Thrombospondin-1 (TSP-1) is a matricellular glycoprotein involved in the regulation of angiogenesis, immune responses, and extracellular matrix remodeling within the tumor microenvironment. Its overexpression and interaction with receptor CD47 have been associated with tumor progression and resistance to therapy. In contrast to CD47/SIRPα blockade, which is constrained by hematological and immunotoxic adverse effects, selective inhibition of the TSP-1/CD47 interaction axis may represent a mechanistically distinct and potentially safer therapeutic approach. TAX2, a 12-amino-acid cyclic peptide, was designed as an orthosteric antagonist of this interaction. Its non-clinical profile was characterized through cross-species binding assays, receptor selectivity profiling, pharmacokinetic and biodistribution analyses in rodents and dogs, in vitro off-target and cytokine release assays, and GLP-compliant toxicology studies. Human pharmacokinetics were predicted using multiple species allometric scaling. TAX2 demonstrated binding to TSP-1 from human, rodent, and canine origin, without measurable interference with CD47/SIRPα signaling under the conditions tested. The peptide exhibited rapid plasma clearance (1-4 h), dose-proportional exposure, and detectable signal in TSP-1-rich tissues and tumor-associated regions in biodistribution studies. No relevant off-target activity or unexpected immunostimulatory effects were observed. TAX2 was well tolerated at doses up to 400 mg/kg in rats and 100 mg/kg in dogs, with no hematological or systemic toxicity, and exposures exceeding the projected clinical range. Overall, these findings establish a translational non-clinical framework for TAX2 as a first-in-class TSP-1/CD47 antagonist with cross-species-reactivity and a favorable pharmacokinetic and safety profile2.
Dendrobium officinale Kimura et Migo (Tiepi Shihu), a yin-nourishing tonic in traditional Chinese medicine, has been historically used for health maintenance and longevity promotion. We evaluated the anti-aging effects of D. officinale whole powder (DOP) and a non-polysaccharide fraction (DOE) and explored underlying mechanisms focusing on conserved PI3K-AKT signaling. Network pharmacology was applied to predict aging-related targets and enriched pathways. Anti-aging activity was assessed in yeast (Saccharomyces cerevisiae) and female flies (Drosophila melanogaster) using lifespan and healthspan assays, a high-sugar diet challenge, and pathway readouts via qRT-PCR and Western blotting. In RAW264.7 macrophages, the PI3K inhibitor LY294002 and the AKT inhibitor MK-2206 were used to evaluate pathway dependence. Network pharmacology identified 355 overlapping targets, enriched in PI3K-AKT, MAPK, Ras, and HIF-1 pathways. We found that dihydroconiferyl alcohol, homovanillyl alcohol, and taxifolin extended yeast lifespan, and these effects were abolished in yeast mutants defective in key aging-related genes. In flies, DOP extended female lifespan, improved climbing performance, and mitigated high-sugar diet-induced lifespan loss and hyperglycemia, accompanied by reduced AKT phosphorylation under dietary stress and enhanced FOXO-associated responses. DOE also extended lifespan, increased AKT/S6K phosphorylation and reduced FOXO in flies. D. officinale was associated with context-dependent modulation of innate immune-related gene expression. However, DOE suppressed AKT activity and increased FOXO in RAW264.7 cells; co-treatment with MK-2206 abolished DOE-induced changes. D. officinale exerts anti-aging effects in yeast and Drosophila models, while mammalian macrophages support a mechanistic role for context-dependent PI3K-AKT signaling regulation. Its distinct fractions act in a context-dependent manner, with AKT serving as a central regulatory node and FOXO-associated responses, supporting its ethnopharmacological use as a longevity-promoting herb.
