This is a formula containing Resveratrol, Vitamin C, N Acetyl Cysteine, Coenzyme Q10 and Zinc. The constituents have been carefully chosen to provide mitochondrial protection from intracellular stress from uric acid and inhibition of the KHK enzyme involved in fructose breakdown into uric acid which can create further intracellular stress and ultimately gout. Increased uric acid is also associated with increased insulin resistance and visceral fat gain KHK is an abbreviation of KetoHexoKinase, another name for Fructokinase. KHK initiates the pathway through which most dietary fructose is metabolized catalyzing the phosphorylation of fructose to fructose 1 phosphate and Uric acid (Diggle et al. 2009).
KHK activity is predominantly present in the liver, kidney, and intestines Resveratrol found in red grape skins much research has been published recently about its involvement as a potential anti-obesity compound . The mechanism of action of Resveratrol has been researched and is considered to be involved in a number of pathways:
- Inhibition of adipogenesis - During early stage of adipogenesis resveratrol prevented the maturation of preadipocytes and at the same time inhibited the insulin signaling system ( Kang et al. 2019)
- Upregulating SIRT 1 gene (skinny gene) - Upregulating the SIRT1 gene promotes fat mobilization from white adipocytes (Howitz et al. 2003)
- Regulating epigenetic gene silencing (of KHK) Decreases mTOR signalling (Unknown, unknown)
- Inhibits glucose uptake (Gwak et al, 2015)
- Directly inhibits phoshofructokinase 1 which is critical for glycolysis and cellular glucose consumption (Gomez et al, 2013)
- Upregulates AMPKinase pathway (Dasgupta et al, 2007)
- Resveratrol and caloric restriction have overlapping effects on gene expression on multiple tissues (Barger et al, 2008)
Vitamin C is a water soluble free radical scavenger and can regenerate vitamin E in cell membranes, so protecting them from further damage. Vitamin C has been shown in 13 randomised controlled trials to significantly reduce serum uric acid (Juraschek et al, 2011). High uric acid upregulates KHK which increases Fructose breakdown into more uric acid so repeating the damaging cycle Vitamin C also protects the DNA, proteins and lipids from oxidative damage N Acetyl Cysteine crosses cell membranes is and intracellular antioxidant. It reduces extracellular cysteine to cysteine, stimulating glutathione synthesis promoting detoxification and acting directly on reactive oxidant radicals (De Vries et al, 1993). NAC has greater bioavailability intracellularly than glutathione and can prevent apoptosis caused by oxidative stress such as that caused by uric acid (Zafarullah et al. 2003).
CoEnzyme Q10 protects against oxidative intracellular stress and is included as it is one of the most significant lipid antioxidant that prevents free radical generation and modification of proteins, lipids and DNA (Muta-Takada et al. 2009). Intracellular stress can be caused by high concentrations of uric acid and depletion of ATP by fructose metabolism Zinc- When fructose is broken down by KHK to Fructose 1 Phosphate and Uric acid , the increase of Fructose 1 phosphate leads to increased triglycerides and increased lipogenesis. Adequate zinc inhibits F-1-Phosphate so inhibiting the generation of increased triglycerides (Coyle et al, 2003). It also protects the DNA, proteins, and lipids from oxidative damage This combination formula is a multifaceted approach towards intracellular protection from oxidative stress protecting the cell against oxidative stress from uric acid, a breakdown product of fructose and purines. High uric acid can upregulate certain enzymes associated with fat storage.
Barger JL, Kayo T, Vann JM, Arias EB, Wang J, et al. (2008) Correction: A Low Dose of Dietary Reservatol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice. PLOS ONE 3(6): 10. 1371/annotation/7b56e94e-3852-413d-b987-fccd0da79081.
Coyle, P., Tichelman, E.M., Pauw, R.T. et al. Zinc inhibition of hepatic fructose metabolism in rats. Biol Trace Elem Res 92, 41–53 (2003). https://doi.org/10.1385/BTER:92:1:41
Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7217-22. doi: 10.1073/pnas.0610068104. Epub 2007 Apr 16. PMID: 17438283; PMCID: PMC1855377.
De Vries N, De Flora S. N-acetyl-l-cysteine. J Cell Biochem Suppl. 1993;17F:270-7. doi: 10.1002/jcb.240531040. PMID: 8412205.
Diggle CP, Shires M, Leitch D, et al. Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J Histochem Cytochem. 2009;57(8):763-774. doi:10.1369/jhc.2009.953190
Gomez LS, Zancan P, Marcondes MC, Ramos-Santos L, Meyer-Fernandes JR, Sola-Penna M, Da Silva D. Resveratrol decreases breast cancer cell viability and glucose metabolism by inhibiting 6-phosphofructo-1-kinase. Biochimie. 2013 Jun;95(6):1336-43. doi: 10.1016/j.biochi.2013.02.013. Epub 2013 Feb 27. PMID: 23454376.
Gwak H, Haegeman G, Tsang BK, Song YS. Cancer-specific interruption of glucose metabolism by resveratrol is mediated through inhibition of Akt/GLUT1 axis in ovarian cancer cells. Mol Carcinog. 2015 Dec;54(12):1529-40. doi: 10.1002/mc.22227. Epub 2014 Oct 12. PMID: 25307508.
Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6. doi: 10.1038/nature01960. Epub 2003 Aug 24. PMID: 12939617.
Juraschek SP, Miller ER 3rd, Gelber AC. Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized controlled trials. Arthritis Care Res (Hoboken). 2011 Sep;63(9):1295-306. doi: 10.1002/acr.20519. PMID: 21671418; PMCID: PMC3169708.
Kang MC, Ding Y, Kim HS, Jeon YJ, Lee SH. Inhibition of Adipogenesis by Diphlorethohydroxycarmalol (DPHC) through AMPK Activation in Adipocytes. Mar Drugs. 2019;17(1):44. Published 2019 Jan 10. doi:10.3390/md17010044
Muta-Takada K, Terada T, Yamanishi H, Ashida Y, Inomata S, Nishiyama T, Amano S. Coenzyme Q10 protects against oxidative stress-induced cell death and enhances the synthesis of basement membrane components in dermal and epidermal cells. Biofactors. 2009 Sep-Oct;35(5):435-41. doi: 10.1002/biof.56. PMID: 19753652.
Unknown, unknown, SIRT1 sirtuin 1 [Homo sapiens (human)], National Center for Biotechnology Information, 21-09-2021 [https://www.ncbi.nlm.nih.gov/gene/23411]
Zafarullah M, Li WQ, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003 Jan;60(1):6-20. doi: 10.1007/s000180300001. PMID: 12613655.
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