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- Ghanem, E, et al.
(författare)
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Luminal adenosine stimulates chloride secretion through A1 receptor in mouse jejunum
- 2005
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Ingår i: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 288:5, s. G972-G977
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Tidskriftsartikel (refereegranskat)abstract
- Adenosine is known to stimulate chloride secretion by mouse jejunum. Whereas the receptor on the basolateral side is believed to be A2B, the receptor involved in the luminal effect of adenosine has not been identified. We found that jejuna expressed mRNA for all adenosine receptor subtypes. In this study, we investigated the stimulation of chloride secretion by adenosine in jejuna derived from mice lacking the adenosine receptors of A1(A1R) and A2A(A2AR) or control littermates. The jejunal epithelium was mounted in a Ussing chamber, and a new method on the basis of impedance analysis was used to calculate the short-circuit current ( Isc) values. Chloride secretion was assessed by the Iscafter inhibition of the sodium-glucose cotransporter by adding phloridzin to the apical bathing solution. The effect of apical adenosine on chloride secretion was lost in jejuna from mice lacking the A1R. There was no difference in the response to basolaterally applied adenosine or to apical forskolin. Furthermore, in jejuna from control mice, the effect of apical adenosine was also abolished in the presence of 8-cyclopentyl-1,3-dipropylxanthine, a specific A1R antagonist. Responses to adenosine were identical in jejuna from control and A2AR knockout mice. This study demonstrates that A1R (and not A2AR) mediates the enhancement of chloride secretion induced by luminal adenosine in mice jejunum.
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- Barker, CJ, et al.
(författare)
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XPR1 Mediates the Pancreatic β-Cell Phosphate Flush
- 2021
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:1, s. 111-118
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Tidskriftsartikel (refereegranskat)abstract
- Glucose-stimulated insulin secretion is the hallmark of the pancreatic β-cell, a critical player in the regulation of blood glucose concentration. In 1974, the remarkable observation was made that an efflux of intracellular inorganic phosphate (Pi) accompanied the events of stimulated insulin secretion. The mechanism behind this “phosphate flush,” its association with insulin secretion, and its regulation have since then remained a mystery. We recapitulated the phosphate flush in the MIN6m9 β-cell line and pseudoislets. We demonstrated that knockdown of XPR1, a phosphate transporter present in MIN6m9 cells and pancreatic islets, prevented this flush. Concomitantly, XPR1 silencing led to intracellular Pi accumulation and a potential impact on Ca2+ signaling. XPR1 knockdown slightly blunted first-phase glucose-stimulated insulin secretion in MIN6m9 cells, but had no significant impact on pseudoislet secretion. In keeping with other cell types, basal Pi efflux was stimulated by inositol pyrophosphates, and basal intracellular Pi accumulated following knockdown of inositol hexakisphosphate kinases. However, the glucose-driven phosphate flush occurred despite inositol pyrophosphate depletion. Finally, while it is unlikely that XPR1 directly affects exocytosis, it may protect Ca2+ signaling. Thus, we have revealed XPR1 as the missing mediator of the phosphate flush, shedding light on a 45-year-old mystery.
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- Chen, M, et al.
(författare)
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Uropathogenic Escherichia coli toxins induce caspase-independent apoptosis in renal proximal tubular cells via ERK signaling
- 2003
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Ingår i: American journal of nephrology. - : S. Karger AG. - 0250-8095 .- 1421-9670. ; 23:3, s. 140-151
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Tidskriftsartikel (refereegranskat)abstract
- <i>Background:</i> Pyelonephritis is a risk factor for renal tubular epithelial cell damage. Recent studies have shown that <i>Escherichia coli</i> and/or its toxins may stimulate apoptotic cell death in renal tubular cells, but the underlying molecular mechanisms remain to be elucidated. <i>Methods:</i> Confluent LLC-PK<sub>1</sub> cells were exposed to <i>E. coli</i> toxins from overnight cultures of the uropathogenic O6K13H1 (O6) and the nonpathogenic W3110. The cell death was studied with morphological and biological assay. <i>Results:</i><i>E. coli</i> soluble toxins from uropathogenic O6:K13:H1(O6) strain were found to induce apoptosis in a dose- and time-dependent manner in LLC-PK1 cells. The expression of FasR and the phosphorylation of ERK1/2 were significantly upregulated by O6 soluble toxins in a time-dependent manner. Cell death was completely inhibited by two specific ERK1/2 inhibitors, but not by a broad caspase inhibitor, zVAD-fmk, implicating a caspase-independent pathway via ERK. Moreover, we found that lysophosphatidic acid could trigger a survival signal through G-proteins and PI3K. <i>Conclusion:</i> We demonstrate that apoptosis induced by uropathogenic <i>E. coli</i> toxins is dependent on ERK1/2. Caspases, although being activated, are not necessary for cell death, and they act after the ERK signaling at which point cells become committed to cell death or can be rescued.
