Olive polyphenol effects in a mouse model of chronic ethanol addiction

Objectives Alcohol addiction elicits oxidative imbalance and it is well known that polyphenols possess antioxidant properties. We investigated whether or not polyphenols could confer a protective potential against alcohol-induced oxidative stress. Methods We administered (per os) for two months 20 mg/kg of olive polyphenols containing mostly hydroxytyrosol in alcoholic adult male mice. Hydroxytyrosol metabolites as hydroxytyrosol sulfate 1 and hydroxytyrosol sulfate 2 were found in the serum of mice administered with polyphenols with the highest amount in animals treated with both polyphenols and alcohol. Oxidative stress was evaluated by FORT (free oxygen radical test) and FORD (free oxygen radical defense) tests. Results Alcoholic mice showed a worse oxidative status than nonalcoholic mice (higher FORT and lower FORD) but polyphenol supplementation partially counteracted the alcohol pro-oxidant effects, as evidenced by FORT. Conclusions A better understanding of the antioxidant protection provided by polyphenols might be of primary interest for drug discovery and dietary-based prevention of the damage associated with chronic alcohol abus

Macrophage Autophagy and Oxidative Stress: An Ultrastructural and Immunoelectron Microscopical Study

The word autophagy broadly refers to the cellular catabolic processes that lead to the removal of damaged cytosolic proteins or cell organelles through lysosomes. Although autophagy is often observed during programmed cell death, it may also serve as a cell survival mechanism. Accumulation of reactive oxygen species within tissues and cells induces various defense mechanisms or programmed cell death. It has been shown that, besides inducing apoptosis, oxidative stress can also induce autophagy. To date, however, the regulation of autophagy in response to oxidative stress remains largely elusive and poorly understood. Therefore, the present study was designed to examine the ratio between oxidative stress and autophagy in macrophages after oxidant exposure (AAPH) and to investigate the ultrastructural localization of beclin-1, a protein essential for autophagy, under basal and stressful conditions. Our data provide evidence that oxidative stress induces autophagy in macrophages. We demonstrate, for the first time by immunoelectron microscopy, the subcellular localization of beclin-1 in autophagic cells

Investigating alcohol consumption during pregnancy for the prevention of Fetal Alcohol Spectrum Disorders (FASD)

The term FASD (Fetal Alcohol Spectrum Disorders) is used to describe the entire spectrum of pathologies and disorders caused by alcohol exposure in uterus. Alcohol assumed in pregnancy passes directly through the placental barrier causing a broad range of symptoms whose severity can greatly vary in degree. The alcohol teratogenic effect may result in physical damage and specific facial anomalies, growth delays, neurological defects along with intellectual disabilities and behavioral problems. Children affected show difficulties in verbal learning, memory, visual-spatial abilities, attention, logic and math abilities, information processing, executive functions as well as in many other domains and in general coping with daily life. Total abstention from alcohol during pregnancy is strongly recommended, as a safe threshold of consumption has not been established yet. Hence, the early identification of alcohol consumption in pregnancy is crucial. Specific methodologies to overcome difficulties related to the identification of alcohol behavior in pregnant women are needed and intervention protocols should be implemented to prevent damage in offsprings. This paper gives an overview on this pathology, from clinical delineation to epidemiology and risk factors with a special focus to promote alcohol-free pregnanc

