Comparative Biochemistry and Physiology C-toxicology & Pharmacology最新文献

Flusilazole is a well-known triazole fungicide applied to various crops and fruits worldwide. Flusilazole residues are frequently detected in the environment, and many researchers have reported the hazardous effects of flusilazole on non-target organisms; however, the developmental toxicity of flusilazole has not been fully elucidated. In this study, we investigated flusilazole-induced developmental defects in zebrafish, which are used in toxicology studies to assess the toxic effects of chemicals on aquatic species or vertebrates. We confirmed that flusilazole exposure affected the viability and hatching rate of zebrafish larvae, and resulted in morphological defects, reduced body length, diminished eye and head sizes, and inflated pericardial edema. Apoptosis, oxidative stress, and inflammation were also observed. These factors interrupted the normal organ formation during early developmental stages, and transgenic models were used to identify organ defects. We confirmed the effects of flusilazole on the nervous system using olig2:dsRed transgenic zebrafish, and on the cardiovascular system using cmlc2:dsRed and fli1:eGFP transgenic zebrafish. Our results demonstrate the developmental toxicity of flusilazole and its mechanisms in zebrafish as well as the detrimental effects of flusilazole.

In this study, the antiparkinson effect of khellin (KL) on rotenone-induced Parkinson's disease (PD) was examined in zebrafish. Initially, In silico evaluations, such as drug likeness and ADME/T analysis, confirmed the pharmacological viability of KL. Molecular docking and molecular dynamics (MD) analysis revealed stable binding interactions between KL and monamine oxidase B (MAO-B). Molecular docking results for KL and pioglitazone (CCl) revealed binding energies of −6.5 and −10.4 kcal/mol, respectively. Later, molecular dynamics (MD) studies were performed to assess the stability of these complexes, which yielded binding energies of −36.04 ± 55.21 and −56.2 ± 80.63 kJ/mol for KL and CCl, respectively. These results suggest that KL exhibits considerable binding affinity for MAO-B. In In vitro studies, according to the DPPH free radical scavenging assay, KL exhibited significant antioxidant effects, indicating that it can promote redox balance with an IC₅₀ value of 22.68 ± 0.5 μg/ml. In vivo studies and evaluation of locomotor activity, social interaction, histopathology and biochemical parameters were conducted in KL-treated zebrafish to measure SOD and GSH antioxidant activity, the oxidative stress marker malondialdehyde (MDA), the inflammatory marker myeloperoxidase (MPO) and MAO-B. However, while the locomotor and social interaction abilities of the rotenone-treated zebrafish were significantly reduced, KL treatment significantly improved locomotor activity (p < 0.001) and social interaction (p < 0.001). KL alleviated PD symptoms, as indicated by significant increases in SOD (p < 0.01), GSH (p < 0.001), MDA (p < 0.001), MAO-B (p < 0.001) and MPO (p < 0.001) in rotenone-induced PD fish (p<0.001) significantly reduced activities. Histopathological studies revealed that rotenone-induced brain hyperintensity and abnormal cellularity of the periventricular gray matter in the optic tectum were significantly reduced by KL treatment. This study provides a strong basis for developing KL as a new candidate for the treatment of Parkinson's disease, with the prospect of improved safety profiles and efficacy.

Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer that can damage various organizations and physiques through oxidative stress. Quercetin (Que) is a rich polyphenol flavonoid with good anti-inflammatory and antioxidant effects. However, the protection mechanism of Que against DEHP exposure-induced IPEC-J2 cell injury and the implication of autophagy, apoptosis and immunity are still unclear. In this experiment, we looked into the toxicity regime of DEHP exposure on IPEC-J2 cells and the antagonistic function of Que on DEHP. In the experiment, 135 μM DEHP and/or 80 μM Que were used to treat the IPEC-J2 cells for 24h. Experiments indicated that DEHP exposure can cause increased reactive oxygen species (ROS) levels leading to oxidative stress, decreased CAT, T-AOC and GSH-Px activities, increased MDA and H₂O₂ accumulation, activated the ASK1/JNK signalling pathway, and further increases in the levels of apoptosis markers Bax, Caspase3, Caspase9, and Cyt-c, while reduced the Bcl-2 expression. DEHP also increased the expression of genes linked to autophagy (ATG5, Beclin1, LC3), while decreasing the expression of P62. Additionally, DEHP exposure led to elevated levels of IL1-β, IL-6, MCP-1, and TNF expression. When exposed to Que alone, there were no significant changes in cellular oxidative stress level, ASK1/JNK signalling pathway expression level, apoptosis, autophagy and cellular immune function. The combination of DEHP and Que treatment remarkably decreased the proportion of autophagy and apoptosis, and recovered cellular immunity. In summary, Que can attenuate DEHP-induced apoptosis and autophagy in IPEC-J2 cells by regulating the ROS/ASK1/JNK signalling pathway and improving the immune dysfunction of IPEC-J2 cells.

