| 1. |
- Annerén, Cecilia, et al.
(författare)
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The FRK/RAK-SHB signaling cascade : a versatile signal-transduction pathway that regulates cell survival, differentiation and profileration
- 2003
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Ingår i: Current molecular medicine. - : Bentham. - 1566-5240 .- 1875-5666. ; 3:4, s. 313-324
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Tidskriftsartikel (refereegranskat)abstract
- Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like FYN-Related Kinase FRK / RAK (also named BSK / IYK or GTK). FRK / RAK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and β-cells, where they both induce PC12 cell differentiation and β-cell proliferation. Furthermore, β-cell apoptosis is augmented by these proteins under conditions that cause β-cell degeneration. The FRK / RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2.Besides regulating apoptosis, proliferation and differentiation, SHB is also a component of the T cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production. In endothelial cells, SHB both promotes apoptosis under conditions that are anti-angiogenic, but is also required for proper mitogenicity, spreading and tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K) prevents early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon, suggesting a role of SHB in development.In summary, SHB is a versatile signal transduction molecule that produces diverse biological responses in different cell types under various conditions. SHB operates downstream of GTK in cells that express this kinase.
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| 2. |
- Benson, Mikael, 1954, et al.
(författare)
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Network theory to understand microarray studies of complex diseases.
- 2006
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Ingår i: Current molecular medicine. - : Bentham Science Publishers. - 1566-5240 .- 1875-5666. ; 6:6, s. 695-701
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Tidskriftsartikel (refereegranskat)abstract
- Complex diseases, such as allergy, diabetes and obesity depend on altered interactions between multiple genes, rather than changes in a single causal gene. DNA microarray studies of a complex disease often implicate hundreds of genes in the pathogenesis. This indicates that many different mechanisms and pathways are involved. How can we understand such complexity? How can hypotheses be formulated and tested? One approach is to organize the data in network models and to analyze these in a top-down manner. Globally, networks in nature are often characterized by a small number of highly connected nodes, while the majority of nodes have few connections. The highly connected nodes serve as hubs that affect many other nodes. Such hubs have key roles in the network. In yeast cells, for example, deletion of highly connected proteins is associated with increased lethality, compared to deletion of less connected proteins. This suggests the biological relevance of networks. Moving down in the network structure, there may be sub-networks or modules with specific functions. These modules may be further dissected to analyze individual nodes. In the context of DNA microarray studies of complex diseases, gene-interaction networks may contain modules of co-regulated or interacting genes that have distinct biological functions. Such modules may be linked to specific gene polymorphisms, transcription factors, cellular functions and disease mechanisms. Genes that are reliably active only in the context of their modules can be considered markers for the activity of the modules and may thus be promising candidates for biomarkers or therapeutic targets. This review aims to give an introduction to network theory and how it can be applied to microarray studies of complex diseases.
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| 5. |
- de Peppo, Giuseppe Maria, 1981, et al.
(författare)
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Human Progenitor Cells for Bone Engineering Applications
- 2013
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Ingår i: Current molecular medicine. - : Bentham Science Publishers. - 1566-5240 .- 1875-5666. ; 13:5, s. 723-734
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Tidskriftsartikel (refereegranskat)abstract
- In this report, the authors review the human skeleton and the increasing burden of bone deficiencies, the limitations encountered with the current treatments and the opportunities provided by the emerging field of cell-based bone engineering. Special emphasis is placed on different sources of human progenitor cells, as well as their pros and cons in relation to their utilization for the large-scale construction of functional bone-engineered substitutes for clinical applications. It is concluded that, human pluripotent stem cells represent a valuable source for the derivation of progenitor cells, which combine the advantages of both embryonic and adult stem cells, and indeed display high potential for the construction of functional substitutes for bone replacement therapies.
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| 6. |
- Jensen, Lasse Dahl, et al.
(författare)
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In vivo angiogenesis and lymphangiogenesis models
- 2009
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Ingår i: Current molecular medicine. - : Bentham Science Publishers. - 1566-5240 .- 1875-5666. ; 9:8, s. 982-991
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis research has become one of the most important areas in biomedical research. At the time of writing this review, there were approximately 3536 articles published in the year of 2008 alone on the topic of angiogenesis. The fast expansion of this research field demands development of rigorous, reliable, stable, convenient, and clinically relevant assay systems for disease diagnosis, prognosis, therapeutic evaluation, drug discovery, and mechanistic studies at the molecular level. Here, we discuss several commonly used in vivo angiogenesis models by systematically analyzing and pointing out pitfalls of each assay. Owing to existence of numerous assays and the limitation of text, it is impossible to discuss all these assays in this article. Here we select several most commonly used angiogenesis assays performed in various species including mice, chicks and zebrafish for further in-depth discussion. We hope this information will be valuable for improving current angiogenesis research.
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| 7. |
- Lutgendorff, Femke, 1981-, et al.
