Linagliptin, a DPP-4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights.

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP-4 inhibitor known for its safe profile, has exhibited noteworthy anti-inflammatory and anti-oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10-week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti-inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.

The hepatocyte epidermal growth factor receptor (EGFR) pathway regulates the cellular interactome within the liver fibrotic niche.

Liver fibrosis is the consequence of chronic liver injury in the presence of an inflammatory component. Although the main executors of this activation are known, the mechanisms that lead to the inflammatory process that mediates the production of pro-fibrotic factors are not well characterized. Epidermal growth factor receptor (EGFR) signaling in hepatocytes is essential for the regenerative processes of the liver; however, its potential role in regulating the fibrotic niche is not yet clear. Our group generated a mouse model that expresses an inactive truncated form of the EGFR specifically in hepatocytes (ΔEGFR mice). Here, we have analyzed the response of WT and ΔEGFR mice to chronic treatment with carbon tetrachloride (CCl4), which induces a pro-inflammatory and fibrotic process in the liver. The results indicated that the hallmarks of liver fibrosis were attenuated in CCl4-treated ΔEGFR mice when compared with CCl4-treated WT mice, coinciding with a faster resolution of the fibrotic process and ameliorated damage. The absence of EGFR activity in hepatocytes induced changes in the pattern of immune cells in the liver, with a notable increase in the population of M2 macrophages, more related to fibrosis resolution, as well as in the population of lymphocytes related to eradication of the damage. Transcriptome analysis of hepatocytes, and secretome studies of extracellular media from in vitro experiments, allowed us to elucidate the specific molecular mechanisms regulated by EGFR that mediate hepatocyte production of both pro-fibrotic and pro-inflammatory mediators; these have consequences for the deposition of extracellular matrix proteins, as well as for the immune microenvironment. Overall, our study uncovered novel mechanistic insights regarding EGFR kinase-dependent actions in hepatocytes that reveal its key role in chronic liver damage. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication.

INTRODUCTION: The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver cells. MATERIALS AND METHODS: To investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum. RESULTS: The loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors. CONCLUSION: YAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell-cell communication originating from NPCs.

HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells.

OBJECTIVE: Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC. DESIGN: Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids. RESULTS: NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for HLA-DPA1*02:01~B1*01:01 (OR 1.99, p=6.7×10-50). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids. CONCLUSION: Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~DPB1*01:01 and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.

Intravital imaging: dynamic insights into liver immunity in health and disease.

Inflammation is a critical component of most acute and chronic liver diseases. The liver is a unique immunological organ with a dense vascular network, leading to intense crosstalk between tissue-resident immune cells, passenger leucocytes and parenchymal cells. During acute and chronic liver diseases, the multifaceted immune response is involved in disease promoting and repair mechanisms, while upholding core liver immune functions. In recent years, single-cell technologies have unravelled a previously unknown heterogeneity of immune cells, reshaping the complexity of the hepatic immune response. However, inflammation is a dynamic biological process, encompassing various immune cells, orchestrated in temporal and spatial dimensions, and driven by multiorgan signals. Intravital microscopy (IVM) has emerged as a powerful tool to investigate immunity by visualising the dynamic interplay between different immune cells and their surroundings within a near-natural environment. In this review, we summarise the experimental considerations to perform IVM and highlight recent technological developments. Furthermore, we outline the unique contributions of IVM to our understanding of liver immunity. Through the lens of liver disease, we discuss novel immune-mediated disease mechanisms uncovered by imaging-based studies.

Liver damage profile in COVID-19 pregnant patients.

