Selective Activation of CNS and Reference Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases.

The transcriptional regulator peroxisome proliferator activated receptor gamma coactivator 1A (PGC-1α), encoded by , has been linked to neurodegenerative diseases. Recently discovered CNS-specific transcripts are initiated far upstream of the reference promoter, spliced to exon 2 of the reference gene, and are more abundant than reference gene transcripts in post-mortem human brain samples. The proteins translated from the CNS and reference transcripts differ only at their N-terminal regions.

-GlcNAcylation Suppresses the Ion Current IClswell by Preventing the Binding of the Protein ICln to α-Integrin.

-GlcNAcylation is a post-translational modification of proteins that controls a variety of cellular processes, is chronically elevated in diabetes mellitus, and may contribute to the progression of diabetic complications, including diabetic nephropathy. Our previous work showed that increases in the -GlcNAcylation of cellular proteins impair the homeostatic reaction of the regulatory volume decrease (RVD) after cell swelling by an unknown mechanism. The activation of the swelling-induced chloride current IClswell is a key step in RVD, and ICln, a ubiquitous protein involved in the activation of IClswell, is -GlcNAcylated.

A TOMM40/APOE allele encoding APOE-E3 predicts high likelihood of late-onset Alzheimer's disease in autopsy cases.

Background: The APOE-ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE-ε4 are at variance.

Methods: We investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages View Article and Find Full Text PDF

Author Correction: Binding of the protein ICln to α-integrin contributes to the activation of ICl current.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Expression of CNS-Specific PPARGC1A Transcripts Is Regulated by Hypoxia and a Variable GT Repeat Polymorphism.

PPARGC1A encodes a transcriptional co-activator also termed peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1-alpha (PGC-1α) which orchestrates multiple transcriptional programs. We have recently identified CNS-specific transcripts that are initiated far upstream of the reference gene (RG) promoter. The regulation of these isoforms may be relevant, as experimental and genetic studies implicated the PPARGC1A locus in neurodegenerative diseases.

Binding of the protein ICln to α-integrin contributes to the activation of ICl current.

ICl is the chloride current induced by cell swelling, and plays a fundamental role in several biological processes, including the regulatory volume decrease (RVD). ICln is a highly conserved, ubiquitously expressed and multifunctional protein involved in the activation of ICl. In platelets, ICln binds to the intracellular domain of the integrin αIIb chain, however, whether the ICln/integrin interaction plays a role in RVD is not known.

Association between Cardiovascular Risk and Diabetes with Colorectal Neoplasia: A Site-Specific Analysis.

Several studies have shown site-specific differences in colorectal cancer (CRC) with respect to the risk factors. CRC was shown to be associated with cardiovascular risk (CVR) factors, but site-specific variations have not been investigated so far. This study aimed to assess the associations between the prevalence and subsite-specific differences of colorectal neoplasia and established CVR scores or known coronary artery disease (CAD) in a large asymptomatic European screening cohort ( = 2098).

The PPARGC1A locus and CNS-specific PGC-1α isoforms are associated with Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. PGC-1α, encoded by PPARGC1A, is a transcriptional co-activator that has been implicated in the pathogenesis of neurodegenerative disorders. We recently discovered multiple new PPARGC1A transcripts that initiate from a novel promoter located far upstream of the reference gene promoter, are CNS-specific and are more abundant than reference gene transcripts in whole brain.

A Potassium-Selective Current Affected by Micromolar Concentrations of Anion Transport Inhibitors.

Background/aims: In the human genome, more than 400 genes encode ion channels, which are ubiquitously expressed and often coexist and participate in almost all physiological processes. Therefore, ion channel blockers represent fundamental tools in discriminating the contribution of individual channel types to a physiological phenomenon. However, unspecific effects of these compounds may represent a confounding factor.

Functional Testing of SLC26A4 Variants-Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria.

The prevalence and spectrum of sequence alterations in the gene, which codes for the anion exchanger pendrin, are population-specific and account for at least 50% of cases of non-syndromic hearing loss associated with an enlarged vestibular aqueduct. A cohort of nineteen patients from Austria with hearing loss and a radiological alteration of the vestibular aqueduct underwent Sanger sequencing of and , coding for connexin 26. The pathogenicity of sequence alterations detected was assessed by determining ion transport and molecular features of the corresponding SLC26A4 protein variants.

Interleukin-4 Induces CpG Site-Specific Demethylation of the Pendrin Promoter in Primary Human Bronchial Epithelial Cells.

Unlabelled: Pendrin is upregulated in bronchial epithelial cells following IL-4 stimulation via binding of STAT6 to an N4 GAS motif. Basal CpG methylation of the pendrin promoter is cell-specific. We studied if a correlation exists between IL-4 sensitivity and the CpG methylation status of the pendrin promoter in human bronchial epithelial cell models.

