Gene/Protein Disease Symptom Drug Enzyme Compound
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Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.
Hum Mol Genet 2009 Feb 15
PMID:Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis. 1901 Jul 93

Endometriosis is a common and chronic disease characterized by persistent pelvic pain and infertility. Estradiol is essential for growth and inflammation in endometriotic tissue. The complete cascade of steroidogenic proteins/enzymes including aromatase is present in endometriosis leading to de novo estradiol synthesis. PGE(2) induces the expression of the genes that encode these enzymes. Upon PGE(2) treatment, coordinate recruitment of the nuclear receptor SF-1 to the promoters of these steroidogenic genes is the key event for estradiol synthesis. SF-1 is the key factor determining that an endometriotic cell will respond to PGE(2) by increased estradiol formation. The presence of SF-1 in endometriosis and its absence in endometrium is determined primarily by the methylation of its promoter. The key steroidogenic enzyme in endometriosis is aromatase encoded by a single gene because its inhibition blocks all estradiol biosynthesis. Aromatase inhibitors diminish endometriotic implants and associated pain refractory to existing treatments in affected women.
Mol Cell Endocrinol 2009 Mar 05
PMID:Steroidogenic factor-1 and endometriosis. 1915 Apr 83

Scottish strawberries were found to be a rich source of phenolic acids, namely benzoic (1287.95 +/- 279.98 mg/kg) and cinnamic (1159.40 +/- 233.96 mg/kg) acids, both free and attached to other plant components. Studies suggest a chemopreventive role for such compounds in several major clinical conditions, but the anticipated benefits are likely to be affected by their bio-availability and metabolic fate. In this pilot study, strawberries (750 g) was consumed by four healthy human volunteers (32 +/- 6 years). Only the benzoic acids were detected in the plasma. Of these, the major free (gentisic, protocatechuic and p-hydroxybenzoic acid) and conjugated (syringic acid) benzoic acids were 26-27% recovered in the urine within 5 h. Cinnamic acids were completely undetected in plasma and only trace amounts were found in the urine. Since, the cinnamic acids escaped absorption early in the gastrointestinal tract, their release and/or metabolism is dependent on the host colonic microbiota. Results indicate that there is a high degree of selective absorption of strawberry phenolic acids into the systemic circulation. If selective absorption of phenolic acids is observed with consumption of other plant-based foods, this is likely to have implications for the bioactive role of these compounds in chronic disease prevention.
Mol Nutr Food Res 2009 May
PMID:Selective bio-availability of phenolic acids from Scottish strawberries. 1920 2

DNA damage by reactive species is associated with susceptibility to chronic human degenerative disorders. Anthocyanins are naturally occurring antioxidants, that may prevent or reverse such damage. There is considerable interest in anthocyanic food plants as good dietary sources, with the potential for reducing susceptibility to chronic disease. While structure-activity relationships have provided guidelines on molecular structure in relation to free hydroxyl-radical scavenging, this may not cover the situation in food plants where the anthocyanins are part of a complex mixture, and may be part of complex structures, including anthocyanic vacuolar inclusions (AVIs). Additionally, new analytical methods have revealed new structures in previously-studied materials. We have compared the antioxidant activities of extracts from six anthocyanin-rich edible plants (red cabbage, red lettuce, blueberries, pansies, purple sweetpotato skin, purple sweetpotato flesh and Maori potato flesh) using three chemical assays (DPPH, TRAP and ORAC), and the in vitro Comet assay. Extracts from the flowering plant, lisianthus, were used for comparison. The extracts showed differential effects in the chemical assays, suggesting that closely related structures have different affinities to scavenge different reactive species. Integration of anthocyanins to an AVI led to more sustained radical scavenging activity as compared with the free anthocyanin. All but the red lettuce extract could reduce endogenous DNA damage in HT-29 colon cancer cells. However, while extracts from purple sweetpotato skin and flesh, Maori potato and pansies, protected cells against subsequent challenge by hydrogen peroxide at 0 degrees C, red cabbage extracts were pro-oxidant, while other extracts had no effect. When the peroxide challenge was at 37 degrees C, all of the extracts appeared pro-oxidant. Maori potato extract, consistently the weakest antioxidant in all the chemical assays, was more effective in the Comet assays. These results highlight the dangers of generalising to potential health benefits, based solely on identification of high anthocyanic content in plants, results of a single antioxidant assay and traditional approaches to structure activity relationships. Subsequent studies might usefully consider complex mixtures and a battery of assays.
Int J Mol Sci 2009 Mar
PMID:Dietary protection against free radicals: a case for multiple testing to establish structure-activity relationships for antioxidant potential of anthocyanic plant species. 1939 39

