Flavobacterium columnare is an important pathogen causing columnaris disease, which can result in high mortality in freshwater fish worldwide. Understanding the immune response in infection status of fish may be essential for developing effective prevention and treatment strategies. In this study, transcriptomes of liver and head kidney tissues in grass carp (Ctenopharyngodon idella) were compared under symptomatic and asymptomatic statuses following the immersion infection of F. columnare. Significant differences in expression of genes were observed between fish showing disease symptoms and those without symptoms. The number of differentially expressed genes (DEGs) between infected and control groups ranged from 4752 to 8,277, while the DEGs between exposed and control groups ranged from 272 to 1,751, suggesting a strong acute inflammatory response in infected groups. KEGG pathway enrichment analysis of infected groups revealed that among the top 30 enriched pathways, liver and head kidney shared 22 and 16 common pathways, respectively. These common enriched pathways are involved in various functions such as metabolism, diseases, cellular processes, biological systems, and information processing, indicating their roles in the immune response to F. columnare. Notably, we investigated in detail the gene expression profiles associated with complement molecules and three classes of cytokines (interleukin, tumor necrosis factor, and interferon) in different organs/tissues and disease states during the pathogenesis of columnaris disease. The findings highlight the importance of inflammatory responses and complement pathways in the pathogenesis of columnaris disease and suggest potential targets for future research and disease management strategies. The present study thus provides valuable insights into the transcriptomic changes and immune responses in grass carp infected with F. columnare, and sheds light on how highly virulent strains of F. columnare cause morbidity and mortality in the host.

Methamphetamine (MA) dependence is associated with immunotoxicity and high rates of neuropsychiatric impairments that persist into remission. Although there are currently no FDA-approved pharmacotherapies for MA use disorders, preclinical and clinical studies are beginning to test interventions that directly impact immune signaling. This study was conducted to investigate the relative contribution of immune cell function to the neuropsychiatric sequelae associated with MA dependence and remission. Participants were enrolled into the following study groups: i) control (CTL) group (n = 62): adults with no lifetime history of dependence on any substance other than nicotine or caffeine; and ii) MA group (n = 98) [MA-remission group (n = 55): adults in remission ≥1 month and ≤ 6 months and MA-active group (n = 43): adults actively using MA and meeting criteria for MA dependence]. Participants completed a clinical interview, urine drug analysis, blood sample collection, and questionnaires. Peripheral blood mononuclear cells were analyzed by flow cytometry. Results suggest that early remission from MA dependence is associated with increased fatigue and persistent sleep and prospective and retrospective memory problems, along with reduced B and CD4+ T cell percentages, compared to the CTL group. Preliminary findings support the hypothesis that the immune system modulates the sleep impairments associated with drug actions and provide implications for future research studies and treatment approaches.

Mulberry-derived postbiotics (MDP) have demonstrated promising bioactive properties, including antioxidant and anti-inflammatory effects; however, their specific role in modulating gut inflammation and microbiota composition remains underexplored. Given the growing interest in functional food ingredients for gut health and managing inflammatory disorders, this study aims to evaluate the effects of MDP in alleviating intestinal inflammation and altering the gut microbiota in an LPS-induced mouse model of systemic inflammation. MDP administration significantly mitigated LPS-induced pathological changes in the intestine, liver, spleen, and kidneys, thereby improving systemic health and immune function. Histological analysis revealed reduced inflammation and tissue damage in the intestinal epithelium, supporting the potential of MDP to improve gut barrier integrity. An antioxidant assay revealed that MDP decreased the malonaldehyde (MDA) levels and increased the enzymatic activities of CAT, SOD, and GSH in response to LPS administration, indicating enhanced cellular antioxidant defenses. Inflammatory cytokine analysis showed that MDP downregulated proinflammatory markers such as TNF-α, IL-1β, IL-6, MYD88, Nrf2 COX-2, and HO1, while upregulating TLR4, resulting in potential anti-inflammatory effects by modulating the TLR4-NF-κb pathway. Moreover, MDP promoted beneficial alterations in gut microbiota composition by increasing the abundance of Firmicutes and Bacteroidetes, which are linked to gut health and inflammation regulation. The changes in gut microbiota composition suggest a potential mechanism by which MDP may help restore gut homeostasis and reduce systemic inflammation. These findings suggest that MDP may serve as promising functional food ingredients that support immune health, reduce inflammation, and promote gut microbiota balance, offering potential applications in fortified foods and nutraceuticals aimed at mitigating inflammatory and metabolic disorders.

Selenoprotein I (SELENOI) was known initially as ethanolamine phosphotransferase 1 (EPT1) and later as a selenoprotein. Because global knockout of Selenoi in mice is embryonically lethal, we generated liver-specific Selenoi knockout (cKO) mice to reveal functions and mechanism of SELENOI in the liver. Compared with control mice, cKO mice (8 weeks old) had no differences in body weight, glucose metabolism, energy expenditure, overall health status, or liver histology. However, these mice had lower (P < 0.05) mRNA levels of 13 selenoprotein genes, contents of Se, GSH, and T-AOC (12-40%), and activities of antioxidant enzymes (17-51%), but higher (P < 0.05) mRNA levels of oxidative stress-related genes (34%-46%) in the liver than the control mice. They had a higher (P < 0.05) ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) due to increases of the former and decreases of the latter, altered PE and PC constituents such as n-6/n-3 PUFA ratios, and elevated mRNA levels (95%-2-fold, P < 0.05) of lipolysis genes, compared with the control mice. The knockout attenuated hepatic injury and fibrosis induced by 14 intraperitoneal injections of CCl4 (0.5 mL/kg). The protection was associated with adaptive cytoprotective mechanisms induced by the overall decline of redox status mediated by SELENOI as a selenoprotein and activations of PPAR signaling, fatty acid desaturase 2 (FADS2), glutathione S-transferase, and lipid peroxide hydrolysis through modulating biosynthesis and(or) constituents of PC, PE, and n-6/n-3 PUFAs mediated by SELENOI as EPT1. Inhibition of FADS2 in CCl4-treated cKO hepatocytes partially removed the protection by the knockout. In conclusion, hepatic SELENOI expression was not essential for survival, but served as a multifunctional regulator of hepatic selenogenome expression, Se metabolism, redox status, biosyntheses and profiles of PC and PE, and resistance to CCI4.

Metabolic dysfunction-associated fatty liver disease (MAFLD) can progress to hepatocellular carcinoma (HCC), yet the immune mechanisms driving this transition remain unclear.

In a chronic Western diet (WD) mouse model, we performed single-nuclei RNA sequencing to track MAFLD progression into HCC and subsequent tumour inhibition upon dietary correction.

