The role of thiamine in nervous tissue

The possibility that thiamine (vitamin B₁) has a role in nervous tissue that is independent of its well-documented coenzyme function is discussed. After reviewing the localization and metabolism of the vitamin and its phosphate esters, the effects of either thiamine deprivation or antimetabolites of thiamine on conduction and transmission, and the relationship between thiamine triphosphate and the genetic, neurological disease, subacute necrotizing encephalomyelopathy (Leigh's disease), it is suggested that despite the lack of hard evidence, it is likely that the vitamin possesses this alternate function.     

Synthesis,physico-chemical properties and effect of adenosine thiamine triphosphate on vitamin B1 metabolism in the liver of alloxan diabetic rats

BackgroundAdenosine thiamine triphosphate (AThTP) is a nucleotide discovered in bacteria and some other living organisms more than a decade ago. No biochemical function for AThTP has been established yet, however, experimental data available indicate its possible involvement in metabolic regulation or cell signaling. Metabolism of AThTP in mammals, as well as the feasibility of its pharmacological application, is essentially unstudied.MethodsPreparative low-pressure chromatography was employed to purify chemically synthesized AThTP with its further analysis by mass spectrometry, HPLC, UV and fluorescence spectroscopy. Enzyme activity assays along with HPLC were used to examine the effects of AThTP and thiamine on vitamin B₁ metabolism in the liver of alloxan-induced diabetic rats.ResultsAn improved procedure for AThTP synthesis and purification is elaborated. Solution stability, optical spectral properties and the molar absorption coefficient for AThTP were determined. The levels of thiamine compounds were found to be increased in the liver of diabetic rats. Neither AThTP nor thiamine treatment affected hepatic vitamin B₁ metabolism. Fasting blood glucose concentration was also unchangeable after AThTP or thiamine administration.General significanceContrast to the widespread view about thiamine deficiency in diabetes, our results clearly shows an adaptive increase in the level of B₁ vitamers in the liver of alloxan diabetic rats with no further rising after AThTP or thiamine treatment at a moderate dose. Neither AThTP nor thiamine is effective in glycaemic control. These findings are to be considered in future studies dealing with thiamine or its analogues application to correct metabolic disturbances in diabetes.     

Thiamine in plants: Aspects of its metabolism and functions

Thiamine diphosphate (vitamin B₁) plays a fundamental role as an enzymatic cofactor in universal metabolic pathways including glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. In addition, thiamine diphosphate has recently been shown to have functions other than as a cofactor in response to abiotic and biotic stress in plants. Recently, several steps of the plant thiamine biosynthetic pathway have been characterized, and a mechanism of feedback regulation of thiamine biosynthesis via riboswitch has been unraveled. This review focuses on these most recent advances made in our understanding of thiamine metabolism and functions in plants. Phenotypes of plant mutants affected in thiamine biosynthesis are described, and genomics, proteomics, and metabolomics data that have increased further our knowledge of plant thiamine metabolic pathways and functions are summarized. Aspects of thiamine metabolism such as catabolism, salvage, and transport in plants are discussed.     

RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew-Wood syndrome

The cellular uptake of vitamin A from its RBP4-bound circulating form (holo-RBP4) is a homeostatic process that evidently depends on the multidomain membrane protein STRA6. In humans, mutations in STRA6 are associated with Matthew-Wood syndrome, manifested by multisystem developmental malformations. Here we addressed the metabolic basis of this inherited disease. STRA6-dependent transfer of retinol from RBP4 into cultured NIH 3T3 fibroblasts was enhanced by lecithin:retinol acyltransferase (LRAT). The retinol transfer was bidirectional, strongly suggesting that STRA6 acts as a retinol channel/transporter. Loss-of-function analysis in zebrafish embryos revealed that Stra6 deficiency caused vitamin A deprivation of the developing eyes. We provide evidence that, in the absence of Stra6, holo-Rbp4 provokes nonspecific vitamin A excess in several embryonic tissues, impairing retinoic acid receptor signaling and gene regulation. These fatal consequences of Stra6 deficiency, including craniofacial and cardiac defects and microphthalmia, were largely alleviated by reducing embryonic Rbp4 levels by morpholino oligonucleotide or pharmacological treatments.     

