B Vitamins Supplementation Can Improve Cognitive Functions and May Relate to the Enhancement of Transketolase Activity in A Rat Model of Cognitive Impairment Associated with High-fat Diets

Objective:To determine whether B vitamin treatment was sufficient to reduce cognitive impairment associated with high-fat diets in rats and to modulate transketolase(TK)expression and activity.Methods:To test this,we separated 50 rats into five groups that were either fed a standard chow diet(controls)or a high-fat diet(experimental groups HO,HI,H2,and H3).HO group animals received no additional dietary supplementation,while H1 group animals were administered 100 mg/kg body weight(BW)thiamine,100 mg/kg BW riboflavin,and 250 mg/kg BW niacin each day,and group H2 animals received daily doses of 100 mg/kg BW pyridoxine,100 mg/kg BW cobalamin,and 5 mg/kg BW folate.Animals in the H3 group received the B vitamin regimens administered to both H1 and H2 each day.Results:Over time,group HO exhibited greater increases in BW and fat mass relative to other groups.When spatial and memory capabilities in these animals were evaluated via conditioned taste aversion(CTA)and Morris Water Maze(MWM),we found B vitamin treatment was associated with significant improvements relative to untreated HO controls.Similarly,B vitamin supplementation was associated with elevated TK expression in erythrocytes and hypothalamus of treated animals relative to those in HO(P<0.05).Conclusion:Together,these findings suggest B vitamin can modulate hypothalamic TK activity to reduce the severity of cognitive deficits in a rat model of obesity.As such,B vitamin supplementation may be a beneficial method for reducing cognitive dysfunction in clinical settings associated with high-fat diets.

Identification of potential P. falciparum transketolase inhibitors: pharmacophore design, in silico screening and docking studies

Transketolase, the most critical enzyme of the non-oxidative branch of the pentose phosphate pathway, has been reported as a novel target in Plasmodium falciparum as it has least homology with the human host. Homology model of P. falciparum transketolase (PfTk) was constructed using the crystal structure of S. cervisiae transketolase as a template, and used for the identification and prioritization of potential compounds targeted against Plasmodium falciparum transketolase. The docking studies with fructose-6-phosphate and thiamine pyrophosphate showed that His31, Asp473, Ser388, Arg361 and His465 formed hydrogen bonds with fructose-6-phosphate while pyrimidine ring of coenzyme interacted with conserved residues of protein viz., Leu121, Glu415, Gly119. The major interacting residues involved in binding of oxythiamine pyrophosphate were similar to cofactor binding site of PfTk. An integrated pharmacophore, co-factor ThDP and substrate fructose-6-pho- sphate, based virtual screening of a small mo- lecule database retrieved eight and thirteen compounds respectively. When screened for their activity against P. falciparum transketolase, one compound in case of ThDP and three compounds in case of fructose-6-phosphate based screening were found active against PfTk. Identification of these novel and chemically diverse inhibitors provides initial leads for optimization of more potent and efficacious drug candidates to treat malarial infection.

A review on research progress of transketolase

Transketolase （TK）, a thiamine diphosphate （ThDP）-dependent enzyme, catalyzes several key reactions of nonoxidative branch of pentose phosphate pathway. TK is a homodimer with two active sites that locate at the interface between the contacting monomers. Both ThDP and bivalent cations are strictly needed for TK activation, just like that for all ThDPdependent enzymes. TK exists in all organisms that have been investigated. Up to now, one TK gene （TKT） and two transketolase-like genes （TKTL1 and TKTL2） have been identified in human genome. TKTL1 is reported to play a pivotal role in carcinogenesis and may have important implications in the nutrition and future treatment of patients with cancer. Research- ers have found TK variants and reduced activities of TK enzyme in patients with neurodegenerative diseases, diabetes, and cancer. Recent studies indicated TK as a novel role in the prevention and therapy of these diseases.

Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco- and lipotoxicity by rational supplementation?

Growing prevalence of diabetes(type 2 as well as type 1) and its related morbidity due to vascular complications creates a large burden on medical care worldwide. Understanding the molecular pathogenesis of chronic micro-, macro- and avascular complications mediated by hyperglycemia is of crucial importance since novel therapeutic targets can be identified and tested. Thiamine(vitamin B1) is an essential cofactor of several enzymes involved in carbohydrate metabolism and published data suggest that thiamine metabolism in diabetes is deficient. This review aims to point out the physiological role of thiamine in metabolism of glucose and amino acids, to present overview of thiamine metabolism and to describe the consequences of thiamine deficiency(either clinically manifest or latent). Furthermore, we want to explain why thiamine demands are increased in diabetes and to summarise data indicating thiamine mishandling in diabetics(by review of the studies mapping the prevalence and the degree ofthiamine deficiency in diabetics). Finally, we would like to summarise the evidence for the beneficial effect of thiamine supplementation in progression of hyperglycemia-related pathology and, therefore, to justify its importance in determining the harmful impact of hyperglycemia in diabetes. Based on the data presented it could be concluded that although experimental studies mostly resulted in beneficial effects, clinical studies of appropriate size and duration focusing on the effect of thiamine supplementation/therapy on hard endpoints are missing at present. Moreover, it is not currently clear which mechanisms contribute to the deficient action of thiamine in diabetes most. Experimental studies on the molecular mechanisms of thiamine deficiency in diabetes are critically needed before clear answer to diabetes community could be given.