Aspirin (Acetylsalicylic acid, ASA), one of the widely used non-steroid anti-inflammatory drugs can easily end up in sewage effluents and thus it becomes necessary to investigate the effects of aspirin on behaviour of aquatic organisms. Previous studies in mammals have shown ASA to alter fear and anxiety-like behaviours. In the great pond snail Lymnaea stagnalis, ASA has been shown to block a ‘sickness state’ induced by lipopolysaccharide injection which upregulates immune and stress-related genes thus altering behavioural responses. In Lymnaea, eliciting physiological stress may enhance memory formation or block its retrieval depending on the stimulus type and intensity. Here we examine whether ASA will alter two forms of associative-learning memory in crayfish predator-experienced Lymnaea when ASA exposure accompanies predator-cue-induced stress during the learning procedure. The two trainings procedures are: 1) operant conditioning of aerial respiration; and 2) a higher form of learning, called configural learning, which here is dependent on evoking a fear response. We show here that ASA alone does not alter homeostatic aerial respiration, feeding behaviour or long-term memory (LTM) formation of operantly conditioned aerial respiration. However, ASA blocked the enhancement of LTM formation normally elicited by training snails in predator cue. ASA also blocked configural learning, which makes use of the fear response elicited by the predator cue. Thus, ASA alters how Lymnaea responds cognitively to predator detection.

Terbuthylazine (TBA) is a common triazine herbicide used in agricultural production, which causes toxic damage in multiple tissues. Hesperidin (HSP) is a flavonoid derivative that has anti-inflammatory, antioxidant and cytoprotective effects, but its role in reducing toxic damage caused by pesticides is still unclear. In this study, we aimed to investigate the toxic effect of TBA exposure on chicken hepatocytes and the therapeutic effect of HSP on the TBA-induced hepatotoxicity. Our results demonstrated that HSP could alleviate TBA exposure-induced endoplasmic reticulum (ER) stress. Interestingly, TBA significantly disrupted the integrity of mitochondria-associated endoplasmic reticulum membrane (MAM), while HSP treatment showed the opposite tendency. In addition, TBA could significantly trigger ferroptosis in liver, and HSP treatment reversed ferroptosis under TBA exposure. These results suggested that HSP could inhibit ER stress and alleviate ferroptosis under TBA exposure via maintaining MAM integrity, which provided a novel strategy to take precautions against TBA toxicity.

Inflammatory bowel disease (IBD) encompasses chronic disorders that cause severe inflammation in the digestive tract. This study evaluates (E)-3-(3,4-dichlorophenyl)-N-(2,6-dioxopiperidin-3-yl) acrylamide (named SKT40), a derivative of dioxopiperidinamide, as a potential novel treatment for IBD. The pharmacological activity of SKT40 indicated positive interactions using network pharmacology and molecular docking in silico. In vivo, adult and larval zebrafish were tested to evaluate the effectiveness of SKT40 at different concentrations (7.5 μM, 10 μM, 15 μM) in preventing dextran sulfate sodium (DSS)-induced intestinal inflammation. The administration of SKT40 resulted in positive effects by reducing reactive oxygen species (ROS), lipid peroxidation, and cell apoptosis in zebrafish larvae. SKT40 demonstrated a significant reduction in intestinal damage in adult zebrafish by increasing antioxidant enzymes that combat the causes of IBD, such as superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and glutathione peroxidase (GPx). It also reduces cellular damage and inflammation, as indicated by decreased levels of lactate dehydrogenase (LDH) and malondialdehyde (MDA). Gene expression analysis identified downregulation in gene expression of inflammatory mediators such as TNF-α, IL-1β, COX-2, and IL-6. Histopathological analysis showed tissue repair from DSS-induced damage and indicated reduced hyperplasia of goblet cells. These findings suggest that SKT40 effectively treats intestinal damage, highlighting its potential as a promising candidate for IBD therapy.

The exploration of sediment pollution caused by PAHs and its impact on microbial communities can provide valuable insights for the remediation of sediments. The spatial distribution of PAHs and their impact on the microbial community within the Pearl River Estuary were investigated in this study. The findings revealed that the total concentration ranges of 16 PAHs were between 24.26 and 3075.93 ng/g, with naphthalene, fluorene, and phenanthrene potentially exerting adverse biological effects. More PAHs were found to accumulate in subsurface sediments, and their average accumulation rates gradually decreased as the number of rings in PAHs increased, ranging from 180 % for 2-ring to 36 % for 6-ring. The phyla Proteobacteria, Bacteroidetes, Actinobacteria, and Chloroflexi were found to dominate both surface and subsurface sediments The correlation between microbial genera and PAHs contents was weak in sediments with low levels of PAHs contamination, while a more significant positive relationship was observed in sediments with high levels of PAHs contamination. The physicochemical properties of sediments, such as pH, soil structure and Cu significantly influence bacterial community composition in highly contaminated sediments. Additionally, the network analysis revealed that certain bacterial genera, including Novosphingobium, Robiginitalea and Synechococcus_CC9902, played a pivotal role in the degradation of PAHs. These findings are significant in comprehending the correlation between bacterial communities and environmental factors in intertidal ecosystems, and establish a scientific foundation for bioremediation of intertidal zones.