Carcinogenesis begins during MAFLD, with tumour cells entering dormancy when HCC is mitigated. Rather than purely tolerogenic, the liver actively engages immune responses targeting myofibroblasts, fibroblasts and hepatocytes to maintain tissue homeostasis. Cytotoxic cells contribute to the turnover of liver cells but do not primarily target the tumour. NKT cells predominate under chronic WD, while monocytes join them in HCC progression on a WD. Upon dietary correction, monocyte-driven immunity confers protection against HCC through targeting tissue homeostatic pathways and antioxidant mechanisms. Crucially, liver tissue response-not merely immune activation-dictates whether tumours grow or regress, emphasising the importance of restoring liver tissue integrity. Also, protection against HCC is linked to a distinct immunological pattern, differing from healthy controls, underscoring the need for immune reprogramming.

These findings reveal the dual roles of similar pathways, where immune patterns targeting different cells shape distinct outcomes. Restoring tissue homeostasis and regeneration creates a tumour-hostile microenvironment, whereas tumour-directed approaches fail to remodel the TME. This underscores the need for tissue remodelling strategies in cancer prevention and treatment.

Excess adiposity impairs immune function and host defense in obese individuals, but studies on this concept in fish remain limited. In aquaculture, rapid growth is often encouraged through intensive farming practices, leading to overfeeding and negatively impacting production. This study aimed to induce obesity in rainbow trout through overfeeding, exploring metabolic abnormalities, immune response alterations, and infection susceptibility via transcriptomic and metabolomic analyses. In the overfed group, fish were fed until they refused to eat, while the control group was fed according to recommended feeding rates for four weeks. Sampling was conducted at weeks 1, 2, and 4 for serological, histopathological, metabolomic, and transcriptomic analyses. After four weeks, mortality rates were compared following Aeromonas salmonicida challenge, and immunological changes assessed one day post-infection. Overfed fish exhibited significant increases in weight gain (WG), body mass index (BMI), elevated AST/ALT levels, hepatocyte hypertrophy, lipid droplet formation, and triglyceride accumulation. At 1, 2, and 4 wpf, the overfed group exhibited distinct metabolic changes, with key alterations in glycolysis/gluconeogenesis, lipid metabolism and amino acid metabolism. KEGG analysis of transcriptomic data revealed a significant decrease in complement and coagulation cascades, including C3, FB, FH, an FI, accompanied by heightened TNF and IL-17 signaling pathways, involving the upregulation of genes such as TNF-α, IL-1β, and IL-6, indicating an enhanced inflammatory response. The overfed group experienced higher mortality post-infection. Excess energy from overfeeding led to hepatic fat accumulation, liver damage, and reduced innate immune responses, particularly in complement activation. These physiological disruptions compromised immune function, highlighting the detrimental effects of overfeeding-induced obesity on fish health. This study offers critical insights into the immunological mechanisms linking obesity to increased disease susceptibility.

Overdosing on acetaminophen (APAP) is the primary cause of drug-induced liver injury. Recent studies have demonstrated that dysregulated lipid metabolism, particularly decreased fatty acid oxidation (FAO), is a key contributor to APAP-induced acute liver injury (AILI). OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1), a crucial member of the OTU deubiquitinase family, has been involved in the metabolic progression of multiple diseases. Nevertheless, its involvement in AILI as well as FAO remains unclear. Here, we aimed to elucidate the effects of OTUB1 on the regulation of FAO in AILI. Our investigation revealed decreased OTUB1 expression in AILI. OTUB1 overexpression not only alleviated liver injury but also improved FAO in vivo and in vitro. Conversely, opposite biochemical changes were observed in hepatocytes with OTUB1 knockdown. Mechanistically, long-chain acyl-CoA synthase 5 (ACSL5), which plays a crucial role in regulating FAO, was identified as a novel substrate of OTUB1 in AILI via mass spectrometry analysis. OTUB1 interacts with ACSL5 and promotes its deubiquitination and stability. Moreover, the protective effect of OTUB1 on FAO in AILI occurred via the deubiquitination of ACSL5. Overall, the present study revealed that the OTUB1-ACSL5 axis plays an essential role in regulating FAO during AILI progression and might be a novel target for therapeutic intervention.

Nonylphenol (NP), a typical nonionic surfactant intermediate, is widely found in aquatic environments and exhibits biological toxicity. In aquatic environments, organisms face risks from co-exposure to NPs and the heavy metal cadmium (Cd); however, the combined toxicity of both has not been well studied. Therefore, this study aimed to evaluate the histological changes, antioxidant capacity, inflammation, and transcriptional responses in the zebrafish liver following exposure to environmental concentrations of 4-n-NP (45.38 and 453.8 nM) and Cd (54.55 nM), both individually and in combination experiments, over 28 days. Our results indicated that the 453.8 nM 4-n-NP-treated group generated significant oxidative stress during the initial 12 days, while on day 28, the combination of high concentrations of 4-n-NP and Cd also produced significant oxidative stress. Additionally, we observed mitochondrial swelling and endoplasmic reticulum expansion in liver cells across the various treatment groups. Significant dehydration of hepatocyte nuclei was observed in the combined exposure group, along with the deformation of nucleoli and solidification of margins. Combined exposure had a synergistic effect and triggered liver injury in zebrafish. The LPS concentration significantly increased in the NlCl group but decreased in the NhCl group, while the total bile acids exhibited 2.14-fold and 1.24-fold increases, respectively. Combined exposure disrupted liver lipopolysaccharide and bile acids in zebrafish. Meanwhile, combined exposure to 453.8 nM 4-n-NP and Cd caused apoptosis and induced DNA damage repair mechanisms, amplifying the toxic effects of each pollutant. Thus, this study contributes to our understanding of the health risks to aquatic organisms from the co-existence of nonionic surfactants and heavy metals. CAPSULE ABSTRACT: We revealed the effects of single and combined exposure to nonylphenols and heavy metals on the zebrafish liver in terms of enzyme activity, inflammation, degree of cellular damage, and gene expression. The accumulation of cellular reactive oxygen species and the occurrence of lipid peroxidation induced more severe cellular structural and functional damage, amplifying the singular toxic effect of the pollutants. Combined exposure showed synergistic effects, inhibiting cell growth and inducing DNA damage repair.

