搜索结果：Molecular pharmaceutics

Nanoprodrug, utilizing precisely engineered nanomaterial as both a carrier and a caging agent, enables targeted delivery and precise release of toxic antitumor drugs into tumor tissues. To further promote the stability and tumor selectivity, a series of hyperbranched polymer-based unimolecular nanoprodrugs were prepared and analyzed. The toxic drug camptothecin was covalently conjugated to the nanostructures through glutathione cleavable linkers to allow for potent release in tumors. A γ-glutamyl transferase responsive moiety was decorated on the nanoprodrugs to tune the surface charges and promote cancer cell uptake. By combining the advantages of stimuli-responsiveness and the stable polymeric nanostructure, the optimized nanoprodrug showed satisfactory cancer/normal cell selectivity, safety, and anticancer efficacy both in vitro and in vivo.

Levetiracetam (LTM) is a commonly used anti-epileptic medication, however its possible cardiovascular (CV) risks are poorly characterized. The present study aimed to investigate the dose-dependent cardiac toxicity induced by LTM in Sprague-Dawley (SD) rats through the assessment of inflammatory signaling, oxidative stress, apoptosis, functional impairment and structural damage. Thirty-six male albino SD rats were randomly distributed into four groups (n = 9) namely the control, LTM (25 mg/kg), LTM (50 mg/kg), and LTM (150 mg/kg). LTM administration significantly increased the expressions of toll-like receptor-4 (TLR4) signaling cascade, as indicated by significant upregulation of myeloid differentiation factor-88 (MyD88), interleukin-1 receptor-associated kinase-4 (IRAK4) and tumor necrosis factor receptor-associated factor-6 (TRAF6). Similarly, there was a paradoxical increase in the expression of nuclear factor kappa B inhibitor alpha (IκBα) in parallel with enhanced activation of nuclear factor-kappa B (NF-κB) which culminated in increased production of pro-inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), and cyclooxygenase-2 (COX-2). Oxidative stress was marked, as shown by higher levels of reactive oxygen species (ROS), malondialdehyde (MDA) with inhibition of antioxidant enzymes such as heme oxygenase-1 (HO-1), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GSR) and glutathione-S-transferase (GST) following LTM exposure. LTM intoxication promoted the concentrations of serum creatine phosphokinase (CPK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin I, troponin T, B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide NT proBNP and C-reactive protein (CRP) in a dose-dependent manner. Moreover, LTM intoxication altered echocardiographic parameters including reduced ejection fraction (EF), heart rate (HR), dilation of left ventricle, and increased ventricular diameter. The levels of Bcl-2 associated X protein (Bax), cysteine-aspartic proteases-3 (caspase-3) and cysteine-aspartic proteases-9 (caspase-9) were increased, accompanied by reduced levels of B-cell lymphoma-2 (Bcl-2) in response to all the tested doses of LTM. Collectively, these findings show that LTM induces cardiotoxicity through modulation of the TLR4/NF-κB-mediated inflammation, oxidative stress, and apoptosis in a dose-dependent manner.

Framework nucleic acids (FNAs) are a class of nucleic acid-based nanostructures characterized by their unique precise structures, excellent biocompatibility and stability, robust loading capacity, and distinctive distribution and metabolic behaviors. They are widely applied in frontier fields such as nanodevices, biosensing, and drug delivery. In recent years, research on FNAs has gradually developed from the design and synthesis of nucleic acid nanostructures to practical applications, particularly in providing precise nanocontainers for heterogeneous molecular drugs such as small molecules, peptides, and proteins. Acting as a drug delivery system, FNA nanocontainers could be utilized to address multiple issues inherent in the application of heterogeneous molecular drugs, including hydrophobicity, affinity, and stability. However, they also face challenges such as low drug carrier capacity, potential immunogenicity, and insufficient long-term stability in vivo, necessitating the development of new strategies. This article focuses on composite drugs of small molecules, peptides, and proteins carried by FNAs, elucidates the design principles of FNA carriers, the interaction modes between FNAs and drug molecules, and the physicochemical properties and biological effects/efficacy of FNA-drug complexes, and summarizes the structure-activity relationship patterns. Furthermore, obstacles limiting clinical transformation are proposed to provide beneficial suggestions for the future development of FNA-based drugs.

