Search Results (236)

Artesunate (ART) is an FDA-approved antimalarial drug and is currently being repurposed for various solid tumor treatments. However, there are no safety or pharmacokinetic (PK) studies in mice exploring its potential application in murine brain tumor models. This study aims to delineate the tolerability and PK of ART in healthy NOD scid gamma (NSG) mice to inform future efficacy studies. The maximum tolerated dose (MTD) of ART following intraperitoneal (IP) administration was determined by a single-dose escalation method. PK and brain penetration of ART and its active metabolite, dihydroartemisinin (DHA), were analyzed using an optimized LC-MS/MS bioanalytical method, following single oral and IP doses (100 mg/kg). A 350 mg/kg IP dose was well tolerated with no evidence of systemic and organ-specific toxicities. Bioanalytical assay results were linear (R² > 0.99) over a range of 5–1000 ng/mL. An optimized extraction method employing low sample volume improved analyte recovery from brain homogenate by 2-fold. PK studies showed rapid absorption with short elimination half-lives (t_1/2: 8–22 min) and higher systemic and brain exposure for ART and DHA following IP administration over oral dosing. We conclude that ART is well-tolerated at high doses (350 mg/kg, IP) in NSG mice, although repeated doses may be necessary for therapeutic efficacy in brain tumors given its rapid elimination kinetics. Full article

Gene therapy and genome editing increasingly depend on the safe, effective, and cell-selective delivery of nucleic acids and protein–nucleic acid complexes. Although viral vectors remain important for applications requiring durable gene expression, non-viral vectors offer advantages in cargo capacity, modularity, transient expression, potential repeat dosing, and avoidance of vector–genome integration. Lipid nanoparticles (LNPs), polymeric nanoparticles, inorganic nanomaterials, extracellular vesicles (EVs), and biomimetic hybrid systems have consequently become central platforms for delivery of siRNA, mRNA, plasmid DNA, antisense oligonucleotides, and CRISPR-based genome editors. Among these, ionizable LNPs are currently the most clinically mature non-viral technology, supported by the clinical success of siRNA therapeutics and mRNA vaccines, as well as the emergence of in vivo CRISPR therapies. Nevertheless, efficient endosomal escape, cell-type-selective targeting, extrahepatic delivery, and repeat-dose tolerability remain substantial barriers. Polymeric vectors provide broad chemical tunability, allowing adjustment of charge density, degradability, stimulus responsiveness, intracellular trafficking, and cargo release. However, toxicity and batch-to-batch reproducibility remain key concerns. EVs provide a biologically derived alternative with favorable membrane interfaces and potential advantages for protein and ribonucleoprotein delivery, but their clinical translation is constrained by heterogeneity, loading efficiency, product characterization, and scalable manufacturing. This review summarizes recent advances in non-viral gene-delivery platforms, compares their strengths and limitations, and discusses future directions in cell-selective delivery, endosomal escape, transient delivery of genome-editing machinery, engineered EVs, hybrid vectors, and manufacturing-oriented development. The field is transitioning from organ-level delivery toward delivery of the correct payload to the correct cell type at a clinically relevant exposure and safety margin. Full article

Established oral squamous cell carcinoma (OSCC) remains constrained by local recurrence, inadequate lesion exposure, systemic toxicity, and therapy resistance. This narrative review evaluates a proposed microneedle–small extracellular vesicle (sEV) system for localized adjunctive treatment in three preclinical contexts: postoperative residual-disease control, local immunomodulation/checkpoint combination, and chemoradiotherapy sensitization. Direct evidence for the combined microneedle–sEV system in OSCC is not yet available; the analysis therefore integrates OSCC-specific sEV mechanisms with oral-mucosal microneedle and cross-disease engineering studies. We focus on whether the proposed microneedle–sEV system can preserve sEV potency, achieve reproducible local delivery, and meet oncologic-safety, manufacturing, and repeated-dose oral-safety requirements. The review provides a preclinical decision framework and comparator-based development criteria rather than a claim of clinical readiness. Full article

