Molecular mechanism of Jianpiyifei II granules in the treatment of chronic obstructive pulmonary disease: Network pharmacology analysis, molecular docking, and experimental assessment.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is defined by persistent airway and lung inflammation, excessive mucus production, remodeling of the airways, and damage to the alveolar tissue. Based on clinical experience, it has been observed that Jianpiyifei II (JPYF II) granules exhibit a significant therapeutic impact on individuals suffering from stable COPD. Nevertheless, the complete understanding of JPYF II's potential mode of action against COPD remains to be further clarified. PURPOSE: To further investigate the underlying mechanism of JPYF II for treating COPD and clarify the role of the IL-17 pathway in the treatment. METHODS: A variety of databases were utilized to acquire JPYF II's bioactive components, as well as related targets of JPYF II and COPD. Cytoscape was utilized to establish multiple interaction networks for the purpose of topological analyses and core-target screening. The Metascape was utilized to identify the function of target genes and crucial signaling pathways. To evaluate the interactions between bioactive ingredients and central target proteins, molecular docking simulations were conducted. Following that, a sequence of experiments was conducted both in the laboratory and in living organisms, which included analyzing the cell counts in bronchoalveolar lavage fluid (BALF), examining lung tissue for histopathological changes, conducting immunohistochemistry, RT‒qPCR, ELISA, and Western blotting. RESULTS: In JPYF II, 88 bioactive ingredients were predicted to have a total of 342 targets. After conducting Venn analysis, it was discovered that 284 potential targets of JPYF II were linked to the provision of defensive benefits against COPD. The PPI network yielded a total of twenty-four core targets. The findings from the analysis of enrichment and gene‒pathway network suggested that JPYF II targeted Hsp90, MAPKs, ERK, AP-1, TNF-α, IL-6, COX-2, CXCL8, and MMP-9 as crucial elements for COPD treatment through the IL-17 pathway. Additionally, JPYF II might modulate MAPK signaling pathways and the downstream transcription factor AP-1 via IL-17 regulation. According to the findings from molecular docking, it was observed that the 24 core target proteins exhibited robust binding affinities towards the top 10 bioactive compounds. Furthermore, the treatment of COPD through the regulation of MAPKs in the IL-17 pathway was significantly influenced by flavonoids and sterols found in JPYF II. In vitro, these observations were further confirmed. In vivo results demonstrated that JPYF II reduced inflammatory cell infiltration in pulmonary tissues and the quantity of inflammatory cells in BALF obtained from LPS- and CS-stimulated mice. Moreover, the administration of JPYF II resulted in the inhibition of IL-17 mRNA and protein levels, phosphorylation levels of MAPK proteins, and expression of phosphorylated AP-1 proteins. It also suppressed the expression of downstream effector genes and proteins associated with the IL-17/MAPK/AP-1 signaling axis in lung tissues and BALF. CONCLUSION: This research reveals that JPYF II improves COPD by controlling the IL-17/MAPK/AP-1 signaling axis within the IL-17 pathway for the first time. These findings offer potential approaches for the creation of novel medications that specifically target IL-17 and proteins involved in the IL-17 pathway to address COPD.

Treatment with JianPiYiFei II granules for patients with moderate to very severe chronic obstructive pulmonary disease: A 52-week randomised, double-blinded, placebo-controlled, multicentre trial.

