Search Results (8,960)

Background/Objectives: Branched-chain fatty acids (BCFAs) exhibit a range of biological activities; however, their limited natural abundance and high cost have constrained in vivo research. Lanolin represents a promising source for enriching BCFAs. Nevertheless, the in vivo application, safety, and dose-effect relationship of BCFAs derived from lanolin (BCFAs-DFL) remain unassessed. Methods: In this study, the acute toxicity in C57BL/6J mice was first evaluated for 7 days by a single oral administration of 5000 mg/kg BW of BCFAs-DFL. Subsequently, 40 mice were divided into four groups (control group, low dose of 100 mg/kg BW, medium dose of 300 mg/kg BW, and high dose of 600 mg/kg BW) and were continuously administered by gavage for 28 days to study the effects of BCFAs-DFL on the growth, blood biochemistry, intestinal morphology, and intestinal flora of the mice. Results: In the acute toxicity test, BCFAs-DFL exhibited no lethality or abnormalities in mice, indicating its non-toxic nature. Throughout the 28-day trial, mice in the medium- and high-dose groups experienced a notable decrease in average daily feed intake (p < 0.05), yet their weight gain remained unaffected (p > 0.05). Hemoglobin and hematocrit levels declined in the high-dose group (p < 0.05). Conversely, serum aspartate aminotransferase and total bilirubin levels escalated in the medium- and high-dose groups, while triglycerides and urea nitrogen levels decreased (p < 0.05). The serum’s total antioxidant capacity and immunoglobulin levels (IgA, IgG) rose in proportion to the dosage (p < 0.05). BCFAs-DFL notably enhanced the villus height of the jejunum and ileum in mice (p < 0.05). Gut microbiota analysis indicated no significant impact on overall α and β diversity. Conclusions: The 28-day intervention revealed that BCFAs-DFL can modulate feeding behavior, TG, T-AOC, and immunoglobulin levels in mice. Additionally, it promotes the development of intestinal villi. Based on various indicators, a dosage of 100 mg/kg BW effectively induces beneficial metabolic regulation, such as the reduction of triglycerides, without causing a burden on liver metabolism. This dosage may represent a more suitable application for potential use. Full article

The epiphytic community of Laminaria hyperborea, dominated by red algae, is typically discarded during industrial processing despite its potential as a source of high-value natural products. This study aims to valorize this underutilized biomass by characterizing its secondary metabolites and evaluating the biological activities of its major bromophenols. A combined chromatographic workflow enabled the isolation and structural elucidation of five bromophenols (1–5), including one previously undescribed compound (5). Among these, compound 4 exhibited the strongest cytotoxicity against the acute myeloid leukemia (AML) cell line MOLM-13 (EC₅₀ = 6.23 μM) and induced pronounced apoptotic features. When tested on two normal cell lines (NRK and H9c2) and in zebrafish larvae, it showed moderate toxicity at higher concentrations, indicating a reasonable selectivity window. In contrast, compound 5 was more toxic to normal cells than to MOLM-13 in vitro, while showing no acute toxicity in zebrafish; however, interpretations are preliminary due to compound purity. Bromophenols 1–4 were also tested for antioxidant activity, with 4 being the most potent (ABTS EC₅₀ = 22.1 μM), although this did not translate into protection against doxorubicin-induced cardiotoxicity. Additionally, non-targeted UHPLC-QTOF MS/MS analysis tentatively identified nine additional bromophenols and provided an estimation of their origin species within the epiphytic assemblage. Full article

The human skin microbiome has gained considerable attention as a resource for the development of innovative probiotics for cosmetic purposes or promoting skin health. However, the evaluation of new probiotic strains to ensure their “generally recognized as safe” (GRAS) status remains challenging. Here, we have subjected the annotated draft genome sequences of four human skin-derived bacterial strains, namely Bacillus subtilis MBF10-19J, Micrococcus luteus MBF05-19J, Staphylococcus hominis MBF12-19J, and Staphylococcus warneri MBF02-19J, to bioinformatic analyses to detect the genes associated with important probiotic traits, as well as undesirable characteristics such as antibiotic resistance, virulence factors, and toxic metabolites. Each bacterium harbors at least one type of adhesin-encoding gene, while only S. hominis MBF12-19J and S. warneri MBF02-19J contain the putative genes encoding enzymes for metabolism improvement. In vitro assays, including antibiotic susceptibility and antimicrobial activity testing, revealed strain-specific safety characteristics that complement the genomic findings. With regard to antibiotic resistance determinants, S. hominis MBF12-19J showed the most favorable profile, S. warneri MBF02-19J and M. luteus MBF05-19J appeared suitable when used with appropriate caution, and B. subtilis MBF10-19J exhibited amoxicillin resistance, i.e., warrants careful evaluation. Further in vivo validation is needed to determine whether these strains do indeed comply with GRAS evaluation frameworks. Full article

