Circulating Citrate Is Reversibly Elevated in Patients with End-Stage Liver Disease: Association with All-Cause Mortality.

Circulating citrate may serve as a proxy for mitochondrial dysfunction which plays a role in the progression of end-stage liver disease (ESLD). This study aimed to determine the extent of alterations in circulating citrate in patients with ESLD, and examined its association with all-cause mortality among ESLD patients while on the waiting list for liver transplantation. Plasma citrate levels were measured using nuclear magnetic resonance spectroscopy in 129 ESLD patients (TransplantLines cohort study; NCT03272841) and compared to levels in 4837 participants of the community-dwelling PREVEND cohort.

Branched-chain amino acids and their metabolites decrease human and rat hepatic stellate cell activation.

Background: End-stage liver diseases (ESLDs) are a significant global health challenge due to their high prevalence and severe health impacts. Despite the severe outcomes associated with ESLDs, therapeutic options remain limited. Targeting the activation of hepatic stellate cells (HSCs), key drivers of extracellular matrix accumulation during liver injury presents a novel therapeutic approach.

Collagen-rich liver-derived extracellular matrix hydrogels augment survival and function of primary rat liver sinusoidal endothelial cells and hepatocytes.

Liver sinusoidal endothelial cells (LSECs) are key targets for addressing metabolic dysfunction-associated steatotic liver disease (MASLD). However, isolating and culturing primary LSECs is challenging due to rapid dedifferentiation, resulting in loss of function. The extracellular matrix (ECM) likely plays a crucial role in maintaining the fate and function of LSECs.

Circulating Trimethylamine-N-Oxide Is Elevated in Liver Transplant Recipients.

Liver transplant recipients (LTRs) have lower long-term survival rates compared with the general population. This underscores the necessity for developing biomarkers to assess post-transplantation mortality. Here we compared plasma trimethylamine-N-oxide (TMAO) levels with those in the general population, investigated its determinants, and interrogated its association with all-cause mortality in stable LTRs.

Extracellular vesicles originating from steatotic hepatocytes promote hepatic stellate cell senescence via AKT/mTOR signaling.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing rapidly due to the obesity epidemic. In the inflammatory stages of MASLD (MASH), activation of hepatic stellate cells (HSCs) leads to initiation and progression of liver fibrosis. Extracellular vesicles (EVs) are released from all cell types and play an important role in intercellular communication.

Inhibition of endogenous hydrogen sulfide production reduces activation of hepatic stellate cells via the induction of cellular senescence.

In chronic liver injury, quiescent hepatic stellate cells (HSCs) transdifferentiate into activated myofibroblast-like cells and produce large amounts of extracellular matrix components, e.g. collagen type 1.

Extracellular vesicles derived from liver sinusoidal endothelial cells inhibit the activation of hepatic stellate cells and Kupffer cells in vitro.

Liver sinusoidal endothelial cells (LSECs) play a crucial role in maintaining liver microcirculation and exchange of nutrients in the liver and are thought to be involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). The activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs) has been considered to be responsible for the onset of liver fibrosis and the aggravation of liver injury. However, the paracrine regulatory effects of LSECs in the development of MASLD, in particular the role of LSEC-derived extracellular vesicles (EVs) remains unclear.

The Coumarin-Derivative Esculetin Protects against Lipotoxicity in Primary Rat Hepatocytes via Attenuating JNK-Mediated Oxidative Stress and Attenuates Free Fatty Acid-Induced Lipid Accumulation.

Coumarin derivates have been proposed as a potential treatment for metabolic-dysfunction-associated fatty liver disease (MAFLD). However, the mechanisms underlying their beneficial effects remain unclear. In the present study, we explored the potential of the coumarin derivate esculetin in MAFLD, focusing on hepatocyte lipotoxicity and lipid accumulation.

Hepatic stellate cells induce an inflammatory phenotype in Kupffer cells via the release of extracellular vesicles.

Liver fibrosis is the response of the liver to chronic liver inflammation. The communication between the resident liver macrophages (Kupffer cells [KCs]) and hepatic stellate cells (HSCs) has been mainly viewed as one-directional: from KCs to HSCs with KCs promoting fibrogenesis. However, recent studies indicated that HSCs may function as a hub of intercellular communications.

Hydroxyurea attenuates hepatic stellate cell proliferation in vitro and liver fibrogenesis in vivo.

Liver fibrosis results from excessive proliferation of, and collagen production by hepatic stellate cells (HSCs) that is caused by chronic liver injury. No drugs are available to cure liver fibrosis. Hydroxyurea is an anti-proliferative drug that is used in benign and malignant disorders.

Protective effects of caffeine against palmitate-induced lipid toxicity in primary rat hepatocytes is associated with modulation of adenosine receptor A1 signaling.

Background: Epidemiological evidence has shown an association between coffee consumption and reduced risk for chronic liver diseases, including metabolic-dysfunction-associated liver disease (MALFD). Lipotoxicity is a key cause of hepatocyte injury during MAFLD. The coffee component caffeine is known to modulate adenosine receptor signaling via the antagonism of adenosine receptors.

