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Non-alcoholic fatty liver disease (NAFLD) is the main cause of chronic liver disease worldwide, affecting one-fourth of the world's population. With more than half of the world's population, the Asia-Pacific region contributed 62.6 % of liver-related fatal incidents in 2015. Currently, liver imaging techniques such as computed tomography (CT), nuclear magnetic resonance (NMR) spectroscopy, and ultrasound are non-invasive imaging methods to diagnose the disease. A liver biopsy is the gold standard test for establishing the definite diagnosis of non-alcoholic steatohepatitis (NASH). However, there are still significant problems with sample variability and the procedure's invasiveness. Numerous studies have indicated various non-invasive biomarkers for both fibrosis and steatosis to counter the invasiveness of diagnostic procedures. Metabolomics could be a promising method for detecting early liver diseases, investigating pathophysiology, and developing drugs. Metabolomics, when utilized with other omics technologies, can result in a deeper understanding of biological systems. Metabolomics has emerged as a prominent research topic, offering extensive opportunities to investigate biomarkers for liver diseases that are both sensitive and specific. In this review, we have described the recent studies involving the use of a metabolomics approach in the diagnosis of liver diseases, which would be beneficial for the early detection and treatment of liver diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ethnopharmacological Relevance: Aloe rubroviolacea (Arabian Aloe) was widely cultured and commonly used in traditional medicine. Aloe species was highly recommended in folk medicine for abdominal pain, intestinal infection, intestinal colic, obesity, and gynaecological pain after childbirth., Aim of the Work: The present work aimed to conduct chemical profiling, in-vitro antioxidant activity, in-vivo oral acute toxicity study of A. rubroviolacea flowers ethanolic extract (ARFEE) along with exploring pancreatic and hepatic protective effects of ARFEE against carbon tetrachloride (CCl 4 ) toxicity in a rat model. Molecular docking study of ARFEE and 3D structure activity relationship was also demonstrated to investigate the proposed antioxidant mechanism., Materials and Methods: The chemical composition was analyzed using gas chromatography-mass spectrometry (GC-MS) and thin layer chromatography (TLC) techniques. Total phenolic and flavonoid contents in ARFEE were estimated by Folin-Ciocalteu and AlCl 3 colorimetric methods, respectively. In-vitro antioxidant DPPH assay was performed using ascorbic acid as a reference standard. Moreover, In-vivo acute toxicity study using fixed doses of ARFEE (0.1, 0.5, 1, 2 and 3 g/kg orally) was conducted. CCl 4 toxicity was induced by using a single dose of CCl 4 (1 ml/kg, i.p.) on 5th day, silymarin (50 mg/kg/day, orally) as a standard and two different doses of ARFEE (250, 500 mg/kg, orally) daily for 5 days before CCl 4 injection., Results: GC-MS analysis displayed the existence of 36 chemical compounds, the majority of which were fatty acids and their esters, in addition to phytosterols. The total phenolic content of ARFEE was 25.09 ± 1.65 mg of gallic acid equivalent/g extract dry weight (mg GAE/g DW), while the total flavonoid content was 17.48 ± 0.64 mg of quercetin equivalent/g extract dry weight (mg QE/g DW). Our results showed that the ARFEE had a potential in-vitro antioxidant activity as strong as ascorbic acid. No mortality or signs of toxicity were observed after ARFEE intake. Additionally, ARFEE ameliorated CCl 4 toxicity on hepatic and pancreatic tissues. Molecular docking study resulted in potent promising natural compounds contained in ARFEE with anti-oxidant potential., Conclusion: Based on oral safety, good anti-oxidant and pancreato- and hepato-protective activities of ARFEE against CCl 4 toxicity, ARFEE is probably a potent agent for treatment of liver ailments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Blossom of Citrus aurantium L. var. amara Engl. (CAVA) has been popularly consumed as folk medicine and dietary supplement owing to its various beneficial effects and especially anti-obesity potential. Our previous study predicted that eriodictyol was probably one of the key active compounds of the total flavonoids from blossom of CAVA. However, effects of eriodictyol in anti-obesity were still elusive., Aim of the Study: This study was performed to explore the precise role of eriodictyol in white adipose tissue (WAT) browning and hepatic lipid metabolism, and simultaneously, to verify the impact of eriodictyol on the total flavonoids of CAVA in losing weight., Materials and Methods: The pancreas lipase assay was conducted and oleic acid-induced HepG2 cells were established to preliminarily detect the lipid-lowering potential of eriodictyol. Then, high fat diet-induced obesity (DIO) mouse model was established for in vivo studies. The biochemical indicators of mice were tested by commercial kits. The histopathological changes of WAT and liver in mice were tested by H&E staining, Oil Red O staining and Sirius Red staining. Immunohistochemical, Western blot assay, as well as RT-qPCR analysis were further performed. Additionally, molecular docking assay was used to simulate the binding of eriodictyol with potential target proteins., Results: In vitro studies showed that eriodictyol intervention potently inhibited pancreatic lipase activity and reversed hepatic steatosis in oleic acid-induced HepG2 cells. Consistently, long-term medication of eriodictyol also effectively prevented obesity and improved lipid and glucose metabolism in diet-induced obesity mice. Obesity-induced histopathological changes in iWAT, eWAT and BAT, and abnormal expression levels of IL-10, IL-6 and TNF-α in iWAT of DIO mice were also significantly reversed by eriodictyol treatment. Eriodictyol administration significantly and potently promoted browning of iWAT by increasing expression levels of thermogenic marker protein of UCP1, as well as brown adipocyte-specific genes of PGC-1α, SIRT1 and AMPKα1. Further assays revealed that eriodictyol enhanced mitochondrial function, as shown by an increase in compound IV activity and the expression of tricarboxylic acid cycle-related genes. Besides, eriodictyol addition markedly reversed hepatic damages and hepatic inflammation, and enhanced hepatic lipid metabolism in DIO mice, as evidenced by its regulation on p-ACC, CPT1-α, UCP1, PPARα, PGC-1α, SIRT1 and p-AMPKα expression. Molecular docking results further validated that AMPK/SIRT1 pathway was probably the underlying mechanisms by which eriodictyol acted., Conclusion: Eriodictyol exhibited significant anti-obesity effect, which was comparable to that of the total flavonoids from blossom of CAVA. These findings furnished theoretical basis for the application of eriodictyol in weight loss., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Stress is considered an independent risk factor for the development of cardiometabolic disorders, especially when it occurs during pregnancy, and it may play an important role in stress-induced fetal programming on the protein-folding homeostasis in hepatic endoplasmic reticulum. The study aimed to determine the effects of prenatal stress on the unfolded protein responses in the liver of male and female offspring of Wistar rats. Pregnant Wistar rats at 90 days old were divided into control and stress groups. The unpredictable stress protocol was performed from the 14th to the 21st day of pregnancy. The offspring of each group were divided into four groups according to sex and intervention. After the lactation period, the dams were anesthetized and euthanized for blood collection to determine plasma corticosterone levels. At 90 days old, the offspring were anesthetized and euthanized for liver tissue collection to measure protein expression of the endoplasmic reticulum stress. Dams submitted to prenatal stress showed an increase in corticosterone levels when compared to the control group. In the male offspring, prenatal stress induced lower body mass at birth and at 90 days compared to control, while females presented lower body mass only at birth. Prenatal stress reduced eIF2α expression in males, while increased p-eIF2α expression similarly in both sexes. Furthermore, only males had a greater p-eIF2α/eIF2α ratio and androgen receptor expression when compared to its respective control group and females. Prenatal stress induced a hepatic programming in the reticulum endoplasmic responses only in males at 90 days old by increasing androgen receptor, eIF2α phosphorylation and activity, while in females stress during pregnancy reduced cHDL and had little impact on hepatic unfolded protein response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Radix Bupleuri (BR, Bupleurum chinense DC.) is a well-known traditional Chinese medicine (TCM) known for its effects on soothing the liver and alleviating depression, and is widely used in clinical settings to manage depressive symptoms. A dosage of 12.5 g crude drug/kg/d of the low-polarity fraction of Radix Bupleuri (LBR) demonstrated effectiveness in treating depression in our previous study. However, the mechanism through which BR ameliorates depression remains unclear. This study aimed to explore the polar fractions of BR and their mechanisms of action in the treatment of depression. Chronic unpredictable mild stress (CUMS) rats were continuously administered BR by oral gavage for 4 weeks. Behavioral and biochemical indicators were evaluated to assess the antidepressant effects of LBR, and transcriptomics was used to explore the relevant pathways. In addition, pseudo-targeted bile acid (BA) metabonomics was used to quantify the BA profiles. Molecular biology techniques have been used to investigate the underlying mechanisms. LBR serves as a more effective active fraction with antidepressant activity. Intervention with LBR, which is characterized by a clearly defined chemical composition, significantly ameliorated depression-like behavior and biochemical indicators in rats subjected to CUMS. Notably, marked improvements were observed in the levels of total bile acids (TBAs) in the blood, liver, and ileum. Mechanistically, liver transcriptome analysis suggested that bile secretion may be a crucial pathway for alleviating depression after LBR treatment. Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) BA metabonomics indicated that TCA, β-MCA, γ-MCA, Tβ-MCA, and UDCA in the liver, Tβ-MCA, TCA, βMCA, GHDCA, and GLCA in the ileum, and β-MCA, CA, and DCA in the hippocampus were the potential therapeutic targets. In addition, molecular biology experiments showed that LBR exerts antidepressant effects by regulating the FXR/SHP/CYP7A1 pathway in the liver, the FXR/FGF15/ASBT pathway in the ileum, and the FXR/CREB/BDNF pathway in the hippocampus. In conclusion, LBR attenuated depression by moderating BA homeostasis through FXR and related genes within the liver-gut-brain axis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Rapamycin (Rapa) is an inhibitor of mTOR complex, and its therapeutic effect on liver function was examined in non-alcoholic fatty liver disease (NAFLD) rats here. And the possible mechanism of Rapa in NAFLD was preliminarily elucidated based on the non-targeted metabolomics analysis. Adult male SD rats were fed with a high-fat and high-cholesterol diet (HFD) to establish NAFLD model. For Rapa group, 0.8 mg/(kg.d) Rapa was given to the HFD rats. Ultra-performance liquid chromatography and Q-Tof-mass spectrometry (UPLC and Q-TOF/MS) analysis were applied for the identification of metabolites in the serum of rats, which were annotated using Kyoto Encyclopedia of Genes and Genomes (KEGG). NAFLD rats presented with disturbed liver function, lipid metabolism and oxidative stress, but Rapa exerted a mitigating influence on the disorders. The metabolite profile data identified 579 metabolites that varied remarkably between the Rapa and HFD groups, with the main classes of amino acids and peptides, benzene, lipids and fatty acids. The differential metabolites were mainly involved in biosynthesis of cofactors, bile secretion, and glycerophospholipid metabolism were mainly enriched. In conclusion, Rapa has a potential protective effect against HFD-induced NAFLD, its hepatoprotective effect may achieved through mediating bile secretion and glycerophospholipid metabolism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Patulin (PAT), a foodborne toxin, causes severe intestinal damage. To mitigate this health threat, mice were pretreated with apple polyphenols (AP) in their drinking water (0.01 % and 0.05 %) for eight weeks, followed by exposure to PAT during the last two weeks. Subsequently, histopathological and biochemical evaluations of intestinal tissues were conducted, alongside assessments of alterations in gut microbiota, colonic content metabolome, and hepatic metabolome. Consequently, AP alleviated PAT-induced villus and crypt injury, mucus depletion, GSH level decline, GSH-Px and SOD activity reduction, and MPO activity elevation. Notably, AP counteracted PAT-mediated microbiota disruptions and promoted the abundance of beneficial bacteria (Dubosiella, Akkermansia, Lachnospiraceae, and Lactobacillus). Furthermore, AP counteracted PAT-induced metabolic disorders in the colonic contents and liver. Ultimately, AP prevented intestinal injury by regulating the gut microbiota and amino acid, purine, butanoate, and glycerophospholipid metabolism in the gut-liver axis. These results underscore the potential of AP to prevent foodborne toxin-induced intestinal damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Ethnopharmacological Relevance: Traditional and medicinal plant treatments for diabetes mellitus (DM) include Bambusa vulgaris (Shrad.), but little is known about the mechanism., Aim of the Study: This study investigated the antioxidant and hepatoprotective effects of B. vulgaris., Materials and Methods: DM was induced by intraperitoneal injection of streptozotocin (60 mg/kg). Thirty (30) male Wistar rats were then divided into six groups: control; diabetic control; metformin (100 mg/kg); 50, 100, and 200 mg/kg of B. vulgaris (BV) treated. Fasting blood glucose and weights of rats were monitored at three-day intervals and sacrifice was done after twenty-one days. The activities of SOD, CAT, and liver marker enzymes were investigated. The expressions of insulin-sensitive (TGR5, GLP-1), pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, ICAM), and antioxidant genes (SOD, CAT) were investigated using RT-PCR. Schrödinger suites and Auto-Dock Vina were used for docking B. vulgaris phytocompounds identified from works of literature with TGR-5. The liver's histology was also assessed., Results: BV increased antioxidant activities and reduced liver marker activities in the serum. BV downregulated the expressions of genes associated with inflammation and upregulated antioxidant and insulin-sensitive genes relative to diabetic control. BV regenerated the liver architectural tissue degenerated by inflammation due to STZ. B. vulgaris phytocompounds like farobin A (-11.493 kcal/mol), orientin (-12.296 kcal/mol), and rutin (-12.581 kcal/mol) have better binding energy with TGR5 than metformin (-1.961 kcal/mol)., Conclusion: The hepatoprotective and ameliorative effect of B. vulgaris in DM could be due to its ability to boost antioxidant status and insulin secretion and reduce inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The hepatotoxicity mechanism of cantharidin (CTD), a major active component of Mylabris was explored based on liver lipidome alterations and spatial distributions in female and male rats using lipidomics and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). After oral CTD exposure, the livers of female rats were screened for 104 differential lipids including lysophosphatidylethanolamine(LysoPE)(20:2/0:0) and diacylglycerol(DG)(18:2/22:4), whereas the livers of male rats were screened for 76 differential lipids including fatty acid(FA)(24:6) and DG(18:0/22:4). According to the MALDI-MSI results, female rats exhibited 12 differential lipids with alteration in the abundance and spatial distribution of phosphatylcholine(PC), phosphatidylethanolamine(PE), lysophosphatidylcholine(LysoPC), and LysoPE in the liver lesion area. On the other hand, male rats exhibited 8 differential lipids with changes in the abundance and spatial distribution of PC, PE, and FA in the liver lesion area. The lipidomics- and MALDI-MSI-detected differential lipids strongly disrupted glycerophospholipid metabolism in both female and male rats. Additionally, phosphatidate phosphatase (Lipin1), choline/ethanolamine phosphotransferase 1 (CEPT1), and phosphatidylethanolamine N-methyltransferase (PEMT) were screened to distinguish CTD hepatoxicity in female and male rats. Western blotting analysis demonstrated a significant elevation in Lipin1 expression in female and male rat livers, accompanied by a decrease in PEMT expression. Furthermore, CEPT1 expression increased significantly in female rat livers and decreased significantly in male rat livers. These findings suggested that CTD could disrupt lipid metabolism in a gender-specific manner. Moreover, the combination of lipidomics and MALDI-MSI could offer valuable insights into CTD-induced hepatotoxicity in rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fenofibrate is a clinically prescribed drug for treating hypertriglyceridemia, which is also a classic peroxisome proliferator-activated receptor α (PPARα) agonist. We previously reported that fenofibrate induced liver enlargement in adult mice partially through activation of the yes-associated protein (YAP) signaling pathway. However, the effects of fenofibrate on liver enlargement and the YAP signaling pathway in aging mice remain unclear. In this study, D-galactose-induced aging mice, naturally aging mice, and senescence-accelerated mice P8 (SAMP8) were used to investigate the effects of aging on fenofibrate-induced liver enlargement and YAP signaling activation. The results showed that fenofibrate-induced liver enlargement in aging mice was consistent with that of adult mice. The effects of fenofibrate on hepatocyte enlargement around the central vein (CV) area and hepatocyte proliferation around the portal vein (PV) area were comparable between adult and aging mice. There was no significant difference in the upregulation of PPARα downstream proteins between the two groups following fenofibrate treatment. Fenofibrate treatment also increased the expression of proliferation-related proteins and activated the YAP signaling pathway to a similar degree in both groups. In summary, these results demonstrate that the fenofibrate-induced liver enlargement and activation of the YAP pathway are consistent between adult and aging mice, indicating that the effects of fenofibrate on promoting liver enlargement and its activation of the PPARα and YAP pathway were independent of aging. These findings offer a new perspective for the clinical use of fenofibrate in elderly patients and provide a new insight for the role of PPARα in liver enlargement., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lipotoxicity is a key pathological feature in the development of non-alcoholic steatohepatitis (NASH), which is characterized by liver injury, inflammation, and fibrosis. Although lipotoxicity has been shown to induce transcriptomic alterations in liver cells, the specific role of epigenetic regulators in NASH remains elusive. In this study, we demonstrate that pharmacological inhibition of histone methyltransferase G9a significantly worsens NASH progression in mice, as evidenced by increased hepatic cell death, inflammation, and fibrosis. Additionally, at a cellular level both genetic and pharmacological inhibition of G9a in HepG2 cells increased their susceptibility to palmitic acid-induced apoptosis and sub-cellular stress. Furthermore, treatment with G9a inhibitor enhanced TGF-β induced activation of primary human hepatic stellate cells (hHSCs), implicating the role of G9a in NASH pathobiology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Global incidence of Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is on the rise while treatments remain elusive. MASLD is a disease of dysregulated systemic and hepatic metabolism. Current understanding of disease pathophysiology as it relates to metabolome changes largely comes from studies on animal models and human plasma. However, human tissue data are crucial for transitioning from mechanisms to clinical therapies. The close relationship between MASLD and comorbidities like obesity, type 2 diabetes and dyslipidemia make it difficult to determine the contribution from liver disease itself. Here, we review recent metabolomics studies in liver tissue from human MASLD patients, which have predominately focused on lipid metabolism, but also include bile acid, tricarboxylic acid (TCA) cycle, and branched chain amino acid (BCAA) metabolism. Several clinical trials are underway to target various of these lipid-related pathways in MASLD. Although only the β-selective thyroid hormone receptor agonist resmetirom has so far been approved for use, many metabolism-targeting pharmaceuticals show promising results for halting disease progression, if not promoting outright reversal. Ultimately, the scarcity of human tissue data and the variability of confounding factors, like obesity, within and between cohorts are