INTRODUCTION: SARS-CoV-2 unsparingly impacts all areas of medicine. Pregnant women are particularly affected by the pandemic and COVID-19 related liver damage seems to be another threat to maternal and fetal health. The aim of this study is to define liver damage profile including bile acids serum levels in COVID-19 pregnant patients and to determine predictors of disease aggravation and poor obstetrics outcomes. METHODS: This study has been carried out in the Obstetrics and Gynecology Department, at the National Medical Institute in Warsaw, Poland between 01.02.2021 and 01.11.2022 The study cohort comprises 148 pregnant patients with COVID-19 and 102 pregnant controls who has been tested negative for SARS-CoV-2. RESULTS: COVID-19 pregnant patients presented liver involvement at admission in 41,9%. Hepatotoxic damage accounted for 27 (19.85%), cholestatic type was diagnosed in 11 (8.09%) and mixed type of liver injury was presented in 19 (13.97%) of patients. Higher serum levels of AST, ALT, GGT, total bilirubin and bile acids as well as mixed type of liver injury at admission were correlated with severe form of an illness. AST and ALT above upper reference limit as well as hepatotoxic type of liver damage predisposed pregnant patients with COVID-19 to poor obstetrics outcomes. CONCLUSION: Hepatic damage in pregnant women with COVID-19 is a common, mild, transaminase-dominant, or mixed type of injury, and often correlates with elevated inflammatory markers. SARS-CoV-2 test should be performed as a part of differential diagnosis in elevated liver function tests. Although bile acids serum levels were commonly elevated they seems to be clinically irrelevant in terms of pregnancy outcomes. Video Abstract.

Extracellular vesicles derived from bone marrow mesenchymal stem cells ameliorate chronic liver damage via microRNA-136-5p.

Chronic liver damage (CLD) encompasses a spectrum of conditions and poses a significant global health challenge, affecting millions of individuals. Currently, there is a deficiency of clinically validated therapeutics with minimal side effects. Emerging evidence underscores the significant potential of extracellular vesicles derived from bone marrow mesenchymal stem cells (BMSC-EVs) as a promising therapeutic method for CLD. This study aimed to evaluate the influence of BMSC-EVs containing microRNA-136-5p (BMSC-EVs-miR-136-5p) on macrophage polarization during chronic liver injury and elucidate the mechanisms associated with the GNAS/PI3K/ERK/STAT3 axis. Surface markers of BMSCs were detected via Immunofluorescent Staining. Subsequently, EVs were harvested from the BMSC culture medium. In vivo fluorescence imaging was employed to locate the BMSC-EVs. Additionally, fluorescence microscopy was used to visualize the uptake of DIR-labeled BMSC-EVs by RAW264.7 cells. Various methods were employed to assess the impact of BMSC-EVs on the expression levels of inflammatory factors (IL-1ß, IL-6, IL-10, and TNF-α), M1/M2 macrophage markers (iNOS and Arg-1), and members of inflammation-related signaling pathways (GNAS, PI3K, ERK, and STAT3) in RAW264.7 cells co-cultured with BMSC-EVs. Loss-of-function approaches targeting miR-136-5p in RAW264.7 cells were subsequently utilized to validate the role of BMSC-EVs-miR-136-5p. The Luciferase Reporter Assay indicates that GNAS was identified to be a target of miR-136-5p, and miR-136-5p demonstrating increased within BMSC-EVs compared to Raw264.7-EVs. BMSC-EVs-miR-136-5p mitigated CCl4-induced liver inflammation and improved liver function by Suppressing the GNAS/STAT3 Signaling. Notably, miR-136-5p suppressed lipopolysaccharide (LPS)-induced inflammation in RAW264.7 cells. BMSC-EVs-miR-136-5p alleviates CLD by activating M2 polarization through the GNAS-mediated PI3K/ERK/STAT3 axis. Accordingly, the members of this axis may serve as therapeutic targets.

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade.

Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Effects of sleep quality in early pregnancy on pregnancy outcomes and mood state.