Elevated heme levels, a consequence of hemolysis, are strongly associated with increased susceptibility to bacterial infections and adverse sepsis outcomes, particularly in older populations. However, the underlying mechanisms remain poorly understood. Using a cecal ligation and puncture (CLP) model of sepsis, we demonstrate that elevated heme levels correlate with Kupffer cell loss, increased bacterial burden, and heightened mortality. Mechanistically, we identify mitochondrial damage as a key driver of heme- and bacterial-induced Kupffer cell PANoptosis, a form of cell death integrating pyroptosis, apoptosis, and necroptosis, as well as cellular senescence. Specifically, heme activates phospholipase C gamma (PLC-γ), facilitating the translocation of cleaved gasdermin D (c-GSDMD) to mitochondria, resulting in GSDMD pore formation, mitochondrial dysfunction, and the release of mitochondrial DNA (mtDNA) during bacterial infection. This mitochondrial damage amplifies PANoptosis and triggers the cGAS-STING signaling pathway, further driving immune senescence. Notably, PLC-γ inhibition significantly reduces mitochondrial damage, cell death, and senescence caused by heme and bacterial infection. Furthermore, we show that hemopexin, a heme scavenger, effectively mitigates sepsis-induced Kupffer cell death and senescence, enhances bacterial clearance, and improves survival outcomes in both young and aged mice. These findings establish mitochondrial damage as a central mediator of heme induced Kupffer cell loss and highlight PLC-γ inhibition and hemopexin administration as promising therapeutic strategies for combating sepsis associated immune dysfunction.

Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8+ T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases.

Illegal melamine analogs are added to food to make it appear as though it contains more protein. These substances have negative impacts on both humans and animals in high quantities. The present paper examines how cobra venom shields rats from melamine-induced hepatotoxicity. The current study was conducted on six groups of adult male rats, as follows: group I (negative control): I.P. injected with distilled water, group II (SV10 μg/kg):I.P injected with 10 μg/kg cobra venom, group III (SV20 μg/kg): I.P. injected with 20 μg/kg cobra venom, group IV (melamine): orally 700 mg/kg melamine, group V (melamine + SV10 μg/kg): treated with 10 μg/kg cobra venom, group VI (melamine + SV20 μg/kg): treated with 20 μg/kg cobra venom. Treatment with snake venom ameliorated liver functions and increased apoptotic level marker Caspase-3, decreased anti-apoptotic level marker BAX. Also, decreased inflammatory level marker IL-2 and expression level of IL-10, INF-γ. treatment with snake venom ameliorated hepatotoxicity induced by melamine in albino rats.

Obesity induction in mice requires high-fat diet exposure. Although hepatic steatosis develops, progression to inflammation and fibrosis, as in humans, requires prolonged exposure and additional dietary factors. Immunosuppression at room temperature may slow this progression. We evaluated thermoneutrality's effect on metabolic dysfunction-associated steatohepatitis (MASH) development using a fibrosis-inducing MASH [Gubra-Amylin NASH (GAN)] diet. Mice were fed either a MASH or chow diet and housed at room temperature or thermoneutrality. MASH diet groups were euthanized monthly from 4 to 7 mo. Serum markers of hepatic function were analyzed, and liver histology assessed steatosis, inflammation, ballooning [nonalcoholic fatty liver disease activity score (NAS) score], and fibrosis via Picrosirius Red staining. MASH diet increased body weight, liver-to-body mass ratio, and hepatic fat, with no difference between housing conditions. Housing temperature had minimal effects on MASH. Serum markers and hepatic fibrosis were similar across groups. NAS score was lower at 4 mo in thermoneutral MASH mice but not by 7 mo. Thermoneutrality did not significantly impact MASH development. These findings, alongside existing literature, suggest thermoneutral housing does not consistently enhance MASH progression in GAN MASH-fed mice.NEW & NOTEWORTHY The development of MASH in mice-does housing temperature make a real difference?

Liver cancer is a leading cause of cancer-associated mortality and is often linked to preexisting liver conditions. Emerging research demonstrates FXR dysregulation, particularly its reduced expression, in the pathogenesis of liver diseases, including inflammation, fibrosis, cholestatic disorders, metabolic dysregulation, and liver cancer. Therefore, this review explores the role of FXR and its agonists in mitigating these conditions.

This article summarizes FXR's involvement in liver disorders, primarily emphasizing on hepatic neoplasms, and examines the potential of FXR agonists in restoring FXR activity in liver diseases, thereby preventing their progression to liver cancer. The information presented is drawn from existing preclinical and clinical studies specific to each liver disorder, sourced from PubMed.

It is well established that FXR expression is downregulated in liver disorders, contributing to disease progression. Notably, FXR agonists have demonstrated therapeutic potential in ameliorating liver diseases, including hepatocellular carcinoma. We believe that activating or restoring FXR expression with agonists offers significant promise for the treatment of liver cancer and other liver conditions. Therefore, FXR modulation by agonists, particularly in combination with other therapeutic agents, could lead to more targeted treatments, improving efficacy while reducing side effects.

The tolerogenic immune microenvironment of the liver (the immune system avoids attacking harmless antigens, such as antigens derived from food and gut microbiota) has garnered significant attention in recent years. Inherent immune cells in the liver play a unique role in regulating this microenvironment. Liver-resident natural killer (LrNK) cells, also known as liver type 1 innate lymphoid cells (ILC1s), are a recently discovered subset of immune cells that possess properties distinct from those of conventional NK (cNK) cells. Accumulating evidence suggests that there are significant differences between LrNK and cNK cells, with LrNK cells potentially exhibiting immunosuppressive functions in the liver. This review summarizes the latest findings on LrNK cells, focusing on their phenotype, heterogeneity, plasticity, origin, development, and the required transcription factors. In addition, immune functions of LrNK cells in various liver diseases, including liver cancer, viral infections, liver injury, and cirrhosis, were analyzed. By elucidating the role of LrNK cells in liver immunity, this review aims to enhance our understanding of the mechanisms underlying liver immunity and contribute to the improvement of liver disease treatment.

Iron restriction is a critical pathomechanism underlying the Anemia of Inflammation and an innate immune response limiting the replication of extracellular pathogens. During infections, innate immune cells detect pathogen-associated molecular patterns (PAMPs) and produce proinflammatory cytokines. Among these, interleukin (IL)-6 is detected by hepatocytes, where it activates the production of the iron-regulated hormone hepcidin that inhibits iron export from macrophages. Consequently, macrophages accumulate iron and hypoferremia (low plasma iron) develops. Whether Toll-like receptors (TLRs) expressed on hepatocytes directly recognize PAMPs and contribute to hepcidin upregulation is still an open question. Stimulation of primary murine hepatocytes with a panel of PAMPs targeting TLRs 1-9 revealed that the TLR5 ligand flagellin and the TLR2:TLR6 ligand FSL1 upregulated hepcidin. Hepcidin was also induced upon treatment with heat-killed Staphylococcus aureus (HKSA) and Brucella abortus (HKBA). The hepcidin response to flagellin, FSL1, HKSA, and HKBA started at an early time point, was independent of autocrine regulation by IL-6, and occurred through the TLR-mitogen-activated protein kinase (MAPK) axis. By analyzing a macrophage:hepatocyte co-culture, we additionally show that the hepcidin response was dependent on TLR2:TLR6 expression in hepatocytes and independent of macrophage cytokine secretion. Ex vivo liver perfusion of mice with FSL1 and HKSA further revealed that PAMPs and pathogens can pass the sinusoidal barrier and reach hepatocytes to cause hepcidin upregulation in a TLR2:TLR6-dependent manner. We conclude that hepatocytes can directly recognize PAMPs and pathogens and promote hepcidin upregulation in a macrophage and cytokine-independent manner. This positions hepatocytes in the spotlight as potential direct drivers of iron restriction.

