| 1. |
- Ekström, J, et al.
(författare)
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Hyperplasia and hypertrophia in the denervated and distended rat urinary bladder
- 1984
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Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 122:1, s. 45-48
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Tidskriftsartikel (refereegranskat)abstract
- The parasympathetically denervated and distended rat urinary bladder was found to have increased fourfold in weight when examined 3 weeks postoperatively. Both in muscularis and mucosa of such a bladder the synthesis of proteins, RNA and DNA was increased severalfold. An increase in the polyamines putrescine, spermidine and spermine was also found; these polyamines are usually linked to protein synthesis. The results suggest that the cells of the two layers increase both in size and number. Hyperplasia was, in a previous study, suggested as a possible explanation for a right-ward shift of the active length-tension curve of muscle strips in the denervated rat urinary bladder.
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| 2. |
- Tucker, R P, et al.
(författare)
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See-saw rocking: an in vitro model for mechanotransduction research.
- 2014
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Ingår i: Journal of the Royal Society Interface. - : The Royal Society. - 1742-5662 .- 1742-5689. ; 11:97
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Tidskriftsartikel (refereegranskat)abstract
- In vitro mechanotransduction studies, uncovering the basic science of the response of cells to mechanical forces, are essential for progress in tissue engineering and its clinical application. Many varying investigations have described a multitude of cell responses; however, as the precise nature and magnitude of the stresses applied are infrequently reported and rarely validated, the experiments are often not comparable, limiting research progress. This paper provides physical and biological validation of a widely available fluid stimulation device, a see-saw rocker, as an in vitro model for cyclic fluid shear stress mechanotransduction. This allows linkage between precisely characterized stimuli and cell monolayer response in a convenient six-well plate format. Models of one well were discretized and analysed extensively using computational fluid dynamics to generate convergent, stable and consistent predictions of the cyclic fluid velocity vectors at a rocking frequency of 0.5 Hz, accounting for the free surface. Validation was provided by comparison with flow velocities measured experimentally using particle image velocimetry. Qualitative flow behaviour was matched and quantitative analysis showed agreement at representative locations and time points. Maximum shear stress of 0.22 Pa was estimated near the well edge, and time-average shear stress ranged between 0.029 and 0.068 Pa. Human tenocytes stimulated using the system showed significant increases in collagen and GAG secretion at 2 and 7 day time points. This in vitro model for mechanotransduction provides a versatile, flexible and inexpensive method for the fluid shear stress impact on biological cells to be studied.
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| 3. |
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| 4. |
- Diehl, Stefan, et al.
(författare)
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A one-dimensional moving-boundary model for tubulin-driven axonal growth.
- 2014
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Ingår i: Journal of Theoretical Biology. - : Elsevier BV. - 1095-8541 .- 0022-5193. ; 358:Online 21 June 2014, s. 194-207
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Tidskriftsartikel (refereegranskat)abstract
- A one-dimensional continuum-mechanical model of axonal elongation due to assembly of tubulin dimers in the growth cone is presented. The conservation of mass leads to a coupled system of three differential equations. A partial differential equation models the dynamic and the spatial behaviour of the concentration of tubulin that is transported along the axon from the soma to the growth cone. Two ordinary differential equations describe the time-variation of the concentration of free tubulin in the growth cone and the speed of elongation. All steady-state solutions of the model are categorized. Given a set of the biological parameter values, it is shown how one easily can infer whether there exist zero, one or two steady-state solutions and directly determine the possible steady-state lengths of the axon. Explicit expressions are given for each stationary concentration distribution. It is thereby easy to examine the influence of each biological parameter on a steady state. Numerical simulations indicate that when there exist two steady states, the one with shorter axon length is unstable and the longer is stable. Another result is that, for nominal parameter values extracted from the literature, in a large portion of a fully grown axon the concentration of free tubulin is lower than both concentrations in the soma and in the growth cone.
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| 5. |
- Jimenez, Javier, et al.
(författare)
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Abnormally decreased NO and augmented CO production in islets of the leptin-deficient ob/ob mouse might contribute to explain hyperinsulinemia and islet survival in leptin-resistant type 2 obese diabetes.
