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  • 2251.
    Zabihi, Sheller
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Wentzel, Parri
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Maternal blood glucose levels determine the severity of diabetic embryopathy in mice with different expression of copper-zinc superoxide dismutase (CuZnSOD)2008Inngår i: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 105, nr 1, s. 166-172Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Excess oxygen radical formation is suggested to be involved in the etiology of diabetic embryopathy. We aimed to investigate the effects of altered maternal antioxidative status in conjunction with a varied severity of the maternal diabetic state on embryonic development by using mice with different gene expression of CuZn superoxide dismutase (CuZnSOD). The mice were wild-type (WT), transgenic (TG), or knockout (KO) with regard to CuZnSOD. Alloxan was used to induce diabetes (DWT, DTG, DKO) in female mice before pregnancy and, noninjected mice served as controls (NWT, NTG, NKO). The minimum alloxan dose required to induce diabetes was 80 mg/kg for WT, 100 mg/kg for TG, and 65 mg/kg for KO mice. When KO mice were made diabetic with 80 mg/kg alloxan, they produced no living offspring. The pregnancies were interrupted on gestational day 18, when maternal diabetic state, that is, blood glucose concentration, as well as fetal outcome, genotype and hepatic isoprostane levels were assessed. The mean maternal blood glucose levels were positively associated with the alloxan dose, that is, the DWT and DTG groups had higher blood glucose concentration than the DKO group, and the DWT and DTG fetuses increased their hepatic isoprostane levels, whereas the DKO fetuses did not. However, in all diabetic groups, increased maternal blood glucose concentration was associated with higher resorption and malformation rates as well as lowered fetal and placental weight. Furthermore, diabetes increased the fraction of WT offspring in the TG and KO groups. We conclude that both fetal antioxidative capacity and maternal diabetic state affect the development of the offspring. However, the maternal diabetic state is the major teratogenic factor and overrides the influence of fetal antioxidative capacity.

  • 2252.
    Zang, Guangxiang
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Christoffersson, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Tian, Geng
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Harun-Or-Rashid, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Medicinsk utvecklingsbiologi.
    Vågesjö, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Barg, Sebastian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Aberrant association between vascular endothelial growth factor receptor-2 and VE-cadherin in response to vascular endothelial growth factor-a in Shb-deficient lung endothelial cells2013Inngår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 25, nr 1, s. 85-92Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vascular permeability is a hallmark response to the main angiogenic factor VEGF-A and we have previously described a reduction of this response in Shb knockout mice. To characterize the molecular mechanisms responsible for this effect, endothelial cells were isolated from lungs and analyzed in vitro. Shb deficient endothelial cells exhibited less migration in a scratch wound-healing assay both under basal conditions and after vascular endothelial growth factor-A (VEGF-A) stimulation, suggesting a functional impairment of these cells in vitro. Staining for VE-cadherin and vascular endothelial growth factor receptor-2 (VEGFR-2) showed co-localization in adherens junctions and in intracellular sites such as the perinuclear region in wild-type and Shb knockout cells. VEGF-A decreased the VE-cadherin/VEGFR-2 co-localization in membrane structures resembling adherens junctions in wild-type cells whereas no such response was noted in the Shb knockout cells. VE-cadherin/VEGFR-2 co-localization was also recorded using spinning-disc confocal microscopy and VEGF-A caused a reduced association in the wild-type cells whereas the opposite pattern was observed in the Shb knockout cells. The latter expressed slightly more of cell surface VEGFR-2. VEGF-A stimulated extracellular-signal regulated kinase, Akt and Rac1 activities in the wild-type cells whereas no such responses were noted in the knockout cells. We conclude that aberrant signaling characteristics with respect to ERK, Akt and Rac1 are likely explanations for the observed altered pattern of VE-cadherin/VEGFR-2 association. The latter is important for understanding the reduced in vivo vascular permeability response in Shb knockout mice, a phenomenon that has patho-physiological relevance.

  • 2253.
    Zang, Guangxiang
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gustafsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jamalpour, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hong, Jongwook
    Karoliska Institutet.
    Genové, Guillem
    Karolinska Institutet.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vascular dysfunction and increased metastasis of B16F10 melanomas in Shb deficient mice as compared with their wild type counterparts2015Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, artikkel-id 234Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Shb is a signaling protein downstream of vascular endothelial growth factor receptor-2 and Shb deficiency has been found to restrict tumor angiogenesis. The present study was performed in order to assess metastasis in Shb deficiency using B16F10 melanoma cells. Methods B16F10 melanoma cells were inoculated subcutaneously on wild type or Shb +/− mice. Primary tumors were resected and lung metastasis determined after tumor relapse. Lung metastasis was also assessed after bone marrow transplantation of wild type bone marrow to Shb +/− recipients and Shb +/− bone marrow to wild type recipients. Primary tumors were subject to immunofluorescence staining for CD31, VE-cadherin, desmin and CD8, RNA isolation and isolation of vascular fragments for further RNA isolation. RNA was used for real-time RT-PCR and microarray analysis. Results Numbers of lung metastases were increased in Shb +/− or −/− mice and this coincided with reduced pericyte coverage and increased vascular permeability. Gene expression profiling of vascular fragments isolated from primary tumors and total tumor RNA revealed decreased expression of different markers for cytotoxic T cells in tumors grown on Shb +/− mice, suggesting that vascular aberrations caused altered immune responses. Conclusions It is concluded that a unique combinatorial response of increased vascular permeability and reduced recruitment of cytotoxic CD8+ cells occurs as a consequence of Shb deficiency in B16F10 melanomas. These changes may promote tumor cell intravasation and metastasis.

  • 2254.
    Zang, Guangxiang
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandberg, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin.
    Welsh, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Barbu, Andreea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Activated pancreatic stellate cells can impair pancreatic islet function in mice2015Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, nr 3, s. 169-180Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Pancreatic or islet fibrosis is often associated with activated pancreatic stellate cells (PSCs). PSCs are considered not only to promote fibrosis, but also to be associated with glucose intolerance in some diseases. We therefore evaluated morphological and functional relationships between islets and PSCs in the normal mouse pancreas and transplanted islets. Methods. Immunohistochemistry was used to map the presence of PSCs in the normal mouse pancreas and islets implanted under the renal capsule. We isolated and cultured mouse PSCs and characterized them morphologically by immunofluorescence staining. Furthermore, we measured their cytokine production and determined their effects on insulin release from simultaneously cultured islets. Results. PSCs were scattered throughout the pancreas, with occasional cells within the islets, particularly in the islet capsule. In islet transplants they were found mainly in the graft periphery. Cultured PSCs became functionally activated and produced several cytokines. Throughout the culture period they linearly increased their production of interleukin-6 and mammalian keratinocyte-derived chemokine. PSC cytokine production was not affected by acute hyperglycemia. Syngeneic islets cocultured with PSCs for 24-48 h increased their insulin release and lowered their insulin content. However, short-term insulin release in batch-type incubations was unaffected after 48 h of co-culture. Increased islet cell caspase-3 activation and a decreased islet cell replication were consistently observed after co-culture for 2 or 7 days. Conclusion. Activated PSCs may contribute to impaired islet endocrine function seen in exocrine pancreatitis and in islet fibrosis associated with some cases of type 2 diabetes.

