Toxicological Profile Research Articles

Comparison of the cytotoxicity and zebrafish embryo toxicity of insect repellent ingredients: p-Menthane-3,8-diol synthesized by green chemistry from Eucalyptuscitriodora and N,N-diethyl-meta-toluamide.

Bio-sourced insect repellents are becoming more popular due to their safer applications. Known for its strong fly-repellent property, Cis, trans-para-menthane-3,8-diol (PMD) is the main component of the lemon eucalyptus essential oil and is synthesized from citronellal. In April 2005, US Centers for Disease Control approved two fly repellents that do not contain N,N-diethyl-meta-toluamide (DEET), including PMD. Due to the intentional and pervasive human exposure caused by DEET as insect repellent, concerns have been raised about its toxicological profile and potential harm to people. We hypothesized PMD would have a different toxicological profile than DEET. We synthesized PMD from Eucalyptus citriodora using green chemistry methods and analyzed its structures by 1H-NMR,13C-NMR, and GC/MS spectral methods. We used MTS assay to determine the percentage inhibition of PMD and DEET on keratinocyte (human epidermal keratinocyte [HaCaT]) cells. The xCelligence system was used and followed at real time. Effects of PMD and DEET on zebrafish embryo development were monitored and levels of lipid peroxidation, glutathione-S-transferase (GST), superoxide dismutase (SOD), and acetylcholinesterase (AchE) were evaluated at 72 h post-fertilization using spectrophotometric methods. Our results showed that while DEET inhibited human keratinocyte cell growth, while imporved cell viability and proliferation was exposed in PMD exposed group. In zebrafish embryos, PMD was less toxic in terms of development, oxidant-antioxidant status, and AChE activities than DEET. Based on these results we suggest an efficient method using green chemistry for the synthesis of PMD, which is found to be less toxic in zebrafish embryos and human keratinocyte cells.

Translational PK/PD framework for antibody-drug conjugates to inform drug discovery and development.

(171/200)ADCs represent a transformative class of medicine that combines the specificity of monoclonal antibodies with the potency of highly cytotoxic agents through linkers, aiming to enhance the therapeutic index of cytotoxic drugs. Given the complex molecular structures of ADCs, combining the molecular characteristics of small-molecule drugs and those of large-molecule biotherapeutics, there are several unique considerations when designing nonclinical-to-clinical PK/PD translation strategies.This complexity also demands a thorough understanding of the ADC's components-antibody, linker, and payload-to the overall toxicological, PK/PD, and efficacy profile. ADC development is a multidisciplinary endeavor requiring a strategic integration of nonclinical safety, pharmacology, and PK/PD modeling to translate from bench to bedside successfully.The ADC development underscores the necessity for a robust scientific foundation, leveraging advanced analytical and modeling tools to predict human responses and optimize therapeutic outcomes.This review aims to provide an ADC translational PK/PD framework by discussing unique aspects of ADC nonclinical to clinical PK translation, starting dose determination, and leveraging PK/PD modeling for human efficacious dose prediction and potential safety mitigation.

