| 1. |
- Svensson, Henrik, 1982, et al.
(författare)
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Adipose tissue and body composition in women six years after gestational diabetes: factors associated with development of type 2 diabetes.
- 2018
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Ingår i: Adipocyte. - : Informa UK Limited. - 2162-397X .- 2162-3945. ; 7:4, s. 229-237
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Tidskriftsartikel (refereegranskat)abstract
- Factors differentiating women at highest risk of progression to type 2 diabetes mellitus (T2DM) after gestational diabetes mellitus (GDM) are incompletely known. Our aim was to characterize adipose tissue and body composition in relation to glucose metabolism in women with a history of GDM and to identify factors associated with development of T2DM. We examined glucose tolerance (OGTT), insulin sensitivity (HOMA-IR), body composition (anthropometry, air displacement plethysmography), and blood chemistry in 39 women 6years after GDM. An adipose tissue biopsy was obtained to assess the size, number, and lipolytic activity of adipocytes, and adipokine release and density of immune cells and blood vessels in adipose tissue. Normal glucose tolerance (NGT) was identified in 31 women and impaired glucose metabolism (IGM) in 8. Women with IGM had higher BMI/fat mass, and related expected adipose tissue features, than women with NGT. Ethnicity was similar in the groups, but numerically there was a higher proportion of European women in the NGT group and a higher proportion of non-European women in the IGM group. BMI was the best discriminator of NGT versus IGM (multivariable logistic regression: OR=1.34, P<0.01). Waist-to-height ratio and adipocyte volume were most strongly associated with HOMA-IR (multivariable linear regression: R2=0.656, P<0.001). After adjustment for BMI/ethnicity, women with IGM had increased serum adipocyte fatty acid-binding protein, weight gain after index pregnancy, and a lower proportion of fat-free mass. These factors, together with high BMI, abdominal fat distribution, and enlarged adipocytes, may increase the risk of progression to T2DM after GDM.
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| 2. |
- Svensson, Henrik, 1982, et al.
(författare)
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Body fat mass and the proportion of very large adipocytes in pregnant women are associated with gestational insulin resistance.
- 2016
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Ingår i: International journal of obesity (2005). - : Springer Science and Business Media LLC. - 1476-5497 .- 0307-0565. ; 40, s. 646-653
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Tidskriftsartikel (refereegranskat)abstract
- Pregnancy is accompanied by fat gain and insulin resistance. Changes in adipose tissue morphology and function during pregnancy and factors contributing to gestational insulin resistance are incompletely known. We sought to characterize adipose tissue in trimesters 1 and 3 (T1/T3) in normal weight (NW) and obese pregnant women, and identify adipose tissue-related factors associated with gestational insulin resistance.
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| 3. |
- Svensson, Henrik, 1982, et al.
(författare)
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Free lipid and computerized determination of adipocyte size.
- 2018
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Ingår i: Adipocyte. - : Informa UK Limited. - 2162-397X .- 2162-3945. ; 7:3, s. 180-182
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Tidskriftsartikel (refereegranskat)abstract
- The size distribution of adipocytes in a suspension, after collagenase digestion of adipose tissue, can be determined by computerized image analysis. Free lipid, forming droplets, in such suspensions implicates a bias since droplets present in the images may be identified as adipocytes. This problem is not always adjusted for and some reports state that distinguishing droplets and cells is a considerable problem. In addition, if the droplets originate mainly from rupture of large adipocytes, as often described, this will also bias size analysis. We here confirm that our ordinary manual means of distinguishing droplets and adipocytes in the images ensure correct and rapid identification before exclusion of the droplets. Further, in our suspensions, prepared with focus on gentle handling of tissue and cells, we find no association between the amount of free lipid and mean adipocyte size or proportion of large adipocytes.
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| 4. |
- Abel, Edvard, 1970, et al.
(författare)
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Early disturbance of microvascular function precedes chemotherapy-induced intestinal injury
- 2005
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Ingår i: Dig Dis Sci. - : Springer Science and Business Media LLC. - 0163-2116. ; 50:9, s. 1729-33
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal injury 4-48 hr after cytotoxic therapy (etoposide phosphate, 100 mg/kg body weight [bw], intravenously [i.v.]) was studied in rats using ligated intestinal loops. Chromium-51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) and rubidium-86 chloride ((86)RbCl) were deposited intraluminally to determine the extent of the increase in intestinal permeability and ion channel disruption. Evans Blue (EB) was used for detection of endothelial leakage. Intestinal morphology was documented. Endothelial dysfunction, as observed by an increased extravasation of EB, was evident already 4 hr after cytotoxic therapy. Intestinal epithelial injury, as observed by an increase in (51)Cr-EDTA permeation and a decrease in (86)Rb absorption, occurred after 48 hr. Finally, histology disclosed a reduced crypt cell proliferation, displayed as a decrease in Ki67-positive cells. The findings suggest that, in the development of intestinal injury after cytotoxic therapy, endothelial disruption is an early event, whereafter epithelial dysfunction and crypt stem cell arrest occur. This knowledge could be of importance in the design of future intervention trials.
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| 5. |
- Al-Olama, Mohamed, et al.
(författare)
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The peptide AF-16 decreases high interstitial fluid pressure in solid tumors.
- 2011
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Ingår i: Acta oncologica (Stockholm, Sweden). - 1651-226X.
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background. The high interstitial fluid pressure (IFP) in solid tumors restricts the access to nutrients, oxygen and drugs. Material and methods. We investigated the ability of the peptide AF-16, involved in water and ion transfer through cell membranes, to lower the IFP in two different solid rat mammary tumors, one chemically induced, slowly growing, and the other transplantable, and rapidly progressing having high cellularity. AF-16 was administered either in the tumor capsule, intranasally or intravenously. The IFP was measured by a miniature fiber optic device. Results. AF-16 significantly lowered the IFP in both the slowly and the rapidly progressing tumors, whether administrated locally or systemically. The AF-16 induced IFP reduction was maximal after 90 min, lasted at least 3 h, and returned to pretreatment levels in less than 24 h. Topical AF-16 transiently reduced the IFP in the DMBA tumors from 17.7 ± 4.2 mmHg to 8.6 ± 2.1 mmHg. Conclusion. We conclude that AF-16 transiently and reversibly lowered the high IFP in solid tumors during a few hours, which might translate into improved therapeutic efficacy.
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| 6. |
- Al-Olama, Mohamed, et al.
(författare)
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Uptake of the antisecretory factor peptide AF-16 in rat blood and cerebrospinal fluid and effects on elevated intracranial pressure
- 2015
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Ingår i: Acta Neurochirurgica. - : Springer Science and Business Media LLC. - 0001-6268 .- 0942-0940. ; 157:1, s. 129-137
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Tidskriftsartikel (refereegranskat)abstract
- AF-16 is a 16-amino-acid-long peptide derived from the amino-terminal part of the endogenous protein, antisecretory factor (AF). AF-16 in vivo has been shown to regulate dysfunctions in the water and ion transport system under various pathological conditions and also to counteract experimentally increased tissue pressure. Rats were subjected to a cryogenic brain injury in order to increase the intracranial pressure (ICP). The distribution of AF-16 in blood and CSF after intravenous or intranasal administration was determined in injured and control rats. ICP was monitored in freely moving, awake rats, by means of an epidural pressure transducer catheter connected to a wireless device placed subcutaneously on the skull. The continuous ICP registrations were achieved by means of telemetry. Intranasal administration of AF-16 resulted in a significantly higher CSF concentrations of AF-16 in injured than in control rats, 1.3 versus 0.6 ng/ml, whereas no difference between injured and control rats was seen when AF-16 was given intravenously. Rats subjected to cryogenic brain injury developed gradually increasing ICP levels. Intranasal administration of AF-16 suppressed the increased ICP to normal values within 30 min. Optimal AF-16 concentrations in CSF are achieved after intranasal administration in rats subjected to a cryogenic brain injury. The ability of AF-16 to suppress an increased ICP was manifested.
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| 7. |
- Bazzurro, V., et al.
