Search Results (390)

Ferulic acid (FA) is a green feed additive. To investigate the molecular mechanisms by which FA attenuates heat stress-induced hepatic and intestinal oxidative stress, as well as cholesterol metabolism disorders in Megalobrama amblycephala (9.75 ± 0.04 g), individuals were fed diets supplemented with 0, 100, or 200 mg/kg FA for eight weeks, followed by exposure to heat stress at 34 °C for 48 h. The results indicated that FA supplementation reduced malondialdehyde levels and downregulation genes involved in inflammatory responses (e.g., interleukin-6), apoptosis (e.g., caspase 8), and endoplasmic reticulum stress (e.g., immunoglobulin binding protein) (p < 0.05), which collectively alleviated heat stress-induced hepatic and intestinal oxidative stress. FA supplementation increased the expression of ATP-binding cassette transporter A1, apolipoprotein A1, and liver X receptor α (p < 0.05), and restored liver and plasma TC levels to pre-stress levels (p < 0.05). Additionally, FA ameliorated the heat stress-induced dysbiosis of the intestinal microbiota and modulated the composition and abundance of metabolites in intestinal contents and plasma, some of which are associated with cholesterol metabolism. In conclusion, dietary FA can alleviate heat stress-induced hepatic and intestinal oxidative stress, maintain the stability of the intestinal microbiota and regulate metabolic profiles, and improve the cholesterol metabolism disorders caused by heat stress. Full article

Purpose: To investigate associations between lipid oxidation biomarkers (oxylipins), antioxidant micronutrients, lipoprotein particles, and apolipoproteins in multiple sclerosis (MS). Methods: Blood and neurological assessments were collected from 30 healthy controls, 68 relapsing remitting MS subjects, and 37 progressive MS subjects. Hydroxy (H) and hydroperoxy lipid peroxidation products of the polyunsaturated fatty acids (PUFAs) arachidonic (20:4, ω-6), linoleic (octadecadienoic acid or ODE, 18:2, ω-6), eicosapentaenoic (20:5, ω-3), and α-linolenic (18:3, ω-3) acids were measured using liquid chromatography–mass spectrometry. Antioxidant micronutrients, including β-cryptoxanthin and lutein/zeaxanthin, were quantified by high-performance liquid chromatography. Lipoprotein and metabolite profiles were obtained using nuclear magnetic resonance spectroscopy. Regression models were adjusted for age, sex, body mass index, and disease status. Results: The 9-hydroxy octadecadienoic acid to 13-hydroxy octadecadienoic acid ratio (9-HODE/13-HODE ratio), which reflects autoxidative versus enzymatic oxidation, was associated with MS status (p = 0.002) and disability on the Expanded Disability Status Scale (p = 0.004). Lutein/zeaxanthin (p = 0.023) and β-cryptoxanthin (p = 0.028) were negatively associated with the 9-HODE/13-HODE ratio. Apolipoprotein-CII, a marker of liver-X-receptor (LXR) signaling, was associated with 9-HODE/13-HODE ratio and other oxylipins. Octadecadienoic fatty acid-derived oxylipins were negatively associated with LC3A, a mitophagy marker, and positively correlated with 7-ketocholesterol, a cholesterol autoxidation product. Conclusions: Autoxidation of PUFAs is associated with greater disability in MS. Higher β-cryptoxanthin and lutein/zeaxanthin were associated with reduced auto-oxidation. Lipid peroxidation shows associations with LXR signaling, mitophagy, inflammation, and cholesterol autoxidation. Full article