PURPOSE: To clarify the relationship between quality of sleep and pregnancy outcomes and to explore how sleep quality affects mood state in the first trimester of pregnancy. METHODS: This prospective cohort study enrolled pregnant women from June 2020 to June 2021. Maternal sleep conditions, daytime sleepiness, and mood state in the first trimester were assessed using four Chinese self-rating scales, namely, the Pittsburgh Sleep Quality Index (PSQI), the Sleep Hygiene Practice Scale (SHPS), Epworth Sleepiness Scale (ESS), and the abbreviated version of the Profile of Mood States (a-POMS). Participants were divided into an exposed group (PSQI score > 5, poor sleep quality group) and a non-exposed group (PSQI score ≤ 5, good sleep quality group). Maternal characteristics, pregnancy outcomes, and the relationship among sleep quality, sleepiness, and mood state were analyzed. Comparisons of sleep hygiene behavior variables between the two subgroups were also analyzed. RESULTS: A total of 2703 pregnant women were enrolled in the study. Poor sleep quality increased the probability of gestational diabetes mellitus (GDM) (1.573, 1.315-1.863), liver function damage (1.467, 1.021-2.107), preterm delivery (1.468, 1.077-2.002), mild sleepiness (1.612, 1.357-1.915), and excessive sleepiness (2.134, 1.686-2.701). Poor maternal sleep quality was significantly associated with the occurrence of preterm premature rupture of membranes (1.947, 1.168-3.243) and perinatal death (1.003, 1.000-1.006). Additionally, a significant positive correlation between the PSQI score and the total mood disturbance (TMD) score was revealed by Spearman's correlation analysis (r = 0.378, P < 0.01). Enter Regression analysis demonstrated that sleep quality (R2 = 0.390, P < 0.01) and sleepiness (R2 = 0.234, P < 0.01) exerted significant direct effects on mood state during pregnancy. Furthermore, Spearman's correlation analysis indicated a positive association between the PSQI score and the SHPS total score (r = 0.227, P < 0.01). CONCLUSIONS: Poor sleep quality is significantly associated with elevated rates of maternal mood disturbances, obstetric complications, and adverse outcomes in infants. The findings suggest that it may be useful to provide comprehensive sleep assessment and education on sleep hygiene during the early stages of pregnancy.

Protective effects of Abrus cantoniensis Hance against liver injury through modulation of intestinal microbiota and liver metabolites.

Abrus cantoniensis Hance (ACH) is an ancient Chinese medicine herb known for its therapeutic effects. This study investigated the potential protective effect of ACH against carbon tetrachloride (CCl4)-induced liver damage in mice. Fifty (n= 50) ICR mice were grouped into five groups. CCl4 was intraperitoneally injected into different mice groups: AM (CCl4 induced), AD (ACH-treated with 25 mg/kg), AZ (ACH-treated with 50 mg/kg), and AG (ACH-treated with100mg/kg) after every three days for a total of 31 days. The control group was denoted as AC. Additionally, groups AD, AZ, and AG received daily doses of ACH via gavage throughout the study period. According to our findings, ACH administration prominently mitigated liver pathological lesions and the increased liver index induced by CCl4 in mice (p < 0.05). Treatment with ACH resulted in a dose-dependent recovery of GSH-px, SOD, and CAT activities (p < 0.001). Moreover, the levels of TNF-α, MDA, and ALT showed significanlty decreasing trends with various doses of ACH (p < 0.001). Furthermore, 16 S rRNA gene sequencing demonstrated that ACH increased the abundance of beneficial genera of Comoclathris, Aureobasidium, and Kazachstania while decreased the presence of pathogenic genera such as Sporobolomyces and Filobasidium. Additionally, ACH treatment ameliorated the changes in liver metabolism due to CCl4 and enhanced the beneficial liver metabolites. In conclusion, ACH shows potential in protecting the liver against oxidative stress and inflammation caused by CCl4 exposure, possibly through its effects on gut microbiota and liver metabolism. Therefore, the use of ACH may offer an effective approach for alleviating CCl4-induced liver injury.

Joint and interactive effects of metal mixtures on liver damage: Epidemiological evidence from repeated-measures study.

