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Background: In carnitine palmitoyltransferase I (CPT-I) deficiency (MIM 255120), free carnitine can be increased with no pathologic acylcarnitine species detectable. As inclusion of CPT-I deficiency in high-risk and newborn screening could prevent potentially life-threatening complications, we tested whether CPT-I deficiency might be diagnosed by electrospray ionization-tandem mass spectrometry (ESI-MS/MS)., Methods: A 3.2-mm spot of whole blood dried on filter paper was extracted with 150 microL of methanol. After derivatization of carnitine and acylcarnitines to their butyl esters, the samples were analyzed by ESI-MS/MS with 37.5 pmol of L-[(2)H(3)]carnitine and 7.5 pmol of L-[(2)H(3)]palmitoylcarnitine as internal standards., Results: In all dried-blood specimens from each of three patients with CPT-I deficiency, we found an invariably increased ratio of free carnitine to the sum of palmitoylcarnitine and stearoylcarnitine [C0/(C16 + C18)]. The ratio in patients was between 175 and 2000, or 5- to 60-fold higher than the ratio for the 99.9th centile of the normal newborn population in Bavaria (n = 177 842). No overlap with the values of children that were known to be supplemented with carnitine was detected [C0/(C16 + C18), 34 +/- 30; mean +/- SD; n = 27]., Conclusions: ESI-MS/MS provides a highly specific acylcarnitine profile from dried-blood samples. The ratio of free carnitine to the sum of palmitoylcarnitine and stearoylcarnitine [C0/(C16 + C18)] is highly specific for CPT-I deficiency and may allow presymptomatic diagnosis.

In the past 40 years, liver transplantation has evolved from a high-risk procedure to one that offers high success rates for reversal of liver dysfunction and excellent patient and graft survival. The liver is the most tolerogenic of transplanted organs; indeed, immunosuppressive therapy can be completely withdrawn without rejection of the graft in carefully selected, stable long-term liver recipients. However, in other recipients, chronic allograft injury, late graft failure and the adverse effects of anti-rejection therapy remain important obstacles to improved success. The liver has a unique composition of parenchymal and immune cells that regulate innate and adaptive immunity and that can promote antigen-specific tolerance. Although the mechanisms underlying liver transplant tolerance are not well understood, important insights have been gained into how the local microenvironment, hepatic immune cells and specific molecular pathways can promote donor-specific tolerance. These insights provide a basis for the identification of potential clinical biomarkers that might correlate with tolerance or rejection and for the development of novel therapeutic targets. Innovative approaches aimed at promoting immunosuppressive drug minimization or withdrawal include the adoptive transfer of donor-derived or recipient-derived regulatory immune cells to promote liver transplant tolerance. In this Review, we summarize and discuss these developments and their implications for liver transplantation.

