Search Results (850)

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

Nano- (NPs) and microplastics (MPs) are ubiquitous and raising concerns about their toxicity. A popular model for studying acute toxicity is Danio rerio. This study investigated the acute toxicity in FET test of polystyrene nanoparticles (500 nm, nanoPS) at different concentrations (0.01, 0.1, and 0.2 mg/mL), with different surface groups (non-modified, amine, carboxyl) and discuss the toxicological contribution of commercially added compounds. Different behavioural tests were used to investigate the neurotoxicity of nanoPS and sodium azide: coiling assay test, light–dark preference test, and colour preference test. Sodium azide and other preservatives are often present in commercially available NP and MP solutions frequently used in microplastic toxicity tests, but their effects on the results remain largely unknown. In the FET test, nanoPS did not increase mortality or affect the heart rate or body length. A higher hatching rate was observed at 48 hpf. Although nanoPS showed no acute toxicity, behavioural tests revealed subtle neurotoxic effects (changes in colour preference), suggesting a potential impact on neurological function. Additionally, sodium azide exhibited toxicity, indicating that additives may confound toxicity assessments. This highlights the need for careful consideration of preservatives in nanoparticle research to avoid misleading conclusions. Full article

Strobilurins are a prominent class of fungicides capable of entering aquatic environments via runoff and leaching from the soil. Findings from previous studies suggest that strobilurins are highly toxic in aquatic environments, and evidence of acute developmental toxicity and altered behavioral responses have been emphasized. The objective here was to determine the effects of a new strobilurin, metyltetraprole (MTP), on zebrafish using developmental endpoints, gene expression, and behavioral locomotor assays. We hypothesized that MTP would cause developmental toxicity and induce hyperactivity in zebrafish (Danio rerio). To test this, developing zebrafish embryos/larvae were exposed to environmentally relevant levels of MTP (0.1, 1, 10, and 100 µg/L) until 7 days post-fertilization. Survival percentages did not differ among the treatment groups. No change in reactive oxygen species production was detected, but two genes involved in the mitochondrial electron transport chain (mt-nd3 and uqcrc2) were altered in abundance following MTP exposure. Moreover, the highest concentration (100 µg/L) of MTP caused notable hyperactivity in the zebrafish in the visual motor response test. Overall, results from this study increase our knowledge regarding sub-lethal effects of MTP, helping inform risk assessment for aquatic environments. Full article

Povidone-iodine (PVP-I), a widely used aquaculture disinfectant, remains poorly understood in terms of sublethal toxicity and damage reversibility. This study employed Macrobrachium rosenbergii as the model organism to evaluate the acute toxicity and sublethal effects of PVP-I through a 4-day exposure experiment followed by a 7-day depuration period. Acute toxicity tests enabled the determination of 24–96 h median lethal concentrations (LC₅₀), with the 96 h LC₅₀ being 5.67 mg/L and the safe concentration (SC) being 1.37 mg/L. Based on this, three sublethal concentrations (1.14, 1.89, and 2.84 mg/L) were tested over a 4-day exposure followed by a 7-day depuration period. Investigated endpoints included gill ultrastructure, apoptosis, and antioxidant and immune-related gene expression. Subacute exposure at 1.89 and 2.84 mg/L induced mitochondrial vacuolization, upregulated apoptosis-related genes (Cyt-c, Caspase-3, Bok), and downregulated antioxidant gene expression (SOD, CAT, GSH-Px). The high-concentration group also showed sustained Toll-like receptor (Toll) gene overexpression and acid phosphatase (ACP) gene suppression. After depuration, antioxidant gene expression normalized; however, apoptotic markers in gill tissue remained impaired. Overall, high PVP-I concentrations cause irreversible gill damage via mitochondrial-mediated apoptosis, whereas lower concentrations (≤1.14 mg/L) allow for greater recovery. These results offer crucial toxicodynamic insights for safer PVP-I use and risk assessment in M. rosenbergii aquaculture. Full article

