Search results for "alpha Subunit"
showing 10 items of 126 documents
A new heterozygous mutation (D196N) in the Gs alpha gene as a cause for pseudohypoparathyroidism type IA in a boy who had gallstones
2011
Background Pseudohypoparathyroidism (PHP) is characterized by hypocalcemia and hyperphosphatemia in association with an increased secretion of parathyroid hormone (PTH) due to decreased target tissue responsiveness to PTH. Patients with PHP type Ia are not only resistant to PTH, but also to other hormones that bind to receptors coupled to stimulatory G protein (Gsalpha). PHP Ia and Albright hereditary osteodystrophy (AHO) are caused by a reduced activity of the Gsalpha protein. Heterozygous inactivating Gs alpha (GNAS) gene mutations have been identified in these patients. Methods We studied a boy with PHP Ia. During follow-up the patient developed elevated liver enzyme serum levels and abd…
Co-administration of human MSC overexpressing HIF-1α increases human CD34+ cell engraftment in vivo
2021
Abstract Background Poor graft function or graft failure after allogeneic stem cell transplantation is an unmet medical need, in which mesenchymal stromal cells (MSC) constitute an attractive potential therapeutic approach. Hypoxia-inducible factor-1α (HIF-1α) overexpression in MSC (HIF-MSC) potentiates the angiogenic and immunomodulatory properties of these cells, so we hypothesized that co-transplantation of MSC-HIF with CD34+ human cord blood cells would also enhance hematopoietic stem cell engraftment and function both in vitro and in vivo. Methods Human MSC were obtained from dental pulp. Lentiviral overexpression of HIF-1α was performed transducing cells with pWPI-green fluorescent pr…
Synthesis of GABAA receptor agonists and evaluation of their alpha-subunit selectivity and orientation in the GABA binding site.
2008
Drugs used to treat various disorders target GABA A receptors. To develop alpha subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [(3)H]muscimol binding and in patch-clamp experiments with heterologously expressed GABA A alpha ibeta 3gamma 2 receptors (i = 1-6). The effects of 5-aminomethyl-3 H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all alpha subunit isoforms. 5-pipe…
Participation of Two Ser-Ser-Phe-Tyr Repeats in Interleukin-6 (IL-6)-Binding Sites of the Human IL-6 Receptor
1996
The alpha-subunit of interleukin-6 (IL-6) receptor is a member of the hematopoietin receptor family. The alignment of its amino acid sequence with those of other members of this family (human somatotropin receptor/murine IL-3 receptor beta and human IL-2 receptor beta) has suggested that amino acids included in two SSFY repeats found in each of its hematopoietin receptor domains, contribute to the binding of the ligand. The involvement of these amino acids in IL-6 binding and signal transduction was studied by site-directed mutagenesis and molecular modelling. We present a computer-derived three-dimensional model of the IL-6/IL-6 receptor complex based on the structure of the human somatotr…
Increased immunosuppressive function of CD4(+)CD25(+)Foxp3(+)GITR+ T regulatory cells from NFATc2((-/-)) mice controls allergen-induced experimental …
2012
The expansion of effector T cells is tightly controlled by transcription factors like nuclear factor of activated T cells (NFAT) family members that mediate early intracellular responses to T cell receptor-mediated signals. In this study we show that, after allergen challenge, NFATc2((-/-)) mice had augmented number of functionally intact CD4(+)CD25(++)GITR(++) T regulatory (T regs) cells in the lung. Anti-GITR antibody treatment inhibited T regulatory cell function and enhanced the number of activated lung CD4(+) T cells associated with increased IL-2 and pSTAT-5 in the airways of NFATc2((-/-)) mice in experimental allergic asthma. This agonistic treatment led to increased inflammation in …
Hypoxia and Aggressive Tumor Phenotype: Implications for Therapy and Prognosis
2008
Abstract Tumor hypoxia, mostly resulting from poor perfusion and anemia, is one of the key factors in inducing the development of cell clones with an aggressive and treatment-resistant phenotype that leads to rapid progression and poor prognosis. Studies in patients with solid tumors suggest that there is a range of hemoglobin (Hb) concentrations that is optimum for tumor oxygenation. When used to achieve an Hb level within this range, erythropoiesis-stimulating agents (ESAs) can be expected to increase tumor oxygenation, and this may favorably influence sensitivity to treatment as well as quality of life. There is no robust evidence that ESAs, when used as indicated, have a negative effect…
Identification of a Novel BRCA1 Alteration in Recurrent Melanocytoma Resulting in Increased Proliferation
2020
Abstract Primary meningeal melanocytomas are rare tumors of the central nervous system. Although they are considered benign neoplasms, some reports describe recurrent rates up to 45%. Little is known about their genetic and epigenetic landscape because of their infrequency. Even less has been described about markers with prognostic value. Here we describe a patient who developed a primary meningeal melanocytoma, suffered 3 recurrences in a period of 6 years and died of the tumor. The genetic and epigenetic changes explored confirmed GNAQ mutation as an initiating event. We found an epigenetic alteration of GSTP1, a feature that has recently been described in meningiomas, from the beginning …
Hypoxia inducible factor-1alpha inactivation unveils a link between tumor cell metabolism and hypoxia-induced cell death.
2008
Hypoxia and the acquisition of a glycolytic phenotype are intrinsic features of the tumor microenvironment. The hypoxia inducible factor-1alpha (HIF-1alpha) pathway is activated under hypoxic conditions and orchestrates a complex transcriptional program that enhances cell survival. Although the consequences of HIF-1alpha inactivation in cancer cells have been widely investigated, only a few studies have addressed the role of HIF-1alpha in the survival of cancer cells endowed with different glycolytic capacities. In this study, we investigated this aspect in ovarian cancer cells. Hypoxia-induced toxicity was increased in highly glycolytic cells compared with poorly glycolytic cells; it was a…
Protein modulation in mouse heart under acute and chronic hypoxia
2011
Exploring cellular mechanisms underlying beneficial and detrimental responses to hypoxia represents the object of the present study. Signaling molecules controlling adaptation to hypoxia (HIF-1α), energy balance (AMPK), mitochondrial biogenesis (PGC-1α), autophagic/apoptotic processes regulation and proteomic dysregulation were assessed. Responses to acute hypoxia (AH) and chronic hypoxia (CH) in mouse heart proteome were detected by 2-D DIGE, mass spectrometry and antigen-antibody reactions. Both in AH and CH, the results indicated a deregulation of proteins related to sarcomere stabilization and muscle contraction. Neither in AH nor in CH the HIF-1α stabilization was observed. In AH, the …
Omalizumab as alternative to chronic use of oral corticosteroids in severe asthma.
2019
Systemic/oral corticosteroids (OCS) have been used for decades in the management of acute asthma exacerbations and chronically in patients with uncontrolled severe asthma. However, while OCS are effective at treating acute exacerbations, there is only empirical evidence regarding the efficacy of OCS at reducing the rate of exacerbations. Evidence, although scarce, is suggestive of high exacerbation rates in severe asthma patients even when receiving maintenance treatment with OCS. In addition, use of OCS is associated with undesirable effects. Despite all this, physicians have continued to use OCS for managing severe asthma and acute exacerbation due to the lack of availability of effective…