Alteration in the Wnt microenvironment directly regulates molecular events leading to pulmonary senescence

In the aging lung, the lung capacity decreases even in the absence of diseases. The progenitor cells of the distal lung, the alveolar type II cells (ATII), are essential for the repair of the gas-exchange surface. Surfactant protein production and survival of ATII cells are supported by lipofibroblasts that are peroxisome proliferator-activated receptor gamma (PPARγ)-dependent special cell type of the pulmonary tissue. PPARγ levels are directly regulated by Wnt molecules; therefore, changes in the Wnt microenvironment have close control over maintenance of the distal lung. The pulmonary aging process is associated with airspace enlargement, decrease in the distal epithelial cell compartment and infiltration of inflammatory cells. qRT-PCR analysis of purified epithelial and nonepithelial cells revealed that lipofibroblast differentiation marker parathyroid hormone-related protein receptor (PTHrPR) and PPARγ are reduced and that PPARγ reduction is regulated by Wnt4 via a β-catenin-dependent mechanism. Using a human in vitro 3D lung tissue model, a link was established between increased PPARγ and pro-surfactant protein C (pro-SPC) expression in pulmonary epithelial cells. In the senile lung, both Wnt4 and Wnt5a levels increase and both Wnt-s increase myofibroblast-like differentiation. Alteration of the Wnt microenvironment plays a significant role in pulmonary aging. Diminished lipo- and increased myofibroblast-like differentiation are directly regulated by specific Wnt-s, which process also controls surfactant production and pulmonary repair mechanisms

GCKR gene functional variants in type 2 diabetes and metabolic syndrome: do the rare variants associate with increased carotid intima-media thickness?

BACKGROUND: Recent studies revealed that glucokinase regulatory protein (GCKR) variants (rs780094 and rs1260326) are associated with serum triglycerides and plasma glucose levels. Here we analyzed primarily the association of these two variants with the lipid profile and plasma glucose levels in Hungarian subjects with type 2 diabetes mellitus and metabolic syndrome; and also correlated the genotypes with the carotid intima-media thickness records. METHODS: A total of 321 type 2 diabetic patients, 455 metabolic syndrome patients, and 172 healthy controls were genotyped by PCR-RFLP. RESULTS: Both GCKR variants were found to associate with serum triglycerides and with fasting plasma glucose. However, significant association with the development of type 2 diabetes mellitus and metabolic syndrome could not be observed. Analyzing the records of the patients, a positive association of prevalence the GCKR homozygous functional variants and carotid intima-media thickness was found in the metabolic syndrome patients. CONCLUSIONS: Our results support that rs780094 and rs1260326 functional variants of the GCKR gene are inversely associated with serum triglycerides and fasting plasma glucose levels, as it was already reported for diabetic and metabolic syndrome patients in some other populations. Besides this positive replication, as a novel feature, our preliminary findings also suggest a cardiovascular risk role of the GCKR minor allele carriage based on the carotid intima-media thickness association

Az 5q31 IBD5-régióban található IGR és SLC22A4/SLC22A5 variánsok lehetséges szerepe a gyulladásos bélbetegség kialakulásában = Possible role of selected IGR and SLC22A4/SLC22A5 loci in development of inflammatory bowel diseases

Az idiopathiás krónikus gyulladásos bélbetegség kialakulásában környezeti tényezők, immunológiai és genetikai faktorok egyaránt szerepet játszanak. Az utóbbi években a CARD15 gén mellett egyre több adat támasztja alá más gének, többek között az 5q31-33 régióban elhelyezkedő IBD5 locus (MIM#606348) szerepét. Egyes tanulmányok ezen régióban az SLC22A4 gén C1672T szubsztitúciójának, illetve az SLC22A5 gén G-207C transzverziójának együttes szerepét hangsúlyozzák, különösen Crohn-betegség kialakulásában, míg más szerzők új minor hajlamosító tényezőket azonosítottak az IBD5 kromoszómarégióban, ezek az IGR-variánsok. Célkitűzés: Az SLC22A4 C1672T és SLC22A5 G-207C mutációk mellett az IGR2096a_1 (rs12521868) és az IGR2198a_1 (rs11739135) polimorfizmusok szerepének vizsgálata gyulladásos bélbetegség kialakulásában. Betegek és módszer: Vizsgálatunk során 440 gyulladásos bélbeteg (206 Crohn- és 234 colitis ulcerosás beteg), valamint 279 kontrollegyén perifériás vérmintájából PCR-RFLP technikával végeztünk DNS-analízist. Eredmények: Sem a C1672T, sem a G-207C allélek, sem a TC haplotípus nem bizonyult rizikófaktornak sem Crohn-betegség, sem colitis ulcerosa esetében. Ezzel ellentétben mindkét minor IGR allél frekvenciája: mind az IGR2096a_1 T (48,1%), mind az IGR2198a_1 C (46,1%) szignifikánsan magasabb volt Crohn-betegségben a kontrollokéhoz (38,5%, 38,4%) képest (p<0,05). Korra és nemre standardizált regressziós analízissel mindkét allélnél fokozott rizikót észleltünk Crohn-betegség vonatkozásában (T-allél: OR=1,694, 95%-os CI: 1,137–2,522, p=0,010, C-allél: OR=1,644, 95%-os CI=1,103–2,449, p=0,015). Colitis ulcerosa esetén nem találtunk összefüggést a két IGR-variáns és a betegség kialakulása között. Következtetés: az IGR minor alléleknek a környező kaukázusi népcsoportoktól eltérően magyarországi populációban szerepük lehet a Crohn-betegség kialakulásában. | The IBD5 locus (MIM#606348) on chromosome 5q31 has been demonstrated to confer increased risk for inflammatory bowel disease. Controversial reports have been published about the significance of individual loci located in this region. Here we investigated the possible genetic association of inflammatory bowel diseases with C1672T of SLC22A4 and G-207C SLC22A5 alleles, and with IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility variants of the IBD5 region located on chromosome 5q31. Patients and methods: Total of 440 patients, 206 with Crohn’s disease, 234 with ulcerative colitis, and 279 controls were studied by PCR-RFLP methods. Results: Neither the C1672T, and G-207C alleles, nor the TC haplotype were found to confer risk for Crohn’s disease or ulcerative colitis. By contrast, both of the minor allele frequencies of IGR2096a_1 T (48.1%) and IGR2198a_1 C (46.1%) were increased in Crohn’s disease subjects as compared with the controls (38.5% and 38.4%, respectively; p<0.05). Using regression analysis adjusted to age and gender these alleles were found to confer risk for Crohn’s disease (OR=1.694, 95% CI: 1.137–2.522; p=0.010 for T allele, OR=1.644, 95% CI=1.103–2.449; p=0.015 for C allele of IGRs). In UC no such associations were found. Conclusions: Our results revealed the susceptibility nature of the examined IGR minor alleles in Hungarians, which nation differs historically from the surrounding Caucasian populations in origin of the founders of the state

