DN). We investigated the effect of combined therapy with AM6545, a 'peripherally' restricted cannabinoid receptor type 1 (CB1R) neutral antagonist, and AM1241, a cannabinoid receptor type 2 (CB2R) agonist, in experimental DN. METHODS: Renal function and structure, podocyte proteins and markers of both fibrosis and inflammation were studied in streptozotocin-induced diabetic mice treated for 14 weeks with vehicle, AM6545, AM1241 and AM6545-AM1241. RESULTS: Single treatment with either AM6545 or AM1241 alone reduced diabetes-induced albuminuria and prevented nephrin loss both in vivo and in vitro in podocytes exposed to glycated albumin. Dual therapy performed better than monotherapies, as it abolished albuminuria, inflammation, tubular injury and markedly reduced renal fibrosis. Converging anti-inflammatory mechanisms provide an explanation for this greater efficacy as dual therapy abolished diabetes-induced renal monocyte infiltration and M1/M2 macrophage imbalance in vivo and abrogated the profibrotic effect of M1 macrophage-conditioned media on cultured mesangial cells. CONCLUSION: 'Peripheral' CB1R blockade is beneficial in experimental DN and this effect is synergically magnified by CB2R activation.

New Pharmacologic Agents That Target Inflammation and Fibrosis in Nonalcoholic Steatohepatitis-Related Kidney Disease.

Epidemiologic data show an association between the prevalence and severity of nonalcoholic fatty liver disease and the incidence and stage of chronic kidney disease (CKD); furthermore, nonalcoholic steatohepatitis (NASH)-related cirrhosis has a higher risk of renal failure, a greater necessity for simultaneous liver-kidney transplantation, and a poorer renal outcome than cirrhosis of other etiologies even after simultaneous liver-kidney transplantation. These data suggest that NASH and CKD share common proinflammatory and profibrotic mechanisms of progression, which are targeted incompletely by current treatments. We reviewed therapeutic approaches to late preclinical/early clinical stage of development in NASH and/or CKD, focusing on anti-inflammatory and antifibrotic treatments, which could slow the progression of both disease conditions. Renin inhibitors and angiotensin-converting enzyme-2 activators are new renin-angiotensin axis modulators that showed incremental advantages over angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers in preclinical models. Novel, potent, and selective agonists of peroxisome proliferator-activated receptors and of farnesoid X receptor, designed to overcome limitations of older compounds, showed promising results in clinical trials. Epigenetics, heat stress response, and common effectors of redox regulation also were subjected to intensive research, and the gut was targeted by several approaches, including synbiotics, antilipopolysaccharide antibodies, Toll-like receptor-4 antagonists, incretin mimetics, and fibroblast growth factor 19 analogs. Promising anti-inflammatory therapies include inhibitors of NOD-like receptor family, pyrin domain containing 3 inflammasome, of nuclear factor-κB, and of vascular adhesion protein-1, chemokine antagonists, and solithromycin, and approaches targeting common profibrogenic pathways operating in the liver and the kidney include galectin-3 antagonists, and inhibitors of rho-associated protein kinase and of epidermal growth factor activation. The evidence, merits, and limitations of each approach for the treatment of NASH and CKD are discussed.

Fatty Liver and Chronic Kidney Disease: Novel Mechanistic Insights and Therapeutic Opportunities.

Chronic kidney disease (CKD) is a risk factor for end-stage renal disease (ESRD) and cardiovascular disease (CVD). ESRD or CVD develop in a substantial proportion of patients with CKD receiving standard-of-care therapy, and mortality in CKD remains unchanged. These data suggest that key pathogenetic mechanisms underlying CKD progression go unaffected by current treatments. Growing evidence suggests that nonalcoholic fatty liver disease (NAFLD) and CKD share common pathogenetic mechanisms and potential therapeutic targets. Common nutritional conditions predisposing to both NAFLD and CKD include excessive fructose intake and vitamin D deficiency. Modulation of nuclear transcription factors regulating key pathways of lipid metabolism, inflammation, and fibrosis, including peroxisome proliferator-activated receptors and farnesoid X receptor, is advancing to stage III clinical development. The relevance of epigenetic regulation in the pathogenesis of NAFLD and CKD is also emerging, and modulation of microRNA21 is a promising therapeutic target. Although single antioxidant supplementation has yielded variable results, modulation of key effectors of redox regulation and molecular sensors of intracellular energy, nutrient, or oxygen status show promising preclinical results. Other emerging therapeutic approaches target key mediators of inflammation, such as chemokines; fibrogenesis, such as galectin-3; or gut dysfunction through gut microbiota manipulation and incretin-based therapies. Furthermore, NAFLD per se affects CKD through lipoprotein metabolism and hepatokine secretion, and conversely, targeting the renal tubule by sodium-glucose cotransporter 2 inhibitors can improve both CKD and NAFLD. Implications for the treatment of NAFLD and CKD are discussed in light of this new therapeutic armamentarium.

Different Serum Free Fatty Acid Profiles in NAFLD Subjects and Healthy Controls after Oral Fat Load.

BACKGROUND: Free fatty acid (FFA) metabolism can impact on metabolic conditions, such as obesity and nonalcoholic fatty liver disease (NAFLD). This work studied the increase in total FFA shown in NAFLD subjects to possibly characterize which fatty acids significantly accounted for the whole increase. METHODS: 21 patients with NAFLD were selected according to specified criteria. The control group consisted of nine healthy subjects. All subjects underwent an oral standard fat load. Triglycerides; cholesterol; FFA; glucose and insulin were measured every 2 h with the determination of fatty acid composition of FFA. RESULTS: higher serum FFA levels in NAFLD subjects are mainly due to levels of oleic, palmitic and linoleic acids at different times. Significant increases were shown for docosahexaenoic acid, linolenic acid, eicosatrienoic acid, and arachidonic acid, although this was just on one occasion. In the postprandial phase, homeostatic model assessment HOMA index positively correlated with the ω3/ω6 ratio in NAFLD patients. CONCLUSIONS: the higher serum levels of FFA in NAFLD subjects are mainly due to levels of oleic and palmitic acids which are the most abundant circulating free fatty acids. This is almost exactly corresponded with significant increases in linoleic acid. An imbalance in the n-3/n-6 fatty acids ratio could modulate postprandial responses with more pronounced effects in insulin-resistant subjects, such as NAFLD patients.

