Toxicity Parameters Research Articles

Assessments of protodioscin's antinociceptive and antidiarrheal properties: in vivo and in silico investigations on macromolecule binding affinity and modulatory effects.

Protodioscin (PRO) is a furostanol saponin with antioxidant and anti-inflammatory properties. However, there is no proof against nociception and diarrhea. The study aims to investigate the antinociceptive and antidiarrheal effects of PRO, comparing its efficacy with diclofenac sodium (DFS) and loperamide (LOP) using in vivo and in silico methods. Antinociceptive activity was evaluated using the acetic acid-induced writhing and formalin-induced paw licking tests, and antidiarrheal effects were assessed via castor oil-induced diarrhea in mice. Mice were divided into groups receiving PRO (2.5 and 10mg/kg, p.o.), DFS (25mg/kg, p.o.), LOP (3mg/kg, p.o.), or combinations. Molecular docking studies were conducted on COX-1, COX-2 enzymes, and the Mu-opioid receptor (MOR), with toxicity predictions performed for safety profiling. In vivo results demonstrated that PRO significantly (p < 0.05) reduced pain and diarrhea in animals. PRO at 10mg/kg, showed comparable efficacy to DFS and LOP (25 and 3mg/kg) in both models. Molecular docking revealed that PRO had stronger binding affinities with COX-1 (‒10.0kcal/mol), COX-2 (‒9.6kcal/mol) enzymes, and MOR (‒7.7kcal/mol) compared to standard drugs. Toxicity predictions indicate PRO is relatively safe in some toxicity parameters. PRO exhibits significant antinociceptive and antidiarrheal activities comparable to DFS and LOP, making it a promising natural alternative for managing pain and diarrhea. Additional clinical trials and pharmacokinetic assessments are required to evaluate its long-term safety for use.

Toxicity assessment of wastewater using a battery of bioassays in two textile wastewater treatment plants from a large industrial park in Guangxi, Southwest China.

Textile effluents are important sources of pollutants in aquatic environments. The textile industry in China has been relocating from developed to less developed regions, yet the potential environmental impact of textile effluents remains unclear. Here, we investigated the acute toxicity of wastewater collected from different processing units of two textile wastewater treatment plants (WWTPs) in a large industrial park in Guangxi province (Southwest China), using whole effluent toxicity testing. Moreover, we explored the relationships between the toxicity of wastewater and its characteristics, including physicochemical parameters, heavy metals, fluorescence intensity, and non-persistent and persistent organic pollutants. Untreated textile effluents were highly toxic to all test organisms, with toxic units reaching 42.9 for lux-modified bacteria, 14.0 for green algae, 10.1 for duckweed, and 17.3 for zebrafish embryos. Their toxicity was reduced significantly but not removed completely, following treatment processes that included coagulation, anaerobic-aerobic process, Fenton oxidation process, chlorine disinfection and wetland treatment systems. In the wetland effluent, both toxicity and physicochemical parameters met the textile effluent discharge standards in China and other countries. The toxicity of wastewater was associated with various characteristics, such as chemical oxygen demand (COD), fluorescence intensity related to fulvic acid-like materials, 4-nonylphenol, bisphenol A, bis(2-ethylhexyl) phthalate, perfluorobutane sulfonic acid, and acenaphthene. These results suggest the effectiveness of the investigated WWTPs in treating textile effluents concerning both physicochemical parameters and acute toxicity. The present study highlights the importance of integrating ecotoxicological data alongside chemical data to enhance the risk assessment and evaluation of the environmental safety of effluent discharges.

Assessment of acute inhalation toxicity of Low-temperature SMOG insect® smoke generators

The purpose of this work is to calculate the parameters of acute inhalation toxicity of the low-temperature insecticide smoke generator SMOK insect®, as well as to establish its hazard class. The active ingredient in the generator is the synthetic pyrethroid cyflutrin.The research was conducted on the basis of the vivarium and the Department of Veterinary and Sanitary Examination of the St. Petersburg State University of Veterinary Medicine.The object of the study was 5 groups of laboratory rats of the Wistar line (4 experimental and 1 control). There were 6 animals in each group (3 females and 3 males).The animals were inhaled with the active substance of low-temperature SMOK insect® generators. Each of the four experimental groups received the following doses of the drug according to DV: 1 – 0.5 mg / l, 2 – 2 mg/ l, 3 – 10 mg/ l, 4 – 20 mg/ l, respectively. The control group did not receive the drug.As a result of the experiment, no dead animals were identified in group 1. In the 2nd group, 1 rat died, in the 3rd - 2, in the 4th all animals died.During the experiment, respiratory depression and asphyxia were noted in animals. The irritating effect of the drug on the mucous membranes was revealed.As a result of the conducted research, it was revealed that the drug SMOK insect® belongs to the 3rd hazard group (moderately dangerous substances) in accordance with State Standard 32646-2014.