The use of quantitative MRI methods for assessment of the abdomen in children has become commonplace over the past decade. Increasingly employed methods include MR elastography, chemical shift encoded (CSE) MR imaging for determination of proton density fat fraction, diffusion-weighted imaging, and a variety of relaxometry techniques, such as T1 and T2* mapping. These techniques can be used in a variety of settings to distinguish normal from abnormal tissue as well as determine the severity of disease. The performance of quantitative MRI methods in the pediatric population presents unique challenges as compared to adult populations. These challenges relate to multiple factors, including patient size, pediatric physiology, inability to breath hold, and greater physical motion during the examination. The purpose of this review article is to review quantitative MRI methods that may be used in clinical practice to assess the pediatric abdomen and to discuss special considerations when performing these techniques in children., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chimeric mice with humanized livers constitute an attractive emergent experimental model for investigating human metabolism and disposition of drugs. The present review was designed to summarize key findings about the use of this model for studying human hepatic drug transporters, which are now recognized as important players in pharmacokinetics and consequently have to be considered from a regulatory perspective during pharmaceutical drug development. The reviewed data indicate that chimeric mice with humanized livers have been successfully used for analysing the implications of human hepatic drug transporters for drug hepatobiliary elimination, drug-drug interactions and drug-induced cholestasis. Such transporter studies have been performed in vivo with chimeric mice and/or in vitro with human hepatocytes isolated from humanized liver and used either in suspension or in culture. The residual presence of mouse hepatocytes and the potential morphological/histological alterations of the humanized liver, as well as its immunodeficient mouse environment, have, however, to be considered when using chimeric mice with humanized livers for transporter studies. Finally, if the proof of concept of applying chimeric mice with humanized livers to hepatic drug transport is established, more experimental data on this topic, including from standardization approaches, are likely required to completely and accurately demonstrate the robustness, convenience and added value of this chimeric mouse model for drug transporter studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: To compare the estimates of attenuation coefficient (AC) for liver fat quantification between 2 Ultrasound systems and to evaluate the quality measure of a pre-released software., Methods: AC were obtained in 30 participants in this single-center IRB-approved, HIPAA compliant study. Images were obtained on the Philips Epiq Elite system using experimental software and the Canon Medical Systems Aplio i800 with released software. Five AC measurements were taken and the median and IQR/M were calculated. Region of interest placement was based on a confidence map. ROI was at the same depth and size for each system. The concordance was estimated using the Lin's concordance correlation coefficient (CCC), the r Pearson's correlation coefficient, the bias-correction factor (Cb), and the Bland-Altman method., Results: The ACs varied from 0.45 to 1.0 dB/cm/MHz for the Philips system and 0.30 to 0.96 dB/cm/MHz for the Canon system. The CCC (95% CI) was 0.792 (0.666-0.918), Pearson's r was 0.839 with Cb of 0.944, and the mean difference was 0.03 (-0.101; 0.162) suggesting the 2 methods are considered to be in agreement. Based on a Philips confidence map to determine the best location for performing the measurements, a depth of 3.5 to 4.0 cm from the liver capsule was determined, which might be significantly different than that of the Canon system., Conclusions: Estimation of the AC of the 2 systems showed a high agreement, that is, a similar trend. Assessment of the placement of the measurement box based on the quality of the measurement might be different between the 2 systems., (© 2021 American Institute of Ultrasound in Medicine.)

A 13-kDa phosphoamidase was isolated as a single band on SDS-PAGE from bovine liver. Its Stokes' radius, sedimentation coefficient, molecular mass, and optimal pH were estimated to be 1.6 nm, 1.8 s, 13 kDa, and 6.5, respectively. The enzyme released P(i) from 3-phosphohistidine, 6-phospholysine, and amidophosphate at rates of 0.9, 0.6, and 2.6 micromol/min/mg protein, respectively. However, it did not dephosphorylate phosphocreatine, N(omega)-phosphoarginine, imidodiphosphate, or O-phosphorylated compounds including inorganic pyrophosphate. It also dephosphorylated succinic thiokinase and nucleoside diphosphate kinase autophosphorylated at His residues, indicating that it works as a protein histidine phosphatase. A thiol reagent, 30 microM N-ethylmaleimide, depressed the activity by half, while a thiol compound, 2-mercaptoethanol, protected the enzyme from heat-inactivation. Five millimolar divalent cations, such as Mg2+ and Mn2+, and 5 mM EDTA, had no effect on the activity.

A glycan chain analysis of the total oligosaccharide pool derived from rat liver arylsulfatase B was carried out by. P4 Gel Permeation Chromatography and sequential exoglycosidase digestion. It was found that 71% of rat liver arylsulfatase B oligosaccharides were sialylated. The relative contribution of particular structures in the total glycan pool was as follows: sialylated biantennary complex type glycans with terminal galactose--65%, high-mannose type glycans--15%, biantennary complex type glycans with core fucose and terminal N-acetylglucosamine--5%, O-linked oligosaccharides--3.5%.

