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Protective Effects of Citral
Retinol (ROL) toxicity is characterized by a decrease in the intracellular NAD+/NADH ratio. Metabolic clearance of retinol involves at least three oxidative reactions, depleting NAD+ and increasing NADH. The 10-carbon terpenoid citral was found to inhibit oxidation of retinol in rat conceptual tissues (Chen, Namkung et al. 1995). Citral at concentrations of 0.01 and 0.05 µM decreased biotransformation of all-trans-ROL (atROL) to all-trans-retinoic acid (atRA) by 88% and 97%, respectively, and at concentrations of 0.1 and 0.5 µM decreased biotransformation of all-trans-retinal (atRAL) to atRA by 60% and 81%, respectively.
Citral has been reported to possess anti-diabetic, anti-mutagenic and anti-inflammatory effects (Lawal, Ogundajo et al. 2017). Citral showed inhibitory effects on inflammation markers TNF-α, COX-2, PPARA, NFKB and PTGS2. PTGS2 activity was suppressed by 60–70%. Potentially related, PTGS1 has been described as required for isomerization and metabolization of atRA (Samokyszyn, Chang et al. 1997).
A recent study on the anti-inflammatory effects of citral showed a reduction in inflammation comparable to reference drug dexamethasone, believed to be the result of cannabinoid receptor type 2 (CB2) induction and suppression of the TLR2/dectin-1 pathway (Gonçalves, Assis et al. 2020). Furthermore, citral was found to prevent pathologic activation of hepatic stellate cells (HSC) (Lee, Jeong et al. 2015). An estimated 80–90% of total body retinol is stored in HSCs, and liver fibrosis (scarring) occurs when HSCs are activated and become collagen type I-producing cells. During HSC activation, ROL is oxidized to RA, and activated HSCs express a natural killer (NK) cell ligand known as retinoid acid early inducible-1 (RAE1), which is not present in quiescent HSCs (Suh and Jeong 2011).
Has anyone here attempted supplementation with citral, and if so, did you observe protective or adverse effects? I’m planning to start supplementing citral (or some lemongrass oil containing citral), and I’ll report back how it went in a month or two.
Bibliography
Chen, H., M. J. Namkung and M. R. Juchau (1995). "Biotransformation of all-trans-retinol and all-trans-retinal to all-trans-retinoic acid in rat conceptal homogenates." Biochemical Pharmacology 50(8): 1257-1264.
Gonçalves, E. C. D., P. M. Assis, L. A. Junqueira, M. Cola, A. R. S. Santos, N. R. B. Raposo and R. C. Dutra (2020). "Citral Inhibits the Inflammatory Response and Hyperalgesia in Mice: The Role of TLR4, TLR2/Dectin-1, and CB2 Cannabinoid Receptor/ATP-Sensitive K+ Channel Pathways." Journal of Natural Products 83(4): 1190-1200.
Lawal, O. A., A. L. Ogundajo, N. O. Avoseh and I. A. Ogunwande (2017). Chapter 18 - Cymbopogon citratus. Medicinal Spices and Vegetables from Africa. V. Kuete, Academic Press: 397-423.
Lee, H., H. Jeong, S. Park, W. Yoo, S. Choi, K. Choi, M.-G. Lee, M. Lee, D. Cha, Y.-S. Kim, J. Han, W. Kim, S.-H. Park and J. Oh (2015). "Fusion protein of retinol-binding protein and albumin domain III reduces liver fibrosis." EMBO molecular medicine 7(6): 819-830.
Samokyszyn, V. M., H. C. Chang and R. L. Compadre (1997). "A theoretical investigation of endocyclic allylic carbon-centered radical formation in retinoic acid." Bioorganic & Medicinal Chemistry Letters 7(18): 2343-2348.
Suh, Y.-G. and W.-I. Jeong (2011). "Hepatic stellate cells and innate immunity in alcoholic liver disease." World journal of gastroenterology 17(20): 2543-2551.
