Bindarit

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI).Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models.In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms.MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice.Intramyocardial injection of recombinant CCL2 (rCCL2, 1μg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice.Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice.Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs).We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30μM) suppressed rCCL2-induced cardiomyocyte proliferation.In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

Ras gene is frequently mutated in cancer. Among different subtypes of Ras gene, K-Ras mutation occurs in nearly 30 % of human cancers. K-Ras mutation, specifically K-Ras (G12D) mutation is prevalent in cancers like lung, colon and pancreatic cancer. During cancer occurrence, mutant Ras remain in activated form (GTP bound state) for cancer cell proliferation. In the quest for a potential K-Ras inhibitor, nitrogen-containing indazole derivatives can show promise as inhibitors, as they have numerous therapeutic properties like anti-inflammatory, anti-viral and anti-tumor. Furthermore, among various indazole derivatives, "Bindarit" is an important therapeutic compound which could have potential inhibitory action against K-Ras due to its structural resemblance with reference compound "Benzimidazole". So, the current study is an attempt to find out the inhibitory effect of Bindarit against K-Ras activation by binding to a pocket which is adjacent to the switch I/II regions of the K-Ras receptor. AutoDock tool was used to investigate the binding affinity of protein ligand interaction and GROMACS package was utilised to assess their interactions in a dynamic setting. Bindarit shows better binding affinity than reference with binding energy of -7.3 kcal/mol. Upon ligand binding conformational changes take place, which could lead to the loss of GTPase activity. Consequently, further downstream signalling of the K-Ras pathway would be blocked and this could lead to the inhibition of K-Ras dependent cancer cell proliferation. However, further validation of present study can be done through experimental assay such as cytotoxic and protein expression analysis.