A library of thirty-one quinazoline derivatives was assessed as potential inhibitors of epidermal growth factor receptor kinase (EGFR) using 3D-QSAR methods, namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Training and test sets were generated by aligning the molecules to the lowest-energy conformer of the most active compound. The optimized models exhibited strong statistical performance, with R² values of 0.981 (CoMFA) and 0.978 (CoMSIA), and cross-validation coefficients (Q²) of 0.645 and 0.729, respectively. External validation confirmed their predictive power, yielding R² values of 0.929 and 0.909. Guided by these models, eighteen new quinazoline candidates were designed and evaluated for drug likeness and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties using in silico approaches. Molecular docking and molecular dynamics simulations highlighted the binding features and stability of these derivatives, with compound Pred65 demonstrating superior affinity and stability compared to Erlotinib. Collectively, the study provides valuable insights for the optimization of quinazoline scaffolds as EGFR inhibitors, supporting the development of promising anticancer leads. Full article

Background: The incidence of dementia, especially Alzheimer’s disease (AD), is rising, with over 55 million affected globally. Therefore, this disease, for which there is no adequate treatment, is more frequent and prevalent in women. Royal jelly, a bee secretion, is known for its health benefits and contains proteins, carbohydrates, lipids, minerals, polyphenols, enzymes, and B vitamins, as well as anti-inflammatory and antioxidant properties relevant to AD. Thus, we aimed to investigate the chemical compounds in royal jelly extract and their effect on neurobehavioral changes in an AD female model. Methods: In vitro studies were used to investigate the chemical and physicochemical properties of the royal jelly extract. In vivo studies, we divided female mice into five groups (n = 25): Control (C), Alzheimer (ALZ), ALZ standard (ALZ-STD, rivastigmine 1 mg/Kg), ALZ-D1 (royal jelly 150 mg/kg), and ALZ-D2 (royal jelly 300 mg/kg). The mice received the treatments orally at 45 days. We induced the AD model by orally administering aluminum chloride at 100 mg/kg and intraperitoneally injecting D-galactose at 120 mg/kg for 45 consecutive days, after which we subjected the animals to the radial arm maze, Morris water maze, elevated plus maze, and forced swim tests. Results: Analyses showed moderate acidity and a rich bioactive profile, with flavonoids being more prevalent. Antioxidant activity tests indicated moderate efficacy, while FTIR-ATR analysis revealed the chemical complexity of royal jelly. The royal jelly extract used in the study did not induce toxicity in vivo. Notably, royal jelly improved cognitive deficits, neurodegeneration, and reduced anxiety in AD. Conclusions: The study suggests that royal jelly extract has promising neuroprotective properties and could be a viable natural therapeutic option for AD. Full article

Guanidinoacetate methyltransferase (GAMT) is an essential enzyme in the biosynthesis of creatine, an important molecule in energy recycling. GAMT loss of function leads to GAMT deficiency (GAMT-D), an autosomal recessive disorder resulting in low creatine levels and the accumulation of a toxic intermediate, guanidinoacetate (GAA). GAMT-D patients present with intellectual disability and epilepsy, emphasizing the detrimental consequences of disturbed creatine metabolisms in the central nervous system (CNS). Current treatments are not curative and may not restore creatine metabolism in the brain. Here, we present a proof-of concept study testing the first CNS-directed, Adeno-associated virus serotype 9 (AAV9)-based gene therapy for the treatment of GAMT-D. the delivery of GAMT construct to cellular models of GAMT-D effectively restored protein and mRNA expression of GAMT while increasing intracellular creatine content and decreasing GAA accumulation. In murine models of GAMT-D, treatment with scAAV9.hGAMT, delivered intrathecally, resulted in increased creatine content as well as significant decreases in GAA accumulation in the CNS and peripheral organs. Overall, we found that scAAV9.hGAMT represents a promising gene therapy for treating GAMT-D, warranting further investigation in animal models to determine an appropriate therapeutic window for both efficacy and safety that allows for translation into human patients in the future. Full article

