Pentachlorophenol (PCP) and dibutyltin dichloride (DBT) contaminate the environment due to their diverse applications. PCP has been found from 0.26 to 5 μM in the serum of exposed individuals and at an average of 0.15 μM in the unexposed. DBT has been detected in human blood at levels up to 0.3 μM. Exposure to these contaminants is linked to pathological conditions including cancer. Interleukin-1 beta (IL-1β) and IL-6 are pro-inflammatory cytokines that when produced inappropriately can cause chronic inflammation, which is linked to pathologies including autoimmune diseases and cancer. PCP and DBT have been shown to increase the production of IL-1β and IL-6 by immune cells in a MAP kinase (MAPK) dependent process. Toll-like receptors (TLRs) activate the signaling pathways linked to MAPK that lead to production of these cytokines. This study demonstrates that PCP-induced production of IL-1β and IL-6 is dependent on TLR4 and TLR8, and independent of TLR1/2, TLR2, and TLR3. Additionally, DBT-induced IL-6 production depends on TLR1/2, whereas IL-1β production does not. Blocking the TLR-linked adapter protein, MyD88, lead to a loss of both PCP and DBT stimulation of IL-1β and IL-6. These findings indicate that both PCP and DBT interact with selected TLRs as part of their mechanisms of elevating the levels of critical pro-inflammatory cytokines, which may contribute to chronic inflammation and its related pathologies.

Chronic inflammation is increasingly recognized as a key driver of tumorigenesis, affecting both the tumor microenvironment and host response. In this context, circulating inflammatory proteins may provide valuable insights into cancer activity. This study evaluated the diagnostic performance of the inflammatory protein ratio (IPR), a composite index derived from serum protein electrophoresis, in detecting active cancer among hospitalized patients. We retrospectively analyzed clinical and laboratory data from 312 adult patients admitted to the Internal Medicine and Aging Department at Policlinico Foggia, Italy, between November 2023 and July 2024. Patients were stratified according to the presence of active cancer, defined by NICE criteria. The diagnostic accuracy of the IPR was compared with that of conventional inflammatory markers, including C-reactive protein (CRP) and the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII). The IPR showed the highest diagnostic performance, with a sensitivity of 88.1%, a specificity of 75.2%, and an area under the receiver operating characteristic curve (AUC) of 0.868. Its negative predictive value reached 97.6%, underscoring its potential as a rule-out tool for malignancy in hospitalized patients. These findings support the IPR as a promising and cost-effective inflammation-based biomarker for cancer detection, warranting further validation in prospective and molecularly characterized cohorts.

The role of hepatic non-parenchymal cells (NPCs) in drug-induced liver injury has been controversial. Utilizing our previously developed perfluoropolyether-based microfluidic devices-characterized by significantly reduced chemical absorption compared to conventional polydimethylsiloxane (PDMS)-we investigated the interactions between primary hepatocytes (PCs) and NPCs under physiologically relevant conditions. When exposed to coumarin or acetaminophen, PCs underwent severe cytotoxicity and showed glutathione (GSH) depletion. Notably, co-culture with NPCs restored drug-induced cytotoxicity and cellular GSH levels, accompanied by increased interleukin-6 (IL-6) secretion. Given previous reports linking IL-6 to cytochrome P450 expression modulation and glutathione synthesis, these findings suggest that IL-6 might be a critical mediator of protective effects exerted by NPCs. Using these microfluidic devices, we clearly demonstrated the protective roles of NPCs without interference from innate immune systems, offering novel insights into hepatocellular protection mechanisms.

Critically ill patients in COVID-19 to the intensive care unit (ICU) may develop multiple organ dysfunction syndrome, with some requiring extracorporeal organ support. This study aimed to assess the effects of combined CytoSorb hemoperfusion (HP) and continuous renal replacement therapy (CRRT) on the improvement of the multiorgan failure of patients with COVID-19.

Fifty-six patients hospitalized in the ICU with a confirmed diagnosis of COVID-19 were included in this quasi-experimental study. All the patients had acute respiratory distress syndrome (ARDS). They were treated with 1-4 sessions of HP therapy.

Serum Interleukin-6 (IL6), C-reactive protein (CRP), d-dimer, procalcitonin (PCT), Neutrophil gelatinase-associated lipocalin (NGAL), ferritin, and bilirubin levels were decreased, while the concentration of albumin was significantly increased after HP/CRRT (p < 0.05). No significant differences were observed in O2 saturation (Sao2) and creatinine levels.

Combined HP and CRRT hold promise as a potential intervention for severe COVID-19 cases with multiple organ dysfunction, leading to improved clinical outcomes.

Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment, yet the roles and mechanisms of TAMs in inflammation-associated oncogenesis remain enigmatic. We report that protein canopy homolog 2 (CNPY2) functions as a novel TLR4 regulator, promoting cytokine production in macrophages. CNPY2 binds directly to TLR4. Cnpy2 deficiency reduces cell surface expression of TLR4, nuclear translocation of NFκB and cytokine production in macrophages. Macrophage-specific CNPY2 deficiency significantly decreases cytokine production in macrophages and reduces hepatocarcinogenesis in a diethylnitrosamine (DEN)-induced liver cancer model. RNA-sequencing analysis revealed Cnpy2 knockout decreased the mRNA level and cell surface expression of two VEGF receptors, Flt1 and Kdr, compared to those in WT counterparts, resulting in inhibition of macrophage tumor infiltration. Cnpy2 knockout inhibits NFκB2/p52-mediated transcription of Flt1 and Kdr in macrophages. These findings demonstrate that CNPY2 regulates macrophages in both inflammation and hepatocarcinogenesis and may serve as a therapeutic target for cancer.

In a previous study, we identified an inverse relationship between adverse perinatal outcomes and iron status during late pregnancy of women recruited from a maternal hospital in Cartagena, Colombia. Some of these outcomes have also been linked to maternal inflammatory states. However, there is currently no clarity regarding the relationship between iron levels and proinflammatory markers during this period.

