The intracellular delivery of therapeutic oligonucleotides is severely limited by the endosomal entrapment bottleneck. This study aims to resolve the "stability-fusogenicity paradox" through the rational design of pH-responsive lipid nanoparticles (LNPs) utilizing 3ß[L-histidinamide-carbamoyl] cholesterol (Hchol). Using Martini 2.2 coarse-grained molecular dynamics simulations (total 25 μs sampling), the Hchol-to-cholesterol ratio was systematically titrated while maintaining distearoylphosphatidylcholine (DSPC) at a constant 10% molar ratio. Results demonstrate that substituting 25% (F2) and 50% (F3) of the sterol fraction with Hchol triggers a morphological phase transition from a compact micellar core (Rg ≈4.61 nm) to stable vesicular-like geometries (Rg ≈11.4 nm) at endosomal pH 4.0. In contrast, 100% Hchol substitution (F5) led to catastrophic structural failure. Solvent accessible surface area (SASA) and mass density profiling confirmed that the AS1411 aptamer remained strictly sequestered within a protected internal water pool, preserving its functional G-quadruplex topology. Mechanistically, Hchol reduced the electrostatic grip of ionizable SM-102 lipids on the aptamer backbone by ~45%, acting as a "fusogenic primer" for the Vesicle Budding-and-Collapse (VBC) mechanism. Our findings identify F2 and F3 as "Goldilocks" formulations that achieve an ideal balance between structural integrity and enhanced endosomal escape potential. This framework provides a robust new paradigm for targeted aptamer delivery in precision oncology.
Throughout history, plants have been used in the treatment of various diseases, forming the foundation of traditional medicine and inspiring modern pharmaceutical research. Notably, Colchicum species, recognized for their therapeutic potential, represent an important group of plants evaluated in both traditional use and modern pharmacology. This study investigates the in vitro cytotoxic, antioxidant, and antimicrobial activities of the methanol extract of Colchicum figlalii, an endemic species found in Muğla, Türkiye. Cytotoxic effects were assessed using the MTT assay on prostate (PC-3), liver (Huh-7), colon (HT-29, SW-48, Caco-2), and malignant mesothelioma (CARM-L12 TG3) cancer cell lines. Strong cytotoxic effects were observed in Caco-2 (IC₅₀ = 4.3 µg/mL) and HT-29 (IC₅₀ = 4.8 µg/mL) cells. Overall, the extract exhibited IC₅₀ values below the 100 µg/mL threshold in all tested cell lines, indicating notable bioactivity and promising potential as an anticancer agent. Antioxidant activity, determined via the DPPH radical scavenging assay, ranged between 78% and 84%, yielding results comparable to the positive control BHA. In antimicrobial analyses, the extract produced notable inhibition zones, particularly against Staphylococcus aureus (17 mm) and Candida albicans (14 mm). However, no inhibition zones were observed at any extract concentration against Enterococcus faecalis. These findings demonstrate that Colchicum figlalii is not only a source of cytotoxic compounds but is also rich in antioxidant and antimicrobial constituents, highlighting its promise as a candidate for novel pharmaceutical or natural product development.
Globally, obesity has become a significant problem and contributes to the development of metabolic syndrome. Metabolic syndrome affects the pharmacokinetics of various opioids, raising drug toxicity. Tramadol is an opioid analgesic used to treat moderate to severe pain. Chronic tramadol misuse can cause oxidative stress, inflammation, and alteration of the γ-aminobutyric acid (GABA) neurotransmitter system. Though some studies pointed out the risk of increased lipid peroxidation and hepatic and renal damage, very little research has been done on how tramadol affects the cardiovascular system in obese conditions. Hence, we sought to investigate the effects of tramadol in high-fat diet-induced obese mice. In this study, an obese mouse group was administered 5 mg/kg of tramadol along with a high-fat diet (HFD). Following six weeks of treatment, we measured body weight, Lee index, food efficiency ratio, organ weight, lipid profile test (triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and Very Low-Density Lipoprotein cholesterol), liver function test (Aspartate aminotransferase and Alkaline Phosphatase), creatinine level, adipocyte cell size, and coronary risk indices (Atherogenic Index of Plasma, Atherogenic coefficient, and Coronary Risk Ratio). Our data indicate that tramadol reduces food intake and the weight of the organs. Body weight reduction is attributed to the reduced food intake in obese mice treated with tramadol. It increases lipid profiles, liver-kidney function markers, and cardiac indices. This study suggests that tramadol harms the cardiac system and induces many cardiac complications. Thus, it is worth announcing that tramadol exaggerates cardiac complications in obese mice.
Allergic airway diseases, including allergic asthma and rhinitis, are characterised by airway inflammation and altered responses to inhaled allergens. The endocannabinoid system (ECS) significantly contributes to the regulation of airway tone and immune system activity. Experimental studies indicate that cannabinoid receptor ligands and inhibitors of endocannabinoid metabolism can modify airway hyperreactivity, inflammatory cell recruitment, and allergic inflammation. However, these effects are not uniform. CB1 and CB2 receptor signalling may produce different outcomes depending on the ligand, responding cell population, tissue, and experimental model. Endocannabinoid-related lipids may likewise exert protective or pro-inflammatory effects through different pathways. Evidence for therapeutic targeting of the ECS is more extensive in allergic asthma, where improvements in airway function or inflammation have been reported. In allergic rhinitis, pharmacological evidence remains limited, and the available clinical findings are insufficient to draw definitive conclusions. The established data suggests the ECS as a potential target in allergic airway diseases while underscoring the need to clarify receptor-dependent and receptor-independent mechanisms mediating their effects and establish efficacy and safety in well-characterized human populations. This review focuses on the role of the ECS in allergic airway diseases and evaluates its potential as a therapeutic target.
Organophosphate (OP) compounds are highly toxic chemicals widely used as pesticides and nerve agents, causing severe peripheral and central nervous system toxicity through disruption of cholinergic signaling. The therapeutic efficacy of butyrylcholinesterase (BChE), a promising bioscavenger against OP poisoning, is limited by poor penetration across the blood-brain barrier (BBB). In this study, biomimetic rhamnolipid-based micelles were developed as a nanocarrier system to enhance BChE delivery and improve protection against OP-induced central neurotoxicity.BChE-loaded micelles were prepared using an ultrasonication-assisted homogenization method and optimized through a 3² factorial design using lecithin and rhamnolipid as formulation variables. Particle size (PS), polydispersity index (PDI), and zeta potential (ZP) were evaluated as critical quality attributes. The optimized formulation exhibited a particle size of 171.2 ± 5.79 nm, PDI of 0.45 ± 0.03, and zeta potential of −16.6 ± 3.6 mV. Encapsulation efficiency was high, indicating successful incorporation of BChE into the micellar structure. In vitro release studies demonstrated a sustained release profile with reduced burst release compared with free BChE. FT-IR and TEM analyses confirmed compatibility of formulation components and nearly spherical morphology of the micelles.Cytotoxicity studies on CaCo-2 and SH-SY5Y cell lines showed that the developed micelles were well tolerated at therapeutically relevant concentrations (0.1–100 µM), while also reducing the cytotoxicity associated with free BChE exposure.These findings suggest that rhamnolipid-based BChE-loaded micelles represent a promising strategy for central nervous system-targeted detoxification and may offer an effective therapeutic platform for the management of OP-induced neurotoxicity.
