Currently, the most promising work seems to be aimed not so much at the development of new drugs, but rather at creating ways of targeted delivery of existing drugs. In this paper, we show that polymeric micelles based on chitosan, heparin grafted with lipoic and oleic acids residues demonstrate the potential for doxorubicin delivery to tumors due to pH-, glutathione-sensitivity. Smart delivery systems use the Aikido principle, i.e. they target tumor cells according to their features. Natural polysaccharides (heparin and chitosan) provide the pH sensitivity of micelles: the release of doxorubicin (Dox) is enhanced in a slightly acidic environment (model tumor microenvironment). Fatty acid residues are necessary for the formation of micelles and solubilization of cytostatics in a hydrophobic core. Lipoic acid residues formed a labile S-S cross-linking between polymer chains (the first method), and also covalently attached doxorubicin molecules through glutathione-sensitive S-S bridges (the second option) – determine Redox sensitivity of micelles to tumors. The characterization of polymeric micelles and prodrugs (Dox-polymer) was carried out using FTIR spectroscopy. The release of doxorubicin from micelles occurs slowly (20% / 6h) in an environment with a pH of 7.4 and the absence of glutathione, while in a slightly acidic environment and in the presence of 10 mM glutathione, the rate increases up 6 times, with an increase in the effective concentration up to 5 times after 7 h. The permeability of free doxorubicin, micellar formulations (covalent S-S crosslinked and not) into Raji, K562, A875 cancer cells was studied using confocal laser scanning microscopy (CLSM), demonstrated an increase in the permeability of micellar formulations based on Dox. Thus, we have presented micellar formulations of doxorubicin for targeted delivery to tumor, what is important in the aspects of reducing non-target toxicity, increasing the selectivity of cytostatics against tumors and overcome multidrug resistance.

Benzimidazole fungicides are a class of highly effective, low-toxicity, systemic broad-spectrum fungicides developed in the 1960s and 1970s, based on the fungicidal activity of the benzimidazole ring structure. They exhibit biological activities including anticancer, antibacterial, and antiparasitic effects. Due to their particularly outstanding antibacterial properties, they are widely used in agriculture to prevent and control various plant diseases caused by fungi. The main products of benzimidazole fungicides include benomyl, carbendazim, thiabendazole, albendazole, thiophanate, thiophanate-methyl, fuberidazole, carbamic acid, and carbendazim salicylate. This article mainly reviews the physicochemical properties, toxicological properties, and disease control efficacy, and pesticide residue and detection technologies of the aforementioned nine benzimidazole fungicides and their main metabolite (2-aminobenzimidazole). On this basis, a brief outlook on the future research directions of benzimidazole fungicides is presented.

The manuscript presents the comprehensive integrative theory of the etiology and pathogenesis of Alzheimer’s disease - the amyloid degradation toxicity hypothesis - and describes the logic that underlies it.The analysis of amyloid biomarkers and stable-isotope label kinetics (SILK) studies suggest that AD diagnosis is associated with higher cellular uptake of beta-amyloid. Uptake of beta-amyloid by cells is needed for its cytotoxicity, so the uptake rate should correlate with the rate of neurodegeneration. Also, the initial step in forming extracellular aggregates cannot occur in the interstitial fluid due to the extremely low concentration of beta-amyloid but can occur intralysosomally. Therefore, the density of extracellular aggregates should positively correlate with the rate of cellular amyloid uptake. The model, which considers that both cytotoxicity and aggregation of beta-amyloid are defined by cellular uptake, successfully reproduces the probability distribution of AD diagnosis in the population. Cellular uptake of beta-amyloid is mediated by endocytosis. Endocytosed beta-amyloid induces lysosomal permeabilization that occurs without plasma membrane damage. Lysosomal permeabilization explains ion disturbances, such as an accumulation of intracellular calcium, caused by cell exposure to extracellular beta-amyloid. Some amyloid fragments, produced from beta-amyloid by lysosomal proteases, can form membrane channels in lysosomal membranes, which are large enough to leak cathepsins to the cytoplasm. Appearance of proteases in the cytoplasm results in necrosis and/or initiation of apoptosis. If the cell survives, the damage of lysosomes leads to autophagy failure and slow recycling of mitochondria, promoting the production of reactive oxygen species and potentiating cell damage.Considering the above, the integrative theory of AD etiology and pathogenesis can be formulated. The etiology of AD is the membrane channel formation by amyloid fragments produced in lysosomes. The pathogenesis includes lysosomal permeabilization by giant membrane channels, which leak lysosomal proteases into the cytoplasm. The correlation between the density of amyloid aggregates and the probability of AD appears because the intensity of cellular uptake defines both aggregation rates in vivo and cytotoxicity of beta-amyloid.The amyloid degradation toxicity hypothesis is the integrative theory of Alzheimer’s disease (AD). It successfully interprets multiple phenomena and paradoxes associated with AD pathobiology at various levels, from molecular and cellular to biomarkers. The hypothesis explains the limitations of currently used biomarkers of AD and proposes etiology-related parameters. These parameters could be measured in humans and become novel diagnostic and prognostic clinical tools. Based on the proposed framework, we foresee the development of effective medications to treat, stall the progression of, or prevent disease development.

As smoke toxicity is unregulated outside of the mass transport industry, there is no set methodology for assessing smoke toxicity of construction products, like OSB, on a large-scale. This research aims to assess the novel design of a modified ISO 9705 room corner test designed for smoke toxicity quantification. Three tests conditions will be assessed to determine if restriction of ventilation is enough to force a fire to transition to under-ventilated flaming, or if the fuel loading is much more important in affecting the fire severity and fire condition. The research found that fuel loading and test geometry has more significant impact on the fire condition than restricting the ventilation. While imposing restrictions on the test rooms ventilation did increase the equivalence ratio, it was not sufficient enough to force the transition into under-ventilated flaming. The addition of a door to the test room did not force the fire to transition to under-ventilated flaming. When doubling the fuel loading, there was sufficient fuel for the fire to transition to under-ventilated flaming. This research has provided the experimental methodologies to assess smoke toxicity at a range of ventilation conditions on a large-scale.

The present review critically examines the advancements in the past 5 years concerning the re-search on the bioavailability of the nanoplastics (NPLs) to freshwater plankton. With a specific emphasis on two bioavailability components: uptake availability and toxico-availability, we dis-cuss the recent progress in the understanding of the adsorption, absorption, trophic transfer and biological effects in phyto- and zooplankton induced by NPLs exposure. The influence of the plankton on the NPLs bioavailability via excretion of the biomolecules and formation of eco-corona is also examined. In spite of the important research developments, there are still con-siderable knowledge gaps with respect to NPLs biouptake and trophic transfer by plankton, as well as a potential adverse effect in natural aquatic systems. As plankton play a critical role in primary production, nutrient cycling and food web structure, understanding the interaction be-tween NPLs and plankton is essential in assessing the potential implications of the nanoplastics pollution for aquatic ecosystem biodiversity and services.

The EPA has banned PFOA and PFOS as persistent organic pollutants, but their residues in environment should not be underestimated. Based on the demand for healthy aquaculture and safe aquatic products, it is necessary to explore alleviative methods for the toxicity of PFOA and PFOS to fish. This study is the first to investigate the protective effects of Lactobacillus rhamnosus against oxidative damage, neurotoxicity, and gut microbial dysbiosis induced by PFOA and PFOS in adult zebrafish. The results showed that L. rhamnosus effectively alleviated PFOA- and PFOS-induced oxidative stress by restoring superoxide dismutase (SOD), catalase (CAT), and lactate dehydrogenase (LDH) levels. Both PFOA and PFOS caused intestinal tissue damage, and the degree of damage is PFOA+PFOS>PFOS>PFOA. L. rhamnosus can restore damaged intestinal villi and lymphocyte numbers and also have a restorative effect on intestinal tissue damage. The up-regulated proportion of beneficial Firmicutes and Actinobacteria was also found after L. rhamnosus feeding. These findings provide new insights for L. rhamnosus to alleviate the toxicity of PFOA and PFOS to zebrafish and promote the progress of research on the successful use of probiotics in freshwater aquaculture.

Developmental hazard evaluation is an important part of assessing chemical risks during pregnancy. Toxicological outcomes from prenatal testing in pregnant animals result from complex chemical-biological interactions, and while New Approach Methods (NAMs) based on in vitro bioactivity profiles of human cells offer promising alternatives to animal testing, most of these assays lack cellular positional information, physical constraints, and regional organization of the intact embryo. Here, we engineered a fully computable model of the embryonic disc in the compucell3d.org modeling environment to simulate epithelial-mesenchymal transition of epiblast cells and self-organization of mesodermal domains (chordamesoderm, paraxial, lateral plate, posterior/extraembryonic). Cell fate in the model is determined by an autonomous homeobox (HOX) clock driven by morphogenetic signals (e.g., FGF, WNT, ATRA, CDX). Executing the model renders a quantitative cell-level computation of mesodermal subpopulations and consequences of perturbation based on known embryogeny. For example, synthetic perturbation of the control network rendered altered phenotypes (cybermorphs) mirroring experimental mouse embryology, with 50% reductions in FGF4, FGF8 and BMP4 signaling resulting in 86%, 98% and 59% reductions, respectively in the posterior mesodermal population, while ATRA exposure also resulted in a 78% decrease in this population. This model enables integration of in vitro chemical bioactivity data for specific molecular targets with known embryology to test mechanistic veracity and quantitative prediction of altered development.

Autism Spectrum Disorder (ASD), a neurodevelopmental disorder characterized by persistent deficits in social interaction and communication manifests in early childhood and is followed by restricted and stereotyped behaviors, interests or activities in adolescence and adulthood (DSM-V). Although genetics and environmental factors have been implicated, the exact causes of ASD have yet to be fully characterized. New evidence suggests that dysbiosis or perturbation in gut microbiota (GM) and exposure to lead (Pb) may play important roles in ASD etiology. Pb is a toxic heavy metal that has been linked to a wide range of negative health outcomes including anemia, encephalopathy, gastroenteric diseases and more importantly cognitive and behavioral problems inherent to ASD. Pb exposure can disrupt GM, which is essential for maintaining overall health. GM, consisting of trillions of microorganisms, has been shown to play a crucial role in the development of various physiological and psychological functions. GM interacts with the brain in a bidirectional manner referred to as “Gut-Brain Axis (GBA).” In this review, following a general overview of ASD and GM, the interaction of Pb with GM in the context of ASD is emphasized. Potential exploitation of this interaction for therapeutic purposes is also touched upon.

Over the past several decades, the extensive use of pyrethroids has led to the development of resistance in many insect populations, including the economically damaging pest tarnished plant bug (TPB), Lygus lineolaris on cotton. To manage TPB resistance, several commercially formulated pyrethroid-containing binary mixtures, in combination with neonicotinoids or avermectin are recommended for TPB control and resistance management in the Mid-south USA. This study aimed to evaluate the toxicity and resistance risks of four formulated pyrethroid-containing binary mixtures (Endigo, Leverage, Athena, and Hero) on one susceptible and two resistant TPB populations which were field-collected in July (Field-R1) and October (Field-R2), respectively. Based on LC50 values, both resistant TPB populations displayed variable tolerance to the four binary mixtures, with Hero showing the highest resistance and Athena the lowest. Notably, the Field-R2 exhibited 1.5-3-fold higher resistance compared to the Field-R1 for all four binary insecticides. Moreover, both resistant TPB populations demonstrated significantly higher resistance ratios toward Hero and Leverage compared to their corresponding individual pyrethroid, while Endigo and Athena showed similar or lower resistance. This study also utilized the calculated additive index (AI) and co-toxicity coefficient (CTC) analysis, which revealed that the two individual components in Leverage exhibited antagonist effects against the two resistant TPB populations. In contrast, the two individual components in Endigo, Hero and Athena displayed synergistic interactions. Considering that Hero is a mixture of two pyrethroids which can enhance the development of TPB resistance, our findings suggest that Endigo and Athena are likely superior products for slowing down resistance development in TPB populations. This study provides valuable insight for selecting the most effective mixtures to achieve better TPB control through synergistic toxicity analysis, while simultaneously reducing economic and environmental risks associated with resistance development in the insect pest.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and biologically heterogeneous disease. Approximately 40% of patients with DLBCL will experience disease relapse or will be refractory to first line chemoimmunotherapy. In recent years there have been several new therapeutic agents approved for the treatment of relapsed/refractory (R/R) DLBCL. These agents include anti-CD19 chimeric antigen receptor T-cell therapies (CAR T-cells) and monoclonal antibodies as polatuzumab and tafasitamab. Nevertheless, despite the high efficacy of all these new therapies, there are still patients who do not respond or relapse, representing an unmet clinical need. This review describes new promising therapies that are under investigation to treat R/R DLBCL.

Glitter particles are considered a model of microplastics, which are used in a wide range of products. In this study, we evaluated the toxicity of green and white glitter dispersions on the embryonic development of the sea urchins Echinometra lucunte, Arbacia lixula, and the mussel Perna perna. The Toxicity Identification and Evaluation (TIE) approach was used to identify possible chemicals related to toxicity. Glitter dispersions were prepared using 0.05% ethanol. The tested dispersions ranged from 50 to 500 mg/L. The white glitter was composed of a vinyl chloride-methyl acrylate copolymer. The effective concentrations of green glitter to 50% embryos (EC50) were 246.1 (235.8 – 256.4) mg/L to A. lixula, 23.0 (20.2 - 25.8) mg/L to P. perna and 105.9 (61.2 - 150.2) mg/L, whereas the EC50 of white glitter to E. lucunter was 272.2 (261.5 – 282.9) mg/L. The EC50 for P. perna could not be calculated; however, the lowest effect concentration was 10 mg/L. The filtered suspension of green glitter had Ag levels exceeding the legal standards for marine waters. TIE showed that metals, volatiles, and oxidant compounds contribute to toxicity. The results showed that glitter may adversely affect marine organisms; however further studies are necessary to determine its environmental risks.

The introduction of cancer therapeutics and nanotechnology has resulted in a paradigm shift from conventional therapy to precision medicine. Nanotechnology, an interdisciplinary field with a focus on biomedical applications, holds immense promise in bringing about novel approaches for cancer detection, diagnosis, and therapy. The past decade has witnessed significant research and material applications related to nanoparticles (NPs). NPs differ from small-molecule drugs as they possess unique physicochemical characteristics, such as a large surface-to-volume ratio, enabling them to penetrate live cells efficiently. Traditional cancer therapies, such as chemotherapy, radiation therapy, targeted therapy, and immunotherapy, have limitations, such as cytotoxicity, lack of specificity, and multiple drug resistance, which pose significant challenges for effective cancer treatment. However, nanomaterials have unique properties that enable new therapeutic modalities beyond conventional drug delivery in the fight against cancer. Moreover, nanoparticles (1-100 nm) have numerous benefits, such as biocompatibility, reduced toxicity, excellent stability, enhanced permeability and retention effect, and precise targeting, making them ideal for cancer treatment. The purpose of this article is to provide consolidated information on various bio-inspired nanoparticles that aid in cancer theragnostics.

