The anti-depression effect and potential mechanism of the petroleum ether fraction of CDB: Integrated network pharmacology and metabolomics.

The combination of Chaidangbo (CDB) is an antidepressant traditional Chinese medicine (TCM) prescription simplified by Xiaoyaosan (a classic antidepressant TCM prescription) through dismantling research, which has the effect of dispersing stagnated liver qi and nourishing blood in TCM theory. Although the antidepressant effect of CBD has been confirmed in animal studies, the material basis and possible molecular mechanism for antidepressant activity in CBD have not been clearly elucidated. Herein, we investigated the effects and potential mechanisms of CDB antidepressant fraction (petroleum ether fraction of CDB, PEFC) on chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice using network pharmacology and metabolomics. First, a UPLC-QE/MS was employed to identify the components of PEFC. To extract active ingredients, SwissADME screening was used to the real PEFC components that were found. Potential PEFC antidepressant targets were predicted based on a network pharmacology approach, and a pathway enrichment analysis was performed for the predicted targets. Afterward, a CUMS mouse depression model was established and LC-MS-based untargeted hippocampal metabolomics was performed to identify differential metabolites, and related metabolic pathways. Finally, the protein expressions in mouse hippocampi were determined by Western blot to validate the network pharmacology and metabolomics deduction. A total of 16 active compounds were screened in SwissADME that acted on 73 core targets of depression, including STAT3, MAPKs, and NR3C1; KEGG enrichment analysis showed that PEFC modulated signaling pathways such as PI3K-Akt signaling pathway, endocrine resistance, and MAPK to exert antidepressant effects. PEFC significantly reversed abnormalities of hippocampus metabolites in CUMS mice, mainly affecting the synthesis and metabolism of glycine, serine, and threonine, impacting catecholamine transfer and cholinergic synapses and regulating the activity of the mTOR signaling pathway. Furthermore, Western blot analysis confirmed that PEFC significantly influenced the main protein levels of the PI3K/Akt/mTOR signaling pathways in the hippocampus of mice subjected to CUMS. This study integrated metabolomics, network pharmacology and biological verification to explore the potential mechanism of PEFC in treating depression, which is related to the regulation of amino acid metabolism dysfunction and the activation of PI3K/Akt/mTOR signaling pathways in the hippocampus. The comprehensive strategy also provided a reasonable way for unveiling the pharmacodynamic mechanisms of multi-components, multi-targets, and multi-pathways in TCM with antidepressant effect.

Juglans mandshurica Maxim.: A Review of Its Traditional Usages, Phytochemical Constituents, and Pharmacological Properties.

Juglans mandshurica Maxim., also known as "Manchurian walnut" (Chinese) and "Onigurumi" (Japanese), is a medicinal plant widely distributed in Western and Central Asia, especially in China. It has been traditionally used to treat cancer, gastric ulcers, diarrhea, dysentery, dermatosis, uterine prolapse, and leukopenia. To date, more than 400 constituents including quinones (e.g. naphthoquinones, anthraquinones, naphthalenones, tetralones), phenolics, flavonoids, triterpenoids, coumarins, lignans, phenylpropanoids, diarylheptanoids, and steroids, were isolated and structurally identified from different plant parts of J. mandshurica. Among them, quinones, phenolics, triterpenoids, and diarylheptanoids, as the major bioactive substances, have been extensively studied and displayed significant bioactivity. Previous studies have demonstrated that J. mandshurica and a few of its active components exhibit a wide range of pharmacologically important properties, such as antitumor, immunomodulatory, anti-inflammatory, neuroprotective, anti-diabetic, antiviral, antimicrobial, and anti-melanogenesis activities. However, many investigations on biological activities were mainly based on crude extracts of this plant, and the major bioactive ingredients responsible for these bioactivities have not been well identified. Further in vitro and in vivo studies on the mechanisms of action of the pure bioactive compounds, and more elaborate toxicity studies as well as clinical studies are needed to ensure safety and effectiveness of the plant for human use. Taken together, the present review will provide some specific useful suggestions guide to further investigations and applications of this plant in the preparation of medicines and functional foods.

Ethnomedicinal Uses, Phytochemistry, Pharmacology, and Toxicology of Species from the Genus Ajuga L.: A Systematic Review.

The present review is aimed at providing a comprehensive summary of the botanical characteristics, ethnomedicinal uses, phytochemical, pharmacological, and toxicological studies of the genus Ajuga L. The extensive literature survey revealed Ajuga L. species to be a group of important medicinal plants used for the ethnomedical treatment of rheumatism, fever, gout, sclerosis, analgesia, inflammation, hypertension, hyperglycemia, joint pain, palsy, amenorrhea, etc., although only a few reports address the clinical use and toxicity of these plants. Currently, more than 280 chemical constituents have been isolated and characterized from these plants. Among these constituents, neo-clerodane diterpenes and diterpenoids, phytoecdysteroids, flavonoids, and iridoids are the major bioactive compounds, possessing wide-reaching biological activities both in vivo and in vitro, including anti-inflammatory, antinociceptive, antitumor, anti-oxidant, antidiabetic, antimicrobial, antifeedant, antidiarrhoeal, hypolipidemic, diuretic, hypoglycaemic, immunomodulatory, vasorelaxant, larvicidal, antimutagenic, and neuroprotective activity. This review is aimed at summarizing the current knowledge of the ethnomedicinal uses, phytochemistry, biological activities, and toxicities of the genus Ajuga L. to reveal its therapeutic potentials, offering opportunities for future researches. Therefore, more focus should be paid to gathering information about their toxicology data, quality-control measures, and the clinical application of the bioactive ingredients from Ajuga L. species.

Phenylethanoid glycosides of Phlomis younghusbandii Mukerjee ameliorate acute hypobaric hypoxia-induced brain impairment in rats.

High altitude cerebral edema (HACE), whose development process is associated with oxidative stress and inflammatory response, is a life-threatening condition caused by rapid ascent speed to high altitudes. Phenylethanoid glycosides (PhGCs) are primary active constituents isolated from Phlomis younghusbandii Mukerjee that reportedly exhibit potent anti-oxidant and anti-inflammatory activities. The present study aims to investigate the protective effect of phenylethanoid glycosides (PhGCs) from P. younghusbandii in acute hypobaric hypoxia (AHH) - stimulated HACE rats and its underlying mechanisms. The expression of pro-inflammatory cytokine levels (IL-1ß, TNF-α, and IL-6) was detected by RT-PCR and ELISA at mRNA and protein levels in brain tissues. Western blotting was carried out to measure the major protein levels (IL-1ß, TNF-α, and NF-κB) in brain tissues. The oxidative stress biomarkers (MDA, SOD, and GSH) were evaluated using kits. Results demonstrate that PhGCs significantly improved pathological changes in brain tissues, reduced the brain's water content, and attenuated the production and mRNA expression of pro-inflammatory cytokines. Furthermore, the increased oxidative stress and the decrease in anti-oxidant stress system under the AHH condition were also abrogated reversely through PhGCs treatment by elevating the levels of SOD and GSH and suppressing the accumulation of MDA. Simultaneously, there was also a significant reduction in NF-κB, IL-1ß, and TNF-α protein expression levels in brain tissues, suggesting that blocking the NF-κB signaling pathway activation prevented the production of pro-inflammatory cytokines. Taken together, these findings indicate that PhGCs may afford a protectively intervene in HACE through the suppression of oxidative stress and inflammatory response via the inhibition of the NF-κB signaling pathway, indicating that PhGCs are promising agents for the treatment of acute HACE.