Allogeneic hematopoietic stem cell transplantation is an established curative therapy for many hematological diseases, but graft-versus-host disease remains a major cause of morbidity and mortality. Tacrolimus, a calcineurin inhibitor, is widely used for prophylaxis because it suppresses T-cell activation. However, its clinical use is complicated by a narrow therapeutic window and marked pharmacokinetic variability. Therapeutic drug monitoring based on trough whole-blood concentrations is routinely used to guide dosing, but this approach has limitations, particularly in transplantation recipients who experience rapid physiological and hematological changes. This review summarizes recent insights into determinants of tacrolimus pharmacology in hematopoietic stem cell transplantation and discusses emerging perspectives for individualized dosing. Tacrolimus exerts its immunosuppressive effects by forming a complex with FK506-binding proteins that inhibits calcineurin and suppresses activation of nuclear factor of activated T cells. Beyond this canonical mechanism, interactions with FK506-binding proteins influence the distribution of tacrolimus within blood cells. Because tacrolimus strongly divides into erythrocytes and leukocytes, whole-blood concentrations reflect systemic exposure and drug binding within circulating blood components. In recipients of hematopoietic stem cell transplantation, marked fluctuations in blood cell counts during conditioning therapy and hematopoietic recovery can alter this distribution, potentially causing changes in concentrations without corresponding changes in pharmacologically active exposure. Genetic variation in drug-metabolizing enzymes further contributes to variability in tacrolimus pharmacokinetics. In particular, polymorphisms in the gene encoding cytochrome P450 3A5 influence tacrolimus metabolism and may affect early dose requirements during the post-transplant period. Additionally, temporal fluctuations in tacrolimus exposure within individual patients are increasingly recognized as clinically relevant. Measures that capture the proportion of time during which concentrations remain within the therapeutic range provide a useful indicator of exposure stability. Tacrolimus therapy after hematopoietic stem cell transplantation is influenced by molecular pharmacology, blood cell-dependent distribution, genetic determinants of metabolism, and temporal variability in drug exposure. Integrating these factors may improve understanding of therapeutic drug monitoring and promote more individualized strategies to maintain stable immunosuppression and improve transplant outcomes.
Multidrug-resistant Stenotrophomonas maltophilia pneumonia lacks effective therapies. Quercetin, a natural flavonoid with anti-inflammatory properties, may offer benefit, but its mechanism remains unclear. We characterized a clinical S. maltophilia isolate, predicted quercetin targets via network pharmacology, validated interactions through molecular docking and 100 ns dynamics simulations, and evaluated efficacy in a murine pneumonia model using histopathology, western blotting, qPCR, and immunohistochemistry. The isolated H-SMA strain exhibited multidrug resistance (resistant to β-lactams, macrolides, aminoglycosides) but remained susceptible to enrofloxacin. Network pharmacology identified eight core inflammatory/apoptotic targets (TNF, IL6, IL1B, IL10, IFNG, CASP3, BCL2, AKT1). Molecular docking and 100 ns dynamics simulations confirmed stable quercetin binding to all targets, with strongest interactions with AKT1 (-8.4 kcal/mol) and CASP3 (3-5 stable hydrogen bonds). In vivo, quercetin (100 mg/kg/d) significantly ameliorated clinical symptoms, reversed body weight loss, attenuated pulmonary histopathological damage, and restored splenic architecture, achieving efficacy comparable to enrofloxacin. Mechanistically, quercetin inhibited phosphorylation of AKT, IκBα, and NF-κB p65, restored Bcl-2/Bax balance, and reduced cleaved Caspase-3 expression. At the transcriptional level, quercetin downregulated pro-inflammatory (TNF, IL1B, IL6, IFNG) and pro-apoptotic (CASP3) genes while upregulating anti-inflammatory (IL10) and anti-apoptotic (BCL2) genes. Immunohistochemistry confirmed reduced pulmonary NF-κB p65 nuclear translocation and cleaved Caspase-3 positivity. Quercetin alleviates S. maltophilia pneumonia through multi-target modulation of AKT/NF-κB signaling and apoptosis pathways, supporting its potential as host-directed therapy for drug-resistant bacterial infections.
Euphorbia milii Des Moul is a plant with a long history of use in traditional medicinal and is widely distributed across tropical and subtropical regions. Traditionally, its sap has been used in folk medicine to treat various conditions such as skin inflammations, pain, and boils. To date, it remains a commonly used herbal medicine in clinical practice. This paper systematically reviews the phytochemistry, pharmacology and toxicology of E. milii to assess its therapeutic potential and guide future studies. A comprehensive literature search was performed based on multiple s databases, including Web of Science, ScienceDirect, PubMed, Elsevier, CNKI, VIP, and Wanfang. Additionally, taxonomic databases such as Flora of China and Plants of the World Online (POWO) were consulted to verify the plant's nomenclature and distribution. To date, 85 compounds have been identified from E. milii, comprising 74 diterpenoids, 6 triterpenoids, 2 steroids, 2 flavonoids, and 1 macrocyclic lactone. These phytochemicals exhibit a broad spectrum of pharmacological activities, including analgesic, anti-inflammatory, antioxidant, antimicrobial, anticancer, anti-gout, molluscicide, and anti-parasitic effects. Given its long history of traditional use, rich phytochemical composition, and diverse pharmacological activities, E. milii can be considered an important botanical resource for applications not only in traditional medicine but also in modern ecological and potential pharmacological contexts. However, in vivo and clinical studies remain limited. Future research should emphasize pharmacokinetic profiling to strengthen the basis for clinical applications and new drug development.
