Publications by authors named "Adil Mardinoglu"

124 Publications

iNetModels 2.0: an interactive visualization and database of multi-omics data.

Nucleic Acids Res 2021 Apr 13. Epub 2021 Apr 13.

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm SE-171 21, Sweden.

It is essential to reveal the associations between various omics data for a comprehensive understanding of the altered biological process in human wellness and disease. To date, very few studies have focused on collecting and exhibiting multi-omics associations in a single database. Here, we present iNetModels, an interactive database and visualization platform of Multi-Omics Biological Networks (MOBNs). This platform describes the associations between the clinical chemistry, anthropometric parameters, plasma proteomics, plasma metabolomics, as well as metagenomics for oral and gut microbiome obtained from the same individuals. Moreover, iNetModels includes tissue- and cancer-specific Gene Co-expression Networks (GCNs) for exploring the connections between the specific genes. This platform allows the user to interactively explore a single feature's association with other omics data and customize its particular context (e.g. male/female specific). The users can also register their data for sharing and visualization of the MOBNs and GCNs. Moreover, iNetModels allows users who do not have a bioinformatics background to facilitate human wellness and disease research. iNetModels can be accessed freely at https://inetmodels.com without any limitation.
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http://dx.doi.org/10.1093/nar/gkab254DOI Listing
April 2021

Multi-omics approaches for revealing the complexity of cardiovascular disease.

Brief Bioinform 2021 Mar 17. Epub 2021 Mar 17.

Centre for Host-Microbiome Interactions, King's College London and also works as a group leader in Science for Life Laboratory, KTH Royal Institute of Technology.

The development and progression of cardiovascular disease (CVD) can mainly be attributed to the narrowing of blood vessels caused by atherosclerosis and thrombosis, which induces organ damage that will result in end-organ dysfunction characterized by events such as myocardial infarction or stroke. It is also essential to consider other contributory factors to CVD, including cardiac remodelling caused by cardiomyopathies and co-morbidities with other diseases such as chronic kidney disease. Besides, there is a growing amount of evidence linking the gut microbiota to CVD through several metabolic pathways. Hence, it is of utmost importance to decipher the underlying molecular mechanisms associated with these disease states to elucidate the development and progression of CVD. A wide array of systems biology approaches incorporating multi-omics data have emerged as an invaluable tool in establishing alterations in specific cell types and identifying modifications in signalling events that promote disease development. Here, we review recent studies that apply multi-omics approaches to further understand the underlying causes of CVD and provide possible treatment strategies by identifying novel drug targets and biomarkers. We also discuss very recent advances in gut microbiota research with an emphasis on how diet and microbial composition can impact the development of CVD. Finally, we present various biological network analyses and other independent studies that have been employed for providing mechanistic explanation and developing treatment strategies for end-stage CVD, namely myocardial infarction and stroke.
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http://dx.doi.org/10.1093/bib/bbab061DOI Listing
March 2021

Systematic analysis of gut microbiome reveals the role of bacterial folate and homocysteine metabolism in Parkinson's disease.

Cell Rep 2021 Mar;34(9):108807

Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK; Science for Life Laboratory (SciLifeLab), KTH - Royal Institute of Technology, Tomtebodavägen 23, 171 65 Solna, Stockholm, Sweden. Electronic address:

Parkinson's disease (PD) is the most common progressive neurological disorder compromising motor functions. However, nonmotor symptoms, such as gastrointestinal (GI) dysfunction, precede those affecting movement. Evidence of an early involvement of the GI tract and enteric nervous system highlights the need for better understanding of the role of gut microbiota in GI complications in PD. Here, we investigate the gut microbiome of patients with PD using metagenomics and serum metabolomics. We integrate these data using metabolic modeling and construct an integrative correlation network giving insight into key microbial species linked with disease severity, GI dysfunction, and age of patients with PD. Functional analysis reveals an increased microbial capability to degrade mucin and host glycans in PD. Personalized community-level metabolic modeling reveals the microbial contribution to folate deficiency and hyperhomocysteinemia observed in patients with PD. The metabolic modeling approach could be applied to uncover gut microbial metabolic contributions to PD pathophysiology.
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http://dx.doi.org/10.1016/j.celrep.2021.108807DOI Listing
March 2021

Seroprevalence of coronavirus disease 2019 (COVID-19) among health care workers from three pandemic hospitals of Turkey.

PLoS One 2021 3;16(3):e0247865. Epub 2021 Mar 3.

Genomic Laboratory (GLAB), Umraniye Teaching and Research Hospital, University of Health Sciences, Istanbul, Turkey.

