Ablation of secreted phosphoprotein-1 in hepatocytes increases fatty acid oxidation and ameliorates alcohol-associated liver disease.

Background: Previously, we demonstrated that Spp1 mice exhibit a greater susceptibility to alcohol-induced liver injury than wild-type (WT) mice. Notably, alcohol triggers the expression of osteopontin (encoded by SPP1) in hepatocytes. However, the specific role of hepatocyte-derived SPP1 in either mitigating or exacerbating alcohol-associated liver disease (AALD) has yet to be elucidated.

Redox-sensitive high-mobility group box-1 isoforms contribute to liver fibrosis progression and resolution in mice.

Background & Aims: High-mobility group box-1 (HMGB1) significantly increases and undergoes post-translational modifications (PTMs) in response to liver injury. Since oxidative stress plays a major role in liver fibrosis and induces PTMs in proteins, we hypothesized that redox-sensitive HMGB1 isoforms contribute to liver fibrosis progression and resolution.

Methods: We used ESI-LC-MS (electrospray ionization-liquid chromatography-mass spectrometry) to study PTMs of HMGB1 during fibrosis progression and resolution.

Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1.

Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSCs), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSCs are the source of NEP.

Intestinal Osteopontin Protects From Alcohol-induced Liver Injury by Preserving the Gut Microbiome and the Intestinal Barrier Function.

Background & Aims: The gut-liver axis plays a key role in the pathogenesis of alcohol-associated liver disease (ALD). We demonstrated that Opn develop worse ALD than wild-type (WT) mice; however, the role of intestinal osteopontin (OPN) in ALD remains unknown. We hypothesized that overexpression of OPN in intestinal epithelial cells (IECs) could ameliorate ALD by preserving the gut microbiome and the intestinal barrier function.

The Specific NLRP3 Antagonist IFM-514 Decreases Fibrosis and Inflammation in Experimental Murine Non-Alcoholic Steatohepatitis.

Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH. Groups of 12-week-old mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD).

Combination of phosphodiesterase-5-inhibitors and beta blockers improves experimental portal hypertension and erectile dysfunction.

Background & Aims: Phosphodiesterase-5 inhibitors (PDE-5-I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side-effects have been reported. Non-selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED.

Aminoguanidine reduces diabetes-associated cardiac fibrosis.

Aminoguanidine (AG) inhibits advanced glycation end products (AGEs) and advanced oxidation protein products (AOPP) accumulated as a result of excessive oxidative stress in diabetes. However, the molecular mechanism by which AG reduces AGE-associated damage in diabetes is not well understood. Thus, we investigated whether AG supplementation mitigates oxidative-associated cardiac fibrosis in rats with type 2 diabetes mellitus (T2DM).

Exploring longitudinal trends and recovery gradients in macroinvertebrate communities and biomonitoring tools along regulated rivers.

Flow regime alteration by dams has been recognized as a major impact factor for aquatic communities. Spain is currently the member state of the EU with the largest number of large reservoirs. With the broad objective of diminishing the ongoing river degradation trend through the management of environmental flows and the use of biomonitoring tools, we investigated the effects of dams on stream macroinvertebrates in several regulated rivers in Spain with contrasting environmental settings.

TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor.

Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD.

Combination of CCl with alcoholic and metabolic injuries mimics human liver fibrosis.

Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl) liver fibrosis model does not reflect human NAFLD or ALD, but CCl may serve as a fibrosis accelerator in addition to another injury.

Compartmentalization of Immune Response and Microbial Translocation in Decompensated Cirrhosis.

Acquired dysfunctional immunity in cirrhosis predisposes patients to frequent bacterial infections, especially spontaneous bacterial peritonitis (SBP), leading to systemic inflammation that is associated with poor outcome. But systemic inflammation can also be found in the absence of a confirmed infection. Detection of bacterial DNA has been investigated as a marker of SBP and as a predictor of prognosis.

Rho-kinase inhibitor coupled to peptide-modified albumin carrier reduces portal pressure and increases renal perfusion in cirrhotic rats.

Rho-kinase (ROCK) activation in hepatic stellate cells (HSC) is a key mechanism promoting liver fibrosis and portal hypertension (PTH). Specific delivery of ROCK-inhibitor Y-27632 (Y27) to HSC targeting mannose-6-phosphate-receptors reduces portal pressure and fibrogenesis. In decompensated cirrhosis, presence of ascites is associated with reduced renal perfusion.

The multikinase inhibitor regorafenib decreases angiogenesis and improves portal hypertension.