The TOXIN knowledge graph: supporting animal-free risk assessment of cosmetics.

The European Union's ban on animal testing for cosmetic products and their ingredients, combined with the lack of validated animal-free methods, poses challenges in evaluating their potential repeated-dose organ toxicity. To address this, innovative strategies like Next-Generation Risk Assessment (NGRA) are being explored, integrating historical animal data with new mechanistic insights from non-animal New Approach Methodologies (NAMs). This paper introduces the TOXIN knowledge graph (TOXIN KG), a tool designed to retrieve toxicological information on cosmetic ingredients, with a focus on liver-related data. TOXIN KG uses graph-structured semantic technology and integrates toxicological data through ontologies, ensuring interoperable representation. The primary data source is safety information on cosmetic ingredients from scientific opinions issued by the Scientific Committee on Consumer Safety between 2009 and 2019. The ToxRTool automates the reliability assessment of toxicity studies, while the Simplified Molecular Input Line Entry System (SMILES) notation standardizes chemical identification, enabling in silico prediction of repeated-dose toxicity via the implementation of the Organization for Economic Co-operation and Development Quantitative Structure-Activity Relationship Toolbox (OECD QSAR Toolbox). The ToXic Process Ontology, enriched with relevant biological repositories, is employed to represent toxicological concepts systematically. Search filters allow the identification of cosmetic compounds potentially linked to liver toxicity. Data visualization is achieved through Ontodia, a JavaScript library. TOXIN KG, filled with information for 88 cosmetic ingredients, allowed us to identify 53 compounds affecting at least one liver toxicity parameter in a 90-day repeated-dose animal study. For one compound, we illustrate how TOXIN KG links this observation to hepatic cholestasis as an adverse outcome. In an ab initio NGRA context, follow-up in vitro studies using human-based NAMs would be necessary to understand the compound's biological activity and the molecular mechanism leading to the adverse effect. In summary, TOXIN KG emerges as a valuable tool for advancing the reusability of cosmetics safety data, providing knowledge in support of NAM-based hazard and risk assessments. Database URL: https://toxin-search.netlify.app/.

Multiple physiological response analyses of Chlorella vulgaris exposed to silver nanoparticles, ciprofloxacin, and their combination.

The combination of silver nanoparticles (AgNPs) and ciprofloxacin (CIP) can be considered an alternative to combat multidrug-resistant microbial infections. However, knowledge about their combined toxicity is scarce after being released in an aquatic environment. The present study evaluated the individual toxicity of AgNPs and CIP and their combined toxicity on the unicellular green microalga Chlorella vulgaris, evaluating cellular responses and conducting metabolomic analysis. The median effective concentrations at 96 h (EC50-96h) for AgNPs, CIP, and the mixture were 132 µg L-1, 7000 µg L-1, and 452 µg L-1, respectively. CIP exhibited a synergistic effect with AgNPs. The toxic ranking for C. vulgaris was AgNPs > AgNPs + CIP > CIP. The growth rate was the most evident parameter of toxicity. Cell diameter significantly increased (p < 0.001) at 96 hours for the highest concentrations tested of AgNPs, CIP, and the mixture, with increases of 24%, 41%, and 19%, respectively, compared to the control. Photosynthetic pigment analyses revealed that C. vulgaris upregulated chlorophyll, carotenoids, and pheophytin. Cell exposure to CIP caused an SOS response involving increased protein and carbohydrate concentrations to tolerate antibiotic stress. Exposure to AgNPs and CIP increased catalase and glutathione S-transferase activity, but the mixture decreased the activity. AgNPs increased malondialdehyde content in exposed cells due to fatty acid peroxidation. These pollutants revealed their potential risks in interfering with survival and metabolism. Our findings highlight the possible hazards of co-pollutants at environmentally relevant quantities, providing insights into the individual and combined ecotoxicity of AgNPs and CIP.

