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Reversing arterial plaque

artery cardiovascular disease lipids matrix gla protein vitamin k2 mk4 vitamin k2 mk7 xanthohumol plaque

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#421 Daniel Cooper

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Posted 13 June 2019 - 05:52 PM

This test was in vitro.  They cultured opossum kidney cells in some sort of buffered isotonic saline and then introduced them to a 500nmol solution of MitoQ.

 

For this test to have any meaning, you'd have to know what sort of concentration taking a normal dose of MitoQ (250mg) would induce in vivo in a human. I don't know what that number is, but 500nmol sounds on the high side of what might be realistic.  I would guess that you might see something in the tens of nmol.  But that's just a guess.

 

The fact of the matter is that if you put cells in any sort of sufficiently concentrated polar solution, the mitochondria will swell and depolarize.  

 

The right question for Greg would be "what plasma concentration of MitoQ have you seen as a peak after a standard dose?".  

 

Perhaps someone could invite Greg over to this thread.

 

 


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#422 Daniel Cooper

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Posted 13 June 2019 - 06:05 PM

FYI - Sent an invite to Greg.


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#423 smithx

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Posted 13 June 2019 - 06:52 PM

Here is the entire abstract, bolding mine. The depolarization and swelling was identified by the researchers to be due to the structure of the MitoQ, and another mitochondrial antioxidant didn't cause the problem even at a very high dose.


Kidney proximal tubules (PTs) contain a high density of mitochondria, which are required to generate ATP to power solute transport. Mitochondrial dysfunction is implicated in the pathogenesis of numerous kidney diseases. Damaged mitochondria are thought to produce excess reactive oxygen species (ROS), which can lead to oxidative stress and activation of cell death pathways. MitoQ is a mitochondrial targeted anti‐oxidant that has shown promise in preclinical models of renal diseases. However, recent studies in nonkidney cells have suggested that MitoQ might also have adverse effects. Here, using a live imaging approach, and both in vitro and ex vivo models, we show that MitoQ induces rapid swelling and depolarization of mitochondria in PT cells, but these effects were not observed with SS‐31, another targeted anti‐oxidant. MitoQ consists of a lipophilic cation (Tetraphenylphosphonium [TPP]) joined to an anti‐oxidant component (quinone) by a 10‐carbon alkyl chain, which is thought to insert into the inner mitochondrial membrane (IMM). We found that mitochondrial swelling and depolarization was also induced by dodecyltriphenylphosphomium (DTPP), which consists of TPP and the alkyl chain, but not by TPP alone. Surprisingly, MitoQ‐induced mitochondrial swelling occurred in the absence of a decrease in oxygen consumption rate. We also found that DTPP directly increased the permeability of artificial liposomes with a cardiolipin content similar to that of the IMM. In summary, MitoQ causes mitochondrial swelling and depolarization in PT cells by a mechanism unrelated to anti‐oxidant activity, most likely because of increased IMM permeability due to insertion of the alkyl chain.

 
Plasma concentrations are not relevant, as pointed out by the researchers, because MitoQ concentrates in the mitochondria and stays there:
 

However, since MitoQ accumulates into mitochondria at very high concentrations, the possibility remains that it could have effects on mitochondrial function other than on ROS levels, not all of which might be beneficial. For example, a recent study has reported that MitoQ can actually increase ROS production in some cancer cells, and this is associated with a decrease in Δψ m and mitochondrial DNA (mtDNA) copy number (Pokrzywinski et al. 2016).

 
The structure of the molecule seems to be at fault:
 

Since SS‐31 did not cause the same mitochondrial swelling as MitoQ, even at a very high dose, we considered that the toxic effects observed with the latter are probably unrelated to its anti‐oxidant activity. To investigate this, we assessed the individual effects of different structural components of MitoQ. We found that TPP (500 nmol/L), the mitochondrial targeting cation of MitoQ, did not induce any acute deleterious effects on mitochondria in OK cells (Fig. 2A–B). However, dodecyltriphenylphosphomium (DTPP) (500 nmol/L), which consists of TPP plus the carbon alkyl chain (but lacks the anti‐oxidant quinone), caused acute mitochondrial swelling and depolarization, identical to that induced by MitoQ (Fig. 2A–B). These findings suggest that the toxic effect of MitoQ on PT cell mitochondria is indeed unrelated to anti‐oxidant activity, and that the carbon alkyl chain plays an important role.

 

They used the same solutions for MitoQ, for SS-31 and for the structural analog of MitoQ and found the depolarization and swelling issue only with MitoQ and its structural analog. So there was clearly no problem which can be blamed on a concentrated polar solution.

 

To me, this looks very bad for MitoQ, and is a compelling argument for avoiding it entirely.

 

 

This test was in vitro.  They cultured opossum kidney cells in some sort of buffered isotonic saline and then introduced them to a 500nmol solution of MitoQ.
 
For this test to have any meaning, you'd have to know what sort of concentration taking a normal dose of MitoQ (250mg) would induce in vivo in a human. I don't know what that number is, but 500nmol sounds on the high side of what might be realistic.  I would guess that you might see something in the tens of nmol.  But that's just a guess.
 
The fact of the matter is that if you put cells in any sort of sufficiently concentrated polar solution, the mitochondria will swell and depolarize.  
 
The right question for Greg would be "what plasma concentration of MitoQ have you seen as a peak after a standard dose?".  
 
Perhaps someone could invite Greg over to this thread.


