Maximum Toxicity Research Articles

The vacuolar anti-Pseudomonal activity of neutrophil primary granule peptidyl-arginine deiminase enzymes.

The role of neutrophils in host defense involves several cell processes including phagocytosis, degranulation of antimicrobial proteins, and the release of neutrophil extracellular traps (NETs). In turn, dysregulated cell activity is associated with the pathogenesis of airway and rheumatic diseases, in which neutrophil-derived enzymes including peptidyl-arginine deiminases (PADs) play a role. Known physiological functions of PADs in neutrophils are limited to the activity of PAD isotype 4 in histone citrullination in NET formation. The aim of this study was to extend our knowledge on the role of PADs in neutrophils and, specifically, bacterial killing within the confines of the phagocytic vacuole. Human neutrophils were fractionated by sucrose gradient ultracentrifuge and PADs localized in subcellular compartments by Western blot analysis. Direct interaction of PADs with Pseudomonas aeruginosa (P. aeruginosa) was assessed by flow cytometry and Western blot overlay. The participation of neutrophil PAD2 and PAD4 in killing of P. aeruginosa was assessed by inclusion of PAD-specific inhibitors. In vitro, bactericidal activity of recombinant human PAD2 or PAD4 enzymes against P. aeruginosa was determined by enumeration of colony-forming units (CFU). Together with neutrophil elastase (NE), PAD2 and PAD4 were localized to primary granules and, following activation with particulate stimuli, were degranulated in to the phagocytic vacuole. In vitro, PAD2 and PAD4 bound P. aeruginosa (p = 0.04) and significantly reduced bacterial survival to 49.1 ± 17.0 (p < 0.0001) and 48.5 ± 13.9% (p < 0.0001), respectively. Higher antibacterial activity was observed at neutral pH levels with the maximum toxicity at pH 6.5 and pH 7.5, comparable to the effects of neutrophil bactericidal permeability increasing protein. In phagosomal killing assays, inclusion of the PAD2 inhibitor, AFM-30a, or PAD4 inhibitor, GSK484, significantly increased survival of P. aeruginosa (AFM-30a, p = 0.05; and GSK484, p = 0.0079). Results indicate that PAD2 and PAD4 possess antimicrobial activity and are directly involved in the neutrophil antimicrobial processes. This study supports further research into the development of PAD-based antimicrobials.

Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy.

226Ac (t½ = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. 226Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an invivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, 226Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical 226Ac-radiopharmaceutical for its theranostic efficacy and present the first 226Ac-targeted α-therapy study. Methods: 226Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [226Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. Results: We present quantitative SPECT images of the invivo biodistribution of [226Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [226Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. Conclusion: This study highlights the theranostic potential of 226Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched 225Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of 226Ac-radiopharmaceuticals.

Mitigation of methylglyoxal-induced hepatotoxicity by Boerhavia diffusa L. aerial extract: Insights from cellular and animal models

BackgroundBoerhavia diffusa (Punarnava), is a perennial herb with a long-standing reputation for its antioxidative and anti-inflammatory properties, dating back to ancient times. Methylglyoxal is an advanced glycation end-product, known to be toxic in liver cell line as well as in mice model. Our objective is to illustrate the protective action of punarnava aerial extracts in methylglyoxal-induced hepatotoxicity in cell line and mice model. MethodsPunarnava aerial parts were collected and different solvent extracts were prepared in methanol, dichloromethane and hexane by maceration followed by their LCMS/MS characterization, determination of total phenolic, total flavonoid contents and antioxidant activity by DPPH reagent. Cell viability of the extracts and methylglyoxal was assessed using different cell lines. In vitro protective effect of punarnava methanolic extract (PME) against methylglyoxal was evaluated by cell migration assay, NO and ROS production assays and Oil Red O staining in HepG2 cell line. BALB/c mice were pretreated with Punarnava methanolic extract (200 mg/kg and 400 mg/kg) for seven days followed by 290 mg/kg methylglyoxal administration for 6 hrs to induce hepatotoxicity. Serum glucose, AST, ALT, ALP and GSH level were checked and liver histopathological damages were identified. ResultsAmong the three Punarnava extracts, PME possessed maximum antioxidant, total phenolic and flavonoid content as well as least cytotoxic to liver cell line. Methylglyoxal showed maximum toxicity in HepG2 cells with IC50 (50 % inhibitory concentration) 3 µM. PME confers protection against methylglyoxal-induced cytotoxicity by decreasing ROS, promoting cell migration and preventing loss of cell viability. No significant change was observed in NO production and Oil Red O staining. PME-treated mice showed decrease in liver ALP levels and glucose with intact cellular morphology compared to hepatocyte steatosis and nuclear degeneration in methylglyoxal-treated group. DiscussionsIndigenous herb Punarnava is effective in protecting liver cells from damage induced by the glycolytic byproduct, methylglyoxal.