Euphorbia hirta L. is traditionally used to treat tumors and has demonstrated anticancer effects. This study evaluated the phytochemical composition, toxicity, and antitumor activity of saline extract (SE) from E. hirta leaves in mice. Phytochemical analysis included thin layer chromatography, high-performance liquid chromatography, and quantification of phenols, flavonoids, and proteins. Acute toxicity (2000 mg/kg) assessed mortality, hematological, biochemical, histological parameters, water/feed intake, and body weight. Genotoxicity was evaluated via comet and micronucleus assays. Antitumor activity was tested in vitro and in vivo on sarcoma 180. SE contained 107.3 mg GAE/g phenolics and 22.9 mg QE/g flavonoids; the presence of gallic and ellagic acids was detected. Protein concentration was 12.16 mg/mL with lectin activity present. No mortality, organ damage, or genotoxic effects occurred in toxicity tests. SE demonstrated in vitro cytotoxicity against sarcoma cells (IC₅₀: 10 µg/mL). In vivo, SE (50–200 mg/kg) reduced tumor weight by 70.2–72.3%. SE modulated IL-2, IL-4, IL-6, IL-17, IFN-γ, and TNF-α in tumor environment. Tumors showed inflammatory infiltrate, necrosis, and fibrosis after treatment. These findings position the extract as a promising candidate for further development as a safe, plant-based antitumor agent. Full article

This study provides an up-to-date assessment of the environmental status in the area of the S/s Stuttgart wreck in the southern Baltic Sea, focusing on macrozoobenthos, sediment chemistry, and contamination in Mytilus trossulus soft tissues. Comparative analyses from 2016 and 2023 revealed increased species richness and distinct benthic assemblages, shaped primarily by depth and distance from the wreck. Among macrozoobenthos, there dominated opportunistic species, characterized by a high degree of resistance to the unfavorable state of the environment, suggesting adaptation to local conditions. Elevated concentrations of heavy metals were detected in sediments, with maximum values of Cd—0.85 mg·kg⁻¹, Cu—34 mg·kg⁻¹, Zn—119 mg·kg⁻¹, and Ni—32.3 mg·kg⁻¹. However, no significant correlations between sediment contamination and macrozoobenthos composition were found. In Mytilus trossulus, contaminant levels were mostly within regulatory limits; however, mercury concentrations reached 0.069 mg·kg⁻¹ wet weight near the wreck and 0.493 mg·kg⁻¹ at the reference station, both exceeding the threshold defined in national legislation (0.02 mg·kg⁻¹) (Journal of Laws of 2021, item 568). Condition indices for Macoma balthica were lower in the wreck area, suggesting sublethal stress. Ecotoxicological tests showed no acute toxicity in most sediment samples, emphasizing the complexity of pollutant effects. The data presented here not only enrich the existing literature on marine pollution but also contribute to the development of more effective environmental protection strategies for marine ecosystems under international protection. Full article

The Adiabatic Sonic Evaporation and Crystallization (ASEC) technology was developed as a disruptive zero-liquid discharge system to treat contaminated mining effluents. This study evaluates its ecotoxicological efficacy using Lemna minor, a freshwater macrophyte, as a sensitive bioindicator. Acute growth inhibition tests were conducted using OECD Guideline 221. Lemna minor was exposed for 7 days to untreated and treated effluents from the Tharsis mine and the Tinto River in southern Spain. The results revealed 100% inhibition of frond growth and biomass in untreated samples (pH < 2.6), indicating acute toxicity. In contrast, effluents treated with ASEC showed growth and biomass accumulation statistically indistinguishable from the control, confirming the system’s efficiency in reducing toxicity and restoring water quality. These findings support the environmental viability of ASEC technology for mine and port effluent treatment. Full article

