I needed to disable self sign-ups because I’ve been getting too many spam-type accounts. Thanks.
PubMed research papers
There's some interesting connections in these papers. Happening upon some of the RA and receptor stuff is almost to be expected, as those seem to pop-up no matter what subject one's looking into.
Retinoids, retinoid analogs, and lactoferrin interact and differentially affect cell viability of 2 bovine mammary cell types in vitro.
Department of Dairy and Animal Science, The Pennsylvania State University, University Park, PA
Finally, the use of the RAR antagonist in conjunction with bLf [bovine lactoferrin] indicated a rescue of the bLf effect in the MeBo cells, suggesting that bLf is acting through the RAR receptor. Conversely, bLf reverted inhibition of cell viability by 9cRA in the BME-UV1 cell type (P<0.05). We conclude that RAR interaction in bovine mammary cell types regulates cell viability in vitro; we hypothesize that the natural ligands mediate regulation of bovine mammary cell viability in vivo and that bLf can either enhance or reverse the retinoid-induced inhibition of cell viability, depending on the type of bovine mammary cell studied. PMID:20434866
J Biol Chem. 1992
Ferritin: a cytoprotective antioxidant strategem of endothelium.
Department of Medicine, University of Minnesota, Minneapolis 55455.
Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome. We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H2O2).
In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin.
After 16 h heme oxygenase and ferritin have increased approximately 50-fold and 10-fold, respectively. Differential induction of these proteins determined that
ferritin is probably the ultimate cytoprotectant.
Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration.
Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis.
Conversely, a site-directed mutant of ferritin (heavy chain Glu62----Lys; His65----Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant. We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin. PMID:1517245
Effect of iron and retinoic acid on the control of transferrin receptor and ferritin in the human promonocytic cell line U937.
University Department of Bacteriology and Immunology, Western Infirmary, Glasgow, U.K.
The effect of changes in iron availability and induction of differentiation on transferrin receptor expression and ferritin levels has been examined in the promonocytic cell line U937. Addition of iron (as 200 micrograms/ml saturated transferrin) or retinoic acid (1 microM) both caused approx. 70% reduction in the average number of surface transferrin receptors, while the iron chelator desferrioxamine caused an 84% increase. Comparable changes also occurred in the levels of transferrin receptor mRNA. Neither iron nor retinoic acid significantly altered the half-life of transferrin receptor mRNA in the presence of actinomycin D (approx. 75 min) but a 10-fold increase in stability occurred in the presence of desferrioxamine.
Iron and retinoic acid both caused an increase in intracellular ferritin levels (approx. 4-and 3-fold, respectively), while desferrioxamine reduced ferritin levels by approx. two-thirds.
The effect of iron and retinoic acid added together did not differ greatly from that of each agent alone.
None of the treatments greatly affected levels of L-ferritin mRNA. Virtually no H-ferritin mRNA was detected in U937 cells. These results show that changes in ferritin and transferrin receptor caused by treatment with retinoic acid are similar to those induced by excess iron, and suggest that changes in these proteins during cell differentiation are due to redistribution of intracellular iron into the regulatory pool(s), rather than to iron-independent mechanisms. PMID:1737056
Biol Trace Elem Res. 2012
Vitamin A modulates the expression of genes involved in iron bioavailability.
Iron bioavailability seems to be regulated by vitamin A (VA) but the molecular events involved in this mechanism are not well understood. It is also known that retinoids mediate most of their function via interaction with retinoid receptors, which act as ligand-activated transcription factors controlling the expression of a number of target genes. Here, we evaluated the VA effects on the modulation of the levels of mRNA encoding proteins involved in the iron bioavailability, whether in the intestinal absorption process or in the liver iron metabolism.
The expression of genes involved in iron intestinal absorption (divalent metal transporter 1, duodenal cytochrome B, ferroportin 1 FPN1, and ferritin) were evaluated in vitro by treating Caco-2 cells with retinoic acid or in vivo by observing the effects of vitamin A deficiency (VAD) in BALB/C mice.
Liver hepcidin and ferritin mRNA levels were upregulated by VAD; however, this condition did not promote any change on the expression of those genes that participate in the iron absorption. Moreover, data from the in vitro analysis showed that VA induced FPN1 gene expression by a hepcidin-independent manner. Therefore, the in vivo results support the idea that VAD may not affect iron absorption but would rather affect iron mobilization mechanisms. On the other hand, our results using Caco-2 cells raises the possibility that VA addition to intestinal epithelium may improve iron absorption through the induction of FPN1 gene expression. PMID:22528770
J Nutr. 2007
Retinoic acid modulates hepatic iron homeostasis in rats by attenuating the RNA-binding activity of iron regulatory proteins.
Department of Food Science and Human Nutrition, Iowa State University
Vitamin A deficiency has been widely associated with perturbations of iron homeostasis, a consequence that can be reversed by retinoid supplementation. Despite the numerous studies that demonstrate an interaction between these 2 nutrients, the mechanistic basis for this relation has not been well characterized. Because iron regulatory proteins (IRP) have been established as central regulators of iron homeostasis, we investigated the potential role of IRP in the regulation of iron homeostasis under conditions of vitamin A deficiency and supplementation with all-trans-retinoic acid (atRA).