(författare)
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Involvement of GABA(A) receptors containing alpha(6) subtypes in antisecretory factor activity on rat cerebellar granule cells studied by two-photon uncaging
- 2022
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 56:5, s. 4505-4513
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Tidskriftsartikel (refereegranskat)abstract
- The antisecretory factor (AF) is an endogenous protein that counteracts intestinal hypersecretion and various inflammation conditions in vivo. It has been detected in many mammalian tissues and plasma, but its mechanisms of action are largely unknown. To study the pharmacological action of the AF on different GABA(A) receptor populations in cerebellar granule cells, we took advantage of the two-photon uncaging method as this technique allows to stimulate the cell locally in well-identified plasma membrane parts. We compared the electrophysiological response evoked by releasing a caged GABA compound on the soma, the axon initial segment and neurites before and after administering AF-16, a 16 amino acids long peptide obtained from the amino-terminal end of the AF protein. After the treatment with AF-16, we observed peak current increases of varying magnitude depending on the neuronal region. Thus, studying the effects of furosemide and AF-16 on the electrophysiological behaviour of cerebellar granules, we suggest that GABA(A) receptors, containing the alpha(6) subunit, may be specifically involved in the increase of the peak current by AF, and different receptor subtype distribution may be responsible for differences in this increase on the cell.
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| 8. |
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| 9. |
- Borenäs, Marcus, et al.
(författare)
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ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition
- 2024
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 1091-6490. ; 121:1
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Tidskriftsartikel (refereegranskat)abstract
- High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and Anaplastic Lymphoma Kinase (ALK), which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR (ataxia telangiectasia and Rad3-related)/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-d ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.
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| 10. |
- Dahlgren, Jovanna, 1964, et al.
(författare)
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Prenatal cytokine exposure results in obesity and gender-specific programming.
- 2001
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Ingår i: American journal of physiology. Endocrinology and metabolism. - 0193-1849. ; 281:2
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Tidskriftsartikel (refereegranskat)abstract
- Prenatal events appear to program hormonal homeostasis, contributing to the development of somatic disorders at an adult age. The aim of this study was to examine whether maternal exposure to cytokines or to dexamethasone (Dxm) would be followed by hormonal consequences in the offspring at adult age. Pregnant rats were injected on days 8, 10, and 12 of gestation with either human interleukin-6 (IL-6) or tumor necrosis factor-alpha (TNF-alpha) or with Dxm. Control dams were injected with vehicle. All exposed offspring developed increased body weight (P < 0.05--0.001), apparently due to an increase of 30--40% in adipose tissue weight (P < 0.05--0.01). Corticosterone response to stress was increased in the IL-6 group (P < 0.05-0.01). Dxm-treated male rats exhibited blunted Dexamethasone suppression test results. In male rats, insulin sensitivity was decreased after IL-6 exposure (P < 0.01), whereas basal insulin was elevated in the TNF-alpha group (P < 0.01). In female rats, plasma testosterone levels were higher in all exposed groups compared with controls (P < 0.01--0.001), with the exception of Dxm-exposed offspring. Males in the TNF-alpha group showed decreased locomotor activity (P < 0.05), and females in the IL-6 group showed increased locomotor activity (P < 0.05). These results indicate that prenatal exposure to cytokines or Dxm leads to increased fat depots in both genders. In females, cytokine exposure was followed by a state of hyperandrogenicity. The results suggest that prenatal exposure to cytokines or Dxm can induce gender-specific programming of neuroendocrine regulation with consequences in adult life.
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| 11. |
- Dowlatshahi Pour, Masoumeh, 1976, et al.
(författare)
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Food-induced changes of lipids in rat neuronal tissue visualized by ToF-SIMS imaging
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Time of flight secondary ion mass spectrometry (ToF-SIMS) was used to image the lipid localization in brain tissue sections from rats fed specially processed cereals (SPC). An IonTof 5 instrument equipped with a Bi cluster ion gun was used to analyze the tissue sections. Data from 15 brain samples from control and cereal-fed rats were recorded and exported to principal components analysis (PCA). The data clearly show changes of certain lipids in the brain following cereal feeding. PCA score plots show a good separation in lipid distribution between the control and the SPC-fed group. The loadings plot reveal that the groups separated mainly due to changes in cholesterol, vitamin E and c18:2, c16:0 fatty acid distribution as well as some short chain monocarboxylic fatty acid compositions. These insights relate to the working mechanism of SPC as a dietary supplement. SPC is thought to activate antisecretory factor (AF), an endogenous protein with regulatory function for inflammation and fluid secretion. These data provide insights into lipid content in brain following SPC feeding and suggest a relation to activating AF.
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| 12. |
- Dowlatshahi Pour, Masoumeh, 1976, et al.
(författare)
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Mass spectrometric profiling of lipids in intestinal tissue from rats fed cereals processed for medical conditions
- 2016
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Ingår i: Biointerphases. - : American Vacuum Society. - 1934-8630 .- 1559-4106. ; 11:2, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- Time-of-flight secondary ion mass spectrometry (ToF-SIMS) was used for lipid profiling of intestine tissue sections from rats fed specially processed cereals and rats fed ordinary feed as a control. This cereal is known to increase the activity of antisecretory factor in plasma and the exact mechanism for the activation process at the cellular level is unclear. ToF-SIMS has been used to track food induced changes in lipid content in intestinal tissue sections to gain insight into the possible mechanisms involved. Data from 20 intestine sections belonging to four different rats from each group of control and specially processed cereals-fed rats were obtained using the stage scan macroraster with a lateral resolution of 5 lm. Data were subsequently subjected to orthogonal partial least squares discriminant analysis. The data clearly show that changes of certain lipids are induced by the specially processed cereal feed. Scores plots show a well-defined separation between the two groups. The corresponding loading plots reveal that the groups separate mainly due to changes of vitamin E, phosphocholine, and phosphosphingolipid fragments, and that for the c18:2 fatty acid. The observed changes in lipids might give insight into the working mechanisms of antisecretory factor in the body, and this has been successfully used to understand the working mechanism of specially processed cereal-induced antisecretory factor activation in intestine.
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| 13. |
- Dowlatshahi Pour, Masoumeh, 1976, et al.
(författare)
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Mass spectrometry imaging as a novel approach to measure hippocampal zinc
- 2019
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Ingår i: Journal of Analytical Atomic Spectrometry. - : Royal Society of Chemistry (RSC). - 0267-9477 .- 1364-5544. ; 34:8, s. 1581-1587
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Tidskriftsartikel (refereegranskat)abstract
- Zinc (Zn2+) is an essential trace element that plays crucial roles in the functioning of hundreds of enzymes and DNA binding transcription factors. Zinc is also an essential neuromodulator and can act as a potent neurotoxin in excitotoxic brain injury after seizures, strokes, and brain trauma where high levels of Zn2+ can cause irreparable brain damage in certain brain regions. However, the mechanism of neurotoxicity has not been fully understood yet and is still under debate. In the present study, we have developed a time of flight secondary ion mass spectrometry (ToF-SIMS) imaging method to investigate the distribution of zinc in the rat brain. The zinc distribution in hippocampus sections from healthy rats and rats exposed to traumatic brain injury was imaged and the results were compared to those from conventional zinc-probe based fluorescence microscopy. Two related zinc species, ZnOH3 + and ZnO2H+, can successfully be visualized by ToF-SIMS in the rat hippocampus. Statistical data analysis of the image data demonstrated a substantial increase of both ZnOH3 + and ZnO2H+ in the zinc related species in the acute brain injury tissue. Our findings positively support the fact that toxic vesicular zinc accumulation might not be the sole source for neuronal degeneration following traumatic brain injuries. Also, we could successfully apply ToF-SIMS imaging for the first time to visualize the zinc content and distribution across hippocampus sections. Consequently, ToF-SIMS is a powerful method to further investigate biological phenomena such as seizures, ischemia, and strokes and also other forms of cellular damage in the central nervous system.
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| 14. |
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| 15. |
- Eriksson, A, et al.
