Glycoconjugate Metabolism Research Articles

Bioinformatic, Enzymatic, and Structural Characterization of Trichuris suis Hexosaminidase HEX-2.

Hexosaminidases are key enzymes in glycoconjugate metabolism and occur in all kingdoms of life. Here, we have investigated the phylogeny of the GH20 glycosyl hydrolase family in nematodes and identified a β-hexosaminidase subclade present only in the Dorylaimia. We have expressed one of these, HEX-2 from Trichuris suis, a porcine parasite, and shown that it prefers an aryl β-N-acetylgalactosaminide in vitro. HEX-2 has an almost neutral pH optimum and is best inhibited by GalNAc-isofagomine. Toward N-glycan substrates, it displays a preference for the removal of GalNAc residues from LacdiNAc motifs as well as the GlcNAc attached to the α1,3-linked core mannose. Therefore, it has a broader specificity than insect fused lobe (FDL) hexosaminidases but one narrower than distant homologues from plants. Its X-ray crystal structure, the first of any subfamily 1 GH20 hexosaminidase to be determined, is closest to Streptococcus pneumoniae GH20C and the active site is predicted to be compatible with accommodating both GalNAc and GlcNAc. The new structure extends our knowledge about this large enzyme family, particularly as T. suis HEX-2 also possesses the key glutamate residue found in human hexosaminidases of either GH20 subfamily, including HEXD whose biological function remains elusive.

Post-prandial response in hepatopancreas and haemolymph of Penaeus monodon fed different diets. Omics insights into glycoconjugate metabolism, energy utilisation, chitin biosynthesis, immune function, and autophagy

Raw materials or bioactive ingredients trigger mechanisms to assimilate nutrients and activate metabolic pathways that promote growth, immune function, or energy storage. Our understanding of these processes at a molecular level remains limited in aquaculture, especially in shrimp. Here, hepatopancreas proteomics and haemolymph metabolomics were used to investigate the post-prandial response of black tiger shrimps (Penaeus monodon) fed a conventional fishmeal diet (FM); a diet supplemented with the microbial biomass Novacq™ (NV); krill meal (KM); or, fasted (FS). Using FM as a control, a 2-fold change in abundance threshold was implemented to determine the significance of proteins and metabolites. NV fed shrimp showed preference for energy derived from carbohydrates indicated by a strong signature of glycoconjugate metabolism and activation of the amino- and nucleotide sugar metabolic pathway. KM activated the glyoxylate and dicarboxylate pathway that denoted shrimp preference for lipidic energy. KM also influenced energy generation by the TCA cycle inferred from higher abundance of the metabolites succinic semialdehyde, citric acid, isocitrate, alpha ketoglutarate and ATP and downregulation of the enzyme isocitrate dehydrogenase that catalyses oxidative decarboxylation of isocitrate. FS shrimp displayed down-regulation of oxidative phosphorylation and resorted to internal lipid reserves for energy homeostasis displaying a strong signature of autophagy. Pyrimidine metabolism was the preferred energy strategy in this group. Our study also provided evidence that during fasting or consumption of specific ingredients, shrimp share common pathways to meet their energy requirements, however, the intensity at which these pathways were impacted was diet dependent.

The development of a broad-spectrum retaining β-exo-galactosidase activity-based probe.

Acid β-galactosidase (GLB1) and galactocerebrosidase (GALC) are retaining exo-β-galactosidases involved in lysosomal glycoconjugate metabolism. Deficiency of GLB1 may result in the lysosomal storage disorders GM1 gangliosidosis, Morquio B syndrome, and galactosialidosis, and deficiency of GALC may result in Krabbe disease. Activity-based protein profiling (ABPP) is a powerful technique to assess the activity of retaining glycosidases in relation to health and disease. This work describes the use of fluorescent and biotin-carrying activity-based probes (ABPs) to assess the activity of both GLB1 and GALC in cell lysates, culture media, and tissue extracts. The reported ABPs, which complement the growing list of retaining glycosidase ABPs based on configurational isomers of cyclophellitol, should assist in fundamental and clinical research on various β-galactosidases, whose inherited deficiencies cause debilitating lysosomal storage disorders.

