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Choi, M. J., Jung, S.-B. -., Lee, S. E., Kang, S. G., Lee, J. H., Ryu, M. J., . . . Shong, M. (2020). An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. Diabetologia
Open this publication in new window or tab >>An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models
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2020 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: Mitochondrial oxidative phosphorylation (OxPhos) is essential for energy production and survival. However, the tissue-specific and systemic metabolic effects of OxPhos function in adipocytes remain incompletely understood. Methods: We used adipocyte-specific Crif1 (also known as Gadd45gip1) knockout (AdKO) mice with decreased adipocyte OxPhos function. AdKO mice fed a normal chow or high-fat diet were evaluated for glucose homeostasis, weight gain and energy expenditure (EE). RNA sequencing of adipose tissues was used to identify the key mitokines affected in AdKO mice, which included fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). For in vitro analysis, doxycycline was used to pharmacologically decrease OxPhos in 3T3L1 adipocytes. To identify the effects of GDF15 and FGF21 on the metabolic phenotype of AdKO mice, we generated AdKO mice with global Gdf15 knockout (AdGKO) or global Fgf21 knockout (AdFKO). Results: Under high-fat diet conditions, AdKO mice were resistant to weight gain and exhibited higher EE and improved glucose tolerance. In vitro pharmacological and in vivo genetic inhibition of OxPhos in adipocytes significantly upregulated mitochondrial unfolded protein response-related genes and secretion of mitokines such as GDF15 and FGF21. We evaluated the metabolic phenotypes of AdGKO and AdFKO mice, revealing that GDF15 and FGF21 differentially regulated energy homeostasis in AdKO mice. Both mitokines had beneficial effects on obesity and insulin resistance in the context of decreased adipocyte OxPhos, but only GDF15 regulated EE in AdKO mice. Conclusions/interpretation: The present study demonstrated that the adipose tissue adaptive mitochondrial stress response affected systemic energy homeostasis via cell-autonomous and non-cell-autonomous pathways. We identified novel roles for adipose OxPhos and adipo-mitokines in the regulation of systemic glucose homeostasis and EE, which facilitated adaptation of an organism to local mitochondrial stress.

Place, publisher, year, edition, pages
Springer, 2020
Keywords
Adipose tissue, Energy metabolism, Insulin resistance, Mitochondria, Mitokine
National Category
Medical Genetics
Identifiers
urn:nbn:se:kth:diva-267995 (URN)10.1007/s00125-019-05082-7 (DOI)000518424800016 ()31925461 (PubMedID)2-s2.0-85077689777 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20200329

Available from: 2020-03-29 Created: 2020-03-29 Last updated: 2020-03-29Bibliographically approved
Sayitoglu, E. C., Georgoudaki, A.-M., Chrobok, M., Ozkazanc, D., Josey, B. J., Arif, M., . . . Duru, A. D. (2020). Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D. Frontiers in Immunology, 11, Article ID 40.
Open this publication in new window or tab >>Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D
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2020 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 11, article id 40Article in journal (Refereed) Published
Abstract [en]

Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but this has not been thoroughly explored in the context of sarcoma immunotherapy. In this study, we investigated the NK cell receptor/ligand immune profile of primary human sarcoma explants. Analysis of tumors from 32 sarcoma patients identified the proliferative marker PCNA and DNAM-1 ligands CD112 and/or CD155 as commonly expressed antigens that could be efficiently targeted by genetically modified (GM) NK cells. Despite the strong expression of CD112 and CD155 on sarcoma cells, characterization of freshly dissociated sarcomas revealed a general decrease in tumor-infiltrating NK cells compared to the periphery, suggesting a defect in the endogenous NK cell response. We also applied a functional screening approach to identify relevant NK cell receptor/ligand interactions that induce efficient anti-tumor responses using a panel NK-92 cell lines GM to over-express 12 different activating receptors. Using GM NK-92 cells against primary sarcoma explants (n = 12) revealed that DNAM-1 over-expression on NK-92 cells led to efficient degranulation against all tested explants (n = 12). Additionally, NKG2D over-expression showed enhanced responses against 10 out of 12 explants. These results show that DNAM-1(+) or NKG2D(+) GM NK-92 cells may be an efficient approach in targeting sarcomas. The degranulation capacity of GM NK-92 cell lines was also tested against various established tumor cell lines, including neuroblastoma, Schwannoma, melanoma, myeloma, leukemia, prostate, pancreatic, colon, and lung cancer. Enhanced degranulation of DNAM-1(+) or NKG2D(+) GM NK-92 cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1(+) or NKG2D(+) GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2020
Keywords
cancer immunotherapy, cancer immunology, sarcoma, natural killer (NK) cell, DNAM-1 (CD226), NKG2D (Natural killer group 2 member D), NK-92 cell line
National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-269481 (URN)10.3389/fimmu.2020.00040 (DOI)000514603100001 ()32082316 (PubMedID)2-s2.0-85079487408 (Scopus ID)
Note

