| 1. |
- Islam, M. Shahidul, et al.
(författare)
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Engineered beta-cells secreting dipeptidyl peptidase IV-resistant glucagon-like peptide-1 show enhanced glucose-responsiveness
- 2005
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Ingår i: Life Sciences. - : Elsevier BV. - 0024-3205 .- 1879-0631. ; 76:11, s. 1239-1248
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes is a polygenic disorder characterized by increased insulin resistance, and impaired insulin secretion leading to abnormalities of glucose and lipid metabolism. Reduced responsiveness of the beta-cells to glucose is a critical feature of this syndrome. Glucagon-like peptide 1, a product of the pro-glucagon gene makes beta-cells competent and has many other anti-diabetic properties. We speculated whether GLP-1-based gene therapy could be an approach for treatment of type 2 diabetes. We started with a clone of rat insulinoma cells (S4 cells), which showed reduced responsiveness to glucose in terms of insulin secretion. We transfected these cells with a plasmid encoding a mutated form of GLP-1 (GLP-1-Gly8), which is resistant to the degrading enzyme dipeptidyl-peptidase IV. Activity of secreted GLP-1-Gly8 was assayed using Chinese hamster lung fibroblasts (CHL) cells that expressed cloned GLP-1 receptor and that were transfected with CRE-Luc. Stable cell lines (Glipsulin cells) obtained by this means produced and stored immunoreactive GLP-1-Gly8. In addition to insulin, the Glipsulin cells secreted the GLP-1-Gly8. The secreted GLP-1-Gly8 was active as evidenced by the ability of the conditioned media to elevate cAMP levels in CHL cells expressing GLP-1 receptors. Glipsulin cells responded to glucose with a 6.8 fold increase in insulin secretion compared to a 2.2 fold increase in the control cells. Our results demonstrate that prolonged exposure to GLP-1-Gly8 secreted by increases glucose-responsiveness of these cells. We speculate that engineering GLP-1-Gly8 secretion by beta-cells is a potential gene therapeutic strategy to treat diabetes.
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| 2. |
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| 3. |
- Islam, M. Shahidul, et al.
(författare)
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Is road-side fishpond water in Bangladesh safe for human use? An assessment using water quality indices
- 2022
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Ingår i: Environmental Challenges. - : Elsevier BV. - 2667-0100. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Pond water is used in everyday life by many people in Bangladesh, however, without sufficient and reliable information regarding water quality and pollution status. For this reason, geospatial analysis and mapping of water quality indices such as metal (MI), contamination (Cd), and physicochemical water quality index (WQI) were assessed to improve the understanding of potential pollution sources. Samples were collected from twenty randomly selected ponds situated in Jashore Sadar Upazila, Bangladesh. Nineteen (19) water quality parameters were measured, including pH, temperature, EC, TDS, total suspended solids (TSS), chloride, alkalinity, total hardness, salinity, Fe, Mn, Pb, Cr, Cd, Co, Zn, Ag, Ni, and Cu. The average concentration of Fe, Mn, Pb, Cd, and Ag was much higher than recommended standards. The WQI ranged from 1.59-5.27, Cd from -0.19-18.28, and MI from 7.81-26.28. The spatial distribution of MI indicates that the south-western and south-eastern region of the study area are stands out with a very high pollution pressure. The spatial distribution of Cd, follows the same trend as for MI. A multitude of different types of pollution sources contributes to the high pollution load such as, municipal wastewater, leachate from landfills, small industry wastewater and stormwater, and agricultural runoff. The studied pond water is highly polluted and not suitable for household use and fish consumption.
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| 4. |
- Islam, M. Shahidul, et al.
(författare)
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Multiple reuse of disposable insulin syringes in hospital
- 1990
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Ingår i: Bangladesh Medical Research Council bulletin. - 0377-9238. ; 16:2, s. 58-61
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Tidskriftsartikel (refereegranskat)abstract
- In a prospective study disposable insulin syringes were repeatedly used for injecting insulin to 92 insulin-taking diabetic patients admitted in hospital with various illnesses. One separate syringe was used for each patient; the syringes were not washed or boiled and were not kept in spirit or in refrigerator during reuse. Syringes were flushed with air, needle recapped and replaced into their plastic cover. Number of injections made using one syringe was 2 to 120 (mean 31.3, SEM 2.3). For the patients' total insulin - taking period in hospital one disposable syringe per patient was enough in all but six cases. There were 2792 reinjections and incidence of infection of the injection site was zero.
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| 5. |
- Islam, M. Shahidul, et al.
(författare)
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Rat insulinoma-derived pancreatic beta-cells express a functional leptin receptor that mediates a proliferative response
- 1997
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 238:3, s. 851-855
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Tidskriftsartikel (refereegranskat)abstract
- In addition to its interaction at hypothalamic sites to affect feeding and energy expenditure, leptin has been shown to exhibit a proliferative response in erythropoietic cells. The functional leptin receptor is also present in pancreatic islets and we now demonstrate that a commonly used clonal insulin secreting beta-cell line, RINm5F, expresses high levels of the Ob-Rb mRNA. Leptin causes an increase in tyrosine phosphorylation of a number of intracellular proteins and a dose related (10 nM-200 nM) increase in expression of the immediate-early gene, c-fos. This precedes a leptin induced proliferative response in serum-deprived RINm5F cells, which suggests that leptin might be involved in the complex regulation of proliferation of the pancreatic beta-cell.
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| 6. |
- Islam, M. Shahidul, et al.
(författare)
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Spatial Distribution and Source Identification of Water Quality Parameters of an Industrial Seaport Riverbank Area in Bangladesh
- 2022
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Ingår i: Water (Switzerland). - : MDPI AG. - 2073-4441. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- The Pasur River is a vital reservoir of surface water in the Sundarbon area in Bangladesh. Mongla seaport is located on the bank of this river. Many industries and other commercial sectors situated in this port area are discharging waste into the river without proper treatment. For this reason, geospatial analysis and mapping of water pollutant distribution were performed to assess the physicochemical and toxicological situation in the study area. We used different water quality indices such as Metal Index (MI), Comprehensive Pollution Index (CPI), and Weighted Arithmetic Water Quality Index Method (WQI) to improve the understanding of pollution distribution and processes determining the quality of river water. Multivariate statistical methods were used to evaluate loads and sources of pollutants in the Pasur River system. The results indicate that the sources of contaminants are both geogenic and anthropogenic, including untreated or poorly treated wastewater from industries and urban domestic waste discharge. The concentration range of total suspended solid (TSS), chloride, iron (Fe), and manganese (Mn) were from 363.2 to 1482.7, 108.2 to 708.93, 1.13 to 2.75, and 0.19 to 1.41 mg/L, respectively, significantly exceeding the health-based guideline of WHO and Bangladeshi standards. The high Fe and Mn contents are contributions from geogenic and anthropogenic sources such as industrial waste and construction activities. The average pH value was 8.73, higher than the WHO and Bangladeshi standard limit. WQI (ranging from 391 to 1336), CPI (6.71 to 23.1), and MI (7.23 to 23.3) were very high and greatly exceeded standard limits indicating that the Pasur River water is highly polluted. The results of this study can be used as a first reference work for developing a surface water quality monitoring system and guide decisionmakers for priorities regarding wastewater treatment.