- 2011
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 170, s. 43-51
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Tidskriftsartikel (refereegranskat)abstract
- The role of the gaseous messengers NO and CO for β-cell function and survival is controversial. We examined this issue in the hyperglycemic-hyperinsulinemic ob/ob mouse, an animal model of type 2 obese diabetes, by studying islets from obese vs lean mice regarding glucose-stimulated insulin release in relation to islet NO and CO production and the influence of modulating peptide hormones. Glucose-stimulated increase in ncNOS-activity in incubated lean islets was converted to a decrease in ob/ob islets associated with markedly increased insulin release. Both types of islet displayed iNOS activity appearing after ~60min in high-glucose. In ob/ob islets the insulinotropic peptides glucagon, GLP-1 and GIP suppressed NOS activities and amplified glucose-stimulated insulin release. The insulinostatic peptide leptin induced the opposite effects. Suppression of islet CO production inhibited, while stimulation amplified glucose-stimulated insulin release. Nonincubated isolated islets from young and adult obese mice displayed very low ncNOS and negligible iNOS activity. In contrast, production of CO, a NOS inhibitor, was impressively raised. Glucose injections induced strong activities of islet NOS isoforms in lean but not in obese mice and confocal microscopy revealed iNOS expression only in lean islets. Islets from ob/ob mice existing in a hyperglycemic in vivo milieu maintain elevated insulin secretion and protection from glucotoxicity through a general suppression of islet NOS activities achieved by leptin deficiency, high CO production and insulinotropic cyclic-AMP-generating hormones. Such a beneficial effect on islet function and survival might have its clinical counterpart in human leptin-resistant type 2 obese diabetes with hyperinsulinemia.
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| 6. |
- Lundquist, Ingmar, et al.
(författare)
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Carbon monoxide stimulates insulin release and propagates Ca2+ signals between pancreatic beta-cells
- 2003
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Ingår i: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 285:5, s. 1055-1063
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Tidskriftsartikel (refereegranskat)abstract
- A key question for understanding the mechanisms of pulsatile insulin release is how the underlying beta-cell oscillations of the cytoplasmic Ca2+ concentration ([Ca2+](i)) are synchronized within and among the islets in the pancreas. Nitric oxide has been proposed to coordinate the activity of the beta-cells by precipitating transients of [Ca2+](i). Comparing ob/ob mice and lean controls, we have now studied the action of carbon monoxide (CO), another neurotransmitter with stimulatory effects on cGMP production. A strong immunoreactivity for the CO-producing constitutive heme oxygenase (HO-2) was found in ganglionic cells located in the periphery of the islets and in almost all islet endocrine cells. Islets from ob/ob mice had sixfold higher generation of CO ( 1 nmol.min(-1).mg protein(-1)) than the lean controls. This is 100-fold the rate for their constitutive production of NO. Moreover, islets from ob/ob mice showed a threefold increase in HO-2 expression and expressed inducible HO (HO-1). The presence of an excessive islet production of CO in the ob/ob mouse had its counterpart in a pronounced suppression of the glucose-stimulated insulin release from islets exposed to the HO inhibitor Zn-protoporhyrin (10 muM) and in a 16 times higher frequency of [Ca2+](i) transients in their beta-cells. Hemin (0.1 and 1.0 muM), the natural substrate for HO, promoted the appearance of [Ca2+](i) transients, and 10 muM of the HO inhibitors Zn-protoporphyrin and Cr-mesoporphyrin had a suppressive action both on the firing of transients and their synchronization. It is concluded that the increased islet production of CO contributes to the hyperinsulinemia in ob/ob mice. In addition to serving as a positive modulator of glucose-stimulated insulin release, CO acts as a messenger propagating Ca2+ signals with coordinating effects on the beta-cell rhythmicity.
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| 7. |
- Mosén, Henrik, et al.