Optical Characteristics of Thiamine in Model Systems and in Holoenzyme

The optical properties of thiamine diphosphate-dependent enzymes change significantly on their interaction with cofactors (thiamine, bivalent metal ions) and substrates. These changes are connected with structural alterations of the active site and the mechanism of its functioning, and in some cases they reflect changes in the optical properties of the coenzyme itself within the protein. The use of optical characteristics, especially together with model systems, appeared to be a rather promising approach for investigation of the active site of thiamine diphosphate-dependent enzymes and the mechanism of its functioning. So, it seemed to be useful to summarize the literature data concerning the optical characteristics of thiamine (thiamine diphosphate) in model systems and the efficiency of their application for study of thiamine diphosphate-dependent enzymes.     

Non-coenzyme role of vitamin B1 in RANKL-induced osteoclastogenesis and ovariectomy induced osteoporosis

Vitamins B are co-enzymes participating in energy metabolic pathways. While some vitamins B are known affecting bone homeostasis, the effects of vitamin B1 (thiamine) on bone health remains unclear. In our study, we used cell counting kit-8, tartrate-resistant acid phosphatase stain, actin cytoskeleton stain, and pit formation assay to evaluate the effect of thiamine on osteoclast differentiation, formation, and function, respectively. Then we used dichloro-dihydro-fluorescein diacetate assay to investigate reactive oxygen species (ROS) generation and removal. Osteoporosis model by ovariectomy was established for animal experiments. We found that thiamine had inhibitory effect on osteoclast differentiation. And its inhibitory role on osteoclast differentiation is in a dose-dependent way. Mechanistically, ThDP suppresses intracellular ROS accumulation and unfolded protein response signaling during osteoclastogenesis via inhibiting Rac-Nox1/2/4 and intracellular inositol-requiring protein-1α/X-box-binding protein pathways, respectively. Osteoporotic mice treated with thiamine rich dietary showed better bone strength relative to thiamine deficient dietary. Our study explored the non-coenzyme inhibitory functions of B1 vitamin in receptor activator of nuclear factor κB ligand induced osteoclastogenesis and uncovered the significance of B1 vitamin in bone health.     

Pathological consequences of copper deficiency and cobalt deficiency

Aspects of the pathology of copper deficiency in several species, and cobalt deficiency in sheep, are summarized. An attempt is made to interpret morphological changes in copper-deficient animals in terms of biochemical defects. The common denominator may be mitochondrial lesions, with a generalized effect on energy-dependent synthetic functions of the cell. In copper deficiency, such defects can be attributed to depletion of copper-dependent enzymes, while deficiency of cobalt in ruminants is, in effect, deficiency of vitamin B12. The pathological consequences of vitamin B12 deficiency form a syndrome, notable features of which are neurological and muscular lesions, in which the metabolic consequences of hepatic damage may play a significant role.     

Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways

The B vitamins are water-soluble vitamins that are required as coenzymes for reactions essential for cellular function. This review focuses on the essential role of vitamins in maintaining the one-carbon transfer cycles. Folate and choline are believed to be central methyl donors required for mitochondrial protein and nucleic acid synthesis through their active forms, 5-methyltetrahydrofolate and betaine, respectively. Cobalamin (B12) may assist methyltetrahydrofolate in the synthesis of methionine, a cysteine source for glutathione biosynthesis. Pyridoxal, pyridoxine and pyridoxamine (B6) seem to be involved in the regeneration of tetrahydrofolate into the active methyl-bearing form and in glutathione biosynthesis from homocysteine. Other roles of these vitamins that are relevant to mitochondrial functions will also be discussed. However these roles for B vitamins in cell function are mostly theoretically based and still require verification at the cellular level. For instance it is still not known what B vitamins are depleted by xenobiotic toxins or which cellular targets, metabolic pathways or molecular toxic mechanisms are prevented by B vitamins. This review covers the current state of knowledge and suggests where this research field is heading so as to better understand the role vitamin Bs play in cellular function and intermediary metabolism as well as molecular, cellular and clinical consequences of vitamin deficiency. The current experimental and clinical evidence that supplementation alleviates deficiency symptoms as well as the effectiveness of vitamins as antioxidants will also be reviewed.     

