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  • 1. Acevedo, Nathalie
    et al.
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Katayama, Shintaro
    Bruhn, Sören
    Andersson, Anna
    Wikberg, Gustav
    Lundeberg, Lena
    Lindvall, Jessica M.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Greco, Dario
    Kere, Juha
    Söderhäll, Cilla
    Scheynius, Annika
    Epigenetic alterations in skin homing CD4(+)CLA(+) T cells of atopic dermatitis patients2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 18020Article in journal (Refereed)
    Abstract [en]

    T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations -(CD4(+), -CD4(+)CD45RA(+) naive, -CD4(+)CLA(+), and -CD8(+)) from adult AD patients and healthy controls (HC). Skin homing -CD4(+)CLA(+) T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in -CD4(+)CLA(+) T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in -CD4(+)CLA(+) T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing -CD4(+)CLA(+) T cells and uncover putative molecules participating in AD pathways.

  • 2. Ambikan, Anoop T.
    et al.
    Svensson-Akusjärvi, Sara
    Krishnan, Shuba
    Sperk, Maike
    Nowak, Piotr
    Vesterbacka, Jan
    Sönnerborg, Anders
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Neogi, Ujjwal
    Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV infection2022In: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, no 9, article id e202201405Article in journal (Refereed)
    Abstract [en]

    Genome-scale metabolic models (GSMMs) can provide novel insights into metabolic reprogramming during disease progression and therapeutic interventions. We developed a context-specific system-level GSMM of people living with HIV (PLWH) using global RNA sequencing data from PBMCs with suppressive viremia either by natural (elite controllers, PLWHEC) or drug-induced (PLWHART) control. This GSMM was compared with HIV-negative controls (HC) to provide a comprehensive systems-level metabo-transcriptomic characterization. Transcriptomic analysis identified up-regulation of oxidative phosphorylation as a characteristic of PLWHART, differentiating them from PLWHEC with dysregulated complexes I, III, and IV. The flux balance analysis identified altered flux in several intermediates of glycolysis including pyruvate, a-ketoglutarate, and glutamate, among others, in PLWHART. The in vitro pharmacological inhibition of OXPHOS complexes in a latent lymphocytic cell model (J-Lat 10.6) suggested a role for complex IV in latency reversal and immunosenescence. Furthermore, inhibition of complexes I/III/IV induced apoptosis, collectively indicating their contribution to reservoir dynamics.

  • 3. Ambikan, Anoop T.
    et al.
    Yang, Hong
    Krishnan, Shuba
    Svensson Akusjarvi, Sara
    Gupta, Soham
    Lourda, Magda
    Sperk, Maike
    Arif, Muhammad
    Zhang, Chenq
    Nordqvist, Hampus
    Ponnan, Sivasankaran Munusamy
    Sonnerborg, Anders
    Treutiger, Carl Johan
    O'Mahony, Liam
    Mardinoglu, Adil
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Neogi, Ujjwal
    Multi-omics personalized network analyses highlight progressive disruption of central metabolism associated with COVID-19 severity2022In: Cell systems, ISSN 2405-4712, Vol. 13, no 8, p. 665-681Article in journal (Refereed)
    Abstract [en]

    The clinical outcome and disease severity in coronavirus disease 2019 (COVID-19) are heterogeneous, and the progression or fatality of the disease cannot be explained by a single factor like age or comorbidities. In this study, we used system-wide network-based system biology analysis using whole blood RNA sequencing, immunophenotyping by flow cytometry, plasma metabolomics, and single-cell-type metabolo-mics of monocytes to identify the potential determinants of COVID-19 severity at personalized and group levels. Digital cell quantification and immunophenotyping of the mononuclear phagocytes indicated a sub-stantial role in coordinating the immune cells that mediate COVID-19 severity. Stratum-specific and person-alized genome-scale metabolic modeling indicated monocarboxylate transporter family genes (e.g., SLC16A6), nucleoside transporter genes (e.g., SLC29A1), and metabolites such as a-ketoglutarate, succi-nate, malate, and butyrate could play a crucial role in COVID-19 severity. Metabolic perturbations targeting the central metabolic pathway (TCA cycle) can be an alternate treatment strategy in severe COVID-19.

