The Travis Corner

[energyandstruct]

Also baicalein is a flavonoid but an anti-estrogen substance and pro GABA. Interesting> . I thought peat said most flavanoids were estrogens

 

[energyandstruct]

The other thing is that I know there are some pharmaceutical PDK inhibitors, like DCA, which Peat has talked about being toxic, perhaps because they don't just inhibit aerobic glycolysis, but inhibit anaerobic glycolysis too, or something. But also some people have gotten good results from them.

 

[Travis]

Thanks travis, this is a lot to chew on and I've copied all of it down. I've tried some of the standard Peat suggestions without a ton of success. Often temporary relief from something like progestE or thyroid doses but seemingly diminishing returns for some reason.

I read Szent-gyorgyi's "cancer and the living state" which is pretty much the only serious biology I've read, besides Ray's articles, and I remember him talking about methylgloxal in the context of life formation on Earth, so I'm excited to hear some less speculative stuff about its specific biological role.

I also got intriguing results from ultra high dose thiamine--2000 mg a few times, which I used because an italian study on fibro got very good results only when they pushed the dose this high. It was a small study and fibro is different from CFS but I figured worth a try. I did get some insomnia and heart palps from it though.

I have skullcap in my garden actually, not much. I may try digging up the roots and doing an extract, but I'll also just go ahead and get some baicalein. Would you think that beta-lapachone would have a similar effect to lapachol? I ask because I already have some lapodin lying around.
​

Yes: β-lapachone is actually slightly more potent (Kᵢ ≈ 4 μM) at inhibing glyoxalase-1 than lapachone, yet I hadn't mentioned that on account of it being less-known. Hinokitiol appears more potent yet (Kᵢ ≈ 3 μM), yet because this is exotic and expensive I didn't mention that either. But certainly: baicalein, lapachol, and β-lapachone are three of the most powerful glyoxalase-1 inhibitors and are also easy-to-find. The only side-effect from lapachol and β-lapachone seems to be a slight displacement of vitamin K from the γ-carboxylglutamyl-forming enzymes, perhaps only relevant in people not supplementing or eating leaves. This vitamin K antagonism is officially why the NIH had sidelined it after it'd gained popularity for treating cancer in the 1970s, yet I think it's fair to assume that had been a cover for discouraging anything unprofitable. Should a person be worried about vitamin K inhibition that they could take baicalein instead (Kᵢ ≈ 7 μM), which may also be less expensive per gram as it's sold in crystalline form. Curcumin also inhibits glyoxalase-1 but since it's not absorbed it doesn't matter.

 

[Amazoniac]

I think I can feel 5,000 IU largely because I have low body fat, and that the same could happen in others using a comparable dose adjusted for BMI. Calcium channels have been highly implicated in joint pain, where a role for Ca²⁺ would seem intuitive because it could signal-for joint attrition. Oral cholecalciferol could tend towards hypercalcemia by increasing intestinal Ca²⁺ absorption, yet hypercalcemia and joint pain has also been induced by retinol. In the latter case, hypercalcemia results from the demineralization of the bones and not 'their remineralization:'

Frame, Boy. "Hypercalcemia and skeletal effects in chronic hypervitaminosis A." Annals of internal medicine (1974)

'The clinical features of vitamin A toxicity in a 7-year-old boy, a 16-year-old boy, and a 46-year-old man included vague skeletal pains and hypercalcemia. Experimental and clinical evidence indicates that hypervitaminosis A can cause bony resorption as well as periosteal calcification. Ingestion of excessive amounts of vitamin A should be considered in the differential diagnosis of hypercalcemia.' ―Frame​

'A 7-year-old boy was admitted with generalized muscular and skeletal discomfort of 6 weeks' duration. For 5 days he had been unable to walk or straighten his legs. He cried readily, complained of a headache, was irritable, and had a poor appetite. Examination showed a thin, pale child who was unable to stand or straighten his flexed legs because of pain. Tenderness was noted along both tibiae. Hemoglobin was 12.7 g/100 ml, and the leukocyte count, 7500/mm³ . Urinalysis was normal. [...] The presence of hypercalcemia prompted an inquiry of medications taken by the patient, which revealed a daily intake of 85,000 units of vitamin A for 2 years, with less than 1,500 units of vitamin D per day. Because of the patient's poor appetite, his parents increased the vitamin A to 160,000 units daily on the advice of a salesman in a health food store several months before admission. Skeletal roentgenograms were normal. The vitamin A level in the serum was 403 IU/100 ml. The excessive ingestion of vitamin A was discontinued, and fluids were forced. He improved rapidly. After 3 weeks the serum calcium had decreased to 10.1 mg/100 ml, and the skeletal discomfort had disappeared.' ―Frame​

