Search Results (2,036)

Tetrabromobisphenol A (TBBPA), a widely utilised brominated flame retardant, demonstrates toxicological effects in aquatic organisms. Tea polyphenols (TPs), natural compounds found in tea leaves, exhibit both antioxidant and anti-inflammatory activities. The kidney is one of the major metabolic organs in common carp and serves as a target organ for toxic substances. This study evaluated the therapeutic potential of TPs in mitigating TBBPA-induced nephrotoxicity in common carp. Common carp were exposed to 0.5 mg/L TBBPA in water and/or fed a diet supplemented with 1 g/kg TPs for 14 days. In vitro, primary renal cells were treated with 60 μM TBBPA and/or 2.5 μg/L TPs for 24 h. Methods included histopathology, TUNEL assay for apoptosis, ROS detection, and molecular analyses. Antioxidant enzymes (SOD, CAT) and inflammatory cytokines (IL-1β, IL-6, TNF-α) were quantified using ELISA kits. Results showed that TBBPA induced oxidative stress, and activated the ROS-PI3K/AKT-NF-κB pathway, thereby resulting in inflammatory responses. TBBPA upregulated apoptosis-related genes (Caspase-3, Bax, and Bcl-2) and induced apoptosis. TBBPA upregulated the expression of RIPK3/MLKL, thereby exacerbating necroptosis. TPs intervention significantly mitigated these effects by reducing ROS, suppressing NF-κB activation, and restoring antioxidant enzyme activities (SOD, CAT). Moreover, TPs attenuated apoptosis and necrosis in the carp kidney, thereby enhancing the survival ability and immunity of common carp. Full article

Background/Objectives: Vitex agnus-castus has been traditionally used to treat hormonal disorders, and recent evidence suggests its potential anticancer properties. However, its effects on gastric cancer remain unclear. Methods: This study examined the cytotoxic, apoptotic, and anti-metastatic effects of hydroalcoholic Vitex agnus-castus seed extract in gastric cancer cells. Antioxidant capacity (DPPH, ABTS) and total phenolic and flavonoid contents were analyzed. Cytotoxicity was assessed using the MTT assay in HGC27, MKN45, and AGS gastric cancer cell lines and CCD-1072Sk fibroblasts. Apoptosis, mitochondrial membrane potential (MMP), and cell cycle changes were evaluated via Annexin V-FITC/PI, Rhodamine 123, and PI staining, respectively. RT-qPCR and gene enrichment analyses were conducted to investigate the molecular mechanisms. Apoptosis-related protein expression was analyzed through enzyme-linked immunosorbent assay (ELISA). Results: The extract exhibited high antioxidant activity and a significant phenolic content. It reduced cell viability in a dose-dependent manner in gastric cancer cells, while exerting low toxicity in fibroblasts. It significantly increased apoptosis, induced G0/G1-phase cell cycle arrest, upregulated pro-apoptotic genes (CASP3, CASP7, TP53, BCL2L11), and downregulated anti-apoptotic genes (XIAP, NOL3). Gene enrichment analysis highlighted pathways like apoptosis, necrosis, and cysteine endopeptidase activity. The extract also disrupted MMP, inhibited migration and spheroid formation, suppressed EMT markers (SNAIL, SLUG, TWIST1, N-CADHERIN), and upregulated E-CADHERIN. The expression of Caspase 3 and Bax proteins increased and Bcl2 protein decreased. Conclusions: These findings suggest that Vitex agnus-castus seed extract exerts strong anticancer effects in gastric cancer cells by promoting apoptosis, reducing proliferation, and inhibiting migration. Further studies are warranted to explore its clinical relevance. Full article

The present study aimed to standardize germinated oat extracts (GOEs) by profiling avenanthramides (AVNs) and phenolic acids and evaluate their neuroprotective effects against Aβ_1-42-induced cytotoxicity in human neuroblastoma (SH-SY5Y) cells. GOEs were standardized to contain 1652.56 ± 3.37 µg/g dry weight (dw) of total AVNs, including 468.52 ± 17.69 µg/g AVN A, 390.33 ± 10.26 µg/g AVN B, and 641.22 ± 13.89 µg/g AVN C, along with 490.03 ± 7.83 µg/g dw of ferulic acid, using a validated analytical method. Treatment with AVN C and GOEs significantly inhibited Aβ_1-42-induced cytotoxicity (p < 0.05). Furthermore, both AVNs and GOEs markedly reduced Aβ_1-42-induced reactive oxygen species (ROS) generation in SH-SY5Y cells, showing significant scavenging activity at concentrations of 25 μg/mL (AVNs) and 50 μg/mL (GOEs) (p < 0.05). RT-PCR analysis revealed that AVNs and GOEs effectively downregulated the expression of inflammation- and apoptosis-related genes triggered by Aβ_1-42 exposure. These findings suggest that GOEs rich in AVNs may serve as a potential functional ingredient for enhancing memory function through the inhibition of neuroinflammation and oxidative stress. Full article