Bystanders to a Public Health Crisis

Per- and polyfluoroalkyl substances (PFAS) are devastating our food systems and our health. Due to widespread use, these synthetic, long-lasting chemicals, are omnipresent at dangerous levels in our envi-ronment and our homes. Recent studies link even small exposure to PFAS to a host of adverse health outcomes, including cancer, autoim-mune diseases, thyroid disease, liver damage, childhood obesity, infer-tility, and birth defects. Food consumption is a primary route of PFAS exposure. PFAS mi-grate from water, soil, fertilizers, pesticides, and compost into virtually every plant, fish, animal, and animal product, and ultimately (in the greatest concentration) into the consumer. In addition, food pro-cessing equipment, disposable dishes, and containers leach dangerous levels of these chemicals into processed food products, further infusing our every meal with PFAS. Consequently, it is no surprise everything from chocolate cake and microwave popcorn to free range eggs, wildcaught fish, organic milk, and organic kale can harbor staggering quantities of these toxic substances. Despite the widespread presence of these substances and strong sci-entific evidence of their harmful impact on humans, federal regulation of PFAS in food is currently nonexistent. At least fifteen agencies have a mandate to ensure the safety of our food. More is not always better. In the case of regulatory agencies, it can lead to fragmented demand for attention, diffusion of responsibilities, and bureaucratic bystander apathy. This story has played out time and again with other toxic con-taminants like polychlorinated biphenyls (PCBs) and pesticides and is playing out yet again with PFAS. Despite our country’s devastating experience with past contaminants and the unprecedented scientific progress of our time, the federal response to new food safety threats has only become more sluggish and inadequate. This article lays a pathway for change, taking the issue of PFAS food contamination as a case study for the broader dysfunction in the food safety regulatory system. Part II reviews the history of federal food regulation and explores the role that each federal actor in the field plays in ensuring the safety of the food supply. Part III provides back-ground on the chemical and toxicological profile of PFAS and their widespread presence in the environment in general and the food sup-ply in particular. Part IV examines possible approaches to more effec-tive regulation of environmental contaminants in food and proposes a readily available but currently overlooked mechanism for combatting the current public health crisis of PFAS in food. Lastly, Part V cata-logues the expected benefits of the solution and addresses anticipated skepticism. It concludes that the proposed approach can effectively protect consumers from PFAS in food today, while simultaneously gar-nering much needed data to usher in a more permanent solution in the future.

[18F]AlF-NOTA-PCP2: a novel PET/CT tracer for enhanced PD-L1 heterogeneity imaging and comparative analysis with [18F]AlF-NOTA-WL12 in glioblastoma xenografts.

The unsatisfactory efficacy of PD-L1 antibodies in glioblastoma (GBM) is largely due to the temporal and spatial heterogeneity of PD-L1 expression. Molecular imaging can enhance understanding of the tumor immune microenvironment and guide immunotherapy. However, highly sensitive imaging agents capable of effectively visualizing PD-L1 heterogeneity are limited. This study introduces a novel PET tracer, offering improved imaging of PD-L1 heterogeneity in GBM xenografts, with a comparative analysis to [18F]AlF-NOTA-WL12. [18F]AlF-NOTA-PCP2 was synthesized with high purity and its affinity for PD-L1 was characterized using surface plasmon resonance (SPR) and cell binding assays. Its specificity for PD-L1 was evaluated both in vitro using various cell lines and in vivo with GBM xenograft models in NOD/SCID mice. PET/CT imaging was conducted to evaluate the tracer's biodistribution, pharmacokinetics, and ability to quantify tumoral spatial heterogeneity of PD-L1 expression. A focused comparative analysis between [18F]AlF-NOTA-PCP2 and [18F]AlF-NOTA-WL12 was conducted, examining binding affinity, biodistribution, pharmacokinetics, and imaging effectiveness in GBM xenografts. Additionally, human radiation dosimetry estimates compared the safety profiles of both tracers. [18F]AlF-NOTA-PCP2 demonstrated high radiochemical purity (> 95%) and a strong affinity for PD-L1, comparable to [18F]AlF-NOTA-WL12. In vitro and in vivo studies confirmed its specificity for PD-L1, with increased uptake in PD-L1 expressing cells and tumors. Toxicological profiles indicated no significant abnormalities in serum biochemical indicators or major organ tissues. MicroPET/CT imaging showed [18F]AlF-NOTA-PCP2's effectiveness in visualizing PD-L1 expression levels and spatial heterogeneity in GBM xenografts. Comparative studies revealed [18F]AlF-NOTA-PCP2's improved pharmacokinetic properties, including higher tumor-to-blood ratios and lower nonspecific liver uptake, as well as reduced radiation exposure compared to [18F]AlF-NOTA-WL12. [18F]AlF-NOTA-PCP2 distinguishes itself as an exceptionally sensitive PET/CT tracer, adept at non-invasively and accurately quantifying PD-L1 expression and its spatial heterogeneity in tumors, especially in GBM. Its favorable pharmacokinetic properties, safety profile, and high affinity for PD-L1 highlight its potential for enhancing the precision of cancer immunotherapy and guiding individualized treatment strategies. While promising, its clinical translation, especially in brain imaging, necessitates further validation in clinical trials.