Purpose/Objective(s): Peritoneal carcinosis can occur in several gastrointestinal or gynecological malignancies and its prognosis is usually poor. With the advent of more effective systemic agents, the overall survival of metastatic patients has been revolutionized and isolated peritoneal or abdominal wall metastases might benefit from local treatments; Stereotactic Body Radiotherapy (SBRT) might be considered in selected patients with oligometastatic presentation. Materials/Methods: Oligometastases were defined according to recent ESTRO/EORTC consensus. Inclusion criteria were as follows: ECOG PS ≤ 2, written informed consent, up to five lesions to be treated at the same time, patients treated with radiotherapy schedules applying minimum 6 Gy per fraction. The primary endpoint of the study was local control (LC); acute and late toxicity, distant progression-free survival (DPFS), time-to-next systemic treatment (TNST), polymetastatic-free survival (PMFS) and overall survival (OS) were secondary endpoints. Toxicity was assessed according to CTCAE criteria v5.0. Statistical associations between clinical variables and outcomes were assessed using Fisher’s exact test, and Kruskal–Wallis test, as appropriate. Survival outcomes were estimated using the Kaplan–Meier method and compared using the log-rank test. Results: Between April 2020 and September 2024 a total of 26 oligometastatic lesions located in the peritoneum or in the abdominal wall detected in 20 patients received SBRT with Helical Tomotherapy. All cases have been assessed by a multidisciplinary team. Only in three patients out of twenty did more than one lesion receive SBRT: two lesions in two patients, and five lesions in a single case of colorectal cancer with ongoing third-line systemic treatment. Median total dose was 30 Gy (27–35 Gy) in five fractions (3–5). The most frequent primary neoplasm was ovarian cancer in 14/20, endometrial in 2/20, while the remaining were colorectal, vaginal, pancreatic and non-small cell lung cancer. Four lesions were located in the abdominal wall, while the remaining twenty-two were located in the peritoneum. Concurrent systemic therapy was administered in 18/20 patients. With a median follow-up of 15 months (range, 6–59), our 1-year LC was 100%, while 1-year DPFS, PMFS, TNTS and OS rates were 54%, 69%, 61% and 83%, respectively. Abdominal wall location and treatment of a subsequent oligometastatic recurrence with a second course of SBRT were both significantly associated with improved OS (p = 0.03 and p = 0.04, respectively). No G ≥ 3 adverse events occurred. Conclusion: Our preliminary data support the use of SBRT in selected cases of oligometastatic disease located in the peritoneum or in the abdominal wall with excellent results in terms of tolerability and promising clinical outcomes. Full article

Background/Objectives: Thymus longicaulis subsp. chaubardii (TL) (Rchb.f.) Jalas is widely used in traditional Turkish medicine for respiratory, digestive and uro-genital disorders. The aim of this study was to determine its phytochemical profile and to evaluate its cytotoxic, genotoxic and acute oral toxicity effects. Methods: The phenolic composition of the methanolic extract was determined by HPLC-DAD. Cytotoxicity and genotoxicity were evaluated in NIH3T3 cells using MTT, comet and micronucleus assays. Acute toxicity was evaluated in rats at doses of 300 and 2000 mg/kg body weight according to the OECD Guideline 420. Results: Rosmarinic acid (87.37 ± 5.39 µg/mg) was the major phenolic compound. TL extract showed >90% cell viability at 50–200 µg/mL, indicating no cytotoxicity. Comet assay revealed a slight increase in DNA damage at 100–200 µg/mL (p < 0.001), though significantly lower than the H₂O₂ group (p < 0.001). No significant (p > 0.05) effect was observed in the micronucleus assay between the treated groups. In rats, TL extract caused no mortality or behavioral changes over 14 days. No significant differences were observed in body or organ weights. Hematologically, platelet count increased (p < 0.001) and eosinophils decreased (p < 0.01 and p < 0.001). Biochemical tests showed lower ALT and AST levels (p < 0.01 and p < 0.05, respectively) and significantly decreased triglycerides in the high-dose group (p < 0.001). Histopathological examination showed no organ damage. Conclusions: The results of this study indicate that TL methanol extract is non-toxic up to 2000 mg/kg and exhibits no significant cytotoxic or genotoxic effects. These findings support its safe use and traditional medicinal value. Full article

The increasing release of nanoparticles into aquatic environments, particularly via wastewater, raises concerns about their biological effects on microbial communities. This study investigated the molecular response of Pseudomonas putida to aluminum oxide nanoparticles (Al₂O₃NPs) under controlled conditions and in synthetic wastewater, both before and after biological treatment. Acute toxicity was evaluated using growth inhibition assays, while the expression of katE, ahpC, and ctaD—genes associated with oxidative stress and energy metabolism—was quantified via RT-qPCR. Exposure to pristine Al₂O₃NPs induced a strong, time-dependent upregulation of all tested genes (e.g., katE and ahpC up to 4.5-fold). In untreated wastewater, this effect persisted but at a lower intensity; bulk Al₂O₃ caused only moderate changes. Treated wastewater samples showed markedly reduced gene expression, indicating partial detoxification. Nanoparticles elicited stronger biological responses than their bulk counterparts, confirming the material form-specific effects. Comparative analysis with Daphnia magna revealed similar patterns of oxidative stress gene activation. These findings highlight the influence of nanoparticle form and environmental matrix on microbial responses and support the use of gene expression analysis as a sensitive biomarker for nanoparticle-induced stress in environmental risk assessment. Full article