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| 7. |
- Islam, M. Shahidul, et al.
(författare)
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Toxicity and source identification of pollutants in an urban river in Bangladesh
- 2023
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Ingår i: Environmental Earth Sciences. - : Springer Science and Business Media LLC. - 1866-6280 .- 1866-6299. ; 82:6
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Tidskriftsartikel (refereegranskat)abstract
- Urban rivers in Asian developing countries are becoming increasingly polluted due to industrialization and lacking treatment of wastewater. We investigated toxicity and likely sources of pollutants for the urban Shitalakshaya River, Bangladesh. Physiochemical variables and heavy metals were examined in water and sediment of an urban river section in Narayanganj City. The spatial distribution of quality indices and cluster groups indicates that the river’s downstream urban-affected areas are the most contaminated. Water and sediment quality guidelines indicate that COD, TSS, Fe, Pb, Zn in water, and Pb, Co, Ni, Cu, Zn, and particularly Pb and Cu in sediment, pose a serious threat to the aquatic ecosystem and human health in the area. Correlation, principal component (PCA), and cluster analysis (CA) indicate that the sources of Mn and Cd are geogenic, COD, TSS, Pb, Zn, Cu anthropogenic, and Fe, Ni, Co both geogenic and anthropogenic. The main anthropogenic pollution sources of the study area are municipal and industrial wastewater, boat and car traffic, runoff from agricultural areas, and stormwater runoff.
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| 8. |
- Webb, Dominic-Luc, et al.
(författare)
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Insulin exocytosis and glucose-mediated increase in cytoplasmic free Ca2+ concentration in the pancreatic beta-cell are independent of cyclic ADP-ribose
- 1996
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Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 271:32, s. 19074-19079
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Tidskriftsartikel (refereegranskat)abstract
- Stimulation of pancreatic beta-cells by glucose gives rise to an increase in the cytoplasmic free calcium concentration ([Ca2+]i) and exocytosis of insulin. Cyclic adenosine 5'-diphosphate ribose (cADPR), a metabolite of beta-NAD+, has been reported to increase [Ca2+]i in pancreatic beta-cells by releasing Ca2+ from inositol 1,4,5-trisphosphate-insensitive intracellular stores. In the present study, we have examined the role of cADPR in glucose-mediated increases in [Ca2+]i and insulin exocytosis. Dispersed ob/ob mouse beta-cell aggregates were either pressure microinjected with fura-2 salt or loaded with fura-2 acetoxymethyl ester, and [Ca2+]i was monitored by microfluorimetry. Microinjection of beta-NAD+ into fura-2-loaded beta-cells did not increase [Ca2+]i nor did it alter the cells' subsequent [Ca2+]i response to glucose. Cells microinjected with the cADPR antagonist 8NH2-cADPR increased [Ca2+]i in response to glucose equally well as those injected with cADPR. Finally, the ability of cADPR to promote exocytosis of insulin in electropermeabilized beta-cells was investigated. cADPR on its own did not increase insulin secretion nor did it potentiate Ca2+-induced insulin secretion. We conclude that cADPR neither plays a significant role in glucose-mediated increases in [Ca2+]i nor interacts directly with the molecular mechanisms regulating exocytosis of insulin in normal pancreatic beta-cells.
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| 9. |
- Azad Khan, A. K., et al.
(författare)
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Predicting first professional M.B.B.S. examination score from the results of H.S.C. examination
- 1980
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Ingår i: Bangladesh Medical Research Council Bulletin. - 0377-9238. ; 6:2, s. 61-72
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Tidskriftsartikel (refereegranskat)abstract
- In a retrospective study carried out in Chittagong Medical College the results of HSC and First-Professional MBBS examination of 725 students were analysed. It was concluded from the analysis that if standard of HSC examination is well maintained the results of the said examination correlates well with students' performance in the First Professional MBBS examination. An analysis of admission into Chittagong Medical College in past 20 academic sessions has been made which shows that an increasing number of students securing high marks in HSC are being admitted into Medical College during recent years. The marking standard of HSC examination has however remained fairly uniform over the years except during early post-liberation period.
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| 10. |
- Azad Khan, A. K., et al.
(författare)
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Stool findings in "chronic dysentery"
- 1981
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Ingår i: Bangladesh Medical Research Council Bulletin. - 0377-9238. ; 7:1, s. 7-11
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Tidskriftsartikel (refereegranskat)abstract
- Faecal samples from 63 subjects with self-diagnosis of "chronic dysentery" and 50 control subjects were examined under light microscope. Vegetative form of E.h. was not detected in any of them. E.h. cyst was found in 6.3% of the "chronic dysentery" subjects and in 16% of the control subjects. E. coli and Giardia were also detected less often in the "chronic dysentery" than the control subjects. Lower incidence of protozoa namely E.h. cyst, E. coli cyst or Giardia in the former group was probably due to frequent intake of antiamoebic agents which are also effective against other intestinal protozoa. Incidence of Ascaris, hookworm, and Trichuris was not appreciably different in the two groups. More subjects in the "chronic dysentery" group had normal stool findings (31%) as compared to the control subjects (16%). It has been inferred that E.h. infection is not the cause of symptoms of "chronic dysentery".
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| 11. |
- Bari, Muhammad R., et al.
(författare)
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H2O2-induced Ca2+ influx and its inhibition by N-(p-amylcinnamoyl) anthranilic acid in the beta-cells : involvement of TRPM2 channels
- 2009
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Ingår i: Journal of Cellular and Molecular Medicine. - : Wiley. - 1582-1838 .- 1582-4934. ; 13:9B, s. 3260-3267
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 melastatin-related transient receptor potential channel (TRPM2), a member of the melastatin-related TRP (transient receptor potential) subfamily is a Ca(2+)-permeable channel activated by hydrogen peroxide (H(2)O(2)). We have investigated the role of TRPM2 channels in mediating the H(2)O(2)-induced increase in the cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) in insulin-secreting cells. In fura-2 loaded INS-1E cells, a widely used model of beta-cells, and in human beta-cells, H(2)O(2) increased [Ca(2+)](i), in the presence of 3 mM glucose, by inducing Ca(2+) influx across the plasma membrane. H(2)O(2)-induced Ca(2+) influx was not blocked by nimodipine, a blocker of the L-type voltage-gated Ca(2+) channels nor by 2-aminoethoxydiphenyl borate, a blocker of several TRP channels and store-operated channels, but it was completely blocked by N-(p-amylcinnamoyl)anthranilic acid (ACA), a potent inhibitor of TRPM2. Adenosine diphosphate phosphate ribose, a specific activator of TRPM2 channel and H(2)O(2), induced inward cation currents that were blocked by ACA. Western blot using antibodies directed to the epitopes on the N-terminal and on the C-terminal parts of TRPM2 identified the full length TRPM2 (TRPM2-L), and the C-terminally truncated TRPM2 (TRPM2-S) in human islets. We conclude that functional TRPM2 channels mediate H(2)O(2)-induced Ca(2+) entry in beta-cells, a process potently inhibited by ACA.
