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.

Traditional Chinese medicine in regulating macrophage polarization in immune response of inflammatory diseases.

ETHNOPHARMACOLOGICAL RELEVANCE: Numerous studies have demonstrated that various traditional Chinese medicines (TCMs) exhibit potent anti-inflammatory effects against inflammatory diseases mediated through macrophage polarization and metabolic reprogramming. AIM OF THE STUDY: The objective of this review was to assess and consolidate the current understanding regarding the pathogenic mechanisms governing macrophage polarization in the context of regulating inflammatory diseases. We also summarize the mechanism action of various TCMs on the regulation of macrophage polarization, which may contribute to facilitate the development of natural anti-inflammatory drugs based on reshaping macrophage polarization. MATERIALS AND METHODS: We conducted a comprehensive review of recently published articles, utilizing keywords such as "macrophage polarization" and "traditional Chinese medicines" in combination with "inflammation," as well as "macrophage polarization" and "inflammation" in conjunction with "natural products," and similar combinations, to search within PubMed and Google Scholar databases. RESULTS: A total of 113 kinds of TCMs (including 62 components of TCMs, 27 TCMs as well as various types of extracts of TCMs and 24 Chinese prescriptions) was reported to exert anti-inflammatory effects through the regulation of key pathways of macrophage polarization and metabolic reprogramming. CONCLUSIONS: In this review, we have analyzed studies concerning the involvement of macrophage polarization and metabolic reprogramming in inflammation therapy. TCMs has great advantages in regulating macrophage polarization in treating inflammatory diseases due to its multi-pathway and multi-target pharmacological action. This review may contribute to facilitate the development of natural anti-inflammatory drugs based on reshaping macrophage polarization.

The extraction, purification, structural features, bioactivities, and applications of Schisandra chinensis polysaccharides: A review.

Schisandra chinensis, as a famous medicinal and food homologous plant, has a long history of medicinal and dietary therapy. It has the functions of nourishing the kidney, calming the heart, tranquilising the mind, tonifying Qi and producing fluid to relieve mental stress, based on the theory of traditional Chinese medicine. Accumulating evidence has shown that S. chinensis polysaccharides (SCPs) are one of the most important bioactive macromolecules and exhibit diverse biological activities in vitro and in vivo, including neuroprotective, hepatoprotective, immunomodulatory, antioxidant, hypoglycemic, cardioprotective, antitumour and anti-inflammatory activities, etc. This review aims to thoroughly review the recent advances in the extraction and purification methods, structural features, biological activities and structure-activity relationships, potential applications and quality assessment of SCPs, and further highlight the therapeutic potentials and health functions of SCPs in the fields of therapeutic agents and functional food development. Future insights and challenges of SCPs were also critically discussed. Overall, the present review provides a theoretical overview for the further development and utilization of S. chinensis polysaccharides in the health food and pharmaceutical fields.

[Mechanism of essential oil from Schizonepeta tenuifolia in treatment of depression based on network pharmacology and experimental verification].

This paper aimed to explore the antidepressant effect of the essential oil from Schizonepeta tenuifolia Briq.(EOST) on the treatment of depression and its mechanism by using a combination of network pharmacology and the mouse model of lipopolysaccharide(LPS)-induced depression. The chemical components in EOST were identified using gas chromatography-mass spectrometer(GC-MS), and 12 active components were selected as the study objects. The targets related to EOST were obtained by Traditional Chinese Medicines Systems Pharmacology(TCMSP) and SwissTargetPrediction database. The targets related to depression were screened out through GeneCards, Therapeutic Target Database(TTD), and Online Mendelian Inheritance in Man(OMIM) database. The Venny 2.1 was applied to screen out the common targets of EOST and depression. The targets were imported into Cytoscape 3.7.2 to generate "drug-active component-diease-target" network diagram. The protein-protein interaction(PPI) network was constructed using STRING 11.5 database and Cytoscape 3.7.2, and the core targets were screened out. DAVID 6.8 database was used for Gene Ontology(GO) func-tional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and subsequently the enrichment results were visualized through the bioinformatics platform. The mouse model of depression was induced by intraperitoneally injecting with LPS in mice. Before modeling, mice were administrated orally with EOST. The antidepressant effect of EOST was evalua-ted by tail suspension test(TST), forced swimming test(FST), and novelty suppressed feeding test(NSFT) after modeling. The content of interleukin(IL)-1ß was determined by enzyme-linked immunosorbent assay(ELISA), and the protein expression levels of IL-1ß and pro IL-1ß in the hippocampus were determined by Western blot. There were 12 main components and 179 targets in EOAT, of which, 116 targets were related to depression, mainly involved in neuroactive ligand-receptor interaction, calcium signaling pathway, and cyclic adenosine monophosphate(cAMP) signaling pathway. Biological processes such as synaptic signal transduction, G-protein coupled receptor signaling pathway, and chemical synaptic transmission were involved. Molecular functions such as neurotransmitter receptor activity, RNA polymerase Ⅱ transcription factor activity, and heme binding were involved. In mice experiments, the results showed that EOST at 100 mg·kg~(-1) and 50 mg·kg~(-1) significantly shortened the immobility time in TST and FST as well as the feeding latency in NSFT compared with the model group, decreased the levels of serum IL-1ß and NO, and reduced the protein expression levels of IL-1ß and pro IL-1ß in the hippocampus. In conclusion, EOST shows a good antidepressant effect in a multi-component, multi-target, and multi-pathway manner. The mechanism may be attributed to the fact that EOST can down-regulate the protein expression levels of IL-1ß and pro IL-1ß, decrease the release of inflammatory factors, and reduce neuroinflammation response.