QC 20200309

Available from: 2020-03-09 Created: 2020-03-09 Last updated: 2020-03-09Bibliographically approved
Pagoni, A., Marinelli, L., Di Stefano, A., Ciulla, M., Turkez, H., Mardinoglu, A., . . . Cacciatore, I. (2020). Novel anti-Alzheimer phenol-lipoyl hybrids: Synthesis, physico-chemical characterization, and biological evaluation. European Journal of Medicinal Chemistry, 186, Article ID 111880.
Open this publication in new window or tab >>Novel anti-Alzheimer phenol-lipoyl hybrids: Synthesis, physico-chemical characterization, and biological evaluation
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2020 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 186, article id 111880Article in journal (Refereed) Published
Abstract [en]

To date, drugs that hit a single target are inadequate for the treatment of neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases. The development of multitarget ligands, able to interact with the different pathways involved in the progession of these disorders, represents a great challenge for medicinal chemists. In this context, we report here the synthesis and biological evaluation of phenol-lipoyl hybrids (SV1-13), obtained via a linking strategy, to take advantage of the synergistic effect due to the antioxidant portions and anti-amyloid properties of the single constituents present in the hybrid molecule. Biological results showed that SV5 and SV10 possessed the best protective activity against Aβ1-42 induced neurotoxicity in differentiated SH-SY5Y cells. SV9 and SV10 showed remarkable antioxidant properties due to their ability to counteract the damage caused by H2O2 in SHSY-5Y-treated cells. Hovewer, SV5, showing moderate antioxidant and good neuroprotective activities, resulted the best candidate for further experiments since it also resulted stable both simulated and plasma fluids.

Place, publisher, year, edition, pages
Elsevier Masson SAS, 2020
Keywords
Alzheimer's disease, Hybrid, Lipoic acid, Polyphenol
National Category
Basic Medicine
Identifiers
urn:nbn:se:kth:diva-267830 (URN)10.1016/j.ejmech.2019.111880 (DOI)000509616800027 ()31753513 (PubMedID)2-s2.0-85075479242 (Scopus ID)
Note

QC 20200306

Available from: 2020-03-06 Created: 2020-03-06 Last updated: 2020-03-16Bibliographically approved
Uhlén, M., Karlsson, M., Zhong, W., Abdellah, T., Pou, C., Mikes, J., . . . Brodin, P. (2019). A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science, 366(6472), 1471-+, Article ID eaax9198.
Open this publication in new window or tab >>A genome-wide transcriptomic analysis of protein-coding genes in human blood cells
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2019 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 366, no 6472, p. 1471-+, article id eaax9198Article in journal (Refereed) Published
Abstract [en]

Blood is the predominant source for molecular analyses in humans, both in clinical and research settings. It is the target for many therapeutic strategies, emphasizing the need for comprehensive molecular maps of the cells constituting human blood. In this study, we performed a genome-wide transcriptomic analysis of protein-coding genes in sorted blood immune cell populations to characterize the expression levels of each individual gene across the blood cell types. All data are presented in an interactive, open-access Blood Atlas as part of the Human Protein Atlas and are integrated with expression profiles across all major tissues to provide spatial classification of all protein-coding genes. This allows for a genome-wide exploration of the expression profiles across human immune cell populations and all major human tissues and organs.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2019
National Category
Genetics
Identifiers
urn:nbn:se:kth:diva-266527 (URN)10.1126/science.aax9198 (DOI)000503861000045 ()31857451 (PubMedID)2-s2.0-85077091174 (Scopus ID)
Note

