Quote from tim on October 19, 2019, 7:40 pm

Apparently molds can deplete thiamine, also sulfites and thiocyanates are a major threat to thiamine status.

My conclusion from a small amount of research is that if one wants optimal thiamine status they should avoid alcohol, caffeine and nicotine and high carb low protein/fat diets.

Quote from lil chick on October 21, 2019, 6:43 am

Quote from tim on October 19, 2019, 7:40 pm

Apparently molds can deplete thiamine, also sulfites and thiocyanates are a major threat to thiamine status.

My conclusion from a small amount of research is that if one wants optimal thiamine status they should avoid alcohol, caffeine and nicotine and high carb low protein/fat diets.

Interesting!  Occasionally on travel I've stayed in moldy places and had attacks.  (And of course on vacation one drinks more alcohol and coffee and eats more pastry!) ...sigh no more fun lol

Quote from Sarabeth on October 21, 2019, 9:23 pm

This is definitely  n=1, and not sure if environmental and dietary molds cause problems via the same mechanisms...but: in the nearly four months since beginning to eat Low A, my most environmental-mold-sensitive child has had greatly increased tolerance. Many fewer headaches!

Quote from hillcountry on October 23, 2019, 8:35 am

Lowering homocysteine levels with folic acid and B-vitamins do not reduce early atherosclerosis, but could interfere with cognitive decline and Alzheimer's disease.
several clinical investigations demonstrated that folates and vitamins administration is able to reduce Hcy serum levels and antagonize some mechanisms favouring neurodegenerative impairments, as mild cognitive impairment, AD and dementia. Thus, contrarily to the atherosclerotic manifestations in hyperhomocysteinemic patients, preventive treatment with folates and B6-12 vitamins reduces Hcy concentration and could prevent or delay cognitive decline and AD.

 

The neurology of folic acid deficiency.
The metabolism of folic acid and the metabolism of vitamin B12 are intimately linked such that deficiency of either vitamin leads to an identical megaloblastic anemia.The neurologic manifestations of folate deficiency overlap with those of vitamin B12 deficiency and include cognitive impairment, dementia, depression, and, less commonly, peripheral neuropathy and subacute combined degeneration of the spinal cord. Clinical responses to treatment with folates are usually slow over weeks and months, probably due to the efficient blood-brain barrier mechanism for the vitamin, perhaps in turn related to the experimentally demonstrated excitatory properties of folate derivatives. The inappropriate administration of folic acid in the presence of vitamin B12 deficiency may lead to both neurologic and, later, hematologic relapse. Folates and vitamin B12 have fundamental roles in central nervous system function at all ages, especially in purine, thymidine, neucleotide, and DNA synthesis, genomic and nongenomic methylation and, therefore, in tissue growth, differentiation and repair. There is interest in the potential role of both vitamins in the prevention of disorders of central nervous system development, mood, dementia, including Alzheimer's disease, and aging.

 

Modest Decreases in Endogenous All-trans-Retinoic Acid Produced by a Mouse Rdh10 Heterozygote Provoke Major Abnormalities in Adipogenesis and Lipid Metabolism.
Pharmacological dosing of all-trans-retinoic acid (atRA) controls adiposity in rodents by inhibiting adipogenesis and inducing fatty acid oxidation. Retinol dehydrogenases (Rdh) catalyze the first reaction that activates retinol into atRA. This study examined postnatal contributions of Rdh10 to atRA biosynthesis and physiological functions of endogenous atRA. Embryonic fibroblasts from Rdh10 heterozygote hypomorphs or with a total Rdh10 knockout exhibit decreased atRA biosynthesis and escalated adipogenesis. atRA or a retinoic acid receptor (RAR) pan-agonist reversed the phenotype. Eliminating one Rdh10 copy in vivo (Rdh10+/- ) yielded a modest decrease (≤25%) in the atRA concentration of liver and adipose but increased adiposity in male and female mice fed a high-fat diet (HFD); increased liver steatosis, glucose intolerance, and insulin resistance in males fed an HFD; and activated bone marrow adipocyte formation in females, regardless of dietary fat. Chronic dosing with low-dose atRA corrected the metabolic defects. These data resolve physiological actions of endogenous atRA, reveal sex-specific effects of atRA in vivo, and establish the importance of Rdh10 to metabolic control by atRA. The consequences of a modest decrease in tissue atRA suggest that impaired retinol activation may contribute to diabesity, and low-dose atRA therapy may ameliorate adiposity and its sequelae of glucose intolerance and insulin resistance.

 

Over-expression of a retinol dehydrogenase (SRP35/DHRS7C) in skeletal muscle activates mTORC2, enhances glucose metabolism and muscle performance.
SRP-35 is a short-chain dehydrogenase/reductase belonging to the DHRS7C dehydrogenase/ reductase family 7. Here we show that its over-expression in mouse skeletal muscles induces enhanced muscle performance in vivo, which is not related to alterations in excitation-contraction coupling but rather linked to enhanced glucose metabolism. Over-expression of SRP-35 causes increased phosphorylation of AktS473, triggering plasmalemmal targeting of GLUT4 and higher glucose uptake into muscles. SRP-35 signaling involves RARα and RARγ (non-genomic effect), PI3K and mTORC2. We also demonstrate that all-trans retinoic acid, a downstream product of the enzymatic activity of SRP-35, mimics the effect of SRP-35 in skeletal muscle, inducing a synergistic effect with insulin on AKTS473 phosphorylation. These results indicate that SRP-35 affects skeletal muscle metabolism and may represent an important target for the treatment of metabolic diseases.

 

Thiamine Deficiency and Neurodegeneration: The Interplay among Oxidative Stress, Endoplasmic Reticulum Stress and Autophagy.
In this review, we discuss the role of oxidative stress, ER stress and autophagy in TD-mediated neurodegeneration. We propose that it is the interplay of oxidative stress, ER stress and autophagy that contributes to TD-mediated neurodegeneration. These results suggest that autophagy is neuroprotective in response to TD-induced neurodegeneration in the CNS. There are several potential mechanisms for TD-induced autophagy. For example, TD is shown to affect mTOR and AMPK pathways which are critical regulators of autophagy. Additionally, TD may activate autophagy through the induction of oxidative stress and/or ER stress because both oxidative stress and ER stress are known to stimulate autophagy.

 

Therapies for mitochondrial diseases and current clinical trials.
Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders that result from dysfunction of the mitochondrial oxidative phosphorylation due to molecular defects in genes encoding mitochondrial proteins. Despite the advances in molecular and biochemical methodologies leading to better understanding of the etiology and mechanism of these diseases, there are still no satisfactory therapies available for mitochondrial disorders. Treatment for mitochondrial diseases remains largely symptomatic and does not significantly alter the course of the disease. Therapeutic strategies for mitochondrial diseases include the use of agents enhancing electron transfer chain function (coenzyme Q10, idebenone, riboflavin, dichloroacetate, and thiamine), agents acting as energy buffer (creatine), antioxidants (vitamin C, vitamin E, lipoic acid, cysteine donors, and EPI-743), amino acids restoring nitric oxide production (arginine and citrulline), cardiolipin protector (elamipretide), agents enhancing mitochondrial biogenesis (bezafibrate, epicatechin, and RTA 408), nucleotide bypass therapy, liver transplantation, and gene therapy.