BACKGROUND: Complementary and alternative therapy is widely used to treat chronic obstructive pulmonary disease (COPD). A Chinese herbal medicine, JianPiYiFei (JPYF) II granules, have been shown to improve COPD patients' quality of life, however long-term effectiveness has not been examined. PURPOSE: To investigate whether long-term treatment with JPYF II granules is effective and safe for patients with stable, moderate to very severe COPD. STUDY DESIGN AND METHODS: A multicentre, randomised, double-blinded, placebo-controlled trial was conducted. Eligible participants from six hospitals were randomly assigned 1:1 to receive either JPYF II granules or placebo for 52 weeks. The primary outcome was the change in St. George's Respiratory Questionnaire (SGRQ) score during treatment. Secondary outcomes included the frequency of acute exacerbations during treatment, COPD Assessment Test (CAT), 6-minute walking test (6MWT), lung function, body mass index, airflow obstruction, dyspnoea, exercise capacity (BODE) index, and peripheral capillary oxygen saturation (SpO2) at the end of treatment. RESULTS: A total of 276 patients (138 in each group) were included in the analysis. JPYF II granules led to a significantly greater reduction in SGRQ score (-7.33 points, 95% CI -10.59 to -4.07; p < 0.0001) which reflects improved quality of life. JPYF II granules improved CAT (-3.49 points, 95% CI -5.12 to -1.86; p < 0.0001) and 6MWT (45.61 metres, 95% CI 20.26 to 70.95; p = 0.0005), compared with placebo. Acute exacerbations were less frequent with JPYF II granules than with placebo (0.87 vs. 1.34 events per patient; p = 0.0043). There were no significant differences between the groups in lung function, BODE index and SpO2. JPYF II granules were well tolerated and no significant adverse effects were noted. CONCLUSIONS: Long-term treatment with JPYF II granules is effective in moderate to very severe COPD, improving quality of life and exercise capacity, decreasing the risk of acute exacerbation, and relieving symptoms.

Inhibition of Inflammation and Regulation of AQPs/ENaCs/Na+-K+-ATPase Mediated Alveolar Fluid Transport by Total Flavonoids Extracted From Nervilia fordii in Lipopolysaccharide-induced Acute Lung Injury.

Aims: The occurrence of vascular permeability pulmonary edema in acute lung injury (ALI) is related to the imbalance of alveolar fluid transport. Regulating the active transport of alveolar fluid by aquaporins (AQPs), epithelial sodium channels (ENaCs), and Na+-K+-ATPase can effectively reduce the edema fluid in the alveolar cavity and protect against ALI. We evaluated the therapeutic effects of total flavonoids, extracted from Nervilia fordii (TFENF), and investigated its potential mechanisms of alveolar fluid transport in a rat ALI model. Materials and methods: A model of lipopolysaccharide (LPS, 5 mg/kg)-induced ALI was established in Sprague-Dawley (SD) rats through the arteriae dorsalis penis. SD rats were divided into six groups, including the vehicle, LPS model, TFENF (6 mg/kg, 12 mg/kg, 24 mg/kg), and dexamethasone group (DEX group, 5 mg/kg). The wet-to-dry (W/D) lung weight ratio, oxygenation index, and histopathological observation were used to evaluate the therapeutic effect of TFENF. The mRNA expression of AQPs, ENaCs, and pro-inflammatory cytokines was determined using real-time polymerase chain reaction, whereas protein expression was determined using immunohistochemistry. The Na + -K + -ATPase activity was assessed using enzyme-linked immunosorbent assay. Results: LPS significantly stimulated the production of inflammatory mediators including tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, and disrupted the water transport balance in the alveolar cavity by inhibiting AQPs/ENaCs/Na + -K + -ATPase. Pretreatment with TFENF reduced the pathological damage and W/D ratio of the lungs and ameliorated the arterial blood oxygen partial pressure (PaO2) and oxygenation index. TFENF further decreased the mRNA level of TNF-α and IL-1ß; increased the expression of AQP-1, AQP-5, αENaC, and ßENaC; and increased Na + -K + -ATPase activity. Moreover, the regulation of AQPs, ßENaC, and Na + -K + -ATPase and the inhibition of TNF-α and IL-1ß by TFENF were found to be dose dependent. Conclusion: TFENF protects against LPS-induced ALI, at least in part, through the suppression of inflammatory cytokines and regulation of the active transport capacity of AQPs/ENaCs/Na + -K + -ATPase. These findings suggest the therapeutic potential of TFENF as phytomedicine to treat inflammation and pulmonary edema in ALI.

The traditional herbal formulation, Jianpiyifei II, reduces pulmonary inflammation induced by influenza A virus and cigarette smoke in mice.