To estimate the relationship between inflammatory markers and serum ferritin in third-trimester pregnancies.

Serum ferritin, hemoglobin, and proinflammatory cytokine levels were determined in women in Cartagena in their third trimester of pregnancy. We analyzed the relationship between ferritin levels and proinflammatory cytokines, as well as the relationship between serum ferritin, hemoglobin, and inflammatory cytokine levels with adverse perinatal outcomes.

The levels of IL-6 were significantly associated with serum ferritin levels (β = 0.42, SE = 0.21, p = 0.04) but not with maternal age. Maternal serum ferritin had a positive weak correlation with the absolute number of lymphocytes and monocytes. Hemoglobin and maternal serum ferritin were weakly and inversely associated with birth weight. Serum ferritin but not IL-6 or IL-8 was associated with preterm birth.

We observed direct and mild associations of serum iron markers (serum ferritin, hemoglobin, and hematocrit) with lymphocyte counts. The inflammation marker, IL-6, was mildly associated with serum ferritin levels in late pregnancy. Women with elevated white blood cell counts and serum ferritin levels tended to have infants with lower birth weights. This fact suggests a potential involvement of iron in inflammatory processes during pregnancy, and conditions associated with inflammation in the final trimester may have adverse effects on perinatal outcomes.

The sequence of events associated with cancer cachexia induction needs to be further characterized. Using the C26 mouse model, we found that prior to cachexia, cancer progression was associated with increased levels of IL-6 and growth differentiation factor 15 (GDF15), highly induced production of positive acute phase proteins (APPs) and reduced levels of most amino acids in the systemic circulation, while signal transducer and activator of transcription 3 (STAT3) signaling was induced (1) in the growing spleen, alongside activation of ribosomal protein S6 (rpS6) and alpha subunit of eukaryotic translation initiation factor-2 (eIF2α) signalings, and (2) in the liver, alongside increased positive-APP expression, decreased albumin expression, and upregulation of autophagy. At the onset of cachexia, rpS6 and eIF2α signalings were concomitantly activated in the liver, with increased expression of activating transcription factor 4 (ATF4) target genes involved in amino acid synthesis and transport, as well as autophagy. Data show that pre-cachectic (pre-Cx) alterations in protein/aa homeostasis are followed by activation of eIF2α signaling in the liver, an adaptive mechanism likely regulating protein/amino acid metabolism upon progression to cachexia.

The present study aimed to investigate the impact of Sparassis latifolia polysaccharides (SLPs) on hepatic immune function in cyclophosphamide (CTX)-induced immunocompromised mice. Our findings demonstrated that SLPs effectively suppressed the production of alanine aminotransferase (ALT), aspartate aminotransferase (AST), inflammatory factors, and acute phase proteins, while improving the hepatic oxidative stress state. Additionally, SLPs exerted inhibitory effects on inflammatory cell infiltration within hepatic tissue. Transcriptomic results revealed that 246 differentially-expressed genes (DEGs) were identified. Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis showed that the more DEGs in SLPs group were mainly related to immune signal transduction and metabolism pathways. And more DEGs were mainly related to MAPK signaling pathway and JAK/STAT signaling pathway. Metabolome analysis demonstrated that SLPs significantly modulated specific metabolites in the liver, including lipids and lipid-like molecules, organic acids and their derivatives, organic heterocyclic compounds, phenylpropanoids and polyketones, organic oxygenates, and benzene. The comprehensive analysis of transcriptome and metabonomics revealed the activation of immune-related signal pathways in mice liver stimulated by CTX. Notably, the involvement of diverse genes and metabolites was observed in the metabolism of arachidonic acid (AA) and JAK/STAT pathway. Correlation analysis also showed that there was a certain correlation between metabolites and differential genes. The present findings offer novel insights into the regulatory mechanism of liver immune injury by SLPs, which exhibits potential application value in improving immunocompromised populations.

Burn injuries in elderly patients result in higher morbidity and mortality compared to younger individuals. This study investigates age-related differences in inflammatory hepatic responses to burn injuries.

Young (8-10 weeks) and aged (20-21 months) female C57BL/6 mice were subjected to a 15% total body surface area burn or sham injury. Serum and liver samples collected at 3, 6-, 9-, 12-, and 24-hours post-injury were analyzed for serum amyloid A (SAA) levels, SAA1 and SAA2 hepatic gene expression, serum cytokines (IL-6, IL-1β, TNF-α, and IL-10), and hepatic STAT3 activation.

Aged mice showed a delayed and dysregulated response. In young mice, SAA levels rose significantly at 6 hours postburn (5.09 ±  0.2-fold), while in aged mice, SAA increased at 12 hours (39.1 ±  2.06-fold), p <  0.01. Hepatic expression of SAA1 and SAA2 also peaked early in young mice (8.357 ±  1.257-fold and 5.91 ±  0.664-fold at 3 hours) but was delayed until 12 hours in aged mice. Young mice demonstrated early IL-6 peaks at 3 hours (990 ±  83.2 pg/ml), while aged mice reached a delayed, higher IL-6 peak at 24 hours (3804 ±  1408 pg/ml, p <  0.05). Similar age-related delays occurred for IL-1β and TNF-α. Aged mice had significantly elevated IL-10 at 6 hours (993.9 ±  99.41 pg/ml vs. 67.69 ±  6.635 pg/ml in young, p <  0.001). STAT3 activation peaked at 3 hours in young mice (2.686 ±  0.226-fold) but was delayed until 24 hours in aged mice (0.5958 ±  0.0368-fold, p <  0.05).

This study identifies age-related variations in inflammatory markers and acute hepatic responses to burn injuries, with aged mice showing delayed and reduced inflammatory responses compared to younger counterparts. These findings underscore the importance of age-specific strategies in burn injury management to enhance outcomes for elderly burn patients.

