Search Results (564)

The increasing use of reclaimed wastewater in agriculture raises growing concerns about the accumulation of priority organic micropollutants in edible crops. In this study, we developed and validated a novel QuEChERS–SPME–GC/MS method for the simultaneous determination of 15 polycyclic aromatic hydrocarbons (PAHs), 3 nitro-PAHs, and 14 polychlorinated biphenyls congeners in Eruca vesicaria (rocket) leaves. The method was optimized to address the matrix complexity of leafy vegetables and included a two-step dispersive solid-phase extraction (d-SPE) cleanup and aqueous dilution prior to SPME. Validation showed excellent performance, with MDLs between 0.1 and 6.7 µg/kg, recoveries generally between 70 and 120%, and precision (RSD%) below 20%. The greenness of the protocol was assessed using the AGREE metric, yielding a score of 0.60. Application to rocket samples irrigated with treated wastewater revealed no significant accumulation of target pollutants compared to commercial samples. All PCB and N-PAH congeners were below detection limits, and PAH concentrations were low and mostly limited to lighter compounds. Human health risk assessment based on toxic equivalent concentrations confirmed that estimated cancer risk (CR) values 10⁻⁹–10⁻⁸ were well below accepted safety thresholds. These findings support the safe use of reclaimed water for leafy crop irrigation under proper treatment conditions and highlight the suitability of the method for trace-level food safety monitoring. Full article

We previously reported that the fathers of the Bien Hoa birth cohort in Vietnam showed altered brain regional gray matter volumes, as measured by magnetic resonance imaging, and social anxiety traits associated with perinatal dioxin exposure. In the present study, we aimed to compare gray matter volumes and social anxiety scale scores between dioxin-exposed fathers in Bien Hoa and unexposed controls in an unsprayed area. Fat-based bioassay-toxic equivalency levels in serum were used to indicate dioxin exposure in adulthood. Results indicated that the longer Bien Hoa residency group (≥30 years) exposed to dioxins during the perinatal period and early childhood showed higher gray matter volumes in the right and left temporal lobes than controls. However, no significant differences in temporal lobe gray matter volumes were found between the shorter Bien Hoa residency group (<30 years) and controls. Furthermore, the longer, but not shorter, Bien Hoa residency group showed higher social–emotional subscale scores than controls. Additionally, fat-based bioassay-toxic equivalency levels were inversely correlated with gray matter volumes in several right temporal gyri. These findings suggest biphasic life stage-dependent adverse effects of dioxin exposure: perinatal dioxin exposure increases gray matter volumes, especially in the temporal lobe, which leads to neurodevelopmental disorders with socio-emotional disturbances, whereas dioxin exposure after brain development decreases cortical gray matter volumes, possibly leading to cognitive dysfunction. Full article

As bisphenol A (BPA) has gradually become restricted in production scenarios, the ecological risk level of its main replacement chemicals, i.e., bisphenol S (BPS) and bisphenol F (BPF), should be noted. To overcome the limitations of toxicity data, two kinds of in silico toxicology models (quantitative structure–activity relationship (QSAR) and interspecies correlation estimation (ICE) models) were used to predict enough toxicity data for multiple species. The accuracy of the coupled in silico toxicology models was verified by comparing experimental and predicted data results. Reliable predicted no-effect concentrations (PNECs) of 8.04, 35.2, and 34.2 μg/L were derived for BPA, BPS, and BPF, respectively, using species sensitivity distribution (SSD). Accordingly, the ecological risk quotient (RQ) values of BPA, BPS, and BPF for aquatic organisms were assessed in 32 major Chinese surface waters; they ranged from nearly 0 to 1.86, but were <0.1 in most cases, which indicated that the overall ecological risk level of BPA and its alternatives was low. However, in some cases, the ecological risks posed by BPA alternatives have reached equivalent levels to those posed by BPA (e.g., Liuxi River, Taihu Lake, and Pearl River), which requires further attention. This study provides evidence that the application of coupled in silico toxicology models can effectively predict toxicity data for new chemicals, avoiding time-consuming and laborious animal experiments. The main findings of this study can support environmental risk assessment and management for new chemicals that lack toxicity data. Full article