Chronic obstructive pulmonary disease (COPD) is a worldwide chronic inflammatory lung disease, and influenza A virus (IAV) infection is a common cause of acute exacerbations of COPD (AECOPD). Therefore, targeting viral infections represents a promising strategy to prevent the occurrence and development of inflammatory flare ups in AECOPD. Jianpiyifei II (JPYFII) is a traditional herbal medicine used in China to treat patients with COPD, and its clinical indications are not well understood. However, investigation of the anti-inflammatory effects and underlying mechanism using an animal model of smoking have been reported in a previous study by our group. In addition, some included herbs, such as Radix astragali and Radix aupleuri, were reported to exhibit antiviral effects. Therefore, the aim of the present study was to investigate whether JPYFII formulation relieved acute inflammation by clearing the IAV in a mouse model that was exposed to cigarette smoke experimentally. JPYFII formulation treatment during smoke exposure and IAV infection significantly reduced the number of cells observed in bronchoalveolar lavage fluid (BALF), expression of proinflammatory cytokines, chemokines, superoxide production, and viral load in IAV-infected and smoke-exposed mice. However, JPYFII formulation treatment during smoke exposure alone did not reduce the number of cells in BALF or the expression of Il-6, Tnf-a, and Il-1ß. The results demonstrated that JPYFII formulation exerted an antiviral effect and reduced the exacerbation of lung inflammation in cigarette smoke (CS)-exposed mice infected with IAV. Our results suggested that JPYFII formulation could potentially be used to treat patients with AECOPD associated with IAV infection.

The ethnopharmacology, phytochemistry, pharmacology and toxicology of the genus Erycibe (Convolvulaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Erycibe belongs to the Convolvulaceae family that contains approximately 70 species mainly distributed from tropical and subtropical Asia to north of Australia. Several Erycibe species are traditionally used in folk medicine for the treatment of various ailments, including rheumatic arthralgia, primary glaucoma, hepatopathies, and infectious and malignant diseases. AIM OF THE REVIEW: This review aims to summarize comprehensive and updated information on traditional medicinal uses, phytochemistry, pharmacology, and toxicology of Erycibe species to provide a reference for the further research and application of the Erycibe genus. MATERIALS AND METHODS: The scientific and extensive literatures between 1975 and 2020 were systematically gathered from scientific databases such as SciFinder Scholar, Science Direct, Web of Science, PubMed, Google Scholar, Scopus, Springer Link and China National Knowledge Infrastructure (CNKI), as well as Chinese herbal classic books, PhD and MSc theses, and several official websites. RESULTS: Erycibe species have been used for the treatment of various rheumatoid diseases, glaucoma, a variety of hepatic diseases, infectious diseases and various malignancies in the traditional and local medicine. Since the 1970s, 153 compounds, including coumarins, quinic acid derivatives, flavonoids, alkaloids, lignans, and others have been isolated from five species of the Erycibe genus. Pharmacological studies have shown that these extracts and compounds from the Erycibe genus have extensive activities consistent with the traditional and local applications, such as anti-glaucoma, anti-arthritic, hepatoprotective and anti-cancer activities, as well as anti-inflammatory, anti-respiratory syncytial virus (RSV), and neuroprotective properties. CONCLUSIONS: Although there are extensive data on the genus Erycibe, certain specific gaps still exist. For herbal preparations containing Erycibe species, clinical toxicological investigation is required for the safety of these herbal preparation therapies, as well as further investigations on pharmacokinetics and bioavailability for guideline for clinical application. Furthermore, more detailed pharmacological, toxicological and clinical researches are needed to assess the alternatives to Erycibe species. Systematic and comprehensive pre-clinical studies are similarly required to estimate the possibility of extracts and compounds from the genus Erycibe with bioactivity developing into new drugs.

