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PubMed research papers
Neurotoxicology. 2018 Dec
https://www.ncbi.nlm.nih.gov/pubmed/30267739
Inhibition of NRF2 signaling and increased reactive oxygen species during embryogenesis in a rat model of retinoic acid-induced neural tube defects.
Key Laboratory of Health Ministry for Congenital Malformation, Shengjing Hospital, China Medical University, Shenyang, PR China.
Exposure to retinoic acid (RA) during pregnancy increases the risk of serious neural tube defects (NTDs) in the developing fetus. The precise molecular mechanism for this process is unclear; however, RA is associated with oxidative stress mediated by reactive oxygen species.
Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of oxidative stress that directs the expression of antioxidant genes and detoxifying proteins to maintain redox homeostasis.
We established a rat model of NTDs in which pregnant dams were administered all-trans (at)RA on gestational day 10, and oxidative stress levels and the spatiotemporal expression of NRF2 and its downstream targets were examined in the resulting embryos and in maternal blood.
In the NTD group, total antioxidative capacity decreased and 8-hydroxy-2'-deoxyguanosine increased in maternal serum and fetal spinal cord tissues.
Plasma GSH content, the GSH/GSSG ratio, and glutathione peroxidase activity in fetal spinal cords were lower in the NTD group relative to controls. We detected NRF2 protein reduction and concomitant upregulation of Kelch-like ECH-associated protein 1 (KEAP1) - a cytoplasmic inhibitor of NRF2 - in the NTD group.
The mRNA and protein levels of downstream targets of NRF2 were downregulated in the spinal cords of NTD embryos.
These data demonstrate substantial oxidative stress and NRF2 signaling pathway disruption in a model of NTDs induced by atRA.
The inhibitory effects of atRA on NRF2 signaling may lower cellular defenses against RA-induced oxidative stress and could play important roles in NTD occurrence during embryonic development.
Biol Psychiatry. 2009 Nov.
The involvement of retinoic acid receptor-alpha in corticotropin-releasing hormone gene expression and affective disorders.
Department of Neurobiology and Biophysics, Hefei National Laboratory for Physical Sciences at Microscale, School of Life Science, University of Science and Technology of China, Anhui, People's Republic of China.
Corticotropin-releasing hormone (CRH) is considered the central driving force in the stress response and plays a key role in the pathogenesis of depression. Retinoic acid (RA) has been suggested by clinical studies to be associated with affective disorders.
First, hypothalamic tissues of 12 patients with affective disorders and 12 matched control subjects were studied by double-label immunofluorescence to analyze the expression of CRH and retinoic acid receptor-alpha (RAR-alpha). Second, critical genes involved in the RA signaling pathways were analyzed in a rat model of depression. Finally, the regulatory effect of RAR-alpha on CRH gene expression was studied in vitro.
We found that the expression of RAR-alpha was colocalized with CRH neurons in human hypothalamic paraventricular nucleus (PVN). The density of RAR-alpha-immunoreactive neurons and CRH-RAR-alpha double-staining neurons was significantly increased in the PVN of patients with affective disorders.
The ratio of the CRH-RAR-alpha double-staining neurons to the CRH-immunoreactive neurons in affective disorder patients was also increased. Recruitment of RAR-alpha by the CRH promoter was observed in the rat hypothalamus.
A dysregulated RA metabolism and signaling was also found in the hypothalamus of a rat model for depression. Finally, in vitro studies demonstrated that RAR-alpha mediated an upregulation of CRH gene expression.
CONCLUSIONS:
These results suggest that RAR-alpha might contribute to regulating the activity of CRH neurons in vivo, and the vulnerable character of the critical proteins in RA signaling pathways might provide novel targets for therapeutic strategies for depression.
PMID:19596122
Sci Rep. 2018 Sep
Differentiation enhances Zika virus infection of neuronal brain cells.
Zika virus (ZIKV) is an emerging, mosquito-borne pathogen associated with a widespread 2015-2016 epidemic in the Western Hemisphere and a proven cause of microcephaly and other fetal brain defects in infants born to infected mothers.
ZIKV infections have been also linked to other neurological illnesses in infected adults and children, including Guillain-Barré syndrome (GBS), acute flaccid paralysis (AFP) and meningoencephalitis, but the viral pathophysiology behind those conditions remains poorly understood.
Here we investigated ZIKV infectivity in neuroblastoma SH-SY5Y cells, both undifferentiated and following differentiation with retinoic acid.
We found that multiple ZIKV strains, representing both the prototype African and contemporary Asian epidemic lineages, were able to replicate in SH-SY5Y cells.
