Occurrence and Ecological Risk of Alkylamine Triazines in Chinese Estuarine Sediments: An Emerging Class of Persistent, Mobile, and Toxic Substances.

Identifying persistent, mobile, and toxic (PMT) substances from synthetic chemicals is critical for chemical management and ecological risk assessment. Inspired by the triazine analogues (e.g., atrazine and melamine) in the original European Union's list of PMT substances, the occurrence and compositions of alkylamine triazines (AATs) in the estuarine sediments of main rivers along the eastern coast of China were comprehensively explored by an integrated strategy of target, suspect, and nontarget screening analysis. A total of 44 AATs were identified, of which 23 were confirmed by comparison with authentic standards. Among the remaining tentatively identified analogues, 18 were emerging pollutants not previously reported in the environment. Tri- and di-AATs were the dominant analogues, and varied geographic distributions of AATs were apparent in the investigated regions. Toxic unit calculations indicated that there were acute and chronic risks to algae from AATs on a large geographical scale, with the antifouling biocide cybutryne as a key driver. The assessment of physicochemical properties further revealed that more than half of the AATs could be categorized as potential PMT and very persistent and very mobile substances at the screening level. These results highlight that AATs are a class of PMT substances posing high ecological impacts on the aquatic environment and therefore require more attention.

Biochar obtained from eucalyptus, rice hull, and native bamboo as an alternative to decrease mobility of hexazinone, metribuzin, and quinclorac in a tropical soil.

Mobile herbicides have a high potential for groundwater contamination. An alternative to decrease the mobility of herbicides is to apply materials with high sorbent capacity to the soil, such as biochars. The objective of this research was to evaluate the effect of eucalyptus, rice hull, and native bamboo biochar amendments on sorption and desorption of hexazinone, metribuzin, and quinclorac in a tropical soil. The sorption-desorption was evaluated using the batch equilibrium method at five concentrations of hexazinone, metribuzin, and quinclorac. Soil was amended with eucalyptus, rice hull, and native bamboo biochar at a rate of 0 (control-unamended) and 1% (w w-1), corresponding to 0 and 12 t ha-1, respectively. The amount of sorbed herbicides in the unamended soil followed the decreasing order: quinclorac (65.9%) > metribuzin (21.4%) > hexazinone (16.0%). Native bamboo biochar provided the highest sorption compared to rice hull and eucalyptus biochar-amended soils for the three herbicides. The amount of desorbed herbicides in the unamended soil followed the decreasing order: metribuzin (18.35%) > hexazinone (15.9%) > quinclorac (15.1%). Addition of native bamboo biochar provided the lowest desorption among the biochar amendments for the three herbicides. In conclusion, the biochars differently affect the sorption and desorption of hexazinone, metribuzin, and quinclorac mobile herbicides in a tropical soil. The addition of eucalyptus, rice hull, and native bamboo biochars is a good alternative to increase the sorption of hexazinone, metribuzin, and quinclorac, thus, reducing mobility and availability of these herbicides to nontarget organisms in soil.

Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET.

BACKGROUND: Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown. METHODS: The expression of MSLN was validated in clinical tissue and serum samples using immunohistochemistry and enzyme-linked immunosorbent assay. The ability of NSCLC cells to penetrate the blood-brain barrier (BBB) was examined using an in vitro Transwell model and an ex vivo multi-organ microfluidic bionic chip. Immunofluorescence staining and western blotting were used to detect the disruption of tight junctions. In vivo BBB leakiness assay was performed to assess the barrier integrity. MET expression and activation was detected by western blotting. The therapeutic efficacy of drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) on BM was evaluated in animal studies. RESULTS: MSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially BBB extravasation. Mechanistically, MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) effectively blocked the development of BM and prolonged the survival of mice. CONCLUSIONS: Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.

Immunological studies on the effects of toltrazuril and neem extract in broiler chickens suffering from coccidiosis.