Small molecules that can modulate or stabilize cell-cell interactions are valuable tools for investigating the impact of collective cell behavior on various biological processes such as development/morphogenesis, tissue regeneration and cancer progression. Recently, we showed that budesonide, a glucocorticoid widely used as anti-asthmatic drug, is a potent regulator of stem cell pluripotency. Here we tested the effect of different budesonide derivatives and identified CHD-030498 as a more effective analogue of budesonide. CHD-030498 was able to prevent stem cell pluripotency exit in different cell-based models, including embryonic stem-to-mesenchymal transition, spontaneous differentiation and 3D gastruloid development, and at lower doses compared to budesonide.

Citation: To be added by editorial staff during production.

Nitrogen (N) strongly affects plant growth and metabolism. For shikonin biosynthesis, although the ammonium toxicity phenomenon has been reported, the effects of nitrogen on the shikonin synthesis remains obscure. In this study, we carried out four different concentrations of NH4+ treatments on Arnebia euchroma hairy roots (AEHR) to clarify the influence of NH4+ on the growth and shikonin accumulation in A. euchroma and the possible mechanism. The results showed that compared with the 0% NH4+ treatment (only nitrate as nitrogen source), 10% NH4+ treatment increased the fresh weight and the dry weight of AEHR, and promoted the synthesis of shikonins; 20% NH4+ treatment started to show the inhibition effects on growth and shikonin accumulation of AEHR and 30% NH4+ treatment exhibited the strongest inhibition effects. With increased percentage of NH4+, AEHRs became shorter and thicker with more branches. To further elucidate the mechanism, we analyzed the time-course of nitrogen assimilation, gene expression level of key enzymes involved in the shikonin biosynthesis pathway, and contents of various endogenous hormones under NH4+ toxicity condition. Results indicated that auxin and cytokinin might regulate the growth and architecture of AEHR under NH4+ toxicity, and jasmonate level was reduced along with the inhibition of shikonin biosynthesis. This first comprehensive investigation into the effects of ammonium/nitrate ratio on shikonin biosynthesis not only provided valuable data for optimizing the in vitro culture and shikonin production in A. euchroma, but also suggested potential fertilizer strategies for its cultivation.

Background: Low-dose aspirin (LDA) is the backbone for secondary prevention of coronary artery disease, though limited by gastric toxicity. This study was aimed to identify novel metabolites that could predict LDA-induced gastric toxicity using pharmacometabolomics. Methods: Pre-dosed urine samples were collected from male Sprague-Dawley rats. The rats were treated with either LDA (10 mg/kg) or 1% methylcellulose (10 ml/kg) per oral for 28 days. The rats' stomachs were examined for gastric toxicity using a stereomicroscope. The urine samples were analyzed using a proton nuclear magnetic resonance spectroscopy. Metabolites were systematically identified by exploring established databases and multivariate analyses to identify the spectral pattern of metabolites related to LDA-induced gastric toxicity. Results: Treatment with LDA resulted in gastric toxicity in 20/32 rats (62.5%). The orthogonal projections to latent structures discriminant analysis (OPLS-DA) model displayed a goodness-of-fit (R2Y) value of 0.947, suggesting a near-perfect reproducibility, a goodness-of-prediction (Q2Y) of -0.185 with perfect sensitivity, specificity and accuracy (100%). Furthermore, the area under the receiver operating characteristic (AUROC) displayed was 1. The final OPLS-DA model had an R2Y value of 0.726 and Q2Y of 0.142 with sensitivity (100%), specificity (95.0%) and accuracy (96.9%). Citrate, hippurate, methylamine, trimethylamine N-oxide and alpha-keto-glutarate were identified as the possible metabolites implicated in the LDA-induced gastric toxicity. Conclusion: The study identified metabolic signatures that correlated with the development of a low dose Aspirin-induced gastric toxicity in rats. This pharmacometabolomic approach could further be validated to predict LDA-induced gastric toxicity in patients with coronary artery disease.

The current research investigated the environmental risk of the polycyclic musk compounds, Galaxolide® (HHCB) and Tonalide® (AHTN), in the marine environments. These substances are lipophilic, bioaccumulated and potentially biomagnified in aquatic organisms. To understand the toxicity of HHCB and AHTN, we performed acute toxicity tests by exposing marine microalgae (Phaeodactylum tricornutum, Tretraselmis chuii and Isochrysis galbana), crustaceans (Artemia franciscana), echinoderms (Paracentrotus lividus), bivalves (Mytilus galloprovincialis), fish (Sparus aurata) and a candidate freshwater microalga (Raphidocelis subcapitata) to environmentally relevant concentrations (0.005 - 5 µg/L) following standardized protocols. The effects of both substances on microalgae growth were incipient and only I. galbana was sensitive to HHCB and AHTN, with IC10 values of 5.22 µg/L and 0.328 µg/L, respectively. Significant (p < 0.01) concentration dependent responses were measured in P. lividus and M. galloprovincialis larvae developments as well as S. aurata mortality tested with HHCB. The effect of HHCB on P. lividus larvae development was the most sensitive endpoint recorded, producing an EC50 value of 4.07 µg/L. Our results show that HHCB represents a high risk to P. lividus larvae development for early life stages in marine environments.

Purpose: To report the early clinical outcomes of combining intensity‐modulated radiation therapy (IMRT) and intensity‐modulated proton therapy (IMPT) in comparison with IMRT alone in treating the oropharynx cancer (OPC) patients. Materials and Methods: The medical records of 148 OPC patients were retrospectively reviewed, who underwent definitive radiotherapy (RT) with concurrent systemic therapy, from January 2016 till December 2019 at Samsung Medical Center. During the 5.5 weeks’ RT course, the initial 16 (or 18) fractions were delivered by IMRT in all patients, and the subsequent 12 (or 10) fractions were either by IMRT in 81 patients (IMRT only) or by IMPT in 67 (IMRT/IMPT combination), respectively, based on comparison of adaptive re-plan profiles and availability of equipment. Propensity‐score matching (PSM) was done on 76 patients (38 from each group) for comparative analyses. Results: With the median follow‐up of 24.7 months, there was no significant difference in overall survival and progression free survival between groups, both before and after PSM. Before PSM, IMRT/IMPT combination group experienced grade ≥3 acute toxicities less frequently: mucositis in 37.0% and 13.4% (p<0.001); and analgesic quantification algorithm (AQA) in 37.0% and 19.4% (p=0.019), respectively. The same trends were observed after PSM: mucositis in 39.5% and 15.8% (p=0.021); and AQA in 47.4% and 21.1% (p=0.016), respectively. In multivariate logistic regression, grade ≥3 mucositis was significantly less frequent in IMRT/IMPT combination group, both before and after PSM (p=0.027 and 0.024, respectively). AQA score ≥3 was also less frequent in IMRT/IMPT combination group, both before and after PSM (p=0.085 and 0.018, respectively). Conclusions: In treating the OPC patients, with comparable early oncologic outcomes, more favorable acute toxicity profiles were achieved following IMRT/IMPT combination than IMRT alone.

Past public health crises (e.g. tobacco, alcohol, opioids, cholera, HIV, lead, pollution, venereal disease, even COVID-19) have been met with interventions targeted both at the individual and all of society. While the healthcare community is very aware that the global pandemic of non-communicable diseases (NCD’s) has its origins in our Western ultraprocessed food diet, society has been slow to initiate any interventions other than public education, which has been ineffective, in part due to food industry interference. This article provides the rationale for such public health interventions, by compiling the evidence that added sugar, and by proxy the ultraprocessed food category, meets the four criteria set by the public health community as necessary and sufficient for regulation — addiction, toxicity, ubiquity, and externalities (how does your consumption affect me?). To its credit, some countries have recently heeded this science and have instituted sugar taxation policies to help ameliorate NCD’s within their borders. This article also supplies scientific counters to food industry talking points, in order to guide both scientists and policy makers in instituting further appropriate public health measures to quell this pandemic.

Some herbicides exert hormetic or biphasic non-monotonic dose-response (NMDR), which is one of the major challenges for ecological risk assessment (ERA) of pesticides pollution. In this study, fish embryo toxicity test (FET) with Javanese medaka (Oryzias javanicus) to sublethal concentration of diuron was determined. Inverted U-shape heart rate was observed at 3 days post-exposure (dpe) and 7 dpe. However, at 13 dpe the heart rate (104 ± 2.90 heartbeat/min.) decreased in 10.00 mg.L-1 exposed-embryos. At 20 dpe, hatchability and survival rate were reduced in 5.00 mg.L-1 and 10.00 mg.L-1 exposed groups. Hormetic developmental deformities were observed in embryo-larvae of Javanese medaka. The results revealed a biphasic effect of low concentrations of diuron on some morphological and physiological features of Javanese medaka embryo-larvae, which might be attributed to endocrine disruption of this herbicide. Further studies to support these effects were recommended.

Nanoparticles (NPs) have various applications in medicine, cosmetics, optics, catalysis, environmental purification, and other areas nowadays. With an increasing annual production of NPs, the risks of their harmful influence to the environment and human health is rising. Currently, our knowledge about the mechanisms of interaction between NPs and living organisms is limited. Additionally, poor understanding of how physical and chemical characteristic and different conditions influence the toxicity of NPs restrict our attempts to develop the standards and regulations which might allow us to maintain the safe living conditions. The marine species and their habitat environment are under continuous stress due to anthropogenic activities which result in the appearance of NPs in the aquatic environment. Our study aimed to evaluate and compare biochemical effects caused by the influence of different types of carbon nanotubes, carbon nanofibers, and silica nanotubes on four marine microalgae species. We have evaluated the changes in growth-rate, esterase activity, membrane polarization, and size changes of microalgae cells using flow cytometry method. Our results demonstrated that toxic effects caused by the carbon nanotubes strongly correlated with the content of heavy metal impurities in the NPs. More hydrophobic carbon NPs with less ordered structure had a higher impact on the red microalgae P. purpureum because of higher adherence between the particles and mucous covering of the algae; silica NPs caused significant inhibition of microalgae growth-rate predominantly produced by mechanical influence.

This study centered on examining 60 different antibiotics by assessing their primary toxicity parameters through the pkCSM database. The parameters included Max. Tolerated Dose (Human) (log mg/kg/day), Oral Rat Acute Toxicity (LD50) (mol/kg), Oral Rat Chronic Toxicity (LOAEL) (log mg/kg_bw/day), and Minnow Toxicity (LC50) (log mM). The results highlight four potential antibiotics—cefotaxime, ceftriaxone, imipenem, and meropenem—that exhibited lower toxicity effects compared to other compounds. These findings imply a relatively favorable safety profile for these antibiotics concerning the specified toxicity parameters. However, it is crucial to interpret these outcomes within the context of the specific clinical application and to consider additional factors for a comprehensive safety assessment. It's essential to acknowledge that evaluating toxicity is intricate, and the determination of what is considered "less toxic" can rely on specific criteria and the context of use. Furthermore, individual responses to antibiotics may vary, and the selection of an antibiotic should be based on diverse factors, including the specific infection being treated, the patient's health, and potential side effects.

Analysing the human body by direct observation can lead to misinterpretation of underlying trends, whereas in vitro organ models facilitate their understanding. Likewise, in vitro organ models serve as valuable tools for assessing the toxicity of compounds. However, none of the existing models had the features we considered critical for toxicity assessment, so we developed an in vitro liver model for toxicity assessment. We used four different types of primary liver cells: Hepatic sinusoidal endothelial cells, hepatic stellate cells, Kupffer cells and hepatocytes. We cultured them in different combinations of composition and volume of cell medium, hepatocyte proportion of total cells, and addition of extracellular matrix. We added rifampicin, ibuprofen and 5-fluorouracil to this model and observed the microanatomy and physiology changes for a week with preclinical and clinical instruments. Among the different model configurations, we selected the feature combination of the in vitro model that had similar biomarker values to those measured by the clinical instruments used in clinical diagnostics. When we exposed the selected model configuration to rifampicin, ibuprofen and 5-fluorouracil, the viability of Kupffer cells and liver sinusoidal endothelial cells was significantly lower than in the untreated samples. In contrast, we observed negligible viability of hepatocytes compared to the untreated samples. We have built an in vitro liver model that resembles the liver microenvironment and we have analysed it with clinical instrumentation to facilitate the data translation. In this sense, we have established that Kupffer and LSEC cells are suitable candidates for the search for clinical diagnostic markers of liver function.

As Li-ion batteries use is spreading, incidents in large energy storage systems (stationary storage containers, …) or in large-scale cell and battery storages (warehouse, recyclers, …), often leading to fire, are occurring on regular basis. Water remains one of the most efficient fire extinguishing agents for tackling those battery incidents and large quantities are usually necessary. Since bat-teries contains various potentially harmful components (metals and their oxides or salts, sol-vents…) and that thermal runway induced battery incidents are accompanied with complex and potentially multistage fume emissions (containing both gas and particles) the potential impact of fire run-off water on the environment should be considered and assessed carefully. The tests presented in this paper focus on the analysis of the composition of run-off waters used to spray NMC Li-ion modules under thermal runaway. It highlights that waters used for fire-fighting are susceptible to contain many metals, including Ni, Mn, Co, Li and Al mixed with other carbonaceous species (soot, tarballs) and sometimes undecomposed solvents used in the elec-trolyte. Extra-polation of pollutant concentrations compared with PNEC values showed that, for large scale incidents, run-off water could be potentially hazardous to the environment.

The most frequent cause of cardiac failure globally is ischemic heart disease, with chemothera-py-related cardiovascular side effects emerging as the second most frequent cause. Cancer therapy can result in acute cardiac events, such as coronary artery spasm, acute myocardial infarction, thromboembolism, myocarditis, bradycardia, tachyarrhythmias, atrio-ventricular blocks, QT pro-longation, torsades de pointes, pericardial effusion and hypotension, as well as chronic conditions, such as hypertension, systolic and diastolic left ventricular dysfunction presenting clinically as heart failure or cardiomyopathy. In cardio-oncology, when referring to cardiac toxicity and cardiovas-cular hypersensitivity, there is a great deal of misunderstanding. When a dose-related cardiovas-cular side effect continues even after the causative medication is stopped, it is referred to as cardi-otoxicity. A fibrotic response is the ultimate outcome of cardiac toxicity, which is defined as a dose-related cardiovascular adverse impact that lasts even after the causative treatment is stopped. Cardiotoxicity can occur after a single or brief exposure. On the other hand, the term cardiac or cardiovascular hypersensitivity describes an inflammatory reaction that is not dose-dependent, can occur at any point during therapy, even with very low medication dosages, and can show up as Kounis syndrome. It may also be accompanied by anti-drug antibodies and tryptase levels. In this comprehensive review, we present the current views on cardiac toxicity and cardiovascular hypersensitivity, together with the reviewed cardiac literature on the chemotherapeutic agents inducing hypersensitivity reactions. Cardiac hypersensitivity seems to be the pathophysiologic basis of coronary artery spasm, acute coronary syndromes such as Kounis syndrome and myocardi-tis caused by cancer therapy.