  • 4. Appelberg, Sofia
    et al.
    Gupta, Soham
    Svensson Akusjärvi, Sara
    Ambikan, Anoop T.
    Mikaeloff, Flora
    Saccon, Elisa
    Végvári, Ákos
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Sperk, Maike
    Ståhlberg, Marie
    Krishnan, Shuba
    Singh, Kamal
    Penninger, Josef M.
    Mirazimi, Ali
    Neogi, Ujjwal
    Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells2020In: Emerging Microbes & Infections, E-ISSN 2222-1751, Vol. 9, no 1, p. 1748-1760Article in journal (Refereed)
    Abstract [en]

    How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected Huh7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients.

  • 5. Arif, Muhammad
    et al.
    Klevstig, Martina
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Doran, Stephen
    Turkez, Hasan
    Uhlén, Mathias
    Clausen, Maryam
    Wikström, Johannes
    Etal, Damla
    Zhang, Cheng
    Levin, Malin
    Mardinoglu, Adil
    Boren, Jan
    Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction2021In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e66921Article in journal (Refereed)
    Abstract [en]

    Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genomewide transcriptomic analysis on tissue samples obtained 6- and 24 hr post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in two independent MI cohorts. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues.

  • 6. Bauer, Susanne
    et al.
    Dittrich, Lars
    Kaczmarczyk, Lech
    Schleif, Melvin
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Jackson, Walker S.
    Translatome profiling in fatal familial insomnia implicates TOR signaling in somatostatin neurons2022In: Life Science Alliance, E-ISSN 2575-1077, Vol. 5, no 11, article id e202201530Article in journal (Refereed)
    Abstract [en]

    Selective neuronal vulnerability is common in neurodegenerative diseases but poorly understood. In genetic prion diseases, in-cluding fatal familial insomnia (FFI) and Creutzfeldt-Jakob dis-ease (CJD), different mutations in the Prnp gene manifest as clinically and neuropathologically distinct diseases. Here we report with electroencephalography studies that theta waves are mildly increased in 21 mo old knock-in mice modeling FFI and CJD and that sleep is mildy affected in FFI mice. To define affected cell types, we analyzed cell type-specific translatomes from six neuron types of 9 mo old FFI and CJD mice. Somatostatin (SST) neurons responded the strongest in both diseases, with unex-pectedly high overlap in genes and pathways. Functional analyses revealed up-regulation of neurodegenerative disease pathways and ribosome and mitochondria biogenesis, and down-regulation of synaptic function and small GTPase-mediated signaling in FFI, implicating down-regulation of mTOR signaling as the root of these changes. In contrast, responses in glutamatergic cerebellar neurons were disease-specific. The high similarity in SST neurons of FFI and CJD mice suggests that a common therapy may be beneficial for multiple genetic prion diseases.

  • 7. Gelpi, Marco
    et al.
    Mikaeloff, Flora
    Knudsen, Andreas D.
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Krishnan, Shuba
    Svenssson Akusjarvi, Sara
    Hogh, Julie
    Murray, Daniel D.
    Ullum, Henrik
    Neogi, Ujjwal
    Nielsen, Susanne D.
    The central role of the glutamate metabolism in long-term antiretroviral treated HIV-infected individuals with metabolic syndrome2021In: Aging, E-ISSN 1945-4589, Vol. 13, no 19, p. 22732-22751Article in journal (Refereed)
    Abstract [en]

