Low Acute Toxicity Research Articles

X-ray Single-Crystal Analysis, Pharmaco-Toxicological Profile and Enoyl-ACP Reductase-Inhibiting Activity of Leading Sulfonyl Hydrazone Derivatives

Taking into consideration the growing resistance towards currently available antimycobacterials, there is still an unmet need for the development of new chemotherapeutic agents to combat the infectious agents. This study presents X-ray single-crystal analysis to verify the structure of leading sulfonyl hydrazone 3b, which has proven its potent antimycobacterial activity against Mycobacterium tuberculosis H37Rv with an MIC value of 0.0716 μM, respectively, low cytotoxicity, and very high selectivity indexes (SI = 2216), and which has been fully characterized by Nuclear Magnetic Resonance (NMR) and High-Resolution Mass Spectrometry (HRMS) methods. Furthermore, this study assessed the ex vivo antioxidant activity, acute and subacute toxicity, and in vitro inhibition capacity against enoyl-ACP reductase of hydrazones 3a and 3b, as 3a was identified as the second leading compound in our previous research. Compared to isoniazid, compounds 3a and 3b demonstrated lower acute toxicity for intraperitoneal administration, with LD50 values of 866 and 1224.7 mg/kg, respectively. Subacute toxicity tests, involving the repeated administration of a single dose of the test samples per day, revealed no significant deviations in hematological and biochemical parameters or pathomorphological tissues. The compounds exhibited potent antioxidant capabilities, reducing malondialdehyde (MDA) levels and increasing reduced glutathione (GSH). Enzyme inhibition assays of the sulfonyl hydrazones 3a and 3b with IC50 values of 18.2 µM and 10.7 µM, respectively, revealed that enoyl acyl carrier protein reductase (InhA) could be considered as their target enzyme to exhibit their antitubercular activities. In conclusion, the investigated sulfonyl hydrazones display promising drug-like properties and warrant further investigation.

Development of Novel β-Carboline/Furylmalononitrile Hybrids as Type I/II Photosensitizers with Chemo-Photodynamic Therapy and Minimal Toxicity.

Chemo-photodynamic therapy is a treatment method that combines chemotherapy and photodynamic therapy and has demonstrated significant potential in cancer treatment. However, the development of chemo-photodynamic therapeutic agents with fewer side effects still poses a challenge. Herein, we designed and synthesized a novel series of β-carboline/furylmalononitrile hybrids 10a-i and evaluated their chemo-photodynamic therapeutic effects. Most of the compounds were photodynamically active and exhibited cytotoxic effects in four cancer cells. In particular, 10f possessed type-I/II photodynamic characteristics, and its 1O2 quantum yield increased by 3-fold from pH 7.4 to 4.5. Most interestingly, 10f exhibited robust antiproliferative effects by tumor-selective cytotoxicities and hypoxic-overcoming phototoxicities. In addition, 10f generated intracellular ROS and induced hepatocellular apoptosis, mitochondrial damage, and autophagy. Finally, 10f demonstrated extremely low acute toxicity (LD50 = 1415 mg/kg) and a high tumor-inhibitory rate of 80.5% through chemo-photodynamic dual therapy. Our findings may provide a promising framework for the design of new photosensitizers for chemo-photodynamic therapy.

Halicin: A New Horizon in Antibacterial Therapy against Veterinary Pathogens.

It is crucial to discover novel antimicrobial drugs to combat resistance. This study investigated the antibacterial properties of halicin (SU3327), an AI-identified anti-diabetic drug, against 13 kinds of common clinical pathogens of animal origin, including multidrug-resistant strains. Employing minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assessments, halicin demonstrated a broad-spectrum antibacterial effect. Time-killing assays revealed its concentration-dependent bactericidal activity against Escherichia coli ATCC 25922 (E. coli ATCC 25922), Staphylococcus aureus ATCC 29213 (S. aureus ATCC 29213), and Actinobacillus pleuropneumoniae S6 (APP S6) after 4 h of treatment at concentrations above the MIC. Halicin exhibited longer post-antibiotic effects (PAEs) and sub-MIC effects (PA-SMEs) for E. coli 25922, S. aureus 29213, and APP S6 compared to ceftiofur and ciprofloxacin, the commonly used veterinary antimicrobial agents, indicating sustained antibacterial action. Additionally, the results of consecutive passaging experiments over 40 d at sub-inhibitory concentrations showed that bacteria exhibited difficulty in developing resistance to halicin. Toxicology studies confirmed that halicin exhibited low acute toxicity, being non-mutagenic, non-reproductive-toxic, and non-genotoxic. Blood biochemical results suggested that halicin has no significant impact on hematological parameters, liver function, and kidney function. Furthermore, halicin effectively treated respiratory A. pleuropneumoniae infections in murine models. These results underscore the potential of halicin as a new antibacterial agent with applications against clinically relevant pathogens in veterinary medicine.