Dynamics of Phytotoxicity Indicators of Ordinary Chernozem when it is Contaminated with Silver Nanoparticles

The dynamics of phytotoxicity indicators (germination and length of radish roots) of ordinary chernozem when contaminated with silver nanoparticles was studied. In laboratory conditions, ordinary chernozem was contaminated with silver nanoparticles (1, 10 and 100 mg/kg) for 3, 10, 30, 90 and 180 days. It was found that the more silver nanoparticles were introduced into the soil, the greater the decrease in germination and length of radish roots. There was no restoration of germination and length of radish roots with an increase in the period from the moment of contamination. In this study, the maximum toxic period from the moment of contamination for each indicator was identified by its sensitivity to silver nanoparticles and informativeness. The maximum toxicity of silver nanoparticles in relation to the root length and germination of radishes was noted on the 10th and 30th days, respectively. The results can be used to assess the phytotoxicity of soils contaminated with silver nanoparticles.

SEVUparin as a potential Adjunctive Treatment in children with severe malaria: A phase I trial safety and dose finding trial (SEVUSMAART).

Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission (<24hours). Lactic acidosis, largely due to impairment of the microcirculatory flow due to parasite sequestration, is a main risk factor for poor outcome. There are no adjuvant treatments for severe malaria that target this complication. Sevuparin, a heparin-like drug, binds to Plasmodium falciparum erythrocyte membrane protein blocking merozoite invasion, preventing cytoadherence and transiently de-sequestering infected erythrocytes. Leading to improved microcirculatory flow by reversing/preventing parasite sequestration. If given early during admission this could result in improvements in outcomes. Sevuparin has been shown to be safe and well tolerated in adults with only some mild transient effects on activated partial thromboplastin time (APTT) were reported, without clinical consequences. A Phase I trial designed to provide data on safety, dosing, feasibility of sevuparin as an adjuvant therapy in Kenya and Zambian children with severe malaria complicated by lactic acidosis (> 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient's APTT results using standard methods. The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021).

Polyethylene Terephthalate Microplastics Generated from Disposable Water Bottles Induce Interferon Signaling Pathways in Mouse Lung Epithelial Cells.

Microplastics (MPs) are present in ambient air in a respirable size fraction; however, their potential impact on human health via inhalation routes is not well documented. In the present study, methods for a lab-scale generation of MPs from regularly used and littered plastic articles were optimized. The toxicity of 11 different types of MPs, both commercially purchased and in-lab prepared MPs, was investigated in lung epithelial cells using cell viability, immune and inflammatory response, and genotoxicity endpoints. The underlying mechanisms were identified by microarray analysis. Although laborious, the laboratory-scale methods generated a sufficient quantity of well characterized MPs for toxicity testing. Of the 11 MPs tested, the small sized polyethylene terephthalate (PETE) MPs prepared from disposable water bottles induced the maximum toxicity. Specifically, the smaller size PETE MPs induced a robust activation of the interferon signaling pathway, implying that PETE MPs are perceived by cells by similar mechanisms as those employed to recognize pathogens. The PETE MPs of heterogenous size and shapes induced cell injury, triggering cell death, inflammatory cascade, and DNA damage, hallmark in vitro events indicative of potential in vivo tissue injury. The study establishes toxicity of specific types of plastic materials in micron and nano size.