Urban particulate matter (UPM) is a major environmental pollutant known to induce systemic inflammation. While its respiratory toxicity is well-documented, the potential vulnerability of the female reproductive system to inhaled UPM remains a critical concern. In this study, we evaluated female reproductive outcomes in a murine model following repeated short-term intratracheal instillation of UPM (40–200 mg/kg) for a month. Our results demonstrate that while UPM exposure induced robust, dose-dependent pulmonary inflammation, characterized by immune cell infiltration (CD45+, F4/80+, and Ly6G+) and upregulation of pro-inflammatory (Il-6, Il-1β, and Tnfα) and fibrotic (Col1a1 and Tgfβ1) markers, no apparent adverse effects were observed in the reproductive endpoints examined. No significant alterations were observed in maternal pregnancy outcomes, including oocyte recovery rates, fertilization competence, gestation duration, litter size, and postnatal development of pups. Furthermore, the mRNA expression of inflammatory markers in the ovaries and uteri was not detectable. Direct in vitro exposure of two-cell embryos to UPM did not interfere with preimplantation embryo development. Although benzanthracene slightly reduced the blastocyst formation rate, UPM and polycyclic aromatic hydrocarbons, major toxic components of UPM, did not severely compromise preimplantation embryo development in vitro. In conclusion, these findings suggest that marked UPM-induced pulmonary inflammation is not accompanied by substantial alterations in the female reproductive outcomes examined under short-term exposure conditions. Full article

Background/Objectives: Breast cancer is the most frequently diagnosed cancer among women worldwide and a leading cause of cancer-related death. Despite the use of bisphosphonates, RANKL inhibitors, chemotherapy, and available endocrine therapies, the five-year survival rate for patients with bone metastases remains approximately 20–30%, underscoring the urgent need for novel, metastasis-specific therapeutic strategies. Recent studies demonstrated that miR-10b can serve as an attractive therapeutic target for the treatment of metastatic breast cancer, particularly in the context of bone metastasis. This study aimed to test antimir-10b therapeutics in a mouse model of breast cancer bone metastasis. Methods: We utilized a previously developed dextran-coated iron oxide nanoparticle-based platform for delivery of antisense anti-miR-10b oligonucleotides to bone metastases. The magnetic properties of the nanoparticles allowed for in vivo imaging of therapeutic delivery to metastatic tumors. Results: We showed the delivery of the therapeutics in the bone colonization model by in vivo imaging as well as significant survival benefits in injected animals. There was a significant inhibition of miR-10b following treatment that resulted in significant upregulation of the downstream target HOXD10 in vitro and a similar trend in vivo. Repeated dosing of the therapeutics was well tolerated, and no systemic toxicity was observed, supporting the safety profile of this approach. Conclusions: Collectively, these studies demonstrated that targeting miR-10b using an image-guided anti-miR-10b nanotherapeutic represents a promising and translatable strategy for targeting breast cancer bone metastases. Full article

Background/Objectives: Skin aging involves interconnected inflammatory, oxidative, hormonal, extracellular matrix (ECM), and cellular senescence-related mechanisms, supporting the need for multitarget approaches. This study aimed to evaluate the effects of a multicomponent natural product-based injectable formulation developed in Korean medicine practice, Dong-An Pharmacopuncture (DAP), on skin aging-related pathways. Methods: A network pharmacology approach was used to identify the active compounds, predicted molecular targets, and signaling pathways associated with DAP. Sixty-two active compounds from 11 constituent materials were screened, and 70 final targets were identified using STITCH-based prediction, intersection with GeneCards-derived skin aging-related targets, and quality filtering. Results: Herb-compound-target network analysis yielded 225 compound–target interactions across 292 edges. Protein-protein interaction analysis identified a highly connected network with 1,334 edges, and hub analysis converged on 10 core targets: TNF, IL6, ESR1, TP53, AKT1, PPARG, EGFR, PTGS2, CASP3, and PPARA. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses identified four major mechanistic axes: inflammatory and oxidative stress regulation, hormonal skin homeostasis, tissue repair and ECM remodeling, and cellular senescence-related regulation. Because DAP is administered by injection, a Good Laboratory Practice-compliant single-dose subcutaneous toxicity study was additionally conducted in Sprague–Dawley rats, which showed no mortality, abnormal clinical signs, or histopathological findings attributable to DAP at 1.0 mL/head. Conclusions: The findings in this study provide a systems-level framework for the predicted multitarget mechanisms of DAP in skin aging-related pathways and support the need for further experimental validation of its predicted mechanisms and repeated-dose safety. Full article

