仔泻康口服液药效学和分子机制研究
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摘要
试验旨在探讨仔泻康口服液治疗仔猪腹泻的药效学和分子机制,为药物的进一步开发提供试验依据。通过小肠推进试验、止泻试验、耳廓肿胀抑制试验、镇痛试验及体外抑菌试验验证仔泻康口服液的药理作用,同时利用网络药理学对仔泻康口服液活性成分进行筛选和靶点预测,并结合生物信息学手段确定仔泻康口服液治疗腹泻的特异性靶点,通过信号通路富集分析探讨其治疗腹泻的分子机制。结果显示,随着剂量的增多,仔泻康口服液抗炎及镇痛效果呈上升趋势,与空白对照组相比差异显著(P<0.05);与空白对照组相比,仔泻康口服液低、中、高剂量组均能显著抑制小鼠小肠碳素墨汁推进距离及推进率,低剂量组差异显著(P<0.05)。仔泻康口服液对大肠杆菌及金黄色葡萄球菌均有抑菌作用,对大肠杆菌效果更明显。本试验利用网络药理学预测了仔泻康口服液的止泻机制,其参与Wnt信号通路,调控细菌侵袭上皮细胞,同时也影响致病性大肠杆菌感染信号等通路;MAPK信号通路通过促进或抑制基因的转录来调控其他炎症介质的生成,同时炎症介质可通过激活MAPK通路和增加细胞表面多种黏附分子的表达促进细胞间黏附和炎症的进展等;NRG/ErbB信号参与神经病理性疼痛的多个方面,在中枢神经系统,主要通过MEK/ERK通路激活小胶质细胞,释放一系列细胞因子和炎性介质,促进神经性疼痛;同时通过调节突触可塑性及中枢去抑制等方式参与神经病理性疼痛;在外周神经系统,NRG/ErbB信号通过调节非髓鞘形成细胞和髓鞘形成施万细胞功能,参与外周神经痛ErbB信号,对镇痛起重要作用等。综上所述,仔泻康口服液可能从肠蠕动、抗炎、镇痛及抑菌4个方面来抑制腹泻。
The purpose of the experiment was to explore the pharmacodynamics and molecular mechanism of Zixiekang oral liquid in treating piglet diarrhea,and provide experimental basis for the further development of the drug.The pharmacological effects of Zixiekang oral liquid were verified by small intestinal propulsion test,diarrhea control test,ear swelling inhibition test,analgesic test and in vitro bacteriostasis test.Meanwhile,the active components of Zixiekang oral liquid were screened by network pharmacology.Target prediction and bioinformatics were used todetermine the specific target of Zixiekang oral liquid for treating diarrhea.The molecular mechanism of the treatment of diarrhea was discussed by signal pathway enrichment analysis.The results showed that the anti-inflammatory and analgesic effects of Zixiekang oral liquid increased with the increase of dosage,and low dose of Zixiekang oral liquid had significant difference compared with blank control group(P<0.05);Compared with blank control group,the low,middle and high dose groups could all inhibit the propelling distance and pushing rate of small intestine carbon ink in mice,and the low dose group had significant difference(P<0.05).Zixiekang oral liquid had bacteriostasis effect on both Escherichia coli and Staphylococcus aureus,and had the more obvious effect on Escherichia coli.In this experiment,the antidiarrhea mechanism of Zixiekang oral liquid was predicted by network pharmacology,and it participated in Wnt signaling pathway to regulate the bacterial invasive epithelial cells,and also affected pathogenic Escherichia coli infection signal pathway;MAPK signaling pathway regulated the production of other inflammatory mediators by promoting or inhibiting the transcription of genes.At the same time,inflammatory mediators could increase the expression of various adhesion molecules on the cell surface by activating the MAPK pathway,and promote the progress of intercellular adhesion and inflammation.NRG/ErbB signal was involved in many aspects of neuropathic pain.In the central nervous system,microglia were activated by MEK/ERK pathway and a series of cytokines and inflammatory mediators were released to promote neuropathic pain.Neuropathic pain was also involved in neuropathic pain by regulating synaptic plasticity and central disinhibition.Peripheral nervous system,NRG/ErbB signal played an important role in analgesia by regulating the function of nonmyelin forming cells and myelin forming Schwann cells and participating in ErbB signal of peripheral neuralgia.In summary,Zixiekang oral liquid might inhibit diarrhea from four aspects:Intestinal peristalsis,anti-inflammation,analgesia and bacteriostasis.
The purpose of the experiment was to explore the pharmacodynamics and molecular mechanism of Zixiekang oral liquid in treating piglet diarrhea,and provide experimental basis for the further development of the drug.The pharmacological effects of Zixiekang oral liquid were verified by small intestinal propulsion test,diarrhea control test,ear swelling inhibition test,analgesic test and in vitro bacteriostasis test.Meanwhile,the active components of Zixiekang oral liquid were screened by network pharmacology.Target prediction and bioinformatics were used todetermine the specific target of Zixiekang oral liquid for treating diarrhea.The molecular mechanism of the treatment of diarrhea was discussed by signal pathway enrichment analysis.The results showed that the anti-inflammatory and analgesic effects of Zixiekang oral liquid increased with the increase of dosage,and low dose of Zixiekang oral liquid had significant difference compared with blank control group(P<0.05);Compared with blank control group,the low,middle and high dose groups could all inhibit the propelling distance and pushing rate of small intestine carbon ink in mice,and the low dose group had significant difference(P<0.05).Zixiekang oral liquid had bacteriostasis effect on both Escherichia coli and Staphylococcus aureus,and had the more obvious effect on Escherichia coli.In this experiment,the antidiarrhea mechanism of Zixiekang oral liquid was predicted by network pharmacology,and it participated in Wnt signaling pathway to regulate the bacterial invasive epithelial cells,and also affected pathogenic Escherichia coli infection signal pathway;MAPK signaling pathway regulated the production of other inflammatory mediators by promoting or inhibiting the transcription of genes.At the same time,inflammatory mediators could increase the expression of various adhesion molecules on the cell surface by activating the MAPK pathway,and promote the progress of intercellular adhesion and inflammation.NRG/ErbB signal was involved in many aspects of neuropathic pain.In the central nervous system,microglia were activated by MEK/ERK pathway and a series of cytokines and inflammatory mediators were released to promote neuropathic pain.Neuropathic pain was also involved in neuropathic pain by regulating synaptic plasticity and central disinhibition.Peripheral nervous system,NRG/ErbB signal played an important role in analgesia by regulating the function of nonmyelin forming cells and myelin forming Schwann cells and participating in ErbB signal of peripheral neuralgia.In summary,Zixiekang oral liquid might inhibit diarrhea from four aspects:Intestinal peristalsis,anti-inflammation,analgesia and bacteriostasis.
引文
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