Hepatic Infiltration Research Articles

Advances in Understanding Lipopolysaccharide-Mediated Hepatitis: Mechanisms and Pathological Features

Lipopolysaccharide (LPS), a key component of Gram-negative bacterial membranes, plays a central role in the pathogenesis of inflammatory liver diseases. In this review, we aimed to explore the role of LPS in hepatic injury. Upon hepatic infiltration, LPS activates Kupffer cells via toll-like receptor 4 (TLR4) signaling, inducing proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. These mediators amplify hepatocyte apoptosis, endothelial damage, and platelet aggregation, thereby contributing to sinusoidal thrombosis and tissue ischemia. Pathological features, such as hepatocyte shrinkage, sinusoidal expansion, and fibrin deposition, are hallmark indicators of LPS-induced hepatic inflammation. Therapeutically, aspirin shows promise for attenuating cytokine release, protecting endothelial integrity, and reducing thrombogenesis. Emerging strategies include targeting TLR4 pathways, modulating the gut–liver axis, and utilizing biomolecular approaches such as RNA interference for LPS suppression. The integration of public health interventions, such as dietary optimization and microbiome regulation, offers additional preventive measures. In this review, the dual roles of LPS in inflammation and thrombosis have been emphasized. Advancing our understanding of LPS-driven mechanisms and enhancing treatment strategies are pivotal for managing hepatic inflammation and its systemic implications. Future research should focus on refining biomarkers, optimizing therapeutic efficacy, and addressing safety concerns for clinical applications.

Predictive model of intrahepatic collateral vessels among hepatic veins in patients with liver tumors involving the caval confluence.

Communicating vessels among hepatic veins in patients with tumors invading/compressing hepatic veins at their caval confluence facilitate new surgical solutions. Although their recognition by intraoperative ultrasound has been described, the possibility of preoperative detection still remains uncertain. We aimed to develop a model to predict their presence before surgery. Patients with caval confluence-located tumors who underwent surgery between 2010 and 2022 were collected and analyzed. A total of 136 eligible patients were assigned randomly into the derivation (n= 96) and validation (n= 40) cohorts. Communicating vessels were recorded as visible or not considering the intraoperative ultrasound findings as reference. A predictive model was built and graphically represented as nomogram. Of 136 patients included, 106 (78%) had communicating vessels. Of patients with communicating vessels, a parenchyma-sparing hepatectomy was performed in 98 (92%; 77% with hepatic vein amputation, 75/98). Of 30 patients without communicating vessels, all underwent an R1 vascular parenchyma-sparing hepatectomy. Operative mortality was nil. No liver congestion occurred. In the former, presence of communicating vessels at the intraoperative ultrasound was detected in 75 (78%) patients, whereas in the validation cohort it was detected in 31 (78%). No differences in the distribution of the variables were found in the 2 cohorts. The model included tumor size at the confluence, tumor number, degree of hepatic vein infiltration, and density of hepatic tissue at contrast-computed tomography, as predictors of communicating vessels in derivation cohort (discrimination was area under the receiver operating characteristic curve= 0.82). Identification of communicating vessels in patients with tumors at the caval confluence opens new surgical options, expanding resectability. The present predictive model may play a useful role in facilitating surgical decision-making, developing and implementing surgical strategies, and guiding resectability improvement efforts.

Analysis of Immunometabolic Profiles in Patients With Chronic Drug-Induced Liver Injury and Validation in Mice to Reveal Potential Mechanisms.

