Toxicity Screening Research Articles

In vitro Antibacterial, ADME and Toxicity Screening of Newly Synthesized 4-(Substituted phenyl)-2-(2-chloroquinolin-3-yl)thiazoles

A series of novel thiazole (Va-o) compounds were synthesized following multi-step synthetic process. Using analytical methods like nuclear magnetic resonance, mass spectrometry and FTIR, the elucidation of the structure of the synthesized compounds was performed. All the 15 novel thiazoles were assessed for their antibacterial activity. The synthesized thiazoles were examined for inhibitory antibacterial activity against a panel Gram-positive strain viz. Staphylococcus aureus (NCTC 65710), Streptococcus pyogenes (MTCC-442), Bacillus subtilis (NCIM 2250) and Gram-negative bacteria Pseudomonas aeruginosa (NCTC 10662) and Escherichia coli (NCTC 10418) by agar well diffusion technique. It was observed that some of the compounds, particularly those having substitution groups like chloro, fluoro and bromo in the phenyl ring bonded to thiazole nucleus, had moderate to good antibacterial activity. Quinoline clubbed thiazoles compounds Vk, Vl, Vn and Vo showed significant antibacterial against all bacterial strains having values of minimum inhibitory concentration (MIC) from 12.5 to 25 µg/mL. The results of antimicrobial investigation suggest that 2-chloroquinoline incorporated thiazole scaffold appears to more promising for developing potent antibacterial agents. Genome gyrase docking experiments (PDB ID: 1KZN) revealed a favourable binding relationship similar to that of the pre-occupied ligand clorobiocin. The study also provides in silico ADME and toxicity studies evaluation which revealed that compounds are impartially compatible and were devoid of potential toxicity except the hepatotoxicity.

Phenazine Cations as Anticancer Theranostics†.

The biological properties of two water-soluble organic cations based on polypyridyl structures commonly used as ligands for photoactive transition metal complexes designed to interact with biomolecules are investigated. A cytotoxicity screen employing a small panel of cell lines reveals that both cations show cytotoxicity toward cancer cells but show reduced cytotoxicity to noncancerous HEK293 cells with the more extended system being notably more active. Although it is not a singlet oxygen sensitizer, the more active cation also displayed enhanced potency on irradiation with visible light, making it active at nanomolar concentrations. Using the intrinsic luminescence of the cations, their cellular uptake was investigated in more detail, revealing that the active compound is more readily internalized than its less lipophilic analogue. Colocalization studies with established cell probes reveal that the active cation predominantly localizes within lysosomes and that irradiation leads to the disruption of mitochondrial structure and function. Stimulated emission depletion (STED) nanoscopy and transmission electron microscopy (TEM) imaging reveal that treatment results in distinct lysosomal swelling and extensive cellular vacuolization. Further imaging-based studies confirm that treatment with the active cation induces lysosomal membrane permeabilization, which triggers lysosome-dependent cell-death due to both necrosis and caspase-dependent apoptosis. A preliminary toxicity screen in the Galleria melonella animal model was carried out on both cations and revealed no detectable toxicity up to concentrations of 80 mg/kg. Taken together, these studies indicate that this class of synthetically easy-to-access photoactive compounds offers potential as novel therapeutic leads.

Exploring the Therapeutic Potential of Spilanthol from Acmella paniculata (Wall ex DC.) R. K. Jansen in Attenuating Neurodegenerative Diseases: A Multi-Faceted Approach Integrating In Silico and In Vitro Methodologies