(författare)
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The role of microbiota and probiotics in stress-induced gastrointestinal damage
- 2008
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Ingår i: Current molecular medicine. - : Bentham Science Publishers Ltd.. - 1566-5240 .- 1875-5666. ; 8:4, s. 282-298
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Tidskriftsartikel (refereegranskat)abstract
- Stress has a major impact on gut physiology and may affect the clinical course of gastro-intestinal diseases. In this review, we focus on the interaction between commensal gut microbiota and intestinal mucosa during stress and discuss the possibilities to counteract the deleterious effects of stress with probiotics. Normally, commensal microbes and their hosts benefit from a symbiotic relationship. Stress does, however, reduce the number of Lactobacilli, while on the contrary, an increased growth, epithelial adherence and mucosal uptake of gram-negative pathogens, e.g. E. coli and Pseudomonas, are seen. Moreover, intestinal bacteria have the ability to sense a stressed host and up-regulate their virulence factors when opportunity knocks. Probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host", and mainly represented by Lactic Acid Bacteria. Probiotics can counteract stress-induced changes in intestinal barrier function, visceral sensitivity and gut motility. These effects are strain specific and mediated by direct bacterial-host cell interaction and/or via soluble factors. Mechanisms of action include competition with pathogens for essential nutrients, induction of epithelial heat-shock proteins, restoring of tight junction protein structure, up-regulation of mucin genes, secretion of defensins, and regulation of the NFκB signalling pathway. In addition, the reduction of intestinal pain perception was shown to be mediated via cannabinoid receptors. Based on the studies reviewed here there is clearly a rationale for probiotic treatment in patients with stress-related intestinal disorders. We are however far from being able to choose the precise combination of strains or bacterial components for each clinical setting. © 2008 Bentham Science Publishers Ltd.
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| 8. |
- Norlin, Maria, et al.
(författare)
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Enzymes in the conversion of cholesterol into bile acids
- 2007
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Ingår i: Current molecular medicine. - : Bentham Science Publishers Ltd.. - 1566-5240 .- 1875-5666. ; 7:2, s. 199-218
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Forskningsöversikt (refereegranskat)abstract
- This article aims to give an overview on the characterization, properties and regulation of enzymes, particularly the cytochrome (CYP) P450 enzymes, in the formation of bile acids from cholesterol. Bile acids are biologically active molecules that promote absorption of dietary lipids in the intestine and stimulate biliary excretion of cholesterol. Bile acids and oxysterols, formed from cholesterol, act as ligands to nuclear receptors regulating the expression of important genes in cholesterol homeostasis. Thus, the bioactivation of cholesterol into bile acids is crucial for regulation of cholesterol homeostasis. The primary human bile acids, cholic acid and chenodeoxycholic acid, are formed from cholesterol via several pathways involving many different enzymes. Many of these enzymes are cytochrome P450 (CYP) enzymes, introducing a hydroxyl group in the molecule. The “classic” pathway of bile acid formation starts with a 7α-hydroxylation of cholesterol by CYP7A1 in the liver. The “acidic” pathway starts with a hepatic or extrahepatic 27-hydroxylation by CYP27A1. There also exist some quantitatively minor pathways which may be of importance under certain conditions. Formation of cholic acid requires insertion of a 12α-hydroxyl group performed by CYP8B1. Oxysterols are precursors to bile acids, participate in cholesterol transport and are known to affect the expression of several genes in cholesterol homeostasis. Enzymes with capacity to form and metabolize oxysterols are present in liver and extrahepatic tissues. The enzymes, nuclear receptors and transcription factors involved in bile acid biosynthesis are potential pharmaceutical targets for the development of new drugs to control hypercholesterolemia and to prevent atherosclerosis and other diseases related to disturbed cholesterol homeostasis. The review will also discuss some inborn errors of bile acid biosynthesis and the recently acquired knowledge on the genetic defects underlying these diseases.
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| 9. |
- Tsartsalis, Athanasios N., et al.
(författare)
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Bone Metabolism Markers in Thalassemia Major-Induced Osteoporosis: Results from a Cross-Sectional Observational Study
- 2019
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Ingår i: Current molecular medicine. - : BENTHAM SCIENCE PUBL LTD. - 1566-5240 .- 1875-5666. ; 19:5, s. 335-341
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Tidskriftsartikel (refereegranskat)abstract
- Background: Thalassemia major (TM) patients eventually face many new health conditions, including endocrinopathies and low bone mineral density, usually observed in the aging general population. Objective: The aim of the current study was to evaluate the biomarkers of bone remodeling in TM patients and to compare them with both osteoporotic and healthy population, in order to investigate the new therapeutic paths. Methods: Sixty-four patients with TM (32 men and 32 women) participated in the study. The patients were evaluated with dual-energy X-ray absorptiometry (DXA) of the lumbar spine and femoral neck and with markers of bone remodeling including receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), C-terminal telopeptide (CTX), and sclerostin. Results were compared with those from 12 postmenopausal women with osteoporosis and 12 women with normal bone mineral density. Results: The statistical analysis of the biochemical markers of bone metabolism revealed overall significant differences between the three groups only for RANKL and OPG/RANKL (p=0.049 and p=0.009). RANKL was higher and OPG/RANKL was lower in TM patients compared to osteoporosis group. Conclusion: Patients with TM do not have a higher probability of suffering from osteoporosis from the general population. However, some markers of osteoclast activity differ between patients with TM and osteoporosis, indicating the possible differences in terms of anti-osteoporotic treatment. The lack of significant differences among the three groups in regards to the levels of CTX and sclerostin may indicate the potential efficacy of the current osteoporotic treatment also for TM patients.
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