Background: In this study, type B gelatin was extracted from Oreochromis niloticus scales under hydrothermal conditions at 60 °C to evaluate the effect of ultrasound-assisted pretreatment on its structural, physicochemical, thermal, and functional properties. Methods: Gelatin obtained with and without ultrasound pretreatment was systematically characterized through molecular weight analysis, proteomic profiling, size determination, surface morphology, proximate composition, thermal behavior, and gelation-related functional properties in order to assess the influence of the extraction method on gelation performance. Results: Ultrasound pretreatment slightly increased gelatin yield from 1.46 to 1.70%, indicating enhanced collagen solubilization. Proteomic analysis confirmed the predominance of fibrillar collagen proteins in both samples, although differences in protein distribution were observed. Furthermore, weight-average molecular weight analysis revealed a reduction from 212.3 ± 11.8 to 170.9 ± 13.2 kDa in the ultrasound-treated sample, suggesting partial fragmentation of collagen chains induced by cavitation effects. Structural modifications were also reflected in increased porosity and surface changes, contributing to improved colloidal stability. However, these changes significantly affect the functional behavior of the gelatin. Ultrasound-treated sample exhibited limited gel-forming capacity and failed to form stable gels at the evaluated concentration, despite complete dissolution. In contrast, gelatin extracted without ultrasound treatment retained higher-molecular-weight fractions and formed stable gels at both 5 and 10% (w/w). Thermal and spectroscopic analyses suggested that the fundamental collagen structure was preserved in both samples, although differences were observed in thermal degradation behavior. Conclusions: These results highlight the importance of controlling ultrasound-assisted extraction conditions to balance collagen recovery with the preservation of molecular integrity required for gelation, providing insights for the development of sustainable fish-derived biomaterials for pharmaceuticals and biomedical applications.

Background/Objectives: Onion (Allium cepa) peems are an underutilized by-product rich in polyphenols. This study evaluated the physicochemical profile, and bioactive potential (antidiabetic, antimicrobial, antioxidant, and anticoagulant) of Moroccan red onion peels using integrated in vivo, in vitro, and in silico approaches. Methods: Moisture, pH, ash content, and mineral elements were determined, followed by phytochemical screening and three extractions: decoction E0, aqueous Soxhlet E1, and hydroethanolic Soxhlet E2 (70/30; ethanol/water, v/v). The measurement of polyphenols, flavonoids, and tannins was carried out using colorimetric methods, while the molecular profile was studied by high-performance liquid chromatography coupled to ultraviolet detection and electrospray ionization mass spectrometry (HPLC/UV-ESI-MS). Biological activities were determined using 2,2-diphenyl-1-picrylhydrazyl, ferric reducing antioxidant power, and total antioxidant capacity assays (in vitro antioxidant); microdilution (antimicrobial); prothrombin time and activated partial thromboplastin time (anticoagulant); and α-amylase/α-glucosidase enzymatic inhibition and oral glucose tolerance tests on normoglycemic rats. Also, acute toxicity was evaluated, and molecular interactions between these proteins and ligands (docking, molecular dynamics, and MM-PBSA) were analyzed. Results: Physicochemical analyses showed an acidic pH (3.06) and high ash content (15.21%), with the concentration of regulated elements remaining within FAO/WHO limits. The extractive content was between 6.90% E0 and 19.18% E2. The E1 extract had the maximum amount of total polyphenols (178.95 mg GAE/g); on the other hand, E2 was the richest in flavonoids by 121.43 mg QE/g. The HPLC/ESI-MS analysis of E0 revealed 20 compounds, among which flavonoids (84.93%) were predominant, with isorhamnetin (30.26%), followed by quercetin and its glycosylated forms. E1 showed the most potent antioxidant effects (IC50 DPPH, 22.38 µg/mL, as that of ascorbic acid). The antibacterial activity of E0 was especially potent towards Enterobacter cloacae and Pseudomonas aeruginosa (MIC 75 µg/mL). A mild dose-dependent anticoagulant effect was seen. Antidiabetic activity was found to be outstanding: α-amylase (IC50 62.75 µg/mL) and α-glucosidase (IC50 8.49 µg/mL, stronger than acarbose) inhibitions were corroborated in vivo by a considerable decrease in the glycemic area under the curve. The molecular docking study in silico demonstrated strong molecular interactions, especially for quercetin 4'-O-glucoside with good binding energies. Conclusions: A. cepa peels from Morocco can be considered a safe plant matrix containing bioactive flavonoids with strong antioxidant and selective antimicrobial activities and promising antidiabetic effects, supported by molecular modeling.