    Metabolic syndrome (MetS) is a significant factor for cardiometabolic comorbidities in people living with HIV (PLWH) and a barrier to healthy aging. The long-term consequences of HIV-infection and combination antiretroviral therapy (cART) in metabolic reprogramming are unknown. In this study, we investigated metabolic alterations in well-treated PLWH with MetS to identify potential mechanisms behind the MetS phenotype using advanced statistical and machine learning algorithms. We included 200 PLWH from the Copenhagen Comorbidity in HIV-infection (COCOMO) study. PLWH were grouped into PLWH with MetS (n = 100) defined according to the International Diabetes Federation (IDF) consensus worldwide definition of the MetS or without MetS (n = 100). The untargeted plasma metabolomics was performed using ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS/MS) and immune-phenotyping of Glut1 (glucose transporter), xCT (glutamate/cysteine transporter) and MCT1 (pyruvate/lactate transporter) by flow cytometry. We applied several conventional approaches, machine learning algorithms, and linear classification models to identify the biologically relevant metabolites associated with MetS in PLWH. Of the 877 identified biochemicals, 9% (76/877) differed significantly between PLWH with and without MetS (false discovery rate < 0.05). The majority belonged to amino acid metabolism (43%). A consensus identification by combining supervised and unsupervised methods indicated 11 biomarkers of MetS phenotype in PLWH. A weighted co-expression network identified seven communities of positively intercorrelated metabolites. A single community contained six of the potential biomarkers mainly related to glutamate metabolism. Transporter expression identified altered xCT and MCT in both lymphocytic and monocytic cells. Combining metabolomics and immune-phenotyping indicated altered glutamate metabolism associated with MetS in PLWH, which has clinical significance.

  • 8. Gunnarsdottir, Frida Björk
    et al.
    Bendahl, Pär-Ola
    Johansson, Alexandra
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Rydén, Lisa
    Bergenfelz, Caroline
    Larsson, Anna-Maria
    Serum immuno-oncology markers carry independent prognostic information in patients with newly diagnosed metastatic breast cancer, from a prospective observational study2023In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 25, article id 29Article in journal (Refereed)
    Abstract [en]

    Background Metastatic breast cancer (MBC) is a challenging disease, and despite new therapies, prognosis is still poor for a majority of patients. There is a clinical need for improved prognostication where immuno-oncology markers can provide important information. The aim of this study was to evaluate serum immuno-oncology markers in MBC patients and their respective relevance for prediction of survival.

    Patients and methods We investigated a broad panel of 92 immuno-oncology proteins in serum from 136 MBC patients included in a prospective observational study (NCT01322893) with long-term follow-up. Serum samples were collected before start of systemic therapy and analyzed using multiplex proximity extension assay (Olink Target 96 Immuno-Oncology panel). Multiple machine learning techniques were used to identify serum markers with highest importance for prediction of overall and progression-free survival (OS and PFS), and associations to survival were further evaluated using Cox regression analyses. False discovery rate was then used to adjust for multiple comparisons.

    Results Using random forest and random survival forest analyses, we identified the top nine and ten variables of highest predictive importance for OS and PFS, respectively. Cox regression analyses revealed significant associations (P < 0.005) of higher serum levels of IL-8, IL-10 and CAIX with worse OS in multivariable analyses, adjusted for established clinical prognostic factors including circulating tumor cells (CTCs). Similarly, high serum levels of IL-8, IL-10, ADA and CASP8 significantly associated with worse PFS. Interestingly, high serum levels of FasL significantly associated with improved OS and PFS. In addition, CSF-1, IL-6, MUC16, TFNSFR4 and CD244 showed suggestive evidence (P < 0.05) for an association to survival in multivariable analyses. After correction for multiple comparisons, IL-8 still showed strong evidence for correlation to survival.

    Conclusion To conclude, we found six serum immuno-oncology markers that were significantly associated with OS and/or PFS in MBC patients, independently of other established prognostic factors including CTCs. Furthermore, an additional five serum immuno-oncology markers provided suggestive evidence for an independent association to survival. These findings highlight the relevance of immuno-oncology serum markers in MBC patients and support their usefulness for improved prognostication.