Rats were fed a control diet or a diet deficient in either vitamin A or iron or both micronutrients. Four parallel groups of rats were supplemented with atRA daily (30 micromol/kg body weight) during the final week of this study. As expected, iron-deficient (-Fe) rats exhibited a decrease in hepatic nonheme iron levels and a subsequent increase in IRP RNA-binding activity,
resulting in diminished ferritin abundance. Interestingly, atRA supplementation inhibited the increase in IRP RNA-binding activity in -Fe rats to a level that was not significantly (P = 0.139) different from control values, and it partially restored ferritin abundance.
This inhibition of IRP RNA-binding activity by atRA supplementation was also associated with a 40% reduction in transferrin receptor abundance. Taken together, these results indicate that IRP represent a mechanistic link between vitamin A and the regulation of iron homeostasis, a key finding toward further understanding this important nutrient-nutrient interaction. PMID:18029484
Nutr Neurosci. 2003
Effect of retinoic acid on ferritin H expression during brain development and neuronal differentiation.
Neuroscience and Department of Nutrition, Food and Exercise Sciences, Florida State University
We have previously shown that brain ferritin H expression, which has been associated with iron utilization, is developmentally regulated. Because retinoic acid (RA) regulates gene expression and is involved in cellular differentiation, we tested the hypothesis that RA regulates ferritin H during brain development and neuronal differentiation. RA, administered to rats on postnatal day 1, produced a 4-fold increase in brain ferritin H mRNA (p < 0.01) after 24 h.
To examine whether RA-stimulated neuronal differentiation contributed to this up-regulation, ferritin and ferritin H mRNA were measured in human neuronal precursor cells (NTera-2, NT2) before and after 4-weeks of RA-stimulated differentiation into post-mitotic neurons. Differentiation resulted in a 2-fold increase in both ferritin and ferritin H mRNA (p < 0.05).
Immunocytochemistry and Northern analysis showed significant elevations in ferritin expression that began as early as 24 h after RA treatment. While there was also a significant increase in the labile iron pool after RA treatment, this did not occur until 72 h. These data show that RA regulates ferritin H expression during rat brain development and neuronal differentiation and suggests a new role for RA in brain iron metabolism. PMID:12608735
Induction of ferritin expression by oxalomalate.
Ferritin is a ubiquitous protein required for intracellular iron storage; its biosynthesis is mainly regulated by iron-regulatory proteins (IRP1 and IRP2) at post-transcriptional level. This regulation prevents iron excess from promoting the formation of reactive oxygen species (ROS). IRP1 is regulated by such factors as intracellular iron levels, the oxidants H(2)O(2) and NO. We recently demonstrated that oxalomalate (OMA, alpha-hydroxy-beta-oxalosuccinic acid), a competitive inhibitor of aconitase, which is an enzyme of the citric acid cycle, remarkably decreases the binding activity of IRP1. The aim of the present study was to investigate whether this molecule could affect the expression of ferritin. The RNA-binding activity of IRP1, evaluated by gel retardation assay, decreased after treatment of several cell lines with 5 mM OMA, with a maximal decrease of about 3-fold after 6 h. This effect remained almost constant up to 48 h after which it returned to basal levels. Intracellular ferritin levels, determined by Western blot analysis, increased in correlation with the OMA-induced decrease of IRP1 binding activity. Furthermore, treatment of cells with OMA caused a rise in ferritin mRNA levels. Interestingly, in cells exposed to iron challenge, OMA-induced overexpression of ferritin prevented formation of ROS and cellular lipid peroxidation. These data show that an inhibitor of aconitase, OMA, besides being involved in energetic metabolism, is able to control ferritin expression, probably through molecular mechanisms of either post-transcriptional regulation or transcriptional modulation, with advantageous consequences for the cell. PMID:15110995
Sarcoidosis Vasc Diffuse Lung Dis. 2000
Calcium oxalate and iron accumulation in sarcoidosis.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
In many patients with sarcoidosis, the granulomas contain inclusion bodies within giant cells. Many giant cells contain crystalline oxalate that chemically coordinates iron on the surface of the crystal. If this iron is incompletely coordinated and capable of redox cycling, then oxalate might contribute to granuloma formation in the lung. Using human tissues, isolated alveolar macrophages and respiratory epithelial cells, we measured the ability of calcium oxalate to sequester iron, stimulate cytokine release and cause granuloma formation. We then studied the effects of in vivo oxalate instillation on pulmonary granuloma formation over 3 to 6 months in rats.
Calcium oxalate present in human sarcoid granulomas sequesters significant amounts of iron and ferritin.
In alveolar macrophage cultures, oxalate accumulates iron and stimulates ferritin production and giant cell formation. In cultured respiratory epithelial cells, calcium oxalate increases the release of two interleukins (IL), IL-8 and IL-6, involved in granuloma formation by 8 to 10 fold within 24 hours. Intratracheal instillation of calcium oxalate crystals into the lungs of rats is associated with pulmonary iron and ferritin accumulation and organic carbonyl formation consistent with sustained oxidative stress. These exposures were accompanied by influx of alveolar macrophages, giant cell formation, and a granulomatous response in the lung. These results support an association between calcium oxalate deposition in the lung, iron mediated oxidative stress and formation of some of the granulomas of sarcoidosis PMID:10957762
Biochemistry. 1996
Anion binding by transferrins: importance of second-shell effects revealed by the crystal structure of oxalate-substituted diferric lactoferrin.
Department of Chemistry and Biochemistry, Massey University, Palmerston North, New Zealand.