The mechanism underlying chronic drug-induced liver injury (DILI) remains unclear. Immune activation is a common feature of DILI progression and is closely associated with metabolism. We explored the immunometabolic profile of chronic DILI and the potential mechanism of chronic DILI progression. Plasma and peripheral blood mononuclear cells from patients with chronic DILI were analyzed using multiplex immunoassays and untargeted metabolomics to reveal their immunometabolic profile. The effects and potential mechanisms of chronic DILI-related metabolite on acute or chronic liver injury induced by LPS or CCl4 in mice were investigated. Patients with chronic DILI exhibited elevated plasma IL-6, IL-12p70, IL-15 and reduced IL-10 levels. The percentage of IL-12+ monocytes was higher, while that of CD206+ monocytes, IL-10+ monocytes, Th2, Treg, and IL-10+ CD4+ T cells were lower in patients with chronic DILI compared to those with acute DILI. We identified the most significantly increased metabolite in patients with chronic DILI was cis-aconitic acid (CAA). Administration of CAA can attenuate liver injury in mice with acute liver injury induced by LPS or CCl4 and promote the spontaneous resolution of liver fibrosis in mice with chronic live injury induced by CCl4. The protective mechanism of CAA against liver injury is associated with the inhibition of hepatic macrophage infiltration and polarization, which is achieved by inhibiting the secretion of neutrophil-derived IL-33 and subsequent phosphorylation of GATA3. CAA, which is elevated in patients with chronic DILI, protects against liver injury by inhibiting hepatic macrophage infiltration and polarization through the suppression of the IL-33/GATA3 pathway, suggesting that CAA may serve as a potential target for regulating tissue repair in liver injury.

The Role of Key Molecules of Pyroptosis in Liver Damage of Rats With Exertional Heat Stroke.

Purpose: This study is aimed at investigating the role of key molecular elements involved in pyroptosis in liver injury caused by exertional heat stroke (EHS). Methods: We established a model of EHS-induced liver injury in Sprague-Dawley rats, with a control group (receiving no treatment) for comparison and 12 rats in each group. Alanine transaminase (ALT) and aspartate transaminase (AST) levels in the blood were detected. Interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) levels were assessed using enzyme-linked immunosorbent assays (ELISA). Pathological changes in liver tissue were examined by hematoxylin and eosin (H&E) staining. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect mRNA and protein expression levels of Caspase-1 and Gasdermin D. Results: Compared to the control group, the liver tissue of the EHS group showed congestion in hepatic sinusoids, hepatocyte edema, eosinophilic changes, necrosis, and infiltration of inflammatory cells. ALT and AST levels in the EHS group were significantly higher than those in the control group (p < 0.05). The mRNA expressions of Caspase-1, Gasdermin D, IL-1β, and IL-18 were significantly increased in the EHS group compared to the control group (p < 0.001). The protein expressions of Caspase-1, cleaved Caspase-1, Gasdermin D, and cleaved Gasdermin D were significantly increased in the EHS group. Conclusion: These findings indicated that hepatic pyroptosis plays an important role in EHS-induced liver injury.

Effects of Ganoderma lucidum Supplementation on Obesity and Metabolic Alterations Induced by High‐Carbohydrate‐High‐Fat Diet in Rats

Ganodermalucidum (GL), commonly called Reishi mushroom, has been utilized in traditional medicine against multiple ailments including obesity and metabolic complications. The purpose of this study was to evaluate the ability of the powdered supplementation of GL (2.5% w/w of diet) and its ability to ameliorate obesity and associated metabolic alterations in high‐carbohydrate‐high‐fat (HCHF) diet–fed obese female Wistar rats. Thus, after 56 days of feeding the mice with different treatments, we measured physiological parameters to evaluate the effect. Phytochemical analysis by HPLC identified the bioactive polyphenols in GL. Results demonstrated that GL supplementation significantly (p &lt; 0.05) prevented the net rise in body weight and reduced organ weights and abdominal fat deposition in obese rats. It improved glucose intolerance, decreasing blood glucose level (6.2 nmol/L) compared to HCHF diet–induced obese rats (8.67 nmol/L). It also significantly ameliorated the plasma lipids parameters including total cholesterol (106.4 mg/dL), triglyceride, LDL‐C (55.26 mg/dL), and VLDL‐C, restored the elevated serum profiles of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), and elevated the antioxidant enzymes including superoxide dismutase (SOD) (42.58 U/g tissue), catalase (CAT) activities, and glutathione (GSH) (62.63 nmol/g tissue) in obese rats. Furthermore, GL prevented hepatic fat infiltration in HCHF diet–fed rats preventing steatosis. Different bioactive polyphenols including catechin, rutin, cinnamic acid, vanillic acid, quercetin, ferulic acid, and kaempferol were detected in GL by HPLC analysis, which might be responsible for its activity. Bangladeshi cultivated GL possesses antiobesity effect and is rich in phenolics that could prevent obesity‐associated metabolic disorders.