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| 12. |
- Bruton, Joseph D., et al.
(författare)
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Ryanodine receptors of pancreatic beta-cells mediate a distinct context-dependent signal for insulin secretion
- 2003
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 17:2, s. 301-303
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Tidskriftsartikel (refereegranskat)abstract
- The ryanodine (RY) receptors in beta-cells amplify signals by Ca2+-induced Ca2+ release (CICR). The role of CICR in insulin secretion remains unclear in spite of the fact that caffeine is known to stimulate secretion. This effect of caffeine is attributed solely to the inhibition of cAMP-phosphodiesterases (cAMP-PDEs). We demonstrate that stimulation of insulin secretion by caffeine is due to a sensitization of the RY receptors. The dose-response relationship of caffeine-induced inhibition of cAMP-PDEs was not correlated with the stimulation of insulin secretion. Sensitization of the RY receptors stimulated insulin secretion in a context-dependent manner, that is, only in the presence of a high concentration of glucose. This effect of caffeine depended on an increase in [Ca2+]i. Confocal images of beta-cells demonstrated an increase in [Ca2+]i induced by caffeine but not by forskolin. 9-Methyl-7-bromoeudistomin D (MBED), which sensitizes RY receptors, did not inhibit cAMP-PDEs, but it stimulated secretion in a glucose-dependent manner. The stimulation of secretion by caffeine and MBED involved both the first and the second phases of secretion. We conclude that the RY receptors of beta-cells mediate a distinct glucose-dependent signal for insulin secretion and may be a target for developing drugs that will stimulate insulin secretion only in a glucose-dependent manner.
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| 13. |
- Gustafsson, Amanda Jabin, et al.
(författare)
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Cellens kalciumjonsignalering : från grundforskning till patientnytta
- 2005
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Ingår i: Läkartidningen. - 0023-7205 .- 1652-7518. ; 102:44, s. 3214-3219
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Tidskriftsartikel (refereegranskat)abstract
- A large number of ion channels, enzymes, pumps and binding proteins participate in the generation of intracellular Ca2+ signals and their decoding. Ca2+ signalling takes place in the form of oscillations, waves and sparks. Such Ca2+ signals occur in almost all cells and regulate diverse cell functions. Perturbation of Ca2+ signalling leads to disease states. Drugs that act on Ca2+-signalling are commonly used in treatment of several diseases. Different molecules involved in Ca2+ signalling are potential targets for development of new therapies. Thus, basic research in Ca2+ signalling increases our understanding of the pathogenesis of diseases at a molecular level and the likelihood of development of new therapeutic modalities.
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| 14. |
- Gustafsson, Amanda Jabin, et al.
(författare)
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Ryanodine receptor-operated activation of TRP-like channels can trigger critical Ca2+ signaling events in pancreatic beta-cells
- 2005
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 19:2, s. 301-303
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Tidskriftsartikel (refereegranskat)abstract
- There is little information available concerning the link between the ryanodine (RY) receptors and the downstream Ca(2+) signaling events in beta-cells. In fura-2 loaded INS-1E cells, activation of RY receptors by 9-methyl 5,7-dibromoeudistomin D (MBED) caused a rapid rise of [Ca(2+)]i followed by a plateau and repetitive [Ca(2+)]i spikes on the plateau. The [Ca(2+)]i plateau was abolished by omission of extracellular Ca(2+) and by SKF 96365. In the presence of SKF 96365, MBED produced a transient increase of [Ca(2+)]i, which was abolished by thapsigargin. Activation of RY receptors caused Ca(2+) entry even when the ER Ca(2+) pool was depleted by thapsigargin. The [Ca(2+)]i plateau was not inhibited by nimodipine or ruthenium red, but was inhibited by membrane depolarization, La(3+), Gd(3+), niflumic acid, and 2-aminoethoxydiphenyl borate, agents that inhibit the transient receptor potential channels. The [Ca(2+)]i spikes were inhibited by nimodipine and ryanodine, indicating that they were due to Ca(2+) influx through the voltage-gated Ca(2+) channels and Ca(2+)-induced Ca(2+) release (CICR). Activation of RY receptors depolarized membrane potential as measured by patch clamp. Thus, activation of RY receptors leads to coherent changes in Ca(2+) signaling, which includes activation of TRP-like channels, membrane depolarization, activation of the voltage-gated Ca(2+) channels and CICR.
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| 15. |
- Haby, Christelle, et al.
(författare)
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Inhibition of serine/threonine protein phosphatases promotes opening of voltage-activated L-type Ca2+ channels in insulin-secreting cells
- 1994
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 298:Pt 2, s. 341-346
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Tidskriftsartikel (refereegranskat)abstract
- The biological activity of many proteins, including voltage-sensitive ion channels, is controlled by their state of phosphorylation. Ca2+ influx through voltage-activated L-type Ca2+ channels serves as the major stimulatory signal in insulin-secreting cells. We have now investigated the extent to which Ca2+ handling in clonal insulin-secreting RiNm5F cells was affected by okadaic acid, an inhibitor of various serine/threonine protein phosphatases. Whole-cell patch-clamp experiments showed that okadaic acid generated an increase in membrane current, suggesting that it promotes Ca2+ influx through L-type voltage-gated Ca2+ channels probably by modifying their phosphorylation state. Okadaic acid was found to provoke a transient rise in the cytoplasmic free Ca2+ concentration ([Ca2+]i) but had no further effect on the K(+)-induced increase. The Ca2+ transient induced by okadaic acid was dependent on the presence of extracellular Ca2+ and was abolished by D600, a blocker of voltage-activated L-type Ca2+ channels. Concomitant with the rise in [Ca2+]i, okadaic acid induced insulin secretion, a phenomenon that was also dependent on extracellular Ca2+. It is proposed that hyperphosphorylation of voltage-activated L-type Ca2+ channels in insulin-secreting cells lowers the threshold potential for their activation.
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| 16. |
- Islam, M. Shahidul, et al.
(författare)
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Ca(2+)-induced Ca2+ release in insulin-secreting cells
- 1992
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Ingår i: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 296:3, s. 287-291
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Tidskriftsartikel (refereegranskat)abstract
- The sulphydryl reagent thimerosal (50 microM) released Ca2+ from a non-mitochondrial intracellular Ca2+ pool in a dose-dependent manner in permeabilized insulin-secreting RINm5F cells. This release was reversed after addition of the reducing agent dithiothreitol. Ca2+ was released from an Ins(1,4,5)P3-insensitive pool, since release was observed even after depletion of the Ins(1,4,5)P3-sensitive pool by a supramaximal dose of Ins(2,4,5)P3 or thapsigargin. The Ins(1,4,5)P3-sensitive pool remained essentially unaltered by thimerosal. Thimerosal-induced Ca2+ release was potentiated by caffeine. These findings suggest the existence of Ca(2+)-induced Ca2+ release also in insulin-secreting cells.
