BACKGROUND:Diabetes mellitus is a major global health concern. DPP-4 (dipeptidyl peptidase-4) inhibitors containing a 2-cyanopyrrolidine scaffold are in clinical use; however, systematic evaluation of amides derived from amino acids adjacent to the N-2 position of GLP-1 (glucagon-like peptide-1) has not been reported. METHODS:A total of eight 2-cyanopyrrolidine derivatives, grouped into three series, were synthesized from N-Boc-protected amino acids via condensation with 2-cyanopyrrolidine followed by deprotection. The compounds were characterized by nuclear magnetic resonance (NMR), elemental analysis, and mass spectrometry (MS). DPP-4 inhibitory activity was evaluated in vitro using a DPP-IV Glo™ assay, with sitagliptin as a control. IC50 (Half Maximal Inhibitory Concentration) values were determined from three independent replicates (n = 3) and calculated by nonlinear regression. RESULTS:Compounds 4d, 4g, and 4h exhibited excellent DPP-4 inhibition, with IC50 values of 1.36 ± 0.09, 5.24 ± 0.31, and 4.83 ± 0.22 nM, respectively. Compound 4d (histidine) was more potent than sitagliptin (6.13 ± 0.42 nM). The bis-cyanopyrrolidine derivatives 4g and 4h also showed strong activity. The remaining compounds (4a-4c, 4e, 4f) displayed moderate inhibition (IC50 112-181 nM). CONCLUSIONS:Aminoacyl-2-cyanopyrrolidine derivatives bearing an imidazole or bis-cyanopyrrolidine structure are potent DPP-4 inhibitors. These findings highlight the importance of neighboring GLP-1 amino acid residues (positions 1 and 3) in inhibitor design. Further cellular and in vivo studies are warranted to evaluate the therapeutic potential of these compounds.
BACKGROUND:Orally disintegrating films (ODFs) disintegrate and dissolve in the mouth, which creates challenges such as bitter taste and particle roughness. One of the most useful methods for suppressing bitterness in solid dosage forms is coating drug particles with a polymer to physically prevent contact between the drug and the taste buds. Because ODFs are extremely thin, the volume available for particle incorporation is limited; therefore, it is necessary to prepare fine coated drug particles with a size smaller than 200 µm, which also helps mitigate particle roughness in the oral cavity. In this study, we designed and prepared ODFs incorporating taste-masked drug particles for easy administration and improved adherence to drug therapy. METHODS:We used quinine hydrochloride (QH) as a model bitter active pharmaceutical ingredient (API), polyvinylacetal diethylaminoacetate (AEA), a pH-dependent polymer, as a coating agent, and hydroxypropyl methylcellulose (HPMC) as the film-forming agent. The ODFs containing taste-masked QH granules and the corresponding granules themselves were evaluated using a taste-sensing system. The disintegration, drug dissolution profiles, and physical properties of the ODFs were also evaluated. RESULTS:We prepared QH granules with the targeted median diameter (d50) and geometric standard deviation (σg), and the initial release of QH from these granules was less than 5% within 2 min. We also demonstrated, using the same system, that ODFs containing these granules delayed and suppressed the emergence of QH-induced bitterness. The disintegration time of the ODFs was less than 30 s, and their tensile strength remained above the 2 MPa threshold required for handling. CONCLUSION:We successfully prepared ODFs that suppressed the bitterness of QH while maintaining a short disintegration time and practical mechanical strength.
BACKGROUND:Rheumatoid arthritis (RA) is a chronic autoimmune disease and one of the most prevalent complex inflammatory disorders. Capparis spinosa L. (C. spinosa) is recognized for its diverse medicinal properties. Traditionally, the plant has been employed to alleviateconditions such as paralysis, gastrointestinal infections, rheumatism, diabetes, anemia, pain, and eye infections. This study aimed to investigate the potential interactions and predicted pharmacological relevance of major compounds identified in the essential oil of C. spinosa leaves using computational approaches. METHODS:Drug-likeness potential was determined using Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling and molecular docking. Gas chromatography-tandem mass spectrometry (GC-MS) was used to characterize the chemical composition of the essential oil. Drug-likeness studies were performed with SwissADME, while molecular docking was conducted using PyRx and BIOVIA Discovery Studio. RESULTS:Fourteen major compounds were computationally screened against RA-associated molecular targets to evaluate their potential ligand-target interactions and drug-likeness characteristics. Absorption, Distribution, Metabolism, and Excretion (ADME) and drug-likeness were evaluated according to Lipinski's "rule of five" to determine whether the compounds exhibited suitable pharmacokinetic properties, consistent with criteria for pharmaceutical development. Six major phytoconstituents, i.e., tau-cadinol (M1), diisobutyl phthalate (M5), (Z)-3-hexenyl benzoate (M7), farnesyl acetone (M8), dibutyl phthalate (M10), and 1-(4-tert-butylphenyl)propan-2-one (M12), identified via GC-MS were docked with tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), nitric oxide synthase (NOS), and cyclooxygenase-2 (COX-2). This is the first report describing an in silico screening of GC-MS-identified compounds from C. spinosa for their predicted pharmacological potential. Docking ligand scores for all ligands against the target proteins ranged from -4.7 to -8.0 kcal mol-1. Diisobutyl phthalate (M5) showed the most favorable binding energies against IL-1β and NOS, relative to the other compounds and co-crystallized ligands; meanwhile, tau-cadinol (M1) exhibited the highest binding energy for TNF-α. Six prevalent phytochemicals demonstrated highly favorable predicted docking affinities toward IL-6 and COX-2, with M10 showing the lowest docking energy values among the tested compounds under the applied computational conditions. CONCLUSIONS:These findings suggest that the examined phytochemicals may exhibit potential affinity toward RA-related molecular targets. As this is a preliminary computational investigation, the results should be interpreted with caution and warrant further computational and experimental studies to confirm their biological and therapeutic relevance.