Specific circulating phospholipids, acylcarnitines, amino acids and biogenic amines are aerobic exercise markers.

Objectives: Regular aerobic exercise provides beneficial effects on human health and reduces all-cause mortality. Aerobic exercise has profound metabolic effects, and specific metabolites may reflect physiological changes. We aimed to identify endogenous metabolites that distinguish the trained from the untrained state to increase the spectrum of analytes amenable for hypothesis testing and to expand understanding of putative beneficial pathways.

Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism.

Objective: Elevated serum ferritin has been linked to type 2 diabetes (T2D) and adverse health outcomes in subjects with the Metabolic Syndrome (MetS). As the mechanisms underlying the negative impact of excess iron have so far remained elusive, we aimed to identify potential links between iron homeostasis and metabolic pathways.

Methods: In a cross-sectional study, data were obtained from 163 patients, allocated to one of three groups: (1) lean, healthy controls (n = 53), (2) MetS without hyperferritinemia (n = 54) and (3) MetS with hyperferritinemia (n = 56).

Clinical and Metabolic Characterization of Lean Caucasian Subjects With Non-alcoholic Fatty Liver.

Objectives: Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity; however, 5-8% of lean subjects also have evidence of NAFLD. We aimed to investigate clinical, genetic, metabolic and lifestyle characteristics in lean Caucasian subjects with NAFLD.

Methods: Data from 187 subjects allocated to one of the three groups according to body mass index (BMI) and hepatic steatosis on ultrasound were obtained: lean healthy (BMI≤25 kg/m, no steatosis, N=71), lean NAFLD (BMI≤25 kg/m, steatosis, N=55), obese NAFLD (BMI≥30 kg/m, steatosis; N=61).

Effects of a 12-week alpine skiing intervention on endothelial progenitor cells, peripheral arterial tone and endothelial biomarkers in the elderly.

Objective: Endothelial dysfunction occurs early during atherogenesis and it can be normalized by exercise training. Unfortunately, patients' compliance with exercise prescription remains low, often because the given choices do not appeal to them. In Alpine regions, skiing is a popular mode of exercise, and therefore we set out to assess whether it can induce antiatherogenic effects.

Does exercise training impact clock genes in patients with coronary artery disease and type 2 diabetes mellitus?

Background: Recent findings revealed negative effects of deregulated molecular circadian rhythm in coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). Physical exercise training (ET) has been shown to promote anti-diabetic and anti-atherogenic responses in skeletal muscle of these patients, but the role of the circadian clock-machinery remains unknown. This study investigated whether mRNA expression of clock genes in skeletal muscle of CAD and T2DM patients is influenced by physical ET intervention.

Associations of Haplotypes Upstream of IRS1 with Insulin Resistance, Type 2 Diabetes, Dyslipidemia, Preclinical Atherosclerosis, and Skeletal Muscle LOC646736 mRNA Levels.

The genomic region ~500 kb upstream of IRS1 has been implicated in insulin resistance, type 2 diabetes, adverse lipid profile, and cardiovascular risk. To gain further insight into this chromosomal region, we typed four SNPs in a cross-sectional cohort and subjects with type 2 diabetes recruited from the same geographic region. From 16 possible haplotypes, 6 haplotypes with frequencies >0.

Parathyroid Hormone is Related to Dysplasia and a Higher Rate of Distal Colorectal Adenoma in Women but Not Men.

Molecular and clinical observations provide evidence for a potential role of parathyroid hormone (PTH) in colorectal cancer development. We therefore aimed to assess the association of PTH with regard to colorectal cancer precursor lesions. A cohort of 1432 participants, 777 men, 58.

Targeting SREBPs for treatment of the metabolic syndrome.

Over the past few decades, mortality resulting from cardiovascular disease (CVD) steadily decreased in western countries; however, in recent years, the decline has become offset by the increase in obesity. Obesity is strongly associated with the metabolic syndrome and its atherogenic dyslipidemia resulting from insulin resistance. While lifestyle treatment would be effective, drugs targeting individual risk factors are often required.

Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man.

Obesity and diabetes affect more than half a billion individuals worldwide. Interestingly, the two conditions do not always coincide and the molecular determinants of "healthy" versus "unhealthy" obesity remain ill-defined. Chronic metabolic inflammation (metaflammation) is believed to be pivotal.

Relations of vitamin D status, gender and type 2 diabetes in middle-aged Caucasians.

Vitamin D (Vit D) deficiency may be linked to the development of obesity-associated complications such as insulin resistance and type 2 diabetes. We therefore evaluated the relationship of Vit D serum concentrations with metabolic parameters and type 2 diabetes in middle-aged Caucasian men and women. One thousand six hundred and thirty-one Caucasians (832 males, 58.