Search Results (1,184)

Vitamin C, a water-soluble micronutrient, is one of the most widely used dietary supplements pertaining to its vital role in maintaining overall human health, particularly through its potent antioxidant and immune-supportive functions. This mini review summarizes key pharmacokinetic constraints of vitamin C and evaluates formulation strategies aimed at improving its systemic availability. Achieving sustained optimal plasma levels of vitamin C remains challenging due to its dose-dependent absorption, tissue saturation, rapid renal clearance, and short half-life. These pharmacokinetic limitations restrict systemic retention, with high oral doses providing only marginal increases in plasma concentrations and necessitating multiple daily administrations. Conventional vitamin C supplements show efficient absorption only at low to moderate doses, while higher intakes are restricted by transporter saturation and increased renal excretion. Alternative delivery systems such as liposomal encapsulation, esterified derivatives, nano-emulsions, and co-formulations with bioenhancers have been examined; however, evidence for prolonged systemic retention remains inconsistent. The sustained-release formulation of vitamin C shows more reliable outcomes, demonstrating prolonged plasma exposure, higher steady-state concentrations, and potential for improved compliance through reduced dosing frequency. While further robust comparative studies are needed, current evidence suggest that advanced formulation approaches, particularly sustained-release delivery, may help overcome these pharmacokinetic limitations, thereby supporting improved clinical utility of vitamin C supplementation. Full article

Long-duration space missions expose astronauts to galactic cosmic radiation (GCR), a complex spectrum of high-charge, high-energy (HZE) ions that pose significant risks of chronic tissue injury. To model these effects, we examined intestinal outcomes in wild-type mice 5 months after low-dose (50 cGy) 33-ion mixed-field GCR simulation (GCRsim). GCRsim induced sustained DNA double-strand breaks (DSBs) and oxidative stress, as shown by elevated γH2AX foci and 4-HNE staining. Intestinal epithelial cells (IECs) exhibited pronounced senescence, marked by increased SA-β-gal activity, p16 upregulation, LaminB1 loss, and induction of senescence-associated secretory phenotype (SASP) cytokines (Cxcl10, IL-6, IL-1β, Icam1). GCRsim also elevated circulating LINE-1 DNA and reduced expression of DNA-degrading nucleases (DNase2, TREX1), indicating impaired extracellular DNA clearance. Targeted molecular study revealed persistent activation of the cGAS–STING pathway, with elevated cGAS, STING, pTBK1, pIKKα/β, and nuclear pIRF3, pIRF7, and p65, consistent with chronic innate immune signaling. Functionally, GCRsim altered nutrient absorption gene expression—upregulating glucose transporters (Slc2a2, Slc2a5, Slc5a1) and gut hormones (Cck, Gip), while downregulating cholesterol/fat transporters (Npc1, Npc1l1). Biochemical markers supported intestinal injury, with decreased serum citrulline and increased intestinal fatty acid-binding protein (I-FABP), indicating barrier compromise. Collectively, these findings demonstrate that GCRsim drives sustained intestinal dysfunction, highlighting the need for countermeasures to protect GI health during deep-space missions. Full article

Background/Objectives: Sublingual vaccination offers a non-invasive route for inducing both systemic and mucosal immunity, yet the formulation properties that govern its success remain poorly defined. This study investigated the relationships among key formulation parameters for sublingual vaccines, such as viscosity, mucoadhesion, and mucosal residence, to understand their impact on in vivo immune responses in the sublingual delivery context. Methods: Ovalbumin (OVA)-based vaccine formulations containing cholera toxin B (CTB) adjuvant and mucoadhesive excipients such as hydroxypropyl methylcellulose (HPMC) or methylglycol chitosan (MGC), were evaluated for: (1) their respective rheological properties—characterized by viscosity and mucoadhesion parameters, as well as (2) in situ mucosal retention (assessed using Cy7-labeled formulations tracked by IVIS in vivo imaging system) and (3) in vivo immunogenicity via systemic (IgG) and mucosal (IgA) responses measured by ELISA, following sublingual administration to mice. Correlations between rheology, in situ/ex situ mucosal residence, and in vivo immune outcomes were determined. Results: Sublingual vaccine formulations containing HPMC exhibited the highest viscosity, mucoadhesion, and mucosal retention profiles, but paradoxically elicited the weakest systemic and mucosal antibody responses. In contrast, chitosan-based formulations enhanced immune responses even at reduced antigen and adjuvant doses, likely due to its permeation-enhancing and adjuvant effects. Correlation analyses revealed that while formulation viscosity and mucoadhesive strength were positively associated with mucosal retention, both rheological and retentive properties showed a significant inverse relationship with immunogenicity in the context of sublingual vaccine delivery. Conclusions: While viscosity and mucoadhesion are essential for in situ retention of sublingual vaccines, prolonged residence driven by excipient’s excessive rheological strength was found to reduce vaccine immunogenicity—likely due to restricted antigen release and mucosal uptake. Accordingly, HPMC appears suboptimal as a sublingual vaccine excipient, while chitosan shows promise for sublingual delivery as a permeation-enhancing adjuvant. These findings may shift the design paradigm for sublingual vaccine formulations, highlighting the need to balance mucosal retention with efficient antigen absorption for maximizing immune responses. Full article