Hexabromocyclododecane (HBCD) is an environmental contaminant due to its use as a flame retardant in a variety of applications ranging from building insulation, furniture upholstery, and housing for appliances and electronics. HBCD is found in wildlife, human breastmilk, and serum. Interleukin 1-beta (IL-1β) and interleukin 6 (IL-6) are pro-inflammatory cytokines, whose dysregulation is associated with chronic inflammation and the pathologies that result, such as tumor growth, rheumatoid arthritis, Crohn's disease, and multiple sclerosis. HBCD has been shown to increase the secretion of both IL-1β and IL-6 from human immune cells. However, it is not clear if these increases are due solely to HBCD effects on the secretory process or whether it is stimulating cellular production of IL-1β and IL-6. This study examines if HBCD can increase the production of IL-1β and IL-6 by immune cells by simultaneously assessing secreted levels and cellular levels of these cytokines. Additionally, the mechanisms for any observed changes in production are investigated. Peripheral blood mononuclear cells were exposed to HBCD over a range of concentrations and lengths of exposure. HBCD was found to stimulate IL-1β and IL-6 production after 6 hrs. of exposure and production was sustained and intensified at 24 hrs. This increase in IL-1β and IL-6 production appears to, in part, be a result of increased mRNA expression. Additionally, the MAPK pathways, specifically the p38 and p44/42 pathways, appear to be required for HBCD-induced increases in IL-1β and IL-6 production.

The generation of hypothyroid and hyperthyroid mouse models is one of the approaches used to investigate the complex interplay between thyroid hormones and the immune system. We present a detailed protocol describing how to induce endotoxic shock by lipopolysaccharide (LPS) administration, and how to investigate the role of immune populations, specifically macrophages, responding to endotoxemia.This book chapter provides the use of different molecular techniques, such as Western Blotting, Immunohistochemistry, q-PCR, Luciferase assays, or ChIP assays, with which researchers can gain valuable insights into the immune system's interaction with hormonal signaling pathways, for instance, examining the effect of thyroid hormones on signaling of STAT3, NF-κB, and ERK in response to LPS, and inflammatory mediators, such as interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNFα) within these cells. The signaling pathways involved and the exploration of the relationship between thyroid hormones and the immune system can be analyzed using several molecular biology technologies in order to clarify their interplay in various disease states.

Drug-induced hepatotoxicity constitutes a major reason for non-approval and post-marketing withdrawal of pharmaceuticals. In many cases, preclinical models lack predictive capacity for hepatic damage in humans. A vital concern is the integration of immune system effects in preclinical safety assessment. The immune-related Adverse Outcome Pathway (irAOP) approach, which is applied within the Immune Safety Avatar (imSAVAR) consortium, presents a novel method to understand and predict immune-mediated adverse events elicited by pharmaceuticals and thus targets this issue. It aims to dissect the molecular mechanisms involved and identify key players in drug-induced side effects. As irAOPs are still in their infancy, there is a need for a model irAOP to validate the suitability of this tool. For this purpose, we developed a hepatotoxicity-based model irAOP for recombinant human IL-2 (aldesleukin). Besides producing durable therapeutic responses against renal cell carcinoma and metastatic melanoma, the boosted immune activation upon IL-2 treatment elicits liver damage. The availability of extensive data regarding IL-2 allows both the generation of a comprehensive putative irAOP and to validate the predictability of the irAOP with clinical data. Moreover, IL-2, as one of the first cancer immunotherapeutics on the market, is a blueprint for various biological and novel treatment regimens that are under investigation today. This review provides a guideline for further irAOP-directed research in immune-mediated hepatotoxicity.

Linoleic acid (LA) is an omega-6 polyunsaturated fatty acid. Conjugated linoleic acid (CLA) is a family of LA isomers that includes both a trans fatty acid and a cis fatty acid. Both fatty acids play a nutritional role in maintaining health. Inflammation is critical in the pathogenesis of many diseases, including cancer. This study found that the combination of LA and CLA (LA/CLA), each of which had no effect, had a strong anti-synergistic effect on inflammatory macrophage RAW264.7 cells in vitro. Cells were cultured in a DMEM containing fetal bovine serum with or without either LA, CLA, or a combination of LA/CLA. The composition of LA and CLA at a comparatively lower concentration synergistically suppressed cell growth, resulting in a reduction in cell number. The underlying mechanism of this effect was based on reduced levels of Ras, PI3K, Akt, MAPK, and mTOR and elevated levels of p21, p53, and Rb, which are associated with cell growth. In addition, the combination of LA and CLA at a lower concentration stimulated potential cell death associated with increased caspase-3 and cleaved caspase-3 levels. Notably, this composition synergistically suppressed the production of TNF-α, IL-6, and PGE2, which are a major mediator of inflammation, with lipopolysaccharide stimulation in RAW264.7 cells This effect was associated with decreased levels of COX-1, COX-2, and NF-κB p65. This study may provide a useful tool for treating inflammatory conditions with the composition of LA and CLA.

Sepsis remains a major global health concern due to its high prevalence and mortality. Changes in body temperature (Tb), such as hypothermia or fever, are diagnostic indicators and play a crucial role in the pathophysiology of sepsis. This study aims to characterize the thermoregulatory mechanisms during sepsis using the cecal ligation and puncture (CLP) model and explore how sepsis severity and ambient temperature (Ta) influence Tb regulation and mortality. Rats were subjected to mild or severe sepsis by CLP while housed at thermoneutral (28 °C) or subthermoneutral (22 °C) Ta, and their Tb was monitored for 12 h. Blood and hypothalamus were collected for cytokines and prostaglandin E2 (PGE2) analysis.

At 28 °C, febrile response magnitude correlated with sepsis severity and inflammatory response, with tail vasoconstriction as the primary heat retention mechanism. At 22 °C, Tb was maintained during mild sepsis but dropped during severe sepsis, linked to reduced UCP1 expression in brown adipose tissue and less effective vasoconstriction. Despite differences in thermoregulatory responses, both Ta conditions induced a persistent inflammatory response and increased hypothalamic PGE2 production. Notably, mortality in severe sepsis was significantly higher at 28 °C (80%) compared to 22 °C (0%).

