Notes

Breakdown of your Particular Section: Detail Educating: Findings as well as Programs.
Major organ systems affected include the blood, bone marrow and nervous system. Megaloblastic anemia results from a defect in thymidine and therefore DNA synthesis in rapidly dividing cells. Nervous system involvement is varied, some of which results from defective myelin synthesis and repair. Cognitive impairment and psychosis may also occur. Diagnosis of B12 deficiency rests on clinical suspicion followed by laboratory testing, which consists of a panel of tests, that together provide clinically reliable predictive indices. B12 metabolism and deficiency is closely intertwined with folate, another B-vitamin. This chapter explores the various aspects of a unique and fascinating micronutrient.Our understanding of brain biology and function is one of the least characterized and therefore, there are no effective treatments for most of neurological disorders. The influence of vitamins, and particularly vitamin B12, in neurodegenerative disease is demonstrated but largely unresolved. Behaviors are often quantified to attest brain dysfunction alone or in parallel with neuro-imaging to identify regions involved. Nevertheless, attention should be paid to extending observations made in animal models to humans, since, first, behavioral tests have to be adjusted in each model to address the initial question and second, because brain analysis should not be conducted for a whole organ but rather to specific sub-structures to better define function. Indeed, cognitive functions such as psychiatric disorders and learning and memory are often cited as the most impacted by a vitamin B12 deficiency. In addition, differential dysfunctions and mechanisms could be defined according sub-populations and ages. Vitamin B12 enters the cell bound to Transcobalamin, through the Transcobalamin Receptor and serves in two cell compartments, the lipid metabolism in the mitochondrion and the one-carbon metabolism involved in methylation reactions. Dysfunctions in these mechanisms can lead to two majors outcomes; axons demyelinisation and upregulation of cellular stress involving mislocalization of RNA binding proteins such as the ELAVL1/HuR or the dysregulation of pro- or anti-oxidant NUDT15, TXNRD1, VPO1 and ROC genes. Finally, it appears that apart from developmental problems that have to be identified and treated as early as possible, other therapeutic approaches for behavioral dysfunctions should investigate cellular methylation, oxidative and endoplasmic reticulum stress and mitochondrial function.Cobalamin (vitamin B12) is required for activity of the enzymes methylmalonyl-CoA mutase and methionine synthase in human cells. Inborn errors affecting cobalamin uptake or metabolism are characterized by accumulation of the substrates for these enzymes, methylmalonic acid and homocysteine, in blood and urine. Inborn errors affecting synthesis of the adenosylcobalamin coenzyme required by methylmalonyl-CoA mutase (cblA and cblB) result in isolated methylmalonic aciduria; inborn errors affecting synthesis of the methylcobalamin coenzyme required by methionine synthase (cblE and cblG) result in isolated homocystinuria. Combined methylmalonic aciduria and homocystinuria is seen in patients with impaired intestinal cobalamin absorption (intrinsic factor deficiency, Imerslund-Gräsbeck syndrome) and with defects affecting synthesis of both cobalamin coenzymes (cblC, cblD, cblF and cblJ). A series of disorders caused by pathogenic variant mutations affecting gene regulators (transcription factors) of the MMACHC gene have recently been described (HCFC1 [cblX disorder] and deficiencies of THAP11, and ZNF143 [the cblK disorder]).Chronic Kidney Disease (CKD) is an emerging public health issue with a fast-growing global prevalence. Impairment in vitamin B12 metabolism is considered a nontraditional risk factor of poor outcomes associated with CKD, and there is greater interest from the scientific community than ever before to explore the role and influence of vitamin B12 in CKD. Homocysteine metabolism forms an important component of the vitamin B12 metabolic pathway. Hyperhomocysteinemia is frequently observed in CKD and End-Stage Kidney Disease (ESKD), but its representation as a prognostic marker for CKD outcomes is still not fully clear. This chapter reviews the vitamin B12 and homocysteine metabolic pathways and their dysfunction in CKD states. Biochemical factors and the MTHFR genetic polymorphisms which disrupt vitamin B12 and homocysteine metabolism are explored. The mechanisms of homocysteine-mediated and vitamin B12-mediated tissue damage in CKD are discussed. This chapter reviews current perspective on definition and measurement of plasma vitamin B12 levels in the CKD population. Updated evidence investigating the prognostic role of vitamin B12 for CKD outcomes is presented. Findings from major clinical trials conducted relating to outcomes from multivitamin (including folic acid and vitamin B12) supplementation in nondialysis and dialysis-dependent CKD are highlighted. The prognostic value of vitamin B12 and effects of vitamin B12 supplementation in the context of kidney transplantation and acute kidney injury is also reviewed. Future research considerations are summarized based on evidence gaps in our knowledge base of this topic. Greater abundance of high-level evidence to guide an approach toward vitamin B12 measurement, monitoring and supplementation in CKD may contribute to improved clinical outcomes.Telomeres are non-coding nucleoprotein structures consisting of a highly conserved tandem repeat DNA sequence that caps the ends of chromosomes in eukaryotes. PF-07265807 cost Telomeres confer chromosomal stability, protect the genome from nucleolytic degradation, avoid aberrant recombination and improper repair, and prevent random fusion of chromosomes. The end-replication problem results in telomere shortening with every cell division, eventually leading to cellular senescence and aging. Telomere length (TL) is thereby an ideal candidate for "biological aging." Telomeres possess guanine-rich repeats, which are highly susceptible to oxidative stress. Epidemiological studies have indicated the association of telomere attrition with mortality and various age-related diseases. Micronutrients comprising vitamins and minerals act as potential modulators of stress and can influence TL. Research has indicated that vitamin B12 (B12) regulates oxidative stress and maintains genomic stability, thereby influencing telomere integrity and cellular aging. The deficiency of B12 leads to elevated levels of homocysteine, which reduces the methylation potential and increases oxidative stress, thereby compromising the TL. Telomere shortening and mitochondrial dysfunction are independently linked to aging. However, they are connected through telomerase reverse transcriptase activity, which regulates mitochondrial biogenesis. Further, experimental evidence indicated the positive association of B12 with relative TL and mitochondrial DNA copy number, an indirect index of mitochondrial biogenesis. The present chapter provides some insights into the role of B12 in influencing TL. Exploring their association might open new avenues to understand the pathophysiology of aging and age-related diseases.Vitamin B12 (cobalamin, Cbl, B12) is a water-soluble micronutrient synthesized exclusively by a group of microorganisms. Human beings are unable to make B12 and thus obtain the vitamin via intake of animal products, fermented plant-based foods or supplements. Vitamin B12 obtained from the diet comprises three major chemical forms, namely hydroxocobalamin (HOCbl), methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). The most common form of B12 present in supplements is cyanocobalamin (CNCbl). Yet, these chemical forms cannot be utilized directly as they come, but instead, they undergo chemical processing by the MMACHC protein, also known as CblC. Processing of dietary B12 by CblC involves removal of the upper-axial ligand (beta-ligand) yielding the one-electron reduced intermediate cob(II)alamin. Newly formed cob(II)alamin undergoes trafficking and delivery to the two B12-dependent enzymes, cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MUT). The catalytic cycles of MS and MUT incorporate cob(II)alamin as a precursor to regenerate the coenzyme forms MeCbl and AdoCbl, respectively. Mutations and epimutations in the MMACHC gene result in cblC disease, the most common inborn error of B12 metabolism, which manifests with combined homocystinuria and methylmalonic aciduria. Elevation of metabolites homocysteine and methylmalonic acid occurs because the lack of an active CblC blocks formation of the indispensable precursor cob(II)alamin that is necessary to activate MS and MUT. Thus, in patients with cblC disease, vitamin B12 is absorbed and present in circulation in normal to high concentrations, yet, cells are unable to make use of it. Mutations in seemingly unrelated genes that modify MMACHC gene expression also result in clinical phenotypes that resemble cblC disease. We review current knowledge on structural and functional aspects of intracellular processing of vitamin B12 by the versatile protein CblC, its partners and possible regulators.Vitamin B12 is assimilated and transported by complex mechanisms that involve three transport proteins, intrinsic factor (IF), haptocorrin (HC) and transcobalamin (TC) and their respective membrane receptors. Vitamin deficiency is mainly due to inadequate dietary intake in vegans, and B12 malabsorption is related to digestive diseases. This review explores the physiology of vitamin B12 absorption and the mechanisms and diseases that produce malabsorption. In the stomach, B12 is released from food carrier proteins and binds to HC. The degradation of HC by pancreatic proteases and the pH change trigger the transfer of B12 to IF in the duodenum. Cubilin and amnionless are the two components of the receptor that mediates the uptake of B12 in the distal ileum. Part of liver B12 is excreted in bile, and undergoes an enterohepatic circulation. The main causes of B12 malabsorption include inherited disorders (Intrinsic factor deficiency, Imerslund-Gräsbeck disease, Addison's pernicious anemia, obesity, bariatric surgery and gastrectomies. Other causes include pancreatic insufficiency, obstructive Jaundice, tropical sprue and celiac disease, bacterial overgrowth, parasitic infestations, Zollinger-Ellison syndrome, inflammatory bowel diseases, chronic radiation enteritis of the distal ileum and short bowel. The assessment of B12 deficit is recommended in the follow-up of subjects with bariatric surgery. The genetic causes of B12 malabsorption are probably underestimated in adult cases with B12 deficit. Despite its high prevalence in the general population and in the elderly, B12 malabsorption cannot be anymore assessed by the Schilling test, pointing out the urgent need for an equivalent reliable test.Bioorganometallic structure found in coenzyme B12 is a key component in B12-dependent enzymatic reactions in natural enzymes. Cleavage of a cobalt-carbon bond in organometallic B12 compound provide reactive intermediate for molecular transformations. Application of the bioorganometallic B12 in organic synthesis have been developed using natural vitamin B12 as well as synthetic vitamin B12 derivatives as a bioinspired catalyst in organic solvent. Vitamin B12 derivatives composed of corrinoid structure should form stable organometallic compound having a cobalt-carbon bond. Using the unique property of the organometallic vitamin B12 derivatives, various catalytic reactions have been developed in synthetic organic chemistry. The dual catalytic system of vitamin B12 derivatives and photocatalyst, such as Ru(II) polypyridyl complex or titanium oxide, could construct light-driven molecular transformations. The B12-dependent enzymes mimic reactions, such as the dechlorination of organic halides and the radical mediated isomerization reactions, catalytically proceed in the dual catalyst system.
Read More: https://www.selleckchem.com/products/pf-07265807.html