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| 17. |
- Islam, M. Shahidul
(författare)
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Calcium signaling in the islets
- 2010
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Ingår i: Advances in Experimental Medicine and Biology. - Dordrecht : Springer Netherlands. - 0065-2598 .- 2214-8019. ; 654, s. 235-259
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Tidskriftsartikel (refereegranskat)abstract
- Easy access to rodent islets and insulinoma cells and the ease of measuring Ca(2+) by fluorescent indicators have resulted in an overflow of data that have clarified minute details of Ca(2+) signaling in the rodent islets. Our understanding of the mechanisms and the roles of Ca(2+) signaling in the human islets, under physiological conditions, has been hugely influenced by uncritical extrapolation of the rodent data obtained under suboptimal experimental conditions. More recently, electrophysiological and Ca(2+) studies have elucidated the ion channel repertoire relevant for Ca(2+) signaling in the human islets and have examined their relative importance. Many new channels belonging to the transient receptor potential (TRP) family are present in the beta-cells. Ryanodine receptors, nicotinic acid adenine dinucleotide phosphate channel, and Ca(2+)-induced Ca(2+) release add new dimension to the complexity of Ca(2+) signaling in the human beta-cells. A lot more needs to be learnt about the roles of these new channels and CICR, not because that will be easy but because that will be difficult. Much de-learning will also be needed. Human beta-cells do not have a resting state in the normal human body even under physiological fasting conditions. Their membrane potential under physiologically relevant resting conditions is approximately -50 mV. Biphasic insulin secretion is an experimental epiphenomenon unrelated to the physiological pulsatile insulin secretion into the portal vein in the human body. Human islets show a wide variety of electrical activities and patterns of [Ca(2+)](i) changes, whose roles in mediating pulsatile secretion of insulin into the portal vein remain questionable. Future studies will hopefully be directed toward a better understanding of Ca(2+) signaling in the human islets in the context of the pathogenesis and treatment of human diabetes.
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| 18. |
- Islam, M. Shahidul, et al.
(författare)
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Coprostanol adsorption behavior in agricultural soil, riverbed sediment, and sand
- 2023
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Ingår i: Journal of Environmental Chemical Engineering. - 2213-3437. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- The occurrence of coprostanol in soil, surface, and groundwater has recently been reported in several studies. Coprostanol indicates the presence of feces from mammals. For this reason, it is important to establish adsorption behavior in different kinds of geologic media. To our knowledge, we present for the first-time adsorption behavior of coprostanol in soil, sediment, and sand and an estimation of its potential bioavailability, fate, and transport behavior. Adsorption experiments were conducted in agricultural soil, riverbed sediment, and sandy soil samples. The Henry model fitted experimental adsorption curves best for soil and sediment samples. Henry adsorption coefficients (KD) were 193.7 L kg−1 for soil, 120.8 L kg−1 for sediment, and 94.8 L kg−1 for sand, which suggests that the adsorption of coprostanol is different in soil (high absorption), sediment (medium), and sand (low). Further, results showed that the Freundlich model fits observed adsorption better as compared to the Langmuir model, indicating that the sorption process is of the multilayer type for the heterogenous surface of soil sample. The Langmuir model fitted best the adsorption in sediment, and sand. This supports the hypothesis that the process here is of a monolayer adsorption type. The mean maximum sorption capacity estimated by the Langmuir model was 345.1 µg g−1 for soil, 133.2 µg g−1 for sediment, and 80.9 µg g−1 for sand. The high adsorption capacity of coprostanol in soil is predominantly controlled by organic matter, high CEC, clay content, possible intermolecular H-bonding, and hydrophobic interaction. The organic carbon content normalized sorption coefficient (KOC) revealed that coprostanol is considered a sub-high adsorbed and slightly mobile compound that has leaching properties and can migrate to groundwater posing potential risks to the groundwater system.
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| 19. |
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| 20. |
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| 21. |
- Islam, M. Shahidul, et al.
(författare)
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Cyclic ADP-ribose in beta cells
- 1993
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Ingår i: Science. - 0036-8075 .- 1095-9203. ; 262:5133, s. 584-586
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Tidskriftsartikel (refereegranskat)
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| 22. |
- Islam, M. Shahidul
(författare)
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Drug policy in the Third World
- 1985
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 2:8445, s. 46-47
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Tidskriftsartikel (refereegranskat)
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| 23. |
- Islam, M. Shahidul, et al.
(författare)
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Effects of caffeine on cytoplasmic free Ca2+ concentration in pancreatic beta-cells are mediated by interaction with ATP-sensitive K+ channels and L-type voltage-gated Ca2+ channels but not the ryanodine receptor
- 1995
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Ingår i: Biochemical Journal. - : Portland Press Ltd.. - 0264-6021 .- 1470-8728. ; 306:Pt 3, s. 679-686
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Tidskriftsartikel (refereegranskat)abstract
- In the pancreatic beta-cell, an increase in the cytoplasmic free Ca2+ concentration ([Ca2+]i) by caffeine is believed to indicate mobilization of Ca2+ from intracellular stores, through activation of a ryanodine receptor-like channel. It is not known whether other mechanisms, as well, underlie caffeine-induced changes in [Ca2+]i. We studied the effects of caffeine on [Ca2+]i by using dual-wavelength excitation microfluorimetry in fura-2-loaded beta-cells. In the presence of a non-stimulatory concentration of glucose, caffeine (10-50 mM) consistently increased [Ca2+]i. The effect was completely blocked by omission of extracellular Ca2+ and by blockers of the L-type voltage-gated Ca2+ channel, such as D-600 or nifedipine. Depletion of agonist-sensitive intracellular Ca2+ pools by thapsigargin did not inhibit the stimulatory effect of caffeine on [Ca2+]i. Moreover, this effect of caffeine was not due to an increase in cyclic AMP, since forskolin and 3-isobutyl-1-methylxanthine (IBMX) failed to raise [Ca2+]i in unstimulated beta-cells. In beta-cells, glucose and sulphonylureas increase [Ca2+]i by causing closure of ATP-sensitive K+ channels (KATP channels). Caffeine also caused inhibition of KATP channel activity, as measured in excised inside-out patches. Accordingly, caffeine (> 10 mM) induced insulin release from beta-cells in the presence of a non-stimulatory concentration of glucose (3 mM). Hence, membrane depolarization and opening of voltage-gated L-type Ca2+ channels were the underlying mechanisms whereby the xanthine drug increased [Ca2+]i and induced insulin release. Paradoxically, in glucose-stimulated beta-cells, caffeine (> 10 mM) lowered [Ca2+]i. This effect was due to the fact that caffeine reduced depolarization-induced whole-cell Ca2+ current through the L-type voltage-gated Ca2+ channel in a dose-dependent manner. Lower concentrations of caffeine (2.5-5.0 mM), when added after glucose-stimulated increase in [Ca2+]i, induced fast oscillations in [Ca2+]i. The latter effect was likely to be attributable to the cyclic AMP-elevating action of caffeine, leading to phosphorylation of voltage-gated Ca2+ channels. Hence, in beta-cells, caffeine-induced changes in [Ca2+]i are not due to any interaction with intracellular Ca2+ pools. In these cells, a direct interference with KATP channel- and L-type voltage-gated Ca(2+)-channel activity is the underlying mechanism by which caffeine increases or decreases [Ca2+]i.
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| 24. |
- Islam, M. Shahidul, et al.