Vitamin D in fetal brain development

In this review we will provide a concise summary of the evidence implicating a role for vitamin D in the developing brain. Vitamin D is known to affect a diverse array of cellular functions. Over the past 10 years data has emerged implicating numerous ways in which this vitamin could also affect the developing brain including its effects on cell differentiation, neurotrophic factor expression, cytokine regulation, neurotransmitter synthesis, intracellular calcium signaling, anti-oxidant activity, and the expression of genes/proteins involved in neuronal differentiation, structure and metabolism. Dysfunction in any of these processes could adversely affect development. Although there are many ways to study the effects of vitamin D on the developing CNS in vivo, we will concentrate on one experimental model that has examined the impact of the dietary absence of vitamin D in utero. Finally, we discuss the epidemiological data that suggests that vitamin D deficiency either in utero or in early life may have adverse neuropsychiatric implications.     

Regional Reductions of Transketolase in Thiamine-Deficient Rat Brain

Abstract: Thiamine deficiency impairs oxidative metabolism and causes metabolic encephalopathy. An early reduction in transketolase (TK) activity may be an important pathogenic event. To assess the role of TK, we have delineated the regional/cellular distribution of TK protein and mRNA in adult rat brain in pyrithiamine-induced thiamine deficiency. TK activity declined in both vulnerable and spared regions. Immunoblots showed a parallel reduction of TK protein. With a few exceptions, immunocytochemistry indicated an overall decline of TK immunoreactivity and the decrease was not specific to vulnerable areas. In contrast to the pronounced, general decline of TK protein, in situ hybridization revealed a regional decrease of 0–25% of TK mRNA in thiamine deficiency. Northern blots indicated a similar level of TK mRNA in whole brain in thiamine deficiency. These results show that the decline of TK activity results from a proportional decrease of TK protein, and the deficiency may be due to an instability of TK protein or an inhibition of TK mRNA translation. The lack of correlation of the distribution, and the absence of specific alteration, of TK in affected regions suggest that the reduced TK may not be linked directly to selective vulnerability in thiamine deficiency.     

Noncoenzyme function of vitamin PP and its biologically active derivatives: the current state of the problem

This review is devoted to the current state of investigations of vitamin PP and nicotinamide dinucleotides noncoenzyme functions. Particular attention has been focused on the role of these compounds in post-translation modification of proteins (mono- and poly-ADP-ribosylation), in regulation of gene activity, calcium homeostasis and Ca2+ signalling as well as in modulation of synaptic transmission. Biological significance of these processes in cell function was elicited. The role of deregulation of vitamin PP mediated signalling mechanisms involved in control over the cell function under conditions of different diseases was emphasized.     

Vitamin B1: Metabolism and functions

The review highlights metabolism and biological functions of vitamin B 1 (thiamine). It considers thiamine transport systems in various organisms enzymes of its biosynthesis and degradation, as well as molecular basis of thiamine-dependent hereditary pathologies. A special attention is paid to discussion of the role of thiamine triphosphate and adenylated thiamine triphosphate, a new thiamine derivative recently discovered in living cells.     

Vitamin requirement study techniques

Vitamin requirement studies have been conducted for 50 years using growth and clinical signs of deficiency for quantitative studies. Histological confirmation of apparent signs confirm and establish subclinical measurements for deficiency. Test diets for these studies with positive experimental control over the test vitamin have been developed using varying degrees of vitamin-free ingredients in the formulations. Haematology values and microanatomical changes reflect failures of a metabolic system and provide convincing data for requirements. Quantitative studies have used specific test diets plus increasing aliquots of the test vitamin, coupled with growth response, tissue storage analysis, and specific enzyme system activity. Results have been reported for levels which support normal growth, clinical enzyme saturation, and maximum liver or other tissue storage levels. Megavitamin intake studies have been correlated with improved resistance to stress and certain fish diseases. Statistical measurement of response to various parameters used become essential for quantitative vitamin requirement determinations. Early studies using vitamin analysis of feedstuffs mixtures coupled with growth response, absence of deficiency signs, and liver or tissue storage have been superseded by diets with more positive control of all nutrients, including the vitamin to be tested. Sparing effects of one vitamin upon another can be demonstrated. Various vitamer forms may have different activity to supply physiological requirements for the vitamin. Most water-soluble vitamins act as co-enzymes in metabolic systems. Some fat-soluble vitamins have molecular functions acting as hormones, free radical traps, intracellular reducing agents, pigments, antioxidants, etc. A guide for vitamin requirements or dietary allowances should be followed when research plans are made to conduct vitamin requirement studies.     