Nematode hexosaminidases – a new biochemical tool for glycan analysis

Hexosaminidases are ubiquitous enzymes with multiple roles in glycoconjugate metabolism as they remove non‐reducing terminal β ‐N‐acetylhexosamine residues from glycans, glycolipids, glycoproteins and glycosaminoglycans. Amongst many functions in non‐invertebrates, hexosaminidases are involved in maturation of N‐glycans.Previous studies of Caenorhabditis elegans Hexosaminidases (Gutternigg, 2007; Dragosits, 2014) prove that this organism possesses five GH20 family genes: four belong to the subfamily 1: HEX‐2; ‐3; ‐4 and ‐5, one to subfamily 2: HEX‐1. C. elegans HEX‐4 was recently shown to remove terminal GalNAc even from structures in which the underlying GlcNAc was substituted with phosphorylcholine. Now, we have begun to characterize hexosaminidase orthologues from pig parasitic nematodes, specifically Oesophagostomum dentatum, Trichuris suis and Trichinella spiralis. Bioinformatics analyses indicate that T. suis and T. spiralis have only two GH20 genes, one orthologous to HEX‐1 and one paralogous to the HEX‐2‐5, whereas the genome of O. dentatum appears to contain one orthologue each of HEX‐1‐5. Phylogenetic analyses are, however, complicated by incorrect database annotations in most nematode species.In terms of in vitro characterisation, the subfamily 1 GH20 enzyme from T. suis was expressed in yeast and observed to favor pNP‐β‐GalNAc with a pH optimum of 6.5; however, it can remove a single GlcNAc from the a1,3‐mannose of the N‐glycan substrate GnGn‐PA, as well as both GalNAc residues from a biantennary LacdiNAc‐containing structure. Thus, this enzyme appears to have the properties akin to both HEX‐2 and HEX‐4 from C. elegans. Homology‐based 3D‐structure prediction of hexosaminidases from C. elegans and T. suis showed no significant differences in the substrate binding pocket.In summary, nematode hexosaminidases have distinct substrate specificities and different numbers of homologues per species exist. These nematodes enzymes are not only interesting due to their roles in glycan biosynthesis; due to their specificities, they are useful as a complement to mass‐based glycomic workflows.

Inherited metabolic disorders of glycoconjugate metabolism.

Inherited metabolic disorders of glycoconjugate metabolism include congenital disorders of glycosylation (CDG) - disorders in biosynthesis of glycoconjugates; and some of the lysosomal storage diseases (LSD) - disorders of their degradation. This review summarizes the brief characteristics of metabolic pathways of synthesis and catabolism of glycoconjugates as well as the latest update of relevant enzymatic defects discovered in population. Every year the number of known subtypes of these disorders dramatically increases as a result of high-throughput analytical infrastructure applied. However, due to the broad spectrum of unspecific clinical symptoms, many patients remain undiagnosed or have wrong diagnosis with ineffective treatment. Thus, disorders of glycoconjugate metabolism should be considered and ruled out in any unexplained syndrome. The collaboration between scientists and physicians plays an important role in the progress of such personalized diagnostics, that is essential mainly for rare diseases (Tab. 2, Fig. 1, Ref. 49). Keywords: congenital disorders of glycosylation, lysosomal storage disorders.

De Novo Sequencing of a Sparassis latifolia Genome and Its Associated Comparative Analyses.