Aging is a complex biological process uniquely shaped in women by hormonal transitions, particularly across the menopause transition. While chronological age alone fails to capture individual health variability, emerging molecular biomarkers offer tools to quantify biological aging and understand mechanisms underlying age-related decline. This review synthesizes the current landscape of aging biomarkers, including senescence-associated secretory phenotype factors, epigenetic clocks, clonal hematopoiesis of indeterminate potential, and telomere length, with a particular emphasis on their relevance to menopause. This narrative review synthesizes human studies, translational research, and foundational basic science identified through PubMed searches through June 2025, examining aging biomarkers in general populations, among women in the menopause transition, and in relation to vasomotor symptoms and hormone therapy. Evidence demonstrates that changes in biological aging biomarkers are observed across multiple molecular systems during midlife, including the menopause transition, reflecting broader age-related biological remodeling. Postmenopausal status, particularly following early or surgical menopause, has been associated with biological aging phenotypes, including elevated senescence-associated secretory phenotype factors, epigenetic age acceleration, clonal hematopoiesis, and shorter leukocyte telomere length, likely reflecting a combination of chronological aging, hormonal changes, and individual biological vulnerability. While severe vasomotor symptoms have been linked to higher epigenetic age, hormone therapy may favorably influence certain senescence markers and biological age discrepancy. Despite these advances, significant limitations constrain clinical translation, as current biomarkers capture overlapping biological processes and lack validated thresholds to define biological aging, especially in women. Future research requires large, longitudinal studies across diverse populations to establish clinically meaningful thresholds and sex-specific calibration. Advancing precision health strategies for women requires a better understanding of how reproductive and hormonal factors modify biomarker trajectories to improve risk prediction and to facilitate the development of targeted interventions for age-related diseases.

Cyclodextrins (CDs) are cyclic oligosaccharides composed of α-(1,4)-linked glucopyranose units that have emerged as multifunctional and versatile pharmaceutical excipients. One of the major challenges in modern drug development is that nearly half of newly discovered drug molecules exhibit poor aqueous solubility, which adversely affects formulation development, bioavailability, and therapeutic efficacy. CDs address this limitation by forming non-covalent inclusion and non-inclusion complexes, thereby enhancing drug solubility, stability, dissolution rate, and overall biopharmaceutical performance. This review provides a comprehensive overview of CDs, including their historical background, structural characteristics, and production through starch conversion by the enzyme cyclodextrin glucanotransferase (CGTase). Special emphasis is placed on the transglycosylation reactions catalyzed by CGTase, including cyclization, coupling, and disproportionation, which play a critical role in CD synthesis. Recent advances in structural elucidation techniques, such as X-ray crystallography, nuclear magnetic resonance spectroscopy, molecular dynamics simulations, and ion mobility mass spectrometry, are also discussed. The pharmaceutical applications of CDs are critically evaluated, with particular emphasis on their roles as solubility enhancers, taste-masking agents, and stabilizers in nanocarrier-based and targeted drug delivery systems. Their applications in cosmetics and dermopharmaceuticals are also explored, particularly in improving formulation stability and enabling controlled drug delivery. Furthermore, the pharmacokinetics, toxicological safety, and regulatory acceptability of various CDs are discussed. Overall, this review highlights the growing importance of CDs as pharmaceutical excipients that bridge supramolecular chemistry and advanced drug delivery systems.

