Depressive disorder is a common mental disorder characterized by depressed mood and loss of interest or pleasure. As the Herbal medicines are mainly used as complementary and alternative therapy for depression. This study aimed at exploring antidepressant activity of Huang-lian Jie-du Decoction (HLJDD), and evaluating active components and potential depression-associated targets. HLJDD was administered on chronic unpredictable mild stress-induced (CUMS) depressive mice. Behavior evaluation was performed through force swimming test (FST), novelty-suppressed feeding test (NSF), and open field test (OFT). Active components of HLJDD, potential targets, and metabolic pathways involved in depression were explored through systemic biology-based network pharmacology assay, molecular docking and metabonomics. FST assay showed that CUMS mice administered with HLJDD had significantly shorter immobility time compared with control mice. Further, HLJDD alleviated feeding latency of CUMS mice in NSFand increased moving distance and duration in OFT. In the following network pharmacology assay, thirty-eight active compounds in HLJDD were identified based on drug-like characteristics, and pharmacokinetics and pharmacodynamics profiles. Moreover, forty-eight molecular targets and ten biochemical pathways were uncovered through molecular docking and metabonomics. GRIN2B, DRD, PRKCA, HTR, MAOA, SLC6A4, GRIN2A, and CACNA1A are implicated in inhibition of depressive symptoms through modulating tryptophan metabolism, serotonergic and dopaminergic synaptic activities, cAMP signaling pathway, and calcium signaling pathway. Further network pharmacology-based analysis showed a correlation between HLJDD and tryptophan metabolism. A total of thirty-seven active compounds, seventy-six targets, and sixteen biochemical pathways were involved in tryptophan metabolism. These findings show that HLJDD acts on potential targets such as SLC6A4, HTR, INS, MAO, CAT, and FoxO, PI3K/Akt, calcium, HIF-1, and mTOR signaling pathways, and modulates serotoninergic and dopaminergic synaptic functions. In addition, metabonomics showed that tryptophan metabolism is the primary target for HLJDD in CUMS mice. The findings of the study show that HLJDD exhibited antidepressant effects. SLC6A4 and MAOA in tryptophan metabolism were modulated by berberine, baicalein, tetrahydroberberine, candicine and may be the main antidepressant targets for HLJDD.

Amelioration of neuroinflammation via modulating microglia is a promising approach for cerebral ischemia therapy. The aim of the present study was to explore gut–brain axis signals in berberine‐modulating microglia polarization following cerebral ischemia. The potential pathway was determined through analyzing the activation of the vagus nerve, hydrogen sulfide (H2S) metabolism, and cysteine persulfides of transient receptor potential vanilloid 1 (TRPV1) receptor. The cerebral microenvironment feature was explored with a metabolomics assay. The data indicated that berberine ameliorated behavioral deficiency in transient middle cerebral artery occlusion rats through modulating microglia polarization and neuroinflammation depending on microbiota. Enhanced vagus nerve activity following berberine treatment was blocked by antibiotic cocktails, capsazepine, or sodium molybdate, respectively. Berberine‐induced H2S production was responsible for vagus nerve stimulation achieved through assimilatory and dissimilatory sulfate reduction with increased synthetic enzymes. Sulfation of the TRPV1 receptor resulted in vagus nerve activation and promoted the c‐fos and ChAT in the nucleus tractus solitaries with berberine. Sphingolipid metabolism is the primary metabolic characteristic with berberine in the cerebral cortex, hippocampus, and cerebral spinal fluid disrupted by antibiotics. Berberine, in conclusion, modulates microglia polarization in a microbiota‐dependent manner. H2S stimulates the vagus nerve through TRPV1 is responsible for the berberine‐induced gut–brain axis signal transmission. Sphingolipid metabolism might mediate the neuroinflammation amelioration following vagus afferent fiber activation.

Berberine, which is a potential antidepressant, exhibits definite efficiency in modulating the gut microbiota. Depressive behaviors in mice induced using chronic unpredictable mild stress (CUMS) stimulation were evaluated by behavioral experiments. The markers of neurons and synapses were measured using immunohistochemical staining. An enzyme‐linked immunosorbent assay was adopted to analyze serum inflammatory cytokines levels and neurotransmitters were evaluated by LC–MS/MS. Untargeted metabolomics of tryptophan metabolism was further performed using LC–MS/MS. The target enzymes of berberine involved in tryptophan metabolism were assayed using AutoDock and GRMACS softwares. Then, antibiotics was utilized to induce intestinal flora disturbance. Berberine improved the depressive behaviors of mice in a microbiota‐dependent manner. Increased neurons and synaptic plasticity were observed following berberine treatment. Meanwhile, berberine decreased serum levels of TNF‐α, IL‐1β, and IL‐4 and increased levels of IL‐10. Moreover, berberine induced retraction of the abnormal neurotransmitters and metabolomics assays revealed that berberine promoted tryptophan biotransformation into serotonin and inhibited the kynurenine metabolism pathway, which was attributed to the potential agonist of tryptophan 5‐hydroxylase 1 (TPH1) and inhibitor of indoleamine 2,3‐dioxygenase 1 (IDO1). In conclusion, berberine improves depressive symptoms in CUMS‐stimulated mice by targeting both TPH1 and IDO1, which are involved in tryptophan metabolism.