Known to be rich in β-glucan, Sparassis latifolia (S. latifolia) is a valuable edible fungus cultivated in East Asia. A few studies have suggested that S. latifolia is effective on antidiabetic, antihypertension, antitumor, and antiallergen medications. However, it is still unclear genetically why the fungus has these medical effects, which has become a key bottleneck for its further applications. To provide a better understanding of this fungus, we sequenced its whole genome, which has a total size of 48.13 megabases (Mb) and contains 12,471 predicted gene models. We then performed comparative and phylogenetic analyses, which indicate that S. latifolia is closely related to a few species in the antrodia clade including Fomitopsis pinicola, Wolfiporia cocos, Postia placenta, and Antrodia sinuosa. Finally, we annotated the predicted genes. Interestingly, the S. latifolia genome encodes most enzymes involved in carbohydrate and glycoconjugate metabolism and is also enriched in genes encoding enzymes critical to secondary metabolite biosynthesis and involved in indole, terpene, and type I polyketide pathways. As a conclusion, the genome content of S. latifolia sheds light on its genetic basis of the reported medicinal properties and could also be used as a reference genome for comparative studies on fungi.

Ganglioside-Dependent Neural Stem Cell Proliferation in Alzheimer's Disease Model Mice.

The aggregation and formation of amyloid plaques by amyloid β-peptides (Aβs) is believed to be one of the pathological hallmarks of Alzheimer’s disease (AD). Intriguingly, Aβs have also been shown to possess proliferative effects on neural stem cells (NSCs). Many essential cellular processes in NSCs, such as fate determination and proliferation, are heavily influenced by cell surface glycoconjugates, including gangliosides. It has recently been shown that Aβ1-42 alters several key glycosyltransferases and glycosidases. To further define the effects of Aβs and to clarify the potential mechanisms of action of those peptides on NSCs, NSCs were cultured from embryonic brains of the double-transgenic mouse model of AD [B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J] coexpressing mutants of amyloid precursor protein (APPswe) and presenilin1 (PSEN1dE9). We found that Aβs not only promoted cell proliferation but also altered expression of several key glycogenes for glycoconjugate metabolism, such as sialyltransferases II and III (ST-II & -III) in AD NSCs. In addition, we found upregulation of epidermal growth factor receptor and Notch1 intracellular domain. Moreover, the increased expression of ST-II and -III coincided with the elevated levels of c-series gangliosides (A2B5+ antigens) in AD NSCs. Further, we revealed that epidermal growth factor signaling and gangliosides are necessary components on Aβ-stimulated NSC proliferation. Our present study has thus provided a novel mechanism for the upregulation of c-series ganglioside expression and increases in several NSC markers to account for the proliferative effect of Aβs on NSCs in AD mouse brain. These observations support the potential beneficial effects of Aβs and gangliosides in promoting neurogenesis in AD brain.

Effect of spent turmeric on kidney glycoconjugates in streptozotocin-induced diabetic rats.

BackgroundCurcumin known to have number of medicinal use and masked the fiber containing ukonan like active polysaccharide in turmeric and its pharmacological effect will be addressed on diabetic nephropathy particularly the glycoconjugates of extracellular components viz., glycoproteins and glycosaminoglycans - heparan sulfate (HS).MethodsMale Wistar rats were maintained on AIN-76 diet containing 10% spent turmeric and were grouped into control and STZ induced diabetes SFC/TFC and SFD/TFD, respectively. Diabetic status was monitored using blood and urine, and at the end, harvested kidneys were used to study the amelioration of glycoprotiens (collagen) and HS by enzymatic digestion, spectrophotometric, hydroxyproline and agarose electrophoretic methods.ResultsIn the present study spent turmeric (10%) fed diabetic rats showed improved glomerular filtration rate (50%), kidney enlargement (60%) and other glycoconjugate metabolism in kidney. Increased collagen content in diabetic group was observed by hydroxyproline estimation (24%) and periodic acid-Schiff’s (PAS) staining. Furthermore, elevated activities of enzymes involved in the synthesis and degradation of glycosaminoglycans (GAGs) were significantly lowered in spent turmeric fed diabetic group. Improvement in total GAGs (43%) and sulfate content (18%) followed by fractionation of GAGs using specific enzymes led to HS (28%) in the spent turmeric fed diabetic group, when compared to starch fed diabetic group and was further confirmed by electrophoresis of GAG.ConclusionThese results clearly indicate beneficial role of spent turmeric in controlling glycoconjugates such as glycoproteins and heparan sulfate related kidney complications during diabetes.