Neurodegenerative diseases (NDDs) are marked by progressive degeneration of neurons within the central nervous system. A notable rise in the prevalence of NDDs has been noticed in the recent past. There is an undeniable requirement for the discovery of innovative therapies aimed at treating NDDs, as current medications predominantly address symptoms rather than provide cures. Approved therapies often experience a decline in therapeutic efficacy over time and are associated with significant side effects. The current investigation explores the potential of spilanthol, the major bioactive compound isolated from Acmella paniculata, in attenuating NDDs through a multi-faceted approach combining in silico, and in vitro methodologies. In silico pharmacokinetic and toxicity screening of spilanthol indicated favorable characteristics for oral delivery, blood–brain barrier permeability, and minimal toxicity. Network pharmacology predicts that spilanthol attenuates neuroinflammation in NDDs by suppressing the toll-like receptor signaling pathway. Molecular docking and dynamics simulations demonstrate robust binding affinities between spilanthol and key proteins in the TLR4 pathway. In vitro experiments conducted using BV-2 microglial cells demonstrate the potential of spilanthol to reduce the production of proinflammatory cytokines and mediators such as NO, TNF-α, and IL-6 induced by lipopolysaccharide. The cumulative findings of the present study indicate that spilanthol mitigates neurodegeneration by alleviating neuroinflammation.

Evaluation of Subchronic toxicity and phytochemical analysis of aqueous extract of Ocimum suave (Lamiciae)

Evaluation of phytochemical content, acute and sub-chronic toxicity of the aqueous leaf extract of Ocimum suave in Wistar rats was carried out. Experimental rats were administered extracts daily for 31days at dose levels of 200, 400 and 800 mg/kg. Acute toxicity and phytochemical screening of aqueous leaf extract were done according to method of Lorke’s Trease and Evans. Biochemical analysis was equally done at the end of the administration of extracts using standard methods. At the end of the study, animals were sacrificed and blood samples taken for biochemical assay. The LD50 was found to be greater than 10,000 mg/kg body weight. Results showed the presence of most phytochemicals tested for. The aqueous extract caused a decrease in ALT activity but AST and CK activities were higher in the treated groups in a dose dependent manner relative to the control. The aqueous leaf extract of Ocimum suave affected mean cell volume, mean cell hemoglobin and mean cell hemoglobin concentration. The aqueous leaf extract caused mean body weight gain, but decrease in relative organ weight. The study suggests that the aqueous extract administered at normal therapeutic doses is not likely to produce severe toxic effects on some hematological and biochemical indices in rats and the organs tested. Chronictoxicity of aqueous leaf extract of Ocimum suave should be done for histological, haematological andbiochemical evaluation. Key Words: Ocimum suave, Toxicity, Wistar Rats, Biochemical assay, Phytochemical, Extract

Computational framework for identifying and evaluating mutagenic and xenoestrogenic potential of food additives

Food additives are chemicals incorporated in food to enhance its flavor, color and prevent spoilage. Some of these are associated with substantial health hazards, including developmental disorders, increase cancer risk, and hormone disruption. Hence, this study aimed to comprehend the in-silico toxicology framework for evaluating mutagenic and xenoestrogenic potential of food additives and their association with breast cancer. A total of 2885 food additives were screened for toxicity based on Threshold of Toxicological Concern (TTC), mutagenicity endpoint prediction, and mutagenic structural alerts/toxicophores identification. Ten food additives were identified as having mutagenic potential based on toxicity screening. Furthermore, Protein-Protein Interaction (PPI) analysis identified ESR1, as a key hub gene in breast cancer. KEGG pathway analysis verified that ESR1 plays a significant role in breast cancer pathogenesis. Additionally, competitive interaction studies of the predicted potential mutagenic food additives with the estrogen receptor-α were evaluated at agonist and antagonist binding sites. Indole, Dichloromethane, Trichloroethylene, Quinoline, 6-methyl quinoline, Ethyl nitrite, and 4-methyl quinoline could act as agonists, and Paraldehyde, Azodicarbonamide, and 2-acetylfuranmay as antagonists. The systematic risk assessment framework reported in this study enables the exploration of mutagenic and xenoestrogenic potential associated with food additives for hazard identification and management.