'A 16-year-old boy had had generalized myalgia and arthralgias for 3 months. He showed emotional lability and had lost 10 lb because of loss of appetite. Examination showed weakness of hand grip caused by pain and tenderness over the small bones of the hands and distal forearms. Serum calcium was elevated, ranging from 12.0 to 14.0 mg/100 ml. The alkaline phosphatase was 10 Bodansky units. Evidence for the correct diagnosis was observed on the skeletal roentgenograms (Figures 1 to 3). Multiple sites of periosteal calcification were noted along the shafts of several of the metacarpals and proximal phalanges. The periosteal calcifications suggested vitamin A intoxication. [...] The demineralization of the sella was so pronounced that the possibility of an intrasellar mass was strongly considered. The patient initially denied ingestion of vitamin supplements. After the roentgenologic changes were noted, the patient was again questioned about vitamin ingestion. A pertinent history was then obtained. The patient wanted to become an aircraft pilot, and, hoping to improve his night vision, he had ingested variable and excessive amounts of vitamin A for several years.' ―Frame​

'A 46-year-old man complained of fatigue, vague chest pains, headaches, and general skeletal discomfort of 6 years' duration. His family physician found elevated serum and urinary calcium concentrations and evidence of renal insufficiency. Nephrocalcinosis was demonstrated on an intravenous pyelogram. He passed several small renal calculi. The patient was seen in a large midwestern clinic where hypercalcemia, averaging 12.6 mg/100 ml was confirmed. [...] In October 1972 the patient was further questioned regarding vitamin ingestion. He admitted to taking up to 50 000 units of vitamin A in a multivitamin preparation daily, at least during 1972, but denied taking vitamin supplements before this time when the hypercalcemia had initially been detected. Some residual frozen serum taken at the time of the parathyroid exploration was located. In this sample the carotene level was 286 μg/100 ml, and the vitamin A level was 625 IU/100 ml (normal, less than 125 IU/100 ml). On the basis of this information, the patient was questioned further about vitamin intake. It was discovered that he was a part-time, door-to-door vitamin salesman. One of the products he sold was a multivitamin preparation containing vitamin A. He admitted taking an average of three capsules per day containing a total of 25,000 units of vitamin A and 1,250 units of vitamin D for 6 to 7 years, the duration of his illness. Periodically, he had increased the dose, thinking that his symptoms indicated a need for larger amounts of these nutritional supplements.' ―Frame​

It appears that salesmen not only prefer to imagine their drugs are completely safe, and any practical dose, but that their side-effects are actually an indication for taking more. I feel this is unrealistic, yet with the sole exception of the 'die-off' reaction: In this situation, increasing the dose may lead to a quicker resolution at the expense of accentuated acute symptoms.

From the known effects of calcitriol and retinoic acid: it would imagine Vitamin D-induced joint pain could more strictly be considered hypercalcemia-related joint pain, perhaps the result of a high Ca²⁺/Mg²⁺ ratio. Perhaps I will try taking a few grams of calcium soon to see if I can feel anything from that. I feel it bears repeating that even a dose of 5,000 IU of vitamin D orally—i.e. directed at the Ca²⁺-responsive intestines—is completely unnatural, unless of course you consider fish liver oil a 'natural food.'

Some of these might interest you:
- A total dietary program emphasizing magnesium instead of calcium. Effect on the mineral density of calcaneous bone in postmenopausal women on hormonal therapy.
- The Role of Nutrients in Bone Health, from A to Z
- Daily Oral Magnesium Supplementation Suppresses Bone Turnover in Young Adult Males
- Do we need to take calcium with vitamin D supplements to prevent falls, fractures, and death? (@Obi-wan)
- Maintenance Dose of Vitamin D: How Much Is Enough?
- Collagen supplementation as a complementary therapy for the prevention and treatment of osteoporosis and osteoarthritis: a systematic review
- Specific Collagen Peptides Improve Bone Mineral Density and Bone Markers in Postmenopausal Women—A Randomized Controlled Study

Are you implying it's better to actually eat the food most correlated with acne—when trying to eliminate acne—than to avoid it?

