Revealing the Effects of the Herbal Pair of Euphorbia kansui and Glycyrrhiza on Hepatocellular Carcinoma Ascites with Integrating Network Target Analysis and Experimental Validation
Authors: Haiyu Zhao
Yanqiong Zhang
Ya Lin
Na Lin
Chen Yan
Qiuyan Guo
Journal: International journal of biological sciences (2016)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Euphorbia kansui; Glycyrrhiza; hepatocellular carcinoma ascites; herb-herb combination; network pharmacology..
Affiliations: 1. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China., 1. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.; 2. College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.

Abstract:  Although the herbal pair of Euphorbia kansui (GS) and Glycyrrhiza (GC) is one of the so-called "eighteen antagonistic medicaments" in Chinese medicinal literature, it is prescribed in a classic Traditional Chinese Medicine (TCM) formula Gansui-Banxia-Tang for cancerous ascites, suggesting that GS and GC may exhibit synergistic or antagonistic effects in different combination designs. Here, we modeled the effects of GS/GC combination with a target interaction network and clarified the associations between the network topologies involving the drug targets and the drug combination effects. Moreover, the "edge-betweenness" values, which is defined as the frequency with which edges are placed on the shortest paths between all pairs of modules in network, were calculated, and the ADRB1-PIK3CG interaction exhibited the greatest edge-betweenness value, suggesting its crucial role in connecting the other edges in the network. Because ADRB1 and PIK3CG were putative targets of GS and GC, respectively, and both had functional interactions with AVPR2 approved as known therapeutic target for ascites, we proposed that the ADRB1-PIK3CG-AVPR2 signal axis might be involved in the effects of the GS-GC combination on ascites. This proposal was further experimentally validated in a H22 hepatocellular carcinoma (HCC) ascites model. Collectively, this systems-level investigation integrated drug target prediction and network analysis to reveal the combination principles of the herbal pair of GS and GC. Experimental validation in an in vivo system provided convincing evidence that different combination designs of GS and GC might result in synergistic or antagonistic effects on HCC ascites that might be partially related to their regulation of the ADRB1-PIK3CG-AVPR2 signal axis. 

Retracted: Yes

PubPeer comments:
 Fig. 7A: Tubulin gel with 9 bands was used to represent the control loading of an experiment with 10 conditions. Could authors check it please? ![file] , 
 The EMBO Journal is aware of the issues reported here and is working with the authors to address these concerns. , 
 According to the literature, murine and human caspase 12 are not functionally equivalent. Indeed most humans carry a polymorphism that results in a truncated, non-functional caspase 12 (for example 100% of Caucasian populations). Even full length human caspase 12 (found in some sub-Saharan populations) is believed to not to have a role in apoptosis, but may be involved in inflammation. In this regards, Figure 7 showing apparently full length (all samples) and active (some samples) caspase 12 in human brain samples is somewhat surprising. , 
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 The journal was informed of potential image aberrations in Fig 7A. The authors claim that the loading control in the originally published figure corresponded to a replicate experiment as many Western blots were run in parallel with the same samples to measure levels of ER stress markers. The control panel in Fig 7A is herewith retracted and replaced with the author-supplied loading control of the experiment shown in Fig 7A. The journal noted that Fig 3 and Appendix Figure 3 were duplicated and that the legend to Appendix Figure 3 did not match the displayed figure. The authors recovered the quantification data for Appendix Figure 3, but not the scanned blots. The authors state that they no longer have access to the laboratory books or primary data and that they cannot definitively say which image was analysed. **The authors withdraw Appendix Figure 3.** The authors also acknowledge that there are undeclared splice sites in Fig 3, but that they could not locate the source data. The source data for Fig 7A are available with this corrigendum notice. The authors apologize for these errors and agree with this corrigendum; no response could be obtained from MR-C. https: www.embopress.org doi full 10.15252 embj.2021109151 , 
 #6  The source data for Fig 7A are available with this corrigendum notice. Here is what they refer to: *** ![file] ,