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The paper highlights how significant characteristics of liver can be modeled in tissue-engineered constructs using unconventional scaffolds. Hepatic lobular organization and metabolic zonation can be mimicked with decellularized plant structures with vasculature resembling a native-hepatic lobule vascular arrangement or silk blend scaffolds meticulously designed for guided cellular arrangement as hepatic patches or metabolic activities. The functionality of hepatocytes can be enhanced and maintained for long periods in naturally fibrous structures paving way for bioartificial liver development. The phase I enzymatic activity in hepatic models can be raised exploiting the microfibrillar structure of paper to allow cellular stacking creating hypoxic conditions to induce in vivo -like xenobiotic metabolism. Lastly, the paper introduces amalgamation of carbon-based nanomaterials into existing scaffolds in liver tissue engineering.

Development of cheap and portable 3D liver models is a need of an hour for drug screening applications in the healthcare and diagnostic sector. An appropriate 3D liver model would support adhesion, proliferation, viability and functionality of the liver cells. With this perspective, the present study delineates the fabrication and characterization of PAMAM conjugated cellulose filter paper-based 3D liver model. Due to the absence of any cell adhesion motif, paper cannot directly be used for cell culture applications, thus, it was functionalized with PAMAM dendrimer using glutaraldehyde. PAMAM derivatized paper (PF) supported significantly higher adhesion, proliferation, and viability of the HepG2 cells in comparison to non-functionalized paper. Moreover, HepG2 cells maintained their functional aspects i.e., expression of mature hepatocyte markers albumin, CK19, CYP3 A4, MDR1 and SULT2 A1 on PF. Further, we showed the application of the PF-based 3D liver model for drug toxicity evaluations against hepatotoxins. The results showed a significantly higher sensitivity of the HepG2 cells in paper-based 3D culture as compared to 2D monolayer culture, which is similar to that of physiological drug-induced responses. In conclusion, PAMAM functionalized filter paper could serve as an efficient biomaterial platform for the development of microscale technologies, liver-associated diagnostics, and drug screening applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Histopathologic evaluation of liver biopsy has played a longstanding role in the diagnosis and management of liver disease. However, the utility of liver biopsy has been questioned by some, given the improved imaging modalities, increased availability of noninvasive serologic tests, and development of artificial intelligence over the past several years. In this review, we discuss the current and future role of liver biopsy in both non-neoplastic and neoplastic liver diseases in the era of improved noninvasive laboratory, radiologic, and digital technologies., (Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

This study investigates whether pulse exposure to Chilean pulp and paper mill effluent solid phase extracted (SPE) extracts via intraperitoneal injection (IP), would result in changes in the activities of the respiratory metabolic enzymes citrate synthase (CS) and lactate dehydrogenase (LDH) in rainbow trout livers. It also investigated if an alteration in liver metabolic capacity influenced the liver detoxification processes and estrogenic effects previously reported. Besides, a comparison of those enzymatic activities with fish IP injected with SPE extracts of two model effluents coming from industries that process 100% different type of feedstock (softwood, SW and hardwood, HW) was also evaluated. An initial induction of the anaerobic metabolism (increase in LDH enzymatic activity) was detected in all Chilean pulp mill effluent extracts evaluated, contrary to the initial unaltered aerobic metabolism (CS enzymatic activity) observed. A compensatory relationship in energy metabolism (Pasteur effect) was observed when comparing both enzymatic activities of fish exposed to those effluent extracts. LDH and CS activities observed in fish injected with Chilean extracts seem to be related to the effects observed in fish injected with SW extracts. This study showed that intraperitoneal injection of pulp and paper mill effluent extracts affected the anaerobic and aerobic metabolic capacities in rainbow trout livers, but this metabolic alteration did not affect detoxification capability or estrogenic effect previously reported., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Wood extractives present in pulp and paper mill effluents may cause reproductive disturbances in fish. A chronic-exposure toxicity experiment using immature rainbow trout (Oncorhynchus mykiss) was conducted in order to assess the endocrine disrupting effects of two Chilean pulp and paper mill specific extracts (solid phase extraction, SPE) obtained from primary and secondary treated effluents. The (anti)estrogenic potencies and toxicity of the wood extractives regularly present in pulp mill effluent such as dehydroabietic acid (DHAA), beta-sitosterol (BS), and model estrogen 17beta-estradiol (E2) were evaluated by analysis of plasma vitellogenin (VTG) levels, gonadal somatic index (GSI) and liver ethoxyresorufin-O-deethylase (EROD) activity, respectively. The protocol involved the use of multiple intra-peritoneal injections (1 injection every 7 days for a total exposure period of 28 days). Analysis of variance/covariance, demonstrated no differences associated with fish gender other than GSI. The phytosterol BS, E2 and both pulp mill effluent extracts showed significant inductions of EROD and increased VTG levels after 4, 7, 14, 21 and 28 of exposure. While fish injected with secondary treated effluent extract showed a delayed induction in VTG levels compared to primary effluent injected fish, no effects on VTG and EROD levels were observed in DHAA injected fish. Moreover simultaneous injection of DHAA+E2 reduced the VTG levels found in E2 injected fish, indicating a potential indirect anti-estrogenic effect of this resin acid. The results of this study indicate that Chilean pulp and paper mill effluent extracts are estrogenic in rainbow trout males and females., ((c) 2010 Elsevier B.V. All rights reserved.)