The threat of antimicrobial resistance (AMR) and the need for sustainable disinfectants have spurred interest in natural antimicrobials such as essential oils (EOs). However, their application is limited by volatility, poor water solubility, and cytotoxicity. Herein, we present the development of bio-based core–shell sub-micro-/nanocapsules (NCs) with encapsulated oregano (OO), thyme (TO), eucalyptus (EuO), and tea tree (TTO) oils to enhance antimicrobial (AM) performance and reduce cytotoxicity. NCs were synthesized via a nanoencapsulation method using chemically modified zein or poly(methyl vinyl ether-co-maleic anhydride) (GZA) as shell polymers, with selected EOs encapsulated in their core (encapsulation efficacy > 98%). Chemical modification of zein with vanillin (VA) and GZA with either dodecyl amine (DDA) or 3-(glycidyloxypropyl)trimethoxysilane (EPTMS) resulted in improvement in particle size distributions, polydispersity indices (PDIs) of synthesized NCs, and in the stability of the NC-dispersions in water. Antibacterial testing against Staphylococcus aureus and cytotoxicity assays showed that encapsulation significantly reduced toxicity while preserving their antibacterial activity. Among the formulations, GZA-based NCs modified with EPTMS provided the best balance between safety and efficacy. Despite this, life cycle assessment revealed that zein-based NCs were more environmentally sustainable due to lower energy use and material impact. Overall, the approach offers a promising strategy for developing sustainable, effective, and safe EO-based antibacterial agents for AM applications. Full article

Many confined-space accidents have happened in wastewater treatment tanks, mainly caused by hazard gases. To identify the factors affecting the distribution of toxic and harmful gases in wastewater treatment tanks, in this study, we collected data on confined-space accidents occurring in wastewater treatment tanks in China and analyzed accident types, the substances that caused the accidents and the purpose of entry. We carried out field tests to detect the concentrations of oxygen, hydrogen sulfide, combustible gas and carbon monoxide in 222 wastewater treatment tanks from 28 industrial enterprises and investigated the influence of wastewater treatment tank type, cover type and industry type on gas distribution. Through continuous monitoring, the concentrations of hydrogen sulfide and carbon monoxide in the regulating tanks of two industrial enterprises were monitored for a few days. The mechanism of harmful gas generation and control approaches were explored and analyzed. The results showed that more than 90% of confined-space accidents in wastewater treatment tanks were poisoning accidents, and the levels of harmful gas in wastewater collection tanks, regulating tanks, hydrolysis acidification tanks, sedimentation tanks and sludge tanks were high, qualifying them as high-risk wastewater treatment tanks prone to accidents. Without disturbance, there is basically no harmful gas in wastewater treatment tanks with completely uncovered tops. In addition, the concentration of toxic and hazardous gases in wastewater treatment tanks is not always stable, instead fluctuating greatly with time. The main purposes of this study are to identify the factors affecting the concentration of toxic and harmful gases in wastewater treatment tanks and to assess the risks of using wastewater treatment tanks. Full article

This study investigates the use of carbon nanotubes (CNTs) in the development of a filter capable of capturing toxic and carcinogenic compounds found in cigarette smoke dispersed in the environment. The aim is to contribute to the reduction in passive exposure to these substances, with potential benefits for public health and air quality. Carbon nanotubes were selected for their exceptional adsorption properties, attributed to their high specific surface area and porous structure. The material’s adsorptive performance was evaluated based on the quantity used, to determine the optimal mass that ensures the best filtering capacity. To test the system, an experimental setup was assembled to simulate real-world smoke emission conditions. Filters containing CNTs were subjected to gravimetric analysis to measure the amount of retained substances, and to gas chromatography to identify the adsorbed chemical compounds. The results confirm the potential of carbon nanotubes as an advanced filtering material, paving the way for robust solutions to mitigate the environmental impact of secondhand smoke. The results indicate that CNT-based filters, particularly those containing 0.06 g of material, are highly effective in retaining several toxic components of cigarette smoke, including nicotine. This configuration achieves a strong reduction in harmful organic species while using a moderate amount of adsorbent, suggesting a promising selectivity of CNTs toward the most hazardous molecules. Full article