The expansion of copper mining on the hyper-arid pacific slope of southern Peru has precipitated growing concern for scarce water resources in the region. Located in the headwaters of the Torata river, in the department of Moquegua, the Cuajone mine, owned by Southern Copper, provides a unique opportunity, in a little-studied region, to examine the relative impact of the landscape-scale mining on water resources in the region. Principal component analysis and cluster analysis of the water chemistry data from 16 sites, collected over three seasons during 2017 and 2018, show distinct statistical groupings indicating that, above the settlement of Torata, water geochemistry is a function of chemical weathering processes acting upon underlying geological units, and confirming that the Cuajone mine does not significantly affect water quality in the Torata river. Impact mitigation strategies that firstly divert channel flow around the mine and secondly divert mine waste to the Toquepala river and tailings dam at Quebrada Honda, below the Toquepala mine, in the department of Tacna, secure water quality in the Torata river for the foreseeable future. In the greater Moquegua river catchment, our results further suggest that water quality has been more significantly impacted by urban effluents and agricultural runoff than the Cuajone mine. The increase in total dissolved solids in the waters of the lower catchment reflects the cumulative addition of dissolved ions through chemical weathering of the underlying geological units, supplemented by rapid recharge of surface waters contaminated by residues associated with agricultural and urban runoff through the porous alluvial aquifer. Concentrations in some of the major ions exceeded internationally recommended maxima for agricultural use, especially in the coastal region. Occasionally, arsenic and manganese contamination also reached unsafe levels for domestic consumption. In the lower catchment, below the Cuajone mine, data and multivariate analyses point to urban effluents and agricultural run-off rather than weathering of exposed rock units, natural or otherwise, as the main cause of contamination.

Mesoporous silica nanoparticles (MSNs) can be used as carrier materials for the controlled release of pesticides while reducing their negative environmental impact. In this study, we screened an active ingredient, p-cymene (PC), with an excellent inhibitory effect on rice bacterial blight. Subsequently, the PC was successfully loaded onto MSNs via physisorption(PC@MSNs). PC@MSNs, characterized by a regular spherical shape, smooth surface, and an MSN average size of 262.9 nm, achieved an 8.6 % drug loading capacity. The release kinetics of the PC from the PC@MSNs demonstrated a sustained release (288 h) pattern influenced by drug diffusion. The efficacy of the PC@MSNs against Xanthomonas oryzae pv. Oryzae paralleled those of PC. Acute toxicity assays re-vealed that the PC@MSNs were less toxic to aquatic life (LC50=257.867 mg/L) and that the formu-lation showed no adverse effects on rice seedling growth. In summary, these results suggest that PC@MSNs can broaden PC's application scope in managing rice diseases.

A significant amount of data is available for bench-scale fire assessments. However, there is little surrounding large-scale tests and even less so for bench-to-large scale comparisons. Large-scale tests require more material, time and preparation, making them more expensive than bench-scale assessments. However, large-scale testing is an essential component to bench-scale fire testing. The bench-scale tests must be representative of both large-scale and real fire behaviour to provide an insight into how a material or product will behave in the event of a fire during its end use application. The few existing studies reviewed in this study show more guidance and data is needed, especially on a large-scale. Unfortunately, the data that is presented is done so in an inconsistent manner using various means of presentation, statistical analysis, and modelling that doesn’t show clear comparisons between bench and large scale. Currently, no bench-scale method shows good agreement with large-scale fire behaviour. Overall, there is a need for more large-scale testing and data for direct comparisons to be made.

(1) Background: The synthesis of core-shell magnetic mesoporous nanoparticles (MMSN) from phase transfer process is usually performed at 100-250 mg scale. At the gram scale, nanoparticles without core or with multicore systems are observed. (2) Methods: Iron oxide core nanoparticles (IO) were synthesized through thermal decomposition procedure of -FeO in oleic acid. Phase transfer from chloroform to water was then performed in order to wrap IO with mesoporous silica shell through the sol-gel procedure. MMSN were then functionalized with DTPA, and used for the separation of metal ions. Their toxicity was evaluated (3) Results: The phase transfer pro-cedure was crucial to obtained MMSN at large scale. Three synthesis parameters were rigorously controlled: temperature, time and glassware. Homogeneous dispersion of MMSN at the gram scale was successfully obtained. After functionalization with DTPA, the MMSN-DTPA were shown to have a strong affinity for Ni ions. Furthermore toxicity was evaluated in cells, zebrafish and through seahorse metabolic assays, and the nanoparticles were found nontoxic. (4) Conclusions: We developed a method of preparation of MMSN at the gram scale. After function-alization with DTPA, the nanoparticles were efficient in metal ion removal and separation, fur-thermore, no toxicity was noticed up to 125 µg.mL-1 in zebrafish.

Hu7691 represents a novel Pan-Akt kinase inhibitor, demonstrating excellent selectivity towards non-AGC kinase families and pronounced inhibitory effects on the proliferation of multiple tumor cell lines. However, there is currently a notable absence of in vivo toxicological research evidence concerning Hu7691. This study represents the first investigation into the 14-day repeated dose toxicity of Hu7691 in male and female Sprague-Dawley (SD) rats. Male rats were administered daily doses of 12.5, 50, 100, and 150 mg/kg, while female rats received doses of 12.5, 25, 50, and 75 mg/kg for 14 consecutive days. Hematological assessments, organ weights, and histopathological examinations revealed corresponding alterations, suggesting potential target organs for toxicity including the spleen, thymus, and gastrointestinal tract. It is worth noting that the test substance may also impact the liver, kidneys, heart, and ovaries. The No Observed Effect Level (NOAEL) was determined to be no greater than 12.5 mg/kg. Based on the observed gender-related toxicity differences in preliminary trials, it is recommended that the high dose reference dose for male animals in formal experiments should not be less than 100 mg/kg, while for female animals, it should be less than 50 mg/kg.

Purpose: Oxidative stress is responsible for over seventy five diseases and other harmful cytological challenges including cancer, type 2 diabetes mellitus, lipid peroxidation, distortion of cell membrane integrity, shortening of telomerase among others. Antioxidant potency of any plant is a very positive remedy to the debilitating effects of prooxidants and oxidants. The study was aimed at investigating the antioxidant potency of methanol extract of Pentaclethra macrophylla stem bark- in vitro and in vivo. Methods: Different phytochemicals were determined using standard methods. Nitric oxide, 1, 1-diphenyl-2- picrylhydrazyl (DPPH) radical scavenging activity, total antioxidant capacity and ferric reducing/anti-radical power were used to investigate the in vitro antioxidant activity. Catalase assay, superoxide dismutase, malondialdehyde and glutathione peroxidase were used to determine the in vivo antioxidant efficacy using six groups of five rats. Results: The result showed various quantities of phytochemicals, including antioxidant phytochemicals-flavonoids, tannins and total phenolics. The in vitro assay showed that 250 μg/ml of extract had the highest percentage inhibition of DPPH radical (93.93%). The 125 μg/ml had the highest scavenging activity of nitric oxide radical (49.47%) while 250μg/ml showed the least with 41.73%. Other methods showed various degrees of activity. The in vivo antioxidant showed that the principal mechanism of antioxidant activity is by modulating the iron-dependent catalase activity. Conclusion: Pentaclethra macrophylla has both in vitro and in vivo antioxidant activities and therefore is useful in ameliorating the debilitating effects of oxidants.

Individual susceptibility to pulmonary oxygen toxicity (PO2tox) is highly variable and currently lacks a reliable biomarker for predicting pulmonary hyperoxic stress. As nitric oxide (NO) is involved in many respiratory system processes and functions, we aimed to determine if expired nitric oxide (FENO) levels can provide an indication of PO2tox susceptibility in humans. Eight U.S. Navy trained divers volunteered as subjects. The hyperoxic exposures consisted of six- and eight-hour hyperbaric chamber dives conducted on consecutive days in which subjects breathed 100% oxygen at 202.65 kPa. Subjects’ individual variability in pulmonary function and FENO was measured twice daily over five days and compared with their post-dive values to assess susceptibility to PO2tox. Only subjects who showed no decrements in pulmonary function following the six-hour exposure conducted the eight-hour dive. FENO decreased by 55% immediately following the six-hour oxygen exposure (n=8, p<0.0001) and by 63% following the eight-hour exposure (n=4, p<0.0001). Four subjects showed significant decreases in pulmonary function immediately following the six-hour exposure. These subjects had the lowest baseline FENO and the lowest post-dive FENO and had clinical symptoms of PO2tox. Individuals with low FENO were the first to develop PO2tox symptoms and deficits in pulmonary function from the hyperoxic exposures. These data suggest that endogenous levels of NO in the lung may protect against the development of PO2tox.

Despite the recent advances in melanoma therapy, the need for new targets and novel approaches to therapy is urgent. We previously reported melanoma actives that work via binding and downregulating spliceosomal proteins hnRNPH1 and H2 (Palrasu et al., 2019). Given lack of knowledge about side effects of using spliceosomal binders in humans, an acute toxicity study was conducted to evaluate these compounds in mice. Male and female mice were treated with compounds 2155-14 and 2155-18 at 50mg/kg/day via subcutaneous injections and the clinical signs of distress were monitored for 21 days and compared with control mice. Additionally, effect of the leads on blood chemistry, blood cell counts, and organs was evaluated. No significant changes were observed in the mice body weight, blood cell count, blood chemistry, or organs following the compound treatment. The results show that our compounds 2155-14 and 2155-18 are not toxic for the study period of three weeks.

Euglenoids are a common component of primary producers in high acidic and organic shallow freshwater systems. They are free-living photosynthetic motile flagellates exhibiting rapid responses to various external stimuli including chemical pollution. The unique combination of diverse physiological processes of Euglena such as photosynthesis, movement, and orientation offers a range of sensitive criteria that respond to aquatic pollutants. This has led to the development of several acute and chronic assay methods to monitor the adverse impacts of potent toxicants in aquatic ecosystems. Euglenoids also reflect the consequences of physical stress factors such as UV radiation. This review summarizes the ecotoxicity studies using euglenoid flagellates as model species and their potential to contribute toward rapid screening of ecological impacts of pollution in the aquatic environment. Factors determining the reliability of Euglena tests are outlined.

We tested the hypothesis that obesity influences the pharmacodynamics of volatile general anesthetics (VGAs) by comparing effects of anesthetic exposure on mortality from traumatic brain injury (TBI) in lean and obese Drosophila melanogaster. We induced TBI with a High-Impact Trauma device. Starvation-selection over multiple generations resulted in an obese phenotype (SS flies). Fed flies served as lean controls (FC flies). Adult (1-7 day old) SS and FC flies were exposed to equianesthetic doses of isoflurane or sevoflurane either before or after TBI. The principal outcome was percent mortality 24 hours after injury, expressed as the Mortality Index at 24 hours (MI24). TBI resulted in lower MI24 in FC than in SS flies (21 (2.35) and 57.8 (2.14), respectively n= 12, p=0.0001). Preexposure to isoflurane or sevoflurane preconditioned FC flies to TBI reducing the risk of death to 0.53 [0.25 to 1.13] and 0.82 [0.43 to 1.58], respectively, but had no preconditioning effect in SS flies. Postexposure to isoflurane or sevoflurane increased the risk of death in SS flies. Only postexposure to isoflurane increased the risk in FC flies (1.39 [0.81 to 2.38]). Thus, obesity affects the pharmacodynamics of VGAs, thwarting the preconditioning effect of isoflurane and sevoflurane in TBI.

Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English-language publications from 2008 – 2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimizing safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found few, but no serious, adverse events associated with phage therapy. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics.

Sorghum is a multipurpose crop, but Cr(VI) toxicity influenced the production of the crop and have established highlighted courtesy, due to robust toxicity and a comparatively less known mode of action. Many reports approve the negative impact of Cr(VI) on plants. Yet, it is not clear that, at what concentrations, Cr(VI) inhibits the growth and nutrient quality of Sorghum. In the present research, toxic effects appeared after 1ppm of Cr treatment. The plant growth decreased 15 – 20% and nutritional quality decreased 30 – 40% significantly with increasing concentration of Cr(VI). Toxic components increased 14 – 16% with increasing concentration of Cr(VI) in both the varieties (HJ 541 and SSG 59-3). Chromium was accumulated more in roots followed by shoots with increasing Cr(VI) treatments (0-4 ppm). Chromium at 4ppm level was becoming lethal to Sorghum. Sorghum cultivar SSG 59-3 was more tolerable to Cr toxicity than HJ 541. Chromium accumulated in Sorghum and increased HCN content and at higher doses adversely affects the nutritive values and growth making it toxic for animal consumption. These findings may be useful for scheming a mitigation strategy for chromium toxicity.

Andean blueberries are wild berries grown and consumed in Ecuador which contain high values of bioactive compounds, mainly anthocyanins, with powerful antioxidant activity. The aim of this study was to evaluate the profile and contents of (poly)phenols and carotenoids in Andean blueberry by HPLC-DAD-MSn and determine a wide range of its biological activities. The antioxidant capacity of this fruit was evaluated in vitro by three different methods and in vivo using the zebrafish animal model, also the toxicity effect was determined by the zebrafish embryogenesis test. Besides, the antimicrobial activity and the capacity of Andean blueberry to produce hemagglutination in blood cells were evaluated. Finally, the bioaccessibility of (poly)phenols and related antioxidant capacity were determined in the different phases of an in vitro digestion. The global results indicated no toxicity of Andean blueberry, weakly bacteriostatic activity, and high contents of anthocyanins and antioxidant capacity, which were partially bioaccesible in vitro (~ 50 % at the final intestinal step), contributing to the knowledge of its health benefits for consumers and its potential use in the food and pharmaceutical industry as functional ingredient.

