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Consumer use of cannabidiol (CBD) is growing, but there are still data gaps regarding its possible adverse effects on reproduction and development. Multiple pathways and signaling cascades involved in organismal development and neuronal function, including endocannabinoid synthesis and signaling systems, are well conserved across phyla, suggesting that Caenorhabditis elegans can model the in vivo effects of exogenous cannabinoids. The effects in C. elegans on oxidative stress response (OxStrR), developmental timing, juvenile and adult spontaneous locomotor activity, reproductive output, and organismal CBD concentrations were assessed after exposure to purified CBD or a hemp extract suspended in 0.5% sesame oil emulsions. In C. elegans, this emulsion vehicle is equivalent to a high-fat diet (HFD). As in mammals, HFD was associated with oxidative-stress-related gene expression in C. elegans adults. CBD reduced HFD-induced OxStrR in transgenic adults and counteracted the hypoactivity observed in HFD-exposed wild-type adults. In C. elegans exposed to CBD from the onset of feeding, delays in later milestone acquisition were irreversible, while later juvenile locomotor activity effects were reversible after the removal of CBD exposure. CBD-induced reductions in mean juvenile population body size were cumulative when chronic exposures were initiated at parental reproductive maturity. Purified CBD was slightly more toxic than matched concentrations of CBD in hemp extract for all tested endpoints, and both were more toxic to juveniles than to adults. Dosimetry indicated that all adverse effect levels observed in C. elegans far exceeded recommended CBD dosages for humans. [ABSTRACT FROM AUTHOR]

This study evaluated 14 new 4,5,6,7‐tetrabromo‐1H‐benzo[d][1,2,3]triazole derivatives (3a‐n) for their antimicrobial activities, identifying compound 3k as the most effective. In vivo oral toxicity tests confirmed its non‐toxic nature. Predictive ADME analysis indicated favorable drug development properties. Molecular docking and dynamics studies were performed to investigate the interactions of compound 3k with Mycobacterium TB (PDB ID 2X22) and glucosamine‐6‐phosphate synthase (PDB ID 2VF5). The reactivity properties and reactive sites were determined using DFT‐derived HOMO and LUMO orbitals, along with MEP, and ESP maps, providing insights into the electron density, electrophilicity, and nucleophilicity. The electronic properties of the TD‐DFT and IEFPCM models were analyzed in solvents such as acetonitrile, ethanol, and DMSO and results were compared using UV‐Vis spectroscopy. Structural–activity relationship (SAR) investigations elucidated biological activities. [ABSTRACT FROM AUTHOR]

Mycetoma, a neglected infection of subcutaneous tissues, poses a significant health burden, especially in tropical regions. It is caused by fungal (eumycetoma) and bacterial (actinomycetoma) pathogens, with current treatments often providing unsatisfactory outcomes. This study aims to discover novel broad-spectrum antimicrobial agents to circumvent the lengthy and costly diagnostic procedures. Eight essential oils (EOs) from the roots and aerial parts of Geigeria alata, Lavandula angustifolia, Melaleuca alternifolia, Myristica fragrans, Pimpinella anisum, Syzigum aromaticum, and Thymus vulgaris were prepared using steam distillation. The in vitro antimycetomal activity against Madurella mycetomatis and Actinomadura madurae strains was assessed using resazurin assays. The chemical compositions of the EOs were analyzed using gas chromatography and mass spectrometry (GC–MS). Promising EOs underwent further in vivo toxicity and efficacy testing in Galleria mellonella larvae models. EOs of G. alata roots, M. fragrans, P. anisum, S. aromaticum, and T. vulgaris showed wide-spectrum dual in vitro antimycetomal activity against all tested strains, with minimum inhibitory concentrations (MICs) ranging from 0.004 to 0.125% v/v. G. alata aerial parts and L. angustifolia EOs demonstrated activity predominantly against A. madurae, while M. alternifolia EO did not inhibit any tested strains. M. fragrans and P. anisum EOs significantly enhanced the survival of M. mycetomatis-infected larvae without inducing toxicity in uninfected larvae. Notably, P. anisum EO tended to enhance the survival of A. madurae-infected larvae, ranking it as the most promising EO among those tested. The investigated EOs, particularly P. anisum, exhibited promising broad-spectrum antimycetomal activity against fungal and bacterial pathogens responsible for mycetoma. These findings highlight the potential of essential oils as a basis for developing novel antimycetomal agents, offering hope for improved treatment strategies for this neglected disease. [ABSTRACT FROM AUTHOR]

Xerosis cutis represents one of the most common dermatological diagnoses, which, when untreated, can be the trigger for open wounds, infections, and other skin diseases. Plant extracts are a valuable option for long-term treatments for xerosis due to their phytocompounds, especially polyphenols, flavonoids, triterpenes, and polysaccharides, with antioxidant, anti-inflammatory, antimicrobial, moisturizing, and reparatory effects. Active substances have different mechanisms; therefore, evaluating the effects on the cells can be a key indicator, providing valuable information in terms of both cytotoxicity and efficacy. The in vitro and in vivo toxicity tests performed for Betulae extractum, Liquiritiae extractum, and Avenae extractum highlighted potential toxic effects at higher concentrations in a dose-dependent relationship, but at lower levels they can be considered safe (12.5 µg/mL for birch and licorice extracts, 50 µg/mL for oat extract). Concerning the re-epithelialization process, the results revealed that all three dry extracts effectively stimulate skin cell migration, highlighting a potential anti-inflammatory effect by increasing the cell migration rate in conditions of induced inflammation associated with oxidative stress. Among the tested concentrations with a potential contribution to wound healing, the following standout: are birch bark extract 3 μg/mL, licorice root extract 7.5 µg/mL, and oat herb (harvested before flowering) extract 7.5 µg/mL. [ABSTRACT FROM AUTHOR]

Simple Summary: In contrast to external beam radiation therapy, our understanding of the dose–response relationship in radiopharmaceutical therapy (RPT) remains limited. Given that the estimation of radiation-induced deoxyribonucleic acid (DNA) damage can correlate with various biological responses, nanoscale dosimetry emerges as a critical tool in lighting this intricate relationship. In this study, we developed a novel simulation-based nanoscale dosimetry platform by identifying optimal DNA physics models and benchmarking against existing data. Leveraging this platform, we conducted a case study to estimate DNA damage, thereby enhancing our comprehension of RPT effects at nanoscales. This research serves as a foundation for future studies on how RPT affects DNA at the nano-level, potentially improving cancer treatment strategies. Radiopharmaceutical therapy (RPT) is evolving as a promising strategy for treating cancer. As interest grows in short-range particles, like Auger electrons, understanding the dose–response relationship at the deoxyribonucleic acid (DNA) level has become essential. In this study, we used the Geant4-DNA toolkit to evaluate DNA damage caused by the Auger-electron-emitting isotope I-125. We compared the energy deposition and single strand break (SSB) yield at each base pair location in a short B-form DNA (B-DNA) geometry with existing simulation and experimental data, considering both physical direct and chemical indirect hits. Additionally, we evaluated dosimetric differences between our high-resolution B-DNA target and a previously published simple B-DNA geometry. Overall, our benchmarking results for SSB yield from I-125 decay exhibited good agreement with both simulation and experimental data. Using this simulation, we then evaluated the SSB and double strand break (DSB) yields caused by a theranostic Br-77-labeled poly ADP ribose polymerase (PARP) inhibitor radiopharmaceutical. The results indicated a predominant contribution of chemical indirect hits over physical direct hits in generating SSB and DSB. This study lays the foundation for future investigations into the nano-dosimetric properties of RPT. [ABSTRACT FROM AUTHOR]