Effect of biochar and iron ore tailing waste amendments on cadmium bioavailability in a soil and peanut seedling system.

Biochar and iron ore tailing waste have been widely separately applied for remediation of various contaminants, but the remediation effect of their combination on cadmium (Cd) pollution is unclear. In this study, the peanut biochar (BC), thermally activated iron ore tailing waste (TS), and the products of the co-pyrolysis of peanut shell and iron ore tailing waste (TSBC) were prepared for stabilizing Cd and reducing its bio-accessibility in soil and peanut seedling system. Present amendments enhanced soil pH, cation exchange capacity, electrical conductivity, and organic carbon content. The application of BC, TS, and TSBC led to decreases in acid-extractable Cd proportion of 2.2-8.81%, 2.43-7.20%, and 7.84-11.57%, respectively, and increases in the residual Cd proportion of 3.48-8.33%, 3.27-11.50%, and 9.02-13.45%, respectively. There were no significant differences in Cd accumulation in peanut roots due to three amendments treatments, especially at low Cd concentrations (i.e., Cd concentration of 0, 1, and 2mg·kg-1), and with a relatively small reduction (2.16-9.05%) in root Cd accumulation under the high Cd treatments of 5 and 10mg·kg-1. The Cd concentrations in seedling roots were significantly positively related to the acid-extractable Cd fraction, with a Pearson correlation coefficient of r = 0.999. The maximum toxicity mitigating effects were found in TSBC treatment, with increases in the ranges of 9.80-17.58% for fresh weight, 5.59-14.99% for dry weight, 5.16-10.17% for plant height, 5.96-10.34% for root length, 5.43-21.67% for chlorophyll a content, 17.17-71.28% for chlorophyll b content, and 13.11-39.60% for carotenoid content in peanut seedlings. Therefore, TSBC is a promising amendment for minimizing Cd contamination in peanut crops and utilizing industrial solid waste materials efficiently.

Influence of multi-stressor combinations of pCO2, temperature, and salinity on the toxicity of Heterosigma akashiwo (Raphidophyceae), a fish-killing flagellate.

Climate change and global warming have led to more frequent harmful algal blooms in the last decade. Among these blooms, Heterosigma akashiwo, a golden-brown phytoflagellate, is one of the 40 species with a high potential to form harmful blooms, leading to significant fish mortality. Climate change leads to rising atmospheric and ocean temperatures. These changes, along with altered rainfall patterns and meltwater input, can cause fluctuations in ocean salinity. Elevated atmospheric carbon dioxide (CO2) levels increase water acidity as oceans absorb CO2. This study investigated the effects of temperature, salinity, and CO2 levels on lipid production, hemolytic activity, and toxicity of H. akashiwo using the design of experiment approach, which can be used to investigate the effect of two or more factors on the same response simultaneously in a precise manner with fewer experiments and materials but in a larger region of the factor space. The lipid content was measured using a high-throughput Nile Red method, and the highest level of lipid content was detected at 25°C, a salinity of 30, and a CO2 concentration of 400 ppm. Hemolytic activity was assessed using rabbit blood erythrocytes in a 96-well plate, and the optimal conditions for achieving the highest hemolytic activity were determined at 15°C, a salinity of 10, and a CO2 concentration of 400 ppm. As the chemical structure of the toxin is not known, we used the toxicity against the cell line RTgill-W1 as the cell toxicity proxy. The maximum toxicity was identified at 15°C, a salinity of 10, and a CO2 level of 700 ppm.

Comparative Evaluation of Cytotoxicity of Zinc Oxide Nanoparticles Mixed With Herbal Extract as an Intracanal Medicament: A Zebrafish Model Study.