(författare)
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Effect of antisecretory factor in ulcerative colitis on histological and laborative outcome: a short period clinical trial.
- 2003
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Ingår i: Scandinavian journal of gastroenterology. - 0036-5521. ; 38:10, s. 1045-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The antisecretory factor (AF) is a 41 kD endogenously produced protein capable of mediating protection against diarrhoea diseases and intestinal inflammation. High concentrations of AF-like proteins are present in egg yolk, and AF can consequently be administrated in the form of egg yolk drinks. In this study, performed in patients suffering from acute onset of ulcerative colitis (UC), we evaluate the influence of orally administrated AF on the histological and clinical laboratory outcome. METHODS: A total of 20 patients fulfilled this prospective, double-blind and randomized protocol. The intake of AF was used as an additive treatment to conventional UC medication. Patient registrations were extended to two outward visits, performed 2-4 and 8-12 weeks after hospital discharge. RESULTS: During AF treatment, a reduction in the histological severity from mucosal biopsies received from the mid-rectum was found. In addition, a lowering in the inflammatory blood parameters ESR, CRP and orosomucoid was demonstrated. CONCLUSION: In the AF-treated group a late and significant lowering of various inflammatory parameters combined with a histological recovery was demonstrated. These findings suggest that administration of AF mediates a long-lasting anti-inflammatory effect in cases of acute UC.
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| 16. |
- Eriksson, Anders, 1957, et al.
(författare)
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Real-time PCR quantification analysis of five mucosal transcripts in patients with Crohn's disease.
- 2008
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Ingår i: European journal of gastroenterology & hepatology. - 0954-691X. ; 20:4, s. 290-6
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Crohn's disease has a genetic background. Onset of the clinical manifestations, however, is suggested to be triggered by environmental factors. Microarray analysis has shown that the expression of transcripts aldolase B, elafin, MST-1, simNIPhom and SLC6A14 are altered in patients with ulcerative colitis. The primary aim of this study was to explore the expressions of these five transcripts in macroscopically inflamed and noninflamed mucosa in patients with Crohn's disease. METHODS: Mucosal specimens obtained from colon in consecutive patients with Crohn's disease (n=23) and controls (n=67) undergoing colonoscopy were analyzed using real-time PCR technique. RESULTS: The expressions of the transcripts aldolase B, elafin, simNIPhom and SLC6A14 were increased, whereas the expression of MST-1 was decreased in noninflamed rectal mucosa in patients with Crohn's disease compared with controls. The expression of aldolase B was increased and the expressions of elafin and simNIPhom were decreased in inflamed colonic mucosa compared with noninflamed rectal mucosa in patients with Crohn's disease. No correlation, between the clinical activity of Crohn's disease (Mayo score or=6) and transcript expression was detected. CONCLUSION: The mucosal transcript pattern in Crohn's disease may, based on the known biological function of the transcripts, explain some of the typical features of Crohn's disease and indicate a possible pathophysiological role of microbes. Our results may thereby contribute to the understanding of the pathogenesis and manifestations of Crohn's disease.
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| 17. |
- Flach, Carl-Fredrik, 1977, et al.
(författare)
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Broad up-regulation of innate defense factors during acute cholera.
- 2007
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Ingår i: Infection and immunity. - 0019-9567. ; 75:5, s. 2343-50
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Tidskriftsartikel (refereegranskat)abstract
- We used a whole-genome microarray screening system (Affymetrix human GeneChips covering 47,000 different transcripts) to examine the gene expression in duodenal mucosa during acute cholera. Biopsies were taken from the duodenal mucosa of seven cholera patients 2 and 30 days after the onset of diarrhea, and the gene expression patterns in the acute- and convalescent-phase samples were compared pairwise. Of about 21,000 transcripts expressed in the intestinal epithelium, 29 were defined as transcripts that were up-regulated and 33 were defined as transcripts that were down-regulated during acute cholera. The majority of the up-regulated genes characterized were found to have an established or possible role in the innate defense against infections; these genes included the LPLUNC1, LF, VCC1, TCN1, CD55, SERPINA3, MMP1, MMP3, IL1B, LCN2, SOCS3, GDF15, SLPI, CXCL13, and MUC1 genes. The results of confirmative PCR correlated well with the microarray data. An immunohistochemical analysis revealed increased expression of lactoferrin in lamina propria cells and increased expression of CD55 in epithelial cells, whereas increased expression of the SERPINA3 protein (alpha1-antichymotrypsin) was detected in both lamina propria and epithelial cells during acute cholera. The expression pattern of CD55 and SERPINA3 in cholera toxin (CT)-stimulated Caco-2 cells was the same as the pattern found in the intestinal mucosa during acute cholera, indicating that the activation of the CD55 and SERPINA3 genes in intestinal epithelium was induced by CT. In conclusion, during acute cholera infection, innate defense mechanisms are switched on to an extent not described previously. Both direct effects of CT on the epithelial cells and changes in the lamina propria cells contribute to this up-regulation.
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| 18. |
- Flach, Carl-Fredrik, 1977, et al.
(författare)
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Cholera toxin induces a transient depletion of CD8+ intraepithelial lymphocytes in the rat small intestine as detected by microarray and immunohistochemistry.
- 2005
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Ingår i: Infection and immunity. - 0019-9567. ; 73:9, s. 5595-602
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Tidskriftsartikel (refereegranskat)abstract
- Cholera toxin (CT), besides causing intestinal hypersecretion after intragastric administration or during cholera infection, affects a multitude of regulatory mechanisms within the gut mucosal network, including T cells. By use of microarray screening, real-time PCR, and immunohistochemistry, we demonstrate here a rapid depletion of jejunal CD8(+) intraepithelial lymphocytes (IEL) in rats after intragastric CT challenge. This depletion may depend on CT-induced migration of IEL, since it was associated with a progressive decrease of CD8(+) cells in the epithelium and a contemporary transient increase of such cells, preferentially at the base of the villi, in the lamina propria. A significant decrease in the total number of villous CD8(+) cells at 6 and 18 h after CT challenge was detected; this possibly reflects an efflux from the jejunal mucosa. The kinetics of the CD8(+) IEL demonstrate the return to normal intraepithelial position at original numbers already 72 h after the single CT dose. The induced migration seems to be dependent on the enzymatic A-subunit of CT, since challenge with neither sorbitol nor CT B-subunit did mimic the effects of CT on CD8(+) IEL. Furthermore, a decrease in the level of both RANTES transcript and protein was detected, most likely as a consequence of the CT-induced migration of CD8(+) IEL. These results point to a complex interaction between CT, epithelial cells, and IEL, resulting in a disturbance of the gut homeostasis, which might have relevance for the strong immunomodulatory effects of intragastrically administered CT.
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| 19. |
- Flach, Carl-Fredrik, 1977, et al.
(författare)
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Cholera toxin induces expression of ion channels and carriers in rat small intestinal mucosa.
- 2004
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Ingår i: FEBS letters. - 0014-5793. ; 561:1-3, s. 122-6
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Tidskriftsartikel (refereegranskat)abstract
- Cholera toxin causes cyclic adenosine monophosphate (cAMP)-induced electrolyte and water secretion in the small intestine. The toxin-induced change in gene expression in rat small intestine was evaluated with microarray technique and the results were confirmed by semiquantitative polymerase chain reaction (PCR). The transporter CNT2 for nucleosides was upregulated between 6 and 18 h after challenge, whereas the level of GLUT1 transporter for glucose became elevated at 6 h. Both changes probably facilitate uptake of these nutrients in the gut. At 18 h, the major chloride channel in the villus, ClC2, was upregulated. Aquaporin 8 was downregulated at 6 h and two mucin-producing genes were upregulated 18 h after toxin challenge. The expression was back to normal after 72 h, which is the turnover time for intestinal epithelial cells.
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| 20. |
- Flach, Carl-Fredrik, 1977, et al.
(författare)
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Detection of elafin as a candidate biomarker for ulcerative colitis by whole-genome microarray screening.