Purpose: To achieve simultaneous T 1, w /proton density fat fraction (PDFF)/ R 2 ∗ mapping in abdomen within a single breadth-hold, and validate the accuracy using state-of-art measurement., Theory and Methods: An optimized multiple echo gradient echo (GRE) sequence with dual flip-angle acquisition was used to realize simultaneous water T 1 (T 1, w )/PDFF/ R 2 ∗ quantification. A new method, referred to as "solving the fat-water ambiguity based on their T 1 difference" (SORT), was proposed to address the fat-water separation problem. This method was based on the finding that compared to the true solution, the wrong (or aliased) solution to fat-water separation problem showed extra dependency on the applied flip angle due to the T 1 difference between fat and water. The B 1 + measurement sequence was applied to correct the B 1 + inhomogeneity for T 1, w relaxometry. The 2D parallel imaging was incorporated to enable the acquisition within a single breath-hold in abdomen., Results: The multi-parametric quantification results of the proposed method were consistent with the results of reference methods in phantom experiments (PDFF quantification: R 2  = 0.993, mean error 0.73%; T 1, w quantification: R 2  = 0.999, mean error 4.3%; R 2 ∗ quantification: R 2  = 0.949, mean error 4.07 s -1 /PDFF/ R 2 ∗ quantification was realized for whole liver within a single breath-hold.1, w /PDFF/ R 2 ∗ quantification was realized for whole liver within a single breath-hold., Conclusion: The proposed method accurately quantified T 1, /PDFF/ R 2 ∗ for the whole liver within a single breath-hold. This technique serves as a quantitative tool for disease management in patients with hepatic steatosis.w /PDFF/ R 2 ∗ for the whole liver within a single breath-hold. This technique serves as a quantitative tool for disease management in patients with hepatic steatosis., (© 2021 International Society for Magnetic Resonance in Medicine.)

Endogenous acceptors in a Golgi apparatus-enriched subcellular fraction from rat liver were labeled with UDP-[3H]GalNAc. The great majority of these acceptors were protected from protease degradation in the absence of detergent. These molecules are therefore present in intact vesicles of the correct topological orientation, which are likely to be similar to the Golgi compartments of the intact cell. Several distinct glycoproteins are labeled, but most are different from those labeled with UDP-[3H]GlcNAc. The enzyme peptide-N4(N-acetyl-beta-glucosiminyl)asparagine amidase releases label from a few specific proteins, indicating that [3H]GalNAc is transferred to N-linked oligosaccharides. Both neutral and anionic N-linked oligosaccharides are found, the great majority of which do not bind to ConA-Sepharose. Most of the [3H]GalNAc found in neutral oligosaccharides is terminal and beta-linked. The negative charge on the anionic molecules is due to sialic acid, and phosphate. A major portion of the [3H] GalNAc in this fraction is acid labile, and is released with kinetics consistent with it being in a phosphodiester linkage. These results show the existence of a whole new class of GalNAc-containing N-linked oligosaccharides, and demonstrates that this in vitro approach can detect previously undescribed structures. O-linked oligosaccharide biosynthesis was also studied in the same labeled rat liver Golgi apparatus preparations. beta-Elimination releases approximately 95% of the peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase (PNGase F)-resistant label which, in the absence of other added nucleotides, is almost exclusively [3H] GalNAcitol. If other unlabeled sugar nucleotides and adenosine 3'-phosphate,5'-phosphosulfate are added during the chase period two anionic O-linked oligosaccharides are synthesized, indicating that the UDP-GalNAc:peptide-N-acetylgalactosaminyltransferase is at least in part functionally co-localized with enzymes that extend and modify O-linked oligosaccharides.