(författare)
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Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells
- 2000
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 24:10, s. 1246-1253
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Previous studies have demonstrated that leptin can stimulate proliferation of insulin-secreting tumor cell lines. The objective of this study was to characterize whether leptin could stimulate proliferation of primary beta-cells too. Since adult beta-cells have very limited capacity for replication, we examined the effect of leptin on islets of Langerhans obtained from fetal rats, in a tissue culture system. METHODS: Leptin receptor mRNA and c-fos mRNA were measured by RT-PCR. Proliferation of fetal rat islet cells was measured by a WST-1 colorimetric assay and [3H]-thymidine incorporation assay. RESULTS: Leptin stimulated proliferation of serum-deprived fetal rat islet cells, as indicated by increased formation of formazan dye from a tetrazolium salt WST-1. Leptin stimulated DNA synthesis in islet cells, as indicated by increased [3H]-thymidine incorporation into DNA. The effect of leptin on islet cell proliferation was on average 39-50% of the effect obtained with 10% fetal bovine serum. Leptin increased c-fos mRNA expression by 2.8-fold in isolated fetal islets after 30 min treatment. In fetal pancreatic islets, both the common extracellular portion (OB-R) and the intact long form (OB-Rb) of the leptin receptor were readily detected by reverse transcriptase polymerase chain reaction. CONCLUSION: Functional leptin receptors are expressed in pancreatic islet cells, as early as during the fetal stage of development of these microorgans. Leptin stimulates proliferation of fetal islet cells and might play a role in determining islet cell mass at birth.
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| 25. |
- Islam, M. Shahidul, et al.
(författare)
-
In situ activation of the type 2 ryanodine receptor in pancreatic beta cells requires cAMP-dependent phosphorylation
- 1998
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 95:11, s. 6145-6150
-
Tidskriftsartikel (refereegranskat)abstract
- Molecular mechanisms that regulate in situ activation of ryanodine receptors (RY) in different cells are poorly understood. Here we demonstrate that caffeine (10 mM) released Ca2+ from the endoplasmic reticulum (ER) in the form of small spikes in only 14% of cultured fura-2 loaded beta cells from ob/ob mice. Surprisingly, when forskolin, an activator of adenylyl cyclase was present, caffeine induced larger Ca2+ spikes in as many as 60% of the cells. Forskolin or the phosphodiesterase-resistant PKA activator Sp-cAMPS alone did not release Ca2+ from ER. 4-Chloro-3-ethylphenol (4-CEP), an agent that activates RYs in other cell systems, released Ca2+ from ER, giving rise to a slow and small increase in [Ca2+]i in beta cells. Prior exposure of cells to forskolin or caffeine (5 mM) qualitatively altered Ca2+ release by 4-CEP, giving rise to Ca2+ spikes. In glucose-stimulated beta cells forskolin induced Ca2+ spikes that were enhanced by 3,9-dimethylxanthine, an activator of RYs. Analysis of RNA from islets and insulin-secreting betaTC-3-cells by RNase protection assay, using type-specific RY probes, revealed low-level expression of mRNA for the type 2 isoform of the receptor (RY2). We conclude that in situ activation of RY2 in beta cells requires cAMP-dependent phosphorylation, a process that recruits the receptor in a functionally operative form.
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| 26. |
- Islam, M. Shahidul, et al.
(författare)
-
Interaction with the inositol 1,4,5-trisphosphate receptor promotes Ca2+ sequestration in permeabilised insulin-secreting cells
- 1991
-
Ingår i: FEBS Letters. - 0014-5793 .- 1873-3468. ; 288:1-2, s. 27-29
-
Tidskriftsartikel (refereegranskat)abstract
- Electropermeabilised insulin-secreting RINm5F cells sequestered Ca2+, resulting in a steady-state level of the ambient free Ca2+ concentration corresponding to 723 +/- 127 nM (mean +/- SEM, n = 10), as monitored by a Ca(2+)-selective minielectrode. Inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) promoted a rapid and pronounced release of Ca2+. This Ca2+ was resequestered and a new steady-state Ca2+ level was attained, which was always lower (460 +/- 102 nM, n = 10, P less than 0.001) than the steady-state Ca2+ level maintained before the addition of Ins(1,4,5)P3. Whereas the initial reuptake of Ca2+ subsequent to Ins(1,4,5)P3 stimulation was relatively slow, the later part of reuptake was fast as compared to the reuptake phases of a pulse addition of extraneous Ca2+. In the latter case the uptake of Ca2+ resulted in a steady-state level similar to that found in the absence of Ins(1,4,5)P3. Addition of Ins(1,4,5)P3 under this condition resulted in a further Ca2+ uptake and thus a lower steady-state Ca2+ level. Heparin, which binds to the Ins(1,4,5)P3 receptor, also lowered the steady-state free Ca2+ concentration. In contrast to Ins(1,4,5)P3, inositol 1,3,4,5-tetrakisphosphate was without effect on Ca2+ sequestration. These findings are consistent with the presence of a high-affinity Ins(1,4,5)P3 receptor promoting continuous release of Ca2+ under basal conditions and/or the Ins(1,4,5)P3 receptor being actively involved in Ca2+ sequestration.
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| 27. |
- Islam, M. Shahidul, et al.
(författare)
-
Mobilization of Ca2+ by thapsigargin and 2,5-di-(t-butyl)-1,4-benzohydroquinone in permeabilized insulin-secreting RINm5F cells : evidence for separate uptake and release compartments in inositol 1,4,5-trisphosphate-sensitive Ca2+ pool
- 1993
-
Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 293:Pt 2, s. 423-429
-
Tidskriftsartikel (refereegranskat)abstract
- We characterized and directly compared the Ca(2+)-releasing actions of two inhibitors of endoplasmic-reticulum (ER) Ca(2+)-ATPase, thapsigargin and 2,5-di-(t-butyl)-1,4-benzohydroquinone (tBuBHQ), in electropermeabilized insulin-secreting RINm5F cells. Ambient free calcium concentration ([Ca2+]) was monitored by Ca(2+)-selective mini-electrodes. After ATP-dependent Ca2+ uptake, thapsigargin and tBuBHQ released Ca2+ with and EC50 of approximately 37 nM and approximately 2 microM respectively. Both agents mobilized Ca2+ predominantly from the Ins(1,4,5)P3-sensitive Ca2+ pool, and in this respect thapsigargin was more specific than tBuBHQ. The total increase in [Ca2+] obtained with thapsigargin and Ins(1,4,5)P3 was, on the average, only 7% greater than that with Ins(1,4,5)P3 alone. In contrast, the total increase in [Ca2+] obtained with tBuBHQ and Ins(1,4,5)P3 was 33% greater than that obtained with only InsP3 (P < 0.05). Although Ca2+ was rapidly mobilized by thapsigargin and tBuBHQ, complete depletion of the Ins(1,4,5)P3-sensitive Ca2+ pool was difficult to achieve. After the release by thapsigargin or tBuBHQ, Ins(1,4,5)P3 induced additional Ca2+ release. The additional Ins(1,4,5)P3-induced Ca2+ release was not altered by supramaximal concentrations of thapsigargin and tBuBHQ, or by Bafilomycin A1, an inhibitor of V-type ATPases, but was decreased by prolonged treatment with the ER Ca(2+)-ATPase inhibitors. These results suggest the existence of distinct uptake and release compartments within the Ins(1,4,5)P3-sensitive Ca2+ pool. When treated with the inhibitors, the two compartments became distinguishable on the basis of their Ca2+ permeability. Apparently, thapsigargin and tBuBHQ readily mobilized Ca2+ from the uptake compartment, whereas Ca2+ from the release compartment could be mobilized only very slowly, in the absence of Ins(1,4,5)P3.