(författare)
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Defective glucose-stimulated insulin release in the diabetic Goto-Kakizaki (GK) rat coincides with reduced activity of the islet carbon monoxide signaling pathway
- 2005
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:3, s. 1553-1558
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Tidskriftsartikel (refereegranskat)abstract
- The Goto-Kakizaki (GK) rat displays a markedly reduced insulin response to glucose, a defect that is thought to be coupled to an impaired glucose signaling in the beta-cell. We have examined whether carbon monoxide (CO), derived from beta-cell heme oxygenase (HO), might be involved in the secretory dysfunction. Immunocytochemical labeling of constitutive HO (HO-2) showed no overt difference in fluorescence pattern in islets from GK vs. Wistar controls. However, isolated islets from GK rats displayed a markedly impaired HO activity measured as CO production (-50%), and immunoblotting revealed an approximately 50% reduction of HO-2 protein expression compared with Wistar controls. Furthermore, there was a prominent expression of inducible HO (HO-1) in GK islets. Incubation of isolated islets showed that the glucose-stimulated CO production and the glucose-stimulated insulin response were considerably reduced in GK islets compared with Wistar islets. Addition of the HO activator hemin or gaseous CO to the incubation media brought about a similar amplification of glucose-stimulated insulin release in GK and Wistar islets, suggesting that distal steps in the HO-CO signaling pathway were not appreciably affected. We conclude that the defective insulin response to glucose in the GK rat can be explained, at least in part, by a marked impairment of the glucose-HO-CO signaling pathway as manifested by a prominent decrease in glucose stimulation of islet CO production and a reduced expression of HO-2. A possible role of HO-1 expression as a compensatory mechanism in the GK islets is presently unclear.
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| 8. |
- Mosén, Henrik, et al.
(författare)
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Impaired glucose-stimulated insulin secretion in the GK rat is associated with abnormalities in islet nitric oxide production.
- 2008
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 1873-1686 .- 0167-0115. ; 151, s. 139-146
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Tidskriftsartikel (refereegranskat)abstract
- We investigated implications of nitric oxide (NO) derived from islet neuronal constitutive NO synthase (ncNOS) and inducible NOS (iNOS) on insulin secretory mechanisms in the mildly diabetic GK rat. Islets from GK rats and Wistar controls were analysed for ncNOS and iNOS by HPLC, immunoblotting and immunocytochemistry in relation to insulin secretion stimulated by glucose or l-arginine in vitro and in vivo. No obvious difference in ncNOS fluorescence in GK vs control islets was seen but freshly isolated GK islets displayed a marked iNOS expression and activity. After incubation at low glucose GK islets showed an abnormal increase in both iNOS and ncNOS activities. At high glucose the impaired glucose-stimulated insulin release was associated with an increased iNOS expression and activity and NOS inhibition dose-dependently amplified insulin secretion in both GK and control islets. This effect by NOS inhibition was also evident in depolarized islets at low glucose, where forskolin had a further amplifying effect in GK but not in control islets. NOS inhibition increased basal insulin release in perfused GK pancreata and amplified insulin release after glucose stimulation in both GK and control pancreata, almost abrogating the nadir separating first and second phase in controls. A defective insulin response to l-arginine was seen in GK rats in vitro and in vivo, being partially restored by NOS inhibition. The results suggest that increased islet NOS activities might contribute to the defective insulin response to glucose and l-arginine in the GK rat. Excessive iNOS expression and activity might be deleterious for the beta-cells over time.
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| 9. |
- Salehi, S Albert, et al.