Background/Objectives: Radotinib is a second-generation tyrosine kinase inhibitor (TKI) that has been used for treatment of chronic myeloid leukemia (CML). This study was performed for the first time to characterize the pharmacokinetics of radotinib, identify the factors contributing to pharmacokinetic variabilities and explore alternative dosing regimens. Methods: A total of 640 plasma concentration–time datapoints obtained from 47 participants were evaluated using nonlinear mixed-effects modeling to estimate pharmacokinetic parameters and evaluate covariate effects. The study population comprised 23 healthy volunteers (HVs) who received a single, oral dose of 400 mg radotinib and 24 CML patients who repeatedly received 300 mg twice daily. Based on the final population pharmacokinetic model, alternative dosing regimens to the current every 12 h regimen were explored using Monte Carlo simulations. Results: A two-compartment model with first-order absorption through transit compartments and first-order elimination incorporating a circadian rhythm effect best described radotinib pharmacokinetics. Disease status significantly affected apparent clearance; it was slower by 39.2% in CML patients compared with HVs (23.0 L/h versus 37.9 L/h), resulting in a longer terminal half-life (28.8 h versus 17.5 h). Age was negatively associated with volume of distribution in the central compartment, with an estimated slope of −0.0129 L/year. A 400 mg once-daily regimen was predicted to provide comparable systemic exposures to those of other TKIs with similar physiochemical and pharmacological properties to radotinib, and a 36% lower exposure than that of the current 300 mg twice-daily regimen. Conclusions: The model developed in this study adequately describes the population pharmacokinetics of radotinib and provides a basis for optimal, individualized radotinib therapy for patients with CML. Full article

Background/Objectives: Breast cancer remains the most prevalent malignancy among women worldwide, with letrozole (LZ) serving as a critical aromatase inhibitor for hormone receptor–positive cases. However, long-term oral administration of LZ is often associated with systemic adverse effects and poor patient compliance. To overcome these limitations, new non-aqueous nanoemulgels (NEMGs) were developed for transdermal delivery of LZ. Methods: The NEMGs were formulated using glyceryl monooleate (GMO), Sepineo P600^®, Transcutol, propylene glycol, and penetration enhancers propylene glycol laurate (PGL), propylene glycol monocaprylate (PGMC), and Captex^®. Physicochemical characterization, solubility, stability, and in vitro permeation studies were conducted using Strat-M^® membranes, while in vivo pharmacokinetics were evaluated in rat models. Results: The optimized GMO/PGMC-based NEMG demonstrated significantly enhanced drug flux, higher permeability coefficients, and shorter lag times compared with other NEMGs and suspension emulgels. In vivo, transdermal application of the GMO/PGMC-based NEMG over an area of 2.55 cm² produced dual plasma absorption peaks, with 57% of the LZ dose absorbed relative to oral administration over 12 days. Shelf-life and accelerated stability assessments confirmed excellent physicochemical stability with negligible crystallization. Conclusions: The developed LZ NEMG formulations offer a stable, effective, and patient-friendly transdermal drug delivery platform for breast cancer therapy. This system demonstrates potential to improve patient compliance and reduce systemic toxicity compared to conventional oral administration. Full article