Structural diversity and bioactivity of polysaccharides from medicinal mushroom Phellinus spp.: A review.

Phellinus spp., an important medicinal fungus mushroom extensively cultivated and consumed in East Asia for over 2000 years, is traditionally considered a precious food supplement and medicinal ingredient. Published studies showed that the polysaccharides are major bioactive macromolecules from Phellinus spp. (PPs) with multiple health-promoting effects, including immunomodulatory, anti-cancer, anti-inflammatory, hepatoprotective, hypoglycemic, hypolipidemic, antioxidant, and other bioactivities. Although the polysaccharides extracted from the fruiting body, mycelium, and fermentation broth of Phellinus spp. have been extensively studied for the extraction and purification methods, structural characteristics, and pharmacological activities, the knowledge for their structures and bioactivity relationship, toxicologic effects, and pharmacokinetic profile is limited. This review systematically summarizes the recent progress in the isolation and purification, chemical structures, bioactivities, and the underlying mechanisms of PPs. Information from this review provides insights into the further development of polysaccharides from PPs as therapeutic agents and functional foods.

Fengreqing Oral Liquid Exerts Anti-Inflammatory Effects by Promoting Apoptosis and Inhibiting PI3K/AKT and NF-κB Signaling Pathways.

Fengreqing oral liquid (FOL), a Chinese patent drug frequently used in clinical practice in China, is effective in treating inflammatory diseases of the upper respiratory tract such as colds and flu. However, its anti-inflammatory effects and mechanisms remain to be elucidated. In this study, the anti-inflammatory effects of FOL and its mechanisms on PI3K/AKT and NF-κB signaling pathways in LPS-induced RAW264.7 cells were explored, as well as the regulatory effect of FOL on apoptosis. In addition, the potential of FOL for the treatment of acute lung injury was explored in LPS-induced ALI mice. The results showed that treatment with FOL significantly reduced the levels of interleukin 1ß (IL-1ß), interleukin 6 (IL-6), nitric oxide (NO), and tumor necrosis factor α (TNF-α) in the supernatant of LPS-induced RAW264.7 cells, and also significantly reduced the phosphorylated protein levels of PI3K and AKT in the PI3K/AKT signaling pathway and also protein levels of NF-κB p50, phosphorylated NF-κB p65, and IκBα in the NF-κB signaling pathway. In addition, the results showed that FOL induced apoptosis in LPS-induced RAW264.7 cells at the level of 80%-90%, and significantly increased the protein expression levels of the pro-apoptotic Bax and cleaved-caspase-3. In LPS-induced ALI mice, FOL administration showed inhibition of IL-1ß, IL-6, and TNF-α in Bronchoalveolar lavage fluid (BALF) and decreased protein expression levels of PI3K, AKT, NF-κB p50, and NF-κB p65, and elevated protein expression levels of Bax and cleaved-caspase-3 significantly. These results suggest that FOL may exert anti-inflammatory effects by inhibiting the PI3K/AKT signaling pathway to promote apoptosis and leading to attenuated activation of the NF-κB signaling pathway.