The Enigma of Norbormide, a Rattus-Selective Toxicant.

Norbormide (NRB) is a Rattus-selective toxicant, which was serendipitously discovered in 1964 and formerly marketed as an eco-friendly rodenticide that was deemed harmless to non-Rattus species. However, due to inconsistent efficacy and the emergence of second-generation anticoagulants, its usage declined, with registration lapsing in 2003. NRBs' lethal action in rats entails irreversible vasoconstriction of peripheral arteries, likely inducing cardiac damage: however, the precise chain of events leading to fatality and the target organs involved remain elusive. This unique contractile effect is exclusive to rat arteries and is induced solely by the endo isomers of NRB, hinting at a specific receptor involvement. Understanding NRB's mechanism of action is crucial for developing species-selective toxicants as alternatives to the broad-spectrum ones currently in use. Recent research efforts have focused on elucidating its cellular mechanisms and sites of action using novel NRB derivatives. The key findings are as follows: NRB selectively opens the rat mitochondrial permeability transition pore, which may be a factor that contributes to its lethal effect; it inhibits rat vascular KATP channels, which potentially controls its Rattus-selective vasoconstricting activity; and it possesses intracellular binding sites in both sensitive and insensitive cells, as revealed by fluorescent derivatives. These studies have led to the development of a prodrug with enhanced pharmacokinetic and toxicological profiles, which is currently undergoing registration as a novel efficacious eco-sustainable Rattus-selective toxicant. The NRB-fluorescent derivatives also show promise as non-toxic probes for intracellular organelle labelling. This review documents in more detail these developments and their implications.

Multiple drug-delivery strategies to enhance the pharmacological and toxicological properties of Mefenamic acid

ObjectiveTo improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS). MethodsThe in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer. ResultsWhen the PSs were resuspended in water, MefeGAL’s, MA’s and their mixture’s apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS. ConclusionsThese preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.

Unlocking the potential of luteolin: A natural migraine management approach through network pharmacology

BackgroundLuteolin, a natural flavonoid, exhibits antioxidant and anti-inflammatory properties and has been investigated for potential health benefits. Its focus on migraine management arises from its ability to mitigate neuroinflammation, a key factor in migraine attacks. MethodspkCSM and Swiss ADME were employed to assess luteolin's pharmacokinetic properties, revealing challenges such as low water solubility and limited skin permeability. OSIRIS Property Explorer is used to check the toxicity. Ligand binding simulations indicated luteolin's potential to interact with calcitonin gene related peptide proteins, crucial in migraine pathophysiology. DisGeNet identified common targets related to migraine, with subsequent network analysis emphasizing promising targets. Results and DiscussionLuteolin demonstrated good intestinal absorption but faced BBB limitations, suggesting a potential for oral administration but questioning direct brain impact. Nanoformulation was proposed to address solubility challenges, emphasizing the need for in vivo validation. The highest binding affinity with CGRP proteins PDBID: 6PFO (−7.63 kcal/mol) suggested a potential for migraine treatment, requiring empirical confirmation. Enrichment network analysis illustrated luteolin's potential in migraine treatment, emphasizing key targets such as PTGS2, AKT1, ESR1, MMP2, and MMP9. Luteolin shows promise for migraine management, evident in its pharmacokinetic, toxicological profiles, and interactions with CGRP proteins. Challenges like low solubility suggest the need for nanoformulations and empirical validation. Target identification and network analysis offer insights, highlighting potential therapeutic avenues in migraine treatment. ConclusionLuteolin holds promise in migraine management, necessitating further research for translation into effective interventions, considering its neuroprotective potential in broader neurological conditions.

