Search Results (605)

Cadmium (Cd) is a toxic environmental heavy metal that exerts harmful effects on multiple tissues, including the kidney, liver, lung, and bone, and is also associated with the development of anemia. However, the precise molecular mechanisms underlying Cd-induced toxicity remain incompletely understood. In this paper, we review the recent molecular mechanisms of Cd-induced toxicity and its modification, with a particular emphasis on our recent findings. Using a combination of DNA microarray analysis, protein–DNA binding assays, and siRNA-mediated gene silencing, we identified several transcription factors, YY1, FOXF1, ARNT, and MEF2A, as novel molecular targets of Cd. The downregulation of their downstream genes, including UBE2D2, UBE2D4, BIRC3, and SLC2A4, was directly associated with the expression of cytotoxicity. In addition, PPARδ plays a pivotal role in modulating cellular susceptibility to Cd-induced renal toxicity, potentially by regulating apoptosis-related signaling pathways. In addition to apoptosis pathways, Cd toxicity through ROS generation, ferroptosis and pyroptosis were summarized. Furthermore, it has been revealed that Cd suppresses the expression of iron transport-related genes in duodenal epithelial cells leading to impaired intestinal iron absorption as well as decreased hepatic iron levels. These findings provide a mechanistic basis for Cd-induced iron deficiency anemia, implicating disrupted iron homeostasis as a contributing factor. Full article

(1) Background: Epidemiological studies link ozone (O₃) exposure to diabetes risk, but mechanisms and early biomarkers remain unclear. (2) Methods: Female mice exposed to 0.5/1.0 ppm O₃ were assessed for glucose tolerance and HOMA (homeostasis model assessment) index. Genes related to impaired glucose tolerance and insulin resistance were screened through the Comparative Toxicogenomics Database (CTD), and verified using quantitative real-time PCR. In addition, liver histopathological observations and the determination of basic biochemical indicators were conducted, and targeted metabolomics analysis was performed on the liver to verify glycogen levels and gene expression. In vitro validation was conducted with HepG2 and Min6 cell lines. (3) Results: Fasting blood glucose and insulin resistance were elevated following O₃ exposure. Given that the liver plays a critical role in glucose metabolism, we further investigated hepatocyte apoptosis and alterations in glycogen metabolism, including reduced glycogen levels and genetic dysregulation. Metabolomics analysis revealed abnormalities in fructose metabolism and glycogen synthesis in the livers of the O₃-exposed group. In vitro studies demonstrated that oxidative stress enhances both liver cell apoptosis and insulin resistance in pancreatic islet β cells. (4) Conclusions: O₃ triggers prediabetes symptoms via hepatic metabolic dysfunction and hepatocyte apoptosis. The identified metabolites and genes offer potential as early biomarkers and therapeutic targets. Full article

Temperature fluctuations caused by climate change and global warming pose a threat to fish. The burbot (lota lota) population is particularly sensitive to increased water temperature, but the systematic impacts of high-temperature exposure on their liver and intestinal health remain unclear. In January of 2025, we collected wild adult burbot individuals from the Ussuri River (water temperature: about 2 °C), China. The burbot were exposed to 2 °C, 7 °C, 12 °C, 17 °C, and 22 °C environments for 96 h; then, the liver and intestinal contents were subsequently collected for histopathology observation, immunohistochemistry, biochemical index assessment, and transcriptome/16S rDNA sequencing analysis. There was obvious liver damage including hepatocyte necrosis, fat vacuoles, and cellular peripheral nuclei. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were elevated and subsequently decreased. Additionally, the malondialdehyde (MDA) level significantly increased with increasing temperature. These results indicate that 7 °C (heat stress temperature), 12 °C (tipping point for normal physiological metabolism status), 17 °C (tipping point for individual deaths), and 22 °C (thermal limit) are critical temperatures in terms of the physiological response of burbot during their breeding period. In the hepatic transcriptome profiling, 6538 differentially expressed genes (DEGs) were identified, while KEGG enrichment analysis showed that high-temperature stress could affect normal liver function by regulating energy metabolism, immune, and apoptosis-related pathways. Microbiomics also revealed that acute heat stress could change the intestinal microbe community structure. Additionally, correlation analysis suggested potential regulatory relationships between intestinal microbe taxa and immune/apoptosis-related DEGs in the liver. This study revealed the potential impact of environmental water temperature changes in cold habitats in winter on the physiological adaptability of burbot during the breeding period and provides new insights for the ecological protection of burbot in the context of global climate change and habitat warming. Full article