Pathogenic mycobacteria have the ability to survive within macrophages and persist inside granulomas. The complex host-pathogen interactions that determine the outcome of a mycobacterial infection process result in marked alterations of the host gene expression profile. Here we used the zebrafish model to investigate the specificity of the host response to infections with two mycobacterium strains that give distinct disease outcomes: an acute disease with early lethality or a chronic disease with granuloma formation, caused by Mycobacterium marinum strains Mma20 and E11, respectively. We performed a microarray study of different stages of disease progression in adult zebrafish and found that the acute and the chronic strains evoked partially overlapping host transcriptome signatures, despite that they induce profoundly different disease phenotypes. Both strains affected many signaling cascades, including WNT and TLR pathways. Interestingly, the strongest differences were observed at the initial stage of the disease. The immediate response to the acute strain was characterized by higher expression of genes encoding MHC class I proteins, matrix metalloproteinases, transcription factors, cytokines and other common immune response proteins. In contrast, small GTPase and histone gene groups showed higher expression in response to the chronic strain. We also found that nearly 1000 mycobacterium-responsive genes overlapped between the expression signatures of infected zebrafish adults and embryos at different stages of granuloma formation. Since adult zebrafish possess an adaptive immune system similar to mammals and zebrafish embryos rely solely on innate immunity, this overlap indicates a major contribution of the innate component of the immune system in the response to mycobacterial infection. Taken together, our comparison of the transcriptome responses involved in acute versus chronic infections and in the embryonic versus adult situation provides important new leads for investigating the mechanism of mycobacterial pathogenesis.
Mol Immunol 2009 Jul
PMID:Specificity of the zebrafish host transcriptome response to acute and chronic mycobacterial infection and the role of innate and adaptive immune components. 1940 17

Aging is a complex process that has been shown to be linked to accumulation of DNA damage. Telomere shortening represents a cell-intrinsic mechanism leading to DNA damage accumulation and activation of DNA damage checkpoints in aging cells. Activation of DNA damage checkpoints in response to telomere dysfunction results in induction of cellular senescence-a permanent cell cycle arrest. Senescence represents a tumor suppressor mechanism protecting cells from evolution of genomic instability and transformation. As a drawback, telomere shortening may also limit tissue renewal and regenerative capacity of tissues in response to aging and chronic disease. In aged organs, telomere shortening may also increase the cancer risk by initiation of chromosomal instability, loss of proliferative competition of aging stem cells, and selection of aberrant growing clones. Consequently, aged individuals are more susceptible and vulnerable to various diseases and show an increased cancer risk. Recently, proteins were discovered, which are induced by telomere dysfunction and DNA damage. It was shown that these proteins represent new biomarkers of human aging and disease. Here, we review the scientific background and experimental data on these newly discovered biomarkers.
J Mol Med (Berl) 2009 Dec
PMID:Role of telomere dysfunction in aging and its detection by biomarkers. 1966 7

