Protective effect of alizarin on vascular endothelial dysfunction via inhibiting the type 2 diabetes-induced synthesis of THBS1 and activating the AMPK signaling pathway.

BACKGROUND: In this study, we investigated the protective effects of alizarin (AZ) on endothelial dysfunction (ED). AZ has inhibition of the type 2 diabetes mellitus (T2DM)-induced synthesis of thrombospondin 1 (THBS1). Adenosine 5'-monophosphate- activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. PURPOSE: The aim of this study was to investigate the ameliorative effect of AZ on vascular injury caused by T2DM and to reveal the potential mechanism of AZ in high glucose (HG)-stimulated human umbilical vein endothelial cells (HUVECs) and diabetic model rats. STUDY DESIGN: HUVECs, rats and AMPK-/- transgenic mice were used to investigate the mitigating effects of AZ on vascular endothelial dysfunction caused by T2DM and its in vitro and in vivo molecular mechanisms. METHODS: In type 2 diabetes mellitus rats and HUVECs, the inhibitory effect of alizarin on THBS1 synthesis was verified by immunohistochemistry (IHC), immunofluorescence (IF) and Western blot (WB) so that increase endothelial nitric oxide synthase (eNOS) content in vitro and in vivo. In addition, we verified protein interactions with immunoprecipitation (IP). To probe the mechanism, we also performed AMPKα2 transfection. AMPK's pivotal role in AZ-mediated prevention against T2DM-induced vascular endothelial dysfunction was tested using AMPKα2-/- mice. RESULTS: We first demonstrated that THBS1 and AMPK are targets of AZ. In T2DM, THBS1 was robustly induced by high glucose and inhibited by AZ. Furthermore, AZ activates the AMPK signaling pathway, and recoupled eNOS in stressed endothelial cells which plays a protective role in vascular endothelial dysfunction. CONCLUSIONS: The main finding of this study is that AZ can play a role in different pathways of vascular injury due to T2DM. Mechanistically, alizarin inhibits the increase in THBS1 protein synthesis after high glucose induction and activates AMPKα2, which increases NO release from eNOS, which is essential in the prevention of vascular endothelial dysfunction caused by T2DM.

Mollugin prevents CLP-induced sepsis in mice by inhibiting TAK1-NF-κB/MAPKs pathways and activating Keap1-Nrf2 pathway in macrophages.

Sepsis is a life-threatening organ dysfunction associated with macrophage overactivation. Targeted therapy against macrophages is considered a promising strategy for sepsis treatment. Mollugin (MLG), a compound extracted from traditional Chinese medicine Rubia cordifolia L., possesses anti-tumor and anti-inflammatory activities. This study aimed to investigate the anti-inflammatory effects and mechanisms of MLG in macrophages and its therapeutic role in CLP-induced sepsis in mice. The results demonstrated that MLG downregulated the inflammatory response induced by LPS or tumor necrosis factor α (TNF-α) in macrophages. Mechanistically, MLG suppressed the phosphorylation of TAK1, the upstream modulator of IKKα/ß and MAPKs, thereby inhibiting the pro-inflammatory signaling transduction of NF-κB and MAPKs. Additionally, MLG also activated the Nrf2 antioxidant pathway, reducing intracellular reactive oxygen species. CETSA and molecular docking analyses revealed that MLG could effectively bind to TAK1 and Keap1, which may be involved in the inhibition of TAK1- NF-κB/MAPKs and activation of Nrf2 mediated by MLG. Animal study demonstrated that MLG ameliorated inflammatory injury of lung and liver in CLP-induced sepsis mice probably by reducing the levels of pro-inflammatory cytokines. Therefore, our study suggests that bi-directional roles of MLG in improving sepsis via blocking the TAK1-NF-κB/MAPKs and activating Nrf2 pathways, indicating its potential as a promising candidate drug for sepsis treatment.

Amorphous selenium inhibits oxidative stress injury of neurons in vascular dementia rats by activating NMDAR pathway.

Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze, Transcranial Doppler TCD, hematoxylin-eosin (HE) staining, Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR pathway.

Effects of different probiotic fermented feeds on production performance and intestinal health of laying hens.