Edited by smithx, 13 June 2019 - 06:54 PM.

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#424 Daniel Cooper

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Posted 13 June 2019 - 07:21 PM

You're making many leaps in your logic there.  Plasma concentrations are certainly relevant. That paper absolutely does not say that concentrations are irrelevant.  

 

Keep in mind, there are studies out there testing MitoQ in vivo in human subjects at doses of 1200mg/day and 3600mg/day that noted no deleterious effects.  You're touting a in vitro study using opossum kidney cells and neither one of us knows if the plasma molarities have any bearing whatsoever on what you'll actually see in a human kidney.  And you are concluding that this takes MitoQ completely off the table as a dangerous substance.  In spite of the fact that we've had humans taking 14x the standard dose and no one measured any damage to their kidneys in the labs.

 

Using your criteria I think I'd have to swear off salt as well.  That stuff will kill you if you get too much of it.

 

Let's find out what the pharmacokinetics of this substance is.  What plasma concentrations you might expect and for how long.  The benefits of MitoQ are too intriguing to dismiss it off this one study.  Unless you're a possum perhaps.

 

 


And btw, MitoQ doesn't enter the mitochondria and "stay there".  If it did it would be useless.  It mops up the ROS generated by energy production in the mitochondria and is thus being continually consumed.

 

 


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#425 Benko

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Posted 13 June 2019 - 07:49 PM

  ***You're touting a in vitro study using opossum kidney cells***

 


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#426 smithx

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Posted 14 June 2019 - 07:27 AM

I'm not making many leaps in logic. I'm quoting the logic of the researchers in the cited paper.

 

MitoQ is preferentially taken up by the mitochondria and attains orders of magnitude higher concentrations there than in plasma. So plasma levels are not particularly germane: intra-mitochondrial concentrations are what is germane.

 

Even for drugs like antibiotics, plasma concentrations are not solely important. For example, many drugs which treat kidney or urinary tract infections may not achieve a minimum inhibitory concentration in blood plasma but are preferentially concentrated in urine, which is what makes them effective in those applications.

 

The researchers showed that MitoQ and its structural analog caused mitochondrial depolarization and swelling, and the solutions they used did not, and neither did far higher concentrations of a different mitochondrial targeted antioxidant. This seems like a compelling result to me, and is notably not something you've acknowledged or referred to at all in your comments, which seem to be an attempt to trivialize these findings rather than address them seriously. I find your responses to be odd and disingenuous.

 

My reason for taking MitoQ was that it was potentially able to produce incremental benefits. This research suggests that it could, instead, cause harm. I'd rather be safe than sorry in this case. If the potential benefits were an order of magnitude higher, I might be more willing to take some bigger risks.

 

 

You're making many leaps in your logic there.  Plasma concentrations are certainly relevant. That paper absolutely does not say that concentrations are irrelevant.  

 

Keep in mind, there are studies out there testing MitoQ in vivo in human subjects at doses of 1200mg/day and 3600mg/day that noted no deleterious effects.  You're touting a in vitro study using opossum kidney cells and neither one of us knows if the plasma molarities have any bearing whatsoever on what you'll actually see in a human kidney.  And you are concluding that this takes MitoQ completely off the table as a dangerous substance.  In spite of the fact that we've had humans taking 14x the standard dose and no one measured any damage to their kidneys in the labs.

 

Using your criteria I think I'd have to swear off salt as well.  That stuff will kill you if you get too much of it.

 

Let's find out what the pharmacokinetics of this substance is.  What plasma concentrations you might expect and for how long.  The benefits of MitoQ are too intriguing to dismiss it off this one study.  Unless you're a possum perhaps.

 

 


And btw, MitoQ doesn't enter the mitochondria and "stay there".  If it did it would be useless.  It mops up the ROS generated by energy production in the mitochondria and is thus being continually consumed.

 


Edited by smithx, 14 June 2019 - 07:55 AM.

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#427 Daniel Cooper

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Posted 14 June 2019 - 02:54 PM

Plasma concentrations are not solely important, but they are relevant (you'll recall your saying they are not relevant)

 

MitoQ is being consumed in the mitochondria mopping up ROSs.  If the concentration is such that it is entering faster than it is being consumed, obviously you will see a buildup as time goes forward.  How fast it is accumulating and for how long is important.  Obviously there is an integration occurring here. 

 

Since we put in MitoQ as essentially a pulse the peak plasma concentration and the duration will determine to what extent it accumulates. 

 

And I keep coming back to the fact that we have in vivo human subjects that have taken substantially high doses (up to 3,600mg) of this compound in real phase 1 and 2 trials that looked fairly intensely at safety and did not see anything concerning.  Recall that MitoQ originally went down a drug development path, not a supplement path.  It failed to pass muster not because of any safety issues, but because they could't show efficacy for their target disease (at that time, Parkinson's). 

 

I'm not saying to discount this in vitro paper at all.  This issue should obviously be looked at.  But in vitro will frequently give different results from in vivo both in the positive and negative direction.  Ultimately though, it's how the compound performs in the target organism that matters. I'm just suggesting that we look at this issue coolly and not be alarmist over this.

 

 


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#428 aribadabar

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Posted Today, 03:48 AM

Guys,

 

I also wondered how meaningful 500 nmol concentration is when the study first came out and here is QfL's calculation for your consideration.

Based on it, the observed deleterious effect looks fairly plausible possibility to also occur to some extent in humans, in vivo.


Edited by aribadabar, Today, 03:50 AM.

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