Search Results (3,597)

Background/Objectives: Nasal biopharmaceutics is the scientific understanding of product and patient factors that determine the rate and extent of drug exposure following nasal administration. The authors considered whether current biopharmaceutics tools are fit for the current and future needs of nasal product development and regulation. Methods: The limitations of current methods were critically assessed, unmet needs were highlighted, and key questions were posed to guide future directions in biopharmaceutics research. Results: The emergence of physiologically based biopharmaceutics models for nasal delivery has the potential to drive the scientific understanding of nasal delivery. Simulations can guide formulation and device development, inform dose selection and generate mechanistic insights. Developments in modeling need to be complemented by advances in experimental systems, including the use of realistic or idealized nasal casts to estimate the regional deposition of nasal sprays and refined in vitro cell culture models to study nasal drug absorption and the influence of mucus. Similarly, improvements are needed to address the practicalities of using animals in non-clinical studies of nasal drug delivery, and greater clinical use of gamma scintigraphy/magnetic resonance imaging is recommended to measure the delivery and nasal retention of different formulations in humans. Conclusions: Nasal drug delivery is a rapidly growing field and requires advances in nasal biopharmaceutics to support product innovation. Key needs are (i) validated clinically relevant critical product attributes for product performance and (ii) established links between how patients administer the product and where in the nose it deposits and dissolves in order to act or be absorbed, leading to its desired clinical effect. Full article

Few studies have explored the holistic public health risk assessment associated with toxic elements (TEs) and their bioaccessibility in integrated urban environmental media including soils, vegetables, atmospheric particles, dust, etc. Urban industrial complex areas like Qingshan-Chemical District (QCD) in the Chinese Wuhan city, located within the Yangtze River Economic Belt, face increasing environmental exposure risks due to industrial activities. This study innovatively assessed the hierarchical risks of toxic metals in 4 environmental media (air PM, dust, soil, vegetables) from the QCD based on field sampling and chemical analysis, and developed an improved fuzzy health risk assessment model based on toxic metals’ in vitro bioaccessibilities of different exposure pathways and triangular fuzzy numbers for handling parameter uncertainties. The study found that the highest health risks were associated with ingestion, particularly from consuming homegrown vegetables. Carcinogenic risks for arsenic (As), lead (Pb), and cadmium (Cd) via ingestion exceeded the admissible threshold of 1.00 × 10⁻⁶, with As showing the highest risk ([1.92 × 10⁻³, 2.37 × 10⁻³]), followed by Cd ([2.98 × 10⁻⁵, 3.67 × 10⁻⁵]) and Pb ([7.92 × 10⁻⁷, 1.48 × 10⁻⁶]). Inhalation risks from soil, dust, and air particulates were below the threshold, indicating lower respiratory concerns. Dermal exposure, especially from soil and dust, posed elevated carcinogenic risks for As ([7.47 × 10⁻⁶, 8.06 × 10⁻⁶]). With the screened priority risk control toxic metals and pathways, the targeted measures including relocating vegetable planting areas, promoting cultivation of low-enrichment crops, building vegetation buffer zones around the industrial park, etc., were proposed. Full article