Evaluation of lithium chloride safety and toxicokinetics for injection in minipigs

Lithium salts are known to treat bipolar disorder. Their high potential as neuroprotective agents in cerebral ischemia determines relevance for preclinical studies for the registration of new drugs based on them. Aim of the study was to investigate the toxic properties and local tolerability with an assessment of the toxicokinetics of the developed lithium chloride preparation for injection in dwarf pigs with repeated intravenous administration. Material and methods. Lithium chloride (solution, for intravenous administration 4.2 %) has been administered to minipigs (control and 3 experimental groups of animals of 3 males and 3 females) for 28 days at doses of 12.6; 29.4 and 63 mg/kg. General toxicity, local irritation, and basic pharmacokinetic parameters (Cmax, AUC0-24, MRT, T1/2, Vss, and Cl) were evaluated. Serum lithium ion concentration was estimated colorimetrically using quinizarin. Results and discussion. Toxic properties of the test drug were revealed, expressed in a change in the clinical state (vomiting after administration, inhibition of behavior and feed refusal), body weight negative dynamics, clinical and laboratory changes, shortening of the “QT” interval, accompanied by abnormalities according to the pathomorphological study results (focal infiltration with single renal tubular necrosis areas, kidneys fibrosis, replacement of thyroid tissue with adipose tissue). There were no signs of locally irritating effects of the test product. To evaluate toxicokinetic parameters, a bioanalytical assay (calibration range – from 0.17 to 5.45 μg/mL) was developed and validated, which is not inferior by its characteristics to the commercial reagent kits. According to the results of biomaterial analysis no lithium accumulation in the pig’s body was found with repeated use of the test drug. Doses of the drug that provide toxic concentrations of lithium (above 3 μg/ml) in the minipig’s serum were identified. The NOAEL was 12.6 mg/kg and the LOAEL was 29.4 mg/kg. Conclusions. The comprehensive approach to the consideration of toxic manifestations and toxicokinetics, including its analytical component of studies of this kind, was noted. The obtained results should be taken into account to assess the benefit/risk ratio in the clinical use of lithium chloride injection.

Real-world outdoor air exposure effects in a model of the human airway epithelium - A comparison of healthy and asthmatic individuals using a mobile laboratory setting.

We developed a mobile laboratory allowing field exposure of lung tissue models to ambient air at localities with various pollution sources (Background, Industrial, Traffic, Urban) in different seasons (summer/fall/winter). In samples originating from healthy and asthmatic individuals, we assessed the parameters of toxicity, lipid peroxidation and immune response; we further performed comprehensive monitoring of air pollutants at sampling sites. We measured lactate dehydrogenase (LDH) and adenylate kinase (AK) production and transepithelial electrical resistance (TEER), analyzed 15-F2t-isopostane (IsoP) and a panel of 20 cytokines/chemokines/growth factors. In the ambient air, we detected particulate matter (PM), and other relevant chemicals (benzene, benzo[a]pyrene (BaP), NOx). In the Traffic locality, we found very high concentrations of ultrafine particles and NOx and observed low TEER values in the exposed samples, indicating significant traffic-related toxicity of the ambient air. In the Urban locality, sampled in winter, we observed high PM and BaP levels. We found lower AK levels in samples from healthy individuals exposed in this locality than in the asthmatic samples. In the samples from the Industrial locality, sampled in summer, we detected higher concentrations of TNFα, MIP-1α, Eotaxin, GROα, GM-CSF, IL-6 and IL-7 than in the Urban locality samples. We hypothesize that pollen or other plant-related components of the ambient air were responsible for this response. In conclusion, our data proved the feasibility of our mobile laboratory for field measurements of the biological response of lung tissue models exposed to ambient air, reflecting not only the levels of toxic compounds, but also season-specific parameters.

