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Dong, J., Zhang, J., Li, Z., Asnake, S., Zhang, D., Olsson, P.-E. & Zhao, G. (2019). Design, synthesis, and biological evaluation of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives as androgen receptor antagonists. Medicinal Chemistry Research, 28(3), 380-386
Open this publication in new window or tab >>Design, synthesis, and biological evaluation of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives as androgen receptor antagonists
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2019 (English)In: Medicinal Chemistry Research, ISSN 1054-2523, E-ISSN 1554-8120, Vol. 28, no 3, p. 380-386Article in journal (Refereed) Published
Abstract [en]

Androgen receptor (AR) signaling is often activated in prostate cancer (PCa) cells, and blockage of this signaling by AR antagonists is an important strategy in PCa therapy. In this study, we designed and synthesized a series of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives, and evaluated their biological activities. AR luciferase reporter assay revealed compound 6f (59.7%) as a potent AR antagonist. Some compounds in this series showed higher anti-proliferative activity against LNCaP cells than Bicalutamide (IC50=35.0M), especially 6g with IC50 value of 13.6 mu M.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
Androgen receptor, Prostate cancer, Antagonists, Pyrazole derivatives
National Category
Pharmacology and Toxicology Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-73118 (URN)10.1007/s00044-019-02291-y (DOI)000459449600013 ()2-s2.0-85060553900 (Scopus ID)
Funder
Knowledge Foundation, 201550084
Note

Funding Agencies:

National Natural Science Foundation of China  21272140 

Key Research and Development Project of Shandong Province  2017CXGC1401 

Available from: 2019-03-14 Created: 2019-03-14 Last updated: 2019-03-14Bibliographically approved
Stylianou, M., Björnsdotter, M., Olsson, P.-E., Ericson Jogsten, I. & Jass, J. (2019). Distinct transcriptional response of Caenorhabditis elegans to different exposure routes of perfluorooctane sulfonic acid. Environmental Research, 168, 406-413
Open this publication in new window or tab >>Distinct transcriptional response of Caenorhabditis elegans to different exposure routes of perfluorooctane sulfonic acid
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2019 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 168, p. 406-413Article in journal (Refereed) Published
Abstract [en]

Although people are exposed daily to per- and polyfluorinated alkyl substances (PFASs), the biological consequences are poorly explored. The health risks associated with PFAS exposure are currently based on chemical analysis with a weak correlation to potential harmful effects in man and animals. In this study, we show that perfluorooctane sulfonic acid (PFOS), often the most enriched PFAS in the environment, can be transferred via bacteria to higher organisms such as Caenorhabditis elegans. C. elegans nematodes were exposed to PFOS directly in buffer or by feeding on bacteria pretreated with PFOS, and this led to distinct gene expression profiles. Specifically, heavy metal and heat shock associated genes were significantly, although inversely, expressed following the different PFOS exposures. The innate immunity receptor for microbial pathogens, clec-60, was shown for the first time to be down-regulated by PFOS. This is in line with a previous study indicating that PFOS is associated with children's susceptibility to certain infectious diseases. Furthermore, bar-1, a gene associated with various cancers was highly up-regulated only when C. elegans were exposed to PFOS pretreated live bacteria. Furthermore, dead bacterial biomass had higher binding capacity for linear and isomeric PFOS than live bacteria, which correlated to the higher levels of PFOS detected in C. elegans when fed the treated E. toll, respectively. These results reveal new aspects concerning trophic chain transport of PFOS.

Place, publisher, year, edition, pages
Academic Press, 2019
Keywords
PFOS biosorption, PFOS isomers, Nematode, Escherichia coli, Food chain
National Category
Environmental Sciences
Identifiers
urn:nbn:se:oru:diva-71130 (URN)10.1016/j.envres.2018.10.019 (DOI)000452938700043 ()30388497 (PubMedID)2-s2.0-85055720038 (Scopus ID)
Funder
Knowledge Foundation, 20140180
Note

Funding Agency:

Örebro University

Available from: 2019-01-08 Created: 2019-01-08 Last updated: 2019-01-08Bibliographically approved
Rai, N., Sjöberg, V., Forsberg, G., Karlsson, S., Olsson, P.-E. & Jass, J. (2019). Metal contaminated soil leachates from an art glass factory elicit stress response, alter fatty acid metabolism and reduce lifespan in Caenorhabditis elegans. Science of the Total Environment, 651, 2218-2227
Open this publication in new window or tab >>Metal contaminated soil leachates from an art glass factory elicit stress response, alter fatty acid metabolism and reduce lifespan in Caenorhabditis elegans
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2019 (English)In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 651, p. 2218-2227Article in journal (Refereed) Published
Abstract [en]