Onychomycoses are nail infections that require prolonged therapy and have high recurrence rates. Dermatophytes are the main etiological agents of these infections, followed by yeasts and non-dermatophyte filamentous fungi. The limited antifungal arsenal used to treat onychomycosis and the change in the susceptibility profile of these agents contribute to the chronicity and recalcitrant profile of infections. The present study aimed to determine the antifungal activity of extracts obtained from pure and mixed cultures of Candida parapsilosis, Trichophyton mentagrophytes, and Trichophyton rubrum. Additionally, in vivo toxicity tests with Galleria mellonella and time-kill assays were carried out. The susceptibility profiles of dermatophytes were determined using a microdilution technique with minimum inhibitory concentrations (MICs) between 250 and 8000 µg/mL. The time-kill assay, compared to growth control, resulted in the death of dermatophytes within 48 h. No toxicity of the extracts was detected in experiments with Galleria mellonella larvae under the test conditions. The extracts of pure and mixed cultures of Candida parapsilosis and dermatophytes present antifungal activity against T. mentagrophytes and T. rubrum. Isolating and identifying compounds in the extracts may allow the development of new therapeutic approaches to control fungal infections. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) are widely used, and their fluorinated state contributes to unique uses and stability but also long half-lives in the environment and humans. PFAS have been shown to be toxic, leading to immunosuppression, cancer, and other adverse health outcomes. Only a small fraction of the PFAS in commerce have been evaluated for toxicity using in vivo tests, which leads to a need to prioritize which compounds to examine further. Here, we demonstrate a prioritization approach that combines human biomonitoring data (blood concentrations) with bioactivity data (concentrations at which bioactivity is observed in vitro) for 31 PFAS. The in vitro data are taken from a battery of cell-based assays, mostly run on human cells. The result is a Bioactive Concentration to Blood Concentration Ratio (BCBCR), similar to a margin of exposure (MoE). Chemicals with low BCBCR values could then be prioritized for further risk assessment. Using this method, two of the PFAS, PFOA (Perfluorooctanoic Acid) and PFOS (Perfluorooctane Sulfonic Acid), have BCBCR values < 1 for some populations. An additional 9 PFAS have BCBCR values < 100 for some populations. This study shows a promising approach to screening level risk assessments of compounds such as PFAS that are long-lived in humans and other species. [ABSTRACT FROM AUTHOR]

Snakebite envenomation is a significant global health issue that requires specific antivenom treatments. In Taiwan, available antivenoms target a variety of snakes, but none specifically target Trimeresurus gracilis, an endemic and protected species found in the high mountain areas of Taiwan. This study evaluated the effectiveness of existing antivenoms against T. gracilis venom, focusing on a bivalent antivenom developed for Trimeresurus stejnegeri and Protobothrops mucrosquamatus (TsPmAV), as well as monovalent antivenoms for Deinagkistrodon acutus (DaAV) and Gloydius brevicaudus (GbAV). Our research involved in vivo toxicity testing in mice and in vitro immunobinding experiments using (chaotropic) enzyme-linked immunosorbent assays, comparing venoms from four pit viper species (T. gracilis, T. stejnegeri, P. mucrosquamatus, and D. acutus) with three types of antivenoms. These findings indicate that TsPmAV partially neutralized T. gracilis venom, marginally surpassing the efficacy of DaAV. In vitro tests revealed that GbAV displayed higher binding capacities toward T. gracilis venom than TsPmAV or DaAV. Comparisons of electrophoretic profiles also reveal that T. gracilis venom has fewer snake venom C-type lectin like proteins than D. acutus, and has more P-I snake venom metalloproteases or fewer phospholipase A2 than G. brevicaudus, T. stejnegeri, or P. mucrosquamatus. This study highlights the need for antivenoms that specifically target T. gracilis, as current treatments using TsPmAV show limited effectiveness in neutralizing local effects in patients. These findings provide crucial insights into clinical treatment protocols and contribute to the understanding of the evolutionary adaptation of snake venom, aiding in the development of more effective antivenoms for human health. Author summary: Trimeresurus gracilis is a protected pit viper species endemic to the mid-to-high-altitude mountainous areas of Taiwan. Due to the lack of a serum specifically targeting T. gracilis envenomation, patients bitten by this species currently receive treatment by employing a bivalent antivenom developed against T. stejnegeri and P. mucrosquamatus, which is believed to potentially possess cross-neutralizing effects. However, the use of the bivalent antivenom has demonstrated limited effectiveness in neutralizing local effects in patients. In response, we conducted investigations into the in vitro immunological reactivity and in vivo neutralization of T. gracilis venom using antivenoms developed against four pit viper species. Our results indicate that the bivalent antivenom was not completely effective in neutralizing T. gracilis venom. Instead, the monovalent antivenom for Gloydius brevicaudus exhibited higher in vitro binding capacities toward T. gracilis venom compared with other antivenoms. These findings may be attributed to a closer phylogenetic relationship between T. gracilis and G. brevicaudus. Furthermore, these observations have the potential to contribute to the development of more effective antivenoms, offering valuable insights for the community focused on neglected tropical diseases. [ABSTRACT FROM AUTHOR]

Allium Cepa Linn. (Onions) has extensively been used in traditional medicine, is one of the important Allium species regularly used in our daily diet, and has been the source of robust phenolic compounds. The current study is intended to evaluate the fecundity-enhancing effect of A. Cepa on the reproductive performance of two successive generations of rats; F0 and F1. A. Cepa extract was initially tested for in vitro antioxidant assay via DPPH and ROS, followed by in vivo toxicity testing. In the fecundity assessment, eighteen pairs of male and female rats (n = 36, 1:1, F0 generation) were divided into three groups and dosed with 75mg/kg and 150 mg/kg daily of A. Cepa extract and saline respectively, up to pre-cohabitation, cohabitation, gestation and lactation period. The reproductive performance, including body weight, live birth index, fertility index, and litter size, was assessed. Various parameters like Hematological, Hormonal (FSH, LH, Testosterone, estradiol), antioxidant markers (SOD, Glutathione peroxidase) and lipid profile of F0 and F1 generations were assessed with evaluation of histopathology of male and female organs. Ethanolic extract of A. Cepa showed the greatest antioxidant potential in DPPH and ROS methods. The continued exposure of the F0 and F1 generations to A. Cepa extract did not affect body weight, fertility index, litter size, and survival index. However, semen pH, sperm motility, sperm count, sperm viability, and semen volume were significantly improved in both generations. We have found pronounced fecundity outcomes in both genders of F0 and F1 generations with A. Cepa 150mg/kg/day extract as compared to control. Results showed that A. Cepa significantly increased (P < 0.05) hemoglobin, follicular stimulating hormone (FSH), luteinizing hormone (LH), plasma testosterone and glutathione peroxidase activities, while total lipid, LDL, and cholesterol were significantly decreased (P < 0.05) in both generations. Histology of both generations of animals reveals enhanced spermatogenesis and enhanced folliculogenesis with improved architecture. Altogether, the present results suggest that A. Cepa extract improved fecundity in both male and female rats by improving hormonal activities and oxidative stress. [ABSTRACT FROM AUTHOR]

Dicyclopentadiene (DCPD) was investigated in a 14-day oral rat toxicity study based on the OECD 407 guideline in combination with plasma metabolomics. Wistar rats received the compound daily via gavage at dose levels of 0, 50 and 150 mg/kg bw. The high dose induced transient clinical signs of toxicity and in males only reduced body weight gain. High dose liver changes were characterized by altered clinical chemistry parameters in both sexes and pathological changes in females. In high dose males an accumulation of alpha-2 u-globulin in the kidney was noted. Comparing the DCPD metabolome with previously established specific metabolome patterns in the MetaMap® Tox data base suggested that the high dose would result in liver enzyme induction leading to increased breakdown of thyroid hormones for males and females. An indication for liver toxicity in males was also noted. Metabolomics also suggested an effect on the functionality of the adrenals in high dose males, which together with published data, is suggestive of a stress related effect in this organ. The results of the present 14-day combined toxicity and metabolome investigations were qualitatively in line with literature data from subchronic oral studies in rats with DCPD. Importantly no other types of organ toxicity, or hormone dysregulation beyond the ones associated with liver enzyme induction and stress were indicated, again in line with results of published 90-day studies. It is therefore suggested that short term "smart" studies, combining classical toxicity with 'omics technologies, could be a 2 R (refine and reduce) new approach method allowing for the reduction of in vivo toxicity testing. • Dicyclopentadiene 14-day toxicity in rats target organs: liver and kidney. • Metabolomics correctly predicts subchronic DCPD toxicity. • "smart" in vivo studies are a NAM that can reduce the need for subchronic in vivo testing. [ABSTRACT FROM AUTHOR]

