Search Results (98)

Multiple rare vascular variations were identified in a 97-year-old female donor during the dissection of the gastrointestinal system. An anomalous middle colic artery originated from the celiac trunk alongside the three normal branches. The left hepatic artery, an accessory left hepatic artery, and the right hepatic artery all originated from the proper hepatic artery. The right hepatic artery exhibited a “caterpillar hump” and an abnormal tripod distal branching pattern, consisting of a very short cystic artery and two short right hepatic arteries (one superior and one inferior). Additionally, an accessory cystic artery arose from the inferior pancreaticoduodenal artery, ascending inferiorly to the common bile duct and cystic duct towards the gallbladder to join the cystic artery posteriorly. The right and middle colic arteries originated from a right colic middle colic common arterial trunk. The left colic artery and the sigmoidal arteries also originated from a left colic-sigmoidal common arterial trunk. Surgical and medical procedures in the pancreaticobiliary region are widespread, and cholecystectomy is one of the most common surgeries performed worldwide. A laparoscopic approach is the current ‘gold standard’ surgical approach. Knowledge of these potential gastrointestinal vascular variations is essential to ensure patient safety and avoid iatrogenic complications. The presence of an unidentified caterpillar-type right hepatic artery poses a significant risk of accidental ligation during cholecystectomy. Similarly, the presence of common colic arterial trunks alters the vascular landscape for laparoscopic colectomy. To ensure favorable surgical outcomes, comprehensive preoperative vascular imaging should be performed to identify such rare configurations. In this article, we discussed the frequency, embryology, physiology, and clinical and surgical implications of the anatomical variations present in this donor. To date, there have been no other reports in the literature describing this specific combination of variations. Full article

We explored the possibility of antioxidant and antifibrotic effects of panthenol (PL) associated with modulation of coenzyme A (CoA) biosynthesis in the liver in a rat model of chronic obstructive cholestasis induced by bile duct ligation (BDL). We found that PL increased alcohol dehydrogenase (ADH) activity in the liver of BDL rats. PL and its analog pantethine increased pantothenate kinase (PANK) activity, restored hepatic CoA levels reduced by BDL, lowered protein-bound CoA, and normalized impaired mitochondrial functions associated with induced oxidative stress after BDL. These effects were accompanied by decreased collagen deposition and improved morphological features of hepatocytes. In contrast, PANK inhibitor, hopantenic acid (HPA), reduced hepatic CoA levels, aggravated hepatocellular damage, and promoted fibrosis. In the human hepatic stellate cell line LX-2, PL exhibited no cytotoxicity over a wide concentration range, increased intracellular CoA levels, decreased reactive oxygen species (ROS) production, and attenuated collagen accumulation associated with oxidative stress in vitro. Importantly, inhibition of ADH by 4-methylpyrazole completely abolished the protective effects of panthenol, indicating that its activity depends on metabolic pathways involving CoA. Notably, PL did not directly reduce H₂O₂ or superoxide anion radical production in cell-free systems but significantly suppressed lipid peroxidation in liposomes and red blood cells in vitro. Ultimately, these findings indicate that the antioxidant and antifibrotic effects of PL are associated with modulation of CoA metabolism and enhanced resistance of biological membranes to oxidative damage. Full article

Background/Objectives: Inflammation and oxidative stress are key factors contributing to the initiation and progression of liver fibrosis in chronic obstructive cholestasis. Pantothenic acid (PA) and some of its derivatives have been reported to exhibit moderate anti-inflammatory, antioxidant, and regenerative effects. This study aimed to evaluate the redox-modulating effects of PA derivatives—panthenol (PL), pantethine (PT), and hopantenic acid (HPA) in a rat model of chronic obstructive cholestasis induced by common bile duct ligation (BDL). Methods: Macroscopic, histological, and ultrastructural alterations in the liver were assessed, along with molecular markers of oxidative stress, inflammation, and parameters of the glutathione (GSH) system. Results: BDL-induced liver injury was associated with enhanced lipid peroxidation, mitochondrial structural alterations, depletion of GSH, increased levels of protein S-glutathionylation (PSSG), and elevated thiobarbituric acid-reactive substances in mitochondria. Treatment with PL and, to a lesser extent, PT was associated with attenuation of hepatocellular ultrastructural damage, reduced bile duct hyperplasia, decreased inflammatory and necrotic changes, and moderate improvement in fibrosis-related parameters. In contrast, HPA (a PA antagonist) did not demonstrate hepatoprotective effects and it was associated with more pronounced liver injury. Conclusions: Chronic BDL is accompanied by suppression of glutathione redox capacity and enhanced oxidative stress. PL and PT, but not HPA, were associated with reduced levels of protein S-glutathionylation and partial restoration of redox balance. The protective effects of PL and PT may contribute to their antifibrotic activity, potentially through direct antioxidant capacity or redox-modulating mechanisms associated with the GSH system. Full article