Sequeira, Jeffrey. "The diagnostic utility of folate receptor autoantibodies in blood." Clinical chemistry and laboratory medicine (2013)

'As we age, the immune system also changes, leading to immunosenescence, and therefore, AuAbs to many antigens are prevalent in the elderly population [ 30 , 31 ]. This trend is also seen for blocking FRα AuAbs, whose prevalence increases from < 2% in those younger-than-16-years age group to approximately 10% in the 18-to-35-years age group, and with approximately 25% of the older-than-65-years age group testing positive for the antibody ( Figure 6 ).' ―Sequeira​

[The above quote is only considering the relatively easy-to-measure blocking FRα autoantibody, yet in general there exists a like amount of those that bind yet do not block. This would make for a 50% prevalence in those over 65 years of age when considering both, which is approaching the very prevalence of the homogenized milk use. Autoantibodies that bind and do not block folate receptor α can still indirectly reduce brain folate uptake, and this could happens by serving as beacon for neutrophils—an immune cell that will damage any anything having a bound antibody using hypochlorite (ClO⁻). For confirmation of the latter statement, one only needs to read a few decent articles on the islet β-cells involved in diabetes mellitus.]

With the cavern that I'm undergoing rehabilitation after accidental casomorphin exposure that lead to worsening of skin quality, probably among other unsuspected issues (I'll eventually let you know the impression about it); I'm implying that you can avoid it and the skin quality must improve, but it doesn't answer how others are able to consume the same product and have a different experience.

Do you still plan to write about 'fatigue syndrome'? Isn't 'chronic' in that term a neoplasm? As you can tell, folate's way isn't unobstructed yet.

 

[Obi-wan]

I can't think of anything besides thiamine, unless of course you'd find a way to increase the expression of the enzyme. Yet there could be a way to do this: Since pyruvate dehydrogenase is under negative regulation by hypoxia inducible factor-1—via transcribing-for pyruvate dehydrogenase kinase—then taking baicalein and/or lapachol should ultimately act to increase it. These phytochemicals are the two most powerful natural glyoxalase-1 inhibitors (Kᵢ ≈ 5–7 μM), acting to increase methylglyoxal by inhibiting its degradation to lactate. Methylglyoxal is very powerful because it selectively reacts with exposed arginyl side-chains on proteins, irreversibly converting them into hydroimidazolone rings. By reacting with 'hot spot' arginine residues is how methylglyoxal been shown to regulate transcription (Yao, 2007), and the transcription factor HIF-1 is also inactivated in this manner (Bento, 2010). Taking a glyoxalase inhibitor such as baicalein could be expected to: increase intracellular methylglyoxal, decrease intracellular lactate, inhibit 15-lipoxygenase (Deschamps, 2006), inactivate hypoxia inducible factor-1α (Bento, 2010) thereby increasing pyruvate dehydrogenase expression. Methylglyoxal had acquired a pathological reputation because it reacts with extracellular proteins in diabetes, yet this only occurs in states where glucose cannot get into the cell where it belongs. Methylglyoxal also forms inside the cell mainly from carbohydrates, and appears to be the biochemical signal for their metabolic rate. Intracellular methylglyoxal has also acquired reputation for powerfully inhibiting cancer, and very likely the reason why baicalein and lapachol have been so successful at treating it.

Kim, Jung-Whan. "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia." Cell metabolism (2006)

'Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1a null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.' ―Jung-Whan​

Bento, C. F. "The chaperone-dependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal." PloS one (2010)

'Methylglyoxal has recently been shown to modify HIF-1α on arginine residues [22], probably leading to changes in protein conformation. Indeed, immunoprecipitation experiments showed that methylgloxal-modified lysine and arginine residues of HIF-1α, increasing its immunoreactivity against N-carboxymethyl-lysine and Nα-acetyl-Nδ(5-hydro-5-methyl)-4-imidazolone (MG-H1) antibodies, respectively. Thus, we hypothesized that modification by methylgloxal might stimulate proteasome-dependent degradation of HIF-1α, as a result of post-translational modifications.' ―Bento​

Yao, Dachun. "High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A." Journal of Biological Chemistry (2007)

'Our studies demonstrate for the first time that methylglyoxal causes post-translational modification of a coregulator protein and that this modification affects gene expression. The extent of this modification reflects the net effect of a variety of intracellular processes, including metabolic flux and reactive oxygen formation, and may thus function as a new integrating signal to coordinately regulate distinct patterns of gene expression.' ―Yao​

It really is all about acetyl-CoA entering the Krebs cycle and Citrate starting the ETC to end with (NADH, ADP to ATP) which results in a electric potential 0f -70 to -80 mVolts resting membrane potential (sodium extracellular/potassium intracellular).

Biotin is a PDK inhibitor
Thiamine is a PDH upregulator
Niacinamide is a FAO inhibitor and increases NAD+ all in Energin by the way...