Background: Desmoid tumors (DTs) are rare, locally aggressive fibroblastic neoplasms with highly heterogeneous clinical behavior. The present work constitutes the second part of a two-part project, following our previously published multidisciplinary review of the diagnostic and therapeutic landscape of DTs. It provides a comprehensive analysis of our institutional experience as a national reference center for sarcoma. We aim to describe real-world diagnostic pathways, management strategies, and clinical outcomes in a high-volume cohort. Methods: We conducted a retrospective cohort study that included patients diagnosed with DT at our center between 2014 and 2024. Demographic, clinical, molecular, treatment, and outcome data were collected. Management strategies were analyzed according to tumor location, symptoms, progression patterns, and multidisciplinary decision-making. Outcomes included response rates, event-free survival (EFS), need for active treatment, response to systemic therapy, and recurrence after local treatments. Results: A total of 109 patients were included (median age 36.8 years; 56.9% women). Somatic CTNNB1 mutations were identified in 23 of 29 tested patients, predominantly T41A, while germline alterations were found in 18 patients, mainly in APC. Initial management was conservative in 40.4% of patients and active in 59.6%, primarily through surgery. After a median follow-up of 41.5 months, 44.9% of patients experienced disease progression. Among patients managed with active surveillance, spontaneous regression occurred in 22.2%, and 58% remained treatment-free. Surgical relapse occurred in 35.8% of patients undergoing upfront resection, with major postoperative complications limited to externally operated cases. Cryoablation achieved radiological responses in most evaluable patients, while systemic therapies showed clinical activity but relevant toxicity, particularly with tyrosine kinase inhibitors. The median EFS for the whole cohort was 57 months. Conservative initial management and R1/2 surgical margins were independently associated with worse EFS. Conclusions: Our results support a personalized, multidisciplinary management strategy for DTs, prioritizing conservative approaches when appropriate and reserving active treatments for progressive or symptomatic disease. Outcomes achieved in a specialized referral center are comparable to those reported in large international retrospective series, underscoring the value of expert multidisciplinary care in optimizing DT management. Full article

Background: Radiotherapy is a common treatment for gynecological malignancies, often accompanied by significant side effects that impact patient nutritional status. The ketogenic diet has been proposed as a complementary nutritional strategy to enhance treatment efficacy, manage side effects, and preserve body composition. However, its safety and feasibility in the oncological setting remain under-investigated. Methods: The KOMPARC study is a prospective, randomized controlled trial evaluating the adherence, safety, and clinical tolerability of a ketogenic diet versus a standard Mediterranean diet in patients with cervical and endometrial cancer undergoing radiotherapy. Before the start of the treatment, patients were randomized to either the ketogenic diet or the standard diet groups. Anthropometric measures, Hand Grip Test, and body composition parameters from bioimpedance analysis were taken before the start of treatment and at the end. Adherence, adverse events, and patient-reported outcomes were monitored throughout the treatment period. Results: A total of 33 patients were enrolled. Adherence rates were comparable between the KD and standard diet groups (46.1% vs. 25.0% interruption rate, p = 0.21). No significant differences were observed in the incidence of gastrointestinal toxicities (p = 0.56), diarrhea (p = 0.81), nausea (p = 0.94), or weight loss (p = 0.24). Both groups experienced significant weight reduction during therapy without differential loss of body cell mass or other body composition parameters. Quality of life assessments indicated varied symptom profiles, with the KD group reporting increased appetite loss and worry about weight. Conclusions: Preliminary findings suggest that the ketogenic diet is a safe and feasible nutritional intervention during radiotherapy for pelvic tumors. These results support further investigation into ketogenic dietary strategies as adjuncts in oncologic care. Full article

Background: Administering several separate childhood vaccines can reduce adherence to immunization schedules due to missed appointments and the burden of repeated injections. A hexavalent formulation targeting diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type B, and poliovirus offers a practical approach to improve compliance and streamline immunization. Methods: Toxicity testing was performed in Wistar rats and New Zealand White rabbits (60 rats and 30 rabbits). Animals were distributed into three groups: hexavalent vaccine + low-dose sIPV, hexavalent vaccine + high-dose sIPV, and control. Each animal received a 0.5 mL intramuscular injection at weeks 0, 4, 8, and 12. Clinical observations were conducted throughout the study. Serum samples were collected one day before each injection and at the endpoint, while liver tissue was collected at the endpoint. ALT and AST concentrations were analyzed using an automated analyzer, and hepatic morphology was evaluated microscopically. Results: No abnormal clinical signs related to vaccination were observed. ALT concentrations showed no significant differences (p > 0.05). AST differences (p < 0.05) were detected between the high-dose group and the control on day 27 in female rabbits and on day 83 in female rats; however, all values remained within normal physiological limits. Histopathological examination revealed no irreversible hepatic lesions, including hydropic degeneration, portal inflammation, focal necrosis, or connective tissue proliferation, and no significant differences were noted (p > 0.05). Conclusions: Repeated administration of the hexavalent vaccine candidate at low and high doses produced no toxicological effects in animal models, supporting its safety for further clinical development. Full article

