| 1. |
- Ahlin, Sofie, 1985, et al.
(författare)
-
Macrophage Gene Expression in Adipose Tissue is Associated with Insulin Sensitivity and Serum Lipid Levels Independent of Obesity.
- 2013
-
Ingår i: Obesity (Silver Spring, Md.). - : Wiley. - 1930-739X .- 1930-7381. ; 21:12
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity-independent links between adipose tissue macrophages and metabolic disturbances. Design and Methods: Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI-matched healthy control group. Results: The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C-peptide, high density lipoprotein cholesterol (HDL-cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group. Conclusion: Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.
|
|
| 2. |
- Macsari, Istvan, et al.
(författare)
-
3-Oxoisoindoline-1-carboxamides : Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models
- 2012
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:15, s. 6866-6880
-
Tidskriftsartikel (refereegranskat)abstract
- The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.
|
|
| 3. |
- Ahlin, Gustav, 1977-, et al.
(författare)
-
Endogenous Gene and Protein Expression of Drug Transporting Proteins in Cell Lines Routinely used in Drug Discovery Programs
- 2009
-
Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 37:12, s. 2275-2283
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the gene and protein expression profiles of important drug transporting proteins in human cell lines commonly used for studies of drug transport mechanisms. Human cell lines used to transiently or stably express single transporters (HeLa, HEK293) and leukaemia cell lines used to study drug resistance by ABC-transporters (HL-60, K562) were investigated, and compared with organotypic cell lines (HepG2, Saos-2, Caco-2 and Caco-2 TC7). For gene expression studies, real-time PCR was used, while monospecific polyclonal antibodies were generated and used to investigate protein expression by immunohistochemistry. Thirty-six transporters were studied for gene expression and nine for protein expression. The antibodies were validated using expression patterns in human tissues. Finally, the function of one ubiquitously expressed transporter, MCT1; SLC16A1 was investigated using 14C-lactic acid as a substrate. In general, the adherent cell lines (HeLa, HEK293) displayed low transporter expression and the expression patterns were barely affected by transfection. The leukaemia cell lines (K562, HL-60) and Saos-2 also had low endogenous transporter expression, while the organotypic cell lines (HepG2 and Caco-2) showed higher expression of some transporters. Comparison of gene and protein expression profiles gave poor correlations, but better agreement was obtained for antibodies with a good validation score, indicating that antibody quality was a significant variable. Importantly, the monocarboxylic acid transporting protein MCT1 was significantly expressed in all, and functional in most of the cell lines, indicating that MCT1 may be a confounding factor when the transport of small anionic drugs is investigated.
|
|
| 4. |
- Ahlin, Gustav, 1977-, et al.
(författare)
-
Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: : predictions of metformin interactions
- 2011
-
Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 11:6, s. 400-411
-
Tidskriftsartikel (refereegranskat)abstract
- Common genetic variants of the liver-specific human organic cation transporter 1 (OCT1; SLC22A1) have reduced transport capacity for substrates such as the antidiabetic drug metformin. The effect of the reduced OCT1 function on drug interactions associated with OCT1 has not been investigated and was, therefore, the focus of the study presented here. HEK293 cells expressing human OCT1-reference or the variants R61C, V408M, M420del and G465R were first used to study the kinetics and inhibition pattern of the OCT1 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP(+)). In the second part OCT1-mediated (14)C-metformin uptake was studied in the presence of drugs administered concomitantly with metformin. Transport studies using ASP(+) showed that the function of the variants decreased in the following order: OCT1-reference = V408M = M420del >R61C > >G465R. Variants M420del and R61C were more sensitive to drug inhibition, with IC(50) values up to 23 times lower than those of the OCT1-reference. Uptake studies using (14)C-metformin were in qualitative agreement with those using ASP(+), with the exception that a larger reduction in transport capacity was observed for M420del. Concomitantly administered drugs, such as verapamil and amitriptyline, revealed potential drug-drug interactions at clinical plasma concentrations of metformin for OCT1-M420del.
|
|
| 5. |
- Ahlin, Gustav, 1977-
(författare)
-
In vitro and in silico prediction of drug-drug interactions with transport proteins
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Drug transport across cells and cell membranes in the human body is crucial for the pharmacological effect of drugs. Active transport governed by transport proteins plays an important role in this process. A vast number of transport proteins with a wide tissue distribution have been identified during the last 15 years. Several important examples of their role in drug disposition and drug-drug interactions have been described to date. Investigation of drug-drug interactions at the transport protein level are therefore of increasing interest to the academic, industrial and regulatory research communities. The gene expression of transport proteins involved in drug transport was investigated in the jejunum, liver, kidney and colon to better understand their influence on the ADMET properties of drugs. In addition, the gene and protein expression of transport proteins in cell lines, widely used for predictions of drug transport and metabolism, was examined. The substrate and inhibitor heterogeneity of many transport proteins makes it difficult to foresee whether the transport proteins will cause drug-drug interactions. Therefore, in vitro assays for OCT1 and OATP1B1, among the highest expressed transport proteins in human liver, were developed to allow investigation of the inhibitory patterns of these proteins. These assays were used to investigate two data sets, consisting of 191 and 135 registered drugs and drug-like molecules for the inhibition of OCT1 and OATP1B1, respectively. Numerous new inhibitors of the transport proteins were identified in the data sets and the properties governing inhibition were determined. Further, antidepressant drugs and statins displayed strong inhibition of OCT1 and OATP1B1, respectively. The inhibition data was used to develop predictive in silico models for each of the two transport proteins. The highly polymorphic nature of some transport proteins has been shown to affect drug response and may lead to an increased risk of drug-drug interactions, and therefore, the OCT1 in vitro assay was used to study the effect of common genetic variants of OCT1 on drug inhibition and drug-drug interactions. The results indicated that OCT1 variants with reduced function were more susceptible to inhibition. Further, a drug-drug interaction of potential clinical significance in the genetic OCT1 variant M420del was proposed. In summary, gene expression of transport proteins was investigated in human tissues and cell lines. In vitro assays for two of the highest expressed liver transport proteins were used to identify previously unknown SLC transport protein inhibitors and to develop predictive in silico models, which may detect previously known drug-drug interactions and enable new ones to be identified at the transport protein level. In addition, the effect of genetic variation on inhibition of the OCT1 was investigated.
