Toxicology Research最新文献

Introduction: Probiotics made from Bacillus subtilis provide a wide spread of health benefits, particularly in the treatment of diarrhea and gastrointestinal problems. Herein, we employed in vitro and in vivo paradigms to assess the potential adverse effects and toxicity of B. subtilis UBBS-14.

Materials and methods: According to Organization for Economic Co-operation and Development (OECD) 423 and 407 requirements, a preclinical investigation was conducted in male and female Sprague-Dawley rats. Acute toxicity was examined following a single peroral (PO) administration of 5,000 mg/kg body weight (bw) i.e. equivalent to 500 billion colony-forming units (CFU) per kg bw. Single administration of B. subtilis UBBS-14 showed no mortality or adverse effects until the 14-day observation period, indicating LD50 is >5,000 mg/kg bw.

Results: Incubation of B. subtilis UBBS-14 with Caco2, HT29, and Raw 264.7 cell lines, showed no cytotoxic effects. This probiotic strain was also found responsive to the majority of antibiotics. For a 28-day repeated dose toxicity study, rats were administered 100, 500, and 1,000 mg/kg bw daily once (10, 50, and 100 billion CFU/kg bw/day, respectively) doses of B. subtilis UBBS-14. No notable changes were seen in the morphology, weight, and histopathology of the critical internal organs. The haematological, biochemical, electrolyte (sodium, potassium, chloride, and calcium), and urine analytical results were within the normal range and equivalent to the vehicle-treated group.

Conclusion: B. subtilis UBBS-14's no-observed-effect level (NOEL) was thus determined to be >1,000 mg/kg bw/day following a 28-day oral dosing.

Silver nanoparticles are the extensively utilized among all nanoparticles due to their antibacterial and wound healing properties making them highly suitable for medical and pharmaceutical applications. The field of nanoparticle toxicity is an emerging field and the present study aims to assess the biochemical, hematological and genotoxicity in Oreochromis mossambicus exposed to different concentrations of silver nanoparticles for 7 and 14 days. Silver nanoparticles were synthesized by reduction of silver nitrate using trisodium citrate and was characterized using X-ray diffraction, SEM, HRTEM and DLS. Hematological parameters like RBC, WBC, Hb, HCT and MCV and for biochemical analysis, antioxidant enzymes SOD, CAT and GPX and serum enzymes AST, ALT, ACP, ALP and LDH were analyzed. Genotoxicity was studied using comet assay. Results obtained showed decrease in erythrocytes, HCT, Hb and MCV while an increase was noted in WBC on day 7 and 14. The antioxidant enzymes SOD, CAT and GPx showed a decrease and the lipid peroxidation product MDA was elevated. The serum enzymes AST, ALT, ACP ALP and LDH showed an increased activity when compared to control. DNA damage was evident by an increase in % TDNA. The results indicate hematological, biochemical and genotoxicity of silver nanoparticles that might be mediated through ROS generation in O. mossambicus.

Hexaconazole is a known fungicide for agricultural purposes. It has bioaccumulation ability which makes it important for its toxicological characterization. There are various neurological impacts of pollutants on human health. Therefore, in this study, we have done predictive analyses of the interaction mechanism of hexaconazole by molecular interaction analysis, molecular dynamics simulation, and Poisson-Boltzmann surface area (MM-PBSA) to assess hexaconazole's potency to disrupt the homeostasis of glucocerebrosidase (-7.9 kcal/mol) and parkin (-5.67 kcal/mol) proteins which have significant roles in the manifestation of Parkinson disease. The findings reveal that hexaconazole has the potency to form stable interactions with glucocerebrosidase and parkin. This research provides a molecular and atomic-level understanding of how hexaconazole exposure may disrupt the homeostasis of glucocerebrosidase and parkin. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration, and hydrogen bonding exhibited the potent molecular interactions of hexaconazole, which may lead to neurological manifestations such as Parkinson disease.

In present study, it was purposed to determine the in vitro effect of the extract obtained from the pomegranate (Punica granatum L.) peel on the breast cancer cell line. MDA-MB-231 cells were exposed to pomegranate peel extract (PoPx) at 37 °C and 5% CO₂ for varying durations (24 and 48 h) and doses (25 and 50 μg/mL). At the end of the incubation periods, argyrophilic nucleolus organizer regions (AgNOR) protein status, cell viability/apoptosis and cell cycle of MDA-MB-231 cells were examined in the Muse Cell Analyzer device. Cell viability was observed to be decreased when the groups treated with PoPx were compared with the control group. The group in which apoptosis was observed with the highest value was 50 μg/mL PoPx group (p < 0.05). In the cell cycle test, the number of cells in the G0/G1 stage was found to be significantly higher in the 25 μg/mL PoPx group compared to the control and 50 μg/mL PoPx groups at the end of the 24-h incubation period (p < 0.05) The results also supported cell cycle and apoptosis, and at the end of 24 h, Total AgNOR area(TAA)/Total nuclear area (NA) ratio and AgNOR numbered decreased on the 50 μg/mL PoPx group and were found to be statistically significant compared to the control group (p < 0.05). Consequently, it was determined that PoPx increased apoptosis on breast cancer cells by various mechanisms and inhibited cell viability/cell growth. This study showed that the widespread consumption of PoPx may be effective in preventing cancer formation and slowing its progression.

