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Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.

ABSTRACT: INTRODUCTION:Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance. AIMS:We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities. RESULTS:We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions. CONCLUSIONS:These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations.

SUBMITTER: Zhang YY

PROVIDER: S-EPMC6493057 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.

Zhang Ying-Ying YY Li Hai-Xia HX Chen Yin-Ying YY Fang Hong H Yu Ya-Nan YN Liu Jun J Jing Zhi-Wei ZW Wang Zhong Z Wang Yong-Yan YY

CNS neuroscience & therapeutics 20131219 3

<h4>Introduction</h4>Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance.<h4>Aims</h4>We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicali ...[more]

PMID: 24351012

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Project description:AimThe variable mechanisms on additive and synergistic effects of jasminoidin (JA)-Baicalin (BA) combination and JA-ursodeoxycholic acid (UA) combination in treating cerebral ischemia are not completely understood. In this study, we explored the differential pure mechanisms of additive and synergistic effects based on pathway analysis that excluded ineffective interference.MethodsThe MCAO mice were divided into eight groups: sham, vehicle, BA, JA, UA, Concha Margaritifera (CM), BA-JA combination (BJ), and JA-UA combination (JU). The additive and synergistic effects of combination groups were identified by cerebral infarct volume calculation. The differentially expressed genes based on a microarray chip containing 16,463 oligoclones were uploaded to GeneGo MetaCore software for pathway analyses and function catalogue. The comparison of specific pathways and functions crosstalk between different groups were analyzed to reveal the underlying additive and synergistic pharmacological variations.ResultsAdditive BJ and synergistic JU were more effective than monotherapies of BA, JA, and UA, while CM was ineffective. Compared with monotherapies, 43 pathways and six functions were found uniquely in BJ group, with 33 pathways and three functions in JU group. We found six overlapping pathways and six overlapping functions between BJ and JU groups, which mainly involved central nervous system development. Thirty-seven specific pathways and 10 functions were activated by additive BJ, which were mainly related to cell adhesion and G-protein signaling; and 27 specific pathways and three functions of synergistic JU were associated with regulation of metabolism, DNA damage, and translation. The overlapping and distinct pathways and functions may contribute to different additive and synergistic effects.ConclusionThe divergence pathways of pure additive effect of BJ were mainly related to cell adhesion and G-protein signaling, while the pure synergistic mechanism of JU depended on metabolism, translation and DNA damage. Such a systematic analysis of pathways may provide an important paradigm to reveal the pharmacological mechanisms underlying drug combinations.

Project description:Silymarin is a bioactive constituent isolated from milk thistle (Silybum marinum). Since its discovery, silymarin has been considered a gold standard drug in treating ailments related to the liver, resulting from alcohol consumption and viral hepatitis. This hepatoprotective nature of silymarin arises out of antioxidative and tissue-regenerating properties of silymarin. However, several recent studies have established the neuroprotective link of silymarin, too. Thus, the current investigation was aimed at exploring the neuroprotective effect of nanosilymarin (silymarin encapsulated inside collagen-based polymeric nanoparticulate drug delivery system). The study aimed at bringing out the role of nanoparticles in enhancing the therapeutic effect of silymarin against neuronal injury, originating out of oxidative-stress-related brain damages in focal cerebral ischemia. Collagen-based micellar nanoparticles were prepared and stabilized using 3-ethyl carbodiimide-hydrochloride (EDC-Hcl) and malondialdehyde (MDA) as crosslinkers. Nanoparticles were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), and Fourier transform infrared (FT-IR) spectroscopy techniques, and the size of nanoparticles was found to be around 48 nm. Male albino Wistar rats were pretreated with three different doses of nanosilymarin of 10, 100, and 1,000 ?g/kg b.wt and a dose of free silymarin of 100 mg/kg b.wt intraperitoneally (i.p.) for 7 days. Focal cerebral ischemia was induced using the middle cerebral artery occlusion (MCAO) model on the eighth day for 1 h followed by 24 h reperfusion. The animals were then evaluated for neurobehavioral, infarct analysis, biochemical, histopathological, and immunohistochemical studies. All the above parameters showed remarkable improvement in nanosilymarin-treated groups in comparison to the silymarin-treated group. Nanoparticle encapsulation of drug enhanced neuroprotection by increasing drug bioavailability and targeting. Thus, the present study concluded with satisfactory results, showing the critical role played by nanoparticles in improving the neuroprotection at very low drug doses.

Project description:BACKGROUND:Ischemic stroke is a deadly disease that poses a serious threat to human life. Superoxide dismutase 3 (SOD3, ECSOD) is the main antioxidant enzyme that removes superoxide anions from cells. This study aimed to investigate the effect of SOD3 overexpression on cerebral ischemia-reperfusion injury in rats. METHODS:GV230-EGFP-ECSOD, the recombinant SOD3-overexpressed vector, was constructed by genetic engineering technology, and mesenchymal stem cells (MSCs) were infected with lentiviral packaging. In animal experiment, cerebral ischemia-reperfusion injury model rats were successfully established. ECSOD-MSCs are the MSCs that successfully transfected with SOD3 overexpression vector. The animals were injected with ECSOD-MSCs (ECSOD-MSC group), normal MSCs (MSCs group), PBS (PBS group), and not do any processing (Model group) via the tail vein. Then MRI was used to detect the infarct volume of rats, modified Neurological Severity Scores (mNSS), and immunohistochemistry were used to evaluate the expression of neurological function and apoptosis-related genes in rats. RESULTS:Western blot analysis revealed that the SOD3 was highly expressed in MSCs. Animal experiments showed that the transplantation of ECSOD-MSCs significantly reduced the infarct volume of ischemic stroke rats (p < 0.05), significantly improved neurological function in rats (p < 0.05), and found proapoptotic gene, Bax, expression was significantly decreased (p < 0.05), the expression of anti-apoptotic gene, Bcl-2, was significantly increased (p < 0.05). The highly expressed SOD3 has no correction with brain infarct volume, and the highly expressed SOD3 has a positive correlation with cell apoptosis. It is speculated that overexpression of SOD3 affects the expression of Bax and Bcl-2, and improves apoptosis to alleviate ischemic stroke. CONCLUSION:Our results indicated that MSCs transfected with SOD3 can effectively alleviate cerebral ischemia-reperfusion injury in rats.

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Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.

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Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.

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