  • 2255.
    Zeller, Kathrin S.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Idevall Hagren, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Stefansson, Anne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Velling, Teet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Jackson, Shaun P.
    Downward, Julian
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Johansson, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    PI3-kinase p110 alpha mediates beta 1 integrin-induced Akt activation and membrane protrusion during cell attachment and initial spreading2010Inngår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 22, nr 12, s. 1838-1848Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Integrin-mediated cell adhesion activates several signaling effectors, including phosphatidylinositol 3-kinase (PI3K), a central mediator of cell motility and survival. To elucidate the molecular mechanisms of this important pathway the specific members of the PI3K family activated by different integrins have to be identified. Here, we studied the role of PI3K catalytic isoforms in beta 1 integrin-induced lamellipodium protrusion and activation of Akt in fibroblasts. Real-time total internal reflection fluorescence imaging of the membrane substrate interface demonstrated that beta 1 integrin-mediated attachment induced rapid membrane spreading reaching essentially maximal contact area within 5-10 min. This process required actin polymerization and involved activation of PI3K. Isoform-selective pharmacological inhibition identified p110 alpha as the PI3K catalytic isoform mediating both beta 1 integrin-induced cell spreading and Akt phosphorylation. A K756L mutation in the membrane-proximal part of the beta 1 integrin subunit, known to cause impaired Akt phosphorylation after integrin stimulation, induced slower cell spreading. The initial beta 1 integrin-regulated cell spreading as well as Akt phosphorylation were sensitive to the tyrosine kinase inhibitor PP2, but were not dependent on Src family kinases, FAK or EGF/PDGF receptor transactivation. Notably, cells expressing a Ras binding-deficient p110 alpha mutant were severely defective in integrin-induced Akt phosphorylation, but exhibited identical membrane spreading kinetics as wild-type p110 alpha cells. We conclude that p110 alpha mediates beta 1 integrin-regulated activation of Akt and actin polymerization important for survival and lamellipodia dynamics. This could contribute to the tumorigenic properties of cells expressing constitutively active p110 alpha.

  • 2256.
    Zeller, Kathrin Stephanie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Riaz, Anjum
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Sarve, Hamid
    SLU, Centrum för bildanalys.
    Li, Jia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Johansson, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    The role of mechanical force and ROS in integrin-dependent signals2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 5, artikkel-id e64897Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cells are exposed to several types of integrin stimuli, which generate responses generally referred to as "integrin signals", but the specific responses to different integrin stimuli are poorly defined. In this study, signals induced byintegrin ligation during cell attachment, mechanical force from intracellular contraction, or cell stretching by external force were compared. The elevated phosphorylation levels of several proteins during the early phase of cell attachment and spreading of fibroblast cell lines were not affected by inhibition ofROCK and myosin II activity, i.e. the reactions occurred independently ofintracellular contractile force acting on the adhesion sites. The contraction-independent phosphorylation sites included ERK1/2 T202/Y204, AKT S473, p130CAS Y410, and cofilin S3. In contrast to cell attachment, cyclic stretching ofthe adherent cells induced a robust phosphorylation only of ERK1/2 and thephosphorylation levels of the other investigated proteins were not or only moderately affected by stretching. No major differences between signaling via alpha 5 beta 1 or alpha v beta 3 integrins were detected. The importance ofmitochondrial ROS for the integrin-induced signaling pathways was investigated using rotenone, a specific inhibitor of complex I in the respiratory chain. While rotenone only moderately reduced ATP levels and hardly affected the signalsinduced by cyclic cell stretching, it abolished the activation of AKT and reduced theactin polymerization rate in response to attachment in both cell lines. In contrast, scavenging of extracellular ROS with catalase or the vitamin C analog Asc-2P did not significantly influence the attachment-derived signaling, but caused a selective and pronounced enhancement of ERK1/2 phosphorylation in response to stretching. In conclusion, the results showed that "integrin signals" are composedof separate sets of reactions triggered by different types of integrin stimulation. Mitochondrial ROS and extracellular ROS had specific and distinct effects on theintegrin signals induced by cell attachment and mechanical stretching.

  • 2257.
    Zhang, A
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ion transport in exocrine glands with reference to cystic fibrosis1999Annet (Annet vitenskapelig)
  • 2258.
    Zhang, A L
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Martinez, J R
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Effects of cholinergic and a-adrenergic agonists on the monovalent ion content of rat submandibular gland acinar cells studied by X-ray microanalysis1997Inngår i: Histochem Cell Biol, Vol. 108, s. 149-Artikkel i tidsskrift (Fagfellevurdert)
  • 2259.
    Zhang, A L
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ion transport in cultured pig tracheal submucosal gland acinar cells studied by X-ray microanalysis1997Inngår i: Eur Resp J, Vol. 10, s. 2204-Artikkel i tidsskrift (Fagfellevurdert)
  • 2260.
    Zhang, A L
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Multiple intracellular pathways for regulation of chloride secretion in cultured pig tracheal submucosal gland cells.1999Inngår i: Eur Respir J, Vol. 13, s. 571-Artikkel i tidsskrift (Fagfellevurdert)
  • 2261.
    Zhang, Ailing
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ion transport in exocrine glands with reference to cystic fibrosis1999Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Aspects of ion transport in rat submandibular gland acinar cells at the subcellular level, and the regulation of chloride secretion and calcium mobilization in cultured pig tracheal gland acinar cells were studied with reference to the disease cystic fibrosis.

    In adult rat submandibular gland acinar cells, both cholinergic and α-adrenergic stimulation induced efflux of K+ and of C1-, but the response was generally less with α-adrenergic stimulation. Little or no change in elemental distribution was observed in the acinar cells of new-born rats after cholinergic stimulation. A clear decrease in Ca content of the secretory granules in adult rat acinar cells was observed after cholinergic stimulation. Incontrast, α-adrenergic stimulation did not significantly affect the Ca concentration. IP3 receptors were localized by immunocytochemistry to the endoplasmic reticulum and to as yet unidentified structures in the apical cytoplasm.