Correlation of Equilibrium Radionuclide Ventriculography Scan with Two-Dimensional Transthoracic Echocardiography for Early Evaluation of the Left Ventricular Ejection Fraction after Anthracycline Treatment in Patients with Acute Lymphoid Leukemia

Introduction: Early diagnosis of cardiac toxicity caused by chemotherapy drugs in acute lymphoid leukemia (ALL) patients can prevent the occurrence of heart failure. Equilibrium radionuclide ventriculography (ERNV) has the advantage of a precise evaluation, while two-dimensional transthoracic echocardiography (2D-TTE) is more widely available. This study aimed to evaluate the correlation of the relevant cardiac toxicity parameters for patients diagnosed with ALL using both of these techniques. Material and methods: Between January 2022 and May 2024, patients with ALL were prospectively evaluated in the hematology department of Imam Khomeini Hospital in Tehran. 2D-TTE and ERNV were performed before and after two cycles of HYPER-CVAD chemotherapy. Patients with cardiac disease, cardiovascular risk or previous anticancer treatment were excluded. Results: Forty-four patients with ALL were included: 24 (54.5%) males and 20 (45.5%) females. The majority of patients (56.8%) were between 20 and 40 years old and had no history of cardiac disease or malignancies. Baseline left ventricular ejection fraction (LVEF) volumes were correlated on 2D-TTE and ERNV (r=0.5; P=0.001). Eleven patients were evaluated after therapy. LVEF values were similar (54.9±8.1 vs. 54.3±4.6; P=0.552) but without a linear correlation (r= 0.3; p=0.409). Only two cardiac parameters were significantly changed after chemotherapy: the pulmonary artery pressure (PAP) on 2D-TTE (24.3±5.5 vs 22.2±5.2; p=0.02) and the time peak filling rate (TTPFR) on ERNV (138.3±39.8 vs 170±52.9 milliseconds; p=0.004). Conclusion: Cardiac function impairment parameters on ERNV and 2D-TTE were similar before and after a cumulative dose of daunorubicin of 100 mg/m2. Before therapy, there was also a linear correlation between values. PAP decreased and TTPFR increased after chemotherapy. Keywords

Ladies project: large database in endometrial cancers for a personalized treatment.

To compare Italian use with current international guidelines and to evaluate oncological outcomes and toxicity patterns of adjuvant radiation therapy (RT) for endometrial cancer (EC) in Italian women. To conduct a retrospective multicentre Italian study a large database was set up. Inclusion criteria were: accrual between 2010 and 2020, treatment with surgery, post-operative external beam RT (EBRT) and/or interventional radiotherapy (IRT) associated or not with adjuvant chemotherapy. Oncological outcomes, acute and late toxicities were analysed according to RT schedule and risk group. A total of 1848 patients, from 16 Italian RT centres were enrolled (median age 65 years, range 27-88). All patients received post-operative RT associated with chemotherapy in 31%. Patients were stratified on the basis of standard risk factors (Bosse et al. in Eur J Cancer 51:1742-50, 2015). After merging intermediate and high-intermediate risk classes into one intermediate group and including advanced and oligometastatic disease in the high-risk group, the low-risk group encompassed 124 patients, the intermediate-risk 1140, and the high risk 576. No low-risk patient developed local relapse (LR). Multivariate analysis showed that intermediate risk patients had a 2.5-fold increased risk of LR if treated with IRT alone vs EBRT-IRT boost. RT schedule did not impact significantly on LR in high risk patients. All acute toxicity parameters were highest in patients who received EBRT with simultaneous integrated boost (EBRT-SIB) and lowest in patients who received only IRT (p < 0.0001). Late toxicity was highest patients who received EBRT-SIB and lowest in those who were given EBRT with sequential boost (p < 0.0001). This retrospective study showed that Italian administration of adjuvant RT for EC is in accordance with current international guidelines. IRT alone for low-risk patients and EBRT associated with vaginal IRT remain standard adjuvant approaches for EC.

Fasting mimicking diet during neo-adjuvant chemotherapy in breast cancer patients: a randomized controlled trial study.

