Inhibitory Effects of Momordicine I on High‐Glucose‐Induced Cell Proliferation and Collagen Synthesis in Rat Cardiac Fibroblasts

Abstract

Diabetes-associated cardiac fibrosis is a severe cardiovascular complication. Momordicine I, a bioactive triterpenoid isolated from bitter melon, has been demonstrated to have antidiabetic properties. This study investigated the effects of momordicine I on high-glucose-induced cardiac fibroblast activation. Rat cardiac fibroblasts were cultured in a high-glucose (25 mM) medium in the absence or presence of momordicine I, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed. Increased oxidative stress plays a critical role in the development of high-glucose-induced cardiac fibrosis; we further explored momordicine I's antioxidant activity and its effect on fibroblasts. Our data revealed that a high-glucose condition promoted fibroblast proliferation and collagen synthesis and these effects were abolished by momordicine I (0.3 and 1 μM) pretreatment. Furthermore, the inhibitory effect of momordicine I on high-glucose-induced fibroblast activation may be associated with its activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of reactive oxygen species formation, TGF-β1 production, and Smad2/3 phosphorylation. The addition of brusatol (a selective inhibitor of Nrf2) or Nrf2 siRNA significantly abolished the inhibitory effect of momordicine I on fibroblast activation. Our findings revealed that the antifibrotic effect of momordicine I was mediated, at least partially, by the inhibition of the TGF-β1/Smad pathway, fibroblast proliferation, and collagen synthesis through Nrf2 activation. Thus, this work provides crucial insights into the molecular pathways for the clinical application of momordicine I for treating diabetes-associated cardiac fibrosis.

Momordicine-I, a Bitter Melon Bioactive Metabolite, Displays Anti-Tumor Activity in Head and Neck Cancer Involving c-Met and Downstream Signaling

“…Although the compound was identified in 1984, the biological function of M-I was not well evaluated. M-I was recently reported to have inhibitory effects on high-glucose-induced cell proliferation and collagen synthesis in rat cardiac fibroblasts [ 31 ] and stimulate insulin secretion in vitro [ 32 ], but to the best of our knowledge, the anticancer effect of M-I was not reported. We initially screened a few metabolites from bitter melon and got a significant inhibition with M-I with IC 50 of less than 8 μg/mL in Cal27 and JHU029 cells.…”

The Study of Combination Ethanol Extract of Averrhoa bilimbi L. and Momordica charantia L. on CD4+CD25+TGF-β+ Spleenocytes of Hyperglycemia Mice

“…The momordicine 1 found in M. charantia L. fruit can significantly improve glucose-induced ROS by activating the Nrf2/HO-1 pathway. Momordicine 1 can inhibit fibrogenesis through modulation of Nrf2-mediated TGF-β1-Smad2/3 signal transduction [28]. While the charantin compound from M. charantia L. fruit can stimulate the pancreas-β cells to produce insulin, increase glycogen sugar reserve deposits in the liver.…”

“…Starfruit contains flavonoids, triterpenoids, and quercetin. Flavonoids are active antihipoglycemic compounds by stimulating insulin secretion [28,29]. Also, the flavonoid is alpha-glucosidase inhibitors which function to delay carbohydrate absorption [30].…”

The Effect of Momordica charantia in the Treatment of Diabetes Mellitus: A Review

“…In T2DM and related cardiovascular diseases, bitter melon extract enhances cardiac function and mitigates postischemic/reperfused infarct zone, which have correlation with reduced expression of caspase-3 in heart [ 121 ]. It is evidenced that MC can be used to treat diabetes-associated cardiac fibrosis because of its inhibitory capacity in fibroblast proliferation and collagen synthesis, which is mediated by suppressing TGF- β 1/Smad pathway and activating Nrf2 [ 122 ]. Polysaccharide from MC is discovered to have powerful angiotensin-converting enzyme inhibitory properties (94.1%) [ 52 ], pointing to its application in various cardiovascular complications.…”