The present study evaluated the toxicity of metal contamination in soils from an art glass factory in Smaland Sweden using a Caenorhabditis elegans nematode model. The aim of the study was to chemically analyze the soil samples and study the biological effects of water-soluble leachates on the nematodes using different physiological endpoints. The total metal content showed that As, Cd and Pb were at levels above the guideline values for soils in areas around the factory. Less than 10% of the total metal content in the soil was found in the water-soluble leachates, however, Al, As, Fe and Pb remained higher than the guideline values for safe drinking water. Exposure of C. elegans to the water-soluble leachates, at both post-hatching larvae stage (L1-young adult) for 48 h and at the young adult stage (L4) for 6 h, showed significant gene alteration. Although the nematodes did not exhibit acute lethality, lifespan was significantly reduced upon exposure. C. elegans also showed altered gene expression associated with stress response and fat metabolism, as well as enhanced accumulation of body fat. The study highlighted the significance of assessing environmental samples using a combination of gene expression analysis, fatty acid metabolism and lifespan for providing valuable insight into the negative impact of metals. The altered fat metabolism and reduced lifespan on exposure to soil leachates motivates further studies to explore the mechanism of the toxicity associated with the metals present in the environment.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Contaminated soil, Water-soluble leachates, Ecotoxicology, Lipid metabolism, Heavy metals, Glass manufacturing
National Category
Environmental Sciences
Identifiers
urn:nbn:se:oru:diva-70482 (URN)10.1016/j.scitotenv.2018.10.067 (DOI)000450551600055 ()30326454 (PubMedID)2-s2.0-85054622934 (Scopus ID)
Funder
Knowledge Foundation, 20150084
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-05Bibliographically approved
Kharlyngdoh, J. B., Pradhan, A. & Olsson, P.-E. (2018). Androgen receptor modulation following combination exposure to brominated flame-retardants. Scientific Reports, 8(1), Article ID 4843.
Open this publication in new window or tab >>Androgen receptor modulation following combination exposure to brominated flame-retardants
2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 4843Article in journal (Refereed) Published
Abstract [en]

Endocrine disrupting compounds can interfere with androgen receptor (AR) signaling and disrupt steroidogenesis leading to reproductive failure. The brominated flame-retardant (BFR) 1, 2-dibromo-4-(1, 2-dibromoethyl) cyclohexane (TBECH), is an agonist to human, chicken and zebrafish AR. Recently another group of alternative BFRs, allyl 2, 4, 6-tribromophenyl ether (ATE), and 2, 3-dibromopropyl 2, 4, 6-tribromophenyl ether (DPTE) along with its metabolite 2-bromoallyl 2, 4, 6-tribromophenyl ether (BATE) were identified as potent human AR antagonists. These alternative BFRs are present in the environment. The aim of the present study was to determine the effect of mixed exposures to the AR agonist and the AR antagonists at environmentally relevant concentrations. In vitro reporter luciferase assay showed that the AR antagonists, when present at concentration higher than TBECH, were able to inhibit TBECH-mediated AR activity. These AR antagonists also promoted AR nuclear translocation. In vitro gene expression analysis in the non-tumorigenic human prostate epithelial cell RWPE1 showed that TBECH induced AR target genes whereas DPTE repressed these genes. Further analysis of steroidogenic genes showed that TBECH up-regulated most of the genes while DPTE down-regulated the same genes. The results indicate that when TBECH and DPTE are present together they will antagonize each other, thereby reducing their individual effects.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:oru:diva-66052 (URN)10.1038/s41598-018-23181-0 (DOI)000427688100036 ()29556062 (PubMedID)2-s2.0-85044191096 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agency:

Örebro University

Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-08-20Bibliographically approved
Goswami, M., Khan, F. A., Ibrisevic, A., Olsson, P.-E. & Jass, J. (2018). Development of Escherichia coli-based gene expression profiling of sewage sludge leachates. Journal of Applied Microbiology, 125(5), 1502-1517
Open this publication in new window or tab >>Development of Escherichia coli-based gene expression profiling of sewage sludge leachates
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2018 (English)In: Journal of Applied Microbiology, ISSN 1364-5072, E-ISSN 1365-2672, Vol. 125, no 5, p. 1502-1517Article in journal (Refereed) Published
Abstract [en]

AIMS: The impact of municipal waste on pathogenic microorganisms released into the environment is a public health concern. The present study aims to evaluate the effects of sewage sludge and antibiotic contaminants on stress response, virulence and antibiotic resistance in a pathogenic Escherichia coli.

