Kuinone - Liquid Vitamin K2 (MK-4)

[DaveFoster]

Do you have some references? I would be interested in seeing the context, as MK-4 is being trialed as we speak for a number of different cancers, including colon and gastric.

PubMed summary of GDF-15: This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The protein is expressed in a broad range of cell types, acts as a pleiotropic cytokine and is involved in the stress response program of cells after cellular injury. Increased protein levels are associated with disease states such as tissue hypoxia, inflammation, acute injury and oxidative stress. [provided by RefSeq, Aug 2016]

Vitamin K2 induces phosphorylation of protein kinase A and expression of novel target genes in osteoblastic cells. - PubMed - NCBI

Vitamin K is known as a critical nutrient required for bone homeostasis and blood coagulation, and it is clinically used as a therapeutic agent for osteoporosis in Japan. Besides its enzymatic action as a cofactor of vitamin K-dependent gamma-glutamyl carboxylase (GGCX), we have previously shown that vitamin K(2) is a transcriptional regulator of bone marker genes and extracellular matrix-related genes, by activating the steroid and xenobiotic receptor (SXR). To explore a novel action of vitamin K in osteoblastic cells, we identified genes up-regulated by a vitamin K(2) isoform menaquinone-4 (MK-4) using oligonucleotide microarray analysis. Among these up-regulated genes by MK-4, growth differentiation factor 15 (GDF15) and stanniocalcin 2 (STC2) were identified as novel MK-4 target genes independent of GGCX and SXR pathways in human and mouse osteoblastic cells. The induction of GDF15 and STC2 is likely specific to MK-4, as it was not exerted by another vitamin K(2) isoform MK-7, vitamin K(1), or the MK-4 side chain structure geranylgeraniol. Investigation of the involved signaling pathways revealed that MK-4 enhanced the phosphorylation of protein kinase A (PKA), and the MK-4-dependent induction of both GDF15 and STC2 genes was reduced by the treatment with a PKA inhibitor H89 or siRNA against PKA. These results suggest that vitamin K(2) modulates its target gene expression in osteoblastic cells through the PKA-dependent mechanism, which may be distinct from the previously known vitamin K signaling pathways.


Regulation of hepcidin through GDF-15 in cancer-related anemia
Regulation of hepcidin through GDF-15 in cancer-related anemia

Serum GDF-15 levels were increased significantly in patients with the severe CRA, compared with the mild or no CRA patients and the controls. Increasing GDF-15 levels corresponded to decreasing hepcidin concentrations. A trend toward a correlation between high levels of GDF-15 and poor prognosis of cancer was also found. Elevation of GDF-15 concentrations suppressed hepcidin expression at high concentrations.


Regulation of the inflammatory response in cardiac repair

Recently, Growth Differentiation Factor (GDF)-15, another member of the TGF-β superfamily, has been identified as a crucial endogenous mediator involved in suppression of the inflammatory response associated with myocardial infarction. (GDF)-15 is upregulated in the infarcted myocardium, primarily localized in cardiomyocytes of the infarct border zone117. GDF-15 −/− mice had a high incidence of cardiac rupture following myocardial infarction associated with accentuated recruitment of neutrophils. GDF-15 restrains inflammation by counteracting conformational activation of neutrophil β2 integrins, thus preventing excessive chemokine-activated leukocyte arrest on the endothelium118.

Growth differentiation factor-15: induction in liver injury through p53 and tumor necrosis factor-independent mechanisms. - PubMed - NCBI
Expression of macrophage inhibitory cytokine-1 (MIC-1), a divergent transforming growth factor-beta family member, and its murine ortholog, growth/differentiation factor-15 (GDF-15), is induced in hepatocytes by surgical and chemical injury and heat shock. Here, we demonstrate that the regulation of GDF-15/MIC-1 expression may be evolutionarily conserved because MIC-1 was induced in diseased human livers. Gdf15 induction was independent of protein synthesis, a hallmark of immediate-early gene regulation. Although tumor necrosis factor (TNF) induced GDF-15 expression, injury-elicited Gdf15 expression was not reduced in mice deficient for both TNF receptor subtypes. Furthermore, although the stress sensor p53 is known to induce GDF-15/MIC-1 expression, injury-elicited Gdf15 expression was unchanged in p53 null mice. Our results demonstrate that GDF-15 induction is an immediate early response to liver injury that can occur through TNF and p53 independent pathways.