Proteins of the transferrin family bind, with high affinity, two Fe3+ ions and two CO3(2)- ions but can also bind other metal ions and other anions. In order to find out how the protein structure and its two binding sites adapt to the binding of larger anions, we have determined the crystal structure of oxalate-substituted diferric lactoferrin at 2.4 A resolution. The final model has a crystallographic R-factor of 0.196 for all data in the range 8.0-2.4 A. Substitution of oxalate for carbonate does not produce any significant change in the polypeptide folding or domain closure. Both binding sites are perturbed, however, and the effects are different in each.
In the C-lobe site the oxalate ion is bound to iron in symmetric 1,2-bidentate fashion whereas in the N-lobe the anion coordination is markedly asymmetric. The difference arises because in each site substitution of the larger anion causes displacement of the arginine that forms one wall of the anion binding site; the movement is different in each case, however, because of different interactions with "second shell" amino acid residues in the binding cleft. These observations provide an explanation for the site inequivalences that accompany the substitution of non-native anions and cations. PMID:8703903
Biometals. 2006
Iron loading: a risk factor for osteoporosis.
Department of Biology and Program in Medical Sciences, Indiana University, Bloomington,
Iron loaded persons are at increased risk for infection, neoplasia, arthropathy, cardiomyopathy and an array of endocrine and neurodegenerative diseases. This report summarizes evidence of increased risk of iron loading for osteoporosis. Iron suppresses bone remodeling apparently by decreasing osteoblast formation and new bone synthesis. Low molecular mass iron chelators as well as a natural protein iron chelator, lactoferrin, may be useful in prevention of osteoporosis. PMID:16648989
Retinoids, retinoid analogs, and lactoferrin interact and differentially affect cell viability of 2 bovine mammary cell types in vitro.
Department of Dairy and Animal Science, The Pennsylvania State University, University Park, PA
Two bovine mammary cell types (BME-UV1 and MeBo cells) were used to evaluate the effect of natural retinoids, retinoid analogs, and bovine lactoferrin (bLf) on cell viability in vitro. Experiments with Alamar Blue showed a linear relationship between fluorescence and cell viability index. The BME-UV1 cells exhibited twice the metabolic activity but required half the doubling time of the MeBo cells. The BME-UV1 cells were very sensitive to all-trans retinoic acid (atRA) inhibition of cell viability (P<0.05) and exhibited a dose-dependent inhibition with 9-cisRA (9cRA; P<0.05). The MeBo cells exhibited some inhibition with these natural ligands (P<0.05), but they were not as sensitive. The addition of bLf had similar inhibitory effects (P<0.05) on cell viability of the 2 mammary cell types. Applications of RA receptor (RAR) agonist indicated that the stimulation of the RAR in both mammary cell types was highly effective in inhibition of cell viability (P<0.05), whereas the application of an RAR antagonist stimulated MeBo cell viability (P<0.05) and inhibited BME-UV1 cell viability (P<0.05). Finally, the use of the RAR antagonist in conjunction with bLf indicated a rescue of the bLf effect in the MeBo cells, suggesting that bLf is acting through the RAR receptor. Conversely, bLf reverted inhibition of cell viability by 9cRA in the BME-UV1 cell type (P<0.05). We conclude that RAR interaction in bovine mammary cell types regulates cell viability in vitro; we hypothesize that the natural ligands mediate regulation of bovine mammary cell viability in vivo and that bLf can either enhance or reverse the retinoid-induced inhibition of cell viability, depending on the type of bovine mammary cell studied. PMID:20434866
Looks like there is some great research going on and ATRA is "on the hot-seat". It makes sense here, in that Brazil probably has a worse problem with Leishmaniasis than say the USA; but upon looking up what that condition is all about, the top-hit via Bing, a "doctor-reviewed" site, says the USA has less than 200,000 cases per year and calls that "rare".
Front Immunol. 2017
All-Trans Retinoic Acid Promotes an M1- to M2-Phenotype Shift and Inhibits Macrophage-Mediated Immunity to Leishmania major.
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil. Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil. Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. Instituto Nacional para Pesquisa Translacional em Saúde e Ambiente na Região Amazônica, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Rio de Janeiro, Brazil.
As key cells, able to host and kill Leishmania parasites, inflammatory monocytes/macrophages are potential vaccine and therapeutic targets to improve immune responses in Leishmaniasis. Macrophage phenotypes range from M1, which express NO-mediated microbial killing, to
M2 macrophages that might help infection. Resistance to Leishmaniasis depends on Leishmania species, mouse strain, and both innate and adaptive immunity. C57BL/6 (B6) mice are resistant and control infection, whereas Leishmania parasites thrive in BALB/c mice, which are susceptible to develop cutaneous lesions in the course of infection with Leishmania major, but not upon infection with Leishmania braziliensis. Here, we investigated whether a deficit in early maturation of inflammatory monocytes into macrophages in BALB/c mice underlies increased susceptibility to L. major versus L. braziliensis parasites. We show that, after infection with L. braziliensis, monocytes are recruited to peritoneum, differentiate into macrophages, and develop an M1 phenotype able to produce proinflammatory cytokines in both B6 and BALB/c mice.
Nonetheless, more mature macrophages from B6 mice expressed inducible NO synthase (iNOS) and higher NO production in response to L. braziliensis parasites, whereas BALB/c mice developed macrophages expressing an incomplete M1 phenotype. By contrast, monocytes recruited upon L. major infection gave rise to immature macrophages that failed to induce an M1 response in BALB/c mice. Overall, these results are consistent with the idea that resistance to Leishmania infection correlates with improved maturation of macrophages in a mouse-strain and Leishmania-species dependent manner.