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To retrospectively analyze the accuracy of radiotherapy using cone beam computed tomography (CBCT), Styrofoam fixation, and breast bracket fixation in the chest wall target area and supraclavicular lymphatic drainage area (supraclavicular target area) of patients with breast cancer.and compare the setting efficiency and comfort satisfaction. A total of 65 patients with postoperative lymphatic metastasis of breast cancer, including 36 cases of Styrofoam fixation and 29 cases of breast bracket fixation, were recruited from March 2021 to August 2022 and retrospectively analyzed. All the patients underwent CBCT scans weekly, and the setup errors of the chest wall and supraclavicular target volume were compared and recorded. The planning target volume (PTV) margins of the two groups were calculated using the correlation MPTV = 2.5Σ + 0.7σ. The setup time and comfort satisfaction scores of the two groups were recorded and analyzed. The correlations among errors in each direction were analyzed using the Pearson correlation analysis. There was a significant difference in the left-right direction (X) axis of the chest wall target area between the Styrofoam and breast bracket groups (1.59 ± 1.47 mm vs. 2.05 ± 1.64 mm, P = 0.012). There were statistical differences in the ventrodorsal direction (Z) and bed angle of the supraclavicular target area, the data were (1.36 ± 1.27 mm vs. 1.75 ± 1.55 mm, P = 0.046; 0.47 ± 0.47° vs. 0.66 ± 0.59°, P = 0.006, respectively). In the X, Y, and Z directions, the respective PTV margins of the two groups in the chest wall target area were 5.01 mm, 5.99 mm, and 5.47 mm in the Styrofoam group, while those in the breast bracket group were 6.10 mm, 6.34 mm, and 6.10 mm, respectively. Moreover, the PTV margins of the supraclavicular target in the three directions were 3.69 mm, 3.86 mm, and 4.28 mm in the Styrofoam group, while those in the breast bracket group were 3.99 mm, 3.72 mm, and 5.45 mm, respectively. The setup time of the two groups was 3.4 ± 1.1 min and 5.5 ± 3.1 min (P = 0.007). The subjective comfort satisfaction scores of the two groups were 27.50 ± 1.24 and 25.44 ± 1.23 (P < 0.001). The application of Styrofoam fixation in radiotherapy of breast cancer in the supraclavicular lymph node area has several advantages as compared to breast bracket fixation, including higher positioning accuracy, smaller external expansion boundary, improved work efficiency, and patients' comfort, which might provide a reference for clinical work. [ABSTRACT FROM AUTHOR]

Chemo-mild photothermal synergistic therapy can effectively inhibit tumor growth under mild hyperthermia, minimizing damage to nearby healthy tissues and skin while ensuring therapeutic efficacy. In this paper, we develop a multifunctional study based on polyhedral oligomeric sesquisiloxane (POSS) that exhibits a synergistic therapeutic effect through mild photothermal and chemotherapy treatments (POSS-SQ-DOX). The nanoplatform utilizes SQ-N as a photothermal agent (PTA) for mild photothermal, while doxorubicin (DOX) serves as the chemotherapeutic drug for chemotherapy. By incorporating POSS into the nanoplatform, we successfully prevent the aggregation of SQ-N in aqueous solutions, thus maintaining its excellent photothermal properties both in vitro and in vivo. Furthermore, the introduction of polyethylene glycol (PEG) significantly enhances cell permeability, which contributes to the remarkable therapeutic effect of POSS-SQ-DOX NPs. Our studies on the photothermal properties of POSS-SQ-DOX NPs demonstrate their high photothermal conversion efficiency (62.3%) and stability, confirming their suitability for use in mild photothermal therapy. A combination index value (CI = 0.72) verified the presence of a synergistic effect between these two treatments, indicating that POSS-SQ-DOX NPs exhibited significantly higher cell mortality (74.7%) and tumor inhibition rate (72.7%) compared to single chemotherapy and mild photothermal therapy. This observation highlights the synergistic therapeutic potential of POSS-SQ-DOX NPs. Furthermore, in vitro and in vivo toxicity tests suggest that the absence of cytotoxicity and excellent biocompatibility of POSS-SQ-DOX NPs provide a guarantee for clinical applications. Therefore, utilizing near-infrared light-triggering POSS-SQ-DOX NPs can serve as chemo-mild photothermal PTA, while functionalized POSS-SQ-DOX NPs hold great promise as a novel nanoplatform that may drive significant advancements in the field of chemo-mild photothermal therapy. [ABSTRACT FROM AUTHOR]

In this research, twenty-four hydrazide–hydrazones of 2,4-dihydroxybenzoic acid were designed, synthesized, and subjected to in vitro and in vivo bioactivity studies. The chemical structure of the obtained compounds was confirmed by spectral methods. Antimicrobial activity screening was performed against a panel of microorganisms for all synthesized hydrazide–hydrazones. The performed assays revealed the interesting antibacterial activity of a few substances against Gram-positive bacterial strains including MRSA—Staphylococcus aureus ATCC 43300 (compound 18: 2,4-dihydroxy-N-[(2-hydroxy-3,5-diiodophenyl)methylidene]benzohydrazide—Minimal Inhibitory Concentration, MIC = 3.91 µg/mL). In addition, we performed the in vitro screening of antiproliferative activity and also assessed the acute toxicity of six hydrazide–hydrazones. The following human cancer cell lines were used: 769-P, HepG2, H1563, and LN-229, and the viability of the cells was assessed using the MTT method. The HEK-293 cell line was used as a reference line. The toxicity was tested in vivo on Danio rerio embryos using the Fish Embryo Acute Toxicity (FET) test procedure according to OECD No. 236. The inhibitory concentration values obtained in the in vitro test showed that N-[(4-nitrophenyl)methylidene]-2,4-dihydroxybenzhydrazide (21) inhibited cancer cell proliferation the most, with an extremely low IC50 (Inhibitory Concentration) value, estimated at 0.77 µM for LN-229. In addition, each of the compounds tested was selective against cancer cell lines. The compounds with a nitrophenyl substituent were the most promising in terms of inhibition cancer cell proliferation. The toxicity against zebrafish embryos and larvae was also very low or moderate. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) generally recurs locally with a dismal median survival of <18 months. Combining thermal therapy with radiation therapy enhances radiation response and improves clinical outcomes. This study evaluates a thermobrachytherapy balloon implant intended for the simultaneous heat and radiation treatment of tumor resection cavities. The data demonstrate that our prototype implant produces spherically symmetric heat and radiation dose distributions around the balloon, while the in vivo experiments confirm our ability to heat ≥40 °C at a 5 mm distance from the balloon surface in highly perfused pig brain tissue. The device is now ready for the finalization of regulatory approvals in anticipation of early-stage clinical investigation. Previous work has reported the design of a novel thermobrachytherapy (TBT) balloon implant to deliver magnetic nanoparticle (MNP) hyperthermia and high-dose-rate (HDR) brachytherapy simultaneously after brain tumor resection, thereby maximizing their synergistic effect. This paper presents an evaluation of the robustness of the balloon device, compatibility of its heat and radiation delivery components, as well as thermal and radiation dosimetry of the TBT balloon. TBT balloon devices with 1 and 3 cm diameter were evaluated when placed in an external magnetic field with a maximal strength of 8.1 kA/m at 133 kHz. The MNP solution (nanofluid) in the balloon absorbs energy, thereby generating heat, while an HDR source travels to the center of the balloon via a catheter to deliver the radiation dose. A 3D-printed human skull model was filled with brain-tissue-equivalent gel for in-phantom heating and radiation measurements around four 3 cm balloons. For the in vivo experiments, a 1 cm diameter balloon was surgically implanted in the brains of three living pigs (40–50 kg). The durability and robustness of TBT balloon implants, as well as the compatibility of their heat and radiation delivery components, were demonstrated in laboratory studies. The presence of the nanofluid, magnetic field, and heating up to 77 °C did not affect the radiation dose significantly. Thermal mapping and 2D infrared images demonstrated spherically symmetric heating in phantom as well as in brain tissue. In vivo pig experiments showed the ability to heat well-perfused brain tissue to hyperthermic levels (≥40 °C) at a 5 mm distance from the 60 °C balloon surface. [ABSTRACT FROM AUTHOR]