The Jurubatiba Sandbank National Park (PARNA Jurubatiba) is an ecological reserve characterized by harsh environmental conditions, including low rainfall, high sun exposure, and sandy soil. Among its native vegetation, Eremanthus crotonoides stands out for its richness in flavonoids, phenolic compounds, and sesquiterpene lactones. The objective of this study was to isolate and quantify sesquiterpene lactones from this species using ¹H NMR and to investigate their anti-SARS-CoV-2 potential and cytotoxicity against cancer cells. UPLC-(ESI)-MS/MS analyses enabled metabolite annotation, and semi-preparative HPLC-DAD allowed the isolation of centratherin and goyazensolide, which were identified by 1D and 2D NMR. In vitro assays showed that centratherin at 10 µM concentration reduced the viability of PC-3 and HCT-116 cancer cells by 100%, while goyazensolide had no noteworthy effects. Furthermore, enzymatic inhibition assays on SARS-CoV2 targets revealed that centratherin exhibited a lower apparent IC₅₀ of 12 µM against PL^pro, while goyazensolide was more active against 3CL^pro, with an IC₅₀ of 71 µM. Notably, the dichloromethane fraction demonstrated promising activity against both enzymes, with IC₅₀ values of 30 µM for PL^pro and 11 µM for 3CL^pro. This study reports, for the first time, the isolation of goyazensolide from E. crotonoides and highlights the potential of both sesquiterpene lactones as SARS-CoV-2 enzyme inhibitors. In contrast to centratherin, goyazensolide fortunately had almost no cytotoxic effects at inhibition concentration on the cells tested. This shows that anticancer and anti-SARS effects can be separated and should have different SARs, an important prerequisite for further development. Full article

Current standard treatments for osteosarcoma have not been changed for decades and have limited and variable success. The advancement of precision medicine technologies, along with the drug-repurposing and fast drug-screening methodologies available, has opened new avenues for the development of more effective therapeutic strategies. In this study, we evaluated the effectiveness of halogenated boroxine (HB) and dextran-coated cerium oxide nanoparticles—DexCeNPs (SD2)—in an in vitro osteosarcoma model. Both agents were tested individually and in combination. The research encompassed assessments of treatment-related cytotoxicity and cell viability, oxidative stress, and apoptotic and necrotic responses, as well as the effects on 3D spheroid models. The results demonstrated that the effects of HB and SD2 were strongly influenced by the dose, exposure time, and cell type. Both exhibited distinguished antitumor activity through cytotoxicity and specific reactive oxygen species (ROS) induction. The combined treatment produced modulated responses that were dependent on the treatment ratio and cell line, suggesting potential synergistic or selective interactions. Notably, the outcomes of the analysis conducted in 3D models revealed reduced toxicity toward non-tumor cells. These findings suggest the improved efficacy of HB and SD2 used in combination as a selective and novel antitumor strategy and underscore the need for further mechanistic studies at the transcriptomic and proteomic levels to elucidate the underlying pathways and clarify the mechanisms of action. Full article

Caffeine is one of the most widely consumed psychoactive substances globally and is a common component of daily diets, particularly among women of reproductive age. Numerous in vitro and in vivo studies have indicated potential adverse effects of prenatal caffeine exposure, including disturbances in fetal growth, metabolic dysregulation, organ malformations, and neurodevelopmental alterations. These findings suggest that caffeine may influence multiple physiological pathways during gestation, including epigenetic modifications and metabolic programming. However, evidence from human studies remains heterogeneous and often inconclusive. Recent cohort studies and meta-analyses have reported that moderate maternal caffeine intake is not significantly associated with increased risks of gestational diabetes mellitus, gestational hypertension, or preeclampsia, although higher intake levels have been linked to anemia, preterm birth, and low birth weight in some populations. Furthermore, emerging data suggest potential associations between prenatal caffeine exposure and early neurodevelopmental outcomes, including behavioral changes, subtle structural brain differences, and alterations in offspring metabolic health and obesity risk. Despite these findings, the magnitude and clinical relevance of these effects remain uncertain, partly due to variability in caffeine sources, dosages, study designs, and reliance on self-reported intake. This review aims to synthesize current evidence on maternal caffeine consumption, its impact on pregnancy complications, fetal development, and long-term child health outcomes. By integrating experimental and clinical data, the study provides a comprehensive overview that may assist clinicians and healthcare professionals in counseling pregnant women regarding caffeine intake and potential risks. Full article

