The novel association between the ST2/IL-33 system and IBD seems to identify that variations in this axis might regulate the inflammatory process in these diseases.

Background-The Brugada syndrome, an inherited syndrome associated with a high incidence of sudden cardiac arrest, has been linked to mutations in 4 different genes, leading to a loss of function in sodium and calcium channel activity.Although the transient outward current (I to ) is thought to play a prominent role in the expression of the syndrome, mutations in I to -related genes have not been identified as yet. Methods and Results-One hundred five probands with the Brugada syndrome were screened for ion channel gene mutations using single-strand conformation polymorphism electrophoresis and direct sequencing. A missense mutation (R99H) in KCNE3 (MiRP2) was detected in 1 proband. The R99H mutation was found 4/4 phenotype-positive and 0/3 phenotype-negative family members.

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Dysregulation of intracellular Ca2+ homeostasis may underlie amyloid β peptide (Aβ) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Aβ1–42 oligomers, the assembly state correlating best with cognitive decline in AD, but not Aβ fibrils, induce a massive entry of Ca2+ in neurons and promote mitochondrial Ca2+ overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Aβ oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca2+ overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca2+ overload, cytochrome c release and cell death induced by Aβ oligomers. Our results indicate that i) mitochondrial Ca2+ overload underlies the neurotoxicity induced by Aβ oligomers and ii) inhibition of mitochondrial Ca2+ overload provides a novel mechanism of neuroprotection by NSAIDs against Aβ oligomers and AD.

BackgroundToll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system recognizing diverse pathogen-derived and tissue damage-related ligands. It has been suggested that TLR signaling contributes to the pathogenesis of age-related, neurodegenerative diseases, including Alzheimer’s disease (AD). AD is associated to oligomers of the amyloid β peptide (Aβo) that cause intracellular Ca2+ dishomeostasis and neuron cell death in rat hippocampal neurons. Here we assessed the interplay between inflammation and Aβo in long-term cultures of rat hippocampal neurons, an in vitro model of neuron aging and/or senescence.MethodsCa2+ imaging and immunofluorescence against annexin V and TLR4 were applied in short- and long-term cultures of rat hippocampal neurons to test the effects of TLR4-agonist LPS and Aβo on cytosolic [Ca2+] and on apoptosis as well as on expression of TLR4.ResultsLPS increases cytosolic [Ca2+] and promotes apoptosis in rat hippocampal neurons in long-term culture considered aged and/or senescent neurons, but not in short-term cultured neurons considered young neurons. TLR4 antagonist CAY10614 prevents both effects. TLR4 expression in rat hippocampal neurons is significantly larger in aged hippocampal cultures. Treatment of aged hippocampal cultures with Aβo increases TLR4 expression and enhances LPS-induced Ca2+ responses and neuron cell death.ConclusionsAging and amyloid β oligomers, the neurotoxin involved in Alzheimer’s disease, enhance TLR4 expression as well as LPS-induced Ca2+ responses and neuron cell death in rat hippocampal neurons aged in vitro.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0802-0) contains supplementary material, which is available to authorized users.

Aging is associated to cognitive decline and susceptibility to neuron death, two processes related recently to subcellular Ca 2+ homeostasis. Memory storage relies on mushroom spines stability that depends on store-operated

Nuñez J, Sanz‐Blasco S, Vignoletti F, Muñoz F, Arzate H, Villalobos C, Nuñez L, Caffesse RG, Sanz M. Periodontal regeneration following implantation of cementum and periodontal ligament‐derived cells. J Periodont Res 2012; 47: 33–44. © 2011 John Wiley & Sons A/SBackground and Objective:  The periodontal regeneration of bone defects is often unsatisfactory and could be largely improved by cell therapy. Therefore, the purpose of this study was to evaluate the regenerative potential of implanting canine cementum‐derived cells (CDCs) and canine periodontal ligament‐derived cells (PDLDCs) in experimentally created periodontal intrabony defects in beagle dogs.Material and Methods:  Cells were obtained from premolars extracted from four beagle dogs. Three‐wall intrabony periodontal defects, 3 mm wide and 4 mm deep, were surgically created in their second and fourth premolars and plaque was allowed to accumulate. Once the defects were surgically debrided, periodontal regeneration was attempted by random implantation of collagen sponges embedded with 750,000 CDCs, 750,000 PDLDCs or culture medium. After 3 mo of healing, specimens were obtained and periodontal regenerative outcomes were assessed histologically and histometrically.Results:  The histological analysis showed that a minimal amount of new cementum was formed in the control group (1.56 ± 0.39 mm), whereas in both test groups, significantly higher amounts of new cementum were formed (3.98 ± 0.59 mm in the CDC group and 4.07 ± 0.97 mm in the PDLDC group). The test groups also demonstrated a larger dimension of new connective tissue, resulting in a significantly more coronal level of histological attachment.Conclusion:  This proof‐of‐principle study suggests that cellular therapy, in combination with a collagen sponge, promoted periodontal regeneration in experimental intrabony periodontal defects.

The classic view for hypothalamic regulation of anterior pituitary (AP) hormone secretion holds that release of each AP hormone is controlled specifically by a corresponding hypothalamic-releasing hormone (HRH). In this scenario, binding of a given HRH (thyrotropin-, growth hormone-, corticotropin-, and luteinizing hormone-releasing hormones) to specific receptors in its target cell increases the concentration of cytosolic Ca 2؉ ([Ca 2؉ ] i ), thereby selectively stimulating the release of the appropriate hormone. However, ''paradoxical'' responses of AP cells to the four wellestablished HRHs have been observed repeatedly with both in vivo and in vitro systems, raising the possibility of functional overlap between the different AP cell types. To explore this possibility, we evaluated the effects of HRHs on [Ca 2؉ ] i in single AP cells identified immunocytochemically by the hormone they stored. We found that each of the five major AP cell types contained discrete subpopulations that were able to respond to several HRHs. The relative abundance of these multi-responsive cells was 59% for lactotropes, 33% for thyrotropes, and in the range of 47-55% for gonadotropes, corticotropes, and somatotropes. Analysis of prolactin release from single living cells revealed that each of the four HRHs tested were able to induce hormone release from a discrete lactotrope subpopulation, the size of which corresponded closely to that in which [Ca 2؉ ] i changes were induced by the same secretagogues. When viewed as a whole, our diverse functional measurements of multi-responsiveness suggest that hypothalamic control of pituitary function is more complicated than previously envisioned. Moreover, they provide a cellular basis for the so-called ''paradoxical'' behavior of pituitary cells to hypothalamic hypophysiotropic agents.The pituitary gland is a major neuroendocrine modulator that regulates many peripheral glands and tissues through the secretion of anterior pituitary (AP) hormones. These hormones include prolactin (PRL), growth hormone (GH), thyrotropin (TSH), adrenocorticotropin, and the gonadotropins [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)]. The secretory activity of the gland is controlled, in turn, by signals derived from the hypothalamus in the form of hypothalamic-releasing hormones (HRHs) such as thyrotropin-releasing hormone (TRH), growth hormone-releasing hormone (GHRH), corticotropin-releasing hormone (CRH), and gonadotropin-releasing hormone (LHRH). The classic view for hypothalamic control of AP hormone secretion holds that each major HRH modulates the secretion of a single pituitary hormone (1), but there are some notable exceptions to this rule. For example, TRH is acknowledged to be a physiological modulator of both TSH and PRL secretion, just as LHRH controls the release of both LH and FSH. In addition to these acknowledged exceptions, there have been sporadic reports about ''paradoxical'' responses to various HRHs. Such observations of AP hormone release elicited by a noncorresp...