Quote from Johannes on August 14, 2021, 4:14 amRetinol (ROL) toxicity is characterized by a decrease in the intracellular NAD+/NADH ratio. Metabolic clearance of retinol involves at least three oxidative reactions, depleting NAD+ and increasing NADH. The 10-carbon terpenoid citral was found to inhibit oxidation of retinol in rat conceptual tissues (Chen, Namkung et al. 1995). Citral at concentrations of 0.01 and 0.05 µM decreased biotransformation of all-trans-ROL (atROL) to all-trans-retinoic acid (atRA) by 88% and 97%, respectively, and at concentrations of 0.1 and 0.5 µM decreased biotransformation of all-trans-retinal (atRAL) to atRA by 60% and 81%, respectively.
Citral has been reported to possess anti-diabetic, anti-mutagenic and anti-inflammatory effects (Lawal, Ogundajo et al. 2017). Citral showed inhibitory effects on inflammation markers TNF-α, COX-2, PPARA, NFKB and PTGS2. PTGS2 activity was suppressed by 60–70%. Potentially related, PTGS1 has been described as required for isomerization and metabolization of atRA (Samokyszyn, Chang et al. 1997).
A recent study on the anti-inflammatory effects of citral showed a reduction in inflammation comparable to reference drug dexamethasone, believed to be the result of cannabinoid receptor type 2 (CB2) induction and suppression of the TLR2/dectin-1 pathway (Gonçalves, Assis et al. 2020). Furthermore, citral was found to prevent pathologic activation of hepatic stellate cells (HSC) (Lee, Jeong et al. 2015). An estimated 80–90% of total body retinol is stored in HSCs, and liver fibrosis (scarring) occurs when HSCs are activated and become collagen type I-producing cells. During HSC activation, ROL is oxidized to RA, and activated HSCs express a natural killer (NK) cell ligand known as retinoid acid early inducible-1 (RAE1), which is not present in quiescent HSCs (Suh and Jeong 2011).
Has anyone here attempted supplementation with citral, and if so, did you observe protective or adverse effects? I’m planning to start supplementing citral (or some lemongrass oil containing citral), and I’ll report back how it went in a month or two.
Bibliography
Chen, H., M. J. Namkung and M. R. Juchau (1995). "Biotransformation of all-trans-retinol and all-trans-retinal to all-trans-retinoic acid in rat conceptal homogenates." Biochemical Pharmacology 50(8): 1257-1264.
Gonçalves, E. C. D., P. M. Assis, L. A. Junqueira, M. Cola, A. R. S. Santos, N. R. B. Raposo and R. C. Dutra (2020). "Citral Inhibits the Inflammatory Response and Hyperalgesia in Mice: The Role of TLR4, TLR2/Dectin-1, and CB2 Cannabinoid Receptor/ATP-Sensitive K+ Channel Pathways." Journal of Natural Products 83(4): 1190-1200.
Lawal, O. A., A. L. Ogundajo, N. O. Avoseh and I. A. Ogunwande (2017). Chapter 18 - Cymbopogon citratus. Medicinal Spices and Vegetables from Africa. V. Kuete, Academic Press: 397-423.
Lee, H., H. Jeong, S. Park, W. Yoo, S. Choi, K. Choi, M.-G. Lee, M. Lee, D. Cha, Y.-S. Kim, J. Han, W. Kim, S.-H. Park and J. Oh (2015). "Fusion protein of retinol-binding protein and albumin domain III reduces liver fibrosis." EMBO molecular medicine 7(6): 819-830.
Samokyszyn, V. M., H. C. Chang and R. L. Compadre (1997). "A theoretical investigation of endocyclic allylic carbon-centered radical formation in retinoic acid." Bioorganic & Medicinal Chemistry Letters 7(18): 2343-2348.
Suh, Y.-G. and W.-I. Jeong (2011). "Hepatic stellate cells and innate immunity in alcoholic liver disease." World journal of gastroenterology 17(20): 2543-2551.