Renal lipid metabolic dysregulation drives tubular injury and fibrosis in chronic kidney disease (CKD), yet endogenous targets governing tubular lipid homeostasis remain incompletely understood. This study aimed to elucidate how calycosin (CAL), an O-methylated isoflavone from Astragali Radix, corrects renal lipid metabolic dysregulation and attenuates fibrosis in CKD. An adenine-induced CKD mouse model and TGF-β1-stimulated HK-2 cells were treated with CAL. Lipidomics and network pharmacology screened candidate targets. Surface plasmon resonance (SPR) and molecular dynamics simulation validated target binding. Adeno-associated virus (AAV)-mediated renal phosphoenolpyruvate carboxykinase 1 (PCK1) overexpression in vivo and lentiviral overexpression in vitro established the regulatory relationship. The PCK1 inhibitor 3-mercaptopicolinic acid served as reverse validation. CAL improved renal function, alleviated fibrosis, and reduced lipid deposition both in vivo and in vitro. Lipidomics revealed that CAL bidirectionally modulated renal lipid metabolism by suppressing glycerophospholipid, sphingolipid, and glycerolipid accumulation while restoring omega-3 PUFA-enriched lipids and decreasing lipid saturation. SPR confirmed direct binding of CAL to PCK1. Gain-of-function experiments demonstrated that PCK1 negatively regulates Twist family BHLH transcription factor 1 (TWIST1) in the kidney. Accordingly, CAL activated the PCK1/TWIST1/carnitine palmitoyltransferase 1 A (CPT1α) axis, restoring fatty acid oxidation and suppressing lipid uptake, thereby attenuating lipotoxicity-driven oxidative stress and tubular apoptosis. This study identifies PCK1 as an endogenous binding target of CAL in the kidney and delineates the PCK1/TWIST1/CPT1α axis as the downstream signaling circuitry through which CAL corrects tubular lipid metabolic disorders and attenuates renal fibrosis, providing mechanistic rationale for targeted CKD therapy.
Macrophages are central regulators of skeletal muscle regeneration, dynamically transitioning from pro-inflammatory (M1-like) to reparative (M2-like) phenotypes to coordinate debris clearance, inflammation modulation, satellite cell activation, and tissue remodeling. This review details the underlying molecular mechanisms, focusing on metabolic reprogramming, such as the shift to oxidative phosphorylation and key roles of AMPK, lactate, and glutamine metabolism. It further examines the transcriptional networks (e.g., PPARγ, Nfix) and multicellular crosstalk that shape the regenerative niche. We analyze macrophage dysfunction in pathological contexts: aging-related impairments in dynamics and metabolism that hinder repair, and in Duchenne Muscular Dystrophy (DMD), where sustained inflammation and trained immunity drive fibrosis. Current challenges include deciphering macrophage heterogeneity beyond the M1-like/M2-like paradigm and bridging translational gaps between models and human disease. The review outlines therapeutic strategies to reprogram macrophage function, spanning pharmacological agents (AMPK/PPARγ agonists, cytokine/chemokine modulation), nanotechnology, cell therapies (e.g., exosomes), and physical interventions. A key feature is the integration of molecular docking analyses, revealing structural interactions between compounds (e.g., AICAR, Cenicriviroc) and targets like AMPK, PPARγ, CCR2, and CCR5. This provides a structural pharmacology foundation for developing targeted immunometabolic therapies to restore muscle regeneration in injury and degenerative diseases.
