Sanguinarine

Sanguinarine (SAN), a bioactive benzophenanthridine alkaloid derived from Macleaya cordata, has gained attention as a plant-based pesticide and veterinary therapeutic. However, its toxicity mechanisms, particularly concerning toxicokinetics (TK) and gut microbiota interactions, remain poorly understood. This research assessed the acute and subacute toxicity, toxicokinetics, oxidative stress reactions, and changes in gut microbiota associated with SAN in Sprague-Dawley rats. A single oral dose by gavage resulted in a LD₅₀ of 1000 mg/kg·bw (male) and 926 mg/kg·bw (female), classifying SAN under GHS Category 4. Subacute exposure (14 days at 1/10, 1/50, and 1/100 LD₅₀) induced multi-organ damage, including pulmonary haemorrhage, hepatic steatosis, and renal tubular necrosis, with females exhibiting relatively higher sensitivity. Surviving rats recovered from toxic damage during the 14-day recovery period. Toxicokinetic analysis demonstrated dose-dependent plasma concentration curves, nonlinear elimination kinetics, and tissue accumulation in the liver and kidneys. Assays measuring oxidative stress showed unexpected rises in overall antioxidant capacity alongside marked inhibition of glutathione peroxidase, indicating targeted redox disruption. Gut microbiota sequencing identified dose-dependent dysbiosis: high-dose SAN reduced Firmicutes/Bacteroidetes ratios, depleted Lactobacillus, and enriched opportunistic pathogens (Klebsiella, Streptococcus), alongside altered short-chain fatty acid (SCFA) profiles. These findings underscore SAN's potential to induce systemic toxicity through oxidative stress, metabolic disruption, and gut microbiome-mediated inflammation. The LOEAL observed in this study for subacute exposure (14 days) to SAN was 10 mg/kg and the safe use of SAN should be emphasized.

Argemone ochroleuca is recognized for its traditional use in managing diabetes; however, no systematic study has explored its molecular mechanisms targeting biological macromolecules. Therefore, current study aimed to elucidate the underlying mechanisms of A. ochroleuca ethanolic extract (AOE) in T2DM management using multi-omics and network pharmacology-based methods, focusing on key regulatory proteins. The AOE yielded 7.04 %, and GC-MS, as well as other data mining approaches, were used to identify 45 phytoconstituents in AOE, from which seven key bioactive compounds-β-sitosterol, 4H-Pyran-4-one, butyrolactone, hexadecanoic acid, sanguinarine, allocryptopine, and berberine - were selected. Thereafter, these compounds were predicted to target several core proteins, including AKT1, INS, TP53, TNF, IL6, and FOXO1, which are involved in T2DM pathology. However, these proteins participate in critical signaling pathways, including the PI3K/Akt, MAPK, AGE/RAGE, and PPARγ pathways, among others. Moreover, Microarray data (GSE184050) validated the relevance of these targets, showing upregulation of INS, TNF, IL6, and downregulation of FOXO1 in T2DM patients. Additionally, AOE demonstrated dose-dependent inhibition of α-amylase (111.21 ± 4.7 μg/ml) and α-glucosidase (135.02 ± 12.08 μg/ml) enzymes, revealing therapeutic effects in STZ-induced diabetic rats by improving glucose metabolism, reducing inflammation, and protecting hepatic and renal tissues. Hence, AOE exerts antidiabetic effects through multi-target modulation of specific proteins, highlighting its clinical potential.