Proarrhythmic drugs, drug levels, and polypharmacy in victims of sudden arrhythmic death syndrome: An autopsy-based study from Denmark

BackgroundSudden arrhythmic death syndrome (SADS), characterized by an unknown or inconclusive cause of death at autopsy, together with a negative or non-lethal toxicology screening, is the most common cause of sudden cardiac death (SCD) in victims under the age of 35. The complete causality of SADS remains unclear, with drugs being a potential risk factor. ObjectiveTo describe the toxicological profiles of SADS victims, focusing on proarrhythmic drugs, drug levels, and polypharmacy. MethodsAll deaths in Denmark from 2000–2019 aged 1–35 years and 2007–2019 aged 36–49 years were examined through death certificates, national registries, and autopsy reports with toxicology screenings. We investigated all sudden unexpected death victims with an autopsy performed, and where cause of death was unknown or inconclusive, including negative or non-lethal drug findings (SADS). ResultsWe identified 477 SADS victims; 313 (66%) had a positive toxicology screening (adjudicated non-lethal), with an average of 2.8 drugs/case. More than half of the SADS victims with a positive toxicology screening had QT-prolonging or brugadogenic drugs present. Polypharmacy was present in 66%, psychotropic polypharmacy in 37%, and QT-prolonging polypharmacy in 22%, with the most frequent overall and QT-prolonging drug combination being an antipsychotic and a psychoanaleptic drug. QT-prolonging drugs were more often present at suprapharmacological levels than non-QT-prolonging drugs. ConclusionA majority of the SADS population had a positive toxicology, with a notably large proportion having proarrhythmic drugs and polypharmacy. This highlights the need for future focus on drugs as a risk factor for SADS.

Comparison of three toxicological profile prediction tools and experimental data, applied on a class of compounds – Vitamin A derivatives

Comparison of three toxicological profile prediction tools and experimental data, applied on a class of compounds – Vitamin A derivatives

Safety assessment of crude aqueous methanol extract of Annona senegalensis stem bark: acute and sub-chronic toxicity studies.

Annona senegalensis Pers., (wild custard apple), is a shrub used traditionally to treat respiratory and skin diseases. Previous studies have demonstrated its anti-malaria, anti-snake envenomation and anti-cancer activities. However, its toxicological profile remains limited, particularly in male and female animals. This study aims to evaluate the safety of crude aqueous methanol extract of Annona senegalensis stem bark (AMEAS) through acute and sub-chronic toxicity studies. The stem bark of A. senegalensis was collected, air-dried, pulverized, and extracted using 70% methanol. Phytochemical screening, elemental analysis, and acute toxicity evaluation were carried out on AMEAS. Sub-chronic toxicity study was conducted on Wistar rats of both sexes at different doses administered orally for 28 days. Elemental analysis revealed the presence of heavy metals and essential mineral elements with the highest contents being calcium (59.88%) and potassium (25.39%). Acute toxicity testing showed no mortality up to 5000 mg/kg, suggesting an LD50 greater than 5000 mg/kg. In the sub-chronic toxicity study, no mortality or significant harmful effects were observed. The blood glucose decreased from 13.68 mMol/L at 250 mg/kg to 10.71 mMol/L at 1000 mg/kg, much lower than the distilled water group (17.06 mMol/L). In conclusion, the extract appeared to be well-tolerated, with no obvious adverse effects. AMEAS is rich in Calcium (Ca) and potassium (K). It has been shown to have LD50 greater than 5000 mg/kg and is assumed to be safe. On repeated use, AMEAS may cause hypoglycemia and weight loss which may be useful in managing diabetes and obesity respectively.