    Cultured cells, derived from pig tracheal gland acinar cells, retained structural characteristics (microvilli, secretory granules and desmosomes) of in situ epithelia. Chloride secretion was induced in these cultured cells by stimulation with cholinergic, or α- or β-adrenergic agonists. CAMP-activated chloride secretion was blocked, but ionomycin-, ATP- and UTP-induced chloride secretion was not affected by pretreatment with cystic fibrosis transmembrane conductance regulator (CFTR) antisense oligodeoxynucleotide. Both ATP and UTP clearly upregulated [Ca2+]i. Pertussis toxin inhibited the calcium response to UTP, but did not change the response to ATP. Pretreatment with U107, a phospholipase C inhibitor, inhibited the calcium response to both ATP and UTP. Immunocytochemistry showed that in these cells, the IP3 receptor was localized in the cytoplasm.

    Our findings indicate 1) that freshly isolated submandibular acinar cells can serve as a suitable in vitro system for the study of ion transport mechanisms in the submandibular gland, that important ion transport systems required for the response are not present in the early stages of postnatal development of the glands, and that the secretory granule could serve as an intracellular calcium store under physiological conditions; 2) that the tracheal gland acinar cell culture system is suitable for studying aspects of ion and water transport by the airwayglands, that there are cAMP- and Ca2+-dependent intracellular pathways for C1- secretion in the airway gland cells, and that ATP and UTP activate calcium mobilization in the cultured cells predominantly via the G protein-phospholipase C-IP3 pathway.

  • 2262.
    Zhang, A-L
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Martinez, J R
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Changes in calcium concentrations in subcellular compartments of rat submndiblar gland acinar cells induced by cholinergic stimulation.1999Inngår i: Histochem Cell Biol, Vol. 112, s. 367-Artikkel i tidsskrift (Fagfellevurdert)
  • 2263.
    Zhang, A-L
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Regulation of incracellular calcium by extracellular nucleotides in pig tracheal submucosal gland cells.1999Inngår i: Resp Physiol, Vol. 118, s. 237-Artikkel i tidsskrift (Fagfellevurdert)
  • 2264. Zhang, Fan
    et al.
    Zhang, Qimin
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sjöholm, Åke
    Involvement of JAK2 and Src kinase tyrosine phosphorylation in human growth hormone-stimulated increases in cytosolic free Ca2+ and insulin secretion2006Inngår i: American Journal of Physiology - Cell Physiology, ISSN 0363-6143, E-ISSN 1522-1563, Vol. 291, nr 3, s. C466-C475Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We previously reported that human growth hormone (hGH) increases cytoplasmic Ca2+ concentration ([Ca2+](i)) and proliferation in pancreatic beta-cells (Sjoholm A, Zhang Q, Welsh N, Hansson A, Larsson O, Tally M, and Berggren PO. J Biol Chem 275: 21033-21040, 2000) and that the hGH-induced rise in [Ca2+](i) involves Ca2+-induced Ca2+ release facilitated by tyrosine phosphorylation of ryanodine receptors (Zhang Q, Kohler M, Yang SN, Zhang F, Larsson O, and Berggren PO. Mol Endocrinol 18: 1658-1669, 2004). Here we investigated the tyrosine kinases that convey the hGH-induced rise in [Ca2+](i) and insulin release in BRIN-BD11 beta-cells. hGH caused tyrosine phosphorylation of Janus kinase (JAK)2 and c-Src, events inhibited by the JAK2 inhibitor AG490 or the Src kinase inhibitor PP2. Although hGH-stimulated rises in [Ca2+](i) and insulin secretion were completely abolished by AG490 and JAK2 inhibitor II, the inhibitors had no effect on insulin secretion stimulated by a high K+ concentration. Similarly, Src kinase inhibitor-1 and PP2, but not its inactive analog PP3, suppressed [Ca2+](i) elevation and completely abolished insulin secretion stimulated by hGH but did not affect responses to K+. Ovine prolactin increased [Ca2+](i) and insulin secretion to a similar extent as hGH, effects prevented by the JAK2 and Src kinase inhibitors. In contrast, bovine GH evoked a rise in [Ca2+](i) but did not stimulate insulin secretion. Neither JAK2 nor Src kinase inhibitors influenced the effect of bovine GH on [Ca2+](i). Our study indicates that hGH stimulates rise in [Ca2+](i) and insulin secretion mainly through activation of the prolactin receptor and JAK2 and Src kinases in rat insulin-secreting cells.

  • 2265.
    Zhang, Suping
    et al.
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Huang, Qian
    Quanzhou Med Coll, Dept Physiol, Quanzhou, Peoples R China.
    Cai, Xiaoxia
    Honghe Hlth Vocat Coll, Dept Basic Med Sci, Mengzi, Peoples R China.
    Jiang, Shan
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Xu, Nan
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Zhou, Qin
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Cao, Xiaoyun
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Hultström, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tian, Jiong
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Lai, En Yin
    Zhejiang Univ, Coll Med, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou, Zhejiang, Peoples R China;Zhejiang Univ, Sch Basic Med Sci, Dept Physiol, Sch Med, Hangzhou, Zhejiang, Peoples R China.
    Osthole Ameliorates Renal Fibrosis in Mice by Suppressing Fibroblast Activation and Epithelial-Mesenchymal Transition2018Inngår i: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, artikkel-id 1650Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Renal fibrosis is a common pathway of virtually all progressive kidney diseases. Osthole (OST, 7-Methoxy-8-(3-methylbut-2-enyl)-2-chromenone), a derivative of coumarin mainly found in plants of the Apiaceae family, has shown inhibitory effects on inflammation, oxidative stress, fibrosis and tumor progression. The present study investigated whether OST mediates its effect via suppressing fibroblast activation and epithelial-mesenchymal transition (EMT) in unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Herein, we found that OST inhibited fibroblast activation in a dose-dependent manner by inhibiting the transforming growth factor-beta 1 (TGF beta 1)-Smad pathway. OST also blocked fibroblast proliferation by reducing DNA synthesis and downregulating the expressions of proliferation- and cell cycle-related proteins including proliferating cell nuclear antigen (PCNA), CyclinD1 and p21 Waf1/Cip1. Meanwhile, in the murine model of renal interstitial fibrosis induced by UUO, myofibroblast activation with increased expression of alpha-smooth muscle actin (alpha-SMA) and proliferation were attenuated by OST treatment. Additionally, we provided in vivo evidence suggesting that OST repressed EMT with preserved E-cadherin and reduced Vimentin expression in obstructed kidney. UUO injury-induced upregulation of EMT-related transcription factors, Snail family transcriptional repressor-1(Snail 1) and Twist family basic helix-loop-helix (BHLH) transcription factor (Twist) as well as elevated G2/M arrest of tubular epithelial cell, were rescued by OST treatment. Further, OST treatment reversed aberrant expression of TGF beta 1-Smad signaling pathway, increased level of proinflammatory cytokines and NF-kappaB (NF-kappa B) activation in kidneys with obstructive nephropathy. Taken together, these findings suggest that OST hinder renal fibrosis in UUO mouse mainly through inhibition of fibroblast activation and EMT.

