A comparative pharmacogenomic analysis of three classic TCM prescriptions for coronary heart disease based on molecular network modeling.

Traditional Chinese medicine (TCM) has evolved over several thousands of years, which has been shown to be efficacious in the treatment of ischemic heart disease. Three classical TCM prescriptions, namely Xuefu Zhuyu Decoction, Zhishi Xiebai Guizhi Decoction, and Gualou Xiebai Banxia Decoction, have been extensively used in the treatment of coronary heart disease (CHD). Based on molecular network modeling, we performed a comparative pharmacogenomic analysis to systematically determine the drug-targeting spectrum of the three prescriptions at molecular level. Wide-area target molecules of CHD were covered, which was a common feature of the three decoctions, demonstrating their therapeutic functions. Meanwhile, collective signaling involved metabolic/pro-metabolic pathways, driving and transferring pathways, neuropsychiatric pathways, and exocrine or endocrine pathways. These organized pharmacological disturbance was mainly focused on almost all stages of CHD intervention, such as anti-atherosclerosis, lipid metabolism, inflammation, vascular wall function, foam cells formation, platelets aggregation, thrombosis, arrhythmia, and ischemia-reperfusion injury. In addition, heterogeneity analysis of the global pharmacological molecular spectrum revealed that signaling crosstalk, cascade convergence, and key targets were tendentious among the three decoctions. After all, it is unadvisable to rank the findings on targeting advantages of the three decoctions. Comparative pharmacological evidence may provide an appropriate decoction scheme for individualized intervention of CHD.

Genome Analysis Reveals a Synergistic Mechanism of Ursodeoxycholic Acid and Jasminoidin in Mice Brain Repair After Ischemia/Reperfusion: Crosstalk Among Muti-Pathways.

Studies have shown that combination drug therapy which corresponding treatment involves multiple genes and targets is more effective against cerebral ischemia. To identify the synergistic mechanism of ursodeoxycholic acid and jasminoidin based on differential pathway network, which protect against brain ischemia-reperfusion injury. Totally 115 mice with focal cerebral ischemia-reperfusion injury were allocated into five groups: sham, vehicle, ursodeoxycholic acid (UA), jasminoidin (JA), and JA and UA combination group (JU). The differentially expressed genes identified by microarray which consisted of 11,644 complementary DNAs were loaded to the GeneGo MetaCore™ software to analyze the enriched pathways and processes among different groups. Of the top 10 pathways and process networks, 5, 6, and 3 overlapping pathways as well as 5, 3, and 4 overlapping process networks were observed between UA and JA, UA and JU, and JA and JU, respectively. Of these, three pathways and three process networks overlapped across the three groups. Interestingly, four representative pathways and six process networks were only noted in the JU group. Gene Ontology process analysis showed 2 processes were shared by all three treatment groups in the top 10 processes. The UA and JA combination resulted in synergistic effects through affecting multi-signal transduction pathways, different locations in the same pathway, and the new signaling pathway emerged in drug combination group, those together may enhance the treatment of cerebral ischemia-reperfusion injury through promoting neural cell apoptosis, decreasing calcium levels, inhibiting inflammation, and protecting neurons.

Mining the Synergistic Core Allosteric Modules Variation and Sequencing Pharmacological Module Drivers in a Preclinical Model of Ischemia.

Identifying the variation of core modules and hubs seems to be critical for characterizing variable pharmacological mechanisms based on topological alteration of disease networks. We first identified a total of eight core modules by using an approach of multiple modular characteristic fusing (MMCF) from different targeted networks in ischemic mice. Interestingly, the value of module disturbance intensity (MDI) increased in drug combination group. Second, we redefined a weak allosteric module and a strong allosteric module. Then, we identified 15 pharmacological module drivers (PMDs) by leave-one-out screening with a cutoff of two folds, which were at least, in part, validated by expression and variation of topological contribution. Finally, we revealed the fusional and emergent variation of PMD in core modules contributing to multidimensional synergistic mechanism in ischemic mice and rats. Our findings provide a new set of drivers that might promote the pharmacological modular flexibility and offer a potential avenue for disease treatment.