Background/Objectives: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive loss of lung function and poor prognosis. Cryptotanshinone (CTS), a small-molecule compound extracted from Salvia miltiorrhiza, possesses diverse pharmacological activities but suffers from poor oral bioavailability, which restricts its clinical development, particularly in pulmonary fibrosis. DST-3, a newly synthesized derivative of CTS, was designed to overcome these limitations. Methods: The antifibrotic effects of DST-3 were investigated in a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice through lung function assessment, histopathological evaluation, hydroxyproline quantification, and cytokine profiling. In vitro, TGF-β1-stimulated MRC5 fibroblasts were employed to explore the mechanism of action, focusing on STAT3/Smad signaling via Western blotting and molecular binding assays. Furthermore, a validated HPLC–MS/MS method was developed for DST-3, and its pharmacokinetic profile was characterized in Sprague–Dawley rats and compared with that of CTS. Results: DST-3 markedly attenuated pulmonary fibrosis in vivo, as evidenced by improved lung function, reduced collagen deposition, and decreased proinflammatory cytokine levels. In vitro, DST-3 inhibited TGF-β1-induced fibroblast activation by directly binding to STAT3 and suppressing STAT3/Smad signaling. Pharmacokinetic analysis demonstrated that, compared with CTS, DST-3 exhibited more rapid absorption, a higher peak plasma concentration, a greater area under the curve (AUC), improved hepatic metabolic stability, and enhanced lung tissue exposure. Conclusions: Our study demonstrates that DST-3 exerts potent antifibrotic effects in vivo and in vitro, primarily through STAT3 pathway inhibition. Its improved pharmacokinetic characteristics further support its potential as a promising candidate for the treatment of pulmonary fibrosis. Full article

Bisphenol AF (BPAF) exposure is increasingly linked to metabolic disorders, yet the molecular initiating events (MIE) and key events (KE) leading to hepatic steatosis remain unclear. We constructed an adverse outcome pathway (AOP) to mechanistically connect BPAF-triggered macrophage–hepatocyte crosstalk to liver fat accumulation. Male C57BL/6 mice received daily oral gavage of 0, 0.5, 4, or 32 mg kg⁻¹ BPAF for 90 d, and Transwell co-cultures of RAW264.7 macrophages and AML12 hepatocytes were used for in vitro validation. Targeted metabolomics, western blotting, and lipid staining quantified succinate, pathway proteins, and steatosis. BPAF dose-dependently increased serum succinate (BMD = 6901.95 nM) and hepatic triglyceride (TG) (BMD = 874.26 nM). Cryo-EM docking revealed BPAF binding to SUCNR1 at 2.9 Å, disrupting the inactive-state conformation. In co-culture, BPAF-exposed macrophages released succinate that bound hepatocyte SUCNR1, suppressed Akt phosphorylation, and activated JNK. These KEs led to a 40% increase in lipid droplets and elevated TG, total cholesterol (TC), and free fatty acids (FFA) without liver weight gain. We propose the first AOP for BPAF-induced hepatic steatosis: BPAF–SUCNR1 binding (MIE) → macrophage succinate release (KE1) → SUCNR1-mediated Akt inhibition/JNK activation (KE2–4) → hepatic lipid accumulation (KE5) → steatosis (AO). These findings provide mechanistic insight for chemical risk assessment of BPAF and structurally related bisphenols. Full article

High non-esterified fatty acids (NEFAs) during negative energy balance in dairy cattle can impair reproduction. While their effects on oocyte maturation and preimplantation embryo development are known, their impact during fertilisation is largely unexplored. This study examined the effects of high NEFA exposure exclusively during in vitro fertilisation (IVF). Bovine oocytes were matured in vitro and fertilised under physiological or high NEFA concentrations. High NEFA concentrations decreased fertilisation, cleavage, and blastocyst rates. Reactive oxygen species production in zygotes was not affected, but blastocysts derived from the High-NEFA group had fewer cells. Spermatozoa exposed to high NEFA concentrations exhibited increased plasma membrane and acrosome damage, higher DNA fragmentation, and reduced mitochondrial membrane potential. The expression of H3K27me3, a repressive histone mark normally erased from fertilisation to embryonic genome activation, was higher in 2-cell than in 4-cell embryos on day 2 after IVF, but only in the High-NEFA group. This delayed H3K27me3 loss, along with increased DNA damage, could partially explain the reduced blastocyst formation observed. In conclusion, high NEFA concentrations can impair pre-implantation embryo development during zygote formation, potentially via effects on both the oocyte and spermatozoon. The latter warrants further investigation using an intracytoplasmic sperm injection model. Full article