Lentiviral vectors (LV) are efficient vehicles for in vivo gene delivery to the liver. LV integration into the chromatin of target cells ensures their transmission upon proliferation, thus allowing potentially life-long gene therapy following a single administration, even to young individuals. The glycoprotein of the vesicular stomatitis virus (VSV.G) is widely used to pseudotype LV, as it confers broad tropism and high stability. The baculovirus-derived GP64 envelope protein has been proposed as an alternative for in vivo liver-directed gene therapy. Here, we perform a detailed comparison of VSV.G- and GP64-pseudotyped LV in vitro and in vivo. We report that VSV.G-LV transduced hepatocytes better than GP64-LV, however the latter showed improved transduction of liver sinusoidal endothelial cells (LSEC). Combining GP64-pseudotyping with the high surface content of the phagocytosis inhibitor CD47 further enhanced LSEC transduction. Coagulation factor VIII (FVIII), the gene mutated in hemophilia A, is naturally expressed by LSEC, thus we exploited GP64-LV to deliver a FVIII transgene under the control of the endogenous FVIII promoter and achieved therapeutic amounts of FVIII and correction of hemophilia A mice., (© 2024. The Author(s).)

Toxic effects of unbleached (sulfate or sulfite) and bleached (sulfate) paper mill effluents were studied in a primary culture of rainbow trout liver cells. The effluents and control water from a clean area were extracted with diethyl ether and added to the cultures dissolved in dimethyl sulfoxide. Plasma membrane integrity was studied by measuring lactate dehydrogenase (LDH) leakage. The cellular content of glutathione (GSH) was used as an indicator of oxidative stress and the formation of reactive intermediates. Dose-response studies indicated that unbleached effluents contained more potent toxic substances than bleached effluents. Both unbleached and bleached effluents contained organic diethyl ether-extractable substances which increased cytochrome P450-dependent 7-ethoxyresorufin-O-deethylase (EROD) activities. The inducing effects were seen at concentrations substantially lower than those decreasing GSH content and increasing LDH leakage. Possible EROD inducing substances in bleached effluents are chlorinated organic compounds. Inducing compounds in unbleached effluents are yet to be identified. Furthermore, at higher concentrations the effluents contained substances that inhibited the cytochrome P450 system. The results show that the trout primary hepatocyte cultures afford a convenient in vitro method for screening cytochrome P450 inducing components extracted from industrial effluents to investigate mechanisms by which wastewaters cause injury in cells.

Juvenile whitefish (Coregonus lavaretus L. s.l.) were exposed by caging in the field to diluted effluents from three operating pulp, paper, and paperboard mills in Southern Lake Saimaa, Finland. The expression of the vitellogenin gene, used as a biomarker of estrogenic contamination of effluents, was measured using a Northern blotting method. Increased mRNA levels, the most specific and reliable evidence for estrogen receptor-mediated actions in vivo, were found in fish caged in the vicinity of one of three mills studied. This mill was found to discharge wood-derived compounds, such as sterols and resin acids, into Lake Saimaa in amounts considerably exceeding those from the other two mills. The increased vitellogenin gene expression suggests that the effluent is a source of estrogenic contaminants., (Copyright 1999 Academic Press.)

