1.
Mondal, Tanmoy, 1981, et al.
(författare)
Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis
2018
Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 33:3
Tidskriftsartikel (refereegranskat) abstract
Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.
2.
Greiff, Lennart, et al.
(författare)
Effects of topical platelet activating factor on the guinea-pig tracheobronchial mucosa in vivo
1997
Ingår i: Acta Physiologica Scandinavica. - 0001-6772. ; 160:4, s. 387-391
Tidskriftsartikel (refereegranskat) abstract
Platelet activating factor (PAF) has been reported to produce a variety of airway effects including epithelial damage and increased airway-lung absorption of hydrophilic tracers. The present study examines effects of PAF on the guinea-pig tracheobronchial mucosa in vivo. Vehicle with and without PAF (4.0 and 8.0 nmol) was superfused onto the tracheobronchial mucosa. The levels of 125I-albumin, previously given intravenously, were determined in tracheobronchial lavage fluids as an index of mucosal exudation of plasma. The mucosa was also examined by scanning electron microscopy. In separate animals, 99mTc-DTPA (a low molecular weight, 492 Da, hydrophilic tracer) was superfused onto the mucosal surface through an oro-tracheal catheter, together with vehicle or PAF (8.0 nmol). A gamma camera determined the disappearance rate of 99mTc-DTPA from the airways as an index of mucosal absorption. PAF produced dose-dependent mucosal exudation of plasma up to 20-fold greater than control (P < 0.001). However, PAF did not damage the epithelium and the absorption ability of the airway mucosa was unaffected. The results, in contrast to previous reports, suggest that PAF may not readily damage the airway mucosa even at large exudative doses of the agent. The present finding support the view that the plasticity of the epithelial junctions allows the creation of valve-like paracellular pathways for unidirectional clearance of extravasated plasma into the airway lumen. We suggest that endogenous PAF may participate in first line respiratory defence reactions by causing lumenal entry of bulk plasma without harming the epithelium.
3.
Korsgren, Magnus, et al.
(författare)
Allergic eosinophil-rich inflammation develops in lungs and airways of B cell-deficient mice
1997
Ingår i: Journal of Experimental Medicine. - 1540-9538. ; 185:5, s. 885-892
Tidskriftsartikel (refereegranskat) abstract
Immunoglobulins (Ig), particularly IgE, are believed to be crucially involved in the pathogenesis of asthma and, equally, in allergic models of the disease. To validate this paradigm we examined homozygous mutant C57BL/6 mice, which are B cell deficient, lacking all Ig. Mice were immunized intraperitoneally with 10 micrograms ovalbumin (OVA) plus alum, followed by daily (day 14-20) 30 min exposures to OVA aerosol (OVA/OVA group). Three control groups were run: OVA intraperitoneally plus saline (SAL) aerosol (OVA/SAL group); saline intraperitoneally plus saline aerosol; saline intraperitoneally plus OVA aerosol (n = 6-7). Lung and large airway tissues obtained 24 h after the last OVA or SAL exposure were examined by light microscopy and transmission electron microscopy (TEM). The Ig-deficient mice receiving OVA/ OVA treatment had swollen and discolored lungs and exhibited marked eosinophilia both in large airway subepithelial tissue (49.2 +/- 12.0 cells/mm basement membrane [BM] versus OVA/ SAL control 1.2 +/- 0.3 cells/mm BM; P < 0.001), and perivascularly and peribronchially in the lung (49.3 +/- 9.0 cells/unit area versus OVA/SAL control 2.6 +/- 0.6 cells/unit area; P < 0.001). The eosinophilia extended to the regional lymph nodes. TEM confirmed the subepithelial and perivascular localization of eosinophils. Mucus cells in large airway epithelium increased from 1.5 +/- 0.8 (OVA/SAL mice) to 39.5 +/- 5.7 cells/mm BM in OVA/OVA treated mice (P < 0.001). OVA/SAL mice never differed from the other control groups. Corresponding experiments in wild-type mice (n = 6-7 in each group) showed qualitatively similar but less pronounced eosinophil and mucus cell changes. Macrophages and CD4+ T cells increased in lungs of all OVA/OVA-treated mice. Mast cell number did not differ but degranulation was detected only in OVA/OVA-treated wild-type mice. Immunization to OVA followed by OVA challenges thus cause eosinophil-rich inflammation in airways and lungs of mice without involvement of B cells and Ig.