The genome of the Tiger Milk mushroom, Lignosus rhinocerotis, provides insights into the genetic basis of its medicinal properties.

BackgroundThe sclerotium of Lignosus rhinocerotis (Cooke) Ryvarden or Tiger milk mushroom (Polyporales, Basidiomycota) is a valuable folk medicine for indigenous peoples in Southeast Asia. Despite the increasing interest in this ethnobotanical mushroom, very little is known about the molecular and genetic basis of its medicinal and nutraceutical properties.ResultsThe de novo assembled 34.3 Mb L. rhinocerotis genome encodes 10,742 putative genes with 84.30% of them having detectable sequence similarities to others available in public databases. Phylogenetic analysis revealed a close evolutionary relationship of L. rhinocerotis to Ganoderma lucidum, Dichomitus squalens, and Trametes versicolor in the core polyporoid clade. The L. rhinocerotis genome encodes a repertoire of enzymes engaged in carbohydrate and glycoconjugate metabolism, along with cytochrome P450s, putative bioactive proteins (lectins and fungal immunomodulatory proteins) and laccases. Other genes annotated include those encoding key enzymes for secondary metabolite biosynthesis, including those from polyketide, nonribosomal peptide, and triterpenoid pathways. Among them, the L. rhinocerotis genome is particularly enriched with sesquiterpenoid biosynthesis genes.ConclusionsThe genome content of L. rhinocerotis provides insights into the genetic basis of its reported medicinal properties as well as serving as a platform to further characterize putative bioactive proteins and secondary metabolite pathway enzymes and as a reference for comparative genomics of polyporoid fungi.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-635) contains supplementary material, which is available to authorized users.

Alcohol abuse and glycoconjugate metabolism.

The relationship between alcohol consumption and glycoconjugate metabolism is complex and multidimensional. This review summarizes the advances in basic and clinical research on the molecular and cellular events involved in the metabolic effects of alcohol on glycoconjugates (glycoproteins, glycolipids, and proteoglycans). We summarize the action of ethanol, acetaldehyde, reactive oxygen species (ROS), nonoxidative metabolite of alcohol--fatty acid ethyl esters (FAEEs), and the ethanol-water competition mechanism, on glycoconjugate biosynthesis, modification, transport and secretion, as well as on elimination and catabolism processes. As the majority of changes in the cellular metabolism of glycoconjugates are generally ascribed to alterations in synthesis, transport, glycosylation and secretion, the degradation and elimination processes, of which the former occurs also in extracellular matrix, seem to be underappreciated. The pathomechanisms are additionally complicated by the fact that the effect of alcohol intoxication on the glycoconjugate metabolism depends not only on the duration of ethanol exposure, but also demonstrates dose- and regional-sensitivity. Further research is needed to bridge the gap in transdisciplinary research and enhance our understanding of alcohol- and glycoconjugate-related diseases.

Therapeutic Targets for Inhibitors of Glycosylation

Small molecule inhibitors of glycoconjugate metabolism are being exploited for therapeutic benefit in a number of human disorders. As examples of this class of compound, imino sugars, as monosaccharide mimics, have a number of advantages for compound design and synthesis to define biological activity. As polyhydroxylated molecules, each chiral centre offers manipulation to generate isomers with restricted or enhanced mimicry, and the endocyclic nitrogen atom is readily modified to gain selectivity, increase potency or improve pharmacodynamics. This review focuses on the discovery of imino sugars that have considerable potential for treating a diverse range of diseases, from lysosomal storage disorders diabetes and cystic fibrosis to viral pathogenesis, and addresses the mechanism of action that is dictated by structural modification.