Background/Objectives: Bile duct ligation (BDL), characterized by marked inflammation and fibrosis, effectively mimics many clinical conditions and is a valuable tool for investigating biliary regeneration. Our objective was to clarify the therapeutic benefits of adipose-derived stem cell (ADSC) treatment and signaling pathways mediating regenerative processes in a rat model of BDL. Methods: The BDL model was performed on Sprague–Dawley rats, and ADSC was administered intrasplenically at a dose of 10⁶ cells per animal. Liver function tests, gene and protein expression analyses, histological evaluation, and immunohistochemistry staining were performed to assess liver function, signaling pathways, inflammation, and fibrosis. Results: ADSC treatment returned liver function to sham levels. ADSC upregulated the Hes1 gene and protein expression in the early and late term. Inflammation, fibrosis, and total damage scores were decreased following ADSC treatment compared with the control. Immunohistochemistry staining revealed higher CD90, CD44, and CD29 stem cell marker expression in the ADSC treatment group. Conclusions: ADSC administration reduced fibrosis and biliary damage and restored liver function, potentially in a manner mediated by upregulated Hes1 expression, supporting its promise in biliary regeneration. Full article

Background/Objectives: Hepatic encephalopathy (HE) is characterized by hyperammonemia, neuroinflammation, oxidative stress, and blood–brain barrier (BBB) dysfunction, with brain endothelial cells being highly vulnerable to ammonia-induced damage. Adiponectin is a cytoprotective adipokine that may enhance endothelial resilience; however, its specific role under hyperammonemic conditions remains unclear. This study aims to investigate the protective effects of adiponectin on brain endothelial function and BBB integrity. Methods: In vivo, male C57BL/6J mice underwent bile duct ligation (BDL) surgery and received daily intraperitoneal adiponectin injections (10 μg/kg/day) for 6 days, starting 5 days post-surgery. On day 11, brain tissues and serum were collected for molecular and cytokine analyses. In vitro, mouse brain endothelial cells (bEnd.3) were pretreated with adiponectin before exposure to ammonia. Assays for tight junction preservation, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and total RNA sequencing were performed. Results: In BDL mice, adiponectin increased the expression of the tight junction protein claudin-5 and synaptic marker PSD95 across the cortex, hippocampus, and striatum, while reducing pro-oxidant (Cyp2e1, Cyp4a1) and apoptotic (Caspase-9) markers. In vitro, adiponectin pretreatment maintained tight junction proteins, suppressed inflammatory markers, restored mitochondrial membrane potential, and decreased ROS generation in ammonia-exposed bEnd.3 cells. Transcriptomic profiling revealed that adiponectin modulates stress-related gene expression under hyperammonemic conditions. Conclusions: Adiponectin enhances cellular stress resistance and maintains BBB structural integrity under ammonia-induced toxicity. These findings suggest that adiponectin serves as a promising therapeutic target for mitigating neurovascular unit dysfunction in hepatic encephalopathy. Full article

Cholangiopathies encompass a wide range of chronic liver diseases that target biliary epithelial cells, leading to significant morbidity and mortality due to their progressive nature, limited treatment options, and complex clinical management. Currently, clinically validated biomarkers capable of distinguishing obstructive cholangiopathies, such as biliary atresia (BA), from other cholangiopathies are lacking, hindering timely intervention. RNA-binding proteins (RBPs) have been increasingly linked to human diseases but their roles in cholangiopathies remain underexplored. We assessed the expression of the RBP epithelial splicing regulatory protein 1 (ESRP1) in murine models of cholangiopathies and in the human system. Our findings demonstrate that ESRP1 is highly and specifically expressed in cholestatic liver injury models, including bile duct-ligated, diethoxycarboncyl-1,4-dihydrocollidine-treated, and Mdr2^−/− mice when compared with other liver injury models. Importantly, ESRP1 is markedly elevated in the livers of patients with BA and cystic fibrosis-related liver disease, localizing to cholangiocytes and peri-biliary hepatic cells, but is minimal in primary sclerosing cholangitis and primary biliary cholangitis. Moreover, patient-derived BA organoids and biliatresone-treated healthy organoids also display ESRP1 expression. Bioinformatics analysis further implicates ESRP1 in key cholangiopathy-associated pathways, warranting deeper mechanistic investigation. Thus, ESRP1 holds potential as a molecular marker for obstructive cholangiopathies, warranting further mechanistic studies. Full article

