• Anti-inflammatory
• Antioxidant
• Bile duct ligation
• Juniperus excelsa
• Liver
• Rat

• Asymmetric dimethylarginine
• Diabetic cardiomyopathy
• Dimethylarginine dimethylaminohydrolase 1
• Endothelial-mesenchymal transition
• Forkhead box protein O1
• LncRNA DANCR

• Animals
• Antioxidants/pharmacology
• Arginine/analogs & derivatives
• Arginine/metabolism
• Arginine/pharmacology
• Brain-Derived Neurotrophic Factor/metabolism
• Hippocampus/drug effects
• Hippocampus/metabolism
• Male
• Maze Learning/drug effects
• Rats
• Rats, Sprague-Dawley
• Resveratrol/pharmacology
• Spatial Behavior/drug effects

• asymmetric dimethylarginine
• cardiovascular risk
• end-stage liver disease
• endothelial dysfunction
• nitric oxide
• transplantation

• Adult
• Arginine/analogs & derivatives
• Cardiovascular Diseases/epidemiology
• Cardiovascular Diseases/etiology
• End Stage Liver Disease/complications
• Heart Disease Risk Factors
• Humans
• Nitric Oxide
• Risk Factors
• Severity of Illness Index

• 045-191348-0139 Ministarstvo Znanosti, Obrazovanja i Sporta

• Atorvastatin
• Biliary duct-ligation
• Liver fibrosis
• NOX1
• Oxidative stress
• Rac1
• Rac1-GTP

• Bax
• Bcl-2
• Cholestasis
• NeuroAid
• Pgc-1α
• Tfam

• Animals
• Apoptosis/drug effects
• Apoptosis/physiology
• Cholestasis/drug therapy
• Cholestasis/genetics
• Cholestasis/metabolism
• Corpus Striatum/drug effects
• Corpus Striatum/metabolism
• Drugs, Chinese Herbal/pharmacology
• Drugs, Chinese Herbal/therapeutic use
• Gene Expression
• Male
• Organelle Biogenesis
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/biosynthesis
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics
• Proto-Oncogene Proteins c-bcl-2/biosynthesis
• Proto-Oncogene Proteins c-bcl-2/genetics
• Rats
• Rats, Wistar
• Transcription Factors/biosynthesis
• Transcription Factors/genetics
• Treatment Outcome
• bcl-2-Associated X Protein/biosynthesis
• bcl-2-Associated X Protein/genetics

Hepatic fibrosis is a major cause of morbidity and mortality worldwide, as it ultimately leads to cirrhosis, which is estimated to affect up to 2% of the global population. Hepatic fibrosis is confirmed by liver biopsy, and the erroneous nature of this technique necessitates the search for noninvasive alternatives. However, current biomarker algorithms for hepatic fibrosis have many limitations. Given that the liver is the largest organ and a major metabolic hub in the body, probing the metabolic signature of hepatic fibrosis holds promise for the discovery of new markers and therapeutic targets. Regarding individual metabolic pathways, accumulating evidence shows that hepatic fibrosis leads to alterations in carbohydrate metabolism, as aerobic glycolysis is aggravated in activated hepatic stellate cells (HSCs) and the whole fibrotic liver; in amino acid metabolism, as Fischer’s ratio (branched-chain amino acids/aromatic amino acids) decreases in patients with hepatic fibrosis; and in lipid metabolism, as HSCs lose vitamin A-containing lipid droplets during transdifferentiation, and cirrhotic patients have decreased serum lipids. The current review also summarizes recent findings of metabolic alterations relevant to hepatic fibrosis based on systems biology approaches, including transcriptomics, proteomics, and metabolomics in vitro, in animal models and in humans.

• Fischer’s ratio
• HSC
• TCA cycle
• aerobic glycolysis
• hepatic fibrosis
• metabolomics
• proteomics
• transcriptomics

While it is well established that various factors can impair the production and flow of bile and lead to cholestatic disease in hepatic and extrahepatic sites, an enhanced assessment of the biomarkers of the underlying pathophysiological mechanisms is still needed to improve early diagnosis and therapeutic strategies. Hence, we investigated fluorescing endogenous biomolecules as possible intrinsic biomarkers of molecular and cellular changes in cholestasis. Spectroscopic autofluorescence (AF) analysis was performed using a fiber optic probe (366 nm excitation), under living conditions and in serum, on the livers of male Wistar rats submitted to bile duct ligation (BDL, 24, 48, and 72 h). Biomarkers of liver injury were assayed biochemically. In the serum, AF analysis distinctly detected increased bilirubin at 24 h BDL. A continuous, significant increase in red-fluorescing porphyrin derivatives indicated the subversion of heme metabolism, consistent with an almost twofold increase in the serum iron at 72 h BDL. In the liver, changes in the AF of NAD(P)H and flavins, as well as lipopigments, indicated the impairment of mitochondrial functionality, oxidative stress, and the accumulation of oxidative products. A serum/hepatic AF profile can be thus proposed as a supportive diagnostic tool for the in situ, real-time study of bio-metabolic alterations in bile duct ligation (BDL) in experimental hepatology, with the potential to eventually translate to clinical diagnosis.