Objective In this study, zebrafish embryos are used to study the cytotoxic effects of a novel intracanal medication (ICM) based on zinc oxide nanoparticles (ZnO NPs) loaded with polyherbal extracts (Azadirachta indica and Solanum xanthocarpum). Material and methods In the present study, a green and sustainable method was employed for the synthesis of ZnO NPs mixed with bark and seed extracts of Azadirachta indica and Solanum xanthocarpum to be used as a polyherbal ICM. Formulation of ZnO NPs was confirmed with color change in mixture produced upon dissolving zinc acetate dihydrate in distilled water followed by slow addition of sodium hydroxide solution and herbal extracts. The effects of these green synthesized ZnO NPs were evaluated through a zebrafish embryo toxicity test. Embryos were exposed to different concentrations (25, 50, and 100 µg/mL) of synthesized experimental doses of ZnO NP and compared with the control embryos. Toxicological endpoints, such as the zebrafish embryo's survival rate, hatching rate, and heart rate, were noted and described. Results A concentration-dependent increase in mortality rate and hatching delay followed by declined heart rate was observed in green synthesized ZnO NP-treated embryos. The maximum toxicity was observed with an increase in the concentration of 100 µg/mL of the experimental dose, and at a low concentration of 25 µg/mL, it does not effectively show any developmental alteration in zebrafish embryos. Conclusion A novel polyherbal ICM loaded with ZnO NPs exhibited a dose-dependent effect on the heart rate, hatching, and mortality rate of the embryos. At optimal concentrations, the medication demonstrated minimal developmental malformations and cytotoxic effects, indicating its safety for use. However, increasing concentrations of the medication resulted in severe developmental malformations.

Study APV20002: Safety and Efficacy Results Through Week 684 for Pediatric Participants Living with HIV-1 Treated with Ritonavir-Boosted Fosamprenavir Oral Solution-Based Antiretroviral Therapy.

APV20002 was a multicenter, international, open-label study that began in 2003 investigating the pharmacokinetics, efficacy, and safety of ritonavir-boosted fosamprenavir (FPV/r) oral solution (OS) in combination with nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) in participants living with HIV-1 aged 4 weeks to <2 years with a primary endpoint at Week 48 (48W). Participants in APV20002 could continue in the study post-48W until FPV OS was locally available in their countries. Children were required to discontinue after reaching >39 kg or if FPV OS had no clinical benefit. Fifty-nine participants were enrolled; 5/59 received a single FPV OS visit for pharmacokinetic determinations. Most (38/54; 70%) were antiretroviral experienced; 39/59 participants had >48 weeks on treatment, 4/39 of whom discontinued after 48 weeks due to an adverse event (AE). At 48W, 88% of participants had HIV-1 RNA <400 copies/mL by Observed analysis; the proportion with HIV-1 RNA <400 copies/mL remained high (84%-100%) through Week 684. The median CD4+ cell count was 1,235 cells/mm3 [n = 51] at baseline, 1,690 cells/mm3 (n = 41) at Week 48, and 1,280 cells/mm3 (n = 21) at Week 180. From baseline to Week 684, 54/59 (92%) participants had ≥1 treatment-emergent AE regardless of causality; 42/59 (71%) had a treatment-emergent grade 2-4 AE, predominantly maximum toxicity: grade 2; 21/59 (36%) and 21/59 (36%) had severe or grade 3/4 AEs. From baseline to Week 684, 14/54 (26%) participants met virologic failure (VF) criteria, 9/14 before 48W. HIV from 1/9 VFs through 48W developed treatment-emergent reduced susceptibility to FPV and 1/9 to lamivudine/emtricitabine. Post-48W, 4/5 participants with VF had phenotype results; all were still susceptible to all study drugs at VF. In conclusion, FPV OS-based ART was efficacious and generally well tolerated in this long-running pediatric study through 684 weeks of treatment, with a safety profile consistent with experience in adults and older children.