- 2006
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Ingår i: Inflammatory bowel diseases. - : Oxford University Press (OUP). - 1078-0998. ; 12:9, s. 837-42
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Tidskriftsartikel (refereegranskat)abstract
- The cause of ulcerative colitis (UC) is largely unknown. Microarray studies are an efficient way of investigating the various genes involved. Here, we have used whole-genome microarrays to clarify the clinical picture and to identify new biomarkers for improved diagnosis. Rectal biopsies were taken from five UC patients and five matched controls, and RNA transcripts were prepared. After labeling, each sample was individually applied to the microarray chips. All transcripts that were more than 10-fold up-regulated in all five patients were analyzed further in seven additional patients and seven controls using quantitative polymerase chain reaction. Of 47,000 transcripts examined, 4 were highly up-regulated in all patients: those encoding elafin, a secreted protease inhibitor, the ion and amino acid transporter B (SLC6A14), and the metabolic enzyme aldolase B, as well as a recently identified transcript named similar to numb-interacting homolog. The up-regulation of these transcripts appears to follow the progression of the disease because elevated expression was detected in the proximal part of the colon in patients with total colitis but not in patients with left-sided colitis. Immunohistologic examination showed very distinct differences in the expression of elafin. Extensive expression was detected in enterocytes and goblet cells of the affected mucosa, whereas there was no detectable expression in unaffected mucosa and in healthy controls. The results implicate four transcripts and proteins of special interest as possible targets for pharmacologic interference and as biomarkers in UC. Of these, elafin may be of special interest because it is a secreted protein that may be measured in body fluids.
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| 21. |
- Flach, Carl-Fredrik, 1977, et al.
(författare)
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Differential expression of intestinal membrane transporters in cholera patients.
- 2007
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Ingår i: FEBS letters. - : Wiley. - 0014-5793. ; 581:17, s. 3183-8
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Tidskriftsartikel (refereegranskat)abstract
- Vibrio cholerae causes the cholera disease through secretion of cholera toxin (CT), resulting in severe diarrhoea by modulation of membrane transporters in the intestinal epithelium. Genes encoding membrane-spanning transporters identified as being differentially expressed during cholera disease in a microarray screening were studied by real-time PCR, immunohistochemistry and in a CaCo-2 cell model. Two amino acid transporters, SLC7A11 and SLC6A14, were upregulated in acute cholera patients compared to convalescence. Five other transporters were downregulated; aquaporin 10, SLC6A4, TRPM6, SLC23A1 and SLC30A4, which have specificity for water, serotonin (5-HT), magnesium, vitamin C and zinc, respectively. The majority of these changes appear to be attempts of the host to counteract the secretory response. Our results also support the concept that epithelial cells are involved in 5-HT signalling during acute cholera.
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| 22. |
- Gabrielsson, Britt, 1957, et al.
(författare)
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Depot-specific expression of fibroblast growth factors in human adipose tissue.
- 2002
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Ingår i: Obesity research. - : Wiley. - 1071-7323 .- 1550-8528. ; 10:7, s. 608-16
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the expression of several fibroblast growth factors (FGFs) and FGF-receptors (FGFRs) in human adipose tissue and adipose-tissue cell fractions obtained from both subcutaneous (sc) and omental (om) depots.
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| 23. |
- Gatzinsky, Kliment, 1959, et al.
(författare)
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Elevated intracranial pressure after head trauma can be suppressed by antisecretory factor—a pilot study
- 2020
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Ingår i: Acta Neurochirurgica. - : Springer Science and Business Media LLC. - 0001-6268 .- 0942-0940. ; 162:7, s. 1629-37
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Tidskriftsartikel (refereegranskat)abstract
- © 2020, The Author(s). Background: Control of intracranial pressure (ICP) is a key element in neurointensive care for directing treatment decisions in patients with severe traumatic brain injury (TBI). The anti-inflammatory protein antisecretory factor (AF) has been demonstrated to reduce experimentally induced high ICP in animal models. This report describes the first steps to investigate the uptake, safety, and influence of AF for reduction of elevated ICP in patients with TBI in a clinical setting. Method: Four patients with severe TBI (Glasgow Coma Scale < 9) that required neurointensive care with ICP monitoring due to signs of refractory intracranial hypertension were investigated. One hundred milliliters of Salovum®, a commercially available egg yolk powder with high contents of AF peptides, was administrated either via nasogastric (patients 1 and 2) or rectal tube (patients 2, 3, and 4) every 8 h for 2 to 3 days as a supplement to the conventional neurointensive care. ICP was registered continuously. Plasma levels of AF were measured by enzyme-linked immunosorbent assay (ELISA) to confirm that Salovum® was absorbed appropriately into the bloodstream. Results: In the first two patients, we observed that when delivered by the nasogastric route, there was an accumulation of the Salovum® solution in the stomach with difficulties to control ICP due to impaired gastric emptying. Therefore, we tested to administer Salovum® rectally. In the third and fourth patients, who both showed radiological signs of extensive brain edema, ICP could be controlled during the course of rectal administration of Salovum®. The ICP reduction was statistically significant and was accompanied by an increase in blood levels of AF. No adverse events that could be attributed to AF treatment or the rectal approach for Salovum® administration were observed. Conclusions: The outcomes suggest that AF can act as a suppressor of high ICP induced by traumatic brain edema. Use of AF may offer a new therapeutic option for targeting cerebral edema in clinical practice.
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| 24. |
- Guo, J P, et al.
(författare)
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The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases.
- 2009
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Ingår i: Genes and immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 10:3, s. 227-36
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variation in the antigen-presenting lectin-like receptor gene complex (APLEC) associates with autoimmunity and arthritis in rats and humans. We hypothesized that the encoded C-type lectin-like receptors might influence innate immunity and responses to infectious agents. To test this hypothesis, we compared in vivo and in vitro phenotypes in DA rats and APLEC-congenic rats. Survival rates following infection with Staphylococcus aureus and Herpes simplex virus differed significantly between the two strains. Likewise, differential delayed type hypersensitivity (DTH), an immunological reaction involving T lymphocytes and macrophages, was observed in response to provocation with the chemical oxazolone. Unstimulated bone marrow-derived macrophages from the two strains appeared to already have polarized activation states with different mRNA levels of CD163 and Dectin-1 receptors. Following stimulation with a panel of microbial agents, differences in induced mRNA and protein levels were shown for interleukin (IL)-6 and IL-10 following stimulation with lipopolysaccharide, mannan and beta-glucan. Expression levels of APLEC gene mRNAs also differed, and both strains had a notably dichotomous expression of the genes, with general downregulation of all four Dcir genes and upregulation of Mincle and Mcl. We suggest that human APLEC genes may similarly regulate infectious diseases, DTH and general macrophage activation status.
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| 25. |
- Gustafsson, A. M., et al.
(författare)
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Low levels of anti-secretory factor in placenta are associated with preterm birth and inflammation
- 2018
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Ingår i: Acta Obstetricia Et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 97:3, s. 349-356
-
Tidskriftsartikel (refereegranskat)abstract
- IntroductionAnti-secretory factor is a protein that regulates secretory and inflammatory processes and preterm birth is associated with inflammation. Therefore, our hypothesis was that anti-secretory factor might play a role in immune reactivity and homeostasis during pregnancy. Material and methodsFollowing spontaneous onset of labor and preterm or term delivery, placenta biopsies were collected. The levels of anti-secretory factor and markers of inflammation (CD68, CD163) and vascularization (CD34, smooth muscle actin) were analyzed by immunohistochemistry. ResultsThe 61 placental biopsies included 31 preterm (<37 weeks of gestation) and 30 term (37-41 weeks) samples. The preterm placentas exhibited lower levels of anti-secretory factor (p = 0.008) and larger numbers of CD68-positive cells (p < 0.001) compared to term. Preterm placentas had blood vessel of smaller diameter (p = 0.036) indicative of immaturity. The level of interleukin-6 in cord blood was higher after very preterm than term birth, suggesting a fetal inflammatory response. The placenta level of anti-secretory factor was positively correlated to the length of gestation (p = 0.025) and negatively correlated to the levels of the inflammatory markers CD68 (p = 0.015) and CD163 (p = 0.028). ConclusionsPreterm delivery is associated with low levels of anti-secretory factor in placenta. Inflammation, a potential trigger of preterm birth, is more pronounced in the preterm placenta and inversely related to the placental level of anti-secretory factor, suggesting both a link and a potential target for intervention.