Our findings reveal that ambient temperature and the inflammatory burden critically influence thermoregulation and survival during early sepsis. These results emphasize the importance of considering environmental factors in preclinical sepsis studies. Although rodents in experimental settings are often adapted to cold environments, these conditions may not fully translate to human sepsis, where cold adaptation is rare. Thus, researchers should carefully consider these variables when designing experiments and interpreting translational implications.

During fasting, bodily homeostasis is maintained due to hepatic production of glucose (gluconeogenesis) and ketone bodies (ketogenesis). The main hormones governing hepatic fuel production are glucagon and glucocorticoids that initiate transcriptional programs aimed at supporting gluconeogenesis and ketogenesis.

Using primary mouse hepatocytes as an ex vivo model, we employed transcriptomic analysis (RNA-seq), genome-wide profiling of enhancer dynamics (ChIP-seq), perturbation experiments (inhibitors, shRNA), hepatic glucose production measurements and computational analyses.

We found that in addition to the known metabolic genes transcriptionally induced by glucagon and glucocorticoids, these hormones induce a set of genes encoding transcription factors (TFs) thereby initiating transcriptional cascades. Upon activation by glucocorticoids, the glucocorticoid receptor (GR) induced the genes encoding two TFs: CCAAT/enhancer-binding protein beta (C/EBPβ) and peroxisome proliferator-activated receptor alpha (PPARα). We found that the GR-C/EBPβ cascade mainly serves as a secondary amplifier of primary hormone-induced gene programs. C/EBPβ augmented gluconeogenic gene expression and hepatic glucose production. Conversely, the GR-PPARα cascade initiated a secondary transcriptional wave of genes supporting ketogenesis. The cascade led to synergistic induction of ketogenic genes which is dependent on protein synthesis. Genome-wide analysis of enhancer dynamics revealed numerous enhancers activated by the GR-PPARα cascade. These enhancers were proximal to ketogenic genes, enriched for the PPARα response element and showed increased PPARα binding.

This study reveals abundant transcriptional cascades occurring during fasting. These cascades serve two separated purposes: the amplification of the gluconeogenic transcriptional program and the induction of a gene program aimed at enhancing ketogenesis.

Fish skin plays an important role in defending against pathogens in water, primarily through the secretion of skin mucus containing various immune-related factors. Local immune responses in the skin activate systemic immune responses by inflammatory cytokines. However, it remains unclear whether immune responses in the skin occur after systemic immune responses caused by pathogen invasion into the fish body. This study aimed to clarify the relationship between systemic immune responses and skin responses after intraperitoneal injection of formalin-killed cells (FKC) of Vibrio anguillarum. Although systemic inflammatory responses were observed in the spleen after injection, expression changes in the skin did not show significant differences. In contrast, expression of hemoglobin subunit genes significantly increased in the skin after FKC injection, suggesting that erythrocytes infiltrate extravascularly.

Drug-induced liver injury (DILI) represents a significant clinical challenge characterized by hepatic dysfunction following exposure to diverse medications. Methotrexate (MTX) is a cornerstone in treating various cancers and autoimmune disorders. However, the clinical utility of MTX is overshadowed by its ability to induce hepatotoxicity. The current study aims to elucidate the hepatoprotective effect of the alcoholic extract of Egyptian Araucaria heterophylla resin (AHR) on MTX-induced liver injury in rats. AHR (100 and 200 mg/kg) significantly decreased hepatic markers (AST, ALT, and ALP), accompanied by an elevation in the antioxidant's markers (SOD, HO-1, and NQO1). AHR extract also significantly inhibited the TGF-β/NF-κB signaling pathway as well as the downstream cascade (IL-6, JAK, STAT-3, and cyclin D). The extract significantly reduced the expression of VEGF and p38 with an elevation in the BCL2 levels, in addition to a significant decrease in the IL-1β and TNF-α levels, with a prominent effect at a high dose (200 mg/kg). Using LC-HRMS/MS analysis, a total of 43 metabolites were tentatively identified, and diterpenes were the major class. This study presents AHR as a promising hepatoprotective agent through inhibition of the TGF-β/NF-κB and JAK/STAT3 pathways, besides its antioxidant and anti-inflammatory effects.

Immunosuppressive regulatory cells (IRCs) play important roles in negatively regulating immune response, and are mainly divided into myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Large numbers of preclinical and clinical studies have shown that inhibition or reduction of IRCs could effectively elevate antitumor immune responses. However, several studies also reported that excessive inhibition of IRCs function is one of the main reasons causing the side effects of cancer immunotherapy. Therefore, the reasonable regulation of IRCs is crucial for improving the safety and efficiency of cancer immunotherapy. In this review, we summarised the recent research advances in the cancer immunotherapy by regulating the proportion of IRCs, and discussed the roles of IRCs in regulating tumour immune evasion and drug resistance to immunotherapies. Furthermore, we also discussed how to balance the potential opportunities and challenges of using IRCs to improve the safety of cancer immunotherapies.

The opioid epidemic continues to be a major public health issue that includes millions of people who inject drugs (PWID). PWID have increased incidence of serious infections, including HIV as well as metabolic and inflammatory sequelae. We sought to discern the extent of systemic alterations in humoral immunity associated with injection drug use, including alterations in the plasma proteome and its regulation of B cell responsiveness. Comprehensive plasma proteomics analysis of HIV negative/hepatitis C negative individuals with a history of recent injection heroin use was performed using mass spectrometry and ELISA. The effects of plasma from PWID and healthy controls on the in vitro proliferation and transcriptional profile of B cell responses to stimulation were determined by flow cytometry and RNA-Seq. The plasma proteome of PWID was distinct from healthy control individuals, with numerous immune-related analytes significantly altered in PWID, including complement (C3, C5, C9), immunoglobulin (IgD, IgM, kappa light chain), and other inflammatory mediators (CXCL4, LPS binding protein, C-reactive protein). The plasma of PWID suppressed the in vitro proliferation of B cells. Transcriptome analysis indicated that PWID plasma treatment increased B cell receptor and CD40 signaling and shifted B cell differentiation from plasma cell-like toward germinal center B cell-like transcriptional profiles. These results indicate that the systemic inflammatory milieu is substantially altered in PWID and may impact their B cell responses.