Chilean Schinus molle has been used in traditional medicine for effects such as antibacterial, antifungal, anti-inflammatory, analgesic, antiviral, antitumoral, antioxidant, antispasmodic, astringent, antipyretic, cicatrizant, cytotoxic, diuretic, among others. In this study, we evaluated the pharmacological potential of Schinus molle seed essential oil extract (SM_EO) through in vitro and in silico approaches. In vitro, the antioxidant potential was analyzed, and antitumor activity was evaluated in non-tumor and human epithelial tumor cell lines. Caenorhabditis elegans was used as a model for evaluating toxicity, and the chemical composition of the SM_EO was analyzed using gas chromatography–mass spectrometry. The oil contained four major monoterpenes: α-phellandrene (34%), β-myrcene (23%), limonene (13%), and β-phellandrene (7%). Based on quantum mechanical calculations, the reactivity of the molecules present in the SM_EO was estimated. The results indicated that α- phellandrene, β-phellandrene, and β-myrcene showed the highest nucleophilic activity. In addition, the compounds following these as candidates for antioxidant and antiproliferative activities were α-phellandrene, β-phellandrene, ρ-cymene, sabinene, caryophyllene, l-limonene, and α-pinene, highlighting β-myrcene. Based on ADME-Tox properties, it is feasible to use these compounds as new drug candidates. Moreover, the antibacterial activity MIC value obtained for B. cereus was equivalent to 2 μg/mL, and for Y. enterocolitica, S. enteritidis, and S. typhimurium, the MIC value was 32.5 μg/μL. SM_EO could selectively inhibit the proliferation of human epithelial mammary tumor MCF7 cells treated with SM_EOs at 64 and 16 ug/mL—a significant increase in BCL-2 in a dose-dependent manner—and showed low toxicity against Caenorhabditis elegans (from 10 to 0.078 mg·mL⁻¹). These findings suggest that SM_EO may be a potential source of bioactive compounds, encouraging further investigation for applications in veterinary medicine, cosmetics, and sanitation. Full article

Chronic infection with the hepatitis B virus (HBV) results in over 1 million deaths annually. Although currently licensed treatments, including pegylated interferon-α and nucleoside/nucleotide analogs, can inhibit viral replication, they rarely eradicate covalently closed circular DNA (cccDNA) reservoirs. Moreover, vaccination does not offer therapeutic benefit to already infected individuals or non-responders. Consequently, chronic infection is maintained by the persistence of cccDNA in infected hepatocytes. For this reason, novel therapeutic strategies that permanently inactivate cccDNA are a priority. Obligate heterodimeric transcription activator-like effector nucleases (TALENs) provide the precise gene-editing needed to disable cccDNA. To develop this strategy using a therapeutically relevant approach, TALEN-encoding mRNA targeting viral core and surface genes was synthesized using in vitro transcription with co-transcriptional capping. TALENs reduced hepatitis B surface antigen (HBsAg) by 80% in a liver-derived mammalian cell culture model of infection. In a stringent HBV transgenic murine model, a single dose of hepatotropic lipid nanoparticle-encapsulated TALEN mRNA lowered HBsAg by 63% and reduced viral particle equivalents by more than 99%, without evidence of toxicity. A surveyor assay demonstrated mean in vivo HBV DNA mutation rates of approximately 16% and 15% for Core and Surface TALENs, respectively. This study presents the first evidence of the therapeutic potential of TALEN-encoding mRNA to inactivate HBV replication permanently. Full article