Background: The prevalence of avian coccidiosis in the poultry industry has grown, resulting in substantial financial losses from high mortality, stunted growth, reduced productivity, and expensive medical expenses. Aim: The purpose of the current study was to assess the immunological effects of neem leaf extract and toltrazuril on broilers that had contracted coccidiosis. Methods: In this investigation, 100 one-day-old Cobb broiler chicks without sexes were employed. The chicks were divided into five equal groups, with 20 birds in each. On the 14th day of life, the birds in groups 2, 3, 4, and 5 received an oral inoculation with 1 × 105 sporulated oocysts of Eimeria tenella (E. tenella) (field isolate). The first group (Gp), which consists of 20 healthy broilers, served as a negative control. Gp (2) contains experimentally infected broilers and nontreated (served as a positive control). Gp (3) contains experimentally infected broilers treated with toltrazuril (1 ml/l drinking water) for two consecutive days. Gp (4) contains experimentally infected broilers treated with neem leaf extract 4% (50 ml/l drinking water) for 5 successive days, and Gp (5) contains experimentally infected broilers treated with toltrazuril (1 ml/l drinking water) and a half dose of neem leaves extract 4% (25 ml/l drinking water) for 5 successive days. For the purpose of estimating body weight growth and feed conversion ratio, each broiler was weighed separately at the start of the trial and again on the 1st and 10th day after treatment. In addition to obtaining intestinal samples for immunohistochemistry, blood samples were also obtained for immunological examination. Results: As compared to the negative control group, the experimentally infested broilers with E. tenella showed significant decreases in serum nitric oxide, lysosome, phagocytic percent, and phagocytic index, along with significant increases in white blood cells (WBCs), lymphocyte, heterophilis, eosinophilis, basophilis, monocyte, serum total protein, γ globulin, fibrinogen, and haptoglobin. When compared to the control positive group, experimentally infested broilers treated with either neem or toltrazuril alone or in combination demonstrated significant increases in serum total protein, nitric oxide, lysozyme, phagocytic percent, and phagocytic index, but significant decreases in WBCs, lymphocytes, heterophile, eosinophile, basophile, and monocyte. The intestinal peroxidase stain of broilers infected with E. tenella exhibited a significant positive expression for CD4, but the infected broilers treated with toltrazuril and half a dosage of neem displayed a negative expression for CD4, identical to the negative control. Conclusion: The broiler chickens infested with E. tenella may have a variety of negative impacts on their immune systems and immunohistopathological findings. Nonetheless, toltrazuril and neem extract, either separately or in combination, function as anticoccidial medications that may enhance the broiler chicks' immune state.

Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents.

This study presents the synthesis of four series of novel hybrid chalcones (20,21)a-g and (23,24)a-g and six series of 1,3,5-triazine-based pyrimido[4,5-b][1,4]diazepines (28-33)a-g and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones 20b,d, 21a,b,d, 23a,d-g, 24a-g and the pyrimido[4,5-b][1,4]diazepines 29e,g, 30g, 31a,b,e-g, 33a,b,e-g exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI50 values between 0.01 and 100 µM and LC50 values in the range of 4.09 µM to >100 µM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against N. gonorrhoeae, S. aureus (ATCC 43300), and M. tuberculosis were exhibited by the pyrimido[4,5-b][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone 29e and triazinyloxy-chalcone 31g were the most active compounds against T. rubrum and T. mentagrophytes and A. fumigatus, respectively (MICs = 62.5 µg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.

Virological and clinical outcomes in outpatients treated with baloxavir or neuraminidase inhibitors for A(H3N2) influenza: A multicenter study of the 2022-2023 season.