All-trans retinoic acid (ATRA) has been proposed as a therapy to differentiate immature myeloid cells into macrophages and help immunity to tumors. To prompt monocyte to macrophage maturation upon L. major infection, we treated B6 and BALB/c mice with ATRA.
Unexpectedly, treatment with ATRA reduced proinflammatory cytokines, iNOS expression, and parasite killing by macrophages.
Moreover, ATRA promoted an M1 to M2 transition in bone marrow-derived macrophages from both strains.
Therefore, ATRA uncouples macrophage maturation and development of M1 phenotype and downmodulates macrophage-mediated immunity to L. major parasites. Cautions should be taken for the therapeutic use of ATRA, by considering direct effects on innate immunity to intracellular pathogens.
PMID:29204144 Free PMC Article
Speaking of infections, here's another great Anthony Mawson paper about a drug used for malaria that may cause an endogenous form of Hypervitaminosis-A by inhibiting ALDH1.
Med Sci Monit. 2013; 19: 579–583. PMID: 23852388
Mefloquine use, psychosis, and violence: A retinoid toxicity hypothesis
Mefloquine use has been linked to severe gastrointestinal and neuropsychiatric adverse effects, including cognitive disturbances, anxiety, depression, psychosis, and violence. The adverse effects of the drug are thought to result from the secondary consequences of hepatocellular injury; in fact, mefloquine is known to cause a transient, anicteric chemical hepatitis. However, the mechanism of mefloquine-associated liver damage and the associated neuropsychiatric and behavioral effects of the drug are not well understood. Mefloquine and other 8-amino-quinolines are the only antimalarial drugs that target the liver-stage malaria parasites, which selectively absorb vitamin A from the host. Vitamin A is also stored mainly in the liver, in potentially poisonous concentrations. These observations suggest that both the therapeutic effectiveness of mefloquine and its adverse effects are related to the ability of the 8-aminoquinolines to alter the metabolism of retinoids (vitamin A and its congeners).
Several lines of evidence support the hypothesis that mefloquine neurotoxicity and other adverse effects reflect an endogenous form of hypervitaminosis A due to a process involving: mefloquine-induced dehydrogenase inhibition; the accumulation of retinoids in the liver; retinoid-induced hepatocellular damage; the spillage of stored retinoids into the circulation; and the transport of these compounds to the gut and brain in toxic concentrations. The retinoid hypothesis could be tested clinically by comparing cases of mefloquine toxicity and untreated controls in terms of retinoid profiles (retinol, retinyl esters, percent retinyl esters, and retinoic acid). Subject to such tests, retinoid profiling could provide an indicator for assessing mefloquine-associated adverse effects.
Retinol potentiates acetaminophen-induced hepatotoxicity in the mouse: mechanistic studies.
This study was designed to elucidate the mechanism of retinol's potentiation of acetaminophen-induced hepatotoxicity.
This demonstrates that there is significantly less hepatic UDPGA available for conjugation following retinol administration. The results suggest that decreased hepatic UDPGA is likely the cause of retinol's potentiation of acetaminophen-induced hepatic injury.
For future reference, this one is also a part of Tim's riboflavin thread (great stuff) at:
https://ggenereux.blog/discussion/topic/riboflavins-role-in-an-important-va-detox-pathway/#postid-6686
Glucuronidation of estrogens and retinoic acid and expression of UDP-glucuronosyltransferase 2B7 in human intestinal mucosa. PMID:10997942
All-trans-retinoic acid was glucuronidated by all segments of intestine from both sexes at levels 50 to 80% of those found with human liver but quite low compared with estrogen glucuronidation.
To our knowledge, this is the first direct demonstration of glucuronidation of estrogens by human intestinal microsomes. Thus, in humans, the intestine may be considered as part of the overall mechanism of detoxification via glucuronidation.
Imagine the class-action lawsuit potential.
Expert Rev Clin Pharmacol. 2015 PMID:25655639
Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms.
Nagoya City University Japan.
Abstract
In contrast to the current belief that cholesterol reduction with statins decreases atherosclerosis, we present a perspective that statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 and 'heme A', and thereby ATP generation.
Statins inhibit the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification.
Statins inhibit the biosynthesis of selenium containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative stress.
An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, reminiscent of the dilated cardiomyopathies seen with selenium deficiency.
Thus, the epidemic of heart failure and atherosclerosis that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs. We propose that current statin treatment guidelines be critically reevaluated.
Turk J Med Sci. 2019 PMID:30761880
The effect of isotretinoin on insulin resistance and adipocytokine levels in acne vulgaris patients
Conclusions:
All data suggests that five months of isotretinoin therapy in AV patients causes insulin resistance and the increase in insulin resistance is not dependent on age, BMI, BFM, and lipid levels of these patients.
Mol Nutr Food Res. 2019 PMID:30811831
Maternal Supplementation with β-Carotene During Pregnancy Disturbs Lipid Metabolism and Glucose Homoeostasis in F1 Female Mice.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, 36110, P. R. China.
Key Laboratory of Ministry of Education for Subtropical Wetland Ecosystem Research, Xiamen University, Xiamen, 36110, P. R. China.