 

Thiamine and selected thiamine antivitamins - biological activity and methods of synthesis.
The development of organic chemistry in the last century allowed the synthesis of various thiamine antimetabolites such as amprolium, pyrithiamine, oxythiamine, or 3-deazathiamine. Results of biochemical and theoretical chemistry research show that affinity to thiamine diphosphate-dependent enzymes of these synthetic molecules exceeds the affinity of native coenzyme. Therefore, some of them have already been used in the treatment of coccidiosis (amprolium), other are extensively studied as cytostatics in the treatment of cancer or fungal infections (oxythiamine and pyrithiamine).

 

Competition for vitamin B1 (thiamin) structures numerous ecological interactions.
Thiamin (vitamin B1) is a cofactor required for essential biochemical reactions in all living organisms, yet free thiamin is scarce in the environment. The diversity of biochemical pathways involved in the acquisition, degradation, and synthesis of thiamin indicates that organisms have evolved numerous ecological strategies for meeting this nutritional requirement. In this review we synthesize information from multiple disciplines to show how the complex biochemistry of thiamin influences ecological outcomes of interactions between organisms in environments ranging from the open ocean and the Australian outback to the gastrointestinal tract of animals. We highlight population and ecosystem responses to the availability or absence of thiamin. These include widespread mortality of fishes, birds, and mammals, as well as the thiamin-dependent regulation of ocean productivity. Overall, we portray thiamin biochemistry as the foundation for molecularly mediated ecological interactions that influence survival and abundance of a vast array of organisms.

 

The role of thiamine dependent enzymes in obesity and obesity related chronic disease states: A systematic review.
The average American consumes 3770 kcal/day and the average person in the UK consumes 3400 kcal/day. With such increased caloric intake, there is an increased load on metabolic pathways, in particular glucose metabolism. Such metabolism requires micronutrients as enzyme co-factors. The recommended daily allowance (RDA) for thiamine is 1.3 mg/day and 0.5 mg thiamine is required to process 1000 kilocalories (kcal). Therefore, despite the appearance of being overfed, there is now increasing evidence that the obese population may nutritionally depleted of essential micronutrients. Thiamine and magnesium therefore play a critical role in glucose metabolism and their deficiency may result in the accumulation of anaerobic metabolites including lactate due to a mismatch between caloric burden and function of thiamine dependent enzymes. It may therefore be postulated that thiamine and magnesium deficiency are under-recognized in obesity and may be important in the progress of obesity and obesity related chronic disease states.

 

Dry Beriberi Due to Thiamine Deficiency Associated with Peripheral Neuropathy and Wernicke's Encephalopathy Mimicking Guillain-Barré syndrome: A Case Report and Review of the Literature.
Beriberi due to thiamine (vitamin B1) deficiency has two clinical presentations. Patients with dry beriberi present with neuropathy, and patients with wet beriberi present with heart failure, with or without neuropathy. Dry beriberi can mimic the most common form of Guillain-Barre syndrome (GBS), an acute inflammatory demyelinating polyradiculoneuropathy (AIDP). Severe thiamine deficiency results in Wernicke's encephalopathy. Symptoms and signs of dry beriberi due to thiamine deficiency can mimic those of acute or chronic GBS. However, thiamine repletion leads to rapid clinical improvement and can prevent irreversible neurologic sequelae, including Korsakoff syndrome. Clinicians should consider thiamine deficiency in malnourished patients presenting with symptoms and signs of GBS.

 

Neurological, Psychiatric, and Biochemical Aspects of Thiamine Deficiency in Children and Adults.
Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes, mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in energy metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on mitochondrial ATP production. This is more evident during rapid growth (i.e., perinatal periods and children) in which thiamine deficiency is commonly associated with either malnutrition or genetic defects. Thiamine deficiency contributes to a number of conditions spanning from mild neurological and psychiatric symptoms (confusion, reduced memory, and sleep disturbances) to severe encephalopathy, ataxia, congestive heart failure, muscle atrophy, and even death. This review discusses the current knowledge on thiamine deficiency and associated morbidity of neurological and psychiatric disorders, with special emphasis on the pediatric population, as well as the putative beneficial effect of thiamine supplementation in autism spectrum disorder (ASD) and other neurological conditions.

 

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies.
Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria, and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anemia and sensory-neural hearing loss, whereas SLC19A3, SLC25A19, and TPK1-related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability, and early death.

 

Thiamine deficiency in the bereaved after cancer-related spousal loss.
From a series of bereaved partners who lost a spouse to cancer, we report on those who developed TD after bereavement. Case 2 was a bereaved 73-year-old male who had lost his wife to hypopharyngeal cancer one month previously after a five-year illness. He had shown a lack of energy for the month preceding his wife's death, but because there was no improvement after her death, his family recommended he seek consultation at our "bereavement clinic." He was suffering from major depressive disorder. Detailed examination revealed that his appetite had been decreased for more than two weeks. Again, the diagnosis of TD was supported by his abnormally low serum thiamine level.    >>>(Makes me wonder about the Frontiers in Endricrinology study about trauma and shock and the liver dumping retinol into blood stream. Could retinol CAUSE thiamine deficiency, like retinoic acid causes folate deficiency?)<<<

 

Thiamine Use in Sepsis: B1 for Everyone?
Every year, sepsis affects nearly 30 million people worldwide, with current annual estimates reporting as many as 6 million deaths. To combat the staggering number of patients who are affected by sepsis, clinicians continue to investigate novel treatment approaches. One treatment approach that has gained interest is the role that vitamins and nutrients play in the body's response to sepsis. Thiamine, in particular, has been studied because of its role in glucose metabolism and lactate production. This review provides a summary of the current literature surrounding the use of thiamine in the treatment of sepsis and describes the function of this essential nutrient in sepsis pathology.

 

Thiamine deficiency affects glucose transport and β-oxidation in rats.
Thiamine is recognized as a cofactor for many enzymes involved in intermediary metabolism responsible for energy production. Animal model of thiamine deficiency (TD) included direct evaluation of glucose uptake by estimation of 3 H-deoxyglucose transport across red blood cells membranes and β-oxidation of fatty acids in isolated leucocytes. Feeding of animals with the thiamine-deficient diet (0.018 mg/kg diet) for 30 days resulted in disturbances in energy production. The thiamine intake was limited not only by vitamin B1 deficiency in the diet, but also by time-dependent drop of feed consumption by rats fed this diet. At the end of experiment, diet consumption in this group of rats was 52% lower than in the control group. This was accompanied by low glucose uptake by erythrocytes of rats suffering vitamin B1 deficiency for longer time. At the end of experimental period, glucose uptake was over 2 times lower in TD erythrocytes than in control RBC. Such drop of energy production was not compensated by delivery of energy from fatty acid degradation. In leucocytes from TD rats, the β-oxidation was also suppressed.