QC 20200205

Available from: 2020-02-05 Created: 2020-02-05 Last updated: 2020-03-02Bibliographically approved
Klevstig, M., Arif, M., Mannila, M., Svedlund, S., Mardani, I., Stahlman, M., . . . Boren, J. (2019). Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia. Journal of Molecular and Cellular Cardiology, 137, 1-8
Open this publication in new window or tab >>Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia
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2019 (English)In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 137, p. 1-8Article in journal (Refereed) Published
Abstract [en]

Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. Materials and methods: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. Results: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. Conclusions: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
MTTP, Polymorphism, Heart, Expression, Function
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-266435 (URN)10.1016/j.yjmcc.2019.09.003 (DOI)000502686600001 ()31533023 (PubMedID)2-s2.0-85073149921 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20200115

Available from: 2020-01-15 Created: 2020-01-15 Last updated: 2020-02-18Bibliographically approved
Benfeitas, R., Bidkhori, G., Mukhopadhyay, B., Klevstig, M., Arif, M., Zhang, C., . . . Mardinoglu, A. (2019). Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis. EBioMedicine
Open this publication in new window or tab >>Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964Article in journal (Refereed) Published
National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:kth:diva-248702 (URN)
Note

QC 20190423

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2020-01-10Bibliographically approved
Benfeitas, R., Bidkhori, G., Mukhopadhyay, B., Klevstig, M., Arif, M., Zhang, C., . . . Mardinoglu, A. (2019). Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis. EBioMedicine, 40, 471-487
Open this publication in new window or tab >>Characterization of heterogeneous redox responses in hepatocellular carcinoma patients using network analysis
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 40, p. 471-487Article in journal (Refereed) Published
Abstract [en]

Background: Redox metabolism is often considered a potential target for cancer treatment, but a systematic examination of redox responses in hepatocellular carcinoma (HCC) is missing. Methods: Here, we employed systems biology and biological network analyses to reveal key roles of genes associated with redox metabolism in HCC by integrating multi-omics data. Findings: We found that several redox genes, including 25 novel potential prognostic genes, are significantly co-expressed with liver-specific genes and genes associated with immunity and inflammation. Based on an integrative analysis, we found that HCC tumors display antagonistic behaviors in redox responses. The two HCC groups are associated with altered fatty acid, amino acid, drug and hormone metabolism, differentiation, proliferation, and NADPH-independent vs - dependent antioxidant defenses. Redox behavior varies with known tumor subtypes and progression, affecting patient survival. These antagonistic responses are also displayed at the protein and metabolite level and were validated in several independent cohorts. We finally showed the differential redox behavior using mice transcriptomics in HCC and noncancerous tissues and associated with hypoxic features of the two redox gene groups. Interpretation: Our integrative approaches highlighted mechanistic differences among tumors and allowed the identification of a survival signature and several potential therapeutic targets for the treatment of HCC. (C) 2018 Published by Elsevier B.V.

Keywords
Hepatocellular carcinoma, Redox metabolism, Systems biology, Precision medicine, Cancer, Transcriptomics, Liver cancer
National Category
Physical Sciences
Identifiers
urn:nbn:se:kth:diva-270854 (URN)10.1016/j.ebiom.2018.12.057 (DOI)000460696900057 ()30606699 (PubMedID)
Note

QC 20200316

Available from: 2020-03-16 Created: 2020-03-16 Last updated: 2020-03-16Bibliographically approved
Lundgren, S., Fagerström-Vahman, H., Zhang, C., Ben-Dror, L., Mardinoglu, A., Uhlén, M., . . . Jirström, K. (2019). Discovery of KIRREL as a biomarker for prognostic stratification of patients within melanoma [Letter to the editor]. Biomarker Research
Open this publication in new window or tab >>Discovery of KIRREL as a biomarker for prognostic stratification of patients within melanoma
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2019 (English)In: Biomarker Research, ISSN 0961-088X, E-ISSN 1475-925XArticle in journal, Letter (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-248690 (URN)10.1186/s40364-018-0153-8 (DOI)000455575200001 ()2-s2.0-85062927349 (Scopus ID)
Note