An Insight into Absorption, Distribution, Metabolism, Excretion, and Toxicity Screening, Molecular Dynamic Simulation, and Molecular Docking of Glycitein as Hepatoprotective Isoflavone

ABSTRACT Background: Several chemicals and metals, as well as a number of pharmaceutical preparations, are reportedly thought to have a major impact on the emergence of liver disease. According to postcommercialization regulatory considerations, it has been regarded as the most predisposing factor for acute liver failure. Thus, according to recent statistics, nearly 1 in 10 people have a liver illness of some form. 5.5 million of them suffer from chronic liver disease. Any type of viral infection, immune system abnormalities, ingestion of too many poisons, cancer, or other genetic condition may result in liver disease. In addition, the liver may get toxified through some drugs Non-steroidal Anti-inflammatory Drugs (NSAIDs), chemicals, radiation, and ions. Objective: This study involves an in-silico evaluation of one of the soy isoflavones glycitein targeting interleukin-6 (IL-6), IL-1 β, tumor necrosis factor (TNF)-α, and estrogen receptors (ERs) in hepatological disorders by the computational method. The docking result of glycitein is being compared with silymarin as a standard hepatoprotective agent. As a final step, two molecular dynamics (MD) simulation experiments for 150 ns were carried out as a refinement step for the proposed approach. Materials and Methods: The proteins were created using PubChem and viewed by PyMol software. To evaluate the hepatoprotective activity of the selected isoflavone glycitein, selection, and modeling of the target enzymes accompanied by the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis using swissADME and pkCSM software was conducted. Furthermore, molecular docking studies using the Auto dock Vina software were carried out to anticipate the binding affinities of Glycitein to the active sites of the intended targets. The proposed method was then refined by the execution of two 150 ns MD simulations and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) studies. Results: All the protein structures were good quality and within the acceptable range. Glycitein exhibited an excellent docking score against IL-6 (−6.4 kcal/mol), IL-1 β (−6.4 kcal/mol), ER (−6.8 kcal/mol), and TNF-α (−6.5 kcal/mol) in comparison with Silymarin which were further screened for drug-likeness and pharmacokinetic parameters including ADMET. Glycitein was found to be the best possible TNF inhibitor hereunder indicated by the MD and MM-PBSA outputs because it demonstrated greater stability and average binding free energy for the ligand-enzyme complex in comparison to Silymarin. Conclusion: The results from the chosen database proved that glycitein is a potent hepatoprotective isoflavone possessing a favorable ADMET profile, lesser or no toxicity, and higher bioavailability which can be further used as a lead compound for preclinical screening.

Toward identification and intervention to address financial toxicity and unmet health-related social needs among adolescents and emerging adults with cancer and their caregivers: A cross-cultural perspective.

We qualitatively explored the unique needs and preferences for financial toxicity screening and interventions to address financial toxicity among adolescents and emerging adults (younger AYAs: 15-25 years) with cancer and their caregivers. We recruited English- or Spanish-speaking younger AYAs who were treated for cancer within the past 2 years and their caregivers. Semi-structured interviews were conducted to explore preferences for screening and interventional study development to address financial toxicity. The data were coded using conventional content analysis. Codes were reviewed with the study team, and interviews continued until saturation was reached; codes were consolidated into categories and themes during consensus discussions. We interviewed 17 participants; nine were younger AYAs. Seven of the 17 preferred to speak Spanish. We identified three cross-cutting themes: burden, support, and routine, consistent, and clear. The burden came in the form of unexpected costs such as transportation to appointments, as well as emotional burdens such as AYAs worrying about how much their family sacrificed for their care or caregivers worrying about the AYA's physical and financial future. Support, in the form of familial, community, healthcare institution, and insurance, was critical to mitigating the effects of financial toxicity in this population. Participants emphasized the importance of meeting individual financial needs by routinely and consistently asking about financial factors and providing clear guidance to navigate these needs. Younger AYAs and their caregivers experience significant financial challenges and unmet health-related social needs during cancer treatment and often rely on key supports to alleviate these unmet needs. When developing interventions to mitigate financial toxicity, clinicians and health systems should prioritize clear, consistent, and tailorable approaches to support younger AYA cancer survivors and their families.