Background: Fixed-dose combinations have advanced in many therapeutic areas, including otorhinolaryngology, where hearing disorders are increasingly prevalent. Objectives: The present study focuses on developing and evaluating a new capsule combining nicergoline (NIC), piracetam (PIR), and hawthorn extract (HE) for the management of sensorineural hearing loss. Methods: The first phase methodology comprised preformulation studies (DSC, FTIR, and PXRD) to assess compatibility among active substances and excipients. Subsequently, four formulations were prepared and tested for flowability, dissolution behavior in acidic and neutral media, and stability under oxidative, thermal, and photolytic stress. Quantification of the active substances and flavonoids was performed using validated spectrophotometric and HPLC-UV methods. Results: Among the tested variants, the F1 formulation (4.5 mg NIC, 200 mg PIR, 50 mg HE, 2.5 mg magnesium stearate, 2.5 mg sodium starch glycolate, and 240.5 mg monohydrate lactose per capsule) displayed optimal technological properties, superior dissolution in acidic media, and was further selected for evaluation. The antioxidant activity of the formulation was confirmed through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, Trolox Equivalent Antioxidant Capacity (TEAC), and iron chelation tests, and was primarily attributed to the flavonoid content of the HE. Acute toxicity tests in mice and rats indicated a high safety margin (LD₅₀ > 2500 mg/kg), while ototoxicity assessments showed no adverse effects on auditory function. Conclusions: The developed formulation displayed good stability, safety, and therapeutic potential, while the applied workflow could represent a model for the development of future fixed-dose combinations. Full article

We adapt previously developed conceptual and numerical models of ciguateric food chains on the Great Barrier Reef, Australia, to model the bioaccumulation of ciguatoxins (CTXs) in parrotfish, the simplest food chain with only two trophic levels. Our model indicates that relatively low (1 cell/cm²) densities of Gambierdiscus/Fukuyoa species (hereafter collectively referred to as Gambierdiscus) producing known concentrations of CTX are unlikely to be a risk of producing ciguateric fishes on the Great Barrier Reef unless CTX can accumulate and be retained in parrotfish over many months. Cell densities on turf algae equivalent to 10 Gambierdiscus/cm² producing known maximum concentrations of Pacific-CTX-4 (0.6 pg P-CTX-4/cell) are more difficult to assess but could be a risk. This cell density may be a higher risk for parrotfish than we previously suggested for production of ciguateric groupers (third-trophic-level predators) since second-trophic-level fishes can accumulate CTX loads without the subsequent losses that occur between trophic levels. Our analysis suggests that the ratios of parrotfish length-to-area grazed and weight-to-area grazed scale differently (allometrically), where the area grazed is a proxy for the number of Gambierdiscus consumed and hence proportional to toxin accumulation. Such scaling can help explain fish size–toxicity relationships within and between trophic levels for ciguateric fishes. Our modelling reveals that CTX bioaccumulates but does not necessarily biomagnify in food chains, with the relative enrichment and depletion rates of CTX varying with fish size and/or trophic level through an interplay of local and regional food chain influences. Our numerical model for the bioaccumulation and transfer of CTX across food chains helps conceptualize the development of ciguateric fishes by comparing scenarios that reveal limiting steps in producing ciguateric fish and focuses attention on the relative contributions from each part of the food chain rather than only on single components, such as CTX production. Full article