Bromoxynil (BML) is a toxic herbicide that is reported to cause various organ toxicities. However, there is not a single investigation conducted to elucidate the adverse impacts of BML on hepatic tissues at different dose concentrations. Therefore, the current investigation was planned to assess the deleterious effects of BML on liver against different dose concentrations. Thirty-six albino rats (Sprague Dawley) were divided into four groups including the control, BML (10 mg/kg), BML (20 mg/kg) and BML (40 mg/kg). Gene expressions were assessed by qRT-PCR while other biochemical parameters were evaluated through ELISA as well as standard assays. The histological procedure was conducted as per the standard protocols of histomorphology. It is revealed that BML intoxication at all tested doses showed notable elevation in the gene expression of tumor necrosis factor-alpha (TNF-α), toll-like receptors-4 (TLR-4), interleukin-1beta (IL-1β), myeloid differentiation primary response protein-88 (MyD88), interleukin-6 (IL-6), tumor necrosis factor receptor-associated factor-6 (TRAF-6), cyclooxygenase-2 (COX-2), nuclear factor kappa-B (NF-κB), Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3) while reducing the gene expression of inhibitor of kappa-B (I-κB). Moreover, BML exposure (10 mg/kg, 20 mg/kg, 40 mg/kg) reduced the activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione (GSH), glutathione S- transferase (GST), heme-oxygenase-1 (HO-1) and glutathione reductase (GSR) while upregulating the levels of reactive oxygen species (ROS) and malondialdehyde (MDA). However, an elevation was observed in the levels of alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) while a reduction in the levels of total proteins and albumin was observed after high dose (20 mg/kg, 40 mg/kg) of BML. There was insignificant elevation among the values of these biomarkers at 10 mg/kg administration of BML. Besides, BML exposure at 10 mg/kg, 20 mg/kg and 40 mg/kg escalated the levels of Bcl-2-associated X protein (Bax), cysteine-aspartic acid protease-9 (Caspase-9) and cysteine-aspartic acid protease-3 (Caspase-3) while reducing the levels of B-cell lymphoma 2 (Bcl-2) in hepatic tissues. Similarly, BML at all tested concentrations showed adverse impacts on hepatic histology. These findings validated the deleterious impacts of BML on hepatic tissues owing to its pro-oxidative, pro-inflammatory and pro-apoptotic potential.

Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified.

We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis.

Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling.

The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.

Chronic HBV infection usually causes cirrhosis and hepatocellular carcinoma. Comparative investigations of acute and chronic HBV cases would help determine the immune responses crucial for viral clearance.

A fast-cleared HBV mouse model was established in Alb-Cre mice via hydrodynamic injection of HBV plasmid, while persistent HBV model mice were generated via recombinant covalently closed circular DNA-adeno-associated virus 8 infection. The single-cell transcriptomes of CD45+ intrahepatic non-parenchymal cells from these mice were conducted. Multiplexed immunohistochemistry and flow cytometry were used to confirm the findings from single-cell transcriptomes. Transwell, coculture, and adoptive transfer experiments were performed to study the generation and functions of macrophages.

Twenty-four clusters of immune cells were identified. Myeloid cells, including granulocytes, monocytes, and dendritic cells, are activated early in HBV fast-cleared mice. Significantly, a cluster of CD3+ macrophages was found in the viral clearance phase, which was confirmed in liver tissue from five acute patients with HBV. These cells highly expressed CXCL1, tumor necrosis factor alpha, and HBsAg-specific T cell receptors. The transwell assay revealed that CD3+ macrophages originate from macrophages (n = 6). T cells and anti-HBsAg antibodies are indispensable for their differentiation, which was further confirmed in T- and/or B-cell-deficient mice. Interestingly, these CD3+ macrophages capable of killing peptide-loaded hepatocytes and engulfing IgG-coated beads were persistently detectable in the mouse liver for 10 weeks after HBV clearance. The expression levels of CD5L and Bcl2, two classical antiapoptotic proteins, increased (p <0.001), suggesting that the CD3+ macrophages are long-term resident populations. Finally, adoptive transfer of CD3+ macrophages accelerated HBV clearance in mice (n = 5, p <0.01).

We identified long-term polyfunctional CD3+ macrophages residing in HBV fast-cleared livers that could help elucidate the immune responses involved in eliminating HBV.

The liver is a special organ with unique immune characteristics and tolerance to foodborne antigens. Chronic infections can develop in newborns after exposure to HBV; however, acute infections usually occur in adults, indicating that immune cells in the liver tissue microenvironment can also effectively fight against the virus. Nevertheless, the mechanisms involved in acute HBV infection have rarely been studied. In this study, we identified a macrophage population with both T cell and macrophage characteristics in the livers of acute HBV model mice and revealed that these macrophages play important roles in HBV clearance. Moreover, we confirmed that this population is derived from macrophages in the presence of virus-specific T cells and antibodies. This finding highlights the complexity of antiviral immune responses in liver microenvironments.

Organ injury is a major problem in liver transplant. Prolonged liver ischemia may result in ischemia/reperfusion injury (IRI), leading to inadequate activation of innate immunity. Hypothermic oxygenated machine perfusion (HOPE) of the graft emerges as a more physiologic method for liver preservation compared with static cold storage (SCS) by reducing IRI, which improves the quality of the graft. Despite being crucial, the immunological aspects of IRI in liver transplantation remained poorly explored.

We designed a pilot study to assess intrahepatic immune responses to HOPE compared with SCS (6 patients in each group). We explored immunologic and inflammatory pathways using both bulk RNA-sequencing and single-cell multiparametric flow cytometry analyses from liver biopsies performed on the graft before and after transplantation.

Despite a limited number of patients and heterogeneous effects on IRI, we observed immune changes in liver biopsies before and after organ storage and distinct functional modulations of intrahepatic immune cells from the transplanted liver that underwent SCS versus HOPE. A significant increase of infiltrated monocytes, conventional type 2 dendritic cells (cDC2s), and neutrophils ( P  < 0.05) and a trend toward reduced immune cell viability were observed after SCS but not after HOPE.