Preclinical evidences suggests that while fasting can reduce the side effects and toxicity of chemotherapy, it can make cancer cells more susceptible to chemotherapy. This study aimed to examine the effects of fasting mimicking diet (FMD) during neo-adjuvant chemotherapy in breast cancer (BC) patients. Forty-four newly diagnosed human epidermal growth factor receptor 2-negative (HER2-negative) patients with BC were randomized equally into two groups (22 each), to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. This FMD was repeated every 3 weeks for 8 cycles. Efficacy, toxicity, hematologic, metabolic, and inflammatory parameters were measured and compared. The occurrence of grade III vomiting and neutropenia in the control group was significantly higher than the FMD group (P = <0.001 and p = 0.04 respectively). Erythrocytes (p = 0.01) and neutrophils (p = 0.002) counts were significantly higher in FMD group compared to control group after cycle 8. There was a significant increase in median glucose and median insulin levels (p = 0.01 and p = 0.005, respectively) in the control group between baseline and after cycle 8. While, the median Insulin-like growth factor-1 (IGF1) (p = 0.006) and hs-CRP (p = 0.02) levels were significantly decreased in the FMD group. At the end of study (after cycle 8), the median glucose level was significantly higher in control group (p = 0.008), while the median hs-CRP level was significantly lower in FMD group (p = 0.01). The Miller and Payne pathological response 4/5 (90-100% tumor cell loss) and the radiologically complete or partial response, as measured by MRI or ultrasound before surgery occurred more frequently in FMD group compared to the controls (p = 0.01). Fasting mimicking diet was well tolerated during chemotherapy and reduced toxicity of chemotherapy and also, had beneficial effects of some metabolic parameters. https://irct.behdasht.gov.ir/user/trial/61386/view.

Acute oral and dermal toxicity parameters of a drug based on D-cyphenothrin, pyriproxyfen and piperonyl butoxide in laboratory animals

The purpose of the research is to study acute oral and dermal toxicity parameters of a drug based on D-cyphenothrin, pyriproxyfen and piperonyl butoxide in laboratory animals.Materials and methods. The study insectoacaricidal drug contains D-cyphenothrin, pyriproxyfen, piperonyl butoxide, hydrogenated castor oil and isopropyl alcohol. The acute toxicity parameters of the drug in 5% solution formulation were studied on 50 white outbred male mice when administered intragastrically, and on 42 outbred male rats when administered orally and on skin. The acute toxicity parameters were calculated using the Litchfield and Wilcoxon method as modified by Z. Rotha, and the drug exposure value on the body was evaluated as per the established classification (GOST 12.1.007). Results and discussion. The following toxicological characteristics were obtained: LD50 of the study drug administered orally to the white mice was 2,656 (2,207.8÷3,187.2) mg/kg, and the white rats, 5,063 (4482÷5818.3) mg/kg. The maximum tolerated dose of the drug was 830 mg/kg for the mice, and 2,075 mg/kg for the rats. Based on the obtained LD50 values, the three-component insectoacaricide can be classified as hazard category 3 (moderately hazardous substances) in experiments on mice, and hazard category 4 (marginally hazardous substances) on rats pursuant to the established hygienic classification. At the same time, different species sensitivity to the drug can be observed in mice and rats. LD50 was more than 30,710 mg/kg in the study of dermal toxicity on the white rats, therefore the drug can be classified as hazard category 4.

Toxicity Effect of Hypnea flagelliformis Algae on Cancerous Mitochondria Obtained from Rat Model of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is recognized as one of the major public health problems and deadly malignancies worldwide. Today, the use of compounds of natural origin in the treatment of cancer and other diseases has been of interest to researchers. Marine compounds such as algae have anti-cancer effects. In addition, Sea algae have nutritional value. This research is designed to investigate the cytotoxic effects of Hypnea flagelliformis (H. flagelliformis) extracts (methanolic, diethyl ether and n-hexane) on HCC mitochondria. HCC was induced by diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF) in rats. Then, toxicity parameters were evaluated. The results showed that all H. flagelliformis extracts (250, 500 and 1000 µg/ml) significantly caused toxicity in HCC mitochondria, and no effect on healthy mitochondria was reported. The results indicate that the use of H. flagelliformis along with selected drugs in the treatment of HCC can help in the treatment of this cancer.

Theoretical-Cheminformatic Study of Four Indolylphytoquinones, Prospective Anticancer Candidates.

