| 1. |
- Andersson, Claes, et al.
(författare)
-
Mebendazole is unique among tubulin-active drugs in activating the MEK-ERK pathway
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity in monocyte/macrophage models and induces ERK signalling. In the present study we investigated whether MBZ induced ERK activation is shared by other tubulin binding agents (TBAs) and if it is observable also in other human cell types. Curated gene signatures for a panel of TBAs in the LINCS Connectivity Map (CMap) database showed a unique strong negative correlation of MBZ with MEK/ERK inhibitors indicating ERK activation also in non-haematological cell lines. L1000 gene expression signatures for MBZ treated THP-1 monocytes also connected negatively to MEK inhibitors. MEK/ERK phosphoprotein activity testing of a number of TBAs showed that only MBZ increased the activity in both THP-1 monocytes and PMA differentiated macrophages. Distal effects on ERK phosphorylation of the substrate P90RSK and release of IL1B followed the same pattern. The effect of MBZ on MEK/ERK phosphorylation was inhibited by RAF/MEK/ERK inhibitors in THP-1 models, CD3/IL2 stimulated PBMCs and a MAPK reporter HEK-293 cell line. MBZ was also shown to increase ERK activity in CD4+ T-cells from lupus patients with known defective ERK signalling. Given these mechanistic features MBZ is suggested suitable for treatment of diseases characterized by defective ERK signalling, notably difficult to treat autoimmune diseases.
|
|
| 2. |
- Blom, Kristin, et al.
(författare)
-
Mebendazole-induced M1 polarisation of THP-1 macrophages may involve DYRK1B inhibition
- 2019
-
Ingår i: BMC Research Notes. - : Springer Nature. - 1756-0500. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity by inducing a M2 to M1 phenotype switch in monocyte/macrophage models. In the present study we investigated the potential role of protein kinases in mediating this effect.Results: MBZ potently binds and inhibits Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) with a Kd and an IC50 of 7 and 360 nM, respectively. The specific DYRK1B inhibitor AZ191 did not mimic the cytokine release profile of MBZ in untreated THP-1 monocytes. However, in THP-1 cells differentiated into macrophages, AZ191 strongly induced a pro-inflammatory cytokine release pattern similar to MBZ and LPS/IFNγ. Furthermore, like MBZ, AZ191 increased the expression of the M1 marker CD80 and decreased the M2 marker CD163 in THP-1 macrophages. In this model, AZ191 also increased phospho-ERK activity although to a lesser extent compared to MBZ. Taken together, the results demonstrate that DYRK1B inhibition could, at least partly, recapitulate immune responses induced by MBZ. Hence, DYRK1B inhibition induced by MBZ may be part of the mechanism of action to switch M2 to M1 macrophages.
|
|
| 3. |
- Blom, Kristin, et al.
(författare)
-
The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation
- 2017
-
Ingår i: Immunopharmacology and immunotoxicology. - : Informa UK Limited. - 0892-3973 .- 1532-2513. ; 39:4, s. 199-210
-
Tidskriftsartikel (refereegranskat)abstract
- Mebendazole (MBZ), a drug commonly used for helminitic infections, has recently gained substantial attention as a repositioning candidate for cancer treatment. However, the mechanism of action behind its anticancer activity remains unclear. To address this problem, we took advantage of the curated MBZ-induced gene expression signatures in the LINCS Connectivity Map (CMap) database. The analysis revealed strong negative correlation with MEK/ERK1/2 inhibitors. Moreover, several of the most upregulated genes in response to MBZ exposure were related to monocyte/macrophage activation. The MBZ-induced gene expression signature in the promyeloblastic HL-60 cell line was strongly enriched in genes involved in monocyte/macrophage pro-inflammatory (M1) activation. This was subsequently validated using MBZ-treated THP-1 monocytoid cells that demonstrated gene expression, surface markers and cytokine release characteristic of the M1 phenotype. At high concentrations MBZ substantially induced the release of IL-1 beta and this was further potentiated by lipopolysaccharide (LPS). At low MBZ concentrations, cotreatment with LPS was required for MBZ-stimulated IL-1 beta secretion to occur. Furthermore, we show that the activation of protein kinase C, ERK1/2 and NF-kappaB were required for MBZ-induced IL-1 release. MBZ-induced IL-1 release was found to be dependent on NLRP3 inflammasome activation and to involve TLR8 stimulation. Finally, MBZ induced tumor-suppressive effects in a coculture model with differentiated THP-1 macrophages and HT29 colon cancer cells. In summary, we report that MBZ induced a pro-inflammatory (M1) phenotype of monocytoid cells, which may, at least partly, explain MBZ's anticancer activity observed in animal tumor models and in the clinic.