This pilot study did not allow us to conclude on IRI but showed that HOPE perfusion dampens liver infiltration of some innate immune cells. It reveals that the inclusion of additional transplanted patients and analysis of later time points after transplantation are needed to draw a definitive conclusion. However, it can guide future studies evaluating the development of new strategies to prevent IRI.

ERCC3, a crucial component of the nucleotide excision repair pathway, is implicated in the development and progression of various cancers and is a potential indicator of poor prognosis. However, the expression and function of ERCC3 in hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate the expression of ERCC3 in HCC tissues and its clinical significance, focusing on elucidating its potential mechanisms and therapeutic value in immunotherapy.

The differential expression and genetic variation characteristics of ERCC3 across various cancers were evaluated using the TCGA database. The expression and prognostic value of ERCC3 in HCC were analyzed by integrating TCGA, GEO, and ICGC datasets. Independent prognostic value of ERCC3 expression levels in HCC was assessed using Cox regression analysis, Kaplan-Meier survival analysis, receiver operating characteristic curves, and nomograms. Pathway association scores were determined using ssGSEA to reveal the biological functions of ERCC3 in HCC and its potential clinical efficacy in immunotherapy. Stable transient cell lines were established by infecting HepG2 cells with lentivirus overexpressing ERCC3. The effects of ERCC3 on HCC cell biological phenotypes were evaluated using RTCA, wound healing, and Transwell assays. Cell cycle distribution and apoptosis were detected by flow cytometry. Transcriptome sequencing was performed to explore the impact of ERCC3 overexpression on the expression of signaling pathway-related genes in HCC.

The study revealed that ERCC3 is aberrantly expressed in various tumors, with significantly higher mRNA and protein levels in HCC tissues compared to normal tissues. High ERCC3 expression was significantly correlated with poor survival outcomes in HCC patients. Multivariate Cox regression analysis revealed that ERCC3 expression level is an independent prognostic factor for overall survival (P = 0.014). Gene sets associated with the high ERCC3 group were significantly involved in multiple immune pathways and tumor progression-related pathways, and ERCC3 expression was significantly correlated with immune checkpoints in HCC. Overexpression of ERCC3 promoted the proliferation and migration of HCC cells and influenced cell cycle progression. Transcriptome sequencing analysis indicated that ERCC3 overexpression regulated the proliferation of HCC cells, participated in multiple pro-inflammatory pathways, induced the formation of an inflammatory tumor microenvironment, and promoted HCC progression.

This study is the first to reveal the association between high ERCC3 expression and poor prognosis in HCC and to elucidate its immunomodulatory role in HCC. Unlike previous studies, we found that ERCC3 promotes HCC progression by regulating the inflammatory microenvironment and immune checkpoints. These findings establish a novel theoretical foundation for the development of targeted immunotherapies for HCC and provide new insights into the molecular mechanisms underlying ERCC3's role in HCC.

In recent years, several global phase III trials have shown that combinations of immune checkpoint inhibitors (ICIs) offer superior efficacy and survival compared to multi-kinase inhibitors, establishing them as the gold standard for treating patients with advanced hepatocellular carcinoma (HCC). This success has led to investigations into expanding the use of immunotherapy into various other settings and populations, including neoadjuvant and adjuvant therapies, patients with decompensated liver function and those awaiting liver transplantation. Despite its proven efficacy, a significant number of patients still develop resistance to immunotherapy, highlighting the need for innovative strategies to address this challenge. Approaches aimed at enhancing tumour immunogenicity, such as combining immunotherapy with transarterial chemoembolization or radiation therapies, show significant promise. Additionally, novel immunotherapeutics - such as triplet therapy, bispecific antibodies, adoptive T-cell therapy and cancer vaccines - are in early development for HCC. These agents have demonstrated potential for synergistic effects with existing ICIs, with initial studies yielding positive outcomes. In this review, we offer our future perspective on immunotherapy, emphasizing emerging indications, novel combination strategies and the development of new immunotherapeutic agents. Overall, the future of immunotherapy in HCC is brimming with extraordinary potential, set to transform the treatment landscape and redefine the possibilities for managing this challenging disease.

Biliary atresia, a rare pediatric liver condition, results in blocked bile ducts, impeding bile secretion and causing significant nutritional challenges. This perspective emphasizes the critical role of nutrition in supporting children with biliary atresia awaiting liver transplantation. The liver's multifaceted functions in energy metabolism, vitamin storage, and waste excretion emphasize the importance of tailored dietary interventions. Medium-chain triglyceride (MCT) oil serves as a crucial energy source, addressing fat malabsorption, while specialized water-soluble formulations deliver essential fat-soluble vitamins. Additionally, weaning strategies and developmental food practices are discussed to ensure optimal growth and development despite dietary restrictions. Feeding assistance through nasogastric or gastrostomy tubes is explored as a means to combat malnutrition and support liver function. The collective efforts of caregivers and healthcare providers are pivotal in preparing these children for successful liver transplantation, aiming to secure their future health and quality of life.

The tumor microenvironment (TME) plays a critical role in the development, progression, and clinical outcomes of hepatocellular carcinoma (HCC). Despite the critical role of natural killer (NK) cells in tumor immunity, there is limited research on their status within the tumor microenvironment of HCC. In this study, single-cell RNA sequencing (scRNA-seq) analysis of HCC datasets was performed to identify potential biomarkers and investigate the involvement of natural killer (NK) cells in the TME.

Single-cell RNA sequencing (scRNA-seq) data were extracted from the GSE149614 dataset and processed for quality control using the "Seurat" package. HCC subtypes from the TCGA dataset were classified through consensus clustering based on differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) was employed to construct co-expression networks. Furthermore, univariate and multivariate Cox regression analyses were conducted to identify variables linked to overall survival. The single-sample gene set enrichment analysis (ssGSEA) was used to analyze immune cells and the screened genes.

A total of 715 DEGs from GSE149614 and 864 DEGs from TCGA were identified, with 25 overlapping DEGs found between the two datasets. A prognostic risk score model based on two genes was then established. Significant differences in immune cell infiltration were observed between high-risk and low-risk groups. Immunohistochemistry showed that HRG expression was decreased in HCC compared to normal tissues, whereas TUBA1B expression was elevated in HCC.

Our study identified a two-gene prognostic signature based on NK cell markers and highlighted their role in the TME, which may offer novel insights in immunotherapy strategies. Additionally, we developed an accurate and reliable prognostic model, combining clinical factors to aid clinicians in decision-making.

Metastasis is a leading cause of cancer-related deaths, with the liver being the most frequent site of metastasis in colorectal cancer. Previous studies have predominantly focused on the influence of the primary tumor itself on metastasis, with relatively limited research examining the changes within target organs.