Bladder cancer (BCa) exhibits molecular heterogeneity that complicates early diagnosis and prognosis, and drives confounding clinical outcomes. Non-muscle invasive and muscle-invasive subtypes, especially for intermediate to high grade, carry a 25%-50% progression-free survival rate, underscoring the need for high-precision prognostic strategy. Urinary extracellular vesicles (uEVs) are promising carriers of tumour-derived RNAs and proteins. However, significant challenges in studying uEVs arise from the diverse cellular origin of uEVs associated with the dynamic composition of urine, which presents roadblocks for developing the clinical utility of uEVs. We developed an AI-driven EV liquid biopsy pipeline that integrates (1) standardised EV isolation via NanoPom magnetic beads, (2) transcriptomic profiling for molecular subtyping and (3) prognostic scoring algorithm. In a discovery cohort of 16 BCa patients including both muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC), we compared NanoPom isolated uEVs with ExoEasy and Fujifilm MagCapture isolated uEVs, for identifying BCa subtype-specific gene signatures, and externally validated them using UCSC Xena. The result outperformed currently reported BCa diagnostic biomarkers from assays including Galeas, CxBladder and Xpert. In a validation cohort composed of seven individuals with MIBC, NMIBC and healthy individuals, we confirmed with plasma-derived EVs for correlating with uEV biomarkers from NGS sequencing. The prognostic score stratified patients into low-, intermediate- and high-grade risk groups based on Xena's BCa survival outcomes. Our AI-driven uEV liquid biopsy pipeline proves the concept for high precision BCa subtyping and prognosis, which could potentially facilitate treatment decision and lead to advanced profiling of bladder tumour biology using uEV liquid biopsy.

Background: Cancer patients are highly susceptible to microbial infections due to immune suppression, necessitating therapeutic strategies that integrate anticancer efficacy with effective antimicrobial intervention. Chalcone-derived nitrogen-fused heterocycles represent a promising platform for developing multi-target agents with relevance to antimicrobial drug delivery, particularly for localized infections. Methods: A series of chalcone-based pyrazoline-thiadiazole nitrogen-fused azole hybrids was synthesized via thiosemicarbohydrazide-functionalized intermediates and fully characterized. Antiproliferative activity was evaluated against MCF-7, HepG-2, HeLa, and HCT-116 cell lines, alongside selectivity toward WI-38 normal fibroblasts. Antibacterial, antibiofilm, and in vivo efficacy were assessed against methicillin-resistant Staphylococcus aureus (MRSA USA300) and Acinetobacter baumannii AB5057. Mechanistic investigations included cell-cycle analysis, apoptosis assays, ERK2, RIPK3, p53, BAX/Bcl-2 quantification, DNA gyrase inhibition, molecular docking, molecular dynamics simulations, and density functional theory calculations. Results: Compound 13 exhibited potent cytotoxicity, particularly against MCF-7 (IC50 = 3.87 ± 0.2 µM), outperforming doxorubicin (IC50 = 4.17 ± 0.2 µM), with high selectivity indices (SI = 10.7 for MCF-7). Mechanistically, compound 13 induced G2/M arrest (40.16% vs. 14.15% control), increased apoptosis to 32.89%, up-regulated ERK2 (3.17-fold), RIPK3 (11.97-fold), and p53 (3.54-fold), and markedly increased the BAX/Bcl-2 ratio (~42-fold). Compounds 7 and 13 displayed bactericidal activity against MRSA and A. baumannii (MIC/MBC = 10 mg/mL), potent antibiofilm effects, and significant in vivo efficacy in an MRSA skin infection model. Compound 13 reduced bacterial load by ~5 log units, outperforming vancomycin. DNA gyrase inhibition (IC50 = 17.10 ± 0.17 µM) and computational studies supported target engagement. Conclusions: Pyrazoline-thiadiazole-based nitrogen-fused azole hybrids, particularly compound 13, demonstrated quantifiable anticancer and antimicrobial efficacy with strong in vivo validation, supporting their potential as multi-target candidates relevant to antimicrobial drug delivery in infection-prone cancer patients.

