Renata Bracale

TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents

Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-alpha. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-alpha downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the reduction of mitochondrial biogenesis observed with TNF-alpha. Our findings demonstrate that TNF-alpha impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.

Pleiotropic Protective Effects of Phytochemicals in Alzheimer's Disease

Alzheimers disease (AD) is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

UCP1 -3826 AG+GG genotypes, adiponectin, and leptin/adiponectin ratio in severe obesity

Background and aims: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) are well-recognized complications of obesity. This study was designed to evaluate the role of the UCP1 -3826 A>G polymorphism, adiponectin levels, leptin/adiponectin ratio (L/A), and main biochemical parameters in 102 unrelated severely obese adults [61 females and 41 males, median body mass index (BMI) = 47.8 kg/m2] with NAFLD, with (MS+) or without MS (MS−) from Southern Italy. Subject and methods: The UCP1 polymorphism was tested by the TaqMan method, main biochemical parameters by routinary methods, adiponectin, and leptin serum levels by enzyme-linked immunosorbent assay. MS was diagnosed according to the American Heart Association criteria, liver steatosis was detected by ultrasound. Results: MS was present in 53% male and 66% female obese patients. Only total cholesterol (p=0.04 males and p=0.002 females) and L/A ratio (p=0.03 males) differed between MS+ and MS− obese patients. At multivariate analysis, severe liver steatosis was significantly associated with: UCP1 (AG+GG) genotypes [odds ratio-confidence interval (OR-CI): 4.25; 1.12–16.13], MS (OR-CI: 8.47; 1.78–40.25), low adiponectin levels (OR-CI: 0.92; 0.87–0.98), high alanine aminotransferase levels (OR-CI: 1.03; 1.00–1.06), age (OR-CI: 1.08; 1.00–1.15), and male gender (OR-CI: 10.78; 1.61–71.96). Conclusion: In addition to traditional factors, total cholesterol and L/A ratio appear to contribute to MS characterization in severe obesity. Furthermore, the UCP1 (AG+GG) genotypes and low adiponectin levels could predispose to a more severe liver steatosis independently of MS presence. Based on our data, polymorphic UCP1 (AG+GG) obese patients with low adiponectin levels appear to be high-risk subjects for worsening of liver steatosis, a NAFLD, possibly requiring a second-step evaluation by liver biopsy.

The absence of polymorphisms in ADRB3, UCP1, PPARγ, and ADIPOQ genes protects morbid obese patients toward insulin resistance

Background and aims: The insulin resistance (IR) is a major metabolic impairment in severe obesity, a multifactorial disease in which the importance of the effect of single nucleotide polymorphisms (SNP) associations in different rather than individual genes was established. The aim of this study was to test the predictive value of presence/absence of polymorphisms/variants in β3-adrenergic receptor (ADRB3), uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor γ (PPARγ), and adiponectin (ADIPOQ) genes in diagnosing the IR in obesity. Subjects and methods: We studied 112 (40 males, 72 females) severely obese (body mass index: 48.5±7.5 kg/m2) subjects recruited from the outpatient obesity clinic of Federico II University Hospital in Naples. Genomic DNA was extracted from peripheral leukocytes with a commercial kit. The gene polymorphisms Trp64Arg in ADRB3, −3826 A>G in UCP1, Pro12Ala in PPARγ, and c.268G>A, c.331 T>C, and c.334C>T in ADIPOQ were characterized by TaqMan assay or by direct sequencing (ADIPOQ). Results and conclusion: Our results demonstrate that −3826A>G UCP1 polymorphism is associated with IR in morbid obesity. Further, the lack of any polymorphisms, Trp64Arg in ADRB3 and/or −3826 A>G in UCP1 and/or Pro12Ala in PPARγ and/or c.268G>A, c.331 T>C and c.334C>T in ADIPOQ, appears a useful prognostic factor (NPV=100%) toward the IR onset in these obese patients representing a further parameter for an earlier and appropriate therapy.

Synergistic Effect of L-Carnosine and EGCG in the Prevention of Physiological Brain Aging

The benefits of multi-target action are well established in a variety of pathological models. Many dietary supplements and nutraceuticals may be useful to slow age-related cognitive declines and the risk of developing neurodegenerative disease. L-Carnosine and EGCG are natural compounds that have received particular attention because of their potential role in modulating oxidative stress associated with aging and chronic conditions. The biological activities of these naturally occurring substances have frequently been used to prevent or reduce senile features; however they have never been evaluated as a combined treatment. In the present study we investigated the combined effect of L-Carnosine and EGCG on the activation of two stress-responsive pathways: HO-1 and Hsp72 (the inducible form of Hsp70), which play an important role in cytoprotection against oxidative stress-induced cell damage. We demonstrated that the neuroprotective effects of EGCG and L-Carnosine are achieved through the modulation of HO-1/Hsp72 systems. Furthermore, the combined action of both compounds resulted in a synergistic increase of HO-1 expression which suggests a crosstalk between the HO-1 and the Hsp72-mediated pathways. Our results indicate that the combined administration of EGCG and L-Carnosine would benefit the treatment and prevention of neurodegenerative diseases by reducing the neuronal damage caused by oxidative stress.