Perspectives on chick embryo models in developmental and reproductive toxicity screening

Teratology, the study of congenital anomalies and their causative factors intersects with developmental and reproductive toxicology, employing innovative methodologies. Evaluating the potential impacts of teratogens on fetal development and assessing human risk is an essential prerequisite in preclinical research. The chicken embryo model has emerged as a powerful tool for understanding human embryonic development due to its remarkable resemblance to humans. This model offers a unique platform for investigating the effects of substances on developing embryos, employing techniques such as ex ovo and in ovo assays, chorioallantoic membrane assays, and embryonic culture techniques. The advantages of chicken embryonic models include their accessibility, cost-effectiveness, and biological relevance to vertebrate development, enabling efficient screening of developmental toxicity. However, these models have limitations, such as the absence of a placenta and maternal metabolism, impacting the study of nutrient exchange and hormone regulation. Despite these limitations, understanding and mitigating the challenges posed by the absence of a placenta and maternal metabolism are critical for maximizing the utility of the chick embryo model in developmental toxicity testing. Indeed, the insights gained from utilizing these assays and their constraints can significantly contribute to our understanding of the developmental impacts of various agents. This review underscores the utilization of chicken embryonic models in developmental toxicity testing, highlighting their advantages and disadvantages by addressing the challenges posed by their physiological differences from mammalian systems.

Abstract 2054: A sensitive and specific human primary stem cell-based in vitro assay for predicting the gastrointestinal toxicity risk of therapeutic agents

Abstract Gastrointestinal (GI) toxicities are the most common drug-induced adverse events in human clinical trials. Drugs that cause GI toxicities often affect the proliferative stem and progenitor cell populations responsible for maintaining the cellular composition, self-renewing capacity, and barrier function of the intestinal epithelium. This disruption leads to impaired GI barrier integrity, culminating in a broad range of clinical symptoms, including diarrhea, inflammation, and increased risk of infection. The impact of GI toxicity is substantial and can cause dose-limiting clinical side-effects that may affect patient compliance and dosing adherence. Common nonclinical animal models, including rats, mice and dogs are often poor predictors of human GI toxicity and safety outcomes. Furthermore, in vivo animal testing poses limited screening throughput, which is particularly important in fields such as oncology, where matrices of double or triple drug combinations represent the standard of care. Additionally, existing cell-based model systems, such as Caco-2 cells, are of limited predictive value as they are tumor-derived and do not reprise native epithelium. Thus, there is a need for the development of assay systems that more accurately recapitulate human biology, have higher throughput testing capabilities, and ultimately improve clinical predictability. To this end, we have developed an assay to assess GI toxicity potential using the RepliGut Planar platform, which consists of a primary human stem cell-derived epithelium in a 96-well Transwell format. Quantitative dose-response curves were generated on proliferative and/or differentiated GI cultures for various test articles utilizing endpoints that assess GI proliferative capacity, cell viability, and epithelial barrier formation and maintenance. An initial set of marketed drugs (including diverse anti-proliferative, cytotoxic, or anti-inflammatory mechanisms) with known clinical incidence of diarrhea were over a 5-log dose range to enable modeling of the Toxic Concentration 50% (TC50). When benchmarked against the known human plasma concentrations (Cmax), this model was able to accurately predict clinical outcomes for diarrheagenic-drugs, as well as non-toxic negative controls, within 30-fold of the clinical Cmax. Overall, this model system provides straightforward and informative screening for GI toxicity that integrates sensitive and robust endpoints, enables screening to support early nonclinical development, and uniquely allows for mechanistic insights. Citation Format: James Levi, Reganne Lorichon, Lauren Boone, Maureen Bunger, Elizabeth Boazak, William R. Thelin. A sensitive and specific human primary stem cell-based in vitro assay for predicting the gastrointestinal toxicity risk of therapeutic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2054.