Per @Travis Threonine and Beta Lapachol (in Lapodin)is a PDH upregulator

PDH turns Pyruvate into Acteyl-CoA
PDK turns Pyruvate into Lactic Acid

Also to jump start this process apple cider vinegar/sodium bicarbonate/potassium bicarbonate which turns into acetate that will directly feed into the Krebs cycle as Acetyl-CoA and adds malate as an intermediate into the Krebs cycle which increases all of the other intermediates and allows the Krebs cycle to consume more Acteyl-CoA thus more Citrate thus more Carbon dioxide , water, and ATP.

Now add K2 for the ETC...

 

[Mito]

Methylglyoxal had acquired a pathological reputation because it reacts with extracellular proteins in diabetes, yet this only occurs in states where glucose cannot get into the cell where it belongs.

So methylglyoxal only forms advanced glycation end products when blood sugar is at diabetic levels?

 

[Broken man]

More productive than avoidance is trying to find out how some people manage to not have problems with those at all. After discovering the difference, thinking: am I doomed? What did I do to deserve this? Is it because of my skin color? Is this an extension of my other failures? Will I ever succeed in something?

This is what I am thinking too, I was living with local farmers for 1 week. Their age is between 25-50. The older men were eating loads of pufa, processed food with zero nutritional value and drinking alot of alcohol. I asked them how long they are living like this. They told me that almost whole life because pufa and processed food is cheap. I can say that they werent looking good, they were fat, bad skin, high pressure, red noses, unable to move much but they had hair even gray or white but they werent bald. I personally think that its connected with gut. Please, do you know how long it takes to change composition of cardiolipin? Thank you.

 

[Broken man]

It really is all about acetyl-CoA entering the Krebs cycle and Citrate starting the ETC to end with (NADH, ADP to ATP) which results in a electric potential 0f -70 to -80 mVolts resting membrane potential (sodium extracellular/potassium intracellular).

Biotin is a PDK inhibitor
Thiamine is a PDH upregulator
Niacinamide is a FAO inhibitor and increases NAD+ all in Energin by the way...

Per @Travis Threonine and Beta Lapachol (in Lapodin)is a PDH upregulator

PDH turns Pyruvate into Acteyl-CoA
PDK turns Pyruvate into Lactic Acid

Also to jump start this process apple cider vinegar/sodium bicarbonate/potassium bicarbonate which turns into acetate that will directly feed into the Krebs cycle as Acetyl-CoA and adds malate as an intermediate into the Krebs cycle which increases all of the other intermediates and allows the Krebs cycle to consume more Acteyl-CoA thus more Citrate thus more Carbon dioxide , water, and ATP.

Now add K2 for the ETC...

Thank you for this.

 

[energyandstruct]

Yes: β-lapachone is actually slightly more potent (Kᵢ ≈ 4 μM) at inhibing glyoxalase-1 than lapachone, yet I hadn't mentioned that on account of it being less-known. Hinokitiol appears more potent yet (Kᵢ ≈ 3 μM), yet because this is exotic and expensive I didn't mention that either. But certainly: baicalein, lapachol, and β-lapachone are three of the most powerful glyoxalase-1 inhibitors and are also easy-to-find. The only side-effect from lapachol and β-lapachone seems to be a slight displacement of vitamin K from the γ-carboxylglutamyl-forming enzymes, perhaps only relevant in people not supplementing or eating leaves. This vitamin K antagonism is officially why the NIH had sidelined it after it'd gained popularity for treating cancer in the 1970s, yet I think it's fair to assume that had been a cover for discouraging anything unprofitable. Should a person be worried about vitamin K inhibition that they could take baicalein instead (Kᵢ ≈ 7 μM), which may also be less expensive per gram as it's sold in crystalline form. Curcumin also inhibits glyoxalase-1 but since it's not absorbed it doesn't matter.

This is great, thank you. The wikipedia page claimed that lapachol was particularly toxic and thats why it's not used, but when i had looked into beta-lapachone toxicity before taking haidut's product, it seemed pretty safe.

 

[energyandstruct]

It really is all about acetyl-CoA entering the Krebs cycle and Citrate starting the ETC to end with (NADH, ADP to ATP) which results in a electric potential 0f -70 to -80 mVolts resting membrane potential (sodium extracellular/potassium intracellular).

Biotin is a PDK inhibitor
Thiamine is a PDH upregulator
Niacinamide is a FAO inhibitor and increases NAD+ all in Energin by the way...

Per @Travis Threonine and Beta Lapachol (in Lapodin)is a PDH upregulator

PDH turns Pyruvate into Acteyl-CoA
PDK turns Pyruvate into Lactic Acid

Also to jump start this process apple cider vinegar/sodium bicarbonate/potassium bicarbonate which turns into acetate that will directly feed into the Krebs cycle as Acetyl-CoA and adds malate as an intermediate into the Krebs cycle which increases all of the other intermediates and allows the Krebs cycle to consume more Acteyl-CoA thus more Citrate thus more Carbon dioxide , water, and ATP.