Role of neuropeptide tyrosine (NPY) in ethanol addiction

Here, an overview of neurophysiological, pharmacological and genetic research on the role of neuropeptide tyrosine (NPY) in ethanol consumption and withdrawal is presented. NPY is abundantly expressed in the extended amygdala and is critically involved in the regulation of negative affective states in rats, also is involved with neurobiological responses to ethanol and other drug of abuse. Genetic, molecular and pharmacological evidences suggest that NPY is an important neurobiological substrate for the predisposition to alcoholism. Administration, as well as the withdrawal of ethanol, alters central NPY expression. Alcohol- preferring rats exhibit basal NPY deficits in central amygdala. In the latter, NPY may rescue dependence-induced increases in anxiety and alcohol drinking. Low NPY levels in some brain regions following ethanol withdrawal contribute to the increased sensitivity to seizure and the heightened levels of anxiety characteristic of withdrawal responses. Mice with deletion of NPY gene exhibit a high-anxiety, high-alcohol-drinking phenotype. Pharmacological and genetic manipulations suggest that central NPY signaling modulates ethanol consumption via Y1, Y2, and Y5 receptors. Analysis of chromosomal regions (QTLs) associated with alcohol consumption identified NPY as one of the genes that influence alcohol dependence and as a promising target for pharmacotherapeutics to combat alcohol associated disorders. Consequently, NPY is a potentially new pharmacological target for the treatment of alcohol diseases

Role of Neuropeptide Tyrosine (NPY) in Ethanol Addiction

Here, an overview of neurophysiological, pharmacological and genetic research on the role of neuropeptide tyrosine (NPY) in ethanol consumption and withdrawal is presented. NPY is abundantly expressed in the extended amygdala and is critically involved in the regulation of negative affective states in rats, also is involved with neurobiological responses to ethanol and other drug of abuse. Genetic, molecular and pharmacological evidences suggest that NPY is an important neurobiological substrate for the predisposition to alcoholism. Administration, as well as the withdrawal of ethanol, alters central NPY expression. Alcohol-preferring rats exhibit basal NPY deficits in central amygdala. In the latter, NPY may rescue dependence-induced increases in anxiety and alcohol drinking. Low NPY levels in some brain regions following ethanol withdrawal contribute to the increased sensitivity to seizure and the heightened levels of anxiety characteristic of withdrawal responses. Mice with deletion of NPY gene exhibit a high-anxiety, high-alcohol-drinking phenotype. Pharmacological and genetic manipulations suggest that central NPY signaling modulates ethanol consumption via Y1, Y2, and Y5 receptors. Analysis of chromosomal regions (QTLs) associated with alcohol consumption identified NPY as one of the genes that influence alcohol dependence and as a promising target for pharmacotherapeutics to combat alcohol associated disorders. Consequently, NPY is a potentially new pharmacological target for the treatment of alcohol diseases

Fetal alcohol spectrum disorders in pediatrics. FASD and the pediatrician

Fetal alcohol syndrome (FAS) is a complex and malformative condition due to the teratogenic effect of alcohol consumed during pregnancy. Several epidemiological studies have shown that maternal alcohol use during pregnancy is the most common preventable cause of mental retardation in childhood. The effects of alcohol on the fetus range from abortion to a spectrum of clinical manifestations called Fetal Alcohol Spectrum Disorders (FASD) that includes partial FAS (PFAS), neonatal Alcohol Related Birth Defects (ARBD) and Alcohol Related Neurodevelopmental Disorders (ARND) up to the most severe disease which is the so-called FAS

Clinical and genetic approach to the dysmorphic child

The child affected by a malformative syndrome represents a care challenge for the pediatrician. He is in fact the heart of the multidisciplinary team that has to manage the patient, trying to control the complications of his/her syndrome and promoting the correct psychophysical development. What we must not forget is that the pediatrician provides a continuous support to the child`s family, assisting them from the diagnosis to the management of problems related to the syndrome. This encourages the continuous follow-up of these children remembering also that the pediatrician is fundamental in the clinical management of the syndrome and for facilitating the social integration of these children

Behavioral responses in people affected by alcohol use disorder and psychiatric comorbidity: correlations with addiction severity