Design, synthesis and biological evaluation of Alisol B derivatives for potential treatment of non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction- associated with fatty liver disease (MAFLD), is one of the most prevalent chronic liver diseases globally. NAFLD is characterized by the accumulation of liver fat unrelated to excessive alcohol consumption. Non-alcoholic steatohepatitis (NASH) is the disease progression of NAFLD and could develop into cirrhosis and hepatocellular carcinoma. In previous studies, the preclinical efficacy of alisol B and alisol B 23-acetate against NASH and metabolic syndrome was identified. However, there is a paucity of literature pertaining to the specialized structural optimization of alisol B for the treatment of NASH. In this study, a series of alisol B derivatives (1-21) were designed, synthesized and evaluated in order to improve the activity of alisol B and to obtain candidate compounds for treating NASH. The effects of the synthesized compounds on de novo lipogenesis and α-SMA gene expression were tested to explore the preliminary structure-activity relationship (SAR). Compounds 14 and 21 were selected for further in vivo investigation. The high-fat diet plus carbon tetrachloride (HFD+CCl4)-induced NASH mice model was employed for biological evaluation in vivo. Compounds 14 and 21 effectively improved hepatic steatosis, ballooning, inflammatory infiltration, and hepatic fibrosis in the livers of HFD+CCl4 mice. Thus, 14 and 21 are promising lead compounds for the treatment of NASH.

M1 macrophage-derived exosomes alleviate leukemia by causing mitochondrial dysfunction.

Acute myeloid leukemia (AML) is one type of blood cancer that initially has a high cure rate but frequently relapses and leading to death. Therefore, there is an urgent need for innovative AML treatments. The leukemia C1498 cells were co-cultured with M1 macrophage-derived exosomes (M1-exo), and the proliferation and apoptosis of C1498 cells were investigated using CCK-8 and flow cytometry, respectively. qPCR and Western blot were applied to determine the PGAM5 expression in M1-exo treated C1498 cells. The role of M1-exo-derived PGAM5 in mitochondria was examined via fluorescence staining. The anti-inflammatory effects of M1-exo-derived PGAM5 and M1-exo were evaluated by flow cytometry, HE staining, and immunohistochemistry in xenograft and nude mouse tumorigenic models. M1-exo exhibited a potent capability to attenuate C1498 cell proliferation, and induce cell apoptosis. In vivo experimentation demonstrated that administration of M1-exo led to a reduction in leukocyte count, alleviated inflammatory infiltration, decreased liver and spleen weights, and significantly diminished tumor size. PGAM5 was elevated in M1-exo, and knockdown of PGAM5 in C1498 cells and M1-exo enhanced proliferation and reduced apoptosis in C1498 cells. Concurrently, M1-exo-derived PGAM5 decreased mitochondrial membrane potential and increased calcium influx in vitro. In vivo, studies showed that knockdown of PGAM5 in M1-exo elevated liver and spleen weights, augmented tumor size, and intensified hepatic inflammatory infiltration. Our study reveals that M1-exo induces mitochondrial dysfunction against leukemia through PGAM5.

Obstructive jaundice of unusual cause.

The most prevalent tumor in women worldwide is breast cancer. Although liver metastases are relatively frequent, pancreatic involvement is unusual. In the case of jaundice in patients with a history of neoplasia, the initial diagnosis is focused on ruling out hepatic infiltration. However, it is essential to consider other, less common but related etiologies of biliary obstruction. The most frequent pancreatic metastatic involvement is usually as nodular lesions; nevertheless, diffuse parenchymal infiltration is also possible, as illustrated in the following case.

