Pathophysiological-Based Nutritional Interventions in Cirrhotic Patients with Sarcopenic Obesity: A State-of-the-Art Narrative Review.

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.

Donafenib in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a global healthcare problem, with a high prevalence in nonindustrialized countries and a rising incidence in industrialized countries. Sorafenib demonstrated its efficacy as the first therapeutic agent for unresectable HCC in 2007. Since then, other multitarget tyrosine kinase inhibitors have demonstrated efficacy in HCC patients. Still, the tolerability of these drugs remains an unsolved problem, with 5-20% of patients permanently discontinuing their therapies due to adverse events. Donafenib is a deuterated form of sorafenib exploiting the increased bioavailability derived from the deuterium-for-hydrogen replacement. In the multicenter, randomized, controlled phase II-III trial ZGDH3, donafenib outperformed sorafenib in terms of overall survival, with favorable safety and tolerability. As a result, donafenib was approved as a possible first-line treatment of unresectable HCC by the National Medical Products Administration (NMPA) of China in 2021. In this monograph, we review the main preclinical and clinical evidence that emerged in the trials of donafenib.

Colonic dysmotility associated with high-fat diet-induced obesity: Role of enteric glia.

The present study was designed to examine the role of enteric glial cells (EGCs) in colonic neuromuscular dysfunctions in a mouse model of high-fat diet (HFD)-induced obesity. C57BL/6J mice were fed with HFD or standard diet (SD) for 1, 2, or 8 weeks. Colonic interleukin (IL)-1ß, IL-6, and malondialdehyde (MDA) levels were measured. Expression of occludin in colonic tissues was examined by western blot. Substance P (SP), S100ß, GFAP, and phosphorylated mitogen-activated protein kinase 1 (pERK) were assessed in whole mount specimens of colonic plexus by immunohistochemistry. Colonic tachykininergic contractions, elicited by electrical stimulation or exogenous SP, were recorded in the presence or absence of fluorocitrate (FC). To mimic exposure to HFD, cultured EGCs were incubated with palmitate (PA) and/or lipopolysaccharide (LPS). SP and IL-1ß levels were assayed in the culture medium by ELISA. HFD mice displayed an increase in colonic IL-1ß and MDA, and a reduction of occludin at week 2. These changes occurred to a greater extent at week 8. In vitro electrically evoked tachykininergic contractions were enhanced in HFD mice after 2 or 8 weeks, and they were blunted by FC. Colonic IL-6 levels as well as substance P and S100ß density in myenteric ganglia of HFD mice were increased at week 8, but not at week 1 or 2. In cultured EGCs, co-incubation with palmitate plus LPS led to a significant increase in both SP and IL-1ß release. HFD-induced obesity is characterized by a hyperactivation of EGCs and is involved in the development of enteric motor disorders through an increase in tachykininergic activity and release of pro-inflammatory mediators.