[Study on electroacupuncture along the visual conductive pathway for ocular cell apoptosis in anterior ischemic optic neuropathy].

OBJECTIVE: To study the protective effect of electroacupuncture (EA) along the visual conductive pathway for the optic nerve tissue of anterior ischemic optic neuropathy (AION) in terms of the structure and apoptosis. METHODS: The AION model of right eye was established with laser in 48 New Zealand white ear rabbits. All rabbits were randomly divided into a model group, an acupuncture group and an acupuncture combined with EA group, 16 rabbits in each one. Other 16 normal left eyes were selected as a blank group. Acupuncture and EA of 30 min were used in the corresponding groups for 3 days at the right "Cuanzhu" (BL 2), "Yuyao" (EX-HN 4) and "Qiaomingxue" (Extra), once a day. There was no intervention in the model group and the blank group. The morphological structure and retinal thickness of lining of the optic nerve were detected with HE stain. The expressions of the Bcl-2 and Bax in the retina were detected with immunohistochemistry. And the concentration of tumor necrosis factor-α (TNF-α) in the retina was detected with enzyme linked immunosorbent assay (ELISA). RESULTS: In the model group, the ganglion cell layer revealed hyperplasia and disorder, and the retina ganglion cells revealed loose arrangements, thin inner nuclear layers, and reduction of cell amounts, some long parts missing cells. However, the above structural damages were much weaker in the acupuncture group and acupuncture combined with EA group. The inner layer of the retina in the model group was thinner than that in the blank group (P<0.05). That in the acupuncture combined with EA group showed significant better results than those in the acupuncture and model groups (both P<0.05), which was not statistically different from that in the normal group (P>0.05). The Bcl-2 count in the model group was lower than that in the blank group (P<0.05), and that in the acupuncture combined with EA group was better than those in the acupuncture and model groups (both P<0.05), not significantly different from that in the blank group (P>0.05). The number of Bax in the model group was higher than that in the blank group (P<0.05), and that in the acupuncture combined with EA group was lower than those in the acupuncture and model groups (both P<0.05), and was similar to that in the blank group (P>0.05). Bcl-2/Bax in the model group was lower than that in the blank group (P<0.05). The value in the acupuncture combined with EA group presented better than those in the acupuncture and model groups (both P<0.05), which had no difference from that in the blank group (P>0.05). TNF-α in the model group was higher than that in the blank group (P<0.05), and no such differences were detected between other groups and the model group (bothP>0.05). CONCLUSIONS: EA along the visual conductive pathway is protective to some extent for optic nerve tissue, which can increase the expression of Bcl-2 and reduce the expression of Bax so as to restrain ganglion cell apoptosis.

Confirming an integrated pathology of diabetes and its complications by molecular biomarker-target network analysis.

Despite ongoing research into diabetes and its complications, the underlying molecular associations remain to be elucidated. The systematic identification of molecular interactions in associated diseases may be approached using a network analysis strategy. The biomarker-target interrelated molecules associated with diabetes and its complications were identified via the Comparative Toxicogenomics Database (CTD); the Search Tool for Recurring Instances of Neighboring Genes was utilized for network construction. Functional enrichment analysis was performed with Database for Annotation, Visualization and Integrated Discovery software to investigate connections between diabetes and its complications. A total of 142 (including 122 biomarkers, 10 therapeutic targets and 10 overlapping molecules) biomarker-target interrelated molecules associated with diabetes and its complications were identified via the CTD database, and analysis of the network yielded 1,087 biological processes and fifteen Kyoto Encyclopedia of Genes and Genomes pathways with significant P­values. Various critical aspects of the networks were examined in the present study: a) Intermolecular horizontal and vertical combinations in biomarkers and therapeutic targets associated with diabetes and its complicationb) network topology properties associated with molecular pathological responsec) contribution of key molecules to integrated regulation; and d) crosstalk between multiple pathways. Based on a multi-dimensional analysis, it was concluded that the integrated molecular pathological development of diabetes and its complications does not proceed randomly, which suggests a requirement for integrated, multi-target intervention.