Hepatic Cells Research Articles

A comprehensive study on the digestion, absorption, and metabolization of tropane alkaloids in human cell models

Tropane alkaloids (TAs) are toxic compounds with potent anticholinergic effects. Herbal infusions are among the most contaminated food commodities; however, the fate of TAs after ingestion remains poorly understood. This study presents a comprehensive investigation into the absorption, and metabolism of five TAs (atropine, scopolamine, tropine, homatropine, and apoatropine) following the digestion of contaminated tea.In vitro human cell models were employed, including gastric (NCI-N87), intestinal (Caco-2:HT29-MTX), and hepatic (HEP-G2) cells. TAs were found to be highly absorbed in the intestinal epithelium, while gastric cells exhibited poor absorption. Metabolism was studied using a custom-made database, revealing that it occurs predominantly in intestinal cells, involving hydroxylation and methylation reactions.Cell metabolomics was conducted using annotation, fragment simulation, and statistical software platforms. Significant statistical differences were observed for 40 tentatively identified compounds. MetaboAnalyst 5.0 was employed to discern the most disturbed metabolic pathways, with amoniacids biosynthesis pathways and TCA cycles being the most affected. These pathways are involved in responses to cellular metabolic stress, neurotransmitter production, cellular energy generation, and the regulation of oxidative stress response. The findings of this study enhance our understanding of the fate of TAs after ingestion, their metabolization and their effects at the cellular level.

Milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 (MOP3) attenuates inflammation and improves survival in hepatic ischemia/reperfusion injury

IntroductionHepatic ischemia/reperfusion injury is a severe clinical condition leading to high mortality as the result of excessive inflammation, partially triggered by released damage-associated molecular patterns. Extracellular cold-inducible RNA-binding protein is a new damage-associated molecular pattern. Current clinical management of hepatic ischemia/reperfusion injury is limited to supportive therapy, necessitating the development of novel and effective treatment strategies. Milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 is a newly invented oligopeptide originating from milk fat globule-epidermal growth factor-VIII. This peptide acts as an opsonic compound that specifically binds to extracellular cold-inducible RNA-binding protein to facilitate its clearance by phagocytes, thereby attenuating inflammation. In this study, we hypothesized that milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 attenuated hepatic ischemia/reperfusion injury by inhibiting extracellular cold-inducible RNA-binding protein–induced inflammation in Kupffer cells. MethodsWe treated Kupffer cells isolated from male C57BL/6 mice with extracellular cold-inducible RNA-binding protein and various doses of milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 for 4 hours, then measured cytokines in the culture supernatants. In addition, mice underwent 70% hepatic ischemia for 60 minutes immediately followed by the intravenous administration of either vehicle or milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3. Blood and ischemic liver tissues were collected 24 hours later, and inflammatory markers including cytokines, liver enzymes, chemokines, myeloperoxidase activity, and Z-DNA-binding protein 1 were measured. Hepatic tissue damage and cell death were evaluated histologically. Survival rates were monitored for 10 days posthepatic ischemia/reperfusion. ResultsThe release of interleukin-6 and tumor necrosis factor-α from extracellular cold-inducible RNA-binding protein–challenged Kupffer cells was significantly reduced by milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 in a dose-dependent manner. In hepatic ischemia/reperfusion mice, milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 treatment significantly decreased serum levels of extracellular cold-inducible RNA-binding protein, interleukin-6, tumor necrosis factor-α, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase. Milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 treatment also significantly reduced mRNA levels of interleukin-6, tumor necrosis factor-α, interleukin-1β, Z-DNA-binding protein 1, and chemokine macrophage inflammatory protein-2, as well as myeloperoxidase activity in hepatic tissues. Histologic evaluation demonstrated that treatment with milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 significantly attenuated tissue damage and cell death in the liver of hepatic ischemia/reperfusion mice. Milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 treatment significantly improved the survival rate of hepatic ischemia/reperfusion mice. ConclusionMilk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 significantly attenuated inflammation and liver tissue damage and improved survival after hepatic ischemia/reperfusion. Thus, milk fat globule-epidermal growth factor-VIII–derived oligopeptide 3 holds promise as a potential future therapeutic strategy for hepatic ischemia/reperfusion injury.

CircMALAT1 promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma via the miR-512-5p/VCAM1 axis.