UVB-induced lens epithelial cell (LEC) senescence is among the important factors involved in the pathogenesis of age-related cataract (ARC). This study aimed to investigate the anti-aging effect of metformin (Met) and to elucidate the molecular mechanisms underlying this effect. RNA sequencing, nontargeted metabolomics analysis and network pharmacology were conducted. The expression of senescence indicators (P53 and P21Cip1) and senescence-associated β-galactosidase (SA-β-gal) activity were assessed. Mitochondrial function and dynamics were evaluated by measuring the mitochondrial membrane potential (MMP), transmission electron microscope (TEM), and Western blotting. Cytosolic mtDNA was visualized by fluorescence staining, and the activation of the SIRT1-PGC-1α pathway and the cGAS-STING pathway were analysed by Western blotting. Our findings indicated that cellular senescence was predominantly responsible for UVB-induced cataract. Met attenuated UVB-induced cataract by inhibiting the senescence phenotype. Mechanistically, Met activated the SIRT1-PGC-1α pathway to inhibit mitochondrial fragmentation. This attenuation of mitochondrial fragmentation reduced mtDNA release into the cytosol, thereby inhibiting the activation of the cGAS-STING-mediated LEC senescence. Our findings on the efficacy of Met pave the way for the development of new pharmacological strategies to prevent cataract development.
BRCA1-associated protein 1 (BAP1) is frequently inactivated in pleural mesothelioma and functions as a tumor suppressor through its deubiquitinating activity. In this study, we investigated the context-dependent interplay between BAP1 and ubiquitin-specific protease 1 (USP1) in mesothelioma cells, focusing on their roles in regulating FANCD2, cell proliferation, and DNA damage responses. Genetic suppression of USP1 selectively inhibited cell proliferation in BAP1-deficient mesothelioma cells, whereas reintroduction of wild-type BAP1 rescued this growth defect; notably, a catalytically inactive BAP1 mutant failed to do so, indicating that BAP1 deubiquitinase activity is required for this compensation. In contrast, depletion of FANCD2 suppressed cell proliferation irrespective of BAP1 status, underscoring the essential role of FANCD2 in mesothelioma cell survival. Although both BAP1 and USP1 were capable of deubiquitinating FANCD2 in vitro, USP1 suppression in mesothelioma cells did not provide clear biochemical evidence of altered FANCD2 ubiquitination. Instead, USP1 knockdown was associated with reduced FANCD2 transcript and protein levels, without markedly affecting FANCD2 mRNA stability. At the cellular level, USP1 depletion impaired FANCD2 focus formation and reduced its colocalization with γ-H2AX in BAP1-deficient cells, consistent with defective DNA damage signaling. Despite these changes, homologous recombination (HR) efficiency was largely preserved, whereas non-homologous end joining activity was modestly increased upon USP1 suppression. Consistent with these in vitro findings, USP1 knockdown suppressed tumor growth in an intrathoracic xenograft model. Collectively, our results indicate that BAP1 and USP1 appear to regulate FANCD2 through distinct, context-dependent mechanisms, with USP1 primarily influencing FANCD2 expression and BAP1 modulating FANCD2 function at the post-translational level. Together, these findings identify USP1 as a context-dependent therapeutic vulnerability in BAP1-deficient mesothelioma and support a working model in which USP1-dependent maintenance of FANCD2 function becomes critical in the absence of functional BAP1.
The article reviews the rapid expansion of office-based anesthesia driven by rising outpatient procedure volumes, cost savings, and patient and provider preference. It highlights the 6 P's: Patient, Procedure, Place, Personnel, Policies, and Practice Management as the core framework for safe practice. As more complex patients undergo ambulatory procedures, thoughtful patient and procedure selection, standardized protocols, accreditation, and robust emergency preparedness are essential. The authors emphasize the need for updated medical education and consistent regulatory oversight to ensure safety across diverse outpatient settings.
This review synthesizes best practices for ambulatory pediatric tonsillectomy with or without adenoidectomy in ambulatory surgery centers. It emphasizes rigorous patient selection-particularly for severe obstructive sleep apnea, age, obesity, and complex comorbidities-along with individualized anesthetic plans (induction and airway choice), multimodal opioid-sparing analgesia, and robust post-operative nausea and vomiting prophylaxis. Standardized post-anesthesia care unit monitoring, discharge criteria, caregiver education, and escalation pathways address common complications (airway events, hemorrhage, pain, dehydration). Preparedness-pediatric advanced life support-certified staff, emergency equipment, and transfer agreements-underpins safety. Quality-improvement initiatives and emerging tools offer avenues to further reduce morbidity and unplanned admissions.