Background S. baicalensis , a traditional herb, has great potential in treating diseases associated with aberrant lipid metabolism, such as inflammation, hyperlipidemia, atherosclerosis and Alzheimer’s disease. Aim of the Study To elucidate the mechanism by which S. baicalensis modulates lipid metabolism and explore the medicinal effects of S. baicalensis at a holistic level. Materials and Methods The potential active ingredients of S. baicalensis and targets involved in regulating lipid metabolism were identified using a network pharmacology approach. Metabolomics was utilized to compare lipids that were altered after S. baicalensis treatment in order to identify significantly altered metabolites, and crucial targets and compounds were validated by molecular docking. Results Steroid biosynthesis, sphingolipid metabolism, the PPAR signaling pathway and glycerolipid metabolism were enriched and predicted to be potential pathways upon which S. baicalensis acts. Further metabolomics assays revealed 14 significantly different metabolites were identified as lipid metabolism-associated elements. After the pathway enrichment analysis of the metabolites, cholesterol metabolism and sphingolipid metabolism were identified as the most relevant pathways. Based on the results of the pathway analysis, sphingolipid and cholesterol biosynthesis and glycerophospholipid metabolism were regarded as key pathways in which S. baicalensis is involved to regulate lipid metabolism. Conclusion According to our metabolomics results, S. baicalensis may exert its therapeutic effects by regulating the cholesterol biosynthesis and sphingolipid metabolism pathways. Upon further analysis of the altered metabolites in certain pathways, agents downstream of squalene were significantly upregulated; however, the substrate of SQLE was surprisingly increased. By combining evidence from molecular docking, we speculated that baicalin, a major ingredient of S. baicalensis , may suppress cholesterol biosynthesis by inhibiting SQLE and LSS, which are important enzymes in the cholesterol biosynthesis pathway. In summary, this study provides new insights into the therapeutic effects of S. baicalensis on lipid metabolism using network pharmacology and lipidomics.

Background: Serious mental illness is a disease with complex etiological factors that requires multiple interventions within a holistic disease system. With heat-clearing and detoxifying effects, Coptis chinensis Franch. is mainly used to treat serious mental illness. Aim of the Study:To explore the underlying mechanisms and therapeutic effect by which Coptis chinensis Franch. treats serious mental illnesses at a holistic level. Methods: A viable network pharmacology approach was adopted to obtain the potential active ingredients of Coptis chinensis Franch., and serious mental illnesses-related targets and signaling pathways. The interactions between crucial target HTR2A and constituents were verified by molecular docking, and the dynamic behaviors of binding were studied by molecular dynamics simulation. In addition, the anti-anxiety effect of Rhizoma Coptidis (the roots of Coptis chinensis Franch.) extract on lipopolysaccharide-stimulated mice was verified. The anxiety-like behavior was measured through the elevated plus-maze test, light-dark box test, and open field test. Radioimmunoassays detected the levels of interleukin-1β, tumor necrosis factor-α, interleukin-10, interleukin-4, 5-hydroxytryptamine, and dopamine in the serum, hippocampus, medial prefrontal cortex, and amygdala. Meanwhile, immunohistochemistry protocols for the assessment of neuronal loss (neuron-specific nuclear protein) and synaptic alterations (Synapsin I) were performed in the hippocampus. Results: Based on scientific analysis of the established networks, serious mental illnesses-related targets mostly participated in the calcium signaling pathway, cyclic adenosine monophosphate signaling pathway, mitogen-activated protein kinase signaling pathway, serotonergic and dopaminergic synapse. Molecular docking and molecular dynamics simulation studies illustrated that berberine, epiberberine, palmatine, and coptisine presented favorable binding patterns with HTR2A. The in vivo experiments confirmed that Rhizoma Coptidis extract ameliorated anxiety-like behaviors by improving the survival of neurons, regulating synaptic plasticity, and inhibiting neuroinflammation. Conclusion:These findings in the present study led to potential preventative and therapeutic strategies for serious mental illnesses with traditional Chinese medicine.