Drug and Chemical Toxicology最新文献

The lack of toxicity data for DHA-rich oil from Schizochytrium sp. (Strain ATCC-20889) leads to its exclusion from the Qualified Presumption of Safety list. Therefore, present study addresses toxicity evaluation of DHA-rich microalgae oil using ex-vivo (cytotoxicity assay) and in-vivo methods (acute (OECD 423 guidelines), sub-chronic (OECD 452 guidelines), and genotoxicity assay). The ex-vivo results showed >90% cell viability of Caco-2 cells after 48 h of treatment (200 µg/mL of DHA). Additionally, the in-vivo acute toxicity study found that microalgae oil was nontoxic and classified under category 5 molecule according to OECD 423 guidelines with a highest degree of safety at 2000 mg/kg b.w. The in-vivo sub-chronic study revealed no significant mortality and changes in feed intake, body weight, haematological, biochemical, neurological, and urine parameters after repeated 180-days administration of DHA-rich microalgae oil at 250 mg/kg, 500 mg/kg, and 1000 mg/kg. Moreover, histopathology evaluation, comet assay, chromosomal aberration, and micronuclei assay also confirmed the nontoxic behavior of DHA-rich oil. Thus, the results from the ex-vivo and in-vivo studies indicate that DHA-rich oil from Schizochytrium sp. (Strain ATCC-20889) is safe for use as a novel food, and can be included in infants, adults, pregnant women, and children formula.

This study investigated the curative effect of black cumin oil (Nigella sativa, NS), which is a phytotherapeutic agent against to cypermethrin (CYP), which is known to have adverse effects on rainbow trout (Oncorhynchus mykiss)'s behavioral changes, oxidative stress-mediated neurotoxicity, hematotoxicity and hepatotoxicity parameters.At the end of the trial period; (i) evaluation of critical swimming speed (U_crit) (ii) hematology indices [white blood cell (WBC), red blood cell (RBC), hemoglobin (Hgb), hematocrit (Hct), mean cell volume (MCV), mean cell hemoglobin) (MCH), mean cell hemoglobin concentration (MCHC)] (iii) Elucidation of the mechanism of functional damage in brain tissue of O. mykiss by neurological parameter [acetylcholinesterase (AChE)] (iv) Evaluation of oxidative damage in oxidative stress-mediated neurotoxicity and hepatotoxicity in liver, gill and brain tissue of O. mykiss with antioxidant enzymes [(Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), Glutathione (GSH)] and [(detection by means of malondialdehyde (MDA)] (v) Obtaining applicable data in the toxicological field using a multi-biomarker approach to investigate the modulation of NS administration via target markers in the physiological pathway of O. mykiss were aimed.As a result of CYP application, it was determined that the Ucrit value of O. mykiss decreased significantly. It was determined that the changes in the values of RBC, Hgb and Hct, which are among the hematology parameters examined in the blood tissue, were statistically significant (p < 0.05). It was determined that WBC value was inhibited by CYP application and NS tried to make a positive contribution to WBC. It was determined that the AChE activity of O. mykiss in the brain tissue had a statistically significant inhibition in the CYP-treated group (p < 0.05). SOD, CAT, GPx, enzyme activities were found to be inhibited by CYP application and were statistically significant (p < 0.05). Acute toxicity of CYP was determined by antioxidant enzyme biomarkers in gill tissue. In the results obtained; While inhibitions were determined in SOD, CAT, GPx activities compared to the control group, an induction occurred in MDA value.NS administration was noted to be an important modulator of the SOD-CAT system against CYP exposure at both concentrations. Thus, it can be said that it indirectly functions as an effective antioxidant through the NS receptor protein and structurally stimulates the synthesis and activity of antioxidative enzymes under oxidative stress.