Xanthogranulomatous cholecystitis infiltrating anterior abdominal wall: a rare case report

Xanthogranulomatous cholecystitis (XGC) is a benign chronic inflammatory disease of the gallbladder often presenting as features of chronic cholecystitis. The disease closely mimics gallbladder carcinoma (GBC) and distinguishing XGC from gallbladder cancer preoperatively is very challenging. Biochemical or radiological investigations cannot differentiate XGC from GBC and they share overlapping symptoms. Reporting here is a 31 year old female patient who presented with features of failed attempt of cholecystectomy due to suspected carcinoma gallbladder at an outside hospital. Even CECT abdomen showed gallbladder mass with hepatic and anterior abdominal wall infiltration. Intraoperatively, there was a mass in the gallbladder with large calculi and extending into the adjacent liver, anterior abdominal wall and part of hepatic flexure of colon. Radical cholecystectomy with en block excision of anterior abdominal wall and part of hepatic flexure of colon was done. Frozen section and final histopathological reports confirmed the diagnosis of XGC.

Grifola frondosa Polysaccharide Ameliorates Inflammation by Regulating Macrophage Polarization of Liver in Type 2 Diabetes Mellitus Rats.

Grifola frondosa polysaccharide (GFP) has a positive effect in regulating type 2 diabetes mellitus (T2DM), but the understanding of its regulatory mechanism is still limited. Accumulating evidence suggests that hepatic inflammation is crucial in the onset and progression of insulin resistance (IR) and T2DM. However, the question of whether GFP can modulate T2DM via regulating hepatic inflammation and the underlying mechanism has not yet been reported. High-fat diet (HFD) fed combined with streptozocin (STZ) injections rat model and Lipopolysaccharides (LPS)-treated bone marrow-derived macrophages (BMDM) model are used. The results showed that GFP intervention reduces weight loss and hyperglycemia symptoms, besides lowers FINS, HOMA-IR, IPGTT-AUC, and IPITT-AUC in T2DM rats. Meanwhile, GFP intervention reduces the secretion level of inflammatory factors and increases the secretion level of anti-inflammatory factors in the liver tissue of T2DM rats. Furthermore, GFP reduces macrophage infiltration in liver tissue, inhibits macrophage M1-type polarization, and promotes M2-type polarization. These results suggest that GFP intervention could attenuate the hepatic inflammatory and insulin resistance in T2DM rats by inhibiting hepatic macrophage infiltration and modulating M1/M2 polarization. The findings provide new evidence for GFP in the early prevention and treatment of T2DM.

The correlation between metabolic dysfunction-associated steatotic liver disease (MASLD) grades and hemodynamic alterations of the portal, hepatic, and splenic vein and spleen size.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver condition worldwide, affecting over 25% of the population. Fatty infiltration in MASLD leads to hemodynamic changes in hepatic circulation, which can be quantitatively assessed using Color Doppler Ultrasonography (US). In this study, we aimed to investigate the correlation of Color Doppler US findings of the portal, hepatic, and splenic venous system within various degrees of MASLD. Between 2021 and 2024, 104 patients referred to Mousavi Hospital at Zanjan University of Medical Sciences were enrolled. Participants were divided into four groups based on the degree of hepatic fatty infiltration on biopsy results: normal, grade 1, grade 2, and grade 3, with 26 subjects in each group (13 men and 13 women). All patients were biopsy proved. Gray-scale and Color Doppler US were used to assess portal and splenic vein peak systolic velocity (PSV), portal and splenic vein diameter, hepatic vein waveform, and spleen size. The Spearman rank correlation was employed to evaluate the relationship between these variables under non-parametric conditions. A significant negative correlation was found between portal vein PSV and MASLD grade (r = - 0.499, p = 0.000). A significant difference was also observed in hepatic venous waveform abnormality between different grades of MASLD (p = 0.043). Accordingly, portal vein PSV and splenic vein PSV had a significantly positive correlation (r = 0.209, p = 0.033). We also observed a positive correlation between the portal vein and splenic diameter (r = 0.210, p = 0.032). Increasing MASLD severity is associated with reduced portal vein PSV and more pronounced abnormalities in hepatic vein flow. Routine assessment of portal and hepatic vein flow using Color Doppler US is recommended to accurately diagnose and monitor the effects of MASLD on hepatic circulation, potentially improving disease management and patient outcomes.

Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population.

Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid-mTOR-FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.

Modulation of SIRT6 related signaling pathways of p-AKT/mTOR and NRF2/HO-1 by memantine contributes to curbing the progression of tamoxifen/HFD-induced MASH in rats

Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disorder marked by hepatic fat accumulation and inflammatory infiltrates which may evolve to cirrhosis. Clinical studies have demonstrated the higher risk of MASH development after tamoxifen (TAM) therapy, especially in obese patients. Therefore, we aimed to evaluate MASH induction by TAM combined with high fat diet (HFD) and the potential interference of memantine (MEMA) with MASH progression via modulation of SIRT6 and its related signaling pathways. MASH was induced in female Wistar rats by co-administration of TAM (25 mg/kg/day, p.o.) and HFD for 5 weeks. Liver function biomarkers, tissue triglyceride and cholesterol, MASH scoring, SIRT6 with its related signals, and lipid synthesis/oxidation markers were estimated. By comparison to MASH group, MEMA improved liver function indices (ALT, AST, ALP, albumin) and reduced the progression of MASH, evidenced by decreased accumulation of lipids in hepatic tissue, improved histological features, and reduced MASH scoring. MEMA enhanced hepatic SIRT6 and downregulated p-AKT/mTOR signaling, that subsequently reduced expressions of the lipid synthesis biomarkers (SREBP1c, SCD), while elevating the lipid oxidation markers (PPAR-α, CPT1). Moreover, MEMA enhanced NRF2/HO-1 signaling, with subsequently improved antioxidant defense and pro-inflammatory/anti-inflammatory cytokines balance. Analysis of SIRT6 correlations with p-AKT/mTOR, NRF2/HO-1, SREBP1c, and PPAR-α further confirmed our results. Consequently, we conclude that MEMA could interfere with MASH progression, at least in part, via enhanced SIRT6 expression and modulation of its related p-AKT/mTOR and NRF2/HO-1 signaling pathways, eventually reducing liver steatosis and inflammation. That could be a promising therapeutic modality for curbing MASH progression.

Rhoifolin Attenuates Concanavalin A-Induced Autoimmune Hepatitis in Mice via JAKs/STATs Mediated Immune and Apoptotic Processes.

Rhoifolin (ROF) exhibits a diverse range of biological activities, encompassing anticancer, hepatoprotective, antidiabetic, antirheumatic, and antiviral properties. However, the specific protective effects and possible mechanisms of the compound against T-cell-mediated autoimmune hepatitis have not been previously elucidated. In the present study, adult male mice were administered Con A (20 mg/kg, intravenously) for 8 h. In the treated groups, mice were pretreated with ROF daily (20 mg/kg and 40 mg/kg, orally) for 7 days before Con A intoxication. The results showed that ROF significantly decreased serum biochemical indices (ALT, AST, ALP, and LDH) and regulated related oxidative stress indicators (MDA, SOD, and GSH), reduced hepatic necrosis areas and immune cells infiltration, inhibited the release of various inflammatory factors (TNF-α, IFN-γ, IL-2, and IL-17), and improved hepatic tissue apoptosis, thereby alleviating hepatic damage induced by Con A. Additionally, we have also confirmed that ROF efficiently inhibited Th1/Th17 cells polarization via modulation of the JAK2/JAK3/STAT1/STAT3 signaling pathways both in vivo and in vitro. Moreover, the molecular mechanism examination also demonstrated that ROF regulated apoptotic cascade signaling through IL-6/JAK2/STAT1/STAT3 controlling BNIP3 activity in primary hepatocytes. These effects were in good agreement with the bioinformatics analysis of ROF treatment for AIH. In conclusion, our findings provide new insights into the potential use of ROF for AIH therapy, which may result from the specific regulation of the T cell subtype polarization and the apoptosis of liver cells via modulation of the JAKs/STATs signaling pathways.