BACKGROUND: The impact of heavy metals on liver function has been examined in numerous epidemiological studies. However, these findings lack consistency and longitudinal validation. METHODS: In this study, we conducted three follow-up surveys with 426 participants from Northeast China. Blood and urine samples were collected, along with questionnaire information. Urine samples were analyzed for concentrations of four metals (chromium [Cr], cadmium [Cd], lead [Pb], and manganese [Mn]), while blood samples were used to measure five liver function indicators (alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin [ALB], globulin [GLB], and total protein [TP]). We utilized a linear mixed-effects model (LME) to explore the association between individual heavy metal exposure and liver function. Joint effects of metal mixtures were investigated using quantile g-computation and Bayesian kernel machine regression (BKMR). Furthermore, we employed BKMR and Marginal Effect models to examine the interaction effects between metals on liver function. RESULTS: The LME results demonstrated a significant association between urinary heavy metals (Cr, Cd, Pb, and Mn) and liver function markers. BKMR results indicated positive associations between heavy metal mixtures and ALT, AST, and GLB, and negative associations with ALB and TP, which were consistent with the g-comp results. Synergistic effects were observed between Cd-Cr on ALT, Mn-Cr and Cr-Pb on ALB, while an antagonistic effect was found between Mn-Pb and Mn-Cd on ALB. Additionally, synergistic effects were observed between Mn-Cr on GLB and Cd-Cr on TP. Furthermore, a three-way antagonistic effect of Mn-Pb-Cr on ALB was identified. CONCLUSION: Exposure to heavy metals (Cr, Cd, Mn, Pb) is associated with liver function markers, potentially leading to liver damage. Moreover, there are joint and interaction effects among these metals, which warrant further investigation at both the population and mechanistic levels.

Vital role of oxidative stress in tadpole liver damage caused by polystyrene nanoparticles.

Polystyrene nanoparticles are emerging as contaminants in freshwater environments, posing potential risks to amphibians exposed to extended periods of water contamination. Using tadpoles as a model, this study aimed to evaluate the toxicity of PS NPs. Pyrolysis-gas chromatography-tandem mass spectrometry (Py-GCMS) analysis revealed a concentration-dependent increase in polystyrene nanoparticles (PS NPs) levels in tadpoles with escalating exposure concentrations. Following exposure to 100 nm fluorescent microspheres, fluorescence was observed in the intestines and gills, peaking at 48 hours. Histopathological analysis identified degenerative necrosis and inflammation in the liver, along with atrophic necrosis of glomeruli and tubules in the kidneys. These results indicate a discernible impact of PS NPs on antioxidant levels, including reduced superoxide dismutase and catalase activities, elevated glutathione content, and increased malondialdehyde levels. Electron microscopy observations revealed the infiltration of PS NPs into Kupffer's cells and hepatocytes, leading to visible lesions such as nuclear condensation and mitochondrial disruption. The primary objective of this research was to elucidate the adverse effects of prolonged PS NPs exposure on amphibians.

Enhanced hepatotoxicity in zebrafish due to co-exposure of microplastics and sulfamethoxazole: Insights into ROS-mediated MAPK signaling pathway regulation.