impediments to the pathophysiological understanding required for efficient development of metabolic treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chitosan was formulated into a microsphere and comprehensively characterized and evaluated for its anti-inflammatory potential and anti-diabetic properties against the high sugar fat diet-induced diabetic animals. The diabetic model was induced through feeding with a high-sugar fat diet. Metformin, a standard antidiabetic drug, and CMS (chitosan microspheres) were administered orally for 90 days as reversal strategies. Upon completion of the study, the following parameters, such as serum biochemistry, cytokine analysis, tissue histology, liver miRNA sequencing, and Shotgun metagenomics studies from stool samples, were performed. SEM images of the microsphere indicated a smooth morphology, while FTIR and DSC respectively, confirmed the presence of functional groups of chitosan and the thermal stability of the formulation. Following HSFD induction, all the parameters analyzed were altered compared to the control group. In both reversal groups, serum biochemical parameters were restored, which was at par with the control. A significant increase in the anti-inflammatory cytokine IL-10, and a remarkable reduction in TNF-α and MCP-1 inflammatory cytokines were observed in both reversal groups. Tissue histology indicated improvements in low-grade inflammation, induced in the diabetic group. miR-203 was upregulated in the CMS-treated group, while miR-103 was downregulated. The study further delved into the impact on gut microbiota and KEGG. Major phyla i.e., Bacteroidetes, Cyanobacteria, Firmicutes, Proteobacteria, and Verrucomicrobia showed restoration, while upregulation of DNA polymerase zeta in T2D showed reversal after the treatment. The formulation showed reversal at par with metformin and also confirms its anti-diabetic and anti-inflammatory activities of CMS, with microfloral and miR regulatory functions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Seasonal rhythms in photoperiod are a predictive cue used by many temperate-zone animals to time cycles of lipid accumulation. The neuroendocrine regulation of seasonal energy homeostasis and rheostasis are widely studied. However, the molecular pathways underlying tissue-specific adaptations remain poorly described. We conducted two experiments to examine long-term rheostatic changes in energy stability using the well-characterized photoperiodic response of the Japanese quail. In experiment 1, we exposed quails to photoperiodic transitions simulating the annual photic cycle and examined the morphology and fat deposition in liver, muscle, and adipose tissue. To identify changes in gene expression and molecular pathways during the vernal transition in lipid accumulation, we conducted transcriptomic analyses of adipose and liver tissues. Experiment 2 assessed whether the changes observed in Experiment 1 reflected constitutive levels or were due to time-of-day sampling. We identified increased expression of transcripts involved in adipocyte growth, such as Cysteine Rich Angiogenic Inducer 61 and Very Low-Density Lipoprotein Receptor, and in obesity-linked disease resistance, such as Insulin-Like Growth Factor Binding Protein 2 and Apolipoprotein D, in anticipation of body mass gain. Under long photoperiods, hepatic transcripts involved in fatty acid (FA) synthesis (FA Synthase, FA Desaturase 2) were down-regulated. Parallel upregulation of hepatic FA Translocase and Pyruvate Dehydrogenase Kinase 4 expression suggests increased FA uptake and inhibition of the pyruvate dehydrogenase complex. Our findings demonstrate tissue-specific biochemical and molecular changes that drive photoperiod-induced adipogenesis. These findings can be used to determine conserved pathways that enable animals to accumulate fat without developing metabolic diseases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tyler Stevenson reports financial support was provided by Leverhulme Trust. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Short-chain chlorinated paraffins (SCCPs) are pervasive organic pollutants recognized for their persistence and bio-toxicity. This study investigated the hepatotoxic mechanisms of SCCPs at environmentally relevant concentration (0.7 μg/kg). The results showed that SCCPs exposure in mice resulted in dysregulated blood and liver lipids, marked by elevated cholesterol levels. Additionally, liver function was compromised, as indicated by increased levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Histopathological examination of liver tissue post-SCCPs exposure revealed hepatocyte enlargement, vacuolar degeneration, and mild ballooning degeneration. Mechanistically, SCCPs induced mitochondrial abnormalities, evidenced by heightened Hoechst 33258 fluorescence, and augmented reactive oxygen species and malondialdehyde levels in liver tissue. This was accompanied by a reduction in total antioxidant capacity, culminating in elevated apoptosis markers, including cytochrome C and caspase-3. Moreover, SCCPs perturbed hepatocellular energy metabolism, characterized by increased glycolysis, lactic acid, and fatty acid oxidation, alongside a disruption in the tricarboxylic acid cycle and a decline in mitochondrial energy metabolic function. Furthermore, SCCPs exposure downregulated the expression of genes involved in bile acid synthesis (cyp27a1, fxr, and shp), thereby precipitating the cholesterol-bile acid metabolism disorders and cholesterol accumulation. Collectively, these findings underscore that SCCPs, even at environmentally relevant levels, can induce lipid dysregulation, mitochondrial disorders and cholesterol deposition in the hepatocytes, contributing to liver damage. The study's insights contribute to a comprehension of SCCPs-induced hepatotoxicity and may inform potential preventative and treatment targets for hepatic damage associated with SCCPs exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Mycotoxins negatively impact intestinal cell viability, leading to the depletion of beneficial bacteria and rendering birds susceptible to intestinal infections such as necrotic enteritis (NE). Furthermore, they impair the effective digestion and absorption of nutrients. This study aimed to evaluate the effects of Bacillus licheniformis supplementation on broiler birds exposed to mycotoxins and subsequent necrotic enteritis infection. A total of 280 one-day-old broiler chicks were divided into eight groups and subjected to B. licheniformis supplementation (1 × 10 6  CFU/kg of feed) and mycotoxin exposure (aflatoxin and ochratoxin A, each at 150 ppb). Clostridium perfringens (3 × 10 10  CFU/ml) was later administered to induce necrotic enteritis. This study evaluated body weight, feed intake, relative organ weights, hematological and serum biochemical parameters and performed histopathological examinations of liver, kidney and intestine. All the obtained data was statistically analyzed (P ≤ 0.05). The results demonstrated that B. licheniformis supplementation reduced the susceptibility to necrotic enteritis in broilers initially exposed to mycotoxins. Body weight and feed intake were significantly decreased in groups challenged with mycotoxins and necrotic enteritis, both individually and concurrently, compared to the control group. Relative weights of the liver, kidney and intestine were significantly higher in treatment groups. Hematological analysis revealed significantly lower erythrogram parameters (TEC, Hb, and PCV) in birds fed mycotoxin-contaminated feed, with or without necrotic enteritis. Hepatic and renal biomarkers were significantly elevated, and serum protein levels (total protein, albumin) were significantly lower. In contrast, birds supplemented with B. licheniformis and challenged with either mycotoxins or NE showed no significant differences in body weight, feed intake, erythrogram and leucogram compared to the control group. However, B. licheniformis did not mitigate these effects when supplemented in group with concurrent challenge of mycotoxins and NE, however, intensity of changes was reduced. In conclusion, B. licheniformis supplementation effectively alleviates the pathological changes induced by mycotoxins and necrotic enteritis when presented individually but is not sufficiently effective against the combined challenge of mycotoxins and necrotic enteritis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The incidence of nonalcoholic fatty liver disease (NAFLD) has been steadily increasing in Western society in recent years and has been recognized as a risk factor for the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying the progression from NAFLD to HCC are still unclear, despite the use of suitable mouse models. To identify the transcriptional and lipid profiles of livers from mice with NAFLD-HCC, we induced both NAFLD and NAFLD-HCC pathologies in C57BL/6J mice and performed RNA-sequencing (RNA-seq) and targeted lipidomic analysis. Our RNA-seq analysis revealed that the transcriptional signature of NAFLD in mice is characterized by changes in inflammatory response and fatty acid metabolism. Moreover, the signature of NAFLD-HCC is characterized by processes typically observed in cancer, such as epithelial to mesenchymal transition, angiogenesis and inflammatory responses. Furthermore, we found that the diet used in this study inhibited cholesterol synthesis in both models. The analysis of lipid composition also showed a significant impact of the provided diet. Therefore, our study supports the idea that a Western diet (WD) affects metabolic processes and hepatic lipid composition. Additionally, the combination of a WD with the administration of a carcinogen drives the progression from NAFLD to HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) and its development into nonalcoholic steatohepatitis (NASH) are challenging health concerns globally. Clinically, the prevalence and severity of NAFLD/NASH are higher in men than in premenopausal women. NAFLD is strongly correlated with obesity, both of which are tied to high-fat/fructose-rich western diets. Therefore, we aimed to investigate sexual dimorphism in NAFLD pathogenesis in male and female C57BL/6 mice fed different diets. Male and female C57BL/67 mice were divided into four groups and kept on a chow (C), chow plus high fructose (CF), high fat (HF), and high fat plus high fructose (HFF) diet for 22 weeks. Liver tissues were collected at the end of the study and processed for NAFLD/NASH-related histology (H&E and trichrome staining), protein expression (SREBP1, SCAP, FABP4, α-SMA, TGF-β and L-PGDS), and biochemical parameters measurement. Our results displayed that female mice exhibited protection against NAFLD and diabesity on HF and HFF diets compared