Phytotoxicity of Two Bauhinia Species on Four Triticum aestivum Varieties in Laboratory Bioassay

Tree–crop interaction studies help to determine the effects of trees on the production and yield of agricultural crops and could help indecisions on suitable crops and tree combinations to increase the overall production from agroforestry systems. Different varieties of agricultural crops might show different responses against the phytotoxic effects of Bauhinia species. This study was conducted to observe the phytotoxicity of two Bauhinia spp., i.e., Bauhinia retusa and Bauhinia variegata, on some Triticum aestivum varieties, i.e., VL-892, VI-829, VL-616, UP-2572, and UP-1109.The leaves and bark of these two species were harvested from the natural population for these experiments. On average, germination and radicle and plumule length of wheat varieties were significantly (p &gt; 0.05) reduced by the leaf and bark extracts of both Bauhinia species. The effect of leaf and bark extracts of both Bauhinia species on seed germination percent of different wheat varieties revealed that the bark and leaf extracts showed maximum toxicity for germination percentage, and minimum influence was observed in radicle and plumule length. However, bark extracts were more toxic as compared to leaf extracts. Under leaf and bark extract concentrations, the VL 829 wheat variety showed stimulatory effects in germination and radicle and plumule growth under both Bauhinia species. On average, radicle and plumule growth of the test crop was increased with an increasing concentration of leaf and bark extract of B. variegata up to 50%, and thereafter, a decrease in radicle and plumule length was recorded. The VL 829 and UP 1109 varieties showed the lowest allelopathic effects and could be grown under both Bauhinia species with minimum yield loss.

The Evaluation of Toxicity Effects of Synthetic Volatile Compounds and Essential Oils on Callosbruchus maculatus L. and its Biology

The biology studies and contact toxicity of synthetic volatile compounds, namely Propionic acid and Benzaldehyde, and essential oils namely, Ocimum basilicum and Mentha piperita, and their different possible combinations evaluated against Callosobruchus maculatus and were carried out at the Department of Entomology, Annamalai University to develop an economically viable and effective alternative to chemical insecticides to manage the stored product insect pests. In the biology study, the egg period was 5±0.07 days. The larval and pupal period together was 21.24±0.67. The total development period recorded from the day of oviposition to adult emergence was 35.03±0.35 days. The maximum contact toxicity was observed in Propionic acid + Benzaldehyde with 8.73 µl LC50. Therefore, in addition to being incorporated into the storage pest management to prevent the development of resistance, combinations of essential oils and synthetic volatiles, such as propionic acid and benzaldehyde, could be used as an alternative to the chemical fumigants that are mostly used to control pests of stored products.

In Silico Pharmacokinetics, Molecular Docking and Molecular Dynamics Simulation Studies of Nucleoside Analogs for Drug Discovery- A Mini Review.

Nucleoside analogs have been widely used as antiviral, antitumor, and antiparasitic agents due to their ability to inhibit nucleic acid synthesis. Adenosine, cytidine, guanosine, thymidine and uridine analogs such as didanosine, vidarabine, remdesivir, gemcitabine, lamivudine, acyclovir, abacavir, zidovusine, stavudine, and idoxuridine showed remarkable anticancer and antiviral activities. In our previously published articles, our main intention was to develop newer generation nucleoside analogs with acylation-induced modification of the hydroxyl group and showcase their biological potencies. In the process of developing nucleoside analogs, in silico studies play an important role and provide a scientific background for biological data. Molecular interactions between drugs and receptors followed by assessment of their stability in physiological environments, help to optimize the drug development process and minimize the burden of unwanted synthesis. Computational approaches, such as DFT, FMO, MEP, ADMET prediction, PASS prediction, POM analysis, molecular docking, and molecular dynamics simulation, are the most popular tools to culminate all preclinical study data and deliver a molecule with maximum bioactivity and minimum toxicity. Although clinical drug trials are crucial for providing dosage recommendations, they can only indirectly provide mechanistic information through researchers for pathological, physiological, and pharmacological determinants. As a result, in silico approaches are increasingly used in drug discovery and development to provide mechanistic information of clinical value. This article portrays the current status of these methods and highlights some remarkable contributions to the development of nucleoside analogs with optimized bioactivity.