Differentiation with resultant expression of mature neuron markers increased infectivity in these cells, and the extent of infectivity correlated with degree of differentiation.
New viral particles in infected cells were visualized by electron microscopy and found to be primarily situated inside vesicles; overt damage to the Golgi apparatus was also observed.
Enhanced ZIKV infectivity in a neural cell line following differentiation may contribute to viral neuropathogenesis in the developing or mature central nervous system.
PMID:30266962 Free PMC Article
hillcountry: ever wonder how Grant's cells are differentiating? I was thinking maybe his alternate system has the additional benefit of making him immune to "Zika".
Big hat-tip to ZJ who posted this 2016 study back in Feb. Read it for the first time today after an interesting response brought it back to the top of the blog. Copying it here makes sense so that there's less chance someone will miss it down the road. I was thinking about how glacially slow the world of medicine is, and how this paper is literally hot-off-the-presses, crucial information for mothers and their doctors. I did a copy-paste and added some bolds and underlines to ZJ's excerpts since I'm making a hand-out flyer of this one. Thanks!
https://www.oatext.com/pdf/JTS-2-133.pdf
Journal of Translational Science – 2016
A Role for the Liver in Parturition and Preterm Birth
Anthony R Mawson
Department of Epidemiology and Biostatistics, School of Public Health, Jackson State University, USA
Neither the mechanisms of parturition nor the pathogenesis of preterm birth are well understood. Poor nutritional status has been suspected as a major causal factor, since vitamin A concentrations are low in preterm infants. However, even large enteral doses of vitamin A from birth fail to increase plasma concentrations of vitamin A or improve outcomes in preterm and/or extremely low birthweight infants. These findings suggest an underlying impairment in the secretion of vitamin A from the liver, where about 80% of the vitamin is stored in potentially toxic concentrations.
Vitamin A accumulates in the liver and breast during pregnancy in preparation for lactation. While essential in low concentration for multiple biological functions, vitamin A in higher concentration can be pro-oxidant, mutagenic, teratogenic and cytotoxic, acting as a highly surface-active, membrane-seeking and destabilizing compound.
Regarding the mechanism of parturition, it is conjectured that by nine months of gestation the hepatic accumulation of vitamin A (retinol) from the liver is such that mobilization and secretion are impaired to the point where stored vitamin A compounds in the form of retinyl esters and retinoic acid begin to spill or leak into the circulation, resulting in amniotic membrane destabilization and the initiation of parturition.
If, however, the accumulation and spillage of stored retinoids reaches a critical threshold prior to nine months, e.g., due to cholestatic liver disease, which is common in mothers of preterm infants, the increased retinyl esters and/or retinoic acid rupture the fetal membranes, inducing preterm birth and its complications, including retinopathy, necrotizing enterocolitis and bronchopulmonary dysplasia. Subject to testing, the model suggests that measures taken prior to and during pregnancy to improve liver function could reduce the risk of adverse birth outcomes, including preterm birth.
In 1953 Peter Medawar raised the question: “How does the pregnant mother contrive to nourish within itself, for many weeks or months, a fetus that is an antigenically foreign body?” [75]. In other words, why does the mother fail to reject her fetus as a foreign piece of tissue?
The suggestion offered here is that the mother does not reject but rather ejects the fetus, normally at around 37 weeks of gestation, as the result of a biochemical rather than an immunological mechanism.
Parturition at term is hypothesized to represent an active process of ejection of the fetus associated with the hepatic accumulation and spillage of stored retinoids due to mild liver dysfunction, which progressively weaken the fetal membranes until they rupture at around the ninth month of gestation.
Based on this template for parturition at term, it is further proposed that spontaneous preterm birth is similarly due to more severe liver dysfunction and to concentrations of retinyl esters and retinoic acid that exceed the threshold for inducing rupture of the fetal membranes before 37 weeks of gestation.
Approaches to the management of pregnancies resulting in preterm birth and its complications suggested by the retinoid toxicity hypothesis could involve the adoption of measures taken prior to and after conception to improve liver function through dietary and lifestyle changes.
hillcountry: I received a polite but dismissive response from an Alzheimer’s coordinator in my area after sending her a copy of the 1992 epidemiology study titled Vitamin A and Alzheimer’s Disease that Grant found. I was hoping to put it at their booth or sign-up table. She said it was interesting, but dated, and that they’d be happy to direct me to more current research. They wouldn’t allow it to be handed-out at their local walk coming up tomorrow, not that they own the sidewalks they’ll be using. I’ll be handing some out anyway, just not from an official spot. Then I thought, hmmm, wonder what I can find out that might be interesting on that score. One thing led to another and finally to an interesting link between retinoic acid and folate deficiency. A review of the results of the following 3 papers could be titled:
Folate Deficiency Mediates Retinoic Acid Toxicity in Neurological Disorders
Neurobiol Dis. 2014 Nov PMID:25131448
Folate deficiency-induced oxidative stress contributes to neuropathy in young and aged zebrafish--implication in neural tube defects and Alzheimer's diseases. The Institute of Basic Medical Science, National Cheng Kung University, Tainan, Taiwan.