Observed significant decrease of serum insulin from 2.25 ± 0.25 ng/ml (day 0) to 1.94 ± 0.17 ng/ml (day 30) might have significant impact on observed energy production disorders. The results from this study indicate that the thiamine deficiency significantly reduces feed intake and causes modest abnormalities in glucose and fatty acid utilization.

 

B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin.
Neurotropic B vitamins play crucial roles as coenzymes and beyond in the nervous system. Particularly vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) contribute essentially to the maintenance of a healthy nervous system. Their importance is highlighted by many neurological diseases related to deficiencies in one or more of these vitamins, but they can improve certain neurological conditions even without a (proven) deficiency. We discussed the main role of B Vitamins on several functions in the peripheral and central nervous system (PNS and CNS) including cellular energetic processes, antioxidative and neuroprotective effects, and both myelin and neurotransmitter synthesis. We also provide an overview of possible biochemical synergies between thiamine, pyridoxine, and cobalamin and discuss by which major roles each of them may contribute to the synergy and how these functions are inter-related and complement each other.

 

Retinoic acid as a therapeutic option in Alzheimer's disease: a focus on cholinergic restoration.
Retinoic acid is a potent cell differentiating factor, which through its nuclear receptors affects a vast range of promoter sites in brain neuronal and glial cells in every step of embryonic and postnatal life. Its capacities, facilitating maturation of neurotransmitter phenotype in different groups of neurons, pave the way for its application as a potential therapeutic agent in neurodegenerative diseases including Alzheimer's disease. Retinoic acid was found to exert particularly strong enhancing effects on acetylcholine transmitter functions in brain cholinergic neurons, loss of which is tightly linked to the development of cognitive and memory deficits in course of different cholinergic encephalopathies. Here, we review cholinotrophic properties of retinoic acid and its derivatives, which may justify their application in the management of Alzheimer's disease and the related neurodegenerative conditions.

 

Association of polymorphisms in STRA6 gene with gestational diabetes mellitus in a Chinese Han population.
Cell and animal experiments have found that in addition to being a retinol transporter, Stimulated by Retinoic Acid 6 (STRA6) also functions as a surface signaling receptor by which retinol regulates insulin responses. Several studies revealed that the STRA6 gene may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM).

 

Adipocyte-specific expression of a retinoic acid receptor α dominant negative form causes glucose intolerance and hepatic steatosis in mice.
Altered RAR signaling in adipocytes resulted in a significant decrease in ATRA levels in visceral and brown adipose tissues as well as liver tissue. This was linked to significant impairments in glucose clearance and elevated hepatic lipid accumulation for chow diet fed mice, indicating the development of metabolic disease, including hepatic steatosis. In addition, we found that adipose RARdn expression in mice fed a chow diet decreased thermogenesis. We conclude that altered RAR signaling and ATRA levels in adipocytes impacts glucose and lipid metabolism in mice.

 

Vitamin B1 (thiamine) and dementia.
perhaps best example of an interaction between nutrition and dementia is related to thiamine (vitamin B1). Throughout the last century, research showed that thiamine deficiency is associated with neurological problems, including cognitive deficits and encephalopathy. Multiple similarities exist between classical thiamine deficiency and Alzheimer's disease (AD) in that both are associated with cognitive deficits and reductions in brain glucose metabolism. Thiamine-dependent enzymes are critical components of glucose metabolism that are reduced in the brains of AD patients

 

Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study.
Administration of parenteral high-dose thiamine was effective in reversing PD motor and nonmotor symptoms. The clinical improvement was stable over time in all the patients. From our clinical evidence, we hypothesize that a dysfunction of thiamine-dependent metabolic processes could cause selective neural damage in the centers typically affected by this disease and might be a fundamental molecular event provoking neurodegeneration. Thiamine could have both restorative and neuroprotective action in PD.

 

Vitamin neurotoxicity.
Vitamin A toxicity is also a good general model of vitamin neurotoxicity, because it shows the importance of the ratio of vitamin and vitamin-binding proteins in producing vitamin toxicity and of CNS permeability barriers. Because vitamin A and analogs enter the CNS better than most vitamins, and because retinoids have many effects on enzyme activity and gene expression, Vitamin A neurotoxicity is more likely than that of most, perhaps all other vitamins.

 

Prevention of retinoic acid-induced early craniofacial abnormalities by vitamin B12 in mice.
All embryos were exposed to 0.4 µM RA and different concentrations of vitamin B12 and scored for their growth in the branchial region at the end of a 48-hour culture period. These results suggest that vitamin B12 may prevent RA-induced craniofacial abnormalities via prevention of an RA-induced decrease of ET-1 and dHAND protein levels in the branchial region during the organogenic period.

 

Cervical cancer pathogenesis is associated with one-carbon metabolism.
Cervical cancer is the most common cancer among women in India and a leading cause of death in these women. Most cases of cervical cancer are associated with human papillomavirus (HPV) infection of the high-risk type. It has been reported that aberrant DNA methylation can be associated with HPV infection and cervical cancer, and folate is directly involved in DNA methylation via one-carbon metabolism. We observed that lower folate and vitamin B(12) status were associated with HPV infection. Taken together, our findings suggest a role of folate and vitamin B(12) in modulating the risk of cervical cancer and HPV infection. CDH1, HIC1, and RARβ genes can be used as potential biomarkers of cervical cancer risk assessment.

 

Association of folate and other one-carbon related nutrients with hypermethylation status and expression of RARB, BRCA1, and RASSF1A genes in breast cancer patients.
Hypermethylation at promoters of RARB, BRCA1, and RASSF1A is associated with reduced transcript levels of the respective gene in primary breast cancer tissue samples. Dietary folate and cobalamin intake is inversely associated with methylated RARB and BRCA1. High dietary intake of riboflavin and pyridoxine is associated with increased methylation in the RARB promoter. Expression levels of the genes were associated with the unmethylated status of related promoters (p < 0.05). The crude dietary folate and adjusted cobalamin intakes were inversely associated with methylated RARB and BRCA1. Low intake of residual folate and cobalamin was correlated with the methylated status of RARB for subjects at <48 years of age, and folate alone was linked to BRCA1 at >48 years of age.

 

Homocysteine, Thioretinaco Ozonide, and Oxidative Phosphorylation in Cancer and Aging: A Proposed Clinical Trial Protocol.

The pancreatic enzyme therapy of cancer promotes catabolism of proteins, nucleic acids, and glycosaminoglycans with excess homocysteinylated amino groups resulting from abnormal accumulation of homocysteine thiolactone in malignant cells. Dietary deficiencies of pyridoxal, folate, cobalamin, and nitriloside contribute to hyperhomocysteinemia in cancer, and in protein energy malnutrition. A deficiency of dietary sulfur amino acids downregulates cystathionine synthase, causing hyperhomocysteinemia.

 

A model of lipid dysregulation and altered nutrient status in Alzheimer's disease.
The current theoretical editorial describes, using clinical, preclinical, and in vitro evidences, how this model contributes not only to amyloidogenesis but also other nonopioid effects, specifically altered lipid metabolism, depletion of vitamin B12, and disruption of the folate-mediated one carbon metabolic pathway.