Mast cells (MCs) belong to the cell network that regulates uterine spiral artery remodeling (uSAR), a critical vascular adaptation supporting placental development and fetal growth. Our previous in vitro study demonstrated that human MCs promote trophoblast invasion, as well as uterine vascular smooth muscle cells (uVSMCs) migration and transition to a synthetic phenotype—essential steps for a successful uSAR. Although MCs are known targets of bisphenol A (BPA), a widespread endocrine-disrupting chemical, its impact on their supportive role in uSAR is unknown. In this study, we used murine cell lines to investigate whether BPA (0.1–100 µM) affects MC-mediated promotion of cellular processes critical for uSAR. Our results showed that BPA exposure hindered MCs’ ability to promote trophoblast invasion and the switch in uVSMCs’ synthetic phenotype and migration. The highest concentrations of BPA altered the expression of genes related to MCs activation and proliferation, and of those involved in trophoblasts invasion. In contrast, low doses induced the expression of pro-inflammatory mediators in MCs without detectable effect on trophoblasts at the transcriptional level. These findings confirmed MCs as key mediators of uSAR, and identified BPA as a disruptor of their function, emphasizing its potential harmful impact on reproductive health. Full article

Background: Folic acid (FA), also known as vitamin B9, functions as a co-factor in many cellular processes. Ultraviolet radiation (UV) has been shown to cause the formation of free radicals, and chronic exposure of the skin to UV radiation has been demonstrated to result in many adverse effects. Skin protection against harmful environmental factors is one of the aims of cosmetic products. One such substance is folic acid. However, aqueous FA solutions decompose after exposure to UV radiation, and the decomposition products can exhibit variable pro/anti-oxidative roles depending on the cell type and its environment. Objectives: The objective of the present study was to demonstrate the effectiveness of folic acid as a UV-protective agent in vitro cell culture model. Methods: The experimental model comprised an in vitro culture of normal human fibroblasts derived from adult skin (NHDF-Ad). Paramagnetic electron resonance (EPR) was used to assess the interaction of folic acid with free radicals after exposure to UV radiation. RT-qPCR was utilized to evaluate the impact of ultraviolet (UV) radiation on the expression of selected cell cycle regulatory genes (CCND1, P53, BAX, and BCL-2) in vitro cultured fibroblasts that were protected by folic acid. Results: EPR studies revealed the antioxidant properties of folic acid. Free radical forms of folic acid are induced during UV irradiation. The strong effect of UV irradiation on interactions of folic acid with free radicals was observed. The interaction was found to be weaker for the irradiated samples. Molecular studies have demonstrated a decline in the BAX/BCL-2 ratio in cells that have been treated with folic acid and exposed to UV radiation in comparison to the BAX/BCL-2 ratio observed in cells that have been exposed exclusively to UV radiation and not treated with folic acid. Conclusions: Whilst molecular and EPR studies both confirm the effectiveness of folic acid as a UV-protective ingredient in cosmetics and pharmaceutical products, further research in this area is required. Full article