Folate is a nutrient essential for the development, function and regeneration of nervous systems. Folate deficiency has been linked to many neurological disorders including neural tube defects in fetus and Alzheimer's diseases in the elderly.
However, the etiology underlying these folate deficiency-associated diseases is not completely understood.
In this study, zebrafish transgenic lines with timing and duration-controllable folate deficiency were developed by ectopically overexpressing a recombinant EGFP-γ-glutamyl hydrolase (γGH).
Impeded neural crest cell migration was observed in the transgenic embryos when folate deficiency was induced in early stages, leading to defective neural tube closure and hematopoiesis.
Adding reduced folate or N-acetylcysteine reversed the phenotypic anomalies, supporting the causal link between the increased oxidative stress and the folate deficiency-induced abnormalities. (hillcountry: we could stack ‘retinoic acid leads to oxidative stress’ papers from here to the moon)
When folate deficiency was induced in aged fish, accumulation of beta-amyloid and phosphorylated Tau protein were found in the fish brain cryo-sections.
Increased autophagy and accumulation of acidic autolysosome were apparent in folate deficient neuroblastoma cells, which were reversed by reduced folate or N-acetylcysteine supplementation.
Decreased expression of cathepsin B, a lysosomal protease, was also observed in cells and tissue with folate deficiency. We concluded that folate deficiency-induced oxidative stress contributed to the folate deficiency-associated neuropathogenesis in both early and late stages of life.
Dev Biol. 2015 Sep PMID:26144049 Free PMC Article
The role of folate metabolism in orofacial development and clefting.
Department of Biology, Virginia Commonwealth University, 1000 West Cary St., Richmond, VA 23284, United States.
Folate deficiency has been associated with numerous diseases and birth defects including orofacial defects. However, whether folate has a role in the face during early orofacial development has been unclear. The present study reveals that pharmacological and antisense oligonucleotide mediated inhibition of DHFR, an integral enzyme in the folate pathway, results in specific changes in the size and shape of the midface and embryonic mouth. Such defects are accompanied by a severe reduction in the muscle and cartilage jaw elements without significant change in neural crest pattern or global levels of methylation.
We propose that the orofacial defects associated with DHFR deficient function are the result of decreased cell proliferation and increased cell death via DNA damage.
In particular, localized apoptosis may also be depleting the cells of the face that express crucial genes for the differentiation of the jaw structures. Folate supplementation is widely known to reduce human risk for orofacial clefts.
In the present study, we show that activating folate metabolism can reduce median oral clefts in the primary palate by increasing cell survival. Moreover, we demonstrate that a minor decrease in DHFR function exacerbates median facial clefts caused by RAR inhibition.
This work suggests that folate deficiencies could be a major contributing factor to multifactorial orofacial defects.
hillcountry: having seen a lot of papers implicating retinoic acid in similar defects, I wondered if PubMed would yield anything connecting retinoic acid to folate deficiency or altered folate metabolism. Sure enough, here’s one.
J Eur Acad Dermatol Venereol. 2008 Jan PMID:18181979
Decreased plasma folate concentration in young and elderly healthy subjects after a short-term supplementation with isotretinoin.
Human Nutrition Unit, Institut National de la Recherche Agronomique, Centre de Theix, Saint-Genes Champanelle, France.
In the last two decades, there has been an increasing use of isotretinoin (13-cis-retinoic acid or 13-CRA) for treatment of severe, and recently mild and moderate, acne in Westernized populations. Recent human and animal studies emphasized alterations caused by 13-CRA administration on folate-dependent, one-carbon metabolism.
Folate deficiency and subsequent hyperhomocysteinemia increase the risk of degenerative diseases.
We determine whether a short-term supplementation with 13-CRA alters folate status and homocysteinemia in young and elderly healthy human subjects.
Twenty young and 20 elderly (age mean, 26.1 and 65.4 years, respectively) healthy male volunteers were supplemented with approximately 0.5 mg/kg/day of 13-CRA for 28 days. Fasting plasma concentrations of 13-CRA, 5-methyltetrahydrofolate (5-mTHF) as the main circulating form of folate, and homocysteine (Hcy), as well as haematologic parameters and biochemical markers of liver and renal function, were measured at baseline and at the end of supplementation. Statistical analyses were carried out using two-way anova and standard tests.