The aim of this study was to investigate the effects of different probiotic fermented diets on production performance and intestinal health of laying hens. A total of 360 healthy 22-wk-age Jingfen No. 6 layers were randomly divided into 4 treatments: basal diet (CON); supplemented with 6% Clostridium butyricum fermented feed (CB); supplemented with 6% Lactobacillus crispatus fermented feed (LC); supplemented with 6% Lactobacillus salivarius fermented feed (LS). The experiment lasted for 8 wk. The results showed that the levels of crude fiber, ß-glucan and pH of feed decreased significantly after fermentation (P < 0.05). Compared with CON group, the feed conversion ratio (FCR) was decreased significantly (P < 0.05), and albumen height and Haugh unit in LC group and LS group were increased significantly (P < 0.05). Fermented feed supplementation significantly improved villus height (VH) of the jejunum and the ratio of villus height to crypt depth (VH/CD) of the ileum (P < 0.05). Additionally, the VH and VH/CD of the duodenum were significantly increased in LS group (P < 0.05). Furthermore, the ACE and chao1 indexes in LS group were extremely significant higher than that in the other 3 groups (P < 0.05). In addition, compared with CON group, the abundance of Rikenellaceae and Methanobacteriaceae was significantly decreased at the family level in LC group and LS group (P < 0.05), while the abundance of Ruminocaceae was significantly higher (P < 0.05). Collectively, feeding Lactobacillus salivarius and Lactobacillus crispatus fermented feed improved the FCR, albumen height and Haugh unit of laying hens, and Lactobacillus salivarius fermented feed supplementation could improve intestinal health by ameliorating intestinal morphology, altering microbial composition and enhancing microbial community richness.

Potential Therapeutic Effect of Citronellal on Diabetic Cardiomyopathy in Experimental Rats.

Diabetic cardiomyopathy (DCM), a cardiovascular complication of patients with diabetes, is a special cardiomyopathy that is independent of coronary heart disease, hypertension, and valvular disease. Citronellal (CT) is a monoterpene compound generated by the secondary metabolism of plants. In this work, the therapeutic effect and mechanism of CT in DCM were investigated. Experimental diabetic rat models were constructed through a high-fat and high-carbohydrate diet combined with low-dosage streptozotocin (STZ) treatment. CT was intragastrically administered at the dosage of 150 mg/kg/day. The cardiac functions of the rats were evaluated via cardiac Doppler ultrasound. Changes in myocardial structure were analyzed through histopathology. Changes in the representative indices of oxidative stress, namely, superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were detected on the basis of a biochemical test. Related protein levels were assayed via immunofluorescence and Western blot analyses. The DCM rats in the nontreatment group experienced diastolic and systolic dysfunctions, associated with myocardial hypertrophy, fibrosis, and cardiomyocyte apoptosis. Moreover, this condition was concurrent with metabolic disorders, the degradation of SOD activity in myocardial tissues, the increase in MDA content, the abnormal activation of sodium-hydrogen exchanger 1 (NHE1), and the aggravation of cell apoptosis (Bax levels were elevated, whereas Bcl-2 levels decreased). Myocardial hypertrophy, fibrosis, oxidative stress, and cell apoptosis were obviously inhibited after treatment with CT (150 mg/kg/day). The abnormal activation of NHE1 was recovered under the action of CT. Our study results showed that CT might play a protective role in the treatment of DCM by repressing the abnormal activation of NHE1.

The Clinical Efficiency and the Mechanism of Sanzi Yangqin Decoction for Chronic Obstructive Pulmonary Disease.

This work is carried out to evaluate the clinical efficacy of Sanzi Yangqin decoction (SZYQD) treating chronic obstructive pulmonary disease (COPD) and to analyze its mechanism. The clinical efficacy of SZYQD treating COPD was evaluated by meta-analysis, and its mechanism was analyzed by network pharmacology. Molecular docking validation of the main active compounds and the core targets was performed by AutoDock vina software. A cigarette smoke (CS) and LPS-induced COPD model in ICR mice was constructed to confirm the effects of luteolin on COPD. Results showed that SZYQD has a greater benefit on the total effect (OR = 3.85, 95% CI [3.07, 4.83], P=1) in the trial group compared with the control group. The percentage of forced expiratory volume in one second (FEV1%) (MD = 0.5, 95% CI [0.41, 0.59], P < 0.00001) and first seconds breathing volume percentage of forced vital capacity (FEV1%/FVC) were improved (MD = 5.97, 95% CI [3.23, 8.71], P < 0.00001). There are 27 compounds in SZYQD targeting 104 disease targets related to COPD. PPI network analysis indicated that EGFR, MMP9, PTGS2, MMP2, APP, and ERBB2 may be the core targets for the treatment of COPD. Molecular docking demonstrated that luteolin in SZYQD showed the strongest binding activity to core targets. Experimental results revealed that the expression of COPD-related targets in lung tissue was significantly increased in the COPD group and was improved in the luteolin group. Our data indicated that SZYQD has a curative effect on COPD and luteolin is a candidate compound for COPD treatment by regulating EGFR, MMP9, PTGS2, MMP2, APP, and ERBB2.