  • 2266.
    Zhang, W
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    A yohimbine-dependent UK14,304 induced ion transient in HT29 cells studied by X-ray microanalysis.1996Inngår i: Scanning Microsc, Vol. 10, s. 293-Artikkel i tidsskrift (Fagfellevurdert)
  • 2267.
    Zhang, W
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Effects of pituitary adenylate cyclase activating polypeptide-27 (PACAP) and vasoactive intestinal polypeptide (VIP) on chloride in HT29 cells studied by X-ray microanalysis.1999Inngår i: Acta Physiol. Scand., Vol. 165, s. 95-Artikkel i tidsskrift (Fagfellevurdert)
  • 2268.
    Zhang, W
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Evidence for muscarinic-3 receptor mediated ion transport in HT29 cells studied by X-ray microanalysis1997Inngår i: Cell Struct Function, Vol. 22, s. 379-Artikkel i tidsskrift (Fagfellevurdert)
  • 2269.
    Zhang, W
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Regulation of ion transport by P2U purinoceptors and a2A adrenoceptors in HT29 cells1997Inngår i: Cell Biol Int, Vol. 21, s. 195-Artikkel i tidsskrift (Fagfellevurdert)
  • 2270.
    Zhang, W
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Volume indiced chloride transport in HT29 cells studied by X-ray microanalysis.1998Inngår i: Microsc Res Techn, Vol. 40, s. 72-Artikkel i tidsskrift (Fagfellevurdert)
  • 2271.
    Zhang, X-Q
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Sundh, Ulla Beckman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Zetterqvist, Örjan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ek, Pia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Immunohistochemical localization of phosphohistidine phosphatase PHPT1 in mouse and human tissues2009Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, nr 2, s. 65-72Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Protein histidine phosphorylation accounts for about 6% of the total protein phosphorylation in eukaryotic cells; still details concerning histidine phosphorylation and dephosphorylation are limited. A mammalian 14-kDa phosphohistidine phosphatase, also denominated PHPT1, was found 6 years ago that provided a new tool in the study of phosphohistidine phosphorylation. The localization of PHPT1 mRNA by Northern blot analysis revealed high expression in heart and skeletal muscle. The main object of the present study was to determine the PHPT1 expression on protein level in mouse tissues in order to get further information on the physiological role of the enzyme. Tissue samples from adult mice and 14.5-day-old mouse embryos were processed for immunostaining using a PHPT1-specific polyclonal antibody. The same antibody was also provided to the Swedish human protein atlas project (HPR) (http://www.proteinatlas.org/index.php). The results from both studies were essentially consistent with the previously reported expression of mRNA of a few human tissues. In addition, several other tissues, including testis, displayed a high protein expression. A salient result of the present investigation was the ubiquitous expression of the PHPT1 protein and its high expression in continuously dividing epithelial cells.

  • 2272.
    Zhou, Suhan
    et al.
    Zhejiang Univ, Sch Med, Sch Basic Med Sci, Affiliated Hosp 1,Kidney Dis Ctr, Hangzhou 310003, Zhejiang, Peoples R China;Zhejiang Univ, Sch Med, Sch Basic Med Sci, Dept Physiol, Hangzhou 310003, Zhejiang, Peoples R China.
    Jiang, Shan
    Zhejiang Univ, Sch Med, Sch Basic Med Sci, Affiliated Hosp 1,Kidney Dis Ctr, Hangzhou 310003, Zhejiang, Peoples R China;Zhejiang Univ, Sch Med, Sch Basic Med Sci, Dept Physiol, Hangzhou 310003, Zhejiang, Peoples R China.
    Guo, Jie
    Zhejiang Univ, Sch Med, Sch Basic Med Sci, Affiliated Hosp 1,Kidney Dis Ctr, Hangzhou 310003, Zhejiang, Peoples R China;Zhejiang Univ, Sch Med, Sch Basic Med Sci, Dept Physiol, Hangzhou 310003, Zhejiang, Peoples R China.
    Xu, Nan
    Zhejiang Univ, Sch Med, Sch Basic Med Sci, Affiliated Hosp 1,Kidney Dis Ctr, Hangzhou 310003, Zhejiang, Peoples R China;Zhejiang Univ, Sch Med, Sch Basic Med Sci, Dept Physiol, Hangzhou 310003, Zhejiang, Peoples R China.
    Wang, Qin
    Zhejiang Univ, Sch Med, Sch Basic Med Sci, Affiliated Hosp 1,Kidney Dis Ctr, Hangzhou 310003, Zhejiang, Peoples R China;Zhejiang Univ, Sch Med, Sch Basic Med Sci, Dept Physiol, Hangzhou 310003, Zhejiang, Peoples R China.
    Zhang, Gensheng
    Zhejiang Univ, Sch Med, Sch Basic Med Sci, Affiliated Hosp 1,Kidney Dis Ctr, Hangzhou 310003, Zhejiang, Peoples R China;Zhejiang Univ, Sch Med, Sch Basic Med Sci, Dept Physiol, Hangzhou 310003, Zhejiang, Peoples R China.
    Zhao, Liang
    Guangzhou Med Univ, Sch Basic Med Sci, Dept Physiol, Guangzhou, Guangdong, Peoples R China; Charite Univ Med Berlin, Inst Vegetat Physiol, Berlin, Germany.
    Zhou, Qin
    Zhejiang Univ, Sch Med, Sch Basic Med Sci, Affiliated Hosp 1,Kidney Dis Ctr, Hangzhou 310003, Zhejiang, Peoples R China;Zhejiang Univ, Sch Med, Sch Basic Med Sci, Dept Physiol, Hangzhou 310003, Zhejiang, Peoples R China.
    Fu, Xiaodong
    Guangzhou Med Univ, Sch Basic Med Sci, Dept Physiol, Guangzhou, Guangdong, Peoples R China.
    Li, Lingei
    Georgetown Univ, Div Nephrol & Hypertens, Washington, DC USA;Georgetown Univ, Hypertens Res Ctr, Washington, DC USA.
    Patzak, Andreas
    Charite Univ Med Berlin, Inst Vegetat Physiol, Berlin, Germany.
    Hultström, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård.
    Lai, En Yin
    Zhejiang Univ, Sch Med, Sch Basic Med Sci, Affiliated Hosp 1, Kidney Dis Ctr, Hangzhou 310003, Zhejiang, Peoples R China;Zhejiang Univ, Sch Med, Sch Basic Med Sci, Dept Physiol, Hangzhou 310003, Zhejiang, Peoples R China; Georgetown Univ, Div Nephrol & Hypertens, Washington, DC USA;Georgetown Univ, Hypertens Res Ctr, Washington, DC USA.
    ADAMTS13 protects mice against renal ischemia-reperfusion injury by reducing inflammation and improving endothelial function2019Inngår i: American Journal of Physiology - Renal Physiology, ISSN 1931-857X, E-ISSN 1522-1466, Vol. 316, nr 1, s. F134-F145Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Acute kidney injury (AKI) is a serious condition without efficient therapeutic options. Recent studies have indicated that recombinant human a disintegrin and metalloprotease with thrombospondin motifs 13 (rhADAMTS13) provides protection against inflammation. Therefore, we hypothesized that ADAMTS13 might protect against AKI by reducing inflammation. Bilateral renal ischemia-reperfusion injury (I/R) was used as AKI models in this study. Prophylactic infusion of rhADAMTS13 was employed to investigate potential mechanisms of renal protection. Renal function, inflammation, and microvascular endothelial function were assessed after 24 h of reperfusion. Our results showed that I/R mice increased plasma von Willebrand factor levels but decreased ADAMTS13 expression. Administration of rhADAMTS13 to I/R mice recovered renal function, histological injury, and apoptosis. Renal inflammation was reduced by rhADAMTS13, accompanied with the downregulation of p38/extracellular signal-regulated protein kinase phosphorylation and cyclooxygenase-2 expression. rhADAMTS13 restored vasodilation in afferent arterioles in I/R mice. Furthermore, rhADAMTS13 treatment enhanced phosphorylation of Akt at Set(473) and eNOS at Ser(1177). Administration of the Akt pathway inhibitor wortmannin reduced the protective effect of rhADAMTS13. Our conclusions are that treatment with rhADAMTS13 ameliorates renal I/R injury by reducing inflammation, tubular cell apoptosis. and improving microvascular endothelial dysfunction. rhADAMIS13 could be a promising strategy to treat AKI in clinical settings.