Background: The metabolic dysfunction-associated steatotic liver disease (MASLD) represents an escalating global health concern, with effective treatments still lacking. Given its complex pathogenesis, multi-targeted strategies are highly desirable. Methods: This study reports the isolation of four flavone C-glycosides (FCGs) from Dianthus superbus L. and explores their potential in treating MASLD. The bioactivity and underlying mechanisms of FCGs were systematically evaluated by integrating network pharmacology, molecular docking, and zebrafish model validation. Results: Network pharmacology analysis revealed that FCGs may modulate multiple MASLD-related pathways, including lipid metabolism, insulin signaling, inflammation, and apoptosis. Molecular docking further confirmed strong binding affinities between FCGs and key protein targets involved in these pathways. In the zebrafish model of MASLD induced by egg yolk powder, FCGs administration markedly attenuated obesity, hepatic lipid accumulation, and liver tissue damage. Furthermore, FCGs improved lipid metabolism and restored locomotor function. Molecular analyses confirmed that FCGs upregulated PPARγ expression to promote lipid metabolism, restored insulin signaling by enhancing INSR, PI3K, and AKT expression, and suppressed inflammation by downregulating TNF, IL-6 and NF-κB. Additionally, FCGs inhibited hepatocyte apoptosis by elevating the BCL-2/BAX ratio. Conclusions: These findings highlight the multi-pathway regulatory effects of FCGs in MASLD, underscoring its potential as a novel therapeutic candidate for further preclinical development. Full article

Background/Objectives: Thiamethoxam (TMX) is one of the most extensively utilized insecticides of the neonicotinoid family; however, its application is associated with notable toxic effects on multiple organs of mammals. Our purpose was to explore the potential hepatoprotective effect of taurine (TAU) and/or gallic acid (GA) against TMX-induced liver damage, with an emphasis on their role in regulating SIRT-1/PGC-1α, NF-κB/iNOS, and p53/Bax/caspase-3 pathways. Methods: Rats were assigned to seven groups (n = 6) and gavaged daily for 28 days with saline (control group), TAU at 50 mg/kg, GA at 20 mg/kg, TMX at 78.15 mg/kg, TMX + TAU, TMX + GA, and TMX + TAU + GA. Results: The findings revealed that TAU and/or GA attenuated TMX-induced liver injury, as demonstrated by the restoration of hepatic performance hallmarks and histological structure. TAU and GA mitigated TMX-mediated oxidative stress and boosted the antioxidant defense mechanism by upregulating the transcription levels of SIRT-1, PGC-1α, Nrf2, and HO-1. Moreover, TAU and GA suppressed TMX-associated inflammatory response by increasing IL-10 concentration and lowering the levels of NF-κB, IL-1β, and iNOS; the mRNA levels of NLRP3; and TNF-α immunoexpression. Both compounds, individually or concurrently, exerted an anti-apoptotic effect in TMX-treated rats, evidenced by increased Bcl-2 expression and reduced p53 mRNA level, Bax expression, and caspase-3 concentration. Conclusions: TAU and/or GA may be regarded as promising remedies that can alleviate TMX-induced hepatotoxicity by activating SIRT-1/PGC-1α signaling and abolishing inflammation and apoptosis. Full article