The combined pollution of microplastics (MPs) and sulfamethoxazole (SMZ) often occurs in aquatic ecosystems, posing a serious threat to animal and human health. However, little is known about the liver damage caused by the single or co-exposure of MPs and SMZ, and its specific mechanisms are still poorly understood. In this study, we investigated the effects of co-exposure to 20 µm or 80 nm MPs and SMZ in both larval and adult zebrafish models. Firstly, we observed a significant decrease in the number of hepatocytes and the liver damage in larval zebrafish worsened following co-exposure to SMZ and MPs. Additionally, the number of macrophages and neutrophils decreased, while the expression of inflammatory cytokines and antioxidant enzyme activities increased after co-exposure in larval zebrafish. Transcriptome analysis revealed significant changes in gene expression in the co-exposed groups, particularly in processes related to oxidation-reduction, inflammatory response, and the MAPK signaling pathway in the liver of adult zebrafish. Co-exposure of SMZ and MPs also promoted hepatocyte apoptosis and inhibited proliferation levels, which was associated with the translocation of Nrf2 from the cytoplasm to the nucleus and an increase in protein levels of Nrf2 and NF-kB p65 in the adult zebrafish. Furthermore, our pharmacological experiments demonstrated that inhibiting ROS and blocking the MAPK signaling pathway partially rescued the liver injury induced by co-exposure both in larval and adult zebrafish. In conclusion, our findings suggest that co-exposure to SMZ and MPs induces hepatic dysfunction through the ROS-mediated MAPK signaling pathway in zebrafish. This information provides novel insights into the potential environmental risk of MPs and hazardous pollutants co-existence in aquatic ecosystems.

Integrated network toxicology, molecular docking, and in vivo experiments to elucidate molecular mechanism of aflatoxin B1 hepatotoxicity.

Due to the rise in temperature and sea level caused by climate change, the detection rate of aflatoxin B1 (AFB1) in food crops has increased dramatically, and the frequency and severity of aflatoxicosis in humans and animals are also increasing. AFB1 has strong hepatotoxicity, causing severe liver damage and even cancer. However, the mechanism of AFB1 hepatotoxicity remains unclear. By integrating network toxicology, molecular docking and in vivo experiments, this research was designed to explore the potential hepatotoxicity mechanisms of AFB1. Thirty-three intersection targets for AFB1-induced liver damage were identified using online databases. PI3K/AKT1, MAPK, FOXO1 signaling pathways, and apoptosis were significantly enriched. In addition, the proteins of ALB, AKT1, PIK3CG, MAPK8, HSP90AA1, PPARA, MAPK1, EGFR, FOXO1, and IGF1 exhibited good affinity with AFB1. In vivo experiments, significant pathological changes occurred in the liver of mice. AFB1 induction increased the expression levels of EGFR, ERK, and FOXO1, and decreased the expression levsls of PI3K and AKT1. Moreover, AFB1 treatment caused an increase in Caspase3 expression, and a decrease in Bcl2/Bax ratio. By combining network toxicology with in vivo experiments, this study confirms for the first time that AFB1 promotes the FOXO1 signaling pathway by inactivating PI3K/AKT1 and activating EGFR/ERK signaling pathways, hence aggravating hepatocyte apoptosis. This research provides new strategies for studying the toxicity of environmental pollutants and new possible targets for the development of hepatoprotective drugs.

Salvia miltiorrhiza polysaccharide mitigates AFB1-induced liver injury in rabbits.

Aflatoxin B1 (AFB1) is one of the common dietary contaminants worldwide, which can harm the liver of humans and animals. Salvia miltiorrhiza polysaccharide (SMP) is a natural plant-derived polysaccharide with numerous pharmacological activities, including hepatoprotective properties. The purpose of this study is to explore the intervention effect of SMP on AFB1-induced liver injury and its underlying mechanisms in rabbits. The rabbits were administered AFB1 (25 µg/kg/feed) and or treatment with SMP (300, 600, 900 mg/kg/feed) for 42 days. The results showed that SMP effectively alleviated the negative impact of AFB1 on rabbits' productivity by increasing average daily weight gain (ADG) and feed conversion rate (FCR). SMP reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels in serum, ameliorating AFB1-induced hepatic pathological changes. Additionally, SMP enhanced superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) activity, and inhibited reactive oxygen species (ROS), malondialdehyde (MDA), 4-Hydroxynonenal (4-HNE), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) expression, thus mitigating AFB1-induced oxidative stress and inflammatory responses. Moreover, SMP upregulated the expression of nuclear factor E2 related factor 2 (Nrf2), heme oxygenase 1 (HO-1), NADPH quinone oxidoreductase 1 (NQO1) and B-cell lymphoma 2 (Bcl2) while downregulating kelch like ECH associated protein 1 (Keap1), cytochrome c (cyt.c), caspase9, caspase3, and Bcl-2-associated X protein (Bax) expression, thereby inhibiting AFB1-induced hepatocyte apoptosis. Consequently, our findings conclude that SMP can mitigate AFB1-induced liver damage by activating the Nrf2/HO-1 pathway and inhibiting mitochondria-dependent apoptotic pathway in rabbits.