While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant further study in real-world settings. In response, we executed a prospective, observational study of the Japanese 2022-2023 influenza season. A cohort of 73 A(H3N2)-diagnosed outpatients-36 treated with baloxavir, 20 with oseltamivir, and 17 with other neuraminidase inhibitors (NAIs)-were analyzed. Viral samples were collected before and after administering an antiviral on days 1, 5, and 10, respectively. Cultured viruses were amplified using RT-PCR and sequenced to detect mutations. Fever and other symptoms were tracked via self-reporting diaries. In the baloxavir cohort, viral detection was 11.1% (4/36) and 0% (0/36) on day 5 and day 10, respectively. Two isolates from day 5 (5.6%, 2/36) manifested I38T/M-substitutions in the polymerase acidic protein (PA). For oseltamivir and other NAIs, viral detection rates were 60.0% (12/20) and 52.9% (9/17) on day 5, and 16.7% (3/18) and 6.3% (1/16) on day 10, respectively. No oseltamivir-resistant neuraminidase mutations were identified after treatment. Median fever durations for the baloxavir, oseltamivir, and other NAI cohorts were 27.0, 38.0, and 36.0 h, respectively, with no significant difference. Two patients harboring PA I38T/M-substitutions did not exhibit prolonged fever or other symptoms. These findings affirm baloxavir's virological and clinical effectiveness against A(H3N2) in the 2022-2023 season and suggest limited clinical influence of post-treatment resistance emergence.

Gedatolisib in combination with palbociclib and endocrine therapy in women with hormone receptor-positive, HER2-negative advanced breast cancer: results from the dose expansion groups of an open-label, phase 1b study.

BACKGROUND: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein. METHODS: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032. FINDINGS: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event. INTERPRETATION: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile. FUNDING: Pfizer and Celcuity.

A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma.

BACKGROUND: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. METHODS: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FINDINGS: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. INTERPRETATION: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FUNDING: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).

Porous poly(bismaleimide-co-divinylbenzene) microspheres as dispersive solid-phase extraction adsorbent coupled to high-performance liquid chromatography for the determination of triazine herbicide residues in vegetable samples.

In this work, monodisperse and nano-porous poly(bismaleimide-co-divinylbenzene) microspheres with large specific surface area (427.6 m2 /g) and rich pore structure were prepared by one-pot self-stable precipitation polymerization of 2,2'-bis[4-(4-maleimidophenoxy) phenyl] propane and divinylbenzene. The prepared poly(bismaleimide-co-divinylbenzene) microspheres were employed as dispersive solid-phase extraction (DSPE) adsorbent for the extraction of triazine herbicides. Under optimized conditions, good linearities were obtained between the peak area and the concentration of triazine herbicides in the range of 1-400 µg/L (R2 ≥ 0.9987) with the limits of detection of 0.12-0.31 µg/L. Triazine herbicides were detected using the described approach in vegetable samples (i.e., cucumber, tomato, and maize) with recoveries of 93.6%-117.3% and relative standard deviations of 0.4%-3.5%. In addition, the recoveries of triazine herbicides remained above 80.7% after being used for nine DSPE cycles, showing excellent reusability of poly(bismaleimide-co-divinylbenzene) microspheres. The adsorption of poly(bismaleimide-co-divinylbenzene) microspheres toward triazine herbicides was a monolayer and chemical adsorption. The adsorption mechanism between triazine herbicides and adsorbents might be a combination of hydrogen bonding, electrostatic interaction, and π-π conjugation. The results confirmed the potential use of the poly(bismaleimide-co-divinylbenzene) microspheres-based DSPE coupled to the high-performance liquid chromatography method for the detection of triazine herbicide residues in vegetable samples.

Protective effects of imeglimin on the development of atherosclerosis in ApoE KO mice treated with STZ.

