Search Results (732)

Simulation of a human neurological disease on an animal model has the advantage of allowing control and manipulation of most of the regulating factors and producing real biological replicas while, beyond several common traits, every human is dynamic and unique. Moreover, one can explore novel therapeutic strategies on animals before asking permission to apply them to humans. Nevertheless, experimental outcomes depend on species, strain, sex, age, hormonal status, diet, exposure to hypoxia, toxins, radiation, external stimuli, stress, and housing conditions. Further complications stem from tissue hetero-cellularity, technological constraints, computational complexity and difficulties integrating the experimental results into a coherent biological picture. Moreover, most diseases are multi-factorial and associated with altered structure and/or expression of several genes. A major problem with genetically engineered animals is that together with the targeted gene(s), numerous other genes are mutated and/or regulated, owing to their interlinkage in functional pathways. This experience-based methodological commentary presents the challenges, relevance and limitations of the mouse, rat and rabbit models we used to decipher the transcriptomic alterations associated with several neurological disorders. Links to publicly accessible databases presenting experimental protocols and expression profiles are provided for readers interested in reanalyzing our data and comparing them with others’ results. Full article

Deoxynivalenol (DON) and patulin (PAT) are common mycotoxins in cereals and fruits, posing health risks for animals and human beings. In order to study their liver toxicity, 24 mice were randomly assigned to four groups, with six replicates in each group (one mouse per cage). The mice were intragastrically administered with DON, PAT, DON + PAT (DP), or without DON and PAT (the control group) for 28 days, respectively. The results showed that body weight gain was significantly reduced by all toxin treatments, compared with the control group, and the lowest body weight gain was observed in the DP group. Histopathology revealed that hepatocyte damage and inflammatory infiltration were more serious in the DP group, exhibiting the highest mRNA abundances of MyD88, IFN-γ, and JAK2. The severity of hepatocyte apoptosis induced in each group followed the order: DON > DP > PAT; the severity of oxidative stress was ranked as DP > DON > PAT. Transcriptomic analysis revealed that numerous differentially expressed genes were regulated by DP treatment, which were mainly enriched in the MAPK, JAK-STAT, and transforming growth factor (TGF)-β signaling pathways. In conclusion, individual exposure to DON or PAT triggered hepatic injury, and their co-exposure further exacerbated liver damage. Full article

The greenhouse whitefly (Trialeurodes vaporariorum) causes substantial yield losses and reduced market value of produce in protected agricultural systems worldwide. This study examined the biocontrol potential of recombinant Bacillus thuringiensis (Bt) toxin proteins harboring the LBW08 gene. Within a decision-support system (DSS) framework, we evaluated the effects of different competent cell lines on toxin expression profiles and assessed the insecticidal performance of two Bt toxin variants (08 and 08bt), both individually and in combination with yellow sticky traps. Our goal was to generate quantitative parameters on population suppression dynamics and cost-effectiveness, providing a basis for DSS-driven pest management recommendations. The 08Bt toxin expressed in JM110 competent cells exhibited superior purity and consistent insecticidal activity against T. vaporariorum nymphs. Notably, the integrated application of 08Bt and yellow sticky traps achieved the highest level of population suppression among all treatments, highest numerical level of population suppression among all treatments, although pairwise differences were not statistically significant, suggesting strong potential for synergistic control. In contrast, no synergistic interaction was observed with the 08 variant. However, the 08 variant combined with traps did not show a comparable numerical improvement. These findings support the development of cost-effective, environmentally sound tactics that can be incorporated into broader IPM strategies for protected agriculture. Full article