Growth Differentiation Factor-15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin-6–Dependent Inflammatory Response to Vascular Injury

http://jaha.ahajournals.org/content/1/6/e002550.full.pdf

Our data suggest that GDF-15 is involved in orchestrating atherosclerotic lesion progression by regulating apoptotic cell death and IL-6–dependent inflammatory responses to vascular injury.


GDF-15 in Cancer Progression, Systemic and Immune Response

http://www.medscape.com/viewarticle/774870_5

GDF-15 is generally considered to be part of the cell's antitumorigenic actions, largely because its expression is crucial for the chemopreventive effects of various compounds.[57,58] However, elevated GDF-15 expression has often been reported during cancer progression, including gastric, ovarian, prostate or breast cancers (see Table 1) with various impact on tumors.[4,65,66] Despite that the GDF-15 expression profile has been well described in various cancers, its specific role in tumor development remains unclear (Figure 1).

Thus, the primary effect of GDF-15 on cancer progression can be linked to the regulation of immune responses in the process of tissue regeneration. GDF-15 has been described as a negative regulator of macrophage activation by suppressing the release of TNF-α, IL-1, IL-2 and MCS-F, thus inhibiting the positive feedback of local inflammatory signaling similar to the effects of TGF-β.

 

[haidut]

PubMed summary of GDF-15: This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The protein is expressed in a broad range of cell types, acts as a pleiotropic cytokine and is involved in the stress response program of cells after cellular injury. Increased protein levels are associated with disease states such as tissue hypoxia, inflammation, acute injury and oxidative stress. [provided by RefSeq, Aug 2016]

Vitamin K2 induces phosphorylation of protein kinase A and expression of novel target genes in osteoblastic cells. - PubMed - NCBI

Vitamin K is known as a critical nutrient required for bone homeostasis and blood coagulation, and it is clinically used as a therapeutic agent for osteoporosis in Japan. Besides its enzymatic action as a cofactor of vitamin K-dependent gamma-glutamyl carboxylase (GGCX), we have previously shown that vitamin K(2) is a transcriptional regulator of bone marker genes and extracellular matrix-related genes, by activating the steroid and xenobiotic receptor (SXR). To explore a novel action of vitamin K in osteoblastic cells, we identified genes up-regulated by a vitamin K(2) isoform menaquinone-4 (MK-4) using oligonucleotide microarray analysis. Among these up-regulated genes by MK-4, growth differentiation factor 15 (GDF15) and stanniocalcin 2 (STC2) were identified as novel MK-4 target genes independent of GGCX and SXR pathways in human and mouse osteoblastic cells. The induction of GDF15 and STC2 is likely specific to MK-4, as it was not exerted by another vitamin K(2) isoform MK-7, vitamin K(1), or the MK-4 side chain structure geranylgeraniol. Investigation of the involved signaling pathways revealed that MK-4 enhanced the phosphorylation of protein kinase A (PKA), and the MK-4-dependent induction of both GDF15 and STC2 genes was reduced by the treatment with a PKA inhibitor H89 or siRNA against PKA. These results suggest that vitamin K(2) modulates its target gene expression in osteoblastic cells through the PKA-dependent mechanism, which may be distinct from the previously known vitamin K signaling pathways.