Abstract 3581: IGFR1 and MEK inhibition synergize to mediate anti-tumor activity in adrenocortical carcinoma

Abstract Adrenocortical carcinoma (ACC) is an aggressive and rare endocrine malignancy with limited treatment options and poor prognosis. IGF2, the ligand for IGFR1, is highly expressed in ACC. However, linsitinib, an IGFR1 inhibitor, failed to improve overall survival over placebo in a randomized, phase 3 clinical trial of metastatic ACC. We hypothesized that combination therapy with IGFR1 inhibition may have greater anti-tumor efficacy in ACC than IGFR1 inhibition alone. To test this hypothesis, we performed high-throughput cell toxicity screening of 2803 clinical-stage compounds with linsitinib in an ACC cell line. MAPK inhibitors were among the top screening hits. MEK inhibitors were chosen for further evaluation given the safety, tolerability, and broad clinical activity of these FDA-approved agents. IGFR1 and MEK inhibitors were strongly synergistic in cytotoxicity across ACC cell lines, ACC organoid short-term cultures derived from surgical tissue resections (PDOs), and PDX-derived organoids (PDXOs). Genetic depletion of IGF2 significantly inhibited growth with cobimetinib and genetic depletion of MEK1 inhibited growth with linsitinib in ACC cell lines. Combination IGFR1 and MEK inhibition downregulated ERK phosphorylation and increased apoptosis compared to either IGFR1 or MEK inhibition alone. Linsitinib combined with cobimetinib significantly reduced tumor growth compared to either linsitinib or cobimetinib alone in an ACC xenograft model. Our study provides preclinical support for testing the combination of IGFR1 and MEK inhibition in patients with ACC. Citation Format: Suresh Kumar, Nai-Yun Sun, Yasuhiro Arakawa, Diana Varghese, Chuong D. Hoang, Jonathan M. Hernandez, Yves Pommier, Craig Thomas, Jaydira Del Rivero, Nitin Roper. IGFR1 and MEK inhibition synergize to mediate anti-tumor activity in adrenocortical carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3581.

Cardiotoxicity Assessment through a Polymer-Based Cantilever Platform: An Integrated Electro-Mechanical Screening Approach.

Preclinical drug screening for cardiac toxicity has traditionally relied on observing changes in cardiomyocytes' electrical activity, primarily through invasive patch clamp techniques or non-invasive microelectrode arrays (MEA). However, relying solely on field potential duration (FPD) measurements for electrophysiological assessment can miss the full spectrum of drug-induced toxicity, as different drugs affect cardiomyocytes through various mechanisms. A more comprehensive approach, combining field potential and contractility measurements, is essential for accurate toxicity profiling, particularly for drugs targeting contractile proteins without affecting electrophysiology. However, previously proposed platform has significant limitations in terms of simultaneous measurement. The novel platform addresses these issues, offering enhanced, non-invasive evaluation of drug-induced cardiotoxicity. It features eight cantilevers with patterned strain sensors and MEA, enabling real-time monitoring of both cardiomyocyte contraction force and field potential. This system can detect minimum cardiac contraction force of ≈2 µN and field potential signals with 50µm MEA diameter, using the same cardiomyocytes in measurements of two parameters. Testing with six drugs of varied mechanisms of action, the platform successfully identifies these mechanisms and accurately assesses toxicity profiles, including drugs not inhibiting potassium channels. This innovative approach presents a comprehensive, non-invasive method for cardiac function assessment, poised to revolutionize preclinical cardiotoxicity screening.

Assessing the in vivo toxicity of titanium dioxide nanoparticles in Schmidtea mediterranea: uptake pathways and (neuro)developmental outcomes