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| 28. |
- Islam, M. Shahidul, et al.
(författare)
-
Sulfhydryl oxidation induces rapid and reversible closure of the ATP-regulated K+ channel in the pancreatic beta-cell
- 1993
-
Ingår i: FEBS Letters. - 0014-5793 .- 1873-3468. ; 319:1-2, s. 128-132
-
Tidskriftsartikel (refereegranskat)abstract
- Effects of sulfhydryl modification on the ATP regulated K+ channel (KATP channel) in the pancreatic beta-cell were studied, using the patch clamp technique. Application of the sulfhydryl oxidizing agents thimerosal and 2,2'-dithio-bis(5-nitropyridine) (DTBNP), in micromolar concentrations, caused complete inhibition of the KATP channel, in inside-out patches. The inhibition was rapid and was reversed by the disulfide reducing agents dithiothreitol and cysteine. Thimerosal, which is poorly membrane permeable, inhibited channel activity, only when applied to the intracellular face of the plasma membrane. In contrast, DTBNP, which is highly lipophilic, caused closure of the KATP channel and consequent depolarization of the membrane potential, also when applied extracellularly. Our results indicate the presence of accessible free SH groups on the cytoplasmic side of the KATP channel in the pancreatic beta-cell. These SH groups are essential for channel function and it is possible that thiol-dependent redox mechanisms can modulate KATP channel activity.
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| 29. |
- Islam, M. Shahidul
(författare)
-
The ryanodine receptor calcium channel of beta-cells : molecular regulation and physiological significance
- 2002
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 51:5, s. 1299-1309
-
Tidskriftsartikel (refereegranskat)abstract
- The list of Ca(2+) channels involved in stimulus-secretion coupling in beta-cells is increasing. In this respect the roles of the voltage-gated Ca(2+) channels and IP(3) receptors are well accepted. There is a lack of consensus about the significance of a third group of Ca(2+) channels called ryanodine (RY) receptors. These are large conduits located on Ca(2+) storage organelle. Ca(2+) gates these channels in a concentration- and time-dependent manner. Activation of these channels by Ca(2+) leads to fast release of Ca(2+) from the stores, a process called Ca(2+)-induced Ca(2+) release (CICR). A substantial body of evidence confirms that beta-cells have RY receptors. CICR by RY receptors amplifies Ca(2+) signals. Some properties of RY receptors ensure that this amplification process is engaged in a context-dependent manner. Several endogenous molecules and processes that modulate RY receptors determine the appropriate context. Among these are several glycolytic intermediates, long-chain acyl CoA, ATP, cAMP, cADPR, NO, and high luminal Ca(2+) concentration, and all of these have been shown to sensitize RY receptors to the trigger action of Ca(2+). RY receptors, thus, detect co-incident signals and integrate them. These Ca(2+) channels are targets for the action of cAMP-linked incretin hormones that stimulate glucose-dependent insulin secretion. In beta-cells some RY receptors are located on the secretory vesicles. Thus, despite their low abundance, RY receptors are emerging as distinct players in beta-cell function by virtue of their large conductance, strategic locations, and their ability to amplify Ca(2+) signals in a context-dependent manner.
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| 30. |
- Islam, M. Shahidul, et al.
(författare)
-
Thiol oxidation by 2,2'-dithiodipyridine causes a reversible increase in cytoplasmic free Ca2+ concentration in pancreatic beta-cells : Role for inositol 1,4,5-trisphosphate-sensitive Ca2+ stores
- 1997
-
Ingår i: Biochemical Journal. - : Portland Press Ltd.. - 0264-6021 .- 1470-8728. ; 321:Pt 2, s. 347-354
-
Tidskriftsartikel (refereegranskat)abstract
- 2,2'-Dithiodipyridine (2,2'-DTDP), a reactive disulphide that mobilizes Ca2+ from ryanodine-sensitive Ca2+ stores in muscle, induced a biphasic increase in cytoplasmic free Ca2+ concentration ([Ca2+]i) in pancreatic beta-cells loaded with fura 2. This increase consisted of an early transient followed by a second, slower, rise. The [Ca2+]i transient was dependent on extracellular Ca2+ and disappeared on treatment with nimodipine. The reactive disulphide caused plasma membrane depolarization, as studied by the perforated-patch configuration of the patch-clamp technique. Hence membrane depolarization and opening of the L-type voltage-gated Ca2+ channels were responsible for the first transient in [Ca2+]i. The second slower increase in [Ca2+]i was prolonged but readily reversed by the disulphide-reducing agent 1,4-dithiothreitol. This increase in [Ca2+]i was not decreased by nimodipine or by omission of extracellular Ca2+, but was eliminated when the Ins(1,4,5)P3-sensitive Ca2+ pool was first depleted by carbachol. Ryanodine or its beta-alanyl analogue did not release Ca2+ from intracellular stores, and a high concentration of ryanodine did not inhibit Ca2+ release by 2,2'-DTDP. The disulphide compound suppressed glucose metabolism and decreased the mitochondrial inner-membrane potential. We conclude that thiol oxidation by 2,2'-DTDP affects Ca2+ homeostasis in beta-cells by multiple mechanisms. However, unlike the situation in muscle, in beta-cells 2,2'-DTDP releases Ca2+ from intracellular pools by mechanisms that do not involve activation of ryanodine receptors. Instead, in these cells the Ins(1,4,5)P3-sensitive intracellular Ca2+ store comprises an alternative target for the Ca(2+)-mobilizing action of the reactive disulphide compound.
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| 31. |
- Källström, Helena, et al.
(författare)
-
Cell signaling by the type IV pili of pathogenic Neisseria
- 1998
-
Ingår i: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 273:34, s. 21777-21782
-
Tidskriftsartikel (refereegranskat)abstract
- Neisseria gonorrhoeae and Neisseria meningitidis are Gram-negative bacterial pathogens that infect human mucosal epithelia. Type IV pilus-mediated adherence of these bacteria is a crucial early event for establishment of infection. In this work, we show that the type IV pili transduce a signal into the eucaryotic host cell. Purified adherent pili, but not pili from a low binding mutant, trigger an increase in the cytosolic free calcium ([Ca2+]i) in target epithelial cells, a signal known to control many cellular responses. The [Ca2+]i increase was blocked by antibodies against CD46, a putative pilus receptor, suggesting a role for this protein in signal transduction. Pilus-mediated attachment was inhibited by depletion of host cell intracellular Ca2+ stores but not by removal of extracellular Ca2+. Further, kinase inhibition studies showed that pilus-mediated adherence is dependent on casein kinase II. In summary, these data reveal a novel function of the type IV pili, namely induction of signal transduction pathways in host cells.