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Central nervous system (CNS) metastases from Wilms tumor (WT) are exceedingly rare. Intracerebral hemorrhage secondary to metastatic WT is even less common, and the management of such cases is further complicated when patients are receiving a direct oral anticoagulant (DOAC) like Rivaroxaban, for which pediatric reversal guidelines are lacking. We report on the case of a 5-year-old boy with relapsed stage IV Wilms tumor who presented with rapidly progressive neurological deterioration caused by brain metastases with extensive intraparenchymal and intraventricular hemorrhage while receiving Rivaroxaban due to prior thrombosis. An emergent craniotomy and tumor resection was safely performed after emergent reversal of anticoagulation with Rivaroxaban using Andexanet alfa, administered in this pediatric patient with off-label consent in the setting of a life-threatening intracranial hemorrhage requiring emergent neurosurgical intervention. No excessive intraoperative bleeding was noted. Treatment for relapsed WT according to the SIOP-UMBRELLA-Protocol was initiated. Three weeks after Andexanet alfa treatment, a thrombotic event in the left iliac veins occurred, requiring anticoagulation with unfractionated heparin. This case highlights the therapeutic challenges of managing intracranial hemorrhage in a pediatric patient requiring emergent neurosurgical debulking in the setting of Rivaroxaban anticoagulation. To our knowledge, this is the second case reporting on Rivaroxaban reversal through Andexanet alfa in children. Early multidisciplinary intervention, meticulous neurosurgical management and continuation of oncologic therapy can lead to favorable outcomes even in such complex presentations.
This study evaluated the polyphenol content of leaf extracts from Artemisia monosperma (AM) and investigated their antioxidant properties, cytotoxic effects, and potential to induce DNA damage in human cancer cell lines. High-performance liquid chromatography (HPLC) quantified polyphenols in methanolic (AMM), ethanolic (AME), and aqueous (AMA) extracts, identifying 13 compounds in AME and 12 in AMA. AMM exhibited the strongest antioxidant activity (IC50 = 24 µg/ml). Both AME and AMM demonstrated potent anticancer activity against HCT-116 (IC₅₀ = 0.38 µg/mL for AMM) and HUH-7 (IC₅₀ = 21.95 µg/mL for AMM) cells, while exhibiting minimal cytotoxicity toward normal skin fibroblast cells (BJ-1; IC₅₀ = 13.05 µg/mL for AMM), with AMM demonstrating particular selectivity for HCT-116 cells. AMM induced DNA fragmentation and modulated apoptosis-related gene expression (Bax, Bcl-2, p53) in HUH-7 cells and caused cell cycle arrest at G0/G1 phase in HCT-116 cells. Molecular docking further supported AMM's apoptosis activity. These results position A. monosperma as a rich source of bioactive polyphenols and antioxidants, with AMM showing promise as a therapeutic agent, especially for colorectal cancer.
Heavy metal (HM) contamination in agricultural soils adjacent to bauxite mining poses a significant risk to the ecological and human health. This study provides a comprehensive assessment of the degree of contamination, the spatial distribution, source apportionment, and probabilistic health risks assessment in bauxite mining-affected agricultural ecosystems in Eastern India. Soil samples (n = 120) were collected from the Rayagada district (Zone 1 = 60) and Koraput district (Zone 2 = 60) regions of Eastern India. Soils in both zones were found to acidic (Zone 1pH: 5.65 ± 0.45 and Zone 2pH: 5.62 ± 0.64) and low electrical conductivity (EC) values of (Zone 1 = 0.04 ± 0.01 and Zone 2 = 0.03 ± 0.01 mS/cm). In Zone 1, average values of Cr (249.05 ± 74.51 mg/kg), Cd (4.73 ± 0.98 mg/kg) and Fe (53,284.20 ± 12,889.27 mg/kg) were significantly greater than Zone 2. Spatial distribution suggested high levels of HMs were associated close to the mining activities. Positive Matrix Factorization (PMF) revealed the four major pollution sources identified in this study, namely industrial, natural/geological, traffic-related, and agricultural inputs. Pollution indices revealed significant pollution (PLI: 1.56 in Zone 1; 1.08 in Zone 2), while ecological risk index values for Cr exceeding 600 in both zones. Although non-carcinogenic risk (HI < 1) was within acceptable limits, carcinogenic risks-primarily attributed to Cr and Pb-were elevated for children (TCR = 1.01E-02). The Sobol sensitivity analysis found chromium, lead, and nickel as important contributors to carcinogenic risk. Overall, the findings emphasize the need for focused management, monitoring and long-term restoration in agricultural land affected by mining.
