Network pharmacology analysis and experimental verification of the antithrombotic active compounds of trichosanthis pericarpium (Gualoupi) in treating coronary heart disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Trichosanthis pericarpium (TP; Gualoupi, pericarps of Trichosanthes kirilowii Maxim) has been used in traditional Chinese medicine (TCM) to reduce heat, resolve phlegm, promote Qi, and clear chest congestion. It is also an essential herbal ingredient in the "Gualou Xiebai" formula first recorded by Zhang Zhongjing (from the Eastern Han Dynasty) in the famous TCM classic "Jin-Guì-Yào-Lüe" for treating chest impediments. According to its traditional description, Gualou Xiebai is indicated for symptoms of chest impediments, which correspond to coronary heart diseases (CHD). AIM OF THE STUDY: This study aimed to identify the antithrombotic compounds in Gualoupi for the treatment of CHD. MATERIALS AND METHODS: A CHD rat model was established with a combination of high-fat diet and isoproterenol hydrochloride (ISO) administration via subcutaneous multi-point injection in the back of the neck. This model was used to evaluate the antithrombotic effect of two mainstream cultivars of TP ("HaiShi GuaLou" and "WanLou") by analyzing the main components and their effects. Network pharmacology, molecular docking-based studies, and a zebrafish (Danio rerio) thrombosis model induced by phenylhydrazine was used to validate the antithrombosis components of TP. RESULTS: TP significantly reduced the body weight of the CHD rats, improved myocardial ischemia, and reduced collagen deposition and fibrosis around the infarcted tissue. It reduced thrombosis in a dose-dependent manner and significantly reduced inflammation and oxidative stress damage. Cynaroside, isoquercitrin, rutin, citrulline, and arginine were identified as candidate active TP compounds with antithrombotic effects. The key potential targets of TP in thrombosis treatment were initially identified by molecular docking-based analysis, which showed that the candidate active compounds have a strong binding affinity to the potential targets (protein kinase C alpha type [PKCα], protein kinase C beta type [PKCß], von Willebrand factor [vWF], and prostaglandin-endoperoxide synthase 1 [PTGS1], fibrinogen alpha [Fga], fibrinogen beta [Fgb], fibrinogen gamma [Fgg], coagulation factor II [F2], and coagulation factor VII [F7]). In addition, the candidate active compounds reduced thrombosis, improved oxidative stress damage, and down-regulated the expression of thrombosis-related genes (PKCα, PKCß, vWF, PTGS1, Fga, Fgb, Fgg, F2, and F7) in the zebrafish model. CONCLUSION: Cynaroside, isoquercitrin, rutin, citrulline, and arginine were identified as the active antithrombotic compounds of TP used to treat CHD. Mechanistically, the active compounds were found to be involved in oxidative stress injury, platelet activation pathway, and complement and coagulation cascade pathways.

Mechanism of Fei-Xian Formula in the Treatment of Pulmonary Fibrosis on the Basis of Network Pharmacology Analysis Combined with Molecular Docking Validation.

OBJECTIVE: This study aimed to clarify the mechanism of Fei-Xian formula (FXF) in the treatment of pulmonary fibrosis based on network pharmacology analysis combined with molecular docking validation. METHODS: Firstly, ingredients in FXF with pharmacological activities, together with specific targets, were identified based on the BATMA-TCM and TCMSP databases. Then, targets associated with pulmonary fibrosis, which included pathogenic targets as well as those known therapeutic targets, were screened against the CTD, TTD, GeneCards, and DisGeNet databases. Later, Cytoscape was employed to construct a candidate component-target network of FXF for treating pulmonary fibrosis. In addition, for nodes within the as-constructed network, topological parameters were calculated using CytoHubba plug-in, and the degree value (twice as high as the median degree value for all the nodes) was adopted to select core components as well as core targets of FXF for treating pulmonary fibrosis, which were subsequently utilized for constructing the core network. Furthermore, molecular docking study was carried out on those core active ingredients together with the core targets using AutoDock Vina for verifying results of network pharmacology analysis. At last, OmicShare was employed for enrichment analysis of the core targets. RESULTS: Altogether 12 active ingredients along with 13 core targets were identified from our constructed core component-target network of FXF for the treatment of pulmonary fibrosis. As revealed by enrichment analysis, the 13 core targets mostly concentrated in regulating biological functions, like response to external stimulus (from oxidative stress, radiation, UV, chemical substances, and virus infection), apoptosis, cell cycle, aging, immune process, and protein metabolism. In addition, several pathways, like IL-17, AGE-RAGE, TNF, HIF-1, PI3K-AKT, NOD-like receptor, T/B cell receptor, and virus infection-related pathways, exerted vital parts in FXF in the treatment of pulmonary fibrosis. CONCLUSIONS: FXF can treat pulmonary fibrosis through a "multicomponent, multitarget, and multipathway" mean. Findings in this work lay foundation for further exploration of the FXF mechanism in the treatment of pulmonary fibrosis.