The Turkistan Region of southern Kazakhstan lies within the Mountains of Central Asia biodiversity hotspot and harbors a flora of beneficial plants whose traditional use is well documented but whose chemistry and conservation status remain, for most species, formally unassessed. Following the PRISMA extension for Scoping Reviews (PRISMA-ScR), with accepted names verified against Plants of the World Online, this scoping review maps—for the first time as a single co-occurring assemblage rather than isolated single-taxon surveys—the evidence for nine regionally important species across the Nitrariaceae, Fabaceae, Apiaceae and Asteraceae. From 4362 records, 82 were charted by structured per-species extraction. The species span a broad chemical space: β-carboline alkaloids, furanocoumarins, sesquiterpene coumarins, sesquiterpene lactones and flavonoid-rich essential oils, sharing a recurring antioxidant and antimicrobial profile overlaid with species-specific effects such as the anthelmintic santonin of Artemisia cina. For most species the underlying data derive from non-Central Asian populations, limiting regional transferability, and safety evidence is sparse: no acute or repeated-dose toxicity study on regionally collected material was identified, although several species contain monoamine oxidase inhibitors, phototoxic furanocoumarins or thujone-rich oils. We propose a tiered, conservation-aware framework and a prioritized research agenda. Provenance was charted for all 82 records, and the country of origin could be established for 35. Full article

An evaluation of the safety profile of palatinose/fructooligosaccharide (P/FOS) and palatinose/invert sugar (P/IS), as novel low-glycemic and functional sweetener combinations, is essential for their application. This study aimed to evaluate the safety of 1000 mg/kg/day of P/FOS and 1000 mg/kg/day of P/IS through a 14-day repeated-dose oral toxicity study using male and female Sprague–Dawley (SD) rats. Clinical signs, such as body weight and organ weights, food/water consumption, hematology results, blood biochemical analysis results, urinalysis results, and histological changes in the liver and kidneys, were recorded in all SD rats. Barely any significant changes in food/water consumption, body weight, and organ weight were observed during the experimental period. Although there were some alterations in the results of hematological analysis, serum biochemical analysis, and urinalysis, these changes were not considered toxicologically significant within the normal ranges in both male and female SD rats administered with P/FOS and P/IS at 1000 mg/kg/day. Additionally, a histopathological analysis of the liver and kidneys showed no toxicological changes in P/FOS- and P/IS-treated SD rats of both sexes at the tested dose. Collectively, the above results confirmed that no overt treatment-related adverse effects of P/FOS and P/IS were observed under the tested conditions. Full article

Antrodia cinnamomea (AC) is a medicinal mushroom native to Taiwan. This study evaluated the genotoxicity and toxicity of red quinoa and barley-based solid-state fermented AC mycelium (RQBACM). The safety of RQBACM was evaluated via a 90-day repeated-dose oral toxicity study in rats and a battery of genotoxicity assays, including the Ames, CHO-K1 chromosomal aberration, and in vivo micronucleus tests. RQBACM exhibited no mutagenicity in the Ames test, regardless of S9 metabolic activation, nor did it induce chromosomal aberrations in CHO-K1 cells. In mice, no significant changes in reticulocyte or micronucleus frequency were observed at doses up to 5000 mg/kg. In the 90-day study, Sprague–Dawley rats receiving up to 3000 mg/kg/day showed no treatment-related adverse effects, except for a slight reduction in body weight in high-dose males. No significant changes were found in hematology, serum biochemistry, urinalysis, organ weights, or histopathology. The no-observed-adverse-effect level (NOAEL) was determined to be 3000 mg/kg/day, supporting the safety of RQBACM for potential human consumption. Full article