The antitumour activity of C21 steroidal glycosides and their derivatives of Baishouwu: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Baishouwu has been used in China for thousands of years since it was first discovered in the late Tang Dynasty and flourished in the Song and Ming Dynasties. The Chinese herbal medicines named Baishouwu include Cynanchum auriculatum Royle ex Wight., Cynanchum bungei Decne. and Cynanchum wilfordii Hemsl. It is described in the Sign of Materia Medica as "sweet, bitter, reinforce liver and kidney, and non-toxic". It is widely used for nourishing the blood to expel wind, reinforcing liver and kidney, strengthening bones and muscles. AIM OF THE REVIEW: In this review, the current research status of the C21 steroidal glycosides and their derivatives of Baishouwu for malignant tumours and their anti-tumour mechanisms are discussed. This may lay the ground for potential application of Baishouwu and its active ingredients in the treatment of tumours. MATERIALS AND METHODS: Scientific databases, including PubMed, Elsevier, Science Direct, Google Scholar, CNKI, WANFANG DATA and VIP were searched to gather data about Baishouwu and its C21 steroidal glycosides and their derivatives. RESULTS: Prior literature indicates that Baishouwu has important biological activities such as anti-tumour, anti-epileptic, reducing cholesterol, protection of liver and kidney and immunomodulatory, which are of increasing interest, especially its anti-tumour activity. Recent studies demonstrate that the C21 steroidal glycosides of Baishouwu, which have prominent antitumour efficacy, are one of its main active ingredients. Presently, a variety of C21 steroidal glycosides have been isolated from Baishouwu medicinal part, the tuberous root. This review summarizes the various antitumour activities of the C21 steroidal glycosides and their derivatives of Baishouwu. CONCLUSIONS: In this review, the antitumour effects and mechanisms of total C21 steroidal glycosides and monomers and derivatives of Baishouwu in vitro and in vivo were summarized. Baishouwu can inhibit tumourigenesis by blocking tumour cell cycle progression, regulating numerous signaling pathways, promoting apoptosis, inhibiting tumour cells proliferation and metastasis, improving immunity and so on. This review provides a theoretical basis for inheriting and developing the medical heritage of the motherland, exploring the resources of traditional Chinese medicine for ethnic minorities and clinical rational drug use.

Recent research advances in polysaccharides from Undaria pinnatifida: Isolation, structures, bioactivities, and applications.

Undaria pinnatifida, one of the most widespread seafood consumed in China and many other nations, has been traditionally utilized as an effective therapeutically active substance for edema, phlegm elimination and diuresis, and detumescence for more than 2000 years. Numerous studies have found that polysaccharides of U. pinnatifida play an indispensable role in the nutritional and medicinal value. The water extraction and alcohol precipitation method are the most used method. More than 40 U. pinnatifida polysaccharides (UPPs) were successfully isolated and purified from U. pinnatifida, whereas only few of them were well characterized. Pharmacological studies have shown that UPPs have high-order structural features and multiple biological activities, including anti-tumor, antidiabetic, immunomodulatory, antiviral, anti-inflammatory, antioxidant, anticoagulating, antithrombosis, antihypertension, antibacterial, and renoprotection. In addition, the structural characteristics of UPPs are closely related to their biological activity. In this review, the extraction and purification methods, structural characteristics, biological activities, clinical settings, toxicities, structure-activity relationships and industrial application of UPPs are comprehensively summarized. The structural characteristics and biological activities as well as the underlying molecular mechanisms of UPPs were also outlined. Furthermore, the clinical settings and structure-activity functions of UPPs were highlighted. Some research perspectives and challenges in the study of UPPs were also proposed.

JFNE-A isolated from Jing-Fang n-butanol extract attenuates lipopolysaccharide-induced acute lung injury by inhibiting oxidative stress and the NF-κB signaling pathway via promotion of autophagy.