Approximately 90% of liver cancer cases are classified as hepatocellular carcinomas (HCCs), with chemotherapy and immunotherapy being the most recommended treatment options. While conventional chemotherapy specifically targets rapidly dividing cancer cells, it can also impact on healthy cells that are proliferating quickly. This collateral damage to healthy cells, along with the potential for cancer cells to develop resistance, presents significant challenges for conventional chemotherapy in liver cancer patients. Hepatic artery infusion of chemotherapy (HAIC) generally leads to reduced toxicity and fewer side effects. The process of catheter insertion is usually performed under local anesthesia, with lidocaine being the preferred choice to combine with various chemotherapeutics in HCC treatment. In our study, we explored the effects of repurposing lidocaine in combination with cisplatin or 5-fluorouracil (5-FU) on two HCC cell lines, HepG2 and Hep3B. Our cytotoxicity analysis revealed that lidocaine functions as a chemosensitizer for cisplatin and 5-FU in both HepG2 and Hep3B cells. Specifically, we observed an increase in the subG1 population and a reduction in cytosolic reactive oxygen species in cisplatin- or 5-FU-treated HepG2 and Hep3B cells. Interestingly, lidocaine selectively decreased the reduced/oxidized glutathione ratio in cisplatin- or 5-FU-treated HepG2 cells but not in Hep3B cells. Furthermore, lidocaine induced endoplasmic reticulum stress, apoptosis, mitochondrial membrane depolarization, lipid peroxidation, and autophagy while suppressing cellular proliferation HepG2 and Hep3B cells. In conclusion, our study demonstrates the synergistic potential of combining lidocaine with cisplatin or 5-FU for the treatment of HCC, indicating that lidocaine may serve as an effective chemosensitizer. These findings highlight a new clinical advantage of using repurposing lidocaine as a chemosensitizer in the current HAIC procedure, suggesting that this combination warrants further exploration through rigorous clinical trials. In the future, we can better optimize therapeutic regimens, potentially leading to improved patient outcomes in HCCs. Full article

Hypoxia represents a critical environmental stressor in aquaculture, significantly disrupting aquatic organisms’ physiological homeostasis and thereby constraining the sustainable development of aquaculture industries. To elucidate the mechanisms underlying hypoxia-induced metabolic regulation in aquatic species, this study employed hybrid yellow catfish (Pelteobagrus vachelli ♀ × Leiocassis longirostris ♂) as a model organism to systematically investigate the multidimensional physiological responses in brain, liver, and muscle tissues under hypoxia (0.7 mg/L) and reoxygenation (7.0 mg/L) conditions. Through qRT-PCR and enzymatic activity analyses, we comprehensively assessed molecular alterations associated with oxygen sensing (HIF-1α gene), respiratory metabolism (PFKL, HK1, PK, CS, and LDHA genes and corresponding enzyme activities), oxidative stress (SOD1, SOD2, GSH-PX, and CAT genes, along with LPO, MDA, PCO, T-SOD, GSH-PX, and CAT levels), apoptosis (Caspase-3, Bax/Bcl-2), inflammatory response (IL-1β, IKKβ), and mitochondrial function (COXIV, PGC-1α, ATP5A1). Key findings demonstrated pronounced HIF-1α activation across all examined tissues. Hepatic tissues exhibited adaptive metabolic reprogramming from aerobic to anaerobic metabolism, whereas cerebral tissues displayed suppressed anaerobic glycolysis during prolonged hypoxia, and muscular tissues manifested concurrent inhibition of both glycolytic and aerobic metabolic pathways. Notably, skeletal muscle exhibited marked oxidative stress accompanied by mitochondrial dysfunction, exacerbated inflammation, and apoptosis activation during hypoxia/reoxygenation cycles. This study delineates tissue-specific adaptive mechanisms to hypoxia in yellow catfish, providing theoretical foundations for both piscine hypoxia physiology research and aquaculture practices. Full article