to male mice fed similar diets. Additionally, female mice showed protection from fibrosis compared to male mice. Both male and female mice fed HF and HFF diet groups displayed the cytosol-to-nuclear translocation of Lipocalin Prostaglandin D 2 Synthase (L-PGDS). Cytoplasmic levels of L-PGDS were absent in females compared to low levels in males, revealing a possible sex-specific mechanism tied to fructose and fat metabolism. Collectively, female mice showed protection against NAFLD and diabesity relative to male mice, accompanied by differential regulation of hepatic lipocalin prostaglandin D 2 synthase., Competing Interests: Declaration of competing interest The authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Accumulation of hemin in cells, tissues, and organs is one of the major pathological conditions linked to hemolytic diseases like malaria. Pro-oxidant hemin confers high toxicity following its accumulation. We tested the cellular toxicity of hemin on HepG2 cells by exploring modulation in various cellular characteristics. Hemin reduces the viability of HepG2 cells and brings about visible morphological changes. Hemin causes perforations on the surface of HepG2 cells observed through SEM. Hemin leads to the extracellular release of liver enzymes and reduces the wound-healing potential of HepG2 cells. Hemin leads to the fragmentation of HepG2 DNA, arrests the cell cycle progression in the S-phase and induces apoptosis in these cells. Western blot analysis revealed that hemin triggers both the extrinsic and intrinsic pathways of apoptosis in HepG2 cells. We have already shown that the cytoprotective protein HSPA8 can polymerize hemin and minimize its toxicity. Similar experiments with hemin in the presence and absence of HSPA8 showed that HSPA8 reverses all the tested toxic effects of hemin on HepG2 cells. The protection from hemin toxicity in HepG2 cells appeared to be due to the extracellular polymerization of hemin by HSPA8., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vishal Trivedi reports financial support was provided by Vishal Trivedi, Professor, IIT Guwahati. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Phantoms representing anatomical deformations are necessary to investigate and improve dynamic treatments. In this study, we aimed to produce a deformable liver phantom by simulating respiratory motion. The dynamically DEformable Liver Phantom (DELP) is designed to create a human-specific respiratory model and to produce synchronised, repeatable motion with this model. For the deformation effect of this movement, an artificial liver was created using silicone material and mold. A stepper motor was used to compress the liver in the inferior direction according to an adjustable respiratory motion. Reference markers (fiducial) placed on the DELP helped to verify the movement and calculate the deformation. In dynamic deformation tests, the greatest amount of deformation was found in the edge region of the silicone liver. The average deformation was 3.45 ± 0.93 mm when 5 mm amplitude movement was applied and 5.98 ± 0.01 mm when 10 mm amplitude movement was applied. DELP is a deformable liver phantom with motion reproducibility. Its performance in radiotherapy application was evaluated using dosimetric equipment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Gynostemma pentaphyllum is a herbaceous vine of Cucurbitaceae family, and its principal pharmacological components, gypenosides (GPs), have been proved to be effective in various liver diseases. However, the mechanisms of GPs on liver injury are still to be studied for further. This investigation utilized the CCl 4 -induced liver injury rat model (LI) to comprehensively explore the mechanism of action of GPs in the treatment of chemical liver injury by comparing the metabolomic changes in four groups rats. In this study, the therapeutic efficacy of GPs in a liver injury rat model induced by weekly gavage of CCl 4 was evaluated by inflammatory factors, oxidative damage indexes, and histopathological sections. Then, GC-MS technology was used to identify the metabolic profile of GPs in treating liver injury. Finally, the content variation of metabolites (BAs and SCFAs) was measured to elucidate the mechanism of GPs in the treatment of CCl 4 -induced liver injury. After 8 weeks of administration, GPs effectively reduced the degree of LI and appeared a substantial tendency of reversing in the levels of MDA, GSH, CYP7E1, CYP7A1 and CYP27A1. Untargeted metabolomics suggested that GPs may play a role in BAs and SCFAs metabolism. Targeted metabolomics and ELISA confirmed the key role of GPs in increasing SCFAs levels and regulating BAs metabolism. Overall, this study indicated that GPs can alleviate CCl 4 -induced liver injury. And GPs may exert beneficial effects on LI by affecting their metabolites (SCFAs and BAs)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Miao Wang reports financial support was provided by Shenyang Pharmaceutical University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We investigated a portable micro-nanochannel biosensor 3D-printed liver microtissues for rapid and sensitive deoxynivalenol (DON) detection. The screen-printed carbon electrode (SPCE) was modified with nanoporous anodic aluminum oxide (AAO), gold nanoparticles (AuNPs), and cytochrome C oxidase (COx) to enhance sensor performance. Gelatin methacrylate hydrogel, combined with hepatocellular carcinoma cells, formed the bioink for 3D printing. Liver microtissues were prepared through standardized and high-throughput techniques via bio-3D printing technology. These microtissues were immobilized onto modified electrodes to fabricate liver microtissue sensors. The peak current of this biosensor was positively correlated with DON concentration, as determined by cyclic voltammetry (CV), within a linear detection range of 2∼40 μg/mL. The standard curve equation is denoted by I CV(μA)  = = 18.76956 + 0.03107C DON(μg/mL) , with a correlation coefficient R 2 was 0.99471(n＝3). A minimum detection limit of 1.229 μg/mL was calculated from the formula, indicating the successful construction of a portable micro-nanochannel bio-3D printed liver microtissue biosensor. It provides innovative ideas for developing rapid and convenient instrumentation to detect mycotoxin hazards after grain production. It also holds significant potential for application in the prediction and assessment of post-production quality changes in grain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The translocator protein, TSPO, has been implicated in a wide range of cellular processes exerted from its position in the outer mitochondrial membrane from where it influences lipid metabolism and mitochondrial oxidative activity. Understanding how this protein regulates a profusion of processes requires further elucidation and to that end we have examined lipid metabolism and used an RNAseq strategy to compare transcript abundance in wildtype and Tspo knockout (KO) mouse liver. The levels of cholesterol, triglyceride and phospholipid were significantly elevated in the KO mouse liver. The expression of cholesterol homeostasis genes was markedly downregulated. Determination of the differential expression revealed that many genes were either up- or downregulated in the KO animals. However, a striking observation within the results was a decrease of transcripts for protein degradation proteins in KO animals while protease inhibitors were enriched. When the entire abundance data-set was analysed with CEMiTool, and revealed a module of proteins that were under-represented in the KO animals. These could subsequently be formed into a network comprising three interlinked clusters at the centre of which were proteins of cytoplasmic ribosomes with gene ontology terms suggesting impairment to translation. The largest cluster was dominated by proteins of lipid metabolism but also contained disparate systems of iron metabolism and behaviour. The third cluster was dominated by proteins of the electron transport chain and oxidative phosphorylation. These findings suggest that TSPO contributes to lipid metabolism, detoxification of active oxygen species and oxidative phosphorylation, and regulates mitochondrial retrograde signalling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Seasonality can influence many physiological traits requiring optimal energetic capacity for life-history stage transitions. In Atlantic salmon, high-energy status is essential for the initiation of maturation. Earlier studies have linked a genomic region encoding vgll3 to maturation age, potentially mediated via body condition. Vgll3 has also been shown to act as an inhibitor of adipogenesis in mice. Here we investigate the influence of season and vgll3 genotypes associating with early (EE) and late (LL) maturation on lipid profiles in the muscle and liver of juvenile Atlantic salmon. We reared Atlantic salmon for two years from fertilization and sampled muscle and liver during the spring and autumn of the second year (at which time some males were sexually mature). We found no seasonal or genotype effect in the muscle lipid profiles of immature males or females. However, in the liver we detected a triacylglycerol enrichment and a genotype specific direction of change in membrane lipids, phosphatidylcholine and phosphatidylethanolamine, from spring to autumn. Specifically, from spring to autumn membrane lipid concentrations increased in vgll3*EE individuals but decreased in vgll3*LL individuals. This could be explained by 1) a seasonally more stable capacity of endoplasmic reticulum (ER) functions in vgll3*EE individuals compared to vgll3*LL individuals or 2) vgll3*LL individuals storing larger lipid droplets from spring to autumn in the liver compared to vgll3*EE individuals at the expense of ER capacity. This genotype specific seasonal direction of change in membrane lipid concentrations provides more indirect evidence of a potential mechanism linking vgll3 with lipid metabolism and storage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