BACKGROUND: Jing-Fang powder consists of Jingjie (Nepeta tenuifolia Benth, (Lamiaceae)). and Fangfeng (Saposhnikovia divaricata (Turcz.) Schischk, (Apiaceae)) Previous studies have revealed that the Jing-Fang powder n-butanol extract (JFNE) has anti-acute lung injury (ALI) and anti-inflammatory properties; however, the active ingredient and mechanism remain unknown. PURPOSE: In the present study, we investigated the anti-inflammatory effect of a bioactive fraction obtained from JFNE(JFNE-A) on lipopolysaccharide (LPS)-induced ALI in mice and explored the underlying mechanism. STUDY DESIGN: The anti-acute lung injury effect and mechanism of JFNE-A was investigated by prophylactic administration of JFNE-A in mice with LPS-induced acute lung injury. METHODS: The expression levels of myeloperoxidase(MPO) in lung tissues of mice and interleukin(IL)-6, tumor necrosis factor(TNF)-α, IL-1ß, IL-5, interferon (IFN)-γ, monocyte chemotactic protein (MCP)-1, macrophage colony stimulating factor (M-CSF), macrophage inflammatory protein (MIP)-1α, and MIP-1ß in bronchi alveolar lavage fluid (BALF) were detected by reagent kit and the histological changes were examined by hematoxylin and eosin (H & E) for general histopathological conditions under a light microscope. In addition, the ultrastructure of the cells in lung tissues were observed and photographed under a transmission electron microscope. The expression levels of protein were detected via Western blotting and the mRNA expression of relative genes were determined of via reverse transcriptase polymerase chain reaction (RT-PCR). What's more, we also further clarified the potential targets of JFNE-A through network pharmacology analysis, which could be utilized in ALI treatment. RESULTS: Our results showed that pretreatment with JFNE-A for 7 days significantly reduced the lung pathological injury score, alleviated pulmonary edema, and decreased the lung tissue MPO level. Mechanistically, JFNE-A dramatically downregulated the protein levels of IL-6, TNF-α, IL-1ß, M-CSF, and IFN-γ in BALF and mRNA expression levels of IL-6, TNF-α, IL-1ß, and IFN-γ in lung tissues. JFNE-A also significantly lowered the protein levels of iNOS and phosphorylated NF-κB (p65) and mRNA expression levels of iNOS, Rela, CHUK, and NF-κB1, and also elevated the protein expression levels of Nrf2, HO-1, and SOD1 and the mRNA expression levels of Nrf2, Hmox1, and Keap-1 in the lungs. Moreover, JFNE-A significantly decreased the protein expression of p62 and increased the ratio of LC3II/LC3I. It also upregulated the mRNA expression levels of Atg5 and Beclin-1, whereas it reduced the mRNA expression level of SQSTM1 and increased autophagosome structures. CONCLUSION: Overall, treatment with JFNE-A ameliorated LPS-induced ALI in mice by suppressing the NF-κB signaling pathways and promoting Nrf2 signaling pathways by accelerating autophagy.

Xiaoyaosan ethyl acetate fraction alleviates depression-like behaviors in CUMS mice by promoting hippocampal neurogenesis via modulating the IGF-1Rß/PI3K/Akt signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyaosan (XYS), a representative and classic traditional Chinese medicine (TCM) prescription with function of dispersing stagnated liver and strengthening spleen, has been used for thousands of years to treat depression. XYS' anti-depression effect has been demonstrated both clinically and experimentally; however, the material basis for this effect has yet to be elucidated. AIM OF THE STUDY: This study aimed to evaluate the impact and underlying action mechanism of XYS' antidepressant active component (Xiaoyaosan ethyl acetate fraction, XYSEF) against chronic unpredictable mild stress (CUMS)-induced depression-like behavior in mice. MATERIALS AND METHODS: First, we established a behavioral despair depression mouse model to preliminarily determine the effective antidepressant dose of XYSEF. Then, we created a CUMS mouse model and used various classic behavioral tests, including SPT, ST, NFST, and TST, to assess XYSEF's antidepressant properties. IGF-1 levels in mouse serum and hippocampus were quantified using ELISA. The average optical density of Nissl bodies in the mouse hippocampal CA3 region was determined utilizing toluidine blue staining. Brdu and DCX expression in the hippocampal dentate gyrus (DG) was assayed using the immunofluorescence method. IGF-1Rß, PI3K, p-PI3K, Akt, p-Akt, Caspase-3, and cleaved Caspase-3 protein levels in the hippocampus were determined with Western blot. RESULTS: The behavioral despair mouse model findings showed that 9.1 and 40 g/kg of XYSEF both significantly shortened the immobility time of mice, suggesting that the effective dose range was 9.1-40 g/kg. Compared to the CUMS mouse model, XYSEF at 20 and 40 g/kg markedly increased the sucrose preference percentage in the SPT and grooming time in the ST, shortened the immobility time in the TST and the feeding latency in the NSFT, and reversed the downregulated IGF-1 content in mouse serum and hippocampus. In addition, XYSEF amplified the average optical density of Nissl bodies in the hippocampal CA3 region, promoted Brdu and DCX expression in DG, and diminished IGF-1Rß, p-PI3K/PI3K, p-Akt/Akt, and cleaved Caspase-3/Caspase-3 protein levels in the hippocampi of CUMS mice. CONCLUSION: XYSEF acted as an antidepressant in mice exhibiting CUMS-induced depression-like behaviors, possibly by promoting hippocampal neurogenesis, reducing neuronal apoptosis, and inhibiting the over-activation of the IGF-1Rß/PI3K/Akt pathway.