|
|
| 6. |
- Ahlin, Gustav, et al.
(författare)
-
Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1
- 2008
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 51:19, s. 5932-5942
-
Tidskriftsartikel (refereegranskat)abstract
- The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
|
| 7. |
- Ahlin, Jane, et al.
(författare)
-
Strategies to develop and strengthen human factors and ergonomics knowledge among stakeholders in Sweden
- 2015
-
Ingår i: Proceedings 19th Triennial Congress of the IEA, Melbourne 9-14 August 2015. - Melbourne : International Ergonomics Association.
-
Konferensbidrag (refereegranskat)abstract
- Knowledge and application of human factors and ergonomics (HFE) has significant potential as auseful tool and solution provider in the development, design and implementation of safe, efficient and sustainable artefacts and systems. Yet, it seems that this HFE knowledge is not utilised to its full potential. In a world of competing financial and commercial priorities, HFE specialists have apparently not succeeded in selling the systems approach as a tool towards improved overall systems performance and human well-being.The present paper describes the strategic and practical workperformed by the Swedish Ergonomics and Human Factors Society (EHSS) to strengthen the quality of human factors and ergonomics knowledge and practice among various stakeholders in Sweden. EHSS view human factors and ergonomics as a systems and design oriented discipline that extends across all aspects of human activity. Beyond the traditional domains of specialization within the discipline, the physical, cognitive and organisational ergonomics, EHSS has identified three focus areas; visual ergonomics, voice ergonomics and ergonomics design for all.Practitioner Summary: This paper presents the strategic and practical work performed by the Swedish Ergonomics and Human Factors Society (EHSS) in order to strengthen the quality of human factors and ergonomics knowledge and practice in Sweden. EHSS has identified three focus areas for its strategic work: visual ergonomics, voice ergonomics and ergonomics design for all.
|
|
| 8. |
- Ahlin, Lina, et al.
(författare)
-
Human capital sorting : The "when" and "who" of the sorting of educated workers to urban regions
- 2018
-
Ingår i: Journal of regional science. - : John Wiley & Sons. - 0022-4146 .- 1467-9787. ; 58:3, s. 581-610
-
Tidskriftsartikel (refereegranskat)abstract
- The sorting of high-ability workers is often advanced as one source of spatial disparities in economic outcomes. There are still few papers that analyze when human capital sorting occurs and whom it involves. Using data on 16 cohorts of university graduates in Sweden, we demonstrate significant sorting to urban regions on high school grades and education levels of parents, i.e., two attributes typically associated with latent abilities that are valued in the labor market. A large part of this sorting has already occurred in deciding where to study, because the top universities in Sweden are predominantly located in urban regions. The largest part of directed sorting on ability indicators occurs in the decision of where to study. Even after controlling for sorting prior to labor market entry, the best and brightest are still more likely to start working in urban regions. However, this effect appears to be driven by Sweden's main metropolitan region, Stockholm. We find no influence of our ability indicators on the probability of starting to work in urban regions after graduation when Stockholm is excluded. Studies of human capital sorting need to account for selection processes to and from universities, because neglecting mobility prior to labor market entry is likely to lead to an underestimation of the extent of the sorting to urban regions.
|
|
| 9. |
- Ahlin, Lina, et al.
(författare)
-
Market Thickness and the Early Labour Market Career of University Graduates : An Urban Advantage?
- 2014
-
Ingår i: Spatial Economic Analysis. - : Informa UK Limited. - 1742-1772 .- 1742-1780. ; 9:4, s. 396-419
-
Tidskriftsartikel (refereegranskat)abstract
- We analyse the influence of market thickness for skills on initial wages and the early job market career of university graduates. Using Swedish micro-level panel data on a cohort of graduates, we show that two out of three graduates move to large cities upon graduation. Large cities increase employment probabilities and yield higher rewards to human capital, even after controlling for employment selection. The premium on initial wages for graduates in urban regions is in the interval of 5-6%, and we estimate a wage-growth premium of about 2-4%. Thicker markets for skills appear as a key reason for the concentration of graduates to larger cities.
|
|
| 10. |
|
|