Endocrine-disrupting pesticides (EDPs) are environmental toxicants capable of perturbing hormonal homeostasis through multiple molecular and cellular mechanisms. Growing evidence indicates that these compounds contribute to a broad spectrum of adverse health outcomes extending beyond classical endocrine dysfunction. This review critically synthesizes current knowledge on the toxicological mechanisms of EDPs and evaluates epidemiological evidence linking exposure to human disease. Mechanistically, EDPs act through modulation of nuclear hormone receptors, disruption of membrane-associated signaling pathways, interference with hormone synthesis, metabolism, and transport, induction of oxidative stress and mitochondrial dysfunction, and epigenetic reprogramming. These molecular events converge on shared biological pathways that affect multiple organ systems and life stages. Human and experimental evidence associates EDP exposure with reproductive dysfunction, endocrine-related cancers, metabolic disorders, thyroid abnormalities, and neurodevelopmental impairments. Particular concern surrounds exposure during critical windows of susceptibility, especially prenatal development and early childhood, when endocrine systems are highly vulnerable to disruption and developmental programming. Across disease endpoints, recurring mechanisms, including endocrine receptor perturbation, oxidative stress, inflammation, and epigenetic alterations, support a unifying toxicological framework linking diverse adverse outcomes. Despite substantial progress, important uncertainties remain regarding chronic low-dose exposure, non-monotonic dose–response relationships, cumulative effects of pesticide mixtures, and the translation of mechanistic findings into human risk assessment. Future research should integrate repeated biomonitoring, advanced mixture modeling, mechanistic biomarkers, and multi-omics approaches within longitudinal life-course studies. Improved integration of toxicological and epidemiological evidence will strengthen causal inference, refine hazard characterization, and support more protective regulatory strategies for reducing the human health burden associated with endocrine-disrupting pesticides worldwide. Full article

Nodularin is a cyanobacterial toxin predominantly produced by Nodularia spumigena Mertens. This cyanobacterium has been associated with fish, bird, and animal deaths, and the toxin can contaminate fish and shellfish intended for human consumption. With climate change, blooms of Nodularia spumigena are becoming more frequent and more widespread, meaning that the risk this cyanobacterium poses to human health must be evaluated. However, toxicity information is scarce, meaning that data from the closely related toxin class, microcystins, are currently used instead. In the current study, the LD₅₀ of nodularin-R by intraperitoneal injection was found to be 50 µg/kg, consistent with previous reports. For the first time, the LD₅₀ of nodularin-R by oral administration was determined using the voluntary consumption of laced cream cheese (7.5 mg/kg), which is similar to that reported for microcystin-LR (10.9 mg/kg). The use of microcystin toxicology data in food safety assessments for nodularin, therefore, seems reasonable—but it is critical that an oral repeated-dose study is performed on nodularin to better understand the risk posed by this toxin through chronic exposure. Full article

Background: Childhood and adolescent acute lymphoblastic leukemia (ALL) survival outcomes have improved significantly, but treatment-related toxicities (TRTs) remain a major concern affecting dose intensity and quality of life. Germline pharmacogenetic variations contribute to inter-individual differences in chemotherapy response, yet consistent replication of associations has been limited by differences in treatment protocols, ethnic backgrounds, and toxicity definitions. Methods: This systematic review and meta-analysis (PROSPERO CRD42021229748) included 68 studies in the qualitative synthesis, with 42 high-quality studies undergoing structured synthesis and, where appropriate, quantitative meta-analysis. Studies focused on the toxicities of thiopurines, methotrexate, glucocorticoids, vincristine, and asparaginase. Results: Meta-analyses showed strong evidence linking the NUDT15 rs116855232 variant to thiopurine-induced myelosuppression (OR 19.0, 95% CI 1.6–224; I² = 86.5%) and a significant association between the TYMS enhancer repeat polymorphism and osteonecrosis (OR 6.66, 95% CI 3.67–12.11; I² = 0%). In contrast, MTHFR variants and VDR polymorphisms showed no significant associations with methotrexate-induced myelosuppression or osteonecrosis, respectively. Narrative synthesis highlighted clinically actionable associations: TPMT and NUDT15 with thiopurine toxicity; CEP72 with vincristine neuropathy; and HLA haplotypes with asparaginase hypersensitivity. Population allele frequency comparisons (IndiGenomes, gnomAD, UK Biobank) showed strong concordance (r = 0.919–0.997), supporting the broad generalisability of identified variants, which remains to be evaluated prospectively. The main limitations included heterogeneous toxicity definitions, non-uniform genetic models, evolving treatment protocols, population heterogeneity, and a lack of harmonised reporting. Conclusions: The review supports routine TPMT and NUDT15 genotyping and highlights the need for harmonised definitions, multi-ethnic studies, standardised data representation, and prospective validation. A literature-based candidate gene list for future PGx association studies was generated. Full article