β-Carotene (BC), a substitute for vitamin A, is widely used for its benefits. The present study investigates whether in-utero BC administration can alter lipid and glucose homoeostasis in offspring. Pregnant mice are supplemented with BC (1 mg kg-1 weight) by oral gavage once every 3 days, for a total of six doses. Increased visceral fat may be caused by up-regulated PPARγ (peroxisome proliferator-activated receptor gamma) and RXRα/β (retinoid X receptors) in liver and adipose tissue, and glucose intolerance is observed in F1 adult females prenatally supplemented with BC, while F1 males do not exhibit these symptoms.
In females, increased serum leptin, resistin, and IL-6 and reduced adiponectin, caused by visceral obesity, may result in downregulated insulin receptor signaling in muscle and further account for glucose intolerance.
Increased pancreatic β-cell mass might compensate for the downregulated insulin gene (ins2). Increased glucagon and α-cell mass, accompanied by upregulated glucagon gene (gcg), might also be risk factors for the development of diabetes.
CONCLUSIONS:
Maternal supplementation with BC disturbs lipid metabolism and induces glucose intolerance in F1 female mice, suggesting that BC supplementation during pregnancy should be used with caution.
It hit me that @Tim and I were sort of hi-jacking @little chick's thread, so I'm continuing the oxidized cholesterol stuff over here.
@Tim - ox-LDL must have been with us a long time, given there's receptors for it. Our modern problems with it seem to be accelerating, like everything else, so maybe it's related to our favorite subject. I'm gonna keep plowing through the studies and see if there's a VA smoking-gun out there in dyslipidemia-land. Somehow I ran across a toxic-aldehyde paper on the EPA/DHA subject. Thought I'd put it here as well, being that it's membrane-related and such.
Lipoprotein Receptor Signaling in Atherosclerosis.
PMID:31834409 December, 2019
Published on behalf of the European Society of Cardiology.
The founding member of the lipoprotein receptor family, low-density lipoprotein receptor (LDLR) plays a major role in the atherogenesis through the receptor-mediated endocytosis of LDL particles and regulation of cholesterol homeostasis.
Since the discovery of the LDLR, many other structurally and functionally related receptors have been identified, which include low-density lipoprotein receptor-related protein (LRP)1, LRP5, LRP6, very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). The scavenger receptor family members, on the other hand, constitute a family of pattern recognition proteins that are structurally diverse and recognize a wide array of ligands, including oxidized LDL.
Among these are cluster of differentiation 36 (CD36), scavenger receptor class B type I (SR-BI) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1).
In addition to the initially assigned role as a mediator of the uptake of macromolecules into the cell, a large number of studies in cultured cells and in in vivo animal models have revealed that these lipoprotein receptors participate in signal transduction to modulate cellular functions. This review highlights the signaling pathways by which these receptors influence the process of atherosclerosis development, focusing on their roles in the vascular cells, such as macrophages, endothelial cells, smooth muscle cells and platelets.
Human genetics of the receptors is also discussed to further provide the relevance to cardiovascular disease risks in humans. Further knowledge of the vascular biology of the lipoprotein receptors and their ligands will potentially enhance our ability to harness the mechanism to develop novel prophylactic and therapeutic strategies against cardiovascular diseases.
this one is kind of interesting, given VA is reputedly so well-researched. How can they claim "equally harmful" in the second sentence? That's pretty bold. Anyway, it's a curious parallel that both ox-LDL and retinoic acid are the more toxic versions of the molecules that preceded the oxidation.
2019 Dec 18
Generation of Retinaldehyde for Retinoic Acid Biosynthesis.
Department of Biochemistry and Molecular Genetics, School of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
The concentration of all-trans-retinoic acid, the bioactive derivative of vitamin A, is critically important for the optimal performance of numerous physiological processes. Either too little or too much of retinoic acid in developing or adult tissues is equally harmful. All-trans-retinoic acid is produced by the irreversible oxidation of all-trans-retinaldehyde. Thus, the concentration of retinaldehyde as the immediate precursor of retinoic acid has to be tightly controlled. However, the enzymes that produce all-trans-retinaldehyde for retinoic acid biosynthesis and the mechanisms responsible for the control of retinaldehyde levels have not yet been fully defined. The goal of this review is to summarize the current state of knowledge regarding the identities of physiologically relevant retinol dehydrogenases, their enzymatic properties, and tissue distribution, and to discuss potential mechanisms for the regulation of the flux from retinol to retinaldehyde.
PMID:31861321
This one is troubling for anyone supplementing EPA/DHA. It found toxic-aldehyde in fish-oil, krill-oil and algal-oil supplements. A bit of backstory on the reason one might turn to marine-based sources of EPA/DHA. @Tim's comments regarding flax-oil have me revisiting this important subject. I'm thinking he's right about regular intake of low-VA seafood and rolling-the-dice in a conservative manner on this. Like he says, there's trade-offs. The reported conversion of plant-sourced omega-3 ALA is 4% for EPA and 10% for DHA and a desired range of daily intake of EPA/DHA is 150-300 milligrams. I've read that 90%-plus are not meeting these levels. Some vegans doing the lecture tour on YouTube say ALA-conversion is a 9-times differential, when comparing required plant-based intake to marine-based, i.e. 4500mg ALA yields an equivalent of 500mg EPA/DHA, and one presenter compared the EPA/DHA in 3 ounces of sardines to 9 tablespoons of ground flax. I suppose that's contingent on one's ALA-conversion-to-EPA-DHA pathways being good. How would one know? It would probably take substantial and expensive membrane-level fatty-acid RBC-testing over time, to know that one is heading in the right direction via diet and/or supplements. One advantage of krill oil is that it's already in phospholipid form, 34g/100g per Wiki, and that form is required for building and integration into cell membranes. It also has astazanthin which reportedly embeds into cell membranes and acts in a protective way. I think algal-derived EPA/DHA also has the phospholipid-advantage (compared to fish-oil). But, here's the down-side.