Background: Large yellow tea (LYT), a distinctive variety made from mature leaves, has recently gained attention for its remarkable health benefits. However, whether these benefits can be transmitted from mother to offspring remains unexplored. Purpose: This study investigated whether maternal LYT consumption confers intergenerational protection against metabolic and behavioral disorders induced by perinatal bisphenol A (BPA) exposure in F1 offspring. Methods: A mouse model of perinatal BPA exposure (0.03% in diet) was established with or without maternal LYT supplementation (2.5% in diet). Metabolic parameters were assessed through biochemical assays and gene expression analysis (RT-PCR). Energy expenditure and spontaneous activity were monitored using a Comprehensive Lab Animal Monitoring System (CLAMS). Hippocampal proteomic profiling was performed using label-free quantitative proteomics. Results: LYT significantly reduced maternal BPA body burden, potentially via limiting absorption, enhancing glucuronidation metabolism, and promoting excretion. Notably, LYT exhibited bidirectional metabolic regulation, alleviating gestational hyperglycemia in dams while restoring hypoglycemia in offspring, and normalizing underweight and hypolipidemia. Mechanistically, the SIRT6 (sirtuin 6)/FOXO1 and SIRT6/SREBP1 pathways may be involved in regulating gluconeogenesis and lipogenesis. Concurrently, LYT rectified BPA-induced hyperactivity and reduced excessive energy expenditure. Proteomic analysis revealed that LYT partially restores BPA-induced dysregulation of cholesterol metabolism and glutamatergic/GABAergic synaptic pathways, which may contribute to rebalancing synaptic homeostasis. Conclusions: These findings suggest that maternal LYT supplementation confers intergenerational protection against BPA-induced metabolic and behavioral disorders in mice, potentially acting through enhanced toxin clearance, bidirectional metabolic regulation, behavioral normalization, and partial restoration of hippocampal synaptic homeostasis. This study provides a theoretical basis for developing natural dietary interventions to mitigate developmental toxicant-induced health risks. Full article

Background/Objective: Cinnamaldehyde (CA) is a naturally occurring bioactive compound derived from the leaves, bark, roots, and flowers of the Chinese medicinal plant Cinnamomum cassia. It exhibits a broad spectrum of pharmacological properties, encompassing antioxidant, antibacterial, anti-diabetic, antifungal, and anticancer activities. Notably, it has shown potential therapeutic benefits in the management of type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). Ochratoxin A (OTA), a common contaminant found in foods such as cereals, coffee, and raisins, is also present in traditional Chinese medicinal materials, including Astragalus and liquorice. T2DM and NAFLD share intertwined pathophysiological pathways, including insulin resistance, dyslipidaemia, chronic low-grade inflammation and oxidative stress, with insulin resistance serving as the common pathological hub for both conditions. Consequently, they frequently co-occur and exacerbate each other. OTA exerts dual-targeted toxicity to the pancreas and liver, which may synergistically drive the development of the comorbidity of T2DM and NAFLD. These two processes are mutually causal and together constitute the pathological basis of metabolic comorbidity. Methods: Network toxicology employs toxicological data, gene expression, and protein–protein interaction (PPI) networks to predict the targets of toxins, while network pharmacology, based on systems biology principles, reveals how drugs exert regulatory effects through multiple targets and pathways. In this study, we employed an integrated network toxicology and network pharmacology approach to jointly decipher the potential mechanisms by which CA intervenes in OTA-induced comorbid T2DM-NAFLD. First, a network toxicology approach was employed to preliminarily screen for core toxicological targets responsible for OTA’s pathogenicity. Subsequently, network pharmacology was used to identify potential targets of CA-mediated intervention in the disease. Finally, the common overlap among the CA intervention targets, OTA toxicity targets, and disease targets was defined as the final set of potential targets for CA-mediated intervention in OTA-induced T2DM-NAFLD comorbidity. A PPI network was constructed using the STRING database, and topological analysis was performed with Cytoscape. Core targets were selected using the median values of six parameters—betweenness centrality, closeness centrality, degree centrality, eigenvector centrality, LAC (local average connectivity) score, and network centrality—as cut-off thresholds, and the top 10 key genes were further identified using the cytoHubba plugin. Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted via the DAVID database, and the results were visualized on the CNSknowall platform. Lastly, molecular docking of the core targets was performed using the CB-DOCK2 platform to validate binding affinity. Results: Based on an integrated analysis of network toxicology, network pharmacology, and molecular docking, 10 key targets were systematically identified. These may serve as potential mediators of cinnamaldehyde in the treatment of OTA-induced T2DM-NAFLD comorbidity. Among these, six targets—albumin (ALB), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), interleukin-6 (IL-6), tumor necrosis factor (TNF), actin beta (ACTB), and estrogen receptor 1 (ESR1)—possess crystal structures amenable to molecular docking. KEGG enrichment analysis revealed that CA and OTA jointly participate in key pathological processes such as the cancer pathway, the lipid and atherosclerosis pathway, the advanced glycation end-products–receptor for advanced glycation end-products (AGE-RAGE) signaling pathway, the phosphatidylinositol 3-kinase–protein kinase B (PI3K-Akt) signaling pathway, the TNF signaling pathway, and the interleukin-17 (IL-17) signaling pathway. OTA exacerbates inflammatory responses, impairs insulin signaling, promotes hepatic steatosis, and disrupts systemic metabolic homeostasis, ultimately contributing to T2DM-NAFLD comorbidity. Conversely, cinnamaldehyde counteracts these pathological processes through multiple mechanisms, including antioxidant and anti-inflammatory effects as well as regulation of glucose and lipid metabolism, thereby restoring metabolic homeostasis. Conclusions: This study has preliminarily identified the toxicological targets of OTA and the potential intervention targets of CA, offering new avenues for preventing and intervening in OTA-induced metabolic toxicity. Furthermore, it provides a theoretical basis for CA as a potential multi-target therapeutic agent and presents novel insights worthy of further investigation into the prevention of T2DM-NAFLD comorbidity. Full article

