Drug and Chemical Toxicology最新文献

This study developed and evaluated a ready-to-use quinestrol nanoparticle-based bait for contraception in female Bandicota bengalensis (lesser bandicoot rat). B. bengalensis in three treatment groups: Control (plain bait), Q (bait with bulk quinestrol, 100 ppm), and QNP (bait with quinestrol nanoparticles, 10 ppm) were evaluated at 15, 45, and 75 days after a five-day treatment in a bi-choice setting. Results showed no significant difference between treated and plain bait consumptions, indicating good acceptability. Ovary weight decreased, and uterine weight increased significantly in the treated groups. Organ histology revealed significant contraceptive effects, including an increased number of atretic follicles, a reduced number of normal follicles in the ovaries, and increased uterine gland numbers and diameter. The 17β-hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase activities were significantly increased. Treated females produced 65-85% fewer pups when bred with untreated males. Quinestrol did not affect body weight, weight of vital organs, the activity of alkaline and acid phosphatases, and aspartate and alanine aminotransferases, indicating its safety. The effects of Q lasted up to 45 days, whereas the effects of QNP persisted for 75 days, despite using 10 times less active ingredient. This research represents a potential advancement in sustainable rodent pest management with extended efficacy and reduced dosage requirements.

Ligustrum lucidum polysaccharide (FLL-P) is a class of important bioactive macromolecules extracted from the traditional Chinese medicinal herb wine-steamed Ligustrum lucidum Ait. As one of the key active components responsible for the pharmacological effects of this herb, its modern pharmacological value has garnered widespread attention. Research has demonstrated that FLL-P exhibits diverse and significant biological activities, with potential applications that far exceed the traditional scope of Chinese medicine. In recent years, chemical modification has been recognized as an effective strategy for enhancing the biological activity of polysaccharides. Consequently, structural modification of FLL-P is anticipated to further augment its activity and broaden its application prospects. However, current research on the chemical modification of FLL-P remains inadequate, particularly concerning the safety evaluation of modified products, which is still extremely limited. This research comprehensively explores the acetylation modifications of FLL-P, encompassing detailed characterization and toxicity assessments. The optimal product, identified as acetylated FLL-P 12.5 (FLL-PA12.5), was established through analyses of the degree of substitution (DS), FT-IR, and NMR. Toxicity tests, both acute and subacute, were conducted on male mice. The findings indicated that FLL-PA12.5 had a median lethal dose (LD₅₀) exceeding 2000 mg/kg and a no-observed adverse effect level (NOAEL) of 250 mg/kg. Administration of FLL-PA12.5 at doses between 250 and 2000 mg/kg resulted in alterations in various oxidative stress-related parameters in different organs of the mice. These findings indicate that FLL-PA12.5 is a promising therapeutic candidate with an acceptable safety profile, warranting further pharmacological exploration.

Paclitaxel (PTX) is an efficacious natural product-derived anticancer agent. It exerts a remarkable disruption of nanopore microtubule dynamics, thus inducing cytotoxic effects on cancer cells. However, its drawback is associated with non-targeted healthy organ damage, including nephrotoxicity. Therefore, we explored the mechanistic protective effect of tert-butylhydroquinone (TBHQ) against PTX-induced nephrotoxicity in male Wistar rats. For this purpose, rats were divided into four (n = 5) groups: normal control, TBHQ control (50 mg/kg body weight, administered from day 1 to day 14), PTX control (2 mg/kg body weight injected from day 1 to day 5) and TBHQ + PTX (with doses indicated above). PTX injection significantly impaired renal function leading to elevated serum urea, creatinine and uric acid levels and caused disruption of histological integrity. PTX markedly reduced the renal antioxidant enzyme mechanisms, Nrf2 and ferroptosis GPX-4 levels, whereas the levels of malondialdehyde MDA, caspase-3, and BAX were conspicuously elevated compared to the control. The renal NF-κB and cytokine (TNF-α, IL-1β and IL-6) expressions were significantly increased due to the PTX injection. TBHQ administration effectively reversed these alterations associated with oxidative inflammation, apoptosis and ferroptosis via restoring renal function, renal antioxidant enzyme activities and reducing MDA levels. TBHQ considerably improved renal Nrf2, GPX-4 and GSH followed by ameliorated histopathological changes. Taken together, our results suggest that TBHQ has protective effects against PTX-induced nephrotoxicity, and is a promising antioxidant agent with the potential to improve quality of life during PTX chemotherapy.