The developmental immaturity of the innate immune system helps explains the increased risk of infection in the neonatal period. Importantly, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for the prevention of hepatocyte apoptosis in adult animals, yet whether developmental immaturity of these pathways increases the risk of hepatic injury in the neonatal period is unknown.

Using a murine model of endotoxemia (LPS 5 mg/kg IP x 1) in neonatal (P3) and adult mice, we evaluated histologic evidence of hepatic injury and apoptosis, presence of p65/NFκB and c-Jun/AP1 activation and associated transcriptional regulation of apoptotic genes.

We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis. This is associated with absent hepatic p65/NFκB signaling and impaired expression of anti-apoptotic target genes. Hepatic c-Jun/AP1 activity was attenuated in endotoxemic P3 mice, with resulting upregulation of pro-apoptotic factors.

These results demonstrate that developmental absence of innate immune p65/NFκB and c-Jun/AP1 signaling, and target gene expression is associated with apoptotic injury in neonatal mice. More work is needed to determine if this contributes to long-term hepatic dysfunction, and whether immunomodulatory approaches can prevent this injury.

Various aspects of developmental immaturity of the innate immune system may help explain the increased risk of infection in the neonatal period. In adult models of inflammation and infection, innate immune signaling pathways such as p65/NFκB and c-Jun/AP1 are responsible for a protective, pro-inflammatory transcriptome and regulation of apoptosis. We demonstrate that in contrast to adults, endotoxemic neonatal (P3) mice exhibit a significant increase in hepatic apoptosis associated with absent hepatic p65/NFκB signaling and c-Jun/AP1 activity. We believe that these results may explain in part hepatic dysfunction with neonatal sepsis, and that there may be unrecognized developmental and long-term hepatic implications of early life exposure to systemic inflammatory stress.

CD36, a scavenger receptor B2 that is dynamically distributed between cell membranes and organelle membranes, plays a crucial role in regulating lipid metabolism. Abnormal CD36 activity has been linked to a range of metabolic disorders, such as obesity, nonalcoholic fatty liver disease, insulin resistance and cardiovascular disease. CD36 undergoes various modifications, including palmitoylation, glycosylation, and ubiquitination, which greatly affect its binding affinity to various ligands, thereby triggering and influencing various biological effects. In the context of tumors, CD36 interacts with autophagy to jointly regulate tumorigenesis, mainly by influencing the tumor microenvironment. The central role of CD36 in cellular lipid homeostasis and recent molecular insights into CD36 in tumor development indicate the applicability of CD36 as a therapeutic target for cancer treatment. Here, we discuss the diverse posttranslational modifications of CD36 and their respective roles in lipid metabolism. Additionally, we delve into recent research findings on CD36 in tumors, outlining ongoing drug development efforts targeting CD36 and potential strategies for future development and highlighting the interplay between CD36 and autophagy in the context of cancer. Our aim is to provide a comprehensive understanding of the function of CD36 in both physiological and pathological processes, facilitating a more in-depth analysis of cancer progression and a better development and application of CD36-targeting drugs for tumor therapy in the near future.

The hepatic acute-phase response is characterized by a massive upregulation of serum proteins, such as haptoglobin and serum amyloid A, at the expense of liver homeostatic functions. Although the transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has a well-established role in safeguarding liver function and its cistrome spans around 50% of liver-specific genes, its role in the acute-phase response has received little attention so far. We demonstrate that HNF4A binds to and represses acute-phase genes under basal conditions. The reprogramming of hepatic transcription during inflammation necessitates loss of HNF4A function to allow expression of acute-phase genes while liver homeostatic genes are repressed. In a pre-clinical liver organoid model overexpression of HNF4A maintained liver functionality in spite of inflammation-induced cell damage. Conversely, HNF4A overexpression potently impaired the acute-phase response by retaining chromatin at regulatory regions of acute-phase genes inaccessible to transcription. Taken together, our data extend the understanding of dual HNF4A action as transcriptional activator and repressor, establishing HNF4A as gatekeeper for the hepatic acute-phase response.

Interleukin (IL)-1β is an apex proinflammatory cytokine produced in response to tissue injury and infection. The output of IL-1β from monocytes and macrophages is regulated not only by transcription and translation but also post-translationally. Release of the active cytokine requires activation of inflammasomes, which couple IL-1β post-translational proteolysis with pyroptosis. Among inflammasome platforms, NOD-like receptor pyrin domain-containing protein 3 (NLRP3) is implicated in the pathogenesis of numerous human disorders in which disease-specific danger-associated molecular patterns (DAMPS) are positioned to drive its activation. As a promising therapeutic target, numerous candidate NLRP3-targeting therapeutics have been described and demonstrated to provide benefits in the context of animal disease models. While showing benefits, published preclinical studies have not explored dose-response relationships within the context of the models. Here, the preclinical pharmacology of a new chemical entity, [(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl][(1-methyl-1H-pyrazol-4-yl)({[(2S)-oxolan-2-yl]methyl})sulfamoyl]azanide (NT-0249), is detailed, establishing its potency and selectivity as an NLRP3 inhibitor. NT-0249 also is evaluated in two acute in vivo mouse challenge models where pharmacodynamic/pharmacokinetic relationships align well with in vitro blood potency assessments. The therapeutic utility of NT-0249 is established in a mouse model of cryopyrin-associated periodic syndrome (CAPS). In this model, mice express a human gain-of-function NLRP3 allele and develop chronic and progressive IL-1β-dependent autoinflammatory disease. NT-0249 dose-dependently reduced multiple inflammatory biomarkers in this model. Significantly, NT-0249 decreased mature IL-1β levels in tissue homogenates, confirming in vivo target engagement. Our findings highlight not only the pharmacological attributes of NT-0249 but also provide insight into the extent of target suppression that will be required to achieve clinical benefit.