METHODS AND RESULTS: The effects of sewage sludge leachates on uropathogenic E. coli CFT073 were determined by monitoring the expression of 45 genes associated with antibiotic/metal resistance, stress response and virulence using RT-qPCR. The E. coli gene expression was validated using sub-inhibitory concentrations of tetracycline and ciprofloxacin. E. coli exposed to sewage sludge or sewage sludge-fly ash leachates altered the expression of 5 antibiotic and metal resistance, 3 stress response and 2 virulence associated genes. When antibiotics were combined with sludge or sludge-fly ash the antibiotic-associated gene expression was altered.

CONCLUSIONS: E. coli treated with two sludge leachates had distinct gene expression patterns that were altered when the sludge leachates were combined with tetracycline, although to a lesser extent with ciprofloxacin.

SIGNIFICANCE AND IMPACT OF STUDY: The E. coli multigene expression analysis is a potential new tool for assessing the effects of pollutants on pathogenic microbes in environmental waters for improved risk assessment.

Place, publisher, year, edition, pages
Blackwell Publishing, 2018
Keywords
Ecotoxicity, Gene expression, Resistance, Sludge, Stress response, Virulence
National Category
Microbiology
Identifiers
urn:nbn:se:oru:diva-67511 (URN)10.1111/jam.14028 (DOI)000447408400024 ()29928772 (PubMedID)2-s2.0-85050482911 (Scopus ID)
Funder
Knowledge Foundation, Dnr 20110177
Available from: 2018-06-26 Created: 2018-06-26 Last updated: 2018-11-01Bibliographically approved
Pradhan, A., Olsson, P.-E. & Jass, J. (2018). Di(2-ethylhexyl) phthalate and diethyl phthalate disrupt lipid metabolism, reduce fecundity and shortens lifespan of Caenorhabditis elegans. Chemosphere, 190, 375-382
Open this publication in new window or tab >>Di(2-ethylhexyl) phthalate and diethyl phthalate disrupt lipid metabolism, reduce fecundity and shortens lifespan of Caenorhabditis elegans
2018 (English)In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 190, p. 375-382Article in journal (Refereed) Published
Abstract [en]

The widespread use of phthalates is of major concern as they have adverse effects on many different physiological functions, including reproduction, metabolism and cell differentiation. The aim of this study was to compare the toxicity of the widely-used di (2-ethydlhexyl) phthalate (DEHP) with its substitute, diethyl phthalate (DEP). We analyzed the toxicity of these two phthalates using Caenorhabditis elegans as a model system. Gene expression analysis following exposure during the L1 to young adult stage showed that DEHP and DEP alter the expression of genes involved in lipid metabolism and stress response. Genes associated with lipid metabolism, including fasn-1, pod-2, fat-5, acs-6 and sbp-1, and vitellogenin were upregulated. Among the stress response genes, ced-1 wah-1, daf-21 and gst-4 were upregulated, while cd-1, cdf-2 and the heat shock proteins (hsp-16.1, hsp-16.48 and sip-1) were down regulated. Lipid staining revealed that DEHP significantly increased lipid content following 1 mu M exposure, however, DEP required 10 mu M exposure to elicit an effect. Both DEHP and DEP reduced the fecundity at 1 mu M concentration. Lifespan analysis indicated that DEHP and DEP reduced the average lifespan from 14 days in unexposed worms to 13 and 12 days, respectively. Expression of lifespan associated genes showed a correlation to shortened lifespan in the exposed groups. As reported previously, our data also indicates that the banned DEHP is toxic to C. elegans, however its substitute DEP has not been previously tested in this model organism and our data revealed that DEP is equally potent as DEHP in regulating C. elegans physiological functions.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Plasticizer, Metabolism, Reproduction, Toxicity, Longevity
National Category
Environmental Sciences
Identifiers
urn:nbn:se:oru:diva-62890 (URN)10.1016/j.chemosphere.2017.09.123 (DOI)000414881600041 ()29020644 (PubMedID)2-s2.0-85030660035 (Scopus ID)
Funder
Swedish Research Council, 201504600Knowledge Foundation, 20140180 20150084
Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2018-01-12Bibliographically approved
Zhang, D., Asnake, S., Zhang, J., Olsson, P.-E. & Zhao, G. (2018). Discovery of novel 5-methyl-1H-pyrazole derivatives as potential anti-prostate cancer agents: design, synthesis, molecular modeling and biological evaluation. Chemical Biology and Drug Design, 91(6), 1113-1124
Open this publication in new window or tab >>Discovery of novel 5-methyl-1H-pyrazole derivatives as potential anti-prostate cancer agents: design, synthesis, molecular modeling and biological evaluation
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2018 (English)In: Chemical Biology and Drug Design, ISSN 1747-0277, E-ISSN 1747-0285, Vol. 91, no 6, p. 1113-1124Article in journal (Refereed) Published
Abstract [en]

Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl-1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide. A13 and A14 also showed improved metabolic stability comparing with 10e in human liver microsomes.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
androgen receptor, AR antagonist, luciferase reporter gene assay, prostate cancer, pyrazole derivative
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:oru:diva-64844 (URN)10.1111/cbdd.13173 (DOI)000431974400006 ()29388326 (PubMedID)2-s2.0-85042562810 (Scopus ID)
Note

Funding Agency:

National Natural Science Foundation of China  21272140

Available from: 2018-02-07 Created: 2018-02-07 Last updated: 2018-08-20Bibliographically approved
Pradhan, A. & Olsson, P.-E. (2018). Germ cell depletion in zebrafish leads to incomplete masculinization of the brain. General and Comparative Endocrinology, 265(SI), 15-21
Open this publication in new window or tab >>Germ cell depletion in zebrafish leads to incomplete masculinization of the brain
2018 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 265, no SI, p. 15-21Article in journal (Refereed) Published
Abstract [en]

Zebrafish sex differentiation is under the control of multiple genes, but also relies on germ cell number for gonadal development. Morpholino and chemical mediated germ cell depletion leads to sterile male development in zebrafish. In this study we produced sterile males, using a dead end gene morpholino, to determine gonadal-brain interactions. Germ cell depletion following dnd inhibition downregulated the germ cell markers, vasa and ziwi, and later the larvae developed as sterile males. Despite lacking proper testis, the gonadal 11-ketotestosterone (11-KT) and estradiol (E2) levels of sterile males were similar to wild type males. Qualitative analysis of sexual behavior of sterile males demonstrated that they behaved like wild type males. Furthermore, we observed that brain 11-KT and E2 levels in sterile males remained the same as in the wild type males. In female brain, 11-KT was lower in comparison to wild type males and sterile males, while E2 was higher when compared to wild type males. qRT-PCR analysis revealed that the liver transcript profile of sterile adult males was similar to wild type males while the brain transcript profile was similar to wild type females. The results demonstrate that proper testis development may not be a prerequisite for male brain development in zebrafish but that it may be needed to fully masculinize the brain.

Place, publisher, year, edition, pages
Academic Press, 2018
Keywords
Dimorphism, Gonads, Reproduction, Sex differentiation, Steroid hormone
National Category
Developmental Biology
Identifiers
urn:nbn:se:oru:diva-68509 (URN)10.1016/j.ygcen.2018.02.001 (DOI)000442712600003 ()29408375 (PubMedID)2-s2.0-85044373533 (Scopus ID)
Funder
Swedish Research Council
Note

Funding Agency:

Örebro University 

Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2018-09-06Bibliographically approved
Saju, J. M., Hossain, M. S., Liew, W. C., Pradhan, A., Thevasagayam, N. M., Tan, L. S., . . . Orban, L. (2018). Heat Shock Factor 5 Is Essential for Spermatogenesis in Zebrafish. Cell reports, 25(12), 3252-3261
Open this publication in new window or tab >>Heat Shock Factor 5 Is Essential for Spermatogenesis in Zebrafish
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2018 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 25, no 12, p. 3252-3261Article in journal (Refereed) Published
Abstract [en]