BACKGROUND: Imeglimin is a new anti-diabetic drug which promotes insulin secretion from pancreatic ß-cells and reduces insulin resistance in insulin target tissues. However, there have been no reports examining the possible anti-atherosclerotic effects of imeglimin. In this study, we investigated the possible anti-atherosclerotic effects of imeglimin using atherosclerosis model ApoE KO mice treated with streptozotocin (STZ). METHODS: ApoE KO mice were divided into three groups: the first group was a normoglycemic group without injecting STZ (non-DM group, n = 10). In the second group, mice were injected with STZ and treated with 0.5% carboxymethyl cellulose (CMC) (control group, n = 12). In the third group, mice were injected with STZ and treated with imeglimin (200 mg/kg, twice daily oral gavage, n = 12). We observed the mice in the three groups from 10 to 18 weeks of age. Plaque formation in aortic arch and expression levels of various vascular factors in abdominal aorta were evaluated for each group. RESULTS: Imeglimin showed favorable effects on the development of plaque formation in the aortic arch in STZ-induced hyperglycemic ApoE KO mice which was independent of glycemic and lipid control. Migration and proliferation of vascular smooth muscle cells and infiltration of macrophage were observed in atherosclerotic lesions in STZ-induced hyperglycemic ApoE KO mice, however, which were markedly reduced by imeglimin treatment. In addition, imeglimin reduced oxidative stress, inflammation and inflammasome in hyperglycemic ApoE KO mice. Expression levels of macrophage makers were also significantly reduced by imeglimin treatment. CONCLUSIONS: Imeglimin exerts favorable effects on the development of plaque formation and progression of atherosclerosis.

Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of coronavirus disease 2019 (COVID-19) and continues to be a major health concern worldwide. Strategies to protect individuals at high risk of COVID-19 are critical but are currently a largely unmet need. We evaluated the oral antiviral drug ensitrelvir, which specifically targets the SARS-CoV-2 3CL protease, for its efficacy as a pre-exposure prophylactic treatment. Aged BALB/c mice were subcutaneously treated with various doses of ensitrelvir 24 h prior to a lethal SARS-CoV-2 challenge infection. Mouse body weight changes, survival rates, and viral titers in the lungs were evaluated, and plasma concentrations of ensitrelvir were determined. A single subcutaneous administration of ensitrelvir at 64 mg/kg or greater 24 h prior to SARS-CoV-2 challenge infection significantly protected aged mice against lethality and inhibited body weight loss. Pharmacokinetic analysis of ensitrelvir in the aged mice suggested that plasma concentrations ≥2.99 µg/mL resulted in a significant prophylactic effect against SARS-CoV-2 infection. In the aged mouse prophylaxis model, SARS-CoV-2 titers were suppressed in the lungs of mice treated with ensitrelvir 24 h prior to challenge infection, suggesting that the prophylactic administration of ensitrelvir exerted its prophylactic effect by suppressing viral proliferation. These findings suggest that ensitrelvir is a candidate drug for pre-exposure prophylactic treatment of individuals at high risk of COVID-19.

Imeglimin mitigates the accumulation of dysfunctional mitochondria to restore insulin secretion and suppress apoptosis of pancreatic ß-cells from db/db mice.

Mitochondrial dysfunction in pancreatic ß-cells leads to impaired glucose-stimulated insulin secretion (GSIS) and type 2 diabetes (T2D), highlighting the importance of autophagic elimination of dysfunctional mitochondria (mitophagy) in mitochondrial quality control (mQC). Imeglimin, a new oral anti-diabetic drug that improves hyperglycemia and GSIS, may enhance mitochondrial activity. However, chronic imeglimin treatment's effects on mQC in diabetic ß-cells are unknown. Here, we compared imeglimin, structurally similar anti-diabetic drug metformin, and insulin for their effects on clearance of dysfunctional mitochondria through mitophagy in pancreatic ß-cells from diabetic model db/db mice and mitophagy reporter (CMMR) mice. Pancreatic islets from db/db mice showed aberrant accumulation of dysfunctional mitochondria and excessive production of reactive oxygen species (ROS) along with markedly elevated mitophagy, suggesting that the generation of dysfunctional mitochondria overwhelmed the mitophagic capacity in db/db ß-cells. Treatment with imeglimin or insulin, but not metformin, reduced ROS production and the numbers of dysfunctional mitochondria, and normalized mitophagic activity in db/db ß-cells. Concomitantly, imeglimin and insulin, but not metformin, restored the secreted insulin level and reduced ß-cell apoptosis in db/db mice. In conclusion, imeglimin mitigated accumulation of dysfunctional mitochondria through mitophagy in diabetic mice, and may contribute to preserving ß-cell function and effective glycemic control in T2D.