Clinical Profile of Acute Poisoning Cases at a Tertiary Care Hospital in Kashmir, India: A Descriptive Cross Sectional Study

Acute poisoning from a variety of substances is common in every part of the world. The sooner the initial resuscitation, decontamination, and use of specific antidotes, the better the outcome. The main objective of this study was to describe the clinical profile and outcome of poisoning cases admitted to SKIMS Medical college, a tertiary care hospital located in central part of Jammu and Kashmir India. Descriptive cross sectional evaluations were conducted on all cases that were admitted to the hospital’s emergency room over a period of one year from March 2022 to February 2023. The following parameters were examined using data taken from hospital medical records: socioeconomic factors, substances consumed, routes of intake, clinical symptomatology and severity of poisoning.300 patients were included in the study with different poisonings of which 35% were males and 65% were females. The most common form of poisoning was due to pesticides followed by rodenticides and opioid intoxication respectively. Majority of the patients had suicidal intent followed by accidental ingestion reported mainly in children. Few patient required intensive care admissions rest all were managed in general ward depicting mild severity of poisoning in majority of the patients. Three patients were brought dead to hospital secondary to opoid overdose and one patient died in hospital who had pesticide ingestion complicated by ventilator associated pneumonia. The less mortality in this study was likely due to mild severity of poisoning, early gut lavage and easy access to hospital. The effects of poisoning on the human body are negative regardless of the agents or method used and this has an impact on the treatment and outcome. Due consideration must be given to clinical, toxicological and epidemiological profiles. Therefore precise and prompt diagnosis, adequate treatment and effective preventative efforts are required. This study highlighted the importance of awareness and for the establishment of poison information centre for the better management and prevention of all poisoning cases.

Pontederia crassipes Biosynthesised Silver Nanoparticles (AgNPs), Characterisation and Activity against Multidrug-Resistant Microbes

Introduction: Pontederia crassipes (water hyacinth) has been singled out as one of the major causes of enormous economic and ecological losses to tropical water systems and habitats. Almost impossible to eradicate, the ominous species is characterized by rapid multiplication, giving rapid and extensive spread that can choke entire rivers and water bodies. However, vast, diverse bioactive secondary metabolites are found in P crassipes which exhibit an expansive assortment of antibacterial properties used in traditional medicine. The rapid emergence of Multi Drug Resistant (MDR) pathogens to common drugs is a pandemic of global proportions. Global health institutions are calling for a coordinated, global action plan to develop new biomaterials to combat the rising threat by MDR strains and improve treatment outcomes and save lives. This study proposes consumption of the water hyacinth lily species through a novel, material biosynthesis approach not only to manage the aquatic infestation but to develop advanced multifunctional, anti-microbial Silver nanoparticles through bio-reduction and capping of Silver salts targeted at MDR microbes. Methodology: After screening for active phytoconstituents of P.crassipes. The Biosynthesis of Novel AgNPs mediated by phenolic, antibacterial lyophilized hydro-ethanolic extracts from P crassipes as both bioreduction and capping agents was investigated. The resultant AgNPs characteristics, toxicological profiles and the antibacterial effects on 10 common microbes including MDR bacterial strains were evaluated. Observations and Results: TEM revealed that cubic and spherical nanometric AgNPs structures were successfully synthesized with particle size range from 10-60nm. With an average zone of inhibition of 29mm and an MIC of 6.25 µg/ml .The nanoparticles were efficacious against selected MDR strains and common infectious bacterial strains tested. In-vivo acute oral toxicity evaluations confirmed the safety of P crassipes. Conclusion: Biogenic P.crassipes mediated AgNPs are feasible, safe and efficacious and have immense potential for optimization into efficient broad spectrum MDR antibacterial agents.b

ProTox 3.0: a webserver for the prediction of toxicity of chemicals.