Metallacarboranes in Medicinal Chemistry: Current Advances and Future Perspectives.

Metallacarboranes, exemplified by cobalt bis(dicarbollide) ([COSAN]-), have excelled their historical metallocene analogue label to become promising in drug design, medical studies, and fundamental biological research. Serving as a unique platform for conjugation with biomolecules, they also constitute an auspicious building block for biologically active derivatives and a carrier for cellular transport of membrane-impermeable cargos. Modified [COSAN]- exhibits specific antimicrobial, antiviral, and anticancer actions showing promise for preclinical trials. Contributing to the ongoing development in medicinal chemistry, metallacarboranes offer desirable physicochemical properties and low acute toxicity. This article presents a critical look at metallacarboranes in the context of their application in medicinal chemistry, emphasizing [COSAN]- as a potential game-changer in drug design and biomedical sciences. As medicinal chemistry seeks innovative building blocks, metallacarboranes emerge as an important novelty with versatile solutions and promising implications.

Antifungal Activity and Mechanism of Camphor Derivatives against Rhizoctonia solani: A Promising Alternative Antifungal Agent for Rice Sheath Blight.

Rice sheath blight, caused by the fungus Rhizoctonia solani, poses a significant threat to rice cultivation globally. This study aimed to investigate the potential mechanisms of action of camphor derivatives against R. solani. Compound 4o exhibited superior fungicidal activities in vitro (EC50 = 6.16 mg/L), and in vivo curative effects (77.5%) at 500 mg/L were significantly (P < 0.01) higher than the positive control validamycin·bacillus (66.1%). Additionally, compound 4o exhibited low cytotoxicity and acute oral toxicity for adult worker honeybees of Apis mellifera L. Mechanistically, compound 4o disrupted mycelial morphology and microstructure, increased cell membrane permeability, and inhibited both PDH and SDH enzyme activities. Molecular docking and molecular dynamics analyses indicated a tight interaction of compound 4o with PDH and SDH active sites. In summary, compound 4o exhibited substantial antifungal efficacy against R. solani, serving as a promising lead compound for further optimization of antifungal agents.

Impact of Cross‐Linking on the Physicochemical and Physiological Characteristics of Barnyard Millet (Echinochloa frumentacea) Grains Starch

Barnyard millet starch (Echinochloa frumentacea) has been investigated for its potential in drug delivery systems due to its unique properties. This study examined the physicochemical and physiological properties of cross‐linked barnyard millet starch (BMS) using varying concentrations of sodium tripolyphosphate (STPP). Physicochemical and physiological properties of the cross‐linked starches are analyzed. Cross‐linking resulted in reduced swelling capacity and solubility of starch samples. Morphological analysis revealed rough surfaces with cavities and minute cracks in cross‐linked starches. Acute and sub‐acute toxicity studies in test animals indicated no adverse effects, with LD50 values within acceptable limits at 2000 mg kg−1. Hematological, biochemical, and lipid profiles showed no significant alterations compared to the control group. The study demonstrated a low acute toxicity level and favorable safety profile for STPP‐cross‐linked starch. These findings highlighted the potential of cross‐linked barnyard millet starch as a carrier in drug delivery system and for food applications. This study supports the potential of cross‐linked barnyard millet starch in pharmaceutical formulations.