Synthetic cannabinoids (SCs) represent one of the rapidly growing groups of new psychoactive substances (NPS) on the illicit drug market. SCs mimic the effects of Δ⁹-tetrahydrocannabinol, but they have a greater affinity to the receptors, resulting in more potent psychoactive effects than traditional substances. The toxicity and high abuse potential of SCs could pose serious health risks to their users. The challenges posed by the SCs require innovative monitoring strategies like the analysis of untreated wastewater, known as wastewater-based epidemiology (WBE). In this review article, we summarized the available literature on the detection and quantification of SCs in raw wastewater samples published between 2013 and 2025. We paid special attention to challenges related to different experimental stages of WBE analysis that hinder the accurate measurement of SCs and their metabolites. The reviewed studies show that wastewater analysis reflected the dynamic evolution of the illicit SCs market. As studies on the analysis of SCs in wastewater remain scarce, large monitoring campaigns and research performed in more locations are needed. Modern analytical hyphenated systems such as LC-MS are essential for the sensitive and accurate quantification of SC biomarkers in wastewater and their sound identification. Future studies should address further stability tests, investigation of SC metabolism, and careful selection of the effective SC extraction method from the complex environmental matrix. Full article

Objectives: Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) commonly relies on somatostatin receptor subtype 2 (SSTR2) agonists such as DOTA-TOC/TATE, which may show limited efficacy due to high hepatic uptake and therapy resistance in some patients. SSTR2 antagonists have demonstrated superior tumor targeting. This study aimed to establish the production and quality control of the Actinium-225-labeled SSTR2 antagonist [²²⁵Ac]Ac-DOTA-LM3 and to report in-human clinical experience with targeted alpha therapy (TAT). Methods: [²²⁵Ac]Ac-DOTA-LM3 was produced by radiolabeling DOTA-LM3 with Actinium-225 under validated conditions. Radiochemical conversion, purity, yield, and stability were assessed using radio-TLC, fractionated radio-HPLC combined with gamma spectroscopy, and in vitro serum stability testing. Clinical feasibility and therapeutic response were evaluated in a patient with metastatic neuroendocrine pancreatic neoplasm refractory to prior ¹⁷⁷Lu-based PRRT. Results: Radiolabeling achieved reproducibly high radiochemical purity (>97%) and decay-corrected yields exceeding 80%. The radiopharmaceutical showed high in vitro stability with minimal release of free Actinium-225 over five days. Fractionated radio-HPLC enabled indirect purity assessment. In the reported patient, [²²⁵Ac]Ac-DOTA-LM3 therapy resulted in partial remission without clinically relevant hematologic, renal, or hepatic toxicity and was associated with marked clinical improvement. Conclusions: [²²⁵Ac]Ac-DOTA-LM3 can be produced with high purity and stability using clinically applicable procedures. In-human results suggest promising efficacy and safety, supporting further clinical investigation of Actinium-225-labeled SSTR2 antagonists for advanced NETs. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. It usually arises in cirrhotic liver, where chronic inflammation and fibrosis create a tumor-permissive microenvironment. Dysregulation of microRNAs (miRNAs), particularly upregulation of the oncomiR miR-221 and loss of the tumor suppressor miR-199a-3p represent key drivers of liver carcinogenesis. The TG221 transgenic mouse, designed to overexpress miR-221 in hepatocytes, provides a relevant in vivo platform for mechanistic studies and for testing preventive and therapeutic approaches. The TG221 model recapitulates miR-221-driven tumorigenesis, including suppression of p27, p57 and Bmf. It is characterized by steatohepatitic injury and accelerated tumor formation after genotoxic challenge. In the cirrhotic CCl₄-induced background, TG221 mice develop fibrosis and cirrhosis followed by dysplastic and malignant lesions, mirroring the natural history of human HCC. Metformin administered during early fibrosis prevented macroscopic tumor formation and suppressed PI3K/AKT/mTOR signaling. Anti-miR-221 and miR-199a-3p mimics reduced tumor burden, restored tumor-suppressive pathways and improved liver integrity, thus indicating feasible chemopreventive strategies. From a therapeutic point of view, miR-199a-3p replacement synergized with palbociclib and overcame sorafenib resistance. A miR-199a-3p-responsive oncolytic adenovirus achieved tumor-selective replication with minimal toxicity. This review highlights the importance of the TG221 transgenic mouse as a powerful model for studying miRNA-driven hepatocarcinogenesis and enables preclinical evaluation of RNA-based chemopreventive and therapeutic approaches. Metformin, miRNA inhibition, miRNA replacement and miRNA-guided viral therapies emerge as promising approaches for advancing precision prevention and treatment strategies in HCC. Full article