2019 Apr
Aldehydes identified in commercially available ω-3 supplements via 1 H NMR spectroscopy.
Cardiovascular disease (CVD) is the leading cause of mortality globally. Studies have suggested that supplementary ω-3 oils may provide cardiovascular protection, although the literature is equivocal. Recently, it has been established that many commercially available ω-3 supplements are unacceptably oxidized, leading to myriad potential health risks. One oxidation product of concern is aldehydes, which have been shown to have mutagenic, cytotoxic, and inflammatory properties that may contribute to many different disease processes, including CVD. The aim of this study was to assess the prevalence of aldehyde contamination in commercially available ω-3 supplements.
We tested 12 different ω-3 oils (6 fish, 4 krill, 2 algae), using 1 H-nuclear magnetic resonance scanning. This work is of a pilot nature, as such we randomly selected and purchased 12 different oils over the counter from various local retailers according to the sales representatives' recommendations.
RESULTS:
The four krill products contained aldehydes at concentrations between 5.652 (±0.496) and 6.779 (±1.817) mMol/L.
Both algae samples contained aldehydes: 1.235 (±0.111) and 1.565 (±0.618) mMol/L.
Two of the six fish oils contained aldehydes 1.568 (±0.291) and 4.319 (±2.361) mMol/L.
There is currently no standard for aldehyde content nor for labeling of ω-3 supplements. Two-thirds (8 of 12) of the ω-3 supplements tested in this study contained aldehydes. Aldehydes have the potential to precipitate serious health problems even at very low absolute intake volumes. These findings may provide reason for sober reflection.
PMID:30529885
Seems like one would be necessarily gambling, in order to achieve the following reported results of supplementing krill-oil.
2017
Lipid-modifying effects of krill oil in humans: systematic review and meta-analysis of randomized controlled trials. PMID:28371906
Meta-analysis of data from 7 eligible trials (14 treatment arms) with 662 participants showed a significant reduction in plasma concentrations of low-density lipoprotein cholesterol (-15.52 mg/dL) and triglycerides (-14.03 mg/dL) following supplementation with krill oil. A significant elevation in plasma concentrations of high-density lipoprotein cholesterol was also observed (6.65 mg/dL), while a reduction in plasma concentrations of total cholesterol did not reach statistical significance (-7.50 mg/dL)
======================================
here's an interesting bit regarding oxLDL
Anti-oxidization of LDL by probucol protects more effectively against early-stage lesion formation than statin-mediated lipid-lowering effects.
====================================
edit 3-7-2020: Wiki informs us on probucol that:
Probucol, sold under the trade name Lorelco among others, is an anti-hyperlipidemic drug[1] initially developed for the treatment of coronary artery disease. Clinical development was discontinued after it was found that the drug may have the undesired effect of lowering HDL in patients with a previous history of heart disease. It may also cause QT interval prolongation.
Probucol was initially developed in the 1970s by a chemical company to maximize airplane tire longevity. Probucol lowers the level of cholesterol in the bloodstream by increasing the rate of LDL catabolism. Additionally, probucol may inhibit cholesterol synthesis and delay cholesterol absorption.[2] Probucol is a powerful antioxidant which inhibits the oxidation of cholesterol in LDLs; this slows the formation of foam cells, which form atherosclerotic plaques. Probucol has also been shown to inhibit ABCA1-dependent cholesterol transport,[3] which may contribute to its known effect of lowering HDL.[4]
======================================
Average body weight gain decreased significantly in groups that received ginger water. In addition, both total cholesterol and serum triacylglycerol were reduced in the groups that received ginger water. Furthermore, mRNA expression of Sterol regulatory element-binding protein 1 (SREBP-1c) in the liver and leptin in adipose tissues were downregulated, while those of adiponectin, hepatic carnitine palmitoyltransferase1 (CPT-1), acyl-coA oxidase (ACO), Glucose transporter 2 (GLUT-2), and pyruvate kinase (PK) were upregulated in ginger water-treated groups. These results clearly revealed the lowering body weight gain effect of ginger water, which most likely occurs at the transcriptional level of energy metabolizing proteins.
========================================
ApoE is an abundant component of chylomicron, VLDL, IDL, and HDL. It binds to multiple types of lipids and is implicated in cholesterol and triglyceride homeostasis. Oxidation of ApoE plays a crucial role in the genesis of atherosclerosis.
It is proposed that heme-containing peroxidases (hPx) are major mediators of lipoprotein oxidization.
Vascular peroxidase 1 (VPO1) is a recently-discovered hPx, which is expressed in cardiovascular system, lung, liver etc. and secreted into plasma. Its plasma concentration is three orders of magnitude of that of myeloperoxidase. If VPO1 mediates ApoE oxidation and affects the lipid metabolism remains to be elucidated. Oxidized ApoE binds weaker to lipid emulsion particles, which mimic the large lipid complexes in vivo. In lipid efflux assay, oxidized ApoE showed reduced capability in efflux of lipids from foam cells. Mice administrated with oxidized ApoE via blood exhibited weaker clearance ability of plasma lipids.
Our data suggest that VPO1 is a new mediator regulating lipid homeostasis, implying a role in genesis and development of atherosclerosis.