Titanium dioxide nanoparticles (TiO2-NPs) in aquatic environments, originating from urban run-off, product use and post-consumer degradation, interact with aquatic organisms through water and sediments. Thorough toxicity assessment requires comprehensive data across all ecosystem compartments especially the benthic zone, which is currently lacking. Moreover, a proper physicochemical characterization of the particles is needed before and during toxicity assessment. In the present work, we used the planarian Schmidtea mediterranea to investigate the effects of TiO2-NPs (5 mg/L and 50 mg/L). Planarians are benthic organisms that play an important role in the food chain as predators. Our study integrated particle characterization with toxicokinetic and toxicodynamic parameters and showed that the uptake of TiO2-NPs of 21 nm occurred through the epidermis and intestine. Epidermal irritation and mucus production occurred immediately after exposure, and TiO2-NPs induced stronger effects in regenerating organisms. More specifically, TiO2-NPs interfered with neuroregeneration, inducing behavioral effects. A delay in the formation of the anterior commissure between the two brain lobes after seven and nine days of exposure to 50 mg/L was observed, probably as a result of a decrease in stem cell proliferation. Our findings underscore the need to incorporate multiple exposure routes in toxicity screenings. Additionally, we highlight the vulnerability of developing organisms and recommend their inclusion in future risk assessment strategies.

Assessment of Mitochondrial Function in the AmE-711 Honey Bee Cell Line: Boscalid and Pyraclostrobin Effects.

There is a growing concern that chronic exposure to fungicides contributes to negative effects on honey bee development, life span, and behavior. Field and caged-bee studies have helped to characterize the adverse outcomes (AOs) of environmentally relevant exposures, but linking AOs to molecular/cellular mechanisms of toxicity would benefit from the use of readily controllable, simplified host platforms like cell lines. Our objective was to develop and optimize an in vitro-based mitochondrial toxicity assay suite using the honey bee as a model pollinator, and the electron transport chain (ETC) modulators boscalid and pyraclostrobin as model fungicides. We measured the effects of short (~30 min) and extended exposures (16-24 h) to boscalid and pyraclostrobin on AmE-711 honey bee cell viability and mitochondrial function. Short exposure to pyraclostrobin did not affect cell viability, but extended exposure reduced viability in a concentration-dependent manner (median lethal concentration = 4175 µg/L; ppb). Mitochondrial membrane potential (MMP) was affected by pyraclostrobin in both short (median effect concentration [EC50] = 515 µg/L) and extended exposure (EC50 = 982 µg/L) scenarios. Short exposure to 10 and 1000 µg/L pyraclostrobin resulted in a rapid decrease in the oxygen consumption rate (OCR), approximately 24% reduction by 10 µg/L relative to the baseline OCR, and 64% by 1000 µg/L. Extended exposure to 1000 µg/L pyraclostrobin reduced all respiratory parameters (e.g., spare capacity, coupling efficiency), whereas 1- and 10-µg/L treatments had no significant effects. The viability of AmE-711 cells, as well as the MMP and cellular respiration were unaffected by short and extended exposures to boscalid. The present study demonstrates that the AmE-711-based assessment of viability, MMP, and ETC functionality can provide a time- and cost-effective platform for mitochondrial toxicity screening relevant to bees. Environ Toxicol Chem 2024;43:976-987. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Prevalence of ocular toxicity induced by antimalarial drugs in patients with rheumatic diseases

Several studies have reported the possibility of ocular toxicity with the use of antimalarial drugs by patients with rheumatic diseases. Thus, the present study intended to investigate the prevalence of such toxicity in these patients and the feasibility of the regression of changes after medication discontinuation. The present retrospective study included the medical records of 598 patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and mixed connective tissue disorders (MCTDs) who took chloroquine (CQ) or hydroxychloroquine (HCQ) and underwent routine ophthalmologic examinations. Moreover, if a patient had any ocular abnormality reported by the examining ophthalmologist, he/she was referred to another ophthalmologist to confirm the primary findings. Also, the patients with abnormal ocular findings who discontinued the drugs were re-examined 12 months after the drug discontinuation to evaluate the rate of regression of the ocular changes. According to our findings, 81 out of 598 patients (13.6%) had ocular toxicity in routine ophthalmologic examinations. However, ocular changes were ruled out in 49 (8.2%) patients using a second examination by another ophthalmologist. Therefore, retinopathy was confirmed in 32 out of 598 (5.4%) cases. Moreover, the patients with eye complications were significantly older than those without ocular toxicity (P = 0.03), while no significant relationship was found between ocular toxicity and other variables. Finally, of 32 patients with ocular toxicity, 12 patients were re-examined 12 months after the drug discontinuation, revealing normal findings in 7 (58%) patients, while 5 (42%) had irreversible ocular abnormalities. According to our findings, the prevalence of HCQ- and CQ-induced retinopathy was quite considerable in patients receiving these drugs. Therefore, despite the current controversies, we recommend that all patients receiving antimalarial drugs undergo screening for ocular toxicity.