 

Association of Folate Metabolites and Mitochondrial Function in Peripheral Blood Cells in Alzheimer's Disease: A Matched Case-Control Study.
In conclusion, mitochondrial function in peripheral blood cells could be associated with risk of AD independent of multiple covariates. AD patients with a folate deficiency or hyperhomocysteinemia had low mitochondrial function in peripheral blood cells.

 

Effects of Folic Acid and Vitamin B12, Alone and in Combination on Cognitive Function and Inflammatory Factors in the Elderly with Mild Cognitive Impairment: A Single-blind Experimental Design.
The combination of oral folic acid plus vitamin B12 in MCI elderly for six months can significantly improve cognitive performance and reduce the levels of inflammatory cytokines in human peripheral blood. The combination of folic acid and vitamin B12 was significantly superior to either folic acid or vitamin B12 alone.

 

A diet rich in taurine, cysteine, folate, B12 and betaine may lessen risk for Alzheimer's disease by boosting brain synthesis of hydrogen sulfide.
Brain levels of SAM are about half as high in AD patients as in controls, and this is thought to explain the reduction of brain H2S in these patients. These considerations suggest that supplementation with cysteine, taurine, and agents which promote methyl group availability - such as SAM, folate, vitamin B12, and betaine - may have potential for boosting brain synthesis of H2S and thereby aiding AD prevention. Indeed, most of these agents have already demonstrated utility in mouse AD models - albeit the extent to which increased H2S synthesis contributes to this protection remains unclear. Moreover, prospective epidemiology has associated low dietary or plasma levels of folate, B12, and taurine with increased dementia risk.

 

Homocysteine oxidation and apoptosis: a potential cause of cleft palate.
Folate deficiency results in elevated homocysteine levels, which may disturb palatogenesis by several mechanisms, including oxidative stress and perturbation of matrix metabolism. We have demonstrated that biologically relevant levels of homocysteine in combination with copper can result in apoptosis as a result of oxidative stress; therefore, homocysteine has the potential to disrupt normal palate development.

 

Antagonism of hypervitaminosis A-induced anterior neural tube closure defects with a methyl-donor deficiency in murine whole-embryo culture.
The interaction of a dietary excess of vitamin A (retinoid) and deficiency of methyl-donor compounds was examined in murine early-organogenesis embryonic development. The six diets were either methyl-donor deficient (designated -FCM: devoid of folic acid, choline and supplemental L-methionine, but having methionine as a component of the protein portion of the diet) or methyl-donor sufficient (designated +FCM: containing folic acid, choline and L-methionine supplementation), in combination with one of three concentrations of retinyl palmitate (0.016, 0.416 or 4.016 g/kg diet). The high dose of retinyl palmitate induced a failure of anterior neuropore closure and hypoplasia of the visceral arches, both of which were significantly ameliorated by simultaneous administration of the methyl-donor-deficient diet. The primary acidic retinoid detected in the rat serum was 9,13-di-cis-retinoic acid, although we hypothesize that teratogenic retinoids were formed by embryonic biotransformation of the retinyl esters to toxic metabolites. Biochemical measurements of metabolites in relevant pathways were performed. We propose that the amelioration of these malformations may be used to determine biochemical pathways critical for retinoid teratogenesis.

 

Decreased plasma folate concentration in young and elderly healthy subjects after a short-term supplementation with isotretinoin.
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.

 

Risk Factors for Birth Defects.
There is a strong link between alcohol use, folic acid deficiency, obesity, uncontrolled maternal diabetes mellitus, uncontrolled maternal phenylketonuria, and monozygotic twins and an increased risk of congenital anomalies. Advanced maternal age confers an increased risk of aneuploidy, as well as nonchromosomal abnormalities. Some medications, including angiotensin converting enzyme inhibitors, retinoic acid, folic acid antagonists, and certain anticonvulsants, are associated with various birth defects.

 

The role of folate metabolism in orofacial development and clefting.
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.

 

Folate deficiency-induced oxidative stress contributes to neuropathy in young and aged zebrafish--implication in neural tube defects and Alzheimer's diseases.
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. 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.

 

ER-mediated anti-tumor effects of shikonin on breast cancer.
Estrogen receptor (ER) is expressed in most Breast cancer (BC) patients. G protein-coupled estrogen receptor (GPER), which is a membrane-bound estrogen receptor, is associated with the tumor development and progression in BC. Shikonin (SK) is a natural compound that is known to have anti-tumor effects. This study aims to assess the effects of shikonin on the cell proliferation, cell cycle and cell apoptosis of BC and whether the effects are related to ER/GPER signaling pathway.

 

Pharmacological Properties and Derivatives of Shikonin-A Review in Recent Years.
Shikonin is the major bioactive component extracted from the roots of Lithospermum erythrorhizon which is also known as "Zicao" in Traditional Chinese Medicine (TCM). Recent studies have shown that shikonin demonstrates various bioactivities related to the treatment of cancer, inflammation, and wound healing. This review aimed to provide an updated summary of recent studies on shikonin. Firstly, many studies have demonstrated that shikonin exerts strong anticancer effects on various types of cancer by inhibiting cell proliferation and migration, inducing apoptosis, autophagy, and necroptosis. Shikonin also triggers Reactive Oxygen Species (ROS) generation, suppressing exosome release, and activate anti-tumor immunity in multiple molecular mechanisms. Examples of these effects include modulating the PI3 K/AKT/mTOR and MAPKs signaling; inhibiting the activation of TrxR1, PKM2, RIP1/3, Src, and FAK; and regulating the expression of ERP57, MMPs, ATF2, C-MYC, miR-128, and GRP78 (Bip). Next, the anti-inflammatory and wound-healing properties of shikonin were also reviewed. Furthermore, several studies focusing on shikonin derivatives were reviewed, and these showed that, with modification to the naphthazarin ring or side chain, some shikonin derivatives display stronger anticancer activity and lower toxicity than shikonin itself. Our findings suggest that shikonin and its derivatives could serve as potential novel drug for the treatment of cancer and inflammation.

 

P53 Promotes Retinoid Acid-induced Smooth Muscle Cell Differentiation by Targeting Myocardin.
TP53 is a widely studied tumor suppressor gene that controls various cellular functions, including cell differentiation. However, little is known about its functional roles in smooth muscle cells (SMCs) differentiation from embryonic stem cells (ESCs). SMC differentiation is at the heart of our understanding of vascular development, normal blood pressure homeostasis, and the pathogenesis of vascular diseases such as atherosclerosis, hypertension, restenosis, as well as aneurysm.

 

Stra8 may inhibit apoptosis during mouse spermatogenesis via the AKT signaling pathway.
Although the mRNA expression level of P53 was decreased, there was no significant difference in the protein expression level in Stra8 overexpressing GC1 spg cells compared with controls. In addition, Caspase 3, one of the executioner caspases, was decreased in Stra8 overexpressing GC1 spg cells compared with the control groups. Therefore, it was suggested that Stra8 may directly or indirectly inhibit caspases through the AKT signaling pathway and ultimately exert an anti apoptotic effect in the male reproductive system.