Is Chinese Medicine Injection Applicable for Treating Acute Lung Injury and Acute Respiratory Distress Syndrome? A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To assess the efficacy and safety of Chinese medicine injection (CMI) for treating acute lung injury/acute respiratory distress syndrome (ALI/ARDS). METHODS: Randomized controlled trials (RCTs) were identified by searching 3 English databases and 4 Chinese databases from their inceptions until February 2019. The Cochrane Handbook was used to evaluate risk of bias in the included studies. Data analysis was conducted using RevMan 5.3.3 software. RESULTS: A total of 19 eligible RCTs involving 1,334 participants was included in this systematic review and meta-analysis. The main meta-analysis showed that CMI combined with conventional therapy (CT) was more effective than CT alone in reducing the acute physiology and chronic health evaluation (APACHE) H score [mean difference (MD): -1.74 points, 95% confidence interval (CI): -2.77 to -0.71, I2=0] and increasing the total effective rate [relative risk (RR): 1.35, 95% CI: 1.17 to 1.56, I2=37%]. Compared with CT, CMI combined with CT showed improvements in the arterial partial pressure of oxygen (PaO2, MD: 9.25 mm Hg, 95% CI: 0.87 to 17.63, I2=98%) and oxygenation index [arterial partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2), MD: 50.75 mm Hg, 95% CI: 35.18 to 66.31, I2=94%]. CMI plus CT was superior to CT in reducing the systemic inflammatory response syndrome (SIRS) score (MD: -0.84 points, 95% CI: -1.26 to -0.42, I2=65%), length of hospital stay (MD: -4.22 days, 95% CI: -6.49 to -1.95, I2=92%), and duration of mechanical ventilation (MD: -2.94 days, 95% CI: -4.68 to -1.21, I2=89%). Only 1 study reported adverse events. CONCLUSIONS: CMI as an adjuvant therapy showed great potential benefits for the treatment of ALI/ARDS. However, we could not make a definite conclusion due to low quality of included studies and uncertain security. Future studies should focus on improving research design, especially in blindness and placebo. The reporting of adverse events was also needed.

Protective effects of Weipixiao decoction against MNNG-induced gastric precancerous lesions in rats.

Gastric cancer is recognized as one of the most common cancer. In-depth research of gastric precancerous lesions (GPL) plays an important role in preventing the occurrence of gastric cancer. Meanwhile, traditional treatment provides a novel sight in the prevention of occurrence and development of gastric cancer. The current study was designed to assess the effects of therapy with Weipixiao (WPX) decoction on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced GPL rats and the underlying molecular mechanisms. After 10-weeks treatment, all rats were sacrificed. Histopathological changes of gastric tissue were assessed via hematoxylin-eosin (HE) and High-iron diamine-Alcian blue-Periodic acid-Schiff (HID-AB-PAS) staining. To be fully evidenced, RT-qPCR, Western blot and immunohistochemistry were used to detect the expressions of LDHA, CD147, HIF-1α, MCT4, PI3K, AKT, mTOR and miRNA-34a, which were crucial factors for evaluating GPL in the aspect of glycolysis pathogenesis. According to the results of HE and HID-AB-PAS staining, it could be confirmed that MNNG-induced GPL rats were obviously reversed by WPX decoction. Additionally, the increased gene levels of LDHA, CD147, MCT4, PI3K, AKT, mTOR and HIF-1α in model group were down-regulated by WPX decoction, while miRNA-34a expression was decreased and up-regulated by WPX decoction. The significantly increased protein levels of LDHA, CD147, MCT4, PI3K, AKT, mTOR and HIF-1α induced by MNNG were attenuated in rats treated with WPX decoction. In brief, the findings of this study imply that abnormal glycolysis in MNNG-induced GPL rats was relieved by WPX decoction via regulation of the expressions of LDHA, CD147, HIF-1α, MCT4, PI3K, AKT, mTOR and miRNA-34a.

Effectiveness and Safety of Oral Cordyceps sinensis on Stable COPD of GOLD Stages 2-3: Systematic Review and Meta-Analysis.