The purpose of the present study was to investigate the development of verapamil-induced cardiorenal failure and the response of epidermal ionocytes in zebrafish embryos to this syndrome. Zebrafish embryos were exposed to verapamil for 24 h at different developmental stages (48, 72, and 96 h post-fertilization). The exposure resulted in the generation of edema in the pericardial and yolk sac regions, with more-pronounced effects observed in later-stage embryos. Cardiac parameters showed a suppressed heart rate at all stages, with a more-significant effect appearing in later stages. Verapamil also affected cardiac parameters including the end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), and cardiac output (CO), indicating negative overall effects on cardiac performance. mRNA levels of heart failure markers (nppa and nppb genes) were upregulated in verapamil-exposed embryos at all stages. Renal function was impaired as FITC-dextran excretion was suppressed. A whole-embryo ion content analysis revealed significant increases in sodium and calcium contents in verapamil-exposed embryos. The density of epidermal ionocytes increased, and the apical membrane of ionocytes was enlarged, indicating upregulation of ion uptake. In addition, mRNA levels of several ion transporter genes (rhcg1, slc9a3, atp6v1a, atp2b1a, trpv6, and slc12a10.2) were significantly upregulated in verapamil-exposed embryos. In summary, prolonged exposure to verapamil can induce cardiorenal failure which triggers compensatory upregulation of ionocytes in zebrafish embryos.

With global warming and increasing eutrophication of water bodies, a variety of algal toxins, including microcystin (MC), released into water by cyanobacterial blooms pose a serious threat to the survival of aquatic organisms. To investigate the mechanism of the Nrf2/Keap1a pathway on resisting MC-induced oxidative stress and apoptosis in Cristata plicata, we cloned the full-length cDNA of CpBcl-2. The cDNA full-length of CpBcl-2 was 760 bp, encoded a 177 amino acid peptide, and contained a highly conserved Bcl-2-like superfamily domain. MC stimulation increased the expression and activity levels of related antioxidant enzymes. After CpNrf2 knockdown, the transcription levels of NAD(P)H quinone redox Enzyme-1 (NQO1) and related antioxidant enzymes activity in the gills and kidney of C. plicata were significantly down-regulated upon MC stress, but that was significantly upregulated after knockdown of CpKeap1a. Additionally, Upon MC stress, the mRNA levels of CpBcl-2 were increased in the gills and kidney after knockdown of CpNrf2 at 24 h, and that of CpBcl-2 were decreased at 72 and 96 h in the CpKeap1a-siRNA+MC group. Moreover, MC stimulation significantly inhibited CpJNK expression in the gills and kidney, but which regulated the Nrf2/Keap1a pathway in C. plicata. However, the JNK inhibitor SP600125 promoted the expression of CpNrf2 and related enzymes with antioxidant response element (ARE-driven enzyme) in the gills and kidney. Then, we speculated that CpKeap1a was a negative regulator of CpNrf2, and C. plicata resisted MC-induced oxidative damage and apoptosis by inhibiting JNK transcription via the Nrf2/Keap1a pathway.

Biodegradable plastics have been commonly developed and applied as an alternative to traditional plastics, which cause environmental plastic pollution. However, biodegradable plastics still present limitations such as stringent degradation conditions and slow degradation rate, and may cause harm to the environment and organisms. Consequently, in this study, zebrafish was used to evaluate the effects of five biodegradable microplastics (MPs), polyglycolic acid (PGA), polylactic acid (PLA), polybutylene succinate (PBS), polyhydroxyalkanoate (PHA) and polybutylene adipate terephthalate (PBAT) exposure on the early development, retina morphology, visually-mediated behavior, and thyroid signaling at concentrations of 1 mg/L and 100 mg/L. The results indicated that all MPs induced decreased survival rate, reduced body length, smaller eyes, and smaller heads, affecting the early development of zebrafish larvae. Moreover, the thickness of retinal layers, including inner plexiform layer (IPL), outer nuclear layer (ONL), and retinal ganglion layer (RGL) was decreased, and the expression of key genes related to eye and retinal development was abnormally altered after all MPs exposure. Exposure to PBS and PBAT led to abnormal visually-mediated behavior, indicating likely affected the visual function. All MPs could also cause thyroid system disorders, among which alterations in the thyroid hormone receptors (TRs) genes could affect the retinal development of zebrafish larvae. In summary, biodegradable MPs exhibited eye developmental toxicity and likely impaired the visual function in zebrafish larvae. This provided new evidence for revealing the effects of biodegradable plastics on aquatic organism development and environmental risks to aquatic ecosystems.