Madecassic acid

Biomed Pharmacother. 2016 Dec;84:845-852.

Madecassic Acid protects against hypoxia-induced oxidative stress in retinal microvascular endothelial cells via ROS-mediated endoplasmic reticulum stress.[Pubmed: 27728894 ]

Madecassic acid (MA) is an abundant triterpenoid in Centella asiatica (L.) Urban. (Apiaceae) that has been used as a wound-healing, anti-inflammatory and anti-cancer agent. Up to now, the effects of MA against oxidative stress remain unclear.
METHODS AND RESULTS:
In this study, we investigated the effect of MA and its mechanisms on hypoxia-induced human Retinal Microvascular Endothelial Cells (hRMECs). hRMECs were pre-treated with different concentrations of MA (0-50μM) for 30min before being incubated under hypoxia condition (37°C, 5% CO2 and 95% N2). Cell apoptosis was evaluated with MTT assay and TUNEL staining, and the expression of apoptosis- and endoplasmic reticulum (ER) stress-related molecules was assessed with western blotting and RT-PCR analysis. Intracellular ROS level was evaluated using DCFH-DA. Intracellular malondialdehyde (MDA), dehydrogenase (LDH), glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD) were evaluated using related Kits. Activating transcription factor 4 (ATF4) nuclear translocation was assessed with western blotting analysis and immunofluorescence staining. MA significantly reduced oxidative stress in hypoxia-induced hRMECs, as shown by increased cell viability, SOD and GSH-PX leakage, decreased TUNEL- and ROS-positive cell ratio, LDH and MDA leakage, caspase-3 and -9 activity, and Bax/Bcl-2 ratio. In addition, MA also attenuated hypoxia-induced ER stress in hRMECs, as shown by reduced mRNA levels of glucose-regulated protein 78 (GRP78), C/EBP homologous transcription factor (CHOP), protein levels of cleaved activating transcription factor 6 (ATF6) and inositol-requiring kinase/endonuclease 1 alpha (IRE1α), phosphorylation of pancreatic ER stress kinase (PERK) and eukaryotic initiation factor 2 alpha (eIF2α), cleaved caspase-12 and ATF4 translocation to nucleus.
CONCLUSIONS:
The current study indicated that the regulation of oxidative stress and ER stress by MA would be a promising therapy to reverse the process and development of hypoxia-induced hRMECs dysfunction.

Nutrients. 2015 Dec 2;7(12):10065-75.

Anti-Diabetic Effects of Madecassic Acid and Rotundic Acid.[Pubmed: 26633490 ]

Anti-diabetic effects of Madecassic acid (MEA) and rotundic acid (RA) were examined.
METHODS AND RESULTS:
MEA or RA at 0.05% or 0.1% was supplied to diabetic mice for six weeks. The intake of MEA, not RA, dose-dependently lowered plasma glucose level and increased plasma insulin level. MEA, not RA, intake dose-dependently reduced plasminogen activator inhibitor-1 activity and fibrinogen level; as well as restored antithrombin-III and protein C activities in plasma of diabetic mice. MEA or RA intake decreased triglyceride and cholesterol levels in plasma and liver. Histological data agreed that MEA or RA intake lowered hepatic lipid droplets, determined by ORO stain. MEA intake dose-dependently declined reactive oxygen species (ROS) and oxidized glutathione levels, increased glutathione content and maintained the activity of glutathione reductase and catalase in the heart and kidneys of diabetic mice. MEA intake dose-dependently reduced interleukin (IL)-1β, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels in the heart and kidneys of diabetic mice. RA intake at 0.1% declined cardiac and renal levels of these inflammatory factors.
CONCLUSIONS:
These data indicated that MEA improved glycemic control and hemostatic imbalance, lowered lipid accumulation, and attenuated oxidative and inflammatory stress in diabetic mice. Thus, Madecassic acid could be considered as an anti-diabetic agent.

Planta Med. 2010 Feb;76(3):251-7.

Anti-inflammatory effects of madecassic acid via the suppression of NF-kappaB pathway in LPS-induced RAW 264.7 macrophage cells.[Pubmed: 19774506]

METHODS AND RESULTS:
We have investigated the anti-inflammatory effects of Madecassic acid and madecassoside isolated from Centella asiatica (Umbelliferae) on lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage cells. Both Madecassic acid and madecassoside inhibited the production of nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and IL-6. However, Madecassic acid more potently suppressed these inflammatory mediators than did madecassoside. Consistent with these observations, Madecassic acid inhibited the LPS-induced expression of iNOS and COX-2 at the protein level and of iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6 at the mRNA level in RAW 264.7 macrophage cells, as determined by Western blotting and RT-PCR, respectively. Furthermore, Madecassic acid suppressed the LPS-induced activation of nuclear factor-kappaB (NF-kappaB), and this was associated with the abrogation of inhibitory kappa B-alpha (IkappaB-alpha) degradation and with the subsequent blocking of p65 protein translocation to the nucleus.
CONCLUSIONS:
These results suggest that the anti-inflammatory properties of Madecassic acid are caused by iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6 inhibition via the downregulation of NF-kappaB activation in RAW 264.7 macrophage cells.

J BUON. 2014 Apr-Jun;19(2):372-6.

Madecassic acid inhibits the mouse colon cancer growth by inducing apoptosis and immunomodulation.[Pubmed: 24965394]

PURPOSE: To investigate the antitumor effects of Madecassic acid and to investigate the mechanism by which Madecassic acid treatment functions in malignancies. METHODS: Mouse colon CT26 cancer cells injected in mice subcutaneously and intraperitoneally were used to evaluate the tumor growth inhibition by Madecassic acid administration. The immunomodulation, cell apoptosis and mitochondrial membrane potential change were evaluated by flow cytometry, cell immunostaining and JC-1 staining, respectively. RESULTS: Madecassic acid inhibited tumor growth in tumor- bearing mice. CT26 cell apoptosis rate and of the cells from ascites was increased after Madecassic acid treatment. Mitochondrial membrane potential in CT26 cells also decreased after Madecassic acid treatment. CD4(+) and CD8(+) T- lymphocytes subpopulations increased, while the ratio of CD4(+)/ CD8(+) decreased in after Madecassic acid administration. CONCLUSIONS: Madecassic acid inhibits in vivo CT26 cell-induced tumor growth by facilitating cell apoptosis and increasing immune defense mechanisms.