Effect of pH on degradation and mineralization of catechol in calcium-aid ozonation: Performance, mechanism and products analysis

Catechol, common in industrial wastewater, is very toxic and non-biodegradable, and its desirable removal is still a challenge. Catalytic ozonation as an effective advanced oxidation process, however was limited by the application of intricately fabricated catalysts. Herein, catalytic ozonation by OH– (generated by common sodium hydroxide) with the aid of calcium was developed for catechol degradation and mineralization in this study. The removal performance, mechanism and products were investigated. The results showed that ozonation at pH 12.5 could achieve complete catechol removal and excellent mineralization (maximum of 75 % COD removal efficiency) within 15 min. The adorable effect of calcium for enhanced organics removal was observed at pH 12.5, with the formation of precipitates as well. Catechol and COD removal were fitted to the pseudo-first-order kinetic model, while the reaction constant was increased by higher pH and calcium concentration. The results of quenching experiment and EPR affirmed •OH and •O2– radicals were pivotal for the enhanced organics removal. In addition, DFT calculation revealed the O atoms were reactive sites for electrophilic and radical attack via molecular electrostatic potential, highest occupied molecular orbital, lowest unoccupied molecular orbital and Fukui index. UPLC-Q-TOF-MS analysis revealed the intermediate products and verified the brilliant performance of catalytic ozonation. According to reactive sites and intermediates identification, the degradation pathway of catechol was proposed. As tawny precipitate appeared after reaction, the characteristics of insoluble product was analyzed using FTIR, XRD and XPS. The component of the precipitate was recognized as calcium oxalate and calcium carbonate, accompanied by the decreased Ca2+ concentration at high pH, which declared the enhanced removal was linked to the precipitation of Ca2+. Finally, toxicity assessment stated the lower acute toxicity, bioconcentration factor, developmental toxicity and mutagenicity of intermediates, indicating that calcium-aid ozonation catalyzed by high pH was useful for both catechol degradation and toxicity reduction. This study provides a reference for understanding the performance and mechanism of catechol degradation. More importantly, as an environmentally friendly process, catalytic ozonation possesses a great application potential for treatment of wastewater containing metal ions in terms of simultaneous removal of organics and metal ions.

Tomotherapy in synchronous and metachronous bilateral breast cancer: Clinical experience.

The objective of this research is to present our firsthand experience and provide up-to-date data for the further study of cases involving simultaneous breast irradiation using helical Tomotherapy, ©Accuray Inc. The radical treatment options for bilateral breast cancer are surgery, chemotherapy, and radiation therapy. Being that radiotherapy for bilateral breast cancer is challenging due to limitations in the geometry of modern radiotherapy equipment, helical Tomotherapy was chosen as an appropriate technique of irradiation. The retrospective review focused on the records of patients who underwent bilateral irradiation of the breast or chest wall and regional lymph nodes using helical Tomotherapy. Only four patients with bilateral breast cancer completed a radiation therapy course in our center from 2018 to 2023. Two patients underwent radical mastectomy with lymph node dissection on both sides before irradiation. For the other two patients, radical mastectomy was done after neoadjuvant chemotherapy. Acute radiation toxicity scoring was based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Only mild adverse effects, such as general weakness and slight skin irritation below Grade 3, were observed, with no instances of skin swelling, dryness, or pigmentation noted. Evaluation of late complications revealed tissue fibrosis in the area of the internal mammary nodes and respiratory failure with various severity. Complications and deterioration in the cardiovascular system were not observed during the follow-up period, which varied from 3 to 48months. Our results show the efficacy of using helical Tomotherapy considering positive outcomes, being that three out of four patients are in remission with low acute toxicity and late complications. There are a small number of articles describing bilateral breast cancer treatment with helical Tomotherapy. On this occasion, our data could contribute to the studies of tolerant doses for organs at risk and improve the parameters of treatment plans for bilateral breast cancer. Since the small sample of patients with bilateral breast cancer limits the study, a larger cohort of patients is essential to obtain statistically reliable results.