Regulation of hepcidin through GDF-15 in cancer-related anemia
Regulation of hepcidin through GDF-15 in cancer-related anemia

Serum GDF-15 levels were increased significantly in patients with the severe CRA, compared with the mild or no CRA patients and the controls. Increasing GDF-15 levels corresponded to decreasing hepcidin concentrations. A trend toward a correlation between high levels of GDF-15 and poor prognosis of cancer was also found. Elevation of GDF-15 concentrations suppressed hepcidin expression at high concentrations.


Regulation of the inflammatory response in cardiac repair

Recently, Growth Differentiation Factor (GDF)-15, another member of the TGF-β superfamily, has been identified as a crucial endogenous mediator involved in suppression of the inflammatory response associated with myocardial infarction. (GDF)-15 is upregulated in the infarcted myocardium, primarily localized in cardiomyocytes of the infarct border zone117. GDF-15 −/− mice had a high incidence of cardiac rupture following myocardial infarction associated with accentuated recruitment of neutrophils. GDF-15 restrains inflammation by counteracting conformational activation of neutrophil β2 integrins, thus preventing excessive chemokine-activated leukocyte arrest on the endothelium118.

Growth differentiation factor-15: induction in liver injury through p53 and tumor necrosis factor-independent mechanisms. - PubMed - NCBI
Expression of macrophage inhibitory cytokine-1 (MIC-1), a divergent transforming growth factor-beta family member, and its murine ortholog, growth/differentiation factor-15 (GDF-15), is induced in hepatocytes by surgical and chemical injury and heat shock. Here, we demonstrate that the regulation of GDF-15/MIC-1 expression may be evolutionarily conserved because MIC-1 was induced in diseased human livers. Gdf15 induction was independent of protein synthesis, a hallmark of immediate-early gene regulation. Although tumor necrosis factor (TNF) induced GDF-15 expression, injury-elicited Gdf15 expression was not reduced in mice deficient for both TNF receptor subtypes. Furthermore, although the stress sensor p53 is known to induce GDF-15/MIC-1 expression, injury-elicited Gdf15 expression was unchanged in p53 null mice. Our results demonstrate that GDF-15 induction is an immediate early response to liver injury that can occur through TNF and p53 independent pathways.


Growth Differentiation Factor-15 Deficiency Inhibits Atherosclerosis Progression by Regulating Interleukin-6–Dependent Inflammatory Response to Vascular Injury

http://jaha.ahajournals.org/content/1/6/e002550.full.pdf

Our data suggest that GDF-15 is involved in orchestrating atherosclerotic lesion progression by regulating apoptotic cell death and IL-6–dependent inflammatory responses to vascular injury.


GDF-15 in Cancer Progression, Systemic and Immune Response

http://www.medscape.com/viewarticle/774870_5

GDF-15 is generally considered to be part of the cell's antitumorigenic actions, largely because its expression is crucial for the chemopreventive effects of various compounds.[57,58] However, elevated GDF-15 expression has often been reported during cancer progression, including gastric, ovarian, prostate or breast cancers (see Table 1) with various impact on tumors.[4,65,66] Despite that the GDF-15 expression profile has been well described in various cancers, its specific role in tumor development remains unclear (Figure 1).

Thus, the primary effect of GDF-15 on cancer progression can be linked to the regulation of immune responses in the process of tissue regeneration. GDF-15 has been described as a negative regulator of macrophage activation by suppressing the release of TNF-α, IL-1, IL-2 and MCS-F, thus inhibiting the positive feedback of local inflammatory signaling similar to the effects of TGF-β.

The only study linking GDF-15 and cancer said there was a "trend for correlation". So, it was not statistically significant and even if there was the correlation was rather weak. Also, all the other studies mention GDF-15 being anti-inflammatory and a defensive mechanism against cancer. So, its elevation is likely adaptive and an attempt to restrain the cancer, not fuel its growth.