  • 9. Haytural, Hazal
    et al.
    Benfeitas, Rui
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Schedin-Weiss, Sophia
    Bereczki, Erika
    Rezeli, Melinda
    Unwin, Richard D.
    Wang, Xusheng
    Dammer, Eric B.
    Johnson, Erik C. B.
    Seyfried, Nicholas T.
    Winblad, Bengt
    Tijms, Betty M.
    Visser, Pieter Jelle
    Frykman, Susanne
    Tjernberg, Lars O.
    Insights into the changes in the proteome of Alzheimer disease elucidated by a meta-analysis2021In: Scientific Data, E-ISSN 2052-4463, Vol. 8, no 1, article id 312Article in journal (Refereed)
    Abstract [en]

    Mass spectrometry (MS)-based proteomics is a powerful tool to explore pathogenic changes of a disease in an unbiased manner and has been used extensively in Alzheimer disease (AD) research. Here, by performing a meta-analysis of high-quality proteomic studies, we address which pathological changes are observed consistently and therefore most likely are of great importance for AD pathogenesis. We retrieved datasets, comprising a total of 21,588 distinct proteins identified across 857 postmortem human samples, from ten studies using labeled or label-free MS approaches. Our meta-analysis findings showed significant alterations of 757 and 1,195 proteins in AD in the labeled and label-free datasets, respectively. Only 33 proteins, some of which were associated with synaptic signaling, had the same directional change across the individual studies. However, despite alterations in individual proteins being different between the labeled and the label-free datasets, several pathways related to synaptic signaling, oxidative phosphorylation, immune response and extracellular matrix were commonly dysregulated in AD. These pathways represent robust changes in the human AD brain and warrant further investigation.

  • 10. Krishnan, Shuba
    et al.
    Nordqvist, Hampus
    Ambikan, Anoop T.
    Gupta, Soham
    Sperk, Maike
    Svensson-Akusjärvi, Sara
    Mikaeloff, Flora
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Saccon, Elisa
    Ponnan, Sivasankaran Munusamy
    Rodriguez, Jimmy Esneider
    Nikouyan, Negin
    Odeh, Amani
    Ahlén, Gustaf
    Asghar, Muhammad
    Sällberg, Matti
    Vesterbacka, Jan
    Nowak, Piotr
    Végvári, Ákos
    Sönnerborg, Anders
    Treutiger, Carl Johan
    Neogi, Ujjwal
    Metabolic Perturbation Associated With COVID-19 Disease Severity and SARS-CoV-2 Replication2021In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 20, article id 100159Article in journal (Refereed)
    Abstract [en]

    Viruses hijack host metabolic pathways for their replicative advantage. In this study, using patient-derived multiomics data and in vitro infection assays, we aimed to understand the role of key metabolic pathways that can regulate severe acute respiratory syndrome coronavirus-2 reproduction and their association with disease severity. We used multiomics platforms (targeted and untargeted proteomics and untargeted metabolomics) on patient samples and cell-line models along with immune phenotyping of metabolite transporters in patient blood cells to understand viral-induced metabolic modulations. We also modulated key metabolic pathways that were identified using multiomics data to regulate the viral reproduction in vitro. Coronavirus disease 2019 disease severity was characterized by increased plasma glucose and mannose levels. Immune phenotyping identified altered expression patterns of carbohydrate transporter, glucose transporter 1, in CD8+ T cells, intermediate and nonclassical monocytes, and amino acid transporter, xCT, in classical, intermediate, and nonclassical monocytes. In in vitro lung epithelial cell (Calu-3) infection model, we found that glycolysis and glutaminolysis are essential for virus replication, and blocking these metabolic pathways caused significant reduction in virus production. Taken together, we therefore hypothesized that severe acute respiratory syndrome coronavirus-2 utilizes and rewires pathways governing central carbon metabolism leading to the efflux of toxic metabolites and associated with disease severity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

  • 11. Mikaeloff, Flora
    et al.
    Gelpi, Marco
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Knudsen, Andreas D.
    Vestad, Beate
    Høgh, Julie
    Hov, Johannes R.
    Benfield, Thomas
    Murray, Daniel
    Giske, Christian G.
    Mardinoglu, Adil
    Trøseid, Marius
    Nielsen, Susanne D.
    Neogi, Ujjwal
    Network-based multi-omics integration reveals metabolic at-risk profile within treated HIV-infection2023In: eLIFE, E-ISSN 2050-084X, Vol. 12, article id e82785Article in journal (Refereed)
    Abstract [en]