Excessive cyanobacterial proliferation and toxin production increasingly threaten freshwater ecosystems, drinking water systems, and public health. Among cyanotoxins, microcystin-LR (MC-LR) is one of the most prevalent variants and is recognized for its hepatotoxicity, with evidence showing it can also alter gut microbiota composition. Previous studies, including our own, demonstrate that MC exposure can induce inflammation, oxidative stress, and changes in gene expression associated with immune responses, even at concentrations below guideline limits. This study investigated the protective effect of an MC-degrading bacterium, Sphingopyxis sp. IM1 (IM1) with a known enzymatic MC degradation pathway, against MC-LR-induced hepatotoxicity under in vitro conditions. Human Hep3B hepatocytes were pretreated with varying ratios of IM1 bacteria and subsequently exposed to 9.95 ppm of MC-LR for 24 h. RT-qPCR analysis demonstrated that MC-LR exposure strongly increased the expression of the inflammatory markers TNFα and TGF-β1, whereas pretreatment with IM1 significantly attenuated these responses. Mass spectrometric analysis of cell pellets and spent culture media demonstrated reduced concentrations of intact MC-LR in IM1-pretreated samples compared to MC-LR-only controls, accompanied by increased detection of tetrapeptide degradation products generated during mlr-mediated MC degradation. These results demonstrate that IM1-mediated degradation of MC-LR attenuates toxin-induced hepatotoxic and inflammatory responses, highlighting the potential of a novel microbial-based therapeutic approach to mitigate MC-induced toxicity. Full article

Nuclear receptors (NRs) of the NR1J1 group have been described in aquatic invertebrates and proposed as the evolutionary counterparts of vertebrate NR1I receptors, known for their role in xenobiotic-sensing and detoxification. In bivalves, previous studies have shown that NR1J1 activity and gene expression are modulated by pharmaceuticals, toxins, natural compounds, and algal extracts. However, their functional properties and diversification remain poorly understood. Here, we investigated the function and evolution of NR1J1 receptors in the bivalves Mytilus galloprovincialis and Ruditapes decussatus. We first identified four nr1j1 paralogs in R. decussatus and then integrated phylogenetic analysis, domain identity comparisons, tissue distribution profiling, and luciferase-based transactivation assays to characterize NR1J1 paralogs from both species. The receptors displayed distinct but partially overlapping transactivation profiles in response to confirmed ligands of NR1I and NR1H receptors, natural compounds, plant extracts, and fish bile, indicating paralog- and species-specific differences in ligand responsiveness. Allocholic acid emerged as the most consistent agonist across paralogs, whereas curcumin, carnosic acid, and Ptychopetalum olacoides extract showed more selective response patterns. Tissue profiling revealed broad but non-uniform expression of nr1j1 paralogs across bivalve tissues. Together, these findings underscore that bivalve NR1J1 receptors constitute a functionally diversified chemical-sensing system and provide a framework for future studies addressing ligand-dependent regulation and detoxification pathways. Full article