Copper pyrithione (CuPT), an emerging biocide used in ship antifouling coatings, may accumulate in marine sediments and pose risks to non-target organisms. However, current research on CuPT toxicity remains limited. Litopenaeus vannamei, one of the world’s most important aquaculture shrimp species, relies heavily on its hepatopancreas for energy metabolism, detoxification, and immune responses. Due to their benthic habitat, these shrimps are highly vulnerable to contamination in sediment environments. This study investigated the toxicological response in the hepatopancreas of L. vannamei exposed to CuPT (128 μg/L) for 3 and 48 h. Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) fluorescence staining revealed increased apoptosis, deformation of hepatic tubule lumens, and the loss of stellate structures in the hepatopancreas after CuPT 48 h exposure. A large number of differentially expressed genes (DEGs) were identified by transcriptomics analysis at 3 and 48 h, respectively. Most of these DEGs were related to detoxification, glucose transport, and immunity. Metabolomic analysis identified numerous significantly different metabolites (SDMs) at both 3 and 48 h post-exposure, with most SDMs associated with energy metabolism, fatty acid metabolism, and related pathways. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of metabolomics and transcriptome revealed that both DEGs and SDMs were enriched in arachidonic acid metabolism, fatty acid biosynthesis, and glycolysis/gluconeogenesis pathways at 3 h, while at 48 h they were enriched in the starch and sucrose metabolism, amino sugar and nucleotide sugar metabolism, and galactose metabolism pathways. These results suggested that CuPT disrupts the energy and lipid homeostasis of L. vannamei. This disruption compelled L. vannamei to allocate additional energy toward sustaining basal physiological functions and consequently caused the accumulation of large amounts of reactive oxygen species (ROS) in the body, leading to apoptosis and subsequent tissue damage, and ultimately suppressed the immune system and impaired the health of L. vannamei. Our study elucidates the molecular mechanisms of CuPT-induced metabolic disruption and immunotoxicity in L. vannamei through integrated multi-omics analyses, providing new insights for ecological risk assessment of this emerging antifoulant. Full article

Lipophenols, combining phenolic and lipid characteristics in an amphiphilic molecule, offer unique bioactive properties with therapeutic potential, including anti-inflammatory and anti-oxidant effects. Thus, palmitoyl-epigallocatechin gallate (PEGCG), a lipophilic derivative of the extensively studied (poly)phenol epigallocatechin gallate (EGCG), has been stressed concerning enhanced stability in lipid-rich environments and bioavailability due to improved cellular uptake. Nonetheless, the effect of lipophilic esterification on some cellular processes, particularly at the mitochondrial level, remains underexplored. According to this knowledge gap, the present study uncovered the cytotoxic and mitochondrial effects of PEGCG, in vitro, upon the liver hepatocarcinoma cell line HepG2. The range of determinations developed, including the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay, flow cytometry, and electron microscopy, allowed describing the distinct biological potential for both EGCG and PEGCG. Thus, while EGCG exhibited minimal cytotoxicity and apoptosis induction, PEGCG reduced cell viability dose-dependently at 24 h and triggered significant mitochondrial damage, including fragmentation and cristae loss, at 1 µmol/L. However, at 48 h, PEGCG-treated cells recovered viability and mitochondrial structure, suggesting the activation of adaptive mechanisms for the molecular changes induced by PEGCG. These findings underscore the dynamic interplay between lipophilic catechins and cellular stress responses, offering valuable insights into the PEGCG’s potential as a therapeutic agent and laying a foundation for further exploration of its biological power. Full article