COVID-19 is a global threat with an increasing number of infections. Research on IgG seroprevalence among health care workers (HCWs) is needed to re-evaluate health policies. This study was performed in three pandemic hospitals in Istanbul and Kocaeli. Different clusters of HCWs were screened for SARS-CoV-2 infection. Seropositivity rate among participants was evaluated by chemiluminescent microparticle immunoassay. We recruited 813 non-infected and 119 PCR-confirmed infected HCWs. Of the previously undiagnosed HCWs, 22 (2.7%) were seropositive. Seropositivity rates were highest for cleaning staff (6%), physicians (4%), nurses (2.2%) and radiology technicians (1%). Non-pandemic clinic (6.4%) and ICU (4.3%) had the highest prevalence. HCWs in "high risk" group had similar seropositivity rate with "no risk" group (2.9 vs 3.5 p = 0.7). These findings might lead to the re-evaluation of infection control and transmission dynamics in hospitals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247865PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928442PMC
March 2021

Spatiotemporal dissection of the cell cycle with single-cell proteogenomics.

Nature 2021 02 24;590(7847):649-654. Epub 2021 Feb 24.

Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden.

The cell cycle, over which cells grow and divide, is a fundamental process of life. Its dysregulation has devastating consequences, including cancer. The cell cycle is driven by precise regulation of proteins in time and space, which creates variability between individual proliferating cells. To our knowledge, no systematic investigations of such cell-to-cell proteomic variability exist. Here we present a comprehensive, spatiotemporal map of human proteomic heterogeneity by integrating proteomics at subcellular resolution with single-cell transcriptomics and precise temporal measurements of individual cells in the cell cycle. We show that around one-fifth of the human proteome displays cell-to-cell variability, identify hundreds of proteins with previously unknown associations with mitosis and the cell cycle, and provide evidence that several of these proteins have oncogenic functions. Our results show that cell cycle progression explains less than half of all cell-to-cell variability, and that most cycling proteins are regulated post-translationally, rather than by transcriptomic cycling. These proteins are disproportionately phosphorylated by kinases that regulate cell fate, whereas non-cycling proteins that vary between cells are more likely to be modified by kinases that regulate metabolism. This spatially resolved proteomic map of the cell cycle is integrated into the Human Protein Atlas and will serve as a resource for accelerating molecular studies of the human cell cycle and cell proliferation.
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http://dx.doi.org/10.1038/s41586-021-03232-9DOI Listing
February 2021

Targeted Gene Candidates for Treatment and Early Diagnosis of Age-Related Macular Degeneration.

Biomed Res Int 2021 2;2021:6620900. Epub 2021 Feb 2.

Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey.

Age-related macular degeneration (AMD) is an eye disease that impairs the sharp and central vision need for daily activities. Recent advances in molecular biology research not only lead to a better understanding of the genetics and pathophysiology of AMD but also to the development of applications based on targeted gene expressions to treat the disease. Clarification of molecular pathways that causing to development and progression in dry and wet types of AMD needs comprehensive and comparative investigations in particular precious biopsies involving peripheral blood samples from the patients. Therefore, in this investigation, dry and wet types of AMD patients and healthy individuals were aimed at investigating in regard to targeted gene candidates by using gene expression analysis for the first time. 13 most potent candidate genes involved in neurodegeneration were selected via in silico approach and investigated through gene expression analysis to suggest new targets for disease therapy. For the analyses, 30 individuals (10 dry and 10 wet types AMD patients and 10 healthy people) were involved in the study. SYBR-Green based Real-Time PCR analysis was performed on isolated peripheral blood mononuclear cells (PBMCs) to analyze differentially expressed genes related to these cases. According to the investigations, only the gene was found to be upregulated for both dry and wet disease types. When the downregulated genes were analyzed, it was found that 11 genes were commonly decreased for both dry and wet types in the aspect of expression pattern. From these genes, , , , and were found to have the most downregulated gene expression properties for both diseases. From these results, it might be concluded that these common upregulated and downregulated genes could be used as targets for early diagnosis and treatment for AMD.
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http://dx.doi.org/10.1155/2021/6620900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872763PMC
February 2021

Acute kidney injury leading to CKD is associated with a persistence of metabolic dysfunction and hypertriglyceridemia.

iScience 2021 Feb 9;24(2):102046. Epub 2021 Jan 9.

Renal Sciences, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, SE5 9NU London, UK.

