Bio-NMG Immunomodulation of macrophages using Methylglyoxal conjugated with chitosan nanoparticles in a liquid oral formulation. This high absorbance form of Methylglyoxal offers the benefits of consuming very large amounts of Mānuka honey. Methylglyoxal (MGO) is a unique, naturally occurring compound found in Mānuka honey that’s responsible for its unique properties that help fight germs. MGO occurs naturally in many foods, plants, and animal cells and has germ-fighting properties. Consuming large amounts of Mānuka honey or Methylglyoxal can cause unwanted side effects. Consuming Methylglyoxal conjugated with chitosan nanoparticles offers much better absorbance without negative side effects.
Dose: 0.5mg/kg/day methylglyoxal in a chitosan encapsulation.
Form: Liquid used orally
Methylglyoxal is found in Manuka Honey in concentration around 250mg/kg with research showing this is responsible for the antibacterial and antiviral activity of the honey. (Ref.) Professor Thomas Henle of University of Dresden, Germany announced in 2008 that research “unambiguously demonstrates for the first time that Methylglyoxal is directly responsible for the antibacterial activity of Manuka honey.”
Methylglyoxal content in Manuka Honey is not all that useful as the amount of Methylglyoxal found in the honey (Manuka) (250mg/kg) for any health improvment purpose other than as a preventative as this is too little. Given the Methylglyoxal dose that is proposed is research we would need to consume kilograms of honey each day, which is not feasible or healthy. This is why, Methylglyoxal is used in the clinical trails and why we are using Methylglyoxal conjugated with chitosan nanoparticles in a liquid oral formulation to enhance its action.
A historical perspective on methylglyoxal research is briefly presented, mentioning the documented anticancer and antiviral effects of methylglyoxal. The idea and the supporting experimental evidence of Albert Szent-Györgyi et al. that methylglyoxal is a natural growth regulator and can act as an anticancer agent are mentioned. Previously a few in vivo studies suggested safe administration of methylglyoxal. However, recent literature abounds with the toxic effects of methylglyoxal. The authors present a brief critical overview of studies indicating both toxic and beneficial effects of methylglyoxal and suggest that the beneficial effects of methylglyoxal outweigh its toxic effects. Encouraged by the studies of Szent-Györgyi et al., the present authors undertook systematic investigations to understand the mechanism of the anticancer effect of methylglyoxal. The results of these investigations led to the proposal that the fundamental changes in malignant cells are critical alterations of glyceraldehyde-3-phosphate dehydrogenase and mitochondrial complex I, and methylglyoxal’s anticancer effect might be mediated by acting on these altered sites. Moreover, a new hypothesis on cancer has been proposed, suggesting that excessive ATP formation in cells may lead to malignancy. Toxicity and pharmacokinetic studies were performed on animals and it was observed that methylglyoxal is potentially safe for humans. A methylglyoxal-based anticancer formulation was developed and a three-phase study of treating a total number of 86 cancer patients was carried out. The results appear to be promising. Most of the cancer patients benefited greatly and a significant number of patients became free of the disease. Contrary to the effect of existing anticancer drugs, this methylglyoxal-based formulation is devoid of any toxic effect and reasonably effective against a wide variety of cancers. The symptomatic improvements of the many patients who died of progressive disease suggest that the formulation could also be used for palliation. The authors urge the scientific community to test the formulation and if found effective then to improve it further.
Methylglyoxal induces mitochondria-dependent apoptosis in sarcoma. In research paper (A. Ghosh et al. (2011) Biochemistry (Moscow), 76, 1051-1060), using several comparable tissue materials, it has been convincingly demonstrated that methylglyoxal, a normal metabolite, inhibits mitochondrial complex I of specifically malignant cells. This suggests a distinct alteration of complex I, a highly important enzyme for energy (ATP) production, in malignancy. The present paper shows that as a consequence of this inhibition mitochondrial membrane potential is drastically reduced in sarcoma tissue but not in normal skeletal muscle. This was estimated spectrofluorimetrically using the dye rhodamine 123. As a consequence, cytochrome c was released from the sarcoma mitochondria as evidenced by Western blot analysis. Moreover, on treatment with methylglyoxal membrane potential collapse of sarcoma 180 cells was also indicated by fluorescence-activated cell sorter analysis. Atomic force microscopic study demonstrated gross structural alteration specifically of tumor mitochondria on methylglyoxal treatment. All these studies suggest that methylglyoxal might initiate an apoptotic event in malignant cells.
Research shows that the accumulation of Methylglyoxal in cancer cells are known to lead to the inhibition of Glyceraldehyde-3-phosphate dehydrogenase, an essential enzyme acting in the glycolsisis pathway. GAPDH inhibition depletes ATP profoundly depriving the cancer cells of energy.
Inactivation of glyceraldehyde-3-phosphate dehydrogenase of human malignant cells by methylglyoxal. The effect of methylglyoxal on the activity of glyceraldehyde-3-phosphate dehydrogenase (GA3PD) of several normal human tissues and benign and malignant tumors has been tested. Methylglyoxal inactivated GA3PD of all the malignant cells (47 samples) and the degree of inactivation was in the range of 25-90%, but it had no inhibitory effect on this enzyme from several normal cells (24 samples) and benign tumors (13 samples). When the effect of methylglyoxal on other two dehydrogenases namely glucose 6-phosphate dehydrogenase (G6PD) and L-lactic dehydrogenase (LDH) of similar cells was tested as controls it has been observed that methylglyoxal has some inactivating effect on G6PD of all the normal, benign and malignant samples tested, whereas, LDH remained completely unaffected. These studies indicate that the inactivating effect of methylglyoxal on GA3PD specifically of the malignant cells may be a common feature of all the malignant cells.