Human serum alpha-fetoprotein (AFP) is elevated in not only hepatocellular carcinoma (HCC) but also benign liver diseases. AFP produced in HCC and benign liver diseases was separated into several isoforms corresponding to different sugar chain structures by several types of lectin affinity electrophoresis, and the HCC-specific AFP isoform was discriminated from those of benign liver diseases. Because a small amount of HCC-specific AFP isoform was detected in cord serum AFP, the whole sugar chain structures of human cord serum AFP were determined, as follows: Neu5Ac alpha 2-->Gal beta 1-->4GlcNAc beta 1-->2Man alpha 1-->6(Neu5Ac alpha 2 -->6Gal beta 1-->4GlcNAc beta 1-->2Man alpha 1-->3)Man beta 1-->4R1 and R2, Gal beta 1-->4GlcNAc beta 1-->2Man alpha 1-->6(Neu5Ac alpha 2-->6Gal beta 1 -->4GlcNAc beta 1-->2Man alpha 1-->3)Man beta 1-->4R1 and R2, and Neu5Ac alpha 2-->3Gal beta 1-->4GlcNAc beta 1-->2Man alpha 1-->6(Neu5Ac alpha 2 -->6Gal beta 1-->4GlcNAc beta 1-->2Man alpha 1-->3)Man beta 1-->4R1 and R2 in the ratio of 81.6:8.9:9.5. R1 and R2 denote GlcNAc beta 1-->4GlcNAcOT (subscript OT represents an NaB3H4-reduced oligosaccharide) and GlcNAc beta 1-->4(Fuc alpha 1-->6)GlcNAcOT, respectively, and the ratio between R1 and R2 in the respective fractions was approximately 19:1. In contrast, the sugar chain structure of HCC highly specific AFP isoform was found to comprise a monosialyl-biantennary sugar chain with additional fucosylation of the proximal N-acetylglucosamine. Fucosylation of AFP produced in fetal liver increased in inverse proportion to the gestation period, in weeks, indicating that fucosylation of AFP in HCC may be related to the dedifferentiation of human hepatocytes through malignant transformation.

The previous claims by others of a novel choline transfer reaction involving CDP-choline and leading to the conversion of [U-14C]glycero-3-phosphate to glycero-3-phosphocholine in liver sub-cellular fractions could not be confirmed. Apparent labelling of glycero-3-phosphocholine, isolated by paper chromatography, was, in fact, explained by contamination by other radioactive metabolites, especially D-glucose. A synergistic effect on gluconeogenesis from [U-14C]glycero-3-phosphate was obtained by incubating well-washed mitochondria with washed microsomes.

Male CD rats were injected with single i.p. doses of benzo(a)pyrene (B(a)P), and peripheral blood lymphocytes (PBLs), livers, and lungs were removed at various times after administration. DNA adducts were analyzed in each tissue by 32P postlabeling with nuclease P1 enhancement. Sister chromatid exchange frequencies were concomitantly measured in cultured whole blood. B(a)P-DNA adducts were observed in all three tissues from animals sacrificed between 1 and 56 days after injection. Maximal adduction levels occurred at about 4 days after administration, followed by a gradual loss of adducts over the period examined. The apparent half-lives of total DNA adducts were 15 days in liver, 17 days in PBLs, and 22 days in lung. Induced sister chromatid exchanges were linearly related to the amount of DNA adducts remaining in the PBLs at the time of harvest up to 56 days and were significantly elevated above concurrent controls up to 14 days. One of the major adducts found in each tissue was N2-(10 beta-[7 beta,8 alpha,9 alpha-trihydroxy-7,8,9,10-tetrahydrobenzo(a) pyrene]yl)deoxyguanosine. An additional novel major adduct was found in the liver DNA and is derived from the further metabolism of B(a)P-trans-7,8-dihydrodiol. A second major novel B(a)P adduct was found in the DNA of lung tissues and accounts for about 40% of the total adducts present. Experimental evidence suggests that this adduct is derived from a metabolic pathway that includes the formation of 9-hydroxy-B(a)P.

It is unresolved why lactate is transported to the liver for further utilization within the physiological purview of Cori cycle, when muscles have more lactate dehydrogenase (LDH) than liver. We point out that the answer lies in thermodynamics/equilibriums. While the utilization of NADH for the reduction of pyruvate to lactate can be mediated via the classical mechanism, the oxidation of lactate (with/without the uphill reduction of NAD + ) necessitates alternative physiological approaches. The latter pathway occurs via interactive equilibriums involving the enzyme, protons and oxygen or diffusible reactive oxygen species (DROS). Since liver has high DROS, the murburn activity at LDH would enable the cellular system to tide over the unfavorable energy barriers of the forward reaction (~476 kJ/mol; earlier miscalculated as ~26 kJ/mole). Further, the new mechanism does not necessitate any "smart decision-making" or sophisticated control by/of proteins. The DROS-based murburn theory explains the invariant active-site structure of LDH isozymes and their multimeric nature. The theoretical insights, in silico evidence and analyses of literature herein also enrich our understanding of the underpinnings of "lactic acidosis" (lowering of physiological pH accompanied by lactate production), Warburg effect (increased lactate production at high pO 2 by cancer cells) and approach for cancer therapy., (© 2021 Wiley Periodicals LLC.)