Psychotria carthagenensis is a shrubby plant, often consumed by traditional populations in religious rituals. Previous studies have shown that this plant's infusion can inhibit the activity of Acetylcholinesterase (AChE) in rats. Despite the therapeutic potential, there is a lack of research regarding its possible toxicological and genotoxic effects. Hence, this study aimed to analyze the chemical profile of the ethanol extract from P. carthagenensis leaves by LC-DAD-MS and assess its possible toxicity and genotoxicity in zebrafish (Danio rerio). Adult zebrafish (N = 9/group) were exposed at different concentrations and the LC₅₀ was calculated. Frequencies of micronucleus (MN) and nuclear abnormalities (NA) were estimated for genotoxic effects, and degree of tissue changes (DTC) was used to assess the liver and gill histopathology. From the LC-DAD-MS analyses, the identified compounds included N-fructosyl valine, ethyl hexoside, 5-O-E-caffeoylquinic acid, N-feruloylagmatime, roseoside, di-O-deoxyhexoyl-hexosyl quercetin, loiolide, and oleamide. The calculated values of LC₅₀ did not vary significantly during the time of exposure. At the concentrations of 1.25, 2.5, 3.75, 5, 7.5, 10 and 15 mg/L, there was no genotoxicity, and only low to moderate toxicity for the tissues was observed, despite mortality of 100% at doses of 20-100 mg/L of P. carthagenensis ethanolic leaf extract. There were changes in cytoplasm of hepatocytes at 1.25 mg/L, and karyorrhexis, karyolysis and megalocytosis at 10 mg/L. In the gills, the alterations were primary lamellar hyperplasia in all concentrations, and at 10 mg/L, secondary lamellar edema and vascular hyperemia were common. Additionally, the chemical composition of P. carthagenensis was expanded.

Valproic acid is an antiepileptic drug associated with skin-related issues like excessive hair growth, hair loss, and skin rashes. In contrast, Moringa oleifera, rich in nutrients and antioxidants, is gaining popularity worldwide for its medicinal properties. The protective properties of M. oleifera extract against skin-related side effects caused by valproic acid were investigated. Female rats were divided into control groups and experimental groups such as moringa, sodium valproate, and sodium valproate + moringa groups. A 70% ethanolic extract of moringa (0.3 g/kg/day) was given to moringa groups, and a single dose of sodium valproate (0.5 g/kg/day) was given to valproate groups for 15 days. In the skin samples, antioxidant parameters (such as glutathione, glutathione-S-transferase, superoxide dismutase, catalase, and total antioxidant capacity), as well as oxidant parameters representing oxidative stress (i.e. lipid peroxidation, sialic acid, nitric oxide, reactive oxygen species, and total oxidant capacity), were examined. Additionally, boron, hydroxyproline, sodium-potassium ATPase, and tissue factor values were determined. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was also carried out for protein analysis in the skin samples. The results showed that moringa could increase glutathione, total antioxidant capacity, sodium-potassium ATPase, and boron levels, while decreasing lipid peroxidation, sialic acid, nitric oxide, total oxidant capacity, reactive oxygen species, hydroxyproline, and tissue factor levels. These findings imply that moringa possesses the potential to mitigate dermatological side effects.

Human red blood cell acetylcholinesterase (RBC-AChE) activity is valuable for detecting potential exposure to cholinesterase inhibiting substances (CIS). A reliable population-based RBC-AChE activity reference range is critical for early and massive clinical and occupational toxicology screening. Previous published studies were often limited to small numbers of subjects, various testing methods, and crude statistical data analyses. We tested 4818 adult subjects with a well-established 17-minute modified Michel method over a 2-year period. We conducted a retrospective data analysis and systematically investigated on the influences to testing values from gender, age, age group, and their combinations and interactions. No significant difference was observed in the testing values between males (mean, medium, interquartile range = 0.76, 0.76, 0.71-0.80 ΔpH/h, respectively) and females (mean, medium, interquartile range = 0.76, 0.76, 0.71-0.81 ΔpH/hour, respectively), when gender was the only factor considered (p = 0.7238). However, with age progression, male testing values exhibited a consistent upward trend, while females did not show any clear patterns. Linear regression analysis of the data revealed that gender, age, and age group more or less affected testing values either as independent variables or with their combinations and interactions. However, more potential factors need to be included to achieve better testing value predictions. We recommend the toxicological testing community to adopt a new set of age group specific RBC-AChE activity reference ranges for males (0.68-0.80, 0.69-0.81, 0.70-0.83, 0.71-0.84, and 0.73-0.87 ΔpH/h for 18-29, 30-39, 40-49, 50-59, and ≥60 years old, respectively) while keeping the current reference range (0.63-0.89 ΔpH/hour) for females.