Background: Liver X receptors (LXRs) are critical regulators of cholesterol homeostasis that modulate T cell function with anti-inflammatory effects. LXR downregulation has been implicated in the pathogenesis of inflammatory bowel disease (IBD), although its underlying mechanisms remain to be fully elucidated. Recent evidence has confirmed the link between T cell senescence and autoimmune diseases. Here, we sought to investigate whether and how LXRs regulate T cell senescence in controlling intestinal inflammation. Methods and Results: We found that LXRβ expression was decreased in the colons of mice with experimental colitis, and LXRβ deficiency (Lxrβ^−/−) significantly aggravated their colitis. Intriguingly, this finding was accompanied by enhanced CD4⁺ T cell senescence both in the colons and spleens of Lxrβ^−/− mice, evidenced by upregulation of SA-β-gal levels and the remarkable expansion of effector memory subclusters in CD4⁺ T cells. Moreover, senescent Lxrβ^−/− CD4⁺ T cells secreted elevated levels of proinflammatory cytokines, especially in effector memory populations, exhibiting a pronounced proinflammatory phenotype. RNA-sequencing further confirmed the role of LXRβ in restricting CD4⁺ T cell senescence. Mechanistically, the absence of LXRβ in CD4⁺ T cells directly enhanced senescence by promoting the cGAS/STING pathway. Blocking STING signaling with a targeted inhibitor significantly alleviated senescence in Lxrβ^−/− CD4⁺ T cells. Conclusions: Our findings demonstrate the role of LXRβ in regulating intestinal CD4⁺ T cell senescence to inhibit colitis development, identifying LXRβ as a potential therapeutic target for treating IBD. Full article

Hepatocellular carcinoma (HCC) is a global health threat, and gut microbiota play a pivotal role in its pathogenesis through the gut–liver axis. However, the literature contains divergent or opposing findings: key microbial metabolites, such as secondary bile acids and indole derivatives, exhibit potent pro- and anti-tumorigenic activities across different studies, hindering a unified understanding of their veritable roles. To resolve this ambiguity, this review proposes a unifying “context dependency” framework. We posit that the functions of gut microbiota and their metabolites are not fixed but are dynamically determined by the host’s physiological and pathological “context,” defined here as the integrated dynamic background shaped by local metabolite concentrations, host immune status, specific receptor expression, and tumor microenvironment (TME) features. This framework is systematically substantiated through an analysis of the dichotomous effects of major microbial metabolites, including bile acids (BAs), short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and indole derivatives. We further elucidate that the key “contextual factors” governing these functional outcomes include the TME, host immune status, metabolite concentration gradients, and the activation patterns of specific signaling pathways (e.g., farnesoid X receptor/takeda G protein-coupled receptor 5, aryl hydrocarbon receptor). This novel framework not only provides a theoretical foundation for integrating existing paradoxical findings but also paves the way for the future development of context-specific precision diagnostic biomarkers and targeted microbial intervention therapies for HCC. Full article

Chronic liver disease (CLD) encompasses a spectrum of progressive disorders, including metabolic dysfunction steatotic-associated liver disease (MASLD) and primary biliary cholangitis (PBC), which together represent a significant global health burden with few effective therapeutic options. The fibrogenic process, common to most forms of CLD, is driven by a complex interplay of cellular stress, inflammation, and wound-healing responses. Nicotinamide adenine dinucleotide phosphate oxidase isoforms 1 and 4 (NOX1 and NOX4) have emerged as key enzymatic sources of reactive oxygen species (ROS), serving as central mediators of hepatic oxidative stress, fibrogenesis, and inflammation. Setanaxib is a first-in-class, orally bioavailable, selective dual inhibitor of NOX1 and NOX4 that has progressed to clinical evaluation. This review synthesizes current knowledge on the molecular pharmacology of the NOX1/4 axis, preclinical evidence from translational models, and clinical trial outcomes to critically assess the therapeutic potential of targeted NOX inhibition in hepatic fibrosis. By attenuating hepatic stellate cell activation, modulating TGF-β signaling, reducing extracellular matrix (ECM) deposition, and regulating hepatic macrophage polarization, setanaxib exhibits pleiotropic antifibrotic effects. The compound also demonstrates favorable pharmacokinetic properties and a good safety profile in patients with PBC, with emerging evidence suggesting meaningful improvements in fatigue and quality of life. Finally, we examine the complex, and sometimes paradoxical, roles of NOX4 in liver pathophysiology, compare the evolving therapeutic landscape with other approaches such as farnesoid X receptor (FXR) agonists, and propose future paradigms integrating artificial intelligence–driven predictive modeling to optimize patient stratification and therapeutic response in this new era of redox-targeted hepatoprotective therapy. Full article