In this article we aime to investigate he anti-aging effect of Nigella sativa oil. Transgenic flies engineered under UAS/GAL4 system were acquired from the Bloomington Drosophila stock center. For methodology, (LC50), 30 flies 2-3 days old were divided into four groups, and exposed to diets of 30, 60, 90, and 120 μL/10 g in 3 replicates at a density of 30 flies per vial. Mortality was recorded daily for 7 consecutive days. For survival, (150) 2-3 days adult flies were divided into four groups (I-IV), 100 flies in each group. Group I which served as control fed on 10 g of diet only, group II was fed 10 g of diet only, group III (AB42 + low dose) was fed on 10 g diet +6.39ul NSO, group IV (AB42 + high dose) was fed 10 diet + 12.77ul NSO. The administration lasted for 28 days. For the third phase, a similar protocol was adopted with each group having (400) flies, this phase lasted f till the last fly died. The effect of NSO was assessed by; Studying the mortality daily. Results revealed the lethal concentration of LC50 NSO to be 25.54 mg it was also observed from the study that exposure to NSO in food media at low doses has increased the lifespan of AB-42 treated flies. In conclusion, findings from this study suggest the efficacy of low-dose NSO increased the survival and life span of the AB-42 flies.

Background: β-d-N4-Hydroxycytidine (NHC) is the active metabolite of molnupiravir, a broad-spectrum antiviral approved by the MHRA for COVID-19 treatment. NHC induces lethal mutagenesis of the SARS-CoV-2 virus, undergoing incorporation into the viral genome and arresting viral replication. It has previously been reported that several nucleoside analogues elicit off-target inhibition of mitochondrial DNA (mtDNA) or RNA replication. Although NHC does not exert these effects in HepG2 cells, HepaRG are proven to be advantageous over HepG2 for modelling nucleoside analogue-induced mitochondrial dysfunction. Therefore, the objective of this work was to assess the mitotoxic potential of NHC in HepaRG cells, a model more closely resembling physiological human liver.

Methods: Differentiated HepaRG cells were exposed to 1-60 μM NHC for 3-14 days to investigate effects of sub-, supra-, and clinically-relevant exposures (in the UK, molnupiravir for COVID-19 is indicated for 5 days and reported Cmax is 16 μM). Following drug incubation, cell viability, mtDNA copy number, mitochondrial protein expression, and mitochondrial respiration were assessed.

Results: NHC induced minor decreases in cell viability at clinically relevant exposures, but did not decrease mitochondrial protein expression. The effects on mtDNA were variable, but typically copy number was increased. At supra-clinical concentrations (60 μM), NHC reduced mitochondrial respiration, but did not appear to induce direct electron transport chain dysfunction.

Conclusions: Overall, NHC does not cause direct mitochondrial toxicity in HepaRG cells at clinically relevant concentrations, but may induce minor cellular perturbations. As HepaRG cells have increased physiological relevance, these findings provide additional assurance of the mitochondrial safety profile of NHC.

Background: Zanthoxylum armatum DC. (ZADC) is a novel food raw material resource, offering both edible and medicinal properties. Recent research has unveiled the toxic nature of ZADC, particularly its close association with the nervous system. In a prior study, we observed that administering methanol extract of Zanthoxylum armatum DC. (MZADC) to rats via gavage at a dose of 1.038 g/kg resulted in various neurotoxicity symptoms, including excessive salivation, reduced mobility, unsteady gait, muscle twitching, and altered respiratory rates.

Materials and methods: We conducted cell-based research to assess the safety of ZADC and elucidate its potential toxic mechanism. In addition, we used experimental methods such as Cell Counting Kit-8, Western blot, and Flow cytometry to detect cytotoxicity in SH-SY5Y cells after intervention with MZADC.

Results: Following exposure of SY-SY5Y cells with MZADC, a substantial decline in cell viability was observed, accompanied by a concentration-dependent increase in intracellular reactive oxygen species (ROS) levels. Additionally, MZADC induced cellular oxidative stress, leading to elevated malonic dialdehyde (MDA) and superoxide dismutase (SOD) concentrations while decreasing glutathione (GSH) levels. Furthermore, MZADC induced apoptosis at varying doses (20, 40, and 60 μg/mL), and this effect was associated with increased Caspase-3, Bax expressions, and reduced Bcl2 and Bcl2/Bax expressions. In addition, the investigation revealed that MZADC induced autophagy inhibition in SH-SY5Y cells by activating the mTOR signaling pathway, resulting in a decrease in LC3II/LCI and Beclin-1, while increasing p-mTOR/mTOR, p62.