This study aimed to determine whether dietary bee pollen protects common carp (Cyprinus carpio) from deltamethrin (DM)-induced oxidative stress by modulating serum paraoxonase (PON) and arylesterase (ARE) activities. DM, a widely used pyrethroid insecticide, can impair antioxidant defenses in aquatic organisms. PON and ARE, two HDL-associated enzymes with antioxidant properties, were used as biomarkers to evaluate oxidative stress. Fish were exposed to two sublethal concentrations of DM (0.018 and 0.036 µg/L) for 14 days, with or without dietary supplementation of 2% chestnut-origin bee pollen. Results showed that while DM exposure significantly reduced serum PON and ARE activities, indicating oxidative stress and enzyme inhibition, bee pollen supplementation effectively counteracted these effects in a dose-dependent manner (p < 0.05). However, co-administration of the bee pollen partially restored both enzyme activities in a dose-dependent manner (p < 0.05). The improvement suggests that bee pollen, rich in flavonoids, phenolic compounds, and vitamins, exerts antioxidant effects that mitigate DM-induced toxicity. Bee pollen alone did not significantly alter PON or ARE activity compared to controls, confirming its safety and potential as a dietary supplement. Overall, this study provides evidence that bee pollen can serve as a natural antioxidant supplement to protect aquatic organisms against pesticide-induced oxidative damage, thereby contributing to the sustainable health management of aquaculture. These findings demonstrate that bee pollen can protect against pesticide-induced oxidative damage and may serve as a natural therapeutic agent in aquaculture.

Background: Carbon tetrachloride (CCl₄) induces hepatotoxicity through oxidative stress, inflammation, and apoptosis. Cirsimaritin, a natural flavonoid with antioxidant and anti-inflammatory activity, has not been extensively investigated for hepatoprotection.

Methods: Male Wistar rats were allocated into four groups (n = 6): control, cirsimaritin-only (80 mg/kg/day), CCl₄-only (1 mL/kg of 1:1 CCl₄: olive oil, i.p., twice weekly), and cirsimaritin + CCl₄. After four weeks, serum liver function markers, oxidative stress indices, cytokines, apoptotic markers, histology, and hepatic expression of Nrf2, HO-1, and NF-κB p65 were assessed.

Results: CCl₄ significantly elevated ALT, AST, ALP, bilirubin, MDA, TNF-α, IL-6, caspase-3, and caspase-9, while reducing albumin, total protein, SOD, CAT, GPx, IL-4, and IL-10 (p < 0.05-0.001). Cirsimaritin co-treatment reversed these alterations by normalizing liver enzymes, restoring antioxidant activity, lowering lipid peroxidation and pro-inflammatory cytokines, elevating anti-inflammatory cytokines, and attenuating apoptosis. Histology confirmed preservation of hepatic architecture. qPCR analysis showed that CCl₄ downregulated Nrf2/HO-1 and upregulated NF-κB p65, whereas cirsimaritin significantly counteracted these molecular changes.

Conclusion: Cirsimaritin protects against CCl₄-induced hepatotoxicity by enhancing antioxidant defenses, correcting cytokine imbalance, and inhibiting apoptosis, at least partly via activation of Nrf2/HO-1 and suppression of NF-κB signaling. These findings highlight cirsimaritin as a promising natural hepatoprotective candidate.