In both groups, isotretinoin supplementation caused a dramatic increase in the circulating concentration of 13-CRA and its derivatives.
It also led to significant increases in serum triglyceride (P < 0.0001) and creatinine (P = 0.002) concentrations and gamma-glutamyltranspeptidase activity (P = 0.0001) and decrease in serum level of urea (P = 0.027).
However, the latter four parameters remained within normal ranges.
These changes were accompanied by a 17.7% and 13.5% decrease in the plasma level of 5-mTHF (P = 0.001) in the young and elderly volunteers, respectively.
Supplementation with 13-CRA did not cause significant variations in their plasma Hcy concentration. However, the latter parameter seemed to respond differently in each group of age (P = 0.046).
Our data indicate that a 28-day supplementation with isotretinoin alters the plasma folate in young and old healthy individuals. This stresses the necessity of studying the long-term effects of retinoid therapy on folate status and homocysteinemia in acne patients, given that alteration in the latter parameters is known to increase the risk of degenerative diseases.
(hillcountry: hopefully, they’ll widen that “necessity of studying the long-term effects” idea to the view that Grant has so well documented. I guess the question here is what is the long-term impact of decades of excess retinoic acid exposure on the cells and tissues in question, and does that impact approximate or exceed the damage due to folate deficiency described above? I’m inclined to think the sub-clinical nature of overall retinoid-toxicity is the sleeping giant, even though the studies that give us much of our information tend to be designed as “acute” in terms of dosage and time-frames. I'll be digging in the archives documenting retinoic acid causing oxidative stress and maybe find something on how that causes the folate deficiency. That would be a great smoking-gun if the chemists already have documented how that might work. Also need to check into “retinoic acid and cathepsin B” over at PubMed as well. That might be another puzzle-piece that helps the argument.)
@hillcountry possible if you could do a dive into thiamine depletion caused by retinoic acid excretion(B1 used up in the excretion process). There seems to be some sort of connection between thiamine and VA overload (especially with 13-CRA accutane users). Also wondering if a zero VA diet, beef/rice provides enough B1 afterwards.
hi Orion, I'll be glad to delve into those subjects. I haven't heard about thiamine depletion yet. Just got into some B-12 stuff that looks pretty important. Thiamine must be so as well. I'll see if I can condense something relevant and practical. I'm finding out a lot about methods of searching PubMed with combinations of words that really speeds things up and surfaces papers that it seems one would have already encountered on more basic searches. This is as fun as beach-combing with a metal-detector; lots of repetitious junk out there, but an occasional coin or ring too.
Quote from Orion on October 4, 2019, 10:50 am@hillcountry possible if you could do a dive into thiamine depletion caused by retinoic acid excretion(B1 used up in the excretion process). There seems to be some sort of connection between thiamine and VA overload (especially with 13-CRA accutane users). Also wondering if a zero VA diet, beef/rice provides enough B1 afterwards.
I wonder if this is why I struggle with thiamine deficiency. It seemed to happen out of the blue.
These two papers seem to go together.
Front Aging Neurosci. 2019 Jul 23
The Synthetic Retinoid Acitretin Increases IL-6 in the Central Nervous System of Alzheimer Disease Model Mice and Human Patients.
Dos Santos Guilherme M1, Stoye NM1, Rose-John S2, Garbers C3, Fellgiebel A1, Endres K1.
1 - Department of Psychiatry and Psychotherapy, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
2 - Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel (CAU Kiel), Kiel, Germany.
3 - Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany.
Abstract
These days, the important role of retinoids in adult brain functionality and homeostasis is well accepted and has been proven by genomic as well as non-genomic mechanisms. In the healthy brain, numerous biological processes, e.g., cell proliferation, neurogenesis, dendritic spine formation as well as modulation of the immune system, have been attributed to retinoid signaling. This, together with the finding that retinoid metabolism is impaired in Alzheimer's disease (AD), led to preclinical and early clinical testing of natural and synthetic retinoids as innovative pharmaceuticals with multifactorial properties. Acitretin, an aromatic retinoid, was found to exert an anti-amyloidogenic effect in mouse models for AD as well as in human patients by stimulating the alpha-secretase ADAM10. The lipophilic drug was already demonstrated to easily pass the blood brain barrier after i.p. administration and evoked increased nest building capability in the 5xFAD mouse model.