Nephrotoxicity is the major side effect of cisplatin, an effective platinum-based chemotherapeutic drug that is applicable in the treatment of several solid-tissue cancers. Studies have indicated that certain water-soluble phenolics offer renal protection. Thus, this study investigates the role of pre and post-treatment of rats with water-soluble phenolics from Phoenix dactylifera (PdP) against nephrotoxicity induced by cisplatin. Rats were either orally pretreated or post-treated with 200 mg/kg body weight of PdP before or after exposure to a single therapeutic dose of cisplatin (5 mg/kg body weight) for 7 successive days intraperitoneally. The protective effects of PdP against Cisplatin-induced nephrotoxicity was based on the evaluation of various biochemical and redox biomarkers, together with histopathological examination of kidney tissues. The composition, structural features, and antioxidative influence of PdP were determined based on chromatographic, spectroscopic, and in vitro antioxidative models. Cisplatin single exposure led to a substantial increase in the tested renal function biomarkers (uric acid, creatinine, and urea levels), associated with an increase in malondialdehyde indicating lipid peroxidation and a significant decline (p < 0.05) in reduced glutathione (GSH) levels in the renal tissue when compared with the control group. A marked decline exists in the kidney antioxidant enzymes (catalase, SOD, and GPx). Nevertheless, treatment with PdP significantly suppressed the heightened renal function markers, lipid peroxidation, and oxidative stress. Spectroscopic analysis revealed significant medicinal phenolics, and in vitro tests demonstrated antioxidative properties. Taken together, results from this study indicate that pre- and/or post-treatment strategies of PdP could serve therapeutic purposes in cisplatin-induced renal damage.

PBAT-modified starch blended film are thermoplastic biodegradable materials with good properties and a wide range of applications. In this study, L-02 cells were used as an in vitro toxicity evaluation system for risk assessment of PBAT-modified starch films with migration studies obtained in different food simulants. Determination of total migration and organic matter revealed that the results were in accordance with the standard except for the total organic matter under 95% (v/v) ethanol food simulant which exceeded the standard. The CCK-8 assay showed that these compounds affect the cell viability of L-02 cells. It was observed that the compounds made the cells express increased AST, ALT, TNF-α, IL-6, IL-1β, and ROS, and decreased SOD, GSH, and ATP. In addition, we explored the effect of migration in PBAT-modified starch composites on protein and gene expression levels in L-02 cells using a transcriptomic approach and found that the AMPK signaling pathway was affected. The expression of AMPK signaling pathway-related proteins was detected by Western Blot, and the expression levels of p-AMPK/AMPK were found to be upregulated, and those of p-mTOR/mTOR, SIRT1, PGC-1α, NRF1 and TFAM were downregulated. The above data suggest that the compounds migrating into the PBAT-modified starch film when exposed to food may induce oxidative stress and inflammation in hepatocytes, and may cause damage to hepatocytes through the AMPK pathway.