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| 26. |
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| 27. |
- Hanner, Per, 1948, et al.
(författare)
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Antisecretory factor-inducing therapy improves the clinical outcome in patients with Meniere's disease
- 2010
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Ingår i: Acta Oto-Laryngologica. - : Informa UK Limited. - 0001-6489 .- 1651-2251. ; 130:2, s. 223-227
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Tidskriftsartikel (refereegranskat)abstract
- Conclusion: Intake of antisecretory factor (AF)-inducing SPC-flakes (R) significantly reduced vertigo in patients suffering from Meniere's disease (MD). The positive effect may be due to a modulation of the transport of water and ions in the endolymphatic space. Objective: To evaluate the effects of a 3-month treatment period with SPC-flakes (R) in patients suffering from MD. Patients and methods: A prospective, double-blind, placebo-controlled study was performed. A total of 51 adult patients with MD were included in the study: 27 subjects treated with SPC-flakes (R) and 24 subjects with control cereals. The patients received SPC-flakes (R) or control cereals (I g per kg body weight per 24 h in two servings) for 3 months. Otoneurological examinations were carried out before and after this period. Results: The severity of MD was classified according to the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) grading system. Fourteen of the 27 patients randomized to intake of the AF-inducing SPC-flakes (R) reported decreased vertigo, compared with 2 of 24 in the control group (p < 0.001). No consistent change in the otoneurological examinations could be demonstrated in any of the groups of patients.
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| 28. |
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| 29. |
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| 30. |
- Hultborn, Ragnar, 1946, et al.
(författare)
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Ex Vivo Vascular Imaging and Perfusion Studies of Normal Kidney and Tumor Vasculature
- 2024
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Ingår i: CANCERS. - 2072-6694. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Organs as well as cancer require a supply of nutrients and oxygen and removal of waste products. These tasks are carried out by the vascular system. Knowledge of the vascular properties in organs and tumors is key for understanding normal and abnormal function. For cancer, vascular function is also highly relevant to understand response to treatment, metastasis, and tumor progression. In this study, we use various techniques to characterize the vascular tree and flow in kidneys with kidney cancer. We connected kidneys to a perfusion system and used barium sulphate contrast to visualize the vascular architecture contact microangiography. Immunohistochemistry was used to visualize the vessels in relation to perfusion. The vascular resistance was measured using the radioactive microspheres and in cases that were feasible, we used micro-CT to characterize the vascular tree. This work aims to suggest the use of these techniques for any organ or tumor available for ex vivo perfusion.Abstract This work describes a comprehensive study of the vascular tree and perfusion characteristics of normal kidney and renal cell carcinoma. Methods: Nephrectomy specimens were perfused ex-vivo, and the regional blood flow was determined by infusion of radioactive microspheres. The vascular architecture was characterized by micronized barium sulphate infusion. Kidneys were subsequently sagitally sectioned, and autoradiograms were obtained to show the perfusate flow in relation to adjacent contact X-ray angiograms. Vascular resistance in defined tissue compartments was quantified, and finally, the tumor vasculature was 3D reconstructed via the micro-CT technique. Results show that the vascular tree of the kidney could be distinctly defined, and autoradiograms disclosed a high cortical flow. The peripheral resistance unit of the whole perfused specimen was 0.78 +/- 0.40 (n = 26), while that of the renal cortex was 0.17 +/- 0.07 (n = 15 with 114 samples). Micro-CT images from both cortex and medulla defined the vascular architecture. Angiograms from the renal tumors demonstrated a significant vascular heterogeneity within and between different tumors. A dense and irregular capillary network characterized peripheral tumor areas, whereas central parts of the tumors were less vascularized. Despite the dense capillarity, low perfusion through vessels with a diameter below 15 mu m was seen on the autoradiograms. We conclude that micronized barium sulphate infusion may be used to demonstrate the vascular architecture in a complex organ. The vascular resistance was low, with little variation in the cortex of the normal kidney. Tumor tissue showed a considerable vascular structural heterogeneity with low perfusion through the peripheral nutritive capillaries and very poor perfusion of the central tumor, indicating intratumoral pressure exceeding the perfusion pressure. The merits and shortcomings of the various techniques used are discussed.
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| 31. |
- Jennische, Eva, 1949, et al.
(författare)
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Dark-field microscopy enhance visibility of CD31 endothelial staining
- 2020
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Ingår i: European journal of histochemistry : EJH. - : PAGEPress Publications. - 2038-8306 .- 1121-760X. ; 64:3
-
Tidskriftsartikel (refereegranskat)abstract
- A simple dark field microscopy technique was used for visualization of blood vessels in normal human renal tissues and carcinoma. Phase contrast condenser ring apt for high power objectives was combined with a 10x objective in order to create a dark field illumination of the specimens examined. The endothelial lining of the vessels had been stained by using CD31 monoclonal antibodies combined with conventional peroxidase immunohistochemistry. The final DAB addition used for this technique induced an intense light scatter in the dark field microscope. This scattered light originating from the endothelial lining made the walls of the bright vessels easily detectable from the dark background.
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| 32. |
- Jennische, Eva, 1949, et al.
(författare)
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Immunohistochemical staining patterns using epitope-specific antibodies indicate conformation variants of antisecretory factor/S5a in the CNS.
- 2006
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Ingår i: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. - : Wiley. - 0903-4641. ; 114:7-8, s. 529-38
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Tidskriftsartikel (refereegranskat)abstract
- Antisecretory factor (AF/S5a/Rpn10) was originally identified through its ability to counteract pathological secretion. AF is also a potent anti-inflammatory agent, a neuromodulator, and an important component of the proteasome. Human AF has a calculated molecular mass of 41 kDa and a pI of 4.7. No family of AF-like proteins has been identified. AF has multiple functions in the cell, and different functional forms could exist as a result of post-translational modifications. Epitope-specific antibodies covering the entire length of AF were used to investigate whether modified forms of AF could be detected in the porcine spinal cord by Western blots, 2D gels, and immunohistochemistry (IHC). Western blot and 2D gels showed that all antisera detected a single protein with very similar molecular mass and pI. However, IHC resulted in an epitope-specific subcellular staining pattern. Antisera recognizing epitopes in the N-terminal part of AF, containing the antisecretory activity, showed a more restricted localisation than antisera directed at the C-terminal part, containing the ubiquitin-binding sites. We suggest that AF can exist in several conformational variants, perhaps due to differences in redox state and/or pH in the various cellular compartments. Such conformational changes could be of functional importance.
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| 33. |
- Jennische, Eva, 1949, et al.
(författare)
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The anterior commissure is a pathway for contralateral spread of herpes simplex virus type 1 after olfactory tract infection
- 2015
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Ingår i: Journal of Neurovirology. - : Springer Science and Business Media LLC. - 1355-0284 .- 1538-2443. ; 21:2, s. 129-147
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex encephalitis (HSE), targeting the limbic system, is the most common cause of viral encephalitis in the Western world. Two pathways for viral entry to the central nervous system (CNS) in HSE have been suggested: either via the trigeminal nerve or via the olfactory tract. This question remains unsettled, and studies of viral spread between the two brain hemispheres are scarce. Here, we investigated the olfactory infection as a model of infection and tropism of herpes simplex virus 1 (HSV-1), the causative agent of HSE, in the CNS of rats. Rats were instilled with HSV-1 in the right nostril and sacrificed 1-6 days post-infection, and tissues were analysed for viral spread using immunohistochemistry and quantitative PCR (qPCR). After nasal instillation, HSV-1 infected mitral cells of the olfactory bulb (OB) on the right side only, followed by limbic encephalitis. As a novel finding, the anterior commissure (AC) conveyed a rapid transmission of virus between the right and the left OB, acting as a shortcut also between the olfactory cortices. The neuronal cell population that conveyed the viral infection via the AC was positive for the water channel protein aquaporin 9 (AQP9) by immunohistochemistry. Quantification of AQP9 in cerebrospinal fluid samples of HSE patients showed increment as compared to controls. We conclude that the olfactory route and the AC are important for the spread of HSV-1 within the olfactory/limbic system of rats and furthermore, we suggest that AQP9 is involved in viral tropism and pathogenesis of HSE.
