Hepatic Infiltration Research Articles

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.

Core-fucose-specific Pholiota squarrosa lectin decreased hepatic inflammatory macrophage infiltration in steatohepatitis mice.

Recent findings in glycobiology revealed direct evidence of the involvement of oligosaccharide changes in human diseases, including liver diseases. Fucosylation describes the attachment of a fucose residue to a glycan or glycolipid. We demonstrated that fucosylated proteins are useful serum biomarkers for nonalcoholic fatty liver disease. Among fucosyltransferases, expression of alpha-1, 6-fucosyltransferase (Fut8), which produces core fucose, is frequently elevated during the progression of human chronic liver diseases. Previously, we discovered core-fucose-specific Pholiota squarrosa lectin (PhoSL) from Japanese mushroom Sugitake. Lectins are bioactive compounds that bind to glycan specifically, and various kinds of lectin have a variety of biological functions. Using high-fat and high-cholesterol (HFHC)-fed steatohepatitic mice, we found that core fucosylation increases in hepatic inflammatory macrophages. Antibody drugs bind to specific antigens and block protein function. We hypothesized that, like antibody drugs, PhoSL could have inhibitory effects on glycoproteins involved in steatohepatitis progression. PhoSL administration dramatically decreased hepatic macrophage infiltration and liver fibrosis-related gene expression. Using mouse macrophage-like cell RAW264.7, we found that PhoSL enhanced core-fucose-mediated activation of macrophage cell death by blocking interferon-γ/signal transducer and activator of transcription 1 (STAT1) signaling. Core-fucose-mediated cell death is a mechanism for the anti-inflammatory effects and anti-fibrotic effects of PhoSL on activated macrophages in steatohepatitic liver. In addition, PhoSL provides an anti-fibrotic effect by blocking transforming growth factor-β/SMAD family member 3 signaling in hepatic stellate cells. In conclusion, we found core-fucose-specific PhoSL administration could suppress steatohepatitis progression by decreasing inflammatory macrophage infiltration and fibrotic signaling in hepatic stellate cells.

Hallazgos bioquímicos y ecográficos en caninos obesos

The aim of this study was to identify comorbidities in obese canines attending Centro de Veterinaria y Zootecnia CES, Medellín, Colombia. Thirty canines with a body condition of 7/9 to 9/9 were evaluated. Those with signs of systemic disease or endocrinopathy were excluded. An evaluation of body condition, abdominal ultrasound (with emphasis on pancreas, liver and adrenal glands), non-invasive blood pressure measurement and blood analysis of cholesterol, triglycerides, glucose and canine-specific pancreatic lipase (cPLI) were performed. The results showed that 19 individuals presented hypertriglyceridemia, and those with higher triglyceride values presented ultrasound findings of vacuolar liver disease (p&lt;0.01). Systolic blood pressure, cholesterol, glucose and cPLI were found within normal ranges and without differences between body condition ranges. The importance of including abdominal ultrasound in the diagnosis of obese patients is highlighted. It is concluded that hypertriglyceridemia associated with obesity leads to the accumulation of hepatic fatty infiltrates and vacuolar liver disease.

Activation of α7 Nicotinic Acetylcholine Receptors Inhibits Hepatic Necroptosis and Ameliorates Acute Liver Injury in Mice.

Acute liver injury is a disease characterized by severe liver dysfunction, caused by significant infiltration of immune cells and extensive cell death with a high mortality. Previous studies demonstrated that the α7 nicotinic acetylcholine receptor (α7nAChR) played a crucial role in various liver diseases. The hypothesis of this study was that activating α7nAChR could alleviate acute liver injury and investigate its possible mechanisms. Acute liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS)/D-galactosamine (D-Gal) in wild type, α7nAChR knockout (α7nAChR-/-) and stimulator of interferon gene (STING) mutation (Stinggt/gt) mice in the presence or absence of a pharmacologic selective α7nAChR agonist (PNU-282987). The effects of α7nAChR on hepatic injury, inflammatory response, mitochondrial damage, necroptosis, and infiltration of immune cells during acute liver injury were assessed. The expression of α7nAChR in liver tissue was increased in LPS/D-Gal-induced acute liver injury mice. Compared to the age-matched wild-type mice, α7nAChR deficiency decreased the survival rate, exacerbated the hepatic injury accompanied with enhanced inflammatory response and oxidative stress, and aggravated hepatic mitochondrial damage and necroptosis. Conversely, pharmacologic activation of α7nAChR by PNU-282987 displayed the opposite trends. Furthermore, PNU-282987 significantly reduced the proportion of infiltrating monocyte-derived macrophages (CD45+CD11bhiF4/80int), M1 macrophages (CD45+CD11b+F4/80+CD86hiCD163low), and Ly6Chi monocytes (CD45+CD11b+MHC [major histocompatibility complex] ⅡlowLy6Chi), but increased the resident Kupffer cells (CD45+CD11bintF4/80hiTIM4hi) in the damaged hepatic tissues caused by LPS/D-Gal. Interestingly, α7nAChR deficiency promoted the STING signaling pathway under LPS/D-Gal stimulation, while PNU-282987 treatment significantly prevented its activation. Finally, it was found that Sting mutation abolished the protective effects against hepatic injury by activating α7nAChR. The authors' study revealed that activating α7nAChR could protect against LPS/D-Gal-induced acute liver injury by inhibiting hepatic inflammation and necroptosis possibly via regulating immune cells infiltration and inhibiting STING signaling pathway.