Oral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. Escherichia coli expressing long-form cytidine deaminase (CDD_L) can degrade gemcitabine, a chemotherapeutic agent, into a non-toxic form, leading to resistance. In contrast, bacteria carrying short form (CDD_S) or lacking CDD did not induce resistance. This study investigates whether oral bacteria can cause gemcitabine resistance in PDAC cells through CDD-mediated degradation. Oral microbes associated with PDAC were selected based on CDD isoforms: Aggregatibacter actinomycetemcomitans carrying CDD_L, Enterococcus faecalis, Streptococcus mutans, Porphyromonas gingivalis, all carrying CDD_S, and Fusobacterium nucleatum lacking CDD. The selected microbes, along with wild-type and CDD-deficient E. coli, were co-incubated with gemcitabine to assess its degradation and PDAC cell proliferation. A. actinomycetemcomitans fully degraded gemcitabine and induced resistance. Surprisingly, CDD_S-expressing oral bacteria partially degraded gemcitabine in a strain-dependent manner. Expressing either CDD_L or CDD_S in CDD-deficient E. coli resulted in equivalent gemcitabine degradation and resistance, indicating that CDD function is independent of isoform length. These findings highlight the role of oral bacteria in gemcitabine resistance and the need for strategies to mitigate microbial-driven resistance in PDAC treatment. Full article

Preservatives are essential for ensuring the stability, safety, and efficacy of pharmaceuticals, cosmetics, and food products. However, synthetic preservatives often raise toxicity concerns. This study evaluated Rosmarinus officinalis (rosemary) leaf extracts and coffee by-products from Coffea arabica and Coffea canephora as potential natural preservatives for emulsions. Antimicrobial activity was assessed against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans, along with cytotoxicity tests on human keratinocytes and antioxidant activity. The most effective extracts were incorporated into an oil-in-water emulsion for evaluation. C. arabica extracts showed the best results among coffee samples, with 43.53 mg GAE/g (gallic acid equivalents) and 2.32 mg QE/g of total phenolics (quercetin equivalents) and flavonoids, and minimum inhibitory concentrations (MICs) of 12.5 mg/mL against Escherichia coli, and 25 mg/mL against Staphylococcus aureus and Pseudomonas aeruginosa. Rosemary extract showed 158.01 ± 23.67 mg GAE/g and 1.95 ± 0.05 mg QE/g, with MICs of 2.5 mg/mL against E. coli, 1.25 mg/mL against P. aeruginosa, 0.3 mg/mL against S. aureus, and 0.08 mg/mL against Candida albicans. However, rosemary extracts displayed complete inhibition of keratinocyte growth at 20 µg/mL. A combination of both extracts had synergistic effects against S. aureus and P. aeruginosa. The emulsion met microbial safety standards in the challenge test for bacteria but not yeast. The results suggest that rosemary extracts enhance the potential of coffee by-product as a preservative system, and as a multifunctional excipient system in cosmetics, offering preservation and antioxidant protection. However, further strategies, such as adding other ingredients or adjusting the formulation pH, are required to ensure yeast inhibition. Full article

The utilization of platinum complexes in medicine continues to be a prevalent treatment modality for diverse tumour types. However, it should be noted that certain platinum complexes are characterized by a high degree of toxicity. In recent years, there has been a focus among scientists on synthesizing “non-classic” platinum complexes, such as those with a trans-configuration, Pt(IV) complexes, and mixed ammine/amine platinum complexes, with the aim of reducing the toxic side effects of certain platinum complexes, including cisplatin. For instance, newly synthesized platinum complexes with a trans-configuration exhibited substantial cytotoxic activity which was comparable to that of the corresponding cis-isomers and cisplatin. This finding challenged the prevailing cis-geometry paradigm and prompted a re-evaluation of the structural activity relationships (SARs) of antitumour platinum complexes. It is widely accepted that Pt(IV) complexes act as prodrugs and release the active Pt(II) species. This property renders them promising candidates as anticancer drugs. Furthermore, it has been established that mixed ammine/amine platinum complexes are less toxic than cisplatin. In addition, compared to cisplatin, they have been observed to have equivalent or greater cytotoxic activity. Full article