Molecular mechanisms of An-Chuan Granule for the treatment of asthma based on a network pharmacology approach and experimental validation.

An-Chuan Granule (ACG), a traditional Chinese medicine (TCM) formula, is an effective treatment for asthma but its pharmacological mechanism remains poorly understood. In the present study, network pharmacology was applied to explore the potential mechanism of ACG in the treatment of asthma. The tumor necrosis factor (TNF), Toll-like receptor (TLR), and Th17 cell differentiation-related, nucleotide-binding oligomerization domain (NOD)-like receptor, and NF-kappaB pathways were identified as the most significant signaling pathways involved in the therapeutic effect of ACG on asthma. A mouse asthma model was established using ovalbumin (OVA) to verify the effect of ACG and the underlying mechanism. The results showed that ACG treatment not only attenuated the clinical symptoms, but also reduced inflammatory cell infiltration, mucus secretion and MUC5AC production in lung tissue of asthmatic mice. In addition, ACG treatment notably decreased the inflammatory cell numbers in bronchoalveolar lavage fluid (BALF) and the levels of pro-inflammatory cytokines (including IL-6, IL-17, IL-23, TNF-alpha, IL-1beta and TGF-beta) in lung tissue of asthmatic mice. In addition, ACG treatment remarkably down-regulated the expression of TLR4, p-P65, NLRP3, Caspase-1 and adenosquamous carcinoma (ASC) in lung tissue. Further, ACG treatment decreased the expression of receptor-related orphan receptor (RORγt) in lung tissue but increased that of Forkhead box (Foxp3). In conclusion, the above results demonstrate that ACG alleviates the severity of asthma in a ´multi-compound and multi-target' manner, which provides a basis for better understanding of the application of ACG in the treatment of asthma.

Effect of sedation on short-term and long-term outcomes of critically ill patients with acute respiratory insufficiency.

BACKGROUND: The present study aimed to determine the short-term and long-term outcomes of critically ill patients with acute respiratory insufficiency who had received sedation or no sedation. METHODS: The data of 91 patients who had received mechanical ventilation in the first 24 hours between November 2008 and October 2009 were retrospectively analyzed. These patients were divided into two groups: a sedation group (n=28) and a non-sedation group (n=63). The patients were also grouped in two groups: deep sedation group and daily interruption and /or light sedation group. RESULTS: Overall, the 91 patients who had received ventilation ≥48 hours were analyzed. Multivariate analysis demonstrated two independent risk factors for in-hospital death: sequential organ failure assessment score (P=0.019, RR 1.355, 95%CI 1.051-1.747, B=0.304, SE=0.130, Wald=50483) and sedation (P=0.041, RR 5.015, 95%CI 1.072-23.459, B=1.612, SE=0.787, Wald=4.195). Compared with the patients who had received no sedation, those who had received sedation had a longer duration of ventilation, a longer stay in intensive care unit and hospital, and an increased in-hospital mortality rate. The Kaplan-Meier method showed that patients who had received sedation had a lower 60-month survival rate than those who had received no sedation (76.7% vs. 88.9%, Log-rank test=3.630, P=0.057). Compared with the patients who had received deep sedation, those who had received daily interruption or light sedation showed a decreased in-hospital mortality rate (57.1% vs. 9.5%, P=0.008). The 60-month survival of the patients who had received deep sedation was significantly lower than that of those who had daily interruption or light sedation (38.1% vs. 90.5%, Log-rank test=6.783, P=0.009). CONCLUSIONS: Sedation was associated with in-hospital death. The patients who had received sedation had a longer duration of ventilation, a longer stay in intensive care unit and in hospital, and an increased in-hospital mortality rate compared with the patients who did not receive sedation. Compared with daily interruption or light sedation, deep sedation increased the in-hospital mortality and decreased the 60-month survival for patients who had received sedation.

Risk factors and prognosis of critically ill cancer patients with postoperative acute respiratory insufficiency.