Premature ovarian insufficiency (POI) is an important factor in female infertility and is often associated with oxidative stress. Alginate oligosaccharides (AOSs), derived from the degradation of alginate, have been demonstrated to have protective effects against various oxidative stress-related diseases. However, the impact of AOSs on POI has not been previously explored. The current study explored the effects of AOSs on ovarian dysfunction in a mouse model of POI induced by D-galactose (D-gal). Female C57BL/6 mice were randomly divided into five groups: the control (CON), POI model (D-gal), and low-, medium-, and high-dose AOS groups (AOS-L, 100 mg/kg/day; AOS-M, 150 mg/kg/day; AOS-H, 200 mg/kg/day). For 42 consecutive days, mice in the D-gal, AOS-L, AOS-M, and AOS-H groups received daily intraperitoneal injections of D-gal (200 mg/kg/day), whereas those in the CON group received equivalent volumes of sterile saline. Following D-gal injection, AOSs were administered via gavage at the specified doses; mice in the CON and D-gal groups received sterile saline instead. AOS treatment markedly improved estrous cycle irregularities, normalized serum hormone levels, reduced granulosa cell apoptosis, and increased follicle counts in POI mice. Moreover, AOSs significantly reduced ovarian oxidative stress and senescence in POI mice, as indicated by lower levels of malondialdehyde (MDA), higher activities of catalase (CAT) and superoxide dismutase (SOD), and decreased protein expression of 4-hydroxynonenal (4-HNE), nitrotyrosine (NTY), 8-hydroxydeoxyguanosine (8-OHdG), and p16 in ovarian tissue. Analysis of the gut microbiota through 16S rRNA gene sequencing and short-chain fatty acid (SCFA) analysis revealed significant differences in gut microbiota composition and SCFA levels (acetic acid and total SCFAs) between control and D-gal-induced POI mice. These differences were largely alleviated by AOS treatment. AOSs changed the gut microbiota by increasing the abundance of Ligilactobacillus and decreasing the abundance of Clostridiales, Clostridiaceae, Marinifilaceae, and Clostridium_T. Additionally, AOSs mitigated the decline in acetic acid and total SCFA levels observed in POI mice. Notably, the total SCFA level was significantly correlated with the abundance of Ligilactobacillus, Marinifilaceae, and Clostridium_T. In conclusion, AOS intervention effectively mitigates ovarian oxidative stress, restores gut microbiota homeostasis, and regulates the microbiota–SCFA axis, collectively improving D-gal-induced POI. Therefore, AOSs represent a promising therapeutic strategy for POI management. Full article

Fungicides are compounds with potentially toxic effects on the human body, but the molecular mechanisms of their action have not yet been explained. The effect of cyprodinil on cell viability, apoptosis level, cell membrane function, cell morphology and expression of antioxidant enzyme genes in the A-375 and DLD-1 cell lines was examined. The cell lines were selected because they can be an excellent in vitro model of neoplastic changes occurring in the skin and large intestine after exposure to a fungicide. The fungicide selected for the study is commonly used in Poland to protect crops against fungi. Our results showed that the tested compound increased cell viability and proliferation, probably activated by mechanisms related to oxidative stress. Cyprodinil caused an increase in glutathione level (in A-375 by about 37% and in DLD-1 by about 28%) and oxidative stress enzymes activity, but not in apoptosis level. Its membrane interactions and its penetration into cells was concentration dependent. It is worth emphasizing that the novelty of our work lies in the use of non-traditional toxicological methods based on molecular analyses using human cell lines. This allowed us to demonstrate not only the toxicity of a single substance but also its behavior within cellular structures. Our findings suggest that cyprodinil may have tumor-promoting properties in skin and colorectal cancer cells. Full article