Additionally, we analyzed the immune-modulatory capacity of acitretin via a multiplex array in the 5xFAD mouse model and evaluated some of our findings in human CSF derived from a pilot study using acitretin. Although several serum analytes did not display changes, Interleukin-6 (IL-6) was found to be significantly increased in both-mouse and human neural material.
This demonstrates that acitretin exerts an immune stimulatory effect-besides the alpha-secretase induction-which could impact the alleviation of learning and memory disabilities observed in the mouse model.
PMID:31396076 PMCID:PMC6664027 DOI:10.3389/fnagi.2019.00182
PLoS One. 2017 Nov 15;12(11):e0188007. doi: 10.1371/journal.pone.0188007. eCollection 2017.
Depot-specific inflammation with decreased expression of ATM2 in white adipose tissues induced by high-margarine/lard intake.
Wang N1, Guo J1,2, Liu F1,3, Wang M1, Li C4, Jia L1, Zhai L1, Wei W1, Bai Y1.
Author information
1 - Department of Child and Adolescent Health, School of Public Health, China Medical University, Shenyang, Liaoning, China.
2 - Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China.
3 - Department of Public Health, Huangshi Central Hospital, Edong Healthcare Group, Huangshi, Hubei, China.
4 - Information Center, the First Hospital of China Medical University, Shenyang, Liaoning, China.
Abstract
A high-fat diet has been recognized as an important risk factor of obesity, with variable impacts of different fatty acid compositions on the physiological process. To understand the effects of a high-margarine/lard diet, which is a major source of trans fatty acids (TFAs)/ saturated fatty acids (SFAs), elaidic acid as a biomarker of margarine intake was used to screen affected adipokines on mature human adipocytes in vitro. Weaned male Wistar rats were fed a high-fat diet enriched with margarine/lard to generate obesity-prone (OP) and obesity-resistant (OR) models, which were then used to explore the inflammatory responses of depot-specific white adipose tissue.
Adiposity, glucose and lipid metabolism parameters and macrophage cell markers were also compared in vivo. In the subcutaneous depot, a high-margarine diet induced elevated IL-6, MCP-1 and XCL1 expression levels in both M-OP and M-OR groups. High-lard diet-fed rats displayed higher protein expression levels of MCP-1 and XCL1 compared with the control group. In the epididymal depot, significantly elevated IL-6 production was observed in M-OP rats, and high-lard diet-fed rats displayed elevated IL-6 and decreased XCL1 expression.
In the retroperitoneal depot, a high-margarine diet caused higher IL-6 and MCP-1 expression levels, a high-lard diet caused elevated IL-6 expression in L-OP/L-OR rats, and elevated XCL1 expression was observed only in L-OP rats. In general, CD206 mRNA levels were notably down-regulated by high-fat diet feeding in the above-mentioned depots. CD11c mRNA levels were slightly upregulated in the subcutaneous depot of OP rats fed a high-margarine/lard diet. In the epidydimal depot, higher expression levels of F4/80 and CD206 mRNA were observed only in high-margarine diet-fed OP rats. These results suggest that depot-specific inflammation with decreased expression of adipose tissue anti-inflammatory M2-type (ATM2) macrophages could be induced by high-margarine/lard intake.
PMID:29141038 PMCID:PMC5687764 Free PMC Article
Can't recall if this one has been posted anywhere yet. Maybe in one of Grant's books? It's another interesting paper by Anthony Mawson. I think I'll do an index post one of these days of just the titles of all the papers we've collected. It could come in handy as the preponderance of evidence continues to grow.
Front Biosci. 2001 Aug 1; 6:D973-85.
Could bronchial asthma be an endogenous, pulmonary expression of retinoid intoxication?
Author information
1 - College of Health Sciences, Des Moines University-Osteopathic Medical Center, 3200 Grand Avenue, Des Moines, Iowa 50312, USA. anthony.mawson@dmu.edu
Abstract
Asthma has become a major public health problem, affecting about 17 million people in the United States, including 4.8 million children. A striking increase in asthma and other forms of atopy has occurred in children in the U.S. and other western countries during the past 30 years.
Several studies have reported an inverse association between childhood infectious illness and the development of atopy, suggesting that certain forms of infection protect against and even inhibit asthma.
This may involve a shift in the balance of CD4 T lymphocyte helper cells from a Th2 to a Th1-type cytokine profile. However, the underlying mechanisms remain uncertain. Based on a review of the literature, it is conjectured that in the absence of certain types of childhood infection, retinoids (vitamin A and its congeners) accumulate in the lung.
Later, upon exposure to known triggers for asthma, retinoid metabolites may be produced in such high concentration that they produce an acute, localized form of retinoid intoxication, recognized as status asthmaticus.
PMID:11502488 DOI:10.2741/mawson