 

The influence of retinoic acid-induced differentiation on the radiation response of male germline stem cells.
Interestingly, also at the protein level, undifferentiated GS [germline stem] cells showed a more pronounced upregulation of p53 in response to IR [ionizing radiation] than differentiating GS cells. The higher p53 protein level in undifferentiated spermatogonia may preferentially induce cell cycle arrest, thereby giving these cells more time to repair inflicted DNA damage and increase their radio-resistance.

 

A novel all-trans retinoic acid derivative inhibits proliferation and induces apoptosis of myelodysplastic syndromes cell line SKM-1 cells via up-regulating p53.
Myelodysplastic syndromes (MDS) are a varied set of hematologic neoplasms and a high risk of progression to acute myeloid leukemia (AML). 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, play an important role in various types of cancer cells as a tumor inhibitor. SKM-1 cells treated with ATPR unveiled elevated mRNA and protein levels of p53. However, silencing p53 suppressed the pro-apoptosis function of ATPR. Consequently, these data provide the first evidence for ATPR increased apoptosis in SKM-1 cells by p53 that is mutually dependent on and obligatorily linked to BNIP3 gene activation.

 

Inhibition of protein phosphatase PPM1D enhances retinoic acid-induced differentiation in human embryonic carcinoma cell line.
The protein phosphatase PPM1D (Wip1) was originally identified as a p53 target product. Activation of PPM1D through various mechanism promotes the tumorigenic potential of various cancers by suppressing p53 and other DNA damage response proteins. Here we report that PPM1D modulates retinoic acid (RA) signalling. PPM1D knockdown resulted in decreased alkaline phosphatase activity of the human teratocarcinoma cell line NT2/D1. RA-induced cell differentiation was promoted by reducing PPM1D activity. RA treatment elicited activation of the MEK-ERK pathway and induced rapid and transient activation of the extracellular signal-regulated kinase 1/2 (ERK-1/2).

 

Chaperone-mediated autophagy as a therapeutic target for Parkinson disease.
Chaperone mediated autophagy (CMA) is one of the key cellular mechanisms in protein homeostasis. Many of the pathogenic pathways thought to be important in PD converge on CMA, thus rendering it an attractive therapeutic target. Recent studies demonstrating the role of retinoic acid derivatives and miRNAs in regulating CMA are promising, and indirect upregulation of CMA by modulating other lysosomal pathways may be helpful.

 

Differentiation enhances Zika virus infection of neuronal brain cells.
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. Here we investigated ZIKV infectivity in neuroblastoma SH-SY5Y cells, both undifferentiated and following differentiation with retinoic acid. Differentiation with resultant expression of mature neuron markers increased infectivity in these cells, and the extent of infectivity correlated with degree of differentiation.

Inhibition of NRF2 signaling and increased reactive oxygen species during embryogenesis in a rat model of retinoic acid-induced neural tube defects.

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. These data demonstrate substantial oxidative stress and NRF2 signaling pathway disruption in a model of NTDs [neural tube defects] 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.

 

Astrocytes as a regulated source of retinoic acid for the brain.
Retinaldehyde dehydrogenases (RALDH) catalyze the synthesis of the regulatory factor retinoic acid (RA). Cultured astrocytes express several of the RALDH enzyme family, and it has been assumed that this can be extrapolated to astrocytes in vivo. However, this study finds that few astrocytes in the rodent brain express detectable RALDH enzymes, and only when these cells are grown in culture are these enzymes upregulated. Factors controlling the expression of the RALDHs in cultured astrocytes were explored to determine possible reasons for differences between in vitro versus in vivo expression. Retinoids were found to feedback to suppress several of the RALDHs, and physiological levels of retinoids may be one route by which astrocytic RALDHs are maintained at low levels. In the case of RALDH2, in vivo reduction of vitamin A levels in rats resulted in an increase in astrocyte RALDH2 expression in the hippocampus. Other factors though are likely to control RALDH expression. A shift in astrocytic RALDH subcellular localization is a potential mechanism for regulating RA signaling. Under conditions of vitamin A deficiency, RALDH2 protein` moved from the cytoplasm to the nucleus where it may synthesize RA at the site of the nuclear RA receptors. Similarly, in conditions of oxidative stress RALDH1 and RALDH2 moved from the cytoplasm to a predominantly nuclear position. Thus, the RALDHs have been revealed to be dynamic in their expression in astrocytes where they may maintain retinoid homeostasis in the brain.

 

Arsenic as an endocrine disruptor: arsenic disrupts retinoic acid receptor-and thyroid hormone receptor-mediated gene regulation and thyroid hormone-mediated amphibian tail metamorphosis.
As [arsenic] had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor-dependent processes by As is also potentially relevant to human developmental problems and disease risk.

 

The involvement of retinoic acid receptor-alpha in corticotropin-releasing hormone gene expression and affective disorders.
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. 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. 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.

 

Nuclear factor-κB regulates the expression of multiple genes encoding liver transport proteins.
In this study we identified the mechanisms underlying the inhibitory effects of NF-κB on the expression of genes encoding multiple liver transport proteins. Well-conserved NF-κB binding sites were found in the promoters of farnesoid X receptor (FXR)-target genes. There was also increased recruitment of the corepressor silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) and histone deacetylase (HDAC)3 and HDAC2 to the NF-κB sites.

 

Retinoid regulated macrophage cholesterol efflux involves the steroidogenic acute regulatory protein.
Elimination of excess cholesteryl esters from macrophage-derived foam cells is known to be a key process in limiting plaque stability and progression of atherosclerotic lesions. We have recently demonstrated that regulation of retinoid mediated cholesterol efflux is influenced by liver X receptor (LXR) signaling in mouse macrophages. The data presented in this article evaluate the importance of the steroidogenic acute regulatory protein (StAR) in retinoid mediated macrophage cholesterol efflux. Overexpression of StAR in mouse RAW 264.7 macrophages increased the effects of both all-trans retinoic acid (atRA) and 9-cis RA on cholesterol efflux, suggesting StAR enhances the efficacy of retinoic acid receptor (RAR) and/or retinoid X receptor (RXR) ligands.

 

Transcriptional control of transglutaminase 2 expression in mouse apoptotic thymocytes.
Transglutaminase 2 (TGM2) is a ubiquitously expressed multifunctional protein, which participates in various biological processes including thymocyte apoptosis. As a result, the transcriptional regulation of the gene is complex and must depend on the cell type. Previous studies from our laboratory have shown that in dying thymocytes the expression of Tgm2 is induced by external signals derived from engulfing macrophages, such as retinoids...

 

Signaling just means the chemical or electrical activation of a cell receptor, which elicits a specific response.