Simple Summary: Vision transformers have been recently spread out to enhance segmentation accuracy, becoming an active area of research and development involved in radiotherapy. We found that the new network architecture did not guarantee improvement. Conventional CNN-based networks struggled with being expanded to the auto-segmentation of tumors from normal organs due to local geometric dependence and difficulty in the hyper-parameter selection. As seen in the development and success of nnU-Net, we emphasized the importance of finding suitable hyper-parameters for the vision transformer. We applied our proposed framework based on VT U-Net v.2 to the prostate target volume segmentation, followed by extensively validating its performance in segmentation accuracy against the other five competing deep neural networks through four-fold cross-validation using CT images. U-Net, based on a deep convolutional network (CNN), has been clinically used to auto-segment normal organs, while still being limited to the planning target volume (PTV) segmentation. This work aims to address the problems in two aspects: 1) apply one of the newest network architectures such as vision transformers other than the CNN-based networks, and 2) find an appropriate combination of network hyper-parameters with reference to recently proposed nnU-Net ("no-new-Net"). VT U-Net was adopted for auto-segmenting the whole pelvis prostate PTV as it consisted of fully transformer architecture. The upgraded version (v.2) applied the nnU-Net-like hyper-parameter optimizations, which did not fully cover the transformer-oriented hyper-parameters. Thus, we tried to find a suitable combination of two key hyper-parameters (patch size and embedded dimension) for 140 CT scans throughout 4-fold cross validation. The VT U-Net v.2 with hyper-parameter tuning yielded the highest dice similarity coefficient (DSC) of 82.5 and the lowest 95% Haussdorff distance (HD95) of 3.5 on average among the seven recently proposed deep learning networks. Importantly, the nnU-Net with hyper-parameter optimization achieved competitive performance, although this was based on the convolution layers. The network hyper-parameter tuning was demonstrated to be necessary even for the newly developed architecture of vision transformers. [ABSTRACT FROM AUTHOR]

Gastric dose parameters comparison for deep inspiration breath-hold (DIBH) or free breathing (FB) mode during radiotherapy (RT) for left-sided breast cancer patients (LSBCPs) has not been investigated before. This study aimed to analyze the impact of Active Breath Coordinator (ABC)-DIBH technique on the dose received by the stomach during RT for LSBCPs and to provide organ-specific dosimetric parameters. The study included 73 LSBCPs. The dosimetric parameters of the stomach were compared between FB and DIBH mode. The correlation between the stomach volume and dosimetric parameters was analyzed. Compared to FB mode, statistically significant reductions were observed in gastric dose parameters in ABC-DIBH mode, including Dmax (46.60 vs 17.25, p < 0.001), D1cc (38.42 vs 9.60, p < 0.001), Dmean (4.10 vs 0.80, p < 0.001), V40Gy (0.50 vs 0.00, p < 0.001), V30Gy (6.30 vs 0.00, p < 0.001), V20Gy (20.80 vs 0.00, p < 0.001), V10Gy (51.10 vs 0.77, p < 0.001), and V5Gy (93.20 vs 9.60, p < 0.001). ABC-DIBH increased the distance between the stomach and the breast PTV when compared to FB, from 1.3 cm to 2.8 cm (p < 0.001). Physiologic decrease in stomach volume was not found from FB to ABC-DIBH (415.54 cm3 vs 411.61 cm3, p = 0.260). The stomach volume showed a positive correlation with V40Gy (r2 = 0.289; p < 0.05), V30Gy (r2 = 0.287; p < 0.05), V20Gy (r2 = 0.343; p < 0.05), V10Gy (r2 = 0.039; p < 0.001), V5Gy (r2 = 0.439; p < 0.001), Dmax (r2 = 0.269; p < 0.05) and D1cc (r2 = 0.278; p < 0.05) in FB mode. While in ABC-DIBH mode, most stomach dosimetric parameters were not correlated with gastric volume. The implementation of ABC-DIBH in LSBCPs radiotherapy resulted in lower irradiation of the stomach. Larger stomach volume was associated with statistically significantly higher dose irradiation in FB mode. To reduce radiotherapy related side effects in FB mode, patients should be fast for at least 2 hours before the CT simulation and treatment. [ABSTRACT FROM AUTHOR]

Aim: In vivo and in vitro toxicity tests of JointAlive® were studied in animal models to support the safe use of JointAlive® as a drug for knee osteoarthritis treatment. Methods: The acute toxicity study in Sprague Dawley (SD) rats was conducted at a 20 g/kg bw/day dose of JointAlive®. For 13-week subchronic toxicity tests, SD rats were orally dosed daily with 0.5, 1.5 and 5 g/kg bw/day of JointAlive®. To assess the potential genotoxicity, Ames test, cellular chromosome aberration and mouse micronucleus test in vivo were carried out. Results: Based on a lack of notable findings other than histopathology finding of co-incidental prostate inflammation at the high dose, the "No Observed Adverse Effect Level (NOAEL)" of JointAlive® was concluded as 5 g/kg bw/day in males and females. Results also indicated that JointAlive® has no risk of genotoxicity. Conclusions: General toxicity and genotoxicity studies empirically demonstrated that JointAlive® poses a low risk of potential health risks, providing safety supports for the application of JointAlive® as a potential drug candidate to treat knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Silver chalcogenide (Ag2X; X = S, Se, Te) quantum dots (QDs) have facilitated the biomedical applications of QDs due to their low toxicity and tunable emission reaching the second near-infrared window (NIR-II window, 1000–1700 nm). The photoluminescence intensity of Ag2S QDs and Ag2Se QDs is considerably enhanced via Pb doping. However, the developed Pb-doped Ag2S QDs lacked in vivo verification, and the toxicity of the Pb-doped Ag2X QDs was only preliminarily assessed. Although QDs containing Pb have been widely introduced into the field of biomedicine, there are still concerns regarding toxicity associated with Pb. In the present study, we prepared polyethylene glycol (PEG)-modified Pb-doped Ag2S QDs with better biocompatibility and tested their in vivo bioimaging and toxicity in comparison with Ag2S QDs modified with the same PEG under identical concentrations. Results indicated that the PEG-modified Pb-doped Ag2S QDs significantly enhanced the brightness of in vivo bioimaging and spatial resolution for vessels inside the tumor without increasing toxicity, assessed based on cell viability post incubation for 96 h, intracellular ROS level, DNA damage, early apoptosis and mitochondrial injury. Our study demonstrated that the PEG-modified Pb-doped Ag2S QDs could serve as an advanced fluorescent probe for various biomedical applications. [ABSTRACT FROM AUTHOR]

Background. Malaria remains a major public health problem in the tropical and subtropical regions. This study aimed of investigating the antimalarial and antioxidant activities of ethanol extract of Lophira lanceolata stem bark. Methodology. The antimalarial activity was determined using the Peter 4-days' suppressive and Rane's curative tests on Swiss albino: these mice were infected with 1 × 10 7 parasitized red blood cells. The percentage reduction of parasitemia was related to each test, and the liver homogenate was used to assay malondialdehyde, superoxide dismutase, nitrogen monoxide, catalase, and glutathione for the evaluation of oxidative stress. During the curative test, blood was collected for hematological parameters, alanine aminotransferase and aspartate aminotransferase to evaluate liver function. Result. The ethanol extract of L. lanceolata showed a dose-dependent suppressive activity with the highest suppression of 88.22% at 500 mg/kg. Suppression produced by the extract was not significantly higher than that of the reference drug with 96.1%. Similarly, the extract at doses 125, 250, and 500 mg/kg showed significant decreases (P < 0.05) in a dose-dependent manner during the curative test. The ethanol extract of L. lanceolata caused a reduction of tissue markers, such as hepatic oxidative stress, as it increased the enzymatic activity of antioxidant enzymes. Conclusion. The ethanol extract of L. lanceolata possesses both antimalarial and antioxidant activities. However, further in vivo toxicity tests are required to guarantee their safety. [ABSTRACT FROM AUTHOR]