Circular RNAs play a pivotal role in the progression of various cancers. In our previous study, we observed high expression of the circRNA MALAT1 (cMALAT1) in intrahepatic cholangiocarcinoma (ICC) cells co-incubated with activated hepatic stellate cells. This study is designed to explore the roles of cMALAT1 and the underlying mechanisms in ICC. We find that cMALAT1 significantly facilitates the progression of ICC both in vitro and in vivo. The binding between cMALAT1 and miR-512-5p is subsequently confirmed through RNA pull-down experiments. As anticipated, the application of miR-512-5p mimics noticeably reverses the cMALAT1 overexpression-induced malignant phenotypes of ICC cells. Furthermore, VCAM1 is identified as a downstream gene of the cMALAT1/miR-512-5p axis. Importantly, silencing of VCAM1 not only effectively suppresses the malignant phenotypes of ICC cells but also significantly impairs the functions of cMALAT1. Our study reveals that cMALAT1 promotes the progression of ICC by competitively binding to VCAM1 mRNA with miR-512-5p, leading to the upregulation of VCAM1 expression and the activation of the PI3K/AKT signaling pathway.

Blockade of 11β-hydroxysteroid dehydrogenase type 1 ameliorates metabolic dysfunction-associated steatotic liver disease and fibrosis

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a key enzyme involved in the conversion of cortisone to active cortisol in the liver. Elevated cortisol levels can trigger oxidative stress, inflammation, and hepatocyte damage, highlighting the importance of 11β-HSD1 inhibition as a potential therapeutic approach. This study aimed to explore the effects of INU-101, an inhibitor of 11β-HSD1, on the development of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Our findings demonstrated that INU-101 effectively mitigated cortisol-induced lipid accumulation, reactive oxygen species generation, and hepatocyte apoptosis. Furthermore, 11β-HSD1 inhibition suppressed hepatic stellate cell activation by modulating β-catenin and phosphorylated SMAD2/3. INU-101 administration significantly reduced hepatic lipid accumulation and liver fibrosis in mice fed fast-food diet. This study suggests that INU-101 holds promise as a clinical candidate for treating MASLD and fibrosis, offering potential therapeutic benefits by targeting the intricate processes involving 11β-HSD1 and cortisol regulation in the liver.

CD47, a novel yap target gene, contributes to hepatic stellate cell activation and liver fibrosis induced by high-fat diet

CD47, a novel yap target gene, contributes to hepatic stellate cell activation and liver fibrosis induced by high-fat diet

Tim-1-mediated extracellular matrix promotes the development of hepatocellular carcinoma.

Tim-1 (T-cell immunoglobulin and mucin domain 1), also known as Kim-1 (kidney injury molecule 1) or hepatitis A virus cellular receptor 1 (HAVCR1), is a transmembrane protein expressed on various immune and epithelial cells. It plays a role in modulating inflammatory and immune responses. In this study, we find that Tim-1 is overexpressed in hepatocellular carcinoma (HCC) samples and that its expression is significantly correlated with postoperative survival. Bulk RNA sequencing reveals a general upregulation of extracellular matrix-related genes in HCC tissues with Tim-1 overexpression. The results of the cell and in vivo experiments reveal that Tim-1 in HCC not only affects biological processes such as the proliferation, migration, and invasion of HCC cells but also broadly promotes extracellular matrix processes by influencing cytokine secretion. Further studies demonstrate that Tim-1 mediates the activation of hepatic stellate cells and upregulates Th1 and Th2 cytokines, thereby promoting HCC progression. Thus, Tim-1 may represent a novel target for future interventions in HCC and liver fibrosis.

Cellular fibronectin-targeted fluorescent aptamer probes for early detection and staging of liver fibrosis