Background: Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is a fatal inflammatory disorder driven by M1 macrophages and the associated inflammatory cascade. Targeted drug delivery to these cells is a promising therapeutic strategy. Methods: L-arginine was conjugated to chitosan of different molecular weights. The resulting curcumin nanocrystals (Arg-CS-Cur) were characterized for conjugation efficiency, zeta potential, stability, and drug release profile. Cellular uptake mechanisms and mitochondrial targeting were investigated in lipopolysaccharide (LPS)-induced M1 macrophages using specific endocytic inhibitors and confocal microscopy. Results: Low-molecular-weight chitosan (MW 50 kDa) showed the highest L-Arg conjugation efficiency (22.31%). The optimized Arg-CS-Cur nanocrystals exhibited high zeta potential (&#xb1;47.5 mV), excellent stability, and a superior drug release. They were internalized by M1 macrophages more efficiently than unmodified CS-Cur or free curcumin (p < 0.05). Uptake occurred via clathrin-mediated endocytosis (p < 0.001) and was mediated by CAT-2, which was highly expressed in M1 macrophages (p < 0.001). Arg-CS-Cur specifically targeted the mitochondria, reducing ROS and NLRP3 expression, thus inhibiting the NLRP3 inflammasome pathway (p < 0.001). Conclusions: This L-arginine-modified chitosan-based nanodelivery system synergistically exploits CAT-2 and clathrin pathways to deliver curcumin to M1 macrophage mitochondria, inhibiting the NLRP3 inflammasome. This dual-targeted strategy offers a promising approach for treating ALI/ARDS.

Dengue virus (DENV) remains a significant public health threat, yet no effective antiviral therapies are currently available. Based on TCM theory, the treatment of dengue emphasizes the principles of clearing heat and detoxifying, cooling blood and dissipating blood stasis. Yinqiao Powder (YQS), a famous clearing heat and detoxifying formula, has a good curative effect on the virus-induced diseases, and theoretically has potential value in the treatment of dengue. This study aims to investigate the antiviral mechanism of YQS against DENV. Time-of-drug-addition assay elucidated phase-specific antiviral target of YQS in dengue infection, while plaque, cytopathic effect (CPE), quantitative real-time PCR, Western blot, and immunofluorescence assays were employed to assess the antiviral efficacy of YQS. Network pharmacology analysis was performed to identify convergent molecular targets between YQS constituents and DENV pathophysiological cascades. The interactions between wogonin and HSP90AA1 were characterized using cellular thermal shift assay, drug affinity responsive target stability, molecular docking, and surface plasmon resonance. Immunofluorescence and co-immunoprecipitation assays were implemented to interrogate whether wogonin modulates E/HSP90AA1 interaction. Ultimately, the in vivo protective activity of YQS was assessed in DENV-2-infected AG129 mice. YQS inhibited DENV-2 infection with an IC50 value of 468.5 &#x3bc;g/ml. YQS reduced progeny virus by over 75% and CPE, suppressed expression of viral RNA and proteins during the adsorption phase across multiple cell lines. The active component wogonin was identified through network pharmacology. Similarly, wogonin exhibited potent inhibition of DENV adsorption, reducing plaque formation by over 45%. Further target study demonstrated that wogonin targeted HSP90AA1 and blocked its interaction with viral E protein. In vivo findings revealed YQS mitigated weight loss, extended survival, diminished serum viral load, and conferred hepatoprotective effects in AG129 mice. YQS potently inhibits DENV infection in vitro and in vivo. The antiviral activity of its component wogonin may contribute to this effect, potentially through binding to the host receptor HSP90AA1 and reducing DENV adsorption.