 

Genome-wide Analysis of RARβ Transcriptional Targets in Mouse Striatum Links Retinoic Acid Signaling with Huntington's Disease and Other Neurodegenerative Disorders. 2017 - Molecular Neurobiology
Retinoic acid (RA) signaling through retinoic acid receptors (RARs), known for its multiple developmental functions, emerged more recently as an important regulator of adult brain physiology. How RAR-mediated regulation is achieved is poorly known, partly due to the paucity of information on critical target genes in the brain. Also, it is not clear how reduced RA signaling may contribute to pathophysiology of diverse neuropsychiatric disorders. We report the first genome-wide analysis of RAR transcriptional targets in the brain. Using chromatin immunoprecipitation followed by high-throughput sequencing and transcriptomic analysis of RARβ-null mutant mice, we identified genomic targets of RARβ in the striatum. Characterization of RARβ transcriptional targets in the mouse striatum points to mechanisms through which RAR may control brain functions and display neuroprotective activity. Namely, our data indicate with statistical significance (FDR 0.1) a strong contribution of RARβ in controlling neurotransmission, energy metabolism, and transcription, with a particular involvement of G-protein coupled receptor (p = 5.0e-5), cAMP (p = 4.5e-4), and calcium signaling (p = 3.4e-3). Many identified RARβ target genes related to these pathways have been implicated in Alzheimer's, Parkinson's, and Huntington's disease (HD), raising the possibility that compromised RA signaling in the striatum may be a mechanistic link explaining the similar affective and cognitive symptoms in these diseases. The RARβ transcriptional targets were particularly enriched for transcripts affected in HD. Using the R6/2 transgenic mouse model of HD, we show that partial sequestration of RARβ in huntingtin protein aggregates may account for reduced RA signaling reported in HD.

 

Retinoic acid enhances progesterone production via the cAMP/PKA signaling pathway in immature rat granulosa cells.
Our results demonstrated that atRA enhanced progesterone production by upregulating the levels of steroidogenic acute regulatory protein (StAR) and cytochrome P450scc (Cyp11a1) mRNAs, but not 3β-hydroxysteroid dehydrogenase mRNA in immature rat GCs. Additionally, analysis of the mechanisms through which atRA upregulated StAR and Cyp11a1 mRNAs revealed that atRA enhanced intracellular cAMP accumulation and phosphorylation of cAMP response-element binding protein (CREB). In addition, H-89, an inhibitor of protein kinase A (PKA), abolished the stimulatory effects of atRA, indicating that atRA enhanced progesterone synthesis through cAMP/PKA signaling. In conclusion, our data demonstrated that atRA has a crucial role in progesterone synthesis in rat GCs during the early follicle stage.

 

Isotretinoin and Timing of Procedural Interventions: A Systematic Review With Consensus Recommendations.
Thirty-two relevant publications reported 1485 procedures. There was insufficient evidence to support delaying manual dermabrasion, superficial chemical peels, cutaneous surgery, laser hair removal, and fractional ablative and nonablative laser procedures for patients currently receiving or having recently completed isotretinoin therapy. Based on the available literature, mechanical dermabrasion and fully ablative laser are not recommended in the setting of systemic isotretinoin treatment.

 

RXR Ligands Negatively Regulate Thrombosis and Hemostasis.

This study identifies a widespread, negative regulatory role for RXR in the regulation of platelet functional responses and thrombus formation and describes novel events that lead to the upregulation of protein kinase A, a known negative regulator of many aspects of platelet function. This mechanism may offer a possible explanation for the cardioprotective effects described in vivo after treatment with RXR ligands.

 

Anti-diabetic action of all-trans retinoic acid and the orphan G protein coupled receptor GPRC5C in pancreatic β-cells.
Down-regulation of Gprc5c led to both moderately reduced glucose-stimulated insulin release and also reduced cAMP content in mouse islets. Potentiation of glucose-stimulated insulin secretion concomitant with enhanced islet cAMP level by all-trans retinoic acid (ATRA) was attenuated upon Gprc5c-KD. ATRA also increased [Ca+2]i in Huh7-cells. Gprc5c over expression in Huh7 cells was associated with increased ERK1/2 activity. Gprc5c-KD in clonal MIN6c4 cells reduced cell proliferation and in murine islets increased apoptosis and the sensitivity of primary islet cells to a cocktail of pro-apoptotic cytokines. Our results demonstrate that agents activating GPRC5C represent a novel modality for the treatment and/or prevention of diabetes by restoring and/or maintaining functional β-cell mass.

 

Epigenetic mechanisms in schizophrenia.
Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs, have been implicated in a number of complex diseases. Schizophrenia and other major psychiatric and neurodevelopmental disorders are associated with abnormalities in multiple epigenetic mechanisms, resulting in altered gene expression during development and adulthood. Polymorphisms and copy number variants in schizophrenia risk genes contribute to the high heritability of the disease, but environmental factors that lead to epigenetic modifications may either reduce or exacerbate the expression of molecular and behavioral phenotypes associated with schizophrenia and related disorders. In the present paper, we will review the current understanding of molecular dysregulation in schizophrenia, including disruption of the dopamine, NMDA, and GABA signaling pathways, and discuss the role of epigenetic factors underlying disease pathology.

 

The ultrastructure of formed white blood elements (neutrophils) in schizophrenia.
A comparative electronmicroscopic study of neutrophils in schizophrenic patients and in healthy control subjects has revealed a certain difference in the ultrastructure of blood cell formation. This difference concerns the coarse-grained chromatin, the osmiophility of nuclear membrane, the enlargement of perinuclear halo, the enlightenment of matrix, the enlargement of glycogen granules, the swelling of mitochondria, the change in the amount of free ribosomes, an increase in the number of azurophilic granules and a decrease in the specific ones.

 

Schizophrenia: an epigenetic puzzle?
Developments in molecular biology over the past three decades have led to an increasing awareness of the importance of epigenetic phenomena in a variety of genome functions. Epigenetic aspects of complex multifactorial diseases including schizophrenia, however, have not been investigated sufficiently. Various facets of epigenetics are reevaluated through their putative relevance to four theories of schizophrenia: neurodevelopmental, dopamine dysfunction, viral, and genetic anticipation with unstable DNA. The heuristic value of the epigenetic model of schizophrenia arises from the possibility of integration of a wide variety of empirical data into a new theoretical framework. It can be hypothesized that in addition to pathological effects of DNA structural mutations and environmental factors, inherited and acquired epigenetic defects, or epimutations, may be of etiological importance in schizophrenia. In addition, the epigenetic model may lead to experiments investigating the molecular substrates of genetic-environmental interactions.

 

Schizophrenia, epigenetics and ligand-activated nuclear receptors: a framework for chromatin therapeutics.
Covalent modifications of DNA and its surrounding chromatin constitute an essential and powerful regulatory mechanism for gene transcription. Epigenetics is the study of this regulatory system. There is now strong albeit indirect evidence that epigenetic mechanisms contribute to the pathophysiology of schizophrenia. Furthermore, the discovery that valproic acid, a widely used psychotropic, has powerful epigenetic effects in clinically relevant concentrations suggests new therapeutic possibilities, i.e., drugs that act on chromatin structure. Fortunately, many proteins engaged in these processes, particularly chromatin remodeling, are accessible to pharmacological agents that have a high likelihood of crossing the blood brain barrier. This review will first summarize the essentials of the epigenetic regulatory system, then address the molecular evidence for altered epigenetic mechanisms in schizophrenia, and finally focus on the retinoic acid family of ligand-activated nuclear transcription factors as a likely system for new drug development in the management of schizophrenia-related symptoms.

chro·ma·tin - A complex of nucleic acids and proteins, primarily histones, in the cell nucleus that stains readily with basic dyes and condenses to form chromosomes during cell division.