(författare)
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Dysfunction of the islet lysosomal system conveys impairment of glucose-induced insulin release in the diabetic GK rat
- 1999
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Ingår i: Endocrinology. - 0013-7227. ; 140:7, s. 3045-3053
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Tidskriftsartikel (refereegranskat)abstract
- Accumulated evidence links an important signal involved in glucose-stimulated insulin release to the activation of the islet lysosomal glycogenolytic enzyme acid glucan-1,4-alpha-glucosidase. We have analyzed the function of the lysosomal system/lysosomal enzyme activities in pancreatic islets of young (6-8 weeks), spontaneously diabetic, GK (Goto-Kakizaki) rats and Wistar control rats in relation to glucose-induced insulin release. The insulin secretory response to glucose was markedly impaired in the GK rat, but was restored by the adenylate cyclase activator forskolin. Islet activities of classical lysosomal enzymes, e.g.. acid phosphatase, N-acetyl-beta-D-glucosaminidase, beta-glucuronidase, and cathepsin D, were reduced by 20-35% in the GK rat compared with those in Wistar controls. In contrast, the activities of the lysosomal alpha-glucosidehydrolases, i.e.. acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase, were increased by 40-50%. Neutral alpha-glucosidase (endoplasmic reticulum) was unaffected. Comparative analysis of liver tissue showed that lysosomal enzyme activities were of the same magnitude in GK and Wistar rats. Notably, in Wistar rats, the activities of acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase were approximately 15-fold higher in islets than in liver. Other lysosomal enzymes did not display such a difference. Normalization of glycemia in GK rats by phlorizin administered for 9 days did not influence either the lysosomal alpha-glucosidehydrolase activities or other lysosomal enzyme activities in GK islets. Finally, the pseudotetrasaccharide acarbose, which accumulates in the lysosomal system, inhibited acid glucan-1,4-alpha-glucosidase activity in parallel with its inhibitory action on glucose-induced insulin release in intact Wistar islets, whereas no effect was recorded for either parameter in intact GK islets. In contrast, acarbose inhibited the enzyme activity equally in islet homogenates from both GK and Wistar rats, showing that the catalytic activity of the enzyme itself in disrupted cells was unaffected. We propose that dysfunction of the islet lysosomal/vacuolar system is an important defect impairing the transduction mechanisms for glucose-induced insulin release in the GK rat.
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| 10. |
- Salehi, S Albert, et al.
(författare)
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Total parenteral nutrition modulates hormone release by stimulating expression and activity of inducible nitric oxide synthase in rat pancreatic islets
- 2001
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Ingår i: Endocrine. - 1355-008X. ; 16:2, s. 97-104
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Tidskriftsartikel (refereegranskat)abstract
- The expression and activities of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) in relation to insulin and glucagon secretory mechanisms were investigated in islets isolated from rats subjected to total parenteral nutrition (TPN) for 10 d. TPN is known to result in significantly increased levels of plasma lipids during the infusion time. In comparison with islets from freely fed control rats, islets taken from TPN rats at d 10 displayed a marked decrease in glucose-stimulated insulin release (4.65 +/- 0.45 ng/[islet x h] vs 10.25 +/- 0.65 for controls) (p < 0.001) accompanied by a strong iNOS activity (18.3 +/- 1.1 pmol of NO/[min x mg of protein]) and a modestly reduced cNOS activity (11.3 +/- 3.2 pmol of NO/[min x mg of protein] vs 17.7 +/- 1.7 for controls) (p < 0.01). Similarly, Western blots showed the expression of iNOS protein as well as a significant reduction in cNOS protein in islets from TPN-treated rats. The enhanced NO production, which is known to inhibit glucose-stimulated insulin release, was manifested as a strong increase in the cyclic guanosine 5'-monophosphate content in the islets of TPN-treated rats (1586 +/- 40 amol/islet vs 695 +/- 64 [p < 0.001] for controls). Moreover, the content of cyclic adenosine monophosphate (cAMP) was greatly increased in the TPN islets (80.4 +/- 2.1 fmol/islet vs 42.6 +/- 2.6 [p < 0.001] for controls). The decrease in glucose-stimulated insulin release was associated with an increase in the activity of the secretory pathway regulated by the cAMP system in the islets of TPN-treated rats, since the release of insulin stimulated by the phosphodiesterase inhibitor isobutylmethylxanthine was greatly increased both in vivo after iv injection and after in vitro incubation of isolated islets. By contrast, the release of glucagon was clearly reduced in islets taken from TPN-treated rats (33.5 +/- 1.5 pg/[islet x h] vs 45.5 +/- 2.2 for controls) (p < 0.01) when islets were incubated at low glucose (1.0 mmol/L). The data show that long-term TPN treatment in rats brings about impairment of glucose-stimulated insulin release, that might be explained by iNOS expression and a marked iNOS-derived NO production in the beta-cells. The release of glucagon, on the other hand, is probably decreased by a direct "nutrient effect" of the enhanced plasma lipids. The results also suggest that the islets of TPN-treated rats have developed compensatory insulin secretory mechanisms by increasing the activity of their beta-cell cAMP system.
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