Heat shock factors (Hsfs) are transcription factors that regulate responses to heat shock and other environmental stimuli. Four heat shock factors (Hsf1-4) have been characterized from vertebrates to date. In addition to stress response, they also play important roles in development and gametogenesis. Here, we study the fifth member of heat shock factor family, Hsf5, using zebrafish as a model organism. Mutant hsf5(-/-) males, generated by CRISPR/Cas9 technique, were infertile with drastically reduced sperm count, increased sperm head size, and abnormal tail architecture, whereas females remained fertile. We show that Hsf5 is required for progression through meiotic prophase 1 during spermatogenesis as suggested by the accumulation of cells in the leptotene and zygotene-pachytene stages and increased apoptosis in post-meiotic cells. hsf5(-/-) mutants show gonadal misregulation of a substantial number of genes with roles in cell cycle, apoptosis, protein modifications, and signal transduction, indicating an important role of Hsf5 in early stages of spermatogenesis.

Place, publisher, year, edition, pages
Cell Press, 2018
National Category
Cell Biology
Identifiers
urn:nbn:se:oru:diva-71238 (URN)10.1016/j.celrep.2018.11.090 (DOI)000453826600003 ()30566854 (PubMedID)2-s2.0-85058181011 (Scopus ID)
Funder
Knowledge Foundation
Note

Funding Agencies:

National Research Foundation, Prime Minister's Office, Singapore under its Competitive Research Programme  NRF-CRP7-2010-001 

National Research, Development and Innovation Office of Hungary through its Frontline Research Grant  KKP 126764 

Temasek Life Sciences Laboratory  

Örebro University 

Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-09Bibliographically approved
Porseryd, T., Caspillo, N. R., Volkova, K., Elabbas, L., Källman, T., Dinnetz, P., . . . Porsch-Hallstrom, I. (2018). Testis transcriptome alterations in zebrafish (Danio rerio) with reduced fertility due to developmental exposure to 17 alpha-ethinyl estradiol. General and Comparative Endocrinology, 262, 44-58
Open this publication in new window or tab >>Testis transcriptome alterations in zebrafish (Danio rerio) with reduced fertility due to developmental exposure to 17 alpha-ethinyl estradiol
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2018 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 262, p. 44-58Article in journal (Refereed) Published
Abstract [en]

17 alpha-Ethinylestradiol (EE2) is a ubiquitous aquatic contaminant shown to decrease fish fertility at low concentrations, especially in fish exposed during development. The mechanisms of the decreased fertility are not fully understood. In this study, we perform transcriptome analysis by RNA sequencing of testes from zebrafish with previously reported lowered fertility due to exposure to low concentrations of EE2 during development. Fish were exposed to 1.2 and 1.6 ng/L (measured concentration; nominal concentrations 3 and 10 ng/L) of EE2 from fertilization to 80 days of age, followed by 82 days of remediation in clean water. RNA sequencing analysis revealed 249 and 16 genes to be differentially expressed after exposure to 1.2 and 1.6 ng/L, respectively; a larger inter-sample variation was noted in the latter. Expression of 11 genes were altered by both exposures and in the same direction. The coding sequences most affected could be categorized to the putative functions cell signalling, proteolysis, protein metabolic transport and lipid metabolic process. Several homeobox transcription factors involved in development and differentiation showed increased expression in response to EE2 and differential expression of genes related to cell death, differentiation and proliferation was observed. In addition, several genes related to steroid synthesis, testis development and function were differentially expressed. A number of genes associated with spermatogenesis in zebrafish and/or mouse were also found to be differentially expressed. Further, differences in non-coding sequences were observed, among them several differentially expressed miRNA that might contribute to testis gene regulation at post-transcriptional level. This study has generated insights of changes in gene expression that accompany fertility alterations in zebrafish males that persist after developmental exposure to environmental relevant concentrations of EE2 that persist followed by clean water to adulthood. Hopefully, this will generate hypotheses to test in search for mechanistic explanations.

Place, publisher, year, edition, pages
Academic Press, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:oru:diva-66918 (URN)10.1016/j.ygcen.2018.03.011 (DOI)000430995100006 ()29526718 (PubMedID)2-s2.0-85044314644 (Scopus ID)
Note

Funding Agencies:

Swedish Baltic Sea Foundation  1556/42/2011 

Stockholm County Council  806/3.1.1/2014 

National Genomics Infrastructure (NGI)  

RFI/VR  

Science for Life Laboratory, Sweden  

Available from: 2018-05-15 Created: 2018-05-15 Last updated: 2018-05-15Bibliographically approved
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