Background. Mitogen-activated protein kinase 3 (MAPK3) mediates the onset, progression, metastasis, drug resistance, and poor prognosis in various malignancies, including glioma, liver, ovarian, thyroid, lung, breast, gastric, and oral cancers. Negative regulation of MAPK3 expression using miRNAs has led to therapeutic effects in cancer. Objectives. The present study performed molecular docking and dynamics simulation to identify potential MAPK3 inhibitors from natural flavonoids, possibly leading to drug development in cancer therapy. Methods. A computational drug discovery approach was performed using the AutoDock tool to identify potential MAPK3 inhibitors from 46 plant-based flavonoids. A cross-validation study was executed using the Schrödinger Maestro docking tool. Molecular dynamics (MD) was executed to evaluate the stability of docked poses between the top-ranked compounds and the MAPK3 catalytic domain. Interactions among the most potent MAPK3 inhibitors and residues within the receptor’s active site were studied using the BIOVIA Discovery Studio Visualizer before and after 100 ns MD simulations. Results. Kaempferol 3-rutinoside-4′-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 exhibited a magnificent binding affinity to the receptor’s active site. In addition, the stability of the docked poses of these compounds seemed to be stable after ∼45 ns computer simulations. Conclusion. The present study suggests that kaempferol 3-rutinoside-4′-glucoside, kaempferol 3-rutinoside-7-sophoroside, rutin, and vicenin-2 could strongly bind to the MAPK3 catalytic site and could be assigned as a potent inhibitor for MAPK3. These findings may be helpful in the treatment of various cancers. However, further validation experiments are needed.

Exploiting human mesenchymal stem cells (hMSCs) was proposed as a promising therapeutic approach for cardiovascular disease due to their capacity to differentiate into cardiac cells. Though modulation of the intracellular signaling pathways dominantly WNT/β catenin and transforming growth factor-β (TGF-β) have been reported to promote differentiation of hMSCs into cardiomyocytes in the prevailing literature, a safe and reproducible system for their clinical application has not yet turned into reality. In the present study, the molecular docking-based strategy was first applied for evaluating the potency of some natural phenolic compounds in the modulation of Wnt and TGF-β signaling pathways using a vital class of crystallographic protein structures of WNT signaling regulators such as Frizzled, Disheveled, GSK3-β, β-catenin, LRP 5/6 extracellular domain, Tankyrase and their variety of active pockets. Then, the impacts of plant-derived chemical compounds on the regulation of the relevant signals for the differentiation of hMSCs into the definitive mesoderm lineage and cardiac progenitors were assessed in vitro. Data obtained revealed the synergistic activity of Wnt and TGF-β superfamily to direct cardiac differentiation in human cardiogenesis by comparing cardiac gene expression in the presence and absence of the TGF-β inhibitors. We found that the inhibitory effect of canonical Wnt/βcatenin is sufficient to cause proper cardiomyocyte differentiation, but the TGF-β pathway plays a vital role in enhancing the expression of the cardiomyocytespecific marker (cTnT). It was found that quercetin, a p38MAPK inhibitor with the high energy dock to the active pocket of Wnt receptors, promotes cardiac differentiation via the inhibition of both Wnt and non-Smad TGF-β pathways.Altogether, data presented here can contribute to the development of a feasible and efficient cardiac differentiation protocol as an "off-the-shelf" therapeutic source using novel natural agents for cardiac repair or regeneration.

Various degenerative diseases, traumatic injuries and cancers are almost hard to treat with conventional therapies, causing death or at least permanent disability. The use of multipotent adipose-derived mesenchymal stem cells (ADMSCs) for cell-based therapeutic applications has lately drawn elevated attention primarily due to their potential for differentiation into mesodermal lineages, which can finally be converted into cardiomyocytes to replace present invasive methods used to treat cardiac diseases. However, some reports hindered their clinical implementation due to concerns about efficacy scalability and reproducibility. In this research, we tested the impacts of using multiple natural small molecules and plant extract on the effectiveness of differentiating human ADMSCs into the definitive mesoderm lineage and cardiac progenitors. First, mesenchymal stem cells separated from human adult fat tissue, are propagated and characterized using flow cytometry and appropriate markers for this purpose. Second, passage cells are transferred to 24 well plates and treated with various plant-derived small molecules — primarily one of the most preserved intracellular signals, WNT/[Formula: see text]-catenin stimulators including resveratrol, stilbene, and multiple plant extracts — and assessed their impacts on differentiation into the definitive mesoderm and cardiac lineages. Obtained results revealed that our suggested strategy to differentiation is more viable and safer than present approaches. Taken together, data presented here showed that in vitro differentiation using plant-derived small molecules could be a potential way to improve the effectiveness of their final differentiation into definitive cardiomyocytes for in vivo applications.