Obesity is associated with the hypertrophy and hyperplasia of adipose tissue, affecting the healthy secretion profile of pro- and anti-inflammatory adipokines. Increased influx of fatty acids and inflammatory adipokines from adipose tissue can induce muscle oxidative stress and inflammation and negatively regulate myocyte metabolism. Muscle has emerged as an important mediator of homeostatic control through the consumption of energy substrates, as well as governing systemic signaling networks. In muscle, obesity is related to decreased glucose uptake, deregulation of lipid metabolism, and mitochondrial dysfunction. This review focuses on the effect of epigallocatechin-gallate (EGCG) on oxidative stress and inflammation, linked to the metabolic dysfunction of skeletal muscle in obesity and their underlying mechanisms. EGCG works by increasing the expression of antioxidant enzymes, by reversing the increase of reactive oxygen species (ROS) production in skeletal muscle and regulating mitochondria-involved autophagy. Moreover, EGCG increases muscle lipid oxidation and stimulates glucose uptake in insulin-resistant skeletal muscle. EGCG acts by modulating cell signaling including the NF-κB, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase (MAPK) signaling pathways, and through epigenetic mechanisms such as DNA methylation and histone acetylation.

The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.

Leptin has a central role in the maintenance of energy homeostasis, and its sensitivity is influenced by both the photoperiod and dietary polyphenols. The aim of this study was to investigate the effect of seasonal consumption of polyphenol-rich fruits on the hypothalamic leptin signaling system in non-obese and obese animals placed under different photoperiods. Non-obese and diet-induced obese male Fischer 344 rats were placed under either a short-day (SD) or long-day (LD) photoperiod and were supplemented with either 100 mg/kg of lyophilized red grapes or cherries. In non-obese animals, both fruits reduced energy balance independent of the photoperiod to which they were placed. However, the hypothalamic gene expression of Pomc was significantly up-regulated only in the SD photoperiod. In contrast, in obese animals only cherry significantly decreased the energy balance, although both fruits were able to counteract the diet-induced increase in hypothalamic AgRP mRNA levels when consumed during the SD photoperiod. In conclusion, the consumption of rich-polyphenol fruits may increase leptin sensitivity through the modulation of the hypothalamic leptin signal pathway mainly when consumed in the SD photoperiod. Therefore, fruit seasonality should be considered, as it can influence energy homeostasis and obesity.

Metabolic syndrome (MetS) is a global epidemic concern. Polyphenols are proposed as good candidates for its prevention, although their mechanisms are not fully understood. The gut microbiota seems to play a key role in polyphenol beneficial effects. Here, we assessed the effects of the citrus polyphenol hesperidin combining an untargeted metabolomics approach, which has an inherent potential to elucidate the host-microbiome interplay, with extensive anthropometric and biochemical characterizations and integrating metabolomics results with our previous 16S rRNA bacterial sequencing data. The rats were fed either a standard or an obesogenic cafeteria diet (CAF) for 17 weeks. After nine weeks, rats were supplemented with vehicle; low- (H1), or high- (H2) hesperidin doses. CAF animals developed MetS features. Hesperidin supplementation in CAF rats decreased the total cholesterol, LDL-C, and free fatty acids. The highest hesperidin dose also ameliorated blood pressure, insulin sensitivity, and decreased markers of arterial stiffness and inflammation. Metabolomics revealed an improvement of the lipidomic profile, decreases in circulating amino acids, and lower excretions of inflammation- and oxidative stress-related metabolites. Bacteroidaceae increases in the CAF-H2 group paralleled higher excretions of microbial-derived metabolites. Overall, our results provide detailed insights into the molecular effects of hesperidin on MetS and suggest that it is a promising prebiotic for the treatment of MetS and related conditions.

Portal hypertension (PH) is a frequent and severe clinical syndrome associated with chronic liver disease. Considering the mechanobiological effects of hydrostatic pressure and shear stress on endothelial cells, we hypothesised that PH might influence the phenotype of liver sinusoidal endothelial cells (LSECs) during disease progression. The aim of this study was to investigate the effects of increased hydrodynamic pressure on LSECs and to identify endothelial-derived biomarkers of PH. Primary LSECs were cultured under normal or increased hydrodynamic pressure within a pathophysiological range (1 vs. 12 mmHg) using a microfluidic liver-on-a-chip device. RNA sequencing was used to identify pressure-sensitive genes, which were validated in liver biopsies from two independent cohorts of patients with chronic liver disease with PH (n = 73) and participants without PH (n = 23). Biomarker discovery was performed in two additional independent cohorts of 104 patients with PH and 18 patients without PH. Transcriptomic analysis revealed marked deleterious effect of pathological pressure in LSECs and identified chromobox 7 (CBX7) as a key transcription factor diminished by pressure. Hepatic CBX7 downregulation was validated in patients with PH and significantly correlated with hepatic venous pressure gradient. MicroRNA 181a-5p was identified as pressure-induced upstream regulator of CBX7. Two downstream targets inhibited by CBX7, namely, E-cadherin (ECAD) and serine protease inhibitor Kazal-type 1 (SPINK1), were found increased in the bloodstream of patients with PH and were highly predictive of PH and clinically significant PH. We characterise the detrimental effects of increased hydrodynamic pressure on the sinusoidal endothelium, identify CBX7 as a pressure-sensitive transcription factor, and propose the combination of two of its reported products as biomarkers of PH. Increased pressure in the portal venous system that typically occurs during chronic liver disease (called portal hypertension) is one of the main drivers of related clinical complications, which are linked to a higher risk of death. In this study, we found that pathological pressure has a harmful effect on liver sinusoidal endothelial cells and identified CBX7 as a key protein involved in this process. CBX7 regulates the expression of E-cadherin and SPINK1, and consequently, measuring these proteins in the blood of patients with chronic liver disease allows the prediction of portal hypertension and clinically significant portal hypertension.