Many studies link pulp and paper mill effluent (PPME) exposure to adverse effects in fish populations present in the mill receiving environments. These impacts are often characteristic of endocrine disruption and may include impaired reproduction, development and survival. While these physiological endpoints are well-characterized, the molecular mechanisms causing them are not yet understood. To investigate changes in gene transcription induced by exposure to a PPME at several stages of treatment, male and female fathead minnows (FHMs) were exposed for 6 days to 25% (v/v) secondary (biologically) treated kraft effluent (TK) or 100% (v/v) combined mill outfall (CMO) from a mill producing both kraft pulp and newsprint. The gene expression changes in the livers of these fish were analyzed using a 22K oligonucleotide microarray. Exposure to TK or CMO resulted in significant changes in the expression levels of 105 and 238 targets in male FHMs and 296 and 133 targets in females, respectively. Targets were then functionally analyzed using gene ontology tools to identify the biological processes in fish hepatocytes that were affected by exposure to PPME after its secondary treatment. Proteolysis was affected in female FHMs exposed to both TK and CMO. In male FHMs, no processes were affected by TK exposure, while sterol, isoprenoid, steroid and cholesterol biosynthesis and electron transport were up-regulated by CMO exposure. The results presented in this study indicate that short-term exposure to PPMEs affects the expression of reproduction-related genes in the livers of both male and female FHMs, and that secondary treatment of PPMEs may not neutralize all of their metabolic effects in fish. Gene ontology analysis of microarray data may enable identification of biological processes altered by toxicant exposure and thus provide an additional tool for monitoring the impact of PPMEs on fish populations., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The feasibility of using liver impressions on Flinders Technology Associates (FTA filter paper for the collection, inactivation, and molecular analysis of fowl adenovirus (FAV) was evaluated. FAV I European Union (EU) serotype 1 spotted on FTA was shown to be inactivated using specific-pathogen-free (SPF) primary chicken embryo liver cell culture as indicated by absence of cytopathic effect. Sensitivity of the polymerase chain reaction (PCR) test using tenfold dilutions of allantoic fluid from 100 to 10-4 for the detection of adenovirus serotype 1 on FTA cards was determined to be 0.0005 mean tissue culture infectious dose per FTA spot. The stability of the DNA from liver impressions on the FTA was found to be 198 days when stored at -20 degrees C. In a trial, inclusion body hepatitis (IBH) was experimentally reproduced in SPF chickens inoculated with FAV I EU serogroup 1, 4, 8, or 11, which presented weakness, pallor, depression, dehydration, and mortality within 6 days after inoculation. PCR performed on FTA liver impressions from the inoculated birds was able to detect all four viruses, and the nucleotide sequence analysis of the amplified PCR products (1219 bp of the hexone gene) revealed the expected serotypes. In addition to the trial, 55 clinical samples were analyzed from liver impressions on FTA cards, and FAV was detected in 11 of 55 (20%). Sequencing analysis showed that the viruses were EU serotypes 4, 5, 9, and 10. The results demonstrate that FTA filter paper inactivates the FAV I and maintains the DNA template for molecular analysis.

The studies were performed on perch (Perca fluviatilis) caught outside Husum and Iggesund kraft pulp mills in 1985 and 1987, respectively, and the results were compared to previous observations from 1984 to 1985 in the receiving waters of the Norrsundet kraft pulp mill. The studies revealed that the biochemical and physiological variables, i.e., EROD activity, gonad size, number of lymphocytes, carbohydrate metabolites, and plasma ion composition, can be used as sensitive and reliable indicators of toxic effects on natural populations of fish exposed to conventional chlorine-bleached kraft mill effluents. However; the effects were generally less pronounced and indicated less geographic extension than those seen in perch previously investigated in the receiving waters of the Norrsundet kraft pulp mill. Based on these studies on perch at Husum and Iggesund and the previous studies at Norrsundet it can be concluded that the chlorine-bleached kraft mill effluents cause serious disturbances to vital biochemical and physiological functions, which can affect the health status and presumably also the survival of the fish. Finally, the responses do not reflect the present situation in the receiving waters since all three mills have taken extensive measures for process alterations and discharge reductions after the time of the investigations.

Adult eels (Anguilla anguilla L.) were exposed for 8, 16, 24, and 72 h to 0, 0.1, 0.3, 0.9, and 2.7 microM abietic acid (AA). Genotoxicity was measured as erythrocytic nuclear abnormalities (ENA), as well as DNA strand breaks in blood and liver. Liver cytochrome P450 (P450) content, liver ethoxyresorufin O-deethylase (EROD), and glutathione S-transferase (GST) activities were determined as biotransformation biomarkers. Liver alanine transaminase (ALT) activity was also measured as an indication of tissue damage. Low AA concentrations, such as 0.1 and 0.3 microM, result in a delayed induction of A. anguilla L. liver EROD activity, whereas the higher AA concentration (2.7 microM AA) also has a delayed effect probably as a consequence of liver tissue high inhibitory concentration. The current eel liver GST activity results demonstrate that only low AA concentrations promote liver increases in GST, whereas high AA concentrations, such as 0.9 and 2.7 microM, do not alter it. The results concerning eel liver ALT activity indicate that significant liver damage is induced by high AA concentrations, such as 2.7 and 0.9 microM. The eel ENA result analysis reveals that AA is a weak ENA inducer in A. anguilla L. Blood DNA integrity results suggest that low AA concentrations promote late decreases in blood DNA integrity; nevertheless, high AA concentrations are early blood genotoxic inducers compared with low AA doses. According to the present research results with respect to eel liver DNA damage, all of the AA exposure concentrations decreased liver DNA integrity.

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.

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%.

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.

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.

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.)

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.)

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.)

Rainbow trout (Salmo gairdneri) were exposed for 10 and 30 days to microbiologically treated effluent of a bleached kraft pulp and paper mill (BKME). Throughout the experiments, the quality of dilution water, taken from an upstream location close to the mill, was allowed to vary both diurnally and seasonally (September-October) in a natural manner. The test concentrations averaged 0 (control), 0.6, 1.2, 2.0, and 5.1% (v/v) of BKME. Conjugates of all major resin acids and chlorinated phenolics of BKME, except chlorocatechols, were detected in trout bile. They comprised 93.1-99.9% of the total amounts in the bile. The level of conjugated resin acids increased linearly with the content of BKME in test water. On the other hand, no increase in concentration of conjugated phenolics was seen above 2.0% BKME. In the blood plasma no conjugates were analyzable. Concentrations of free resin acids in the blood plasma, but not in the bile, significantly increased at high test concentrations of BKME. No active excretion of free resin acids from plasma to bile can be inferred, but some of the phenolics--particularly 3,4,5,6-tetrachloroguaiacol--seem to be concentrated in the bile as a free compound. Changes in several biochemical parameters did not display any simple relationship with the external concentrations of BKME. In intermediate exposure concentrations, however, liver RNA and protein concentrations were decreased after 10 days but increased after 30 days. Condition of fish, relative size of the liver, and concentrations of liver glycogen and water were unresponsive to BKME at the dilutions investigated.