Integrated lipidomic and transcriptomics to explore the effects of ethyl acetate extract of Herpetospermum pedunculosum on nonalcoholic fatty liver disease in mice

Ethnopharmacological relevanceHerpetospermum pedunculosum (Ser.) C.B. Clarke (HP), a traditional Tibetan medicine used to treat hepatobiliary diseases, was confirmed that lignans-enriched ethyl acetate extract of HP (EAHP) could alleviate the hepatic injury by modern pharmacological evidence. However, the effects and potential mechanisms of EAHP against nonalcoholic fatty liver disease (NAFLD) are still unknown. Aim of the studyTo reveal the effects of EAHP on NAFLD and explore the potential mechanisms from the perspective of lipidomics and transcriptomics. Materials and methodsUPLC‒Q–TOF‒MS analysis was carried out to investigate the chemical components of EAHP. A Choline-deficient, L-amino acid defined, high fat diet (CDAHFD) was used to establish a NAFLD mouse model. The anti-NAFLD effects of various dosages of EAHP were evaluated by biochemical indexes and histological analysis. Hepatic lipidomic and transcriptomic analysis and multiple bioinformatics methods were used to screen biomarkers and signaling pathways. The levels of the corresponding genes were verified by qPCR. Results36 kinds of compounds were identified by UPLC‒Q–TOF‒MS analysis. Oral treatment with EAHP significantly decrease the liver index and the levels of ALT and AST in the serum. The measurements lipid content and Oil Red O staining results suggested that EAHP ameliorated lipid metabolism disorders by reducing the content of TG and LDL-C, increasing HDL-C in the liver. H&E staining and ELISA revealed that EAHP restored hepatic inflammatory infiltration and decrease the levels of IL-1β, IL-6, TNF-α, and increase IL-10 in the serum. Lipidomic analysis showed that EAHP could regulate CDAHFD-induced lipid metabolic disorder. The different lipid metabolites included TG, phosphatidyl choline (PC), diacylglycerol (DG), phosphatidylethanolamine (PE), phosphatidylinositol (PI), ceramide (Cer). Transcriptomic analysis revealed that Bmp8b, Nbl1, Rgma, Sphk1, Thbs1, and Ugt8a were important regulators, which were associated with TGF-β signaling pathway and sphingolipid metabolism. The expressions of above genes detected by were qPCR consistent with transcriptomic data. ConclusionsThe ameliorative effects of EAHP on NAFLD are potentially attributable to the regulation of sphingolipid metabolism and TGF-β signaling pathway, etc., which results in abnormal hepatic lipid metabolism and inflammatory response.

Long-Term Survival in Canine Hepatosplenic T-Cell Lymphoma Treated with Toceranib Phosphate Following Splenectomy: A Case of Atypical Lymphoma

Toceranib phosphate (toceranib) is approved for canine mast cell tumor treatment. However, no long-term response to toceranib in canine HSTCL has been reported. Here, we describe a case of a 10-year-old castrated mixed-breed dog that presented with a 3-month history of weight loss, polydipsia, and polyuria. The clinicopathological and imaging abnormalities included icterus, biliary obstruction, and splenomegaly with multiple diffuse splenic hypoechoic nodules. On day 21, a cholecystectomy was performed to remove the obstruction, followed by a liver biopsy and splenectomy. Cytology of the spleen and liver showed many small lymphocytes with intracytoplasmic granules (sGLs). Splenic and hepatic infiltration of neoplastic CD3/granzyme B-positive small cells and lymphocytic cholecystitis with granzyme B-negative small cells were noted. T-cell receptor gene clonal rearrangements were observed in the liver tissues. The dog was diagnosed with a hepatosplenic T-cell lymphoma (HSTCL) of sGLs concurrent with lymphocytic cholecystitis. The icterus resolved after surgery, but there was progressive elevation of liver enzyme levels. Toceranib was administered from day 39, resulting in decreased liver enzyme levels, and the dog remained in good condition. The dog stayed in remission after toceranib administration and survived for 460 days. Toceranib should be considered an effective treatment option for canine HSTCL.

Selective HLA Class II Allele-Restricted Activation of Atabecestat Metabolite-Specific Human T-Cells.