Background: The STING (Stimulator of Interferon Genes) pathway plays a vital role in the body’s innate immune defense system, primarily involved in DNA sensing and type I interferon production. While STING is well-established in various immune cells, its role in natural killer (NK) cells, particularly within the context of liver fibrosis, remains inadequately explored. Aim: The current study investigates the relationship between STING expression, NK cell activity, and insulin receptor (IR) signaling in patients with metabolic dysfunction-associated steatohepatitis (MASH). Methods: Peripheral NK cells were isolated from healthy controls and MASH patients with varying stages of liver fibrosis (early: F1/F2; advanced: F3/F4). The expressions of STING, IR, NK cell activation markers (CD107a, NKp46), and NK cell inhibitory markers (LAIR-1, Siglec-7) were assessed using flow cytometry. NK cell cytotoxicity against primary hepatic stellate cells (pHSCs) was evaluated through apoptosis assays. STING agonists (2′3′-cGAMP and DMXAA) were used to stimulate NK cells, and their effects on STING expression, NK cell activation, and cytotoxicity were measured. Additionally, the impact of insulin signaling on STING expression and NK cell function was examined. Results: Our results demonstrate that STING expression in NK cells correlates with disease severity in liver fibrosis. NK cells from MASH patients with advanced fibrosis (F3/F4) showed inhibited STING protein levels that were statistically comparable to healthy NK cells and accompanied by impaired cytotoxicity and decreased IFN-γ production. In contrast, NK cells from early fibrosis (F1/F2) exhibited higher STING expression and better functional activity. STING agonist treatment (2′3′-cGAMP) restored STING expression and enhanced NK cell activity across all fibrosis stages. Furthermore, insulin treatment and combined insulin and 2′3′-cGAMP treatment synergistically upregulated both IR and STING expressions, leading to improved NK cell function and increased cytotoxicity, particularly in advanced fibrosis. Conclusion: Our results highlight the potential of targeting STING and insulin signaling pathways as a therapeutic approach in restoring NK cell function and enhance immune surveillance in liver fibrosis. Full article

Trichlorfon is an antiparasitic agent widely used to control pests and parasites in farmed fish. Tambaqui (C. macropomum) is the most commercially important characid species farmed in the Amazon region. Trichlorfon exposure is known to cause physiological damage in fish due to its organophosphate nature. In this study, we used RNA-Seq to investigate the hepatic response of tambaqui following exposure to 0.435 mg/L of trichlorfon. The analysis revealed activation of several metabolic pathways, particularly those related to tumor processes, immune responses, and apoptosis. Additionally, we identified upregulation of solute carrier (SLC) genes, which may facilitate trichlorfon entry into hepatocytes. These findings enhance our understanding of fish responses to antiparasitic agents and support further research into the molecular impacts of organophosphate compounds in aquaculture species. Full article

The global burden of liver diseases continues to rise, encompassing diverse pathologies such as viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). In recent years, TNFR1-associated death domain protein (TRADD), a pivotal adaptor molecule in the TNF signaling pathway, has been found to play a dual regulatory role in the pathogenesis of liver diseases. Through its death domain, TRADD binds to TNFR1 and dynamically recruits downstream factors (e.g., TRAF2, RIPK1, FADD) to form Complex I or IIa, thereby activating pro-survival or pro-apoptotic signals that dictate hepatocyte fate and modulate the inflammatory microenvironment. This review systematically summarizes the molecular structure and functional networks of TRADD, along with its mechanistic roles in liver diseases: in HCC, TRADD expression correlates with tumor differentiation and is regulated by miRNA targeting; in ALD and MASLD, TRADD-mediated apoptosis is closely linked to fibrotic progression; and in acute liver injury, TRADD signaling is modulated by factors such as HO-1 to mitigate damage. Furthermore, TRADD inhibitors and antisense oligonucleotides demonstrate therapeutic potential. This review highlights the clinical translational value of TRADD as a diagnostic, therapeutic, and prognostic biomarker for liver diseases, providing a theoretical foundation for future precision medicine strategies. Full article