Oxaliplatin and modified magnetic nanoparticles (magnetite‐lysine) are inserted into microspheres of previously synthesized poly(lactic acid‐co‐glycolic acid‐b‐ethylene glycol) PLGA‐PEG to evaluate the in vitro hyperthermal potential and the acute toxicity in mice. The used nanoparticles are synthesized by the coprecipitation method, using Fe II and Fe III, and modification with lysine is performed during the synthesis. The drug and the magnetic nanoparticles are inserted into the polymer beads through oil in water (O/W) emulsion. The obtained composites are then characterized by Fourier‐transform infrared (FTIR), Thermogravimetric analysis (TGA), X‐ray Diffraction (XRD), and submitted to magnetic hyperthermia and acute toxicity tests. The hyperthermia tests are conducted according to an experimental design. The magnetite‐lysine nanoparticles reached the temperature for the desired application and are able to raise the temperature by 6 °C at the higher investigated current, time, and concentration conditions. According to the proposed statistical study, only the test time exerted significant positive influence on the observed temperature increase, although synergies between time and concentration and between current and concentration are also significant. In vivo acute toxicity tests are also conducted with swiss mice and revealed that the prepared materials and procedures can be regarded as safe and of low toxicity. [ABSTRACT FROM AUTHOR]

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Consumer demand for natural and healthier products has led to an increasing interest in the bioactive and therapeutic properties of plant extracts. In this study, we evaluated the phenolic compounds profile, bioactivities, and toxicities of plant extracts from eight European flora species, including Calendula officinalis L., Calluna vulgaris (L.) Hull, Hippophae rhamnoides L., Juglans regia L., Mentha cervina L., Rubus idaeus L., Sambucus nigra L., and Vitis vinifera L. The aim was to identify potential preservatives of natural origin. Phenolic compounds were identified by HPLC-DAD-ESI-MS. Caffeic acid derivatives, ellagitannins, flavonols, and flavones were the major phenolic compounds identified. The total phenolic content varied from 16.0 ± 0.2 (V. vinifera) to 123 ± 2 mg/g (H. rhamnoides) of dry extract. All extracts showed antioxidant potential and exhibited activity against some of the microorganisms tested. S. nigra showed the highest activity in the inhibition of oxidative hemolysis (OxHLIA) assay and H. rhamnoides, notably, had the lowest IC50 values in TBARS and DPPH assays, as well as the lowest minimum inhibitory concentration (MIC) values. Regarding in vitro cytotoxicity, in tumor and non-tumor cell lines, although some extracts revealed toxicity against normal cells, it was found that the samples C. vulgaris, V. vinifera and R. idaeus might be used against tumor cells since the active concentration is much lower than the one causing toxicity. In vivo acute toxicity tests using Artemia franciscana suggest low toxicity for most extracts, with LC50 > 400 mg/L. These results showed the potential of the studied extracts as natural preservatives, given their richness in compounds with bioactive properties, highlight their potential value to the production chain. [ABSTRACT FROM AUTHOR]

Simple Summary: Accurate in vivo boron dosimetry is crucial for successfully implementing Boron Neutron Capture Therapy in clinical settings. This investigation uses a Compton camera detector and Monte Carlo algorithms to evaluate different imaging methods for dosimetry and tumor monitoring. The study employed the Maximum Likelihood Expectation Maximization method for dosimetry tomography, while morphological filtering and Deep Learning techniques with Convolutional Neural Networks were explored for tumor monitoring. The research is significant as it addresses the critical need for precise in vivo boron dosimetry in Boron Neutron Capture Therapy. The findings highlight the potential of the Maximum Likelihood Expectation Maximization method for accurately assessing the boron dose and demonstrate the promising results of the Convolutional-Neural-Network-based approach for tumor monitoring. The research emphasizes the importance of optimizing imaging methods and clinical parameters in this treatment, paving the way for improved treatment outcomes and enhanced patient care. Boron Neutron Capture Therapy (BNCT) is an innovative and highly selective treatment against cancer. Nowadays, in vivo boron dosimetry is an important method to carry out such therapy in clinical environments. In this work, different imaging methods were tested for dosimetry and tumor monitoring in BNCT based on a Compton camera detector. A dedicated dataset was generated through Monte Carlo tools to study the imaging capabilities. We first applied the Maximum Likelihood Expectation Maximization (MLEM) iterative method to study dosimetry tomography. As well, two methods based on morphological filtering and deep learning techniques with Convolutional Neural Networks (CNN), respectively, were studied for tumor monitoring. Furthermore, clinical aspects such as the dependence on the boron concentration ratio in image reconstruction and the stretching effect along the detector position axis were analyzed. A simulated spherical gamma source was studied in several conditions (different detector distances and boron concentration ratios) using MLEM. This approach proved the possibility of monitoring the boron dose. Tumor monitoring using the CNN method shows promising results that could be enhanced by increasing the training dataset. [ABSTRACT FROM AUTHOR]

Background. Reduction of oxidative stress during malaria infection is considered as being of great benefit so long as treatment and drug development approaches are concerned. This study had the aim of evaluating the antimalarial and antioxidant activities of the ethanolic extract of Terminalia macroptera in Swiss albino mice infected with the Plasmodium berghei NK65 strain. Methods. In vivo, the antiplasmodial activity of the plant ethanolic extract was tested in a four-day suppressive and curative assay using P. berghei in Swiss albino mice. The extract was administered to the mice at doses of 125, 250, and 500 mg/kg per day. Then, parameters, such as parasite suppression and survival time of the mice, were evaluated. Furthermore, the effect of plant extract on liver damage, oxidative stress indicators, and lipid profile changes in P. berghei-infected mice were studied. Results. Administration of T. macroptera significantly suppressed P. berghei infection by 55.17%, 70.69%, and 71.10% at doses of 125, 250, and 500 mg/kg, respectively, whereas chloroquine had 84.64% suppression relative to the untreated group 1% Dimethyl sulfoxide (1% DMSO) at day 4 (post-infection) in the four-day suppressive test. This suppression activity rate was dose-dependent. The curative test also presented a significant reduction in parasitemia and an extension of the survival time of the treated groups. Treatment of infected parasitized mice with the extract of T. macroptera had a significant (p < 0.05) reduction in parameters, such as total protein, aspartate aminotransferase, and alanine aminotransferase. Infection may also lead to a significant increase in the enzymatic activity of liver catalase and superoxide dismutase compared with the normal control group. The non-enzymatic antioxidant activity in parasitized mice was significantly reduced in malondialdehyde and increased in glutathione and nitric oxide when compared with the normal control group. Conclusions. These findings support the ethnobotanical use of T. macroptera stem bark as an antimalarial remedy coupled with antioxidant activity. However, further in vivo toxicity tests are required to ascertain its safety. [ABSTRACT FROM AUTHOR]

Background: Vaccination is widely used in fish aquaculture for three primary reasons: to prevent bacterial disease spreading, minimize antibiotic use and fight antibiotic resistance. Vaccine production is an expensive and consuming process, mainly in terms of money, resources, and animals for quality control. The replace, reduce, and refine (3Rs) philosophy suggests developing and validates alternative methods to animal testing for scientific purposes, even for biologicals and vaccines. Aim: The current study explored the potential use of mouse and fish cells in the in vitro toxicity grade assessment through different methods, as an alternative assay to in vivo residual toxicity tests for autogenous fish vaccine control. Methods: BF2 and L929 cell lines were exposed to vaccine dilutions in two different ways of administration and toxicity grade was recorded by MTS assay, compared to the in vivo gold standard test. Results: Autogenous vaccines (AVs) caused no reactions in the in vivo test. In the in vitro assay, the different toxicity grade recorded was statistically significant between the cell lines adopted and the AVs way of administration. Conclusions: Data obtained represent the first application of 3Rs method to fish AVs produced in Italy, more investigations are needed to collect solid results and standardize new in vitro methods for vaccine quality control. [ABSTRACT FROM AUTHOR]

