Optimization of Statin-Loaded Delivery Nanoparticles for Treating Chronic Liver Diseases by Targeting Liver Sinusoidal Endothelial Cells.

In this study, we developed functionalized polymeric micelles (FPMs) loaded with simvastatin (FPM-Sim) as a drug delivery system to target liver sinusoidal endothelial cells (LSECs) for preserving liver function in chronic liver disease (CLD). Polymeric micelles (PMs) were functionalized by coupling peptide ligands of LSEC membrane receptors CD32b, CD36 and ITGB3. Functionalization was confirmed via spectroscopy and electron microscopy.

Proteomic Analysis of Dysfunctional Liver Sinusoidal Endothelial Cells Reveals Substantial Differences in Most Common Experimental Models of Chronic Liver Diseases.

Molecular markers of dedifferentiation of dysfunctional liver sinusoidal endothelial cells (LSEC) have not been fully elucidated. We aimed at deciphering the molecular profile of dysfunctional LSEC in different pathological scenarios. Flow cytometry was used to sort CD11b/CD32b and CD11b/CD32b LSEC from three rat models of liver disease (bile duct ligation-BDL; inhaled carbon tetrachloride-CCl4; and high fat glucose/fructose diet-HFGFD).

Smart and eco-friendly N-isopropylacrylamide and cellulose hydrogels as a safe dual-drug local cancer therapy approach.

Local cancer treatment by in situ injections of thermo-responsive hydrogels (HG) offers several advantages over conventional systemic anti-cancer treatments. In this work, a biodegradable and multicompartmental HG composed of N-isopropylacrylamide, cellulose, citric acid, and ceric ammonium nitrate was developed for the controlled release of hydrophilic (doxorubicin) and hydrophobic (niclosamide) drugs. The formulation presented ideal properties regarding thermo-responsiveness, rheological behavior, drug release profile, biocompatibility, and biological activity in colon and ovarian cancer cells.

Synergic effect of atorvastatin and ambrisentan on sinusoidal and hemodynamic alterations in a rat model of NASH.

In non-alcoholic steatohepatitis (NASH), decreased nitric oxide and increased endothelin-1 (ET-1, also known as EDN1) released by sinusoidal endothelial cells (LSEC) induce hepatic stellate cell (HSC) contraction and contribute to portal hypertension (PH). Statins improve LSEC function, and ambrisentan is a selective endothelin-receptor-A antagonist. We aimed to analyse the combined effects of atorvastatin and ambrisentan on liver histopathology and hemodynamics, together with assessing the underlying mechanism in a rat NASH model.

Steatosis as main determinant of portal hypertension through a restriction of hepatic sinusoidal area in a dietary rat nash model.

Background & Aims: Portal hypertension (PH) can be present in pre-cirrhotic stages, even in absence of fibrosis in non-alcoholic steatohepatitis (NASH) patients. Liver endothelial dysfunction (ED) has been shown as responsible for this effect in short-term dietary animal models. We evaluated the persistence of PH and underlying mechanisms in a long-term rat model of NASH.

Simvastatin-loaded polymeric micelles are more effective and less toxic than conventional statins in a pre-clinical model of advanced chronic liver disease.

Chronic liver disease (CLD) has no effective treatments apart from reducing its complications. Simvastatin has been tested as vasoprotective drug in experimental models of CLD showing promising results, but also limiting adverse effects. Two types of Pluronic® carriers loading simvastatin (PM108-simv and PM127-simv) as a drug delivery system were developed to avoid these toxicities while increasing the therapeutic window of simvastatin.

Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disorder in developed countries, with the associated clinical complications driven by portal hypertension (PH). PH may precede fibrosis development, probably due to endothelial dysfunction at early stages of the disease. Our aim was to characterize liver sinusoidal endothelial cell (LSEC) dedifferentiation/capillarization and its contribution to PH in NASH, together with assessing statins capability to revert endothelial function improving early NASH stages.

Emricasan Ameliorates Portal Hypertension and Liver Fibrosis in Cirrhotic Rats Through a Hepatocyte-Mediated Paracrine Mechanism.