Methylglyoxal to control and eliminate cancer cells through the use of all of the following mechanisms. Methylglyoxal is known to induce apoptosis by:
1) inhibiting protein synthesis,
2) forming adducts with nucleic acids,
3) increasing intracellular oxidative stress by complexing nonenzymatically with GSH,
4) reducing cancer cell ATP production by inhibiting mitochondrial respiration, and
5) inhibiting glutathione reductase activity.
By binding to cancer cell surface sulfhydryl and arginine groups it further exposes these cells to the immune system. In addition, methylglyoxal has been shown to induce a specific immune response toward cancer cells. Since cancer cells contain very low levels or lack entirely glyoxalase II activity, the current patent adds depletion of GSH as an additional mechanism. This mechanism further promotes apoptosis by trapping GSH in the glyoxalase I reaction product S-lactoylglutathione and not allowing it to be recycled.
Delivery of methylglyoxal is complicated by the pharmacokinetics of oral administration and a high level of catabolism within the bloodstream by the glyoxalases. A limited number of studies on the oral uptake of methylglyoxal have demonstrated less than 5% uptake. Once in the bloodstream, the circulation half-life has been estimated to be from 30 to 120 minutes. Although the Vmax for other ketoaldehydes with the glyoxalases is lower than methylglyoxal, so too is their therapeutic index relative to inducing apoptosis in cancer cells. Thus while methylglyoxal remains the ketoaldehyde of choice, further steps must be taken to ensure adequate bioavailability of the agent in the bloodstream.
Dicarbonyl compounds have been studied for over 50 years because they possess cancerostatic properties at relatively low concentrations.
Of particular interest is the dicarbonyl compound, methylglyoxal (also known as pyruvaldehyde). Containing just a (3) carbon backbone, it is an extremely small, water soluble, and highly reactive compound. Due to its size and reactivity as an electron acceptor, it is a unique chemical and biochemical compound. Of critical importance are the following facts:
1) methylglyoxal is a naturally occurring metabolite in living systems,
2) methylglyoxal is catabolized to D-lactic acid by the glyoxalase enzyme system consisting of glyoxalase I and glyoxalase II,
3) methylglyoxal forms a nonenzymatic hemithioacetal adduct with GSH, and
4) methylglyoxal in the absence of glyoxalase II activity causes GSH to become trapped in the glyoxalase I intermediate S-lactoylglutathione thus depleting GSH levels.
Albert Szent-Gyorgyi in the 1960’s, advanced the hypothesis that methylglyoxal might act as a natural brake on cell division by keeping cells in the resting state.
Subsequent work by his team and others showed that methylglyoxal treatment of cancer cells at levels of approximately 1-3 mM caused protein synthesis inhibition, arrested cell growth, and induced apoptosis.
Normal cells were not affected. These findings and much additional research over the intervening 40 years have supported and expanded this work.
Of particular significance is the recent work of Manju Ray. She and her team have enhanced the understanding of the action of methylglyoxal at the cellular level, studied and reported the pharmacokinetics and toxicity, and conducted human cancer clinical trials. Additionally, there are a number of worldwide anecdotal cases of people self-administering methylglyoxal to treat cancer.
The majority of the early studies involving methylglyoxal and its cancerostatic action were conducted either with cultured cancer cells or with mice that had been innoculated intraperitoneally with cancer cells. This work consistently and repeatedly reported that concentrations approaching 3 mM were required to achieve 95-100% cell death.
Methylgloxal administered orally cannot achieve these levels (216 mg/kg) in mammals based on pharmacokinetic bioavailability data. (IV) administration of methylglyoxal at these levels has not been reported.
Delivery of methylglyoxal to the bloodstream by any means results in its rapid catabolism. Pharmacokinetic studies in mice have shown that a single oral dose of methylglyoxal of 200 mg results in a peak blood concentration of approximately 20 nmol/cc or 0.02 mM at 4 hours with total clearance after 12 hours.
These levels are significantly lower than the 1-3 mM reported to induce significant cancer cell death. The presence of high levels of GSH and a full complement of glyoxalase enzymes makes delivering and maintaining pharmaceutical levels of methylglyoxal in the bloodstream unattainable.
It is likely this is the reason that the limited number of previous clinical trials utilizing methylglyoxal to treat cancer have reported mixed results.
Bio-NMG – Methylglyoxal conjugated with chitosan nanoparticles in a liquid oral formulation of 0.5mg/kg/day is a development of a novel sustained release (SR) Methylglyoxal delivery system by using non-toxic, biocompatible, biodegradable and non-antigenic carriers of nanometer size greatly increasing bioactivity and easily reaching blood therapeutic levels (concentrations) compared to standard Methylglyoxal.
Methylglyoxal, a normal metabolite may have potent anticancer effects. It can enhance macrophage mediated immunity in murine model by the production of Reactive Oxygen Intermediates (ROIs) and Reactive Nitrogen Intermediates (RNIs) through membrane bound enzyme NADPH-oxidase and iNOS-synthase pathways.