Using an orthotopic mouse model of colorectal cancer, single-cell sequencing was employed to profile the transcriptomic landscape of pre-metastatic and metastatic livers. The analysis focused on identifying cellular and molecular changes within the hepatic microenvironment, with particular emphasis on inflammatory pathways and immune cell populations.

A neutrophil subpopulation with high Prok2 expression was identified, showing elevated levels in the pre-metastatic and metastatic liver. Increased infiltration of Prok2⁺ neutrophils correlated with poor prognosis in liver metastatic colorectal cancer patients. In the liver metastatic niche (MN), these neutrophils showed high App and Cd274 (PD-L1) expression, suppressing macrophage phagocytosis and promoting T-cell exhaustion.

A Prok2⁺ neutrophil subpopulation infiltrated both pre-metastatic and macro-metastatic liver environments, potentially driving immunosuppression through macrophage inhibition and T-cell exhaustion. Targeting Prok2⁺ neutrophils could represent a novel therapeutic strategy for preventing liver metastasis in colorectal cancer patients.

Liver tissue-resident memory T (TRM) cells play a pivotal role in hepatic immune responses. Their unique residence within liver sinusoids allow continuous antigen surveillance. In this review, we highlight the role of liver TRM cells in protective immunity and disease pathology. Comparisons between human and murine liver TRM cells reveal species-specific characteristics, suggesting the need for human-focused studies. One key finding is the involvement of liver TRM cells in viral hepatitis, where they can both control infection and contribute to liver damage. Liver TRM cells also exhibit dual roles in metabolic-associated steatotic liver disease, promoting inflammation and fibrosis while also contributing to fibrosis resolution. In autoimmune liver diseases, such as autoimmune hepatitis and primary sclerosing cholangitis, the presence of liver TRM cells correlates with disease severity. In this review, we underscore the importance of liver TRM cells in vaccine development, particularly vaccines against malaria. Future research should focus on the mechanisms governing TRM-cell formation, maintenance, and function, with the aim of supporting their protective roles while mitigating detrimental effects. Advancing our understanding of liver TRM cells will enhance our knowledge of liver immunology and inform novel therapeutic strategies for liver disease management.

Hepatitis B virus (HBV) infection is a well-documented independent risk factor for developing hepatocellular carcinoma (HCC). Consequently, extensive research has focused on elucidating the mechanisms by which HBV induces hepatocarcinogenesis. The majority of studies are dedicated to understanding how HBV DNA integration into the host genome, viral RNA expression, and the resulting protein transcripts affect cellular processes and promote the malignant transformation of hepatocytes. However, considering that most acute HBV infections are curable, immune suppression potentially contributes to the critical challenges in the treatment of chronic infections. Regulatory T cells (Tregs) are crucial in immune tolerance. Understanding the interplay of Tregs within the liver microenvironment following HBV infection could offer novel therapeutic approaches for treating HBV infections and preventing HBV-related HCC. Two viewpoints to targeting Tregs in the liver microenvironment include means of reducing their inhibitory function and decreasing Treg frequency. As these strategies may disrupt the immune balance and lead to autoimmune responses, careful and comprehensive profiling of the patient's immunological status and genetic factors is required to successfully employ this promising therapeutic approach.

Understanding T cell clonal relationships and tissue-specific adaptations is crucial for deciphering human immune responses, particularly within the gut-liver axis. We performed paired single-cell RNA and T cell receptor sequencing on matched colon (epithelium, lamina propria), liver, and blood T cells from the same human donors. This approach tracked clones across sites and assessed microenvironmental impacts on T cell phenotype. While some clones were shared between blood and tissues, colonic intraepithelial lymphocytes (IELs) exhibited limited overlap with lamina propria T cells, suggesting a largely resident population. Furthermore, tissue-resident memory T cells (TRM) in the colon and liver displayed distinct transcriptional profiles. Notably, our analysis suggested that factors enriched in the liver microenvironment may influence the phenotype of colon lamina propria TRM. This integrated single-cell analysis maps T cell clonal distribution and adaptation across the gut-liver-blood axis, highlighting a potential liver role in shaping colonic immunity.

Avian pathogenic Escherichia coli (APEC) infection has high morbidity and mortality, and multiple stressors encountered during rearing place poultry in a state of stress. However, research on how poultry cope with APEC infection under stress situation is still limited. In this study, we established a broiler stress model by corticosterone (CORT) administration subcutaneously for 7 consecutive days, followed by APEC challenge intramuscularly. CORT treatment significantly reduced body weight (BW) and average daily gain (ADG) while increasing feed conversion ratio (FCR) (P < 0.01). APEC infection significantly decreased ADG (P < 0.01). CORT treatment and APEC infection elevated plasma corticosterone and heterophil to lymphocyte (H/L) ratio (P < 0.05). Additionally, plasma aspartate aminotransferase (AST), AST to alanine aminotransferase (AST/ALT) ratio, and lactate dehydrogenase (LDH) levels increased significantly (P < 0.01). Histopathological analysis revealed structural damage of liver, indicating that CORT treatment and APEC infection induced liver injury. However, CORT pretreatment broilers exhibited a milder histopathological lesions and significantly lower AST, ALT, and LDH levels (P < 0.05) compared to APEC infection alone. CORT treatment and APEC infection increased plasma levels of lysozyme (LZM), total protein (TP), and globulin (GLOB) (P < 0.05), while CORT pretreatment further elevating their concentrations compared to APEC infection alone, suggesting an enhanced innate immune response. Liver transcriptomic analysis identified 768, 335, and 567 differentially expressed genes (DEGs) following CORT, APEC, or both treatments, respectively, enriched in cytokine-cytokine receptor interaction, PPAR signaling pathway, Toll-like receptor signaling pathway, MAPK signaling pathway, steroid hormone biosynthesis pathway, arachidonic acid metabolism, and phagosome pathway, etc., indicating that CORT treatment regulates lipid metabolism and immunity, while APEC infection induces inflammation and disrupts lipid metabolism. Notably, CORT pretreatment may mitigate APEC induced liver injury by enhancing phagosome function. Moreover, glucocorticoid receptor (GR) may regulate DEGs expressions, thus affected broilers response to CORT, APEC, or both treatments. These results suggest that CORT treatment, APEC infection, or both significantly affect the growth performance, immune response and liver function of broilers, while lipid metabolism may play a crucial role.

Metabolic dysfunction-associated fatty liver disease (MAFLD) can progress to hepatocellular carcinoma (HCC), yet the immune mechanisms driving this transition remain unclear.

In a chronic Western diet (WD) mouse model, we performed single-nuclei RNA sequencing to track MAFLD progression into HCC and subsequent tumor inhibition upon dietary correction.