In a laboratory investigation, fourhorn sculpin (Myoxocephalus quadricornis) were exposed for 5-9 months to waste water from pine and birch lines from a bleached kraft pulp plant. The bleached kraft mill effluents (BKME) affected both the carbohydrate metabolism and the xenobiotic metabolism. Thus, an elevated muscle glycogen content in fish exposed to effluent from the pine pulp line suggests a metabolic imbalance. A liver enlargement and a strong elevation of the hepatic cytochrome P-450-dependent ethoxyresorufin-O-deethylase activity after exposure to the bleached pine pulp effluents indicate the presence of cytochrome P-450-inducing agents in the BKME. The results also demonstrate that many physiological test parameters may be used as good indicators of sublethal disturbances in fish to BKME exposure.

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 (

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.)

Introduction: Epidemiological studies highlight the presence of associations between per- and polyfluoroalkyl substances (PFAS) exposure with liver damage. In 2013, PFAS contamination was discovered in Veneto (Italy), leading to the implementation of a Surveillance Program (SP). Our objective is to investigate the association between PFAS exposure and biomarkers of liver function using single-pollutant and mixture approaches, while exploring the sex-specific differences and the mediating role of obesity in the association., Methods: The study included 42,094 subjects aged ≥20 years participating in the SP. We used generalized additive models to investigate the association between several PFAS and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, adjusting for possible confounders and stratifying by sex. Results were back-transformed to show predicted percentage changes in outcomes per ln-unit increase in PFAS levels; furthermore, we explored the role of BMI in the abovementioned causal pathway, considering it as a potential confounder or mediator PFAS joint effect was investigated using Quantile G-computation., Results: One ln-unit increase in PFHxS concentrations was associated with a 1.49% (95%CI: 0.87, 2.12) and a 0.84% (95% CI: 0.27, 1.40) increase in ALT levels, in males and females respectively; one ln-unit increase in PFOA concentrations was associated with a 1.03% (95%CI: 0.50, 1.55) increase in ALT levels in males, and a 0.52% (95% CI: 0.22, 0.82) and a 0.60% (95% CI: 0.25, 0.96) increase in AST levels in females and males. PFOS showed no association with ALT and AST levels. Quantile G-computation revealed that an interquartile increase in the PFAS mixture was associated with a 3.02% increase (95% CI: 1.65, 4.43) and a 1.65% (95% CI: 0.77, 2.5) increase in ALT levels, in females and males. Mediation analysis suggested that BMI suppressed the association between PFAS and ALT levels, with positive direct effects higher than the total effects., Conclusion: Our findings suggest sex-specific associations between PFAS exposure and liver function biomarkers and underscore the need for additional studies on potential mediators., 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.)

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.)

Synthetic fabrics, especially polyester, are a primary source of microplastic fibers (MFs), but there is limited data on their accumulation and dose related health impact in living organisms. This study examined the effects of ingested polyester microfibers (PE-MFs) on hematology, histopathology, and serum biochemistry in albino mice. Mice were given varying doses of PE-MFs (100, 200, 400 and 800 μg/d/mice) for a duration of thirty-five days and a notable decreases in certain hematological parameters such as RBCs, Hb, and platelets, and increases in MCV and MCH was noted at (p < 0.05) thereby indicating possible inflammatory response within the body resulting from ingestion of these MFs. Liver enzymes (ALT, AST, and alkaline phosphatase) and histopathological changes in the liver and gastrointestinal tract also exhibited significant variations, with higher levels seen in the group receiving the highest dose of PE-MFs (800 μg/d/mice). In summary, increased exposure to PE-MFs led to a dose-related impact and notable alterations in histopathological, hematological, and serum biomarkers in albino mice. This study highlights the potential hazards associated with dietary exposure to PE-MFs in mammals and emphasizes the need for further research in this field., 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.)

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.)