Toxicity Screening of Fungal Extracts and Metabolites, Xenobiotic Chemicals, and Indoor Dusts with In Vitro and Ex Vivo Bioassay Methods.

It is controversial how useful bioassays are for identifying the in vivo toxicity of hazardous environmental exposures. In this study, fruiting bodies of forest mushrooms (n = 46), indoor mold colonies (n = 412), fungal secondary metabolites (n = 18), xenobiotic chemicals such as biocides and detergents (n = 6), and methanol extracts of indoor dusts from urban buildings (n = 26) were screened with two different bioactivity assays: boar sperm motility inhibition (BSMI) and inhibition of cell proliferation (ICP) tests. For the forest mushrooms, the toxicity testing result was positive for 100% of poisonous-classified species, 69% of non-edible-classified species, and 18% of edible-classified species. Colonies of 21 isolates of Ascomycota mold fungal species previously isolated from water-damaged buildings proved to be toxic in the tests. Out of the fungal metabolites and xenobiotic chemicals, 94% and 100% were toxic, respectively. Out of the indoor dusts from moldy-classified houses (n = 12) and from dry, mold-free houses (n = 14), 50% and 57% were toxic, respectively. The bioassay tests, however, could not differentiate the samples from indoor dusts of moldy-classified buildings from those from the mold-free buildings. Xenobiotic chemicals and indoor dusts were more toxic in the BSMI assay than in the ICP assay, whereas the opposite results were obtained with the Ascomycota mold colonies and fungal secondary metabolites. The tests recognized unknown methanol-soluble thermoresistant substances in indoor settled dusts. Toxic indoor dusts may indicate a harmful exposure, regardless of whether the toxicity is due to xenobiotic chemicals or microbial metabolites.

Investigation of Active Compounds in Propolis Structure Against Sars Cov-2 Main Protease by Molecular Docking Method: In Silico Study

It was aimed to investigate the active ingredients limonin, quercetin and kaempferol in propolis against SARS-CoV-2 main protease(MPro) using in silico methods. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening of ligands assists US to state their absorption properties, toxicity, and drug-likeness. Ligand molecules obtained from PubChem in smiles format were loaded on SWISSADME and PROTOX-II webservers for ADMET screening. The three compounds in propolis were obtained from the PubChem database. Compounds were located at the active site of the SARS-CoV-2 MPro receptor with PDB ID:6LU7. Molecular docking work was done with Autodock program. Molecular docking results were found as -8.7 kcal/mol in limonin, -7.5 kcal/mol in quercetin and -7.7 kcal/mol in kaempferol. In silico ADMET estimation showed they have a potential for antiviral therapy. In conclusion, we thought that propolis active components limonin, quercetin and kaempferol have the potential to be a SARS CoV-2 MPro inhibitor.

Evaluating the Therapeutic Potential of Curcumin and Synthetic Derivatives: A Computational Approach to Anti-Obesity Treatments.

