Entropy-based divergent and convergent modular pattern reveals additive and synergistic anticerebral ischemia mechanisms

Abstract

Module-based network analysis of diverse pharmacological mechanisms is critical to systematically understand combination therapies and disease outcomes. We first constructed drug-target ischemic networks in baicalin, jasminoidin, ursodeoxycholic acid, and their combinations baicalin and jasminoidin as well as jasminoidin and ursodeoxycholic acid groups and identified modules using the entropy-based clustering algorithm. The modules 11, 7, 4, 8 and 3 were identified as baicalin, jasminoidin, ursodeoxycholic acid, baicalin and jasminoidin and jasminoidin and ursodeoxycholic acid-emerged responsive modules, while 12, 8, 15, 17 and 9 were identified as disappeared responsive modules based on variation of topological similarity, respectively. No overlapping differential biological processes were enriched between baicalin and jasminoidin and jasminoidin and ursodeoxycholic acid pure emerged responsive modules, but two were enriched by their co-disappeared responsive modules including nucleotide-excision repair and epithelial structure maintenance. We found an additive effect of baicalin and jasminoidin in a divergent pattern and a synergistic effect of jasminoidin and ursodeoxycholic acid in a convergent pattern on ''central hit strategy'' of regulating inflammation against cerebral ischemia. The proposed module-based approach may provide us a holistic view to understand multiple pharmacological mechanisms associated with differential phenotypes from the standpoint of modular pharmacology.

Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage

“…Such multiple interactions and complexity are summarized in Figure 3 and have been suggested in pathophysiology reviews by Lipton ( 68 ) and others ( 14 , 20 , 40 , 70 – 72 , 91 , 92 , 99 ). Given the numerous highly variable, possibly nonlinear, biological and health system/social factors that contribute to post insult brain damage, it is unsurprising that clinical studies directed at improving only one of numerous complex interacting factors tend to show no or little effect.…”

“…DNA based systems have inherent variation in genes and in translation of important proteins thereby leading to a large number of disparate and interacting factors ( 14 , 68 – 72 ) contributing to S with also an unknown number of as yet unknown other factors with correspondingly unknown variability and weighting. Such uncertainty supports the need to do proper foundational studies before clinical efficacy trials.…”

Prediction of hepatocellular carcinoma risk in patients with chronic liver disease from dynamic modular networks

“…From the perspective of Modular Pharmacology, sequential AMs might contribute to illustrating the molecular mechanism of the pathological progression from CHB to HCC. CAMs , OAMs and DEMs might have pharmacological implications at the systems level and serve as universal or specific therapeutic targets in disease treatment [ 33 , 34 ]. Further, OAMs might play an important role in the pathological progression from CHB to cirrhosis to HCC, and therefore had considerable clinical value in predicting early-stage HCC risk.…”

Divergence and Convergence of Cerebral Ischemia Pathways Profile Deciphers Differential Pure Additive and Synergistic Mechanisms

“…The additive effect of BJ was suggested to rest on the cross-talks of pathways from BA and JA at horizontal and vertical levels, including enhanced action in virus-mediated immune response . The synergistic effect of JU may regulate inflammation through a few key molecules in the network to treat ischemic stroke (Yu et al, 2016). All of these findings provide a hint for distinction between additive and synergistic effects.…”

“…In previous studies, combination of BA and JA (BJ) have been demonstrated to exert an additive effect, while combination of JA and UA (JU) acted synergistically in treating cerebral ischemia (Chen et al, 2013;Yu et al, 2016;Zhang et al, 2016;. The monocomponents of BA, JA, or UA was proved to have multiple pharmacological functions, such as antiinflammatory (Chen et al, 2018;Kang et al, 2018;Ko et al, 2019), antioxidant (Srinivas, 2010), neuroprotective (Wu et al, 2018;, antiplatelet (Lee et al, 2015), and protein response (Vang et al, 2014).…”