Optimization and characterization of pyraclostrobin nanoemulsion for pesticide delivery: Improving activity, reducing toxicity, and protecting ecological environment

Nanoemulsion provides an effective way for the efficient, safe, and environmentally friendly use of pesticides. In this study, the influence of different type emulsifiers on the formation and stability of nanoemulsion were tested and an optimal pyraclostrobin nanoemulsion with long-term stability was obtained. Pyraclostrobin (2.5 %), #602 (phenylethyl phenol polyoxyethylene ether, 6 %), and #600 P (tristyryl- phenol polyoxyethylene ether phosphate, 2 %) were dissolved in methyl benzoate (2.5 %) and co-emulsifier ethanol (20 %) with deionized water replenished to 100 %. Compared with microemulsion (ME), the nanoemulsion using a lower dosage of emulsifier kept the system stable for a long time, reducing pollution of the environment. Compared with the commercial ME and suspension concentrate (SC), the nanoemulsion had a lower contact angle and surface tension, and higher maximum retention. In addition, adding 0.01 % AEO-3 (dodecyl alcohol polyol ethylene ether) to the dilution of nanoemulsion can significantly improve the target deposition of the nanoemulsion and improve the utilization rate of the pesticide. Besides, the use of methyl benzoate, an environmentally friendly solvent, resulted in the nanoemulsion with high bactericidal activity and low acute toxicity to zebrafish, thus reducing the environmental pollution of such chemicals.

Bioassay Study of Azadirachtin And Plumbagin on Pericallia ricini (Lepidoptera: Arctiidae)

In recent years, the overuse of commercially obtainable synthetic pesticides against phytophagous insects has augmented their bioaccumulation in the biosphere, foremost to increased resistance and reduced soil biodiversity. Moreover, extreme uses of insecticides enter various environmental resources as an outcome of overflow, initiating deleterious health problems to agriculturalists and consumers of agricultural products. Hence, more attention is being paid towards the expansion of substitute eco-friendly insecticides that will help in an effective pest management system and also prevent longstanding exposure that causes diseases. As a result, important ecologically friendly and harmless alternative practice strategies to artificial compounds are essential. Azadirachtin and plumbagin (phytoproducts) have been identified as an extraordinary biocontrol agent with low toxicity and high efficacy among many plant products for latent chemotherapeutic compounds in plant pest and disease management systems. The biocidal effectiveness of neem is attributed to its azadirachtin active ingredient, which affect some metabolic processes in insects such as protein synthesis, deviations in biological fitness, reduced sexual communication, and chitin synthesis. Similarly, Plumbagin (Napthaquinones) have established substantial attention in agricultural chemistry because of a novel action mode, extremely high activity against a broad spectrum of insects, low acute toxicity to mammals, and environmentally benign characteristics. The present study indicated that Azadirachtin and Plumbagin can be significant alternatives to Chemical insecticides for Pericallia ricini control in short-cycle crops.

Daily Online Adaptive Radiation Therapy of Postoperative Endometrial and Cervical Cancer With PTV Margin Reduction to 5 mm: Dosimetric Outcomes, Acute Toxicity, and First Clinical Experience

PurposeThis study evaluated the first clinical implementation of daily iterative cone-beam computed tomography (iCBCT)-guided online adaptive radiotherapy (oART) in the postoperative treatment of endometrial and cervical cancer. Methods and MaterialsSeventeen consecutive patients treated with daily iCBCT-guided oART were enrolled in this prospective study, with a reduced uniform three-dimensional PTV margin of 5 mm. Treatment plans were designed to deliver 45 or 50.4 Gy in 1.8 Gy daily fractions to PTV. Pre- and posttreatment ultrasound and iCBCT scans were performed to record intrafractional bladder and rectal volume changes. The accuracy of contouring, oART procedure time, dosimetric outcomes and acute toxicity were evaluated. ResultsThe average time from first iCBCT acquisition to completion of treatment was 22 min and 26 s. During this period, bladder volume increased by 44 cm3 using iCBCT contouring, while rectal volume remained stable (62.9 cm3 pretreatment vs. 61.9 cm3 posttreatment). A total of 91.6% of influencers and 88.1% of CTVs required no or minor edits. The adapted plan was selected in all (434) fractions and significantly improved the dosimetry coverage for CTV and PTV, especially the vaginal PTV coverage by nearly 7% (p<0.05). The adapted bladder Dmean was 104.61 cGy, and the rectum Dmean was 123.67 cGy, significantly lower than the scheduled plan of 108.24 and 128.19 cGy, respectively. The bone marrow, femur head left and right dosimetry were also improved with adaptation. Grade 2 acute gastrointestinal and genitourinary toxicities were 24% and 0, respectively. There was a Grade 3 acute toxicity of decreased white blood cell count in one patient. ConclusionsDaily oART was associated with favourable dosimetry improvement and low acute toxicity, supporting its safety and efficacy for postoperative treatment of endometrial and cervical cancer. These results need to be validated in a larger prospective randomized controlled cohort.