OBJECTIVE To validate the feasibility of electronic portal imaging device (EPID)- based in vivo dosimetry system for the verification of small animal radiation research METHODS The workflow can be divided into three steps. In the first part, external body of the rat phantom was modeled based on the computed tomography (CT) dataset of a real rat previously scanned for another radiobiological experiment and the structure set was exported to 3D Slicer program to convert DICOM file to. stl file format. Tissue-equivalent rat phantom was, then, printed using Makerbot Replicator Z18 3D-printer. In the second part, treatment plans were created for different anatomical sites including whole brain and total lung irradiation using Elekta Versa HD linear accelerator. In the last part, measurements were performed with EPID-based 3D in vivo dosimetry system. During the analysis, 3D γ analysis method was used and γ evaluation criteria were set to 3 mm distance-to-agreement and 3% dose differences for local dose. RESULTS According to our analysis, EPID measurement for each modality and anatomical site met the protocol value except for % γ ≤ 1 and γ mean values for total lung irradiation, but both of these parameters met the proposed minor variation criteria. CONCLUSION Implementation of EPID-based 3D in vivo dosimetry for preclinical radiation research with small animals seems to be feasible. [ABSTRACT FROM AUTHOR]

Galleria mellonella (greater wax moth) larvae are used widely as surrogate infectious disease models, due to ease of use and the presence of an innate immune system functionally similar to that of vertebrates. Here, we review G. mellonella– human intracellular bacteria pathogen infection models from the genera Burkholderia, Coxiella, Francisella, Listeria , and Mycobacterium. For all genera, G. mellonella use has increased understanding of host–bacterial interactive biology, particularly through studies comparing the virulence of closely related species and/or wild-type versus mutant pairs. In many cases, virulence in G. mellonella mirrors that found in mammalian infection models, although it is unclear whether the pathogenic mechanisms are the same. The use of G. mellonella larvae has speeded up in vivo efficacy and toxicity testing of novel antimicrobials to treat infections caused by intracellular bacteria: an area that will expand since the FDA no longer requires animal testing for licensure. Further use of G. mellonella –intracellular bacteria infection models will be driven by advances in G. mellonella genetics, imaging, metabolomics, proteomics, and transcriptomic methodologies, alongside the development and accessibility of reagents to quantify immune markers, all of which will be underpinned by a fully annotated genome. [ABSTRACT FROM AUTHOR]

The first-line chemotherapy is associated with chief shortfalls such as non-specific distribution causing severe dose-dependent toxicities and development of tumor resistance. The current preliminary study aimed to identify the safe and effective non-oncology drugs as an alternative to toxic chemotherapeutics to treat osteosarcoma, and overcome new drug’s shortage and development challenges. The different category non-oncology drugs (alone and in combinations) were screened for in vitro cytotoxicity behavior via MTT dye reduction assay and cell cycle arresting behavior using flow cytometer against human osteosarcoma (Saos-2 and MG-63) cells. The molecular docking of selected therapeutics was executed against cyclin-dependent kinase 1 (CDK1), cell cycle regulator overexpressed in cancer. The identified combination was further tested for in vivo toxicities in rats at two different doses. The current study revealed niclosamide (NSD), ketoconazole (KCZ), simvastatin (SVN) combination that causes substantial cytotoxicity (IC50 values are in picomoles) at 1:1:3 molar ratio when compared to other molar ratios. This combination has also caused substantial arrest of Saos-2 and MG-63 cells at S and G2/M phase. Additionally, all three drugs demonstrated better interaction with CDK1 indicating anticancer potential via inhibition of CDK1. Furthermore, the in vivo toxicity study revealed no significant changes in hematological and biochemical parameters, body weights of rats, weights of vital organs, daily food and water intake, and general behavior of rats. The obtained preliminary results revealed the potential application of this combination on non-oncology drugs in the safe and effective treatment of osteosarcoma. However, further in-depth studies are required before clinical application. [ABSTRACT FROM AUTHOR]

In photodynamic therapy (PDT), a photosensitizer (PS) excited with a specific wavelength, and in the presence of oxygen, gives rise to photochemical reactions that lead to cell damage. Over the past few years, larval stages of the G. mellonella moth have proven to be an excellent alternative animal model for in vivo toxicity testing of novel compounds and virulence testing. In this article, we report a series of preliminary studies on G. mellonella larvae to evaluate the photoinduced stress response by a porphyrin (PS) (TPPOH). The tests performed evaluated PS toxicity on larvae and cytotoxicity on hemocytes, both in dark conditions and following PDT. Cellular uptake was also evaluated by fluorescence and flow cytometry. The results obtained demonstrate how the administration of PS and subsequent irradiation of larvae affects not only larvae survival rate, but also immune system cells. It was also possible to verify PS's uptake and uptake kinetics in hemocytes, observing a maximum peak at 8 h. Given the results obtained in these preliminary tests, G. mellonella appears to be a promising model for preclinical PS tests. [ABSTRACT FROM AUTHOR]

Background. There are about 13 parasitic infections that are responsible for significant morbidity and mortality but have not received the attention they deserve; thus, they are now known as "neglected tropical diseases" (NTDs). This study was aimed at evaluating the antihelminthic activities of Lophira lanceolata using an automated high-throughput method. Methods. The antihelminthic activity effect of the extracts against H. polygyrus was determined using an automated high-throughput method. For the egg-hatching test, 100 μL of embryonated egg suspension (60 eggs) was added to 100 μL of various concentrations of extracts, levamisole, and 1.5% DMSO in a 96-well round-bottom microtitre plate. After mixing, the 96-well microplate was placed in WMicroTracker and incubated for 24 h at 25°C; the movements were recorded every 30 minutes. The same procedure was used for the larval motility assays, where 100 μL of L1 or L2 larvae (50 larvae) were put in contact with 100 μL of various concentrations of extracts. Results. The ovicidal activity (hatching) had an IC50 of 1.4 mg/mL for the ethanol extract. The aqueous and ethanol extracts of L. lanceolata showed larvicidal activity on the L1 larvae with IC50 of 1.85 mg/mL and 2.4 mg/mL, respectively, as well as on the L2 larvae with IC50 values of 1.08 mg/mL and 1.02 mg/mL for the aqueous and ethanol extracts, respectively. These results showed that the aqueous extract exhibited a stronger inhibitory power on the hatching rate of parasites than ethanol extracts, while the contrary effect was observed for the larval motility assays. Conclusion. This study provides scientific data on the use of L. lanceolata by the local population for the treatment of helminthiases. However, in vivo and toxicity tests are necessary to assess its activity and safety. [ABSTRACT FROM AUTHOR]

Purpose: The research was focused on determining basic mechanical properties, surface, and phase structure taking into consideration basic cytotoxicity analysis towards human cells. Methods: Biological tests were performed on human C-12302 fibroblasts cells using 3D-printed Ti6Al4V alloy (Ti64), produced by laser-based powder bed fusion (LB-PBF) and Alumina Toughened Zirconia 20 (ATZ20), produced by lithography-based ceramic manufacturing (LCM). Surface modifications included electropolishing and hydroxyapatite or hydroxyapatite/zinc coating. Structure analysis was carried out using a variety of techniques such as X-Ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM), followed by mechanical properties evaluation using nanoindentation testing. Results: Samples subjected to surface modifications showed diversity among surface and phase structure and mechanical properties. However, the cytotoxicity towards tested cells was not significantly higher than the control. Though, a trend was noted among the materials analysed, indicating that HAp/Zn coating on Ti64 and ATZ20 resulted in the best biological performance increasing cell survivability by more than 10%. Conclusions: Hydroxyapatite coating on Ti64 and ATZ20 resulted in the best biological properties. Tested materials are suitable for in vivo toxicity testing. [ABSTRACT FROM AUTHOR]