Liver fibrosis is a key process in the progression of chronic liver disease to cirrhosis. Currently, early diagnosis and precise staging of liver fibrosis remain great challenges. Extracellular matrix (ECM) molecules expressed specifically during liver fibrosis are ideal targets for bioimaging and detection of liver fibrosis. Here, we report that fluorescent probes based on a nucleic acid aptamer (ZY-1) targeting cellular fibronectin (cFN), a critical ECM molecule significantly accumulating during liver fibrosis, are promising bioimaging agents for the staging of liver fibrosis. In the work, the outstanding binding affinity of ZY-1 to cFN was validated through an in vitro model of human-derived hepatic stellate cells (HSCs). Subsequently, we constructed different ZY-1-based fluorescent probes and explored the real-time imaging performance of these fluorescent probes in CCl4-induced mouse models of different liver fibrosis stages. The ZY-1-based fluorescent probes, for the first time, effectively identified and distinguished early-stage liver fibrosis (stage 3 of Ishak 6) from advanced liver fibrosis (stage 5 of Ishak 6). The proof-of-concept study provides compelling evidences that ZY-1-based probes are a promising tool for the early diagnosis and staging of liver fibrosis and paves the way for further development of clinical-related diagnosis strategies for fibrotic diseases of the liver and other organs. Statement of significanceCurrently, early diagnosis and accurate staging of liver fibrosis continue to present significant challenges. This study demonstrates that fluorescent probes based on the nucleic acid aptamer ZY-1, which targets cellular fibronectin (cFN)—a crucial extracellular matrix (ECM) molecule that significantly accumulates during liver fibrosis—are promising bioimaging agents for staging liver fibrosis. The ZY-1-based fluorescent probes effectively identified and differentiated early-stage liver fibrosis from advanced liver fibrosis. This proof-of-concept study not only provides compelling evidence that ZY-1-based probes show promise for the early diagnosis and staging of liver fibrosis but also paves the way for further investigations into the use of ZY-1 in detecting other diseases associated with cFN.

Metformin: Beyond Type 2 Diabetes Mellitus.

Metformin was developed from an offshoot of Guanidine. It is known to be the first-line medication for type 2 diabetes mellitus, polycystic ovarian syndrome, and weight reduction. Metformin has also been shown to have effectiveness in the management of non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, and various carcinomas like hepatocellular, colorectal, prostate, breast, urinary bladder, blood, melanoma, bone, skin, lung and so on. This narrative review focuses on the effect of metformin on non-alcoholic fatty liver disease, liver cirrhosis, and hepatocellular carcinoma. The search platforms for the topic were PubMed, Scopus, and Google search engine. Critical words for searching included 'Metformin,' AND 'Indications of Metformin,' AND 'Non-Alcoholic Fatty Liver Disease,' AND 'Metformin mechanism of action,' AND 'NAFLD management,' AND 'NAFLD and inflammation,' AND 'Metformin and insulin,' AND 'Metformin and inflammation,' AND 'Liver cirrhosis,' AND 'Hepatocellular carcinoma.' Lifestyle modification and the use of hypoglycemic agents can help improve liver conditions. Metformin has several mechanisms that enhance liver health, including reducing reactive oxygen species, nuclear factor kappa beta (NF-κB), liver enzymes, improving insulin sensitivity, and improving hepatic cell lipophagy. Long-term use of metformin may cause some adverse effects like lactic acidosis and gastrointestinal disturbance. Metformin long-term overdose may lead to a rise in hydrogen sulfide in liver cells, which calls for pharmacovigilance. Drug regulating authorities should provide approval for further research, and national and international guidelines need to be developed for liver diseases, perhaps with the inclusion of metformin as part of the management regime.

Liver Fibrosis Leading to Cirrhosis: Basic Mechanisms and Clinical Perspectives.

Liver fibrosis is the pathological deposition of extracellular matrix rich in fibrillar collagen within the hepatocytes in response to chronic liver injury due to various causes. As the condition advances, it can progress to cirrhosis, the late stages of which are irreversible. Multiple pathophysiological mechanisms and cell types are responsible for the progression of liver fibrosis and cirrhosis. Hepatic stellate cells and myofibroblast activation represent a key event in fibrosis. Capillarization of liver sinusoidal endothelial cells further contributes to extracellular matrix deposition and an increase in portal pressure. Macrophages and neutrophils produce inflammatory cytokines and participate in activating hepatic stellate cells. Although initially believed to be irreversible, early stages of fibrosis are now found to be reversible. Furthermore, advances in noninvasive imaging and serum studies have changed and improved how cirrhosis can be evaluated and monitored. Although there are currently no specific approved therapies to reverse liver fibrosis, management of underlying diseases has been found to halt the progression, and to an extent, even reverse liver fibrosis, preventing further liver injury and cirrhosis-related complications.