Interaction with chemicals, present in drugs, food, environments, and consumer goods, is an integral part of our everyday life. However, depending on the amount and duration, such interactions can also result in adverse effects. With the increase in computational methods, the in silico methods can offer significant benefits to both regulatory needs and requirements for risk assessments and the pharmaceutical industry to assess the safety profile of a chemical. Here, we present ProTox3.0, which incorporates molecular similarity and machine-learning models for the prediction of 61 toxicity endpoints such as acute toxicity, organ toxicity, clinical toxicity, molecular-initiating events (MOE), adverse outcomes (Tox21) pathways, several other toxicological endpoints and toxicity off-targets. All the ProTox 3.0 models are validated on independent external sets and have shown strong performance. ProTox envisages itself as a complete, freely available computational platform for in silico toxicity prediction for toxicologists, regulatory agencies, computational chemists, and medicinal chemists. The ProTox 3.0 webserver is free and open to all users, and there is no login requirement and can be accessed via https://tox.charite.de. The web server takes a 2D chemical structure as input and reports the toxicological profile of the compound for each endpoint with a confidence score and overall toxicity radar plot and network plot.

“GC-MS profiling, sub-acute toxicity study and total phenolic and flavonoid content analysis of methanolic leaf extract of Schima wallichii (D.C.) Korth-a traditional antidiabetic medicinal plant”

Ethnopharmacological relevanceSchima wallichii (D.C.) Korth is traditionally used in Manipur, India for treatment of diabetes and hypertension. However, there is no data reported regarding safety profile of this medicinal plant upon repeated per oral administration over a period of time. Aim of the studyIn the current study phytochemical profile, toxicological profile and total phenolic and flavonoid compound content of Schima wallichii leaves extract were evaluated. Materials and methodsGas chromatography coupled to mass spectrometry was performed for chemical profiling by using Gas Chromatography-Mass Spectrometry/Mass Spectrometry (GC-MS/MS), Shimadzu, TQ8040 system. A 28 days sub-acute toxicity study was carried out using albino Wistar rats by administering 3 different doses (200, 400 and 800 mg/kg body weight per oral) of methanol leaves extract. Changes in body weights were recorded weekly. Serum biochemical parameters were estimated as well as blood-cell count was done to check the effect of extract on haematopoietic system. Histopathology of vital organs viz. kidney, heart, brain, liver was performed to find any pathological indications. Since, liver is main the site for xenobiotic metabolism, estimation of the level of glutathione, catalase and lipid peroxidation were done. Further, total phenolic and flavonoid compound content estimation was performed for the leaves extract. ResultsGC-MS revealed 14 major compounds with area percentage >1% of which quinic acid, n-Hexadecanoic acid, 9,12,15-Octadecatrienoic acid, (Z,Z,Z)-, Octatriacontyl trifluoroacetate, are three major compounds. No mortality was observed after the treatment with extract. Blood-cell count and biochemical parameters didn't show significant deviation as compared to control group. Histopathology study of vital organs viz. (liver, kidney, heart and brain) showed normal cellular construction comparing to control group. There was no sign of membrane lipid peroxidation, depletion of catalase level and glutathione level in liver. The result demonstrates that NOAEL (no-observed-adverse-effect levels) in the sub-acute toxicity was above 800 mg/kg. The leaves extract showed significant total phenol and flavonoid content. ConclusionThe present study revealed that Schima wallichii possessed important bioactive compounds with therapeutic values. The plant was safe for consumption after repeated high doses administration in rats and possesses significant amount of total phenol and flavonoid content.