Cordyceps sinensis (CS) is a complementary medicine used for Chronic Obstructive Pulmonary Disease (COPD) of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 2-3. Many randomized controlled trials have been conducted to evaluate the effect of CS alone or in combination with other herbs on stable COPD. To provide a synthesis of the evidence, we searched nine major electronic databases for randomized controlled trials on CS published before 21st December 2016. Fifteen interventional studies, including 1,238 participants, met the inclusion criteria. Meta-analysis showed that both CS preparations and CS formulae showed the potential benefits in lung function, exercise endurance, life quality, and improvement of symptoms. No serious adverse events were reported. So CS may be a promising treatment for patients with stable COPD of GOLD stages 2-3. No studies were placebo-controlled or of high methodological quality, which limits the conclusions.

Protective Effect of Jianpiyifei II Granule against Chronic Obstructive Pulmonary Disease via NF-κB Signaling Pathway.

Jianpiyifei II granule (JPYF II) is an oriental herbal formula used clinically in China to treat chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate the anti-inflammatory and antioxidative activities of JPYF II in a mouse model of COPD induced by lipopolysaccharide (LPS) and cigarette smoke (CS) and in RAW264.7 cells stimulated with cigarette smoke extract (CSE). Mice were given LPS via intratracheal instillation on days 1 and 15 and exposed to CS generated from 4 cigarettes/day for 28 days. The mice were treated with 0.75, 1.5, or 3 g/kg/d JPYF II by intragastric administration in low, middle, and high dose groups, respectively, for two weeks. RAW264.7 cells were stimulated by CSE and treated with JPYF II at doses of 12.5, 25, or 50 µg/mL. In the mouse model of LPS and CS-induced COPD, JPYF II decreased inflammatory cell counts in broncho alveolar lavage fluid (BALF), in addition to mRNA expression of proinflammatory cytokines and metalloproteinases (MMPs) in lung tissues. In addition, JPYF II elevated catalase (CAT) and glutathione peroxidase (GSH-Px) activities and reduced the levels of malondialdehyde (MDA) and IκBα and p65 phosphorylation and inflammatory cell infiltration in the lung tissues. In RAW264.7 cells stimulated with CSE, JPYF II inhibited the mRNA levels of inflammatory mediators and the phosphorylation of IκBα and p65. Our results suggest that JPYF II enhanced anti-inflammatory and antioxidative activities in a mouse model of COPD induced by LPS and CS and in RAW264.7 cells stimulated with CSE via inhibition of the NF-κB pathway.

A Novel Approach to Estimate ROS Origination by Hyperbaric Oxygen Exposure, Targeted Probes and Specific Inhibitors.

BACKGROUND/AIMS: Reactive oxygen species (ROS) are considered fundamental in various physiological/pathophysiological processes and prevention/treatment measures such as hyperbaric oxygen (HBO) therapy. In this study, the origination of ROS in human umbilical vein endothelial cells was investigated under basal and HBO conditions. METHODS: Whole cell or mitochondria-targeted fluorescent probes were applied to mark superoxide anion (O2-), and the ROS produced from mitochondrial respiratory chain (MRC), NADPH oxidase (NOX) and xanthine oxidase (XO) were identified by flow cytometry, confocal imaging and microplate fluorometry with or without specific inhibitors. An algorithm was established to calculate ROS proportion of each source. RESULTS: HBO increased ROS to about 2.14-2.44 fold in mitochondria and 1.32-1.42 fold in whole cell. Then ROS levels were significantly decreased by MRC inhibition about 30% and 16%, respectively. NOX or XO inhibition did not affect HBO-induced ROS generation. Based on these data, it could be further estimated that mitochondrial ROS accounted for 32%-39% of basal whole-cell ROS including 3% from MRC complex II, and NOX accounted for at least 24%-29%. Following HBO treatment, almost all increased ROS originated from mitochondria, and MRC complex II contributed at least 45%-60%. CONCLUSION: This study provided a simple but effective method to estimate the origination of intracellular ROS and found that MRC were the main source of HBO-induced ROS generation.

Endothelia-Targeting Protection by Escin in Decompression Sickness Rats.