Background: Reliable analgesia is essential to ensure animal welfare and experimental validity in preclinical disease models. However, evidence on the efficacy and side effects of analgesics remains limited. This study investigated the effects of three commonly used analgesics on animal well-being in a murine model of cholestasis. Methods: Thirty male C57BL/6J mice underwent transmitter implantation followed by bile duct ligation (BDL) and received continuous metamizole (3 g/L), tramadol (1 g/L), or carprofen (0.15 g/L) via drinking water before and after surgery. Welfare was evaluated using multiple parameters, including body weight, a distress score, drinking volume, burrowing and nesting behavior, mouse grimace scale (MGS), and telemetric data (heart rate, heart rate variability: SDNN and RMSSD, core body temperature, and locomotion). Additionally, liver and gastrointestinal tissues were analyzed histologically for necrosis and immune cell infiltration. Results: Even prior to surgery, analgesic-specific reductions in body weight, drinking behavior, and burrowing and nesting activity were observed. After transmitter implantation, metamizole treatment led to significantly reduced body weight, drinking volume, and locomotion compared to the other two analgesics. Following BDL, all treatment groups exhibited pronounced distress, weight loss, and reduced activity. Tramadol treatment resulted in slightly improved MGS and SDNN values, indicating minor benefits without sustained welfare restoration. In contrast, carprofen treatment was associated with reduced survival and inflammatory alterations in the forestomach. Conclusions: None of the tested analgesic regimens fully restored animal welfare after BDL. However, tramadol provided modest advantages, suggesting it may represent the most suitable option among the tested analgesics for the BDL model. Full article

Background and Objectives: Neuroinflammation plays a significant role in liver and neurological disorders via its disruption of neurotransmission, which alters cerebral function, resulting in cognitive and motor impairment, fatigue, anxiety, and depression. A key interaction exists between GABAergic neurotransmission and neuroinflammation, whereby excessive GABA_A receptor activation exacerbates cognitive and behavioural impairment. Golexanolone, a novel GABA_A-receptor-modulating steroid antagonist (GAMSA), primarily attenuates GABAergic potentiation via GABA_A-positive steroid allosteric receptor modulators such as allopregnanolone. This review aims to summarize new evidence showing that golexanolone improves peripheral inflammation, neuroinflammation, and neurological alterations in animal models of different neurological pathologies. We provide an overview of the first clinical trial using this novel compound. Results: In rat models of hyperammonemia and minimal hepatic encephalopathy (MHE), peripheral inflammation induces microglia and astrocyte activation and neuroinflammation, altering GABAergic neurotransmission and resulting in cognitive and motor impairment. Golexanolone’s unique dual action reduces peripheral inflammation and glial activation, thus normalizing neurotransmission and cognitive and motor function. Furthermore, a phase II study in cirrhotic patients with MHE shows that golexanolone is well tolerated and improves cognition. Similarly, in a model of primary biliary cholangitis (PBC) involving bile-duct ligation, peripheral inflammation, neuroinflammation, and altered neurotransmission—associated with fatigue, impaired memory, and locomotor gait and motor incoordination—were reversed by the dual action of golexanolone. In the Parkinson’s disease (PD) rat model induced by neurotoxin 6-OHDA, rats exhibited fatigue, anhedonia, impaired memory, and locomotor gait and motor incoordination, which were associated with microglia and astrocyte activation in the substantia nigra and striatum, in addition to tyrosine hydroxylase (TH) loss. Golexanolone reduces microglia and astrocyte activation, partially reduces TH loss, and improves fatigue, anhedonia, memory, locomotor gait, and motor incoordination. Golexanolone also normalizes elevated levels of α-synuclein. Conclusions: These findings suggest that golexanolone has beneficial therapeutic effects for treating fatigue, depression, motor, and cognitive impairment across diverse neuroinflammatory conditions, including synucleinopathies. Full article