Hospital admission and mortality rates in anorexia nervosa: Experience from an integrated medical-psychiatric outpatient treatment

Objectives: To evaluate the effectiveness of an integrated medical-psychiatric treatment of major eating disorders. Design: Historical cohort study. Setting: Outpatient Unit for Protein Energy Malnutrition of the Department of Clinical and Experimental Medicine, “Federico II” University of Naples, time of study: January 1994 to December 1997 Participants: 147 female patients with restrictive or bulimic anorexia nervosa (mean age 19.8±13.7, BMI 14.7±2.1 Kg/m2) consecutively attending the outpatient unit between January 1994 and December 1997. Main outcome measures: Hospitalization and mortality rates were evaluated up to Jan 1999 with a minimum follow-up of 18 months. Results: There were 23 admissions to the Clinical Nutrition ward for 19 patients (i.e. 12.9%) mostly due to severe protein energy malnutrition, and 2 deaths, only 1 strictly related to anorexia (mortality rate 0.7%). Conclusions: Integrated outpatient medical-psychiatric treatment for major eating disorders is an effective and inexpensive procedure that reduces mortality and admissions due to medical complications in the medium term.

Muscle uncoupling protein 3 expression is unchanged by chronic ephedrine/caffeine treatment: results of a double blind, randomised clinical trial in morbidly obese females.

Ephedrine/caffeine combination (EC) has been shown to induce a small-to-moderate weight loss in obese patients. Several mechanisms have been proposed, among which an increased thermogenic capacity of skeletal muscle consequent to the EC-induced up-regulation of uncoupling protein 3 (UCP3) gene expression. We did a parallel group double-blind, placebo-controlled, 4-week trial to investigate this hypothesis. Thirteen morbidly obese women (25–52 years of age, body-mass index 48.0±4.0 kg/m2, range 41.1–57.6) were randomly assigned to EC (200/20 mg, n = 6) or to placebo (n = 7) administered three times a day orally, before undergoing bariatric surgery. All individuals had an energy-deficit diet equal to about 70% of resting metabolic rate (RMR) diet (mean 5769±1105 kJ/day). The RMR analysed by intention to treat and the UCP3 (long and short isoform) mRNA levels in rectus abdominis were the primary outcomes. Body weight, plasma levels of adrenaline, noradrenaline, triglycerides, free fatty acids, glycerol, TSH, fT4, and fT3 were assessed, as well as fasting glucose, insulin and HOMA index, at baseline and at the end of treatments. Body weight loss was evident in both groups when compared to baseline values (overall −5.2±3.2%, p<0.0001) without significant differences between the treated groups. EC treatment increased the RMR (+9.2±6.8%, p = 0.020), differently from placebo which was linked to a reduction of RMR (−7.6±6.5%, p = 0.029). No significant differences were seen in other metabolic parameters. Notably, no changes of either UCP3 short or UCP3 long isoform mRNA levels were evident between EC and placebo group. Our study provides evidence that 4-week EC administration resulted in a pronounced thermogenic effect not related to muscle UCP3 gene expression and weight loss in morbidly obese females under controlled conditions. Trial Registration ClinicalTrials.gov NCT02048215

Hemodialysis Arteriovenous Access Occlusion Using the Amplatzer Vascular Plug in Patients with Intractable Arm Edema

Objectives: Vascular occlusion of hemodialysis arteriovenous access (AVA) using an Amplatzer vascular plug (AVP; St. Jude Medical, St. Paul, MN, USA) is an arising and alternative practice in selected patients; however, few reported cases can be found in the literature. Herein, we report on our experience with endovascular treatment of complicated AVA. Materials and Methods: From September 2015 to December 2016, 3 patients at our clinic underwent an occlusion of hemodialysis AVA with 2 different Amplatzer vascular plugs: 2 patients with type II and 1 patient with type IV. Of these, 1 patient was treated for an autologous radiocephalic fistula, the second patient was treated for an autologous brachiocephalic fistula located at the elbow, and the third was, instead, treated for a radiocephalic forearm fistula. The reason for closing the AVA in all patients was due to the presence of dialysis-associated steal syndrome with critical hand ischemia and intractable ipsilateral edema. Results: All AVAs were treated using an AVP. No plug migration, access revascularization, persistent ischemia, nor other complications were observed. Conclusion: This report suggests that the use of AVP for embolization of complicated AVA is a safe and reasonable alternative to open surgery in selected patients.