"The 10-carbon terpenoid citral was found to inhibit oxidation of retinol in rat conceptual tissues (Chen, Namkung et al. 1995). Citral at concentrations of 0.01 and 0.05 µM decreased biotransformation of all-trans-ROL (atROL) to all-trans-retinoic acid (atRA) by 88% and 97%, respectively, and at concentrations of 0.1 and 0.5 µM decreased biotransformation of all-trans-retinal (atRAL) to atRA by 60% and 81%, respectively. "
Judging by the description, it's just a detoxification retarder. I wouldn't use it.
I sometimes wonder if the amount of vitamin C in limes was equal to the ability of limes to counteract scurvy. I do agree with the thought that scurvy might have an aspect of VA toxicity. It also seems to me to perhaps be a b-vitamin deficiency thing, since fresh meat seemed to help. But I also wonder though, if the citral in the limes also had an effect beyond the vitie C.
Here is one example of lemon juice being recommended for acanthosis nigricans: (not that I think it's a great article over-all, it just mentions this home cure)
5 Natural Remedies For Hyperpigmentation (Dark Spots on Your Neck, Cheek, Belly, Etc)
I often ponder the parallels to furniture finishing here, LOL. IMO oil-plus-carotenes creates a hard molecule, very much like old fashioned furniture finishes. An alcohol spill will mar such a surface. Does alcohol "dissolve" this molecule, and is that why we see VA mobilizing with alcohol? (this has stringent limits, I think over 1/2 a shot or 1 shot depending on body weight, else you end up worse off liver-wise).
Lemon oil is a known thing that people will use to overhaul a finish. Turpentine is what we clean the brushes with. In the olden days, people actually used! turpentine as medicine. I think like alcohol, the limits were there-- if you went too far it killed you rather than cured you.
Probably the same for lemon essence. It's probably a plant poison, but a helpful one in small quantities.
Quote from Даниил on August 14, 2021, 5:56 amJudging by the description, it's just a detoxification retarder. I wouldn't use it.
What do you mean by detoxification retarder? As I understand it, most of retinol’s adverse effects aren’t directly caused by ROL but rather when it’s metabolized to RAL and RA. I don’t think ROL is detrimental as long as it stays esterified and doesn't get metabolized. In fact, the only adverse effects caused directly by ROL/retinyl esters (RE) that I’m aware of are through STRA6: when a ROL-RBP4-TTR complex is transported into cells via STRA6, SOCS3 and PPARG are induced through the JAK2/STAT5 pathway (Berry, Jin et al. 2011). SOCS3 and PPARG are believed to inhibit insulin responses and promote lipogenesis instead of lipid β-oxidation.
ROL itself can be eliminated without metabolization by conjugation with glucuronic acid, though the rate of elimination is controversial. As citral has only been reported to inhibit RDH and RALDH, there are still plenty of other pathways for ROL to be metabolized, for example via short-chain dehydrogenases (e.g. DHRS9), steroid dehydrogenases (e.g. HSD17B6) and cytochrome P450 (e.g. CYP1A1). One of these pathways might be capable of metabolizing ROL in a slower, safer way.
Quote from lil chick on August 14, 2021, 7:36 amI often ponder the parallels to furniture finishing here, LOL. IMO oil-plus-carotenes creates a hard molecule, very much like old fashioned furniture finishes. An alcohol spill will mar such a surface. Does alcohol "dissolve" this molecule, and is that why we see VA mobilizing with alcohol? (this has stringent limits, I think over 1/2 a shot or 1 shot depending on body weight, else you end up worse off liver-wise).
Lemon oil is a known thing that people will use to overhaul a finish. Turpentine is what we clean the brushes with. In the olden days, people actually used! turpentine as medicine. I think like alcohol, the limits were there-- if you went too far it killed you rather than cured you.
Probably the same for lemon essence. It's probably a plant poison, but a helpful one in small quantities.