Improving access to melarsomine therapy: treating canine heartworm infection in a high-volume, outpatient community clinic setting.

BACKGROUND: Models that provide high-quality veterinary care for more affordable prices are emerging, but not well documented outside of wellness and preventative care. Effective treatment guidelines for heartworm disease have been developed by the American Heartworm Society; however, not all owners are able to access treatment due to the high costs associated with sick and emergency care services. METHODS: To increase access to high-quality adulticidal treatment of canine heartworm disease, we developed and implemented a technician-leveraged heartworm treatment protocol for high-volume, outpatient community clinic settings based on the American Heartworm Society guidelines. Modifications were few and included limited pre-treatment blood work, pre-injection sedation, post-injection pain medication, and a reduced exercise restriction period. We monitored retention rates for 556 dogs throughout treatment, evaluated treatment success (defined as no antigen detection 9 months post treatment) for patients that returned for post-treatment antigen testing, and reported on adverse reactions and therapy adherence throughout treatment. RESULTS: Of the patients that began adulticide therapy, 539/556 (97%) successfully completed the three-injection series. No microfilariae were detected in 99% (428/433) of those who returned for post-injection microfilaria testing. Among those that returned for or reported the results of post-injection antigen testing, no antigen was detected for 99% (245/248) and no microfilariae were detected for 99.5% (200/201). During the course of treatment, 483/539 (90%) of patients experienced at least one adverse reaction, with the most frequently reported types being behavioral and injection site reactions. 25/539 (4.6%) of owners sought additional medical care for adverse reactions at some point during the treatment course. The overall mortality rate was 1.3% (7/556). CONCLUSIONS: This study represents the first evaluation of a heartworm treatment protocol optimized for implementation in a high-volume, outpatient community clinic setting. Our findings align with those previously reported in private practice or tertiary referral centers, illustrating that through the inclusion of pre-treatment blood work, employing short-acting or reversible sedatives, ensuring proper analgesia, minimizing the use of ancillary diagnostics, reducing the duration of in-clinic monitoring while focusing on outpatient care, and maximizing technician involvement, we can deliver effective and safe melarsomine therapy at a more affordable cost to pet owners.

Mechanistic insight into biotransformation of novel triazine-based flame retardant 1,3,5-tris(2,3-dibromopropyl)-1,3,5-triazinane-2,4,6-trione by human cytochrome P450s.

The escalating focus on the environmental occurrence and toxicology of emerging pollutants underscores the imperative need for a profound exploration of their metabolic transformations mediated by human CYP450 enzymes. Such investigations have the potential to unravel the intricate metabolite profiles, substantially altering the toxicological outcomes. In this study, we integrated the computational simulations with in vitro metabolism experiments to investigate the metabolic activity and mechanism of an emerging pollutant, 1,3,5-tris(2,3-dibromopropyl)-1,3,5-triazinane-2,4,6-trione (TDBP-TAZTO), catalyzed by human CYP450s. The results highlight the important contributions of CYP2E1, 3A4 and 2C9 to the biotransformation of TDBP-TAZTO, leading to the identification of four distinct metabolites. The effective binding conformations governing biotransformation reactions of TDBP-TAZTO within active CYP450s are unveiled. Structural instability of primary hydroxyTDBP-TAZTO products suggests three potential outcomes: (1) generation of an alcohol metabolite through successive debromination and reduction reactions, (2) formation of a dihydroxylated metabolite through secondary hydroxylation by CYP450, and (3) production of an N-dealkylated metabolite via decomposition and isomerization reactions in the aqueous environment. The formation of a desaturated debrominated metabolite may arise from H-abstraction and barrier-free Br release during the primary oxidation, potentially competing with the generation of hydroxyTDBP-TAZTO. These findings provide detailed mechanistic insight into TDBP-TAZTO biotransformation by CYP450s, which can enrich our understanding of the metabolic fate and associated health risk of this chemical.