A mitokondriális DNS és mutációi: újabb ismeretek egy új területen = Mitochondrial DNA and its mutations: novel fields in a new era

Az utóbbi két évtizedet tartják a klinikai mitokondriális DNS-kutatás aranykorának. Folyamatosan bővül a patológiás variánsok száma, amelyek betegséggel társulnak, illetve bővül az ismeretanyag azokról az entitásokról, melyek hátterében a mitokondriális DNS kóros elváltozásai állnak. A cirkuláris mitokondriális DNS öröklődése eltér a Mendel-féle szabályoktól, anyai öröklésmenetet mutat; számos vonatkozásban eltérő sajátosságokkal rendelkezik a nukleáris DNS-hez viszonyítva. A molekuláris biológiai módszerek terjedésével egyre több kórkép ismerhető fel, noha a diagnosztika manapság is komoly kihívást jelent. Napjainkban a mitokondriális medicina számos orvosi szubspecialitáshoz kapcsolódóan jelentős előrelépéseket mutatott; így körvonalazódott a mitokondriális gasztroenterológia, endokrinológia, otológia, oftalmológia, nefrológia, hematológia, onkológia, reproduktív medicina és pszichiátria, mintegy az adott szubspecialitás mitokondriális DNS-sel kapcsolatos, többé-kevésbé részleges önállósodással megjelenő territóriuma. A jelen összefoglaló közlemény a mitokondriális medicina rövid, általános összefoglalása mellett e fejezetekre próbál rátekintést nyújtani. | The past two decades are considered as the golden age of the clinical research of mitochondrial DNA. The number of disease-associated pathologic variants is still expanding; the available knowledge about the entities caused by the abnormalities of the mitochondrial DNA is gradually increasing. The inheritance of the mitochondrial DNA exhibits maternal transmission; the properties are different from the nuclear genome in many respects. Albeit the establishment of correct diagnosis of several mitochondrial diseases still means diagnostic challenge, more and more entities can be identified due to the available molecular biology methods. Nowadays, significant progress of mitochondrial medicine can be observed in relation to several medical subspecialties; thus, mitochondrial gastroenterology, endocrinology, otology, ophthalmology, nephrology, hematology, oncology, reproductive medicine and psychiatry have been partially separated as the more or less circumscribed territory of the specific subspecialty. Besides the short overview of the general aspects of the mitochondrial medicine the present review provides an outlook to these chapters

Prevalence of SLC22A4 1672T and SLC22A5 −207C combination defined TC haplotype in Hungarian ulcerative colitis patients

Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract. The aim of this study was to verify the prevalence rate of the haplotype called TC, determined by combination of two functional alleles of OCTN cation transporter genes (SLC22A4 1672T and SLC22A5 -207C combination variants) in ulcerative colitis patients and unrelated healthy controls. The "TC haplotype" has recently been suggested to confer risk for UC. A total of 121 unrelated Hungarian subjects with UC and 110 matched controls were genotyped for the two single nucleotide polymorphisms. The genotypes were determined by using PCR/RFLP assay and direct sequencing. The SLC22A4 1672T allele frequency was 46.7% in the patients with UC and 46.4% in the controls, whereas the SLC22A5 -207C allele occurred in 48.8% of the patients and 51.4% of the controls. The prevalence of the TC haplotype was 19% in the patient group and 22.7% in controls. Since there was no accumulation of the TC haplotype in the patient group, our observation suggests that carrying the TC haplotype is not associated with a higher risk for UC in the Hungarian population