Now add K2 for the ETC...

Obi-wan, did you have thughts on sodium acetate lowering the respiratory exchange ratio? Peat mentioned it might be problematic. I''m going to try it regardless, lots of people getting good results with it

 

[ATP]

I would like to know your opinion on the carnivorous diet Travis. A lot of people are trying it, obviously because of the popularity of it on social media recently.

I’ve heard all of the generic reasons why people think it is apparently very effective for some, but I am really interested in your perspective.

 

[Amazoniac]

This is what I am thinking too, I was living with local farmers for 1 week. Their age is between 25-50. The older men were eating loads of pufa, processed food with zero nutritional value and drinking alot of alcohol. I asked them how long they are living like this. They told me that almost whole life because pufa and processed food is cheap. I can say that they werent looking good, they were fat, bad skin, high pressure, red noses, unable to move much but they had hair even gray or white but they werent bald. I personally think that its connected with gut. Please, do you know how long it takes to change composition of cardiolipin? Thank you.

- Biosynthesis, remodeling and turnover of mitochondrial cardiolipin

"The half-life of CL is several-fold longer than the half-life of other phospholipids. This was first observed in rats labeled with 32P phosphate [66] or 2H2O [67] and later confirmed in cell cultures and flies [45,68]. For instance, there is no measurable CL turnover in Drosophila over a period of 9 days, which is remarkable given that these animals only live 60 days and showplenty of turnover in all other phospholipids during the 9 day period [45]."

But that's the full cycle, remodeling shouldn't take that long.

"The life of a CL molecule can be divided into 3 phases. The first is its biosynthesis in the inner mitochondrial membrane; the second is the remodeling of its fatty acids and its assembly into the inner membrane; and the third is its degradation and oxidative modification and its potential translocation out of the inner membrane. While the first step is relatively well established, the other two are still under scrutiny as theirmechanisms are not fully understood and their functional implications are not very clear."​

- Emerging roles of cardiolipin remodeling in mitochondrial dysfunction associated with diabetes, obesity, and cardiovascular diseases

"Thyroid hormone is a major physiological modulator of oxidative stress and mitochondrial respiration[68]. Thyroid hormone has been shown to increase mitochondrial mass, mitochondrial cytochrome c content, respiratory rate, and capacity of oxidative metabolism[69]. Hyperthyroidism is associated with significant mitochondrial dysfunction. Cardiovascular tissues are particularly sensitive to ROS damage associated with hyperthyroidism, because of the high energy demand of the heart. For example, hyperthyroid hearts displayed tachycardia and low functional recovery. Their mitochondria exhibited higher level of H2O2 production and susceptibility to swelling during reperfusion[70]. Both the levels of CL and lipid composition are profoundly altered by thyroid hormone status. Hyperthyroidism and hypothyroidism reciprocally affect the level of oxidative stress, lipid peroxidation, CL synthesis and remodeling[71],[72]. The hepatic and cardiac CL contents were elevated in rats treated by thyroxine, which was accompanied by an increase in CL synthase activity and level of ROS production[73],[74]. Moreover, cardiac mitochondrial MLCL AT activity was stimulated in hyperthyroid rats[75], and decreased in rats made hypothyroid[76]. Consistent with increased level of ROS production, hyperthyroidism is associated with a marked loss of C18:2, concurrent with a significant increases in polyunsaturated fatty acids such as arachidonic acid (C20:4) and DHA (C22:6)[72]. These changes increased the double bond index by 27% and CL peroxidizibility by 266%, which is likely to contribute to the elevated level of oxidative stress associated with hyperthyroidism[77]. In support of a possible role of ALCAT1 in pathological remodeling of CL, ALCAT1 mRNA expression was significantly up-regulated by hyperthyroidism and down-regulated by hypothyroidism[78]."​

- Phosphatidylglycerol Incorporates into Cardiolipin to Improve Mitochondrial Activity and Inhibits Inflammation

"CL remodeling alters the CL profile depending on the availability of fatty acyl chains in the environment, which can be manipulated by nutrient deprivation and lipid supplementation[25,26]."​

- Lipid Replacement Therapy: A natural medicine approach to replacing damaged lipids in cellular membranes and organelles and restoring function (refs. 1 and 2 are worth checking out)
- Cardiolipin remodeling: a regulatory hub for modulating cardiolipin metabolism and function
- Formation and Regulation of Mitochondrial Membranes

- Balancing Vitamins A And E
- MitoLipin - Liquid Saturated Phosphatidylcholine (PC) Mix

Hopefully this is useful in your search for a precise answer. The term 'cardiolipin remodeling days' should probably lead to it, but it isn't limited to remodeling because synthesis from scratch also counts.
tyw has some posts on the fixed nature of some of these phospholipids regardless of the conditions.