|
|
| 4. |
- Fryknäs, Mårten, et al.
(författare)
-
Screening for phenotype selective activity in multidrug resistant cells identifies a novel tubulin active agent insensitive to common forms of cancer drug resistance
- 2013
-
Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 13, s. 374-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Drug resistance is a common cause of treatment failure in cancer patients and encompasses a multitude of different mechanisms. The aim of the present study was to identify drugs effective on multidrug resistant cells. Methods: The RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 was screened for cytotoxicity in response to 3,000 chemically diverse compounds using a fluorometric cytotoxicity assay (FMCA). Follow-up profiling was subsequently performed using various cellular and biochemical assays. Results: One compound, designated VLX40, demonstrated a higher activity against 8226/Dox40 cells compared to its parental counterpart. VLX40 induced delayed cell death with apoptotic features. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. Strong connections to tubulin inhibitors and microtubule cytoskeleton were retrieved. The mechanistic hypothesis of VLX40 acting as a tubulin inhibitor was confirmed by direct measurements of interaction with tubulin polymerization using a biochemical assay and supported by demonstration of G2/M cell cycle arrest. When tested against a broad panel of primary cultures of patient tumor cells (PCPTC) representing different forms of leukemia and solid tumors, VLX40 displayed high activity against both myeloid and lymphoid leukemias in contrast to the reference compound vincristine to which myeloid blast cells are often insensitive. Significant in vivo activity was confirmed in myeloid U-937 cells implanted subcutaneously in mice using the hollow fiber model. Conclusions: The results indicate that VLX40 may be a useful prototype for development of novel tubulin active agents that are insensitive to common mechanisms of cancer drug resistance.
|
|
| 5. |
- Nygren, Thomas, 1972-, et al.
(författare)
-
Lärarstudenters ämnesdidaktiska reflektioner i geografi, historia, religion och samhällskunskap
- 2022
-
Ingår i: Nordidactica. - Karlstad : Karlstads universitet. - 2000-9879. ; 12:3, s. 122-148
-
Tidskriftsartikel (refereegranskat)abstract
- In this study we investigate subject didactic reflections of 183 teacher students in civics, history, geography or religion in primary, elementary or secondary schools. We ask teacher students to reflect on what they perceive to be important and difficult to teach in their subject and also what methods they think would be productive. A comparative content analysis shows that a majority of the teacher students view academic knowledge and skills as important and challenging to teach in their respective subjects, and pupil-centered methods as those that primarily should be used in teaching. We do, however, find significant differences between the four subjects, for example concerning focus on facts and teacher-centered methods versus attitudes and values and student-centered methods. The students’ subject didactic reflections indicate important insights about teaching but they generally lack insights into pupils’ subject specific difficulties and how different methods may be used to support pupils’ learning.
|
|
| 6. |
- Selvin, Tove, et al.