Background: Acute cholecystitis (AC) is characterized by gallbladder inflammation and is commonly accompanied by disordered gallbladder motility. Although laparoscopic cholecystectomy is the standard treatment, it carries procedure-related risks. Low-intensity pulsed ultrasound (LIPUS), a safe and noninvasive modality widely applied for muscle repair, may offer therapeutic benefits for AC-associated motility dysfunction. Methods: In vivo, LIPUS (0.5 W/cm²) was applied for 15 min daily to acute cholecystitis guinea pigs over three consecutive days, starting 24 h after reversing common bile duct ligation (CBDL) surgery. In vitro, LIPUS (0.5 W/cm²) was delivered for 5 min to isolated gallbladder muscle strips and for 30 s to isolated interstitial cells of Cajal (ICCs). Gallbladder function and histology were assessed in vitro and in vivo using immunofluorescence, Western blotting, calcium imaging, muscle strip contractility testing, and related molecular methods. Results: LIPUS increased intracellular Ca²⁺ by activating the Ano1 channel in ICCs, thereby enhancing gallbladder smooth muscle contractility. At 72 h, the LIPUS 72 h (+) group showed a 71.3% increase in gallbladder muscle tone (p = 0.0001) and a 40.7% reduction in inflammation scores (p = 0.0001) compared with the LIPUS 72 h (−) group. Conclusions: LIPUS alleviates gallbladder contractile dysfunction in acute cholecystitis by acting on ICCs through mechanisms involving the promotion of ICC recovery and a reduction in inflammation. Full article

Liver fibrosis, a progressive condition with limited pharmacotherapies, poses a global health challenge. Scutellarin (SCU), a flavonoid derived from Erigeron breviscapus, has demonstrated anti-fibrotic activity and modulates gut microbiota. Emerging evidence suggests that SCU may also influence the hepatic microbiome. However, its clinical utility is constrained by poor water solubility and low oral bioavailability. Here, we developed an SCU-loaded nanoemulsion (SCE) to enhance solubility and liver-targeted delivery. In vitro, SCE increased SCU uptake in hepatic stellate cells (HSCs) and significantly inhibited TGF-β1-induced fibrogenesis. In a bile duct ligation (BDL) mouse model, oral administration of SCE improved hepatic SCU accumulation and produced superior anti-fibrotic efficacy. SCE treatment attenuated fibrosis and collagen deposition in the liver and improved liver function markers. Mechanistic investigations using 16S rRNA sequencing revealed that SCU treatment was associated with beneficial microbiota changes, although its main therapeutic effects were achieved through enhanced hepatic targeting. Notably, the SCE formulation was well-tolerated, showing no significant toxicity in vitro or in vivo. In conclusion, the SCU-loaded nanoemulsion achieved enhanced hepatic delivery of SCU and exerted potent anti-fibrotic effects via multiple mechanisms, including direct suppression of fibrogenesis and ancillary modulation of the gut–liver microbiome, offering a promising therapeutic strategy for liver fibrosis. Full article

Background: Liver fibrosis, a consequence of various chronic liver diseases, is characterized by excessive accumulation of extracellular matrix (ECM), leading to impaired liver function and potentially progressing to cirrhosis or hepatocellular carcinoma. The molecular mechanisms underlying liver fibrosis are complex and not fully understood. In vivo experiments are essential for studying the molecular mechanisms of the disease. However, the diverse principles behind mouse modeling techniques for liver fibrosis can complicate the elucidation of specific fibrotic mechanisms. Methods: Five distinct liver fibrosis models were utilized: CONTROL, NASH (non-alcoholic steatohepatitis), BDL (bile duct ligation), TAA (thioacetamide), and CCl₄ (carbon tetrachloride). Patents for these drugs were reviewed using Patentscope^® and Worldwide Espacenet^®. ScRNA-seq was performed to analyze and compare the cellular and molecular differences in these models. Results: The analysis revealed that, particularly in the drug-induced fibrosis models, hepatic stellate cells (HSCs), Kupffer cells, and T-cell subsets exhibit distinct regulatory patterns and dynamic remodeling processes across different liver fibrosis models. These findings highlight the heterogeneity of immune responses and extracellular matrix (ECM) remodeling in various models, providing important insights into the complex mechanisms underlying liver fibrosis. Conclusions: The study enhances our understanding of liver fibrosis development and provides valuable insights for selecting the most representative animal models in future research. This comprehensive analysis underscores the importance of model-specific immune responses and ECM remodeling in liver fibrosis. Full article

Background: Creating a model for acute liver failure in animal models is essential for research on liver regeneration and cancer. Current surgical techniques allow for a maximum of 80% partial hepatectomy in rats, with low survival rates due to poor inflow control. The common resection technique involves ligation at the liver lobe neck, causing peri-operative blood loss and postoperative blood loss. Methods: A 90% partial hepatectomy was performed on 5 rats using a bile duct-saving portal ligation technique, involving two hilum dissections for bile duct preservation. The first dissection controlled the blood supply to the median and left lateral lobes, and the second to the right inferior and superior lobes. Before closing, all rats were given 5 mL of 10% dextrose intraperitoneally and had access to ClearH₂O DietGel Recovery and 20% dextrose. Weight and behavior were closely monitored for seven days post-operatively. Results: This method resulted in 100% survival, with a 3.1% increase in liver mass and 12.3% increase in liver-to-body mass ratio. Conclusions: This technique is the first bile duct-saving portal ligation for rodent models of acute liver failure, with long-term survival and complete hepatic regeneration. Our procedure offers a viable 90% hepatectomy model for research with improved survival and regeneration outcomes. Full article