Cepharanthine Suppresses Herpes Simplex Virus Type 1 Replication Through the Downregulation of the PI3K/Akt and p38 MAPK Signaling Pathways.

Cepharanthine (CEP) is a naturally occurring isoquinoline alkaloid extracted from Stephania cepharantha Hayata. Although its underlying molecular mechanism is not fully understood, this compound is reported as a promising antiviral drug. In the present study, we explore the anti-HSV-1 effects and the underlying molecular mechanisms of CEP in vitro. Our results show that CEP could significantly inhibit the formation of plaque and the expression of viral proteins and exhibit a general suppression of replication-associated genes. Whereas HSV-1 infection increases the expressions of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and p38 mitogen-activated protein kinase (p38 MAPK) in host cells, CEP was effective indirectly inhibiting phosphorylation levels of the targets in PI3K/Akt and p38 MAPK signaling pathways. Moreover, CEP markedly decreased G0/G1 phase and increased G2/M phase cells and decreased the expression of cyclin-dependent kinase1 (CDK1) and cyclinB1 in a dose-dependent manner. Additionally, CEP increased apoptosis in infected cells, reduced B cell lymphoma-2 (Bcl-2) protein levels, and increased the protein levels of Bcl-associated X protein (Bax), cleaved-caspase3, and nuclear IκB kinaseα (IκBα). Collectively, CEP could arrest the cell cycle in the G2/M phase and induce apoptosis in infected cells by inhibiting the PI3K/Akt and p38 MAPK signaling pathways, hence further reducing HSV-1 infection and subsequent reproduction.

Anti-type I allergic effects of Jing-Fang powder extracts via PI3K/Akt pathway in vitro and in vivo.

Jing-Fang powder (Schizonepeta tenuifolia Briq. and Saposhnikovia divaricata (Turcz.) Schischk.) was used to treat chronic bronchitis, asthma and chronic urticaria. Based on the preliminary results of screening research on the antiallergic effective parts of Jing-Fang powder, its ethyl acetate extract fractions (JFEE) and isolate D (JFEE-D) showed the best anti-allergic effect. RBL-2H3 cell activation degranulation model and mice passive cutaneous anaphylaxis (PCA) reaction model were used to investigate the effects and mechanisms of JFEE and JFEE-D on IgE-mediated type I allergic reactions. LC-MS was utilized to determine the composition of JFEE and JFEE-D. We found that JFEE and JFEE-D significantly reduced ß-HEX, histamine, IL-4, IL-6 levels in cell supernatants, and improved the degree and morphology of cell degranulation. JFEE and JFEE-D significantly inhibited the increase of ear vascular permeability and abnormal increase of serum IgE, TNF-α, IL-6 levels. JFEE and JFEE-D inhibited mRNA expression of PI3K and Akt and down-regulated protein expression of PI3K, Akt, p-Akt, and PLCγ1 in sensitized RBL-2H3 cells. The combined use of JFEE and JFEE-D with pathway inhibitor Wortmannin revealed synergistic down-regulation of PI3K, Akt, and p-Akt protein expression. The combined use of pathway agonist IGF-1, JFEE and JFEE-D down-regulated increase of p-Akt/Akt protein expression. Moreover, JFEE and JFEE-D significantly inhibited protein expression of PI3K, p-Akt and PLCγ1 in PCA model mice. These results show that JFEE and JFEE-D inhibit type I allergic reactions by inhibiting PI3K/Akt signaling pathway.