Purpose: Automatic and accurate three-dimensional (3D) segmentation of liver with severe diseases from computed tomography (CT) images is a challenging task. Fully convolutional networks (FCNs) have emerged as powerful tools for automatic semantic segmentation, with multiple potential applications in medical imaging. However, the use of a large receptive field and multiple pooling layers in the network leads to poor localization around object boundaries. The network usually makes pixel-wise prediction independently, making it difficult to respect local label consistency and enforce the smoothness of the object boundary., Methods: We have developed an automatic liver segmentation method based on a novel framework that integrates fully convolutional network predictions into active contour models (ACM). We use only a single network architecture to generate a pixel label map containing spatial regional information (foreground and background) as well as layered boundary information. We exploit the structured network outcome to define an external constraint force of active contour models. A unique property of the designed force is that both its strength and direction are adaptive to its position and relative distance to the object boundary. The resulting integrated active contour models have the advantages of incorporating both high-level and low-level image information simultaneously, while enforcing the smoothness of the contour. Because the external constraint force can push the evolving contour to the liver boundary and exists everywhere in the image domain, it allows us to place the initial contour far away from the liver boundary. It potentially allows us to control the evolution of the contour in order to preserve the topology of the liver., Results: We have trained and evaluated our model on 73 liver CT scans from a clinic study. The integrated ACM model yields mean dice coefficients (DICE) 95.8 ± 1.4 (%). Without further fine-tuning the network weights for two independent datasets, it yields mean DICE 96.2 ± 0.9 (%) for the SLIVER07 training dataset, and mean DICE 94.3 ± 2.7 (%) for the LiTS training dataset. In comparison with FCN alone model, the integrated ACM model yields improvements in terms of surface distance and DICE values for almost all the cases. Furthermore, the initialization of the active contour can be very far away from the liver boundary., Conclusions: Experimental results for segmenting livers (with severe diseases on CT images resulting in shape and density abnormalities) have revealed that our proposed model improves segmentation results in comparison with FCN alone. Without further fine-tuning the network weights for two independent datasets, the model is capable of handling image variations from different datasets due to its inherent deformable nature. It is relatively easy to integrate more advanced (either existing or future) FCN architecture into our framework to further improve the segmentation performance., (© 2019 American Association of Physicists in Medicine.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

Background: As cell-free nanotherapeutics, extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have shown potential therapeutic action against liver diseases. However, their effects on autoimmune hepatitis (AIH) are not yet well understood., Methods and Results: In this study, we utilized a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model to investigate the effects of MSC-EVs on AIH. We found that MSC-EVs provide significant protection against Con A-induced hepatitis in C57BL/6 male mice, with their effectiveness being critically dependent on the gut microbiota. MSC-EVs modulate the composition of the gut microbiota, particularly by increasing the abundance of norank_f__Muribaculaceae, and impact liver metabolic profiles, leading to significant amelioration of liver injury. The identification of Acetyl-DL-Valine as a protective metabolite underscores the therapeutic potential of targeting gut‒liver axis interactions in liver diseases., Conclusion: Overall, our data demonstrate that MSC-EVs exhibit nanotherapeutic potential in Con A-induced hepatitis and provide new insights into the treatment of autoimmune hepatitis., Competing Interests: Declarations. Ethics approval and consent to participate: All experiments were performed in accordance with the institutional guidelines of the Third Affiliated Hospital of Sun Yat-sen University. The use of animals in this study was approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University and was conducted in accordance with the ARRIVE guidelines 2.0. The approved study is titled “Mechanism of mesenchymal stem cells in relieving ConA-induced liver failure”, with approval granted on December 25, 2023 (Approval number: IACUC-F3-24-0102). The umbilical cords were obtained from healthy mothers at the Third Affiliated Hospital of Sun Yat-sen University with parental consent. The procedure for isolating UC-MSCs was approved by the Research Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University. The approved study is titled “A Multicenter Randomized Controlled Clinical Study on the Treatment of Hepatitis B-Related Acute-on-Chronic Liver Failure with Allogeneic Human Umbilical Cord Mesenchymal Stem Cells”, with approval granted on December 30, 2020 (Approval number: 2020-14). Informed consent was obtained from all the subjects and/or their legal guardian(s) under the ethical committee of the Third Affiliated Hospital of Sun Yat-sen University. Consent for publication: All the authors confirm their consent for publication. Competing interests: The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this paper., (© 2024. The Author(s).)