Paralytic shellfish poisoning toxins (PSPTs) are a class of neurotoxins most known for causing illness from consuming contaminated shellfish. These toxins are also present in freshwater systems with the concern that they contaminate drinking and recreational waters. This review provides (1) a complete list of the 84+ known PSPTs and important chemical features; (2) a complete list of all environmental freshwater PSPT detections; (3) an outline of the certified PSPT methods and their inherent weaknesses; and (4) a discussion of PSPT toxicology, the weaknesses in existing data, and existing freshwater regulatory limits. We show ample evidence of production of freshwater PSPTs by cyanobacteria worldwide, but data and method uncertainties limit a proper risk assessment. One impediment is the poor understanding of freshwater PSPT profiles and lack of commercially available standards needed to identify and quantify freshwater PSPTs. Further constraints are the limitations of toxicological data derived from human and animal model exposures. Unassessed mouse toxicity data from 1978 allowed us to calculate and propose toxicity equivalency factors (TEF) for 11-hydroxysaxitoxin (11-OH STX; M2) and 11-OH dcSTX (dcM2). TEFs for the 11-OH STX epimers were calculated to be 0.4 and 0.6 for 11α-OH STX (M2α) and 11β-OH STX (M2β), while we estimate that TEFs for 11α-OH dcSTX (dcM2α) and 11β-OH dcSTX (dcM2β) congeners would be 0.16 and 0.23, respectively. Future needs for freshwater PSPTs include increasing the number of reference materials for environmental detection and toxicity evaluation, developing a better understanding of PSPT profiles and important environmental drivers, incorporating safety factors into exposure guidelines, and evaluating the accuracy of the established no-observed-adverse-effect level. Full article

Weeds present a pervasive challenge in agricultural fields. The integration of herbicide-resistant crops with chemical weed management offers an effective solution for sustainable weed control while reducing labor inputs, particularly in large-scale intensive farming systems. Consequently, the development of herbicide-resistant cultivars has emerged as an urgent priority. In this study, we found that the G311E mutant gene of Arabidopsis MATE (multidrug and toxic compound extrusion) family transporter DTX6, designated DTX6m, confers robust resistance to bipyridyl herbicides paraquat and diquat in rice. DTX6m-overexpression lines exhibited marked resistance to these two herbicides, tolerating diquat concentrations up to 5 g/L, which is five-fold higher than the recommended field application dosage. Agronomic assessments demonstrated that grain yields of DTX6m-overexpressing plants were statistically equivalent to those of wild-type plants. Moreover, the plants displayed beneficial phenotypic changes, such as accelerated flowering and a slight reduction in height. Seed morphometric analysis indicated that in comparison with the wild-type control, DTX6m-transgenic lines exhibited altered grain dimensions while maintaining consistent 1000-grain weight. Nutritional assays further demonstrated that DTX6m increased the levels of free amino acids in seeds, while normal protein and starch contents were retained. Collectively, these results establish that DTX6m effectively boosts rice resistance to paraquat and diquat, validating DTX6m as a candidate gene for engineering plant herbicide resistance and also implying a potential role for DTX6m in amino acid homeostasis in plants. Full article

Background/Objectives: Vitexin and isovitexin are bioactive flavonoids with promising pharmacological effects; however, they have poor bioavailability. Microencapsulation with biodegradable polymers is a promising strategy for improving their stability, bioavailability, and biocompatibility. This study aimed to optimize the formulation parameters to obtain microspheres with desired properties in terms of size, loading ratio, and vitexin–isovitexin release. Methods: Microspheres were prepared using alginate as the core matrix and a chitosan outer layer. A Design of Experiment approach using response surface methodology was employed. The hypoglycemic effects of the obtained microspheres were evaluated. Results: The formulation using 1.17% low-viscosity alginate, 7.60% calcium chloride, 5.78% Tween 80, and 5.00% Span 80 resulted in microspheres with optimal mean size (10.78 µm), high loading ratio (22.45%) and encapsulation efficiency (68.92%). The in vitro release of vitexin–isovitexin from microspheres was completed within 24 h in controlled manner. The microspheres were found to be non-toxic in vivo and exhibited hypoglycemic effects after 21 days at doses equivalent to 30 and 60 mg/kg of vitexin–isovitexin. The potential mechanisms might involve increasing the size of Islets of Langerhans and improving pancreatic β-cell function and insulin resistance, as observed in alloxan-induced diabetic mice. Conclusions: This work successfully developed alginate–chitosan-based microspheres for the controlled release of vitexin–isovitexin while maintaining their bioactivities. Full article