BACKGROUND:Disrupted bile acid homeostasis represents a central feature of cholestatic liver injury, for which effective therapeutic options remain limited. Saxifraga umbellulata Hook. f. et Thoms. (SU) has traditionally been used in Tibetan medicine to treat hepatobiliary disorders, yet the pharmacological basis of SU remains unclear. Therefore, this study aimed to evaluate the effects of SU on cholestatic liver injury and explore the regulatory mechanisms underlying these effects. METHODS:A mouse model of cholestatic liver injury was established by administering α-naphthyl isothiocyanate (ANIT). The effects of SU were evaluated using serum biochemical measurements, liver histopathology, and targeted profiling of hepatic bile acids. Protein expression associated with farnesoid X receptor (FXR) signaling was assessed by Western blotting in liver and ileal tissues. Representative triterpenoids in the SU extract were further examined using molecular docking and HepG2 cell experiments. RESULTS:SU administration reduced serum markers of hepatocellular injury and cholestasis and lessened hepatic necrosis and inflammatory cell infiltration in ANIT-treated mice. SU also shifted the altered hepatic bile acid profile toward a more balanced state, including partial correction of the disturbed proportions of primary and secondary bile acids. These metabolic changes were accompanied by reduced hepatic CYP7A1 expression and increased expression of BSEP and MRP2. In addition, SU increased ileal FXR and FGF15 expression and hepatic FGFR4 expression, a pattern consistent with coordinated regulation of the intestinal FXR-FGF15/hepatic FGFR4 axis. Meanwhile, molecular docking and HepG2 cell experiments suggested that cucurbitacin IIb and saxifragic acid may contribute to the observed FXR-related responses. CONCLUSIONS:SU mitigated ANIT-induced cholestatic liver injury and promoted partial recovery of hepatic bile acid homeostasis. The protective effects of SU were associated with coordinated changes in hepatic and intestinal FXR-related signaling and with reduced inflammatory injury. These results provide experimental evidence supporting the traditional use of SU for hepatobiliary disorders and highlight cucurbitacin IIb and saxifragic acid as potential bioactive triterpenoids.
Skin hyperpigmentation is a common dermatological condition characterized by excessive melanin accumulation in the epidermis, dermis, or both, resulting from disorders such as melasma, post-inflammatory hyperpigmentation, drug-induced hyperpigmentation, and solar lentigo. Conventional treatments are mainly based on tyrosinase inhibition; however, many depigmenting agents have limitations, including low stability, poor skin permeation, prolonged treatment durations, and adverse effects such as irritation and dermatitis. In this context, nanotechnology-based delivery systems have emerged as promising alternatives for the topical administration of depigmenting compounds. Therefore, this review discusses recent advances in nanotechnology-based strategies for treating skin hyperpigmentation, with a primary focus on lipid-based nanosystems, including liposomes, nanoemulsions, solid lipid nanoparticles, and nanostructured lipid carriers. A total of 33 studies published between 2000 and 2025 were analyzed. The reviewed studies demonstrated that nanoencapsulation may improve the physicochemical stability, enable controlled release, enhance skin permeation/retention, and increase the therapeutic performance of depigmenting agents while reducing toxicity and adverse effects. In vitro studies also reported enhanced tyrosinase inhibition, high cell viability, and increased accumulation of active compounds in different skin layers. Overall, nanotechnology-based delivery systems represent a promising and versatile approach for improving the efficacy and safety of topical treatments for skin hyperpigmentation.