(författare)
-
Immuno-oncological effects of standard anticancer agents and commonly used concomitant drugs : an in vitro assessment
- 2024
-
Ingår i: BMC Pharmacology & Toxicology. - : BioMed Central (BMC). - 2050-6511. ; 25:1
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundIt has become evident in the field of oncology that the outcome of medical treatment is influenced by the combined effect exerted on both cancer- and immune cells. Therefore, we evaluated potential immunological effects of 46 standard anticancer agents and 22 commonly administered concomitant non-cancer drugs.MethodsWe utilized a miniaturized in vitro model system comprised of fluorescently labeled human colon and lung cancer cell lines grown as monocultures and co-cultured with activated peripheral blood mononuclear cells (PBMCs). The Bliss Independence Model was then applied to detect antagonism and synergy between the drugs and activated immune cells.ResultsAmong the standard anticancer agents, tyrosine kinase inhibitors (TKIs) stood out as the top inducers of both antagonism and synergy. Ruxolitinib and dasatinib emerged as the most notably antagonistic substances, exhibiting the lowest Bliss scores, whereas sorafenib was shown to synergize with activated PBMCs. Most concomitant drugs did not induce neither antagonism nor synergy. However, the statins mevastatin and simvastatin were uniquely shown to synergize with activated PBMC at all tested drug concentrations in the colon cancer model.ConclusionWe utilized a miniaturized tumor-immune model to enable time and cost-effective evaluation of a broad panel of drugs in an immuno-oncology setting in vitro. Using this approach, immunomodulatory effects exerted by TKIs and statins were identified.
|
|
| 7. |
- Selvin, Tove, et al.
(författare)
-
Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death.
- 2023
-
Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated the discovery of new cancer drugs. However, most phenotypic screening platforms used in the field of oncology are based solely on cancer cell populations and do not allow for the identification of immunomodulatory agents.We developed a phenotypic screening platform based on a miniaturized co-culture system with human colorectal cancer- and immune cells, providing a model that recapitulates part of the tumor immune microenvironment (TIME) complexity while simultaneously being compatible with a simple image-based readout. Using this platform, we screened 1,280 small molecule drugs, all approved by the Food and Drug Administration (FDA), and identified statins as enhancers of immune cell-induced cancer cell death.The lipophilic statin pitavastatin had the most potent anti-cancer effect. Further analysis demonstrated that pitavastatin treatment induced a pro-inflammatory cytokine profile as well as an overall pro-inflammatory gene expression profile in our tumor-immune model.Our study provides an in vitro phenotypic screening approach for the identification of immunomodulatory agents and thus addresses a critical gap in the field of immuno-oncology. Our pilot screen identified statins, a drug family gaining increasing interest as repurposing candidates for cancer treatment, as enhancers of immune cell-induced cancer cell death. We speculate that the clinical benefits described for cancer patients receiving statins are not simply caused by a direct effect on the cancer cells but rather are dependent on the combined effect exerted on both cancer and immune cells.
|
|
| 8. |
- Ahlborg, Mikael G., et al.
(författare)
-
SoCap YMH - youth mental health, social capital and help-seeking : a study protocol
- 2024
-
Ingår i: Frontiers in Public Health. - : Frontiers Media S.A.. - 2296-2565. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The increase in adolescents reporting mental health problems presents a major public health challenge. The complex association between mental health and social capital motivates further investigation of social capital as a crucial aspect in shaping adolescents' help-seeking knowledge, attitudes, and behaviours.Aim: This protocol presents a project that aims to investigate social capital in relation to help-seeking and mental health in close collaboration with adolescents and key stakeholders in the school setting, in the southern part of Sweden.Methods: A mixed-method design with three interconnected work packages (WP) will be undertaken with an emphasis on co-production where adolescents are involved throughout the process. WP1 is a development and validation of two questionnaire instruments for assessing social capital and help-seeking in adolescence. WP2 is a longitudinal quantitative study involving 1,500 adolescents from two regions representing rural and suburban/urban settings. Adolescents aged 15 will be asked to complete questionnaires concerning social capital, mental health, and help-seeking in a baseline and one-year follow-up, allowing for investigation of the role of social capital for help-seeking. WP3 is designed to elucidate experiences and knowledge of adolescents and key stakeholders via collaborative World Café workshops. These will be held along the project to evolve the generated knowledge and maximize it's applicability during and after the project is finalized.Conclusion: The results are expected to further the understanding of the relationship between adolescents' social capital, mental health, and help-seeking, to contribute to a deeper understanding of the mechanisms behind the paradoxical help-seeking patterns among adolescents today and to narrow the gap between research and practice to produce sustainable and efficient strategies, which may facilitate help-seeking and improve the mental health of adolescents within existing organizational structures.
|
|
| 9. |
- Ahlborg, Mikael, 1985-, et al.