Objectives: Currently, there are a lack of data on the use of systemic lidocaine infusion in critically ill surgical patients, particularly regarding optimal dosing and monitoring. This study aimed to assess the feasibility of conducting a subsequent full-scale, randomized controlled trial (RCT) on the use of systemic lidocaine infusion in surgical intensive care units (ICUs). Methods: A single-center, prospective, single-arm pilot trial was conducted at the surgical intensive care unit (ICU) at Houston Methodist Hospital. The study population included 12 subjects over 18 years old who were admitted to the surgical ICU after open abdominal surgery. A low-dose lidocaine infusion of 10–30 mcg/kg/min within 1 h of ICU admission. Results: The feasibility outcomes encompassed recruitment, retention, and withdrawal rates. The study initially screened 18 participants, all of whom were successfully enrolled, resulting in a recruitment rate of 100%. However, 6 participants (33.3%) from the enrolled group were subsequently withdrawn for various reasons, resulting in a retention rate of 12 participants (66.7%). All 12 remaining participants were included in the analysis at the baseline stage. The safety outcomes included adverse events and serum lidocaine levels, with no serious adverse events reported. Dizziness and hypertension were the most frequently reported adverse events in their respective categories, affecting 16.7% of patients each. Four patients (33%) exhibited elevated lidocaine levels exceeding 5 mcg/mL; however, no clinical features of lidocaine toxicity were observed. This study adhered to the CONSORT 2010 extension for pilot and feasibility trials. In accordance with these guidelines, no formal hypothesis testing for efficacy was performed. The exploratory outcomes included a reduction in opioid requirements, as measured by morphine milligram equivalents (MMEs), and pain scores. The median MMEs decreased from 22.6 on postoperative day 0 to 2.5 on day 3. The pain scores decreased by 1.09 units per day (β = −1.09; 95% CI: −1.82 to −0.36; p = 0.003); however, the absence of a control group limits the robustness of this observation. Conclusions: A large-scale, randomized controlled trial to evaluate the safety and efficacy of systemic lidocaine infusion in the surgical intensive care unit (ICU) seems feasible, with minor adjustments to the eligibility criteria and improved collaboration among nurses, anesthesiologists, and surgeons. Full article

A bioassay for dioxin analysis of human samples has the advantages of cost effectiveness and requiring only a small sample volume. Using a DR-EcoScreen bioassay, we measured the biological equivalency (BEQ) levels in serum samples from 32 men exposed to dioxins in Bien Hoa and 32 unexposed men in Hanoi, Vietnam. For the Bien Hoa men, the World Health Organization toxic equivalent (WHO-TEQ) levels of dioxins had already been measured by instrumental analysis. The difference in fat-based BEQ levels between exposed and unexposed men was greater than for crude BEQ levels, with a strong correlation between fat-based BEQ and WHO-TEQ levels. The fat-based BEQ levels in Bien Hoa men with longer residency but lower WHO-TEQ levels were significantly higher than those in unexposed men and Bien Hoa men with shorter residency but higher WHO-TEQs, suggesting that fat-based BEQ may be an effective marker of dioxin-like activity. Additionally, comparisons of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and TEQs between shorter- and longer-residency groups indicated that higher levels of polychlorinated dibenzo-p-dioxins (PCDDs), particularly TCDD, contribute to increased BEQ levels. Taken together, the DR-EcoScreen bioassay may be useful to analyze dioxin-like activity associated with WHO-TEQs of men in a dioxin contamination hotspot originating from Agent Orange in Vietnam. Full article