Human & experimental toxicology最新文献

IntroductionVitamin D overdose, often stemming from excessive supplementation rather than dietary intake. It has been associated with various conditions such as cardiovascular disorders. This study aimed to investigate the effects of vitamin D toxicity on cardiac tissue.MethodsSixteen Wistar rats (250 ± 50 g) were randomly divided into two groups: the control group and the high-dose vitamin D group (40,000 IU/kg). Vitamin D was administered via gavage for 8 weeks. The expression of sirtuin 1 (SIRT1), the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1-α), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) genes in cardiac tissue was evaluated. Blood samples were analysed for lactate dehydrogenase (LDH) levels. Moreover, oxidative stress markers, including malondialdehyde (MDA) and superoxide dismutase (SOD), were measured in tissue samples. Histopathological evaluations were also conducted.ResultsThe expression of SIRT1, PGC1-α, Bcl-2, and the SOD levels were significantly decreased in the vitamin D-treated group. In addition, the values indicated a significant increase in the expression of Bax along with LDH and MDA levels in the vitamin D-treated group compared to the control group.DiscussionLong-term administration of high-dose vitamin D significantly increased oxidative stress and apoptosis in cardiac tissue, likely mediated by the SIRT1/PGC1-α pathway.Graphical abstractThe illustration of the suggested mechanism underlying high-dose vitamin D-induced cardiotoxicity.

IntroductionThis study investigated the molecular mechanism by which HuA influences the expression of pyruvate carboxylase via retinoid X receptor alpha (RXRA), thereby affecting the progression of obstructive sleep apnea (OSA).MethodsBioinformatics analysis including screening of differentially expressed genes (DEGs) and searching the downstream target genes of RXRA were conducted. Cognitive function, neuronal damage, oxidative stress, and inflammation were evaluated in chronic intermittent hypoxia (CIH) mouse models. The Morris water maze test was used to assess swimming path length, escape latency, and platform crossing times. H&E and Nissl staining was performed to evaluate pathological changes and neuronal counts in brain tissue. ELISA was utilized to measure the oxidative stress levels and inflammatory cytokines. RXRA enrichment in the pyruvate carboxylase promoter region in CIH was assessed using Chromatin Immunoprecipitation (ChIP), and the effect of RXRA on pyruvate carboxylase promoter activity was analyzed using dual-luciferase assay.ResultsRXRA was identified as a potential regulatory target gene of HuA. Pyruvate carboxylase was identified as a RXRA target gene and a significant DEG in OSA. CIH-induced cognitive impairment, neuronal damage, oxidative stress, and inflammation in mice, while such symptoms were alleviated by HuA treatment. In OSA, suppression of RXRA expression led to reduced pyruvate carboxylase expression. HuA treatment enhanced RXRA expression, thereby promoting pyruvate carboxylase expression. HuA alleviated CIH-induced cognitive impairment, neuronal damage, oxidative stress, and inflammation via the RXRA/pyruvate carboxylase axis.ConclusionIn summary, HuA alleviates CIH-induced cognitive impairment, neuronal damage, oxidative stress, and inflammation by promoting the RXRA/pyruvate carboxylase axis.