Acute kidney injury (AKI) is characterized by a rapid decline or sudden loss of renal function over hours to days. Pathophysiological triggers such as renal ischemia–reperfusion (IR) injury and the accumulation of uremic toxins (UTs), notably indoxyl sulfate (IS), can initiate AKI and affect vascular beds distant from the ischemic site, like the aorta. In this context, purinergic signaling becomes relevant, since its components regulate vascular tone and inflammatory responses. This study aimed to evaluate the impact of AKI induced by IR with or without IS administration on purinergic signaling in the aorta of mice. Renal ischemia was induced by the occlusion of the left renal pedicle for 60 min, followed by reperfusion for 8 days (IR 8) or 15 days (IR 15). Some animals were also treated with saline solution or IS for 15 days. The IR15 group exhibited increased plasma IS concentrations and upregulated adenosine receptor gene expression. Furthermore, in the IR+IS group, there was increased expression of A1, A2a, NTPDase 1, and 2. This shift toward an adenosine-enriched signaling environment may represent a key mechanism linking renal injury to systemic vascular inflammation. Full article

Zymoseptoria tritici (Desm. Quaedvlieg & Crous), known as the wheat leaf spot disease agent, is a highly virulent fungus that induces blotch and necrosis on leaves. Although it is known to cause severe infections under humid conditions, recent observations suggest that it can also infect wheat leaves under drought and high-temperature conditions, possibly influenced by global warming. Recent findings showed that Z. tritici could easily tolerate various abiotic stresses, including drought, water stress, salinity, and temperature. It has been evident that the fungus can tolerate pesticide stress, as indicated by the increased frequency and number of pesticide applications throughout the growing season. Under stress conditions, the fungi, unlike crop plants, could easily tolerate stress by rapidly modifying gene expression and reducing spore production and mycelial growth without downregulating major biochemical components that play significant roles in pathogenicity and virulence. Z. tritici can accumulate melanin under stress conditions; therefore, an increase in pathogenicity under drought or salinity stress is not unexpected. Recent studies have shown that the pathogenicity of the fungus is increasing, and more virulent, toxin-producing pathogens might emerge in the future. Since drought and high-temperature stresses significantly affect crop plants, the adaptation of pathogenic microorganisms to these conditions could be inevitable if abiotic stress persists. Under these circumstances, the crop loss would be more pronounced. A critical aspect of this process is the assessment of DNA integrity in both wheat and the pathogen under drought stress conditions. The organism that better maintains DNA integrity is considered to exhibit greater drought tolerance. Therefore, our main target should be DNA health when developing or breeding new wheat varieties, considering double- or even multiple-stress conditions. We should finally state that we are very optimistic about generating highly stress-tolerant wheat varieties via metabolomic and proteomic approaches without compromising quality. However, the impact and combination of stress factors are becoming increasingly complex. Full article

Patients with chronic kidney disease (CKD) are exposed to high levels of uremic toxins and have an increased risk of cardiovascular disease. Among these toxins, indolic compounds such as indoxyl sulfate (IS) are predictors of cardiovascular events and mortality in CKD patients and induce a procoagulant and proinflammatory vascular phenotype through activation of the aryl hydrocarbon receptor (AhR). Targeting AhR activation by indolic toxins may therefore help prevent cardiovascular complications in CKD. To this end, we investigated in vitro whether natural dietary AhR ligands (galangin, quercetin, curcumin and indole-3-carbinol) could antagonize IS-induced AhR activation and the associated inflammatory response in endothelial cells. The activation of the AhR genomic pathway was assessed by measuring the expression of AhR target genes (CYP1A1, CYP1B1, and AHRR) in endothelial cells and by evaluating AhR-dependent transcriptional activity using a CALUX-AHRE luciferase reporter assay in HG40/6 cells. In parallel, endothelial inflammation was evaluated by analyzing the expression of AhR-related inflammatory genes: F3/tissue factor, PTGS2/COX-2, CCL2/MCP-1, and CXCL8/IL-8. Quercetin was the only ligand capable of antagonizing IS-induced AhR transcriptional activity, as well as the upregulation of the endothelial AhR target genes CYP1A1 and CYP1B1. In contrast, galangin, curcumin, and I3C exhibited no inhibitory effects. Moreover, none of the tested dietary AhR ligands suppressed the IS-induced upregulation of endothelial inflammatory genes; instead, they tended to potentiate IS-induced inflammatory responses at high concentrations. In conclusion, among the AhR ligands tested, quercetin was the only one that attenuated IS-induced activation of the AhR genomic pathway in endothelial cells. However, it may also enhance IS-mediated endothelial inflammation, an effect also observed at specific concentrations of galangin, curcumin, and I3C. These findings suggest that the potential beneficial effects of natural dietary AhR ligands should be carefully considered in the context of CKD patients exhibiting high levels of indolic uremic toxins. Full article