Steatotic liver disease (SLD) represents a major global health burden, with environmental toxicants emerging as critical contributors alongside metabolic dysfunction. Bisphenol F (BPF), an increasingly prevalent replacement for bisphenol A, is widely detected in human biological samples and environment, yet its hepatotoxic mechanisms remain incompletely characterized. This review synthesizes current evidence on BPF-induced SLD, with a particular focus on resolving the “pregnane X receptor (PXR) paradox”, the mismatch between BPF’s weak direct activation of PXR and the PXR-like metabolic effects observed in vivo. Comprehensive analysis of mechanistic pathways reveals that BPF-induced SLD develops predominantly through PXR-independent mechanisms involving oxidative stress, endoplasmic reticulum dysfunction, Drp1-mediated mitochondrial fission, NLRP3/NF-κB-driven inflammation, dysregulated post-translational modifications, and epigenetic remodelling. These converging pathways collectively disrupt hepatic lipid metabolism, promote triglyceride accumulation, and establish a self-perpetuating cycle of metabolic dysfunction. Notably, weak indirect PXR modulation via oxidative stress represents a secondary, non-causal mechanism unsupported by functional validation. This framework distinguishes toxicant-induced steatosis from metabolic dysfunction-associated steatotic liver disease while highlighting critical evidence gaps—particularly the absence of causal PXR validation studies and human epidemiological data. Therapeutic opportunities exist at validated convergence points including mitochondrial dynamics (Drp1), inflammatory signalling (NLRP3/NF-κB), and energy metabolism (AMPK-mTOR), though combination strategies targeting multiple pathways will likely be required for durable disease reversal. These findings necessitate the expansion of regulatory screening paradigms to incorporate cellular stress pathway biomarkers alongside traditional nuclear receptor endpoints, ensuring comprehensive hepatotoxic risk assessment of emerging BPA substitutes. Full article

Polyphenols, as natural compounds abundant in plant-derived foods, have been recognised for their human health benefits. This study evaluates the multifunctional properties of Biombalance^TM (BB), a grape seed extract rich in oligomeric procyanidins, in various in vitro and in vivo models. BB was studied to assess (i) its antimicrobial effects in different bacterial species; (ii) its protective effects against oxidative and inflammatory stress in Caco-2 cells; and (iii) its effects in mice, which were fed a standard diet with or without BB at two different doses (BB1X and BB2X) to understand the impacts of BB on microbiota and gut homeostasis. BB selectively inhibited several bacterial species, including Staphylococcus aureus, Helicobacter pylori, and Blautia coccoides. In addition, BB protected Caco-2 cells against hydrogen peroxide (H₂O₂)-induced oxidative damage and lipopolysaccharide (LPS)-induced oxidative and inflammatory stress. In vivo, BB supplementation upregulated the expression of antioxidant and homeostasis genes in the colon, ileum, and liver, accompanied by dose-dependent changes in the gut microbiota composition. Functional predictions indicated favourable modulation of microbial metabolic pathways, including those involved in antioxidant capacity and glutamate degradation. Furthermore, BB positively influenced key gut–brain axis mediators, including GLP-1, the GLP-1 receptor, and NPY. These findings highlight the potential of Biombalance^TM to support health and gut–brain communication and to protect against oxidative and inflammatory stress in the gut. Full article