Background: Visceral leishmaniasis (VL) is a neglected tropical disease with limited therapeutic options, often restricted by toxicity, high costs, and resistance. Chalcones are promising scaffolds for the development of antiparasitic agents. Objectives: This study aimed to synthesize novel acetamides derived from 4-hydroxychalcones and evaluate their antileishmanial activity, cytotoxicity, potential synergy with amphotericin B (AmB), and mechanisms of action through in silico analyses. Methods: Six chalcone–acetamides (3a–c, 4a–c) were synthesized and characterized by IR, NMR, and HRMS. In vitro activity against Leishmania infantum promastigotes and axenic amastigotes was assessed by colorimetric assays. Cytotoxicity was tested in human erythrocytes and PBMCs. Synergy with AmB was analyzed by the combination index. Molecular docking targeted parasite enzymes, and ADMET tools predicted pharmacokinetic and safety profiles. Results: Phenyl-substituted derivatives (3a–c) were inactive, while cyclohexyl-substituted analogs (4a–c) were active. Compound 4b displayed the strongest effect (IC₅₀: 7.02 μM for promastigotes, 3.4 μM for amastigotes), with low cytotoxicity and high Selectivity Indices. In combination with AmB, compound 4b reduced the effective dose (DRI: 2.87) and increased the therapeutic window. Docking revealed favorable interactions of compound 4b with deubiquitinase DUB16 and tryparedoxin peroxidase I, suggesting enzyme inhibition. ADMET predictions supported good absorption and low toxicity. Conclusions: Compound 4b demonstrated potent and selective antileishmanial activity, synergism with AmB, and predicted safety. These findings highlight chalcone derivative 4b as a promising lead for future preclinical development in VL therapy. Full article

Diabetes mellitus is largely driven by oxidative stress that disrupts insulin signaling, leading to failure in insulin-mediated glucose absorption. Exploration of natural bioactive compounds is fueled by their promising role in correcting redox imbalance. This study aims to investigate the antidiabetic effect of the methanolic extract of Praecitrullus fistulosus, potentially by transcriptional modulation in streptozotocin–nicotinamide-induced diabetic rats. Male Wistar albino rats (n = 36) were assigned to six groups: normal control; diabetic control; standard drug group; and three treatment groups receiving P. fistulosus extract orally at doses of 200, 400, and 600 mg/kg body weight, respectively, for 30 consecutive days. Diabetes was induced in all groups, except for normal control, by intraperitoneal co-administration of streptozotocin and nicotinamide. Nicotinamide (100 mg/kg) was injected 15 min prior to a single dose of streptozotocin (50 mg/kg). Baseline and endpoint assessments of weight and blood glucose levels were performed. Blood was processed to assess insulin-related indices, lipid profile, and oxidative stress markers. q-PCR and Western blotting were utilized to explore the underlying molecular mechanisms. The diabetic control-group rats exhibited impaired glucose tolerance due to the marked reduction in serum insulin levels, compromised β-cell function, and substantial rise in lipid profile and oxidative stress parameters. Oral administration of P. fistulosus methanolic extract effectively mitigated these alterations in a dose-dependent manner, accompanied by the upregulation of both gene and protein expression involved in the insulin-signaling cascade. Full article

Optical fiber radiation sensing probes made using inorganic scintillator materials have notable advantages in achieving high spatial resolution and building sensing arrays due to their small size and excellent linearity, serving as a key tool for dose measurement in precision radiotherapy. This study establishes a theoretical model for scintillator luminescence coupling into optical fibers, and derives a fluorescence intensity calculation formula based on the fiber’s numerical aperture and fluorescence self-absorption. The light intensity response to scintillator length for different absorption coefficients is established based on numerical simulation, providing a nonlinear fitting equation, resulting in a novel “effective length of scintillator” concept. Five probes with scintillator lengths of 0.2 mm, 0.5 mm, 1.0 mm, 1.5 mm, and 2.0 mm were prepared in the laboratory using a 3:1 mass ratio mixture of UV-setting epoxy and Gd₂O₂S:Tb powder. Tests in a clinical radiation delivery setting showed good agreement between experimental data and theory, confirming optimum effective length of the scintillator as 0.62 mm. This study indicates that inorganic scintillators for end-constructed probes do need not need to be excessively long. Analyzing the effective length can reduce scintillator usage, simplify fabrication and processing, and enhance the probe’s spatial resolution without decreasing the signal-to-noise ratio, thus offering new insights for optimizing optical fiber radiation probes. Full article