Glycoconjugates in the detection of alcohol abuse

Up to 30% of all hospital admissions and health-care costs may be attributable to alcohol abuse. Ethanol, its oxidative metabolites, acetaldehyde and ROS (reactive oxygen species), non-oxidative metabolites of alcohol [e.g. FAEEs (fatty acid ethyl esters)] and the ethanol-water competition mechanism are all involved in the deregulation of glycoconjugate (glycoprotein, glycolipid and proteoglycan) metabolic processes including biosynthesis, modification, transport, secretion, elimination and catabolism. An increasing number of new alcohol biomarkers that are the result of alcohol-induced glycoconjugate metabolic errors have appeared in the literature. Glycoconjugate-related alcohol markers are involved in, or are a product of, altered glycoconjugate metabolism, e.g. CDT (carbohydrate-deficient transferrin), SA (sialic acid), plasma SIJ (SA index of apolipoprotein J), CETP (cholesteryl ester transfer protein), β-HEX (β-hexosaminidase), dolichol, EtG (ethyl glucuronide) etc. Laboratory tests based on changes in glycoconjugate metabolism are useful in settings where the co-operativeness of the patient is impaired (e.g. driving while intoxicated) or when a history of alcohol use is not available (e.g. after trauma). In clinical practice, glycoconjugate markers of alcohol use/abuse let us distinguish alcoholic from non-alcoholic tissue damage, having important implications for the treatment and management of diseases.

Effect of bitter gourd and spent turmeric on glycoconjugate metabolism in streptozotocin-induced diabetic rats

Aim Changes in glycoconjugate metabolism during the development of diabetic complications and their modulation by feeding bitter gourd and spent turmeric as fiber-rich source. Method This was studied by measuring the contents of total sugar, uronic acid, amino sugar, and sulfate in the streptozotocin-induced diabetic rats. Results Total sugar content decreased in liver, spleen, and brain, while an increase was observed in heart and lungs. Uronic acid content in liver, spleen, and brain decreased, and marginal increase was observed in testis. Amino sugar content decreased in liver, spleen, lungs and heart during diabetes, and augmentation was observed to different extents. Decrease in sulfation of glycoconjugates was observed in liver, spleen, lungs and heart during diabetes and was significantly ameliorated by bitter gourd and spent turmeric, except brain. Protein content decreased in liver, while an increase was observed in brain. The studies clearly showed alteration in glycoconjugate metabolism during diabetes and amelioration to different extents by feeding bitter gourd and spent turmeric. Conclusion Improvement is due to slow release of glucose by fiber in the gastrointestinal track and short-chain fatty acid production from fiber by colon microbes.

Clinical, biochemical, and cytochemical studies on a Japanese Salla disease case associated with a renal disorder

We report the first Japanese case of Salla disease. A 5-year-old male patient developed unique proteinuria with other clinical manifestations, including coarse facies, dysostosis multiplex, mild mitral valve regurgitation, umbilical and inguinal herniation, and mild developmental delay. Pathological analysis of biopsied kidney tissues showed marked vacuolation of podocytes, mesangial cells, capillary endothelial cells, and tubular cells. Biochemical studies involving thin-layer chromatography and mass spectrometry revealed increased excretion of free sialic acid (N-acetylneuraminic acid) into the patient's urine. Immuno- and lectin staining of the patient's cells demonstrated the accumulation of sialyl and asialyl glycoconjugates in lysosomes and late endosomes. A defect in sialyl glycoconjugate metabolism is thought to have occurred in the patient's cells, besides impairment of the lysosomal transport of free sialic acid residues. A renal disorder should be considered as an important manifestation, not only in infantile free sialic acid storage disease but also in Salla disease.

Hypothalamic digoxin, hemispheric chemical dominance and sarcoidosis.

