| 1. |
- Aguilar, Helena, et al.
(författare)
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VAV3 mediates resistance to breast cancer endocrine therapy
- 2014
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Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 16:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha transcriptional regulatory plasticity. Here, we identify VAV3 as a critical component in this process.METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERalpha was evaluated by molecular docking analyses, an agonist fluoligand assay, and short-hairpin (sh) RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot of signaling and proliferation markers and shRNA-mediated protein depletion in viability and clonogenic assays were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine the association with therapy response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase) but instead a result of binding to ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha depletion and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.CONCLUSIONS: This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.
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| 2. |
- Asiimwe, Savina, et al.
(författare)
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Ethnobotanical study of nutri-medicinal plants used for the management of HIV/AIDS opportunistic ailments among the local communities of western Uganda
- 2013
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Ingår i: Journal of Ethnopharmacology. - : Elsevier BV. - 0378-8741 .- 1872-7573. ; 150:2, s. 639-648
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Tidskriftsartikel (refereegranskat)abstract
- Ethnopharmacological relevance: Herbal remedies are a source of therapeutics for nearly 80% of the population in Uganda. Poor health facilities and limited access to antiretroviral drugs have perpetuated and increased the use of traditional medicine especially in rural areas for the treatment of opportunistic ailments of HIV/AIDS. To document the traditional uses of nutri-medicinal plants in the management of immunocompromised ailments associated with HIV/AIDS. To document the parts and growth forms of plants used, methods of preparation and administration of the herbal remedies. Materials and methods: The study was conducted in Mbarara and Isingiro districts of western Uganda between December 2010 and May 2011. Ethnobotanical information was collected from 64 respondents who were sampled based on recommendations of local elders and administrators. Ethnobotanical data on the use of nutri-medicinal plants for traditional treatment of HIV/AIDS opportunistic ailments were collected by employing semi-structured interviews with selected respondents, house hold visits and field observations as described by (Martin, 1995a). The respondents were mainly traditional medical practitioners who treat patients who are already receiving antiretroviral drugs. Fidelity levels of plant species and informant consensus factor were determined to show the percentage of informants claiming the use of certain plant species for the same major purpose and to analyse people's knowledge of plant use. Results: The study revealed 81 plant species most of which were herbs (49%). Leaves (71%) were the most frequently used parts in remedy preparations which were mainly administered orally (85%). The majority of plants (54%) were harvested from wild populations. Hibiscus sabdariffa L, Plumeria obtusa L, and Abutilon guineense (Shumach.) Baker. F and Exell were the nutri-medicinal plants that scored the highest Fidelity level values. The informant's consensus about usages of plants ranged from 0.75 to 0.80. Plants that are presumed to be effective in treating a certain disease have higher informant consensus factor (ICF) values. Family Asteraceae accounted for 18% of the total species recorded. Thirteen species (16%) of the plants are edible and provide nutritional support. Conclusion: The study recorded plant species with potential to treat ailments associated with immunocompromised people living with HIV/AIDS in western Uganda. Such studies can help stimulate confidence in traditional medicine and enhance appreciation of herbal medicine among the people and to appreciate the value of the plant resources and therefore enhance conservation efforts of the plant species. The high consensus means the majority of informants agree on the use of plant species and this reflects the intercultural relevance and the agreement in the use of the nutri-medicinal plants to the people. We recommend the documented plants for further Ethnopharmacological studies.
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| 3. |
- Barmpatsalou, Vicky, et al.
(författare)
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Development and validation of a porcine artificial colonic mucus model reflecting the properties of native colonic mucus in pigs
- 2023
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier. - 0928-0987 .- 1879-0720. ; 181
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Tidskriftsartikel (refereegranskat)abstract
- Colonic mucus plays a key role in colonic drug absorption. Mucus permeation assays could therefore provide useful insights and support rational formulation development in the early stages of drug development. However, the collection of native colonic mucus from animal sources is labor-intensive, does not yield amounts that allow for routine experimentation, and raises ethical concerns. In the present study, we developed an in vitro porcine artificial colonic mucus model based on the characterization of native colonic mucus. The structural properties of the artificial colonic mucus were validated against the native secretion for their ability to capture key diffusion patterns of macromolecules in native mucus. Moreover, the artificial colonic mucus could be stored under common laboratory conditions, without compromising its barrier properties. In conclusion, the porcine artificial colonic mucus model can be considered a biorelevant way to study the diffusion behavior of drug candidates in colonic mucus. It is a cost-efficient screening tool easily incorporated into the early stages of drug development and it contributes to the implementation of the 3Rs (refinement, reduction, and replacement of animals) in the drug development process.
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| 4. |
- Barmpatsalou, Vicky, et al.