  • 2273.
    Zhou, Yunting
    et al.
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Li, Wei
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Zhou, Junming
    Nanjing Univ, Jingling Hosp, Dept Outpatient, Army Engn Univ, Nanjing, Jiangsu, Peoples R China.
    Chen, Juan
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Wang, Xiaohang
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Cai, Min
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Li, Fengfei
    Nanjing Med Univ, Nanjing Hosp 1, Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Xu, Wei
    Kings Coll London, Sch Life Course Sci, Dept Diabet, Guys Campus, London, England.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sun, Zilin
    Southeast Univ, Inst Diabet, Sch Med, Zhongda Hosp,Dept Endocrinol, Nanjing, Jiangsu, Peoples R China.
    Lipotoxicity reduces beta cell survival through islet stellate cell activation regulated by lipid metabolism-related molecules2019Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 380, nr 1, s. 1-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Islet stellate cells (ISCs) activation is mainly associated with islet fibrosis, which contributes to the progression of type 2 diabetes. However, the molecular mechanism underlying this process is not fully understood.

    Methods: In order to investigate this process the current study examined ectopic fat accumulation in rats with high-fat diet (HFD) induced obesity. Levels of lipotoxicity-induced ISC activation and islet function were assessed via intraperitoneal glucose and insulin tolerance tests, and immunohistochemistry. The expression of lipid metabolism- and ISC activation-related markers was evaluated in cultured ISCs treated with palmitic acid (PA) using quantitative PCR and western blotting. We also overexpressed sterol regulatory element-binding protein (SREBP)-1c in ISCs by lentiviral transduction, and assessed the effects on insulin release in co-cultures with isolated rat islets.

    Results: HFD increased body weight and ectopic fat accumulation in pancreatic islets. Lipotoxicity caused progressive glucose intolerance and insulin resistance, upregulated a-smooth muscle actin, and stimulated the secretion of extracellular matrix. Lipotoxicity reduced the expression of lipid metabolism-related molecules in ISCs treated with PA, especially SREBP-1c. Overexpression of SREBP-1c in ISCs improved islet viability and insulin secretion in co-cultures.

    Conclucions: These results indicate that lipotoxicity-induced ISC activation alters islet function via regulation of lipid metabolism, suggesting that therapeutic strategies targeting activated ISC may be an effective treatment for prevention of ISC activation-associated islet dysfunction.

  • 2274.
    Zollbrecht, Christa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Persson, A. Erik G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lundberg, Jon O.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Weitzberg, Eddie
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Carlström, Mattias
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Nitrite-mediated reduction of macrophage NADPH oxidase activity is dependent on xanthine oxidoreductase-derived nitric oxide but independent of S-nitrosation2016Inngår i: Redox Biology, ISSN 0090-7324, E-ISSN 2213-2317, Vol. 10, s. 119-127Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Inorganic nitrite has shown beneficial effects in cardiovascular and metabolic diseases partly via attenuation of NADPH-oxidase (NOX)-mediated oxidative stress. However, the exact mechanisms are still unclear. Here we investigated the role of S-nitrosation or altered expression of NOX subunits, and the role of xanthine oxidoreductase (XOR) in nitrite-derived nitric oxide (NO) production. Methods: Mouse macrophages were activated with LPS in the presence or absence of nitrite. NOX activity was measured by lucigenin-dependent chemiluminescence. Gene and protein expression of NOX2 subunits and XOR were investigated using qPCR and Western Blot. S-nitrosation of Nox2 and p22phox was studied with a Biotin Switch assay. Uric acid levels in cell culture medium were analyzed as a measure of XOR activity, and NO production was assessed by DAF-FM fluorescence. Results: NOX activity in activated macrophages was significantly reduced by nitrite. Reduced NOX activity was not attributed to decreased NOX gene expression. However, protein levels of p47phox and p67phox subunits were reduced by nitrite in activated macrophages. Protein expression of Nox2 and p22phox was not influenced by this treatment and neither was their S-nitrosation status. Increased uric acid levels after nitrite and diminished NO production during XOR-inhibition with febuxostat suggest that XOR is more active during nitrite-treatment of activated macrophages and plays an important role in the bioactivation of nitrite. Conclusions: Our findings contribute to the mechanistic understanding about the therapeutic effects associated with nitrite supplementation in many diseases. We show that nitrite-mediated inhibition of NOX activity cannot be explained by S-nitrosation of the NOX enzyme, but that changes in NOX2 expression and XOR function may contribute.