Ethanol Extract of Propolis Attenuates Liver Lipid Metabolism Disorder in High-Fat Diet-Fed SAMP8 Mice.

The prevalence of high-fat diet (HFD) consumption is increasing among middle-aged and older adults, which accelerates the aging process of this population and is more likely to induce lipid metabolism disorders. But the alleviation of ethanolic extract of propolis (EEP) on lipid metabolism disorders during aging remains unclear. This study assesseed the impact of EEP intervention (200 mgkg-1bw) on aging and lipid metabolism disorders in HFD-fed senescence accelerate mouse prone 8 (SAMP8) mice. Findings indicate that EEP ameliorates hair luster degradation and weight gain, reduces systemic inflammation and metabolism levels, enhances hepatic antioxidant enzyme activities, and improves the hepatic expression of senescence-associated secretory phenotype and aging-related genes in HFD-fed SAMP8 mice. Histological staining demonstrates that EEP improves hepatic lipid deposition and inflammatory cell infiltration. Transcriptomic and lipidomic analysis reveal that EEP promotes fatty acid β-oxidation by activating PPAR pathway, resulting in reduced hepatic lipid deposition, and attenuates bile acid (BA) accumulation by improving BA metabolism, which were ensured through qPCR validation of key genes and immunoblot validation of key proteins. CONCLUSIONS: EEP can regulate lipid metabolic dysregulation during aging accompanied by an HFD, potentially delaying the onset and progression of age-related diseases. This provides new approach for supporting healthy aging.

Nicotinamide N-methyltransferase inhibition mitigates obesity-related metabolic dysfunction.

To assess the effects of a small-molecule nicotinamide N-methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet-induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo. DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age- and strain-matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ. 5A1MQ treatment dose-dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ-treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice. This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity.

Mid1 aggravates hepatic ischemia-reperfusion injury by inducing immune cell infiltration.

Hepatic ischemia-reperfusion injury (HIRI) represents a major risk factor in liver transplantation and resection surgeries. Kupffer cells (KCs) produce proinflammatory cytokines and lead to hepatic neutrophil infiltration in the liver, which is one of the leading causes of HIRI. Mid1 is involved in immune infiltration, but the role of Mid1 remains poorly understood. Herin, our study aimed to investigate the effect of Mid1 on HIRI progression. Male C57BL/6 mice aged 6 weeks were used for the HIRI model established. The function of Mid1 on liver injury and hepatic inflammation was evaluated. Invitro, KCs were used to investigate the function and mechanism of Mid1 in modulating KC inflammation upon lipopolysaccharide (LPS) stimulation. We found that Mid1 expression was up-regulated upon HIRI. Mid1 inhibition alleviated liver damage, as evidenced by neutrophil infiltration, intrahepatic inflammation, and hepatocyte apoptosis. Invitro experiments further revealed that Mid1 knockdown reduced the secretion of proinflammatory cytokines and chemokines in KCs. Moreover, silenced-Mid1 suppressed proinflammatory responses by the inhibition of NF-κB, JNK, and p38 signaling pathways. Taken together, Mid1 contributes to HIRI via regulating the proinflammatory response of KCs and inducing neutrophil infiltration. Targeting Mid1 may be a promising strategy to protect against HIRI.

Untargeted lipidomics uncover hepatic lipid signatures induced by long-term exposure to polystyrene microplastics in vivo

ObjectiveThis study evaluated the effects of long-term polystyrene microplastics (PS-MPs) exposure on hepatic lipid metabolism in vivo by lipidomics. ResultsH&E staining showed long-term PS-MPs exposure could trigger the hepatic inflammatory cell infiltration and hepatic steatosis in SD rats, indicating long-term PS-MPs exposure caused hepatoxicity. Lipidomics revealed that the concentrations of 8 lipid metabolites in the liver were altered after exposure to PS-MPs for both 6 and 12 months, namely LdMePE (16:0), LPC (18:1), LPC (18:2), LPC (20:4), PC (17:0_20:4), PC (18:2_22:6), PC (22:6_13:0) and SM (d18:1_24:0), which were all statistically different from the control groups detected at both time points after PS-MPs exposure, suggesting the mainly metabolic pathway was glycerolipid metabolism. ConclusionThis study showed chronic exposure to PS-MPs could cause hepatotoxicity and induce hepatic lipidomics alterations in vivo, which could provide an essential clue for the safety assessment of PS-MPs.