A rare haplotype of the vitamin D receptor gene is protective against diabetic nephropathy

Background. Vitamin D and its analogues are reported to have renoprotective effects in chronic kidney disease including diabetic nephropathy (DN). Vitamin D3 is converted to 1,25(OH) D3 by CYP2R1 and CYP27B1. The biological action of 1,25(OH) D3 is mediated via its receptor. VDR, CYP27B1 or CYP2R1 gene variants could modify the biological activity of vitamin D3. We have conducted the first case- control association study to determine the relationship between polymorphisms in VDR, CYP27B1 and CYP2R1 genes, and the risk of DN in individuals with type 1 diabetes.

ADP ribose is an endogenous ligand for the purinergic P2Y1 receptor

The mechanism by which extracellular ADP ribose (ADPr) increases intracellular free Ca2+ concentration ([Ca2+](i)) remains unknown. We measured [Ca2+](i) changes in fura-2 loaded rat insulinoma INS-1E cells, and in primary beta-cells from rat and human. A phosphonate analogue of ADPr (PADPr) and 8-Bromo-ADPr (8Br-ADPr) were synthesized. ADPr increased [Ca2+](i) in the form of a peak followed by a plateau dependent on extracellular Ca2+. NAD(+), cADPr, PADPr, 8Br-ADPr or breakdown products of ADPr did not increase [Ca2+](i). The ADPr-induced [Ca2+](i) increase was not affected by inhibitors of TRPM2, but was abolished by thapsigargin and inhibited when phospholipase C and IP3 receptors were inhibited. MRS 2179 and MRS 2279, specific inhibitors of the purinergic receptor P2Y1, completely blocked the ADPrinduced [Ca2+](i) increase. ADPr increased [Ca2+](i) in transfected human astrocytoma cells (1321N1) that express human P2Y1 receptors, but not in untransfected astrocytoma cells. We conclude that ADPr is a specific agonist of P2Y1 receptors. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Genetic Variation in the Serotonin 2A Receptor and Suicidal Ideation in a Sample of 270 Irish High-Density Schizophrenia Families

Genetic variation in the serotonin 2A receptor (HTR2A) has been associated with both schizophrenia and suicidal behavior. Our sample comprised 270 Irish high-density schizophrenia families (n = 1,408 subjects, including 755 with psychotic illness). Diagnoses were generated using a modified SCID. All patients who had at least one episode of psychosis were rated on the Operation Criteria Checklist for Psychotic Illness (OPCRIT). Lifetime history of suicidal ideation was determined from medical records and psychiatric interviews and was scored in the OPCRIT. Twelve SNPs were selected for study. Ten of these were tagSNPs derived from HapMap data, along with His452Tyr and T102C. We tested for association with psychotic illness as a whole, as well as stratified by the presence of suicidal ideation, using FBAT and PDTPHASE. Single-marker as well as haplotype-based tests using a

The trace amine associated receptor (TAAR6) gene is not associated with schizophrenia in the Irish Case-Control Study of Schizophrenia (ICCSS) sample

To replicate previous association between TAAR6 and schizophrenia, including our own finding in the Irish Study of High Density Schizophrenia Families (ISHDSF) sample, we genotyped 12 single nucleotide polymorphisms (SNPs) in the Irish Case-Control Study of Schizophrenia (ICCSS) sample. Only rs9389020 provided nominal evidence for association (p

Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation, causes neurogenic inflammation in the airways and other tissues in rodents

Acetaminophen [N-acetyl-p-aminophenol (APAP)] is the most common antipyretic/analgesic medicine worldwide. If APAP is overdosed, its metabolite, N-acetyl-p-benzo-quinoneimine (NAPQI), causes liver damage. However, epidemiological evidence has associated previous use of therapeutic APAP doses with the risk of chronic obstructive pulmonary disease (COPD) and asthma. The transient receptor potential ankyrin-1 (TRPA1) channel is expressed by peptidergic primary sensory neurons. Because NAPQI, like other TRPA1 activators, is an electrophilic molecule, we hypothesized that APAP, via NAPQI, stimulates TRPA1, thus causing airway neurogenic inflammation. NAPQI selectively excites human recombinant and native (neuroblastoma cells) TRPA1. TRPA1 activation by NAPQI releases proinflammatory neuropeptides (substance P and calcitonin gene-related peptide) from sensory nerve terminals in rodent airways, thereby causing neurogenic edema and neutrophilia. Single or repeated administration of therapeutic (15-60 mg/kg) APAP doses to mice produces detectable levels of NAPQI in the lung, and increases neutrophil numbers, myeloperoxidase activity, and cytokine and chemokine levels in the airways or skin. Inflammatory responses evoked by NAPQI and APAP are abated by TRPA1 antagonism or are absent in TRPA1-deficient mice. This novel pathway, distinguished from the tissue-damaging effect of NAPQI, may contribute to the risk of COPD and asthma associated with therapeutic APAP use.-Nassini, R., Materazzi, S., Andre, E., Sartiani, L., Aldini, G., Trevisani, M., Carnini, C., Massi, D., Pedretti, P., Carini, M., Cerbai, E., Preti, D., Villetti, G., Civelli, M., Trevisan, G., Azzari, C., Stokesberry, S., Sadofsky, L., McGarvey, L., Patacchini, R., Geppetti, P. Acetaminophen, via its reactive metabolite N-acetyl-p-benzo-quinoneimine and transient receptor potential ankyrin-1 stimulation causes neurogenic inflammation in the airways and other tissues in rodents. FASEB J. 24, 4904-4916 (2010). www.fasebj.org