Background and Objectives: ADAM17, a sheddase that regulates cytokine and receptor ectodomains, amplifies inflammatory signaling. Acute liver injury (ALI) is driven by dysregulated inflammation, accompanied by both oxidative and endoplasmic reticulum (ER) stress responses. We investigated whether pharmacological inhibition of ADAM17 with GW280264X mitigates lipopolysaccharide (LPS)-induced acute liver injury by targeting these pathways. Methods: Male C57BL/6J mice received intraperitoneal LPS (10 mg/kg). GW280264X (500 µg/kg, i.p.) was administered at one and three hours post-LPS treatment. At the fifth hour, serum and liver samples were collected to determine serum ALT/AST levels and to perform hematoxylin and eosin (H&E) staining. Inflammatory (TNF-α), oxidative (MDA, 4-HNE, Fe²⁺, GSH; NRF2/KEAP1), endoplasmic reticulum (ER) stress (GRP78, ATF6, CHOP), and ferroptosis-related (GPX4, SLC7A11) markers, along with ADAM17 protein levels, were analyzed using ELISA, colorimetric assays, and Western blotting. Results: LPS triggered hepatic injury. This was accompanied by marked elevations in TNF-α, oxidative indices (MDA, 4-HNE, Fe²⁺) and ER stress proteins (GRP78, ATF6, CHOP), together with depletion of hepatic GSH. GW280264X significantly reduced AST levels, attenuated inflammatory, oxidative, and ER stress responses, and improved hepatic histopathology. GPX4 and SLC7A11 tended to increase following treatment, but the changes did not reach statistical significance and should be interpreted cautiously due to the limited sample size (n = 5). Similarly, ADAM17 protein levels tended to decrease, although the change was not statistically significant. Conclusions: Pharmacological inhibition of ADAM17 with GW280264X may confer early hepatoprotection in LPS-induced ALI by attenuating inflammatory, oxidative and ER stress pathways. ADAM17 inhibition yielded partial and statistically non-significant protective effects at this early stage; therefore, these findings should be considered exploratory. Future studies with larger sample sizes and longer observation periods are warranted to confirm the durability and mechanistic basis of this response. Full article

Androgen receptor (AR) signaling has a pivotal role in hepatic lipid homeostasis, as well as in core metabolic functions such as lipogenesis, fatty acid oxidation, and insulin sensitivity. Dysregulation of AR function has been demonstrated in both animal and human studies to disrupt these crucial metabolic pathways, thereby promoting hepatic steatosis. Several causes can lead to AR dysregulation, including genetic mutations or polymorphisms, epigenetic and post-transcriptional modifications, as well as various endocrine disturbances. Prompted by a diagnostically challenging case of a lean 34-year-old male with persistent ALT-predominant transaminasemia, unexplained suboptimal dyslipidemia despite adherence to drug therapy and a healthy lifestyle, and chronically elevated creatine phosphokinase levels irrespective of statin use or exercise intensity, we highlight the overlooked mechanistic link between AR dysfunction and liver–muscle disruption in lean-MASLD patients. Considering the pivotal role of AR in liver–muscle crosstalk, we emphasize the importance of evaluating AR signaling pathways through targeted genetic testing in cases of lean-MASLD among the male population, as well as addressing other extrahepatic manifestations, such as neuromuscular diseases, closely related to AR dysfunction. This clinical strategy may ultimately optimize lean-MASLD management, particularly in view of the emerging utilization of AR-targeted therapeutic modalities, and may also facilitate the management of systemic manifestations associated with altered AR signaling pathways. Full article

Hepatic stellate cells (HSC) play a crucial role in the fibrotic response of the liver when they transdifferentiate from quiescent cells (qHSC) to myofibroblast (MFB). Ca²⁺ responses mediated by purinergic P2Y receptors are not fully characterized in qHSC and MFB. The objective of this study was to compare the expression of purinergic receptors with the capacity to mobilize intracellular Ca²⁺ in both phenotypes, as well as to explore the potential role of these signals in HSCs activation. Isolated mouse HSC were quiescent on day 2 and became MFB on day 7 when cultured in high stiffness substrate. Both phenotypes expressed the transcripts of P2ry1, P2ry2, P2ry6 and P2x7, and exhibited a similar Ca²⁺ response to UDP, UTP and Bz-ATP, indicating comparable activity in P2Y6, P2Y2 and P2X7 receptors. In contrast, P2y12 transcript was detected only in MFB. Remarkably, P2Y1 receptor was identified in qHSC, an observation that had not yet been reported. Evidence of P2Y1 receptor functionality was obtained from stimulation with ADP. ADP-elicited Ca²⁺ mobilization was more potent in qHSC in comparison to MFB. Interestingly, ADP stimulation worsens the transdifferentiation of qHSC to MFB after 4 or 7 days in culture, strongly suggesting the role of this purinergic receptor in HSC activation. Full article