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.)

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.)

Due to the low contrast of abdominal CT (Computer Tomography) images and the similar color and shape of the liver to other organs such as the spleen, stomach, and kidneys, liver segmentation presents significant challenges. Additionally, 2D CT images obtained from different angles (such as sagittal, coronal, and transverse planes) increase the diversity of liver morphology and the complexity of segmentation. To address these issues, this paper proposes a Detail Enhanced Convolution (DE Conv) to improve liver feature learning and thereby enhance liver segmentation performance. Furthermore, to enable the model to better learn liver features at different scales, a Multi-Scale Feature Fusion module (MSFF) is added to the skip connections in the model. The MSFF module enhances the capture of global features, thus improving the accuracy of the liver segmentation model. Through the aforementioned research, this paper proposes a liver segmentation network based on detail enhancement and multi-scale feature fusion (DEMF-Net). We conducted extensive experiments on the LiTS17 dataset, and the results demonstrate that the DEMF-Net model achieved significant improvements across various evaluation metrics. Therefore, the proposed DEMF-Net model can achieve precise liver segmentation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Determining organic micropollutants in liver samples of apex species is of foremost importance for biomonitoring studies, as it can provide evidence of environmental pollution and exposure of living organisms to chemicals. This review aims to provide a 4-year overview and summarize the trends in the extraction methodologies to determine both polar and non-polar organic micropollutants in liver samples from organisms of higher trophic levels. The dominant extraction techniques including ultrasound-assisted extraction (UAE), pressurized liquid extraction (PLE), Soxhlet, and QuEChERS, as well as additional steps and/or modifications applied in the reviewed studies, are presented and critically discussed. The latest trends in these methods as well as a comparison between them considering elapsed time, robustness, cost, and environmental fingerprint are also provided., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no known financial conflicts of interest or personal relationships that may have influenced the research presented in this paper. Nikolaos S. Thomaidis is a guest editor of ABC but was not involved in the peer review of this paper., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

Acetaminophen (APAP) has emerged as a predominant contributor to acute liver failure (ALF) in United States. Alismatis rhizoma, a commonly used traditional herbal medicine, contains small molecular components with extensive hepatoprotective activity. However, the specific role of Alismatis rhizoma polysaccharide (ARP) in liver protection remains unclear. ARP50 and ARP70, derived through graded alcohol precipitation and refinement, predominantly consisted of varying proportions of glucose, galactose, and arabinose. In vitro experiments on free radical scavenging demonstrated notable antioxidant capabilities of ARP50 and ARP70. To investigate the hepatoprotective effects, an APAP-induced acute liver injury (ALI) model was established in mice. ARP50 and ARP70 exerted dose-dependent therapeutic effects on APAP-induced liver injury. Further analysis of liver metabolites revealed that ARPs facilitated the reconstruction of the liver antioxidant system by modulating the metabolism network centered on l-glutamine. In addition, the abundance of gut microbiota was altered under the influence of ARPs. ARP50 significantly reduced the levels of Pseudarthrobacter and markedly increased the levels of Faecalibacterium，At the same time, ARP50 could increase the levels of acetic acid in the liver and serum. Meanwhile, ARP70 significantly increased the abundance of Dubosiella, Muribaculum, Ileibacterium, and Prevotellaceae UCG 001, while reducing the abundance of Escherichia Shigella and Pseudarthrobacter. The results indicated that ARPs could exert a protective effect against APAP-induced acute liver injury by reshaping the liver metabolic profile and modulating the gut microbiota., 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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

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.)