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| 34. |
- Jennische, Eva, 1949, et al.
(författare)
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The peptide AF-16 abolishes sickness and death at experimental encephalitis by reducing increase of intracranial pressure.
- 2008
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Ingår i: Brain research. - : Elsevier BV. - 0006-8993. ; 1227, s. 189-97
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Tidskriftsartikel (refereegranskat)abstract
- Elevated intracranial pressure (ICP) is strongly aggravating the injury at brain inflammation, resulting in persistent neurological and psychiatric malfunctions. There is no efficient pharmacological treatment to achieve beneficial ICP reduction. Here, the peptide AF-16, comprising the amino terminal part of the endogenous protein Antisecretory Factor (AF), was used to suppress the raised ICP in experimental herpes simplex encephalitis (HSE) in rats. Intranasal instillation of the peptide AF-16 counteracted the ICP elevation and the prevalence of ICP spikes, abrogated the neurological morbidity, and abolished the mortality in a dose-dependent manner. AF-16, 25 microg twice daily intranasally, rescued all animals with HSE and abrogated neurological malfunction. In contrast, only 10% of the rats survived if treated with the vehicle. A single intranasal dose of 25 microg AF-16 to a rat displaying overt HSE symptoms reduced the ICP to normal levels within an hour. No effects on viral replication or antigen distribution were demonstrable. Thus, AF-16 abolished the prevalence of sickness signs, ICP elevation, neurological malfunctions and completely prevented deaths. We advocate use of AF-16 for suppression of elevated ICP.
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| 35. |
- Jernås, Margareta, 1961, et al.
(författare)
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Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression
- 2006
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Ingår i: The FASEB Journal. - : Wiley. - 1530-6860 .- 0892-6638. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Enlarged adipocytes are associated with insulin resistance and are an independent predictor of type 2 diabetes. To understand the molecular link between these diseases and adipocyte hypertrophy, we developed a technique to separate human adipocytes from an adipose tissue sample into populations of small cells (mean 57.6+-3.54 um) and large cells (mean 100.1+-3.94 um). Microarray analysis of the cell populations separated from adipose tissue from three subjects identified 14 genes, of which five immune-related, with more than fourfold higher expression in large cells than small cells. Two of these genes were serum amyloid A (SAA) and transmembrane 4 L six family member 1 (TM4SF1). Real-time RT-PCR analysis of SAA and TM4SF1 expression in adipocytes from seven subjects revealed 19-fold and 22-fold higher expression in the large cells, respectively, and a correlation between adipocyte size and both SAA and TM4SF1 expression. The results were verified using immunohistochemistry. In comparison with 17 other human tissues and cell types by microarray, large adipocytes displayed by far the highest SAA and TM4SF1 expression. Thus, we have identified genes with markedly higher expression in large, compared with small, human adipocytes. These genes may link hypertrophic obesity to insulin resistance/type 2 diabetes.
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| 36. |
- Johansson, Ewa, 1964, et al.
(författare)
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Development of monoclonal antibodies for detection of Antisecretory Factor activity in human plasma.
- 2009
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Ingår i: Journal of immunological methods. - : Elsevier BV. - 1872-7905 .- 0022-1759. ; 342:1-2, s. 64-70
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Tidskriftsartikel (refereegranskat)abstract
- Antisecretory Factor (AF) is expressed in most tissues and can be demonstrated in plasma and other body fluids. Most of the AF in plasma is in an inactive form and activation of AF occurs after exposure to bacterial toxins or after intake of various dietary components. Patients with chronic diseases involving disturbances in inflammatory and secretory processes may benefit from an AF-inducing diet. The aim of the present study was to develop an in vitro assay for the analysis of AF-activity in human plasma. Monoclonal antibodies were raised against a native form of AF prepared from human placenta. Nine clones of the monoclonal antibodies recognizing AF and AF peptides were identified. With the aid of these antibodies, we developed a sensitive ELISA method for direct detection of AF-activity in human plasma. The AF activity in plasma from five healthy volunteers was low, 0.112+/-0.022 (absorbance at 405 nm), before intake of the AF-inducing diet with the SPC-Flakes, and increased significantly (p<0.05) to 0.444+/-0.068 after >or=6 weeks on the diet. A comparison of the plasma-AF values, obtained by the bioassay and the immunogenic assay (indirect ELISA), shows that there is a significant correlation (r=0.85) between the values from the two methods. The results indicate that the ELISA measures AF-activity and has the potential to be an important tool for the analysis of AF-activity in further clinical studies on AF-therapy.
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| 37. |
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| 38. |
- Johansson, Ewa, 1964, et al.
(författare)
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Identification of flotillin-1 as an interacting protein for antisecretory factor
- 2008
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Ingår i: Regulatory Peptides. - : Elsevier BV. - 0167-0115. ; 146:1-3, s. 303-309
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Tidskriftsartikel (refereegranskat)abstract
- Antisecretory factor (AF) also named S5a/Rpn10 was originally identified through its capacity to inhibit intestinal hypersecretion and was later shown to be a component in the proteasome complex. AF is also a potent anti-inflammatory agent and can act as a neuromodulator. In this study we used yeast two-hybrid screens, with yeast strain PJ692A transformed with the bait vector pGBKT7 (AF aa 1–105) against yeast strain Y187 pretransformed with human brain or placenta cDNA libraries, to identify AF-binding proteins. Flotillin-1 was identified as a specific interacting factor with AF. Immunohistochemistry showed co-localization of AF and flotillin-1 in nervous tissue. Flotillin-1 is an integral membrane protein and a component of lipid rafts, a membrane specialization involved in transport processes. Intracellular AF may affect secretory processes by regulating the localization of signal proteins to lipid rafts. © 2007 Elsevier B.V. All rights reserved. Keywords: S5a/Rpn10; Two-yeast hybrid; Lipid raft; Dot blot; Immunofluorescence
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| 39. |
- Johansson, Ewa, 1964, et al.
(författare)
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Specially processed cereals diet increases plasma levels of active antisecretory factor and up-regulates rat hepatic glutathione S-transferase mu.
- 2011
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Ingår i: Nutrition. - : Elsevier BV. - 1873-1244 .- 0899-9007. ; 27:9, s. 949-954
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Antisecretory factor (AF) inhibits pathologic fluid secretion and inflammation. AF is expressed in most tissues and is secreted into the blood. Challenge with bacterial enterotoxins increases AF activity. The plasma level of active AF is also increased after intake of certain food constituents, such as specially processed cereals, SPC. The exact molecular events that mediate these responses have remained obscure. The objective of this study was to investigate changes in protein expression in liver after SPC diet. METHODS: Rats were fed SPC or standard rodent diet for 18 d. The induction of AF in plasma was tested by ELISA. Changes in the liver proteome were analyzed by using 2D DIGE and LC-MS/MS. Further characterizations were done with Western blot and immunohistochemistry studies. RESULTS: The AF activity was increased after intake of SPC. Equivalent to recombinant AF, 6.6 ± 1.09 ng/well could be detected in control plasma compared to 26 ± 5.73 ng/well in plasma after SPC treatment. We found that the protein level of glutathione S-transferase mu (GST mu) was significantly up-regulated 1.2-fold in rat liver after stimulation with SPC (wheat). The result was further confirmed by Western blot analysis. Immunohistochemistry showed staining for GST mu1 and AF preferentially in the central parts of the liver lobuli. CONCLUSION: Given the known role of GST mu1 in inducing defense, our results suggest that SPC-induced GST mu1 up-regulation can contribute to the positive clinical effects seen by SPC treatment.