Unveiling structural features, chemical reactivity, and bioactivity of a newly synthesized purine derivative through crystallography and computational approaches

We introduce the synthesis and characterization of a novel purine derivative, 2-amino-6‑chloro-N,N-diphenyl-7H-purine-7-carboxamide. X-ray crystallography was utilized to elucidate its molecular and crystal structure. A comprehensive crystal packing analysis uncovered a network of diverse intermolecular interactions, including classical and unconventional hydrogen bonding. Remarkably, a unique halogen···π (C—Cl···π(ring)) interaction was identified and theoretically analyzed within a multi-approach quantum mechanics (QM) framework, revealing its lone-pair⋯π (n→π*) nature. Furthermore, insights into the electronic and chemical reactivity properties are provided by means of Conceptual Density Functional Theory (CDFT) at wB97X-D/aug-cc-pVTZ level. The compound's drug-likeness, pharmacokinetics, and toxicology profiles are assessed using ADMETlab 2.0. Finally, molecular docking simulations were conducted to evaluate its bioactivity as a potential cyclooxygenase-2 (COX-2) inhibitor. This study significantly advances our understanding of purine structure and reactivity, offering valuable insights for the development of targeted purine-based COX-2 inhibitors and anticancer therapeutics.

Design and Evaluation of NSAID Derivatives as AKR1C3 Inhibitors for Breast Cancer Treatment through Computer-Aided Drug Design and In Vitro Analysis.

Breast cancer is a major global health issue, causing high incidence and mortality rates as well as psychological stress for patients. Chemotherapy resistance is a common challenge, and the Aldo-keto reductase family one-member C3 enzyme is associated with resistance to anthracyclines like doxorubicin. Recent studies have identified celecoxib as a potential treatment for breast cancer. Virtual screening was conducted using a quantitative structure-activity relationship model to develop similar drugs; this involved backpropagation of artificial neural networks and structure-based virtual screening. The screening revealed that the C-6 molecule had a higher affinity for the enzyme (-11.4 kcal/mol), a lower half-maximal inhibitory concentration value (1.7 µM), and a safer toxicological profile than celecoxib. The compound C-6 was synthesized with an 82% yield, and its biological activity was evaluated. The results showed that C-6 had a more substantial cytotoxic effect on MCF-7 cells (62%) compared to DOX (63%) and celecoxib (79.5%). Additionally, C-6 had a less harmful impact on healthy L929 cells than DOX and celecoxib. These findings suggest that C-6 has promising potential as a breast cancer treatment.

SEDATIVE EFFECT OF U-49900 (3,4-DICHLORO-N-(2-(DIETHYLAMINO)CYCLOHEXYL)-N-METHYL-BENZAMIDE) IN ADULT ZEBRAFISH

U-49900 is a chemical analogue of a selective μ-opioid receptor agonist U-47700. Despite the growing abuse of synthetic opioids, including U-49900, its psychopharmacological and toxicological profiles remain poorly understood. The zebrafish (Danio rerio) is a promising model organism in neuroscience, and is often used for the psychopharmacological evaluation of neurotropic drugs. The psychopharmacological profile of U-49900 was evaluated here in adult zebrafish at 1, 5, 10 and 25 mg/l (water immersion) tested in the novel tank test. U-49900 at 25 mg/l for 20 min reduces the distance traveled and the number of top entries in the novel tank test (p0.001 vs. control group), but unalters other parameters in this test. Overall, the sensitivity of zebrafish to synthetic non-fentanyl opioids like U-49900 suggests the possibility of developing high-throughput screening platforms for finding effective therapies for pathological conditions caused by synthetic opioids.

Evaluation of the safety and quality of Brazil nuts (Bertholletia excelsa) using the tools of dna sequencing technology and aflatoxin profile.