Bisphenols are widely used in the synthesis of polycarbonate plastics, epoxy resins and thermal paper, which are used in manufacturing items of daily use. Packaged foods and drinks are the main sources of exposure to bisphenols. These chemicals affect humans and animals by disrupting the estrogen, androgen, progesterone, thyroid, and aryl hydrocarbon receptor functions. Bisphenols exert numerous harmful effects because of their interaction with receptors, ROS formation, lipid peroxidation, mitochondrial dysfunction, and cell signal alterations. Both cohort and case-control studies have determined an association between bisphenol exposure and increased risk of cardiovascular diseases, neurological disorders, reproductive abnormalities, obesity, and diabetes. Prenatal exposure to bisphenol results in developmental disorders in animals. These chemicals also affect the immune cells and play a significant role in initiating the inflammatory response. Exposure to bisphenols exhibit age, gender, and dose-dependent effects. Even at low concentrations, bisphenols exert toxicity, and hence deserve a critical assessment for their uses. Since bisphenols have a global influence on human health, the need to discover the underlying pathways involved in all disease conditions is essential. Furthermore, it is important to promote the use of alternatives for bisphenols, thereby restricting their uses.

Heavy metals and organic pollutants are ubiquitous environmental pollutants affecting the quality of soil, water and air. Over the past 5 decades, many strategies have been developed for the remediation of polluted water. Strategies involving aquatic plant use are preferable to conventional methods. In this study, an attempt was made to provide a brief review on recent progresses in research and practical applications of phytoremediation for water resources with the following objectives: (1) to discuss the toxicity of toxic chemicals pollution in water to plant, animals and human health (2) to summarise the physicochemical factors affecting removal of toxic chemicals such as heavy metals and organic contaminants in aqueous solutions by aquatic plants; (3) to summarise and compare the removal rates of heavy metals and organic contaminants in aqueous solutions by diverse aquatic plants; and (4) to summarise chemometric models for testing aquatic plant performance. More than 20 aquatic plants specie have been used extensively while duckweed (L. minor), water hyacinth (Eichhornia crassipes), water lettuce (P. stratiotes) are the most common. Overall, chemometrics for performance assessment reported include: Growth rate (GR), Growth rate inhibition (% Inhibition), Metal uptake (MU), translocation/transfer factor (TF), bioconcentration factor (BCF), Percent metal uptake (% MU), Removal capacity (RC) and Tolerance index (TI) while absorption rate have been studied using the sorption kinetics and isotherms models such as pseudo-first-order (PFO), pseudo-second-order (PSO), Freundlich, Langmuir and Temkin. Using modeling and interpretation of adsorption isotherms for performance assessment is particularly good and increases level of accuracy obtained from adsorption processes of contaminant on plant. Conclusion was drawn by highlighting the gap in knowledge and suggesting key future areas of research for scientists and policymakers.

Current problem facing researchers globally is microplastics as well as toxic chemical pollution of the ecosystem. Microplastics carry toxic chemicals in the ecosystem.serving as a vector for transport. In this study, a review of the literature has been conducted with the following objectives: (1) to summarise the concentrations of toxic chemicals such heavy metals and hydrophobic organic contaminants sorped on microplastics; (2) to evaluate their spatial distribution regarding adsorbed contaminant (3) to discuss plausible mechanism by which microplastics adsorp or desorp toxic chemicals in the environment; (4) to discuss implications of their occurrence in air, water and soil media; and (5) to discuss the impact of ingested microplastics to human health. Microplastics are ubiquitous environmental contaminant. Concentrations of sorped toxic chemical varied with location which represents a local problem; industrialized areas (especially areas experiencing crude oil related activities or have history of crude oil pollution) have higher concentrations than less industrialized areas. Ingestion of microplastics has been demonstrated in a range of marine and soil organisms as well as edible plants, thus possible contaminating the base of the food-web. Potential health effect to human is by particle localization, chemical toxicity and microbal toxins. We conclude by highlighting the gap in knowledge and suggesting key future areas of research for scientists and policymakers.

In intermediary metabolism, enzymes are mainly for the specific provision of one small molecule from another, B from A, for its further use. But there are also decades of work relating to another evolved purpose, which is to prevent untoward effects of odd compounds of various origins, and of ordinary intermediates, whose improper concentrations may be avoided by hydrolases and other activities of metabolic correction.

The present study aimed at investigating the in vitro and in vivo susceptibility of malaria parasites to crude extracts and fractions from Polyalthia suaveolens, Uvaria angolensis, and Monodora tenuifolia. The ethanolic extracts were prepared by maceration, and were further partitioned using water, dichloromethane, hexane, and methanol. The most promising fraction was subjected to column chromatography and the sub-fractions tested for activity in vitro. The antiplasmodial effect of extracts and fractions was tested against the Chloroquine resistant (PfK1) strain in 96 wells microtiter plate format using SYBR green florescence assay. The promising fraction was further assessed for cytotoxicity and acute toxicity in Swiss albino mice and subsequently against the rodent malaria parasite, P. berghei. Qualitative phytochemical screening was also performed on the promising fraction. The methanol fractions exerted the overall better effect with that of the twigs of P. suaveolens (PStw(Ace)) showing the highest potency with a IC50 value of 3.24 µg/mL followed by the fractions of leaf of M. tenuifolia (MoTel(Ace), IC50= 3.84 µg/ml) and stem bark of P. suaveolens (IC50= 4.90 µg/ml). The phytochemical screening showed the presence of alkaloids, lactones, and phenols in the more active fraction of P. suaveolens (PStw(Ace)). The chromatographic fractionation of this fraction led to 12 sub-fractions with PS8 sub-fraction being the most active (IC50= 4.42 µg/mL). In vivo, oral administration of 2000 mg/kg b.w of fraction PStw(Ace) in mice showed no signs of toxicity. Also, fraction PStw(Ace) at 400 mg/kg b.w exerted the highest suppressive effect against P. berghei strain B throughout the 4 days experiment (% parasitaemia below 5.2%). Overall, the results achieved supported the use of the three plants in the traditional treatment of malaria in Cameroon. More interestingly, the methanolic fraction of the twigs extract from P. suaveolens might be of interest in future development of an antimalarial phytodrug.

Human exposure to foodborne inorganic nanoparticles (NPs) is a growing concern. However, identifying potential hazards linked to NP ingestion often requires long-term exposure in animals. Owing these constraints, intestinal organoids are a promising alternative to in vivo experiments, as such an in vitro approach should enable rapid and reliable assessment of the effects on the gut of ingested chemicals. However, this remains to be validated for inorganic substances. In our study, a transcriptomic analysis and immunofluorescence staining were performed to compare the effects of food-grade TiO2 (fg-TiO2) on enteroid-derived monolayers (EDMs) from murine intestinal organoids to known impacts of TiO2 on intestinal epithelium. After validating their ability to dose-dependently respond to a pro-inflammatory cytokine cocktail, EDMs were exposed to 0.1, 1 or 10 µg fg-TiO2/mL for 24h. In line with known data, a dose-related increase of muc2, vilin 1 and chromogranin A gene markers of cell differentiation was observed. In addition, fg-TiO2 induced apoptosis and dose-dependent genotoxicity, while a decreased expression of genes encoding for antimicrobial peptides, and of genes related to tight junction function was observed. These results validated the use of EDMs as a reliable model for toxicity testing of foodborne NPs likely to affect the intestinal barrier.

Anastatica hierochuntica L. (Brassicaceae) has been claimed to treat various conditions including complicated childbirth. The principal objective of this research was to provide scientific evidence on the contractile effect of the aqueous and hydroethanolic extracts of the whole plant from A. hierochuntica during labor. Qualitative and quantitative methods helped identify and quantify the phytoconstituents in both extracts. The antioxidant activity was studied using four standard methods. The inhibitory power of the extracts on pro-inflammatory enzymes such as 15-lipoxygenase and phospholipase A2 was determined. The contractile effects of the extracts were evaluated using isolated pregnant mice uteri. Steroids, triterpenoids, flavonoids, tannins, coumarins, and reduced compounds were identified in both extracts. The extracts demonstrated the ability to reduce oxidative stress. The hydroethanolic extract displayed the most significant anti-lipoxygenase activity with an IC50 value of 55.82 ± 1.15 µg/mL. The lethal dose (LD50) of extracts was estimated to be superior to 2000 mg/kg bw. The ability of the samples to produce one cm amplitude of contraction at 50% effective concentrations (EC50) was 1.51 ± 0.08 mg/mL for aqueous extract and 3.57 ± 0.61 mg/mL for hydroethanolic extract. These findings could provide evidence for using Anastatica hierochuntica to augment labor.

Management of calcium and phosphate in biofluids is key to maintaining physiological mineral homeostasis (i.e., appropriate mineralization of hard tissues and an absence of mineral deposition in soft tissues). This review describes and contrasts the ways vertebrates manage calcium phosphate in two biological fluids (breast milk and serum) and illustrates the benefits of mineral sequestration by proteins. In milk, phosphoprotein-sequestered calcium magnesium phosphates provide nutritional support, whereas in serum, protein-sequestered calcium phosphates control transport and delivery of calcium and phosphate to tissues for biological function or excretion. In addition, subsets of sequestered phosphates in serum have been identified as culprits underlying ectopic deposition of calcium phosphates and toxicity.

We have established earlier a cell line from the human limbal area to study cell growth and response to the toxic effects of antibiotics used in ophthalmology. In the recent work, the effect of multi-walled carbon nanotubes (MWCNTs) in cornea damage was investigated in vitro and in vivo in mice. In the in vitro experiments, the physiological effects of multi-walled carbon nano-tube (MWCNT) bundles on corneal wound healing were mimicked in vitro by a reepithelization limbal stem cell model. Murine in vivo experiments were performed with intact, non-functionalized MWCNTs to confirm the validity of in vitro tests. The MWCNTs of 10 -30 nm outer diameter at low concentration (5 µg/ml) did not interfere with the wound healing of the damaged limbal cell monolayer. Higher than 50 µg/ml concentrations: a) generated MWCNT aggregates, b) restrained the movement and prolonged the time of wound healing, c) increased the amplitudes of the oscillations of the cells, and d) resulted in scar formation affecting both cor-neal function and refraction. Chromatin condensation, a sensitive test of the viability of cells, including limbal stem cells revealed that the presence of a low concentration of nanotubes (5 µg/ml), did not significantly affect the viability of limbal cells. Chromatin condensation was completed and metaphase chromosomes were seen at higher MWCNT concentration proving that their aggregates did not affect the viability of limbal cells. This concentration of MWCNTs (5 µg/ml) did impact neither the reepithelization in vitro nor in vivo in the scratched eyes of mice. Scar formation took place at higher than 50 µg/ml concentrations and the healing of the cornea was prevented by the lack of movement of increasingly larger macroaggregates. In vivo murine experiments vali-dated in vitro monolayer regrowth followed by time-lapse microscopy portraying realistically the reepithelization of the damaged cornea that process was gradually slowed down by macro aggregate formation and caused the scarring of the cornea.

Advanced Hepatocellular carcinoma (HCC) is no longer a terminal illness. This change was mainly attributed to the development of new treatments including tyrosine-kinase inhibitors (TKIs), vascular endothelial growth factor (VEGF) inhibitors and immune checkpoint inhibitors (ICPIs) but the financial toxicity of treating advanced HCC is of a major concern specially in low middle-income countries (LMICs) where the patients are still battling for their most basic rights. Most of advanced HCC patients in LMICs have very limited accessibility to the new treatments including ICPIs. Searching for out of the box solutions to improve access to treatments -mainly ICPIs- is an utmost necessity for LMICs advanced HCC patients.

Silicon nanoparticles (SiNPs) are highly promising for biological and biomedical applications, including bioimaging, due to their unique opltical properties (i.e. strong fluorescence and very high photostability). Their low or negligible in vitro toxicity has been reported, but in vivo toxicity and biological effects of SiNPs are still uncertain. Uncoated SiNPs were dispersed in distilled water via sonication, and their rapid aggregation was observed (319.0 ± 2.4 nm particle size). In vivo toxicity was studied using Danio rerio embryos and larvae. Rapid aggregation in their incubation medium was observed; besides that, SiNPs at 25 mg/L or higher concentration induced swim bladder malformation and/or death of the fish. The estimated LC50 value for 7-day larvae was 180 mg/L. This is the first in vivo toxicity study of uncoated and unfunctionalized SiNPs. To achieve better stability in biological media and lower toxicity, SiNPs should be covered with hydrophilic layers, but their absorption by cellular membranes may be weaker in this case.

Context: Persea Americana is reported to have medicinal value. Calcium Carbide (CaC2), a fruit-ripening agent, has been shown to be toxic to body organs. Objective: To determine the effect of avocado seed extract (ASE) on CaC2-induced hepatotoxicity in rats. Methodology: Four experimental groups, each of 5 adult wistar rats were fed respectively with normal diets (group A); 250mg/kg ASE (group B); 100mg/kg CaC2 (group C); combination of 100mg/kg CaC2 and 250mg/kg ASE – group D. Changes in the rats’ behaviours, body weights, and liver function were assessed over 21 days. Data were analyzed using SPSS. The cumulated rat weights, rat liver weights and serum liver enzyme levels for groups B, C, and D rats were compared to group A. Results: Abnormal behavior was most observed in group C rats. Rats in group A showed a significant increase in weight before and three weeks following administration of feeds while rats in groups B, C, and D showed significant decrease in weight – more marked in group C rats. Only the mean liver weights of rats in group C showed significant decrease compared to that in group A, p = 0.001. Similarly, only the cumulated liver enzyme levels of rats in group C demonstrated significant increase when compared to group A rats - indicating hepatotoxicity. Conclusion In this study, hepatotoxicity occurred in CaC2-administered rats. However, the combination of CaC2 and ASE showed no liver toxicity indicating a mitigating effect of ASE to CaC2-induced hepatotoxicity.

Coronavirus disease (COVID-19) is the current global public health threat with no specific, effective, and approved treatment available till date. The outbreak of COVID-19 has led the world into an unimagined and uncertain situation by disrupting the economies, claiming human lives, and leaving many into secondary mental health problems. As per the latest WHO report, approximately 8.2 million people are infected, and nearly 0.44 million lives are lost to COVID. The infection has spread to over 200 countries and territories around the world. The world is in search of efficient diagnostics and therapeutics, including vaccines, biologics and drugs. With the rapid increase in rates of infection and time constraints, drug repurposing seems to be a potential and viable option to find the promising anti-COVID therapeutics. In the wake of a rapid increase in the number of clinical trials involving drugs for repurposing, we aim to provide information on the safety concerns related to the drugs currently investigated in trials. This review also highlights the possible mechanisms of actions, adverse drug reactions, and contraindications of the drugs under repurposing evaluation.