In an abstract sense, I believe that the HSC mechanism is the body’s “queue” for when the conventional elimination pathways are saturated. I think that there are safe pathways for the elimination of retinol and ethanol, and once those pathways are at capacity, any extra retinol/ethanol is esterified and stored in HSCs, until capacity becomes available in the other pathways. Some circumstantial evidence for that is the STRA6 transport mechanism I described above. Since retinol can also enter cells through passive diffusion, there is no biological requirement for a transporter. In fact, many other species lack a transporter like STRA6. The fact that it not just exists but also recruits lipogenic signaling molecules, and requires both CRBP (intracellular retinol transport protein) and LRAT (the enzyme catalyzing retinol esterification) is evidence that the body takes great care to safely store retinol in HSCs.
I’m not too familiar with alcohol metabolism, but I believe about 5% of ethanol is esterified, for example to linoleic acid ethyl ester (LAEE). LAEE has been reported to activate HSCs (Li, Hu et al. 2003). Recall that in activated HSCs, retinol is oxidized to RA and the cells are then either destroyed by NK cells or malignantly proliferate. That’s one possible mechanism that could explain how alcoholism depletes liver retinol.
I don’t think alcohol has any clinical value. What I am arguing for citral is that it essentially does the opposite of alcohol. It competitively inhibits ROL oxidation in HSCs, thereby preventing their activation and subsequent injury.
Bibliography
Berry, D. C., H. Jin, A. Majumdar and N. Noy (2011). "Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses." Proc Natl Acad Sci U S A 108(11): 4340-4345.
Li, J., W. Hu, J. J. Baldassare, P. S. Bora, S. Chen, J. E. Poulos, R. O'Neill, R. S. Britton and B. R. Bacon (2003). "The ethanol metabolite, linolenic acid ethyl ester, stimulates mitogen-activated protein kinase and cyclin signaling in hepatic stellate cells." Life Sciences 73(9): 1083-1096.
I find it interesting that the side-chain of retinol, and the interior chains in beta-carotene, turpentine, cholesterol, and steroids etc are made up of isoprene units. As is citral. So, there's a least a plausible chemical interaction between citral and vA /RA.
Squeezing a lime into a beer is very refreshing, it is called a michelada.
Sailors often associated scurvy cures with acidity, which makes good sense and is not far from the truth. Other cures brought aboard ships included acidic food and beverages including vinegar and sauerkraut. It wasn't until 1918 that it was proven that citric acid itself is useless against scurvy (and I assume vinegar's acetic acid too), and shortly thereafter that the newly-identified Vitamin C was the anti-scorubic needed.
...
The initial confusion over the definition of limes, and the later decision to switch from lemons to limes, proved fairly disastrous to the British. Incidents of scurvy in the Navy crept up again and new false medial theories with other problematic solutions came back into vogue.
Look at the timing, 1918. Isn't that close to the time Vitamin A was discovered? Given that Grant hasn't had scurvy, I wonder if the initial "proof" of Vitamin C as anti-scorbutic was just as fraudulent as the Vitamin A discovery. Maybe the sailors were right and it is the acidity that matters.
Interesting stuff, let us know how the citral testing goes @johannes2
I do drink real lemonade a few times per week, just one cup serving, but maybe this is not strong enough for any effect.
Quote from Johannes on August 14, 2021, 10:03 amQuote from Даниил on August 14, 2021, 5:56 amJudging by the description, it's just a detoxification retarder. I wouldn't use it.
What do you mean by detoxification retarder? As I understand it, most of retinol’s adverse effects aren’t directly caused by ROL but rather when it’s metabolized to RAL and RA. I don’t think ROL is detrimental as long as it stays esterified and doesn't get metabolized. In fact, the only adverse effects caused directly by ROL/retinyl esters (RE) that I’m aware of are through STRA6: when a ROL-RBP4-TTR complex is transported into cells via STRA6, SOCS3 and PPARG are induced through the JAK2/STAT5 pathway (Berry, Jin et al. 2011). SOCS3 and PPARG are believed to inhibit insulin responses and promote lipogenesis instead of lipid β-oxidation.