(författare)
-
SoCap YMH - youth mental health, social capital and help-seeking : a study protocol
- 2024
-
Ingår i: Frontiers in Public Health. - Lausanne : Frontiers Media S.A.. - 2296-2565. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The increase in adolescents reporting mental health problems presents a major public health challenge. The complex association between mental health and social capital motivates further investigation of social capital as a crucial aspect in shaping adolescents' help-seeking knowledge, attitudes, and behaviours. Aim: This protocol presents a project that aims to investigate social capital in relation to help-seeking and mental health in close collaboration with adolescents and key stakeholders in the school setting, in the southern part of Sweden. Methods: A mixed-method design with three interconnected work packages (WP) will be undertaken with an emphasis on co-production where adolescents are involved throughout the process. WP1 is a development and validation of two questionnaire instruments for assessing social capital and help-seeking in adolescence. WP2 is a longitudinal quantitative study involving 1,500 adolescents from two regions representing rural and suburban/urban settings. Adolescents aged 15 will be asked to complete questionnaires concerning social capital, mental health, and help-seeking in a baseline and one-year follow-up, allowing for investigation of the role of social capital for help-seeking. WP3 is designed to elucidate experiences and knowledge of adolescents and key stakeholders via collaborative World Café workshops. These will be held along the project to evolve the generated knowledge and maximize it's applicability during and after the project is finalized. Conclusion: The results are expected to further the understanding of the relationship between adolescents' social capital, mental health, and help-seeking, to contribute to a deeper understanding of the mechanisms behind the paradoxical help-seeking patterns among adolescents today and to narrow the gap between research and practice to produce sustainable and efficient strategies, which may facilitate help-seeking and improve the mental health of adolescents within existing organizational structures. Copyright © 2024 Ahlborg, Morgan, Svedberg, Nygren, Eriksson and Westberg.
|
|
| 10. |
- Ahlborg, Mikael, 1985-
(författare)
-
Social capital and inequalities in mental health among young adolescents in Sweden
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to explore social capital and inequalities in mental health among young adolescents in Sweden. This is a compilation thesis comprising four studies. Studies I and II are quantitative studies of crosssectional data from the Swedish Health Behaviour in School-aged Children survey. The aim of Study I was to investigate socioeconomic inequalities in health using both a subjective and an objective measure of socioeconomic status among Swedish adolescents. The findings showed that subjective socioeconomic status robustly and independently predicted mental health problems, poor life satisfaction and poor general health perception. The association between objective socioeconomic status and mental health was weakened, and even reversed, when subjective socioeconomic status was accounted for in regression models. A Latent Profile Analysis was applied in Study II with the aim of identifying distinct profiles of family, school and peer social capital in a nationally representative sample of adolescents and to explore health outcomes in those profiles. The findings showed that five distinct profiles best represented the data for 11 and 15-year olds, while a four-profile model was optimal for 13-year olds. Significant inequalities were identified between profiles when these were examined in terms of mental health problems and life satisfaction. The design of Study III was a qualitative semi-structured interview study. The aim was to explore social capital from the perspective of adolescents in relation to mental health. Adolescents spoke of having access to a safe space, feeling connected to others and predictability as important aspects of social relationships and networks in relation to mental health. The aim of Study IV was to identify and evaluate the design and psychometric properties of instruments for assessing social capital specifically developed and validated for self-reporting among adolescents (10-19 years). The design was a systematic review, in which 20 instruments were identified. The results revealed a lack of instruments that covered both the multidimensionality of social capital and contextual relevance in relation to adolescents. The conclusion from this thesis is that social capital may be useful for identifying vulnerable individuals and for differentiating between the natural imbalance of adolescence and what may lead to serious illness. Longitudinal research and refinement of the operationalization of the concept are, however, needed to enhance the understanding of these findings.
|
|
