Xenobiotica最新文献

1. To study the effects of calycosin on palmitic acid-induced HepG2 cells, as well as the potential mechanisms of action.

2. Potential targets of calycosin for the alleviation of insulin resistance were predicted by network pharmacology. Glucose concentration in the culture medium was determined by the GOD-POD method. The model of insulin resistance was established by palmitic acid-induced HepG2 cells. Effects of palmitic acid and calycosin on HepG2 cell activity were determined using an MTT assay kit. The expression levels of AKT1 and FOXO3a were detected by western blot. The expression level of hsa-miR-324-3p was detected by RT-qPCR. Dual luciferase reporter assay to detect targeting of AKT1 by hsa-miR-324-3p.

3. AKT1 was predicted and validated as a potential target of calycosin for treatment of insulin resistance. The model of insulin resistance was successfully established by palmitic acid-induced HepG2 cells. Up-regulation of AKT1 expression inhibits FOXO3a entry into the nucleus. Calycosian was demonstrated to concentration-dependently increase the sensitivity of insulin resistance cells to insulin. The hsa-miR-324-3p was proven to exist in insulin-resistant cells. Hsa-miR-324-3p was found to target AKT1 involved in the alleviation of insulin resistance.

4. Calycosin inhibits FOXO3a nuclear translocation by regulating the hsa-miR-324-3p/AKT pathway, thus alleviating insulin resistance.

Astragalin (AST), a flavonoid, shows promise for neurodegenerative diseases like Parkinson's disease (PD), cognitive impairment (CI), and depression. However, its efficacy in treating neurodegenerative diseases and the underlying molecular mechanisms remain unclear.This study aims to evaluate the metabolite profile, pharmacokinetics, toxicity, molecular targets, and potential biological activities of AST. Thirty-one AST metabolites formed through Phase II reactions (O-glucuronidation, O-sulfation, and methylation) were found.AST and its metabolites partially violate Lipinski's Rule of Five, including molecular weight and hydrogen bond donors, impacting drug-likeness. However, AST and its metabolites have favourable safety and potential anti-neurodegenerative and antidepressant effects.AST shows strong binding affinities with key neuroinflammatory targets, including IL1B, IL6, TNF, NOS2, PTGS2, SERT, caspase-3, caspase-8, and GABAa receptor, and network analysis highlights its association with neuroinflammatory pathways.Collectively, these findings support AST as a potential neurotherapeutic candidate and offer a basis for further in vitro and in vivo validation.

This study aimed to investigate the therapeutic potential of Aloe-emodin (AE) for irritable bowel syndrome (IBS), focusing on its effects and underlying mechanisms.Deoxycholic acid (DCA)-induced IBS rats (Sprague-Dawley) were orally administered AE. Body weight and faecal pellet were monitored. Anxiety-like behaviour, visceral hypersensitivity, colon permeability were assessed via the open-field (OF) test, abdominal Withdrawal Reflex (AWR) score, FITC-dextran fluorescence, respectively. Enzyme-linked immunosorbent assay (ELISA) quantified substance P (SP), 5-hydroxytryptamine (5-HT), TNF-α, and IL-6 levels. Hypoxia inducible factor-1α (HIF-1α) expression was analysed via qRT-PCR. The mechanism of AE on IBS was evaluated in LPS-treated NCM460 injury.AE alleviated IBS symptoms (improved weight gain, reduced faecal output/water content, increased centre exploration time, lowered AWR scores, decreased colon permeability, SP, 5-HT, and pro-inflammatory cytokine levels). HIF-1α upregulation in colonic tissues and LPS-induced NCM460 cells was suppressed by AE treatment. The protective effect of AE was reversed by HIF-1α overexpression in IBS rats. AE enhanced cell proliferation, reduced cellular permeability, and inflammation in LPS-stimulated NCM460 cells. HIF-1α overexpression partially reversed the protective effects of AE in LPS-induced NCM460 injury.AE ameliorated IBS symptoms by promoting cell proliferation, suppressing cell permeability, and inflammation of colonic epithelial cells via regulating HIF-1α.

Adipose-derived stem cells (ADSCs) offer a novel approach for treating orthopaedic diseases. Flurbiprofen is a non-steroidal anti-inflammatory analgesic drug used in bone injury therapy. However, its cytotoxicity to ADSCs remains unclear.The differentiation potential of ADSCs was analysed in vitro using the differentiation induction method. Microscopic analysis, Live/Dead staining, MTT assay, and CCK8 assay were used to determine the cytotoxic effects of flurbiprofen on ADSCs at different concentration gradients. Vascular endothelial growth factor (VEGF) levels were measured by ELISA to reflect flurbiprofen's effects on the activity and paracrine function of ADSCs. ANOVA was applied, with p < 0.05 considered significant and p < 0.01 highly significant.Live cell concentration decreased dose-dependently with flurbiprofen treatment, particularly on the 7th day. The level of VEGF decreased significantly with the increase of the concentration of flurbiprofen in a certain concentration range, which indicated that flurbiprofen could inhibit the activity and secreted proteins of ADSCs.Our study showed that small doses of flurbiprofen did not affect the secretion of proteins by cells and cell activity. Therefore, it is necessary to pay attention to the concentration of flurbiprofen in the clinical application of ADSCs therapy for orthopaedic diseases.