 

[Obi-wan]

Obi-wan, did you have thughts on sodium acetate lowering the respiratory exchange ratio? Peat mentioned it might be problematic. I''m going to try it regardless, lots of people getting good results with it

I think it actually increases it. I have dropped the potassium bicarbonate for now (it was giving me fatigue). I have also started doing 10 drops of Energin and Lapodin in OJ after each meal so 3x per day. I have done this in the past with no results but now I feel it each time I do it. Maybe knocking down the Lactic acid with sodium acetate changed things...

 

[Obi-wan]

https://chrismasterjohnphd.com/2016/08/24/insulin-resistance-isnt-all-about-carbs-and-insulin/ just listened to this. Great podcast

Energin supports mitochondria oxygen metabolism which produces ROS as a by product
Lapodin/Threonine prevents the glutathione antioxidant system so more ROS to kill the cancer cell with Methylglyoxal (@Travis )
Sodium acetate helps to further knock out Lactic acid and maintain cellular potential

 

[energyandstruct]

Yes: β-lapachone is actually slightly more potent (Kᵢ ≈ 4 μM) at inhibing glyoxalase-1 than lapachone, yet I hadn't mentioned that on account of it being less-known. Hinokitiol appears more potent yet (Kᵢ ≈ 3 μM), yet because this is exotic and expensive I didn't mention that either. But certainly: baicalein, lapachol, and β-lapachone are three of the most powerful glyoxalase-1 inhibitors and are also easy-to-find. The only side-effect from lapachol and β-lapachone seems to be a slight displacement of vitamin K from the γ-carboxylglutamyl-forming enzymes, perhaps only relevant in people not supplementing or eating leaves. This vitamin K antagonism is officially why the NIH had sidelined it after it'd gained popularity for treating cancer in the 1970s, yet I think it's fair to assume that had been a cover for discouraging anything unprofitable. Should a person be worried about vitamin K inhibition that they could take baicalein instead (Kᵢ ≈ 7 μM), which may also be less expensive per gram as it's sold in crystalline form. Curcumin also inhibits glyoxalase-1 but since it's not absorbed it doesn't matter.

I can only find baicalin to buy. is this a prodrug for baicalein and can I safely assume it has basically equivalent effects for this purpose?

I will try and do a root tincture of any skullcap plants on my property, but that takes time, and I'd like to try this soon. It also seems like baicalein has other generally protective effects, on GABA, estrogen, etc

 

[energyandstruct]

The A2 milk has less opiate effects; but what is less known is that even Holsteins have some A2 and that essentially cows express both isoforms. Selective breeding can enrich the A2∶A1 ratio but the DNA study I'd read indicates that every breed still has both; even goats and sheep still have some A1.

I ought to look for that study on A2 and see if they'd used pure recombinant A2—or otherwise purified—or if they had used goat or sheep milk. I think you can expect brands marketed as 'A2 milk' to release less β-casomorphin but you'd still also expect some to be present. This can either be seen as a pro or a con, and if it's not desired than the best and safest antidotes are probably coffee and natural L-dopa.

Of course opiates at that level are generally harmless and eating them can be fun. The only reason I don't is that I find they interfere with motivation a bit, but so does ethanol and serotonin and I don't really do them either. All I drink is coffee, water, and raw fruit and vegetable juices—but I do smoke like a veritable chimney! and am about to go γ-tocopherol shopping right now to counteract all this inhaled nitric oxide. I'm fairly certain if a person were to read the same studies on this that I had, they'd almost be forced to conclude that lung cancer is driven mostly by nitric oxide. The logic for this is straightforward: (1) Gamma-tocopherol radically lowers lung cancer in mice in vivo; (2) the very large NHANES study using α-tocopherol could not lower lung cancer incidence but had actually raised it, likely on account of α-tocopherol's known ability displace γ-tocopherol); (3) gamma-tocopherol is lowered in smokers and increases quickly after cessation; (4) this molecule is known for its unique ability to complex-with and remove ṄO₂ and peroxynitrite; and (5) peroxynitrite is a substrate for cyclooxygenase, the very molecule added to arachidonic acid to form prostaglandin H₂—the precursor of the notoriously carcinogenic prostaglandin E₂.