IntroductionCigarette smoking extract (CSE) can cause endothelial cell (EC) dysfunction, and then promote the occurrence and development of atherosclerosis. However, the molecular mechanisms underlying CSE-induced EC dysfunction are unknown. Sirt1, as a deacetylase, is involved in various biological processes of ECs. Therefore, this study investigated whether CSE induces apoptosis and mitochondrial dysfunction in human umbilical vein endothelial cells (HUVECs) via Sirt1-dependent mechanisms.MethodsHUVEC activity was assessed using MTT and crystal violet staining following treatment with different concentrations of CSE. Lentiviral transfection technology was used to generate HUVECs overexpressing Sirt1. Apoptosis was detected by Tunnel staining. MitoTracker™ Deep Red FM and JC-1 were used to assess mitochondrial structure and membrane potential. ELISA was used to detect the expression of superoxide dismutase (SOD) and malondialdehyde (MDA). qPCR was used to determine mRNA expression. Atherosclerosis was evaluated by oil red O staining in ApoE-KO mice after cigarette smoke exposure.ResultsCSE decreased Sirt1 and sonic hedgehog (SHH) expression, leading to mitochondrial dysfunction and apoptosis in HUVECs. Overexpressing Sirt1 or activating the SHH signaling pathway attenuated CSE-induced apoptosis and mitochondrial dysfunction. However, inhibiting the SHH signaling axis attenuated the protective effect of Sirt1 overexpression on CSE-induced apoptosis and mitochondrial dysfunction. In vivo studies also showed that cigarette smoke exacerbated atherosclerosis in ApoE-KO mice, downregulating Sirt1, SHH, and Gli1 expression in the aorta. Additionally, cigarette smoke increased Bax expression and decreased Bcl-2 expression in ApoE-KO mice aortas.DiscussionsSmoking can affect all stages of the atherosclerosis process, and the specific mechanism remains unclear. This study confirms that CSE can induce mitochondrial dysfunction and apoptosis of HUVECs by reducing Sirt1 expression and inhibiting SHH signaling activation. These findings provide new insights into the prevention and treatment of smoking-induced atherosclerosis.

PurposeThis study investigated the mechanism by which Rosmarinic acid (RA) may alleviate doxorubicin (DOX)- induced cardiomyocyte apoptosis.MethodsThe target genes of RA, DOX-related differentially expressed genes, and GEO database related genes were retrieved by bioinformatics analyses. The results of these analyses were further intersected to identify candidate genes. The protein-protein interaction network was constructed to develop the pharmacophore model. The molecular docking was simulated to determine the core target B-cell lymphoma 2-like 1 (BCL2L1) for subsequent molecular mechanism investigation in vitro. The effects of DOX and RA on the apoptosis of H9c2 cells were assessed using the CCK8 assay. The present study investigated the effect of RA on DOX-induced oxidative stress in cardiomyocytes. This investigation was conducted using an ELISA test and a DCFH-DA probe. The JC-1 probe was utilized to assess the effect of RA on DOX-induced cardiomyocyte mitochondrial membrane permeability. A Western blot assay was conducted to ascertain the activation of multiple signaling molecules, including those belonging to the BCL-2 and caspase-3 families, within the apoptosis pathway.ResultsA total of 17 differentially expressed genes (DEGs) were screened, and five genes were selected as hub DEGs. A subsequent KEGG enrichment analysis revealed that these DEGs were significantly enriched in various biological processes and pathways, including the MAPK signaling pathway, autophagy, apoptosis, and the TNF signaling pathway. The pharmacophore model and molecular docking of five candidate targets with RA were successfully established. It is noteworthy that DOX treatment led to a suppression of SOD and GSH levels, an exacerbation of oxidative stress, and a promotion of cardiomyocyte apoptosis. Furthermore, it has been demonstrated to suppress mitochondrial membrane permeability. Subsequent RT-qPCR analysis of the hub genes revealed that only BCL2L1 exhibited significant alterations. Treatment with DOX altered the expression levels of apoptosis-associated proteins, BCL-2 family members, and caspase-3 family members. However, the administration of RA mitigated the deleterious effects of DOX on cardiomyocytes.ConclusionsThe protective effects of RA may against myocardial cell apoptosis are likely mediated through its activation of BCL2L1 and inhibition of caspase cascade protein expression in myocardial cells.