In cirrhosis, liver microvascular dysfunction is a key factor increasing hepatic vascular resistance to portal blood flow, which leads to portal hypertension. De-regulated inflammatory and pro-apoptotic processes due to chronic injury play important roles in the dysfunction of liver sinusoidal cells. The present study aimed at characterizing the effects of the pan-caspase inhibitor emricasan on systemic and hepatic hemodynamics, hepatic cells phenotype, and underlying mechanisms in preclinical models of advanced chronic liver disease.

Ischemia/Reperfusion Injury in the Aged Liver: The Importance of the Sinusoidal Endothelium in Developing Therapeutic Strategies for the Elderly.

The liver endothelium plays a key role in the progression and resolution of liver diseases in young and adult individuals. However, its role in older people remains unknown. We have herein evaluated the importance of the sinusoidal endothelium in the pathophysiology of acute liver injury, and investigated the applicability of simvastatin, in aged animals.

Effects of aging on liver microcirculatory function and sinusoidal phenotype.

The socioeconomic and medical improvements of the last decades have led to a relevant increase in the median age of worldwide population. Although numerous studies described the impact of aging in different organs and the systemic vasculature, relatively little is known about liver function and hepatic microcirculatory status in the elderly. In this study, we aimed at characterizing the phenotype of the aged liver in a rat model of healthy aging, particularly focusing on the microcirculatory function and the molecular status of each hepatic cell type in the sinusoid.

Effects of warm ischemia and reperfusion on the liver microcirculatory phenotype of rats: underlying mechanisms and pharmacological therapy.

Warm ischemia and reperfusion (WIR) causes hepatic damage and may lead to liver failure, however the mechanisms involved are largely unknown. Here we have characterized the microcirculatory status and endothelial phenotype of livers undergoing WIR, and evaluated the use of simvastatin in WIR injury prevention. Male Wistar rats received simvastatin, or vehicle, 30 min before undergoing 60 min of partial warm ischemia (70%) followed by 2 h or 24 h of reperfusion.

A novel form of the human manganese superoxide dismutase protects rat and human livers undergoing ischaemia and reperfusion injury.

Hepatic microcirculatory dysfunction due to cold storage and warm reperfusion (CS+WR) injury during liver transplantation is partly mediated by oxidative stress and may lead to graft dysfunction. This is especially relevant when steatotic donors are considered. Using primary cultured liver sinusoidal endothelial cells (LSECs), liver grafts from healthy and steatotic rats, and human liver samples, we aimed to characterize the effects of a new recombinant form of human manganese superoxide dismutase (rMnSOD) on hepatic CS+WR injury.

Modulation of autophagy for the treatment of liver diseases.

Introduction: Autophagy is a cellular process essential for survival and homeostasis that confers cellular protection toward a wide range of deleterious stimuli. It has a highly complex regulation with several autophagic proteins also belonging to other main signaling pathways as cell proliferation or apoptosis. In addition, autophagy has an important role in cell metabolism.

Simvastatin maintains function and viability of steatotic rat livers procured for transplantation.

Background & Aims: Liver grafts obtained from healthy rat donors develop acute microcirculatory dysfunction due to cold-storage and warm-reperfusion injuries. These detrimental effects are avoided adding simvastatin to the cold-storage solution. Considering the importance of increasing organ donor pool for transplantation, we characterized whether simvastatin pretreatment can protect steatotic grafts from cold-storage and warm-reperfusion injuries.

Effects of simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction.

Unlabelled: Endothelial dysfunction drives vascular derangement and organ failure associated with sepsis. However, the consequences of sepsis on liver sinusoidal endothelial function are largely unknown. Statins might improve microvascular dysfunction in sepsis.

The transcription factor KLF2 mediates hepatic endothelial protection and paracrine endothelial-stellate cell deactivation induced by statins.

Background & Aims: Statins improve hepatic endothelial function and liver fibrosis in experimental models of cirrhosis, thus they have been proposed as therapeutic options to ameliorate portal hypertension syndrome. The transcription factor Kruppel-like factor 2 (KLF2) may be induced by statins in liver sinusoidal endothelial cells (SEC), orchestrating an efficient vasoprotective response. The present study aimed at characterizing whether KLF2 mediates statins-derived hepatic protection.