For someone who doesn't have that much money but wants to try A2 milk, could I just switch to goat milk/cheese, or find a provider of jersey milk around me? I live in rural area where it's often cheap to buy raw milk.
Also what do you think of the use of colostrum in immuno-deficient people, or people who have concurrent high bands of IgG and overall low IgG/low bands? Same with IVIG, what do you think about that?

 

[Travis]

I'm implying that you can avoid it and the skin quality must improve, but it doesn't answer how others are able to consume the same product and have a different experience.

Acne largely appears to be a dose-dependent function of androgens and/or insulin-like growth factor. Differential expression of sex steroid-binding globulin can explain some more individual response, and the varying concentrations of IGF-1 by country can explain it some more. Milk IGF-1 concentrations are increased considerably by rBGH (Prosser, 1989), a Monsanto product used in the United States yet banned by most countries.

'Six lactating, non-pregnant Jersey cows were given subcutaneous injections of recombinantly derived bovine growth hormone for 7 d. Milk yield was increased by 4-5 kg/d on day 7, compared with the average yield of 107 kg/d for the 7 days preceding treatment. Concentrations of insulin-like growth factor 1 in the milk increased from 0.44 nmol/l during the 7 days preceding treatment to 1.6 nmol/l on day 7 of treatment. Taking the increase in milk yield into account the total increase in the secretion of IGF-1 into milk of one udder half was 6-fold. Plasma concentrations of total IGF-1 rose from 15.5 nmol/l on the day preceding treatment to 56.9 nmol/l on day 7 of treatment.' ―Prosser​

Stearic acid consumption, omega−3 fatty acid intake, and temperature also influence sebum viscosity; and yet, a high production rate of too-viscous sebum would merely cause a whitehead without certain bacteria being trapped inside the pore. This induces another layer of complexity because acne could also be a function of skin microbiota. The chemical composition of comedogenic sebum has been sufficiently elucidated (Powell, 1970), vide infra, and the changes are fully consistent with induction of SREBP:

​

I can think of two things that can powerfully activate SREBP and activate lipogenesis in sebocytes: androgens (Rosignoli, 2003), and insulin-like growth factor (Smith, 2008). Both of these are strongly linked to acne, and both are also found in dairy products—especially in the United States. Based on the demonstrated liposomal encapsulation of bovine xanthine oxidase consequent of homogenization (Ross, 1980), milk processed in this way could also be expected to increase IGF-1 persorption in an analogous manner. I can't say much about the Italian cheese where you live—besides it being a bit too salty (e.g. Romano)—yet in America most brands of cheese certainly appear to be linked to acne in a dose-dependent manner.

 

[energyandstruct]

Same effect as acetyl CaA going into the Krebs cycle but different minerals. Inner potassium keeps a high potential in a cell so as Travis said keep a higher potassium to sodium ratio. Plus I feel a difference with potassium bicarbonate where sodium bicarbonate just gives me more energy

hmm where do u get potassium bicarbonate?

 

[Travis]

So methylglyoxal only forms advanced glycation end products when blood sugar is at diabetic levels?

No, methylglyoxal forms them continuously in everybody as we speak. When glucose cannot get into the cell as seen in diabetes, methylglyoxal will exist in the extracellular space—i.e. in the lymph or plasma. People having membranes allowing-for a high glucose flux should have relatively little extracellular methylglyoxal, yet concentrations within the cell could be just as high as seen in diabetes or even higher. All of the negative publications involving methylglyoxal that I've seen had involved advanced glycation end products on extracellular proteins, not the intracellular ones where methylglyoxal has been show to control transcription and enzymatic rates. Glyoxalase-1 and -2 normally serve to keep methylglyoxal concentrations withing a suitable range using a glutathione cofactor, and for this reason—and a few others—the intracellular methylglyoxal concentrations probably don't correlate all that well with glycolytic rate. Yet I think you'd almost be certain that a low glucose flux would correlate well with high plasma methylgloxal concentrations, primarily because of the negligible amounts of glyoxalase-1 and -2 existing in the extracellular space—and also the lower glutathione. Methylglyoxal is too reactive to travel very far from its origin, and I would guess its biological half life is on the order of minutes.

