Cornus officinalis Sieb. et Zucc. is a widely utilized medicinal and edible plant, yet its principal antioxidant compounds and underlying molecular mechanisms remain largely elusive. To address this, an integrated screening strategy was developed. By combining spectrum-effect relationship analysis, target component knockout, metabolomics, and network pharmacology, several core antioxidant candidates were identified, and CDK2 was predicted as a key target. Subsequent screening in an H₂O₂-induced HepG2 cell model pinpointed cornuside as the most potent antioxidant compound. Efficacy evaluations demonstrated that cornuside effectively alleviates oxidative stress in vitro and in an AAPH-induced zebrafish model in vivo by restoring endogenous antioxidant enzyme reserves and mitigating apoptosis. Mechanistically, molecular docking and Cellular Thermal Shift Assays (CETSA) explicitly verified that cornuside directly binds to the CDK2 protein, which robustly activates the downstream NRF2/NQO1 signaling pathway. Furthermore, specific siRNA-mediated silencing of CDK2 in HepG2 cells completely abolished the antioxidant protection and NRF2/NQO1 activation mediated by cornuside, confirming its absolute target dependency. Through this systematic screening and validation pipeline, cornuside was conclusively identified as the key antioxidant constituent of C. officinalis. It mitigates oxidative stress and apoptosis by directly targeting CDK2 to activate the NRF2/NQO1 pathway, providing a robust pharmacological basis for its functional application.

Food intake is usually addressed in pharmacotherapy as a dosing condition or a source of food–drug interactions, yet this view treats food largely as a passive background exposure. To address the separation between therapeutic nutrition and food–drug interaction management, this narrative review proposes a clinically applicable role-based framework that classifies food as a therapeutic agent, an antagonist of pharmacotherapy, or an enabler of treatment according to the dietary exposure, drug and formulation, disease state, timing, and clinical intent. In this framework, food may function as a therapeutic agent, an antagonist of pharmacotherapy, or an enabler of treatment, depending not on the food itself but on the clinical context in which it is consumed. Therapeutic roles include dietary patterns, medically tailored meals, nutrients, and food-derived bioactive compounds that support disease control, symptom relief, nutritional rehabilitation, or treatment responsiveness. Antagonistic roles occur when food reduces efficacy, increases toxicity, or destabilizes response through altered absorption, metabolism, transport, pharmacodynamics, adherence, or food-access constraints. Enabling roles occur when meal timing, composition, or nutritional support increases or stabilizes drug exposure (exposure enablement), reduces gastrointestinal or other treatment-related adverse effects (tolerability enablement), or improves adherence and dosing feasibility (adherence/feasibility enablement). Mechanisms include gastrointestinal physiology, formulation behavior, enzyme and transporter activity, nutrient–drug pharmacodynamics, microbiome effects, and artificial nutrition. Applying this framework requires structured dietary assessment, explicit prescribing instructions, diet-sensitive medication review, and interprofessional care. By classifying food roles conditionally rather than assigning fixed properties to foods, this framework can support more precise prescribing, safer food–drug management, food/formulation design, and patient-centered care.

In the ethnic regions of Yunnan province, China, Cinnamomum chago is recognized as a nutraceutical food that possesses significant economic, ecological, and medicinal value. Although studies have highlighted the seeds of C. chago with high content in polyphenols, flavonoids, and tannins, the studies of components and biological activities of C. chago are under investigated. To explore the functional components hidden in the edible and medical plant C. chago, ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and feature-based molecular networking (FBMN) strategies were applied to investigate the antioxidant components in C. chago. A total of 104 compounds including 43 lipids, 21 phenols, 20 alkaloids, 10 amino acids, 6 organic acids and 4 terpenoids were identified by MS/MS analysis for the first time. It is noteworthy that there are 4 previously undescribed lipids were characterized. The n-butanol fraction (n-BuF) of C. chago extracts exhibited the strongest antioxidant capacity in radical-scavenging assays. Namely, the n-BuF effectively mitigated oxidative stress in H₂O₂-induced HepG2 cells by significantly reducing intracellular ROS levels and apoptosis via the Nrf2/NQO1 pathway. The results highlighted that the kernels of C. chago hold great potential as a source for developing functional and nutritional foods.