Conclusion: Consequently, this study suggests that MZADC triggers the mTOR pathway through oxidative stress in SH-SY5Y cells, ultimately leading to apoptosis. Understanding the toxicity mechanisms associated with ZADC can offer a valuable theoretical and experimental basis for its development and utilization.

Acrylamide is an alkene known to induce neurotoxicity in humans and experimental animals. However, the effects of acrylamide on the development of myelin sheath are unclear. The present study was to explore the effects of acrylamide exposure during pregnancy and lactation on the development of myelin sheath in offspring rats. Four groups of thirty-two pregnant Sprague-Dawley rats were exposed to 0, 4.5, 9 and 18 mg/kg BW acrylamide by gavage from gestational day 15 to postnatal day 13. The corpus callosum of nine offspring rats per group were dissected in postpartum day 14. Structural changes and lipid contents in myelin sheaths were examined by transmission electron microscopy(TEM) and Luxol Fast Blue staining(LFB). The expression of MBP and PLP was evaluated by immunohistochemistry and Western blotting. TEM showed that the myelin sheaths in the 18 mg/kg group were disordered compared with control group. Luxol Fast Blue staining gradually decreased with increasing acrylamide maternal exposure. The immunohistochemistry and Western Blotting results showed that maternal exposure to acrylamide caused a decreasing trend in MBP and PLP in the corpus callosum of rats at postnatal day 14. Furthermore, these reduced protein levels may be neurodevelopmental toxicity's mechanism in response to maternal exposure to acrylamide.

Background: Bladder cancer (BLCA) is one of the most prevalent cancers worldwide. Ferroptosis is a newly discovered form of non-apoptotic cell death that plays an important role in tumors. However, the prognostic value of ferroptosis-related genes (FRGs) in BLCA has not yet been well studied.

Method and materials: In this study, we performed consensus clustering based on FRGS and categorized BLCA patients into 2 clusters (C1 and C2). Immune cell infiltration score and immune score for each sample were computed using the CIBERSORT and ESTIMATE methods. Functional annotation of differentially expressed genes were performed by Gene Ontology (GO) and KEGG pathway enrichment analysis. Protein expression validation were confirmed in Human Protein Atlas. Gene expression validation were performed by qPCR in human bladder cancer cell lines lysis samples.

Result: C2 had a significant survival advantage and higher immune infiltration levels than C1. Additionally, C2 showed substantially higher expression levels of immune checkpoint markers than C1. According to the Cox and LASSO regression analyses, a novel ferroptosis-related prognostic signature was developed to predict the prognosis of BLCA effectively. High-risk and low-risk groups were divided according to risk scores. Kaplan-Meier survival analyses showed that the high-risk group had a shorter overall survival than the low-risk group throughout the cohort. Furthermore, a nomogram combining risk score and clinical features was developed. Finally, SLC39A7 was identified as a potential target in bladder cancer.

Discussion: In conclusion, we identified two ferroptosis-clusters with different prognoses using consensus clustering in BLCA. We also developed a ferroptosis-related prognostic signature and nomogram, which could indicate the outcome.

Morphine is an analgesic in the opiate family, isolated from many plants. It can inhibit androgen biosynthesis by Leydig cells. Whether morphine directly inhibits androgen biosynthesis and underlying mechanism remains unclear. To investigate the influence of morphine on androgen secretion by rat immature Leydig cells (ILCs) and possible mechanism. Rat ILCs were treated with 0.5-50 μM morphine for 3 h in vitro. Morphine at ≥0.5 μM significantly reduced total androgen secretion. Morphine at 50 μM also compromised luteinizing hormone (LH, 10 mg/kg), 8Br-cAMP (1 mM), and 22R-hydroxycholesterol (20 μM) stimulated total androgen, androstanediol, and testosterone secretion, without affecting pregnenolone, progesterone, androstenedione mediated androgen secretion and testosterone and dihydrotestosterone mediated androstanediol secretion. Further analysis revealed that morphine at ≥0.5 μM downregulated Star expression and at ≥5 μM downregulated Cyp11a1 expression. Morphine also significantly reduced STAR (≥0.5 μM) and reduced CYP11A1 (≥5 μM) levels. 0.5 μM naloxone significantly antagonized morphine-mediated action. In conclusion, morphine might cause side effects by suppressing androgen biosynthesis via u opioid receptor.