Chrysin is a dietary flavonoid with antioxidant and anti-inflammatory activity, but its clinical potential is limited by poor oral bioavailability. This randomized double-blind three period crossover trial evaluated the pharmacokinetics of a novel micellar chrysin formulation co-encapsulated with quercetin and rutin (LMC) compared with a non-micellar chrysin formulation (NMC) and unformulated chrysin (UFC). Secondary objectives included in vitro permeability (Caco-2) and a 30-day safety assessment of daily LMC supplementation. Sixteen healthy adults received a single oral dose of each formulation in randomized order separated by a 7-day washout. Plasma chrysin was quantified over 24 h to determine pharmacokinetic parameters. In vitro Caco-2 assays evaluated permeability, and clinical biochemistry of 15 participants were assessed weekly during 30 days of daily LMC use. LMC achieved >2-fold higher systemic exposure than unformulated chrysin (AUC_0–24 = 914.8 ± 697.5 ng·h/mL; C_max = 87.3 ± 59.4 ng/mL; both p < 0.05) and >2.6-fold higher than NMC, supported by >10-fold higher in vitro permeability. Daily LMC supplementation was well tolerated, with only mild, reversible adverse events and no clinically relevant safety changes, despite higher systemic exposure. Small, but significant, reductions in fasting glucose were observed in both sexes. The novel micellar chrysin–quercetin–rutin formulation substantially improved bioavailability and was well tolerated during 30 days of daily use, supporting its potential as an advanced delivery strategy for flavonoids with poor oral absorption and identifying glucose regulation as a physiological effect of interest. Full article

The endothelium, once considered merely a vascular lining responsible for selective permeability to water and electrolytes, is now recognised as a key regulator of vascular tone through the release of mediators such as oxylipins, nitric oxide, and hyperpolarizing factors. This in vitro study investigated the biological activity of Vesvein, a natural formulation containing Diosmin/Hesperidin, Ruscus aculeatus, Bromelain, and Ananas comosus, on intestinal and endothelial cells. Vesvein enhanced intestinal cell viability and preserved barrier integrity, as demonstrated by increased tight junction expression at both single and double concentrations. In endothelial cells, the compound improved parameters linked to venous insufficiency, elevating nitric oxide production by approximately 1.39-fold at a single dose and 1.65-fold at a double dose. These findings indicate a potential role for Vesvein in supporting endothelial health and vascular function in vitro. Preliminary evidence from intestinal models further suggests preserved barrier properties, which may positively influence absorption and bioavailability, thereby enhancing its vascular benefits. Full article

Background: Flaxseed (Linum usitatissimum L.) represents a unique source of bioactive compounds with demonstrated health benefits. The main aim of the research was to investigate the chemical composition, content of bioactive compounds and biological activities of various types of flaxseed and their defatted forms. Methods: Proximate composition (crude fat, protein, ash, digestible carbohydrates, fiber) was determined, and fatty acid profiles were analyzed via GC-MS (gas chromatography–mass spectrometry). Mineral content was measured by atomic absorption spectrometry, while total and individual polyphenols were quantified spectrophotometrically and by HPLC (high-performance liquid chromatography). Antioxidant activity was assessed using three assays. In vitro functional assays evaluated the effects of flaxseed extracts on lactic acid bacteria adhesion in two cellular models, nitric oxide production in liposaccharide (LPS)-stimulated RAW 264.7 macrophages, proliferation and apoptosis of MCF-7 breast cancer cells. Results: Significant differences (p ≤ 0.05) were observed in the proximate composition: brown flaxseed exhibited the highest crude fat content, whereas defatted seeds had higher levels of digestible carbohydrates and ash. α-Linolenic acid was the dominant fatty acid, with the highest concentration in defatted golden flaxseed. Defatted forms generally displayed increased mineral concentrations, particularly calcium, magnesium, potassium, and iron. The polyphenolic content and antioxidant activity were highest in defatted brown flaxseed, which also exhibited the greatest diversity of individual polyphenols. Flaxseed extracts modulated the adhesion of lactic acid bacteria, reduced the production of nitric oxide in RAW 264.7 macrophages, inhibited the proliferation of MCF-7 breast cancer cells in a dose- and time-dependent manner, and induced apoptosis of the mentioned cells. Conclusions: Flaxseed, especially the brown type, could be a promising source of bioactive compounds with antioxidant, anti-inflammatory and anticancer potential, supporting its use in nutritional and functional applications. Full article