Therapeutic potential of salvigenin to combat atrazine induced liver toxicity in rats via regulating Nrf-2/Keap-1 and NF-κB pathway.

Atrazine (ATR) is the second most extensively used herbicide which adversely affects the body organs including liver. Salvigenin (SGN) is a flavonoid which demonstrates a wide range of biological and pharmacological abilities. This study was planned to assess the protective ability of SGN to avert ATR induced liver damage in rats. Thirty-two rats (Rattus norvegicus) were divided into four groups including control, ATR (5 mg/kg), ATR (5 mg/kg) + SGN (10 mg/kg) and SGN (10 mg/kg) alone supplemented group. ATR exposure reduced the expression of Nrf-2 while instigating an upregulation in Keap-1 expression. Furthermore, the activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), heme­oxygenase-1 (HO-1) and glutathione reductase (GSR) contents were decreased while increasing reactive oxygen species (ROS) and malondialdehyde (MDA) levels after ATR treatment. Moreover, ATR poisoning increased the levels of ALT, AST, and ALP while reducing the levels of total proteins, and albumin in hepatic tissues of rats. Besides, ATR administration escalated the expressions of Bax and Caspase-3 while inducing a downregulation in the expressions of Bcl-2. Similarly, ATR intoxication increased the levels of Interleukin-6 (IL-6), Nuclear factor kappa-B (NF-κB), Interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and the activity of cyclooxygenase-2 (COX-2). Furthermore, ATR disrupted the normal histology of hepatic tissues. However, SGN treatment remarkably protected the liver tissues via regulating antioxidant, anti, inflammatory, anti-apoptotic as well as histology parameters. Therefore, it is concluded that SGN can be used as therapeutic agent to combat ATR-induced hepatotoxicity.

TMT-based quantitative proteomics analysis of Sprague-Dawley rats liver reveals Triphenyltin induced liver damage and lipid metabolism disorders.

Triphenyltin (TPT) is a widely used pesticide that has a negative impact on biological health and production efficiency. In addition, TPT poses a threat to human health through the food chain and environmental pollution. However, the exact mechanism of TPT toxicity remains unclear. In this study, we investigated the hepatotoxicity of TPT and its effects on lipid metabolism using male SD rats as an animal model. Our results from HE and serum biochemical analysis suggested that TPT could damage liver structure and function, resulting in disruption of lipid metabolism. We therefore proceeded to analyze the proteomic response of rat liver tissue after 28 days of treatment with 2 mg/kg/d TPT. Our study demonstrates that TPT has a variety of effects on liver protein expression in rats. Through bioinformatic analysis, we observed significant changes in proteins related to fatty acid oxidation and synthesis due to TPT exposure. Furthermore, western blot and RT-qPCR experiments confirmed that TPT can affect lipid metabolism through the PPAR pathway. These findings suggest that TPT exposure can lead to liver damage, lipid accumulation and metabolic disorders.

Mechanisms underlying the combination effect of arsenite and high-fat diet on aggravating liver injury in mice.