Endothelial dysfunction is involved in the pathogenesis of decompression sickness (DCS) and contributes substantively to subsequent inflammatory responses. Escin, the main active compound in horse chestnut seed extract, is well known for its endothelial protection and anti-inflammatory properties. This study aimed to investigate the potential protection of escin against DCS in rats. Escin was administered orally to adult male rats for 7 d (1.8 mg/kg/day) before a simulated air dive. After decompression, signs of DCS were monitored, and blood and pulmonary tissue were sampled for the detection of endothelia related indices. The incidence and mortality of DCS were postponed and decreased significantly in rats treated with escin compared with those treated with saline (P < 0.05). Escin significantly ameliorated endothelial dysfunction (increased serum E-selectin and ICAM-1 and lung Wet/Dry ratio, decreased serum NO), and oxidative and inflammatory responses (increased serum MDA, MPO, IL-6 and TNF-α) (P < 0.05 or P < 0.01). The results suggest escin has beneficial effects on DCS related to its endothelia-protective properties and might be a drug candidate for DCS prevention and treatment.

A systematic review and meta-analysis of the herbal formula Buzhong Yiqi Tang for stable chronic obstructive pulmonary disease.

OBJECTIVE: To systematically evaluate the efficacy and safety of Buzhong Yiqi Tang (BZYQT) for stable chronic obstructive pulmonary disease (COPD). METHODS: Three electronic English databases (PubMed, EMBASE and CENTRAL) and four Chinese databases (CBM, CNKI, CQVIP and WFMO) were searched from their inceptions until 30th June 2016. Participants were diagnosed with COPD according to the Chinese Medical Association's COPD diagnosis and treatment guidelines or Global Initiative for Chronic Obstructive Lung Disease (GOLD), and were in stable stage. Randomized controlled trials (RCTs) of oral BZYQT, alone or combined with conventional treatment, compared with conventional treatment alone or plus placebo were included in the review. Clinical improvement and the six-minute walking test (6MWT) were the primary outcome measures. The secondary outcome measures were defined as forced expiratory volume in one second (FEV1), forced vital capacity (FVC), respiratory muscle strength index with maximum inspiratory pressure (MIP), COPD Assessment Test (CAT), and frequency of acute exacerbations. To assess risk of bias the Cochrane, Risk of Bias tool was used, and statistical analysis was performed using RevMan 5.3.0 software. RESULTS: Sixteen studies (1400 participants) were included. The results of meta-analysis indicated patients receiving BZYQT alone or BZYQT in combination with conventional treatment showed a significant increase in clinical improvement (RR 1.25, 95% CI 1.18 to 1.33, I2=0%), enhanced exercise capacity 6MWT (MD 51.22m, 95% CI 45.56 to 56.89, I2=44%), improved lung function FVC (L) (MD 0.26 liters, 95% CI 0.18 to 0.33, I2=37%), reduced respiratory muscle fatigue MIP (MD 0.46 liters, 95% CI 0.11 to 0.80, I2=0%), and improved quality of life CAT (MD -2.56 points, 95% CI -3.40 to -1.72, I2=0%) when compared with conventional treatment alone, or plus placebo. BZYQT also showed small but significant improvements in FEV1% and decreased acute exacerbations of COPD. Four studies reported that no adverse events occurred, other studies did not mention adverse events. The finding should be considered with caution because the included studies had methodological shortfalls. CONCLUSIONS: BZYQT improves clinically important outcomes for patients with stable COPD, such as improved clinical symptoms, exercise capacity, lung function and quality of life. Moreover, it has an excellent safety profile. However further evaluation is needed to validate these preliminary findings in high quality RCTs.

Chinese herbal medicine (weijing decoction) combined with pharmacotherapy for the treatment of acute exacerbations of chronic obstructive pulmonary disease.