Fibrosis is the pathophysiological hallmark of progressive chronic kidney disease (CKD). The kidney is a highly metabolically active organ, and it has been suggested that disruption in its metabolism leads to renal fibrosis. We developed a longitudinal mouse model of acute kidney injury leading to CKD and an model of epithelial to mesenchymal transition to study changes in metabolism, inflammation, and fibrosis. Using transcriptomics, metabolic modeling, and serum metabolomics, we observed sustained fatty acid metabolic dysfunction in the mouse model from early to late stages of CKD. Increased fatty acid biosynthesis and downregulation of catabolic pathways for triglycerides and diacylglycerides were associated with a marked increase in these lipids in the serum. We therefore suggest that the kidney may be the source of the abnormal lipid profile seen in patients with CKD, which may provide insights into the association between CKD and cardiovascular disease.
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http://dx.doi.org/10.1016/j.isci.2021.102046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843454PMC
February 2021

A Resilient Health System in Response to Coronavirus Disease 2019: Experiences of Turkey.

Front Public Health 2020;8:577021. Epub 2021 Jan 7.

Ministry of Health (Turkey), Ankara, Turkey.

Turkey's response experience thus far with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic affords the globe and the region a unique opportunity for and distinctive insights into combating this novel virus. The country's pandemic response, having one of the lowest case fatality ratio (2.8%; 52.5 infections/million population), particularly among the elderly (the high-risk group), rising to the occasion to shoulder its long-standing role in global solidarity and humanitarian support by providing personal protective equipment (globally scarce) to many countries in their desperate time of fight against the pandemic while also meeting its own critical domestic needs, stands out. This paper aims to highlight key decisions, actions, and partnerships behind Turkey's successful fight against the SARS-CoV-2 pandemic that have enabled the country to turn the corner, as well as the components of its success story.
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http://dx.doi.org/10.3389/fpubh.2020.577021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817944PMC
February 2021

Editorial: Redox Homeostasis and Cancer.

Oxid Med Cell Longev 2020 18;2020:5487381. Epub 2020 Dec 18.

Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

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http://dx.doi.org/10.1155/2020/5487381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803288PMC
December 2020

Discovery of Functional Alternatively Spliced Transcripts in Human Cancers.

Cancers (Basel) 2021 Jan 19;13(2). Epub 2021 Jan 19.

Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17165 Stockholm, Sweden.

Pyruvate kinase muscle type () is a key enzyme in glycolysis and plays an important oncological role in cancer. However, the association of expression and the survival outcome of patients with different cancers is controversial. We employed systems biology methods to reveal prognostic value and potential biological functions of transcripts in different human cancers. Protein products of transcripts were shown and detected by western blot and mass spectrometry analysis. We focused on different transcripts of and investigated the associations between their mRNA expression and the clinical survival of the patients in 25 different cancers. We find that the transcripts encoding PKM2 and three previously unstudied transcripts, namely ENST00000389093, ENST00000568883, and ENST00000561609, exhibited opposite prognostic indications in different cancers. Moreover, we validated the prognostic effect of these transcripts in an independent kidney cancer cohort. Finally, we revealed that ENST00000389093 and ENST00000568883 possess pyruvate kinase enzymatic activity and may have functional roles in metabolism, cell invasion, and hypoxia response in cancer cells. Our study provided a potential explanation to the controversial prognostic indication of , and could invoke future studies focusing on revealing the biological and oncological roles of these alternative spliced variants of .
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http://dx.doi.org/10.3390/cancers13020348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835739PMC
January 2021

Glycyl-L-Prolyl-L-Glutamate Pseudotripeptides for Treatment of Alzheimer's Disease.

Biomolecules 2021 Jan 19;11(1). Epub 2021 Jan 19.

Science for Life Laboratory, KTH-Royal Institute of Technology, 24075 Stockholm, Sweden.

So far, there is no effective disease-modifying therapies for Alzheimer's Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.
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http://dx.doi.org/10.3390/biom11010126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835747PMC
January 2021

Low Shear Stress Increases Recombinant Protein Production and High Shear Stress Increases Apoptosis in Human Cells.

iScience 2020 Nov 7;23(11):101653. Epub 2020 Oct 7.

KTH - Cell Technology Group (CETEG), Department of Industrial Biotechnology, 106 91, Stockholm, Sweden.

Human embryonic kidney cells HEK293 can be used for the production of therapeutic glycoproteins requiring human post-translational modifications. High cell density perfusion processes are advantageous for such production but are challenging due to the shear sensitivity of HEK293 cells. To understand the impact of hollow filter cell separation devices, cells were cultured in bioreactors operated with tangential flow filtration (TFF) or alternating tangential flow filtration (ATF) at various flow rates. The average theoretical velocity profile in these devices showed a lower shear stress for ATF by a factor 0.637 compared to TFF. This was experimentally validated and, furthermore, transcriptomic evaluation provided insights into the underlying cellular processes. High shear caused cellular stress leading to apoptosis by three pathways, i.e. endoplasmic reticulum stress, cytoskeleton reorganization, and extrinsic signaling pathways. Positive effects of mild shear stress were observed, with increased recombinant erythropoietin production and increased gene expression associated with transcription and protein phosphorylation.
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http://dx.doi.org/10.1016/j.isci.2020.101653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593556PMC
November 2020

Potential Anticancer Effect of Carvacrol Codrugs on Human Glioblastoma Cells.

