Scientia Pharmaceutica

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.