This study presents a comprehensive methodology for the synthesis, characterization, and evaluation of selenium nanoparticles (SeNPs) for their anthelmintic properties against Trichinella spiralis. SeNPs were synthesized via a chemical reduction method, with a color change from clear white to brownish-red indicating nanoparticle formation. X-ray diffraction (XRD) analysis revealed broad peaks at 2θ ranges of 20-33° and 48-58°, confirming the semi-crystalline nature of the nanoparticles. UV-Vis absorption spectroscopy identified a characteristic peak at around 295 nm. High-resolution transmission electron microscopy (HRTEM) showed spherical, monodispersed SeNPs with smooth surfaces, ranging from 30 to 106 nm in size, with an average diameter of 69 nm. Forty-two male rats were divided into six groups, including healthy controls and T. spiralis-infected rats treated with varying doses of SeNPs. Body and organ weight indexes were assessed at the start, during the intestinal and muscular phases. Significant body weight increases were observed during the intestinal phase, particularly in the positive control group. Organ weight analysis showed a significant decrease in liver weight in the high-dose SeNP group compared to controls. SeNP treatment significantly reduced the number of adult worms in the intestines and encysted larvae in muscles. The high-dose group reduced adult worms and encysted larvae more than the low-dose group. Scanning electron microscopy (SEM) revealed morphological alterations in adult T. spiralis worms, including wrinkled architecture, torn cuticles, and severe sloughing in high-dose treated worms. During the muscular phase, significant decreases in hemoglobin and red blood cell count were observed in the positive control group, while SeNP treatment restored these levels. Liver enzyme activities (AST, ALT, and ALP) were elevated in infected untreated groups but were enhanced with SeNP treatment. Antioxidant enzyme activities (CAT, and SOD) increased in SeNP-treated groups, with higher doses showing greater efficacy in reducing oxidative stress markers (MDA) and inflammatory markers (TNF-α, and IL-6). Histological analysis showed significant restoration of normal intestinal architecture in high-dose SeNP-treated infected rats, including the reduction of villus atrophy and leukocyte infiltration. In diaphragm muscles, high-dose SeNP treatment minimized encysted larval deposition and restored normal muscle architecture. We can conclude that the study demonstrates the potential of SeNPs as an effective anthelmintic agent against T. spiralis, highlighting their synthesis, characterization, and therapeutic efficacy., 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.)

This study investigates whether Cerastes cerastes venom (CCV) administrated at different doses (3 and 6μg/mouse) and times (a week pre-infection, the first week post-infection, and the fifth week post-infection) possesses antischistosomal activity on Schistosoma mansoni infected mice. The results showed that treatment with half lethal dose (6 μg/mouse) of CCV, at various time schedules, led to a significant decrease in the total worm burden. However, quarter lethal dose (3μg/mouse) of CCV showed a significant decrease in the total worm burden only when administered a week pre-infection. The total number of deposited eggs by females of S. mansoni was significantly decreased in the liver and the intestine of mice treated with 3μg/mouse or 6μg/mouse CCV, associated with significant alterations in the oogram pattern with significant elevation in dead eggs levels and significant decrease in the number of mature eggs. Histological examinations illustrated a significant decrease in the number and diameter of hepatic granulomas in high dose (6μg/mouse) CCV-treated groups, while it was significant only a week pre-infection in low dose (3μg/mouse) CCV-treated groups. CCV also caused several tegumental changes in treated female and male worms, including loss of the normal surface architecture, tubercular destruction, loss of tubercles' spines, oedema, erosion, membrane blebbing, and swelling. S. mansoni-infected mice groups treated with CCV (6μg/mouse) a week before infection and at fifth week post-infection had, in all individuals up to a dilution of 1:1600, higher levels of antibodies against adult worm antigen. The current investigation found that C. cerastes venom has potential antischistosomal action in a time and dose-dependent manner (more enhanced antischistosomal effects at a dose of 6 μg and in the group treated in a week before infection), in addition to its potential immunomodulatory effect against schistosomiasis infection. More studies will be required to identify the venom's active ingredients that affect the host's immunology. This information could be used in the future to develop novel antischistosomal therapies., 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 Inc.)

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.)