Brazil nuts (BNs) result from sustainable extraction and are widely exploited in the Amazon region. Due to the production characteristics in the forest and the nutritional characteristics of these nuts, the occurrence of fungal contamination and the presence of aflatoxins are extensively discussed in the literature as a great aspect of interest and concern. This study aims to evaluate the microbial profile through DNA sequencing and amplification of 16S and ITS genes for bacterial and fungal analysis, respectively, and the presence of mycotoxins using high-performance liquid chromatography with fluorescence detection (HPLC-FD) from different fractions of the nuts processed. The BN samples, harvest A (HA) and harvest B (HB), from two different harvests were collected in an extractive cooperative in the Amazon region for microbiological analysis (from DNA extraction and amplification of 16S genes, bacteria analysis, and ITS for fungi) and mycotoxins (aflatoxins AFB1, AFB2, AFG1, and AFG2) using HPLC-FD/KobraCell®. The samples showed a very different microbiome and aflatoxin profile. Genera such as Rothia (HA) and Cronobacter (HB) were abundant during the analysis of bacteria; as for fungi, the genera Aspergillus, Fusarium, Penicillium, and Alternaria were also considered prevalent in these samples. Soil microorganisms, including those pathogenic and related to inadequate hygienic-sanitary production practices, as well as aflatoxins, were found in the samples. However, they were within the established limits permitted by Brazilian legislation. Nuts have a diverse microbiota and are not restricted to fungi of the genus Aspergillus. The microbiological and toxicological profile can vary significantly within the same nut in the same extraction region and can be exacerbated by global climate changes. Therefore, it is necessary to advance sanitary educational actions by applying good production practices and inspection programs to ensure the sustainability and quality of the BN production chain.

Toxicological profile and potential health concerns through metals and trace elements exposure in brick kiln workers from Lahore, Pakistan.

This study examined levels of lead (Pb), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), and arsenic (As) in blood, hair, and nails of 18 brick kiln workers from three brick kiln units located around a metropolitan city, Lahore, Pakistan. All the trace elements except Hg and As were detected in the studied matrices of Brick kiln workers. In general, brick kiln workers reflect the highest concentration of Pb, followed by Cd, Cr, and Cu. Of the pollutants analyzed, Pb has the highest mean (min-max) concentrations at 0.35 (0.09-0.65) in blood(μg/mL), 0.34 (0.14-0.71) in hairs(μg/g), and 0.44 (0.32-0.59) in nails(μg/g) of brick kiln workers. Following Pb, the trend was Cd 0.17 (0.10-0.24), Cu 0.11(0.03-0.27), and Cr 0.07 (0.04-0.08) in blood(μg/mL), followed by Cr 0.11(0.05-0.20), Cd 0.09 (0.03-0.13), and Cu 0.08 (0.04-0.16) in hairs(μg/g) and Cu 0.16 (0.05-0.36), Cd 0.13 (0.11-0.17), and Cr 0.10 (0.05-0.14) in nails(μg/g) respectively. Relatively higher concentrations of metals and other trace elements in blood depicts recent dietary exposure. The difference of trace elements except Pb was non-significant (P > 0.05) among studied matrices of workers as well as between Zigzag and traditional exhaust-based brick kilns. The concentrations of Pb, Cd and Cr in blood of brick kilns workers are higher than the values reported to cause health problems in human populations. It is concluded that chronic exposure to metals and other trace elements may pose some serious health risks to brick kiln workers which needs to be addressed immediately to avoid future worst-case scenarios.

Gold Nanoparticles (AuNPs)-Toxicity, Safety and Green Synthesis: A Critical Review.

In recent years, the extensive exploration of Gold Nanoparticles (AuNPs) has captivated the scientific community due to their versatile applications across various industries. With sizes typically ranging from 1 to 100 nm, AuNPs have emerged as promising entities for innovative technologies. This article comprehensively reviews recent advancements in AuNPs research, encompassing synthesis methodologies, diverse applications, and crucial insights into their toxicological profiles. Synthesis techniques for AuNPs span physical, chemical, and biological routes, focusing on eco-friendly "green synthesis" approaches. A critical examination of physical and chemical methods reveals their limitations, including high costs and the potential toxicity associated with using chemicals. Moreover, this article investigates the biosafety implications of AuNPs, shedding light on their potential toxic effects on cellular, tissue, and organ levels. By synthesizing key findings, this review underscores the pressing need for a thorough understanding of AuNPs toxicities, providing essential insights for safety assessment and advancing green toxicology principles.