 

Regulation of multiple dopamine signal transduction molecules by retinoids in the developing striatum.
our study raises the hypothesis that retinoid signaling may coordinately activate the transcriptional program that is associated with the dopamine signaling pathway in developing striatal neurons. Using the ribonuclease protection assay, we found that both all-trans retinoic acid and 9-cis retinoic acid significantly up-regulated dopamine D1 receptor, heterotrimeric G protein olfactory, adenylyl cyclase type V and dopamine- and cyclic adenosine 3':5'-monophosphate-regulated phosphoprotein mRNAs in the lateral ganglionic eminence culture

 

Regulation of ornithine aminotransferase gene expression and activity by all-trans retinoic acid in Caco-2 intestinal epithelial cells.
We conclude that exposure of Caco-2 cells to RA induces OAT expression for increasing ornithine catabolism. This leads to a reduced availability of intracellular ornithine for polyamine synthesis, thereby decreasing cell proliferation. These novel findings indicate a functional role for OAT in regulating intestinal polyamine synthesis and growth.

 

Distinct retinoic acid receptor (RAR) isotypes control differentiation of embryonal carcinoma cells to dopaminergic or striatopallidal medium spiny neurons.
Here we show that RA treatment during EC embryoid body formation is a highly robust protocol for generation of striatal-like GABAergic neurons which display molecular characteristics of striatopallidal medium spiny neurons (MSNs), including expression of functional dopamine D2 receptor.

 

GABAA receptor subunit deregulation in the hippocampus of human foetuses with Down syndrome.
We hypothesized that increased levels of the amyloid precursor protein (APP), and particularly its neurotoxic β-amyloid (1-42) fragment, could disrupt α3 gene expression, likely by facilitating premature neuronal differentiation. Indeed, we find increased APP content in the hippocampi of the Down foetuses. In a corresponding cellular model, soluble β-amyloid (1-42) administered to cultured SH-SY5Y neuroblastoma cells, augmented by retinoic acid-induced differentiation towards a neuronal phenotype, displayed a reduction in α3 subunit levels. In sum, this study charts a comprehensive regional and subcellular map of key GABAA receptor subunits in identified neuronal populations in the hippocampus of healthy and Down syndrome foetuses and associates increased β-amyloid load with discordant down-regulation of α3 subunits.

 

Novel clinical features of glycine receptor antibody syndrome: A series of 17 cases.
Patients with a positive serum GlyRα1-IgG were identified during a 2-year period from July 2016 to December 2018 at 2 academic centers and followed prospectively. All patients in this series were evaluated in the Neuroimmunology and Autoimmune Neurology clinics at the University of Utah or the University of Colorado. Thirteen of 17 patients had phenotypes more typically associated with glutamic acid decarboxylase (GAD65) antibody syndromes, consisting of stiff-person syndrome (SPS) with parkinsonism or cerebellar signs. One patient with parkinsonism had a presentation similar to rapidly progressive multiple system atrophy with severe dysautonomia. Ten of 17 patients had various visual symptoms including visual snow, spider web-like images forming shapes and 3-dimensional images, palinopsia, photophobia, visual hallucinations, synesthesia, and intermittent diplopia. Three of 17 patients presented with primarily autoimmune epilepsy accompanied by psychiatric symptoms.

 

Stiff-person syndrome: insights into a complex autoimmune disorder.
Stiff-person syndrome (SPS) is characterised by progressive rigidity and muscle spasms affecting the axial and limb muscles. Since its initial description in 1956, marked progress has been made in the clinical characterisation, understanding of pathogenesis and therapy of this disorder. SPS can be classified according to the clinical presentation into classic SPS and SPS variants: focal or segmental-SPS, jerking-SPS and progressive encephalomyelitis with rigidity and myoclonus. Most patients with SPS have antibodies directed against the glutamic acid decarboxylase, the rate-limiting enzyme for the production of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Antibodies directed against GABA(A) receptor-associated protein, and the glycine-α1 receptor can also be observed. Paraneoplastic SPS is commonly associated with antiamphiphysin antibodies and breast cancer. Treatment of SPS with drugs that increase the GABAergic tone combined with immunotherapy can improve the neurological manifestations of these patients. The prognosis, however, is unpredictable and spontaneous remissions are unlikely.

 

Treatment and Resolution of Filamentary Keratitis in a Patient with Stiff Person Syndrome.
A 26-year-old woman with several autoimmune conditions was referred because of filamentary keratitis. Conservative management using lubrication, mucolytics, and bandage contact lenses failed to adequately relieve symptoms. Despite the addition of oral prednisone, cyclosporine, and azathioprine, the patient's condition persisted with numerous filaments and severe dry eye. One month later, the patient had an episode of sudden muscle cramps in her back, for which she was hospitalized. Investigations revealed a diagnosis of stiff person syndrome, positive for glutamic acid decarboxylase autoantibodies. Plasmapheresis and high-dose intravenous steroids were provided as initial therapy. On follow-up, her filamentary keratitis resolved and at the last visit, her ocular symptoms had completely resolved.

 

 

 

 

 

 

Quote from hillcountry on January 7, 2020, 9:14 am

here's a few more odds and ends

 

all-trans retinoic acid modulates gene expression through a redox mechanism … since the effects seen were blocked by an antioxidant that is analogue to α-tocopherol. However, it was not analyzed in that work whether retinoic acid altered redox environment parameters, as for instance by inducting oxidative damage or increasing the rates of reactive species.

 

Therefore, vitamin A is favoring an increase in H₂O₂ production that may lead to hydroxyl radical (OH) formation

 

increased Mn-SOD (manganese SOD - the mitochondrial SOD) enzyme activity, as well as MAO enzyme activity was observed increased. These two enzymes differ in location (Mn-SOD is a mitochondrial matrix enzyme, and MAO is located at the outer mitochondrial membrane), but both produce H₂O₂ during the reaction of dismutation of O₂ ^-• and degradation of dopamine, respectively (^{Halliwell 2006}, ^{Edmondson 2014}). Then, mitochondria seem to be a potential source of H₂O₂ in the case of increased vitamin A intake as a supplement.

 

(hc - Lima Beans are a manganese-rich food and low-oxalate to boot)

 

Thereby, vitamin A affects neuronal redox status not by directly inducing the production of O₂ ^-•, for example, but also through increasing the consumption and consequent excretion of GSH, weakening the antioxidant power of cells.