 

[DaveFoster]

The only study linking GDF-15 and cancer said there was a "trend for correlation". So, it was not statistically significant and even if there was the correlation was rather weak. Also, all the other studies mention GDF-15 being anti-inflammatory and a defensive mechanism against cancer. So, its elevation is likely adaptive and an attempt to restrain the cancer, not fuel its growth.

That's what I was thinking; I think the last study clarified that, but I wanted to make sure, as there's a lot of double-think going on with the research here.

Thanks for clearing it up.

 

[haidut]

That's what I was thinking; I think the last study clarified that, but I wanted to make sure, as there's a lot of double-think going on with the research here.

Thanks for clearing it up.

And here is one direct study of vitamin K2 (MK-4) for gastric cancer treatment.
Vitamin K2-induced antitumor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines. - PubMed - NCBI

 

[DaveFoster]

And here is one direct study of vitamin K2 (MK-4) for gastric cancer treatment.
Vitamin K2-induced antitumor effects via cell-cycle arrest and apoptosis in gastric cancer cell lines. - PubMed - NCBI

Wow, that's very cool. Thanks. I'm a little worried about gastric cancer myself as I grow old, so this is helpful.

 

[DaveFoster]

I am about to post some studies on steroids showing if dissolve them in DMSO you get 3 - 10 times better bioavailability. So, at a minimum, I expect 1 drop of Kuinone to be about equal to 4mg - 5mg Thorne or other products, which matches well your guess and experience.

Do you mean DMSO brings 3-10 better topical bioavailability compared to topical with oil as a vehicle? Or do you mean 3-10 times better compared to oral K2 (powder or without oil?)

Ignore this part: I found the answer for anyone looking. In other words, does 1 mg in DMSO = 3-10 mg oral or 3-10 mg topical in oil? The study you posted suggests the difference is just in topical absorption, if I understand correctly. I've been taking 8 - 12 mg, and I'm curious to know if I'm actually taking the equivalent of a 40-60 mg oral dose if it's potentiated.

"Based on blood tests I have seen a 5mg dose of topical Kuinone for a week resulted in the same blood levels of vitamin K as 15mg of oral vitamin K2 from a vendor that sells capsules (not Thorne). Based on that and the studies of DMSO effects on steroids and other substances bioavailability I'd venture an educated guess that topical Kuinone dose of say 1mg is probably equivalent to an oral dose of at least 3mg - 5mg vitamin K2 from another vendor."

I'm not sure why people would be rubbing Thorne K2 on their skin, either. Is there some kind of irritation with oral?

Also, your OP says DMSO as an ingredient but does not list ethanol; I have the bottle and it says ethanol. Was this to dilute the DMSO to 1% to avoid irritation or does this improve solubility similar to StressNon?

 

[haidut]

Do you mean DMSO brings 3-10 better topical bioavailability compared to topical with oil as a vehicle? Or do you mean 3-10 times better compared to oral K2 (powder or without oil?)

Ignore this part: I found the answer for anyone looking. In other words, does 1 mg in DMSO = 3-10 mg oral or 3-10 mg topical in oil? The study you posted suggests the difference is just in topical absorption, if I understand correctly. I've been taking 8 - 12 mg, and I'm curious to know if I'm actually taking the equivalent of a 40-60 mg oral dose if it's potentiated.


I'm not sure why people would be rubbing Thorne K2 on their skin, either. Is there some kind of irritation with oral?

Also, your OP says DMSO as an ingredient but does not list ethanol; I have the bottle and it says ethanol. Was this to dilute the DMSO to 1% to avoid irritation or does this improve solubility similar to StressNon?

So, as the quote you found says, topical Kuinone was found to achieve the same blood concentrations as a dose about 3-4 times higher using oral Thorne.
Thanks for the heads up, I changed the original post to also say ethanol. We added ethanol to dilute the DMSO a bit and also as an anti-oxidant to keep the vitamin K stable for longer.