Background/Objectives: Breast cancer is a disease with a high mortality rate worldwide; consequently, urgent achievements are required to design new greener drugs, leaving natural products and their derivatives as good options. A constant antineoplastic effect has been observed when the phytoproduct contains an indole fragment. Methods: Therefore, the objective of this work was to carry out a thoughtful computational study to perform an appropriate evaluation of four novel molecules of the class of the 3-indolylquinones as phytodrug candidates for antineoplastic activity: thymoquinone (TQ), 2,6-dimethoxy-1,4-benzoquinone (DMQ), 2,3-dimethoxy-5-methyl-1,4-benzoquinone (DMMQ), and 2,5-dihydroxy-1,4-benzoquinone (DHQ). It is important to highlight that the obtained computational results of the target compounds were compared-correlated with the theoretical and experimental literature data previously reported of several indolylquinones: indolylperezone, indolylisoperezone, indolylmenadione, and indolylplumbagin (IE-IH, respectively). Results: The results revealed that the studied structures possibly presented antineoplastic activity, in addition to the fact that the reactivity parameters showed that two of the evaluated compounds have the option to present IC50 values lower than or similar to 25 mg/mL, activity like that of indolylisoperezone; moreover, they show molecular coupling to PARP-1. Finally, the prediction of the calculated physicochemical parameters coincides with the Lipinski and Veber rules, indicating that the adsorption, metabolism, and toxicity parameters are acceptable for the studied compounds, obtaining high drug score values. Conclusions: Finally, a comparison between the proposed molecules and others previously synthesized was appropriately performed, establishing that the synthesis of the studied compounds and the determination of their pharmacological properties in an experimental manner are of interest.

Association between smoking status, toxicity and survival in the checkpoint inhibitor immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing T-cell-mediated immune responses against tumors. However, their use can lead to immune-related adverse events (irAEs), impacting patient outcomes. This single-center, observational study investigates the relationship between immune-related adverse events (irAEs) and survival outcomes in 151 patients treated with ICIs, with or without chemotherapy, at the Department of Clinical Oncology and Chemotherapy in the Independent Public Hospital No. 4 in Lublin. Statistical analyses were performed using the log-rank test, and multivariable Cox proportional hazard model (p < 0.05). IrAEs were observed in 38% of patients, with the most common being thyroid dysfunction (11.9%) and dermal toxicity (6.6%). Individual toxicity groups presented similar median values of "pack-years", suggesting that smoking did not have a direct impact on the degree of toxicity. No relationship between the number of "pack-years" and the time of occurrence of toxicity symptoms and the number of toxicity sites was found. Smoking status did not have a moderating effect on the toxicity parameter in survival analysis (OS) and progression free survival analysis (PFS). Pack-years of smoking significantly impacted both OS (HR = 1.01, p = 0.014) and PFS (HR = 1.01, p = 0.011). The results suggested that smoking, measured in pack-years, had no appreciable effect on the amount of toxicity experienced by patients and no correlation between smoking status, irAEs and efficiency of the treatment was found. Despite results not reaching statistical significance, other potential mechanisms by which smoking may influence cancer treatment cannot be ruled out.

Preparation of gallic acid-loaded chitosan nanoparticles and their chemoprotective effects on N-ethyl-N-nitrosourea-induced hepatotoxicity and mortality in rats.

N-ethyl-N-nitrosourea (ENU) as n-nitrosamine and alkylating agent, ubiquitous within living cells and in the environment can act as a full carcinogen and induce tumor formation in various tissues such as liver. In this study, gallic acid-loaded chitosan nanoparticles (GANPs) were synthesized and evaluated for their chemopreventive effect against ENU-induced hepatotoxicity and mortality in rats. Twenty-four male Wistar rats were divided into four groups including: control, ENU (single doses of 50mg/kg via intraperitoneal injection), GA + ENU and GANPs + ENU. Animals were orally pretreated with GA (50 mg/kg) and GANPs (50 mg/kg) for 30 days, and liver injuries induced by ENU on the 31st day of study. After ENU administration, weight changes and mortality were monitored during 30 days, and then the animals were sacrificed and alpha-fetoprotein (AFP) as a tumor marker, liver function tests (ALT, AST and ALP), oxidative stress markers (GSH and MDA), mitochondrial toxicity parameters, and histopathological assessment were evaluated. Except for AFP and MDA, ENU caused significant elevation of liver enzymes, mitochondrial ROS formation, collapse of mitochondrial membrane potential depletion of GSH, histopathological abnormalities and mortality in rats. Our data showed that GANPs significantly increased the survival of rats by up to 66%, delayed in death time and prevented weight changes after exposure to ENU. Moreover, GANPs restored liver enzyme levels, ROS formation, mitochondrial dysfunction, GSH levels, and histopathological abnormalities towards normal. Our findings suggest that GANPs revealed a significant protective effect against deadly toxicity induced by ENU as an alkylating full carcinogen agent in liver tissue.