Trametes versicolor Laccase-Based Magnetic Inorganic-Protein Hybrid Nanobiocatalyst for Efficient Decolorization of Dyes in the Presence of Inhibitors.

In the present investigation, an ecofriendly magnetic inorganic-protein hybrid system-based enzyme immobilization was developed using partially purified laccase from Trametes versicolor (TvLac), Fe3O4 nanoparticles, and manganese (Mn), and was successfully applied for synthetic dye decolorization in the presence of enzyme inhibitors. After the partial purification of crude TvLac, the specific enzyme activity reached 212 U∙mg total protein-1. The synthesized Fe3O4/Mn3(PO4)2-laccase (Fe3O4/Mn-TvLac) and Mn3(PO4)2-laccase (Mn-TvLac) nanoflowers (NFs) exhibited encapsulation yields of 85.5% and 90.3%, respectively, with relative activities of 245% and 260%, respectively, compared with those of free TvLac. One-pot synthesized Fe3O4/Mn-TvLac exhibited significant improvements in catalytic properties and stability compared to those of the free enzyme. Fe3O4/Mn-TvLac retained a significantly higher residual activity of 96.8% over that of Mn-TvLac (47.1%) after 10 reuse cycles. The NFs showed potential for the efficient decolorization of synthetic dyes in the presence of enzyme inhibitors. For up to five reuse cycles, Fe3O4/Mn-TvLac retained a decolorization potential of 81.1% and 86.3% for Coomassie Brilliant Blue R-250 and xylene cyanol, respectively. The synthesized Fe3O4/Mn-TvLac showed a lower acute toxicity towards Vibrio fischeri than pure Fe3O4 nanoparticles did. This is the first report of the one-pot synthesis of biofriendly magnetic protein-inorganic hybrids using partially purified TvLac and Mn.

Enhanced degradation and removal of ciprofloxacin and ofloxacin through advanced oxidation and adsorption processes using environmentally friendly modified carbon nanotubes.

This study explores the utilization of adsorption and advanced oxidation processes for the degradation of ofloxacin (OFL) and ciprofloxacin (CIP) using a green functionalized carbon nanotube (MWCNT-OH/COOH-E) as adsorbent and catalyst material. The stability and catalytic activity of the solid material were proved by FT-IR and TG/DTG, which also helped to elucidate the reaction mechanisms. In adsorption kinetic studies, both antibiotics showed similar behavior, with an equilibrium at 30min and 60% removal. The adsorption kinetic data of both antibiotics were well described by the pseudo-first-order (PFO) model. Different advanced oxidation processes (AOPs) were used, and the photolytic degradation was not satisfactory, whereas heterogeneous photocatalysis showed high degradation (⁓ 70%), both processes with 30min of reaction. Nevertheless, ozonation and catalytic ozonation have resulted in the highest efficiencies, 90%, and 70%, respectively, after 30-min reaction. For AOP data modeling, the first-order model better described CIP and OFL in photocatalytic and ozonation process. Intermediates were detected by MS-MS analysis, such as P313, P330, and P277 for ciprofloxacin and P391 and P332 for ofloxacin. The toxicity test demonstrated that a lower acute toxicity was observed for the photocatalysis method samples, with only 3.1 and 1.5 TU for CIP and OFL, respectively, thus being a promising method for its degradation, due to its lower risk of inducing the proliferation of bacterial resistance in an aquatic environment. Ultimately, the analysis of MWCNT reusability showed good performance for 2 cycles and regeneration of MWCNT with ozone confirmed its effectiveness up to 3 cycles.