Background: Anemoside B4 (AB4), the major bioactive saponin from Pulsatilla chinensis, exhibits anti-inflammatory, anti-tumor, anti-apoptotic, and analgesic properties. However, its clinical translation for ulcerative colitis (UC) is constrained by poor epithelial permeability and low oral bioavailability. Objective: This study’s objective was to engineer and optimize thermosensitive rectal in situ gels (ISGs) of AB4, incorporating suitable absorption enhancers to improve mucosal permeation, bioavailability, and therapeutic efficacy against UC. Methods: Screening of effective permeation enhancers was conducted using Caco-2 cell monolayers and Franz diffusion cells. Critical formulation variables such as poloxamer 407 (P407), poloxamer 188 (P188), and hydroxypropyl methyl cellulose (HPMC) were optimized, employing single-factor experiments coupled with the Box–Behnken design response surface methodology (BBD-RSM). Comprehensive characterization encompassed in vitro release kinetics, in vivo pharmacokinetics, rectal tissue tolerability, rectal retention time, and pharmacodynamic efficacy in a UC model. Results: We used 2.5% hydroxypropyl-β-cyclodextrin (HP-β-CD) and 1.0% sodium caprate (SC) as the appropriate absorption enhancers, and the amounts of P407, P188, and HPMC were 17.41%, 4.07%, and 0.44%, respectively, to yield the corresponding in situ gels HP-β-CD-AB4-ISG and SC-AB4-ISG. The gel characterization, such as gelation temperature, gelation time, pH, gelation strength, etc., was in accordance with requirements. The ISGs did not stimulate or damage rectal tissue and remained in the rectum for a prolonged period. More importantly, an improvement in bioavailability and alleviation of UC were noted. Conclusion: Absorption enhancer-assisted, poloxamer-based thermosensitive rectal ISGs provide a safe, convenient, and effective platform for targeted delivery of AB4 to the colorectum. This strategy addresses key limitations of oral dosing and warrants further clinical development for UC and related colorectal inflammatory diseases. Full article

High-temperature sintering for ceramsite preparation is a safe and effective approach to recycle solid waste. Flux components are critical in ceramsite sintering, as they can reduce sintering temperature, modulate the viscosity and content of the liquid phase, and ultimately optimize ceramsite performance. However, existing studies on lead–zinc tailings (LZTs) and coal gangue (CG)-based ceramsite lack systematic exploration of key fluxes (Na₂O, MgO, CaO, Fe₂O₃), limiting the high-value utilization of these wastes. Under fixed sintering conditions (preheating at 400 °C for 30 min, sintering at 1250 °C for 30 min, heating rate of 10 °C/min), this work systematically investigated the effects of these fluxes (in the forms of carbonates, except for Fe₂O₃) on LZTs-CG ceramsite. The mechanical properties, mineral composition, microstructure and heavy metal leaching of samples were analyzed using various methods, including uniaxial compression, X-ray diffraction (XRD), scanning electron microscopy (SEM), and inductively coupled plasma optical emission spectrometry (ICP-OES). Results showed that, while Fe₂O₃ exerted a non-monotonic influence, Na₂O, MgO, and CaO improved apparent density and compressive strength, concurrently reducing water absorption, with these effects enhancing in a dose-dependent manner. Na₂O, MgO and Fe₂O₃ facilitated the formation of labradorite, cordierite and hematite, respectively. All fluxes weakened the diffraction peaks of quartz and mullite. ICP-OES results indicated that the fluxes slightly increased Pb and Zn leaching, yet the highest values (0.1975 mg/L for Pb, 0.0485 mg/L for Zn) were well below the limits specified in the Chinese national standard GB 5086.2-1997 (Leaching Toxicity of Solid Waste—Horizontal Vibration Extraction Procedure). This work shows optimized flux composition enables high-performance, eco-safe LZTs-CG ceramsite, supporting LZTs and CG high-value utilization and sustainable development. Full article

