Causes and consequences of impaired methionine synthase activity in acquired and inherited disorders of vitamin B12 metabolism.

Methyl-Cobalamin (Cbl) derives from dietary vitamin B12 and acts as a cofactor of methionine synthase (MS) in mammals. MS encoded by MTR catalyzes the remethylation of homocysteine to generate methionine and tetrahydrofolate, which fuel methionine and cytoplasmic folate cycles, respectively. Methionine is the precursor of S-adenosyl methionine (SAM), the universal methyl donor of transmethylation reactions. Impaired MS activity results from inadequate dietary intake or malabsorption of B12 and inborn errors of Cbl metabolism (IECM). The mechanisms at the origin of the high variability of clinical presentation of impaired MS activity are classically considered as the consequence of the disruption of the folate cycle and related synthesis of purines and pyrimidines and the decreased synthesis of endogenous methionine and SAM. For one decade, data on cellular and animal models of B12 deficiency and IECM have highlighted other key pathomechanisms, including altered interactome of MS with methionine synthase reductase, MMACHC, and MMADHC, endoplasmic reticulum stress, altered cell signaling, and genomic/epigenomic dysregulations. Decreased MS activity increases catalytic protein phosphatase 2A (PP2A) and produces imbalanced phosphorylation/methylation of nucleocytoplasmic RNA binding proteins, including ELAVL1/HuR protein, with subsequent nuclear sequestration of mRNAs and dramatic alteration of gene expression, including SIRT1. Decreased SAM and SIRT1 activity induce ER stress through impaired SIRT1-deacetylation of HSF1 and hypomethylation/hyperacetylation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), which deactivate nuclear receptors and lead to impaired energy metabolism and neuroplasticity. The reversibility of these pathomechanisms by SIRT1 agonists opens promising perspectives in the treatment of IECM outcomes resistant to conventional supplementation therapies.

Intraspecific Variation of Phytochemicals, Antioxidant, and Antibacterial Activities of Different Solvent Extracts of Albizia coriaria Leaves from Some Agroecological Zones of Uganda.

Albizia coriaria Welw ex. Oliver is a customary African medicinal plant, which has a long history of utilization in the management of oxidative stress-induced and bacterial diseases. However, there is no report on the phytochemicals, antioxidant, and antibacterial activities of its leaves. The aim of this study was therefore to compare the phytochemicals, antioxidant, and antibacterial potential of A. coriaria leaves from Jinja, Kole, and Mbarara districts of Uganda. Shade-dried leaf samples were ground into powder and successively extracted with ethyl acetate, ethanol, and distilled water. Phytochemical screening indicated the presence of alkaloids, phenols, saponins, flavonoids, cardiac glycosides, tannins, and terpenes as the major secondary metabolites in the extracts. Total phenolic and flavonoid contents and total in vitro antioxidant activity were found to be the highest for ethanolic extracts, with the highest contents (101.72 ± 0.22 mg GAE/g DW; 13.23 ± 0.03 mg QE/g DW) and antioxidant potential (IC50 = 18.65 ± 0.06 mg/mL) being for leaves from Mbarara district. Antibacterial activity of the extracts determined by agar disc diffusion method revealed that ethanolic extracts had higher antibacterial activities with mean zones of inhibition of 6.00 ± 1.73 to 10.00 ± 1.73 mm, 5.00 ± 1.00 to 12.30 ± 1.53 mm, 17.00 ± 0.00 to 25.00 ± 2.65 mm, and 9.00 ± 1.73 to 16.00 ± 1.73 mm for Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Salmonella typhi, respectively. Ethyl acetate extracts of A. coriaria leaves from Kole and Mbarara had lower antibacterial activities, while aqueous extracts and ethyl acetate extract of leaves from Jinja showed no antibacterial activity. The current study for the first time established that A. coriaria leaves possess therapeutic phytochemicals with significant in vitro antioxidant and antibacterial activities, which lend credence to their use in traditional management of oxidative stress-induced conditions and bacterial diseases in Uganda. Structural elucidation of the responsible pure compounds for the observed bioactivities as well as toxicity studies of the extracts is recommended.

Programming by Methyl Donor Deficiency during Pregnancy and Lactation Produces Cardiomyopathy in Adult Rats Subjected to High Fat Diet.

SCOPE: Vitamin B12 and folate (methyl donors) deficiency is frequent during pregnancy. Experimental rat models with methyl donor deficit during pregnancy and lactation (Initial methyl donor deficit (iMDD)) produce impaired myocardium fatty acid oxidation and mitochondrial energy metabolism at weaning. METHODS AND RESULTS: The consequences of iMDD on heart of rat pups under normal diet after weaning and high fat diet (HF) between day (D) 50 and D185 are investigated. iMDD/HF induces increased histological fibrosis and increased B-type natriuretic peptide blood level. Inflammation is evidenced by increased protein expression of NFkB, Caspase1, and IL1ß and fibrosis by increased expression of αSMA, col1a1, and col1a2 in females, but not in males. Fibrosis is related to increased angiotensin at D50 and D185 and increased protein expression of TGFB1 and AT1 angiotensin receptors at D185. The limited fibrosis in males is consistent with increased expression of AT2, the antagonist receptor of AT1. The increased expression of GLUT4 and decreased expression of PGC1α and PPARα reflect a shift from fatty acid oxidation to glycolysis. CONCLUSION: Developmental programming by iMDD produces cardiomyopathy in female offspring exposed to HF. The cardiomyopathy is linked to inflammation and fibrosis through angiotensin-AT2 and TGFB1 pathways and alteration of energy metabolism.

Sirt1-PPARS Cross-Talk in Complex Metabolic Diseases and Inherited Disorders of the One Carbon Metabolism.

Sirtuin1 (Sirt1) has a NAD (+) binding domain and modulates the acetylation status of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) and Fork Head Box O1 transcription factor (Foxo1) according to the nutritional status. Sirt1 is decreased in obese patients and increased in weight loss. Its decreased expression explains part of the pathomechanisms of the metabolic syndrome, diabetes mellitus type 2 (DT2), cardiovascular diseases and nonalcoholic liver disease. Sirt1 plays an important role in the differentiation of adipocytes and in insulin signaling regulated by Foxo1 and phosphatidylinositol 3'-kinase (PI3K) signaling. Its overexpression attenuates inflammation and macrophage infiltration induced by a high fat diet. Its decreased expression plays a prominent role in the heart, liver and brain of rat as manifestations of fetal programming produced by deficit in vitamin B12 and folate during pregnancy and lactation through imbalanced methylation/acetylation of PGC1α and altered expression and methylation of nuclear receptors. The decreased expression of Sirt1 produced by impaired cellular availability of vitamin B12 results from endoplasmic reticulum stress through subcellular mislocalization of ELAVL1/HuR protein that shuttles Sirt1 mRNA between the nucleus and cytoplasm. Preclinical and clinical studies of Sirt1 agonists have produced contrasted results in the treatment of the metabolic syndrome. A preclinical study has produced promising results in the treatment of inherited disorders of vitamin B12 metabolism.