Background: Total glycosides of peony (TGP) have therapeutic potential for immune-related and inflammatory skin diseases, but their skin absorption is not satisfactory. This study aims to investigate how Evodia rutaecarpa volatile oil (VO-ER) enhances the permeability of TGP. Methods: Safety assessment was conducted through cell delivery and skin erythema tests. The chemical composition of VO-ER was identified via GC-MS. The study was conducted using modified Franz diffusion cells, microdialysis, confocal laser scanning microscopy (CLSM), attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), molecular docking and molecular dynamics simulations (MD), laser Doppler flowmetry (LDF), and the western blotting method. Results: The study found that VO-ER promotes the permeation of total glycosides of peony in a concentration-dependent manner by disrupting the intercellular lipid tissue structure, downregulating the expression of claudin-1, claudin-7, and occludin, and improving local microcirculation, thereby promoting the absorption of TGP. Conclusions: VO-ER enhances the transdermal absorption of TGP through multiple mechanisms, such as disrupting the skin lipid barrier, downregulating tight junction proteins, and improving local skin microcirculation. This study provides a theoretical basis for VO-ER as a safe and effective new transdermal penetration enhancer, offering support for the development of topical preparations containing Evodia rutaecarpa and Paeonia lactiflora.

While the Blood-Brain Barrier (BBB) is essential for the protection and function of the Central Nervous System (CNS), it also represents a challenge for drug delivery in the treatment of CNS disorders due to its limited permeability and high expression of efflux transporters. Crossing the BBB becomes even more difficult when dealing with biomolecular therapeutics (e.g., monoclonal antibodies and Antisense Oligonucleotides) due to their hydrophilic nature and high molecular weight. Over the years, different strategies have been developed in order to maximize the ability of biopharmaceuticals to cross the BBB and be delivered to the CNS. Both non-invasive techniques, mainly consisting of developing innovative vectors or using non-conventional routes of administration (e.g., intranasal delivery), and invasive methods, such as intracerebroventricular/intrathecal administration, have been tested individually and in combination. Given the improvements achieved nowadays with both approaches, here, we plan to compare the advances in invasive techniques, such as those based on the use of device-assisted strategies, and the employment of the intranasal route of administration. We are also interested in reporting the applicability of both strategies in the treatment of aggressive forms of cancer, such as glioblastoma, as well as neurodegenerative diseases, in order to determine which technique can be considered a better choice in each specific case.

Background/Objectives: Drug repurposing offers a time- and cost-efficient strategy for accelerating the development of anticancer therapies by leveraging the established safety profiles of existing pharmaceuticals. This study aimed to investigate the anticancer potential of three tetracycline analogues chemically modified tetracycline-3 (COL-3), doxycycline (DOX), and minocycline (MIN) in leukemia models, with a particular focus on their cytotoxic effects and modulation of the JAK2/STAT3 signaling pathway. Methods: Cytotoxicity was evaluated in K562, KG-1a and Jurkat cell lines using luminescence-based viability assays, whereas the mechanisms of cell death were analyzed by Annexin-V/7-AAD staining and Western blotting. Results: COL-3 displayed the highest cytotoxic potency across all cell lines, with Jurkat cells showing the greatest overall sensitivity. Flow cytometry revealed that tetracycline analogues primarily induced apoptosis, although the molecular mechanisms differed between cell lines. In K562 and KG-1a cells, apoptosis occurred largely through JAK2/STAT3-independent mechanisms, involving differential regulation of BCL-2 family proteins: COL-3 reduced BCL-2 expression, whereas DOX and MIN increased BAX expression. In contrast, Jurkat cell apoptosis correlated with suppression of phosphorylated JAK2 and STAT3 and downregulation of BCL-2, implicating a JAK2/STAT3-dependent mechanism. Conclusions: Taken together, these findings demonstrate that tetracycline analogues exert cell line-specific anticancer activities through distinct molecular pathways. Among them, COL-3 emerges as the most potent analogue and acts through both JAK/STAT-dependent and -independent mechanisms. This work supports further investigation of COL-3 as a candidate for drug repurposing strategies in hematological malignancies.