Transthoracic CT-guided biopsy performed with the coaxial technique is a minimally invasive procedure that facilitates the diagnosis of lung lesions (nodules or masses) and/or mediastinopulmonary lesions suspected of malignancy. This procedure is the source of several complications, the most frequent of which is pneumothorax. To describe the epidemiological, diagnostic, and therapeutic aspects of iatrogenic pneumothorax after CT-guided biopsy performed using the coaxial technique. Prospective longitudinal study, conducted over a period of 2 years and 10 months, from April 1, 2023, to February 1, 2026, at the Mohammed V Military Teaching Hospital in Rabat, including all patients who presented with a pneumothorax following a transthoracic CT-guided biopsy, according to the coaxial technique, confirmed clinically and/or radiologically. The study included 30 cases of pneumothorax following CT-guided biopsy according to the coaxial technique. Biopsies were performed in 217 patients, and the incidence of pneumothorax was 13.8%. The median age was 68 years [58.8-71.5], with a predominance of males (90%). The most frequent characteristics observed among patients with pneumothorax were pulmonary emphysema (73.3%), lower-lobe lesions (33.3%), and central lesions with a median depth of 3.6 cm [2.9-4.2]. Procedure-related characteristics included practitioner status and biopsy needle diameter (18-gauge). Most patients were asymptomatic (60%). Diagnosis was established by chest CT during the procedure in 26.7% of cases and by chest X-ray after the procedure in 73.3% of cases. Small pneumothorax was the most common presentation (40%). Treatment was conservative in 53.3% of cases, and intervention was required in 46.7% (7 cases drained and 7 cases exsufflated). A complication was observed in 5 cases, after initial treatment. Only one patient underwent thoracoscopic pleurodesis after 14 days of chest drainage. The median length of hospital stay was 4 days [2-5.75]. Pneumothorax is a major complication of CT-guided transthoracic biopsy, whether performed coaxially or non-coaxially. In our descriptive series, pulmonary emphysema, lower-lobe location, and lesion depth were frequent characteristics among patients who developed pneumothorax. We believe that the radiologist's experience is a determining factor in preventing a very high incidence of pneumothorax cases.
Endotracheal intubation is performed by health care providers from different training backgrounds and in diverse locations. The first pass failure rate has been reported to be variable, and complications can arise from multiple intubation attempts. This is a hypothesis-generating descriptive analysis of first pass endotracheal intubation failure performed by a critical care transport team. Secondary outcomes included patient and procedural factors associated with failure. This is a retrospective chart review of adults (≥18 years) intubated by a critical care transport service between January 2017 and June 2024. One intubation attempt was defined as the insertion of the laryngoscope past the lips. First pass failure was defined as failure to place an endotracheal tube through the vocal cords on the first intubation attempt. There were 388 patients intubated with 54 first pass failures (13.9%). Multiple reasons for failure were cited in 20 first pass intubation failures (37.0%). The most common reasons for failure were desaturation during intubation (7; 13.0%); contamination with blood, secretions, emesis, or foreign bodies (23; 42.6%); and anatomy (33; 61.1%). There was an association between first pass failure and retrospectively documented predicted difficult airway (adjusted odds ratio, 2.96; 95% confidence interval, 1.57-5.56). First pass failure occurred in 13.9% of intubations. This descriptive analysis serves as a starting point for further quality improvement work that includes a systematic review of intubations with objective data (ie, video-recorded laryngoscopy) and the use of an airway failure taxonomy to describe errors.
Post-traumatic stress disorder (PTSD) frequently emerges following early-life trauma, yet the temporal dynamics of PTSD-like phenotypes and their pharmacological modulation during development remain poorly understood. In the present study, we investigated time-dependent behavioral and endocrine alterations in a peripubertal rat stress-restress model and assessed the effects of fluoxetine across early and delayed post-treatment stages. Male peripubertal rats were exposed to a combined stress-restress paradigm and treated with fluoxetine for 21 days. Anxiety-like behavior, social behavior, stress-coping behavior, and spontaneous locomotor activity were assessed immediately after treatment completion and again after a drug-free washout period, the duration of which (3-4 weeks) depended on the behavioral parameter evaluated. Serum corticosterone levels were measured as an index of hypothalamic-pituitary-adrenal axis activity. PTSD-like stress induced robust but domain-specific behavioral alterations that evolved over time. Anxiety-like behavior persisted across both observation phases but was expressed through different behavioral components at early versus delayed stages. Basal sociability was markedly reduced following stress exposure and was largely normalized by fluoxetine, whereas social novelty-related alterations were more selective and resistant to pharmacological modulation. Stress-exposed animals exhibited increased activity and reduced immobility in the forced swim test, reflecting altered stress-coping strategies rather than reduced depressive-like behavior. Consistently, spontaneous locomotor activity was elevated at early stages, indicating hyperarousal, which attenuated over time but was not robustly normalized by fluoxetine. Endocrine assessment revealed a biphasic corticosterone profile, with elevated levels in the early phase and reduced levels at the delayed stage; fluoxetine did not normalize corticosterone concentrations. These findings demonstrate that PTSD-like phenotypes induced during the peripubertal period are dynamic and strongly time-dependent, and that fluoxetine exerts selective, domain-specific effects rather than uniform normalization. The study highlights the importance of developmental stage and timing of assessment when evaluating behavioral outcomes and pharmacological efficacy in preclinical models of PTSD.