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| 40. |
- Jönsson, Linus, 1973, et al.
(författare)
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Early Regenerative Response in the Intrathoracic Porcine Esophagus-The Impact of the Inflammation.
- 2014
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Ingår i: Artificial Organs. - : Wiley. - 0160-564X. ; 38:6, s. 439-446
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Tidskriftsartikel (refereegranskat)abstract
- In order to improve the treatment of children born with long-gap esophageal atresia, a porcine model was developed for studying esophageal regrowth using a bridging graft composed of a silicone stented Biodesign mesh. The aim of the study was to investigate how leakage and contact between the native muscle and Biodesign mesh affected the early healing response. Resection of 3cm of intrathoracic esophagus was performed in 10 newly weaned piglets. They were fed through a gastrostomy 8-10 days prior to sacrifice. In order to achieve nonleaking anastomoses, the silicone stent and suturing technique had to be adjusted between the first four and second six piglets. The technical adjustment decreased leakage. A nonleaking anastomosis could not be achieved when the native muscle layers were sewn less central on the bridging graft compared with the mucosa. If there was leakage, the inflammatory response increased, with islets of perivascular T-lymphocytes and infiltration of macrophages in the native muscle layers. In the bridging area, new vessels were seen in the submucosa in 9 of 10 piglets between 4 and 10 days after surgery. Smooth muscle cells also appeared to move from the cut muscle edges of both the muscularis mucosa and the lamina muscularis and were seen as a layer of several cells under newly formed mucosa. Double staining of the basal membrane of the ingrowing vessels and the pericytes showed that the basal membrane was thinner over some of the pericytes, but there was no accumulation of immature-looking cells in the submucosa of the bridging area. In this porcine model, where esophageal regrowth was studied by using a bridging graft composed of a silicone stented Biodesign mesh, we can conclude that leakage increased the inflammatory response in early healing. Ingrowth of new vessels was seen in the bridging area and movement of smooth muscle cells was found under newly formed mucosa.
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| 41. |
- Jönsson, Linus, 1973, et al.
(författare)
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Macrophage Phenotype Is Associated With the Regenerative Response in Experimental Replacement of the Porcine Esophagus.
- 2016
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Ingår i: Artificial organs. - : Wiley. - 1525-1594 .- 0160-564X. ; 40:10, s. 950-958
-
Tidskriftsartikel (refereegranskat)abstract
- A porcine model for bridging circumferential defects in the intrathoracic esophagus has been developed in order to improve the treatment of children born with long-gap esophageal atresia. The aim of this study was to identify factors beneficial for tissue regeneration in the bridging area in this model and to describe the histological progression 20 days after replacement with a silicone-stented Biodesign mesh. Resection of 3cm of intrathoracic esophagus and replacement with a bridging graft was performed in six newly weaned piglets. They were fed through a gastrostomy for 10 days, and then had probe formula orally for another 10 days prior to sacrifice. Two out of six piglets had stent loss prior to sacrifice. In the four piglets with the stent in place, a tissue tube, with visible muscle in the wall, was seen at sacrifice. Histology showed that the wall of the healing area was well organized with layers of inflammatory cells, in-growing vessels, and smooth muscle cells. CD163+ macrophages was seen toward the esophageal lumen. In the animals where the stent was lost, the bridging area was narrow, and histology showed a less organized structure in the bridging area without the presence of CD163+ macrophages. This study indicates that regenerative healing was seen in the porcine esophagus 20 days after replacement of a part of the intrathoracic esophagus with a silicone-stented Biodesign mesh, if the bridging graft is retained. If the graft is lost, the inflammatory pattern changes with invasion of proinflammatory, M1 macrophages in the entire wall, which seems to redirect the healing process toward scar formation.
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| 42. |
- Jönsson, Linus, 1973, et al.
(författare)
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Piglet model for studying esophageal regrowth after resection and interposition of a silicone stented small intestinal submucosa tube.
- 2011
-
Ingår i: European surgical research. Europäische chirurgische Forschung. Recherches chirurgicales européennes. - : S. Karger AG. - 1421-9921. ; 46:4, s. 169-79
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate the use and subsequent healing of a silicone stented small intestinal submucosa (SIS) tube as a full-circumference replacement following surgical resection of the esophagus in piglets. Material and Methods: Three centimeters of the intrathoracic esophagus was replaced with a silicone stented SIS tube (Cook Medical) in 6 growing piglets. The esophageal stent was retained for 4 weeks. Esophageal dilations were performed, if needed, after stent removal. Results: The piglets were sacrificed 1-17 weeks after surgery. Recurrent dilations were needed after stent removal. Histology showed that the gap between the resection margins was filled with new loose connective tissue consisting of fibroblasts and few inflammatory cells. In this tissue, intense angiogenesis was seen at the early time points, which then gave way to the proliferation of immature-looking smooth-muscle-like cells in the submucosa, which appeared to stem from the pericytes of the ingrowing capillaries. Conclusions: Through using a stented SIS tube as a circumferential esophageal replacement in a piglet model, this study suggests that pericytes from ingrowing capillaries may play a role in the remodeling of the SIS mesh. It remains to be seen if this process gives a favorable end result because stricture formation after stent removal remains a problem.
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| 43. |
- Kaya, Ibrahim, et al.
(författare)
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Brain region-specific amyloid plaque-associated myelin lipid loss, APOE deposition and disruption of the myelin sheath in familial Alzheimer's disease mice
- 2020
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 154:1, s. 84-98
-
Tidskriftsartikel (refereegranskat)abstract
- There is emerging evidence that amyloid beta (A beta) aggregates forming neuritic plaques lead to impairment of the lipid-rich myelin sheath and glia. In this study, we examined focal myelin lipid alterations and the disruption of the myelin sheath associated with amyloid plaques in a widely used familial Alzheimer's disease (AD) mouse model; 5xFAD. This AD mouse model has A beta(42) peptide-rich plaque deposition in the brain parenchyma. Matrix-assisted laser desorption/ionization imaging mass spectrometry of coronal brain tissue sections revealed focal A beta plaque-associated depletion of multiple myelin-associated lipid species including sulfatides, galactosylceramides, and specific plasmalogen phopshatidylethanolamines in the hippocampus, cortex, and on the edges of corpus callosum. Certain phosphatidylcholines abundant in myelin were also depleted in amyloid plaques on the edges of corpus callosum. Further, lysophosphatidylethanolamines and lysophosphatidylcholines, implicated in neuroinflammation, were found to accumulate in amyloid plaques. Double staining of the consecutive sections with fluoromyelin and amyloid-specific antibody revealed amyloid plaque-associated myelin sheath disruption on the edges of the corpus callosum which is specifically correlated with plaque-associated myelin lipid loss only in this region. Further, apolipoprotein E, which is implicated in depletion of sulfatides in AD brain, is deposited in all the A beta plaques which suggest apolipoprotein E might mediate sulfatide depletion as a consequence of an immune response to A beta deposition. This high-spatial resolution matrix-assisted laser desorption/ionization imaging mass spectrometry study in combination with (immuno) fluorescence staining of 5xFAD mouse brain provides new understanding of morphological, molecular and immune signatures of A beta plaque pathology-associated myelin lipid loss and myelin degeneration in a brain region-specific manner.
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| 44. |
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| 45. |
- Kaya, Ibrahim, 1989, et al.
(författare)
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Multimodal chemical imaging of a single brain tissue section using ToF-SIMS, MALDI-ToF and immuno/histochemical staining
- 2021
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Ingår i: The Analyst. - : Royal Society of Chemistry (RSC). - 0003-2654 .- 1364-5528. ; 146:4, s. 1169-1177
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Tidskriftsartikel (refereegranskat)abstract
- Cluster ion beam ToF-SIMS and/or MALDI-ToF mass spectrometry imaging (using 1,5-DAN matrix via sublimation) of a single coronal rat brain tissue section followed by classical-or immuno-histochemical staining faclilated a new multimodal chemical imaging workflow allowing complementary correlation of the lipid molecular ion images with the immuno/histological features within cerebellum region of the same brain tisue section.