Aim. In this study, we investigated in people suffering from alcohol use disorder (AUD) with or without dual diagnosis (concomitant psychiatric disability) how they feel their dependence condition. We predicted that AUD people with a dual diagnosis could feel potentiated their addiction.Methods. Alcohol habits and psychiatric conditions of 183 AUD men and 62 AUD women were measured by using the DSM-5, the severity of alcohol dependence questionnaire (SADQ), the alcohol anamnesis and psychiatric examination by the symptom check list 90-R (SCL-90-R).Results. We have shown that alcohol drinking does not correlate with both psychiatric examination and self-reported psychopathology. SADQ shows that severe alcohol dependence correlates with highest psychiatric symptoms and with the levels of alcohol consumption.Conclusions. This finding suggests that high SADQ scores may represent a tool to early disclose only patients with dual diagnosis. SADQ may provide information to address pharmacological interventions because revealing aspects of the dark side of addiction potentiated by AUD associated psychopathology.

Oxidative stress inhibition by resveratrol in alcohol dependent mice

Objective uncontrolled ingestion of alcohol has dramatic consequences on the entire organism also associated with the oxidation process induced by alcohol by elevating radical oxygen species (ROS). Resveratrol, a non-flavonoid phenol, shows well-documented antioxidant properties. We investigated the potential antioxidant ability of this natural compound in a mouse model of alcohol addiction. Methods we administered (per os) for two months 10 mg/kg/day of resveratrol in alcoholic adult male mice. Oxidative stress was evaluated by measuring serum free oxygen radicals defense (FORD) and free oxygen radicals (FORT) levels. Resveratrol metabolites were measured in the serum of mice administered with resveratrol. Finally, the effect of resveratrol on alcohol-induced alteration of BDNF in the liver was investigated. Results prolonged consumption of resveratrol strongly counteracts serum ROS formation caused by chronic alcohol intake, without effects on natural, free oxygen radical defense. The presence of resveratrol metabolites only in the serum of animals supplemented with resveratrol potentiates the evidence that the antioxidant effect observed is due to the ingestion of the natural compound. Moreover, resveratrol supplementation can counteract alcohol-induced BDNF elevation in the liver, the main target of organ alcohol-induced damage. Conclusion the consumption of resveratrol through metabolite formation may play a protective role, by decreasing free radical formation, and by modulating BDNF involved in hepatic disruption induced by chronic alcohol consumption. Further investigation about the mechanism underlying the protective effect could reinforce the potential use of resveratrol as a dietary supplement to prevent damage associated with chronic alcohol abuse

Metabolic remodeling of the tumor microenvironment: migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth.

Migration stimulating factor (MSF) is a genetically truncated N-terminal isoform of fibronectin that is highly expressed during mammalian development in fetal fibroblasts, and during tumor formation in human cancer-associated myofibroblasts. However, its potential functional role in regulating tumor metabolism remains unexplored. Here, we generated an immortalized fibroblast cell line that recombinantly overexpresses MSF and studied their properties relative to vector-alone control fibroblasts. Our results indicate that overexpression of MSF is sufficient to confer myofibroblastic differentiation, likely via increased TGF-b signaling. In addition, MSF activates the inflammation-associated transcription factor NFκB, resulting in the onset of autophagy/mitophagy, thereby driving glycolytic metabolism (L-lactate production) in the tumor microenvironment. Consistent with the idea that glycolytic fibroblasts fuel tumor growth (via L-lactate, a high-energy mitochondrial fuel), MSF fibroblasts significantly increased tumor growth, by up to 4-fold. Mechanistic dissection of the MSF signaling pathway indicated that Cdc42 lies downstream of MSF and fibroblast activation. In accordance with this notion, Cdc42 overexpression in immortalized fibroblasts was sufficient to drive myofibroblast differentiation, to provoke a shift towards glycolytic metabolism and to promote tumor growth by up to 2-fold. In conclusion, the MSF/Cdc42/NFκB signaling cascade may be a critical druggable target in preventing Warburg-like cancer metabolism in tumor-associated fibroblasts. Thus, MSF functions in the metabolic remodeling of the tumor microenvironment by metabolically reprogramming cancer-associated fibroblasts toward glycolytic metabolism