Nickel (Ni) is a heavy metal element and environmental pollutant that significantly threatens human health. Selenoprotein M (SelM) is a selenium-containing protein with antioxidant properties. However, the role of SelM deficiency in Ni -induced colonic tissue damage in mice remains unclear. To address this, in vivo and in vitro models were established, including SelM knockout (SelM^(−/−)) and/or nickel chloride (NiCl₂)-treated mice. In vitro, an MCEC model was used to establish Ni exposure and SelM knockdown conditions. The results showed that NiCl₂ induced significant inflammatory cell infiltration and lesions in the microstructure of the mouse colon. Additionally, Ni exposure was found to enhance the production of reactive oxygen species (ROS) in mice’s colonic tissue, activating oxidative stress, which in turn led to the formation of autophagosomes and the onset of inflammation. Significantly, SelM knockout exacerbated these outcomes. The oxidative stress inhibitor NAC and the autophagy inhibitor 3-MA were introduced to elucidate the underlying mechanisms further. The results showed that autophagy was reduced following NAC treatment, and inflammation was alleviated after 3-MA administration. Taken together, these findings suggest that SelM alleviated Ni -induced colonic inflammation in mice through suppression of oxidative stress-mediated excessive autophagy. Full article

Lung-protective ventilation and other experimental conditions raise arterial carbon dioxide tension (PaCO₂) and alter pH. Short-term benefits are reported in non-infectious settings, whereas infection and/or prolonged exposure are typically harmful. This scoping review systematically maps immune-mediated effects of hypercapnia on innate immunity and alveolar epithelial repair. Scoping review per Levac et al. and PRISMA Extension for Scoping Reviews (Open Science Framework protocol: 10.17605/OSF.IO/WV85T; post hoc). We searched original preclinical studies (in vivo/in vitro) in PubMed, Web of Science, ScienceDirect, Cochrane Reviews, and SciELO (2008–2023). PaCO₂ (mmHg) was prioritized; %Fraction of inspired Carbon Dioxide (%FiCO₂) was recorded when PaCO₂ was unavailable; pH was classified as buffered/unbuffered. Data were organized by context, PaCO₂, and exposure duration; synthesis used heat maps (0–120 h) and a narrative description for >120 h. Mechanistic axes extracted the following: NF-κB (canonical/non-canonical), Bcl-2/Bcl-xL–Beclin-1/autophagy, AMPK/PKA/CaMKKβ/ERK1/2 and ENaC/Na,K-ATPase trafficking, Wnt/β-catenin in AT2 cells, and miR-183/IDH2/ATP. Thirty-five studies met the inclusion criteria. In non-infectious models, a “protective window” emerged, with moderate PaCO₂ and brief exposure (65–95 mmHg; ≤4–6 h), featuring NF-κB attenuation and preserved epithelial ion transport. In infectious models and/or with prolonged exposure or higher PaCO₂, harmful signals predominated: reduced phagocytosis/autophagy (Bcl-2/Bcl-xL–Beclin-1 axis), AMPK/PKA/ERK1/2-mediated internalization of ENaC/Na,K-ATPase, depressed β-catenin signaling in AT2 cells, impaired alveolar fluid clearance, and increased bacterial burden. Chronic exposures (>120 h) reinforced injury. Hypercapnia is a context-, dose-, time-, and pH-dependent double-edged modulator. The safe window is narrow; standardized, parallel reporting of PaCO₂ and pH—with explicit comparisons of buffered vs. unbuffered hypercapnia—is essential to guide clinical translation. Full article

Background/Objectives: Lipid-based formulations are widely used to enhance the oral bioavailability of poorly water-soluble drugs. However, for weakly basic drugs with higher solubility under acidic conditions, precipitation and recrystallisation after gastric emptying can compromise a formulation’s ability to maintain the drug in a solubilised, absorbable state. To address this, we evaluated an enteric coating strategy to preserve the biopharmaceutical performance of a silica-solidified lipid-based formulation. Methods and Results: The model weakly basic BCS Class IV drug, abiraterone acetate, was loaded into a lipid-based formulation and solidified using mesoporous silica nanoparticles. In an in vitro lipolysis model, introducing the formulation only after the onset of the intestinal phase led to lower precipitation and over 50% greater drug presence in the aqueous phase compared to a two-stage gastric–intestinal digestion. In an in vivo pharmacokinetic study in Sprague Dawley rats, the silica–lipid formulation (6 mg/kg), delivered in gelatine minicapsules enteric-coated with Eudragit L100-55, resulted in a 2.6-fold higher systemic exposure compared to the non-coated formulation (p < 0.0001). Conclusions: These findings support the use of enteric coating for lipid-based formulations and silica nanoparticles containing weakly basic drugs as a strategy to maintain formulation integrity until reaching the small intestine. Full article