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| 46. |
- Kaya, Ibrahim, et al.
(författare)
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On-Tissue Chemical Derivatization of Catecholamines Using 4-(N-Methyl)pyridinium Boronic Acid for ToF-SIMS and LDI-ToF Mass Spectrometry Imaging
- 2018
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 90:22, s. 13580-13590
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Tidskriftsartikel (refereegranskat)abstract
- The analysis of small polar compounds with ToF-SIMS and MALDI-ToF-MS have been generally hindered by low detection sensitivity, poor ionization efficiency, ion suppression, analyte in-source fragmentation, and background spectral interferences from either a MALDI matrix and/or endogenous tissue components. Chemical derivatization has been a well-established strategy for improved mass spectrometric detection of many small molecular weight endogenous compounds in tissues. Here, we present a devised strategy to selectively derivatize and sensitively detect catecholamines with both secondary ion ejection and laser desorption ionization strategies, which are used in many imaging mass spectrometry (IMS) experiments. Chemical derivatization of catecholamines was performed by a reaction with a synthesized permanent pyridinium-cation-containing boronic acid molecule, 4-(N-methyl)pyridinium boronic acid, through boronate ester formation (boronic acid-diol reaction). The derivatization facilitates their sensitive detection with ToF-SIMS and LDI-ToF mass spectrometric techniques. 4-(N-Methyl)pyridinium boronic acid worked as a reactive matrix for catecholamines with LDI and improved the sensitivity of detection for both SIMS and LDI, while the isotopic abundances of the boron atom reflect a unique isotopic pattern for derivatized catecholamines in MS analysis. Finally, the devised strategy was applied, as a proof of concept, for on-tissue chemical derivatization and GCIB-ToF-SIMS (down to 3 μm per pixel spatial resolution) and LDI-ToF mass spectrometry imaging of dopamine, epinephrine, and norepinephrine in porcine adrenal gland tissue sections. MS/MS using collision-induced dissociation (CID)-ToF-ToF-SIMS was subsequently employed on the same tissue sections after SIMS and LDI mass spectrometry imaging experiments, which provided tandem MS information for the validation of the derivatized catecholamines in situ. This methodology can be a powerful approach for the selective and sensitive ionization/detection and spatial localization of diol-containing molecules such as aminols, vic-diols, saccharides, and glycans along with catecholamines in tissue sections with both SIMS and LDI/MALDI-MS techniques. © 2018 American Chemical Society.
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| 47. |
- Kaya, Ibrahim, et al.
(författare)
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Spatial Lipidomics Reveals Region and Long Chain Base Specific Accumulations of Monosialogangliosides in Amyloid Plaques in Familial Alzheimer's Disease Mice (5xFAD) Brain
- 2020
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 11:1, s. 14-24
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Tidskriftsartikel (refereegranskat)abstract
- Ganglioside metabolism is significantly altered in Alzheimer's disease (AD), which is a progressive neuro-degenerative disease prominently characterized by one of its pathological hallmarks, amyloid deposits or "senile plaques". While the plaques mainly consist of aggregated variants of amyloid-beta protein (A beta), recent studies have revealed a number of lipid species including gangliosides in amyloid plaques along with A beta peptides. It has been widely suggested that long chain (sphingosine) base (LCBs), C18:1-LCB and C20:1-LCB, containing gangliosides might play different roles in neuronal function in vivo. In order to elucidate region-specific aspects of amyloid-plaque associated C18:1-LCB and C20:1-LCB ganglioside accumulations, high spatial resolution (10 mu m per pixel) matrix assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) of gangliosides in amyloid plaques was performed in hippocampal and adjacent cortical regions of 12 month old 5xFAD mouse coronal brain sections from two different stereotaxic coordinates (bregma points, -2.2 and -2.7 mm). MALDI-IMS uncovered brain-region (2 and 3D) and/or LCB specific accumulations of monosialogangliosides (GMs): GM1, GM2, and GM3 in the hippocampal and cortical amyloid plaques. The results reveal monosialogangliosides to be an important component of amyloid plaques and the accumulation of different gangliosides is region and LCB specific in 12 month old 5xFAD mouse brain. This is discussed in relation to amyloid-associated AD pathogenesis such as lipid related immune changes in amyloid plaques, AD specific ganglioside metabolism, and, notably, AD-associated impaired neurogenesis in the subgranular zone.
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| 48. |
- Kim, Malin, et al.
(författare)
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Antisecretory factor modulates GABAergic transmission in the rat hippocampus.
- 2005
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Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 129:1-3, s. 109-18
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Tidskriftsartikel (refereegranskat)abstract
- Antisecretory Factor (AF) is a protein that has been implicated in the suppression of intestinal hypersecretion and inflammation. Intestinal secretion and inflammation are partly under local and central neural control raising the possibility that AF might exert its action by modulating neural signaling. In the present study we have investigated whether AF can modulate central synaptic transmission. Evoked glutamatergic and GABAergic synaptic transmissions were investigated using extracellular recordings in the CA1 region of hippocampal slices from adult rats. AF (0.5 microg/ml) suppressed GABA(A)-mediated synaptic transmission by about 40% while having no effect on glutamatergic transmission. Per oral administration of cholera toxin as well as feeding of rats with a diet containing hydrothermally processed cereals, known to upregulate endogenous AF plasma activity, mimicked the effect of exogenously administered AF on hippocampal GABAergic transmission. Our results identify AF as a neuromodulator and further raise the possibility that the hippocampus and AF are involved in a gut-brain loop controlling intestinal secretion and inflammation.
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| 49. |
- Lange, Stefan, 1948, et al.
(författare)
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Antisecretory factor AF-16 improves vascular access to a rat mammary tumour.
- 2020
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Ingår i: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. - : Wiley. - 1600-0463. ; 128:5, s. 387-389
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Tidskriftsartikel (refereegranskat)abstract
- Tumor tissue often has an insufficient nutritional supply, in part due to compression of the vascular network from an increased interstitial fluid pressure. We have shown that the antisecretory factor peptide AF-16 can reduce this pressure in experimental rat breast tumors. In this work we studied if AF-16 administration opened up to an increased vascular volume in these tumors. Sprague-Dawley rats were given dimethylbenxanthracene and developed mammary tumors which were studied. Evans Blue was used as an intravascular volume indicator. Under anesthesia the rats were given AF-16 or solvent intranasally, and Evans Blue was injected i.v. 45 min later. Tumors and various organs were dissected and Evans Blue was extracted and colorimetrically quantified. Tumors had a significantly higher vascular volume after AF-16 administration as compared to other organs. Liver and renal vascular volumes were also increased but to a lesser degree than in the tumors. The results indicate that AF16 could be a candidate for increasing vascular access for chemotherapy in cancer therapy.
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| 50. |
- Lange, Stefan, 1948, et al.
(författare)
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Food-induced antisecretory factor activity is correlated with small bowel length in patients with intestinal resections.
- 2003
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Ingår i: APMIS : acta pathologica, microbiologica, et immunologica Scandinavica. - : Wiley. - 0903-4641. ; 111:10, s. 985-8
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Tidskriftsartikel (refereegranskat)abstract
- Specially processed cereals (SPC) can increase antisecretory factor (AF) activity in humans with an intact intestine. The aim of the present study was to investigate whether AF synthesis could be induced in patients who had been subjected to intestinal resections. Eight patients with varying extents of intestinal resections due to Crohn's disease and six healthy controls participated. All subjects received 54 g SPC daily for 2 weeks. Plasma AF activity was determined before, during and after the treatment period. Baseline diet and medications were kept unchanged. The patients registered the daily number of bowel movements. The SPC diet increased AF activity in all controls. In the patients there was a significant correlation between the length of the remaining small intestine and AF induction (r=0.94, p<0.01) and only those patients with a remaining small intestine of about 3 m reached AF values comparable to those in healthy subjects. It is concluded that small bowel length is related to the ability of humans to induce AF activity by dietary means.
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