Datura metel L., a poisonous medicinal plant is used safely after Shodhana in Ayurveda. It is listed in Schedule E1 of Drugs and Cosmetics Act, as a poisonous medicinal plant to be used with caution. Although known for its toxic effects and reduction of toxicity by Shodhana. However, the toxicity mechanism, effect of Shodhana, and toxicity profile after repeated dosing are missing. Shodhita and Ashodhita Datura metel seeds were subjected to extraction using 70% ethanol and phytochemicals analyzed by LC-MS. Acute and 28-day repeated-dose toxicity studies were conducted as per OECD 423 and OECD 407. Network pharmacology, molecular docking, and dynamics were used to predict the potential multicomponent multitarget interactions and toxicity mechanisms. Ashodhita D. metel exhibited toxicity viz., neurotoxicity and hepatotoxicity, characterized by weight loss, altered organ weights, disrupted hematological, biochemical, behavioral and histological abnormalities. On the contrary, Shodhita D. metel was found safe with NOAEL 100 mg/kg. Whereas it was found to be 25 mg/kg for Ashodhita D. metel. Atropine and Scopolamine are predicted to disrupt cholinergic function and cause inflammation mediated through NFK-β1 and MAPK-1, altering neurotrophin, cAMP, PI3K-AKT, NOD-like receptor, AGE-RAGE, and IL-17 pathways. Atropine and scopolamine major toxic chemicals of D. metel were predicted to disrupt cholinergic function and induce inflammation, potentially mediated through NFK-β1 and MAPK-1 pathways. The Shodhana purification process was found to be effective in mitigating toxicity.

Methamphetamine (Meth), a psychoactive drug, has been shown to reduce testicular weight and decrease sperm count, indicating its potential role in contributing to male infertility. We therefore assessed Meth's effects (0.1-100 μM) on TM4 Sertoli cell viability, toxicity, and proliferation (trypan blue exclusion assay), mitochondrial activity (MA) (XTT assay), while transepithelial electrical resistance (TEER) was used to examine monolayer permeability. The acute study (only 24-hour Meth exposure) mimics recreational users and the chronic study, the Meth addicts who require daily doses (24-96 hours). Acute Meth treatment had minimal impact on TM4 Sertoli cell viability and toxicity, while chronic exposure resulted in reduced cell viability and increased toxicity in a dose-related manner. Acute exposure suppressed cell division at 72 hours, while chronic exposure suppressed cell division at both 72 and 96 hours. Long-term suppression of MA was observed for both acute and chronic Meth exposure (20 µM and 100 µM). Both acute and chronic Meth exposure affected permeability across the blood-testis barrier (BTB), which persisted for up to 96 hours. Given the pivotal role of Sertoli cells in spermatogenesis, our findings provide a two-pronged mechanism for Meth-induced male infertility and indicate that short-term exposure may have long-term effects on the germinal epithelium.

Ginkgo biloba extract (GBE) has demonstrated therapeutic potential in paraquat (PQ)-induced injury; however, its molecular mechanism remains unclear. The cell viability, lactate dehydrogenase (LDH) release, and apoptosis of RLE-6TN cells were assessed using CCK-8, LDH assay, and flow cytometry. Oxidative stress was evaluated using the DCFH-DA probe, while inflammatory cytokine levels (TNF-α, IL-1β, and IL-6) were measured via ELISA. The expression of miR-155-5p was analyzed using qRT-PCR. Bioinformatics analysis, dual-luciferase reporter assay, and RNA immunoprecipitation (RIP) assay were employed to investigate the interaction between SIRT1 and miR-155-5p. Protein expression levels of SIRT1, TLR4, phosphorylated P65 (p-P65), and total P65 were determined by western blotting. The results showed that miR-155-5p expression was upregulated in PQ-induced cell injury. Knockdown of miR-155-5p improved cell viability and reduced apoptosis, oxidative stress, and inflammatory damage in PQ-treated cells. In RLE-6TN cells, miR-155-5p directly targeted the SIRT1/TLR4 axis. GBE mitigated PQ-induced cell injury by modulating the miR-155-5p/SIRT1/TLR4 axis, thereby enhancing cell viability and reducing apoptosis, oxidative stress, and inflammation. This study indicates that GEB may protect against PQ-induced RLE-cell injury by regulating the miR-155-5p/SIRT1/TLR4 signaling pathway and that miR-155-5p could be a promising biomarker for PQ intoxication, providing novel insights into potential therapeutic strategies for PQ poisoning.

