Sialic acid and TRP channels.
An addition. I can't update my very long post on Substack but I can on Wordpress. Just a fact, there are differences.
Glycan polysialic acid (PSA) a homopolymer of sialic acid, may also be regulatory of transient receptor potential canonical (TRPC) ion channels TRPC1, -4 and -5. Inhibition of the neural cell adhesion molecule (NCAM) which has glycan polysialic acid (PSA) covalently attached, led to opening of the channels allowing calcium to enter the cortical neurons and CHO cells. (Amores-Bonet, et al, 2022) Suggesting that having adequate poly-sialated NCAM helps keep the TRPC channels closed - reducing risk of excess activation by calcium which would lead to release of endocannabinoids from the cell membrane possibly.
“The neural cell adhesion molecule (NCAM) plays important functional roles in the developing and mature nervous systems. Here, we show that the transient receptor potential canonical (TRPC) ion channels TRPC1, −4, and −5 not only interact with the intracellular domains of the transmembrane isoforms NCAM140 and NCAM180, but also with the glycan polysialic acid (PSA) covalently attached to the NCAM protein backbone. NCAM antibody treatment leads to the opening of TRPC1, −4, and −5 hetero- or homomers at the plasma membrane and to the influx of Ca2+ into cultured cortical neurons and CHO cells expressing NCAM, PSA, and TRPC1 and −4 or TRPC1 and −5.” (Amores-Bonet, et al, 2022)
Polysialic glycan is made up of multiple sialic acids connected together and two polysialyltransferases, polysialyltransferase (PST) and sialyltransferase X (STX), work in coordination to build the homopolymer of sialic acid on NCAM. (Nakayama, et al, 1998) It requires the nucleotide UDP and N-acetyl-glucosamine to make sialic acid, and production might be limited functionally during ill health or aging. (Rawal and Zhao, 2021)
Dietary sources of nucleotides include meats, fish, mushrooms, Nutritional Yeast Flakes, and breast milk – always suggestive that something is essential or semi-essential to have in our diet. (Dancey, Attree and Brown, 2006)
Dietary sources of N-acetyl-glucosamine (NAG) include the shell of shellfish and insects and is in fungi. (Gaderer, et al, 2017) NAG is available as a supplement and may protective against edematous malnutrition, and inflammatory bowel disease. (Salvatore, et al, 2000, Amadi, et al, 2009) Glucosamine/chondroitin for arthritis is a different form and would not be equivalent chemically for sialic acid production. (Glucosamine, N-Acetyl-D-Glucosamine)
Addition - STX and PST are expressed differentially in embryonic tissues versus adult, and within different areas of the adult brain and body. Both STX and PST are involved in polysialic formation within the hippocampus. (Angata, et al, 1997)
“STX is primarily expressed in embryonic tissues, but only modestly in adult heart, brain, and thymus. PST, on the other hand, is continuously expressed in adult heart, brain, thymus, spleen, small and large intestines, and peripheral blood leukocytes. In various parts of adult brain, the relative amount of PST and STX appears to be substantially different depending on the regions. The analysis by in situ hybridization of mouse adult brain, however, suggests that polysialic acid in the hippocampal formation is synthesized by both STX and PST. HeLa cells doubly transfected with the isolated STX cDNA and N-CAM cDNA supported neurite outgrowth much better than HeLa cells expressing N-CAM alone. However, polysialic acid synthesized by PST appears to be a better substratum than that synthesized by STX. Moreover, the genes for PST and STX were found to reside at chromosome 5, band p21 and chromosome 15, band q26, respectively. These results, taken together, strongly suggest that PST and STX are expressed distinctly in tissue-specific and cell-specific manners and that they apparently have distinct roles in development and organogenesis.” (Angata, et al, 1997)
…and alcohol use during pregnancy may be affecting polysialis during fetal development and later in life. The polysialis of NCAM is a type of posttranslational glycosylation. Aberrant posttranslational modification of proteins can be a causal factor in nociceptive pain. Alcohol use disrupts glycosylation and may affect fetal development leading to Fetal Alcohol Syndrome which has many similarities to congenital disorders of glycosylation (CDG) however disrupted glycosylation does not continue after birth for infants born with FAS. (Binkhorst, et al, 2012)
“In this report, we propose a completely novel concept regarding the pathogenesis of FAS. Based on our observation that transferrin isoelectric focusing (TIEF) – the most widely used screening tool for congenital disorders of glycosylation (CDG) – was transiently abnormal in a newborn with FAS and a confirmed maternal history of gestational alcohol abuse, we came to believe that FAS exemplifies a congenital disorder of glycosylation secondary to alcohol-inflicted disruption of (N-linked) protein glycosylation. Various pieces of evidence were found in the literature to substantiate this hypothesis. This observation implies, among others, that one might need to consider the possibility of maternal alcohol consumption in newborns with transient glycosylation abnormalities.” (Binkhorst, et al, 2012)
That article includes Retinoid Toxicity as a possible causal factor in FAS, however the idea that the sperm DNA may be damaged by the father’s drinking is not considered at all. Only maternal drinking during a pregnancy is considered. The physical deformities are not seen in sperm related alcohol use but the male’s use of alcohol prior to conception has been linked to ADHD - less physical changes than FAS but possibly causal. It takes 73 days to grow a sperm. Are all men not drinking for 73 days prior to conceiving a baby? Probably not - not drinking by males prior to conception is not an educational message that is stressed at all. Only women are blamed and shamed about prenatal health habits.