Nuclear receptors are ligand-activated transcription factors that, in response to lipophilic hormones, vitamins, and dietary lipids, regulate numerous aspects of mammalian physiology. Bile acid receptors represent well-defined targets for the development of novel therapeutic approaches for metabolic and inflammatory diseases. The farnesoid X receptor (FXR) was identified as an orphan steroid receptor-like nuclear receptor, and its activation is crucial in many physiological functions of the liver. A vital function of FXR is to influence the amount of bile acids in hepatocytes by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting enterohepatic circulation, thereby protecting hepatocytes from toxic bile acid accumulation. FXR activation induces distinctive changes in circulating cholesterol in animal models and humans. We present an evaluation of the interaction of various obeticholic acid analogs and other bile salts by studying their binding energies and receptor-ligand interactions using AutoDock 4.2.6 software. The results open the possibility of using new alternatives by deriving structures at position 3 of the steroid nucleus. Full article

This study aimed to investigate the effects of naringin (NG) on growth performance, antioxidant status, intestinal barrier function, and immune stress in broilers challenged with lipopolysaccharide (LPS). A total of 144 one-day-old Ross 308 broiler chicks were randomly allocated into 2 treatment groups, with six replicates per group and 12 birds per replicate. The groups consisted of a control group (fed a basal diet) and an NG group (fed the basal diet supplemented with 200 mg/kg NG). The trial lasted 21 days; to evaluate the impact of NG on the late-stage growth performance of broilers, the rearing trial continued until 35 days. Body weight was recorded on days 21 and 35 to evaluate growth performance. A 2 × 2 factorial design was implemented in which broilers were challenged with or without LPS, and their diets were supplemented with or without NG. On day 21, two birds per replicate were intraperitoneally injected with 0.5 mg/kg body weight (BW) LPS, while another two birds received an equal volume of saline, in each group of 12 birds. Birds were slaughtered 3 h post-injection for sample collection. Dietary NG supplementation had no significant effect on growth performance (p > 0.05). However, NG markedly improved plasma liver function markers following LPS challenge (p < 0.05). NG significantly increased hepatic glutathione peroxidase (GSH-Px) activity, duodenal and ileal catalase (CAT) activity, and ileal GSH-Px activity (p < 0.05) while reducing malondialdehyde (MDA) levels in the liver, duodenum, jejunum, and ileum, as well as hydrogen peroxide (H₂O₂) levels in the jejunum and ileum (p < 0.05). Dietary NG supplementation significantly upregulated the relative mRNA expression of Toll-like receptor 4 (TLR4) and interferon-gamma (IFN-γ) in the liver (p < 0.05) and attenuated the LPS-induced upregulation of tumor necrosis factor-alpha (TNF-α) mRNA expression in the jejunum (p < 0.05). NG reduced serum diamine oxidase (DAO) levels (p < 0.05), increased villus height in the duodenum and jejunum (p < 0.05), and increased the villus-height-to-crypt-depth (VH/CD) ratio in the jejunum (p < 0.05). Moreover, NG markedly upregulated the relative mRNA expression of zonula occludens-1 (ZO-1) and occludin in the duodenum while drastically downregulating the relative expression of mucin-2 in the duodenum and ileum (p < 0.05). NG further reduced mucin-2 expression in the jejunum and mitigated the LPS-induced downregulation of ZO-1 in the ileum (p < 0.05). In addition, NG significantly upregulated the expression of X-linked inhibitor of apoptosis protein (XIAP) and B-cell lymphoma 2 (Bcl-2) and downregulated the expression of matrix metalloproteinase-13 (MMP-13) in the liver of LPS-challenged broilers (p < 0.05). Conclusions: Dietary NG supplementation alleviated LPS-induced intestinal and hepatic injury in broilers. NG attenuated the adverse effects of LPS challenge on intestinal barrier function and enhanced antioxidant capacity in broilers by modulating intestinal tight junction expression and antioxidant enzyme activity. NG may serve as a promising eco-friendly additive to enhance resilience against immune stress in broilers. Full article