Novel magnetic porous organic polymer containing amino and triazine bifunctional groups for efficient adsorption of nitroimidazoles.

In this paper, a novel magnetic hyper-crosslinked polymer with amino and triazine bifunctional groups (M-NH2-THCP) was developed. M-NH2-THCP has strong nitroimidazoles (NDZs) enrichment effect, and therefore it was used as an adsorbent to extract five NDZs from lake water, catfish and shrimp meat prior to HPLC. Polar interaction, π-π stacking interaction, hydrogen bond and Lewis acid-base interaction were attested to be the major adsorption mechanism. The method has a good linearity in the range of 0.1-100 ng mL-1 for lake water, 10-400 ng g-1 for catfish and shrimp muscle with R2 > 0.9964. The limits of detection of NDZs were 0.03-0.04 ng mL-1 for lake water, 1.0-2.0 ng g-1 for catfish and 2.0-2.5 ng g-1 for shrimp, which is superior to most reported method. The method recoveries were 87.6-119 %, and relative standard deviations were less than 8.7 %. M-NH2-THCP holds great application potential in pollutants enrichment, separation and removal.

Zeolite 13X incorporated with Zn-Ce oxide nanocatalyst for removal of Reactive Red 120 dye: RSM-based approach.

In this study, the photocatalytic removal of Reactive Red 120 (RR120) dye was examined using zeolite 13X incorporated with Zn-Ce under UV irradiation. The synthesis of Zn-Ce nanoparticles incorporated with zeolite 13X was conducted through the co-precipitation method, and the features of the prepared nanocatalyst were analyzed using various techniques. The SEM and BET analyses indicated successful incorporation of ZnO-Ce oxides on the surface of zeolite 13X and a specific surface area of 359.39 m2/gm, respectively. Further, the average size of crystal grains was 28 nm. The response surface methodology (RSM) approach was employed to optimize operating parameters. The quadratic model suggested by the RSM approach, characterized by a high regression coefficient (R2 = 0.9632), indicates a high level of reliability. Moreover, under optimal conditions (catalyst loading of 4 mg, pH of 3, H2O2 amount of 0.2 mL, UV power of 25 W, and reaction time of 60 min), the highest RR120 dye removal percentage was 99.97%. Kinetic data indicated an increase in the reaction rate constant from 0.0631 to 0.1796 min-1. The zeolite 13X incorporated with Zn-Ce photocatalyst exhibited excellent stability over 5 cycles, with only a 5.50% decrease in RR120 dye removal yield. This study demonstrates the promising potential of zeolite 13X incorporated with Zn-Ce nanoparticles for the removal of RR120 dye from aqueous suspension.

Formation and control of disinfection by-products during the trichloroisocyanuric acid disinfection in swimming pool water.