American alligators (Alligator mississippiensis) are apex predators and sentinel species in the coastal wetland ecosystem along the Gulf of Mexico. There is concern for alligator exposure and susceptibility to chemical contaminants due to their high trophic level and lower metabolic capability. At present, their hepatic biotransformation capacity to metabolize or detoxify contaminants has not been comprehensively determined. In this study, the hepatic biotransformation capability of juvenile American alligators to metabolize two commonly found environmental pharmaceuticals: carbamazepine (CBZ) or nicotine (NCT) was evaluated. The formation of their respective primary metabolites, i.e., carbamazepine-10,11-epoxide (CBZ-E) and cotinine (CTN), was evaluated at 10 μM (within the human therapeutic range). The in vitro S9 and a novel in situ liver perfusion assays were used to characterize and compare metabolic ability in isolated hepatic enzymes vs. whole organ (liver). For CBZ, the perfused livers exhibited only 30% of intrinsic formation clearance (CL f,int ) relative to the S9 assay. The metabolism of NCT was not detectable in the S9 assay and was only observed in the perfused liver assay. Compared to the corresponding rat models (S9 or perfused livers),alligators' CL f,int was 2060% for CBZ and 50% for NCT of rats. Additionally, NCT exposure increased lactate levels in perfused livers indicating metabolic stress. This study provides insight into the hepatic capability of alligators to metabolize CBZ and NCT using an established in vitro (S9) system and a newly developed in situ liver perfusion system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Investigations indicated that sn-2 palmitate have positive effects on brain development, although its mechanism remains largely unexamined. This research delved into how a diet abundant in sn-2 palmitate influenced the cognitive behavior of mice and elucidated the associated mechanisms using metabolomics and lipidomics. The study demonstrated that dietary sn-2 palmitate led to improved working memory and cognition in mice, as well as an increase in brain BDNF concentration when compared to those fed blend vegetable oil (BVO). This was because sn-2 palmitate feeding promoted the synthesis of very long-chain fatty acids (VLCPUFAs) for the lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE) in the liver. This led to more efficient delivery of VLCPUFAs to the brain, as indicated by elevated concentration of LPC/LPE-VLCPUFAs in the liver and heightened expression of the major facilitator superfamily domain containing 2a (MFSD2A). In essence, this paper offered a potential mechanism by which sn-2 palmitate enhanced mouse neurodevelopment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Increasing energy expenditure in brown adipose (BAT) tissue by cold-induced lipolysis is discussed as a potential strategy to counteract imbalanced lipid homeostasis caused through unhealthy lifestyle and cardiometabolic disease. Yet, it is largely unclear how liberated fatty acids (FA) are metabolized. We investigated the liver and BAT lipidome of mice housed for 1 week at thermoneutrality, 23 °C and 4 °C using quantitative mass spectrometry-based lipidomics. Housing at temperatures below thermoneutrality triggered the generation of phosphatidylethanolamine (PE) in both tissues. Particularly, the concentrations of PE containing polyunsaturated fatty acids (PUFA) in their acyl chains like PE 18:0_20:4 were increased at cold. Investigation of the plasma's FA profile using gas chromatography coupled to mass spectrometry revealed a negative correlation of PUFA with unsaturated PE in liver and BAT indicating a flux of FA from the circulation into these tissues. Beta-adrenergic stimulation elevated intracellular levels of PE 38:4 and PE 40:6 in beige wildtype adipocytes, but not in adipose triglyceride lipase (ATGL)-deficient cells. These results imply an induction of PE synthesis in liver, BAT and thermogenic adipocytes after activation of the beta-adrenergic signaling cascade., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Arsenic has been ranked as the most hazardous substance by the U.S. Agency for Toxic Substances and Disease Registry. Environmental arsenic exposure-evoked health risks have become a vital public health concern worldwide owing to the widespread existence of arsenic. Multi-omics is a revolutionary technique to data analysis providing an integrated view of bioinformation for comprehensively and systematically understanding the elaborate mechanism of diseases., Objectives: This study aimed at uncovering the potential contribution of liver-microbiota-gut axis in chronic inorganic arsenic exposure-triggered biotoxicity in chickens based on multi-omics technologies., Methods: Forty Hy-Line W-80 laying hens were chronically exposed to sodium arsenite with a dose-dependent manner (administered with drinking water containing 10, 20, or 30 mg/L arsenic, respectively) for 42 d, followed by transcriptomics, serum non-targeted metabolome, and 16S ribosomal RNA gene sequencing accordingly., Results: Arsenic intervention induced a serious of chicken liver dysfunction, especially severe liver fibrosis, simultaneously altered ileal microbiota populations, impaired chicken intestinal barrier, further drove enterogenous lipopolysaccharides translocation via portal vein circulation aggravating liver damage. Furtherly, the injured liver disturbed bile acids (BAs) homoeostasis through strongly up-regulating the BAs synthesis key rate-limiting enzyme CYP7A1, inducing excessive serum total BAs accumulation, accompanied by the massive synthesis of primary BA-chenodeoxycholic acid. Moreover, the concentrations of secondary BAs-ursodeoxycholic acid and lithocholic acid were markedly repressed, which might involve in the repressed dehydroxylation of Ruminococcaceae and Lachnospiraceae families. Abnormal BAs metabolism in turn promoted intestinal injury, ultimately perpetuating pernicious circle in chickens. Notably, obvious depletion in the abundance of four profitable microbiota, Christensenellaceae, Ruminococcaceae, Muribaculaceae, and Faecalibacterium, were correlated tightly with this hepato-intestinal circulation process in chickens exposed to arsenic., Conclusion: Our study demonstrates that chronic inorganic arsenic exposure evokes liver-microbiota-gut axis disruption in chickens and establishes a scientific basis for evaluating health risk induced by environmental pollutant arsenic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Agpat5 (1-acylglycerol-3-phosphate O-acyltransferase 5) is a broadly expressed lipid regulatory enzyme involved in glycerophospholipid metabolism. Multiple genetic studies in mice and humans have identified that Agpat5 is associated with plasma insulin, cholesterol, and alanine aminotransferase levels. Despite the strong genetic evidence on Agpat5, no study has investigated its liver-specific role in physiology. Here, we conducted a series of metabolic studies under four distinct dietary conditions to assess the impact of liver-specific Agpat5 deletion on plasma insulin levels, glucose tolerance, plasma cholesterol levels, and hepatic steatosis. Liver-specific deletion of Agpat5 did not affect plasma insulin levels, glucose tolerance, plasma cholesterol levels, or hepatic steatosis in mice fed a chow diet, high-fat diet, or Western diet. However, when mice consumed a chow diet combined with liquid sucrose, liver-specific deletion of Agpat5 resulted in significantly decreased plasma insulin levels and improved glucose tolerance without alterations in body weight or fat mass. Using global lipidomics, we identified that Agpat5 specifically modulated levels of phosphatidylglycerol and cardiolipin within the livers of mice consuming liquid sucrose. Overall, our findings indicate a liver-specific role of Agpat5 in contributing to hyperinsulinemia and glucose tolerance in the absence of body weight changes when consuming liquid sucrose., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Brian W. Parks reports financial support was provided by National Heart Lung and Blood Institute. Judith A. Simcox reports financial support was provided by Howard Hughes Medical Institute. Judith A. Simcox reports financial support was provided by Juvenile Diabetes Research Foundation Limited. Judith A. Simcox reports financial support was provided by National Institute of Diabetes and Digestive and Kidney Diseases. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Robotic liver surgery is experiencing a period of great development, but some hurdles still need to be overcome. Parenchymal transection remains one of the most technically challenging steps. The lack of dedicated instruments and the flourishing of several techniques didn't allow surgeons to reach a standard technique so far. The aim of the present paper is to provide an overview of the different robotic liver transection techniques described to date, highlighting the strengths and weaknesses of each one. We conducted an extensive search on PubMed, Scopus and Web of Science, inserting the following keywords: "robotic liver transection, robotic hepatic transection" and focusing particularly on technical reports and paper regarding new surgical methods. This search resulted in a total of 13 different surgical techniques. All the methods described can be classified into two categories the "hybrid techniques" and the "fully robotic techniques" which are based, respectively, on the combined use of laparoscopic and robotic instrumentation or exclusively robotic devices. Another fundamental difference is the division between "one-surgeon" and "two-surgeon techniques", which depends on the level of expertise required of the assistant surgeon at the operating table. This is the first comprehensive review on this topic. Although the existing literature does not allow one technique to be established as superior to the others, the adoption of a standardized method of robotic hepatic transection is highly desirable to optimize surgical results and to allow better comparability of outcomes within the scientific community., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Background & Aims: Metabolic steatohepatitis (MASH) is closely related to metabolic disorders, and the main characteristics of MASH are hepatocyte steatosis with hepatocyte injury and inflammation. In severe cases, MASH can develop into liver cirrhosis. At present, there is no effective treatment for MASH. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a popular target for the development of cholesterol-lowering drugs and therapeutic interventions for cardiovascular disease. The present study aimed to explore the role of PCSK9 in methionine- and choline-deficient (MCD) diet-induced MASH progression and its targeted intervention., Methods: PCSK9 expression was determined in a MASH mouse model, and the role of PCSK9 in the regulation of lipid metabolism, inflammation, and fibrosis was investigated using PCSK9 knockout (PCSK9 -/- ) mice fed a MCD diet. An adeno-associated virus was used to alter PCSK9 expression in MASH mice., Results: Following the MCD diet, C57BL/6J wild-type (WT) mice developed marked steatohepatitis and elevated hepatic PCSK9 expression, and circulating PCSK9 expression. PCSK9 -/- mice showed significantly alleviated MCD-induced hepatic steatosis, with lower serum ALT levels, lower serum AST levels, smaller hepatic vacuoles, and less hepatic lipid deposition. PCSK9 -/- mice on the MCD diet showed a significantly reduced levels of inflammation and fibrogenesis. Moreover, adeno-associated virus (AAV)-mediated PCSK9 silencing in mouse livers significantly relieved liver steatosis, inflammation, and fibrosis., Conclusions: The present study demonstrated an important role of PCSK9 in MASH, suggesting that inhibition of PCSK9 may represent a novel and effective therapeutic strategy for MASH treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Backgrounds: Hepatic ischemia-reperfusion injury (IRI) triggers macrophage activation, which in turn mediates inflammatory responses and affects tissue repair and injury severity. Pentraxin 3 (PTX3) is vital in immune regulation and inflammatory processes. In this study, we aim to investigate the potential role of PTX3 in macrophage-mediated hepatic IRI., Methods: Gene expression profiles and single-cell data were obtained from the Gene Expression Omnibus (GEO) database. Immunohistochemistry was used to evaluate the expression levels of PTX3, CD68, and CD86 in samples from the human and mouse hepatic IRI models. The effects of PTX3 knockdown or overexpression on macrophage polarization were assessed in Raw264.7. PTX3 knockdown/ overexpression in Raw264.7 and co-culturing with AML12 were performed under conditions of hypoxia-reoxygenation (H/R) to examine pyroptosis and injury in AML12., Results: PTX3 expression was significantly upregulated in both human and mouse hepatic IRI model samples. Bulk and single-cell RNA-seq data analyses revealed that PTX3 is associated with inflammatory response pathways and macrophage activation. Macrophages with high PTX3 expression exhibit M1-like characteristics. Similarly, overexpression of PTX3 promotes M1 polarization of Raw264.7 after H/R, while the knockdown group exhibits reduced M1 polarization. Co-culture results indicated that pyroptosis in AML12 was significantly reduced after H/R in the PTX3 knockdown group, whereas the PTX3 overexpression group exhibited the opposite outcome., Conclusion: PTX3 regulates macrophage polarization during hepatic IRI, consequently influencing hepatocellular pyroptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatotoxicity is caused due to intake of drug or any chemical above the therapeutic range or as overdose. Current therapies for the management of hepatotoxicity are associated with several side effects. The present study was envisaged to explore the hepatoprotective potential of Ehretia laevis (E. laevis) in paracetamol (PCM) induced hepatotoxicity. All the plant extracts and fractions were evaluated for antioxidant and antiproliferative potential using various in vitro assays. Hepatotoxicity was induced in rats using a standardized single oral dose of PCM (3 g/kg). The aqueous fraction of E. laevis (AFEL) exhibited significant antioxidant and antiproliferative activity as compared to methanol extract of E. laevis (MEEL) in vitro. Moreover, treatment with AFEL (25, 50 and 100 mg/kg) decreased serum hepatic markers, attenuate the oxidative stress, inflammation and histopathological changes. LC-MS analysis of AFEL showed the presence of rutin, quercetin and kaempferol. Rutin was found to be in higher concentration, therefore it was docked on TNF-α. Its overall binding mode supports its capability to make complex with TNF-α. The finding of the study suggested significant antioxidant, antiproliferative, and hepatoprotective potential of E. laevis in paracetamol induced hepatotoxicity which could be attributed to the presence of various polyphenols., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetes mellitus (DM) represents a highly prevalent metabolic disorder across the globe. This study aimed to determine the ameliorative efficacy of glibenclamide (Gli) and obeticholic acid (OCA) against biochemical and pathological changes related to alloxan-induced diabetes. Twenty male Wistar rats were allocated into four groups; Control group, Diabetic group: received intraperitoneal injection of alloxan (120 mg/kg) for induction of diabetes, Diabetic + Gli group: Diabetic rats treated daily with oral Gli (5 mg/kg) and Diabetic + OCA group: Diabetic rats treated daily with oral OCA (10 mg/kg). All rats were subjected to 30 days treatments. Our results indicated that Gli successfully ameliorated hyperglycemia and dyslipidemia with a significant decline in serum pancreatic lipase activity and increased insulin level, while OCA had the same effect but without any enhancement in serum insulin levels. Additionally, the disturbances in liver function-related parameters and the evoked oxidative stress, interleukin(IL)-6 and IL-10 in the liver and pancreas were abrogated upon treatment with Gli and OCA. Furthermore, Gli and OCA increased AMP-activated protein kinase (P-AMPK), insulin receptor substrate 1 (IRS1), farnesoid X receptor (FXR), and glucagon-like peptide-1 receptor (GLP-1R) expressions and downregulated sterol regulatory element binding protein-1c mRNA expression. Besides, Gli and OCA have alleviated diabetes-induced histopathological distortions in hepatic and pancreatic tissues and enhanced the immunoexpression of insulin, and proliferating cell nuclear antigen with decreased immune reactivity of glucagon within pancreatic tissues. Gli and OCA decreased the immune reactivity of nuclear factor kappa B and increased the glycogen content of hepatic tissues. In conclusion, OCA is efficacious in the management of dyslipidemia and hyperglycemia of DM and its related oxidative stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rationale: Hepatotoxicity and nephrotoxicity are significant adverse effects caused in cancer patients treated with 5-Flurouracil (5-FU), a pyrimidine analogue anti-metabolite anticancer drug. The purpose of this research was to evaluate the impact of PPAR α/γ agonist (Saroglitazar; SARO) on 5-FU-induced hepatorenal damage in rats., Methods: Male rats were randomly assigned to four groups: control, 5-FU, 5-FU + SARO (2 mg/kg), and 5-FU + SARO (4 mg/kg). Rats received 75 mg/kg 5-FU intraperitoneally once weekly for three weeks. Saroglitazar (2 and 4 mg/kg/day) was orally supplied by oral syringe for three consecutive weeks. On day 22, rats were euthanized and their livers and kidneys were subjected to morphological, biochemical, histological, and immunohistochemical analysis., Results: Saroglitazar treatment significantly decreased serum liver and kidney function biomarkers. In addition, it successfully modulated liver and kidney levels of inflammatory mediators and markers (NF-κB P65, TNF-α, cleaved caspase-1, IL-1β and p-p38 MAPK) and oxidative stress-related parameters (MDA, GSH, SOD, Keap1, Nrf-2 and HO-1) in a dose dependent manner. Furthermore, SARO could attenuate 5-FU-induced activation of cleaved caspase-3 as well as improved histopathological examination of both liver and kidney tissues., Significance: Saroglitazar may be a viable therapy option for 5-FU toxicity as it halts the interaction network of NF-kB and Nrf2 signaling pathways and apoptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

SHP-1, as a protein tyrosine phosphatase, plays a key role in inflammation-related diseases. However, its function and regulatory mechanism in the imbalance of inflammatory response and acute liver injury during sepsis are still unknown. Herein, we constructed a murine model of Escherichia coli (E. coli) sepsis and demonstrated the function and novel mechanism of SHP-1 in sepsis. Overexpression of SHP-1 significantly reduced the mortality rate of mice and alleviated the histopathological deterioration of liver. In addition, it inhibited the expression and release of pro-inflammatory mediators in liver tissue and serum, but upregulated the expression of anti-inflammatory molecules. Silencing SHP-1 exhibited the completely opposite effects. Furthermore, the transcriptome data of mice liver showed that SHP-1 suppressed the progression of sepsis by negatively regulating the activation of multiple inflammation-related signaling pathways. More importantly, we fully revealed the regulation mechanism of SHP-1 on both canonical and non-canonical nuclear factor kappa-B (NFκB) signaling pathways during sepsis for the first time. SHP-1 significantly inhibited the phosphorylation and nuclear translocation of p50, while p65 inhibition was mainly achieved by inhibiting its transcription and translation levels. Meanwhile, SHP-1 inhibited the phosphorylation and nuclear translocation of p52, thereby inhibiting the activation of non-canonical NFκB signaling pathways. In summary, SHP-1 negatively regulated canonical and non-canonical NFκB signaling pathways, thereby blocking the occurrence of excessive inflammatory response and acute liver injury caused by E. coli sepsis. Our findings systematically elucidate the role and mechanism of SHP-1 during sepsis, providing new insights into the prevention and treatment of inflammation and immune-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatopulmonary syndrome (HPS) is a liver disease-induced pulmonary complication manifested with arterial hypoxemia. Hepatic cholestasis, encountered in several clinical situations, leads to biliary cirrhosis and HPS, both of which are best reproduced by rat common bile duct ligation (CBDL). Experience from liver transplantation suggests hepatoprotective-based therapy would be most effective in HPS treatment Dipeptidyl peptidase-4 (DPP-4) enzyme is involved in different pathogenic mechanisms of liver diseases. Vildagliptin (Vild) is a DPP-4 inhibitor which possesses favorable anti-inflammatory, anti-oxidant and anti-fibrotic effects. The present work explored hepatoprotective mechanisms of Vild and their participation in its prophylactic effectiveness in HPS induced by CBDL in rats. Male Wistar rats weighing 220-280 g were allocated into 4 groups: normal control, sham, CBDL and CBDL + Vild groups. i.p. saline was administered to the first 3 groups and i.p. Vild (10 mg/kg/day) was given to the fourth group for 6 weeks starting 2 week before CBDL. CBDL produced liver fibrosis, arterial hypoxemia and decreased survivability of rats. It altered liver functions and induced oxidative stress, pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)], vasodilatory molecules [endothelin-1 (ET-1), and inducible and endothelial nitric oxide synthases] and angiogenesis-associated protein [vascular endothelial growth factor-A (VEGF-A)] in liver and lung. Vild ameliorated liver fibrosis, and improved hypoxemia and survivability of CBDL rats and reversed these biochemical alterations. Prophylactic Vild administration attenuated CBDL-induced HPS in rats via direct hepatoprotective effects in the form of anti-oxidant, anti-inflammatory, anti-angiogenic and anti-fibrotic effects beside inhibition of pathological intrahepatic