Resveratrol (RES) is a natural polyphenolic compound characterized by poor aqueous solubility and significant first-pass metabolism, resulting in extremely low oral bioavailability. Although resveratrol-loaded nanostructured lipid carriers (RES-NLCs) have shown potential in enhancing oral absorption, direct experimental evidence for their intestinal lymphatic transport mechanism remains limited, and existing explanations is largely based on indirect inference. RES-NLCs were prepared, and their pharmacokinetics and lymphatic transport characteristics were evaluated using a laboratory-established mesenteric lymph duct–jugular vein assisted reflux model in rats. Simultaneously, a 28-day repeated-dose toxicity study was conducted in ICR mice. Pharmacokinetic results showed that compared with RES-Sol, RES-NLCs increased Cmax by approximately 2.3-fold, improved relative bioavailability by 7-fold, and achieved an absolute bioavailability of 176%. The lymphatic transport model confirmed that RES-NLCs are absorbed via the intestinal lymphatic pathway. In the 28-day repeated-dose toxicity study, no mortality or obvious clinical symptoms were observed at a dose of 10 mg/kg. The RES-NLCs group exhibited increased liver coefficient and decreased spleen coefficient. Hematological analysis showed a mild increase in red blood cell count, along with decreases in mean corpuscular volume and red blood cell distribution width coefficient of variation. Serum biochemistry revealed significant elevations in aspartate aminotransferase and alanine aminotransferase (p = 9 × 10⁻⁵ and p = 4.02 × 10⁻⁷, respectively). However, no significant differences were observed in the organ coefficients of the heart, lungs, kidneys, or brain. Body composition and magnetic resonance imaging showed no abnormalities, and histopathological examination of major organs including the liver, stomach, and intestines revealed no structural damage. These findings provide direct evidence that RES-NLCs enhance the oral bioavailability by promoting intestinal lymphatic uptake, suggesting that this system may serve as an effective delivery platform for poorly soluble hydrophobic drugs. Full article

The reproductive and developmental toxicity of diquat (DQ), a widely used herbicide, during pregnancy remains insufficiently characterized. This study investigated the effects of repeated DQ exposure on fetal development and maternal metabolism in pregnant Sprague–Dawley rats. The rats were administered sublethal doses of DQ (28.88 and 57.57 mg/kg), and maternal serum sex hormones, fetal skeletal development, and serum metabolomic profiles were evaluated. Compared with controls, serum estradiol levels were significantly decreased in the high-dose exposure group, whereas luteinizing hormone and follicle-stimulating hormone levels remained unchanged. Significant alterations in malondialdehyde, superoxide dismutase, and glutathione levels indicated oxidative stress in exposed rats. Severe fetal skeletal ossification deficits and developmental delays were observed, with incomplete or failed ossification of the occipital bone, sternum, caudal vertebrae, and pelvis, with litter-level incidences reaching 100%. Metabolomic analysis identified distinct serum metabolic profiles between DQ-exposed and control groups, suggesting ovarian steroidogenesis, phenylalanine metabolism, and aldosterone synthesis and secretion as key pathways affected by DQ toxicity. These findings suggest that repeated maternal exposure to DQ induces oxidative stress, disrupts metabolic and hormonal homeostasis, and causes delayed fetal skeletal development. This study provides novel evidence for understanding the reproductive and developmental toxicity of DQ and its potential metabolic mechanisms. Full article

Selenium (Se) is an essential trace element; however, excessive exposure may cause adverse effects because of its narrow safety margin. This study evaluated the toxicological and genotoxic effects of Se-biofortified broccoli seedlings in male and female Swiss mice. Animals received control or Se-enriched broccoli seedlings orally for 40 days (15, 45, or 70 µg Se/kg body weight (BW)). General toxicity (body weight gain), hematological (complete blood count), biochemical (creatinine, bilirubin, aspartate aminotransferase, alanine aminotransferase, and urea), histopathological, and micronucleus evaluations were performed. No significant changes in body weight or hematological parameters were detected. Biochemical alterations were restricted to males, with increased urea (51.90 ± 2.14 mg/dL) and decreased aspartate aminotransferase (128.4 ± 14.45 U/L) after 45 µg Se/kg BW. The highest Se dose increased spleen (0.60 ± 0.04 g/100 g BW) and ovary (0.29 ± 0.03 g/100 g BW) weights in females, decreased liver weight (5.82 ± 0.10 g/100 g BW), increased testis weight (0.76 ± 0.04 g/100 g BW) in males, induced renal and splenic histological alterations, and increased micronucleated polychromatic erythrocytes (0.46 ± 0.04). These findings indicate that 15 µg Se/kg BW was the safest dose evaluated. Future studies should investigate Se speciation and sex-dependent toxicological responses. Full article