Expression of TWEAK/Fn14 axis in the context of metabolic dysfunction associated-fatty liver disease: an approach in liver regeneration

Background: One of the pathways involved in liver regeneration processes is TWEAK/Fn14 (tumor necrosis factor-related weak inducer of apoptosis/fibroblast growth factor-inducible 14), which has been proposed to act directly and selectively on hepatic progenitor cells; however, its role in the regeneration of steatotic liver metabolic dysfunction associated fatty liver disease has not been fully elucidated. Objective: To evaluate the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals as biochemical cues for possible liver regeneration in MAFLD. Materials and methods: A prospective study was carried out where the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals were observed as biochemical indications of a possible liver regeneration in a condition of tissue damage caused by excessive lipid accumulation. The expression of TWEAK, Fn14 and heat shock proteins in hepatic steatosis of non-alcoholic origin was assessed using immunohistochemistry and western blotting. Results: The histological classification of the tissues under study corresponded to microvesicular steatosis. We report a high level of expression of heat shock proteins in the cytoplasm. The expression of TWEAK and Fn14 in liver tissue affected by lipid accumulation was localized in the cytoplasm of hepatocytes, showing a higher intensity of reactivity for Fn14 compared to its ligand TWEAK. Conclusion: The expression of TWEAK/Fn14 axis was positive suggesting reactivity of the signaling pathway in metabolic dysfunction associated fatty liver disease.

Cycloastragenol Suppresses Hepatic Stellate Cells Activation to Alleviate Liver Fibrosis Through the PI3K/Akt/mTOR Signaling Pathway and Autophagy

Liver fibrosis is a pathological process of various liver diseases, and a large number of studies have shown that liver fibrosis is reversible. Natural products are one of the important sources of drugs for treating liver fibrosis. The present study evaluated the protective effect of cycloastragenol (CAG) on liver fibrosis and the underlying mechanism. The mouse model of liver fibrosis was established by intraperitoneal injection of carbon tetrachloride (CCl4) and olive oil. Subsequently, CAG was administrated orally at different doses(2.5 mg/kg/d, 5 mg/kg/d, 10mg/kg/d), and the degree of liver fibrosis was assessed using hematoxylin-eosin, Van Gieson, and Sirius Red staining. Alanine aminotransferase, aspartate aminotransferase, hyaluronic acid, and hydroxyproline levels were detected using biochemical analyses. The mRNA and protein expression levels of α-SMA, LC3, P62, PI3K, Akt, and mTOR in the liver tissue were assessed by reverse-transcription polymerase chain reaction and western blot, respectively. The expression of fibrogenesis-related marker α-SMA in the liver tissue was assessed using immunofluorescence. As expected, CAG alleviated liver fibrosis and suppressed hepatic stellate cell activation. And then, CAG inhibited autophagy and activated the PI3K/Akt/mTOR signaling pathway. Thus, CAG attenuated CCI4-induced liver fibrosis in mice by inhibiting autophagy and by activating the PI3K/Akt/mTOR signaling pathway.

A Protocol for the Isolation of Oval Cells without Preconditioning.

Oval cells (OCs) is the name of hepatic progenitor cells (HPCs) in rodents. They are a small population of cells in the liver with the remarkable ability to proliferate and regenerate hepatocytes and cholangiocytes in response to acute liver damage. Isolating OCs generally requires a pretreatment with special diets, chemicals, and/or surgery to induce hepatic damage and OC proliferation in mice. Unfortunately, these pretreatments are not only painful for the mice but also increase the cost of the assays, and the effects on the different organs as well as on various liver cells are still unclear. Therefore, the search for a protocol to obtain OCs without prior liver damage is mandatory. In our study, we present a protocol to isolate murine OCs from healthy liver (HL-OCs) and compare them with OCs isolated from mice pretreated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC-OCs). Our results demonstrated that cells derived from untreated mice exhibited similar behavior to those from treated mice in terms of surface marker expression, proliferation, and differentiation capacity. Therefore, given the impracticability of isolating human cells with prior hepatotoxic treatment, our model holds promise for enabling the isolation of progenitor cells from human tissue in the future. This advancement could prove invaluable for translational medicine in the understanding and treatment of liver diseases.

Role of WISP1 in Stellate Cell Migration and Liver Fibrosis.

