Type 2 diabetes mellitus (T2DM) has been associated with cognitive impairment and an increased risk of dementia in women. This study examined the effects of subchronic metformin treatment on recognition memory and brain pathology in female diabetic mice. T2DM was induced by streptozotocin and nicotinamide injections. Then, the mice received metformin (50, 150, or 250 mg/kg) orally for 28 days. Recognition memory was assessed using the Novel Object Recognition Test (n = 72). Biochemical analyses of whole-brain homogenates evaluated insulin, tau, and insoluble Aβ42 (n = 4). Histological analyses evaluated neuronal damage and amyloid-like deposits in the hippocampal Cornu Ammonis 1 (CA1) region, cerebral cortex, and cerebellum (n = 4). The diabetic mice exhibited hyperglycemia, hyperinsulinemia, dyslipidemia, impaired recognition memory, and neuronal damage. Metformin reduced blood glucose levels and improved recognition memory. Metformin also normalized serum and brain insulin levels and reduced neuronal damage in the CA1 region, cortex, and cerebellum. Metformin reduced cerebellar Congo red-positive amyloid-like deposits and decreased insoluble Aβ42 levels in whole-brain homogenates. However, at 250 mg/kg, metformin increased total and phosphorylated tau levels. These results suggest that metformin mitigates recognition memory deficits, attenuates neuronal damage, and reduces cerebellar amyloid-like deposits in female mice.
Accumulating evidence indicates extensive crosstalk between prostaglandin- and histamine-mediated signaling pathways. Histamine has been shown to induce COX-2 (Cyclooxygenase-2) expression and stimulate prostaglandin synthesis, whereas prostaglandins potentiate the vascular and inflammatory effects of histamine, creating a positive feedback loop that sustains inflammation. Based on these considerations, in silico molecular docking study of interaction of new cytisine and TGIQ (tetrahydroisoquinoline) derivatives with COX-2 and the histamine H1 receptor was performed. Among the synthesized compounds, compound 1 exhibited the highest binding affinity toward Cyclooxygenase-2 (COX-2). Within the binding pocket of the human H1 histamine receptor, the binding affinity profile differed markedly from that observed for COX-2, with compound 4 exhibiting the highest therapeutic potential and the strongest binding affinity, surpassing all reference compounds. The high anti-inflammatory efficacy of the studied compounds was confirmed in formalin- and histamine rat models. THIQ derivatives were shown to possess a higher anti-inflammatory index than cytisine derivatives. Comparative evaluation of the anti-inflammatory activity of isoquinoline and quinolizidine derivatives revealed that the isoquinoline derivatives possess marked anti-inflammatory properties combined with low toxicity, making them promising candidates for the development of novel, highly effective and safe anti-inflammatory agents for both oral and topical administration.
Macrophomina phaseolina, a necrotrophic fungus with global distribution, has emerged as a source of bioactive natural products. This study evaluated the antiviral potential of metabolites from M. phaseolina against herpes simplex virus 1 (HSV-1). A crude extract of M. phaseolina was obtained from the culture medium, and the secreted metabolites were purified using chromatographic techniques. Major metabolites were identified using NMR and HRMS techniques. The antiviral activity of these metabolites was assessed using Vero cells and virus quantitation through qPCR. In addition, a viral gene expression and intracellular genome quantification was performed using qPCR. Six metabolites were isolated: (−)-botryodiplodin, mellein, hydroxymellein, acetylphomalactone, asperlin, and isoasperlin. Their structures were elucidated through NMR and HRMS. Most metabolites showed limited antiviral efficacy; however, (−)-botryodiplodin demonstrated potent activity, with an EC50 of 2.44 µg/mL and a selectivity index of 4.79. In addition, acyclovir was included as a control, demonstrating >97% antiviral inhibition. Mechanistic studies showed that (−)-botryodiplodin inhibited HSV-1 production, reduced viral genome levels, and suppressed immediate–early, early, and late viral gene expressions. These findings demonstrate that (−)-botryodiplodin acts as an early-stage inhibitor of HSV-1 prior to viral transcription, establishing this natural metabolite as a promising chemical scaffold for the rational design of novel antiviral agents.
Citrus bioflavonoids, especially hesperidin, have garnered interest for their pharmacological attributes. The clinical applicability of hesperidin is constrained by its limited absorption. This study aimed to prepare and characterize liquisolid systems of citrus bioflavonoid extract (CBE) to enhance hesperidin release. Solubility investigations revealed that N-methyl-2-pyrrolidone (NMP) with 1–3% sodium dodecyl sulfate (SDS) yielded the greatest solubility (25% w/w) of hesperidin. Six CBE liquisolid (CBE-LS) formulations were successfully fabricated with CBE concentrations in NMP-based liquid medicaments of 10–25%, with or without SDS. All CBE-LS formulations exhibited acceptable flowability and content uniformity. FTIR data suggested potential intermolecular associations between CBE and 1%SDS-NMP-based CBE-LS. PXRD demonstrated a complete transformation to a non-crystalline state of CBE exclusively in CBE-LS formulated with 10–15% CBE concentrations. CBE-LS improved the release efficiency of hesperidin by 2.5–3.8-fold. CBE-LS exhibited relatively low cytotoxicity to Caco-2 cells. Tablets of CBE-LS (CBE-LST) based on 20% CBE in 1% SDS-NMP systems were successfully produced, exhibiting satisfactory tablet characteristics, content consistency, and enhanced release efficiency. CBE-LST exhibited no marked physical changes over three months upon storage, but the percentage of remaining hesperidin was significantly affected by storage temperature. This study highlights the potential of liquisolid systems as a useful approach for enhancing the release of oral formulations containing hesperidin and CBE.
Natural compounds, including curcumin, resveratrol and other polyphenols, exhibit biologically significant antimicrobial, anticancer and antioxidant activities, making them promising candidates for drug development. These bioactive compounds have been applied in the management of chronic diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. However, their clinical application is severely hindered by physicochemical limitations, such as poor aqueous solubility, rapid metabolism, and limited bioavailability. Lipid-based delivery systems, particularly liposomal delivery platforms, offer a strategy for addressing these barriers. Liposomes are lipid-bilayer vesicles whose safety and biocompatibility depend on formulation composition, surface modification, dose, administration route, impurities and formulation-specific biological interactions, including potential toxicity and immune reactions. Depending on their composition and design, liposomes can provide controlled release, biodegradability and opportunities for surface modification to support targeted delivery. Their performance relative to other carriers depends on the encapsulated compound, administration route and intended application. A key feature of liposomes is their ability to encapsulate both hydrophobic and hydrophilic compounds, allowing them to carry a wide range of molecules. This review critically examines liposomal formulation strategies for natural compounds, distinguishing improvements in physicochemical properties and pharmacokinetics from preclinical biological activity and demonstrated clinical benefit. Emphasis is placed on recent advances in liposomal formulations of curcumin, resveratrol and other polyphenols, along with insights into their biomedical applications.