4.
Persson, Carl, et al.
(författare)
The mouse trap
1997
Ingår i: Trends in Pharmacological Sciences. - 0165-6147. ; 18:12, s. 465-467
Tidskriftsartikel (refereegranskat) abstract
Mouse models of asthma are now being used extensively in drug research. However, the successful unravelling of combinatorial interplays of cells and molecules in the murine airways may not be matched by equally successful demonstrations of an asthma-like pathophysiology. Here, Carl Persson, Jonas Erjefalt, Magnus Korsgren and Frank Sundler discuss the fact that major features of asthma may still need to be demonstrated in the airways of allergic mice.
5.
Persson, Carl, et al.
(författare)
Unbalanced research
2001
Ingår i: Trends in Pharmacological Sciences. - 0165-6147. ; 22:10, s. 538-541
Tidskriftsartikel (refereegranskat)
6.
7.
Turczynska, Karolina, et al.
(författare)
Regulation of vascular smooth muscle mechanotransduction by microRNAs and L-type calcium channels.
2013
Ingår i: Communicative & Integrative Biology. - : Informa UK Limited. - 1942-0889. ; 6:1, s. 22278-22278
Tidskriftsartikel (refereegranskat) abstract
The phenotype of smooth muscle cells is regulated by multiple environmental factors including mechanical forces. Mechanical stretch of mouse portal veins ex vivo has been shown to promote contractile differentiation by activation of the Rho-pathway, an effect that is dependent on the influx of calcium via L-type calcium channels. MicroRNAs have recently been demonstrated to play a significant role in the control of smooth muscle phenotype and in a recent report we investigated their role in vascular mechanosensing. By smooth muscle specific deletion of Dicer, we found that microRNAs are essential for smooth muscle differentiation in response to stretch by regulating CamKIIδ and L-type calcium channel expression. Furthermore, we suggest that loss of L-type calcium channels in Dicer KO is due to reduced expression of the smooth muscle-enriched microRNA, miR-145, which targets CamKIIδ. These results unveil a novel mechanism for miR-145 dependent regulation of smooth muscle phenotype.
8.
Eklund, Erik, et al.
(författare)
Proteoglycan production in disomic and trisomy 7-carrying human synovial cells.
2002
Ingår i: Matrix Biology. - 1569-1802. ; 21:4, s. 325-335
Tidskriftsartikel (refereegranskat) abstract
To gain further insight into the synthesis and structure of the synovial matrix of joints, we have established cell cultures from synovial specimens and elaborated their production of hyaluronan and proteoglycans. The cultures secreted mainly the small proteoglycan decorin, but also considerable amounts of the related biglycan and the large proteoglycan versican. Only minor amounts of heparan sulfate proteoglycans were found. All cultures also had a high production of hyaluronan, which highlights the important role for normal joint function of these cells. In joint diseases, a common feature is the presence of an extra chromosome 7 (trisomy 7) in the synovial cells. To study the possible consequences of trisomy 7 on the synovial cell function, we extended our study to cultures that had been sub-cloned to contain high amounts of trisomy 7-carrying cells. These cell cultures had approximately four times more versican than their disomic counterparts in the cell culture medium, indicating that versican may be a mediator in the processes of joint destructive disorders. To find an explanation for this increase in versican, we investigated the expression/secretion of PDGF-AA and IL-6, cytokines with their genes located to chromosome 7. Indeed, both these cytokines were increased in the cultures with high frequencies of trisomy 7. We then added the two cytokines to cell cultures of disomic synovial cells, but only cells treated with IL-6 displayed an increased amount of versican. Thus, we suggest that the increased amount of versican in cultures of trisomy 7-carrying cells relates to an autocrine loop involving an increased IL-6 production.