(författare)
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Physiological properties, composition and structural profiling of porcine gastrointestinal mucus
- 2021
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier. - 0939-6411 .- 1873-3441. ; 169, s. 156-167
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Tidskriftsartikel (refereegranskat)abstract
- The gastrointestinal mucus is a hydrogel that lines the luminal side of the gastrointestinal epithelium, offering barrier protection from pathogens and lubrication of the intraluminal contents. These barrier properties likewise affect nutrients and drugs that need to penetrate the mucus to reach the epithelium prior to absorption. In order to assess the potential impact of the mucus on drug absorption, we need information about the nature of the gastrointestinal mucus. Today, most of the relevant available literature is mainly derived from rodent studies. In this work, we used a larger animal species, the pig model, to characterize the mucus throughout the length of the gastrointestinal tract. This is the first report of the physiological properties (physical appearance, pH and water content), composition (protein, lipid and metabolite content) and structural profiling (rheology and gel network) of the porcine gastrointestinal mucus. These findings allow for direct comparisons between the characteristics of mucus from various segments and can be further utilized to improve our understanding of the role of the mucus on region dependent drug absorption. Additionally, the present work is expected to contribute to the assessment of the porcine model as a preclinical species in the drug development process.
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| 5. |
- Björnsdottir, Halla, et al.
(författare)
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Phenol-soluble Modulin α Peptide Toxins from aggressive Staphylococcus aureus induce rapid Formation of neutrophil extracellular Traps through a reactive Oxygen species-independent Pathway
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils have the ability to capture and kill microbes extracellularly through the formation of neutrophil extracellular traps (NETs). These are DNA and protein structures that neutrophils release extracellularly and are believed to function as a defense mechanism against microbes. The classic NET formation process, triggered by, e.g., bacteria, fungi, or by direct stimulation of protein kinase C through phorbol myristate acetate, is an active process that takes several hours and relies on the production of reactive oxygen species (ROS) that are further modified by myeloperoxidase (MPO). We show here that NET-like structures can also be formed by neutrophils after interaction with phenol-soluble modulin alpha (PSM alpha) that are cytotoxic membrane-disturbing peptides, secreted from community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). The PSMa-induced NETs contained the typical protein markers and were able to capture microbes. The PSMa-induced NET structures were disintegrated upon prolonged exposure to DNase-positive S. aureus but not on exposure to DNase-negative Candida albicans. Opposed to classic NETosis, PSMa-triggered NET formation occurred very rapidly, independently of ROS or MPO, and was also manifest at 4 degrees C. These data indicate that rapid NETs release may result from cytotoxic membrane disturbance by PSMa peptides, a process that may be of importance for CA-MRSA virulence.
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| 6. |
- Dubbelboer, Ilse R, et al.
(författare)
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Gastrointestinal mucus in dog : Physiological characteristics, composition, and structural properties
- 2022
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier. - 0939-6411 .- 1873-3441. ; 173, s. 92-102
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Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal (GI) mucus is continuously secreted and lines the entire length of the GI tract. Essential for health, it keeps the noxious luminal content away from the epithelium. Our aim was to characterize the composition and structure of mucus throughout the various GI segments in dog.Mucus was collected from the stomach, small intestine (duodenum, jejunum, ileum), and large intestine (cecum, proximal and distal colon) from dogs. Composition was determined by multi-omics. Structural properties were investigated using cryoSEM and rheology.GI mucus contained 74-95% water and maintained a pH around 6.5. The proteome was similar across the different GI segments. The highest abundant secreted gel-forming mucin in the gastric mucus was mucin 5AC, whether mucin 2 had highest abundance in the intestinal mucus. Lipid and metabolite abundance was generally higher in the jejunal mucus than the colonic mucus. CryoSEM microscopy revealed smaller pore size in small intestinal mucus, which increased in the large intestine. All mucus samples showed shear-thinning behavior and characteristics of gel-like structure.In conclusion, the mucus is a highly viscous and hydrated material. These data provide an important baseline for future studies on human and canine intestinal diseases and the dog model in drug absorption.
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| 7. |
- Hekim, Zeynep, et al.
(författare)
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The role of climate and fisheries on the temporal changes in the Bothnian Bay foodweb
- 2016
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Ingår i: ICES Journal of Marine Science. - : Oxford University Press (OUP). - 1054-3139 .- 1095-9289. ; 73:7, s. 1739-1749
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Tidskriftsartikel (refereegranskat)abstract
- Climate change, eutrophication, and fishing are main pressures associated with changes in the abiotic and biotic environment in several sub-basins of the Baltic Sea. Identifying the nature of such changes is of relative importance for fisheries and environmental management. The Bothnian Bay is the northernmost sub-basin in the Baltic Sea and the responses of the foodweb to long-term changes in combined pressures have not been investigated. In this study, we explore long-term changes in the Bothnian Bay foodweb, represented by key species across all trophic levels over the past 34 years, and identify potential environmental and anthropogenic drivers. The results indicate that salinity is the most important driver to explain changes in the composition of the offshore biota in the Bothnian Bay. These changes are probably driven by indirect effects of salinity rather than bottom-up effects. A decline in the herring spawning-stock biomass was most plausibly attributed to an increased competition for food due to a parallel increase in vendace, which uses the same food resources (zooplankton and zoobenthos) and may benefit from declining salinity due to its limnic origin. A strong increase in the abundance of grey seal and ringed seal populations was seen in the late 2000s but was not related to any of the pressure variables analysed. Temperature and nutrients were not identified as important drivers of changes in the overall biota. Our study explores correlative relationships between variables and identifies potential interactions in the foodweb to generate hypotheses for further studies.
