Evodiamine as the Active Compound of Evodiae fructus to Inhibit Proliferation and Migration of Prostate Cancer through PI3K/AKT/NF-κB Signaling Pathway.

Evodiae fructus (EF) is a traditional Chinese medicine which is widely used for the treatment of obesity, inflammation, cardiovascular disease, and diseases of the central nervous system. Recent studies have demonstrated the anticancer property of EF, but the active compounds of EF against prostate cancer and its underlying mechanism remain unknown. In this study, a network pharmacology-based approach was used to explore the multiple ingredients and targets of EF. Through protein-protein interaction (PPI), Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, the potential targets and corresponding ingredients of EF against prostate cancer cells were obtained. CCK8 and colony formation assays were performed to evaluate the antiproliferative effect of the active compounds on DU145 cells. Cell cycle analysis, Annexin V-FITC/PI staining assay, and Hoechst 33258 staining assay were used to explore the way of evodiamine-induced cell death. The capacities of cell migration after evodiamine treatment were evaluated by wound-healing assay. PharmMapper database was used to predict the potential targets of evodiamine against cancer cell migration. Western blot assay was performed to investigate the signaling pathway through which evodiamine inhibits cell proliferation and migration. The binding of evodiamine to PI3K and AKT was verified by molecular docking. As a consequence, 24 active compounds and 141 corresponding targets were obtained through a network pharmacology-based approach. The results of PPI analysis, GO enrichment, and KEGG pathway enrichment indicated that molecules in the PI3K/AKT/NF-κB signaling pathway were the potential targets of EF against prostate cancer, and evodiamine was the potential active compound. In vitro study demonstrated that evodiamine displays antiproliferative effect on DU145 cells obviously. Evodiamine induces G2/M cell cycle arrest by Cdc25c/CDK1/cyclin B1 signaling. Additionally, evodiamine also promotes mitochondrial apoptosis and inhibits cell migration through PI3K/AKT/NF-κB signaling in DU145 cells. In conclusion, evodiamine is the active compound of EF to inhibit proliferation and migration of prostate cancer through PI3K/AKT/NF-κB signaling pathway, indicating that evodiamine may serve as a potential lead drug for prostate cancer treatment.

Polyphenols in edible herbal medicine: targeting gut-brain interactions in depression-associated neuroinflammation.

Supplementing with edible herbal medicine is an important strategy because of its role in nutrition. Many polyphenols, which are universal components in edible herbal medicines, have low bioavailability. Therefore, gut microbiota is a key determinant of polyphenol bioactivity. Polyphenols can alter the abundance of flora associated with neuroinflammation by reversing intestinal microbiota dysbiosis. Intestinal flora-mediated chemical modification of polyphenols can result in their conversion into active secondary metabolites. The current review summarizes the main edible medicines used in anti-depression and details the interactions between polyphenols and gut microbiota; in addition, it provides insights into the mechanisms underlying the possible suppression of neuroinflammation associated with depression, by polyphenols in edible herbal medicine. A better understanding of polyphenols with bioactivities that are crucial in edible herbal medicine may facilitate their use in the prevention and treatment of neuroinflammation associated with depression.

Xiaoyaosan inhibits neuronal apoptosis by regulating the miR-200/NR3C1 signaling in the prefrontal cortex of chronically stressed rats.