Objective: Studies have shown that fine particulate matter (PM 2.5 ) has adverse effects on the liver function, but epidemiological evidence is limited, especially regarding pregnant women. This study aims to investigate the association between PM 2.5 exposure in early pregnancy and maternal liver function during pregnancy., Methods: This retrospective cohort study included 13,342 pregnant participants. PM 2.5 and Ozone (O 3 ) exposure level, mean temperature, and relative humidity for each participant were assessed according to their residential address. The levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) were measured during the second and third trimesters. Data on PM 2.5 and O 3 exposure level were sourced from Tracking Air Pollution in China (TAP), while the mean temperature and relative humidity were obtained from the ERA5 dataset. The Generalized Additive Model (GAM) was used to analyze the associations between PM 2.5 exposure and maternal liver function during pregnancy, adjusting for potential confounding factors., Results: According to the results, each 10 μg/m 3 increase in PM 2.5 was associated with an increase of 3.57% (95% CI: 0.29%, 6.96%) in ALT and 4.25% (95% CI: 2.33%, 6.21%) in TBIL during the second trimester and 4.51% (95% CI: 2.59%, 6.47%) in TBIL during the third trimester, respectively. After adjusting for O 3 , these associations remained significant, and the effect of PM 2.5 on ALT during the second trimester was further strengthened. No significant association observed between PM 2.5 and AST., Conclusions: PM 2.5 exposure in early pregnancy is associated with increasement of maternal ALT and TBIL, suggesting that PM 2.5 exposure may have an adverse effect on maternal liver function. Although this finding indicates an association between PM 2.5 exposure and maternal liver function, more research is needed to confirm our findings and explore the underlying biological mechanisms., 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.)

This study assessed the concentrations and temporal trends of perfluorinated compounds (PFCs) in the muscle and liver tissues of Baltic cod (Gadus morhua) from 2017 to 2023. The Environmental Quality Standard (EQS) for biota and the Estimated Weekly Intake (EWI) for human consumers were calculated to evaluate potential health risks associated with PFC exposure. Significant variations in PFC concentrations were observed across different compounds and sampling years. Perfluorooctanoic acid (PFOA) had a mean concentration ranging from 0.03 ng g⁻ 1 wet weight (ww) to 0.17 ng g⁻ 1 ww (mean: 0.093 ng g⁻ 1 ww), while perfluorononanoic acid (PFNA) ranged from 0.05 ng g⁻ 1 ww to 0.97 ng g⁻ 1 ww (mean: 0.46 ng g⁻ 1 ww). Perfluorooctane sulfonate (PFOS) demonstrated mean concentrations between 1.98 ng g⁻ 1 ww and 9.03 ng g⁻ 1 ww (mean: 4.78 ng g⁻ 1 ww). PFOSA exhibited the lowest liver sequestration factor, indicating a higher elimination potential. The EQS for biota, expressed in PFOA-equivalents, ranged from 9.36 ng g⁻ 1 ww to 28.5 ng g⁻ 1 ww (mean: 18.5 ng g⁻ 1 ww), showing an overall increasing trend over the study period. The EWI for Baltic cod muscle (ΣPFAS-4) indicated an average exposure of 1.84 ng kg⁻ 1 body weight (bw) per week for adults, with a maximum of 3.46 ng kg⁻ 1 bw per week. For cod liver consumers, the maximum exposure reached 6.45 ng kg⁻ 1 bw per week, exceeding the Tolerable Weekly Intake (TWI) in some cases. The rising PFC concentrations in Baltic cod, especially in liver tissues, pose health risks to consumers. Ongoing monitoring and risk assessments are essential to reduce the impacts of PFC exposure from seafood., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Lidia Wolska reports financial support was provided by Medical University of Gdansk Department of Environmental Toxicology. 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 Inc. All rights reserved.)

The charring tissue generated by the high temperature during microwave ablation can affect the therapeutic effect, such as limiting the volume of the coagulation zone and causing rejection. This paper aimed to prevent tissue carbonization while delivering an appropriate thermal dose for effective ablations by employing a treatment protocol with real-time bioelectrical impedance monitoring. Firstly, the current field response under different microwave ablation statuses is analyzed based on finite element simulation. Next, the change of impedance measured by the electrodes is correlated with the physical state of the ablated tissue, and a microwave ablation carbonization control protocol based on real-time electrical impedance monitoring was established. The finite element simulation results show that the dielectric properties of biological tissues changed dynamically during the ablation process. Finally, the relative change rule of the electrical impedance magnitude of the ex vivo porcine liver throughout the entire MWA process and the reduction of the central zone carbonization were obtained by the MWA experiment. Charring tissue was eliminated without water cooling at 40 W and significantly reduced at 50 W and 60 W. The carbonization during MWA can be reduced according to the changes in tissue electrical impedance to optimize microwave thermal ablation efficacy., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Additional information: None of the experiments were performed on in vivo animals. All ex vivo porcine liver was chosen as the material for the experiment. Fresh ex vivo porcine liver was obtained from the local slaughterhouse and used the same day., (© 2024. The Author(s).)