  • 2275.
    Åkerblom, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Frk/Shb Signalling in Pancreatic Beta-cells: Roles in Islet Function, Beta-cell Development and Survival as Implicated in Mouse Knockout Models2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The adaptor protein Shb and the non-receptor tyrosine kinase Frk have been implicated in intracellular signalling in insulin-producing beta cells. In this thesis, knockout mice are used to further elucidate the role of Shb and Frk for beta cell number, cytokine-induced cell death, and glucose homeostasis. In addition, the effect of Shb deficiency upon tumour growth is studied in a mouse model of endogenous tumourigenesis.

    Previously, overexpression of Frk has been associated with increased beta cell replication, and increased susceptibility to cytokine induced beta cell destruction. To test whether Frk has a non-redundant role in regulating beta cell mass, beta cell number in Frk-/- mice was assessed at different stages of life. The results showed that Frk is involved in regulating beta cell number during embryonal and early postnatal life, but is probably redundant in the adult.

    An earlier study had suggested that Shb participates in cytokine-induced beta cell death, a model of autoimmune diabetes. To test this further, Shb-/- islets were exposed to cytokines, or to an ER-stress inducing agent. Shb knockout islets exhibited decreased cell death, and this effect appeared to be independent of NO, JNK, p38 MAP kinase, FAK and c-Abl, but may involve an augmented induction of Hsp70.

    Furthermore, glucose homeostasis in Shb-/- mice was impaired, with elevated basal blood sugar concentration and reduced glucose-induced insulin secretion.

    Previously Shb deficient mice had showed an impaired ability to sustain growth of implanted tumour cells, due to reduced angiogenesis. Tumour growth and angiogenesis were here assessed in an inheritable tumour model. Shb deficient mice exhibited fewer tumours, and reduced vessel density in small tumours, indicating impaired angiogenesis. However, a few large tumours developed in Shb-/- mice, suggesting that tumours can escape the angiogenic restriction caused by the absence of Shb.

    Delarbeid
    1. A role of FRK in regulation of embryonal pancreatic beta cell formation
    Åpne denne publikasjonen i ny fane eller vindu >>A role of FRK in regulation of embryonal pancreatic beta cell formation
    2007 (engelsk)Inngår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 270, nr 1-2, s. 73-78Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The fyn-related-kinase (FRK) is a non-receptor tyrosine kinase expressed in various tissues, and among them, is the islets of Langerhans. The role of FRK in pancreatic beta cells has been addressed by studies of knockout or FRK transgenic mice. These experiments have shown that FRK overexpression in beta cells leads to an increased susceptibility to the beta cell toxin streptozotocin and to cytotoxic cytokines, suggesting that FRK may participate in events leading to beta cell destruction. However, these mice also exhibit an increased relative beta cell volume and increased beta cell replication following partial pancreatectomy, suggesting a positive role for FRK in the regulation of beta cell number as well. To further assess the significance of FRK for beta cell replication, we studied the beta cell area and islet cell replication in FRK null mice. We currently observed that the FRK knockout mouse showed no difference in the insulin positive cell area or in the percentage of Ki67-stained proliferating islet cells at adulthood, when compared to wild-type control. In addition, adult FRK(-/-) mice performed normally when subjected to an intravenous glucose tolerance test. To elucidate whether FRK affects pancreatic beta cell number during embryogenesis and shortly after birth, pancreata were collected from FRK(-/-) mice at these stages. Histological analysis of insulin stained pancreatic sections showed that the insulin positive cell area in FRK(-/-) mice was reduced at embryonal day 15 and at birth to 31 and 70% of that of wild-type mice, respectively. FRK(-/-) pancreas weight on day 1 neonatally was similar to that of the control, indicating that the obtained results were not due to altered pancreatic growth. Taken together, these results show that FRK affects beta cell number during embryogenesis and early in life, but is probably redundant for beta cell number and function in adult animals under normal conditions.

    Emneord
    Animals, Animals, Newborn, Embryo, Mammalian/*cytology/*enzymology, Insulin-Secreting Cells/*cytology/*enzymology, Mice, src-Family Kinases/deficiency/*metabolism FRK; beta cell; development; replication; neogenesis; tyrosine kinase
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-13082 (URN)10.1016/j.mce.2007.02.009 (DOI)000246920500010 ()17416457 (PubMedID)
    Tilgjengelig fra: 2008-01-21 Laget: 2008-01-21 Sist oppdatert: 2017-12-11
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  • 2276.
    Åkerblom, Björn
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Annerén, Cecilia
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    A role of FRK in regulation of embryonal pancreatic beta cell formation2007Inngår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 270, nr 1-2, s. 73-78Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The fyn-related-kinase (FRK) is a non-receptor tyrosine kinase expressed in various tissues, and among them, is the islets of Langerhans. The role of FRK in pancreatic beta cells has been addressed by studies of knockout or FRK transgenic mice. These experiments have shown that FRK overexpression in beta cells leads to an increased susceptibility to the beta cell toxin streptozotocin and to cytotoxic cytokines, suggesting that FRK may participate in events leading to beta cell destruction. However, these mice also exhibit an increased relative beta cell volume and increased beta cell replication following partial pancreatectomy, suggesting a positive role for FRK in the regulation of beta cell number as well. To further assess the significance of FRK for beta cell replication, we studied the beta cell area and islet cell replication in FRK null mice. We currently observed that the FRK knockout mouse showed no difference in the insulin positive cell area or in the percentage of Ki67-stained proliferating islet cells at adulthood, when compared to wild-type control. In addition, adult FRK(-/-) mice performed normally when subjected to an intravenous glucose tolerance test. To elucidate whether FRK affects pancreatic beta cell number during embryogenesis and shortly after birth, pancreata were collected from FRK(-/-) mice at these stages. Histological analysis of insulin stained pancreatic sections showed that the insulin positive cell area in FRK(-/-) mice was reduced at embryonal day 15 and at birth to 31 and 70% of that of wild-type mice, respectively. FRK(-/-) pancreas weight on day 1 neonatally was similar to that of the control, indicating that the obtained results were not due to altered pancreatic growth. Taken together, these results show that FRK affects beta cell number during embryogenesis and early in life, but is probably redundant for beta cell number and function in adult animals under normal conditions.