BACKGROUND: Depression is a prevalent emotion disorder which is thought to be due to neuronal structural alterations and/or functional impairment within specific brain regions. Several studies have shown that microRNAs are involved in the pathogenesis of depression. As a Chinese herbal formula, Xiaoyaosan (XYS) could have antidepressive effects, although the mechanisms associated with microRNAs are poorly understood. PURPOSE: In this study, we investigated whether inhibition of the miR-200a/b-3p/NR3C1 pathway in the prefrontal cortex is involved in the anti-neuronal apoptosis and anti-stress effects of XYS and then further delineated the underlying mechanism. METHODS: To evaluate the efficacy of XYS in relieving stress behaviors and altering the expression of miRNAs involved in the regulation of these behaviors in vivo, a chronic unpredictable mild stress (CUMS) rodent model and RNA-seq were performed. Primary cortical neurons were used to evaluate the molecular function of miR-200a/b-3p and detect the in vitro neuroprotective function of paeoniflorin, which is one of the main components of XYS. To investigate the function of miR-200a/b-3p in stress behaviors, stereotactic microinjection of AAV2/9-Syn-miR-200a/b-3p was performed to deliver the treatment to the rat mPFC. RESULTS: XYS reduced the anxiety and depression-like behaviors associated with chronic stress and reduced the expression of miR-200a/b-3p and neuronal apoptosis in the prefrontal cortex (PFC). The overexpression of miR-200a/b-3p in primary cortical neurons reduced the expression of the target gene NR3C1, increased the protein expression of cleaved caspase-3 and Bax, and decreased the anti-apoptotic protein Bcl-2. One of the active ingredients of XYS, paeoniflorin, can inhibit miR-200a/b-3p-mediated apoptosis of primary neurons and abnormal expression of apoptosis-related proteins. After overexpressing miR-200a/b-3p in vivo (vmPFC), the rats eventually showed significant anxiety-like behaviors similar to those caused by chronic stress. CONCLUSION: Our findings indicate that XYS can inhibit the CUMS-induced expression of miR-200a/b-3p, regulate miR-200a/b-3p/NR3C1 signaling in the PFC caused by chronic stress, and reduce neuronal apoptosis and stress-related behaviors.

Xiaoyaosan Improves Antibiotic-Induced Depressive-Like and Anxiety-Like Behavior in Mice Through Modulating the Gut Microbiota and Regulating the NLRP3 Inflammasome in the Colon.

Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1ß, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.

Rapid rehabilitation technique with integrated traditional Chinese and Western medicine promotes postoperative gastrointestinal function recovery.

BACKGROUND: During the perioperative period, the characteristic therapy of traditional Chinese medicine is effective in improving postoperative rehabilitation. In large-scale hospitals practicing traditional Chinese medicine, there is accumulating experience related to the promotion of fast recovery in the perioperative period. AIM: To evaluate the efficacy and safety of Yikou-Sizi powder hot compress on Shenque acupuncture point combined with rapid rehabilitation technique. METHODS: This prospective, multicenter, randomized, controlled study included two groups: Treatment group and control group. The patients in the treatment group and control group received Yikou-Sizi powder hot compress on Shenque acupuncture point combined with rapid rehabilitation technique and routine treatment, respectively. Clinical observation regarding postoperative recovery of gastrointestinal function was performed, including the times to first passage of flatus, first defecation, and first normal bowel sounds. The comparison between groups was conducted through descriptive analysis, χ 2, t, F, and rank-sum tests. RESULTS: There was a statistically significant difference in the time to postoperative first defecation between the treatment and control group (87.16 ± 32.09 vs 109.79 ± 40.25 h, respectively; P < 0.05). Similarly, the time to initial recovery of bowel sounds in the treatment group was significantly shorter than that in the control group (61.17 ± 26.75 vs 79.19 ± 33.35 h, respectively; P < 0.05). However, there was no statistically significant difference in the time to initial exhaust between the treatment and control groups (51.54 ± 23.66 vs 62.24 ± 25.95 h, respectively; P > 0.05). The hospitalization expenses for the two groups of patients were 62283.45 ± 12413.90 and 62059.42 ± 11350.51 yuan, respectively. Although the cost of hospitalization was decreased in the control group, the difference was not statistically significant (P > 0.05). This clinical trial was safe without reports of any adverse reaction or event. CONCLUSION: The rapid rehabilitation technique with integrated traditional Chinese and Western medicine promotes the recovery of postoperative gastrointestinal function and is significantly better than standard approach for patients after colorectal surgery.

Puerarin attenuates pressure overload-induced cardiac hypertrophy.