Lipid metabolism is a vital biological process essential for human health, encompassing key pathways necessary for the survival and homeostasis of all organisms. Liver X Receptors (LXRs) are extensively acknowledged as pivotal regulators of lipid homeostasis and inflammatory responses. Pharmacological activation of Liver X Receptor (LXR) has been shown to increase expression of ApoE and ABCA1 proteins, reducing neurodegeneration in murine models of Alzheimer’s disease. Because previous reports determined that Nectandra reticulata (Lauraceae) extract has agonistic LXRs activity, the objective of this study was to determine the metabolites present in this extract and to evaluate their in silico and in vitro agonistic activity. The chromatographic analysis revealed the presence of three glycosylated flavonols. The in silico study showed that isolated flavonoids generate a hydrogen bond with T302 and T316 (LXRα and LXRβ, respectively). The in vitro study showed that the flavonoids increased the expression of mRNA of both APOE and ABCA1 target genes of LXRs, as observed by qRT-PCR. The bioactive flavonoids isolated in this study possess a documented antioxidant effect; when combined with their LXR agonist activity, they become promising bioactive candidates for use in nutraceutical formulations aimed at promoting brain health and anti-inflammatory effects. Full article

Hypersensitized P2X3 receptor signaling has been described to play a role in several disorders, including chronic cough. The goal of our in vitro and in vivo studies was to investigate the biotransformation and the influence of CYP3A4 inhibition on the pharmacokinetics of the selective P2X3 antagonist filapixant. Metabolic turnover of filapixant in human liver microsomes and hepatocytes was moderate to high, indicating a complex metabolic pattern with mainly oxidative biotransformation. In recombinant CYP enzymes, depletion of filapixant was observed mainly with CYP3A4 and, to a significantly lesser extent, with CYP1A1, 2D6, 2J2, and 3A5. Drug depletion of [³H]filapixant and metabolite formation in human liver microsomes was significantly inhibited in the presence of strong CYP3A4 inhibitors, whereas other CYP isoform–selective inhibitors showed no or very minor effects. Co-administration of multiple daily doses of 200 mg itraconazole with 80 mg filapixant in humans increased the AUC and C_max of filapixant to 4.01 and 1.89-fold, respectively, indicating that filapixant is a moderately sensitive CYP3A4 substrate. Co-administration of itraconazole also prolonged the half-life of filapixant from 12.1 h to 22.8 h. Overall, changes in AUC, C_max, and half-life indicate that both the bioavailability and elimination of filapixant were affected. Filapixant was well tolerated alone and in combination with itraconazole. Full article

Gut microbiota changes have emerged as central players in the pathogenesis of both metabolic dysfunction-associated steatohepatitis (MASH) and inflammatory bowel disease (IBD). Although these diseases affect distinct primary organs, they share converging mechanisms driven by dysbiosis, including loss of beneficial short-chain fatty acid-producing taxa such as Faecalibacterium prausnitzii and Roseburia, enrichment of pro-inflammatory Enterobacteriaceae, and disruption of bile acid and tryptophan metabolism. These shifts compromise epithelial barrier integrity, promote the translocation of microbial products such as lipopolysaccharide, and trigger toll-like receptor 4-mediated activation of inflammatory cascades dominated by tumor necrosis factor-alpha, interleukin-6, and transforming growth factor-beta. In MASH, this dysbiotic environment fuels hepatic inflammation, insulin resistance, and fibrogenesis, while in IBD it sustains chronic mucosal immune activation. Shared features include impaired butyrate availability, altered bile acid pools affecting farnesoid X receptor and Takeda G protein-coupled Receptor 5 signaling, and defective aryl hydrocarbon receptor activation, all of which link microbial dysfunction to host metabolic and immune dysregulation. Understanding these overlapping pathways provides a deeper understanding of the role of the gut-liver and gut-immune axes as unifying frameworks in disease progression. This narrative review synthesizes current evidence on gut microbiota in MASH and IBD, underscoring the need for longitudinal, multi-omics studies and microbiome-targeted strategies to guide personalized therapeutic approaches. Full article