ROL itself can be eliminated without metabolization by conjugation with glucuronic acid, though the rate of elimination is controversial. As citral has only been reported to inhibit RDH and RALDH, there are still plenty of other pathways for ROL to be metabolized, for example via short-chain dehydrogenases (e.g. DHRS9), steroid dehydrogenases (e.g. HSD17B6) and cytochrome P450 (e.g. CYP1A1). One of these pathways might be capable of metabolizing ROL in a slower, safer way.
Quote from lil chick on August 14, 2021, 7:36 amI often ponder the parallels to furniture finishing here, LOL. IMO oil-plus-carotenes creates a hard molecule, very much like old fashioned furniture finishes. An alcohol spill will mar such a surface. Does alcohol "dissolve" this molecule, and is that why we see VA mobilizing with alcohol? (this has stringent limits, I think over 1/2 a shot or 1 shot depending on body weight, else you end up worse off liver-wise).
Lemon oil is a known thing that people will use to overhaul a finish. Turpentine is what we clean the brushes with. In the olden days, people actually used! turpentine as medicine. I think like alcohol, the limits were there-- if you went too far it killed you rather than cured you.
Probably the same for lemon essence. It's probably a plant poison, but a helpful one in small quantities.
In an abstract sense, I believe that the HSC mechanism is the body’s “queue” for when the conventional elimination pathways are saturated. I think that there are safe pathways for the elimination of retinol and ethanol, and once those pathways are at capacity, any extra retinol/ethanol is esterified and stored in HSCs, until capacity becomes available in the other pathways. Some circumstantial evidence for that is the STRA6 transport mechanism I described above. Since retinol can also enter cells through passive diffusion, there is no biological requirement for a transporter. In fact, many other species lack a transporter like STRA6. The fact that it not just exists but also recruits lipogenic signaling molecules, and requires both CRBP (intracellular retinol transport protein) and LRAT (the enzyme catalyzing retinol esterification) is evidence that the body takes great care to safely store retinol in HSCs.
I’m not too familiar with alcohol metabolism, but I believe about 5% of ethanol is esterified, for example to linoleic acid ethyl ester (LAEE). LAEE has been reported to activate HSCs (Li, Hu et al. 2003). Recall that in activated HSCs, retinol is oxidized to RA and the cells are then either destroyed by NK cells or malignantly proliferate. That’s one possible mechanism that could explain how alcoholism depletes liver retinol.
I don’t think alcohol has any clinical value. What I am arguing for citral is that it essentially does the opposite of alcohol. It competitively inhibits ROL oxidation in HSCs, thereby preventing their activation and subsequent injury.
Bibliography
Berry, D. C., H. Jin, A. Majumdar and N. Noy (2011). "Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses." Proc Natl Acad Sci U S A 108(11): 4340-4345.
Li, J., W. Hu, J. J. Baldassare, P. S. Bora, S. Chen, J. E. Poulos, R. O'Neill, R. S. Britton and B. R. Bacon (2003). "The ethanol metabolite, linolenic acid ethyl ester, stimulates mitogen-activated protein kinase and cyclin signaling in hepatic stellate cells." Life Sciences 73(9): 1083-1096.
As far as I know, dehydrogenases and p450 work only with atra. I also don't know how effective retinol glucuronidation is. Also, it will simply be excreted with bile. But I am not sure that it will be quickly
By itself, retinol causes, at least, atherosclerosis.
http://www.hennapage.com/henna/how/terp.html
"Many essential oils contain terpenes which are hydrocarbon solvents. Hennotannic acid, the dye in henna, is hydrophobic rather than hydrophilic, thus water is not the most effective means to release and darken henna."
Henna contains orange plant pigments, and it is well known that terpenes in essential oils "release" the dye.
(I dyed my hair with henna for a long time and wonder whether this added to my vegetable toxin load)