BACKGROUND: Puerarin is the most abundant isoflavonoid in kudzu root. It has been used to treat angina pectoris and myocardial infarction clinically. However, little is known about the effect of puerarin on cardiac hypertrophy. METHODS: Aortic banding (AB) was performed to induce cardiac hypertrophy in mice. Puerarin premixed in diets was administered to mice after one week of AB. Echocardiography and catheter-based measurements of hemodynamic parameters were performed at 7 weeks after starting puerarin treatment (8 weeks post-surgery). The extent of cardiac hypertrophy was also evaluated by pathological and molecular analyses of heart samples. Cardiomyocyte apoptosis was assessed by measuring Bax and Bcl-2 protein expression and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. In addition, the inhibitory effect of puerarin (1 µM, 5 µM, 10 µM, 20 µM, 40 µM) on mRNA expression of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in Ang II (1 µM)-stimulated H9c2 cells was investigated using quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Echocardiography and catheter-based measurements of hemodynamic parameters at 7 weeks revealed the amelioration of systolic and diastolic abnormalities. Puerarin also decreased cardiac fibrosis in AB mice. Moreover, the beneficial effect of puerarin was associated with the normalization in gene expression of hypertrophic and fibrotic markers. Further studies showed that pressure overload significantly induced the activation of phosphoinositide 3-kinase (PI3K)/Akt signaling and c-Jun N-terminal kinase (JNK) signaling, which was blocked by puerarin treatment. Cardiomyocyte apoptosis and induction of Bax in response to AB were suppressed by puerarin. Furthermore, the increased mRNA expression of ANP and BNP induced by Ang II (1 µM) was restrained to a different extent by different concentrations of puerarin. CONCLUSION: Puerarin may have an ability to retard the progression of cardiac hypertrophy and apoptosis which is probably mediated by the blockade of PI3K/Akt and JNK signaling pathways.

Baicalein protects against cardiac hypertrophy through blocking MEK-ERK1/2 signaling.

Baicalein, a flavonoid present in the root of Scutellaria baicalensis, is well known for its antibacterial, antiviral, anti-inflammatory, antithrombotic, and antioxidant effects. Here we show that baicalein also attenuates cardiac hypertrophy. Aortic banding (AB) was performed to induce cardiac hypertrophy secondary to pressure overload in mice. Mouse chow containing 0.05% baicalein (dose: 100 mg/kg/day baicalein) was begun 1 week prior to surgery and continued for 8 weeks after surgery. Our data demonstrated that baicalein prevented cardiac hypertrophy and fibrosis induced by AB, as assessed by echocardiographic and hemodynamic parameters and by pathological and molecular analysis. The inhibitory action of baicalein on cardiac hypertrophy was mediated by effects on mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinases (ERK1/2) signaling and GATA-4 activation. In vitro studies performed in rat cardiac H9c2 cells confirmed that baicalein attenuated cardiomyocyte hypertrophy induced by angiotensin II, which was associated with inhibiting MEK-ERK1/2 signaling. In conclusion, our results suggest that baicalein has protective potential for targeting cardiac hypertrophy and fibrosis through suppression of MEK-ERK1/2 signaling. Baicalein warrants further research as a potential antihypertrophic agent that might be clinically useful to treat cardiac hypertrophy and heart failure.

Parthenolide, an inhibitor of the nuclear factor-κB pathway, ameliorates dextran sulfate sodium-induced colitis in mice.