Glioblastoma (GBM) is one of the most aggressive and treatment-resistant brain tumors, largely due to the restrictive nature of the blood-brain barrier (BBB). This barrier significantly limits the efficient delivery of therapeutic agents to the tumor site, thereby reducing treatment efficacy. This review evaluates the potential of dextran (Dex)-based nanoparticles (NPs) as an advanced platform for enhancing BBB penetration and enabling targeted GBM therapy. Dex, a biocompatible and biodegradable polysaccharide, offers key advantages including ease of functionalization, high drug-loading capacity, and improved systemic stability. Recent studies demonstrate that Dex-based nanocarriers enhance drug transport across the BBB via receptor-mediated and adsorptive transcytosis mechanisms, resulting in improved accumulation at tumor sites. Furthermore, surface engineering strategies facilitate active targeting of GBM cells, thereby increasing therapeutic efficacy while reducing systemic toxicity. Comparative evidence indicates that Dex-based nanocarriers outperform conventional delivery systems in terms of targeting efficiency, biocompatibility, and tailored drug release. These systems also show potential for co-delivery of multiple therapeutic agents, supporting combination treatment approaches for improved clinical outcomes. Emerging preclinical studies highlight improved survival outcomes and enhanced pharmacokinetic profiles associated with Dex-based nanocarriers, reinforcing their therapeutic relevance. Despite these promising findings, challenges related to large-scale manufacturing, reproducibility, and regulatory approval remain significant barriers to clinical translation. Future research should focus on clinical validation, scalable synthesis approaches, and long-term safety assessment to facilitate successful translation into clinical practice. Overall, Dex-based NPs represent a versatile and highly promising strategy to overcome existing limitations in GBM treatment and advance targeted nanomedicine approaches for brain cancer therapy.
Kidney ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. This study assessed the renooprotective effects of morin hydrate (MH) and its association with inflammatory and mitochondrial regulatory pathways in an I/R rat model. Molecular docking predicted the potential binding of MH with thioredoxin interacting protein (TXNIP)-thioredoxin (TRX) complex. Rats were assigned to four groups: sham, I/R, and I/R + MH (20 or 40 mg/kg). Renal function, oxidative stress markers, inflammatory mediators, apoptosis-related proteins, mitochondrial markers, and histopathology were assessed. Docking analysis suggested a potential interaction of MH with the TXNIP-TRX interface (ΔG=-8.0 kcal/mol). In vivo, MH reduced I/R-induced increase in serum creatinine and blood urea nitrogen. MH restored mitochondrial-related parameters, including NADH dehydrogenase, cytochrome c oxidase subunit 2, and ATP levels, and mitigated oxidative stress, as indicated by reduced carbonyl protein levels and restored glutathione content. MH was also associated with reduced TXNIP, NOD-like receptor protein 3 (NLRP3), and proinflammatory cytokine levels. Apoptotic markers, including phosphorylated apoptosis signal-regulating kinase 1, caspase-3, and the Bax/Bcl2 ratio, were reduced. MH was associated with downregulation of Forkhead box protein O1 (FOXO1) and dynamin-related protein-1 and, upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitofusin-1. Histological findings supported these results. MH attenuated renal I/R injury and was associated with reduced oxidative stress, inflammation, and apoptosis, along with improved mitochondrial-related parameters. These findings suggest that MH-mediated renoprotection is associated with coordinated changes in TXNIP/NLRP3 signaling and FOXO1/PGC-1α-related mitochondrial responses. Further research is necessary to elucidate the underlying mechanisms.