Although Rosmarinus officinalis L. (rosemary) is widely consumed as a prominent source of natural antioxidants, its specific bioactive constituents and precise molecular targets against oxidative stress remain elusive. This study aimed to identify the core functional ingredients of rosemary and elucidate their underlying protective mechanisms. Through an integrated screening strategy combining untargeted metabolomics, spectrum-effect analysis, and a component knock-out method, rosmarinic acid (RA) was identified as the pivotal dietary antioxidant. The efficacy of RA was validated in hydrogen peroxide (H₂O₂)-challenged HepG2 cells and 2,2′-azobis (2-amidinopropane) dihydrochloride (AAPH)-challenged zebrafish models, where RA effectively mitigated oxidative damage by suppressing reactive oxygen species (ROS) accumulation and apoptosis. Mechanistically, RA upregulated peroxisome proliferator-activated receptor gamma (PPARγ) expression and activated downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/NAD(P)H quinone dehydrogenase 1 (NQO1) pathway. Concurrently, RA attenuated mitogen-activated protein kinase 1 (MAPK1) and signal transducer and activator of transcription 1 (STAT1) phosphorylation and inhibited cleaved-Caspase-3 activation. Crucially, molecular docking (binding affinity: −9.038 kcal/mol) and cellular thermal shift assay (CETSA) confirmed the direct physical binding of RA to PPARγ. In conclusion, RA is the core bioactive compound in rosemary that exerts potent cytoprotective effects by directly targeting PPARγ to activate the antioxidant Nrf2/NQO1 axis. These findings provide a robust scientific basis for utilizing rosemary and RA as functional food ingredients to combat oxidative stress-related pathologies.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline. Tetrahydroxy stilbene glucoside (TSG) has been demonstrated to improve learning and memory in aged mice; however, its underlying mechanisms remain incompletely understood. This study aimed to elucidate the effects of TSG on cognitive impairment in APP/PS1 mice through analysis of gut microbiota and associated metabolites. Behavioral tests, immunohistochemistry, and 16S rDNA sequencing revealed that TSG treatment improved cognitive function and alleviated neuroinflammation. Furthermore, TSG restored gut microbiota homeostasis and normalized aberrant metabolite profiles, accompanied by elevated levels of short-chain fatty acids (SCFAs). Correlation analysis indicated associations between alterations in gut microbiota, metabolites, and SCFAs. Notably, TSG promoted the production and content of SCFAs, especially acetic acid, propionic acid, and hexanoic acid. These findings suggest that TSG mitigates AD-related pathology possibly via modulation of specific gut microbial communities and their metabolic outputs, providing a basis for further therapeutic exploration.

Macrophages are the core effector cells of the innate immune system. The dysregulation of amino acid, glucose, lipid, and energy metabolism in macrophages has a profound impact on inflammatory pathways. A comprehensive analysis of metabolites in macrophages can identify inflammatory metabolic biomarkers, elucidate inflammatory metabolic pathways, and provide a deep understanding of inflammation. Metabolomics technology, as a high-throughput detection method for analyzing small molecule metabolites in the body, can reveal the relationship of metabolic networks by detecting changes in the metabolites of macrophages. Therefore, this review summarizes the application of metabolomics in macrophages, comprehensively elaborates the metabolic network within macrophages, and aims to provide a new perspective for the discovery of potential inflammatory biomarkers and therapeutic targets.

Natural remedies are often used as standalone treatments or as complementary approaches to modern medicine for controlling type 2 diabetes. Gardenia jasminoides, a substance used in both food and medicine, has been clinically employed in traditional Chinese medicine to treat hyperglycemia. Here, we first identified crocetin as the compound responsible for the primary hypoglycemic activity of G. jasminoides and revealed that G protein-coupled receptor kinase 5 (GRK5) is the key target through which crocetin improves glucose homeostasis and insulin resistance. To identify the bioactive components in G. jasminoides, we conducted high-resolution mass spectrometry analysis and bioactivity-guided fractionation, confirming that crocetin is the primary bioactive constituent. We demonstrated the direct binding of crocetin to GRK5 via cellular thermal shift (CETSA) and surface plasmon resonance (SPR) assays. Further knockdown experiments confirmed the essential role of GRK5 in enhancing crocetin-mediated improvements in glucose metabolism. Additionally, we explored direct downstream targets of GRK5 and demonstrated for the first time that AKT2 is a novel GRK5-interacting protein. Collectively, these findings reveal that crocetin is a promising glucose-regulating phytochemical that targets GRK5 to phosphorylate AKT2, thereby improving glucose homeostasis.