Tauroursodeoxycholic acid (TUDCA) can activate farnesoid X receptor (FXR) to involve in the formation of gallstones. Here, this study aimed to probe the potential mechanism of TUDCA-FXR network in the formation of bile duct stone. The levels of TUDCA, FXR and NCK1 were decreased, while the level of miR-107 was increased in the serum of bile duct stone patients. FXR expression was positively correlated with TUDCA or NCK1 expression in patients, moreover, TUDCA pretreatment in biliary epithelial cells increased the levels of FXR and NCK1, and rescued the decrease of NCK1 caused by FXR knockdown in cells. Then functional analysis showed FXR knockdown caused apoptosis and endoplasmic reticulum stress (ERS) as well as suppressed proliferation in biliary epithelial cells in vitro, which were attenuated by TUDCA pretreatment or NCK1 overexpression Mechanistically, NCK1 was a target of miR-107, which was up-regulated by FXR silencing, and FXR knockdown-induced decrease of NCK1 was rescued by miR-107 inhibition. Additionally, miR-107 expression was negatively correlated with TUDCA expression in bile duct stone patients, and TUDCA pretreatment in biliary epithelial cells decreased miR-107 expression by FXR. Functionally, the pretreatment of TUDCA or FXR agonist suppressed miR-107-evoked apoptosis and ERS in biliary epithelial cells. In conclusion, TUDCA up-regulates FXR expression to activate NCK1 through absorbing miR-107, thus suppressing the apoptosis and ERS in biliary epithelial cells, these results provided a theoretical basis for elucidating the mechanism of bile duct stone formation.

Streptozotocin (STZ) is used as a diabetes-inducing agent in experimental animal studies. However, it is known that STZ-induced diabetic animals show significant increases in oxidative stress parameters and neurodegeneration besides their blood glucose level. In this study, the acute and subacute toxic effects of STZ on the liver, sciatic nerve, and brain tissues were investigated in vivo rat model. Sprague-Dawley rats were divided into two groups; while 50 mg/kg STZ was administered ip to the STZ group, only saline was administered to the control group. After STZ administration, three units (100 U/mL) of subcutaneous insulin glargine were applied daily to prevent the formation of diabetes. At 24 h, 1,2, and 4 weeks after applications, rats from each group were sacrificed and tissues were removed under anesthesia. At the end of the study, compared to the control, a significant decrease in SOD and GST activity and an increase in lipid peroxidation were detected in the liver and sciatic tissues of rats in the STZ-treated group in the first 24h. Considering the TUNEL, NFκB, and NOS2 expressions, it was noted that while the effects of STZ on the liver were observed in the acute stage (24h), it had subacute effects on the brain. When apoptosis-related gene expression (Bcl-2, Bax, CASP3, CASP8, CASP9, TNF-α) and immunohistochemistry were evaluated, the apoptotic effect of STZ was observed mostly in sciatic nerve tissues. Within the scope of the study, it was revealed that STZ did not only show selective toxicity to pancreatic β cells but also very toxic to other tissues and organs.

The use of stem cells can attenuate testicular injury and promote sperm production. The adipose-derived stromal vascular fraction (SVF) has become an attractive cell source for cell-based therapies. In this study, we aimed to investigate the therapeutic efficacy of SVF on busulfan-induced testicular damage in rats. Twenty-four male rats were randomly divided into control, busulfan, SVF, and busulfan + SVF groups. Testicular damage was induced by intraperitoneal administration of busulfan (35 mg/kg). SVF obtained from human adipose tissue using Lipocube SVF™ was injected into rats 5 weeks after busulfan administration. At the end of the 8th week, rats were sacrificed, and histopathological, biochemical, and western blotting analyses were performed. No harmful effects of SVF on healthy testis tissue and sperm parameters were detected. SVF improved busulfan-induced oxidative stress in both testis tissue and serum. SVF injection to damaged testicular tissue resulted in increases in the healthy spermatozoon numbers and decreases in the abnormal tail numbers. Additionally, SVF increased bax/Bcl, DAZL, and TGF-β1 levels whereas decreased ATG5 and NF-kB levels. According to the results we obtained in this study, we suggest that SVF is beneficial in restoring damaged tissue by primarily being a multipotent cell source, by inhibiting oxidative stress and converting necrotic cell death to apoptotic cell death. In the future, clinical applications should bring higher benefits. Since SVF is the patient's own tissue, being harmless, it will offer an advantageous supportive treatment option for patients already weakened by cancer and anticancer therapy.