vasodilatation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Microplastics (MPs) are a threat of growing concern for living organisms as they exist in all ecosystems. The bidirectional communication between the gut, its microbiota, and the liver, has been conceptualized as gut-liver axis and may be influenced by environmental factors. MPs can cause intestinal and hepatic injuries, but there is still limited research exploring their impact on gut-liver axis. The aim of this study was to assess the effects of MP ingestion on gut-liver axis balance in gilthead seabream (Sparus aurata) fed with a diet enriched with polystyrene (PS)-MPs (0, 25, or 250 mg/kg b.w./day) for 21 days. PS-MPs affected the composition of gut microbiota, enhancing the evenness of gut microbial species. We also observed the impoverishment of core microbiota, suggesting reduced stability and permanence of microbiota members. Furthermore, PS-MPs reduced predominant bacteria in the gut of gilthead seabreams, increasing low-abundance species, including potential harmful taxa. On the other hand, PS-MPs increased the gene expression of immune and inflammatory mediators (i.e., TLR2, TLR5, and COX-2) in the liver. PS-MP exposure also increased serum triglycerides and bile acids (BAs) without modifying cholesterol. Moreover, the hepatic BA metabolism was impacted by PS-MPs which increased the expression of genes involved in primary BA kinetic (i.e., CYP27A1 and LXRa), which in turn can modulate intestinal microbial community. Indeed, PICRUSt2 mapping of BA-related functions predicted the increase of factors involved in BA metabolism. Specifically, K01442 (choloylglycine hydrolase) and K00076 (7α-hydroxysteroid dehydrogenase) were augmented by PS-MPs, suggesting a possible adaptation or co-evolution of gut microbiota to the modified hepatic BA metabolism. Thus, the obtained results showed that ingested PS-MPs impact the gut microbiota architecture and functions, the hepatic innate immunity, and the BA metabolism, suggesting the involvement of the gut-liver axis in MP-induced toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Dechlorane plus (DP), a widely used flame retardant, was added to Annex A of the Stockholm Convention on Persistent Organic Pollutants in 2023. This study aimed to investigate the effects of DP on glucose and lipid metabolism by orally exposing eight-week-old male mice to environmentally relevant concentrations of DP (0.5, 1, and 5 mg/kg/day) for six weeks. The in vivo effects of DP on liver histomorphology, glucose and lipid metabolism, intestinal microbiota, and the associated molecular mechanisms were assessed. Pathological examination revealed that exposure to 1 and 5 mg/kg/day DP induced hepatic damage, characterized by structural disarray of the hepatic cords and vacuolar degeneration of liver cells, while 0.5 and 1 mg/kg/day DP exposure led to significant triglycerides (TG) accumulation in the liver. Metabolite analysis showed a marked increase in hepatic pyruvate, glycogen, and TG in mice exposed to 0.5 and 1 mg/kg/day DP, while 5 mg/kg/day exposure resulted in elevated glycogen levels and reduced pyruvate and glucose concentrations. The underlying mechanisms involved the transcriptional regulation of key enzymes related to glucose and lipid metabolism, as well as the activation of the PI3K/AKT pathway. Exposure to 5 mg/kg/day DP upregulated genes associated with glycogenesis (GK), glycolysis (HK1 and PK), and fatty acid synthesis (SREBP1, FAS, and ACC1), while downregulating genes involved in gluconeogenesis (PCK1) and fatty acid β-oxidation (CPT1 and PPARA). The activated PI3K/AKT pathway regulated key proteins (GLUT4, GSK3β, and FoxO1), playing distinct roles in glucose and lipid metabolism. High-throughput 16S rDNA sequencing revealed that 5 mg/kg/day DP exposure altered the composition and diversity of intestinal microbiota, reducing the relative abundance of beneficial probiotics at both the phylum and genus levels. These findings offer new insights into the complex mechanisms through which DP affects glucose and lipid metabolism in mammals, contributing to a more comprehensive evaluation of its toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

When amino acids are plentiful in the diet, the liver upregulates most enzymes responsible for amino acid degradation. In particular, the activity of urea cycle enzymes increases in response to high-protein diets to facilitate the excretion of excess nitrogen. KLF15 has been established as a critical regulator of amino acid catabolism including ureagenesis and we have recently identified FoxO transcription factors as an important upstream regulator of KLF15 in the liver. Therefore, we explored the role of FoxOs in amino acid metabolism under high-protein diet. Our findings revealed that the concentrations of two urea cycle-related amino acids, arginine and ornithine, were significantly altered by FoxOs knockdown. Additionally, using KLF15 knockout mice and an in vivo Ad-luc analytical system, we confirmed that FoxOs directly regulate hepatic Ass1 expression under high-protein intake independently from KLF15. Moreover, ChIP analysis showed that the high-protein diet increased FoxOs DNA binding without altering the nuclear protein amount. Therefore, FoxOs play a direct role in regulating ureagenesis via a KLF15-independent pathway in response to high-protein intake., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Dictamnine(DIC), as the key pharmacological component of the classical Chinese herbal medicine cortex dictamni, possesses multiple pharmacological activities such as anti-microbial, anti-allergic, anti-cancer, and anti-inflammatory activities, however it is also the main toxicant of cortex dictamni induced hepatic damage, yet the underlying molecular mechanisms causing hepatic damage are still largely unknown. With the purpose of explore possibilities hepatotoxicity of dictamnine in zebrafish and to identify the key regulators and metabolites involved in the biological process, we administered zebrafish to dictamnine at a sub-lethal dose (

Clinically, patients with lipid metabolism disorders caused by factors such as high-fat diet (HFD) developed severer liver damage and lipid metabolism disorders after treatment with cyclophosphamide (CTX). This can lead to elevated levels of inflammatory cytokines, which in turn lead to changes in levels of various liver and kidney transporters, to increase drug accumulation, which may be a way to exacerbate liver injury. The role of organic anion transport peptides (OATPs), an important uptake transporter, in the transport process of CTX and in the aggravation of liver injury induced by CTX in HFD mice is unclear. The aim of this study was to characterize the hepatotoxicity and lipid metabolism disorders of HFD mice exposed to CTX and to investigate the possible mechanism from the perspective of drug in vivo process and transporter regulation. It has been verified that CTX induced severer liver injury in HFD mice compared with the control group, accompanied with upregulated Interleukin-1β (IL-1β) expression and down-regulated OATPs expression in liver and renal, and increased blood CTX concentration. This suggested that the down-regulation of OATPs involved in IL-1β may play an important role in HFD-CTX-induced liver injury, and then experiments in Hep G2 cells was used to validate the hypothesis. Pharmacokinetic and primary hepatocyte uptake experiments confirmed that OATPs may be an important factor involved in the in vivo process of CTX. In summary, this study demonstrated that HFD mice exhibited severer liver toxicity after exposure to CTX, which may be caused by the disorder of lipid levels and the up-regulation of inflammatory factors, and then the downregulation of liver and renal OATPs to increase the accumulation of CTX in vivo. These findings suggest that IL-1β and OATPs may be involved in the interactive regulation of CTX accumulation and endogenous lipid disturbance, and play very important role in the aggravation of liver injury induced by CTX in HFD mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Hepatic ischemia-reperfusion (I/R) injury stands as a recurring clinical challenge in liver transplantation, leading to mitochondrial dysfunction and cellular imbalance. Mitochondria, crucial for hepatocyte metabolism, are significantly damaged during hepatic I/R and the extent of mitochondrial damage correlates with hepatocyte injury. PINK1/Parkin-mediated mitophagy, is a specialized form of cellular autophagy, that maintains mitochondrial quality by identifying and removing damaged mitochondria, thereby restoring cellular homeostasis. Taxifolin (TAX), a natural flavonoid, possesses antioxidant, anti-inflammatory and anticancer properties. This study aimed at investigating the effects of TAX on hepatic I/R and the underlying mechanisms., Methods: C57BL/6 mice were pretreated with TAX or vehicle control, followed by 60 min of 70% hepatic ischemia. After 6 h of reperfusion, the mice were euthanized. In vitro, TAX-pretreated primary hepatocytes were subjected to oxygen glucose deprivation/reperfusion (OGD/R)., Results: Hepatic I/R caused mitochondrial damage and apoptosis in hepatocytes, but TAX pretreatment mitigated these effects by normalizing mitochondrial membrane potential and inhibiting reducing apoptotic protein expression. TAX exerted its protective effects by enhancing mitophagy via the PINK1/Parkin pathway. Moreover, silencing the PINK1 gene in primary hepatocytes reversed the beneficial effects of TAX., Conclusion: The results of the study demonstrate that promoting mitophagy through the PINK1/Parkin pathway restores mitochondrial function and protects the liver from I/R, suggesting that it may have therapeutic potential for the treatment of hepatic I/R., Competing Interests: Declaration of competing interest The other authors declare no competing interests. Funding sources had no influence in study design; nor in the collection, analysis and interpretation of data; nor in the writing of this report; and no interest in the decision to submit the paper for publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Metal alloys, pure titanium, metal-ceramics, and ceramic materials are used for fixed dental prostheses, which contained lead and potentially involved hepatotoxicity. To investigate the connection between fixed dental prostheses, blood lead levels, and liver function. A cross-sectional study enrolled 3624 American adults were conducted. Multivariate linear regression models and smooth curve fittings were used to describe correlations between the number of fixed dental prostheses, blood lead levels, and four liver function markers. Mediation analysis suggested an intermediary association of blood lead levels between prosthesis count and liver function. Here, number