Elevations in hepatic enzymes were detected in several trial patients exposed to the Alzheimer's drug atabecestat, which resulted in termination of the drug development program. Characterization of hepatic T-lymphocyte infiltrates and diaminothiazine (DIAT) metabolite-responsive, human leukocyte antigen (HLA)-DR-restricted, CD4+ T-lymphocytes in the blood of patients confirmed an immune pathogenesis. Patients with immune-mediated liver injury expressed a restricted panel of HLA-DRB1 alleles including HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01. Thus, the objectives of this study were to (i) generate DIAT-responsive T-cell clones from HLA-genotyped drug-naive donors, (ii) characterize pathways of DIAT-specific T-cell activation, and (iii) assess HLA allele restriction of the DIAT-specific T-cell response. Sixteen drug-naive donors expressing the HLA-DR molecules outlined above were recruited, and T-cell clones were generated. Cellular phenotype, function, and HLA-allele restriction were assessed using culture assays. Peptides displayed by HLA class II molecules in the presence and absence of atabecestat were analyzed by mass spectrometry. Several DIAT-responsive CD4+ clones, displaying no reactivity toward the parent drug, were successfully generated from donors expressing HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01 but not from other donors expressing other HLA-DRB1 alleles. T-cell clones were activated following direct binding of DIAT to HLA-DR proteins expressed on the surface of antigen presenting cells. DIAT binding did not alter the HLA-DRB1 peptide binding repertoire, indicative of a binding interaction with the HLA-associated peptide rather than with the HLA protein itself. DIAT-specific T-cell responses displayed HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01 restriction. These data demonstrate that DIAT displays a degree of selectivity toward HLA protein and associated peptides, with expression of certain alleles increasing and that of others decreasing, the likelihood that a drug-specific T-cell response develops.

Comparative Assessment of Beeswax Alcohol and Coenzyme Q10 (CoQ10) to Prevent Liver Aging, Organ Damage, and Oxidative Stress in Hyperlipidemic Zebrafish Exposed to D-Galactose: A 12-Week Dietary Intervention.

The current study was designed to compare in vivo efficacy between beeswax alcohol (BWA) and coenzyme Q10 (CoQ10) to treat fatty liver changes, oxidative stress, and damages in major organs of zebrafish by 12 weeks with high-cholesterol (HC) and galactose (Gal) supplementation. At week 12, the HC control and HC+Gal control groups showed 96% and 92% survivability, respectively, while co-supplementation of the 0.5% BWA and 1.0% BWA groups exhibited 96% and 100% survivability. However, co-supplementation of the 0.5% CoQ10 and 1.0% CoQ10 groups revealed the lowest survivability, around 92% and 89%, respectively. The 0.5% BWA and 1.0% BWA groups showed 21% (p < 0.001) and 41% (p < 0.001), respectively, lower total cholesterol (TC) than the HC+Gal control, while the 1.0% CoQ10 group showed only 15% lower TC than the control. Interestingly, the 0.5% BWA and 1.0% BWA groups showed 22% (p < 0.001) and 38% (p < 0.001), respectively, lower triglyceride (TG) than the HC+Gal control. However, both the 0.5% CoQ10 and 1.0% CoQ10 groups showed similar TG levels as the control, suggesting that CoQ10 supplementation had no effect on lowering serum TG. The 1.0% BWA group showed the highest plasma HDL-C and HDL-C/TC (%) up to 3.2-fold and 5.5-fold, respectively, higher than those of the HC+Gal control, while the 1.0% CoQ10 group showed 2.4-fold and 2.8-fold higher plasma HDL-C and HDL-C/TC (%), respectively, than the control. The plasma aspartate transaminase (AST) and alanine transaminase (ALT) levels were lowest in the 1.0% BWA group, 51% and 72%, respectively, lower than HC+Gal control, suggesting the lowest extent of hepatic damage. In hepatic tissue, neutrophil infiltration and interleukin (IL)-6 production were the lowest in the 1.0% BWA group, around 67% and 85%, respectively, lower than the HC+Gal control. Fatty liver change, cellular apoptosis, and cell senescence in hepatic tissue were remarkably lowered in the 1.0% BWA group, while the CoQ10 group showed much less effect than the BWA group. In kidney, ovary, and testis tissue, the 1.0% BWA group showed the lowest production of reactive oxygen species, the extent of cellular senescence, and cellular apoptosis with the healthiest cell morphology. In conclusion, supplementation of BWA remarkably protected the liver, kidney, ovary, and testis from oxidative damage by cholesterol and galactose consumption, with the least serum AST and ALT levels, inflammatory parameters, and senescence markers.