Natural compounds such as curcumin, a polyphenolic compound derived from the rhizome of turmeric, have gathered remarkable scientific interest due to their diverse metabolic benefits including anti-obesity potential. However, curcumin faces challenges stemming from its unfavorable pharmacokinetic profile. To address this issue, synthetic curcumin derivatives aimed at enhancing the biological efficacy of curcumin have previously been developed. In silico modelling techniques have gained significant recognition in screening synthetic compounds as drug candidates. Therefore, the primary objective of this study was to assess the pharmacokinetic and pharmacodynamic characteristics of three synthetic derivatives of curcumin. This evaluation was conducted in comparison to curcumin, with a specific emphasis on examining their impact on adipogenesis, inflammation, and lipid metabolism as potential therapeutic targets of obesity mechanisms. In this study, predictive toxicity screening confirmed the safety of curcumin, with the curcumin derivatives demonstrating a safe profile based on their LD50 values. The synthetic curcumin derivative 1A8 exhibited inactivity across all selected toxicity endpoints. Furthermore, these compounds were deemed viable candidate drugs as they adhered to Lipinski's rules and exhibited favorable metabolic profiles. Molecular docking studies revealed that both curcumin and its synthetic derivatives exhibited favorable binding scores, whilst molecular dynamic simulations showed stable binding with peroxisome proliferator-activated receptor gamma (PPARγ), csyclooxygenase-2 (COX2), and fatty acid synthase (FAS) proteins. The binding free energy calculations indicated that curcumin displayed potential as a strong regulator of PPARγ (-60.2 ± 0.4 kcal/mol) and FAS (-37.9 ± 0.3 kcal/mol), whereas 1A8 demonstrated robust binding affinity with COX2 (-64.9 ± 0.2 kcal/mol). In conclusion, the results from this study suggest that the three synthetic curcumin derivatives have similar molecular interactions to curcumin with selected biological targets. However, in vitro and in vivo experimental studies are recommended to validate these findings.

Design, Manufacture and Characterization of a Liver- Chip Model: A Platform for Disease Modeling and Toxicity Screening

Design, Manufacture and Characterization of a Liver- Chip Model: A Platform for Disease Modeling and Toxicity Screening

Hepa-ToxMOA: a pathway-screening method for evaluating cellular stress and hepatic metabolic-dependent toxicity of natural products.

In the field of drug discovery, natural products have emerged as therapeutic agents for diseases such as cancer. However, their potential toxicity poses significant obstacles in the developing effective drug candidates. To overcome this limitation, we propose a pathway-screening method based on imaging analysis to evaluate cellular stress caused by natural products. We have established a cellular stress sensing system, named Hepa-ToxMOA, which utilizes HepG2 cells expressing green fluorescent protein (GFP) fluorescence under the control of transcription factor response elements (TREs) for transcription factors (AP1, P53, Nrf2, and NF-κB). Additionally, to augment the drug metabolic activity of the HepG2 cell line, we evaluated the cytotoxicity of 40 natural products with and without S9 fraction-based metabolic activity. Our finding revealed different activities of Hepa-ToxMOA depending on metabolic or non-metabolic activity, highlighting the involvement of specific cellular stress pathways. Our results suggest that developing a Hepa-ToxMOA system based on activity of drug metabolizing enzyme provides crucial insights into the molecular mechanisms initiating cellular stress during liver toxicity screening for natural products. The pathway-screening method addresses challenges related to the potential toxicity of natural products, advancing their translation into viable therapeutic agents.

Design, synthesis and exploration of novel triazinoindoles as potent quorum-sensing inhibitors and radical quenchers.

Background: Antimicrobial resistance has become a critical health concern, and quorum-sensing exacerbates the resistance by facilitating cell-to-cell communication within the microbial community, leading to severe pathogenic outbreaks. Methods & results: Novel 1-(2-((5H-[1,2,4]-triazino[5,6-b]indol-3-yl)thio)acetyl)indoline-2,3-diones were synthesized. The title compounds exhibit outstanding anti-quorum-sensing efficacy, and compound 7g demonstrated the maximum proficiency (IC50=0.0504μg/ml). The hybrids displayed potent antioxidant action, and compound 7c showed the highest antioxidant ability (IC50=40.71μg/ml). Molecular docking of the isatin hybrids against DNA gyrase and quorum-sensing receptor CviR validated the observed in vitro findings. The befitting pharmacokinetic profile of the synthesized drug candidates was ascertained through absorption, distribution, metabolism, excretion and toxicity screening. Conclusion: The remarkable biocompetence of the synthesized triazinoindoles may help to combat drug-resistant infections.