Curr Drug Deliv 2020 Oct 27. Epub 2020 Oct 27.

Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum. Turkey.

Background: Essential oils are considered as promising sources of novel anticancer compounds. Carvacrol (CVC), the major constituent of many aromatic plants including oregano and thymus, is endowed with curative properties on different cancers including liver, colon, and lung. Little information is available regarding the potentials of CVC for the treatment of brain cancers, notably glioblastoma multiforme (GBM).

Objective: In this work, we investigated, the in vitro effect of CVC codrugs (CVC1-8), synthesized by direct-coupled codrug strategies, on human glioblastoma cell line (U87-MG) for the first time.

Method: Cell viability was detected by MTT and LDH assays while expression levels of important genes (such as EGFR, NFKB1A, AKT1, AKT2, and others) associated with GBM and inflammatory pathway were detected by PCR array.

Results: Results showed that CVC1-8 codrugs induced cytotoxicity and positive alterations in molecular responses on U87MG cells. Particularly, important pathways (such as PI3K/PTEN/AKT) involved in the onset and progression of GBM resulted in modulated by CVC3 and CVC8.

Conclusion: Our results suggest that CVC3 and CVC8 could be suitable candidates for further investigation to develop new strategies for the prevention and/or treatment of GBM.
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http://dx.doi.org/10.2174/1567201817666201027123424DOI Listing
October 2020

Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning.

Cancers (Basel) 2020 Sep 21;12(9). Epub 2020 Sep 21.

Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden.

Modern drug discovery through de novo drug discovery entails high financial costs, low success rates, and lengthy trial periods. Drug repositioning presents a suitable approach for overcoming these issues by re-evaluating biological targets and modes of action of approved drugs. Coupling high-throughput technologies with genome-wide essentiality screens, network analysis, genome-scale metabolic modeling, and machine learning techniques enables the proposal of new drug-target signatures and uncovers unanticipated modes of action for available drugs. Here, we discuss the current issues associated with drug repositioning in light of curated high-throughput multi-omic databases, genome-wide screening technologies, and their application in systems biology/medicine approaches.
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http://dx.doi.org/10.3390/cancers12092694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563533PMC
September 2020

Safety Assessments of Nickel Boride Nanoparticles on the Human Pulmonary Alveolar Cells by Using Cell Viability and Gene Expression Analyses.

Biol Trace Elem Res 2020 Sep 9. Epub 2020 Sep 9.

Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK.

Nickel boride is generally used in the steel industry as a melting accelerator due to its feature of creating a protective and stable attribute at high temperatures. It is also used to improve the hardenability of the steel with boron addition in the production. Thus, safety studies and biocompatibility analysis of nickel boride should be performed comprehensively to understand the limitations of use in various areas. In the present study, nickel boride nanoparticles (NiB NPs) were synthesized by a single-step method and molecule characterizations were performed via the use of X-ray diffraction analysis (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and energy dispersive X-ray (EDX) analyses. Cytotoxicity properties of NiB NPs were identified on human pulmonary alveolar epithelial cells (HPAEpiC) by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR), and lactate dehydrogenase (LDH) assays. Illumina human ht-12 v4.0 whole-genome microarray analysis was conducted to investigate NiB NPs effects on gene expression regulations of HPAEpiC cells. The database for annotation, visualization, and integrated discovery (DAVID) analysis was performed to reveal the relationship between NiB NP application and cellular pathway alterations. According to cytotoxicity analysis, the IC value for NiB NP application was found as 81.99 mg/L concentration. Microarray analysis of NiB NP application was shown for the first time that 693 gene expression changes (FC ≥ 2) occurred significantly over 40.000 gene probes and NiB NPs were observed to affect microtubule regulation, centrosome organization, and phosphoprotein synthesis.
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http://dx.doi.org/10.1007/s12011-020-02374-7DOI Listing
September 2020

Drug Repositioning for P-Glycoprotein Mediated Co-Expression Networks in Colorectal Cancer.

Front Oncol 2020 13;10:1273. Epub 2020 Aug 13.

Department of Bioengineering, Istanbul Medeniyet University, Istanbul, Turkey.