Commonly found colonizing the human microbiota, Candida albicans is a microorganism known for its ability to cause infections, mainly in the vulvovaginal region known as vulvovaginal candidiasis (VVC). This pathology is, in fact, one of the main C. albicans clinical manifestations, changing from a colonizer to a pathogen. The increase in VVC cases and limited antifungal therapy make C. albicans an increasingly frequent risk in women's lives, especially in immunocompromised patients, pregnant women and the elderly. Therefore, it is necessary to develop new therapeutic options, especially those involving natural products associated with nanotechnology, such as lycopene and mesoporous silica nanoparticles. From this perspective, this study sought to assess whether lycopene, mesoporous silica nanoparticles and their combination would be an attractive product for the treatment of this serious disease through microbiological in vitro tests and acute toxicity tests in an alternative in vivo model of Galleria mellonella. Although they did not show desirable antifungal activity for VVC therapy, the present study strongly encourages the use of mesoporous silica nanoparticles impregnated with lycopene for the treatment of other human pathologies, since the products evaluated here did not show toxicity in the in vivo test performed, being therefore, a topic to be further explored. [ABSTRACT FROM AUTHOR]

Due to their worldwide distribution and persistence, mercury (Hg), and nano- and microplastics (NMPs) pose major threats to global ocean ecosystems. Hg and NMPs co-exist in the ocean and can interact with each other. However, information on the toxicity of this interaction to marine biota remains limited. Thus, we investigated the toxicological interaction between HgCl 2 (Hg) and NMPs by studying the influence of different sizes of polystyrene beads (0.05-, 0.5-, and 6-μm) on Hg accumulation in the brackish water flea Diaphanosoma celebensis. The Hg adsorption capacity of NPs (0.05-μm) was higher than that of MPs (0.5- and 6-μm). Only the group co-exposed to both Hg and NPs showed increased Hg content in D. celebensis. Multixenobiotic resistance (MXR) activity and transcriptional modulation of transporter genes (ABCBs and ABCCs) were decreased by NMP exposure, particularly by NPs, suggesting MXR disruption by NPs. However, only the activity of multidrug resistance-associated proteins (MRPs; ABCCs) increased with Hg exposure and decreased upon NP+Hg co-exposure, indicating an important role of ABCC in Hg efflux. Furthermore, in vivo toxicity tests showed a synergistic toxic interaction between Hg and NPs on the reproduction of D. celebensis. Our findings suggest that NPs have the potential to enhance the toxicity of Hg, increasing Hg accumulation not only by serving Hg as a carrier but also by disrupting MXR. [Display omitted] • The Hg absorption capacity of NPs was higher than that of MPs. • D. celebensis co-exposed to Hg and NPs exhibited higher Hg accumulation. • Hg and NP co-exposure had synergistic effects on reproduction of D. celebensis. • NPs potentially enhance Hg toxicity by disrupting ABC transporter activity. [ABSTRACT FROM AUTHOR]

Studies show that more consumers are using natural health products in the modern world. We have noticed a growing demand in markets and the professional community for mouthwashes that contain natural compounds. The objective of this study was to assess the chemical characterization and microbiological potential of the essential oil Piper arboreum (EOPa) to provide data to enable the development of a low-cost mouthwash. The evaluation of the antibacterial and bacterial resistance modulating activity was performed by the microdilution method to determine the minimum inhibitory concentration. The chemical components were characterized by gas chromatography coupled with mass spectrometry, which identified 20 chemical constituents, with caryophyllene oxide being one of the major compounds. The EOPa showed an MIC ≥ 1024 µg/mL for all bacterial strains used in the tests. When evaluating the modulating activity of EOPa combined with chlorhexidine, mouthwash and antibiotics against the bacterial resistance, the oil limited synergistic activity between the MIC of the products tested in combination (37% to 87.5%). Therefore, we recommend expanding the tests with greater variation in the EOPa concentration and the products used, as well as toxicity assessments and in vivo testing, with the purpose of the development of a possible low-cost mouthwash base that is accessible to the most vulnerable populations. [ABSTRACT FROM AUTHOR]

Proper burn wound management considers patient's compliance and provides an environment to accelerate wound closure. Sticky hydrogels are conducive to wound management. They can act as a preventive infection patch with controlled drug delivery and diverse surface adherence. A hypothesis-driven investigation explores a bioinspired polydopamine property in a gelatin-based hydrogel (GbH) where polyvinyl alcohol and starch function as hydrogel backbone. The GbH displayed promising physical properties with O–H group rich surface. The GbH was sticky onto dry surfaces (glass, plastic and aluminium) and wet surfaces (pork and chicken). The GbH demonstrated mathematical kinetics for a transdermal formulation, and the in vitro and in vivo toxicity of the GbH on test models confirmed the models' healthy growth and biocompatibility. The quercetin-loaded GbH showed 45–50% wound contraction on day 4 for second-degree burn wounds in rat models that were equivalent to the silver sulfadiazine treatment group. The estimates for tensile strength, biochemicals, connective tissue markers and NF-κB were restored on day 21 in the GbH treated healed wounds to imitate the normal level of the skin. The bioinspired GbH promotes efficient wound healing of second-degree burn wounds in rat models, indicating its pre-clinical applicability. [ABSTRACT FROM AUTHOR]

Diabetic mellitus is considered to be a global public health issue with high prevalence in Asian countries including India. Pharmaceutical approach using a wide range of existing drugs is problematic because of their side effects, toxicity and resistance. Natural ingredients are promising for the treatment of Diabetic mellitus including seaweeds. This study evaluates the toxicity and safety of a novel antidiabetic compound 11-methoxy-2-methyltridecane-4-ol extracted and isolated from the marine macroalgae Gracilaria edulis. The toxicity impact of this compound was assessed using Artemia franciscana model, Red Blood Cells hemolysis assay (RBC), cytotoxicity assay using 3T3-L1 mouse preadipocytes cell line models and in vivo acute toxicity tests using rat (Rattus norvegicus) model. The cytotoxicity tests with 1000 µg/mL concentration of 11-methoxy-2-methyltridecane-4-ol compound on A. franciscana, red blood cell hemolysis and 3T3-L1 mouse preadipocytes cell line did not show any adverse effects. Acute toxicity study on hematological and biochemical parameters of experimental and control rats (Rattus norvegicus) at a dose of 500 mg/kg body weight recorded values within the normal range. The results of present study are indicative of the nontoxic nature and safety of this bioactive compound suggesting its utilization as a novel drug for long term treatment of Diabetes mellitus. [ABSTRACT FROM AUTHOR]

We examined the need for new in vivo avian toxicity testing for three common industrial chemicals (1,2 dichloropropane, 1,1,2-trichloroethane and triphenyl phosphate) based on estimated avian exposures using fugacity and multimedia fate models for current conditions of use compared to hazard information including existing in vivo test data for the chemicals and analogs, interspecies correlation estimates and results from hundreds of acute avian dietary toxicity studies. The data indicated that acute avian toxicity is not likely to be observed below 10 ppm in the diet for any chemical with the exception of those with a specific mode of toxic action. Modeling indicated low exposure potential for terrestrial birds to any of the three chemicals, with estimated dietary concentration of less than 0.001 ppm. Despite uncertainty associated with the underlying data sources, the four order of magnitude gap between potential exposure and a minimum hazard threshold suggests that additional avian in vivo testing would not generate valuable data. However, a weight of evidence approach for integrating data is necessary to engender greater confidence among government decision-makers in cases where data from a particular in vivo study is not expected to improve risk decision-making and an existing data gap can remain unfilled. • A risk-based approach to inform the need for in vivo avian toxicity testing. • Application of many publicly available data sources to characterize avian toxicity. • Use of fugacity and multimedia fate modeling to characterize avian exposure. • Higher-tier avian toxicity testing is not supported for many industrial chemicals. [ABSTRACT FROM AUTHOR]