  • 2277.
    Åkerblom, Björn
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Barg, Sebastian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Calounova, Gabriela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Mokhtari, Dariush
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Impaired glucose homeostasis in Shb-/- mice2009Inngår i: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 203, nr 2, s. 271-279Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Src homology 2 domain-containing protein B (SHB) is an adapter protein involved in the regulation of beta-cell and endothelial cell function. We have recently obtained the Shb knockout mouse, and consequently, the aim of this study was to assess the effect of Shb deletion upon beta-cell function and blood glucose homeostasis. Shb-/- mice display an elevated basal blood glucose concentration, and this increase is maintained during insulin challenge in insulin sensitivity tests. To assess glucose-induced insulin secretion, pancreata were perfused, and it was observed that Shb-/- first phase insulin secretion was blunted during glucose stimulation. Gene expression of Shb-/- islets shortly after isolation was altered, with increased pancreatic and duodenal homeobox gene-1 (Pdx1) gene expression and reduced expression of Vegf-A. Islet culture normalized Pdx1 gene expression. The microvascular density of the Shb-/- islets was reduced, and islet capillary endothelial cell morphology was changed suggesting an altered microvascular function as a contributing cause to the impaired secretory activity. Capacitance measurements of depolarization-induced exocytosis indicate a direct effect on the exocytotic machinery, in particular a dramatic reduction in readily releasable granules, as responsible for the insulin-secretory defect operating in Shb-/- islets. Shb-/- mice exhibited no alteration of islet volume or beta-cell area. In conclusion, loss of Shb impairs insulin secretion, alters islet microvascular morphology, and increases the basal blood glucose concentration. The impaired insulin secretory response is a plausible underlying cause of the metabolic impairment observed in this mutant mouse.

  • 2278.
    Åkerblom, Björn
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Zang, Guangxiang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Zhuang, Zhen W.
    Calounova, Gabriela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Simons, Michael
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Heterogeneity among RIP-Tag2 insulinomas allows vascular endothelial growth factor-A independent tumor expansion as revealed by studies in Shb mutant mice: implications for tumor angiogenesis2012Inngår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 6, nr 3, s. 333-346Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The Shb adapter protein is a signaling intermediate that operates downstream of vascular endothelial growth factor receptor-2 (VEGFR-2) in endothelial cells. The Shb knockout mouse displays a dysfunctional microvasculature and impaired growth of subcutaneously implanted tumor cells. We decided to investigate tumor growth and angiogenesis in the absence of Shb in an inheritable tumor model, the RIP-Tag2 mouse, which produces insulinomas in a manner highly dependent on de novo angiogenesis. We observed a reduced tumor incidence and burden in both RIP-Tag2 Shb-/- and RIP-Tag2 Shb+/- mice. This correlated with a reduced microvascular density, measured as percentage of insulinoma area positive for CD31 staining, and altered vascular morphology. However, treatment with a VEGF-A blocking antibody was without effect on the Shb mutant tumor volume whereas it significantly inhibited tumor volume in the wild-type mice, suggesting that in mice with reduced Shb expression tumor angiogenesis was primarily sustained by VEGF-A independent pathway(s). This notion was further substantiated by gene expression analysis of angiogenic markers showing reduced VEGF-A expression in Shb deficient tumors. Considerable heterogeneity with respect to the gene expression profiles of other angiogenic markers and the signal-transduction characteristics was observed between different tumors, suggesting that multiple “rescue” pathways could be operating. The numbers of invasive tumors or metastases were unchanged in the Shb mutant. It is concluded that the Shb mutant background reduces tumor frequency by chronically suppressing VEGF-A dependent angiogenesis. However, VEGF-A independent angiogenesis supports a significant degree of tumor expansion in Shbdeficient mice, indicating heterogeneity in the mechanisms by which tumor expansion is promoted. Interference with Shb signaling may provide novel means for future cancer therapy.

  • 2279.
    Öberg-Welsh, Charlotte
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Protein tyrosine kinases in insulin producing cells: Expression and putative importance for beta-cell function1997Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Protein tyrosine kinases are of importance for cell replication and differentiation in manysystems. The mechanisms controlling the replication and differentiation of insulin producingcells are unknown. The present study was therefore conducted in order to characterize theexpression of various tyrosine kinases in insulin producing cells, and to assess the possibleimportance of these for beta-cell function by addition of ligands to the tyrosine kinasereceptors expressed to in vitro cultures of fetal islet-like structures.

    Several tyrosine kinases were found to be expressed in different preparations of insulinproducing cells, among them the receptors Flk-1, c-Kit, the FGF receptor 4 and the IGF-Ireceptor. Flk-1 and c-Kit were expressed mainly in ductal epithelium, whereas the FGFR4was widely expressed throughout the pancreatic parenchyma. The ligand to Flk-1, VEGF,stimulated after culture both insulin release to the culture medium and insulin contents/DNAin fetal rat islet-like structures. In addition, it caused an increased replication of isolatedductal epithelial cells. The possibility that VEGF is a duct cell mitogen may be ofimportance, since the increase in beta-cell mass during fetal development is largely due toneoformation of islet cells from stem cells located in the ductal epithelium. SCF, the ligand toc-Kit increased the insulin/DNA content in fetal rat islet-like structures, but decreased theDNA content in the same culture system, whereas both acidic FGF and growth hormonestimulated the insulin accumulation to the culture medium. Taken together, the data indicatethat ligands to tyrasine kinase receptors or receptors signalling through cytoplasmic tyrosinekinases may play a role for islet development and/or function. Specifically, VEGF may playa role in this process by stimulating proliferation of the ductal epithelium, which may be aprerequisite for neoformtation of islet cells from stem cells in the epithellum.

    Furthermore, a novel tyrosine kinase, Bsk, was cloned from insulin producing cells, and itsstructure and function has been investigated. Bsk is a member of the Src-family of cytoplasmictyrosine kinases, highly homologous to the human gene Frk. The Bsk gene is expressed inpancreas, liver, lung and kidney. Transfection of NIH3T3 fibroblasts with Bsk cDNAcontaining mutations of carboxyterminal regulatory tyrosine residues 497 and 504 results ininhibited cell growth and a decrease in thymidine incorporation rate. Cell cycle analysisrevealed that this is a consequence of Gl-prolongation. This suggests a role for Bsk in theregulation of cell proliferation, although the exact function of the gene product remains to beelucidated.

  • 2280.
    Öberg-Welsh, Charlotte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Annerén, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Mutation of C-terminal tyrosine residues Y497/Y504 of the Src-family member Bsk/Iyk decreases NIH3T3 cell proliferation1998Inngår i: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 16, nr 2, s. 111-124Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To elucidate the properties of the Src-family member Bsk/Iyk, NIH3T3 cells were transfected with wild-type Bsk/Iyk or Bsk/Iyk carrying Y497F, Y504F or Y497/504F mutations. These positions are putatively homologous to tyr-527 in Src. The Bsk/IykY497/504F cells displayed a decreased cell growth rate, parallelled by an augmentation of the fraction of cells in G1-phase. The Bsk/IykY497/504F double-mutation decreased the [3H]thymidine incorporation. No effects on NIH3T3 cell growth could be seen in cells expressing wild-type Bsk/Iyk or the other Bsk/Iyk mutants. In vitro kinase reactions performed on immunoprecipitates from NIH3T3 cells expressing wild-type or mutated Bsk/Iyk revealed increased relative [32P]-incorporation into Bsk/Iyk isoforms containing the Y504F and Y497/504F mutations compared with wild-type Bsk/Iyk. The Y497F and Y497/504F mutations elevated the proportion of [32P]-incorporation into a 57 kDa Bsk/Iyk product relative to that into the 60 kDa isoform. The Y497F Bsk/Iyk mutant not only increased the relative amount of p57 Bsk/Iyk but also transferred this isoform to the nuclear subcellular fraction. The results suggest that Bsk/Iyk has unique regulatory properties, and that this kinase might serve a role in inhibiting cell replication.