Objective. To evaluate the efficacy and safety of Weijing decoction combined with routine pharmacotherapy (RP) for the treatment of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Methods. Randomized controlled trials (RCT) evaluating Weijing decoction for AECOPD were included. English, Chinese, and Japanese databases were searched from their respective inceptions to June 2013. The methodological quality was assessed according to the Cochrane Collaboration's risk of bias tool. All data were analyzed and synthesized using RevMan 5.2 software. Results. Fifteen (15) studies involving 986 participants were included. Participants were diagnosed with COPD in the acute exacerbation stage. In addition, most of studies reported that they included participants with the Chinese medicine syndrome, phlegm-heat obstructing the Lung. Weijing decoction combined with RP improved lung function (forced expiratory volume in one second; FEV1), arterial blood gases (PaO2 and PaCO2), clinical effective rate, and reduced inflammatory biomarkers (TNF-α and IL-8) when compared with RP alone. No severe adverse events were reported in these studies. Conclusions. Weijing decoction appeared to be beneficial for AECOPD and well-tolerated when taken concurrently with RP, such as antibiotics, bronchodilators (oral and inhaled), and mucolytics.

ß-Asarone prevents autophagy and synaptic loss by reducing ROCK expression in asenescence-accelerated prone 8 mice.

ß-Asarone is an active component of the Acori graminei rhizome that is a traditional Chinese medicine clinically used in treating dementia in China. However, the cognitive effect of ß-asarone and its mechanism has remained elusive. Here, we used asenescence-accelerated prone 8 (SAMP8) mice, which mimic many of the salient features of Alzheimer׳s disease (AD), to further investigate whether modulation of the ROCK signaling pathway and/or autophagy, synaptic loss is involved in the effects of ß-asarone on learning and memory. SAMP8 mice at the age of 6 months were intragastrically administered by ß-asarone or a vehicle daily for 2 months. Senescence-accelerated-resistant (SAMR1) mice were used as the control. Our results demonstrate that autophagy and ROCK expression were increased significantly in 8 months SAMP8 mice, which were concomitant with that SAMP8 mice at the same age displayed a significant synaptic loss and cognitive deficits. The up-regulation of ROCK expression and autophage in the hippocampus of SAMP8 were significantly reduced by ß-asarone, and prevents synaptic loss and improved cognitive function of the SAMP8 mice. ß-asarone decreased neuronophagia and lipofuscin in the hippocampus of SAMP8 mice, but did not reduce Aß42 levels and malondialdehyde levels and superoxide dismutase activities. Moreover, suppression of ROCK2 by siRNA significantly reduced the effects of ß-asarone on the autophage and synaptic proteins expression in PC12 cells damage induced by Aß1-40. Taken together, ß-asarone prevents autophagy and synaptic loss by reducing ROCK expression in SAMP8 mice.

Bioavailability enhancement of osthole after oral administration of Bushen Yizhi prescription extract to rats followed by Cnidium monnieri (L.) Cusson fruits extract in comparison to pure osthole at different doses.

ETHNOPHARMACOLOGICAL RELEVANCE: Bushen Yizhi prescription (BSYZ) is a traditional Chinese compound prescription, which is commonly used in China for treating ShenXu and hypophrenia based on traditional Chinese medicine and Alzheimer's Disease according to modern Chinese medicine. Cnidium monnieri (L.) Cusson fruits (CM) is treated as the main herb of BSYZ, and its main active ingredient Osthole (OST) is considered as one of the major active ingredients of BSYZ. Even though OST plays an important role in the BSYZ its bioavailability is poor. In order to investigate whether the bioavailability of OST was influenced by BSYZ and CM extract, the comparative evaluations on pharmacokinetics of OST after oral administration of pure OST at different doses, CM and BSYZ extract were studied. MATERIALS AND METHODS: 30 rats were randomly assigned to five groups and orally administered with pure OST at different doses (15, 75 and 150 mg/kg), CM (15 mg/kg OST) and BSYZ (15 mg/kg OST) extract. At different predetermined time points after administration, the concentrations of OST in rat plasma were determined by using the HPLC-UV method, and main pharmacokinetic parameters were investigated. RESULTS: The results showed that the pharmacokinetic parameters of OST were significantly different (p<0.05) among the groups. The AUC(0→t), AUC(0→∞) and Cmax of OST were significantly increased after oral administration of BSYZ extract, followed by CM extract, in comparison to pure osthole at different doses. CONCLUSIONS: This present study indicated that the bioavailability of pure OST after oral administration was extremely low and it was dramatically enhanced because of the synergistic effect of the traditional Chinese Bushen Yizhi prescription.