Microplastics (MPs) are a major concern in marine ecosystem because MPs are persistent and ubiquitous in oceans and are easily consumed by marine biota. Although many studies have reported the toxicity of MPs to marine biota, the toxicity of environmentally relevant types of MPs is little understood. We investigated the toxic effects of fragmented polyethylene terephthalate (PET) MP, one of the most abundant MPs in the ocean, on the marine rotifer Brachionus koreanus at the individual and molecular level. No significant rotifer mortality was observed after exposure to PET MPs for 24 and 48 h. The ingestion and egestion assays showed that rotifers readily ingested PET MPs in the absence of food but not when food was supplied; thus, there were also no chronic effects of PET MPs. In contrast, intracellular reactive oxygen species levels and glutathione S-transferase activity in rotifers were significantly increased by PET MPs. Transcriptomic and metabolomic analyses revealed that genes and metabolites related to energy metabolism and immune processes were significantly affected by PET MPs in a concentration-dependent manner. Although acute toxicity of PET MPs was not observed, PET MPs are potentially toxic to the antioxidant system, immune system, and energy metabolism in rotifers. [Display omitted] • Toxic effects of PET fragments as environmentally relevant MPs were investigated. • PET MP was not acutely toxic to the marine rotifer Brachionus koreanus. • PET MP increased intracellular ROS levels and antioxidant enzyme activity. • Multiomics analysis showed immunotoxicity and metabolic disorder induced by PET MP. • PET MPs are potentially toxic to immune system and energy metabolism in rotifers. [ABSTRACT FROM AUTHOR]

Tire wear particles (TWP) stand out as a major contributor to microplastic pollution, yet their environmental impact remains inadequately understood. This study delves into the cocktail effects of TWP leachates, employing molecular, cellular, and organismal assessments on diverse biological models. Extracted in artificial seawater and analyzed for metals and organic compounds, TWP leachates revealed the presence of polyaromatic hydrocarbons and 4-tert-octylphenol. Exposure to TWP leachates (1.5 to 1000 mg peq L−1) inhibited algae growth and induced zebrafish embryotoxicity, pigment alterations, and behavioral changes. Cell painting uncovered pro-apoptotic changes, while mechanism-specific gene-reporter assays highlighted endocrine-disrupting potential, particularly antiandrogenic effects. Although heavy metals like zinc have been suggested as major players in TWP leachate toxicity, this study emphasizes water-leachable organic compounds as the primary causative agents of observed acute toxicity. The findings underscore the need to reduce TWP pollution in aquatic systems and enhance regulations governing highly toxic tire additives. [Display omitted] • TWP leachate cocktail toxicity examined across organizational levels. • Organic compounds like PAHs and thiazoles leach into seawater from TWP. • Effects on organisms and cells: Altered algae growth, fish embryo development, cytotoxicity. • Toxic mechanisms imply oxidative stress and endocrine disruption. • Emphasizes the need for further studies on toxicity drivers. [ABSTRACT FROM AUTHOR]

In addition to the ongoing global problem of healthcare-acquired infections, the COVID-19 pandemic continues to pose a serious threat to the health of the global population. This unprecedented pandemic situation has reinforced the need for the development of technologies that can curb the transmission of viruses among human beings and help to control the infection. Existing disinfection techniques using either ultraviolet light or harsh chemicals pose safety risks and are not suitable for use in the presence of humans. Thus, the need for a safe and effective disinfection technique that can be used in the presence of humans to control viral transmission is evident. A technique that can continuously disinfect air and surfaces in indoor environments, where the chances of viral transmission are high, can be an indispensable tool to fight such a pandemic. The Airlens Minus Corona (AMC) device provided by Persapien Innovations has been developed to achieve this goal. In this study, the antiviral functionality and biocompatibility of AMC were evaluated. Activated water mist (AWM) generated from this device was tested in vitro and in vivo for its toxicity to cell lines and in animal model. The AWM was found to be non-cytotoxic to L-929 cell lines and had no sign of clinical toxicity in an animal model (rabbit). This device was further used to inactivate animal viruses and bacteriophages. The AWM was found to be effective in the complete inactivation of influenza A H1N1 virus within 5 minutes of direct treatment. This device was also found to be effective in inactivating >90% of bacteriophage particles. [ABSTRACT FROM AUTHOR]

Clitoria ternatea Linn. (CT), or butterfly pea, is an Ayurvedic plant traditionally used as a brain tonic. Recently, it was reported to be of use in treating central nervous system (CNS) disorders, i.e., as an antistress treatment and antidepressant. In the present study, we report a detailed phytochemical profile of the ethyl acetate fraction of the flower of CT (CTF_EA) with significant neuroprotective and anti-neuroinflammatory properties in both LPS-activated BV-2 and SK-N-SH cells. Concurrently, the molecular network (MN) derived from the CTF_EA metabolome allows putative identification of flavonol 3-O-glycosides, hydrocinnamic acids, and primary metabolites. Molecular docking studies suggest that CTF_EA preferentially targets iNOS, resulting in a decrease in nitric oxide (NO). Furthermore, no toxic effects on normal embryonic development, blood vessel formation, and apoptosis are observed when CTF_EA is tested for in vivo toxicity in zebrafish models. The overall preliminary results suggest the anti-neuroinflammatory and neuroprotective effects of CT and provide scientific support for the efficacy of this medicinal plant at local and traditional levels. However, studies on the targeted isolation of bioactive metabolites, in-depth pharmacological efficacy, and safety in mammalian models are urgently needed to expand our understanding of this plant before it is developed into a promising therapeutic agent for brain-related diseases. [ABSTRACT FROM AUTHOR]

The article presents an interview with Anneli Kruve and Pilleriin Peets talking about latest research in machine learning and nontargeted liquid chromatography–mass spectrometry (LC–MS). Topics include predicting toxicity based on tandem mass spectrometry (MS2) featuring with higher toxicity as well as evaluating the mixture toxicity of the sample; and methods relying on the correct structural identification of the detected features.

Inter-species differences in toxicodynamics are often a critical source of uncertainty in safety evaluations and typically dealt with using default adjustment factors. In vitro studies that use cells from different species demonstrated some success for estimating the relationships between life span and/or body weight and sensitivity to cytotoxicity; however, no apparent investigation evaluated the utility of these models for risk assessment. It was hypothesized that an in vitro model using dermal fibroblasts derived from diverse species and individuals might be utilized to inform the extent of inter-species and inter-individual variability in toxicodynamics. To test this hypothesis and characterize both inter-species and inter-individual variability in cytotoxicity, concentration-response cytotoxicity screening of 40 chemicals in primary dermal fibroblasts from 68 individuals of 54 diverse species was conducted. Chemicals examined included drugs, environmental pollutants, and food/flavor/fragrance agents; most of these were previously assessed either in vivo or in vitro for inter-species or inter-individual variation. Species included humans, the typical preclinical species and representatives from other orders of mammals and birds. Data demonstrated that both inter-species and inter-individual components of variability contribute to the observed differences in sensitivity to cell death. Further, it was found that the magnitude of the observed inter-species and inter-individual differences was chemical-dependent. This study contributes to the paradigm shift in risk assessment from reliance on in vivo toxicity testing to higher-throughput in vitro or alternative approaches, extending the strategy to replace use of default adjustment factors with experimental characterization of toxicodynamic inter-individual variability and to also address toxicodynamic inter-species variability. [ABSTRACT FROM AUTHOR]

The main purpose of this investigation was to evaluate the effect of anticancer active compounds (I–VIII) on zebrafish development in order to select the safest molecules. Larval mortality, embryo hatchability and malformations were end-points used to assess the acute toxicity among embryos and larvae from compounds-/pemetrexed-treated and control groups. LC50 and MNLC (maximal non-lethal concentration) were determined. Lipophilicity-dependent structure–toxicity relationships were established. The results clearly indicated that the majority of test molecules are safe for zebrafish individuals and simultaneously are less toxic than an anticancer agent – pemetrexed. The subsequent aim of this study was to elucidate the molecular mechanism of antiproliferative activity of the most selective compounds. Substantially increased activation of caspase-6 and -8 in cancerous cell lines confirmed the proapoptotic action of molecules examined. Considering the safety for zebrafish individuals, the title compounds as inducers of apoptosis are promising drug candidates in the preclinical phase of drug development. [ABSTRACT FROM AUTHOR]