Aflatoxin B1 (AFB1), a highly potent Group 1 human carcinogen produced by Aspergillus flavus (A. flavus), poses a significant contamination risk to corn silage, a threat that is further intensified by rising global temperatures. This study aimed to characterize the combined effects of temperature and co-inoculation with the lactic acid bacterium Limosilactobacillus fermentum (L. fermentum) on AFB1 production and the expression of key biosynthetic genes in A. flavus colonizing corn silage. Corn silage was incubated at 20 °C, 30 °C, and 37 °C with and without L. fermentum. Using qRT-PCR and HPLC, we found that elevated temperatures, particularly 37 °C, strongly induced the expression of the aflatoxin biosynthetic cluster, including the regulatory gene aflR and structural genes such as omtA and ordA. Co-inoculation with L. fermentum consistently reduced in the final AFB1 concentration by approximately 50–60% at all three temperatures. Molecular analysis revealed that this reduction was associated with transcriptional repression at 30 °C and 37 °C. L. fermentum consistently and markedly down-regulated the expression of aflR and all structural genes. A particularly pronounced suppression was observed for the late-pathway gene ordA at 30 °C. These findings provide molecular evidence supporting the incorporation of selected L. fermentum strains into silage inoculant formulations to mitigate the AFB1 risk under high-temperature conditions. Full article

Heavy metals in the soil inhibit plant growth, which significantly reduce the crop yield and quality. Natural Resistance-Associated Macrophage Proteins (NRAMP) are widely distributed on the plasma and vacuolar membranes of plant roots, stems, and leaves. The NRAMP gene family plays a crucial role in modulating plant heavy-metal uptake, sequestration, distribution, and translocation, while the molecular evolution and mechanisms underlying these processes remain unclear. Here, we reviewed recent progress on plant NRAMP genes, focusing on their structural characteristics and functions in the absorption, transport, accumulation, and detoxification of various heavy metals. Furthermore, we performed an evolutionary analysis of NRAMP in green plants, indicating expansion and tandem duplication in ferns. In addition, their key amino acid sequences and secondary structures were highly conserved across plant species. The expression of diverse tissue showed that NRAMP genes displayed distinct spatial regulation in the leaves and roots. We also explored the underlying molecular mechanisms and regulatory pathways by which NRAMP genes influence heavy metal uptake. Therefore, by integrating structural conservation, molecular evolution, tissue- and single-cell expression patterns, ion-stress-responsive expression, regulatory pathways, and the Cd–Mn nutrient–toxin trade-off, this review provides a framework for identifying unresolved NRAMP functions and for guiding future strategies in low-heavy-metal crop breeding, metal homeostasis engineering, and phytoremediation. Full article