BACKGROUND: Activation of nuclear factor-kappa B (NF-κB), which controls transcription of various pro-inflammatory cytokine genes, has been shown to play a critical role in the pathogenesis of ulcerative colitis (UC). Parthenolide, a sesquiterpene lactone compound isolated from extracts of the herb Feverfew (Tanacetum parthenium), has been demonstrated to be a potent inhibitor of NF-κB activation. This study was designed to investigate the effects of parthenolide on an experimental murine colitis model. MATERIALS AND METHODS: Experimental colitis was induced by dextran sulfate sodium (DSS), and mice were divided into 3 groups: normal control, DSS+saline, and DSS+parthenolide. The disease activity index (DAI) and histological score were observed. The tumor necrosis factor (TNF)-α and interleukin (IL)-1ß levels were measured by enzyme-linked immunosorbent assay. Phospho-IκBα, IκBα and phospho-NF-κB p65 expression were assessed by western blot analysis. Myeloperoxidase (MPO) activity was determined by using MPO assay kit. RESULTS: Administration of parthenolide significantly reduced the severity of DSS-induced colitis as assessed by DAI and histological score, and resulted in downregulation of MPO activity and phospho-NF-κB p65 expression by the blockade of phosphorylation and subsequent degradation of IκB protein, strikingly reduced the production of TNF-α and IL-1ß. CONCLUSION: Parthenolide exerts beneficial effects in experimental colitis and may therefore provide a useful therapeutic approach for the treatment of UC.

Glial-derived neurotrophic factor regulates intestinal epithelial barrier function and inflammation and is therapeutic for murine colitis.

Although enteric glial cells (EGCs) have been demonstrated to play a key role in maintaining intestinal epithelial barrier integrity, it is not known how EGCs regulate this integrity. We therefore hypothesized that glial-derived neurotrophic factor (GDNF) produced by EGCs might be involved in this regulation. Here we investigated the role of GDNF in regulating epithelial barrier function in vivo. Recombinant adenoviral vectors encoding GDNF (Ad-GDNF) were administered intracolonically in experimental colitis induced by dextran sulphate sodium (DSS). The disease activity index (DAI) and histological score were measured. Epithelial permeability was assayed using Evans blue dye. The anti-apoptotic potency of GDNF in vivo was evaluated. The expression of tumour necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and myeloperoxidase (MPO) activity were measured by ELISA assay and/or RT-PCR. The expression of ZO-1, Akt, caspase-3, and NF-kappaB p65 was analysed by western blot assay. Our results showed that GDNF resulted in a significant reduction in enhanced permeability, inhibited MPO activity, IL-1beta and TNF-alpha expression, and increased ZO-1 and Akt expression. Moreover, GDNF strongly prevented apoptosis in vivo and significantly ameliorated experimental colitis. Our findings indicate that GDNF participates directly in restoring epithelial barrier function in vivo via reduction of increased epithelial permeability and inhibition of mucosal inflammatory response, and is efficacious in DSS-induced colitis. These findings support the notion that EGCs are able to regulate intestinal epithelial barrier integrity indirectly via their release of GDNF in vivo. GDNF is namely an important mediator of the cross-talk between EGCs and mucosal epithelial cells. GDNF may be a useful therapeutic approach to the treatment of inflammatory bowel disease.

[The inhibitive effect of tea polyphenols on oxidized low density lipoprotein intake in cultured rat mesangial cells].

OBJECTIVE: To study the inhibitive effect of tea polyphenols (TP) on oxidized low density lipoprotein (OX-LDL) intake in cultured rat mesangial cells. METHOD: Rat mesangial cells incubated in 80 mg.L-1 OX-LDL were treated with TP at different concentrations. Total cholesterol (TC) content of the mesangial cells and proportion of mesangial cells containing lipid droplets were measured, and ultrastructure observation was performed. RESULT: Foam cells were observed in mesangial cells stimulated by OX-LDL, and both the TC content and the proportion of lipid-droplet-containing cell were higher in these cells than in mesangial cells cultured in lipid free conditions. There were concentration-dependent decreases both in TC content and lipid-droplet-containing cell proportions when treated with TP from 40 ng.L-1 to 40 mg.L-1. The number of lipid droplets was also decreased in TP treated mesangial cells. CONCLUSION: TP has an inhibitive effect on OX-LDL intake in cultured rat mesangial cells, which is in a concentration-dependent manner from 40 ng.L-1 to 40 mg.L-1.