Nuclear receptors are involved in multiple biological processes, among which RORγ can regulate the expression of inflammation-related genes and is thus frequently used as a therapeutic target for cancer. Canine mammary cancer is one of the most common tumor diseases in dogs, with a relative incidence rate of 46.71% for CMT in China over the past five years, severely threatening the life and health of dogs. Therefore, the search for novel drugs targeting canine mammary cancer is of great significance. This study aims to investigate how the RORγ inhibitors W6134 and XY018 affect the expression of inflammatory genes through histone modifications in CMT-N7 cells. These results show that W6134 and XY018 can upregulate signaling pathways related to inflammation and apoptosis and influence the expression of associated genes. The close link between RORγ and inflammation-related genes further confirms that RORγ may serve as a therapeutic target for canine cancer. Additionally, ChIP-qPCR was used to detect the enrichment of histone markers such as P300, H3K27ac, H3K4me1, H3K9la, and H3K9bhb at the target loci of CXCL10 and MECOM genes. Collectively, our findings provide molecular evidence for the protective role of RORγ in canine mammary cancer, potentially by regulating inflammatory pathways via histone modifications, offering new insights for improving the cure rate and survival of affected dogs. Full article

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

Gestational diabetes mellitus (GDM) and iron deficiency anemia (IDA) are the most common pregnancy-related conditions resulting in adverse maternal and fetal complications. MicroRNAs (miRNAs), particularly miR-182-3p and miR-24-3p, are promising biomarkers as they act as regulatory elements in various diseases; however, their roles in GDM and IDA are unclear. The present study aimed to analyze the expression and functional relevance of miR-182-3p and miR-24-3p in GDM and IDA. Experimental validation via RT-PCR revealed significant upregulation of both miRNAs in GDM and IDA samples. We identified common target genes and signaling pathways associated with these miRNAs, using a combination of data mining, bioinformatic tools (miRDB, TargetScan, miRTarBase, and miRWalk), and differentially expressed gene (DEGs) analysis using the GEO, OMIM, MalaCards, and GeneCards datasets. GO and KEGG pathway analyses revealed that the shared miRNA–mRNA in target genes were enriched in insulin signaling, apoptosis, and inflammatory pathways—key mechanisms implicated in GDM and IDA. Furthermore, hub genes such as IRS1, PIK3CA, CASP3, MAPK7, and PDGFRB were identified, supporting their central role in metabolic dysregulation during pregnancy. These findings demonstrate the potential of miR-182-3p and miR-24-3p as diagnostic biomarkers and therapeutic targets in managing GDM and IDA, offering new insights into the molecular interplay underlying pregnancy complications. Full article

Resistance to cytarabine (Ara-C) remains a major obstacle to the successful treatment of acute myeloid leukemia (AML). Therefore, modulating Ara-C resistance is indispensable for improving clinical outcomes. We previously demonstrated that sodium caseinate (SC), a salt derived from casein, the principal milk protein, inhibits proliferation and modulates the expression of Ara-C resistance-related genes in chemoresistant cells. However, it remains unclear whether the combination of SC with antineoplastic agents enhances apoptosis, modulates chemoresistance-related genes, and prolongs the survival of tumor-bearing mice implanted with chemoresistant cells. Here, we investigated the effects of SC in combination with Ara-C or daunorubicin (DNR) on cell proliferation, apoptosis, the expression of chemoresistance-associated genes, and the survival of tumor-bearing mice. Crystal violet assays, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunofluorescence, flow cytometry, and Kaplan–Meier survival curves were used to evaluate the effects of combinations in chemoresistant cells. We demonstrate that the IC₂₅ concentration of SC, when combined with antileukemic agents, increases the sensitivity of chemoresistant WEHI-CR50 cells to Ara-C by downregulating SIRT1 and MDR1, upregulating the expression of ENT1 and dCK, enhancing apoptosis, and prolonging the survival of WEHI-CR50 tumor-bearing mice. Our data suggest that SC in combination with antileukemic agents could be an effective adjuvant for Ara-C-resistant AML. Full article

Background: DEAD/H box 5 (DDX5) serves as a transcriptional coactivator for several transcription factors including E2F1, the primary target of the tumor suppressor pRB. E2F1 physiologically activated by growth stimulation activates growth-related genes and promotes cell proliferation. In contrast, upon loss of pRB function due to oncogenic changes, E2F1 is activated out of restraint by pRB (deregulated E2F1) and stimulates tumor suppressor genes such as ARF, which activates the tumor suppressor p53, to suppress tumorigenesis. We have recently reported that DDX5 augments deregulated E2F1 activity to induce tumor suppressor gene expression and apoptosis. During the analyses, we noted that over-expression of E2F1 increased DDX5 expression, suggesting a feed forward loop in E2F1 activation through DDX5. Objective: We thus examined whether the DDX5 gene is a target of deregulated E2F1. Method: For this purpose, we performed promoter analysis and ChIP assay. Result: The DDX5 promoter did not possess typical E2F binding consensus but contained several GC repeats observed in deregulated E2F1 targets. Insertion of point mutations in these GC repeats decreased responsiveness to deregulated E2F1 induced by over-expression of E2F1, but scarcely affected responsiveness to growth stimulation. ChIP assays showed that deregulated E2F1 induced by over-expression of E2F1 or expression of E1a, which binds pRB and releases E2F1, bound to the DDX5 gene, while physiological E2F1 induced by growth stimulation did not. Conclusions: These results suggest that the DDX5 gene is a target of deregulated E2F1, generating a feed forward loop mediating tumor suppressive E2F1 activity. Full article