The isoprenoid pathway produces three key metabolites: endogenous digoxin (membrane sodium-potassium ATPase inhibitor, immunomodulator and regulator of neurotransmitter/amino acid transport), dolichol (regulates N-glycosylation of proteins) and ubiquinone (free radical scavenger). The role of the isoprenoid pathway in the pathogenesis of sarcoidosis in relation to hemispheric dominance was studied. The isoprenoid pathway-related cascade was assessed in patients with systemic sarcoidosis with pulmonary involvement. The pathway was also assessed in patients with right hemispheric, left hemispheric and bihemispheric dominance for comparison to find out the role of hemispheric dominance in the pathogenesis of sarcoidosis. In patients with sarcoidosis there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels and low ubiquinone and elevated free radical levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was an increase in the cholesterol:phospholipid ratio and a reduction in the glycoconjugate level of red blood cell (RBC) membrane in this group of patients. The same biochemical patterns were obtained in individuals with right hemispheric dominance. In individuals with left hemispheric dominance the patterns were reversed. Endogenous digoxin, by activating the calcineurin signal transduction pathway of T cells, can contribute to immune activation in sarcoidosis. An altered glycoconjugate metabolism can lead to the generation of endogenous self-glycoprotein antigens in the lung as well as other tissues. Increased free radical generation can also lead to immune activation. The role of a dysfunctional isoprenoid pathway and endogenous digoxin in the pathogenesis of sarcoidosis in relation to right hemispheric chemical dominance is discussed. All the patients with sarcoidosis were right-handed/left hemispheric dominant according to the dichotic listening test, but their biochemical patterns were suggestive of right hemispheric chemical dominance. Hemispheric chemical dominance has no correlation with handedness or the dichotic listening test.

Isoprenoid pathway dysfunction in chronic fatigue syndrome.

The isoprenoid pathway was assessed in 15 patients with chronic fatigue syndrome (CFS). The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance has any correlation with these disease states. The isoprenoid metabolites - digoxin, dolichol and ubiquinone - RBC membrane Na+-K+ ATPase activity, serum magnesium and tyrosine/tryptophan catabolic patterns were assessed. The free radical metabolism, glycoconjugate metabolism and RBC membrane composition were also assessed. Membrane Na+-K+ ATPase activity and serum magnesium levels were decreased while HMG-CoA reductase activity and serum digoxin levels were increased in CFS. There were increased levels of tryptophan catabolites - nicotine, strychnine, quinolinic acid and serotonin - and decreased levels of tyrosine catabolites -dopamine, norepinephrine and morphine - in CFS. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual glycosaminoglycans (GAG) fractions and lysosomal enzymes in CFS. Reduced levels of ubiquinone, reduced glutathione and free radical scavenging enzymes as well as increased lipid peroxidation products and nitric oxide were noticed in CFS. The biochemical patterns in CFS correlated with those obtained in right hemispheric dominance. The role of hypothalamic digoxin and neurotransmitter-induced immune activation, altered glycoconjugate metabolism and resultant defective viral antigen presentation, NMDA excitotoxicity and cognitive and mitochondrial dysfunction in the pathogenesis of CFS is stressed. CFS occurs in individuals with right hemispheric dominance.

Isoprenoid pathway related cascade in multiple myeloma.

This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in multiple myeloma. The following parameters were assessed: isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+ - K+ ATPase activity, and serum ubiquinone levels. Serum tryptophan, serotonin, nicotine, strychnine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions, the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins, cholesterol and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of lipid peroxidation products and NO increased. Hyperdigoxinemia related altered intracellular Ca++ mediated oncogene activation, dolichol induced altered glycoconjugate metabolism and ubiquinone deficiency related mitochondrial dysfunction can contribute to the pathogenesis of multiple myeloma. The biochemical findings reported could be the cause or the consequence of multiple myeloma.

Hypothalamic digoxin and brain function.