Colorectal cancer (CRC) is one of the most fatal types of cancers that is seen in both men and women. CRC is the third most common type of cancer worldwide. Over the years, several drugs are developed for the treatment of CRC; however, patients with advanced CRC can be resistant to some drugs. P-glycoprotein (P-gp) (also known as Multidrug Resistance 1, MDR1) is a well-identified membrane transporter protein expressed by ABCB1 gene. The high expression of MDR1 protein found in several cancer types causes chemotherapy failure owing to efflux drug molecules out of the cancer cell, decreases the drug concentration, and causes drug resistance. As same as other cancers, drug-resistant CRC is one of the major obstacles for effective therapy and novel therapeutic strategies are urgently needed. Network-based approaches can be used to determine specific biomarkers, potential drug targets, or repurposing approved drugs in drug-resistant cancers. Drug repositioning is the approach for using existing drugs for a new therapeutic purpose; it is a highly efficient and low-cost process. To improve current understanding of the MDR-1-related drug resistance in CRC, we explored gene co-expression networks around ABCB1 gene with different network sizes (50, 100, 150, 200 edges) and repurposed candidate drugs targeting the ABCB1 gene and its co-expression network by using drug repositioning approach for the treatment of CRC. The candidate drugs were also assessed by using molecular docking for determining the potential of physical interactions between the drug and MDR1 protein as a drug target. We also evaluated these four networks whether they are diagnostic or prognostic features in CRC besides biological function determined by functional enrichment analysis. Lastly, differentially expressed genes of drug-resistant (i.e., oxaliplatin, methotrexate, SN38) HT29 cell lines were found and used for repurposing drugs with reversal gene expressions. As a result, it is shown that all networks exhibited high diagnostic and prognostic performance besides the identification of various drug candidates for drug-resistant patients with CRC. All these results can shed light on the development of effective diagnosis, prognosis, and treatment strategies for drug resistance in CRC.
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http://dx.doi.org/10.3389/fonc.2020.01273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438820PMC
August 2020

Integration of molecular profiles in a longitudinal wellness profiling cohort.

Nat Commun 2020 09 8;11(1):4487. Epub 2020 Sep 8.

Science for Life Laboratory, Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.

An important aspect of precision medicine is to probe the stability in molecular profiles among healthy individuals over time. Here, we sample a longitudinal wellness cohort with 100 healthy individuals and analyze blood molecular profiles including proteomics, transcriptomics, lipidomics, metabolomics, autoantibodies and immune cell profiling, complemented with gut microbiota composition and routine clinical chemistry. Overall, our results show high variation between individuals across different molecular readouts, while the intra-individual baseline variation is low. The analyses show that each individual has a unique and stable plasma protein profile throughout the study period and that many individuals also show distinct profiles with regards to the other omics datasets, with strong underlying connections between the blood proteome and the clinical chemistry parameters. In conclusion, the results support an individual-based definition of health and show that comprehensive omics profiling in a longitudinal manner is a path forward for precision medicine.
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http://dx.doi.org/10.1038/s41467-020-18148-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479148PMC
September 2020

Anticancer effects of novel NSAIDs derivatives on cultured human glioblastoma cells.

Z Naturforsch C J Biosci 2020 Sep 4. Epub 2020 Sep 4.

Department of Pharmacology, G. D'Annunzio University, Chieti, Italy.

Several epidemiologic, clinical and experimental reports indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) could have a potential as anticancer agents. The aim of this study was the evaluation of cytotoxic potential in human glioblastoma cells of novel synthesized NSAID derivatives, obtained by linking, through a spacer, α-lipoic acid (ALA) to anti-inflammatory drugs, such as naproxen (AL-3, 11 and 17), flurbiprofen (AL-6, 13 and 19) and ibuprofen (AL-9, 15 and 21). The effects on the level of gene expression were also determined using quantitative real-time polymerase chain reaction (qRT-PCR) analysis. According to our results, NSAID derivatives exhibited concentration dependent cytotoxic effects on U87-MG cell line when compared with the control group. Moreover, treatment of the most active compounds (AL-3, AL-6 and AL-9) caused upregulation of tumor suppressor gene PTEN and downregulation of some oncogenes such as AKT1, RAF1 and EGFR. In conclusion, our results revealed that AL-3, AL-6 and AL-9 could be suitable candidates for further investigation to develop new pharmacological strategies for the prevention of cancer.
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http://dx.doi.org/10.1515/znc-2020-0093DOI Listing
September 2020

Systems Biology Approaches to Understand the Host-Microbiome Interactions in Neurodegenerative Diseases.

Front Neurosci 2020 8;14:716. Epub 2020 Jul 8.

Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom.