Lipopolysaccharide (LPS) can induce systemic inflammation and affect the growth and development of poultry. As a kind of traditional Chinese medicine, polysaccharide of Atractylodes macrocephala Koidz (PAMK) can effectively improve the growth performance of animals and improve the immunity of animal bodies.

The purpose of this study was to investigate the effects of PAMK on LPS-induced inflammatory response, proliferation, differentiation and apoptosis of chicken embryonic myogenic cells.

We used chicken embryonic myogenic cells as a model by detecting EdU/MYHC immunofluorescence, the expression of inflammation, proliferation, differentiation-related genes and proteins and the number of apoptotic cells in the condition of adding LPS, PAMK, belnacasan (an inhibitor of Caspase1) or their combinations.

The results showed that LPS stimulation increased the expression of inflammatory factors, inhibited proliferation and differentiation, and excessive apoptosis in chicken embryonic myogenic cells, and PAMK alleviated these adverse effects induced by LPS. After the addition of belnacasan (inhibitor of Caspase1), apoptosis in myogenic cells was inhibited, and therefore, the number of apoptotic cells and the expression of pro-apoptotic genes Caspase1 and Caspase3 were increased. In addition, belnacasan inhibited the increased expression of inflammatory factors, inhibited proliferation, differentiation and excessive apoptosis in chicken embryonic myogenic cells induced by LPS.

This study provides a theoretical basis for further exploring the mechanism of action of PAMK and exogenous LPS on chicken embryonic myogenic cells and lays the foundation for the development and application of green feed additives in animal husbandry industry.

Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies.

Hepatitis B virus (HBV) reactivation is a major problem that must be overcome during chemotherapy for HBV-related hepatocellular carcinoma (HCC). However, the mechanism underlying chemotherapy-associated HBV reactivation is still not fully understood, hindering the development of improved HBV-related HCC treatments.

A meta-analysis was performed to assess the HBV reactivation risk during transcatheter arterial chemoembolization (TACE). To investigate the regulatory effects and mechanisms of 5-FU on HBV replication, an HBV mouse model was established by pAAV-HBV1.2 hydrodynamic injection followed by intraperitoneal 5-FU injection, and different in vitro models (HepG2.2.15 or Huh7 cells) were established. Realtime RT‒qPCR, western blotting, luciferase assays, and immunofluorescence were used to determine viral parameters. We also explored the underlying mechanisms by RNA-seq, oxidative stress evaluation and autophagy assessment.

The pooled estimated rate of HBV reactivation in patients receiving TACE was 30.3 % (95 % CI, 23.1%-37.4 %). 5-FU, which is a chemotherapeutic agent commonly used in TACE, promoted HBV replication in vitro and in vivo. Mechanistically, 5-FU treatment obviously increased autophagosome formation, as shown by increased LC3-II levels. Additionally, 5-FU impaired autophagic degradation, as shown by marked p62 and mCherry-GFP-LC3 upregulation, ultimately promoting HBV replication and secretion. Autophagy inhibition by 3-methyladenine or chloroquine significantly altered 5-FU-induced HBV replication. Furthermore, 5-FU-induced autophagy and HBV replication were markedly attenuated with a reactive oxygen species (ROS) scavenger.

Together, our results indicate that ROS-induced autophagosome formation and autophagic degradation play a critical role in 5-FU-induced HBV reactivation.

Hyperinsulinemia is the key feature of equine metabolic syndrome (EMS) which leads to debilitating sequelae. Hyperinsulinemia-associated laminitis (HAL) is one of the major sequelae of EMS, although the pathophysiological mechanisms are not well elucidated. Using an equine model, we hypothesized that expression of inflammatory markers would be increased in digital lamellae and striated muscle following prolonged hyperinsulinemia. Healthy Standardbred horses (5.4 ± 1.9 years) were alternately assigned to a prolonged euglycemic-hyperinsulinemic clamp (pEHC) or control group (n = 4 per group). Following a 48 h pEHC or a 48 h infusion of a balanced electrolyte solution (controls), biopsies were collected from digital lamellar tissue, skeletal muscle and cardiac muscle were obtained. All hyperinsulinemic horses developed laminitis regardless of previous health status at enrollment. Protein expression was quantified via Western blotting. A significant (P < 0.05) upregulation of the protein expression of heat shock protein 90 (HSP90), alpha 2 macroglobulin (A2M) and fibrinogen (α, β isoforms), as well as inflammatory cytokines including interleukin-1β were detected in digital lamellae following prolonged hyperinsulinemia. In contrast, protein expression of cytokines and acute phase proteins in heart and skeletal muscle was unchanged following hyperinsulinemia. Upregulation of inflammatory cytokines and acute phase proteins in digital lamellae during prolonged hyperinsulinemia may reveal potential biomarkers and novel therapeutic targets for equine endocrinopathic laminitis. Further, the lack of increase of inflammatory proteins and acute phase proteins in striated muscle following prolonged hyperinsulinemia may highlight potential anti-inflammatory and cardioprotective mechanisms in these insulin-sensitive tissues.

Methotrexate (MTX) is an antimetabolite agent widely used to manage a variety of tumors and autoimmune diseases. Nonetheless, MTX-induced intestinal intoxication is a serious adverse effect limiting its clinical utility. Inflammation and oxidative stress are possible mechanisms for MTX-induced intestinal toxicity. Vinpocetine (VNP) is a derivative of the alkaloid vincamine with potent anti-inflammatory and antioxidant effects. The current study investigated the protective intestinal impact of VNP in attenuating MTX-induced intestinal intoxication in rats.

VNP was administered orally in a dose of 20 mg/kg, while MTX was injected intraperitoneal in a dose of 20 mg/kg.