Albumin is the most abundant protein synthesized exclusively by the hepatocytes in the liver. Once secreted into plasma, it helps in the maintenance of osmotic pressure, as well as the exertion of defensive roles such as anti-oxidative and anti-inflammatory functions. Dysregulation in the synthesis and clearance of albumin is observed in various hepatic and extra-hepatic diseases. Abnormal levels of albumin could be either a cause or an effect of various pathological ailments, including hepatic, cardiac, renal, neurological, etc. Owing to its long half-life and multiple binding sites in its heart-shaped structure, it interacts with various internal agents, such as hormones, or external substances like drugs, which is why transportation can be one of its many functions. Additionally, albumin’s drug interactions, as well as displacement of albumin–drug binding, could have serious clinical consequences, and careful considerations should be made in determining an appropriate drug regimen to achieve a desired therapeutic outcome with minimal side effects. Moreover, albumin also undergoes several post-translational modifications that can influence its physiological roles, including drug binding and antioxidant functions. Furthermore, it has a complicated role in physiology, where it can help in maintaining plasma oncotic pressure and prevent endothelial cell apoptosis but can have adverse effects on the lungs and kidneys. These adverse effects are mainly attributed to ER stress and inflammasome activation. This narrative review provides an overview of the general biology of albumin and its effects in physiology, with a focus on its beneficial and adverse effects and the underlying molecular mechanisms. Full article

Ellagic acid (EA) is a natural polyphenol found in various fruits, nuts, and mushrooms. It exhibits a variety of biological activities, including potent antioxidant, anti-inflammatory, anti-obesity, and neuroprotective properties. EA exerts hepatoprotective effects through multiple mechanisms, including (1) scavenging reactive oxygen species (ROS) and enhancing endogenous antioxidant defenses (e.g., by activating Nrf2/ARE), (2) modulating inflammatory signaling pathways (e.g., inhibiting NF-κB, TNF-α, and IL-6), and (3) regulating apoptosis (e.g., downregulating the Bax/Bcl-2 ratio) and fibrosis (e.g., inhibiting TGF-β/Smad signaling). Despite its promising preclinical efficacy, the clinical applicability of EA is currently limited by its poor bioavailability. This could potentially be overcome by advanced delivery systems or by directly administering its active microbial metabolites, known as urolithins. EA and its derivatives also modulate the gut microbiota, promoting the growth of beneficial species and reducing gut permeability and hepatic inflammation. Preliminary clinical trials and other emerging evidence suggest that EA may reduce liver inflammation, oxidative stress, and metabolic dysregulation. However, more extensive human studies are needed to confirm its efficacy and safety in managing liver disease. This review highlights the therapeutic potential of EA in the treatment of liver diseases, particularly metabolic-dysfunction-associated steatotic liver disease (MASLD). Full article

Enterovirus (EV) infections in neonates can be transmitted vertically or horizontally, with symptoms ranging from mild to severe, including myocarditis, meningoencephalitis, and hepatitis. Neonates with EV-induced myocarditis may present severe cardiovascular disease with sudden onset of arrhythmia. Neonatal arrhythmias, particularly in low birth weight or critically ill infants, can impair cardiac function and worsen outcomes. EV targets cardiomyocyte receptors, inducing apoptosis pathways and triggering cardiac conduction disturbances. We present an extremely low-birth-weight preterm infant (GW 27 + 6) who developed EV-induced myocarditis, complicated with a sudden onset of supraventricular tachycardia (SVT), pericardial effusion and bi-atrial enlargement. Despite multi-agent regimen, including propranolol, flecainide, and amiodarone, the infant showed persistent junctional rhythm until seven months of age, later transitioning to atrial rhythm with stable cardiac function. A review of previously published rhythm disturbances due to EV-induced myocarditis is presented. Newborns with EV-induced arrhythmia may require a multi-modal treatment such as a multi-agent medical regimen or, in severe non-responsive cases, an electrophysiological approach. EV infections may cause long-term cardiovascular comorbidities (such as left ventricular dysfunction or mitral valve regurgitation), necessitating continuous monitoring through echocardiography and ECG. Collaboration between neonatologists and pediatric cardiologists is crucial for effective treatment and follow-up. Full article