Lead (Pb) is a toxic environmental heavy metal that induces serious clinical defect on all organs with the nervous system being the primary target. Curcumin is the main active constituent of turmeric rhizome (Curcuma longa) with strong antioxidant and anti-inflammatory properties. This study is aimed at evaluating the therapeutic potentials of curcumin on Pb-induced neurotoxicity. Thirty six male Sprague Dawley rats were randomly assigned into five (5) groups with 12 rats in the control (normal saline) and 6 rats for the lead treated group (LTG) (50 mg/kg lead acetate for 4 weeks), recovery group (RC) (50 mg/kg lead acetate for 4 weeks), treatment group 1 (Cur100) (50 mg/kg lead acetate for 4 weeks, followed by 100 mg/kg curcumin for 4 weeks) and treatment group 2 (Cur200) (50 mg/kg lead acetate for 4 weeks, followed by 200 mg/kg curcumin for 4 weeks) groups each. All experimental groups received the oral treatments through orogastric-tube on alternate days. Motor function was assessed using horizontal bar method while Pb concentration in the cerebellum of the rats were evaluated using ICP-MS techniques. Pb-administered rats showed significant decrease in motor scores, SOD activity with increase MDA levels and Pb concentration in their cerebellum with marked alterations in the histological architecture of the cerebellar cortex layers. However, treatment with curcumin improved the motor score, reduced Pb concentration in the cerebellum and ameliorates the markers of oxidative stress as well as restored the histological architecture of the cerebellum. The results this in study suggested that curcumin attenuates Pb-induced neurotoxicity via inhibition of oxidative stress and chelating activity.

Lead (Pb) is a toxic environmental heavy metal that induces serious clinical defect on all organs with the nervous system being the primary target. Curcumin is the main active constituent of turmeric rhizome (Curcuma longa) with strong antioxidant and anti-inflammatory properties. This study is aimed at evaluating the therapeutic potentials of curcumin on Pb-induced neurotoxicity. Thirty six male Sprague Dawley rats were randomly assigned into five (5) groups with 12 rats in the control (normal saline) and 6 rats for the lead treated group (LTG) (50 mg/kg lead acetate for 4 weeks), recovery group (RC) (50 mg/kg lead acetate for 4 weeks), treatment group 1 (Cur100) (50 mg/kg lead acetate for 4 weeks, followed by 100 mg/kg curcumin for 4 weeks) and treatment group 2 (Cur200) (50 mg/kg lead acetate for 4 weeks, followed by 200 mg/kg curcumin for 4 weeks) groups each. All experimental groups received the oral treatments through orogastric-tube on alternate days. Motor function was assessed using horizontal bar method while Pb concentration in the cerebellum of the rats were evaluated using ICP-MS techniques. Pb-administered rats showed significant decrease in motor scores, SOD activity with increase MDA levels and Pb concentration in their cerebellum with marked alterations in the histological architecture of the cerebellar cortex layers. However, treatment with curcumin improved the motor score, reduced Pb concentration in the cerebellum and ameliorates the markers of oxidative stress as well as restored the histological architecture of the cerebellum. The results this in study suggested that curcumin attenuates Pb-induced neurotoxicity via inhibition of oxidative stress and chelating activity.

The [PSI⁺] nonsense-suppressor determinant of Saccharomyces cerevisiae is related to formation of heritable amyloids of the Sup35 (eRF3) translation termination factor. [PSI⁺] amyloids have variants in amyloid structure and in the strength of suppressor phenotype. Appearance of [PSI⁺], its propagation and manifestation depend primarily on chaperones. Besides chaperones, the Upf1/2/3, Siw14 and Arg82 proteins restrict [PSI⁺] formation, while Sla2 can prevent the [PSI⁺] toxicity. Here, we identify two more non-chaperone proteins involved in [PSI⁺] detoxification. We show that simultaneous lack of the Pub1 and Upf1 proteins causes lethality of [PSI⁺] cells with a strong, but not with weak suppressor phenotype. This lethality results from excessive depletion of the Sup45 (eRF1) termination factor due to its sequestration into Sup35 polymers. We also show that Pub1 acts to restrict excessive Sup35 prion polymerization, while Upf1 interferes with Sup45 binding to Sup35 polymers. These data allow considering the Pub1 and Upf1 proteins as a novel [PSI⁺] detoxification system.

Despite widespread industrial use, the environmental safety of Hydroquinone (HQ), a benzene compound from plants used in processes like cosmetics, remains uncertain. This study evaluated the ecotoxicological impact of HQ on soil and river environments, utilizing non-target indicator organisms from diverse trophic levels: Daphnia magna, Vibrio fischeri, Allium cepa, and Eisenia fetida. For a more environmentally realistic assessment, microbial communities from a river and un-treated soil underwent 16S rRNA gene sequencing, with growth and changes in community-level physiological profiling assessed using Biolog EcoPlate™ assays. The water indicator D. magna exhibited the highest sensitivity to HQ (EC50 = 0.142 µg/mL), followed by V. fischeri (EC50 = 1.446 µg/mL), and A. cepa (LC50 = 7.631 µg/mL), while E. fetida showed the highest resistance (EC50 = 234 mg/Kg). Remarkably, microbial communities mitigated HQ impact in both aquatic and terrestrial environments. River microorganisms displayed minimal inhibition, except for a significant re-duction in polymer metabolism at the highest concentration (100 µg/mL). Soil communities demonstrated resilience up to 100 µg/mL, beyond which there was a significant decrease in population growth and the capacity to metabolize carbohydrates and polymers. Despite microbial mitigation, HQ remains highly toxic to various trophic levels, emphasizing the necessity for en-vironmental regulations.

Industrial hemp (Cannabis sativa L.), due to its bioactive compounds (terpenes and cannabinoids), has gained an increasing interest in different fields, including medical purposes. The evaluation of the safety profile of hemp essential oil (EO) and its encapsulated form (nanoemulsion, NE) is a relevant aspect for potential therapeutic applications. This study aimed to evaluate the toxicolog-ical effect of hemp EOs and NEs from cultivars Carmagnola CS and Uso 31, on three cell lines se-lected as models for topical and inhalant administration, by evaluating the cytotoxicity and the cytokine expression profiles. Results show that EOs and their NEs have comparable cytotoxicity, if considering the quantity of EO present in the NE. Moreover, cells treated with EOs and NEs showed, in most of the cases, lower levels of pro-inflammatory cytokines compared to Etoposide used as positive control, and the basal level of inflammatory cytokines was not altered, suggest-ing a safety profile of hemp EOs and their NEs to support their use for medical applications.

Background. Many anticancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (compound B) showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds, in comparison with 4 popular anticancer drugs. Methods: Tumor-specificity (TSM, TSE, TSN) was evaluated as the ratio of mean CC50 for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. Results: Compounds A and B showed one-order of magnitude higher TSM as compared with newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two order of magnitude lower TSE than compounds A and B. Compounds A and B showed higher TSM, TSE and TSN values than doxorubicin, 5-FU and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that compounds A and B may inhibit the signaling pathway of estrogen-related receptors.

Extracorporeal membrane oxygenation (ECMO) can be a life-saving intervention in cases of potentially reversible refractory respiratory failure. One such indication can be bleomycin-induced lung injury. However, in some cases, the injury can be so severe that it becomes irreversible and creates complex medical decisions regarding life support and the continuation of care when no additional therapeutic options are feasible, particularly in cases of patients who were young and fully functional prior to an acute illness. In cases of full pulmonary replacement with mechanical support and the degree of functionality that can be attained utilizing modalities such as ECMO can obscure the true severity of illness and make end-of-life decisions significantly harder for families and caregivers.

Gossypol is a complex plant polyphenol reported to be cytotoxic and anti-inflammatory, but little was known about its effect on gene expression in macrophages. The objective was to explore gossypol’s toxicity and its effect on gene expression involved in inflammatory responses, glucose transport and insulin signaling pathway in mouse macrophages. Mouse RAW264.7 macrophages were treated with multiple concentrations of gossypol for 2-24 h. Gossypol toxicity was estimated by MTT assay and soluble protein content. qPCR analyzed the expression of anti-inflammatory tristetraprolin family (TTP/ZFP36), proinflammatory cytokine, glucose transporter (GLUT) and insulin signaling genes. Cell viability was greatly reduced by gossypol, accompanied with dra-matic reduction of soluble protein content in the cells. Gossypol treatment resulted in an increase of TTP mRNA level 6-20 fold and increased ZFP36L1, ZFP36L2 and ZFP36L3 mRNA levels by 26-69 fold. Gossypol increased proinflammatory cytokine TNF, COX2, GM-CSF, INFγ and IL12b mRNA levels up to 39-458 fold. Gossypol treatment upregulated mRNA levels of GLUT1, GLUT3 and GLUT4 genes as well as INSR, AKT1, PIK3R1 and LEPR but not APP genes. This study demonstrated that gossypol induced macrophage death and reduced soluble protein content that was accom-panied with massive stimulation of anti-inflammatory TTP family and proinflammatory cytokine gene expression as well as elevation of gene expression involved in glucose transport and insulin signaling pathway in mouse macrophages.

The assessment of an organization/product's environmental footprint is based on the protocols developed by the Joint Research Centre of the European Union, which take into account 16 impact categories. Among the categories covered are toxicity to freshwater ecosystems and to humans. Standard protocols use only chemical parameters as input data, preventing the true impact of entire complex mixtures, such as emissions discharged into the environment, from being determined. Biological assays allow us to bridge this gap: in the current study, assays were used to determine baseline toxicity towards aquatic organisms (green algae, luminescent bacteria, and crustaceans) as well as specific toxicity (mutagenicity and carcinogenicity). Expected impacts were compared using two approaches (standard and bioassay-centered results obtained are not always in line and, in general, the traditional method underestimates impacts). This demonstrates the importance of these assays and suggests that they be used in LCA (Life Cycle Assessment) protocols as well.

The research was conducted in the Kırklareli stream, which flows southwest through the city of the same name toward the village of Kavaklı. The aim of the study is to evaluate water analysis results and assess the potential that the European Union drinking water standard for lead can be achieved in the Kırklareli stream by reliance on the low solubility of lead phosphate minerals. The present study used Visual MINTEQ 3.1 for all water chemistry simulations. The European Union drinking water standard for lead, which is 10 μg L⁻¹, is exceeded at least once and as many as three times at seven of the ten sites during the 2018 sampling season. Although the database solubility of hydroxypyromorphite is exceeded in most samples, it appears this may be the result of major ion substitutions in the hydroxypromorphite that forms in the Kırklareli stream which increases the effective solubility of lead in the stream.

Acute chemical ablation of lateral line hair cells is an important tool to understand lateral line-mediated behaviors in free-swimming fish larvae and adults. However, lateral line-mediated behaviors have not been described in fish larvae prior to swim bladder inflation, possibly because single doses of ototoxin do not effectively silence lateral line function at early developmental stages. To determine if ototoxins can effectively silence the lateral line during early development, we repeatedly expose zebrafish larvae to the ototoxin neomycin during a 36-hour period from 3-4 days post-fertilization (dpf). We use simultaneous transgenic and vital dye labeling of hair cells to compare 6- hour and 12-hour repeated treatment timelines and neomycin concentrations between 0–400 µM in terms of larval survival, hair cell death, regeneration, and functional recovery. Following exposure to neomycin, we find that the emergence of newly functional hair cells outpaces cellular regeneration, likely due to the maturation of ototoxin-resistant hair cells that survive treatment. Furthermore, hair cells of 4 dpf larvae exhibit faster recovery compared to 3 dpf larvae. Our data suggest that the rapid functional maturation of ototoxin-resistant hair cells limits the effectiveness of chemical-based methods to disrupt lateral line function. Furthermore, we show that repeated neomycin treatments can continually ablate lateral line hair cells between 3–4 dpf in larval zebrafish.

The cork oak (Quercus suber L.), endemic essence of the Mediterranean Basin, is commonly used in traditional pharmacopoeia. The main objective of this work is to enhance the valorization of this plant species through the study of the anticandidosic activity of cork oak bark methalonic extracts in order to develop an efficient natural formulation for Candidiasis treatment.The anticandidosic activity of methanolic extracts of Q. suber bark stemming from decoction, maceration and Soxhlet methods of extraction in was tested on five different Candida albicans strains. Our results showed that all the tested extracts displayed an inhibitive activity, which varies according to the obtained extract and the tested strain. The best anticandidosic potential was observed with extracts obtained with Soxhlet method. The study of the acute toxicity showed that the lethal dose is 1150 mg/kg in mice, which remained moderately toxic according to Hodge and Sterner classification scale. Thus, this extract can be used in phytotherapy without danger in doses that are below 300 mg/kg of corporal weight. Based on these results, we can conclude that Cork oak bark extracts can be used to treat Candida albicans infections.

In recent years, many studies have highlighted the consistent finding of amoxicillin in waters destined for wastewater treatment plants, in addition to superficial waters of rivers and lakes in both Europe and North America. In this paper, the amoxicillin degradation pathway was investigated by simulating the chlorination process normally used in a wastewater treatment plant to reduce similar emerging pollutants at three different pH values. The structures of 16 isolated degradation byproducts (DPs), one of which was isolated for the first time, were separated on a C-18 column via a gradient HPLC method. Then, combining mass spectrometry (MALDI-MS/TOF) and nuclear magnetic resonance, we compared commercial standards and justified a proposed formation mechanism beginning from the parent drug. Microbial growth inhibition bioassays with Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus were performed to determine the potential loss of antibacterial activity in isolated degradation byproducts. An increase of antibacterial activity in the DPs was observed compared to the parent compound.

Disruption of epigenetic regulation by environmental toxins is an emerging point of focus for understanding the latter’s impact on human health. Polybrominated diphenyl ethers (PBDEs), one such toxin, are an environmentally pervasive class of brominated flame retardants that have been extensively used as coatings on a wide range of consumer products. Their environmental stability, propensity for bioaccumulation, and known links to adverse health effects have evoked extensive research to characterize underlying biological mechanisms of toxicity. Of particular concern is the growing body of evidence correlating human exposure levels to behavioral deficits related to neurodevelopmental disorders. The developing nervous system is particularly sensitive to influence by environmental signals, including dysregulation by toxins. Several major modes of actions have been identified, but a clear understanding of how observed effects relate to negative impacts on human health has not been established. Here we review the growing body of evidence for epigenetic disruptions induced by PBDEs, including DNA methylation, chromatin dynamics, and non-coding RNA expression while discussing potential relationship between PBDEs and neurodevelopmental disorders.

The air is not the same as thousands and hundreds of years ago. In the air, suspended particles originate from natural phenomena like dust storms or volcanic activities, as well as anthropogenic pollutants such as fuel engine exhaust and everyday activities at home. The total particles in the air can be classified by sizes, such as PM10, PM2.5 or ultrafine particles. However, there are many other important factors in addition to the particle size, influencing the particle behavior and affecting our health. The surface area, chemical and biological composition, aspect ratio, and the charge are all factors characteristic of particles. OoC microfluidic chips are very useful for the pollutant toxicity measurements on various body tissues. A better understanding of pollutants will help to trace these to the potential sources. The data from the on-the-ground and satellite monitoring can be integrated into models, helping to predict and prevent pollution exposure.