Designing efficient nanocarriers for targeted cancer therapy requires a deep understanding of drug-nanomaterial interactions at the molecular level. In this study, the adsorption behavior of four clinically relevant anticancer drugs, 6-mercaptopurine (6-MP), hydroxyurea (HU), chlormethine (CM), and 5-fluorouracil (5-FU), on a CC1 nanocage was systematically investigated using density functional theory (DFT). Geometry optimizations and thermodynamic analyses were performed at the &#x3c9;B97XD/6-31G(d, p) level, while optical properties were assessed through time-dependent DFT (TD-DFT) calculations at the B3LYP/6-31G(d, p) level. The computed adsorption energies and electronic descriptors revealed that all drug-nanocage interactions are spontaneous and exothermic in an aqueous medium, with 5-FU exhibiting the strongest binding (-&#x2009;8.68&#xa0;kcal/mol). TD-DFT spectra displayed redshifts in absorption peaks after adsorption, signifying charge transfer between the drugs and the CC1 framework. Moreover, topological (QTAIM) and Non-Covalent Interaction (NCI) analyses confirmed that van der Waals forces primarily stabilize the complexes. The short recovery times predicted for the drug-loaded nanocage suggest efficient release kinetics under physiological conditions. Overall, this theoretical study provides a molecular-level perspective on CC1 nanocage-drug interactions, offering useful insights for the rational design of carbon-based nanocarriers in targeted anticancer drug delivery.

To search for safe and efficient anti-fatigue active molecules, 16 capsaicin (CAP) derivatives were synthesized by replacing the unsaturated carbon-carbon double bond in capsaicin with a rigid benzene ring via condensation, chlorination, and amidation reactions using vanillylamine hydrochloride as the starting material, with yields ranging from 44.1 to 79.1%. Their structures were confirmed by 1H-NMR, 13C-NMR, and MS (electrospray ionization [ESI]). In vitro assays demonstrated that N8 exerted superior transient receptor potential vanilloid 1 (TRPV1) agonistic activity compared to CAP at a concentration of 10 &#x3bc;M, upregulated peroxisome proliferator-activated receptor gamma coactivator 1&#x3b1; (PGC-1&#x3b1;) expression in a concentration-dependent manner (1.25-10 &#x3bc;M), and showed no significant toxicity to C2C12 myotube cells at 0.78-100 &#x3bc;M. In vivo evaluations in mice (15 mg/kg, 31-d gavage) demonstrated that N8 had no adverse effect on body weight but significantly prolonged rotarod duration (143.5%, p < 0.001) and forced swimming time (75.6%, p < 0.001), increased serum lactate dehydrogenase (LDH) levels (p < 0.01), decreased serum urea nitrogen (SUN) levels (p < 0.001) and lactic acid (LA) accumulation (p < 0.001), and elevated hepatic and muscle glycogen contents (p < 0.001) compared with the fatigue control group. Mechanistic studies via Western blot, mitochondrial fluorescence staining, cellular thermal shift assay, and molecular docking revealed that N8 had better binding stability to TRPV1 than CAP (relative binding rate at 65&#xb0;C: 86.7 vs. 21.5%), activated the TRPV1 channel, synergistically upregulated the expression of cluster of differentiation 36 (CD36), carnitine palmitoyltransferase 1M (CPT1M), SURF1, and cytochrome c1 (CYC1), promoted mitochondrial biogenesis, and optimized muscle energy metabolism. These results indicate that N8 demonstrates superior anti-fatigue activity both in vitro and in vivo compared to CAP, making it a potential candidate for anti-fatigue drug development.