Industry currently generates numerous substances, such as food additives, whose environmental impacts, particularly in marine environments, remain inadequately assessed. This study employed Aurelia aurita for the first time as a model organism to evaluate the toxicity of such compounds. The main goal was to evaluate the toxicity of two food additives, 2-methyl-1-phenylpropan-2-ol (S1) and 1-phenylethan-1-ol (S2), on A. aurita ephyrae, comparing the results with other organisms representing different trophic levels, specifically the alga Phaeodactylum tricornutum and the crustacean Artemia salina. Acute toxicity tests were conducted on each organism. In A. aurita, S1 exhibited high toxicity (LC₅₀ ≈ 10 mg/L), while S2 had lower toxicity (LC₅₀ ≈ 80 mg/L). The pulsation frequency data for A. aurita revealed that S1 initially increased the pulsation rates at lower concentrations (maximum at 10 mg/L), followed by a significant decrease at higher concentrations. Conversely, S2 showed a steady decrease in pulsation rates up to 10 mg/L, with a slight increase at concentrations of 15, 20, and 25 mg/L. The results demonstrate varying sensitivities to the toxic effects of the two compounds across different trophic levels, with A. aurita ephyrae being the most sensitive. This suggests the potential efficacy of jellyfish as novel ecotoxicological models due to their heightened sensitivity, enabling the detection of lower contaminant concentrations in test samples. Further research is required to enhance the efficiency of ecotoxicological assays using this model. Full article

Background/Objectives: Endophytic fungi are valuable sources of bioactive compounds with potential therapeutic applications. This study aimed to evaluate the antifungal activity of secondary metabolites produced by Fusarium sp. isolated from Dizygostemon riparius, with particular focus on the impact of culture medium supplementation with halogenated and metallic additives on metabolite production. Methods: The fungus was cultivated in standard Czapek medium and media supplemented with NH₄Br or MnCl₂. Methanolic extracts were obtained, fractionated, and chemically characterised via LC-ESI-HRMS. In vitro antifungal assays, including MIC and MFC determinations and biofilm inhibition tests, were performed against Candida albicans strains. In vivo toxicity and efficacy were assessed using Tenebrio molitor larvae. Results: Fifteen metabolites were annotated, including known antifungals such as fusaric acid and cyclosporin A. Fractions EMBr4 and EMC5 demonstrated fungicidal activity with MIC values close to fluconazole and significantly inhibited biofilm formation and maturation. In vivo, these fractions displayed low acute toxicity and improved survival in infected larvae, comparable to fluconazole treatment. Conclusions: The results indicate that culture medium modulation enhances the production of bioactive metabolites by Fusarium sp., leading to extracts with notable antifungal efficacy and safety. EMBr4 and EMC5 are promising candidates for further development as antifungal agents, particularly for targeting biofilm-associated Candida infections. These findings support the potential of endophytic fungi as sources of novel therapeutics and warrant further mechanistic and pharmacological investigations. Full article