BACKGROUND: This study aimed to investigate the risk factors and outcome of critically ill cancer patients with postoperative acute respiratory insufficiency. METHODS: The data of 190 critically ill cancer patients with postoperative acute respiratory insufficiency were retrospectively reviewed. The data of 321 patients with no acute respiratory insufficiency as controls were also collected. Clinical variables of the first 24 hours after admission to intensive care unit were collected, including age, sex, comorbid disease, type of surgery, admission type, presence of shock, presence of acute kidney injury, presence of acute lung injury/acute respiratory distress syndrome, acute physiologic and chronic health evaluation (APACHE II) score, sepsis-related organ failure assessment (SOFA), and PaO2/FiO2 ratio. Duration of mechanical ventilation, length of intensive care unit stay, intensive care unit death, length of hospitalization, hospital death and one-year survival were calculated. RESULTS: The incidence of acute respiratory insufficiency was 37.2% (190/321). Multivariate logistic analysis showed a history of chronic obstructive pulmonary diseases (P=0.001), surgery-related infection (P=0.004), hypo-volemic shock (P<0.001), and emergency surgery (P=0.018), were independent risk factors of postoperative acute respiratory insufficiency. Compared with the patients without acute respiratory insufficiency, the patients with acute respiratory insufficiency had a prolonged length of intensive care unit stay (P<0.001), a prolonged length of hospitalization (P=0.006), increased intensive care unit mortality (P=0.001), and hospital mortality (P<0.001). Septic shock was shown to be the only independent prognostic factor of intensive care unit death for the patients with acute respiratory insufficiency (P=0.029, RR: 8.522, 95%CI: 1.243-58.437, B=2.143, SE=0.982, Wald=4.758). Compared with the patients without acute respiratory insufficiency, those with acute respiratory insufficiency had a shortened one-year survival rate (78.7% vs. 97.1%, P<0.001). CONCLUSION: A history of chronic obstructive pulmonary diseases, surgery-related infection, hypovolemic shock and emergency surgery were risk factors of critically ill cancer patients with postoperative acute respiratory insufficiency. Septic shock was the only independent prognostic factor of intensive care unit death in patients with acute respiratory insufficiency. Compared with patients without acute respiratory insufficiency, those with acute respiratory insufficiency had adverse short-term outcome and a decreased one-year survival rate.

Prognosis of patients with shock receiving vasopressors.

BACKGROUND: Consensus guidelines suggested that both dopamine and norepinephrine may be used, but specific doses are not recommended. The aim of this study is to determine the predictive role of vasopressors in patients with shock in intensive care unit. METHODS: One hundred and twenty-two patients, who had received vasopressors for 1 hour or more in intensive care unit (ICU) between October 2008 and October 2011, were included. There were 85 men and 37 women, with a median age of 65 years (55-73 years). Their clinical data were retrospectively collected and analyzed. RESULTS: The median simplified acute physiological score 3 (SAPS 3) was 50 (42-55). Multivariate analysis showed that septic shock (P=0.018, relative risk: 4.094; 95% confidential interval: 1.274-13.156), SAPS 3 score at ICU admission (P=0.028, relative risk: 1.079; 95% confidential interval: 1.008-1.155), and norepinephrine administration (P<0.001, relative risk: 9.353; 95% confidential interval: 2.667-32.807) were independent predictors of ICU death. Receiver operating characteristic curve analysis demonstrated that administration of norepinephrine ≥0.7 µg/kg per minute resulted in a sensitivity of 75.9% and a specificity of 90.3% for the likelihood of ICU death. In patients who received norepinephrine ≥0.7 µg/kg per minute there was more ICU death (71.4% vs. 44.8%) and in-hospital death (76.2% vs. 48.3%) than in those who received norepinephrine <0.7 µg/kg per minute. These patients had also a decreased 510-day survival rate compared with those who received norepinephrine <0.7 µg/kg per minute (19.2% vs. 64.2%). CONCLUSION: Septic shock, SAPS 3 score at ICU admission, and norepinephrine administration were independent predictors of ICU death for patients with shock. Patients who received norepinephrine ≥0.7 µg/kg per minute had an increased ICU mortality, an increased in-hospital mortality, and a decreased 510-day survival rate.

Two acute kidney injury risk scores for critically ill cancer patients undergoing non-cardiac surgery.

BACKGROUND: Several risk scoures have been used in predicting acute kidney injury (AKI) of patients undergoing general or specific operations such as cardiac surgery. This study aimed to evaluate the use of two AKI risk scores in patients who underwent non-cardiac surgery but required intensive care. METHODS: The clinical data of patients who had been admitted to ICU during the first 24 hours of ICU stay between September 2009 and August 2010 at the Cancer Institute, Chinese Academy of Medical Sciences & Peking Union Medical College were retrospectively collected and analyzed. AKI was diagnosed based on the acute kidney injury network (AKIN) criteria. Two AKI risk scores were calculated: Kheterpal and Abelha factors. RESULTS: The incidence of AKI was 10.3%. Patients who developed AKI had a increased ICU mortality of 10.9% vs. 1.0% and an in-hospital mortality of 13.0 vs. 1.5%, compared with those without AKI. There was a significant difference between the classification of Kheterpal's AKI risk scores and the occurrence of AKI (P<0.001). There was no significant difference between the number of Abelha's AKI risk scores and the occurrence of AKI (P=0.499). Receiver operating characteristic curves demonstrated an area under the curve of 0.655±0.043 (P=0.001, 95% confidence interval: 0.571-0.739) for Kheterpal's AKI risk score and 0.507±0.044 (P=0.879, 95% confidence interval: 0.422-0.592) for Abelha's AKI risk score. CONCLUSION: Kheterpal's AKI risk scores are more accurate than Abelha's AKI risk scores in predicting the occurrence of AKI in patients undergoing non-cardiac surgery with moderate predictive capability.