============================================
I was a little surprised when I went to the link Grant posted on one thread.
https://tools.myfooddata.com/recipe-nutrition-calculator.php?foods=170174-173468-170563-170178-173735-168875-173847&serv=wt1-wt1-wt2-wt2-wt1-wt1-oz&qty=1-1-2-2-1-1-8&portion=1
That's a really useful site. I opened the FATS portion to view the breakdown and saw the Omega 6-to-Omega 3 ratio at almost 45-to-1, which runs counter to anything I've ever read about what it should be; like 10x too much. The other troubling thing is no reporting on EPA or DHA levels, although there's plenty of other fatty-acid molecules quantified. The way I understand it (and I could well be 180-degrees wrong) is that for optimal cell-membranes, one wants flexible fatty-acids incorporated in their construction (and maintenance?). I've watched numerous videos concerning the difference between saturated fats and these higher-order, higher-carbon PUFA's. Sure, the body will use whatever it has to get the job done, but a lack of the essential raw materials makes a big difference I would think. It could be the case that membranes don't have to be as well-made if the cells aren't exposed to high-levels of VA? Or, maybe, cell-membranes constructed from predominantly more-saturated fats can be A-OK? Or, is it possible that even given the 45-to-1 ratio, there's sufficient Omega 3's in that diet to build supple membranes? I really don't know, so I thought I'd dig into the EPA and DHA literature and see what I can find about that sub-set of the overall. I'll probably be posting a lot of papers here, so I'll just keep editing it for coherence as opposed to new posts. All comments welcome. I'm not a newbie to EPA/DHA, but I haven't ever done a deep=dive on it. I'm only a bit over a year into low-VA, and I'm thinking I want to get this part right too, if it is indeed as important as some say.
FASEB J. 2019 Dec 19
EPA and DHA attenuate deoxynivalenol-induced intestinal porcine epithelial cell injury and protect barrier function integrity by inhibiting necroptosis signaling pathway.
Deoxynivalenol (DON) is one of the most common mycotoxins that contaminates food or feed and cause intestinal damage. Long-chain n-3 polyunsaturated fatty acids (PUFA) such as EPA and DHA exert beneficial effects on intestinal integrity in animal models and clinical trials. Necroptosis signaling pathway plays a critical role in intestinal cell injury. This study tested the hypothesis that EPA and DHA could alleviate DON-induced injury to intestinal porcine epithelial cells through modulation of the necroptosis signaling pathway. Intestinal porcine epithelial cell 1 (IPEC-1) cells were cultured with or without EPA or DHA (6.25-25 μg/mL) in the presence or absence of 0.5 μg/mL DON for indicated time points. Cell viability, cell number, lactate dehydrogenase (LDH) activity, cell necrosis, transepithelial electrical resistance (TEER), fluorescein isothiocyanate-labeled dextran 4kDa (FD4) flux, tight junction protein distribution, and protein abundance of necroptosis related signals were determined. EPA and DHA promoted cell growth indicated by higher cell viability and cell number, and inhibited cell injury indicated by lower LDH activity in the media. EPA and DHA also improved intestinal barrier function, indicated by higher TEER and lower permeability of FD4 flux as well as increased proportions of tight junction proteins located in the plasma membrane. Moreover, EPA and DHA decreased cell necrosis demonstrated by live cell imaging and transmission electron microscopy. Finally, EPA and DHA downregulated protein expressions of necroptosis related signals including tumor necrosis factor receptor (TNFR1), receptor interacting protein kinase 1 (RIP1), RIP3, phosphorylated mixed lineage kinase-like protein (MLKL), phosphoglycerate mutase family 5 (PGAM5), dynamin-related protein 1 (Drp1), and high mobility group box-1 protein (HMGB1). EPA and DHA also inhibited protein expression of caspase-3 and caspase-8. These results suggest that EPA and DHA prevent DON-induced intestinal cell injury and enhance barrier function, which is associated with inhibition of the necroptosis signaling pathway. PMID:31909535
Eur J Clin Nutr. 2020 Jan 2
Early-onset coronary atherosclerosis in patients with low levels of omega-3 fatty acids.
Coronary artery calcification (CAC) can reliably predict cardiovascular events. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are thought to inhibit vascular calcification on a cellular level and in animal models, however, the correlation in humans is controversial. In symptomatic patients, CAC was quantified according to Agatstons' method using non-contrast coronary CT. We assessed the association of EPA and DHA with early-onset coronary atherosclerosis, defined as presence of CAC above the 75th Agatston-Score (AS) percentile in sex adjusted age categories. Erythrocyte fatty acid composition was analyzed with a standardized methodology. The percentage of EPA and DHA in relation to all fatty acids present in the erythrocyte membrane is regarded the Omega-3 Index®. Low levels of EPA and DHA (Omega-3 Index) are associated with early-onset coronary atherosclerosis. This finding needs to be validated in larger cohorts and might help understand the beneficial cardiovascular effects of omega-3 fatty acids. PMID:31896827
Molecules. 2019 Dec 28.
Concentration-Dependent Effects of N-3 Long-Chain Fatty Acids on Na,K-ATPase Activity in Human Endothelial Cells.
