Natural products are often used as stand-alone treatments or as complementary approaches alongside modern medicine to manage type 2 diabetes mellitus. Gardenia jasminoides, a substance used as both food and medicine, has been used in traditional Chinese medicine to manage hyperglycemia. Here, we combined spectrum-effect analysis, bioactivity-guided component knockout, untargeted metabolomics, and network pharmacology to identify crocetin as a major glucose-regulating constituent of G. jasminoides and G protein-coupled receptor kinase 5 (GRK5) as a candidate molecular target. Cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) analyses demonstrated binding between crocetin and GRK5. In an insulin-resistant HepG2 cell model, crocetin increased GRK5 protein abundance and enhanced phosphoinositide 3-kinase (PI3K)/AKT2 signaling and glucose transporter 4 (GLUT4) expression; GRK5 knockdown attenuated these effects and the associated increase in glucose consumption. Reciprocal co-immunoprecipitation further demonstrated an association between GRK5 and AKT2. Collectively, these findings support a model in which crocetin binds GRK5 and promotes GRK5-dependent AKT2 signaling, thereby improving cellular glucose homeostasis.
Despite the tremendous advances in human immunodeficiency virus (HIV) therapies, HIV-associated neurocognitive disorders remain prevalent. In this study, we investigated the age-dependent progression of cognitive deficits in glycoprotein 120 transgenic (gp120tg) mice, with neuronal pyroptosis identified as a central mechanism in glycoprotein 120 (gp120) induced pathogenesis. Cognitive impairments were observed in 6-, 9-, and 12-month-old gp120 mice, and these deficits correlated with age-associated gut microbiota dysfunction. Notably, a significant reduction in the abundance of Akkermansia muciniphila was found in the gut microbiota of these mice compared to age-matched wild-type controls. Oral administration of A. muciniphila with tryptophan metabolic capacities alleviated cognitive impairment and neuronal pyroptosis in gp120tg mice. Kynurenic acid, a tryptophan metabolite with u03B17 nicotinic acetylcholine receptor (u03B17nAChR) inhibitory properties, attenuated gp120-induced neuronal pyroptosis via blockade of u03B17nAChR/NF-u03BAB signaling. The u03B17nAChR, a receptor involved in neuroinflammation and neuronal survival, plays a pivotal role in the regulation of immune responses and neuronal excitability. This mechanism may account, in part, for the anti-pyroptosis effects observed in gp120 mice with A. muciniphila treatment. Our findings shed light on the therapeutic potential of A. muciniphila and strategies targeting u03B17nAChR inhibition against gp120-mediated neuropathology.
Encapsulation of curcumin (Cur) into nanomaterials has been a promising strategy for enhancing its unfavorable properties and maximizing its health benefits. In this study, a novel Cur-loaded mesoporous polydopamine (PDA)-based nanoparticles (Cur-MPNs) further decorated with polyethylene glycol-chitosan (PC) complexes were fabricated for the first time. The results show that the MPNs-PC nanocomposite exhibits a satisfactory loading capacity and superior stability. In vitro studies revealed that nano-encapsulated Cur exhibited enhanced antioxidant activities and pH-responsive release behaviors. More importantly, the MTT assay showed reductions in viability of human MCF-7, A549, and HCT-116 cells upon exposed to Cur-loaded nanovehicles. The representative HCT-116 cell apoptosis model, employing flow cytometry and fluorescent microscopy analyses, convincingly demonstrated that the encapsulated Cur more effectively induced apoptosis. This signifies that these MPNs-PC formulations possess considerable potential as an encapsulated system for Cur with intensified biological characteristics.