The mechanisms underlying the remarkable capacity of the liver to regenerate are still not completely understood. Particularly, the cross-talk between cytokines and cellular components of the process is of utmost importance because they represent potential avenues for diagnostics and therapeutics. WNT1-inducible-signaling pathway protein 1 (WISP1) is a cytokine member of the CCN family, a family of proteins that play many different roles in liver pathophysiology. WISP1 also belongs to the earliest and strongest upregulated genes in mouse livers after CCl4 intoxication and has recently been shown to be secreted by tumor cells and to bind to type 1 collagen to cause its linearization in vitro and in tumor tissue in vivo. We show that WISP1 expression is strongly induced by TGFβ, a critical cytokine in wound healing processes. Additionally, secretion of WISP1 protein by hepatic stellate is increased in cells upon TGFβ stimulation (~seven-fold increase). Furthermore, WISP1 facilitates the migration of mouse hepatic stellate cells through collagen in vitro. However, in WISP1 knockout mice, no difference in stellate cell accumulation in damaged liver tissue and no influence on fibrosis was obtained, probably because the knockout of WISP1 was compensated by other factors in vivo.

Leveraging adrenergic receptor blockade for enhanced nonalcoholic fatty liver disease treatment via a biomimetic nanoplatform

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation, steatosis and fibrosis. Sympathetic nerves play a critical role in maintaining hepatic lipid homeostasis and regulating fibrotic progression through adrenergic receptors expressed by hepatocytes and hepatic stellate cells; however, the use of sympathetic nerve-focused strategies for the treatment of NAFLD is still in the infancy. Herein, a biomimetic nanoplatform with ROS-responsive and ROS-scavenging properties was developed for the codelivery of retinoic acid (RA) and the adrenoceptor antagonist labetalol (LA). The nanoplatform exhibited improved accumulation and sufficient drug release in the fibrotic liver, thereby achieving precise codelivery of drugs. Integration of adrenergic blockade effectively interrupted the vicious cycle of sympathetic nerves with hepatic stellate cells (HSCs) and hepatocytes, which not only combined with RA to restore HSCs to a quiescent state but also helped to reduce hepatic lipid accumulation. We demonstrated the excellent ability of the biomimetic nanoplatform to ameliorate liver inflammation, fibrosis and steatosis. Our work highlights the tremendous potential of a sympathetic nerve-focused strategy for the management of NAFLD and provides a promising nanoplatform for the treatment of NAFLD.

The processing mechanism of vinegar-processed Curcumae Rhizome enhances anti hepatic fibrotic effects through regulation of PI3K/Akt/mTOR signaling pathway

BackgroundHepatic fibrosis, a chronic pathological condition resulting from various forms of persistent liver injury, in the later stage, it can evolve into cirrhosis and even liver cancer. Curcumae Rhizoma (CR), traditionally recognized for its properties in line qi break blood, eliminate accumulation and relieve pain. According to traditional Chinese medicine (TCM) principles, vinegar-processing enhances CR's ability to enter the liver meridian and act on the blood level, potentially augmenting its therapeutic effects on hepatic diseases. Therefore, vinegar-processed Curcumae Rhizoma (VCR) is frequently employed in treating liver fibrosis and related hepatic conditions. However, the underlying mechanisms of vinegar processing in enhancing its therapeutic efficacy remain unclear. MethodsThe anti-liver fibrosis effects of CR and VCR were verified at individual and cellular levels. Subsequently, HPLC-Q-TOFMS and pharmacokinetic analysis were utilized to elucidate the potential bioactive substances underlying the enhanced anti-fibrotic efficacy of VCR. Building upon these findings, network pharmacology and metabolomics were integrated to screen for key effect components and regulatory pathways. Finally, the mechanisms of action were further analyzed and validated at the tissue and cellular levels through Western blotting (WB) and molecular docking studies. ResultsBoth CR and VCR exhibited therapeutic effects against hepatic fibrosis, with VCR demonstrating enhanced efficacy after vinegar processing. 6 sesquiterpenes including furanodiene and curdione, showed significant alterations in plasma exposure and hepatic distribution post-processing. VCR significantly improved pathological liver conditions, lipid accumulation, and fibrosis severity. Additionally, VCR markedly reduced the expression of α-SMA in the liver and attenuated the elevations in liver function markers such as ALT and AST. Combined network pharmacology, metabolomics, and hepatic tissue WB analysis revealed that the reduced phosphorylation of the PI3K/Akt/mTOR pathway is a critical mechanism in VCR's anti-fibrotic effects. Experiments on LX-2 cells demonstrated that four sesquiterpenes, including furanodiene and curdione, effectively inhibited the proliferation of activated hepatic stellate cells (HSCs). Furanodiene, in particular, promoted apoptosis in activated HSCs by reducing phosphorylation levels of the PI3K/Akt/mTOR pathway proteins, increasing BAX expression, and activating downstream caspase-3 to achieve the effect of anti-liver fibrosis. ConclusionVinegar-processing significantly increases the plasma exposure and hepatic distribution of components such as furanodiene in VCR, enhancing anti-fibrotic efficacy by downregulating the phosphorylation levels of the PI3K/Akt/mTOR pathway and promoting HSC apoptosis. This study provides a comprehensive explanation of the vinegar-processing mechanism and its role in enhancing the anti-fibrotic effects of VCR, offering insights for its clinical application in liver fibrosis treatment and reference for the mechanistic study of other vinegar-processed herbal medicines.