The study assessed the biochemical differences between right hemispheric-dominant and left hemispheric-dominant individuals. The chemical hemispheric-dominance in various systemic and neuropsychiatric diseases was also studied. The isoprenoid metabolites, digoxin, dolichol and ubiquinone, glycoconjugate metabolism, free radical metabolism and the RBC membrane composition, were studied in individuals with differing hemispheric-dominance. The digoxin levels and RBC membrane Na+-K+ATPase activity were also studied in systemic and neuropsychiatric diseases. The results showed that right hemispheric-dominant individuals had elevated digoxin levels, increased free radical production and reduced scavenging, increased tryptophan catabolites and reduced tyrosine catabolites, increased glycoconjugate levels and increased cholesterol : phospholipid ratio of RBC membranes. Left hemispheric-dominant individuals had the opposite patterns. This patterns could be correlated with various systemic and neuropsychiatric diseases. Right hemispheric-dominance represents a hyperdigoxinaemic state with membrane sodium-potassium ATPase inhibition. Left hemispheric-dominance represents the reverse pattern with hypodigoxinaemia and membrane sodium-potassium ATPase stimulation. Hemispheric-dominance could predispose to various systemic and neuropsychiatric diseases.

Hypothalamic digoxin – central role in conscious perception, neuroimmunoendocrine integration and coordination of cellular function – relation to hemispheric dominance

A family with a high prevalence of Parkinson’s disease, schizophrenia, neoplasms, syndrome-X, rheumatoid arthritis and epilepsy has been described. The psychological behavioural patterns of the family were as follows – creativity and high IQ, hypersexual behaviour, reduced appetite and eating behaviour, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less of bonding and affectionate behaviour and left handedness. Digoxin, an endogenous Na +–K + ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na +–K + ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites – serotonin, quinolinic acid, strychnine and nicotine and decreased levels of hyperpolarising tyrosine catabolites dopamine, noradrenaline and morphine contributing to membrane Na +–K + ATPase inhibition in all the above disorders and the indexed family. Digoxin induced membrane Na +–K + ATPase inhibition can result in increased intracellular Ca 2+ and reduced Mg ++ levels leading to glutamate excitotoxicity, oncogene activation and immune activation. Digoxin induced altered Ca ++/Mg ++ ratios, reduced ubiquinone and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure and mitochondrial function leading to the diverse disorders described above including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/left hemispheric dominant and left-handed/right hemispheric dominant individuals. The biochemical patterns in the indexed family and the diverse disorders studied correlated with those obtained in right hemispheric dominance. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and co-ordinate the functions of various cellular organelles.

HYPOTHALAMIC DIGOXIN, CEREBRAL CHEMICAL DOMINANCE AND MYALGIC ENCEPHALOMYELITIS

The isoprenoid pathway was assessed in 15 patients with chronic fatigue syndrome. The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance had any correlation with these disease states. The isoprenoid metabolites--digoxin, dolichol, and ubiquinone--RBC membrane Na+-K+ ATPase activity, serum magnesium and tyrosine/tryptophan catabolic patterns were assessed. The free-radical metabolism, glycoconjugate metabolism, and RBC membrane composition was also assessed. Membrane Na+-K+ ATPase activity and serum magnesium levels were decreased while HMG CoA reductase activity and serum digoxin levels were increased in myalgic encephalomyelitis (ME). There were increased levels of tryptophan catabolites--nicotine, strychnine, quinolinic acid, and serotonin--and decreased levels of tyrosine catabolites--dopamine, noradrenaline, and morphine in ME. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual GAG fractions, and lysosomal enzymes in ME. Reduced levels of ubiquinone, reduced glutathione, and free-radical scavenging enzymes, as well as increased lipid peroxidation products and nitric oxide, were noticed in ME. The biochemical patterns in ME correlated with those obtained in right hemi spheric chemical dominance. The role of hypothalamic digoxin and neurotransmitter induced immune activation, altered glycoconjugate metabolism, and resultant defective viral antigen presentation, NMDA excitotoxicity and cognitive dysfunction, and mitochondrial dysfunction related myalgia in the pathogenesis of ME is stressed. ME occurs in individuals with right hemispheric chemical dominance.