Derivation of toxicity parameters from field data: Analysis of lake zooplankton species responses to metals and acidity

The WHAM-FTOXβ model describes the toxic effects of mixtures of protons and metal cations towards biological species, using a set of intrinsic parameters for the cations (αH, αM*) and a sensitivity parameter (β) for each species. We applied the model to extensive water chemistry and zooplankton species occurrence data for four lakes contaminated with acidity and metals (Al, Ni, Cu, Zn) at Sudbury, Ontario, over the period 1973-2018, during which cation contamination declined, and zooplankton species numbers increased. Assuming that the appearance of a species resulted solely from decreases in water toxicity, and that αH and αM* values previously derived from laboratory toxicity test data could be applied in the field, we used the field data to estimate values of β for individual lake zooplankton species. Results for lake-species pairs with 20 or more species occurrences (from six samplings per year) were analysed. In most cases, the number of occurrences increased over time from zero to five or six per year, then remained at the high level. For a minority of pairs, occurrences per year increased initially, but subsequently declined, and so data only from the initial period were used to estimate β. The β values derived for the lake zooplankton are reasonably consistent with values derived from laboratory data for a range of other species. The findings support the application of WHAM-FTOXβ to describe toxic effects of mixtures of cations in the field, and the toxicity model might be combined with ecological theory to interpret natural population responses.

QSAR prediction of toxicity for a new 1,2,4-triazole derivatives with 2-bromo-5-methoxyphenyl fragment

New derivatives of 1,2,4-triazole are promising research targets due to their unique biological properties, including antimicrobial, antifungal, antitumor, and antioxidant activities. The introduction of the 2-bromo-5-methoxyphenyl fragment into the triazole structure potentially enhances these properties. However, the issue of toxicity for such compounds remains a critical factor for their further application. To reduce experimental costs and time, QSAR (Quantitative Structure-Activity Relationship) methods are widely applied, allowing to predict compounds toxicity based on their molecular structure. The aim of this study was to evaluate the toxicity of new derivatives of 5-(2-bromo-5-methoxyphenyl)-4-R-1,2,4-triazole-3-thiols, their acids, and esters using the QSAR method to predict parameters of acute toxicity (LD50) and to assess the influence of various radicals on the toxicity of the compounds. Materials and methods. The objects of this study were derivatives of 5-(2-bromo-5-methoxyphenyl)-4-R-1,2,4-triazole-3-thiols, synthesized at the Department of Toxicological and Inorganic Chemistry of Zaporizhzhia State Medical and Pharmaceutical University. The nearest neighbor method was used for toxicity evaluation, applying the Toxicity Estimation Software Tool (TEST). The prediction of rats lethal dose (LD50) was based on the structural similarity of the studied compounds with known substances that have experimental toxicity data. Results. The QSAR analysis revealed that structural modifications in the derivatives of 5-(2-bromo-5-methoxyphenyl)-4-R-1,2,4-triazole-3-thiols significantly influence their toxicity. Specifically, increasing the size of the radicals, especially through the introduction of aromatic fragments, contributed to the enhanced safety of the compounds, as evidenced by the increase in LD50 values. The highest LD50 values were observed for compounds containing phenyl radicals. Conclusions. The results of this study indicate the feasibility of using QSAR models to predict the toxicity of 1,2,4-triazole derivatives containing a 2-bromo-5-methoxyphenyl fragment. The observed trend of increasing safety with the introduction of larger aromatic radicals can be used for the rational design of new compounds with improved toxicological properties.