Background And Aims: Angiogenesis is critically involved in the development of liver fibrosis, portal hypertension (PHT) and hepatocellular carcinoma (HCC). Regorafenib is a novel second-line therapy for HCC, but might also be beneficial in fibrosis and PHT even in absence of HCC. This study investigated the effects of regorafenib in experimental models without HCC.

Use of intrapartum ultrasound in term pregnant women with contractions before hospital admission.

Introduction: The aim of this study was to test the hypothesis that transperineal ultrasound can be used to decide whether to admit a pregnant woman due to labor.

Material And Methods: In this analytical cross-sectional observational study, transperineal ultrasound was performed on pregnant women with intact membranes who came to the hospital due to contractions. A decision was made to admit women due to labor based on the ultrasound measurements.

Efficacy of carbetocin for preventing postpartum bleeding after cesarean section in twin pregnancy.

This is a prospective observational study whose goal was to compare the effectiveness of carbetocin and oxytocin for prevention of postpartum hemorrhage (PPH) when they are administered in twin pregnancies undergoing a cesarean section. We enrolled 166 twin pregnancies at term undergoing elective or emergency cesarean section. We compared the effect of a single 100 µg dose of carbetocin with the use of oxytocin as a protocol (20 IU in Ringer lactate 500 ml in 10-15 min).

High Mobility Group Box-1 Drives Fibrosis Progression Signaling via the Receptor for Advanced Glycation End Products in Mice.

High-mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) increased in response to liver injury. Because HMGB1 is a ligand for the receptor for advanced glycation endproducts (RAGE), we hypothesized that induction of HMGB1 could participate in the pathogenesis of liver fibrosis though RAGE cell-specific signaling mechanisms. Liver HMGB1 protein expression correlated with fibrosis stage in patients with chronic hepatitis C virus (HCV) infection, primary biliary cirrhosis (PBC), or alcoholic steatohepatitis (ASH).

Flows, ecology and people: is there room for cultural demands in the assessment of environmental flows?

The science and practice of environmental flows - aimed at the protection of ecosystem values and functions in regulated rivers - has progressively recognized the relevance of incorporating socio-cultural demands of local communities in the calculation of water requirements of rivers' habitats and services. This review paper synthesizes the concept of cultural flows, and presents the main approaches explored or conducted up to this date to provide such flows in rivers of different regions and typology. This work highlights the necessity of integrating cultural demands in future attempts to protect and restore altered flow patterns, due to the multiple interactions between flow, ecology and people which typically characterize rivers and other aquatic systems.

Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease.

The aim of this study was to investigate the role of osteopontin (OPN) in hematopoietic stem cell (HPSC) mobilization to the liver and its contribution to alcoholic liver disease (ALD). We analyzed young (14-16 weeks) and old (>1.5 years) wild-type (WT) littermates and global knockout ( ) mice for HPSC mobilization to the liver.

"Tipping" extracellular matrix remodeling towards regression of liver fibrosis: novel concepts.

Fibrosis development was initially conceived as an incessant progressive condition. Nowadays, it has become evident that fibrotic tissue undergoes a continuous two-way process: fibrogenesis and fibrinolysis, characterizing the remodeling of extracellular matrix (ECM). However, in established fibrosis, this two-way process is tipped towards fibrogenesis and this leads to a self-perpetuating accumulation of ECM, a distinct metabolic unit, together with other cells and processes promoting fibrosis deposition.

Rationale for the use of statins in liver disease.

The evolution of chronic liver injuries from benign and manageable dysfunction to life threatening end-stage liver disease with severe complications renders chronic liver disease a global health burden. Because of the lack of effective medication, transplantation remains the only and final curative option for end-stage liver disease. Since the demand for organ transplants by far exceeds the supply, other treatment options are urgently required to prevent progression and improve end-stage liver disease.

Key Events Participating in the Pathogenesis of Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality worldwide. It ranges from fatty liver to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma.The most prevalent forms of ALD are alcoholic fatty liver, alcoholic hepatitis (AH) and alcoholic cirrhosis, which frequently progress as people continue drinking.

Cartilage oligomeric matrix protein participates in the pathogenesis of liver fibrosis.

Background & Aims: Liver fibrosis is characterized by significant accumulation of extracellular matrix (ECM) proteins, mainly fibrillar collagen-I, as a result of persistent liver injury. Cartilage oligomeric matrix protein (COMP) is largely found in the ECM of skeletal tissue. Increased COMP expression has been associated with fibrogenesis in systemic sclerosis, lung fibrosis, chronic pancreatitis, cirrhosis and hepatocellular carcinoma.

Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury.

Objective: Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.