 

[LeeLemonoil]

I think I can feel 5,000 IU largely because I have low bodyOral cholecalciferol could tend towards hypercalcemia by increasing intestinal Ca²⁺ absorption, yet hypercalcemia and joint pain has also been induced by retinol. In the latter case, hypercalcemia results from the demineralization of the bones and not 'their remineralization:'

Frame, Boy. "Hypercalcemia and skeletal effects in chronic hypervitaminosis A." Annals of internal medicine (1974)

'The clinical features of vitamin A toxicity in a 7-year-old boy, a 16-year-old boy, and a 46-year-old man included vague skeletal pains and hypercalcemia. Experimental and clinical evidence indicates that hypervitaminosis A can cause bony resorption as well as periosteal calcification. Ingestion of excessive amounts of vitamin A should be considered in the differential diagnosis of hypercalcemia.' ―Frame​

'A 7-year-old boy was admitted with generalized muscular and skeletal discomfort of 6 weeks' duration. For 5 days he had been unable to walk or straighten his legs. He cried readily, complained of a headache, was irritable, and had a poor appetite. Examination showed a thin, pale child who was unable to stand or straighten his flexed legs because of pain. Tenderness was noted along both tibiae. Hemoglobin was 12.7 g/100 ml, and the leukocyte count, 7500/mm³ . Urinalysis was normal. [...] The presence of hypercalcemia prompted an inquiry of medications taken by the patient, which revealed a daily intake of 85,000 units of vitamin A for 2 years, with less than 1,500 units of vitamin D per day. Because of the patient's poor appetite, his parents increased the vitamin A to 160,000 units daily on the advice of a salesman in a health food store several months before admission. Skeletal roentgenograms were normal. The vitamin A level in the serum was 403 IU/100 ml. The excessive ingestion of vitamin A was discontinued, and fluids were forced. He improved rapidly. After 3 weeks the serum calcium had decreased to 10.1 mg/100 ml, and the skeletal discomfort had disappeared.' ―Frame​

'A 16-year-old boy had had generalized myalgia and arthralgias for 3 months. He showed emotional lability and had lost 10 lb because of loss of appetite. Examination showed weakness of hand grip caused by pain and tenderness over the small bones of the hands and distal forearms. Serum calcium was elevated, ranging from 12.0 to 14.0 mg/100 ml. The alkaline phosphatase was 10 Bodansky units. Evidence for the correct diagnosis was observed on the skeletal roentgenograms (Figures 1 to 3). Multiple sites of periosteal calcification were noted along the shafts of several of the metacarpals and proximal phalanges. The periosteal calcifications suggested vitamin A intoxication. [...] The demineralization of the sella was so pronounced that the possibility of an intrasellar mass was strongly considered. The patient initially denied ingestion of vitamin supplements. After the roentgenologic changes were noted, the patient was again questioned about vitamin ingestion. A pertinent history was then obtained. The patient wanted to become an aircraft pilot, and, hoping to improve his night vision, he had ingested variable and excessive amounts of vitamin A for several years.' ―Frame​

'A 46-year-old man complained of fatigue, vague chest pains, headaches, and general skeletal discomfort of 6 years' duration. His family physician found elevated serum and urinary calcium concentrations and evidence of renal insufficiency. Nephrocalcinosis was demonstrated on an intravenous pyelogram. He passed several small renal calculi. The patient was seen in a large midwestern clinic where hypercalcemia, averaging 12.6 mg/100 ml was confirmed. [...] In October 1972 the patient was further questioned regarding vitamin ingestion. He admitted to taking up to 50 000 units of vitamin A in a multivitamin preparation daily, at least during 1972, but denied taking vitamin supplements before this time when the hypercalcemia had initially been detected. Some residual frozen serum taken at the time of the parathyroid exploration was located. In this sample the carotene level was 286 μg/100 ml, and the vitamin A level was 625 IU/100 ml (normal, less than 125 IU/100 ml). On the basis of this information, the patient was questioned further about vitamin intake. It was discovered that he was a part-time, door-to-door vitamin salesman. One of the products he sold was a multivitamin preparation containing vitamin A. He admitted taking an average of three capsules per day containing a total of 25,000 units of vitamin A and 1,250 units of vitamin D for 6 to 7 years, the duration of his illness. Periodically, he had increased the dose, thinking that his symptoms indicated a need for larger amounts of these nutritional supplements.' ―Frame​

It eption of the 'die-off' reaction: In this situation, increasing the dose may lead to a quicker resolution at the expense of accentuated acute symptoms.

From the known effects of calcitriol and retinoic acid: it would imagine Vitamin D-induced joint pain could more strictly be considered hypercalcemia-related joint pain, perhaps the result of a high Ca²⁺/Mg²⁺ ratio. Perhaps I will try taking a few grams of calcium soon to see if I can feel anything from that. I feel it bears repeating that even a dose of 5,000 IU of vitamin D orally—i.e. directed at the Ca²⁺-responsive intestines—is completely unnatural, unless of course you consider fish liver oil a 'natural food.'

Could hypervitaminos A when freeing up formerly boneintegrated Ca-ions also lead to overexitatory effects in the CNS?