• BDL model
• bilirubin
• endogenous porphyrins
• energy metabolism
• extrahepatic cholestasis
• oxidative stress
• spectrofluorometry

• ADMA
• Angiotensin II
• Hypertension
• Nitric oxide
• RVLM

The methylated derivative of l-arginine, asymmetric dimethylarginine (ADMA) is synthesized in different mammalian tissues including the brain. ADMA acts as an endogenous, nonselective, competitive inhibitor of all three isoforms of nitric oxide synthase (NOS) and may limit l-arginine supply from the plasma to the enzyme via reducing its transport by cationic amino acid transporters. Hepatic encephalopathy (HE) is a relatively frequently diagnosed complex neuropsychiatric syndrome associated with acute or chronic liver failure, characterized by symptoms linked with impaired brain function leading to neurological disabilities. The l-arginine—nitric oxide (NO) pathway is crucially involved in the pathomechanism of HE via modulating important cerebral processes that are thought to contribute to the major HE symptoms. Specifically, activation of this pathway in acute HE leads to an increase in NO production and free radical formation, thus, contributing to astrocytic swelling and cerebral edema. Moreover, the NO-cGMP pathway seems to be involved in cerebral blood flow (CBF) regulation, altered in HE. For this reason, depressed NO-cGMP signaling accompanying chronic HE and ensuing cGMP deficit contributes to the cognitive and motor failure. However, it should be remembered that ADMA, a relatively little known element limiting NO synthesis in HE, may also influence the NO-cGMP pathway regulation. In this review, we will discuss the contribution of ADMA to the regulation of the NO-cGMP pathway in the brain, correlation of ADMA level with CBF and cognitive alterations observed during HE progression in patients and/or animal models of HE.

• Asymmetric dimethylarginine
• Cerebral blood flow
• Hepatic encephalopathy
• L-Arginine
• Nitric oxide synthase

Bile duct ligation (BDL)-treated rats display cholestasis and liver damages. The potential protective activity of melatonin in young BDL rats in terms of apoptosis, mitochondrial function, and endoplasmic reticulum (ER) homeostasis has not yet been evaluated. Three groups of young male Sprague-Dawley rats were used: one group received laparotomy (Sham), a second group received BDL for two weeks (BDL), and a third group received BDL and intraperitoneal melatonin (100 mg/day) for two weeks (BDL + M). BDL group rats showed liver apoptosis, increased pro-inflamamtory mediators, caspases alterations, anti-apoptotic factors changes, and dysfunction of ER homeostasis. Melatonin effectively reversed apoptosis, mainly through intrinsic pathway and reversed ER stress. In addition, in vitro study showed melatonin exerted its effect mainly through the melatonin 2 receptor (MT2) in HepG2 cells. In conclusion, BDL in young rats caused liver apoptosis. Melatonin rescued the apoptotic changes via the intrinsic pathway, and possibly through the MT2 receptor. Melatonin also reversed ER stress induced by BDL.

• apoptosis
• bile duct ligation
• endoplasmic reticulum
• melatonin
• mitochondria

• asymmetric dimethylarginine
• bile duct ligation
• etanercept
• intrathecal
• spatial memory
• tumor necrosis factor-α
• young age

Asymmetric-dimethylarginine (ADMA) competes with L-arginine for each of the three isoforms of nitric oxide synthase: endothelial; neuronal; inducible. ADMA is synthesized by protein methyltransferases followed by proteolytic degradation. ADMA is metabolized to citrulline and dimethylamine, by dimethylarginine dimethylaminohydrolase (DDAH) and enters cells through cationic amino-acid transporters extensively expressed in the liver. The liver plays a crucial role in ADMA metabolism by DDAH-1 and, as has been recently demonstrated, it is also responsible for ADMA biliary excretion. A correlation has been demonstrated between plasma ADMA levels and the degree of hepatic dysfunction in patients suffering from liver diseases with varying aetiologies: plasma ADMA levels are increased in patients with liver cirrhosis, alcoholic hepatitis and acute liver failure. The mechanism by which liver dysfunction results in raised ADMA concentrations is probably due to impaired activity of DDAH due to severe inflammation, oxidative stress, and direct damage to DDAH. High plasma ADMA levels are also relevant as they are associated with the onset of multi-organ failure (MOF). Increased plasma concentration of ADMA was identified as an independent risk factor for MOF in critically-ill patients causing enhanced Intensive Care Unit mortality: a significant reduction in nitric oxide synthesis, leading to malperfusion in various organs, eventually culminating in multi organs dysfunction.

• Liver
• Asymmetric dimethylarginine
• Nitric oxide
• Nitric oxide-synthase
• Multiple organ failure

• Animals
• Arginine/analogs & derivatives
• Arginine/blood
• Arginine/metabolism
• Biomarkers/blood
• Critical Illness
• Humans
• Liver/metabolism
• Liver/pathology
• Liver Diseases/blood
• Liver Diseases/etiology
• Liver Diseases/metabolism
• Liver Diseases/pathology
• Liver Diseases/therapy
• Multiple Organ Failure/etiology
• Multiple Organ Failure/metabolism
• Prognosis
• Risk Factors
• Signal Transduction
• Up-Regulation