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- Dare, Anna J., et al.
(författare)
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Prioritizing Surgical Care on National Health Agendas : A Qualitative Case Study of Papua New Guinea, Uganda, and Sierra Leone
- 2016
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Little is known about the social and political factors that influence priority setting for different health services in low- and middle-income countries (LMICs), yet these factors are integral to understanding how national health agendas are established. We investigated factors that facilitate or prevent surgical care from being prioritized in LMICs. Methods and Findings: We undertook country case studies in Papua New Guinea, Uganda, and Sierra Leone, using a qualitative process-tracing method. We conducted 74 semi-structured interviews with stakeholders involved in health agenda setting and surgical care in these countries. Interviews were triangulated with published academic literature, country reports, national health plans, and policies. Data were analyzed using a conceptual framework based on four components (actor power, ideas, political contexts, issue characteristics) to assess national factors influencing priority for surgery. Political priority for surgical care in the three countries varies. Priority was highest in Papua New Guinea, where surgical care is firmly embedded within national health plans and receives significant domestic and international resources, and much lower in Uganda and Sierra Leone. Factors influencing whether surgical care was prioritized were the degree of sustained and effective domestic advocacy by the local surgical community, the national political and economic environment in which health policy setting occurs, and the influence of international actors, particularly donors, on national agenda setting. The results from Papua New Guinea show that a strong surgical community can generate priority from the ground up, even where other factors are unfavorable. Conclusions: National health agenda setting is a complex social and political process. To embed surgical care within national health policy, sustained advocacy efforts, effective framing of the problem and solutions, and country-specific data are required. Political, technical, and financial support from regional and international partners is also important.
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- Dare, E, et al.
(författare)
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Characterization of the phosphatidylinositol-specific phospholipase C isozymes present in the bovine parathyroid and in human kidney HEK293 cells stably transfected with the human parathyroid Ca2+-sensing receptor
- 1998
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Ingår i: Journal of molecular endocrinology. - : Bioscientifica. - 0952-5041 .- 1479-6813. ; 21:1, s. 7-17
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Tidskriftsartikel (refereegranskat)abstract
- The regulation of parathyroid hormone secretion by the chief cells of the parathyroid is mediated by a 7-transmembrane (7-TM) Ca2+-sensing receptor (CaR), which signals via activation of pertussis toxin-insensitive G proteins, causing stimulation of phosphatidylinositol-specific phospholipase C (PI-PLC). We have identified the PI-PLC isoforms expressed in two model systems utilized for studying CaR signal transduction, i.e. dispersed bovine parathyroid cells and a human embryonic kidney cell line (HEK 293) stably transfected with the human parathyroid CaR-cDNA. All of the eight PI-PLC isozymes examined in this study were found to be expressed to varying extents in the bovine parathyroid gland and in the CaR-transfected HEK cells as assessed by immunoblotting. We localized the expression of the more abundant isozymes (beta1, beta2, beta3, gamma1, gamma2, delta2) to the chief cells of the bovine parathyroid by immunocytochemistry, while the two less abundant isozymes (delta1, beta4) were not detectable in parathyroid sections. G proteins activated by 7-TM receptors are known to activate mainly PI-PLC of the beta class. Therefore, beta1, beta2, beta3 and beta4, all expressed in the bovine parathyroid, are candidate isozymes for coupling to the CaR. A comparison of the levels of expression of PI-PLC isozymes between CaR-transfected HEK cells and non-transfected HEK cells suggested that the expression of the CaR in this human cell line does not cause a significant up-regulation of any of the PLCbeta and PLCgamma isozymes. PLCdelta2, showing predominantly nuclear localization in the parathyroid, was the sole PI-PLC isozyme with higher levels of expression in CaR-transfected HEK cells.
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