Neurodegenerative diseases (NDDs) comprise a broad range of progressive neurological disorders with multifactorial etiology contributing to disease pathophysiology. Evidence of the microbiome involvement in the gut-brain axis urges the interest in understanding metabolic interactions between the microbiota and host physiology in NDDs. Systems Biology offers a holistic integrative approach to study the interplay between the different biologic systems as part of a whole, and may elucidate the host-microbiome interactions in NDDs. We reviewed direct and indirect pathways through which the microbiota can modulate the bidirectional communication of the gut-brain axis, and explored the evidence of microbial dysbiosis in Alzheimer's and Parkinson's diseases. As the gut microbiota being strongly affected by diet, the potential approaches to targeting the human microbiota through diet for the stimulation of neuroprotective microbial-metabolites secretion were described. We explored the potential of Genome-scale metabolic models (GEMs) to infer microbe-microbe and host-microbe interactions and to identify the microbiome contribution to disease development or prevention. Finally, a systemic approach based on GEMs and 'omics integration, that would allow the design of sustainable personalized anti-inflammatory diets in NDDs prevention, through the modulation of gut microbiota was described.
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http://dx.doi.org/10.3389/fnins.2020.00716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360858PMC
July 2020

Current Status of COVID-19 Therapies and Drug Repositioning Applications.

iScience 2020 Jul 20;23(7):101303. Epub 2020 Jun 20.

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm 17121, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK. Electronic address:

The rapid and global spread of a new human coronavirus (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Drug repositioning is an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. Here, we review current information concerning the global health issue of COVID-19 including promising approved drugs and ongoing clinical trials for prospective treatment options. In addition, we describe computational approaches to be used in drug repurposing and highlight examples of in silico studies of drug development efforts against SARS-CoV-2.
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http://dx.doi.org/10.1016/j.isci.2020.101303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305759PMC
July 2020

Skeletal Muscle Transcriptomic Comparison between Long-Term Trained and Untrained Men and Women.

Cell Rep 2020 06;31(12):107808

Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Learning, Informatics, Management and Ethics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 141 52 Huddinge, Sweden.

To better understand the health benefits of lifelong exercise in humans, we conduct global skeletal muscle transcriptomic analyses of long-term endurance- (9 men, 9 women) and strength-trained (7 men) humans compared with age-matched untrained controls (7 men, 8 women). Transcriptomic analysis, Gene Ontology, and genome-scale metabolic modeling demonstrate changes in pathways related to the prevention of metabolic diseases, particularly with endurance training. Our data also show prominent sex differences between controls and that these differences are reduced with endurance training. Additionally, we compare our data with studies examining muscle gene expression before and after a months-long training period in individuals with metabolic diseases. This analysis reveals that training shifts gene expression in individuals with impaired metabolism to become more similar to our endurance-trained group. Overall, our data provide an extensive examination of the accumulated transcriptional changes that occur with decades-long training and identify important "exercise-responsive" genes that could attenuate metabolic disease.
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http://dx.doi.org/10.1016/j.celrep.2020.107808DOI Listing
June 2020

Adipose tissue morphology, imaging and metabolomics predicting cardiometabolic risk and family history of type 2 diabetes in non-obese men.

Sci Rep 2020 06 19;10(1):9973. Epub 2020 Jun 19.

The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.

We evaluated the importance of body composition, amount of subcutaneous and visceral fat, liver and heart ectopic fat, adipose tissue distribution and cell size as predictors of cardio-metabolic risk in 53 non-obese male individuals. Known family history of type 2 diabetes was identified in 25 individuals. The participants also underwent extensive phenotyping together with measuring different biomarkers and non-targeted serum metabolomics. We used ensemble learning and other machine learning approaches to identify predictors with considerable relative importance and their intricate interactions. Visceral fat and age were strong individual predictors of ectopic fat accumulation in liver and heart along with markers of lipid oxidation and reduced glucose tolerance. Subcutaneous adipose cell size was the strongest individual predictor of whole-body insulin sensitivity and also a marker of visceral and ectopic fat accumulation. The metabolite 3-MOB along with related branched-chain amino acids demonstrated strong predictability for family history of type 2 diabetes.
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http://dx.doi.org/10.1038/s41598-020-66199-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305301PMC
June 2020

Improvement in the Current Therapies for Hepatocellular Carcinoma Using a Systems Medicine Approach.

Adv Biosyst 2020 06 8;4(6):e2000030. Epub 2020 Apr 8.