The multifaceted roles of B lymphocytes in metabolic dysfunction-associated steatotic liver disease.

Recent evidence suggests that adaptive immune cells are important contributors to metabolic dysfunction-associated steatotic liver disease (MASLD, formerly non-alcoholic fatty liver disease, NAFLD). In liver biopsies from MASLD patients, the accumulation of intrahepatic B cells is positively correlated with the MASLD activity score. Hepatic B-cell infiltration is observed in experimental models of metabolic dysfunction-associated steatohepatitis (MASH, formerly non-alcoholic steatohepatitis, NASH). Intrahepatic B2 cells have been shown to contribute to MASLD/MASH by activating T cells, macrophages and hepatic stellate cells, and by producing pathogenic IgG antibodies. In mice fed a MASH diet, selective depletion of B2 cells reduces steatohepatitis and fibrosis. Intestinal B cells are metabolically activated in MASH and promote T-cell activation independently of TCR signaling. In addition, B cells have been shown to contribute to liver fibrosis by activating monocyte-derived macrophages through the secretion of IgA immunoglobulins. Furthermore, our recent study indicates that certain B cell subsets, very likely regulatory B cells, may play a protective role in MASLD. This review summarizes the molecular mechanisms of B cell functions and discusses future research directions on the different roles of B cells in MASLD and MASH.

Hepatoprotective Effect of Camel Thorn Polyphenols in Concanavalin A-Induced Hepatitis in Mice.

To explore the prophylactic and therapeutic effects of Alhagi maurorum ethanolic extract (AME) in concanavalin A (Con A)-induced hepatitis (CIH) as well as possible underlying mechanisms. Polyphenols in AME were characterized using high performance liquid chromatography (HPLC). Swiss albino mice were divided into 4 groups. Normal group received intravenous phosphate-buffered saline (PBS); Con A group received 40 mg/kg intravenous Con A. Prophylaxis group administered 300 mg/(kg·d) AME orally for 5 days before Con A intervention. Treatment group received intravenous Con A then administered 300 mg/kg AME at 30 min and 3 h after Con A intervention. After 24 h of Con A injection, hepatic injury, oxidative stress, and inflammatory mediators were assessed. Histopathological examination and markers of apoptosis, inflammation, and CD4+ cell infiltration were also investigated. HPLC analysis revealed that AME contains abundant polyphenols with pharmacological constituents, such as ellagic acid, gallic acid, ferulic acid, methylgallate, and naringenin. AME alleviated Con A-induced hepatic injury, as manifested by a significant reduction in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase (P<0.01). Additionally, the antioxidant effect of AME was revealed by a significant reduction in oxidative stress markers (nitric oxide and malondialdehyde) and restored glutathione (P<0.01). The levels of proinflammatory cytokines (tumor necrosis factor-α, interferon-γ, and interleukin-6) and c-Jun N-terminal kinase (JNK) activity were reduced (P<0.01). Histopathological examination of liver tissue showed that AME significantly ameliorated necrotic and inflammatory lesions induced by Con A (P<0.01). Moreover, AME reduced the expression of nuclear factor kappa B, pro-apoptotic protein (Bax), caspase-3, and CD4+ T cell hepatic infiltration (P<0.01). The expression of anti-apoptotic protein Bcl-2 was increased (P<0.01). AME has hepatoprotective and ameliorative effects in CIH mice. These beneficial effects are likely due to the anti-inflammatory, antioxidant, and anti-apoptotic effects of the clinically important polyphenolic content. AME could be a novel and promising hepatoprotective agent for managing immune-mediated hepatitis.