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| 32. |
- Lemmens, Raf, et al.
(författare)
-
Ca2+-induced Ca2+ release from the endoplasmic reticulum amplifies the Ca2+ signal mediated by activation of voltage-gated L-type Ca2+ channels in pancreatic beta-cells
- 2001
-
Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 276:13, s. 9971-9977
-
Tidskriftsartikel (refereegranskat)abstract
- Stimulus-secretion coupling in pancreatic beta-cells involves membrane depolarization and Ca(2+) entry through voltage-gated L-type Ca(2+) channels, which is one determinant of increases in the cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)). We investigated how the endoplasmic reticulum (ER)-associated Ca(2+) apparatus further modifies this Ca(2+) signal. When fura-2-loaded mouse beta-cells were depolarized by KCl in the presence of 3 mm glucose, [Ca(2+)](i) increased to a peak in two phases. The second phase of the [Ca(2+)](i) increase was abolished when ER Ca(2+) stores were depleted by thapsigargin. The steady-state [Ca(2+)](i) measured at 300 s of depolarization was higher in control cells compared with cells in which the ER Ca(2+) pools were depleted. The amount of Ca(2+) presented to the cytoplasm during depolarization as estimated from the integral of the increment in [Ca(2+)](i) over time (integralDelta[Ca(2+)](i).dt) was approximately 30% higher compared with that in the Ca(2+) pool-depleted cells. neo-thapsigargin, an inactive analog, did not affect [Ca(2+)](i) response. Using Sr(2+) in the extracellular medium and exploiting the differences in the fluorescence properties of Ca(2+)- and Sr(2+)-bound fluo-3, we found that the incoming Sr(2+) triggered Ca(2+) release from the ER. Depolarization-induced [Ca(2+)](i) response was not altered by, an inhibitor of phosphatidylinositol-specific phospholipase C, suggesting that stimulation of the enzyme by Ca(2+) is not essential for amplification of Ca(2+) signaling. [Ca(2+)](i) response was enhanced when cells were depolarized in the presence of 3 mm glucose, forskolin, and caffeine, suggesting involvement of ryanodine receptors in the amplification process. Pretreatment with ryanodine (100 microm) diminished the second phase of the depolarization-induced increase in [Ca(2+)](i). We conclude that Ca(2+) entry through L-type voltage-gated Ca(2+) channels triggers Ca(2+) release from the ER and that such a process amplifies depolarization-induced Ca(2+) signaling in beta-cells.
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| 33. |
- Nakagawa, Kei, et al.
(författare)
-
Relationship between nitrate, heavy metal, and sterols contents in Japanese agricultural soils with risk of groundwater pollution
-
Ingår i: Chemosphere. - 1879-1298. ; , s. 142335-142335
-
Tidskriftsartikel (refereegranskat)abstract
- In Japanese agricultural lands, nitrate-nitrogen contamination of soil and groundwater often occurs due to the application of livestock excrements and compost. Therefore, rural soils in Japan were sampled and analyzed for nitrate-nitrogen leaching, heavy metal content, and sterols associated with livestock excrement and compost to calculate contamination risk indicators. The results were analyzed using self-organizing maps and cluster analysis. Nitrate-nitrogen content using water extraction was detected in most of the sampled soils. In addition, many samples from areas that were already severely contaminated with nitrate-nitrogen showed particularly high concentrations. Coprostanol, an indicator of fecal contamination, was detected in more than half of the samples. The main source of nitrate-nitrogen contamination in these areas is livestock excrement and compost. Self-organization maps showed that areas with high nitrate-nitrogen contamination also corresponded to areas with high copper and zinc soil contents. The self-organization maps and cluster analysis resulted in five clusters: a nitrate-contaminated group mainly originating from livestock excrement and compost, a heavy metal-contaminated group, a general group, a nitrate-contaminated group mainly originating from chemical fertilizers, and a contaminated group with potentially hazardous substances requiring attention. Authorities and decision-makers can use the results to prioritize areas requiring remediation.
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| 34. |
- Quynh, Nguyen Thi Thu, et al.
(författare)
-
Effects of galnon, a non-peptide galanin-receptor agonist, on insulin release from rat pancreatic islets
- 2005
-
Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 328:1, s. 213-220
-
Tidskriftsartikel (refereegranskat)abstract
- Galanin is a neurotransmitter peptide that suppresses insulin secretion. The present study aimed at investigating how a non-peptide galanin receptor agonist, galnon, affects insulin secretion from isolated pancreatic islets of healthy Wistar and diabetic Goto-Kakizaki (GK) rats. Galnon stimulated insulin release potently in isolated Wistar rat islets; 100 microM of the compound increased the release 8.5 times (p<0.001) at 3.3 mM and 3.7 times (p<0.001) at 16.7 mM glucose. Also in islet perifusions, galnon augmented several-fold both acute and late phases of insulin response to glucose. Furthermore, galnon stimulated insulin release in GK rat islets. These effects were not inhibited by the presence of galanin or the galanin receptor antagonist M35. The stimulatory effects of galnon were partly inhibited by the PKA and PKC inhibitors, H-89 and calphostin C, respectively, at 16.7 but not 3.3 mM glucose. In both Wistar and GK rat islets, insulin release was stimulated by depolarization of 30 mM KCl, and 100 microM galnon further enhanced insulin release 1.5-2 times (p<0.05). Cytosolic calcium levels, determined by fura-2, were increased in parallel with insulin release, and the L-type Ca2+-channel blocker nimodipine suppressed insulin response to glucose and galnon. In conclusion, galnon stimulates insulin release in islets of healthy rats and diabetic GK rats. The mechanism of this stimulatory effect does not involve galanin receptors. Galnon-induced insulin release is not glucose-dependent and appears to involve opening of L-type Ca2+-channels, but the main effect of galnon seems to be exerted at a step distal to these channels, i.e., at B-cell exocytosis.
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| 35. |
- Westaway, Kenneth C., et al.
(författare)
-
A New Insight into Using Chlorine Leaving Group and Nucleophile Carbon Kinetic Isotope Effects To Determine Substituent Effects on the Structure of SN2 Transition States
- 2007
-
Ingår i: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 111:33, s. 8110-8120
-
Tidskriftsartikel (refereegranskat)abstract
- Chlorine leaving group k(35)/k(37), nucleophile carbon k(11)/k(14), and secondary alpha-deuterium [(k(H)/k(D))(alpha)] kinetic isotope effects (KIEs) have been measured for the S(N)2 reactions between para-substituted benzyl chlorides and tetrabutylammonium cyanide in tetrahydrofuran at 20 degrees C to determine whether these isotope effects can be used to determine the substituent effect on the structure of the transition state. The secondary alpha-deuterium KIEs indicate that the transition states for these reactions are unsymmetric. The theoretical calculations at the B3LYP/aug-cc-pVDZ level of theory support this conclusion; i.e., they suggest that the transition states for these reactions are unsymmetric with a long NC-C-alpha and reasonably short C-alpha-Cl bonds. The chlorine isotope effects suggest that these KIEs can be used to determine the substituent effects on transition state structure with the KIE decreasing when a more electron-withdrawing para-substituent is present. This conclusion is supported by theoretical calculations. The nucleophile carbon k(11)/k(14) KIEs for these reactions, however, do not change significantly with substituent and, therefore, do not appear to be useful for determining how the NC-C-alpha transition-state bond changes with substituent. The theoretical calculations indicate that the NC-C-alpha bond also shortens as a more electron-withdrawing substituent is placed on the benzene ring of the substrate but that the changes in the NC-C-alpha transition-state bond with substituent are very small and may not be measurable. The results also show that using leaving group and nucleophile carbon KIEs to determine the substituent effect on transition-state structure is more complicated than previously thought. The implication of using both chlorine leaving group and nucleophile carbon KIEs to determine the substituent effect on transition-state structure is discussed.