VNP administration attenuated drastic histological changes induced by MTX and preserved both normal villus and crypt histology. VNP significantly attenuated oxidative injury by upregulating intestinal Nrf2 and HO-1 expression. VNP attenuated inflammation by reducing MPO, NO2-, TNF-α, and IL-1β levels mediated by downregulating NF-κB, NDAPH-oxidase, IRF3, p-JAK-1, and p-STAT-3 expressions. Moreover, VNP potently counteracted intestinal necroptosis by effectively downregulating RIPK1, RIPK3, MLKL, and caspase-8 proteins.

Therefore, VNP may represent a promising approach that can attenuate intestinal toxicity in patients receiving MTX.

In this research, the proinflammatory cytokine interleukin-8 (IL-8) was shown to play a key role in inflammatory responses in fish. This study involved the cloning of the gene that encodes IL-8 in Asian seabass (Lates calcarifer) as well as analyses of its expression and function in this fish. The expression levels of LcIL-8 indicated that it was broadly expressed in most analyzed tissues, with the most predominant expression in the whole blood 6 to 24 h after infection with S. iniae at concentrations of 105 colony-forming units (CFU)/fish (p < 0.05). After fish were immersed in F. covae, the LcIL-8 transcript was upregulated in the gills, liver and intestine, and the highest expression level was observed in the gills. However, LcIL-8 was downregulated in all the tested tissues at 48 and 96 h after infection with the two pathogenic strains, indicating that Lc-IL8 has a short half-life during the early immune responses to pathogens. Moreover, the MIC of the rLcIL-8 protein against S. iniae was 10.42 ± 3.61 µg/mL. Furthermore, functional analyses clearly demonstrated that 10 and 100 µg of the rLcIL-8 protein efficiently enhanced the phagocytic activity of Asian seabass phagocytes in vitro (p < 0.05). Additionally, in vivo injection of S. iniae following the rLcIL-8 protein indicated that 50 and 100 µg of rLc-IL-8 were highly effective in protecting fish from this pathogen (p < 0.001). The obtained results demonstrate that rLcIL-8 possesses a biological function in the defense against bacterial infections in Asian seabass.

Nonalcoholic fatty liver disease (NAFLD) is a major hepatic disorder occurring in non-alcohol-drinking individuals. Salvianic acid A or Danshensu (DSS, 3-(3, 4-dihydroxyphenyl)-(2R)-lactic acid), derived from the root of Danshen (Salvia miltiorrhiza), has demonstrated heart and liver protective properties. In this work, we investigated the antioxidant activity and hepatoprotective activity of Danshensu alone and in combination with different agents, such as probiotic bacteria (Lactobacillus casei and Lactobacillus acidophilus), against several assays. The inhibition mechanism of the methylation gene biomarkers, such as DNMT-1, MS, STAT-3, and TET-1, against DSS was evaluated by molecular docking and RT-PCR techniques. The physicochemical and pharmacokinetic ADMET properties of DSS were determined by SwissADME and pkCSM. The results indicated that all lipid blood test profiles, including cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), were reduced after the oral administration of Danshensu combined with probiotics (L. casei and L. acidophilus) that demonstrated good, efficient free radical scavenging activity, measured using anti-oxidant assays. ADMET and drug-likeness properties certify that the DSS could be utilized as a feasible drug since DSS showed satisfactory physicochemical and pharmacokinetic ADMET properties.

CRC with liver metastases is a major contributor to cancer-related mortality. Despite advancements in liver resection techniques, patient survival remains a concern due to high recurrence rates. This study seeks to uncover prognostic biomarkers that predict overall survival in patients undergoing curative hepatic resection for CRC liver metastases.

Prospectively collected serum samples from a cohort of 49 patients who received curative hepatic resection for CRC liver metastases were studied. The patients are part of a cohort, previously analyzed for perioperative complications (see methods). Various preoperative serum markers, clinical characteristics, and factors were analyzed. Univariate and multivariate Cox regression analyses were conducted to determine associations between these variables and disease-free survival as well as overall survival.

For disease-free survival, univariate analysis highlighted the correlation between poor outcomes and advanced primary tumor stage, high ASA score, and synchronous liver metastases. Multivariate analysis identified nodal-positive primary tumors and synchronous metastases as independent risk factors for disease-free survival. Regarding overall survival, univariate analysis demonstrated significant links between poor survival and high preoperative IL-8 levels, elevated neutrophil-lymphocyte ratio (NLR), and presence of metastases in other organs. Multivariate analysis confirmed preoperative IL-8 and having three or more liver metastases as independent risk factors for overall survival. The impact of IL-8 on survival was particularly noteworthy, surpassing the influence of established clinical factors.

This study establishes preoperative IL-8 levels as a potential prognostic biomarker for overall survival in patients undergoing curative liver resection for CRC liver metastases. This study underscores the importance of incorporating IL-8 and other biomarkers into clinical decision-making, facilitating improved patient stratification and tailored treatment approaches. Further research and validation studies are needed to solidify the clinical utility of IL-8 as a prognostic marker.

suppression of methylation inhibitors (epigenetic genes) in hepatocarcinogenesis induced by diethylnitrosamine using glycyrrhetinic acid.

In the current work, we investigated the effect of sole GA combined with different agents such as doxorubicin (DOX) or probiotic bacteria (Lactobacillus rhamanosus) against hepatocarcinogenesis induced by diethylnitrosamine to improve efficiency. The genomic DNA was isolated from rats' liver tissues to evaluate either methylation-sensitive or methylation-dependent resection enzymes. The methylation activity of the targeting genes DLC-1, TET-1, NF-kB, and STAT-3 was examined using specific primers and cleaved DNA products. Furthermore, flow cytometry was used to determine the protein expression profiles of DLC-1 and TET-1 in treated rats' liver tissue.