Molecular chaperones, especially heat shock proteins (HSPs) have vital functions in cells’ responses to stress. Here, we cloned and sequenced the complete complementary DNA encoding HSP90 (MjHSP90) from the shrimp Marsupenaeus japonicus. The MjHSP90 cDNA comprised 3162 bp, including a 2172 bp coding region encoding a 724 amino acid-protein (predicted molecular mass = 83.12 kDa). Homology and phylogenetic analyses showed that MjHSP90 was highly conserved and most homologous to Litopenaeus vannamei HSP90. MjHSP90 is expressed in all tested tissues, with high expression in gill tissue and the hepatopancreas. Cold stress significantly upregulated MjHSP90 expression in the gill and hepatopancreas (p < 0.05). Following RNA interference knockdown of MjHSP90, the cold stress-related death rate of the shrimp increased significantly, accompanied by significantly upregulated expression of apoptosis-related genes Mjcaspase-3 and Mjbcl-2 (p < 0.05) and an increase in the number of apoptotic cells. The results indicated that MjHSP90 might play a pivotal role in the shrimp’s immune response to cold stress. Full article

Background: Colorectal cancer (CRC) is a prevalent gastrointestinal malignancy, ranking third in incidence and second in cancer-related mortality. Despite therapeutic advances, challenges such as chemotherapy toxicity and drug resistance persist. Thus, there is an urgent need for novel CRC treatments. However, developing new drugs is time-consuming and resource-intensive. As a more efficient approach, drug repurposing offers a promising alternative for discovering new therapies. Methods: In this study, we screened 1068 small molecular compounds from an FDA-approved drug library in CRC cells. Menadione was selected for further study based on its activity profile. Mechanistic analysis included a cell death pathway PCR array, differential gene expression, enrichment, and network analysis. Gene expressions were validated by RT-qPCR. Results: We identified menadione as a potent anti-tumor drug. Menadione induced three programmed cell death (PCD) signaling pathways: necroptosis, apoptosis, and autophagy. Furthermore, we found that the anti-tumor effect induced by menadione in CRC cells was mediated through a key gene: MAPK8. Conclusions: By employing methods of cell biology, molecular biology, and bioinformatics, we conclude that menadione can induce multiple forms of PCD in CRC cells by activating MAPK8, providing a foundation for repurposing the “new use” of the “old drug” menadione in CRC treatment. 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

The midgut of Antheraea pernyi plays a critical role in antiviral defense. However, its transcriptional complexity remains poorly understood. Here, a full-length (FL) transcriptome atlas of A. pernyi midgut was developed by integrating PacBio Iso-Seq and RNA-seq techniques. The transcriptome sequences included 1850 novel protein-coding genes, 17,736 novel alternative isoforms, 1664 novel long non-coding RNAs (lncRNAs), and 858 transcription factors (TFs). In addition, 2471 alternative splicing (AS) events and 3070 alternative polyadenylation (APA) sites were identified. Moreover, 3426 and 4796 differentially expressed genes (DEGs) and isoforms were identified after ApNPV infection, respectively, besides the differentially expressed lncRNAs (164), TFs (171), and novel isoforms of ApRelish (1) and ApSOCS2 (4). Enrichment analyses showed that KEGG pathways related to metabolism were suppressed, whereas GO terms related to DNA synthesis and replication were induced. Furthermore, the autophagy and apoptosis pathways were significantly enriched among the upregulated genes. Protein–protein interaction network (PPI) analysis revealed the coordinated downregulation of genes involved in mitochondrial ribosomes, V-type and F-type ATPases, and oxidative phosphorylation, indicating the disruption of host energy metabolism and organelle acidification. Moreover, coordinated upregulation of genes associated with cytoplasmic ribosomes was observed, suggesting that the infection by ApNPV interferes with host translational machinery. These results show that ApNPV infection reprograms energy metabolism, biosynthetic processes, and immune response in A. pernyi midgut. Our study provides a foundation for elucidating the mechanisms of A. pernyi–virus interactions, particularly how the viruses affect host defense strategies. 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