Potential toxicity of iron ore tailings after the overflow of a mining dam in Nova Lima (Minas Gerais State, Brazil)

In January 2022, the Pau Branco Mine dam in Nova Lima (MG), under the responsibility of Vallourec, overflowed after intense rainfall and iron ore tailings impacted surrounding soils and aquatic ecosystems. These tailings can alter the natural composition of soils and rivers, poising risks on soil biota. This study consists of a preliminary evaluation of potential toxicity of terrigenous materials impacted by tailings from the Pau Branco Mine, based on acute bioassays with earthworms (Eisenia andrei) and germination tests with lettuce (Lactuca sativa). The physical and chemical characterization and determination of toxic metals in the samples supported the interpretation of the ecotoxicological data. The results indicated that the tailing deposition induced the increase in particle density, due to the increase in iron concentrations in the samples. As a consequence, the water holding capacity (WHC) of the materials and organic matter concentrations were dramatically reduced. Given that the mining tailings exhibit fine texture, their depositions on soils increased the percentage of fines particles (silt) in the samples. Metal determination revealed geochemical anomalies for nickel, copper and chromium, whose concentrations exceeded the threshold limits defined by Brazilian law for soil and aquatic sediment quality. The bioassays with earthworms showed no significant earthworm mortality, indicating low acute toxicity. However, earthworm biomass was significantly reduced, suggesting that they were submitted to some stress induced by the exposure to contaminants and/or by the reduction of the organic matter contents (food scarcity) and WHC (water scarcity). The bioassays with lettuce showed no significant effects on germination levels. However, the seedling biomass was significantly reduced due, possibly, to the reduction of WHC and especially due to the increase of fines particles in the samples, which tends to inhibit the establishment of the root systems.

Moderate hypofractionated radiotherapy to the prostate bed with or without pelvic lymph nodes: a prospective trial.

Hypofractionated radiotherapy in the treatment of prostate cancer has been widely studied. However, in the postoperative setting it has been less explored. The objective of this prospective study is to evaluate the safety and efficacy of hypofractionated radiotherapy in postoperative prostate cancer. A prospective study was designed to include patients with prostate cancer with an indication of postoperative radiotherapy as adjuvant or salvage. A hypofractionated radiotherapy scheme of 51 Gy in 17 fractions was performed with the possibility of treating the pelvis at a dose of 36 Gy in 12 fractions sequentially. Safety was evaluated based on acute and late toxicity [according to the Radiation Therapy Oncology Group (RTOG) scale and Common Terminology Criteria Adverse Events (CTCAE) v4.03], International Prognostic Scoring System (IPSS) over time, and quality of life. From August 2020 to June 2022, 31 patients completed treatment and were included in this report. 35.5% of patients received elective treatment of the pelvic nodal areas. Most patients reported minimal or low acute toxicity, with an acute gastrointestinal (GI) and genitourinary (GU) grade 3 or greater toxicity of 3.2% and 0%, respectively. The evolution in time of the IPSS remained without significant differences (p = 0.42). With the exception of a significant improvement in the domains of hormonal and sexual symptoms of the Expanded Prostate Cancer Index Composite (EPIC) questionnaire, the rest of the domains [EPIC, European Organization for Research and Treatment of Cancer (EORTC) Core quality of life questionnaire (C-30) and Prostate Cancer module (PR-25)] were maintained without significant differences over time. With a follow-up of 15.4 months, late GI and GU grade 2 toxicity was reported greater than 0% and 9.6%, respectively. Hypofractionated radiotherapy in postoperative prostate cancer appears to be safe with low reports of relevant acute or late toxicity. Further follow-up is required to confirm these results. The protocol was approved by the accredited Medical Ethical Committee of Pontificia Universidad Católica de Chile. All participants accepted and wrote informed consent.

Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2′,4′-BNA/LNA with 9-(aminoethoxy)phenoxazine

An increasing number of antisense oligonucleotides (ASOs) have been approved for clinical use. However, improvements of both efficacy and safety in the central nervous system (CNS) are crucial for the treatment with CNS diseases. We aimed to overcome the crucial issues by our development of various gapmer ASOs with anovel nucleoside derivative including a 2',4'-BNA/LNA with9-(aminoethoxy)phenoxazine (BNAP-AEO). The various gapmer ASOs with BNAP-AEO were evaluated for thermal stability, invitro and invivo efficacy, and acute CNS toxicity. Thermal stability analysis of the duplexes with their complementary RNAs showed that ASOs with BNAP-AEO had a higher binding affinity than those without BNAP-AEO. Invitro assays, when transfected into neuroblastoma cell lines, demonstrated that ASOs with BNAP-AEO, had a more efficient gene silencing effect than those without BNAP-AEO. Invivo assays, involving intracerebroventricular injections into mice, revealed ASOs with BNAP-AEO potently suppressed gene expression in the brain. Surprisingly, the acute CNS toxicity in mice, as assessed through open field tests and scoring systems, was significantly lower for ASOs with BNAP-AEO than for those without BNAP-AEO. This study underscores the efficient gene-silencing effect and low acute CNS toxicity of ASOs incorporating BNAP-AEO, indicating the potential for future therapeutic applications.

Efficacy of Fluorinated Nematicides for Management of Root-knot Nematodes in California Processing Tomatoes.

California is the primary US producer of processing tomatoes. After decades-long excellent protection against the common tropical Meloidogyne spp. M. incognita, M. javanica, and M. arenaria (root-knot nematode: RKN) by Mi-resistant tomato cultivars, resistance-breaking RKN populations are spreading throughout the San Joaquin Valley. For some time, nematicidal crop management tools have diminished under CA State regulatory pressure. In recent years, new non-volatile compounds have been developed with novel modes of action. In this project with susceptible processing tomato grown on an M. incognita-infested site, the efficacy of three fluorinated nematicides was evaluated in 10 field trials from 2011 to 2021. Seven trials included fluensulfone, six included fluazaindolizine, and five included fluopyram. On average, tomato root-galling (0 - 10 scale) at harvest was reduced by 3.2, 2.3, and 2.5 by fluazaindolizine, fluensulfone, and fluopyram, respectively, compared to the untreated control. These reductions in root-galling corresponded with estimated yield gains of approximately 21%, 14%, and 15%, respectively, over the untreated control. The reproduction of RKN during the tomato crop was not affected by the nematicides. The tested compounds have a very low acute mammalian toxicity and are more target-specific than previous generations of nematicides. However, there is considerable concern about the persistence of synthetic per- and polyfluoroalkyl substances (PFAS) in the environment, including pharmaceuticals and pesticides containing fluorine with the C-F3 functional group.

Metabolomics Provides Novel Insights into the Potential Toxicity Associated with Heated Tobacco Products, Electronic Cigarettes, and Tobacco Cigarettes on Human Bronchial Epithelial BEAS-2B Cells.

Smoking is an established risk factor for various pathologies including lung cancer. Electronic cigarettes (e-cigs) and heated tobacco products (HTPs) have appeared on the market in recent years, but their safety or, conversely, their toxicity has not yet been demonstrated. This study aimed to compare the metabolome of human lung epithelial cells exposed to emissions of e-cigs, HTPs, or 3R4F cigarettes in order to highlight potential early markers of toxicity. BEAS-2B cells were cultured at the air-liquid interface and exposed to short-term emissions from e-cigs set up at low or medium power, HTPs, or 3R4F cigarettes. Untargeted metabolomic analyses were performed using liquid chromatography coupled with mass spectrometry. Compared to unexposed cells, both 3R4F cigarette and HTP emissions affected the profiles of exogenous compounds, one of which is carcinogenic, as well as those of endogenous metabolites from various pathways including oxidative stress, energy metabolism, and lipid metabolism. However, these effects were observed at lower doses for cigarettes (2 and 4 puffs) than for HTPs (60 and 120 puffs). No difference was observed after e-cig exposure, regardless of the power conditions. These results suggest a lower acute toxicity of e-cig emissions compared to cigarettes and HTPs in BEAS-2B cells. The pathways deregulated by HTP emissions are also described to be altered in respiratory diseases, emphasizing that the toxicity of HTPs should not be underestimated.