Computer prediction of toxicity of new S-alkyl derivatives of 1,2,4-triazole

1,2,4-Triazole derivatives are of researchers’ significant interest due to their diverse biological properties, such as antimicrobial, anti-inflammatory, anticancer, and antioxidant activities. The integration of a 2-bromo-4-fluorophenyl fragment into the triazole structure can significantly enhance these activities. However, the evaluation of the toxicity of such compounds remains a critically important aspect for their practical application. To reduce the time and cost of experimental studies, QSAR (Quantitative Structure-Activity Relationship) methods are actively used, allowing the prediction of toxicity based on the molecular structure of compounds. Aim of the study. To assess the toxicity of new S-derivatives of 5-(2-bromo-4-fluorophenyl)-4-R-1,2,4-triazol-3-thiols using the QSAR method, specifically to predict acute toxicity parameters (LD50), and to determine the influence of different (length) radicals on the toxicity of these compounds. Materials and methods. The objects of the virtual study were derivatives of 5-(2-bromo-4-fluorophenyl)-4-ethyl-1,2,4-triazol-3-thiols. They were evaluated at the Department of Toxicological and Inorganic Chemistry of the Zaporizhzhia State Medical and Pharmaceutical University. The toxicity assessment was conducted using the nearest neighbor method via the Toxicity Estimation Software Tool (TEST). The prediction of the lethal dose (LD50) for rats was based on the structural similarity of the studied compounds with known substances, for which experimental toxicity data are available. Results. The conducted QSAR analysis demonstrated that structural changes in S-derivatives of 5-(2-bromo-4-fluorophenyl)-4-ethyl-1,2,4-triazol-3-thiols significantly affect the predicted toxicity. The primary factor influencing the changes in LD50 values is the variation of radicals at the 5th position of the triazole ring. Conclusions. The results of the study showed, that the toxicity of new S-alkyl derivatives of triazol-3-thiols depends on the type of alkyl substituent. Compounds with propyl to heptyl fragments exhibit increased toxicity, while derivatives with thiol, octyl, nonyl, and decyl residues are characterized by lower toxicity.

Screening of Optimal Phytoconstituents through in silico Docking, Toxicity, Pharmacokinetic, and Molecular Dynamics Approach for Fighting against Polycystic Ovarian Syndrome.

Polycystic ovarian syndrome (PCOS) is a hormonal disorder caused by excessive secretion of male sex hormones in females. Herbal remedies for PCOS are lightning up as they bypass the adverse effects and are profoundly safe on prolonged usage. The present study included a selection of 34 herbs pursuing biological effects on the uterus, and their major chemical constituents were subjected to a series of in silico techniques using different software. The proteins contributing majorly to the hormonal functions like Human cytochrome P450 CYP17A1 (3RUK), Progesterone (1E3K), and estrogen receptor (1X7R) were selected for the study. Molecular docking studies were performed using AutoDock 1.5.7. The pharmacokinetic properties were predicted using the SwissADME online tool, while toxicity parameters were assessed with OSIRIS toxicity explorer and pkCSM. Molecular dynamics simulations and free energy calculations were performed using the Schrödinger suite. Constituents with a basic steroidal nucleus demonstrated high binding energy values. An analysis of all the in silico techniques showed that Sarsasapogenin from Asparagus racemosus exhibited strong binding energies of -10.88 kcal/mol, -10.51 kcal/mol, and -9.79 kcal/mol with the selected specific proteins. In molecular dynamics simulations, Sarsasapogenin displayed ideal stability, with RMSD fluctuations below 3 Å and RMSF slightly higher than the corresponding peak of apoprotein. Additionally, it showed a favorable druglikeness profile and non-toxic effects across all screened parameters. From the list of the selected constituents, sarsasapogenin was found to be ideal, and further research on it for targeting PCOS is expected to yield promising results.

Structure-Tissue Exposure/Selectivity Relationship (STR) on Carbamates of Cannabidiol.

The structure-tissue exposure/selectivity relationship (STR) aids in lead optimization to improve drug candidate selection and balance clinical dose, efficacy, and toxicity. In this work, butyrocholinesterase (BuChE)-targeted cannabidiol (CBD) carbamates were used to study the STR in correlation with observed efficacy/toxicity. CBD carbamates with similar structures and same molecular target showed similar/different pharmacokinetics. L2 and L4 had almost same plasma exposure, which was not correlated with their exposure in the brain, while tissue exposure/selectivity was correlated with efficacy/safety. Structural modifications of CBD carbamates not only changed drug plasma exposure, but also altered drug tissue exposure/selectivity. The secondary amine of carbamate can be metabolized into CBD, while the tertiary amine is more stable. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters can be used to predict STR. Therefore, STR can alter drug tissue exposure/selectivity in normal tissues, impacting efficacy/toxicity. The drug optimization process should balance the structure-activity relationship (SAR) and STR of drug candidates for improving clinical trials.