Microalgae are highly attractive to various industrial sectors and can serve as indicators of aquatic environmental health. An essential step for cultivating microalgae is assessing the cell density, which is traditionally performed through viable cell counting by optical microscopy (OM). However, this method has some limitations, such as the time involved in the process of counting, and the need for specialized training of laboratory personnel. Spectrophotometry is an affordable alternative, especially when applied to culture growth and toxicological tests. We chose the wavelength of 680 nm to detect the optical density (OD) of the green freshwater microalga Desmodesmus subspicatus and green the marine microalga Tetraselmis sp. The correlation between the number of cells and OD was suitable for both microalgae and accuracy was comparable to traditional OM counting. In toxicological tests, the OD technique allowed the monitoring of microalgal growth in the presence of the chemicals potassium dichromate, potassium chloride and sodium dodecyl sulfate (SDS), with results very close to those reported in the scientific literature. This study sheds light on this well-known technique, which is an important contribution since few articles have explored its potentialities and fragilities, showing the successful application to monitoring green microalgal cultures and toxicological assays.

ABSTRACT Heavy metals have been classified as dangerous environmental pollutants. Interest in feasible ways to reduce heavy metals pollution is a noble goal. Adsorption is an effective method based on its effectiveness and low- cost. Nowadays, low-cost bio-sorbents have been utilized to replace costly expensive adsorbents. Rich cellulose materials are effective heavy metal adsorbents, and their performance can be enhanced via chemical modification. The present work reviews the steady progress in the utilization of agriculture by-product wastes as heavy metal bio-sorbent. The unique advantages of these by-products such as renewability, abundance, simple processing, and low cost, justifier this work. The results confirm that the chemically treated agro-wastes exhibit high- removal efficiency (reaches 95% in most cases). The adsorption isotherm studies indicate that the concentration of the metal ions has a significant effect on the adsorption process. The Freundlich model provides a physical adsorption model of the metal ions on the bio-sorbent surface. Langmuir isotherm offers an estimate of the effect of different factors on the efficiency of the process. The adsorption kinetics studies offer an idea of reaction pathways including the adsorption mechanism and the efficiency of the metal ion removal. Applying the pseudo-first-order and pseudo-second-order models describes the adsorption kinetics. This information can be utilized in developing effective strategies to remove heavy metal ions using chemically treated agro-waste. The data confirmed that chemical modification is a significant parameter in the efficiency of metal ion removal. The feasibility and effectiveness of using these cellulosic by-products as bio-sorbent should be given attention and encouraged.

Given the dramatic increase of L. sceleratus population in southeastern Aegean Sea, there is growing interest in assessing the toxicity of this pufferfish and the factors controlling its tetrodotoxin (TTX) content. In the present study, liver, gonads, muscle and skin of L. sceleratus specimens from Rhodes island, Greece were subjected to multi-analyte profiling using liquid chromatography - tandem mass spectrometry (LC-MS/MS) in order to quantitate TTX and evaluate whether this biotoxin interrelates with hormones. TTX and its analogues 4-epiTTX, 11-deoxyTTX, 11-norTTX-6-ol, 4,9-anhydroTTX and5,11-6,11-dideoxyTTX were detected in all tissue types. Liver and gonads were the most toxic tissues, with the highest TTX concentrations being observed in the ovaries of female specimens. Only 22% of the analyzed muscle samples were non-toxic according to the Japanese toxicity threshold (2.2 μg TTX eq g-1), confirming the high poisoning risk from from the inadvertent consumption of this species. Four steroid hormones (i.e., cortisol, testosterone, androstenedione and β-estradiol) and the gonadotropin-releasing hormone (GnRH) were detected in the gonads. Androstenedione dominated in female specimens, while GnRH was more abundant in males. A positive correlation of TTX and its analogues with β-estradiol was observed. Though, a model incorporating sex rather than β-estradiol as independent variable was proved more efficient in predicting TTX concentration, implying that other sex-related characteristics are more important than specific hormone-regulated processes.

Carrageenan (car-), used in the pharmaceutical as well as food industry, is marine sulfated polysaccharides. The carrageenan blends (CB) of kappa (κ-), iota (ι-), and lambda (λ-) of 50/50 weight by weight are multipurpose and biocompatible hydrophilic polymers. They were subjected to adsorption of copper (Cu2+) ions. The aim of the study was to conduct extensive rheological and mechanical studies rendering them suitable for biological purposes. The rheology was conducted at various temperatures using a frequency curve, frequency sweep, loss modulus, and storage modulus analysis. Models of rheology like Ostwald, Bingham, and Modified Bingham models were utilized. The rheological results demonstrated non-Newtonian/pseudo-plastic behavior at various temperatures. The models of rheology demonstrated good flow properties and rheological performance of these materials. These materials could be exploited for their application in pharmaceuticals, food, and cosmetics. Thus, our study reflects that these CB can be safely exploited in the healthcare, pharmaceutical, and food industry. However, further studies should be conducted to evaluate their effectiveness in clinical studies.

Phthalate esters (PAEs) are a ubiquitous kind of environmental endocrine-disrupting chemicals, causing environmental and health issues. EstJ6 is an effective phthalate-degrading hydrolase, and its mutant with a combination of three non-conservative distal mutations has an improved activity against PAEs with unknown molecular mechanisms. Herein, we attempt to fill the significant gap between distal mutations and the activity of this enzyme using computational approaches. We find mutations result in a redistribution of enzyme’s preexisting conformational states and dynamics changes of key functional regions, especially the lid over the active site. The outward motion of the lid upon mutations should make it easier for substrates or products to enter or exit. Additionally, the stronger substrate binding affinity and conformational rearrangements of catalytic reaction-associated residues in mutant, accompanied by the strengthened communication within the protein, might contribute to the elevated catalytic efficiency. Finally, an attempt has been done to improve the thermostability of EstJ6 upon introducing a distal disulfide bond between residues A23 and A29, and the simulation results are as expected. Together, our work explored the allosteric effects caused by distal mutations, which could provide insights into the rational design of esterases for industrial applications in the future.

TomoBreast hypothesized that hypofractionated 15 fractions/3 weeks image-guided radiation therapy (H-IGRT) can reduce lung-heart toxicity, as compared with normofractionated 25-33 fractions/5-7 weeks conventional radiation therapy (CRT). 123 women with stage I-II operated breast cancer were randomized to receive CRT (N=64) or H-IGRT (N=59). The primary endpoint used a four-items measure of the time to 10% alteration in any of patient self-reported measure, physician clinical evaluation, echocardiography or lung function tests, analyzed by intention-to-treat without exclusion. Results found comparable survivals, but H-IGRT significantly reduced the toxicity measured by lung diffusion capacity and alveolar volume as compared with CRT, G1 in 53% (31/59) versus 72% (44/61) patients, P=0.006; G2, 29% versus 48%, P=0.020. H-IGRT significantly reduced the risk of composite cardio-pulmonary alteration at 5 years, 10.2% versus 26.7%, P=0.024. In conclusion, TomoBreast is a proof-of-concept that image-guided radiation-therapy can improve the overall balance of lung-heart outcomes in breast cancer adjuvant therapy. Furthermore, the significance of the findings supports the efficacy of a small trial size design, which can be critical when clinical research resources are limited.

Heavy metals have adverse effects on microalgae growth and metabolism. Photosynthesis and lipid profile are quite sensitive to heavy metal toxicity. The impact of chromium (Cr) on growth and photosynthetic activity of Dictyosphaerium pulchellum and Micractinium pusillum exposed to different concentrations (0 – 500 μg L-1) was investigated for 11 days. The influence of Cr on cell density and cell number followed similar trends, indicating a possible correlation among these growth responses. A significant (p &lt; 0.05) increase in lipid content was observed with the increasing concentration of Cr however, growth was suppressed at higher concentrations exceeding 100 μg L-1. Addition of Cr in the cell culture medium showed a negative effect on quantum yield (Fv/Fm) and a photosynthetic inhibition of &gt; 65% was noted in both species at 500 μg L-1. However, the lipid gravimetric analysis presented inner cell lipid content up to 36% and 30% of dry weight biomass for D. pulchellum and M. pusillum, respectively. The effects of chromium on growth and lipid accumulation in both microalgae species was concentration and exposure time dependent. This shows that an appropriate concentration of chromium in culture medium could be beneficial for higher lipid accumulation in freshwater eukaryotic microalgae species.

Risk assessment of chemicals is usually conducted for individual chemicals whereas mixtures of chemical are occurring in the environment. Considering that neuroactive chemicals are a group of contaminants that dominate in the environment, it is then imperative to understand the combined effects from mixtures. The commonly used models to predict mixture effects, namely concentration addition (CA) and independent action (IA), are thought suitable for mixtures of similarly or dissimilarly acting components, respectively. For mixture toxicity prediction, one important challenge is to clarify whether to group neuroactive substances based on similar mechanisms of action, e.g. same molecular target or rather similar toxicological response, e.g. hyper- or hypoactivity (effect direction). We addressed this by using the spontaneous tail coiling (STC) of zebrafish embryos, which represents the earliest observable motor activity in the developing neural network, as a model to elucidate the link between mechanism of action and toxicological response. Two questions were asked: 1.) Can the mixture models CA or IA be used to predict combined effects for neuroactive chemical mixtures when the components share a similar mode of action (i.e. hyper- or hypoativity) but show different mechanism of action? 2.) Will a mixture of chemicals where the components show opposing effect directions result in an antagonistic combined effect? Results indicate that mixture toxicity of chemicals such as propafenone and abamectin as well as chlorpyrifos and hexaconazole that are known to show different mechanisms of action but similar effect directions were predictable using CA and IA models. This could be interpreted with the convergence of effects on the neural level leading to either a collective activation or inhibition of synapses. We also found antagonistic effects for mixtures containing substances with opposing effect direction. Finally, we discuss how the STC may be used to amend risk assessment.

Assessment of drugs toxicity and associated biomarker genes is one of the most important tasks in the pre-clinical phase of drug development pipeline as well as in the toxicogenomic studies. There are few statistical methods for the assessment of doses of drugs (DDs) toxicity and their associated biomarker genes. However, these methods consume more time for computation of the model parameters using the EM (Expectation-Maximization) based iterative approaches. To overcome this problem, in this paper, an attempt is made to propose an alternative approach based on hierarchical clustering (HC) for the same purpose. There are several types of HC approaches whose performance depends on different similarity/distance measures. Therefore, we explored suitable combinations of distance measures and HC methods based on Japanese Toxicogenomics Project (TGP) datasets for better clustering/co-clustering between DDs and genes as well as to detect toxic DDs and their associated biomarker genes. We observed that Word’s HC method with each of Euclidean, Manhattan and Minkowski distance measures produces better clustering/co-clustering results. For an example, in case of glutathione metabolism pathway (GMP) dataset LOC100359539/Rrm2, Gpx6, RGD1562107, Gstm4, Gstm3, G6pd, Gsta5, Gclc, Mgst2, Gsr, Gpx2, Gclm, Gstp1, LOC100912604/Srm, Gstm4, Odc1, Gsr, Gss are the biomarker genes and Acetaminophen_Middle, Acetaminophen_High, Methapyrilene_High, Nitrofurazone_High, Nitrofurazone_Middle, Isoniazid_Middle, Isoniazid_High are their regulatory (associated) DDs explored by our proposed co-clustering algorithm based on the distance and HC method combination Euclidean: Word. Similarly, for the PPAR signaling pathway (PPAR-SP) dataset Cpt1a, Cyp8b1, Cyp4a3, Ehhadh, Plin5, Plin2, Fabp3, Me1, Fabp5, LOC100910385, Cpt2, Acaa1a, Cyp4a1, LOC100365047, Cpt1a, LOC100365047, Angptl4, Aqp7, Cpt1c, Cpt1b, Me1 are the biomarker genes and Aspirin_Low, Aspirin_Middle, Aspirin_High, Benzbromarone_Middle, Benzbromarone_High, Clofibrate_Middle, Clofibrate_High, WY14643_Low, WY14643_High, WY14643_Middle, Gemfibrozil_Middle, Gemfibrozil_High are their regulatory DDs. These results are validated by the available literature and functional annotation.

The creation of mitochondria-targeted vector systems is a new tool for the treatment of socially significant diseases. Phosphonium groups provide targeted delivery of drugs through biological barriers to organelles. For this purpose, a new class of alkyl(diethylamino)(phenyl) phosphonium iodides (bromides) 1 containing one, two, or three diethylamino groups were obtained by the reaction of alkyl iodides (bromides) with (diethylamino)(phenyl)phosphines under mild conditions and high yields. The structure of compounds 1 was established by NMR and XRD. In vitro a high cytotoxicity against the lines M-Hela, HuTu 80, PC3, DU-145, PANC-1 and MCF-7 was found. Selectivity index are in the range of 0.06-4.0 M (SI 17-277) for the most active compounds. ROS production, mitochondrial localization and the process of cellular apoptosis were investigated. Decorated by 1 of lipid systems (liposomes and solid lipid nanoparticles) improve the cytotoxicity and a decrease in toxicity against normal cell lines. Compounds 1 induce apoptosis proceeding along the mitochondrial pathway. Aminophosphonium salts 1 also exhibit a high selective activity against the Gram-positive bacteria strains S. aureus 209P, B. segeus 8035, including methicillin-resistant strains of S. aureus (MRSA-1, MRSA-2), comparable to the activity of the fluoroquinolone antibiotic norfloxacin. A moderate in vivo toxicity in CD-1 mice was established for the lead compounds.

We report the isolation of two novel degrading bacterial strains active against the potential environmental pollutant acetamino-phen/paracetamol. Streptomyces Chrestomyceticus (RS2) and Streptomyces Flavofuscus (M33) collected from El-Natrun Valley, Egypt, water, sediment, and sand samples were taxonomically characterized via conidiophores morphologic characterization under Trans-mission Electron Microscope (TEM). Genotypic identification, done based on their 16S rRNA gene sequence analysis followed by BLAST alignment and deposited on the NCBI as 2 novel strains. The phylogenetic tree was constructed using an appropriate software. Acetaminophen degradation-products chemical structure was identified by GC/LC MS. The biological antimicrobial activity of some selected acetaminophen degradation-products extracts and derived compounds was examined against panel of test micro-organisms and found to be have high anti-microbial effect. In addition, in silico cheminformatics Swiss ADMET evaluation of these selected deg-radation extract for gastric absorption, distribution, hepatic metabolism, renal excretion as well as distribution to CNS and finally not mutagenic/teratogenic or genotoxic virtually. In vitro cytotoxic activity of these selected bio-degradation products was performed against HepG2 and MCF7 cancer cell lines, revealing that M33 and RS2 extract effect on acetaminophen/paracetamol bio-degradation products are potentially safe with higher IC50 on HepG2 and MCF7, in comparison to acetaminophen/paracetamol with IC50 of 108.5 μg/ml. Moreover, the in vivo acute oral single dose toxicity experiment was conducted, being compared with acetamino-phen/paracetamol to confirm that the bio-degradation products have lower toxicity than acetaminophen in vivo and in silico.