Rheumatoid Arthritis (RA) greatly affects patient's life. Systematic reviews of recent epidemic trend and the pathogenesis of RA are inadequate. Although multiple health benefits of lactic acid bacteria (LAB) were reported, comprehensive reviews addressing the mechanisms by which LAB alleviate RA remain limited. This review systematically examines the epidemiology and pathogenesis of RA, emphasizing the potential modulatory role of LAB in maintaining intestinal homeostasis. Drawing on both animal and clinical evidence, the review critically evaluates the molecular mechanisms by which LAB may alleviate RA, thereby offering a theoretical foundation for microbiota-based therapeutic interventions. Meanwhile, it highlighted the challenges and opportunities of LAB for RA. Genetic predisposition, environmental factors, and immune system dysfunction play very important roles in causing RA. LAB provided numerous advantages and had great potential for improving RA as its ability to regulate intestinal barrier, modulate related enzyme activity, inhibit oxidative damage, restore unbalanced gut microbiota, produce bioactive metabolites, and regulate gut-joint immune axis. In addition, this review advice to screen effective LAB by cell models and metabolites, to determined the optimal intake dose of LAB through dose-effect relationship studies, to promote the understanding of LAB by investigating the mechanism, and to improve the design of the clinical study to improve the lives of RA patients. This will contribute to understanding the epidemiological characteristics, pathogenesis, and treatment of RA, and promote the development of targeted therapeutic RA products such as LAB.

Purpose: The objective of this study was to engineer and optimize a mucoadhesive, positively charged stearylamine-enriched liposomal platform, termed Aminosomes, to circumvent the biophysical barriers limiting the ocular bioavailability of Brimonidine Tartrate (BT), an alpha-2 adrenergic receptor agonist for glaucoma management. Methods: Aminosomes were synthesized using a tailored ethanol injection technique and optimized via a 32 &#xd7; 21 full factorial design. Molecular integrity and crystallinity were assessed using Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The mucoadhesive potential was validated through a mucin interaction assay based on zeta potential shifts. In vitro release kinetics were evaluated using the dialysis membrane diffusion technique, while the therapeutic potential and ocular safety were validated through in vivo pharmacodynamic profiling of intraocular pressure (IOP) reduction, alongside comprehensive biocompatibility assessments via Draize irritancy protocol and histopathological examination. Results: The optimized Aminosomes exhibited nanometric dimensions, monodisperse size distribution, robust positive surface charge, and superior drug loading. FTIR and XRD analyses confirmed the chemical compatibility of the formulation components, as well as the successful encapsulation of BT and its transition to an amorphous state within the lipidic matrix. The mucoadhesion test demonstrated a high binding affinity for mucin. The in vitro release profile demonstrated a sustained-release pattern (78.8% over 12 h). Non-compartmental pharmacodynamic analysis of IOP-reduction data revealed a 2.8-fold increase in AUC0-24h, 3.5-fold extension in t1/2, and 5.2-fold prolongation in mean residence time (MRT) relative to the standard solution. Conclusions: The optimized Aminosomes demonstrated superior mucoadhesive anchoring, enhanced and sustained therapeutic flux without inducing ocular toxicity, offering a robust strategy for enhancing the pharmacodynamics of BT.

Metabolic diseases, particularly type 2 diabetes mellitus (T2DM) and obesity, have been traditionally understood through glucose-centric models. However, hyperglycaemia is a downstream consequence of systemic immune-metabolic dysregulation, with the gut microbiota acting as a central upstream regulator through defined molecular signalling pathways. This review examines four principal microbiota-host signalling axes through which ecological disruption drives systemic metabolic disease: short-chain fatty acid (SCFA) depletion impairing free fatty acid receptor (FFAR2/FFAR3) and AMP-activated protein kinase (AMPK) signalling; altered bile acid (BA) biotransformation perturbing farnesoid&#x202f;X&#x202f;receptor (FXR) and TGR5 signalling; increased intestinal permeability facilitating lipopolysaccharide (LPS) translocation and Toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-&#x3ba;B) activation; and diminished indole production reducing aryl hydrocarbon receptor (AhR)-driven interleukin-22 (IL-22) secretion. Therapeutic strategies targeting these pathways, including SCFA prodrugs, FXR modulators, TGR5 agonists, and next-generation probiotics, offer disease-modifying potential beyond glycaemic lowering and highlight the need for a multidimensional clinical endpoint framework spanning inflammatory, hepatic, and barrier biomarkers to enable comprehensive translational evaluation of microbiota-directed therapies.