From growth inhibition to ultrastructural changes: Toxicological assessment of lambda cyhalothrin and fosetyl aluminium against Bacillus subtilis and Pseudomonas aeruginosa

In modern agricultural practices, agrochemicals and pesticides play an important role in protecting the crops from pests and elevating agricultural productivity. This strategic utilization is essential to meet global food demand due to the relentless growth of the world's population. However, the indiscriminate application of these substances may result in environmental hazards and directly affect the soil microorganisms and crop production. Considering this, an in vitro study was carried out to evaluate the pesticides' effects i.e. lambda cyhalothrin (insecticide) and fosetyl aluminum (fungicide) at lower, recommended, and higher doses on growth behavior, enzymatic profile, total soluble protein production, and lipid peroxidation of bacterial specimens (Pseudomonas aeruginosa and Bacillus subtilis). The experimental findings demonstrated a concentration-dependent decrease in growth of both tested bacteria, when exposed to fosetyl aluminium concentrations exceeding the recommended dose. This decline was statistically significant (p < 0.000). However, lambda cyhalothrin at three times of recommended dose induces 10% increase in growth of Pseudomonas aeruginosa (P. aeruginosa) and 76.8% decrease in growth of Bacillus subtilis (B. subtilis) respectively as compared to control. These results showed the stimulatory effect of lambda cyhalothrin on P. aeruginosa and inhibitory effect on B. subtilis. Pesticides induced notable alterations in biomarker enzymatic assays and other parameters related to oxidative stress among bacterial strains, resulting in increased oxidative stress and membrane permeability. Generally, the maximum toxicity of both (P. aeruginosa and B. subtilis) was shown by fosetyl aluminium, at three times of recommended dose. Fosetyl aluminium induced morphological changes like cellular cracking, reduced viability, aberrant margins and more damage in both bacterial strains as compared to lambda cyhalothrin when observed under scanning electron microscope (SEM). Conclusively the, present study provide an insights into a mechanistic approach of pyrethroid insecticide and phosphonite fungicide induced cellular toxicity towards bacteria.

Bis-arylidene oxindoles for colorectal cancer nanotherapy

Oxindoles are potent anti-cancer agents and are also used against microbial and fungal infections and for treating neurodegenerative diseases. These oxindoles are earlier established as estrogen receptor (ER)-targeted agents for killing ER (+) cancer cells. Our previously developed bis-arylidene oxindole, Oxifen (OXF) exhibits effective targeting towards ER (+) cancer cells which has a structural resemblance with tamoxifen. Herein, we have designed and synthesized few structural analogues of OXF such as BPYOX, ACPOX and ACPOXF to examine its cytotoxicity in different cancer as well as non-cancer cell lines and its potential to form self- aggregates in aqueous solution. Among these series of molecules, ACPOXF showed maximum toxicity in colorectal cancer cell line which are ER (-) but it also kills non-cancer cell line HEK-293, thereby reducing its cancer cell selectivity. Incidentally, ACPOXF exhibits self-aggregation, without the help of a co-lipid with nanometric size in aqueous solution. ACPOXF self-aggregate was co-formulated with glucocorticoid receptor (GR) synthetic ligand, dexamethasone (Dex) (called, ACPOXF-Dex aggregate) which could selectively kill ER (-) colorectal cancer cells and also could increase survivability of colon-tumour bearing mice. ACPOXF-Dex induced ROS up-regulation followed by apoptosis through expression of caspase-3. Further, we observed upregulation of antiproliferative factor, p53 and epithelial-to-mesenchymal (EMT) reversal marker E-cadherin in tumour mass. In conclusion, a typical structural modification in ER-targeting Oxifen moiety resulted in its self-aggregation that enabled it to carry a GR-ligand, thus broadening its selective antitumor property especially as colon cancer therapeutics.