Napier grass (Cenchrus purpureus Schumach) is an important forage crop and livestock feed. However, its yield and quality in Kenya are often limited by Napier grass headsmut and stunt disease. Napier grass genetic improvements through mutation breeding and selection could avail cultivars with increased forage. This study investigated the response of embryogenic calli to different levels of colchicine in inducing polyploidy in the two germplasms of Napier grass; South africa and Bana grass. The experiments were carried out as a factorial experiment in a completely randomized design (CRD). The colchicine concentrations used were 0, 0.05, 0.1, and 0.2%, and the exposure durations were 24, 48, and 72 h. During the shoot regeneration stage, culturing explants on an MS medium (Murashige and Skoog) supplemented with 0.2 mg L⁻¹ Benzyl Adenine (BAP), 0.1 mg L⁻¹ dichlorophenoxyacetic acid (2, 4-D), and 0.1 mg L⁻¹ indole-3-butyric acid (IBA) was more suitable for shoot regeneration. Chromosome doubling was confirmed by genomic DNA and the stomata size and number. Culturing explants on an MS medium supplemented with 1 mg L⁻¹ IBA, 1 mg L⁻¹ 2, 4-D, and 0.5 mg L⁻¹ BAP was more suitable in inducing embryogenic calli in both genotypes. Polyploidy results revealed that a 0.1% concentration of colchicine with two days of treatment established the maximum number of octoploid plantlets induced in vitro, while a 0.2% concentration was very toxic. The stomata size and number of derived octoploid plantlets were bigger with a lower density, a shorter plant height, and a smaller stem diameter, and despite being the first to produce tillers, they were significantly higher than their progenitors. Induced mutants also had a significantly higher number of chromosomes and showed different band patterns and distances during gel electrophoresis. However, we recommend the use of flow cytometry to confirm the ploidy level. The superior mutant plantlets can be selected and recommended for characterization across representative agro-ecologies for large-scale production and used in Cenchrus purpureus breeding programs in Kenya and its environments. Full article

Background/Objectives: Thyroid dysfunction (hypo- and hyperthyroidism) and cancer incidence have increased over the past decades, possibly linked to environmental contributions from endocrine disrupting chemicals (EDCs). Glyphosate is one of the most widely used herbicides globally and has endocrine-disruptive properties. Because of the sensitivity of the thyroid gland to endocrine disruption and the increased glyphosate exposure worldwide, this comprehensive review aimed to summarize studies investigating the link between glyphosate/glyphosate-based herbicides (GBHs) and thyroid dysfunction in human, animal, and in vitro studies. Methods: PubMed, Scopus, and Embase were used to search for original studies assessing glyphosate or GBH exposure and thyroid-related outcomes through December 2024. Data were extracted on study design, population or model, exposure, and thyroid outcomes. A total of 28 studies, including 9 human, 3 in vitro, and 16 animal studies were included. Results: Human studies showed mixed findings with some suggesting associations between glyphosate exposure and altered thyroid hormone levels, while others found no significant effects. Animal studies, particularly in rodents and amphibians, showed thyroid hormone disruption and altered gene expression, especially after perinatal or developmental exposure. In vitro studies reported changes in thyroid-related gene transcription and cell viability, however at concentrations exceeding those seen in humans. Conclusions: While there is some evidence that glyphosate may disrupt thyroid function, differences in study populations, exposure assessment methods, species models, and exposure doses complicated the comparison and summarization of the results. Further mechanistic and longitudinal studies are needed to clarify the thyroid-specific risks of glyphosate exposure. Full article