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Compound Nujia honey paste (Nujia), a classic formulation from Traditional Uyghur Medicine, has been historically used for depression treatment and is listed in the Catalog of Ancient Classical Famous Formulas issued by the National Administration of Traditional Chinese Medicine and the National Medical Products Administration. Clarifying its pharmacodynamic material basis is essential for understanding its efficacy, yet this remains incompletely characterized. This study aimed to systematically elucidate Nujia's antidepressant efficacy and mechanisms by combining chemical analysis, computational prediction, and experimental validation in a CUMS rat model, providing a comprehensive approach to understanding its action. This study employed LC/MS to analyze the chemical constituents and blood-absorbed compounds of Nujia. This was combined with network pharmacology and molecular docking to predict and verify its potential antidepressant targets and signaling pathways. Using behavioral tests, ELISA, histopathology, Western blot, and qRT-PCR in a CUMS rat model, the research thoroughly evaluated Nujia's therapeutic effects and mechanisms, fostering trust in the findings. In this study, LC/MS analysis identified 124 chemical constituents from Nujia, and further analysis determined 26 blood-absorbed compounds (including 10 prototype compounds). Network pharmacology analysis revealed that its potential antidepressant effects are closely associated with core targets such as AKT1 and TNF, a prediction subsequently verified by molecular docking results. In the CUMS-induced rat model of depression, intervention with Nujia significantly ameliorated depression-like behaviors in the animals and alleviated neuropathological damage in the hippocampus and prefrontal cortex. Mechanistic investigations revealed that Nujia upregulated the levels of monoamine neurotransmitters (5-HT, DA, NE) and neurotrophic factors (BDNF, NGF) in serum, while downregulating the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-18). Further molecular experiments confirmed that Nujia likely mitigates neuroinflammation by inhibiting the TNF-α/NF-κB signaling pathway, and inhibits neuronal apoptosis by activating the PI3K/AKT signaling pathway and its downstream anti-apoptotic proteins. Furthermore, Nujia significantly upregulated the expression of key synaptic plasticity proteins (SYP, GAP43, and PSD95) in hippocampal tissue, thereby enhancing synaptic structure and function. These findings underscore the complex, multi-target mechanisms underlying Nujia's antidepressant effects, encouraging further exploration of its therapeutic potential. This study systematically elucidates that Nujia achieves its antidepressant therapeutic effects by mediating multi-pathway synergistic actions, including but not limited to the TNF-α/NF-κB and PI3K/AKT signaling pathways, to ameliorate neuroinflammation, attenuate apoptosis, and enhance synaptic plasticity. Show less

Aurantii Fructus (AF)is a traditional Chinese medicine historically used to regulate Qi and alleviate emotional distress, suggesting potential psychotropic effects. This study investigates its therapeutic value for depression based on this traditional indication. To evaluate the rapid antidepressant-like effect of a single acute dose of AF extract in a chronic unpredictable mild stress (CUMS) mouse model and elucidate its underlying molecular mechanisms through integrated transcriptomic and metabolomic analyses. AF flavonoid content was quantified by HPLC. Male mice underwent a 4-week CUMS protocol. A single oral dose of AF was administered 2 h prior to behavioral testing (NSF, TST, SPT, and OFT), with ketamine serving as a positive control. Hippocampal transcriptome analysis was performed by RNA sequencing, and serum metabolites were profiled via LC-MS in both positive and negative ion modes. Pearson correlation analysis assessed relationships between key targets and behavioral outcomes. Pathway involvement was functionally validated in a separate experiment using a hypoxanthine synthesis inhibitor. AF contained narirutin (1.32 mg/g), hesperidin (3.19 mg/g), neohesperidin (22.89 mg/g), naringenin (0.03 mg/g), and nobiletin (0.08 mg/g). Acute AF administration rapidly reversed CUMS-induced depressive-like behaviors, significantly decreasing latency to feed and increasing food consumption in the NSF test, reducing immobility time in the TST, and elevating sucrose preference in the SPT, without altering locomotor activity. Transcriptomic analysis revealed specific downregulation of hippocampal caspase-4 expression by AF. Metabolomic profiling showed AF normalized elevated serum hypoxanthine levels. Serum hypoxanthine levels negatively correlated with hippocampal caspase-4 expression and behavioral improvements, whereas caspase-4 expression positively correlated with behavioral deficits. Pharmacological inhibition of hypoxanthine synthesis abolished AF's antidepressant effects and prevented its normalization of hippocampal caspase-4, NF-κB, GDNF, and BDNF expression. Acute AF produces rapid, ketamine-like antidepressant effects by targeting the hypoxanthine-caspase-4 pathway. This study reveals a novel purinergic mechanism underlying AF's traditional use for emotional disorders and offers a promising therapeutic strategy for rapid-acting antidepressant development. Show less