of fixed dental prostheses was significantly positive correlated with blood lead levels (p < 0.0001), but specifically negative correlated with alanine aminotransferase, lactate dehydrogenase, and gamma glutamyl transferase levels in males. Moreover, mediation analysis confirmed a mediating role for blood lead levels in the association between the number of prostheses and alanine aminotransferase levels in males only, with a mediation effect rate of 74.27% (p = 0.0020). An increased count of fixed prostheses is associated with changes in liver function markers in a gender-dependent manner, with blood lead levels serving as a potential mediator in males., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Exposure to metals during pregnancy has been associated with adverse birth outcomes, but its impact on fetal liver function remains poorly understood. This study for the first time aimed to investigate the association between maternal and umbilical cord blood Metals levels and umbilical liver enzymes. A comprehensive analysis was conducted on 450 mother-newborn pairs in 2022, measuring 13 Metals in serum samples from pregnant women during the third trimester and umbilical cord blood samples. Regression analyses were utilized to examine the relationship between levels of maternal and umbilical cord blood Metals and the levels of gamma-glutamyl transferase (GGT), umbilical alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). G-comp analyses evaluated the combined effect of metals exposure on umbilical liver enzymes. Elevated levels of certain Metals in cord blood and maternal samples were positively linked with increased umbilical GGT, ALP, ALT, and AST levels. Notably, zinc (Zn) levels in cord blood exhibited an inverse correlation with umbilical liver enzyme levels. Furthermore, g-comp analyses revealed significant positive associations between exposure to metals mixtures and umbilical liver enzyme levels. An increase of one quartile in the mixture of maternal and umbilical Metals was linked with 99.45 U/L (95% CI:37.72, 161.19, p < 0.01), 2.79 (95% CI: 0.92, 4.65, p < 0.01), and 87.17 (95% CI: 53.96, 120.38, p < 0.01) increase in ALP, ALT and GGT levels. Further examination of the weight of Metals revealed As, Cd, Ni, Pb, Hg and Cr with the highest positive effects and Zn with the highest negative effect in the mixture effect on the umbilical liver enzyme. In summary, our results underscore the potential influence of prenatal heavy metal exposure on fetal liver function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: There is no clear information on the regulation of liver blood flow by the autonomic nervous system. We conducted this study to investigate whether quiescent hepatic stellate cells (qHSCs) regulate liver blood flow in response to the sympathetic neurotransmitter norepinephrine (NE)., Methods: qHSCs isolated from mice were cultured in Dulbecco's modified Eagle medium without fetal bovine serum for 1 day on collagen gel. NE-induced qHSC contraction was evaluated using the quantitative single-cell contraction measurement method that we had developed previously. For the measurement of liver perfusion pressure in situ, a buffer solution was perfused from the portal vein in mice., Results: NE-induced a reversible contraction of qHSCs. This contraction was suppressed by the nonmuscle myosin II inhibitor blebbistatin, the myosin light chain kinase inhibitor ML-9, the Rho kinase inhibitor H-1152, the calmodulin inhibitor W-7, the store-operated calcium channel inhibitor YM-58483, and the IP 3 receptor inhibitor xestospongin C. In contrast, the transient receptor potential C channel inhibitor SKF96365 did not affect the NE-induced contraction., Conclusion: These results suggest that qHSCs contract in response to NE., New & Noteworthy: The present study provides direct evidence for the first time that norepinephrine (NE) induces a reversible contraction of isolated single quiescent hepatic stellate cells (qHSCs) and further suggests that the NE-mediated qHSC contraction participates in the regulation of liver blood flow in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Our previous findings indicate that caloric restriction (CR) stimulates the production and secretion of taurine-conjugated bile acids in mice. Subsequent processing by gut microbiota leads to increased levels of deconjugated bile acids, taurine, and various taurine conjugates in the intestine. Furthermore, we demonstrated that carbohydrate restriction and protein restriction, to a smaller extent, mirror the impact of CR in terms of hepatic production of bile acids but not their secretion. We hypothesized that modulating dietary macronutrient levels would influence taurine homeostasis in the liver and intestine of ad libitum-fed and CR animals., Materials and Methods: Ad libitum-fed male mice were allocated to receive either a control, low-protein (LP), low-fat (LF), or low-carbohydrate (LC) diet. Meanwhile, CR groups were given 80 % of their regular voluntary food intake as a control, high-protein (HP), high-fat (HF), or high-carbohydrate (HC) diet., Key Findings: While CR did not affect the taurine levels and its conjugates in the liver, alteration in carbohydrates and protein intake impacted it. Conversely, in the intestine, CR increased the amount of free and conjugated taurine, whereas the various diets did not affect it or disrupt the CR-specific phenotype. Notably, variations in diet composition impacted the expression of the taurine transporter (Slc6a6) and glutathione-S transferases (GST) in the intestine as well as cysteine dioxygenase (Cdo) in the liver., Significance: The liver and the intestine show distinct responses to dietary interventions, with hepatic taurine being affected by the diet composition, while intestinal taurine is governed by energy availability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The rising prevalence and severe consequences of nonalcoholic fatty liver disease (NAFLD) have driven the quest for preventive medications. Complanatoside A (CA) is the marked flavonoid of Astragali complanati semen, a traditional Chinese herb that acts on the liver meridian and is widely used to treat liver problems. CA has been proven to have considerable lipid-lowering and liver-protective effects in vitro. However, the efficacy of CA in preventing NAFLD has yet to be shown in vivo., Methods: First, the effectiveness of CA against NAFLD was assessed using a high-fat diet (HFD) mouse model. Second, the CA protective mechanism against NAFLD was investigated using a combined metabolomics and network pharmacology strategy. Differential metabolites were identified by metabolomics-based analyses, and metabolic pathway analysis was accomplished by MetaboAnalyst. Potential therapeutic targets were obtained through network pharmacology. Finally, key targets were identified via compound-target networks and validated by molecular docking and western blotting., Results: CA prevented NAFLD mainly by reducing liver lipid accumulation in HFD mice. Metabolomics identified 22 potential biomarkers for CA treatment of NAFLD, primarily involving glycerophospholipid and arachidonic acid metabolism. Fifty-one potential targets were determined by network pharmacology. Co-analysis revealed that albumin, peroxisome proliferator-activated receptor-alpha, retinoid X receptor alpha, interleukin-6, and tumor necrosis factor alpha were key targets., Conclusion: This experiment revealed that CA has a preventive effect on NAFLD, primarily by regulating the peroxisome proliferator-activated receptor-alpha/retinoid X receptor alpha pathway. Furthermore, it provides evidence supporting the potential use of CA in the long-term prevention of NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bisphenols (BPs) are widely distributed in daily life as typical endocrine disruptors. In this study, we examined the distribution of bisphenol A (BPA) and BPA alternatives in liver (n = 149) and bile (n = 102) tissues from the patients with liver cancer, and calculated the hepatobiliary transport efficiency of BPs (T B-L ). Seven BPs were detected in both liver (median: 0.859 ng/g; range: 0.0200-26.7 ng/g) and bile (median: 0.307 ng/mL; range: 0.0200-26.7 ng/mL), and BPA was the predominant in both liver (mean: 1.89 ng/g) and bile (mean: 1.65 ng/mL). The T B-L of BPs was reported for the first time and found to be negatively correlated with the molecular weight and Log K ow of BPs. Furthermore, BPA and ∑BPs in liver showed a significant negative correlation with age, and a significant difference was found in BPs in liver and bile in hepatocellular carcinoma patients with different genders (p < 0.05). For liver function indicators, levels of BPs showed significant positive correlation with γ-glutamyl transferase (GGT) and alanine aminotransferase (ALT), especially BPBP levels in bile. This suggests that BPs may have some correlation with hepatocellular carcinoma. This is the first report on distribution characteristics of BPs in the liver and bile of hepatocellular carcinoma patients, and is the first study to report the hepatobiliary transport efficiency of BPs. The results should contribute to the understanding of BPs accumulation in the liver and bile and further relationship with hepatocellular carcinoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bisphenol S (BPS) is commonly used for the industrial production of thermal paper, polycarbonate plastics, epoxy resins and other materials. Studies have reported that BPS can lead to triglyceride (TAG) or/and cholesterol (CHO) accumulation in the liver in zebrafish and mice, but the reasons for the different types of lipids that accumulate in the liver following BPS exposure are unclear. Here, the influences of lower-dose (10 mg/kg body weight/day) and high-dose (50 mg/kg body weight/day) BPS exposure to male SD rats on the accumulation of different lipids in the liver were explored. The results indicated that BPS treatment increased the levels of acetyl-CoA and glycogen in the liver. A lower dose of BPS upregulated the mRNA and protein expression levels of sterol regulatory element-binding protein 1 (srebp1), which is involved in the de novo synthesis of TAG in the liver, thus promoting the synthesis of glycerides (diacetylglyceride and TAG). However, a higher dose of BPS induced CHO accumulation, but inhibited the mRNA expression of genes (i.e., srebp2, hmgcr and hmgcs) involved in the de novo synthesis of CHO in the liver. Excessive accumulation of glycerides and CHO led to destruction of the physiological structure of rat liver, causing disorders in liver function. Our data provide new insight into the different mechanisms by which glyceride and CHO accumulate in the liver after BPS exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)