The role of forkhead box M1-methionine adenosyltransferase 2 A/2B axis in liver inflammation and fibrosis

Methionine adenosyltransferase 2 A (MAT2A) and MAT2B are essential for hepatic stellate cells (HSCs) activation. Forkhead box M1 (FOXM1) transgenic mice develop liver inflammation and fibrosis. Here we examine if they crosstalk in male mice. We found FOXM1/MAT2A/2B are upregulated after bile duct ligation (BDL) and carbon tetrachloride (CCl4) treatment in hepatocytes, HSCs and Kupffer cells (KCs). FDI-6, a FOXM1 inhibitor, attenuates the development and reverses the progression of CCl4-induced fibrosis while lowering the expression of FOXM1/MAT2A/2B, which exert reciprocal positive regulation on each other transcriptionally. Knocking down any of them lowers HSCs and KCs activation. Deletion of FOXM1 in hepatocytes, HSCs, and KCs protects from BDL-mediated inflammation and fibrosis comparably. Interestingly, HSCs from Foxm1Hep−/−, hepatocytes from Foxm1HSC−/−, and HSCs and hepatocytes from Foxm1KC−/− have lower FOXM1/MAT2A/2B after BDL. This may be partly due to transfer of extracellular vesicles between different cell types. Altogether, FOXM1/MAT2A/MAT2B axis drives liver inflammation and fibrosis.

Cabozantinib prevents the progression of metabolic dysfunction-associated steatohepatitis by inhibiting the activation of hepatic stellate cell and macrophage and attenuating angiogenic activity

Cabozantinib, a multiple tyrosine kinase inhibitor targeting AXL, vascular endothelial growth factor receptor (VEGFR), and MET, is used clinically to treat certain cancers, including hepatocellular carcinoma. This study aimed to assess the impact of cabozantinib on liver fibrosis and hepatocarcinogenesis in a rat model of metabolic dysfunction-associated steatohepatitis (MASH). MASH-based liver fibrosis and hepatocarcinogenesis were induced in rats by feeding them a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for eight and 16 weeks, respectively. Cabozantinib (1 or 2 mg/kg, daily) was administered concurrently with the diet in the fibrosis model and after eight weeks in the carcinogenesis model. Treatment with cabozantinib significantly attenuated hepatic inflammation and fibrosis without affecting hepatocyte steatosis and ballooning in CDAHFD-fed rats. Cabozantinib-treated rats exhibited a marked reduction in α-smooth muscle actin+ activated hepatic stellate cell (HSC) expansion, CD68+ macrophage infiltration, and CD34+ pathological angiogenesis, along with reduced hepatic AXL, VEGF, and VEGFR2 expression. Consistently, cabozantinib downregulated the hepatic expression of profibrogenic markers (Acta2, Col1a1, Tgfb1), inflammatory cytokines (Tnfa, Il1b, Il6), and proangiogenic markers (Vegfa, Vwf, Ang2). In a cell-based assay of human activated HSCs, cabozantinib inhibited Akt activation induced by GAS6, a ligand of AXL, leading to reduced cell proliferation and profibrogenic activity. Cabozantinib also suppressed lipopolysaccharide-induced proinflammatory responses in human macrophages, VEGFA-induced collagen expression and proliferation in activated HSCs, and VEGFA-stimulated proliferation in vascular endothelial cells. Meanwhile, administration of cabozantinib did not affect Ki67+ hepatocyte proliferation or serum albumin levels, indicating no negative impact on regenerative capacity. Treatment with cabozantinib also reduced the placental glutathione transferase+ preneoplastic lesions in CDAHFD-fed rats. In conclusion, cabozantinib shows promise as a novel option for preventing MASH progression.