Cell-laden bioprinting is a promising biofabrication strategy for regenerating bioactive transplants to address organ donor shortages. However, there has been little success in reproducing transplantable artificial organs with multiple distinctive cell types and physiologically relevant architecture. In this study, an omnidirectional printing embedded network (OPEN) is presented as a support medium for embedded 3D printing. The medium is state-of-the-art due to its one-step preparation, fast removal, and versatile ink compatibility. To test the feasibility of OPEN, exceptional primary mouse hepatocytes (PMHs) and endothelial cell line-C166, were used to print hepatospheroid-encapsulated-artificial livers (HEALs) with vein structures following predesigned anatomy-based printing paths in OPEN. PMHs self-organized into hepatocyte spheroids within the ink matrix, whereas the entire cross-linked structure remained intact for a minimum of ten days of cultivation. Cultivated HEALs maintained mature hepatic functions and marker gene expression at a higher level than conventional 2D and 3D conditions in vitro. HEALs with C166-laden vein structures promoted endogenous neovascularization in vivo compared with hepatospheroid-only liver prints within two weeks of transplantation. Collectively, the proposed platform enables the manufacture of bioactive tissues or organs resembling anatomical architecture, and has broad implications for liver function replacement in clinical applications., 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 Ltd.. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases accompanied by lipid and glucose metabolism disorder. Didymin has been reported to have various hepatoprotective effects, however, its potential effects and mechanisms on NAFLD remain unclear from the perspective of the whole., Purpose: To investigate the underlying mechanism of didymin against NAFLD using multi-omics technologies., Methods: Rats were fed with a high-fat diet (HFD) for 8 weeks to induce NAFLD, followed by didymin treatment for 8 weeks. Next, biochemical analysis and histopathological examinations were performed to evaluate the effects of didymin. The key regulating pathways were predicted using transcriptomics, metabolomics and proteomics, and the target pathways were then verified by detecting the key genes/proteins using various experiments., Results: Didymin markedly mitigated liver injury and excessive lipid droplet accretion. An integrative multi-omics analysis suggested that the PPAR signaling cascade and insulin signaling pathway might serve as pivotal mechanisms underlying the modulation of lipid and glucose homeostasis by didymin. Further dissection identified five pivotal genes (PPARα, PPARβ, FABP4, ANGPTL4, and PLIN2) and four genes (HK1, HK3, GCK, and PTPN1) as potential hubs within these pathways. Subsequent validation experiments, including qPCR and Western blot, demonstrated upregulated expression of PPARα and PPARβ, indicating the activation of the PPAR pathway by didymin. Concurrently, didymin appeared to modulate the insulin signaling pathway, as evidenced by the upregulated expression of HK1 and downregulated expression of PTPN1. Notably, the manipulation of PPARα, PPARβ, and PTPN1 expression in LO2 cells through silence or overexpression confirmed that didymin significantly reduced lipid accumulation, with its molecular targets likely being the PPAR and insulin pathways., Conclusions: Our findings demonstrate that didymin has a protective effect on NAFLD, and its underlying mechanism may be associated with the regulation of the PPAR and insulin signaling pathways., 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 GmbH. All rights reserved.)

The occurrence of heat stress in poultry houses is inevitable and leads to oxidative stress in the birds. Lycopene, a natural hydrocarbon carotenoid, possesses potent antioxidant properties. This study aimed to investigate the impact of lycopene on growth performance, meat quality, cecal microflora, and liver metabolome in broilers subjected to heat stress. A total of 480 yellow feather broilers were randomly allocated into 4 treatment groups: birds fed standard diet (Con), birds fed standard diet and supplemented with lycopene (Lyc), birds fed standard diet and subjected to heat stress (Hs), and birds fed with lycopene and subjected to heat stress (Hs-Lyc). As compared with the normal temperature groups, Hs decreased the average daily gain (ADG) of birds during d 1 to 28, lowered the pH value either in breast meat or thigh meat, increased the L* value of breast meat, and decreased the a* value of thigh meat. In comparison with non-Lyc feeding birds, Lyc supplement elevated the ADG during d 1 to 56, increased the pH of breast meat, decrease the L* and b* values of thigh meat, simultaneously increase the a* value of thigh meat. The L* of breast meat and pH of thigh meat exhibited significant differences under Hs-Lyc treatment. Lyc-treated birds exhibited higher elasticity, gumminess, and resilience in breast meat than those in non-Lyc feeding birds. The cecal metagenome analysis indicated that Hs-Lyc treatment increased the abundance of Phocaeicola salanitronis and Prevotella sp.CAG:1058, Bacteroides sp.An269, and Bacteroides sp.An19 at the species level compared with other treatments. The hepatic untargeted metabolome analysis showed that administration of Lyc upregulated 20 metabolites and downregulated 60 metabolites compared to the Con birds. Futhermore, the Hs-Lyc treatment upregulated 34 metabolites and downregulated 45 metabolites compared to the Hs birds. The correlation between the metagenome and metabolome showed that Lyc supplementation induced significant alterations in the citrate cycle, metabolism of butanoate, glycolysis/gluconeogenesis, glyoxylate and dicarboxylate, alanine, aspartate, and glutamate compared with standard supplement. In contrast, Hs-Lyc treatment induced alterations in the citrate cycle, metabolism of pyruvate, glyoxylate, and dicarboxylate, glycolysis/gluconeogenesis, arginine, proline, alanine, aspartate, and glutamate compared with the standard supplement of heat-challenged broilers. In summary, dietary Lyc supplementation promoted the growth performance, changed the meat quality, modulated the cecal metagenome and hepatic metabolome in heat-stressed broilers., Competing Interests: DISCLOSURES 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.)