Carcinogenesis begins during MAFLD, with tumor cells entering dormancy when HCC is mitigated. Rather than purely tolerogenic, the liver actively engages immune responses targeting myofibroblasts, fibroblasts and hepatocytes to maintain tissue homeostasis. Cytotoxic cells contribute to turnover of liver cells but do not primarily target the tumor. NKT cells predominate under chronic WD, while monocytes join them in HCC progression on a WD. Upon dietary correction, monocyte-driven immunity confers protection against HCC through targeting tissue homeostatic pathways and antioxidant mechanisms. Crucially, liver tissue response-not merely immune activation-dictates whether tumors grow or regress, emphasizing the importance of restoring liver tissue integrity. Also, protection against HCC is linked to a distinct immunological pattern, differing from healthy controls, underscoring the need for immune reprogramming.

These findings reveal the dual roles of similar pathways, where immune patterns targeting different cells shape distinct outcomes. Restoring tissue homeostasis and regeneration creates a tumor-hostile microenvironment, whereas tumor-directed approaches fail to remodel the TME. This underscores the need for tissue remodeling strategies in cancer prevention and treatment.

Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population.

Metabolic dysfunction-associated steatotic liver disease [MASLD] is a pervasive multifactorial health burden. Post-translational modifications [PTMs] of amino acid residues in protein domains demonstrate pivotal roles for imparting dynamic alterations in the cellular micro milieu. The crux of identifying novel druggable targets relies on comprehensively studying the etiology of metabolic disorders. This review article presents how different chemical moieties of various PTMs like phosphorylation, methylation, ubiquitination, glutathionylation, neddylation, acetylation, SUMOylation, lactylation, crotonylation, hydroxylation, glycosylation, citrullination, S-sulfhydration and succinylation presents the cause-effect contribution towards the MASLD spectra. Additionally, the therapeutic prospects in the management of liver steatosis and hepatic fibrosis via targeting PTMs and regulatory enzymes are also encapsulated. This review seeks to understand the function of protein modifications in progression and promote the markers discovery of diagnostic, prognostic and drug targets towards MASLD management which could also halt the progression of a catalogue of related diseases.

A considerable knowledge gap exists in predicting severe Pneumocystis pneumonia (PCP) outcomes following PCP diagnosis.

In this retrospective cohort, we studied immunocompromised patients with PCP admitted to 5 University Health Network centers in Canada (2011-2022). The study outcome included severe PCP, a composite of 21-day ICU admission or 28-day all-cause mortality. Adjusted odds ratios (aOR) estimated the association between severe PCP and comorbidities as well as clinical and laboratory variables at diagnosis.

A total of 44 out of 182 (24.2%) immunocompromised patients (19 [10.4%] HIV-infected, 55 [30.2%] hematologic malignancies, 32 [17.6%] hematopoietic stem cell transplants, 32 [17.6% solid tumors, 26 solid organ transplants [14.3%], 12 (6.6%) autoimmune diseases, and 6 (3.3%) other immunosuppressive conditions) developed composite outcomes (40 ICU admissions [21.9%], 18 deaths [9.9%]). Patients with composite outcomes more often had acute-onset PCP (< 7 days) (18/34 [52.9%] vs. 38/126 [30.1%], p = 0.013), shortness of breath (39/44 [88.6%] vs. 96/136 [70.6%], p = 0.002), chronic liver disease (15/44 [34.1%] vs. 9/138 [6.5%], p < 0.001), hypoalbuminemia (median [IQR] albumin (g/L): 27 [25-31] vs. 32 [29-35], p < 0.001), elevated lactate dehydrogenase (median [IQR] LDH (U/L): 537 [324-809] vs. 340 [237-475], p < 0.001), lymphopenia (median [IQR] absolute lymphocyte count [(10*9/L),]: 0.4 [0.2-0.6] vs. 0.7 [0.3-1.2], p < 0.001), or required supplemental oxygen (39/44 [88.6%] vs. 60/136 [44.1%], p < 0.001) than those without composite outcomes. In multivariable analysis, chronic liver disease (aOR: 11.6, 95% CI: 2.2-61.3) and requiring supplemental oxygen on admission (aOR: 19.7, 95% CI: 3.0-128.5) were significantly associated with severe PCP.

Alongside hypoxemia upon admission, chronic liver disease appears to significantly predict severe PCP in immunocompromised patients. This biologically plausible finding warrants further investigation.

Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) and its progressive form, Metabolic Dysfunction Associated Steatohepatitis (MASH), represent significant health concerns associated with the metabolic syndrome. These conditions are characterized by excessive hepatic fat accumulation, inflammation, and potential progression to cirrhosis and hepatocellular carcinoma. Neutrophils are innate immune cells that play a pivotal role in the development of MASLD and MASH. They can infiltrate the hepatic microenvironment in response to inflammatory cytokines and damage associated molecular patterns (DAMPs) derived from the liver and exacerbate tissue damage by releasing of reactive oxygen species (ROS), cytokines, and neutrophil extracellular traps (NETs). Moreover, neutrophils can disrupt the metabolism of hepatocytes through key factors such as neutrophil elastase (NE) and human neutrophil peptides-1 (HNP-1), leading to inflammation and fibrosis, while myeloperoxidase (MPO) and lipocalin (LCN2) are involved in inflammatory and fibrotic processes. In contrast, neutrophils contribute to liver protection and repair through mechanisms involving microRNA-223 and matrix metalloproteinase 9 (MMP9). This dual role of neutrophils highlights their significance in the pathogenesis of MASLD and MASH. This review summarizes current understanding from recent studies on the involvement of neutrophils in MASLD and MASH. Understanding complex roles of neutrophils within the liver's unique microenvironment offers insights into novel therapeutic strategies, emphasizing the need for further research to explore neutrophil-targeted interventions for managing MASLD and MASH. [BMB Reports 2025; 58(3): 116-123].