QC 20190425

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2020-03-05Bibliographically approved
Turanli, B., Zhang, C., Kim, W., Benfeitas, R., Uhlén, M., Yalcin Arga, K. & Mardinoglu, A. (2019). Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning. EBioMedicine, 42, 386-396
Open this publication in new window or tab >>Discovery of therapeutic agents for prostate cancer using genome-scale metabolic modeling and drug repositioning
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 42, p. 386-396Article in journal (Refereed) Published
Abstract [sv]

Background: Genome-scale metabolic models (GEMs)offer insights into cancer metabolism and have been used to identify potential biomarkers and drug targets. Drug repositioning is a time- and cost-effective method of drug discovery that can be applied together with GEMs for effective cancer treatment. Methods: In this study, we reconstruct a prostate cancer (PRAD)-specific GEM for exploring prostate cancer metabolism and also repurposing new therapeutic agents that can be used in development of effective cancer treatment. We integrate global gene expression profiling of cell lines with >1000 different drugs through the use of prostate cancer GEM and predict possible drug-gene interactions. Findings: We identify the key reactions with altered fluxes based on the gene expression changes and predict the potential drug effect in prostate cancer treatment. We find that sulfamethoxypyridazine, azlocillin, hydroflumethiazide, and ifenprodil can be repurposed for the treatment of prostate cancer based on an in silico cell viability assay. Finally, we validate the effect of ifenprodil using an in vitro cell assay and show its inhibitory effect on a prostate cancer cell line. Interpretation: Our approach demonstate how GEMs can be used to predict therapeutic agents for cancer treatment based on drug repositioning. Besides, it paved a way and shed a light on the applicability of computational models to real-world biomedical or pharmaceutical problems.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Medical and Health Sciences Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:kth:diva-248689 (URN)10.1016/j.ebiom.2019.03.009 (DOI)000466175100052 ()30905848 (PubMedID)2-s2.0-85063114920 (Scopus ID)
Note

QC 20190424

Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2020-01-10Bibliographically approved
Zhang, C., Aldrees, M., Arif, M., Li, X., Mardinoglu, A. & Aziz, M. A. (2019). Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling. Frontiers in Oncology, 9, Article ID 681.
Open this publication in new window or tab >>Elucidating the Reprograming of Colorectal Cancer Metabolism Using Genome-Scale Metabolic Modeling
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2019 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 9, article id 681Article in journal (Refereed) Published
Abstract [en]

Colorectal cancer is the third most incidental cancer worldwide, and the response rate of current treatment for colorectal cancer is very low. Genome-scale metabolic models (GEMs) are systems biology platforms, and they had been used to assist researchers in understanding the metabolic alterations in different types of cancer. Here, we reconstructed a generic colorectal cancer GEM by merging 374 personalized GEMs from the Human Pathology Atlas and used it as a platform for systematic investigation of the difference between tumor and normal samples. The reconstructed model revealed the metabolic reprogramming in glutathione as well as the arginine and proline metabolism in response to tumor occurrence. In addition, six genes including ODC1, SMS, SRM, RRM2, SMOX, and SAT1 associated with arginine and proline metabolism were found to be key players in this metabolic alteration. We also investigated these genes in independent colorectal cancer patients and cell lines and found that many of these genes showed elevated level in colorectal cancer and exhibited adverse effect in patients. Therefore, these genes could be promising therapeutic targets for treatment of a specific colon cancer patient group.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019
Keywords
colorectal cancer, genome scale metabolic model, polyamine metabolism, personalized medicine, transcriptomics
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:kth:diva-255737 (URN)10.3389/fonc.2019.00681 (DOI)000477876200001 ()2-s2.0-85072220274 (Scopus ID)
Note

QC 20190814

Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-10-04Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-4254-6090

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