Increased muricide and decreased avoidance and discrimination learning in thiamine deficient rats.

This study assessed the effects of diet-induced thiamine deficiency in rats on two aspects of behavior, aggression and learning. Evidence of enhanced aggression (increased mouse killing) was noted with severe thiamine deficiency, but before the onset of overt neurological signs of thiamine deprivation. This behavioral change was rapidly reversible with thiamine. A similar degree of thiamine deficiency failed to alter learning of two-way shuttle-box avoidance acquisition. Animals with a gross neurological deficit did exhibit a major impairment in shuttle-box performance, but this was probably due to ataxia. However, when such rats were administered thiamine with total reversal of the neurological signs, testing in a three chambered Y-maze avoidance-discrimination apparatus also revealed impaired learning of both responses. These data demonstrate the presence of enhanced aggression during thiamine deprivation and of a persistent learning impairment in rats following reversal of this vitamin deficiency.     

Vitamin E: underestimated as an antioxidant

Some 80 years after its discovery, vitamin E has experienced a renaissance which is as surprising as it is trivial. Although vitamin E is essential for reproduction, in rats at least, and deficiency causes neurological disorders in humans, the main interest in the last decades has concentrated on its antioxidant functions. This focus has highly underestimated the biological importance of vitamin E, which by far exceeds the need for acting as a radical scavenger. Only recently has it become clear that vitamin E can regulate cellular signaling and gene expression. Out of the eight different tocols included in the term vitamin E, alpha-tocopherol often exerts specific functions, which is also reflected in its selective recognition by proteins such as the alpha-tocopherol transfer protein and alpha-tocopherol-associated proteins. Vitamin E forms other than alpha-tocopherol are very actively metabolised, which explains their low biopotency. In vivo, metabolism may also attenuate the novel functions of gamma-tocopherol and tocotrienols observed in vitro. On the other hand, metabolites derived from individual forms of vitamin E have been shown to exert effects by themselves. This article focuses on the metabolism and novel functions of vitamin E with special emphasis on differential biological activities of individual vitamin E forms.     

The effect of thiamine deficiency on the turnover of lactate dehydrogenase in mouse tissues

• 1.1. Groups of mice were subjected to different degrees of thiamine deprivation in their diet. In particular, the effects of complete thiamine deficiency and a continuation of minimal nutritional levels of thiamine were compared.
• 2.2. The effects of these treatments on the turnover characteristics of lactate dehydrogenase and total soluble protein have been studied by means of double labelling experiments, and determinations of the relative emphases of synthesis and degradation of these tissue components.
• 3.3. Marked divergences from normal were apparent with each of these nutritional regimens-complete thiamine deficiency causing a considerably increased rate of degradation for both total protein and lactate dehydrogenase in all tissues; whereas maintenance of minimal levels of thiamine led to increased degradation of total protein in liver, but reduced rates of degradation for lactate dehydrogenase in brain, heart and liver.
• 4.4. The significance of these results has been discussed in relation to the relative influence of vitamin and calorie deficiencies on turnover parameters, the individuality of specific tissue behaviour, differences in protein redistribution in response to separate physiological perturbations, and the role of thiamine in specific proteolysis.

