Coumestrol is a novel inducer of mitochondrial biogenesis through the activation of Sirt1, it suppresses the accumulation of HIF-1α via suppression of SPHK1 pathway in hypoxic PC-3 cells. Coumestrol can function by inhibiting oncogenic disease, at least in part, through CKII inhibition-mediated cellular senescence. Coumestrol treatment is effective in preventing neuronal loss in all times of administration as well as able to rescue the Na+, K+ -ATPase activity, suggesting its potential benefits for either prevention or therapeutics use against cerebral ischemia in males.
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Wherever possible, you should prepare and use solutions on the same day. However, if you need to make up stock solutions in advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20C. Generally, these will be useable for up to two weeks. Before use, and prior to opening the vial we recommend that you allow your product to equilibrate to room temperature for at least 1 hour.
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J Agric Food Chem. 2014 May 14;62(19):4298-305.
Coumestrol induces mitochondrial biogenesis by activating Sirt1 in cultured skeletal muscle cells.[Pubmed: 24712520
The mitochondrion is a central organelle in cellular energy homeostasis; thus, reduced mitochondrial activity has been associated with aging and metabolic disorders. This paper provides biological evidence that Coumestrol, which is a natural isoflavone, activates mitochondrial biogenesis.
METHODS AND RESULTS:
In cultured myocytes, Coumestrol activated the silent information regulator two ortholog 1 (Sirt1) through the elevation of the intracellular NAD(+)/NADH ratio. Coumestrol also increased the mitochondrial contents and induced the expression of key proteins in the mitochondrial electron transfer chain in cultured myocytes. A Sirt1 inhibitor and Sirt1-targeting siRNAs abolished the effect of Coumestrol on mitochondrial biogenesis. Similar to an increase in mitochondrial content, Coumestrol improved myocyte function with increased ATP concentration.
Taken together, the data suggest that Coumestrol is a novel inducer of mitochondrial biogenesis through the activation of Sirt1.
Biochem Pharmacol. 2015 Jan 1;93(1):42-8.
Coumestrol inhibits carotid sinus baroreceptor activity by cAMP/PKA dependent nitric oxide release in anesthetized male rats.[Pubmed: 25449602
Phytoestrogens could offer multiple beneficial effects on the cardiovascular system. Here, we have examined the effects of Coumestrol (CMT) on carotid baroreceptors activity (CBA) and the possible mechanisms in male rats. The functional parameters of carotid baroreceptors were measured by recording sinus nerve afferent discharge in anesthetized male rats with perfused isolated carotid sinus.
METHODS AND RESULTS:
The levels of protein expression were determined by using ELISA and Western blotting. CMT (1 to 100μmolL(-1)) inhibited CBA, which shifted the functional curve of the carotid baroreceptor to the right and downward, with a marked decrease in the peak slope and the peak integral value of carotid sinus nerve discharge in a concentration dependent manner. These effects were not blocked by a specific estrogen receptor antagonist ICI 182,780, but were completely abolished by nitric oxide (NO) synthase inhibitor l-NAME (N(G)-nitro-l-arginine methyl ester). Furthermore, a NO donor, SIN-1(3-morpholion-sydnon-imine), could potentiate these inhibitory effects of CMT. CMT stimulated the phosphorylation of Ser(1176)-eNOS (endothelial nitric oxide synthase) in a dose-dependent manner in carotid bifurcation tissue over a perfusion period of 15min.
The rapid activation of eNOS by CMT was blocked by a highly selective PKA (protein kinase A) inhibitor H89. In addition, inhibition of PI3K (phosphatidylinositol-3-kinase) and ERK (extracellular signal-regulated kinase) pathways had no effect on eNOS activation by CMT. CMT inhibited CBA via eNOS activation and NO synthesis. These effects were mediated by the cAMP/PKA pathway and were unrelated to the estrogenic effect.
Food Chem. 2013 Nov 1;141(1):381-8.