Patients with cirrhosis often exhibit cardiac autonomic dysfunction (CAD), characterized by enhanced cardiac sympathetic activity and diminished cardiac vagal tone, leading to increased morbidity and mortality. This study delineates the cellular and molecular mechanisms associated with altered neuronal activities causing cirrhosis-induced CAD. Biliary and nonbiliary cirrhotic rats were produced by common bile duct ligation (CBDL) and intraperitoneal injections of thioacetamide (TAA), respectively. Three weeks after CBDL or TAA injection, the assessment of heart rate variability revealed autonomic imbalance in cirrhotic rats. We observed increased excitability in stellate ganglion (SG) neurons and decreased excitability in intracardiac ganglion (ICG) neurons in cirrhotic rats compared to sham-operated controls. Additionally, threshold, rheobase, and action potential duration exhibited opposite alterations in SG and ICG neurons, along with changes in afterhyperpolarization duration. A- and M-type K⁺ channels were significantly downregulated in SG neurons, while M-type K⁺ channels were upregulated, with downregulation of the N- and L-type Ca²⁺ channels in the ICG neurons of cirrhotic rats, both in transcript expression and functional activity. Collectively, these findings suggest that cirrhosis induces an imbalance between cardiac sympathetic and parasympathetic neuronal activities via the differential regulation of K⁺ and Ca²⁺ channels. Thus, cirrhosis-induced CAD may be associated with impaired autonomic efferent functions within the homeostatic reflex arc that regulates cardiac functions. Full article

Liver fibrosis is an important step in the transformation of chronic liver disease into cirrhosis and liver cancer, and structural changes and functional disorders of liver sinusoidal endothelial cells (LSECs) are early events in the occurrence of liver fibrosis. Therefore, it is necessary to identify the key regulatory genes of endothelial dysfunction in the process of liver fibrosis to provide a reference for the diagnosis and treatment of liver fibrosis. In this study, we identified 230 common differentially expressed genes (Co-DEGs) by analyzing transcriptomic data of primary LSECs from three different liver fibrosis mouse models (carbon tetrachloride; choline-deficient, l-amino acid-defined diet; and nonalcoholic steatohepatitis). Enrichment analysis revealed that the Co-DEGs were mainly involved in regulating the inflammatory response, immune response, angiogenesis, formation and degradation of the extracellular matrix, and mediating chemokine-related pathways. A Venn diagram analysis was used to identify 17 key genes related to the progression of liver cirrhosis. Regression analysis using the Lasso–Cox method identified genes related to prognosis among these key genes: SOX4, LGALS3, SERPINE2, CD52, and LPXN. In mouse models of liver fibrosis (bile duct ligation and carbon tetrachloride), all five key genes were upregulated in fibrotic livers. This study identified key regulatory genes for endothelial dysfunction in liver fibrosis, namely SOX4, LGALS3, SERPINE2, CD52, and LPXN, which will provide new targets for the development of therapeutic strategies targeting endothelial dysfunction in LSECs and liver fibrosis. Full article

The aim of this work was to test whether we can treat cholestasis with dietary approaches applied after the onset of the disease. The effects of intermittent fasting and dietary restriction on liver damage caused by common bile duct ligation (BDL) in rats were studied, with particular attention paid to changes in the activity of enzymes of energy metabolism and antioxidant protection. Morphological changes in liver tissue and serum markers of liver damage were assessed in rats with BDL kept for one month on ad libitum diet, intermittent fasting, or 35% dietary restriction. We studied parameters of glucose metabolism (activity of glycolysis and gluconeogenesis enzymes), TCA cycle, and indicators of oxidative stress and redox status of the liver tissue. Dietary restriction resulted in an increase in gluconeogenesis activity, antioxidant capacity, and autophagy activation. When implemented after BDL, none of the dietary restriction protocols reduced the level of oxidative stress, detrimental morphological and biochemical alterations, or the fibrosis progression. Thus, under severe damage and oxidative stress developing in cholestasis, dietary restrictions are not hepatoprotective and can only be used in a pre-treatment mode. Full article