IntroductionMushrooms, belonging to the phyla Ascomycota and Basidiomycota, comprise approximately 14,000 known species, among which a small fraction are toxic. While toxic mushrooms are primarily associated with adverse health effects, recent research highlights their potential as sources of bioactive compounds with promising therapeutic applications.MethodsA systematic review was conducted using four major electronic databases: Web of Science, Google Scholar, PubMed, and ScienceDirect. The literature search, completed on July 1, 2024, utilized keywords including "Poisonous mushrooms," "Mushroom toxins," "Mycotoxins," "Beta-glucans," "Psilocybin," and "Therapeutic applications." Articles were selected based on specific inclusion criteria, focusing on studies investigating the biochemical, toxicological, and pharmacological properties of toxic mushroom compounds. Studies unrelated to mushrooms, non-peer-reviewed sources, or those with outdated or incomplete data were excluded.ResultsThis review examines key toxic mushroom compounds such as amanitins, phallotoxins, ibotenic acid, muscimol, orellanine, and gyromitrin, emphasizing their biosynthesis, structural features, and health effects. Despite their toxicity, compounds like beta-glucans, polysaccharides, lectins, and psilocybin exhibit immune-modulating, anticancer, and neuroprotective properties. These bioactive compounds have shown promise in targeting cancer stem cells and enhancing neurotransmitter activity, positioning them as potential therapeutic agents.DiscussionUnderstanding the therapeutic potential of toxic mushroom-derived bioactive compounds bridges toxicology and pharmacology, offering novel avenues for drug discovery. Comparative analysis with existing treatments highlights their unique advantages in modern medicine.

IntroductionCyclosporine is a calcineurin inhibitor that is widely used to decrease the incidence of organ transplant rejection and in the management of immunological diseases. However, these effects may be associated with increased incidence of nephrotoxicity. This work aimed to the exploration of the impact of omarigliptin with or without shikonin on a rodent model of cyclosporine nephrotoxicity and the precise determination of the mechanisms that may represent the basis of these effects.MethodsIn a Wistar rat model of cyclosporine-elicited nephrotoxicity, the effect of omarigliptin and shikonin, each alone and in combination, was determined at the level of the biochemical parameters and the histomorphological changes.ResultsOmarigliptin and/or shikonin administered to cyclosporine-injected animals induced a significant restoration of renal functions and glucagon-like peptide-1 (GLP-1) and augmentation of the antioxidant defenses, associated with increased sirtuin 1 expression and its related signaling changes in comparison to animals that received cyclosporine alone. Additionally, omarigliptin and/or shikonin elicited a significant amelioration of the inflammatory response and cellular differentiation and a significant improvement of the renal tissue disruptive changes elicited by cyclosporine. These effects were evident with omarigliptin/shikonin combination when compared to the groups treated with each agent alone.ConclusionOmarigliptin/shikonin combination suggests potential therapeutic benefit for the mitigation of cyclosporine nephrotoxicity, possibly via their effects on dipeptidyl peptidase 4 activity and GLP-1 levels with subsequent modulation of the redox status, cellular proliferation, and the inflammatory pathways.

IntroductionRare earth elements (REEs) are increasingly used across various industries, raising concerns regarding their potential health impacts. Exposure to REEs has been linked to systemic diseases affecting the respiratory, nervous, and immune systems. We aimed to explore the effects of REE exposure on neurological health.MethodsWe performed high-throughput sequencing to identify differentially expressed proteins in the plasma of REE-exposed patients compared to healthy individuals. Additionally, in the mouse model, we employed western blotting, quantitative real-time PCR (qRT-PCR), and kits to verify the association between REE exposure and brain damage.ResultsWe identified 144 differentially expressed proteins in the plasma of REE-exposed patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that these proteins were primarily related to synaptic functions and the glutamate synaptic pathway. A protein-protein interaction network constructed using the STRING database revealed strong interactions among brain injury-related proteins following REE exposure. In animal experiments, western blot analysis showed that exposure to Nd₂O₃ significantly increased protein levels of calcium channel voltage-dependent P/Q-type alpha 1A subunit, phospholipase A2 group IVA, and SH3 and multiple ankyrin repeat domains 1. qRT-PCR results confirmed increased expression of corresponding genes. Concurrently, elevated levels of malondialdehyde and nitric oxide and decreased total antioxidant capacity were observed.DiscussionOverall, our findings suggest that Nd₂O₃ exposure is closely associated with brain damage, and the glutamate synaptic pathway plays a significant role. Our study provides novel insights into the molecular mechanisms underlying Nd₂O₃-induced neurotoxicity.