Iron supplementation and gestational diabetes in midpregnancy.

OBJECTIVE: Iron supplementation in pregnancy seems beneficial for neonatal/maternal outcomes, but it was associated with diabetes and hypertension in the general population. STUDY DESIGN: We investigated the association between iron supplementation during midpregnancy and metabolic/hypertensive abnormalities in 500 consecutive gestational diabetes mellitus (GDM) and 500 normoglycemic women. RESULTS: Iron-supplement users (n = 212/1000) showed significantly higher values of prepregnancy body mass index (BMI), actual BMI, waist circumference, blood pressure, fasting glucose, Homeostasis-Model-Assessment-Insulin-Resistance, and lower high-density lipoprotein-cholesterol than nonusers. The prevalence of GDM (70.8% vs 44.4%), hypertension (25.9% vs 9.8%), metabolic syndrome (25.9% vs 10.4%) was significantly higher in the former with a 2- to 3-fold-increased risk at multiple regression analyses. Most glucose values of the oral glucose tolerance test were significantly higher in iron supplemented women, both in GDM and normoglycemic individuals. CONCLUSION: Iron supplementation is associated with glucose impairment and hypertension in midpregnancy; its potential harmful effects might be carefully debated regarding its effectiveness.

Associations of dietary and serum copper with inflammation, oxidative stress, and metabolic variables in adults.

There are conflicting data on the associations between copper and glycemia, plasma lipids, and atherosclerotic diseases. Copper has both pro-oxidant and antioxidant effects. We performed a cross-sectional analysis to investigate the associations between dietary copper intake and metabolic variables and serum high-sensitivity C-reactive protein (hs-CRP) in asymptomatic subjects from a population-based cohort (n = 1197) and between serum copper concentration and markers of oxidative stress, including plasma nitrotyrosine (NT) and total antioxidant status (TAS), hs-CRP, and metabolic variables in a subgroup of men from this cohort (n = 231). In all subjects, diastolic blood pressure and circulating glucose, uric acid, and total and LDL-cholesterol concentrations significantly decreased, whereas the hs-CRP concentration increased, from the lowest to the highest tertile of copper intake. In the male subgroup, glucose and total and LDL-cholesterol and TAS decreased, whereas hs-CRP and NT concentrations increased from the lowest to the highest tertile of serum copper concentration. In multiple regression models, dietary copper intake was inversely associated with diastolic blood pressure (P = 0.002), fasting glucose (P < 0.001), total cholesterol (P < 0.001), LDL-cholesterol (P < 0.001), and uric acid (P < 0.001) and was directly associated with the hs-CRP concentration (P < 0.001). Serum copper concentrations were inversely associated with glucose (P < 0.001), total cholesterol (P < 0.001), LDL-cholesterol (P < 0.001), and TAS (P < 0.001) and were directly associated with hs-CRP (P < 0.001) and NT concentrations (P < 0.001). Marginal copper deficiency is associated with an unfavorable metabolic pattern, but copper supplementation might not be recommended in view of its association with inflammation and markers of oxidative stress.

Efficacy of antioxidant treatment in reducing resistin serum levels: a randomized study.

OBJECTIVES: Few in vitro studies have examined the participation of resistin, a recently discovered adipokine, in oxidative processes. We investigated whether in vivo treatment with the antioxidant vitamin C might affect resistin serum levels. DESIGN: Randomized prospective open trial. SETTING: San Giovanni Battista Hospital, Turin, Italy. PARTICIPANTS: Eighty healthy individuals. INTERVENTION: Administration of 2 g of ascorbic acid orally for 2 wk (n = 40; experimental group) or no supplementation (n = 40; control group). OUTCOME MEASURES: The primary end point was the between-group difference in the before-after change in resistin serum level after vitamin C supplementation. Secondary endpoints were the within- and between-group changes in glucose, insulin, lipid parameters, C-reactive protein fasting values, and markers of oxidative stress. RESULTS: In the experimental group, vitamin C supplementation was significantly associated with both resistin concentration reduction (from 4.3 +/- 1.5 to 2.9 +/- 0.8 ng/ml; 95% confidence interval [CI] -1.87, -1.03) and ascorbic acid level increase (from 9.4 +/- 2.9 to 19.0 +/- 5.2 mg/l; 95% CI 7.9, 11.2). In the control group, resistin levels did not change significantly (from 4.2 +/- 1.0 to 4.3 +/- 0.9 ng/ml; 95% CI -0.07, 0.37). The between-group differences were highly significant (p < 0.001). Vitamin C supplementation was also associated with a statistically significant reduction in nitrotyrosine level and incremental increase in reduced glutathione. In a linear regression model, within-individual changes in vitamin C concentrations were inversely correlated with changes in resistin levels in both groups (each unit increase of vitamin C corresponded to a decrease of about 0.10 units of resistin levels (95% CI 0.13, 0.08; p < 0.001). CONCLUSION: This is to our knowledge the first randomized trial in humans that has demonstrated that short-term vitamin C supplementation could significantly reduce resistin levels, independent of changes in inflammatory or metabolic variables. Future investigations of resistin participation in oxidative processes are warranted.