Studying Hepatic Stellate Cell Senescence.

Hepatic stellate cells (HSCs) are the key effector cells in liver fibrosis. They are the main producers of excessive amounts of extracellular matrix components during fibrogenesis and therefore a potential target for the treatment of liver fibrosis. Induction of senescence in HSCs may be a promising strategy to slow down, stop, or even reverse fibrogenesis.

Branched Chain Amino Acids Are Associated with Physical Performance in Patients with End-Stage Liver Disease.

Decreased circulating branched chain amino acids (BCAA) represent a prominent change in amino acid profiles in patients with end-stage liver disease (ESLD). These alterations are considered to contribute to sarcopenia and hepatic encephalopathy and may relate to poor prognosis. Here, we cross-sectionally analyzed the association between plasma BCAA levels and the severity of ESLD and muscle function in participants of the liver transplant subgroup of TransplantLines, enrolled between January 2017 and January 2020.

Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes.

Bone morphogenetic protein (BMP)-9, a member of the TGFβ-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21.

Arginase 1 expression is increased during hepatic stellate cell activation and facilitates collagen synthesis.

Activation of hepatic stellate cells (HSC) is a key event in the initiation of liver fibrosis. Activated HSCs proliferate and secrete excessive amounts of extracellular matrix (ECM), disturbing liver architecture and function, leading to fibrosis and eventually cirrhosis. Collagen is the most abundant constituent of ECM and proline is the most abundant amino acid of collagen.

Molecular and Antioxidant Characterization of Fruit Extract and Its Protective Effect against Diclofenac-Induced Acute Liver Injury in an In Vivo Rat Model.

A molecular characterization of the main phytochemicals and antioxidant activity of (OR) fruit extract was carried out, as well as an evaluation of its hepatoprotective effect against diclofenac (DF)-induced acute liver injury was evaluated. Phenols, flavonoids and betalains were quantified, and antioxidant characterization was performed by means of the ABTS, DPPH and FRAP assays. UPLC-QTOF-MS/MS was used to identify the main biocompounds present in OR fruit extract was carried out via.

Differential effects of oleate on vascular endothelial and liver sinusoidal endothelial cells reveal its toxic features in vitro.

Several fatty acids, in particular saturated fatty acids like palmitic acid, cause lipotoxicity in the context of non-alcoholic fatty liver disease . Unsaturated fatty acids (e.g.

Responses of retinal and brain microvasculature to streptozotocin induced diabetes revealed by global expression profiling.

This study aims to determine the effects of diabetes in the retinal and brain microvasculature through gene expression profiling. Twelve male Wistar rats were randomly divided into two groups: streptozotocin-induced diabetic rats and time-matched nondiabetic rats. The retinal microvessels (RMVs) and brain microvessels (BMVs) were mechanically isolated from individual rats.

Hepatoprotective Effect of Fruit Biocomponents in a Rat Model of Thioacetamide-Induced Liver Fibrosis.

Liver fibrosis is a chronic disease associated with oxidative stress that has a great impact on the population mortality. Due to their antioxidant capacity, we evaluated the protective effect of Opuntia robusta fruit (Or) on liver fibrosis. A nutraceutical characterization of Or was performed and a model of fibrosis was induced with thioacetamide (TAA) in Wistar rats.

Modulation of Oxidative Stress-Induced Senescence during Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease is characterized by disturbed lipid metabolism and increased oxidative stress. These conditions lead to the activation of different cellular response mechanisms, including senescence. Cellular senescence constitutes an important response to injury in the liver.

A Potential Role for Bile Acid Signaling in Celiac Disease-Associated Fatty Liver.

Celiac disease (CeD) is a chronic autoimmune disorder characterized by an intolerance to storage proteins of many grains. CeD is frequently associated with liver damage and steatosis. Bile acid (BA) signaling has been identified as an important mediator in gut-liver interaction and the pathogenesis of non-alcoholic fatty liver disease (NAFLD).

Scopoletin and umbelliferone protect hepatocytes against palmitate- and bile acid-induced cell death by reducing endoplasmic reticulum stress and oxidative stress.

Background: The number of patients with non-alcoholic fatty liver disease (NAFLD) is rapidly increasing due to the growing epidemic of obesity. Non-alcoholic steatohepatitis (NASH), the inflammatory stage of NAFLD, is characterized by lipid accumulation in hepatocytes, chronic inflammation and hepatocyte cell death. Scopoletin and umbelliferone are coumarin-like molecules and have antioxidant, anti-cancer and anti-inflammatory effects.

α-1 Adrenergic receptor antagonist doxazosin reverses hepatic stellate cells activation via induction of senescence.

Background: Activated hepatic stellate cells (aHSCs) are the main effector cells during liver fibrogenesis. α-1 adrenergic antagonist doxazosin (DX) was shown to be anti-fibrotic in an in vivo model of liver fibrosis (LF), but the mechanism remains to be elucidated. Recent studies suggest that reversion of LF can be achieved by inducing cellular senescence characterized by irreversible cell-cycle arrest and acquisition of the senescence-associated secretory phenotype (SASP).