Background: Gestational diabetes mellitus (GDM) is a metabolic disorder that arises during pregnancy and heightens the risk of placental dysplasia. Ginsenoside Re (Re) may stabilize insulin and glucagon to regulate glucose levels, which may improve diabetes-associated diseases. Purpose: This study aims to investigate the mechanism of Re in high glucose (HG)-induced apoptosis of trophoblasts through endoplasmic reticulum stress (ERS)-related protein CHOP/GADD153. Research Design: Human trophoblast cells HTR-8/SVneo were treated with HG to simulate the HG environment in vitro, while normal glucose (NG) was used as the control. Study Sample: NG (5 mM) or HG (25 mM)-cultured HTR-8/SVneo cells were treated with 10, 20 or 40 μM Re. HG-cultured cells were treated with 5 mM ERS inducer 2-Deoxy-D-glucose (2-DG) and transfected with oe- CHO. Data Collection and/or Analysis: Cell viability and apoptosis were detected by CCK-8 and flow cytometry; LDH release, superoxide dismutase (SOD), malonaldehyde (MDA) and glutathione (GSH) levels were detected using kits; the apoptosisrelated proteins and ERS-related proteins were assessed by western blot. Results: Re (10, 20 or 40 μM) had no significant effect on NG-treated HTR-8/SVneo cell viability. Re (20 or 40 μM) could enhance the viability of HG-treated trophoblasts. Re (40 μM) inhibited apoptosis of HGtreated trophoblasts, ERS and alleviated oxidative stress evidenced by suppressed phosphorylation of PERK, IRE1α, reduced protein expression of ATF6, CHOP/GADD153, and inhibited MDA accumulation, GSH and SOD loss. ERS activation or CHOP/GADD153 overexpression reversed Re's inhibition on HG-induced apoptosis of trophoblasts. Conclusions: Re repressed HG-induced placental trophoblast apoptosis by mediating ERS-related protein CHOP/GADD153.

Background: It is well-known that ultraviolet B (UVB) causes cataracts by inducing pyroptosis and the production of reactive oxygen species (ROS) in human lens epithelial cells (HLECs). The transcription factor E2F1 (E2F1) serves as a positive regulator of disrupted pathways involved in histone modification and cell cycle regulation. However, its function in UVB-treated HLECs remains unknown.Purpose: This study aims to investigate the function of E2F1 in UVB-treated HLECs, with a particular focus on its interaction with NLRP3 and its impact on oxidative stress and pyroptosis. Research Design: HLECs were irradiated with UVB, and cell damage was assessed using CCK-8, ROS, and pyroptosis detection. The interaction between E2F1 and NLRP3 was confirmed using Chromatin immunoprecipitation (ChIP)-qPCR and dual-luciferase reporter assays.Study Sample: The study was conducted using UVB-treated HLECs.

Data collection and/or analysis: Collected data were statistically analyzed using one-way analysis of variance (ANOVA).

Results: Our results show that HLECs were much more susceptible to oxidative stress, pyroptosis, and E2F1 in response to UVB-irradiation, but that E2F1 down-regulation effectively counteracted these effects. E2F1 was then suggested as a potential NLRP3 transcription factor by bioinformatics studies. At the same time, luciferase and CHIP assays showed that E2F1 could bind to the NLRP3 promoter and enhance NLRP3 transcription. In addition, the protective effects of si-E2F1 against oxidative stress and pyroptosis in HLECs are counteracted by overexpressing NLRP3.

Conclusions: All of the above provided the possibility to demonstrate that E2F1 plays a crucial role in regulating oxidative stress and pyroptosis in UVB-induced HLECs through inhibiting NLRP3, and it promotes oxidative stress-induced pyroptosis by suppressing NLRP3 expression.