Arsenic (As) is a highly toxic metalloid that can be found in insufficiently purified drinking water and exerts adverse effects on the physiology of living organisms that can negatively affect human health after subchronic exposure, causing several diseases, such as liver damage. A high-fat diet, which is increasing in frequency worldwide, can aggravate hepatic pathology. However, the mechanisms behind liver injury caused by the combinatory effects of As exposure and a high-fat diet remain unclear. In this study, we investigated such underlying mechanisms by focusing on three different aspects: As biotransformation, pathological liver damage, and differential expression of signaling pathway components. We employed mice that were fed a regular diet or a high-fat diet and exposed them to a range of arsenite concentrations (As(III), 0.05-50 mg/L) for 12 weeks. Our results showed that a high-fat diet increased the absorption of As into the liver and enhanced liver toxicity, which became progressively more severe as the As concentration increased. Co-exposure to a high-fat diet and As(III) activated PI3K/AKT and PPAR signaling as well as fatty acid metabolism pathways. In addition, the expression of proteins related to lipid cell function, lipid metabolism, and the regulation of body weight was also affected. Our study provides insights into the mechanisms that contribute to liver injury from subchronic combinatory exposure to As and a high-fat diet and showcases the importance of a healthy lifestyle, which may be of particular benefit to people living in areas with high As(III) concentrations, as a means to reduce or prevent aggravated liver damage.

Protective effect of chlorogenic acid on liver injury in heat-stressed meat rabbits.

This study investigated the protective effects of chlorogenic acid (CGA) on production performance and liver function of rabbits under heat stress (HS) condition. A total of 120 healthy New Zealand weaned rabbits with similar initial body weight, were randomly divided into 3 treatments with 20 replicates per treatment and 2 weaned rabbits per replicate: control (CON) group (rabbits were housed at 25 ± 1°C and fed a basal diet), HS group (rabbits were housed at 35 ± 1°C and fed a basal diet), and HS + CGA group (rabbits were housed at 35 ± 1°C and fed a basal diet supplemented with 800 mg/kg CGA). The trial lasted for 28 days. The results showed that HS challenge decreased (p < 0.05) growth performance, induced oxidative stress and hepatic apoptosis, and caused liver damage in rabbits. However, dietary CGA supplementation increased (p < 0.05) body weight gain and feed efficiency, and enhanced (p < 0.05) antioxidative capacity in serum and liver in HS-challenged rabbits; attenuated HS-induced increases in urea nitrogen (p = 0.03), alanine aminotransferase (p = 0.03), aspartate aminotransferase (p = 0.01), caspase-8 (p = 0.02), and caspase-3 (p = 0.04) as well as decrease albumin (p = 0.04). Moreover, supplementation with CGA upregulated Nrf2/HO-1 pathway-related genes expressions, including Nrf2 (p = 0.009), HO-1 (p = 0.03) and SOD1 (p = 0.04) in HS-challenged rabbits. Our findings demonstrated that dietary CGA supplementation could alleviate HS-induced decline in growth performance, and protect against HS-induced liver damage partially through enhancing antioxidant capacity via acting Nrf2/HO-1 pathway and inhibiting hepatic apoptosis in rabbits.

Aronia Melanocarpa Elliot Anthocyanins Inhibits Alcoholic Liver Disease by Activation of α7nAChR.

The study wanted to explore the preventative effects of Aornia melanocarpa Elliot anthocyanins (AMA) to Alcoholic liver disease (ALD) by bioinformatics prediction and experimental verification. We founded 419 differentially expressed genes (DEGs) in GSE28619 related to ALD from GEO database, COL1A1 was selected by the core gene module construction and molecular docking. Mice were treated by intragastric administration of gradient 50% ethanol, AMA alleviated liver injury by ALD and ameliorated the model's body weight, lessened the liver inflammation according to histopathological evaluation, increased serum liver biochemical index (AST, ALT, TC, TG and LDL-C) and decreased HDL-C, reversed the expression of enzymes (ALDH and GSH-PX), decreased cytokines expression (Ki67, TNF-α and IL-6), reversed the expression of α7nAChR and collagen I, downregulated the PI3K-Akt pathway and Keap1/HO-1 pathway (p-PI3K, PI3K, p-Akt, Akt, Keap1, Nrf2, HO-1,GSK-3ß and Bcl-2), indicated that α7nAChR and collagen I may be the AMA action targets.