9.
Cheng, Fang, et al.
(författare)
Differences in the uptake and nuclear localization of anti-proliferative heparan sulfate between human lung fibroblasts and human lung carcinoma cells
2001
Ingår i: Journal of Cellular Biochemistry. - : Wiley. - 0730-2312 .- 1097-4644. ; 83:4, s. 597-606
Tidskriftsartikel (refereegranskat) abstract
Heparan sulfate inhibits the proliferation of normal human lung fibroblasts (HFL-1) but not of a human lung carcinoma cell-line (A549). in this study we investigated possible mechanisms and structural requirements by which anti proliferative heparan sulfates exerts its effects on binding, uptake and subcellular localisation. Both HFL-1 and A549 cells were incubated with I-125- or rhodamine-labeled L-iduronate-rich antiproliferative heparan sulfate species as well as L-iduronate-poor inactive ones. The anti proliferative heparan sulfate was bound to the cell surface on both HFL-1 and A549 cells, but to a lesser extent and with less affinity to A549 cells. Both cell types bound the anti proliferative heparan sulfate with one high- and with one low affinity site. The L-iduronate-poor heparan sulfate bound to a lesser extent and with less affinity to both cell types compared to the anti proliferative heparan sulfate. The antiproliferative heparan sulfate accumulated in the cytoplasm of HFL-1 cells after 24 h incubation, but after 72 h it was found evenly distributed in the nucleus. The time-scale for anti proliferative activity correlated with nuclear localization. In contrast, in A549 cells it was only found near the nuclear membrane. The inactive heparan sulfate was taken up in considerably smaller amounts compared to the antiproliferative heparan sulfate and could not be detected in the nucleus of either HFL-1 or A549 cells. Our data suggest that the anti proliferative activity of L-iduronate-rich heparan sulfate on normal fibroblasts may be due to direct effects on nuclear processes, such as gene transcription.
10.
Vieira, João
(författare)
Profiling Plasma Metabolite Alterations in Diet-Induced Obesity and Diabetes Using NMR Metabolomics
2023
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Diets rich in saturated fat and sedentary lifestyles markedly contribute to obesity and metabolic syndrome-related diseases, including type 2 diabetes mellitus (T2D). Metabolite profiling plays a pivotal role in understanding these metabolic diseases. This thesis comprises insights from four distinct studies to illuminate metabolic imbalances induced by diet-induced obesity (DIO), covering topics related to the duration of dietary regimens, potential benefits of dietary interventions on the brain and metabolism, and the impact of underlying T2D on post-stroke recovery. Using a combination of proton nuclear magnetic resonance (1H-NMR) spectroscopy and mass spectrometry (MS), study I initially demonstrated the superiority of the combined approach in characterizing the effects of DIO on plasma metabolites. The robustness of this method was further validated in a human cohort, underscoring its translational potential in unravelling metabolic imbalances. In study II, female mice exposed to high-fat diet (HFD) exhibited brain metabolism alterations and memory deficits, which were mitigated by taurine and N-acetylcysteine (NAC) supplementation. These supplements not only ameliorated HFD-induced memory impairment but also elicited distinct effects on metabolic alterations within the hippocampus. Systemically, 1H-NMR metabolomics data in study III revealed that NAC and taurine treatments impacted plasma metabolites. Ultimately, as explored in study IV using 1H-NMR metabolomics, unique metabolite changes in male mice with T2D following transient middle cerebral artery occlusion were reported. Specifically, metabolite changes that link T2D to poor neurological outcomes after stroke were observed. In summary, this thesis underscores the significance of metabolite profiling in elucidating the complexities of metabolic diseases, memory impairment, and post-stroke recovery in DIO mouse models. It also emphasizes the translational character of such findings to human pathophysiology.