It has been shown that fluoxetine is cytotoxic on pancreatic beta-cells via induction of mitochondrial dysfunction and oxidative stress. We investigated the direct effect of fluoxetine on isolated pancreatic mitochondria and evaluate the potential protective effects of betanin and thymoquinone.Mitochondria were isolated from rat pancreas and treated with various concentrations of fluoxetine (10-8000 µM). Then, protective effect of betanin (100-500 µM) and thymoquinone (10-100 µM) on fluoxetine-induced mitochondrial toxicity were studied (60 min). The activity of succinate dehydrogenases (SDH), reactive oxygen species (ROS) formation, mitochondrial swelling, mitochondrial membrane potential (MMP) collapse, malondialdehyde (MDA) production and glutathione level were analysed.Fluoxetine directly caused toxicity in pancreatic isolated mitochondria at concentration of 500 μM and higher. Except MDA and GSH, fluoxetine caused significantly SDH activity reduction, MMP collapse, mitochondrial swelling and ROS formation in pancreatic mitochondria. However, our results showed that only betanin protected fluoxetine-induced mitochondrial dysfunction, while thymoquinone had no impact on mitochondrial toxicity induced by fluoxetine.We can conclude that fluoxetine is directly toxic on pancreas isolated mitochondria, which may be related to its diabetogenic potential in humans. Moreover, our finding suggested that use of betanin may be beneficial for prevention of diabetogenic effect of fluoxetine.

Permethrin, a pyrethroid commonly used to grow crops worldwide, may affect the aquatic environment and show toxicological impact on non-target organisms.Farmed shrimp, Litopenaeus vannamei, can be included among these organisms since enzymatic antioxidant defense responses were disrupted in gills and hepatopancreas after exposure to this xenobiotic.Phase II biotransformation (Glutathione S-Transferase - GST activity) was affected as well as Acetylcholinesterase - AchE activity.Phase II biotransformation (Glutathione S-Transferase - GST activity) was affected as well as Acetylcholinesterase - AchE activity.1.

Senkyunolide A (Sen A) has been shown to have neuroprotective effects, which leads to its inclusion in the daily diet of the elderly, thereby increasing the risk of adverse interactions with other drugs. To offer a reference for the clinical prescription and administration of Sen A, its impact on the activity of cytochrome P450 enzymes (CYP450s) was investigated.Pooled human liver microsomes were utilised to conduct the probe substrate assay. Concentration-dependent and time-dependent evaluation was carried out with 0 - 100 μM of Sen A and incubation time of 0-30 min. The inhibition of CYP450s was fitted with competitive or non-competitive inhibition models to characterise the effects of Sen A.Sen A significantly inhibited the activities of CYP1A2, 2C9, and 3A4 with IC₅₀ values of 16.59, 14.73, and 11.51 μM, respectively. Both the inhibition of CYP1A2 and 2C9 followed a competitive pattern with the Ki values of 7.08 and 6.56 μM, respectively. In contrast, the inhibition of CYP3A4 was non-competitive (Ki = 5.19 μM) and time-dependent with the KI and K_inact of 0.404 μM^-1 and 0.013 min^-1, respectively.Careful administration of Sen A and related herbs is advised when used concurrently with drugs metabolised by CYP1A2, 2C9, and 3A4.

Crack cocaine is a highly addictive drug that may induce a plethora of health problems in users.The underlying pathophysiological and toxicity mechanisms promoted by crack cocaine use are still unclear.Here, we used the Drosophila melanogaster model to evaluate the dose-dependent effects of crack cocaine ingestion on several developmental and lifelong parameters, as well as the expression levels of key mitochondrial, endoplasmic reticulum, and antioxidant genes.Canton-S flies were fed increasing concentrations of crack cocaine and subjected to development, longevity, and negative geotaxis assays.Subsequently, we analyzed gene expression in L3 larvae and adult heads by quantitative real-time PCR. Crack cocaine increased larval lethality (>80%), and it affected the locomotor abilities of both larvae and adults (20-30%).This was associated with increased levels of mtDNA and transcripts for Marf, Pink1, Catalase, and Sod2 at low concentrations, suggesting mitochondrial biogenesis and remodelling.Mitochondrial and ER stress were evident at high crack concentrations, as indicated by a decrease in mtDNA copy number and increased transcript levels of parkin, spargel, Ire1, PEK, and CaMKII.Taken together, our data suggest that crack cocaine may lead to distinct harmful effects that are often apparent at very low doses, increasing adverse outcomes at high doses.

Myclobutanil, a pesticide commonly employed in agricultural practices for fruits, vegetables, and crops, is capable of crossing the blood-brain barrier (BBB) and persisting in cerebrospinal fluid, posing significant risks to human health. Consequently, it is crucial to systematically explore the molecular toxicological mechanisms underlying its neurotoxic effects.This study employed a systems-level approach that integrated weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network construction, followed by molecular docking and molecular dynamics (MD) simulations for validation.A total of 75 key targets were identified using cheminformatics tools (SEA, SwissTargetPrediction, TargetNet) and disease databases (GeneCards, OMIM, DisGeNET). Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis revealed that Myclobutanil exposure induces neurotoxicity through multiple signalling pathways, particularly the Pathways of neurodegeneration-multiple diseases and PI3K-Akt signalling pathway.Transcriptomic analysis and WGCNA identified RAF1 as a significantly correlated target with Myclobutanil exposure. Molecular docking and MD simulations further confirmed a strong binding affinity between RAF1 and Myclobutanil, suggesting that RAF1 plays a pivotal role in Myclobutanil exposure neurotoxicity.This prospective study yields predictive insight into the molecular events underlying Myclobutanil exposure neurotoxicity and highlights candidate therapeutic targets that remain to be validated in vivo.