Immune remodulation in pediatric inherited metabolic liver diseases.

Inherited metabolic liver diseases arise from genetic mutations that lead to disruptions in liver metabolic pathways and are predominantly observed in pediatric populations. The spectrum of genetic metabolic liver disorders is diverse, encompassing a range of conditions associated with aberrations in iron, copper, carbohydrate, lipid, protein, and amino acid metabolism. Historically, research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations. Nevertheless, emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment, both within the liver and systemically. This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases, aiming to expand the horizons of researchers in this discipline, and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.

Development Postnatal of the Kidney and Liver in Albino Rat Rattus Rattus, Histological and Biochemical Study

Objective: The primary goal of the current study was to look at histological, histochemical, and biochemical aspects of the development structure of rat's kidney and liver. Materials and Method: Seventy eight samples of kidney and liver were obtained from rats at days; 1, 5, 10, 15, 36 and 90 after birth and processed for histological, histochemical and biochemical techniques. Results: Up to the fifth day, new nephron anlages develop in the renal cortex. After ten days, the final anlages form into functional nephrons, and fifteen days after the corticis forms, the cortex seems mature. The collecting ducts and loops of Henle expand longitudinally to form the renal medulla. The immature medulla is structurally similar to the later inner stripe of the outer zone and cannot be split into distinct zones. Within ten days, the inner zone was developed, and within fifteen days, the outside zone's stripe. The kidney tubule's diameter increased with age, the renal medulla was mature at 36 days, the kidney was covered in a moderate amount of collagen fiber, and the henle loops were lengthy at certain ages, but short at adult age. Adults had larger corpuscle and nephron lumens. In contrast, the thick renal capsule at other ages contained less collagen fibers. A tiny renal gap encircling the glomeruli and a notably greater quantity of fibers were visible in adult Bowman's capsules. The liver was encased in a thin capsule on the first day of birth and a thick capsule between 36 and 90 days later. On day 15, the cells surrounding the central veins began to arrange themselves in a regular fashion. The hepatic parenchyma could be seen by symmetrical hepatic cords, which emerged from the central veins as radiating columns. After five days, Von Kuffer cells began to line the sinusoids next to the endothelial cells. On the tenth day, the hepatic sinusoids took on a more regular appearance, stretching between the hepatic cords and joining the central veins. The hepatic lobules with their central vein were visible at the age of 15 days. The capsule then thickened and elastic fibers started to show up. The reticular fibers also thickened and spread, and in 36 days, collagen fibers started to show up in the portal areas. Based on histochemical data, every PAS, AB, and PAS-AB stain was highly reacted with brush in renal and hepatic cells. In conclusion: The kidney and liver developed differently after birth and reached their mature, typical structures in 36 days.

Inhibition of heme-thiolate monooxygenase CYP1B1 prevents hepatic stellate cell activation and liver fibrosis by accumulating trehalose.

Activation of extracellular matrix-producing hepatic stellate cells (HSCs) is a key event in liver fibrogenesis. We showed that the expression of the heme-thiolate monooxygenase cytochrome P450 1B1 (CYP1B1) was elevated in human and mouse fibrotic livers and activated HSCs. Systemic or HSC-specific ablation and pharmacological inhibition of CYP1B1 attenuated HSC activation and protected male but not female mice from thioacetamide (TAA)-, carbon tetrachloride (CCl4)-, or bile duct ligation (BDL)-induced liver fibrosis. Metabolomic analysis revealed an increase in the disaccharide trehalose in CYP1B1-deficient HSCs resulting from intestinal suppression of the trehalose-metabolizing enzyme trehalase, whose gene we found to be a target of RARα. Trehalose or its hydrolysis-resistant derivative lactotrehalose exhibited potent antifibrotic activity in vitro and in vivo by functioning as an HSC-specific autophagy inhibitor, which may account for the antifibrotic effect of CYP1B1 inhibition. Our study thus reveals an endobiotic function of CYP1B1 in liver fibrosis in males, mediated by liver-intestine cross-talk and trehalose. At the translational level, pharmacological inhibition of CYP1B1 or the use of trehalose/lactotrehalose may represent therapeutic strategies for liver fibrosis.