The increasing demand for trichloroisocyanuric acid (TCCA) in swimming pool disinfection highlights the need to evaluate its applicability in terms of disinfection by-product (DBP) formation. Nevertheless, there is limited understanding of DBP formation and control during TCCA disinfection, particularly concerning the effects of various management parameters. This study aimed to fill this knowledge gap by comprehensively investigating DBP formation during TCCA chlorination, with a particular focus on assessing the contribution and interaction of influencing factors using Box-Behnken Design and response surface methodology. Results indicated that the concentrations of trichloroacetaldehyde, chloroform, dichloroacetic acid, trichloroacetic acid, and dichloroacetonitrile produced by TCCA disinfectant were 42.5%, 74.0%, 48.1%, 94.7% and 42.6% of those by the conventional sodium hypochlorite disinfectant, respectively. Temperature exhibited the most significant impact on chloroform formation (49%), while pH played a major role in trichloroacetaldehyde formation (44%). pH2 emerged as the primary contributor to dichloroacetic acid (90%) and trichloroacetic acid (93%) formation. The optimum water quality conditions were determined based on the minimum total DBPs (pH = 7.32, Temperature = 23.7 °C, [Cl-] = 437 mg/L). Chlorine dosage and contact time exhibited greater influence than precursor concentration on chloroform, dichloroacetonitrile, trichloroacetaldehyde, trichloroacetic acid, and total DBPs. Although the interaction between water quality parameters was weak, the interaction between disinfection operating parameters demonstrated substantial effects on DBP formation (8.56-19.06%). Furthermore, the DBP predictive models during TCCA disinfection were provided for the first time, which provides valuable insights for DBP control and early warning programs.

Toxoflavin analog D43 exerts antiproliferative effects on breast cancer by inducing ROS-mediated apoptosis and DNA damage.

Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.

Mechanistic interpretation of the sorption of terbuthylazine pesticide onto aged microplastics.

Microplastics (MPs) pose a global concern due to their ubiquitous distribution. Once in the environment, they are subject to aging, which changes their chemical-physical properties and ability to interact with organic pollutants, such as pesticides. Therefore, this study investigated the interaction of the hydrophobic herbicide terbuthylazine (TBA), which is widely used in agriculture, with artificially aged polyethylene (PE) MP (PE-MP) to understand how aging affects its sorption. PE was aged by an accelerated weathering process including UV irradiation, hydrogen peroxide, and ultrasonic treatment, and aged particles were characterized in comparison to pristine particles. Sorption kinetics were performed for aged and pristine materials, while further sorption studies with aged PE-MP included determining environmental factors such as pH, temperature, and TBA concentration. Sorption of TBA was found to be significantly lower on aged PE-MP compared to pristine particles because aging led to the formation of oxygen-containing functional groups, resulting in a reduction in hydrophobicity and the formation of negatively charged sites on oxidized surfaces. For pristine PE-MP, sorption kinetics were best described by the pseudo-second-order model, while it was intra-particle diffusion for aged PE-MP as a result of crack and pore formation. Sorption followed a decreasing trend with increasing pH, while it became less favorable at higher temperatures. The isotherm data revealed a complex sorption process on altered, heterogeneous surfaces involving hydrophobic interactions, hydrogen bonding, and π-π interactions, and the process was best described by the Sips adsorption isotherm model. Desorption was found to be low, confirming a strong interaction. However, thermodynamic results imply that increased temperatures, such as those resulting from climate change, could promote the re-release of TBA from aged PE-MP into the environment. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) confirmed TBA sorption onto PE.

Short-term responses of temperate and subarctic marine diatoms to Irgarol 1051 and UV radiation: Insights into temperature interactions.

Phytoplankton face numerous pressures resulting from chemical and physical stressors, primarily induced by human activities. This study focuses on investigating the interactive effects of widely used antifouling agent Irgarol 1051 and UV radiation on the photo-physiology of marine diatoms from diverse latitudes, within the context of global warming. Our findings clearly shown that both Irgarol and UV radiation have a significant inhibitory impact on the photochemical performance of the three diatoms examined, with Irgarol treatment exhibiting more pronounced effects. In the case of the two temperate zone diatoms, we observed a decrease in the inhibition induced by Irgarol 1051 and UVR as the temperature increased up to 25°C. Similarly, for the subarctic species, an increase in temperature resulted in a reduction in the inhibition caused by Irgarol and UVR. These results suggest that elevated temperatures can mitigate the short-term inhibitory effects of both Irgarol and UVR on diatoms. Furthermore, our data indicate that increased temperature could significantly interact with UVR or Irgarol for temperate diatoms, while this was not the case for cold water diatoms, indicating temperate and subarctic diatoms may respond differentially under global warming.