Background: The hepatotoxicity induced by acetaminophen (APAP), a commonly used antipyretic, analgesic and anti-inflammatory drug in clinical practice, has received accumulated attention. Artemisia argyi essential oil (AAEO), a volatile oil component extracted from traditional Chinese medicine Artemisia argyi H.Lév. & Vaniot, has great hepatoprotective effects. However, the potential role of AAEO in APAP-induced hepatotoxicity has not been characterized. The present study aimed to investigate the effects of AAEO on hepatic metabolic changes in mice exposed to APAP., Methods: In this study, 300.00 mg/kg acetaminophen was used to establish liver injury model in C57BL/6 J mice. Hepatoprotective effect of AAEO on APAP-induced hepatotoxicity in mice was investigated by detecting liver function enzymes and histopathological examination. Secondly, UPLC-MS/MS was used to analyze the to analyze the small molecule metabolites and metabolic pathways induced by AAEO treatment; In addition, the effect of AAEO on APAP-induced oxidative stress and inflammation were evaluated by detecting the levels of glutathione peroxidase 4, malondialdehyde, reactive oxygen species and inflammatory factors. Finally, the active components of AAEO were preliminarily screened by cellular assays. The hepatoprotective effect of AAEO against APAP-induced hepatotoxicity was examined through the Western blotting, after the CYP2E1 gene was knocked down in AML12 cells by siRNA transfection., Results: Compared with the APAP group, AAEO could reduce the abnormal increase in the levels of liver function enzymes caused by APAP. AAEO could enhance the antioxidant capacity by down-regulating the biosynthesis pathway of unsaturated fatty acids and promoting the activity of antioxidant enzymes SOD and CAT in liver tissue induced by APAP. Our study revealed that AAEO promoted GSH synthesis and covalently combined to form APAP-GSH conjugates to reduce the accumulation of APAP in liver tissue. In addition, the chemical constituents in AAEO were analyzed by GC-MS/MS, and it was determined to identify that dihydro-beta-ionone and (-)-verbenone in AAEO might have a significant protective effect on hepatocyte survival after APAP exposure. Further studies on the hepatoprotective mechanism of AAEO indicated that it might reduce the production of toxic metabolites by regulating CYP2E1 levels., Conclusion: AAEO exerted hepatoprotective effects on acetaminophen-induced hepatotoxicity in mice via regulating the activity of CYP2E1 and regulating the γ-glutamyl cycle pathway., Competing Interests: Declaration of competing interest All authors declare that they do not have any conflicts of interest regarding the publication of this paper. We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Experimental models of liver injury have been established utilizing thioacetamide (TAA), a classic liver toxic chemical that causes organ damage via oxidative stress and inflammatory induction. This study examined the impact of Febuxostat (a xanthine oxidase inhibitor; Febu, 10-15 mg/kg, orally) against TAA (500 mg/kg, i.p.) -induced liver injury in rats. Febu significantly attenuated TAA-induced alterations in liver function parameters, in addition to promoting hepatic antioxidant effects through a significant elevation of Heme-oxygenase-1(HO-1), nuclear factor erythroid 2-related factor2 (Nrf2), reduced glutathione (GSH) and superoxide dismutase (SOD) levels and reduction in hepatic malondialdehyde (MDA) content. Moreover, Febu improved the hepatic anti-inflammatory status by increasing the anti-inflammatory cytokine Interleukin (IL-10) level and reducing the levels of the pro-inflammatory cytokines (Nuclear factor kappa B (NF-κB), IL-1β, high-mobility group box1 (HMGB1), receptor for advanced glycation end products (RAGE), and toll-like receptor4 (TLR4) levels, in addition to suppressing the increased protein and mRNA expression levels of tumor necrosis factor alpha (TNF-α) and IL-6, hepatic expression of TNF-α and activated mitogen-activated protein kinases (p-JNK/p-p38 MAPK). Histopathologically, Febu markedly normalized TAA-induced alteration in liver sections. In conclusion, Febu, in a dose-dependent fashion, refines TAA-induced hepatotoxicity by enhancing antioxidant capabilities and decreasing inflammatory signals., 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.)