Coumestrol induces senescence through protein kinase CKII inhibition-mediated reactive oxygen species production in human breast cancer and colon cancer cells.[Pubmed: 23768371
METHODS AND RESULTS:
An inhibitor of the protein kinase CKII (CKII) was purified from leaves of Glycine max (L.) Merrill and was identified as Coumestrol by structural analysis. Coumestrol inhibited the phosphotransferase activity of CKII toward β-casein, with an IC50 of about 5 μM. It acted as a competitive inhibitor with respect to ATP as a substrate, with an apparent Ki value of 7.67 μM. Coumestrol at 50μM resulted in 50% and 30% growth inhibition of human breast cancer MCF-7 and colorectal cancer HCT116 cells, respectively. Coumestrol promoted senescence through the p53-p21(Cip1/WAF1) pathway by inducing reactive oxygen species (ROS) production in MCF-7 and HCT116 cells. The ROS scavenger N-acetyl-l-cysteine (NAC), NADPH oxidase inhibitor apocynin and p22(phox) siRNA almost completely abolished this event. Overexpression of CKIIα antagonised cellular senescence mediated by Coumestrol, indicating that this compound induced senescence via a CKII-dependent pathway.
Since senescence is an important tumour suppression process in vivo, these results suggest that Coumestrol can function by inhibiting oncogenic disease, at least in part, through CKII inhibition-mediated cellular senescence.
Bioorg Med Chem Lett. 2014 Jun 1;24(11):2560-4.
Coumestrol suppresses hypoxia inducible factor 1α by inhibiting ROS mediated sphingosine kinase 1 in hypoxic PC-3 prostate cancer cells.[Pubmed: 24768446
Among many signals to regulate hypoxia inducible factor 1α (HIF-1α), sphingosine kinase 1 (SPHK1) is also involved in various biological activities such as cell growth, survival, invasion, angiogenesis, and carcinogenesis. Thus, in the present study, molecular mechanisms of Coumestrol were investigated on the SPHK1 and HIF-1α signaling pathway in hypoxic PC-3 prostate cancer cells.
METHODS AND RESULTS:
Coumestrol significantly suppressed SPHK1 activity and accumulation of HIF-1α in a time- and concentration-dependent manner in hypoxic PC-3 cells. In addition, Coumestrol inhibited the phosphorylation status of AKT and glycogen synthase kinase-3β (GSK 3β) signaling involved in cancer metabolism. Furthermore, SPHK1 siRNA transfection, sphigosine kinase inhibitor (SKI), reactive oxygen species (ROS) enhanced the inhibitory effect of Coumestrol on the accumulation of HIF-1α and the expression of pAKT and pGSK 3β in hypoxic PC-3 cells by combination index.
Overall, our findings suggest that Coumestrol suppresses the accumulation of HIF-1α via suppression of SPHK1 pathway in hypoxic PC-3 cells.
Neurol Res. 2014 Mar;36(3):198-206.
Coumestrol treatment prevents Na+, K+ -ATPase inhibition and affords histological neuroprotection to male rats receiving cerebral global ischemia.[Pubmed: 24512013
In this study, we investigated the possible mechanisms underlying the neuroprotective effects of Coumestrol, a potent isoflavonoid with antioxidant activities and binding affinities for both estrogen receptors (ER) ER-alpha and ER-beta that are comparable to those of 17beta-estradiol, in a model of global ischemia in male subjects.
METHODS AND RESULTS:
Wistar rats underwent global ischemia (10 minutes) or sham surgery and received a single intracerebroventricular (icv) infusion of 20 μg of Coumestrol or vehicle 1 hour before ischemia or 0, 3, 6, or 24 hours after reperfusion. The data analysis revealed an extensive neuronal death in the CA1 hippocampal subfield at 7 days, and a significant decrease in the Na+, K+ -ATPase activity at 1 and 24 hours after ischemia, and both injuries were attenuated by Coumestrol administration.
Coumestrol treatment was effective in preventing neuronal loss in all times of administration as well as able to rescue the Na+, K+ -ATPase activity, suggesting its potential benefits for either prevention or therapeutics use against cerebral ischemia in males.