Therapeutic properties of Scutellaria baicalensis in db/db mice evaluated using Connectivity Map and network pharmacology

Abstract

We have reported that an extract of Scutellaria baicalensis (ESB) has effects against obesity and hypertriglyceridemia in type 2 diabetic animal model (db/db mouse). In the present study, we tried to explain the pharmacological effects of ESB by integrating gene expression information from db/db mouse liver with that of ESB-treated HepG2 hepatocellular carcinoma cells. Using Connectivity Map (cmap) analysis, we found an inverse relationship in the pharmaceutical profiles based on gene expression between db/db mouse liver and ESB-treated HepG2 cells. This inverse relationship between the two data sets was also observed for pathway activities. Functional network analysis showed that biological functions associated with diabetes and lipid metabolism were commonly enriched in both data sets. We also observed a similarity in distribution of cmap enrichment scores between db/db mouse liver and human diabetic liver, whereas there was an inverse pattern of cmap enrichment scores in human diabetic liver compared with ESB-treated HepG2 cells. This relationship might explain the pharmacological activities of ESB against db/db mouse and possible effectiveness of ESB against human diabetes. We expect that our approach using in vitro cell lines could be applied in predicting the pharmacological effectiveness of herbal drugs in in vivo systems.

Evaluation of Animal Models by Comparison with Human Late-Onset Alzheimer’s Disease

“…In accordance with the results of the direct measurement of pathway activity, upregulated and downregulated AD genes showed reciprocal associations with signaling pathways (pathway clusters 1 and 6) and metabolism pathways (pathway cluster 3), respectively. We reported previously the reciprocal regulation of biological functions between signaling pathways and metabolic pathways in diverse biological situations [ 15 , 17 , 18 ] which suggests that the reciprocal regulation of gene expression and biological functions may be the global regulatory mechanism that is predetermined in the promoter sequences of genes. Protein modification such as glycosylation, acetylation, and phosphorylation is also thought to play an important role in the reciprocal regulation of metabolism and signaling processes [ 54 ].…”

“…Probes on arrays with signal intensities that were 1.4-fold higher than the local background were selected exclusively, as described previously [ 17 , 18 ], and were then normalized using the quantile method, which can adjust the variability within and between samples [ 19 ]. Hierarchical clustering based on the expression levels of genes was performed using the Gene Cluster 3.0 program and visualized using the Java TreeView program [ 20 ].…”

“…After a random permutation of 1000, statistical significance was presented as nominal p values and FDR q values. As another measurement of pathway enrichment using the expression values of all genes included in each pathway, pathway activity was examined by calculating the cumulative effect of the expression of all genes in each pathway [ 15 , 18 ]. In brief, the log-transformed expressional ratios of genes relative to the normal control in each pathway were added linearly with a weight of − 1 for genes that acted as repressors, which were defined as proteins that inhibited the process of signal transduction of the pathway.…”

Similarity of therapeutic networks induced by a multi-component herbal remedy, Ukgansan, in neurovascular unit cells

“…pathway activity. As a measure of pathway activity, the expression values of genes included in the pathway were used as previously reported by us 29,30,50 . In brief, for each pathway, the log-transformed values of expression ratios of genes compared to the control were added linearly.…”

“…In recent years, many herbal medicine studies applied network-based approaches to overcome the lack of information on the targets of the identified herbal constituents 27,28 . We also reported that combining omics and pharmacogenomics network approaches can reveal the therapeutic properties of herbal drugs 29,30 . However, unfortunately, most network-based studies of herbal drugs are based on limited experimental evidence that does not fully reflect the diverse aspects of the disease.…”