ADB-BUTINACA, as a new psychoactive substance, can induce physical and psychological dependence. However, the systemic biological impact of ADB-BUTINACA on hepatic metabolomics remains uncertain. The metabolic spectrum in rat livers following exposure to three varying doses of ADB-BUTINACA (0.1, 1, and 5 mg/kg·bw) were analyzed using ultra-high-performance liquid chromatography coupled with high-resolution quadrupole-orbitrap mass spectrometry and molecular docking techniques. Non-target metabolomic technology demonstrated that ADB-BUTINACA induced significant changes in 42 metabolites and disturbed 11 metabolic pathways especially the taurine and hypotaurine metabolism, β-alanine metabolism, and arachidonic acid metabolism, implicates the potential for ADB-BUTINACA to induce not merely cardiac dysfunction but also neurological anomalies. Molecular docking into the hepatotoxic targets of ADB-BUTINACA unveiled its potential for competitive binding with pantetheinase. This interaction may disrupt the coenzyme A (CoA) synthesis pathway, resulting in energy and lipid metabolism imbalances, and ultimately causing hepatotoxic effects. Cellular experiments confirmed reduced HepG2 cell viability and elevated reactive oxygen species (ROS) levels in HepG2 and Huh7 cells. These findings align with our metabolomic findings, supporting the hypothesis that ADB-BUTINACA induces hepatotoxicity via oxidative stress, as well as disruptions in energy and lipid metabolism. This work not only broadens the knowledge of ADB-BUTINACA' toxicological profile but also contributes to efforts aimed at diagnosing and preventing ADB-BUTINACA-induced hepatotoxicity., 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.)

Ambient fine particulate matter (PM 2.5 ) is a significant contributor to air pollution. PM 2.5 exposure poses a substantial hazard to public health. In recent years, the adverse effects of maternal PM 2.5 exposure on fetal health have gradually gained public attention. As the largest organ in the body, the liver has many metabolic and secretory functions. Liver development, as well as factors that interfere with its growth and function, are of concern. This review utilized the adverse outcome pathway (AOP) framework as the analytical approach to demonstrate the link between maternal PM 2.5 exposure and potential neonatal liver injury from the molecular to the population level. The excessive generation of reactive oxygen species (ROS), subsequent endoplasmic reticulum (ER) stress, and oxidative stress were regarded as the essential components in this framework, as they could trigger adverse developmental outcomes in the offspring through DNA damage, autophagy dysfunction, mitochondrial injury, and other pathways. To the best of our knowledge, this is the first article based on an AOP framework that elaborates on the influence of maternal exposure to PM 2.5 on liver injury occurrence and adverse effects on liver development in offspring. Therefore, this review offered mechanistic insights into the developmental toxicity of PM 2.5 in the liver, which provided a valuable basis for future studies and prevention strategies., 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.)

Liver ischemia-reperfusion (I/R) injury is a detrimental complication of organ transplantation, shock, and sepsis. However, the available drugs to mitigate I/R injury remain limited. Jujuboside A (JuA) is renowned for its antioxidant, anti-inflammatory, and anti-apoptotic properties; nevertheless, its potential in liver I/R injury remains unknown. Thus, this study aimed to explore the role and underlying mechanisms of JuA in liver I/R injury. Mouse models of I/R and AML12 cell models of hypoxia/reoxygenation (H/R) were constructed. Haematoxylin and eosin staining, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) detection, and cell viability analysis were used to assess liver injury. To evaluate oxidative stress, inflammation, apoptosis, and mitochondrial damage, immunofluorescence staining, transmission electron microscopy analysis, enzyme-linked immunosorbent assay, and flow cytometry were conducted. Moreover, molecular docking techniques and western blot were employed to identify downstream target molecules and pathways affected by JuA. The results showed that JuA pretreatment effectively attenuated liver necrosis and ALT and AST level elevations induced by I/R while enhancing AML12 cell viability following H/R. Furthermore, JuA pretreatment suppressed oxidative stress triggered by I/R and H/R, thereby inhibiting the level of pro-inflammatory factors and NLRP3 inflammasome activation. Notably, JuA pretreatment alleviated mitochondrial damage and apoptosis. Mechanistically, JuA pretreatment resulted in the activation of the AKT/NRF2/HO-1 signalling pathways, whereas MK2206, the inhibitor of AKT, partially reversed the hepatoprotective effects of JuA during liver I/R. Collectively, our findings illustrated that JuA mitigated oxidative stress, inflammation, apoptosis, and mitochondrial damage by facilitating the AKT/NRF2/HO-1 signalling pathway, thereby alleviating liver I/R injury., Competing Interests: Declaration of competing interest The authors declare no 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.)

Pollution is a major global concern affecting biodiversity, particularly of freshwater species. Populations have developed mechanisms to deal with pollution, such as the chemical defensome, which is a set of genes involved in maintaining internal stability. Pollution significantly affects the Maipo River basin in Chile. This area is home to the endemic silverside fish Basilichthys microlepidotus, whose populations are affected by pollution to different degrees. We assessed gene expression in the liver and gill of this species, focusing on whole-transcriptome and chemical-defensome levels, to identify both independent and shared mechanisms in response to pollution. The results showed that 14-18 genes were consistently expressed differently among populations in polluted areas. These genes were primarily involved in liver cell mitosis and in responses to organic chemicals and carcinogenic processes. Genes expressed differently in the gill were more abundant in immune system biological processes. All populations consistently downregulated chemical-defensome genes in the liver. In differentially expressed chemical-defensome genes, shared biological processes included virus response, cellular redox homeostasis and transport, organic cyclic compound response and DNA-templated transcription regulation. Studying chemical-defensome genes can help reveal common ways that pollution builds up over time, and examining the whole transcriptome can elucidate the context in which this response develops., 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.)