Glutathione (GSH), a tripeptide particularly concentrated in the liver, is the most important thiol reducing agent involved in the modulation of redox processes. It has also been demonstrated that GSH cannot be considered only as a mere free radical scavenger but that it takes part in the network governing the choice between survival, necrosis and apoptosis as well as in altering the function of signal transduction and transcription factor molecules. The purpose of the present review is to provide an overview on the molecular biology of the GSH system; therefore, GSH synthesis, metabolism and regulation will be reviewed. The multiple GSH functions will be described, as well as the importance of GSH compartmentalization into distinct subcellular pools and inter-organ transfer. Furthermore, we will highlight the close relationship existing between GSH content and the pathogenesis of liver disease, such as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), chronic cholestatic injury, ischemia/reperfusion damage, hepatitis C virus (HCV), hepatitis B virus (HBV) and hepatocellular carcinoma. Finally, the potential therapeutic benefits of GSH and GSH-related medications, will be described for each liver disorder taken into account.

Childhood obesity is a leading public health problem worldwide, as it is increasingly prevalent and therefore responsible for serious obesity-related comorbidities, not only in childhood but also in adulthood. In addition to cardio-metabolic obesity-related disorders, recent evidence suggests that excess adipose tissue in turn is associated with immune cell infiltration, increased adipokine release, and the development of low-grade systemic inflammation obesity. Exercise is considered a non-pharmacological intervention that can delay obesity-related comorbidities, improving cardiovascular fitness and modulating the inflammatory processes. It has been reported that the anti-inflammatory effect of regular exercise may be mediated by a reduction in visceral fat mass, with a subsequent decrease in the release of adipokines from adipose tissue (AT) and/or by the induction of an anti-inflammatory environment. In this narrative review, we discuss the role of AT as an endocrine organ associated with chronic inflammation and its role in obesity-related complications, focusing on the effect of exercise in reducing inflammation in children and adolescents with obesity. Regular physical exercise must be considered as a natural part of a healthy lifestyle, and promoting physical activity starting from childhood is useful to limit the negative effects of obesity on health. The crucial role of the immune system in the development of obesity-induced inflammatory processes and the efficacy of exercise as an anti-inflammatory, non-pharmacological intervention may provide possible targets for the development of new treatments and early preventive strategies.

Nonalcoholic fatty liver disease (NAFLD) is a continuum of liver abnormalities often starting as simple steatosis and to potentially progress into nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Because of its increasing prevalence, NAFLD is becoming a major public health concern, in parallel with a worldwide increase in the recurrence rate of diabetes and metabolic syndrome. It has been estimated that NASH cirrhosis may surpass viral hepatitis C and become the leading indication for liver transplantation in the next decades. The broadening of the knowledge about NASH pathogenesis and progression is of pivotal importance for the discovery of new targeted and more effective therapies; aim of this review is to offer a comprehensive and updated overview on NAFLD and NASH pathogenesis, the most recommended treatments, drugs under development and new drug targets. The most relevant in vitro and in vivo models of NAFLD and NASH will be also reviewed, as well as the main molecular pathways involved in NAFLD and NASH development.

Childhood obesity is characterized by an increased risk of several metabolic derangements including insulin resistance (IR). The strongest recommendations to prevent obesity and related complications are a balanced and adequate diet and practicing physical activity from early childhood. In this review, we propose to present the effects of healthy lifestyle strategies, including physical exercise and dietary approaches, on the management of IR and related metabolic derangements. All types of exercise (aerobic, resistance and combined training) effectively reduce IR in pediatric patients with obesity; it seems that aerobic and combined training stimulate greater improvements in IR compared to resistance training. Balanced normocaloric or hypocaloric dietary approaches are also valid strategies to address IR; it is not possible to assess the long-term impact of varying macronutrients on cardiometabolic risk. The glycemic index/load evaluation is a useful dietary approach to glucose metabolism control. Similarly, they should adopt the principle of the Mediterranean diet. Randomized studies with longer monitoring are needed to define the benefits of nutritional supplementation on IR. Considering that healthy style acquisition could track to later ages, programs of healthy lifestyle starting with children offer a better preventive strategy to preserve metabolic control and children’s health.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are some of the biggest public health challenges due to their spread and increasing incidence around the world. NAFLD is characterized by intrahepatic lipid deposition, accompanied by dyslipidemia, hypertension, and insulin resistance, leading to more serious complications. Among the various causes, drug administration for the treatment of numerous kinds of diseases, such as antiarrhythmic and antihypertensive drugs, promotes the onset and progression of steatosis, causing drug-induced hepatic steatosis (DIHS). Here, we reviewed in detail the major classes of drugs that cause DIHS and the specific molecular mechanisms involved in these processes. Eight classes of drugs, among the most used for the treatment of common pathologies, were considered. The most diffused mechanism whereby drugs can induce NAFLD/NASH is interfering with mitochondrial activity, inhibiting fatty acid oxidation, but other pathways involved in lipid homeostasis are also affected. PubMed research was performed to obtain significant papers published up to November 2021. The key words included the class of drugs, or the specific compound, combined with steatosis, nonalcoholic steatohepatitis, fibrosis, fatty liver and hepatic lipid deposition. Additional information was found in the citations listed in other papers, when they were not displayed in the original search.

Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.