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE 17121, Sweden.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death primarily due to the lack of effective targeted therapies. Despite the distinct morphological and phenotypic patterns of HCC, treatment strategies are restricted to relatively homogeneous therapies, including multitargeted tyrosine kinase inhibitors and immune checkpoint inhibitors. Therefore, more effective therapy options are needed to target dysregulated metabolic and molecular pathways in HCC. Integrative genomic profiling of HCC patients provides insight into the most frequently mutated genes and molecular targets, including telomerase reverse transcriptase, the TP53 gene, and the Wnt/β-catenin signaling pathway oncogene (CTNNB1). Moreover, emerging techniques, such as genome-scale metabolic models may elucidate the underlying cancer-specific metabolism, which allows for the discovery of potential drug targets and identification of biomarkers. De novo lipogenesis has been revealed as consistently upregulated since it is required for cell proliferation in all HCC patients. The metabolic network-driven stratification of HCC patients in terms of redox responses, utilization of metabolites, and subtype-specific pathways may have clinical implications to drive the development of personalized medicine. In this review, the current and emerging therapeutic targets in light of molecular approaches and metabolic network-based strategies are summarized, prompting effective treatment of HCC patients.
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http://dx.doi.org/10.1002/adbi.202000030DOI Listing
June 2020

A systems biology approach for studying neurodegenerative diseases.

Drug Discov Today 2020 07 19;25(7):1146-1159. Epub 2020 May 19.

Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK; Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE-17121, Sweden. Electronic address:

Neurodegenerative diseases (NDDs), such as Alzheimer's (AD) and Parkinson's (PD), are among the leading causes of lost years of healthy life and exert a great strain on public healthcare systems. Despite being first described more than a century ago, no effective cure exists for AD or PD. Although extensively characterised at the molecular level, traditional neurodegeneration research remains marred by narrow-sense approaches surrounding amyloid β (Aβ), tau, and α-synuclein (α-syn). A systems biology approach enables the integration of multi-omics data and informs discovery of biomarkers, drug targets, and treatment strategies. Here, we present a comprehensive timeline of high-throughput data collection, and associated biotechnological advancements and computational analysis related to AD and PD. We hereby propose that a philosophical change in the definitions of AD and PD is now needed.
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http://dx.doi.org/10.1016/j.drudis.2020.05.010DOI Listing
July 2020

Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates.

Biomolecules 2020 05 9;10(5). Epub 2020 May 9.

Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden.

Cyclic dipeptides administered by both parenteral and oral routes are suggested as promising candidates for the treatment of neurodegeneration-related pathologies. In this study, we tested Cyclo (His-Pro) isomers (cHP1-4) for their anti-Alzheimer potential using a differentiated human neuroblastoma cell line (SH-SY5Y) as an Alzheimer's disease (AD) experimental model. The SH-SY5Y cell line was differentiated by the application of retinoic acid (RA) to obtain mature neuron-like cells. Amyloid-beta 1-42 () peptides, the main effector in AD, were administered to the differentiated cell cultures to constitute the in vitro disease model. Next, we performed cell viability analyses 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays) to investigate the neuroprotective concentrations of cyclodipeptides using the in vitro AD model. We evaluated acetylcholinesterase (AChE), α- and β-secretase activities (TACE and BACE1), antioxidant potency, and apoptotic/necrotic properties and performed global gene expression analysis to understand the main mechanism behind the neuroprotective features of cHP1-4. Moreover, we conducted sister chromatid exchange (SCE), micronucleus (MN), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) analyses to evaluate the genotoxic damage potential after applications with cHP1-4 on cultured human lymphocytes. Our results revealed that cHP1-4 isomers provide a different degree of neuroprotection against -induced cell death on the in vitro AD model. The applications with cHP1-4 isomers altered the activity of AChE but not the activity of TACE and BACE1. Our analysis indicated that the cHP1-4 increased the total antioxidant capacity without altering total oxidative status levels in the cellular AD model and that cHP1-4 modulated the alterations of gene expressions by exposure. We also observed that cHP1-4 exhibited noncytotoxic and non-genotoxic features in cultured human whole blood cells. In conclusion, cHP1-4 isomers, especially cHP4, have been explored as novel promising therapeutics against AD.
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http://dx.doi.org/10.3390/biom10050737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277666PMC
May 2020

Genome-Scale Metabolic Modeling of Glioblastoma Reveals Promising Targets for Drug Development.

Front Genet 2020 17;11:381. Epub 2020 Apr 17.

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.

Glioblastoma (GBM) is an aggressive type of brain cancer with a poor prognosis for affected patients. The current line of treatment only gives the patients a survival time of on average 15 months. In this work, we use genome-scale metabolic models (GEMs) together with other systems biology tools to examine the global transcriptomics-data of GBM-patients obtained from The Cancer Genome Atlas (TCGA). We reveal the molecular mechanisms underlying GBM and identify potential therapeutic targets for effective treatment of patients. The work presented consists of two main parts. The first part stratifies the patients into two groups, high and low survival, and compares their gene expression. The second part uses GBM and healthy brain tissue GEMs to simulate gene knockout in a GBM cell model to find potential therapeutic targets and predict their side effect in healthy brain tissue. We (1) find that genes upregulated in the patients with low survival are linked to various stages of the glioma invasion process, and (2) identify five essential genes for GBM, whose inhibition is non-toxic to healthy brain tissue, therefore promising to investigate further as therapeutic targets.
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http://dx.doi.org/10.3389/fgene.2020.00381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181968PMC
April 2020

The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alcoholic fatty liver disease.