In this manuscript, we reassess the data on beta-amyloid-induced changes of intracellular ions concentrations published previously by Abramov et al. (2003, 2004). Their observations made using high-resolution confocal microscopy with fast temporal resolution of images formed by fluorescent ion-sensitive fluorescent probes in living cells represent an unequivocal support for the amyloid channel theory. However, closer look reveals multiple facts which cannot be explained by channel formation in plasma membrane. Recently proposed amyloid degradation toxicity hypothesis provides the interpretation to these facts by considering that channels are formed in the lysosomal membranes.

The postnatal rodent spinal cord in-vitro is a useful model to investigate early pathophysiological changes after injury. While low dose nicotine (1µM) induces neuroprotection, how higher doses affect spinal networks is unknown. Using spinal preparations of postnatal wild-type Wistar rat and Wnt1Cre2:Rosa26Tom double-transgenic mouse, we studied the effect of nicotine (0.5-10µM) on locomotor networks in-vitro. Nicotine 10µM induced motoneuron depolarization, suppressed monosynaptic reflexes, and decreased fictive locomotion in rat spinal cord. Delayed fall in neuronal numbers (including motoneurons) of central and ventral regions emerged without loss of dorsal neurons. Conversely, nicotine (0.5-1µM) preserved neurons throughout the spinal cord and strongly activated the Wnt1 signaling pathway. High-dose nicotine enhanced expression of S100 and GFAP in astrocytes suggesting their response to stress. Excitotoxicity induced by kainate was contrasted by nicotine (10µM) in the dorsal area and persisted in central and ventral regions with no change basal Wnt signaling. When combining nicotine with kainate, the activation of Wnt1 was reduced compared to kainate/sham. The present results suggest that high dose nicotine was neurotoxic to central and ventral spinal neurons as the neuroprotective role of Wnt signaling became attenuated. This also corroborates the risk of cigarette smoking for the foetus/newborn since tobacco contains nicotine.

Flavonoids comprise a large group of structurally diverse polyphenolic compounds of plant origin and are abundantly found in human diet such as fruits, vegetables, grains, tea, dairy products, red wine and so on. Major classes of flavonoids include flavonols, flavones, flavanones, flavanols, anthocyanidins, isoflavones, and chalcones. Owing to their potential health benefits and medicinal significance, flavonoids are now considered as an indispensable component in a variety of medicinal, pharmaceutical, nutraceutical, and cosmetic preparations. However, flavonoids play a significant role in preventing cardiovascular diseases (CVDs), which could be mainly due to their antioxidant, antiatherogenic, and antithrombotic effects. Epidemiological and in vitro/in vivo evidences of antioxidant effects support the cardioprotective function of dietary flavonoids. Further, the inhibition of LDL oxidation and platelet aggregation following regular consumption of food containing flavonoids and moderate consumption of red wine might protect against atherosclerosis and thrombosis. A study suggests that daily intake of 100 mg of flavonoids through diet may reduce the risk of developing morbidity and mortality due to coronary heart disease (CHD) by approximately 10%. This review summarizes dietary flavonoids with their sources and potential health implications in CVDs including various redox-active cardioprotective (molecular) mechanisms with antioxidant effects. Pharmacokinetic (oral bioavailability, drug metabolism), toxicological and therapeutic aspects of dietary flavonoids are also addressed herein with future directions for the discovery and development of useful drug candidates/ therapeutic molecules.

BODIPY dyes have recently raised attention as potential photosensitizers. In this work, commercial and novel photosensitizers (PSs) based on BODIPY chromophores (haloBODIPYs and orthogonal dimers strategically designed with intense bands in the blue, green or red region of the Visible spectra and high singlet oxygen production) were covalently linked to mesoporous silica nanoparticles (MSNs) further functionalized with PEG and folic acid (FA). MSNs of approximately 50 nm in size with different functional groups were synthesized to allow multiple alternatives of PS-PEG-FA decoration of their external surface. Different combinations varying the type of PS (commercial Rose Bengal, Thionine and Chlorine e6 or custom-made BODIPY-based), the linkage design and the length of PEG are detailed. All the nanosystems were physicochemically characterized (morphology, diameter, size distribution and PS loaded amount) and photophysically studied (absorption capacity, fluorescence efficiency, and singlet oxygen production) in suspension. For the most promising PS-PEG-FA silica nanoplatforms, the biocompatibility in dark conditions and the phototoxicity under suitable irradiation wavelengths (blue, green, or red) at regulated light doses (10-15 J/cm2) were compared with PSs free in solution in HeLa cells in vitro.

Terpenoids are toxic compounds produced by plants as a defense strategy against insect herbivores. We tested the effect of Origanum vulgare terpenoids on the generalist herbivore Spodoptera littoralis and the response of the plant to herbivory. Terpenoids were analyzed by GC-FID and GC-MS and quantitative gene expression (qPCR) was evaluated on selected plant genes involved in both terpene biosynthesis. The insect detoxification response to terpenes was evaluated by monitoring antioxidant enzymes activity and expression of insect genes involved in terpene detoxification. O. vulgare terpenoid biosynthesis and gene expression was modulated by S. littoralis feeding. The herbivore-induced increased level of terpenoids (particularly carvacrol and p-cymene) interacted with the herbivore by decreasing larval survival and growth rate. The assimilation by S. littoralis of more than 50% of ingested terpenes correlated with the possible toxic effects of O. vulgare terpenoids. In choice test experiments, carvacrol and γ-terpinene mediated the larval feeding preferences, wherease the prolonged feeding on O. vulgare terpenoids (particularly on γ-terpinene) exerted relevant antinutritional effects on larvae. S. littoralis was found to react to O. vulgare terpenoids by increasing its antioxidant enzymes activities and gene expression, although this was not sufficient to sustain the toxicity of O. vulgare terpenoids.

: Microplastics and nanoplastics (MNPs) are becoming an increasingly severe global problem due to their widespread distribution and complex impact on living organisms. Apart from their environmental impact, the effects of MNPs on living organisms have also continued to attract attention. The harmful impact of MNPs has been extensively documented in marine invertebrates and larger marine vertebrates like fish. However, the research on the toxicity of these particles on mammals is still limited, and their possible effects on humans are poorly understood. Considering that MNPs are commonly found in food or food packaging, humans are primarily exposed to them through ingestion. It would be valuable to investigate the potential harmful effects of these particles on gut health. This review focuses on recent research exploring the toxicological impacts of micro- and nanoplastics on the gut, as observed in human cell lines and mammalian models. Available data from various studies indicate that the accumulation of MNPs in mammalian models and human cells may result in adverse consequences, in terms of epithelial toxicity, immune toxicity, and disruption of gut microbiota. The paper also discusses the current research limitations and prospects in this field, aiming to provide a scientific basis and reference for further studies on the toxic mechanisms of micro- and nanoplastics.

In the European Union (EU), cannabidiol products require pre-marketing authorisation under the novel food regulation. Currently, 19 CBD applications are under assessment at the European Food Safety Authority (EFSA). During the initial assessment of the application files, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) located several knowledge gaps in their 07 June 2022 statement on safety of cannabidiol as a novel food that need to be addressed before the evaluation of CBD can be concluded. Namely, the effect of CBD on the liver, gastrointestinal tract, endocrine system, nervous system, psychological function, and reproductive system needs to be clarified. Nevertheless, the available literature allows a benchmark dose (BMD)-response modelling of several bioassays, resulting in a BMD lower confidence limit (BMDL) of 20 mg/kg bw/day for liver toxicity in rats. Human data in healthy volunteers found increases in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in a study at 4.3 mg/kg bw/day, which was defined by EFSA NDA panel as a lowest observed adverse effect level (LOAEL). The EFSA NDA panel currently concluded that the safety of CBD as a novel food cannot be evaluated, leading to a so-called clock stop of the applications until the applicants provide the required data. Meanwhile, the authors suggest that CBD products still available as food supplements on the EU market despite the lack of authorisation must be considered as “unsafe”. Products exceeding a health-based guidance value of 10 mg/day must be considered as being “unfit for consumption” (Article 14(1) and (2) (b) of Regulation No 178/2002), while the ones in exceedance of the human LOAEL must be considered “injurious to health” (Article 14(1) and (2) (a) of Regulation No 178/2002).

Modern oncological therapy utilizes various types of immunotherapy. Immune checkpoint inhib-itors (ICIs), chimeric antigen receptor T cells (CAR-T) therapy, cancer vaccines and bispecific an-tibodies are improving patients’ outcomes. However, stimulation of the immune system, benefi-cial in terms of fighting against cancer, generates the risk of harm to other cells in a patient's body. Kidney damage belongs to the relatively rare adverse events (AEs). Best described, but still, su-perficially, are renal AEs in patients treated with ICIs. International guidelines issued by Euro-pean Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) cover the management of immune-related adverse events (irAEs) during ICI therapy. There are scarce data concerning renal adverse drug reactions of other immunotherapeutic methods. This implicates the need for the collection of safety data during ongoing clinical trials and in the re-al-life world to characterize the hazard related to the use of new immunotherapies and manage-ment of irAEs.

When you type” Iodine” in google scholar, you will end up with 2,200,000 articles that are titled with anything regarding iodine, except “what is it”. Here in this short note review, a summary of iodine that includes its origin, structure, types, sources, uses, concentration, toxicity, and iodine intake and how to measure it, was collected and infused in a nutshell.

The issue of workplace toxicity constitutes a major problem for employers, employees and society at large. Toxicity in a workplace context relates to damaging behaviours perpetrated by individuals and organisations that netatively impact on the health and wellbeing of others. Workplace toxicty is habitually associated with activities such as bullying, harrassment, unethical and even illegal acts. In this article, today’s workplace is likenened to a cage where ambition and greed drive people to engage in toxic behaviour to fight for whatever scarce rewards are on offer. Set against a backdrop of continuous demands on employees in a era of constant change and challenge, leadership practice in the 21st century is understandably seeped in complexity. Whilst conditions of scarcity are in fact constructed by employers in today’s lean environments, workplace toxicity has significant implications for organisational leaders in terms of work place disputes, absenteeism and litigation etc. Twentieth century hierarchial and autocratic leadership models are now deemed to be both obsolete and wholly inadedgate to inform leadership practice in the knowledge era. This conceptual article looks at the efficacy of complexity leadership theory (CLT) in empowering today’s leader to better understand and address 21st century workplace toxicity.

Serum transferrin (sTf) plays a pivotal role in regulating iron biodistribution and homeostasis within the body. The molecular details of sTf Fe(III) binding, blood transport, and cellular delivery through transferrin receptor-mediated endocytosis are generally well-understood. Emerging interest exists in exploring sTf complexation of nonferric metals as it facilitates the therapeutic potential and toxicity of several of them. This review explores recent X-ray structural and physiologically relevant metal speciation studies to understand how sTf partakes in the bioactivity of key non-redox active hard Lewis acidic metals. It challenges preconceived notions of sTf structure function correlations that were based exclusively on the Fe(III) model by revealing distinct coordination modalities that nonferric metal ions can adopt and different modes of binding to metal-free and Fe(III)-bound sTf that can directly influence how they enter into cells and, ultimately, how they may impact human health. This knowledge informs on biomedical strategies to engineer sTf as a delivery vehicle for metal-based diagnostic and therapeutic agents in the cancer field. It is the intention of this work to open new avenues for characterizing the functionality and medical utility of nonferric-bound sTf and to expand the significance of this protein in the context of bioinorganic chemistry.

Immune checkpoint inhibitors (ICIs) – anti-programmed death-1 (PD-1) and their ligands (PD-L1 and PD-L2) have become widely used in the treatment of several malignancies. Many immune-related adverse events have been linked to these agents. However, tuberculosis (TB) reactivation during their use is increasingly reported. Herein, we present a 58-year-old lady with advanced non-small cell lung cancer (NSCLC) ALK-negative, EGFR wild, and PD-L1 Immune histochemistry (IHC) strongly positive in 95% of tumor cells. The patient presented with high-grade fever and a history of productive cough for a 1-week duration. A few days later, she was diagnosed with pulmonary tuberculosis following the 6th cycle of Pembrolizumab, an anti-PD-1 monoclonal antibody. AFB smear and TB PCR from BAL were positive (rifampin resistance not detected), and she was accordingly started on Anti-TB medications. Immunotherapy was held. Of note, the patient had a history of sick contact with a patient with active TB infection ten years ago, but there was no documentation of latent TB or previous TB infection. Her HIV status is negative. Her sputum AFB smear continued to be positive after four weeks of anti-TB medications. Later, the patient was discharged after her sputum was cleared from AFB (negative x 2 sets). We assumed that our patient developed reactivation of pulmonary tuberculosis secondary to an immune checkpoint inhibitor (Pembrolizumab). She was not re-challenged with Pembrolizumab following TB diagnosis. To our knowledge, this is the first reported case from the Arab and the Middle East; it reinforces the previous observations of the association between ICIs administration and the development of MTB. Nevertheless, further studies in the clinical setting are necessary to establish the exact mechanism involved in this association. Oncologists' awareness & prompt recognition of this potential hazardous consequence are essential. Since there is no clear evidence whether LTBT prior PD-1/PD targeted immunotherapy is required, targeted LTBT before starting ICIs immunotherapy with TB chemoprophylaxis; yet to be explored, particularly in the regions where the MTB prevalence is high.

The abnormal assembly of α-synuclein (α-Syn) is an initial step in the formation of Lewy bodies in the brain, which finally causes the neuronal death, being considered as a pathological hallmark in Parkinson’s disease (PD). Certain food bioactives or their metabolites at very low concentrations can trespass the blood brain barrier (BBB) that might, thereafter, act simultaneously. The aim of this work was to evaluate the inhibitory and destabilising capacities on α-Syn kinetics and the neuroprotective effects of three well-known bioactive compounds able to cross the BBB and present in foods; melatonin (MEL), protocatechuic acid (PCA) and hydroxytyrosol (HT), and their combinations. For this purpose, different in vitro techniques (Thioflavin T (ThT), Transmission Electronic Microscopy (TEM), electrophoresis and MTT assay) were used. All tested compounds and their combinations were able to abolish the toxicity induced by α-Syn. In addition, the combination of PCA (100 µM) +HT (100 µM) showed the highest inhibitory effect against α-Syn fibril formation and destabilises α-Syn fibrils (88 and 62%, respectively). This is the first time that MEL, PCA and HT prove a joint effect against α-Syn aggregation and toxicity when they are tested together.