Endometriosis is a chronic disease characterized by the presence of ectopic endometrial tissue outside of the uterus with mixed traits of benign and malignant pathology. In this study we analyzed in endometrial and endometriotic tissues the differential expression of a panel of genes that are involved in preservation of stemness status and consequently considered as markers of stem cell presence. The expression profiles of a panel of 13 genes (SOX2, SOX15, ERAS, SALL4, OCT4, NANOG, UTF1, DPPA2, BMI1, GDF3, ZFP42, KLF4, TCL1) were analyzed by reverse transcription-polymerase chain reaction in human endometriotic (n = 12) and endometrial samples (n = 14). The expression of SALL4 and OCT4 was further analyzed by immunohistochemical methods. Genes UTF1, TCL1, and ZFP42 showed a trend for higher frequency of expression in endometriosis than in endometrium (P < 0.05 for UTF1), whereas GDF3 showed a higher frequency of expression in endometrial samples. Immunohistochemical analysis revealed that SALL4 was expressed in endometriotic samples but not in endometrium samples, despite the expression of the corresponding mRNA in both the sample groups. This study highlights a differential expression of stemness-related genes in ectopic and eutopic endometrium and suggests a possible role of SALL4-positive cells in the pathogenesis of endometriosis.
Mol Med
PMID:Expression pattern of stemness-related genes in human endometrial and endometriotic tissues. 1969 Jun 22

The biological concept of microchimerism, the bidirectional trafficking and stable long-term persistence of small numbers of allogeneic (fetal and maternal) cells in a genetically different organ, has gained considerable attention. Microchimerism is a common phenomenon in many species, including humans, and microchimeric cells can modify immunological recognition or tolerance, affect the course and outcome of various diseases and demonstrate stem cell-like or regenerative potential. Here, we review current knowledge of the biology of microchimerism and show how long-term allogeneic co-existence within an organism can impact on existing paradigms in chronic disease, cancer biology, regenerative medicine and fetal-maternal immunology. We discuss diagnostic challenges, clinical applications and future research directions in this exciting and rapidly emerging field of allogeneic fetal-maternal cell exchange.
Trends Mol Med 2009 Nov
PMID:Fetal-maternal exchange of multipotent stem/progenitor cells: microchimerism in diagnosis and disease. 1982 78

Cardiovascular disease is a chronic disease influenced by many factors, with activated blood platelets being one of them. Platelets play a central role in the formation of plaques within blood vessels, contributing to early inflammatory events. Consumption of diets rich in plant-based products protects against the development of cardiovascular disease. Polyphenols, which are secondary plant metabolites found in a wide range of foodstuffs and beverages, may be partially responsible for these effects. Their protective properties include inhibitory effects on platelet function in vitro and in vivo. However, the bioavailability of many polyphenols is poor and it is unclear whether sufficient quantities can be obtained by dietary means to exert protective effects. Consequently, this review summarizes 25 well-controlled human intervention studies examining the effect of polyphenol-rich diets on platelet function. These studies report a huge variety of research methods, study designs, and study subjects, resulting in controversial assertions. One consistent finding is that cocoa-related products, however, have platelet-inhibiting effects when consumed in moderate amounts. To assess whether other classes of dietary polyphenols, or their metabolites, also beneficially affect platelet function requires more well-controlled intervention studies as well as the adoption of more uniform methods to assess platelet aggregation and activation.
Mol Nutr Food Res 2010 Jan
PMID:Impact of dietary polyphenols on human platelet function--a critical review of controlled dietary intervention studies. 2005 56

Control of blood phenylalanine (Phe) levels throughout the life of a person diagnosed with phenylketonuria (PKU) is the biochemical management strategy necessary to provide the best potential for optimal outcome. Psychosocial support mechanisms comprise the other aspects of PKU management that are necessary to overcome the hurdles of living with this chronic disease and to adhere to the rigors of its management. Additional psychosocial support may be required, in light of increasing evidence that control of blood Phe levels in PKU can still lead to subtle but measurable cognitive function deficits as well as a predisposition to certain psychiatric symptoms and disorders. An all encompassing PKU management strategy that goes beyond simply treating blood Phe levels can empower and enable people born with PKU to achieve similar life goals as those born without PKU. This review looks at PKU management strategies that go beyond treating Phe levels, specifically (1) the roles psychologists play in managing PKU from infancy through adulthood and how they help PKU families and caregivers deal with the disease and the burden of its management; (2) understanding the challenges of transitioning into adulthood as an individual with PKU and addressing unmet needs in this population; (3) how non-traditional practices can be utilized in PKU. The objective is to emphasize that management of PKU goes well beyond addressing the biochemical nature of this disease in order to achieve optimal patient outcomes.
Mol Genet Metab 2010
PMID:Outcomes beyond phenylalanine: an international perspective. 2012 76


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