Mol Syst Biol 2020 04;16(4):e9495

Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, Sweden.

The prevalence of non-alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l-serine, N-acetyl-l-cysteine (NAC), nicotinamide riboside (NR), and l-carnitine by performing a 7-day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome-scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long-term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials.
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http://dx.doi.org/10.15252/msb.209495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184219PMC
April 2020

In vitro neuroprotective effects of farnesene sesquiterpene on alzheimer's disease model of differentiated neuroblastoma cell line.

Int J Neurosci 2020 Apr 19:1-10. Epub 2020 Apr 19.

Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.

To investigate neuroprotective properties of the farnesene sesquiterpene on the experimental Alzheimer's disease model . Human neuroblastoma cell line (SHSY-5Y) was differentiated into neuron-like cells by using retinoic acid to constitute the Alzheimer's Disease model. β-amyloid 1-42 protein was applied to the transformed cells for 24 and 48 hours in a wide dose ranges (3.125-200 μM) to establish AD cytotoxicity. Then, farnesene was applied to cell cultures in a wide spectrum dose interval (1.625-100 μg/ml) to investigate neuroprotective effect against β-amyloid for 24 and 48 hours. 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release tests were executed to determine cytotoxicity in the Alzheimer model. Nuclear DNA integrity of cells was examined under the fluorescent microscope using the Hoechst 33258 staining method. Furthermore, acetylcholinesterase (AChE) activity, total antioxidant capacity (TAC) and total oxidative status (TOS) levels were analyzed to understand the protection mechanism of the farnesene application on the cell culture model. Finally, flow cytometry analysis was used to find out the cell death mechanism after beta-amyloid and farnesene application to the cell culture. Cell viability tests revealed significant neuroprotection against β-amyloid toxicity in both 24 and 48 hours and the Hoechst 33258 fluorescence staining method showed a significant decrease in necrotic deaths after farnesene application in the cell cultures. Finally, flow cytometry analysis put forth that farnesene could decrease necrotic cell death up to 3-fold resulted from beta-amyloid exposure. According to the investigations, farnesene can potentially be a safe, anti-necrotic and neuroprotective agents against Alzheimer's disease.
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http://dx.doi.org/10.1080/00207454.2020.1754211DOI Listing
April 2020

Publisher Correction: MEMOTE for standardized genome-scale metabolic model testing.

Nat Biotechnol 2020 Apr;38(4):504

Science for Life Laboratory, KTH -Royal Institute of Technology, Stockholm, Sweden.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41587-020-0477-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138757PMC
April 2020

The in vitro cytotoxic, genotoxic, and oxidative damage potentials of the oral artificial sweetener aspartame on cultured human blood cells

Turk J Med Sci 2020 04 9;50(2):448-454. Epub 2020 Apr 9.

Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17121, Sweden

Background/aim: Aspartame (APM, L-aspartyl-L-phenylalanine methylester) is a low-calorie, nonsaccharide artificial sweetener widely used in foods and beverages. When metabolized by the body, APM is broken down into aspartic acid, phenylalanine amino acids, and a third substance, methanol. Since the amino acid phenylalanine serves as a neurotransmitter building block affecting the brain, and methanol is converted into toxic formaldehyde, APM has deleterious effects on the body and brain. Thus, its safety and, toxicity have been the subjects of concern ever since it was first discovered. Although many studies have been performed on it, due to the presence of conflicting data in the literature, there are still numerous question marks concerning APM.Therefore, the safety of aspartame was tested using in vitro methods.

Materials And Methods: We aimed to evaluate the in vitro cytotoxic effects by using 3-(4,5-dimetylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release tests, genotoxic damage potential by using chromosome aberration (CA) assay, and antioxidant/oxidant activity by using total antioxidant capacity (TAC) and total oxidative stress (TOS) analysis in primary human whole blood cell cultures.

Results: The results of the MTT test showed that APM led to significant decreases in cell viability in a clear concentration-dependent manner. Moreover, an increase in CA frequency was found in the cells treated with APM. However, APM treatments did not cause any significant changes in TAC and TOS levels in whole blood cultures.

Conclusion: Overall, the obtained results showed that APM had genotoxicity potential and a concentration-dependent cytotoxic activity in human blood cells.
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http://dx.doi.org/10.3906/sag-2001-113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164759PMC
April 2020