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SubStack is nice for writers and readers, however, WordPress also has advantages for writers and readers in that the Archives are more searchable, taggable, categorizable and can be opened, closed, or updated at anytime - more like a webpage maybe than some blog services. The more I’ve thought about it, the more I realize that using WordPress has really made my research easier over the last decade+. I can find anything I tagged or titled with a memorable label - compared to my paper filing system that is a big bonus and it means readers can also access the tags, categories and helpful titles, or maybe my quirky titles are memorable for some readers too.
My favorite title (helped my health a lot to figure out the answer): And what do osmomechanical stress, changes of temperature, chili powder, curry powder, ginger, Benicar, hormone D, steroids, and cannabinoids have in common? And all I have to do to find it is enter “and what do” into the search box on my WordPress site.
If you skimmed my very long post/paper (on SubStack), (updated on transcendingsquare.com, then you would know the answer. ;-)
*Regarding my very long paper - it is really two papers - the hyperinflammation and Retinoid Toxicity/schizophrenia hypothesis is a separate topic than how pomegranate phytonutrients might help histamine excess due to Retinoid toxicity or other reasons. The special journal supplement is specifically about nociceptive pain, so the second half is focused more on that question. Now I need to be the editior asking the question of which story to tell and how much of the supporting material to include as it all needs to be cited or supported with evidence suggesting plausibility of my or other’s theories. I need to narrow to the nociceptive/pharmacology theme and the other info is background for why there is a potentially very large group of people who might be helped.
LongCovid is likely involving Retinoid Toxicity and that means tomato sauce and carrots would no longer be healthy foods for those individuals - that is News to Use - unless liver, kidney, and brain damage is an acceptable prospect.
Disclaimer: This information is provided for educational purposes within the guidelines of Fair Use. It is not intended to provide individual guidance. Please seek a health care provider for individualized health care guidance.
Reference List
(Angata, et al, 1997) Angata K, Nakayama J, Fredette B, Chong K, Ranscht B, Fukuda M. Human STX polysialyltransferase forms the embryonic form of the neural cell adhesion molecule. Tissue-specific expression, neurite outgrowth, and chromosomal localization in comparison with another polysialyltransferase, PST. J Biol Chem. 1997 Mar 14;272(11):7182-90. doi: 10.1074/jbc.272.11.7182. PMID: 9054414. https://www.jbc.org/article/S0021-9258(18)41055-1/fulltext
(Amadi, et al, 2009) Amadi, B., Fagbemi, A.O., Kelly, P., et al., (2009) Reduced production of sulfated glycosaminoglycans occurs in Zambian children with kwashiorkor but not marasmus, The American Journal of Clinical Nutrition, 89(2), February 2009, pp 592–600, https://doi.org/10.3945/ajcn.2008.27092 https://academic.oup.com/ajcn/article/89/2/592/4596718
(Amores-Bonet, et al, 2022) Amores-Bonet L, Kleene R, Theis T, Schachner M. Interactions between the Polysialylated Neural Cell Adhesion Molecule and the Transient Receptor Potential Canonical Channels 1, 4, and 5 Induce Entry of Ca2+ into Neurons. Int J Mol Sci. 2022 Sep 2;23(17):10027. doi: 10.3390/ijms231710027. PMID: 36077460; PMCID: PMC9456277. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9456277/
(Dancey, Attree and Brown, 2006) Dancey CP, Attree EA, Brown KF. Nucleotide supplementation: a randomised double-blind placebo controlled trial of IntestAidIB in people with Irritable Bowel Syndrome [ISRCTN67764449]. Nutr J. 2006;5:16. Published 2006 Jun 8. doi:10.1186/1475-2891-5-16 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513247/
(Gaderer, et al, 2017) Gaderer, R., Seidl-Seiboth, V., de Vries, R. P., et al, (2017) N-acetylglucosamine, the building block of chitin, inhibits growth of Neurospora crassa, Fungal Genetics and Biology, Volume 107, pp 1-11, ISSN 1087-1845, https://doi.org/10.1016/j.fgb.2017.07.005. https://www.sciencedirect.com/science/article/pii/S1087184517301044
(Glucosamine) ‘Glucosamine’, MayoClinic.org, [Online] Accessed: 14/10/1022 https://www.mayoclinic.org/drugs-supplements-glucosamine/art-20362874
(N-Acetyl-D-Glucosamine) N-Acetyl-D-Glucosamine, PubChem CID 439174, pubchem.ncbi.nlm.gov, [Online] Accessed: 14/10/2022, https://pubchem.ncbi.nlm.nih.gov/compound/N-Acetyl-D-Glucosamine
(Naayama, et al, 1998) Nakayama J, Angata K, Ong E, Katsuyama T, Fukuda M. Polysialic acid, a unique glycan that is developmentally regulated by two polysialyltransferases, PST and STX, in the central nervous system: from biosynthesis to function. Pathol Int. 1998 Sep;48(9):665-77. doi: 10.1111/j.1440-1827.1998.tb03967.x. PMID: 9778105.https://pubmed.ncbi.nlm.nih.gov/9778105/
(Rawal and Zhao, 2021) Punam Rawal and Liqin Zhao. Sialometabolism in Brain Health and Alzheimer’s Disease. Front. Neurosci., 30 March 2021, https://doi.org/10.3389/fnins.2021.648617 https://www.frontiersin.org/articles/10.3389/fnins.2021.648617/ful
(Salvatore, et al, 2000) Salvatore S, Heuschkel R, Tomlin S, Davies SE, Edwards S, Walker-Smith JA, French I, Murch SH. A pilot study of N-acetyl glucosamine, a nutritional substrate for glycosaminoglycan synthesis, in paediatric chronic inflammatory bowel disease. Aliment Pharmacol Ther. 2000 Dec;14(12):1567-79. doi: 10.1046/j.1365-2036.2000.00883.x. PMID: 11121904. https://pubmed.ncbi.nlm.nih.gov/11121904/