The mechanism and candidate compounds of aged citrus peel (chenpi) preventing chronic obstructive pulmonary disease and its progression to lung cancer.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an important risk factor for developing lung cancer. Aged citrus peel (chenpi) has been used as a dietary supplement for respiratory diseases in China. OBJECTIVE: To explore the mechanism and candidate compounds of chenpi preventing COPD and its progression to lung cancer. METHODS: The active components and potential targets of chenpi were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Disease-associated targets of COPD and lung cancer were collected in the Gene Cards and TTD database. The component-target network and PPI network were constructed using the Cytoscape 3.8.0 software. David database was used for GO and KEGG enrichment analysis. The main active components were verified by using the autodock Vina 1.1.2 software. Mouse lung cancer with COPD was induced by cigarette smoking (CS) combined with urethane injection to confirm preventing the effect of hesperetin (the candidate compound of chenpi) on COPD progression to lung cancer and its underlying mechanisms. RESULTS: The network analysis revealed that the key active components of chenpi (nobiletin, naringenin, hesperetin) regulate five core targets (AKT1, TP53, IL6, VEGFA, MMP9). In addition, 103 potential pathways of chenpi were identified. Chenpi can prevent COPD and its progression to lung cancer by getting involved in the PI3K-Akt signaling pathway and MAPK signaling pathway. Molecular docking indicated that hesperetin had better binding activity for core targets. In mouse lung cancer with COPD, treatment with hesperetin dose-dependently improved not only lung tissue injury in COPD but also carcinoma lesions in lung cancer. Meanwhile, hesperetin could suppress the protein expression of AKT1, IL6, VEGFA, MMP9 and up-regulate the protein expression of TP53, and thus reduced the risk of COPD progression to lung cancer. CONCLUSION: Hesperetin is a candidate compound of chenpi that helps in preventing COPD and its progression to lung cancer by regulating AKT1, IL6, VEGFA, MMP9 and TP53.

Research on Effect and Mechanism of Xuefu Zhuyu Decoction on CHD Based on Meta-Analysis and Network Pharmacology.

Xuefu Zhuyu Decoction (XFZY) is an ancient compound widely used in the treatment of coronary heart disease. However, its efficacy evaluation is not complete and its mechanism of action is not clear enough. In an attempt to address these problems, the efficacy was evaluated by meta-analysis and the mechanism was elucidated by the network pharmacology method. We systematically searched relevant studies in PubMed, Chinese National Knowledge Infrastructure Database (CNKI), Cochrane Library, Wanfang Data, and other databases from 2007 to 2019. The association between XFZY treatment and CHD was estimated by risk ratio (RR) and corresponding 95% confidence intervals (95% CIs). The compounds and the potential protein targets of XFZY were obtained from TCMSP, and active compounds were selected according to their oral bioavailability and drug similarity. The potential genes of coronary heart disease were obtained from TTD, OMIM, and GeneCards. The potential pathways related to genes were determined by GO and KEGG pathway enrichment analyses. The compound-target and compound-target-pathway networks were constructed. Molecular docking validates the component and the target. A total of 21 studies including 1844 patients were enrolled in the present meta-analysis, indicating that XFZY has a greater beneficial on total effect (fixed effect RR = 1.30; 95% Cl: 1.24-1.36; P=0.82; I 2 = 0.0%) and electrocardiogram efficacy (fixed effect RR = 1.40; 95% Cl: 1.26-1.56; P=0.96; I 2 = 0.0%) compared with the control group. A total of 1342 components in XFZY were obtained, among which, 241 were chosen as bioactive components. GO and KEGG analyses got top 10 significantly enriched terms and 10 enriched pathways. The C-T network included 192 compounds and 3085 targets, whereas the C-T-P network included 10 compounds, 109 targets, and 5 pathways. There was a good binding activity between the components and the targets. XFZY has the curative effect on coronary heart disease, and its mechanism is related to 10 compounds, 10 core targets, and 5 pathways.

Qigong-Based Therapy for Treating Adults with Major Depressive Disorder: A Meta-Analysis of Randomized Controlled Trials.

This current meta-analysis review was conducted to examine the effectiveness of Qigong-based therapy on individuals with major depressive disorder. Six electronic databases (PubMed, PsycINFO, Cochrane Library, and Web of Science, Chinese National Knowledge Infrastructure, and Wangfang) were employed to retrieve potential articles that were randomized controlled trials. The synthesized effect sizes (Hedges' g) were computerized to explore the effectiveness of Qigong-based therapy. Additionally, a moderator analysis was performed based on the control type. The pooled results indicated that Qigong-based therapy has a significant benefit on depression severity (Hedges' g = -0.64, 95% CI -0.92 to -0.35, p < 0. 001, I² = 41.73%). Specifically, Qigong led to significantly reduced depression as compared to the active control groups (Hedges' g = -0.47, 95% CI -0.81 to -0.12, p = 0.01, I² = 22.75%) and the passive control groups (Hedges' g = -0.80, 95% CI -1.23 to -0.37, p < 0.01, I² = 48.07%), respectively. For studies which reported categorical outcomes, Qigong intervention showed significantly improved treatment response rates (OR = 4.38, 95% CI 1.26 to 15.23, p = 0.02) and remission rates (OR = 8.52, 95% CI 1.91 to 37.98, p = 0.005) in comparison to the waitlist control group. Conclusions: Qigong-based exercises may be effective for alleviating depression symptoms in individuals with major depressive disorder. Future well-designed, randomized, controlled trials with large sample sizes are needed to confirm these findings.