Qualitative Phytochemical Screening, Fatty Acid Profile and Biological Studies of the Bark of &lt;i&gt;Mallotus nudiflorus&lt;/i&gt; (Pitali) Plant

In the present study, the Mallotus nudiflorus (L.) plant has been taken to determine the in-vitro analysis to find out the therapeutic value. The bioassays of the raw extract of methanol of bark of M. nudiflorus and by Kupchan’s extraction method collecting n-Hexane (HEX), Dichloromethane (DCM), Chloroform (CHCl3), Ethylacetate (EA) and Aqueous (AQ) fractions were scrutinized to find out its therapeutic value. The findings of phytochemical screening of the methanol extract of barks revealed the presence of several secondary metabolites. By using the GC-FID method the result showed that M. nudiflorus contained four bound fatty acids and four free fatty acids. EA fraction had the maximum phenolic content among all the fractions at (133.67±0.99) mg of GAE/g where the Folin- Ciocalteu reagent was used as an oxidizing agent. The antioxidant activity was measured in terms of its ability to scavenge free radicals (DPPH assay). Among all extractives, the greatest ability to scavenge for free radicals was shown by EA extract with an IС50 value (12.08±0.15) μg/ml. In the toxicity of brine shrimp test, the HEX fraction had the maximum toxicity with an LC50 value of (0.12±0.01) μg/ml. Cell cytotoxicity was observed for sample CHCl3 and EA on both the Vero (kidney epithelial cells taken from an African green monkey) and HeLa (a human cervical cancer cell) cell line. All the fractions were subjected to in vitro microbial screening, which revealed that DCM, CHCl3, and EA fractions showed growth inhibition, particularly against various Gram-positive and Gram-negative bacteria by disc diffusion method. The maximum zone of inhibition in the antimicrobial activity was produced by CHCl3 fraction against Staphylococcus aureus (17 mm). The results of in vitro experiments have demonstrated that the extracts from the barks of M. nudiflorus have great potential for medicinal uses and might be studied for further chemical exploration.

In silico and in vitro biopesticidal activity of Melia dubia (Cav.) plant leaves extract phytocompounds against selected enzymes, proteins, cell lines and Callosobruchus maculatus (Fab.)

Most synthetic pesticides have negative impacts on both human health and the environment, which has led to a global economic and ecological emergency for insect pest control. Crude extracts of phytocompounds from Melia dubia Cav. were tested for their pesticidal effects on a certain enzyme cell line. An in silico molecular docking analysis of phytocompounds showed that the enzymes Glutathione S-Transferase (7RKA), Mytocontrial (5H3F), Acetylcholinesterase (7QAK), GABA receptor (7WGT), and DNA nucleotidylexotransferase (6GO4) interacted strongly with the phytocompounds. Compared to Dichlorvos and Malathion, the substances Guanosine (1) and Medroxyprogesterone (2) showed higher in-silico biopesticidal efficacy against Callosobruchus maculatus (Fab.). A silica gel column chromatographic technique was used to isolate Compounds 1 and 2. In vitro studies revealed that, after 96 hours, Guanosine (90.4% and LC50 value 5.63 mg/ml) caused the maximum toxicity of C. maculatus compared to the reference pesticides Dichlorvos (84.6% and LC50 value 5.94 mg/ml) and Malathion (92% and LC50 value 5.62 mg/ml). Comparing the results to the reference drugs, guanosine (1) showed potential as a pesticidal agent. Therefore, these particular compounds may provide alternative treatments that enhance the plants under investigation's historical use.

INFRARED THERMAL IMAGING CONTROL OF RADIATION DERMATITIS DYNAMICS.