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| 36. |
- Westaway, Kenneth C., et al.
(författare)
-
Determining the Transition-State Structure for Different S(N)2 Reactions Using Experimental Nucleophile Carbon and Secondary alpha-Deuterium Kinetic Isotope Effects and Theory
- 2008
-
Ingår i: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 112:41, s. 10264-10273
-
Tidskriftsartikel (refereegranskat)abstract
- Nucleophile C-11/C-14 [k(11)/k(14)] and secondary alpha-deuterium [(k(H)/k(D))(alpha)] kinetic isotope effects (KIEs) were measured for the S(N)2 reactions between tetrabutylammonium cyanide and ethyl iodide, bromide, chloride, and tosylate in anhydrous DMSO at 20 degrees C to determine whether these isotope effects can be used to determine the structure of S(N)2 transition states. Interpreting the experimental KIEs in the usual fashion (i.e., that a smaller nucleophile KIE indicates the Nu-C-alpha transition state bond is shorter and a smaller (k(H)/k(D))(alpha) is found when the Nu-LG distance in the transition state is shorter) suggests that the transition state is tighter with a slightly shorter NC-C-alpha, bond and a much shorter C-alpha-LG bond when the substrate has a poorer halogen leaving group. Theoretical calculations at the B3LYP/aug-cc-pVDZ level of theory support this conclusion. The results show that the experimental nucleophile C-11/C-14 KIEs can be used to determine transition-state structure in different reactions and that the usual method of interpreting these KIEs is correct. The magnitude of the experimental secondary alpha-deuterium KIE is related to the nucleophile-leaving group distance in the S(N)2 transition state (R-TS) for reactions with a halogen leaving group. Unfortunately, the calculated and experimental (k(H)/k(D))(alpha)'s change oppositely with leaving group ability. However, the calculated (k(H)/k(D))(alpha)'s duplicate both the trend in the KIE with leaving group ability and the magnitude of the (k(H)/k(D))(alpha)'s for the ethyl halide reactions when different scale factors are used for the high and the low energy vibrations. This suggests it is critical that different scaling factors for the low and high energy vibrations be used if one wishes to duplicate experimental (k(H)/k(D))(alpha)'s. Finally, neither the experimental nor the theoretical secondary alpha-deuterium KIEs for the ethyl tosylate reaction fit the trend found for the reactions with a halogen leaving group. This presumably is found because of the bulky (sterically hindered) leaving group in the tosylate reaction. From every prospective, the tosylate reaction is too different from the halogen reactions to be compared.
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| 37. |
- Westerblad, H., et al.
(författare)
-
Effects of ryanodine receptor agonist 4-chloro-m-cresol on myoplasmic free Ca2+ concentration and force of contraction in mouse skeletal muscle
- 1998
-
Ingår i: Cell Calcium. - 0143-4160 .- 1532-1991. ; 24:2, s. 105-115
-
Tidskriftsartikel (refereegranskat)abstract
- In single mouse skeletal muscle fibers injected with fluorescent Ca2+ indicator Indo-1, 4-chloro-m-cresol (chlorocresol, 4-CmC) and its lipophilic analogue 4-chloro-3-ethylphenol (4-CEP) increased resting myoplasmic free [Ca2+] ([Ca2+]i) in a dose-dependent manner. In this regard, 4-CEP was more potent than 4-CmC and both were more potent than caffeine. High concentrations of 4-CmC (1 mM) or 4-CEP (500 microM) caused large and irreversible increase in resting [Ca2+]i leading to contracture. 4-CmC potentiated the [Ca2+]i increase and force of contraction induced by tetanic stimulation. Unlike caffeine, 4-CmC did not affect the activity of sarcoplasmic reticulum Ca2+ pump or the myofibrillar Ca2+ sensitivity. A low concentration of 4-CEP (20 microM) had no effect on resting [Ca2+]i on its own, but it enhanced the resting [Ca2+]i increase induced by caffeine and also potentiated the [Ca2+]i increase and contraction induced by tetanic stimulation. However, a relatively high concentration of 4-CEP (200 microM) inhibited tetanic stimulation-induced [Ca2+]i increase and contraction. Dantrolene, a muscle relaxant, inhibited 4-CmC-induced [Ca2+]i increase under resting conditions. However, when 4-CEP was applied in the presence of dantrolene, there was an exaggerated increase in [Ca2+]i. We conclude that 4-CmC and 4-CEP are potent agonists that can increase [Ca2+]i rapidly and reversibly by activating ryanodine receptors in situ in intact skeletal muscle fibers. These compounds, specially 4-CmC, may be useful for mechanistic and functional studies of ryanodine receptors and excitation-contraction coupling in skeletal muscles.
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| 38. |
- Woolcott, Orison O, et al.
(författare)
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Arachidonic acid is a physiological activator of the ryanodine receptor in pancreatic beta-cells.
- 2006
-
Ingår i: Cell Calcium. - : Elsevier BV. - 0143-4160 .- 1532-1991. ; 39:6, s. 529-37
-
Tidskriftsartikel (refereegranskat)abstract
- Pancreatic beta-cells have ryanodine receptors but little is known about their physiological regulation. Previous studies have shown that arachidonic acid releases Ca(2+) from intracellular stores in beta-cells but the identity of the channels involved in the Ca(2+) release has not been elucidated. We studied the mechanism by which arachidonic acid induces Ca(2+) concentration changes in pancreatic beta-cells. Cytosolic free Ca(2+) concentration was measured in fura-2-loaded INS-1E cells and in primary beta-cells from Wistar rats. The increase of cytosolic Ca(2+) concentration induced by arachidonic acid (150microM) was due to both Ca(2+) release from intracellular stores and influx of Ca(2+) from extracellular medium. 5,8,11,14-Eicosatetraynoic acid, a non-metabolizable analogue of arachidonic acid, mimicked the effect of arachidonic acid, indicating that arachidonic acid itself mediated Ca(2+) increase. The Ca(2+) release induced by arachidonic acid was from the endoplasmic reticulum since it was blocked by thapsigargin. 2-Aminoethyl diphenylborinate (50microM), which is known to inhibit 1,4,5-inositol-triphosphate-receptors, did not block Ca(2+) release by arachidonic acid. However, ryanodine (100microM), a blocker of ryanodine receptors, abolished the effect of arachidonic acid on Ca(2+) release in both types of cells. These observations indicate that arachidonic acid is a physiological activator of ryanodine receptors in beta-cells.
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