     

Role of oxygen in the vital activity of aerobic organisms]

New experimental data that underlie construction of an adaptive-metabolic conception as to curative effect of hyperbaric oxygenation are systematized in the aspect of evolution. Oxygen under high pressure (300 kPa, 60 min) exerts a specific effect on functions of redox and antiredox systems and nonspecific effect determining adaptation mechanisms of functional (regulatory, effector), metabolic (bioenergy, detoxication, biosynthetic) and morphogenetic (cellular and intracellular regeneration) types at different (hyper-, normo- and hypobiotic) levels of vital activity as dependent on the metabolic activity of the functional structures under pathology conditions.     

Defects in pyruvate kinase cause a conditional increase of thiamine synthesis in Salmonella typhimurium.

As genomic sequence data become more prevalent, the challenges in microbial physiology shift from identifying biochemical pathways to understanding the interactions that occur between them to create a robust but responsive metabolism. One of the most powerful methods to identify such interactions is in vivo phenotypic analysis. We have utilized thiamine synthesis as a model to detect subtle metabolic interactions due to the sensitivity allowed by the small cellular requirement for this vitamin. Although purine biosynthesis produces an intermediate in thiamine synthesis, mutants blocked in the first step of de novo purine biosynthesis (PurF) are able to grow in the absence of thiamine owing to an alternative synthesis. A number of general metabolic defects have been found to prevent PurF-independent thiamine synthesis. Here we report stimulation of thiamine-independent growth caused by a mutation in one or both genes encoding the pyruvate kinase isozymes. The results presented herein represent the first phenotype described for mutants defective in pykA or pykF, and thus identify metabolic interactions that exist in vivo.     

Chronic alcoholism in rats induces a compensatory response, preserving brain thiamine diphosphate, but the brain 2-oxo acid dehydrogenases are inactivated despite unchanged coenzyme levels

Thiamine-dependent changes in alcoholic brain were studied using a rat model. Brain thiamine and its mono- and diphosphates were not reduced after 20 weeks of alcohol exposure. However, alcoholism increased both synaptosomal thiamine uptake and thiamine diphosphate synthesis in brain, pointing to mechanisms preserving thiamine diphosphate in the alcoholic brain. In spite of the unchanged level of the coenzyme thiamine diphosphate, activities of the mitochondrial 2-oxoglutarate and pyruvate dehydrogenase complexes decreased in alcoholic brain. The inactivation of pyruvate dehydrogenase complex was caused by its increased phosphorylation. The inactivation of 2-oxoglutarate dehydrogenase complex (OGDHC) correlated with a decrease in free thiols resulting from an elevation of reactive oxygen species. Abstinence from alcohol following exposure to alcohol reactivated OGDHC along with restoration of the free thiol content. However, restoration of enzyme activity occurred before normalization of reactive oxygen species levels. Hence, the redox status of cellular thiols mediates the action of oxidative stress on OGDHC in alcoholic brain. As a result, upon chronic alcohol consumption, physiological mechanisms to counteract the thiamine deficiency and silence pyruvate dehydrogenase are activated in rat brain, whereas OGDHC is inactivated due to impaired antioxidant ability.     

JNK1 is inactivated during thiamine deficiency-induced apoptosis in human neuroblastoma cells

Thiamine deficiency results in selective neuronal damage. A number of mechanisms have been proposed to account for brain damage associated with thiamine deficiency and to account for the focal nature of the loss of neurons. One proposed mechanism is programmed cell death. We found efficient induction of apoptosis in human neuroblastoma cells when the cells were deprived of thiamine. Although extensive mitochondrial damage was seen, the release of cytochrome c was not the triggering mechanism for thiamine deficiency-induced apoptosis. Instead, the activity of the cJun amino terminal kinase Jnk1 was lost, and this loss correlated temporally with induction of apoptosis. The loss was specific for Jnk1; Jnk2/3 activity remained unchanged. Loss of Jnk1 activity was not found in lymphoblasts, a cell type that did not undergo apoptosis when deprived of thiamine. These findings suggest that thiamine deficiency results in a cellular stress that brings about the loss of Jnk1 activity and the loss of its function of protecting cells from programmed cell death. We postulate that focal sensitivity to thiamine deficiency results, in part, from specific neuronal cell types being susceptible to the inactivation of Jnk1 in response to depletion of cellular thiamine.