Cyanobacteria, microorganisms performing oxygenic photosynthesis, must adapt their metabolic processes to environmental challenges such as day and night changes. PipX, a unique regulatory protein from cyanobacteria provides a mechanistic link between signalling protein PII, a widely conserved (in bacteria and plants) transducer of carbon/nitrogen/energy richness, and the transcriptional regulator NtcA, which controls a large regulon involved in nitrogen assimilation. PipX is also involved in translational regulation by interaction with the ribosome-assembly GTPase EngA. However, increases of the PipX/PII ratio are toxic, presumably by abnormally increased binding of PipX to other partner(s). Here we present mutational and structural analyses of reported PipX-PII and PipX-NtcA complexes, leading to identification of single amino acid changes that decrease or abolish PipX toxicity. Four out of 11 mutations decreasing toxicity did not decrease PipX levels, suggesting that the targeted residues (F12, D23, L36, R54) provide toxicity determinants. In addition, one of those four mutations (D23A) argued against the over-activation of NtcA as the cause of PipX toxicity. Since most mutations at residues contacting PII decreased PipX levels, PipX stability would depend on its ability to bind to PII, a conclusion supported by the light-induced decrease in PipX levels observed in Synechococcus elongatus PCC7942.

Targeted cancer therapy has grown exponentially in the last decade, representing the largest frontier in the modern concept of precision medicine. This renaissance is largely due to our rapidly evolving ability to biochemically harness our immune systems to target cancer-specific antigens. Combined with an increasing armamentarium of surgical and non-invasive techniques for cancer mitigation we have upgraded cancer therapy from a non-specific assault on cell-division to a multi-modal, targeted approach. This renaissance has resulted in an increase in the perioperative footprint of patients with advanced cancer. The scope of the perioperative clinician has evolved from one of passive/reactive management of complications to a proactive approach that starts in the preoperative optimization phase and continues into the postoperative period. The perioperative world should not exist in a silo, and thus involvement of the oncology team is paramount. To provide safe oncologic care, it is essential to be up to date in newer cancer therapies, lest we act on erroneous and/or outdated information. Oncologists should weigh in on immune status, recent chemotherapeutic exposures, and potentially evolving toxicities. These might involve critical changes to perioperative infectious prophylaxis, steroid administration, and coagulopathy management. First, patients living beyond the typical life-expectancy for their cancer will carry a high burden of cancer-related downstream effects. General metabolic issues will include malnutrition, cachexia, and gastric outlet obstruction. Severe protein-calorie malnutrition, as well as hepatic and renal dysfunction can impact the metabolism and clearance of drugs. The cardiovascular, endocrinologic, pulmonary, and central nervous system implications of new cancer therapies will be discussed extensively below. Second, we have to enhance our ability to manage a cancer population who may be experiencing increasing novel chemotherapeutic toxicities. Newer agents differ from historical agents, which were blunt-force tools aimed at nonspecific destruction of cell-division. These drugs are efficacious but physiologically costly. Newer immunogenic therapies have a slightly improved acute safety profile, and a more complex chronic toxicity profile that may be overt or insidious. Chronic toxicities can present overtly or as a smoldering undertone to other active medical conditions such as sepsis, pneumonia, failure to thrive, or renal failure. The new therapies discussed in this review occur in the context of an overall increasingly multi-faceted cancer care machine. An example is screening for esophageal cancer in patients with Barrett's esophagus, or periodic chest CTs for patients with a strong history of tobacco use. These interventions are more likely to detect disease while it is still resectable, and resections will commonly accompany neo-adjuvant therapy. These approaches commonly involve new immunotherapies whose efficacy is higher-yield with a lower disease burden. In a recent example, the immune-checkpoint inhibitors (ICIs) ipilimumab plus nivolumab have significantly increased survival rate for squamous cell esophageal cancer when combined with standard chemotherapy. Surgical resection has evolved to one that often accompanies neoadjuvant chemo and radiation. The increasing efficacy of this approach may de-necessitate many major resections, and increase the number of sub-anatomic resections and minimally invasive procedures. Improved techniques - notably for hepatectomy, whipple procedure, prostatectomy, nephrectomy - have increased the safety profile and decreased the perioperative physiologic burden. This has enabled a broader subset of patients (due to cancer burden or due to medical comorbidities) to qualify for the operation, and increased the involvement of anesthesia and their perioperative services. With an increase in surgical candidacy comes an increase in post-surgical complications, and post-surgical maintenance such as drains, embolizations, imaging studies, etc. In the non-OR anesthesia realm, there have been considerable advancements in cancer “micro-treatments” such as hepatic metastasis embolization, tumor ablation, and peri-tumor vascular embolization. There are an ever-increasing number of IR-guided embolizations for bleeding tumors, aspiration of malignant effusions, and drainage of abscesses. This review serves to provide insight into new categories of chemotherapy and their perioperative implications.

Keywords: head-and-neck cancer; chemoradiation; cisplatin; carboplatin; loco-regional control; metastases-free survival; overall survival; toxicity.

Introduction: Wound healing is a multifaceted biological process, and diabetic wounds add more complexity to it. In diabetic wounds, the combination of chloroform fractions of Achyranthes aspera L. (A.aspera) leaves with β-Glucans has not been investigated. The additive effect of these two (A.aspera + β-Glucans) would benefit the inflammatory phase of diabetic wounds, as improper treatment will lead to chronic injuries. Therefore, the goal of this research work was to assess the in-vivo wound healing and anti-inflammatory effects of a combination of chloroform fractions of A.aspera leaves and β-Glucans in a variety of wound models in STZ-induced diabetic rats. Methods: Preliminary phytochemical analyses of A.aspera were conducted to identify various phytoconstituents in the test extract. Acute and sub-acute dermal toxicity tests of A.aspera were carried out on mice and rats, respectively, to see whether there were any abnormalities. Excision and incision wound models, cotton pellet-induced granuloma models, rat paw edema and burn wounds were used to test wound healing and anti-inflammatory actions. To induce diabetes, streptozotocin (STZ) was administered intraperitoneally at a dosage of 65 mg/kg (i.p.). A.aspera (10% w/w) and β-Glucans (2% w/w) ointments were tested separately and in combination for wound healing activities. Silver sulfadiazine (1 % w/w) ointment was used to treat the positive control groups. Excision wound model rats that had been treated with basic ointment were used as negative controls, as were incision wound model rats that had not been treated. A.aspera (400 mg/kg, po) and β-Glucans (30 mg/kg, po) were tested separately and in combination for anti-inflammatory efficacy. Positive control groups were given indomethacin (10 mg/kg, po) for cotton pellet-induced granuloma and rat paw oedema models. Negative controls for both anti-inflammatory activity models were provided 2% Tween 80. The groups were made up of six rats, and the treatments were given topically and orally to assess wound healing and anti-inflammatory effects. The levels of hydroxyproline and hexosamine and the antioxidant enzymes (SOD and CAT) in the granulation tissue were measured in excision wound model. Healed excision wound skin was examined histopathologically. Results: The A.aspera and β-Glucans combination resulted in a significant percentage of wound contraction and a shorter epithelialization time (P<0.01). The combination was found to be the most effective, with the highest percentage of edema reduction (55 %; p<0.01). The combination also exhibited favourable hydroxylamine, hexosamine and anti-oxidant profiles supported by histopathology data. Conclusion: This research showed that the immunomodulatory effect of β-Glucans had significantly enhanced the wound healing, anti-inflammatory, and anti-oxidant potential of A.aspera in diabetic wounds.

The responses of the aromatic and medicinal plant Salvia sclarea (clary sage) to 900 µM Zn exposure for 8 days in a hydroponic culture were investigated. The tolerance mechanisms under excess Zn exposure were assessed by changes in nutrient uptake, photosynthetic characteristics and leaf structure. The uptake and the distribution of Zn, as well as some essential nutrient elements such as: Ca, Mg, Fe, Mn and Cu, were examined by inductively coupled plasma mass spectrometry (ICP-MS). The results revealed that Salvia sclarea is a Zn accumulator plant that tolerates significantly high toxic levels of Zn in the leaves by increasing the leaf content of Fe, Ca and Mn ions to protect the photosynthetic function and even stimulate photosystem I (PSI) and photosystem II (PSII) activities. Additionally, the leaf photosynthetic pigments and the total phenolic and anthocyanin content were also studied. Data showed that the exposure to excess Zn significantly increases the synthesis of phenolic compounds in the leaves which plays an important role in the Zn detoxification and protection against oxidative stress. Lipid peroxidation and electrolyte leakage in leaves used as clear indicators for heavy metal damage were slightly increased. All these data highlight that Salvia sclarea is an economically interesting plant for phytoextraction and/or phytostabilization of Zn contaminated soils.

Promoter is a small region of DNA sequence in response to various transcription factors, which initiates a particular gene expression. The promoter-engineered bio-sensor can activate or repress gene expression through transcription factor recognizing specific molecules, such as polyamine, sugars, lactams, amino acids, organic acids or redox molecule, however, the reported applications of promoter enhanced bio-sensor are not too much. This review paper highlights the strategies of construction of promoter-gene engineered bio-sensor with human and bacteria’s genetic promoter array for high-throughput screening (HTS) molecular drugs, study of membrane protein’s localization and nucleocytoplasmic shuttling mechanism of regulating factor, enzyme activity, detection of the toxicity of intermediate chemicals, and probing bacteria density to improve value-added product titer. These bio-sensors’s sensitivity and specificity can be further improved by proposed approaches of Mn²⁺ and Mg²⁺ added random Error-prone PCR and site-directed mutagenesis which is applied for construction of bacteria’s “mutant library”. It is expected to establish flexible HTS platform (Bio-sensor array) to large-scale screen transcription factor-acting drugs, reducing the toxicity of intermediate compounds, and constructing gene dynamic regulatory system in “push and pull” mode to effectively regulate the valuable medicinal product production. This proposed novel promoter-engineered biosensors aided synthetic genetic circuit construction will maximize the efficiency of bio-synthesis of medicinal compound, which will greatly promote the development of microbial metabolic engineering and biomedical science.

LONP1 is the principal AAA+ unfoldase and bulk protease in the mitochondrial matrix, so its deletion causes embryonic lethality. The AAA+ unfoldase CLPX and the peptidase CLPP also act in the matrix, conspicuously during stress periods, but their substrates are poorly defined. Mammalian CLPP deletion triggers infertility, deafness, growth retardation, and cGAS-STING activated cytosolic innate immunity. CLPX mutations impair heme biosynthesis and heavy metal homeostasis. CLPP and CLPX are conserved from bacteria to human, despite their secondary role for proteolysis. Based on recent proteomic-metabolomic evidence from knockout mice and patient cells, we propose that CLPP acts on phase-separated ribonucleoprotein granules, and CLPX on multi-enzyme condensates, near the inner mitochondrial membrane, as first-aid system. Trimming within assemblies, CLPP rescues stalled processes in mitoribosomes, in mitochondrial RNA granules and nucleoids, and in D-foci-mediated degradation of toxic double-stranded mtRNA / mtDNA. Unfolding multi-enzyme condensates, CLPX maximizes PLP-dependent delta-transamination, and rescues malformed nascent peptides. Overall, their actions occur in granules with multivalent or hydrophobic interactions, separated from the aqueous phase. Thus, the role of CLPXP in the matrix is compartment-selective, like peptidases MPP at precursor import pores, m-AAA and i-AAA at either IMM face, PARL within the IMM, and OMA1/HTRA2 in the intermembrane space.

From 2020 to 2023 many people around the world were forced to wear masks for large proportions of the day based on mandates and laws. We aimed to study the potential of face masks for the content and release of inanimate toxins. A scoping review of 1003 studies was performed (database search in PubMed/MEDLINE, qualitative and quantitative evaluation). Twenty-four studies were included (experimental time 17 min to 15 days) evaluating content and/or release in 631 masks (273 surgical, 228 textile and 130 N95 masks). Most studies (63%) showed alarming results with high micro- and nanoplastics (MPs and NPs) release and exceedances could also be evidenced for volatile organic compounds (VOCs), xylene, acrolein, per-/polyfluoroalkyl substances (PFAS), phthalates (including di(2-ethylhexyl)-phthalate, DEHP) and for Pb, Cd, Co, Cu, Sb and TiO₂. Of course, masks filter bacteria, dirt and plastic particles and fibers from the air we breathe and have specific indications, but according to our data they also carry risks. Depending on the application, a risk-benefit analysis is necessary. However, mask mandates during the SARS-CoV-2 pandemic have been generating an additional source of potentially harmful exposition to toxins at population level with almost zero distance to the airways.

P-glycoprotein (P-gp), a membrane-bound transporter, can eliminate xenobiotics by transporting them out of the cells or blood-brain barrier (BBB) at the expense of ATP hydrolysis. Thus, P-gp mediated efflux plays a pivotal role in altering the absorption and disposition of a wide range of substrates. Nevertheless, the mechanism of P-gp substrate efflux is rather complex since it can take place through active transport and passive permeability in addition to multiple P-gp substrate binding sites. A nonlinear quantitative structure-activity relationship (QSAR) model was developed in this study using the novel machine learning-based hierarchical support vector regression (HSVR) scheme to explore the perplexing relationships between descriptors and efflux ratio. The predictions by HSVR were found to be in good agreement with the observed values for the molecules in the training set (n = 50, r² = 0.96, q²_CV = 0.94, RMSE = 0.10, s = 0.10) and test set (n = 13, q² = 0.80–0.87, RMSE = 0.21, s = 0.22). When subjected to a variety of statistical validations, the developed HSVR model consistently met the most stringent criteria. A mock test also asserted the predictivity of HSVR. Consequently, this HSVR model can be adopted to facilitate drug discovery and development.

Metalloproteinases are zinc-dependent endopeptidases that function as primary effectors of tissue remodelling, cell-signalling, and many other roles. Their regulation is ferociously complex, and is exquisitely sensitive to their molecular milieu, making in vivo studies challenging. Phenanthroline (PhN) is an inexpensive, broad-spectrum inhibitor of metalloproteinases that functions by chelating the catalytic zinc ion, however its use in vivo has been limited due to suspected off-target effects. PhN is very similar in structure to phenanthrene (Phe), a well-studied poly aromatic hydrocarbon (PAH) known to cause toxicity in aquatic animals by activating the aryl hydrocarbon receptor (AhR). We show that zebrafish are more sensitive to PhN than Phe, and that PhN causes a superset of the effects caused by Phe. Morpholino knock-down of the AhR rescues the effects of PhN that are shared with Phe, suggesting these are due to PAH toxicity. The effects of PhN that are not shared with Phe (specifically disruption of neural crest development and angiogenesis) involve processes known to depend on metalloproteinase activity. Furthermore these PhN-specific effects are not rescued by AhR knock-down, suggesting that these are bona fide effects of metalloproteinase inhibition, and that PhN can be used as a broad spectrum metalloproteinase inhibitor for studies with zebrafish in vivo.