 

[DaveFoster]

So, as the quote you found says, topical Kuinone was found to achieve the same blood concentrations as a dose about 3-4 times higher using oral Thorne.
Thanks for the heads up, I changed the original post to also say ethanol. We added ethanol to dilute the DMSO a bit and also as an anti-oxidant to keep the vitamin K stable for longer.

No problem; thanks for the reply. That explains why Kuinone doesn't irritate my skin at all.

 

[DaveFoster]

@haidut

You mentioned that transdermal application of Kuinone affects all organs nearly identically except the liver.

If someone wants to take K2 to lower AST and ALT enzymes, would oral be better for this purpose, or should either work? A lower transdermal dose would behave like a higher oral dose as well, so would this further detract from the effect?

 

[haidut]

@haidut

You mentioned that transdermal application of Kuinone affects all organs nearly identically except the liver.

If someone wants to take K2 to lower AST and ALT enzymes, would oral be better for this purpose, or should either work? A lower transdermal dose would behave like a higher oral dose as well, so would this further detract from the effect?

Transdermal route achieve higher blood levels with a much lower dose, so for people trying to each an organ other than the liver that would be the way to go. For liver health, oral is probably the best route even though if there was a way to calculate how much of the transdermal dose goes back to the liver and how much of an oral dose stays in the liver we would have a much better idea. So, not now I'd do oral for liver health and topical for everything else.

 

[DaveFoster]

Transdermal route achieve higher blood levels with a much lower dose, so for people trying to each an organ other than the liver that would be the way to go. For liver health, oral is probably the best route even though if there was a way to calculate how much of the transdermal dose goes back to the liver and how much of an oral dose stays in the liver we would have a much better idea. So, not now I'd do oral for liver health and topical for everything else.

Very helpful; thanks haidut.

 

[johnwester130]

I now know Thorne Research Vitamin K2 buy the vitamin mk4 as an oil to begin with.

The powder is the altered product

 

[raypeatclips]

How do you guys manage to take this? A single drop on my thigh has left a ridiculous yellow stain about 2 inches wide which doesn't come off with normal washing. I don't like taking it orally.

 

[Regina]

How do you guys manage to take this? A single drop on my thigh has left a ridiculous yellow stain about 2 inches wide which doesn't come off with normal washing. I don't like taking it orally.

My rat is not getting a stain from topical kuinone. She uses it fairly liberally on her arms and elbows. She's also okay with the taste. Sometimes does orally instead.

 

[raypeatclips]

My rat is not getting a stain from topical kuinone. She uses it fairly liberally on her arms and elbows. She's also okay with the taste. Sometimes does orally instead.

Maybe you have a newer batch than me, I think I remember haidut saying he changed to a different colour K2. Not sure that it agrees with me at the moment. By the way, Kuinione isn't in the lab section, so is safe for human use. :)

 

[BobbyDukes]

Maybe you have a newer batch than me, I think I remember haidut saying he changed to a different colour K2. Not sure that it agrees with me at the moment. By the way, Kuinione isn't in the lab section, so is safe for human use. :)

Yeah. Your batch is way old, dude. I've got the old one too, and it stains like anything. It's also way stinkier (garlic).

The new batch you can rub on your skin with no staining whatsoever, and little odour. It's an immense product.

 

[Regina]

Maybe you have a newer batch than me, I think I remember haidut saying he changed to a different colour K2. Not sure that it agrees with me at the moment. By the way, Kuinione isn't in the lab section, so is safe for human use. :)

 

[superhuman]

When using K2 topical how much is absorbed vs oral? also if taken oral doesnt one also have to have a decent amount of fat in the meal to absorb it better?

 

[haidut]

When using K2 topical how much is absorbed vs oral? also if taken oral doesnt one also have to have a decent amount of fat in the meal to absorb it better?

As mentioned in other threads, usually chemicals dissolved in DMSO have close to 100% absorption. Oral absorption varies and just like you said depends on fat intake and the health of the person's GI tract.

 

[superhuman]

@haidut That is awesome. Thanx