Duguetia confinis Engl. & Diels (Annonaceae) inhibitory and cytotoxic effects on breast adenocarcinoma growth both in vitro and in vivo

BackgroundBreast cancer is ranked as the most common malignant tumor in women globally with ∼ 2.3 million new cases (11.7 %) diagnosed in 2020. The multiple drawbacks associated with treatments, prompt researchers and patients to search for alternative therapy. Plants continue to offer encouraging leads, in particular those of the Annonaceae family, to which belongs Duguetia confinis, used by Cameroonian traditional healers to fight cancers. This study was aimed at investigating the effect of Duguetia confinis against human breast cancer cells. This was carried out by investigating the cytotoxicity, underlying mechanism of action and chemopreventive potential of D. confinis on 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer. MethodsTo achieve this goal, the ethanolic extract of the bark of D. confinis was prepared and assayed for its ability to inhibit cell growth, cell proliferation and clone formation. Furthermore, cell death mechanisms, cell cycle progression and anti-metastatic potential were investigated. The in vivo study consisted in a once-off administration of 50 mg/kg BW DMBA (in olive oil, s.c) from the 10th day after pretreatment with D. confinis extract (50 and 100 mg/kg BW) or standards [tamoxifen (3.3 mg/kg) and letrozole (1 mg/kg)] or leaf extract of Annona muricata L. (200 mg/kg as pharmacological control). Normal and negative controls received vehicle (3 % ethanol). The treatment of animals was done for 20 weeks, followed by the assessment of the incidence, burden and volume of tumors, breast cancer biomarker (CA 15-3), antioxidant status, inflammatory status and histopathology profile. The LD50 of D. confinis extract was estimated according to OECD guideline 423. ResultsD. confinis displayed cytotoxicity at 80 μg/mL on all the tested breast cancer cell lines. It induced apoptosis and caused a blockade at G0/G1; S-phase of MDA-MB 231 cells, thus, suggesting anticancer potential. A significant concentration-dependent antimetastatic potential was observed with D. confinis extract at 50 (p < 0.05) and 100 (p < 0.01) μg/mL, evidenced by a reduction in cell migration, chemotaxis and increased adhesion to extracellular matrix. With respect to the chemopreventive study, D. confinis was able to prevent the onset of breast adenocarcinoma in Wistar rats by preventing the growth of tumor mass and volume, as well as the histopathological severity of the disease. This was achieved through the modulation of antioxidant parameters (SOD, CAT, MDA) and inflammatory parameters (IL-12, IL-6, INF- gamma, TNF). Also, the LD50 of D. confinis extract was greater than 2000 mg/kg, indicating low acute toxicity and thus, favorable for therapeutic use. ConclusionIn summary, this study outlines for the first time the beneficial effect of D. confinis as a plant candidate in the fight against breast cancer just like other species of the Annonaceae family. However, further research studies are still warranted regarding its bioactive components, and in depth investigation of its anticancer mechanism of action are also needed.

Characteristics and health risks of the inhalable fraction of metal additive manufacturing powders

AbstractMetal additive manufacturing (AM) is gaining traction but raises worker health concerns due to micron‐sized powders, including fine inhalable particles. This study explored particle and surface characteristics, electrochemical properties, metal release in artificial lysosomal fluid (ALF), and potential toxicity of virgin and sieved virgin Fe‐based powders, stainless steel (316L), Fe, and two tooling steels. Virgin particles ranged in size from 1 to 100 µm, while sieved particles were within the respirable size range (&lt;5–10 µm). Surface oxide composition differed from bulk composition. The Fe powder showed low corrosion resistance and high metal release due to a lack of protective surface oxide. Sieved particles of 316L, Fe, and one tooling steel released more metals into ALF than virgin particles, with the opposite was observed for the other tooling steel. Sieved particles had no notable impact on cell viability or micronuclei formation in human bronchial epithelial cells. Inflammatory response in human macrophages was generally low, except for the Fe powder and one tooling steel, which induced increased interleukin‐8 (IL‐8/CXCL‐8) and monocyte chemoattractant protein‐1 (MCP‐1/CCL‐2) secretion. This study underscores distinctions between virgin and sieved Fe‐based powders and suggests relatively low acute toxicity.