Our results demonstrated the activity of GA to reduce the methylation activity in TET-1 and DLC-1 by 33.6% and 78%, respectively. As compared with the positive control. Furthermore, the association of GA with DOX avoided the methylation activity by 88% and 91% for TET-1 and DLC-1, respectively, as compared with the positive control. Similarly, the combined use of GA with probiotics suppressed the methylation activity in the TET-1 and DLC-1 genes by 75% and 81% for TET-1 and DLC-1, respectively. Also, GA and its combination with bacteria attenuated the adverse effect in hepatocarcinogenesis rats by altering potential methylomic genes such as NF-kb and STAT3 genes by 76% and 83%, respectively.

GA has an ameliorative effect against methylation inhibitors in hepatocellular carcinoma (HCC) by decreasing the methylation activity genes.

High-fat diet (HFD) consumption is associated with various metabolic disorders and diseases. Both pre-pregnancy and maternal obesity can have long-term consequences on offspring health. Furthermore, consuming an HFD in adulthood significantly increases the risk of obesity and metabolic disorders. However, an intriguing phenomenon known as the obesity paradox suggests that obesity may confer a protective effect on mortality outcomes in sepsis. In sepsis, activation of the cholinergic anti-inflammatory pathway (CAP) can help mitigate systemic inflammation. We employed a metabolic programming model to explore the relationship between maternal HFD consumption and offspring response to sepsis.

We fed female mice either a standard diet (SC) or an HFD during the pre-pregnancy, pregnancy, and lactation periods. Subsequently, we evaluated 28-day-old male offspring.

Notably, we discovered that offspring from HFD-fed dams (HFD-O) exhibited a higher survival rate compared with offspring from SC-fed dams (SC-O). Importantly, inhibition of the m1 muscarinic acetylcholine receptor (m1mAChR), involved in the CAP, in the hypothalamus abolished this protection. The expression of m1mAChR in the hypothalamus was higher in HFD-O at different ages, peaking on day 28. Treatment with an m1mAChR agonist could modulate the inflammatory response in peripheral tissues. Specifically, CAP activation was greater in the liver of HFD-O following agonist treatment. Interestingly, lipopolysaccharide (LPS) challenge failed to induce a more inflammatory state in HFD-O, in contrast to SC-O, and agonist treatment had no additional effect. Analysis of spleen immune cells revealed a distinct phenotype in HFD-O, characterized by elevated levels of CD4+ lymphocytes rather than CD8+ lymphocytes. Moreover, basal Il17 messenger RNA (mRNA) levels were lower while Il22 mRNA levels were higher in HFD-O, and we observed the same pattern after LPS challenge.

Further examination of myeloid cells isolated from bone marrow and allowed to differentiate showed that HFD-O macrophages displayed an anti-inflammatory phenotype. Additionally, treatment with the m1mAChR agonist contributed to reducing inflammatory marker levels in both groups. In summary, our findings demonstrate that HFD-O are protected against LPS-induced sepsis, and this protection is mediated by the central m1mAChR. Moreover, the inflammatory response in the liver, spleen, and bone marrow-differentiated macrophages is diminished. However, more extensive analysis is necessary to elucidate the specific mechanisms by which m1mAChR modulates the immune response during sepsis.

Chronic stress deteriorates the immune function of fish, thereby increasing their vulnerability to infections. However, the molecular and cellular mechanisms underlying stress-mediated immunosuppression and infection susceptibility in fish remain largely unknown. Understanding these mechanisms will contribute to improving fish welfare and their farm production. Herein, we review the challenges of sturgeon aquaculture in subtropical countries, where current climate change has giving rise to significant temperature increments during summer. This leads to the exposure of fish to stressful conditions during these months. Chronic heat stress deserves attention considering the rapid warming rate of the planet. It is already affecting wild fish populations, with disastrous consequences for sturgeons, which are one of the most endangered fish species in the world. In this context, we discuss the most recent advances through the studies on the effects of chronic heat stress on the innate immune components of sturgeons. To this end, we summarise the findings of studies focusing on the aquaculture of Russian sturgeons and observations made on other Acipenser species. Special attention is given to acute-phase proteins, as they might be valuable biomarkers of heat stress and infection, with applicability in monitoring the fish health status in farms.

Xenobiotics are primarily metabolized by hepatocytes in the liver, and primary human hepatocytes are the gold standard model for the assessment of drug efficacy, safety, and toxicity in the early phases of drug development. Recent advances in single-cell genomics demonstrate liver zonation and ploidy as main drivers of cellular heterogeneity. However, little is known about the impact of hepatocyte specialization on liver function upon metabolic challenge, including hepatic metabolism, detoxification, and protein synthesis.

Here, we investigate the metabolic capacity of individual human hepatocytes in vitro. We assess how chronic accumulation of lipids enhances cellular heterogeneity and impairs the metabolisms of drugs. Using a phenotyping five-probe cocktail, we identify four functional subgroups of hepatocytes responding differently to drug challenge and fatty acid accumulation. These four subgroups display differential gene expression profiles upon cocktail treatment and xenobiotic metabolism-related specialization. Notably, intracellular fat accumulation leads to increased transcriptional variability and diminishes the drug-related metabolic capacity of hepatocytes.

Our results demonstrate that, upon a metabolic challenge such as exposure to drugs or intracellular fat accumulation, hepatocyte subgroups display different and heterogeneous transcriptional responses.

SSc-ILD (scleroderma associated interstitial lung disease) is a complex rheumatic disease characterized in part by immune dysregulation leading to the progressive fibrotic replacement of normal lung architecture. Because improved treatment options are sorely needed, additional study of the fibroproliferative mechanisms mediating this disease has the potential to accelerate development of novel therapies. The contribution of innate immunity is an emerging area of investigation in SSc-ILD as recent work has demonstrated the mechanistic and clinical significance of the NLRP3 inflammasome and its associated cytokines of TNFα (tumor necrosis factor alpha), IL-1β (interleukin-1 beta), and IL-18 in this disease. In this review, we will highlight novel pathophysiologic insights afforded by these studies and the potential of leveraging this complex biology for clinical benefit.