Objectives: Cyclosporin A (CsA) is an immunosuppressive drug that is highly effective. CsA, similar to other drugs with limited oral bioavailability due to poor membrane permeability, requires the use of absorption enhancers in its formulations. Phe-Cys-Ile-Gly-Arg-Leu (FCIGRL-OH), a peptide fragment of Zonula occludens toxin (ZOT), has been studied for its potential to enhance drug absorption by regulating intercellular tight junctions. This study aimed to evaluate the effects of four novel modified peptides, which have been substituted or dimerized at the C-terminus or cysteine moiety of FCIGRL-OH, as improved versions of FCIGRL-OH on the intestinal permeation of CsA. Methods: The four modified peptides used were FCIGRL-NH₂ (Pep-1), homo-dimer peptides derived from FCIGRL-OH and Pep-1 (Pep-2, Pep-3), and a peptide in which the cysteine in Pep-1 was replaced with N₃-substituted dipropionic acid (Pep-4). Pharmacokinetic analysis was performed following intraduodenal administration of CsA with each of four peptides in the presence of levan and benzalkonium chloride (BC) in rats. Results: Results showed that each of Pep-2, Pep-3, and Pep-4 significantly increased intestinal absorption of CsA in the presence of levan and BC. In particular, the area under the curve (AUC_0–360min) for CsA was significantly enhanced by 2.01-fold (p < 0.01) and 2.03-fold (p < 0.05) when treated with Pep-3 and Pep-4, respectively, at a dose of 10 mg·kg⁻¹. Additionally, the maximum plasma concentration (C_max) of CsA increased by 2.46-fold (p < 0.01) with Pep-3 and by 2.37-fold (p < 0.01) with Pep-4. Conclusions: These study findings indicate that Pep-2, particularly Pep-3 and Pep-4, are involved in tight junction opening as novel absorption enhancers for intestinal delivery of CsA. Full article

Background: Natural compounds such as fisetin have promising in breast cancer treatment, but their poor pharmacokinetics limit their therapeutic application. This study utilized a synergistic approach by combining fisetin-loaded Nigella sativa (N.S.) oil nanovesicles (FIS-NSs) and carbohydrate-based microneedles (FIS-NSs-MNs) to improve breast cancer management. Methods: Chemical composition of NS petroleum ether extract using gas chromatography–mass spectrometry (GC/MS). FIS-NSs were prepared and characterized for particle size, polydispersity, zeta potential, encapsulation efficiency, and stability. These vesicles were embedded into gelatin, hyaluronic acid, and carboxymethyl cellulose microneedles. In vitro drug release, ex vivo permeation, cytotoxicity against breast cancer cells, and in vivo antitumor efficacy in Ehrlich tumor models were evaluated. Results: Optimized FIS-NSs displayed nanoscale size (190 ± 0.74 nm), low P.D.I (0.25 ± 0.07), high surface charge (+37 ± 0.57 mV), and high encapsulation (88 ± 0.77%). In vitro investigations showed sustained FIS release (~85% over 72 h), while ex vivo permeation showed higher absorption than free fisetin. Both FIS-NSs and FIS-NSs-MNs showed dose-dependent cytotoxicity against breast cancer cells, with lower IC₅₀ than free fisetin (24.7 µM). In vivo, FIS-NSs-MNs and tumor burden inhibition (~77%), reduced oxidative stress (54%), restored antioxidant defenses, and decreased inflammatory markers. Immunohistochemical analysis for caspase-3 showed apoptosis activation within tumor tissues. Conclusions: These findings demonstrate that FIS administration via NS-MNs improves drug stability, penetration, and apoptotic activity, resulting in enhanced anticancer effects. This innovative nanovesicle–microneedle platform provides a non-invasive, effective, and patient-friendly approach for the effective treatment of breast cancer, with potential for broader applications in oncological nanomedicine. Full article