  • 2281.
    Öberg-Welsh, Charlotte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, Stellan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Andersson, Arne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Effects of vascular endothelial growth factor on pancreatic duct cell replication and the insulin production of fetal islet-like cell clusters in vitro1997Inngår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 126, nr 2, s. 125-132Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have previously shown that the tyrosine kinase receptor Flk-1 and its ligand, vascular endothelial growth factor (VEGF), may play a role in the development of fetal rat islet-like structures in vitro, possibly by stimulating the maturation of endocrine precursor cells in the pancreatic ductal epithelium. In order to further assess this, adult rat pancreatic ducts and fetal porcine islet-like cell clusters (ICC) were cultured in the presence of VEGF. In ducts, VEGF stimulated the mitogenesis in the epithelium. Culture of ICC in the presence of VEGF significantly enhanced their insulin content, but decreased the insulin accumulation to the culture medium. Glucose-stimulated acute insulin release was not affected by VEGF. Northern blot analysis after partial pancreatectomy in adult rats revealed induction of VEGF mRNA 3 days after the operation. Immunohistochemistry of fetal rat pancreas showed staining mainly in the islets of Langerhans. We conclude that VEGF directly stimulates the replication of the ductal epithelium, a possible prerequisite for β-cell formation. This could require local production of VEGF, which may alter in response to physiological demands.

  • 2282. Öhlund, Malin
    et al.
    Franzén, Petra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Andersson, Göran
    Ström Holst, Bodil
    Lau, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Laser Microdissection of Pancreatic Islets Allows for Quantitative Real-Time PCR Detection of Islet-Specific Gene Expression in Healthy and Diabetic Cats2014Inngår i: Journal of Gastroenterology, Pancreatology & Liver Disorders, ISSN 2374-815X, Vol. 1, nr 4, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Feline diabetes mellitus shares many similarities with human type 2 diabetes mellitus, including clinical, physiological and pathological features of the disease. The domestic cat spontaneously develops diabetes associated with insulin resistance in their middle age or later, with residual but declining insulin secretion. Humans and cats share largely the same environment and risk factors for diabetes, such as obesity and physical inactivity. Moreover, amyloid formation and loss of beta cells are found in the islets of the diabetic cat, as in humans. Altogether, the diabetic cat is a good model for type 2 diabetes in humans. The aims of the present study were to isolate feline islets using laser microdissection and to develop a quantitative method for detection of mRNA levels in islets of healthy and diabetic cats.Results: By using the laser microdissection technique, we were able to meticulously sample islets from both healthy and diabetic cats. Insulin staining of separate sections showed many beta cells in islets from healthy cats, whereas few insulin positive cells were found in islets from diabetic cats. By quantitative real-time PCR, mRNA levels of the islet-specific genes INS, PDX1IAPPCHGA and IA-2could be detected in both healthy and diabetic cats.Conclusions: Laser microdissection allows distinct studies of islets without contamination of acinar cells. Previous attempts in isolating feline islets with different collagenase-based protocols have led to damaged islets or islets coated with exocrine acinar cells, which either way compromise the results obtained from gene expression studies. The use of the laser microdissection technique eliminates these problems as shown in this study. Differences in gene expression between healthy and diabetic cats can reveal underlying mechanisms for beta cell dysfunction and decreased beta cell mass in human type 2 diabetes.

  • 2283.
    Öhnstedt, E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vågesjö, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Lofton Tomenius, Hava
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Roos, S.
    Swedish Univ Agr Sci, Uppsala, Sweden.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Bioengineering of the local wound environment accelerates wound healing by increasing macrophage density and induces a phenotype shift in the wound macrophages2018Inngår i: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, nr S1, s. 79-79Artikkel i tidsskrift (Annet vitenskapelig)
  • 2284.
    Öhnstedt, Emelie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Ilya Pharma AB, Dag Hammarskiolds Vag, Uppsala, Sweden.
    Lofton Tomenius, Hava
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Ilya Pharma AB, Dag Hammarskiolds Vag, Uppsala, Sweden.
    Vågesjö, Evelina
    Ilya Pharma AB, Dag Hammarskiolds Vag, Uppsala, Sweden.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Ilya Pharma AB, Dag Hammarskiolds Vag, Uppsala, Sweden.
    The discovery and development of topical medicines for wound healing2019Inngår i: Expert Opinion on Drug Discovery, ISSN 1746-0441, E-ISSN 1746-045X, Vol. 14, nr 5, s. 485-497Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Introduction: Chronic, nonhealing skin wounds claim >3% of the health-care budget in industrialized countries, and the incidence is rising. Currently, two parallel trends influence innovations within the field of wound healing: the need to reduce spread of antibiotic resistance and the emerging use of health economy and value-based models.Areas covered: This review focuses on the discovery of drug candidates and development of treatments aiming to enhance wound healing in the heterogeneous group of patients with nonhealing wounds.Expert opinion: Nonhealing wounds are multifaceted and recognized as difficult indications. The majority of products currently in use are medical device dressings, or concepts of negative pressure or hyperbaric oxygen treatment. Global best practice guidelines for the treatment of diabetic foot ulcers recommend debridement, redressing, as well as infection control, and are critical to the lack of coherent clinical evidence for many approved products in active wound care. To accelerate wound healing, there is an emerging trend toward biologics, gene therapy, and novel concepts for drug delivery in research and in the pipeline for clinical trials. Scientific delineation of the therapeutic mechanism of action is, in our opinion, vital for clinical trial success and for an increased fraction of medical products in the pharmaceutical pipeline.

  • 2285. Östenson, C-G
    et al.
    Abdel-Halim, S M
    Andersson, A
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Efendic, S
    Studies on the pathogenesis of NIDDM in the GK (Goto-Kakizaki) rat1996Inngår i: Lessons from Animal Diabetes IV, 1996, Vol. 17, s. 299-Kapittel i bok, del av antologi (Annet vitenskapelig)
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