Cr(VI) is widely used in industry and has high toxicity, making it one of the most common environmental pollutants. Long-term exposure to Cr(VI) can cause metabolic disorders and tissue damage. However, the effects of Cr(VI) on liver and gut microbes in fish have rarely been reported. In this study, 240 fish were randomly divided into 3 groups: the control group, low-dose Cr(VI) group (0.5 mg/L), and high-dose Cr(VI) group (2 mg/L). The mechanism by which Cr(VI) affects the enterohepatic axis of common carp was elucidated via multiomic analysis, serology, histomorphology, and physiological and biochemical indices. The results revealed that Cr(VI) stress led to hepatocyte damage, nuclear lysis, inflammatory cell infiltration, and vacuolated degeneration. The structure of the intestinal villi was severely damaged, and the length and width of the intestinal villi were significantly reduced. We also found that the accumulation of Cr(VI) in tissues increased in a concentration-dependent manner, and the content of Cr(VI) in each tissue increased in the order of gut > gill > liver > muscle. Multiple omics studies have revealed that chronic Cr(VI) stress leads to disturbances in the intestinal flora, with a significant reduction in the abundance of the beneficial bacterium Akkermansia and a significant increase in the abundance of the harmful bacterium Escherichia/Shigella. Intestinal injury and dysbiosis lead to an increase in blood LPS levels, further inducing metabolic disorders in the liver. The metabolites in the liver, including geniposide, leucine, C17 sphingosine, and 9,10-DiHODE, were significantly increased, whereas the beneficial metabolites, such as carnitine propionate and palmitoyl ethanolamide, were significantly reduced. In conclusion, our results suggest that chronic Cr(VI) stress leads to disturbances in gut microbial homeostasis and disturbed fatty acid and amino acid metabolism in the liver. LPS released into the bloodstream reaches the liver through the portal circulation, further exacerbating Cr(VI) stress-induced hepatotoxicity. This study revealed the mechanism of Cr(VI) toxicity to the liver-microbiota-gut axis of common carp. Our study provides new insights into the effects of Cr(VI) on the liver-microbiota-gut axis.

B cells are an attractive platform for engineering to produce protein-based biologics absent in genetic disorders, and potentially for the treatment of metabolic diseases and cancer. As part of pre-clinical development of B cell medicines, we demonstrate a method to collect, ex vivo expand, differentiate, radioactively label, and track adoptively transferred non-human primate (NHP) B cells. These cells underwent 10- to 15-fold expansion, initiated IgG class switching, and differentiated into antibody-secreting cells. Zirconium-89-oxine-labeled cells were infused into autologous donors without any preconditioning and tracked by PET/CT imaging. Within 24 h of infusion, 20% of the initial dose homed to the bone marrow and spleen and distributed stably and equally between the two. Interestingly, approximately half of the dose homed to the liver. Image analysis of the bone marrow demonstrated inhomogeneous distribution of the cells. The subjects experienced no clinically significant side effects or laboratory abnormalities. A second infusion of B cells into one of the subjects resulted in an almost identical distribution of cells, suggesting possibly a non-limiting engraftment niche and feasibility of repeated infusions. This work supports the NHP as a valuable model to assess the potential of B cell medicines as potential treatment for human diseases.

Sepsis is a life-threatening organ failure resulting from a poorly regulated infection response. Organ dysfunction includes hepatic involvement, weakening the immune system due to excretory liver failure, and metabolic dysfunction, increasing the death risk. Although experimental studies correlated excretory liver functionality with immune performance and survival rates in sepsis, the proteins and pathways involved remain unclear. This study identified protein kinase C-α (PKCα) as a novel target for managing excretory liver function during sepsis. Using a preclinical murine sepsis model, we found that both PKCα knockout and the use of a PKCα-inhibitor midostaurin successfully restored liver function without hindering the host's response or ability to clear the pathogen, highlighting PKCα's vital role in excretory liver failure. In septic animals, both approaches significantly boosted survival rates. Midostaurin is the clinically approved active pharmaceutical ingredient in Rydapt, approved for the adjuvant treatment of FTL3-mutated AML. Here, it reduced plasma bile acids and related inflammation in those patients, opening a translational avenue for therapeutics in sepsis. Conclusively, our research underscores the significance of PKCα in controlling excretory liver function during inflammation. This suggests that targeting this protein could restore liver function without compromising the immune system, thereby decreasing sepsis mortality and supporting the recent paradigm that the liver is a hub for the host response to infection that might, in the future, result in novel host-directed therapies supporting the current state-of-the-art intensive care medicine in patients with sepsis-associated liver failure.

Purinergic signaling regulates many metabolic functions and is implicated in liver physiology and pathophysiology. Liver functionality is modulated by ionotropic P2X and metabotropic P2Y receptors, specifically P2Y1, P2Y2, and P2Y6 subtypes, which physiologically exert their influence through calcium signaling, a key second messenger controlling glucose and fat metabolism in hepatocytes. Purinergic receptors, acting through calcium signaling, play an important role in a range of liver diseases. Ionotropic P2X receptors, such as the P2X7 subtype, and certain metabotropic P2Y receptors can induce aberrant intracellular calcium transients that impact normal hepatocyte function and initiate the activation of other liver cell types, including Kupffer and stellate cells. These P2Y- and P2X-dependent intracellular calcium increases are particularly relevant in hepatic disease states, where stellate and Kupffer cells respond with innate immune reactions to challenges, such as excess fat accumulation, chronic alcohol abuse, or infections, and can eventually lead to liver fibrosis. This review explores the consequences of excessive extracellular ATP accumulation, triggering calcium influx through P2X4 and P2X7 receptors, inflammasome activation, and programmed cell death. In addition, P2Y2 receptors contribute to hepatic steatosis and insulin resistance, while inhibiting the expression of P2Y6 receptors can alleviate alcoholic liver steatosis. Adenosine receptors may also contribute to fibrosis through extracellular matrix production by fibroblasts. Thus, pharmacological modulation of P1 and P2 receptors and downstream calcium signaling may open novel therapeutic avenues.

In ovo stimulation has been studied intensively as an alternative to antibiotic use in poultry production. We investigated the potential use of a probiotic in combination with a phytobiotic as a prophybiotic for in ovo stimulation and reported its beneficial effects on the gut microbiome of broiler chickens. The current study further investigates the gene expression in the immune-related organs of these chickens to understand the tissue-specific immunomodulatory effects of the treatments. The selected prophybiotic (Leuconostoc mesenteroides with garlic aqueous extract) and its probiotic component alone were injected into ROSS308 chicken eggs on the 12th day of incubation, and gene expression in cecal tonsils, spleen, and liver at 35 days of age was determined using qPCR method. The relative expression of each treatment was compared to the positive control, chickens injected with physiological saline in ovo. The results displayed a downregulation of pro- and anti-inflammatory cytokines in the cecal tonsils of the probiotic group and the liver of the prophybiotic group. The spleen displayed upregulated AVBD1 in both groups and upregulated IL1-β in the probiotic group. The probiotic group displayed increased expression of genes related to metabolism of energy (COX16), protein (mTOR), and lipids (CYP46A1) whereas the prophybiotic group displayed reduced expression of genes related to cholesterol synthesis (SREBP1) and glucose transportation (SLC2A2) in the liver. In conclusion, Leuconostoc mesenteroides differentially modulated gene expression in chickens when administered in ovo in combination with garlic aqueous extract. Further in ovo studies with different prophybiotic combinations are required to optimize the benefits in broiler chickens.