Background: The combined diphtheria–tetanus–acellular pertussis (three-component), Haemophilus influenzae type b (Hib, conjugate), and ACYW135 meningococcal (conjugate) vaccine (DTaP-Hib-MCV4) offers a promising alternative to single-component vaccines, potentially simplifying immunization schedules and improving vaccination coverage. Methods: We evaluated the safety, immunogenicity, and protective efficacy of DTaP-Hib-MCV4 in animal models. Acute and long-term toxicity studies were conducted in Sprague-Dawley (SD) rats with equal numbers of male and female animals. Immunogenicity was assessed in female NIH mice and SD rats using a three-dose regimen at 14-day intervals. Orbital blood was collected 14 days post-immunization to measure IgG titers against pertussis, diphtheria, tetanus, Hib, and meningococcal antigens. The protective efficacy was determined using potency tests for the pertussis, diphtheria, and tetanus components; passive protection studies for Hib; and serum bactericidal antibody (SBA) titers against A/C/Y/W135 meningococcal serogroups. Results: Acute and repeated-dose toxicity studies in SD rats showed no signs of abnormal toxicity or irritation at either high (three doses/rat) or low (one dose/rat) doses levels. The no-observed-adverse-effect level (NOAEL) for DTaP-Hib-MCV4 was established at three doses/rat after 8 weeks of repeated intramuscular administration and a 4-week recovery period. Specific IgG antibodies against all the vaccine components were detected in animal sera at both one and three doses/rat, with no evidence of immunotoxicity. Following two-dose primary immunization in murine models, the combined vaccine elicited robust antigen-specific antibody responses, with geometric mean titers (GMTs) as follows: 1,280,000 for pertussis toxin (PT); 761,093 for filamentous hemagglutinin (FHA); 1,159,326 for pertactin (PRN); 1,659,955 for diphtheria toxoid (DT); 1,522,185 for tetanus toxoid (TT); 99 for Haemophilus influenzae type b (Hib); and 25,600, 33,199, 8300, and 9051 for serogroups A, C, Y, and W135 of Neisseria meningitidis, respectively. In the rat models, three-dose primary immunization also elicited robust antigen-specific antibody responses. Protection studies demonstrated efficacy against pertussis, tetanus toxin, and diphtheria toxin challenges. In the Hib challenge study, none of the 10 animals given anti-DTaP-Hib-MCV4 antiserum developed bacteremia after the live Hib challenge (vs. 5814/0.1 mL in the negative control, p < 0.001). In addition, the SBA titers against meningococcal serogroups exceeded the protective threshold (≥1:8) in 92.2% of the immunized mice and 100% of the immunized rats. Crucially, the combined vaccine induced potent immune responses and protective efficacy, with antibody levels and protection against each component antigen comparable to or greater than those of the individual components: DTaP, Hib, and MCV4. Conclusions: These findings demonstrate that the DTaP-Hib-MCV4 combined vaccine is both safe and immunogenic, supporting its potential as a viable alternative to individual vaccines. This combined vaccine may streamline immunization programs and enhance vaccination coverage. Full article

Prostate cancer is one of the most prevalent malignancies in men, posing a significant public health challenge due to its high incidence and long-term treatment-related toxicities. Long-lived patients often experience prolonged side effects that can severely diminish their quality of life. Despite advancements in radiotherapy techniques like IMRT and VMAT, some patients still experience acute and late side effects. Current treatment protocols do not account for individual variability in normal-tissue radiosensitivity, highlighting the need for predictive tools and a personalised treatment approach. Genetic factors and molecular regulators like microRNAs (miRNAs) contribute to these variations by influencing DNA repair, inflammation, and apoptosis. This review explores potential biomarkers of radiotoxicity, focusing on immune-related factors such as IL-6 and TGF-β1, SNPs influencing radiosensitivity, miRNAs involved in radiation responses, and functional assays including the radiation-induced lymphocyte apoptosis (RILA) test. These approaches offer promising tools for identifying radiosensitive patients and enabling risk-adapted radiotherapy. Full article

Glufosinate-ammonium (GLA) is a broad-spectrum herbicide widely used for weed control. However, its potential toxic effects on non-target aquatic organisms, especially in freshwater ecosystems, are of growing concern. This study investigates the toxic effects of GLA on Biomphalaria glabrata, a freshwater snail highly sensitive to environmental pollutants and commonly used as a model organism in toxicological studies. Acute toxicity tests revealed that the 96-h LC50 of GLA for adult snails was 3.77 mg/L, indicating moderate toxicity, while the LC50 for embryos was 0.01576 mg/L, indicating extremely high toxicity. Chronic exposure experiments further showed that at high concentrations (0.5 mg/L), the shell diameter and body weight of the snails not only failed to increase but also decreased, and they ceased to lay eggs. Moreover, their hepatopancreas and gonads suffered significant damage. Even at an environmentally relevant concentration of 0.05 mg/L, the body length, body weight, and reproductive capacity of the snails were inhibited, and damage to the hepatopancreas and gonads was observed. These findings provide important data for assessing the potential risks of GLA to aquatic ecosystems and offer a scientific basis for formulating environmental protection policies and optimizing herbicide usage standards. Full article