Chattonella marina is an ichthyotoxic, bloom-forming raphidophyte known for its hemolytic activity. However, the mechanisms by which nitrogen (N) and phosphorus (P) limitation influence this hemolytic toxicity remain poorly understood. In this study, both N and P limitation reduced growth, photosynthetic efficiency (F_v/F_m, Y_II, rETR_max), and the expression of nutrient-uptake, tetrapyrrole/chlorophyll biosynthesis genes. Nevertheless, the two nutrients produced opposite effects on toxicity: N limitation lowered hemolytic activity and ROS levels to near zero, whereas P limitation kept both relatively high, similar to nutrient-replete controls. The addition of the antioxidant NAC (N-Acetyl-L-cysteine) reduced hemolytic activity, confirming that ROS contributes to toxicity. Transcriptome data showed that under N limitation, genes for nitrogen uptake and initial reduction (NRT, NR, glnA) were upregulated, while downstream assimilation genes (nirA, GLT1) were downregulated. In contrast, under P limitation, all the nitrogen-metabolism-related genes (NRT, NR, glnA, nirA, GLT1) were downregulated. In the tetrapyrrole pathway, most genes were downregulated under both nutrient-limited conditions, except for HemD, suggesting a bottleneck that may result in the accumulation of porphyrin intermediates within the tetrapyrrole/chlorophyll biosynthesis pathway. Together, the secondary products derived primarily from the reaction of ROS with tetrapyrrole-based compounds appear to be the main contributors to hemolytic toxicity. Consequently, high levels of both ROS and porphyrin intermediates under P-limited conditions, as well as high ROS levels but low porphyrin intermediates under nutrient-sufficient conditions, may both contribute to the high hemolytic toxicity of C. marina. In contrast, under N limitation, despite the accumulation of porphyrin intermediates, the strong suppression of photosynthetic electron transport limits both ROS production and the synthesis of nitrogen-containing toxins, resulting in low hemolytic activity. These findings demonstrate that nutrient conditions regulate hemolytic activity in C. marina in a nutrient-specific manner. Full article

Aflatoxin B1 (AFB1) is a prevalent and highly toxic mycotoxin in the food and feed chain and can directly injure the intestinal epithelium. Yet, its upstream determinants linking epithelial stress to cytotoxicity remain insufficiently defined. Here, we used porcine intestinal epithelial IPEC-J2 cells to characterize AFB1-induced cytotoxic and transcriptomic responses and to determine the role of the tight-junction scaffold, Cingulin-like 1 (CGNL1), a candidate gene identified through genome-scale CRISPR knockout library screening. The results showed that AFB1 exposure reduced cell viability in a dose-dependent manner and induced oxidative stress. RNA-seq profiling analysis revealed broad transcriptional remodeling, with activation of inflammatory pathways (including NF-κB and JAK–STAT signaling). Based on our constructed CGNL1-knockout IPEC-J2 cell line (CGNL1-KO IPEC-J2) using CRISPR/Cas9, it was found that CGNL1 deficiency markedly alleviated AFB1-induced cytotoxicity and oxidative stress. Comparative transcriptomics analysis showed that CGNL1 knockout attenuated AFB1-triggered aberrant expression of some CGNL1-dependent AFB1-responsive genes related to immune response under AFB1 challenge. Together, these findings identify CGNL1 as a potential modulator of epithelial susceptibility to AFB1 and support its involvement in the regulation of toxin-induced oxidative response. Full article

The ATP-binding cassette subfamily G member 2 (ABCG2), also known as breast cancer resistance protein (BCRP), is an efflux transporter expressed in key pharmacokinetic tissues and biological barriers. It regulates exposure to many endogenous compounds, drugs, and environmental toxins. Genetic variability in ABCG2 has been recognised as an important contributor to interindividual variability in drug response, especially in terms of efficacy and toxicity. This narrative review summarises current knowledge on the clinical relevance of ABCG2 genetic variants, with a focus on their effects on pharmacokinetics, adverse drug reactions and drug–drug–gene interactions, as well as their potential implementation in personalised therapy. A literature search was performed in PubMed, Scopus and the Clinical Pharmacogenomics Database (ClinPGx), with an emphasis on clinically relevant studies and available pharmacogenomic guidelines. The most investigated ABCG2 variant, c.421C>A (rs2231142; p.Gln141Lys), is consistently associated with reduced transporter activity and increased systemic exposure to several substrate drugs, including statins, allopurinol and anticancer agents, which may influence both treatment response and the risk of toxicity. Although growing evidence supports the clinical relevance of ABCG2 genotyping, its routine implementation remains limited. Integration of ABCG2 variability into polygenic models and clinical decision-support tools may further improve individualised treatment, particularly in patients with multimorbidity and polypharmacy. Full article