N-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) seem to prevent endothelial dysfunction, a crucial step in atherogenesis, by modulating the levels of vasoactive molecules and by influencing Na,K-ATPase activity of vascular myocytes. The activity of endothelial Na,K-ATPase controls the ionic homeostasis of the neighboring cells, as well as cell function. However, controversy exists with respect to the vascular protective effect of EPA and DHA. We argue that this dispute might be due to the use of different concentrations of EPA and DHA in different studies. Therefore, this study was designed to define an optimal concentration of EPA and DHA to investigate endothelial function. For this purpose, human endothelial cells were exposed for 24 h to different concentrations of DHA or EPA (0-20 μM) to study membrane fluidity, peroxidation potential and Na,K-ATPase activity. EPA and DHA were linearly incorporated and this incorporation was mirrored by the linear increase of unsaturation index, membrane fluidity, and peroxidation potential. Na,K-ATPase activity peaked at 3.75 μM of EPA and DHA and then gradually decreased. It is noteworthy that DHA effects were always more pronounced than EPA. Concluding, low concentrations of EPA and DHA minimize peroxidation sensitivity and optimize Na,K-ATPase activity. PMID:31905689
Nutr Res. 2019 Nov
Cross-sectional study of the combined associations of dietary and supplemental eicosapentaenoic acid + docosahexaenoic acid on Omega-3 Index.
Studies have linked an Omega-3 Index (O3I), which measures eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in red blood cell membranes, of ≥8% with improved health. Previous studies found that the American Heart Association (AHA) recommendation of 1-2 seafood meals per week does not achieve an O3I ≥8% even with an EPA + DHA supplement; however, these studies did not assess the frequency or amount of supplemental intake. Among participants in a predominantly US and Canadian cohort with high nutrient supplement use, we hypothesized that those adhering to the AHA guidelines would not have an average O3I ≥8% but that those taking a daily supplement would. Fish consumption and EPA + DHA supplement use were reported by 1795 participants; 985 also completed a blood spot test for O3I. A majority (71%) consumed <2 servings per week of fatty fish, and 61% took an EPA + DHA supplement. The amount of EPA + DHA for 1 serving (based on the product label) significantly differed among the >400 supplement products (50-3570 mg). O3I was ≥8.0% in 19% of participants. Among non-supplement takers, 3% of those consuming 1 fish serving per week and 17% consuming ≥2 achieved an O3I ≥8.0%. Among those consuming ≥2 fish servings per week, only those also taking an average of 1100 mg/d of supplemental EPA + DHA had a median O3I ≥8.0%. Based on the relationship between supplemental EPA + DHA intake and O3I for non-fish eaters (R2 = 0.40, P < .0001), an average of ~1300 mg/d of EPA + DHA achieved an O3I of 8.0%. This study suggests that following the AHA guidelines does not produce an O3I ≥8% nor does taking 1 serving per day of most omega-3 supplements. PMID:31757628
Lipids Health Dis. 2019 Nov 6
Omega-3 polyunsaturated fatty acids status and cognitive function in young women.
Research indicates that low omega-3 polyunsaturated fatty acid (n-3 PUFA) may be associated with decreased cognitive function. This study examined the association between n-3 PUFA status and cognitive function in young Australian women. This was a secondary outcome analysis of a cross-sectional study that recruited 300 healthy women (18-35 y) of normal weight (NW: BMI 18.5-24.9 kg/m2) or obese weight (OB: BMI ≥30.0 kg/m2). Participants completed a computer-based cognition testing battery (IntegNeuro™) evaluating the domains of impulsivity, attention, information processing, memory and executive function.
The Omega-3 Index (O3I) was used to determine n-3 PUFA status (percentage of EPA (20:5n-3) plus DHA (22:6n3) in the red cell membrane) and the participants were divided into O3I tertile groups. Potential confounding factors of BMI, inflammatory status (C-reactive Protein), physical activity (total MET-min/wk), alpha1-acid glycoprotein, serum ferritin and hemoglobin, were assessed.
Cognitive function in the attention domain was lower in women with lower O3I, but still within normal range. This reduced but normal level of cognition potentially provides a lower baseline from which cognition would decline with age. Further investigation of individuals with low n-3 PUFA status is warranted. PMID:31694658 Free PMC Article
Clin Hemorheol Microcirc. 2019 Oct 19.
Erythrocyte deformability and aggregability in patients undergoing colon cancer surgery and effects of two infusions with omega-3 fatty acids.
An adequate erythrocyte function is vital for tissue oxygenation and wound healing. The erythrocyte membrane phospholipid composition plays an important role in erythrocyte function and administration of omega-3 fatty acids may provide a means to improve it.
To investigate peri-operative erythrocyte function and effects of omega-3 fatty acids. Forty-four patients undergoing elective laparoscopic colon resection for non-metastasized cancer were randomized between intravenous omega-3 poly-unsaturated fatty acids (n-3 PUFAs) or placebo (saline). Peri-operative blood samples were analyzed with a Lorrca MaxSIS Ektacytometer and erythrocyte membrane phospholipids were determined with gas chromatography.
Patient and operation characteristics were equal between groups. There was a significant increase in erythrocyte membrane eicosapentaenoic acid (EPA) but not docosahexaenoic acid (DHA) in the n-PUFA group. There were no significant differences in erythrocyte deformability but the aggregation index (AI) was significantly lower and the aggregation half time (T½) was significantly higher in the n-3 PUFA group.
This study confirms rapid changes in erythrocyte membrane phospholipid composition after administration of intravenous n-3 PUFAs. Erythrocyte deformability parameters were not affected but erythrocyte aggregability was decreased in the n-3 PUFA group. Further investigation is necessary to gain more insights in the effects of n-3 PUFA and the postoperative inflammatory response on erythrocyte function. PMID:31658051