This research leverages the traditional Chinese medicine systems pharmacology (TCMSP) and Encyclopedia of traditional Chinese medicine (ETCM) to identify Chinese herbal remedies for (AKI) treatment. Lycii Fructus was found to be a potential candidate, and its pharmacological effects and molecular mechanisms were explored. Key targets of Lycii Fructus for AKI were identified and integrated into a "Herb-Ingredient-Target-Disease" (HITD) network. Through network pharmacology (NP) and literature review, physcion (PHY), a compound found in Lycii Fructus, was identified as a potential active ingredient targeting the Bcl2 gene, with apoptosis (Apo) proposed as the mechanism for its effects on AKI. To investigate this, a cisplatin-induced Apo model in human renal tubular epithelial cells (HK-2) was established. The study revealed that dose-dependent PHY administration substantially reduced cisplatin-induced Apo in HK-2 cells, as shown by CCK-8 assays and flow cytometry. We treated HK-2 with cisplatin at 5 mg L^-1, treatment is carried out with different concentrations of PHY, to investigate the effect of PHY on the survival rates, the apoptosis rates and expressions of Bcl2/Bax protein of cells. CCK-8 assays showed, the survival rates of the cells in the groups with PHY therapeutic concentrations of 20 μmol L^-1,40 μmol L^-1 and 60 μmol L^-1, the increase value compared with the cisplatin group were 8.40%, 31.67% and 37.19% respectively (P < 0.01) as well as apoptosis rates of the cells in the groups with PHY therapeutic concentrations of 40 μmol L^-1 and 60 μmol L^-1, the decrease in compared with the cisplatin group were 14.20% and 26.28% respectively (P < 0.01). Overall, PHY alleviated cisplatin-induced Apo in HK-2 cells by activating the Apo signaling.

Gastrodin (GAS) is a potent pharmaceutical compound extracted from the dried roots of a Chinese medicinal herb, Gastrodia elata Blume. It has been used as a neuroprotective treatment for a range of neurological disorders. Bisphenol A (BPA) has been implicated in the induction of attention-deficit hyperactivity disorder (ADHD)-like symptoms. We investigated the neuroprotective effects of GAS against BPA-induced ADHD-like symptoms in the rat model. Weanling male Wistar rats treated with BPA (50 µg/kg b.w. × 30 days per os) on completion of treatment were subsequently treated with GAS at two doses (30 and 60 mg/kg b.w. i.p. × 7 days). After 24 hours of completion of the treatment regimen, neurobehavioral parameters such as open field test (OFT), novel object recognition (NOR), and elevated plus maze (EPM) test were evaluated. Lipid peroxidation, reduced glutathione (GSH), monoamine oxidase (MAO) activity, and dopamine (DA) levels were measured in the cerebral cortex (CC) and hippocampus (HC) regions of the brain. Additionally, to asses astrocyte activatio the expression of glial fibrillary acidic protein (GFAP) was analyzed by immunostaining. Results show that GAS treatment ameliorated locomotory activity (OFT), memory dysfunction (NOR), and anxious (EPM) behavioral alterations in BPA-treated animals. GAS treatment also reduced lipid peroxidation, enhanced GSH, MAO activity, and DA levels, and reduced GFAP-positive cells in the CC and HC regions thus providing experimental evidence for a neuroprotective role for GAS against BPA-induced ADHD-like symptoms. GAS demonstrated potential preventive effects against BPA-induced ADHD-like symptoms in rats which highlights its therapeutic value.