Radiation-induced dermatitis impairs the quality of life of cancer patients and may lead to the need of interrupting radiotherapy. The grade of dermatitis is subjectively assessed by the visual examination. There is an urgent need for both objective and quantitative methods for assessing the current grade of dermatitis and predicting its severity at an early stage of radiotherapy. The aim of the study was to evaluate the advantages and limitations of infrared thermography for monitoring the current level of radiation-induced dermatitis and predicting its severity by quantitative analysis of the thermal field dynamics in the irradiated zone. 30 adult patients were examined by infrared thermography during the course of 2D conventional radiotherapy for malignant tumors of various types and localizations. Our approach for quantifying the thermal field caused by dermatitis alone was applied. A statistical (correlation and ROC) analysis was performed. Dermatitis of varying severity was observed in 100% of the patients studied. The dynamics in the intensity of the anomalous thermal fields in the irradiated zone correlated with the dynamics of dermatitis grades, excluding the case of a radiosensitive tumor (correlation coefficient 0.74÷0.84). It was found that the maximum toxicity (dermatitis grade ≥ 3) develops in patients who how significant hyperthermia in the area of interest (≥ 0.7 °C) at an early stage of radiotherapy. The ROC analysis demonstrated the "good quality" of the prognosis method (AUC = 0.871). The non-invasive and cheap infrared thermography is a suitable tool for objective quantitative monitoring the current dermatitis grade during radiotherapy as well as predicting its severity for any tumor location.

Quality Control of Coumarins, Furocoumarins and Polymethoxyflavones in Citrus Essential Oils: In Silico Analysis

AbstractCitrus essential oils (EOs) contain a variety of secondary metabolites, including coumarins (Cs), furocoumarins (FCs) and polymethoxyflavones (PMFs), all with different biological activities. While Regulation (EC) No 1334/2008 strictly regulates the use of coumarins, undesirable side effects of consuming furocoumarins remain without established maximum toxicity limits for human dietary intake. This study is based on an in‐silico approach aimed at determining these toxicity limits for the oxygenated heterocyclic compounds of citrus EOs approved for use in food. In addition, an innovative quantitative structure‐property relationship (QSPR) using the linear retention index system was explored to characterize the oxygenated heterocyclic compounds (COHs) present in these essential oils. Molecular docking of the studied compounds provided crucial insights into the structure‐odor relationships, offering insights into their mechanisms of action. In addition, an analysis of the pharmacokinetic and pharmacodynamic properties through ADME‐Tox deconstruction provides insight into the potential side effects of their consumption. The results are consolidated by dynamic simulations, providing crucial data for the development of regulations on the maximum toxicity limits of citrus EOs, given the health implications of the various compounds such as coumarins, furocoumarins and polymethoxyflavones present in these essential oils.

Neurotoxic Effects of Nanoparticles and Their Pathogenesis.

A recent study on the deployment of nanoparticles in the consumer and healthcare sectors has shown highly serious safety concerns. This is despite the fact that nanoparticles offer a vast array of applications and great promise. According to studies on how nanoparticles interact with neurons, the central nervous system experiences both negative and positive impacts (CNS). With a maximum concentration of 0.1-1.0 wt.%, nanoparticles can be incorporated into materials to impart antibacterial and antiviral properties. Depending on the host or base materials utilised, this concentration may be transformed into a liquid phase release rate (leaching rate). For instance, nanoparticulate silver (Ag) or copper oxide (CuO)-filled epoxy resin exhibits extremely restricted release of the metal ions (Ag+ or Cu2+) into their surroundings unless they are physically removed or deteriorated. Nanoparticles are able to traverse a variety of barriers, including the blood-brain barrier (BBB) and skin, and are capable of penetrating biological systems and leaking into internal organs. In these circumstances, it is considered that the maximum drug toxicity test limit (10 g ml 1), as measured in artificial cerebrospinal solution, is far lower than the concentration or dosage. As this is a fast-increasing industry, as the public's exposure to these substances increases, so does their use. Thus, neurologists are inquisitive about how nanoparticles influence human neuronal cells in the central nervous system (CNS) in terms of both their potential benefits and drawbacks. This study will emphasise and address it.