 

vitamin A intake increased mitochondrial O₂ ^-• production in different rat tissues including brain

 

increased access to retinoids may lead to an increased expression of nNOS and augmented rates of NO production, which favors increased production of peroxynitrite (ONOO^-), a reactive specie that give rise to nitryl cation (NO₂ ⁺⁾, nitrogen diozide radical (•NO₂), and hydroxyl radical (•OH) through a reaction called homolytic fission

 

In cerebral cortex and cerebellum, retinol palmitate supplementation at clinical doses (1,000 to 9,000 IU/kg.day^-1) for 3, 7, or 28 days induced oxidative stress and mitochondrial dysfunction, as assessed through quantification of lipid peroxidation, protein carbonylation, and oxidation of protein thiol groups

 

Vitamin A supplementation also affected the levels of one of the most important neurotrophins in the mammalian brain experimentally. It was reported that retinol palmitate supplementation (1,000 to 9,000 IU/day^-1) for 28 days decreased brain-derived neurotrophic factor (BDNF) in the rat hippocampus (^{De Oliveira et al. 2011a}). BDNF regulates neuronal plasticity, bioenergetics, mitochondrial biogenesis, and neuronal survival, to cite a few

 

By decreasing BDNF levels, vitamin A impairs not only neuronal plasticity that is necessary to the learning and memory processes, but also the ability of this organelle to produce adequate amounts of ATP needed to counteract acute and chronic stress

 

Recently, it was suggested that mefloquine (a drug used to prevent and treat malaria) may elicit its deleterious effects by altering the concentrations of retinoids in circulation, leading to cognitive disturbances, as for example, anxiety, depression, psychosis, and violence (^{Mawson 2013}). A better link goes to the whole paper = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718722/

The author suggests that mefloquine would be able to impair retinoid metabolism in liver, causing posterior spillage of retinoids from liver to blood at toxic concentrations.

 

Furthermore, retinol and retinoids possess antioxidant ability, since such effects have been demonstrated in different experimental models. However, it is mainly an issue of dosage. Depending on retinoid concentration, but also other factors, as for instance age, gender, and some nutritional parameters, as well as exposition to environmental toxicants, retinoids may favor a pro-oxidant state and cell damage with consequent increased rates of cell death and inflammation. Some of the effects discussed here are summarized in Figure 1.

 

Disturbances related to nervous functions also appear on the list of side effects resulting from excessive vitamin A intake, as for instance confusion, irritability, anxiety, depression, and suicide ideation (^{Snodgrass 1992}). such central effects are more commonly observed after chronic vitamin A exposition.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155722/

Here, we provide evidence that grape skin and grape seed extracts increase the inhibition effect on Aβ aggregation. However, after intravenous injection, resveratrol is rapidly metabolized into both glucuronic acid and sulfate conjugations of the phenolic groups in the liver and intestinal epithelial cells (within less than 2 h), which are then eliminated.

 

Berry et al. claimed that STRA6 binds only holo-retinol/retinol binding protein complex (holo-RBP), not apo-RBP, and that holo-RBP's binding to STRA6 causes insulin resistance (1). These claims are exactly the opposite of the conclusions from two studies in Molecular and Cellular Biology by independent groups who showed that RBP's effect on insulin resistance does not depend on STRA6 and that apo-RBP triggers insulin resistance (2, 3). Contrary to the claim by Berry et al., obesity is associated with significantly higher apo-RBP, but normal holo-RBP (4), and that the RBP-to-retinol ratio is elevated in patients with type 2 diabetes (5).

Quote from lil chick on January 8, 2020, 8:41 am

Thank you @hillcountry.  The snippet about the stiff-person syndrome is very sobering to me, given that I just came off of exactly what is written here:  "sudden muscle cramps in the back".  I see this in my family a lot.

And isn't this what happens to almost every person in old age?  Stiffening?  Is this because so many of us eventually end up high VA?  And for young people to be getting stiff-person syndrome, shouldn't they be afraid that something is very wrong with the world?

I do see stiffening of the ligements as being a real, and scary VA toxicity thing.  I think ligaments shorten too, not just stiffen (see photo at bottom.  No amount of stretching will straighten those pinkies.).   I would not be suprised to find that this is what gout is about as well.   Interesting what fixed her:  steroids and plasmapheresis.

definition:  plasmapheresis:  a method of removing blood plasma from the body by withdrawing blood, separating it into plasma and cells, and transfusing the cells back into the bloodstream. It is performed especially to remove antibodies in treating autoimmune conditions.

I wonder, would plasmapheresis get rid of circulating VA?  I also see that almost all of the idiopathic/mysterious diseases in my family tree are given steroids and that they do seem to help.  Grant used steroids on his hands though and did find that where he used it, there seems to be some sort of price that you pay?  Healing-wise?  In alternative writings, I've heard steroids called  the sleaziest of medicines.  Of course, they do relieve suffering in the short term, though.

cut from prior post: 

Treatment and Resolution of Filamentary Keratitis in a Patient with Stiff Person Syndrome.
A 26-year-old woman with several autoimmune conditions was referred because of filamentary keratitis. Conservative management using lubrication, mucolytics, and bandage contact lenses failed to adequately relieve symptoms. Despite the addition of oral prednisone, cyclosporine, and azathioprine, the patient's condition persisted with numerous filaments and severe dry eye. One month later, the patient had an episode of sudden muscle cramps in her back, for which she was hospitalized. Investigations revealed a diagnosis of stiff person syndrome, positive for glutamic acid decarboxylase autoantibodies. Plasmapheresis and high-dose intravenous steroids were provided as initial therapy. On follow-up, her filamentary keratitis resolved and at the last visit, her ocular symptoms had completely resolved.

 

Quote from hillcountry on January 8, 2020, 2:21 pm

Yes, it's really sobering to consider all of the things these molecules can do. The ligament side of it is worth exploring. We're pretty sure about what it can do to bones, so the same is likely true for the connective tissues. Grant has probably itemized this somewhere, maybe in the list of symptoms from the Wolbach-Howe studies. (btw - we just had a litter of mice born here. Can't wait until spring to let them free romp in the woods. Their running-wheel is a bit noisy at night, but it's nothing compared to two Irish Setters above us, Ha!!)

Plasmapheresis has an extensive literature. I'd bet there are cumulative benefits if one needs to get some of the trash out that way, over time, including VA. I wonder about the inflammatory signaling molecules, how much they float around and if they'd get scooped-up in the same operation to some positive effect. 

I watched a couple of Dr. Ron Rosedale videos yesterday and it sent me off into looking at the connections between leptin and retinol. Sure enough, a minefield of info there. Doing those combinational searches seems to yield studies one might not run across otherwise. 

Here's an alternative take on Uric Acid and Gout you might find interesting. Amber O'Hearn eats carnivore. 

https://www.youtube.com/watch?v=lnKdvwngRdM

Quote from lil chick on January 9, 2020, 7:28 am

Interesting talk! 

Regarding gout, it could be that what I have been calling gout in myself is not actually gout but just shortened ligaments, and the fact that it has affected one big toe just make me THINK of gout.    Of course, there could be an intersection there between the shortened ligaments and the formation of crystals.  My stiff toe has never "blown up".

She has a unique style, but I'd wear that!   Which makes me think we have similar architecture. 

One of my favorite musings is that body style is another clue to your ancestral diet.