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| 8. |
- Karlson, Agnes M. L., et al.
(författare)
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Linking consumer physiological status to food-web structure and prey food value in the Baltic Sea
- 2020
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Ingår i: Ambio. - Stockholm : Springer Netherlands. - 0044-7447 .- 1654-7209. ; 49:2, s. 391-406
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Tidskriftsartikel (refereegranskat)abstract
- Declining physiological status in marine top consumers has been observed worldwide. We investigate changes in the physiological status and population/community traits of six consumer species/groups in the Baltic Sea (1993-2014), spanning four trophic levels and using metrics currently operational or proposed as indicators of food-web status. We ask whether the physiological status of consumers can be explained by food-web structure and prey food value. This was tested using partial least square regressions with status metrics for gray seal, cod, herring, sprat and the benthic predatory isopod Saduria as response variables, and abundance and food value of their prey, abundance of competitors and predators as predictors. We find evidence that the physiological status of cod, herring and sprat is influenced by competition, predation, and prey availability; herring and sprat status also by prey size. Our study highlights the need for management approaches that account for species interactions across multiple trophic levels.
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| 9. |
- Karlsson, Agnes
(författare)
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Jämförelser av olika kväveisotop-baserade metoder för att bestämma födovävsposition i torsk: betydelse för miljögiftsövervakning
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Kväveisotoper (δ15N) kan ge information om var i födoväven en organism befinner sig. Detta eftersom den tyngre kväveisotopen anrikas likt miljögifter upp i födoväven. Inom miljögiftsövervakningen kan information om födovävsposition hjälpa till att förklara variationer i miljögiftshalter mellan år som inte nödvändigtvis reflekterar förändringar i belastningen. Födovävsposition används även i statusbedömningar av miljögiftshalter som baseras på miljökvalitetsnormer. Beräkningar av födovävsposition kan dock göras på flera sätt med hjälp av δ15N. Det vanligaste är bulk-analyser av δ15N från muskelvävnad i fisk som sedan normaliseras mot samma mätningar i en baslinjeorganism, vanligtvis blåmussla. En nyare metod är att analysera δ15N i enskilda aminosyror som extraheras från muskelvävnad i organismen av intresse, t.ex fisk och då behövs inte en baslinejorganism vilket är praktiskt eftersom dessa inte alltid är tillgängliga från samma plats och tid som fisken provtagits från. Det finns slutligen olika sätt att beräkna födovävsposition enligt aminosyrametoden beroende på vilka aminosyror som används. Denna studie jämför de estimat av födovävsposition som beräknas utifrån bulk-metoden med olika beräkningsvarianter av aminosyra-metoden (olika aminosyror som ingår) och jämför trenderna över tid. Metoderna skiljer sig i både absoluta värden och trender över tid och samtliga aminosyrametoder visar på ökningar över tid som inte nödvändigtvis reflekterar en reell ökning av födovävspositionen. Bulk-metoden underskattar istället födovävsposition jämfört med vad som är ekologiskt förväntat, men visar inte på ökning över tid. En av aminosyra-metoderna rekommenderas då de absoluta värdena är närmast födovävsposition 4 som är förväntat för torsk i denna storlek men anledningar till en ökning över tid behöver utredas vidare.
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| 10. |
- Karlsson, Agnes, et al.
(författare)
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Temporala och spatiala trender i föreslagna baslinjeorganismer för implementering av stabila isotoper i miljögiftsövervakningen
- 2019
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The report summarises the long-term changes in the stable isotope composition of Blue mussels (Mytilus edulis) from Kvädöfjärden (1981-2017) and the spatial variation in the isotope composition in Blue mussels and the Baltic clam, Limecola balthica (syn. Macoma balthica), from 14 stations throughout the Baltic Proper (coast and offshore stations) and the west coast of Sweden.Time series and the spatial variability of analysed isotopes in Blue mussels and the Baltic clam are presented.The δ13C values were rather stable over time and the year-to-year variation corresponds well to observations in the Askö area, suggesting the two reference stations are rather similar regarding ultimate carbon sources. However, the pattern for δ15N increased over time in Kvädöfjärden (although not during the last 25 years). The difference in δ15N between years in Kvädöfjärden was sometimes equivalent to one trophic level (i.e. a trophic shift of 3.4 per mill).Spatial comparisons of the isotope composition in mussels revealed large differences (equivalent to the trophic shift) among stations and between species, highlighting the need for site-specific isotope baselines when normalizing contaminant data to a specific trophic position according to the WFD (Water Framework Directive).
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