    Multiomics technologies improve the biological understanding of health status in people living with HIV on antiretroviral therapy (PWH). Still, a systematic and in-depth characterization of metabolic risk profile during successful long-term treatment is lacking. Here, we used multi-omics (plasma lipidomic, metabolomic, and fecal 16 S microbiome) data-driven stratification and characterization to identify the metabolic at-risk profile within PWH. Through network analysis and similarity network fusion (SNF), we identified three groups of PWH (SNF-1–3): healthy (HC)-like (SNF-1), mild at-risk (SNF-3), and severe at-risk (SNF-2). The PWH in the SNF-2 (45%) had a severe at-risk metabolic profile with increased visceral adipose tissue, BMI, higher incidence of metabolic syndrome (MetS), and increased di- and triglycerides despite having higher CD4+ T-cell counts than the other two clusters. However, the HC-like and the severe at-risk group had a similar metabolic profile differing from HIV-negative controls (HNC), with dysregulation of amino acid metabolism. At the microbiome profile, the HC-like group had a lower α-diversity, a lower proportion of men having sex with men (MSM) and was enriched in Bacteroides. In contrast, in at-risk groups, there was an increase in Prevotella, with a high proportion of MSM, which could potentially lead to higher systemic inflammation and increased cardiometabolic risk profile. The multi-omics integrative analysis also revealed a complex microbial interplay of the microbiome-associated metabolites in PWH. Those severely at-risk clusters may benefit from personalized medicine and lifestyle intervention to improve their dysregulated metabolic traits, aiming to achieve healthier aging.

  • 12. Mikaeloff, Flora
    et al.
    Svensson Akusjärvi, Sara
    Ikomey, George Mondinde
    Krishnan, Shuba
    Sperk, Maike
    Gupta, Soham
    Magdaleno, Gustavo Daniel Vega
    Escos, Alejandra
    Lyonga, Emilia
    Okomo, Marie Claire
    Tagne, Claude Tayou
    Babu, Hemalatha
    Lorson, Christian L.
    Vegvari, Akos
    Banerjea, Akhil C.
    Kele, Julianna
    Hanna, Luke Elizabeth
    Singh, Kamal
    de Magalhaes, João Pedro
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Neogi, Ujjwal
    Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection2022In: Communications Biology, E-ISSN 2399-3642, Vol. 5, no 1, article id 27Article in journal (Refereed)
    Abstract [en]

    Despite successful combination antiretroviral therapy (cART), persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic flexibility and adaptation in people living with HIV (PLWH). Our study investigated alterations in the plasma metabolic profiles by comparing PLWH on long-term cART(>5 years) and matched HIV-negative controls (HC) in two cohorts from low- and middle-income countries (LMIC), Cameroon, and India, respectively, to understand the system-level dysregulation in HIV-infection. Using untargeted and targeted LC-MS/MS-based metabolic profiling and applying advanced system biology methods, an altered amino acid metabolism, more specifically to glutaminolysis in PLWH than HC were reported. A significantly lower level of neurosteroids was observed in both cohorts and could potentiate neurological impairments in PLWH. Further, modulation of cellular glutaminolysis promoted increased cell death and latency reversal in pre-monocytic HIV-1 latent cell model U1, which may be essential for the clearance of the inducible reservoir in HIV-integrated cells. Mikaeloff et al. use untargeted and targeted LC-MS/MS-based plasma metabolic profiling to discover dysregulated metabolism including that of glutaminolysis in individuals living with HIV. Furthermore, decreased levels of neurosteroids were detected suggesting a potential connection between HIV and neurological impairment.

  • 13. Mohammadi, Elyas
    et al.
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Turkez, Hasan
    Boren, Jan
    Nielsen, Jens
    Uhlen, Mathias
    Mardinoglu, Adil
    Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning2020In: Cancers, ISSN 2072-6694, Vol. 12, no 9, article id 2694Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 14. Mohammadi, Elyas
    et al.
    Tahmoorespur, Mojtaba
    Benfeitas, Rui
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Altay, Ozlem
    Javadmanesh, Ali
    Lam, Simon
    Mardinoglu, Adil
    Sekhavati, Mohammad Hadi
    Improvement of the performance of anticancer peptides using a drug repositioning pipeline2022In: Biotechnology Journal, ISSN 1860-6768, E-ISSN 1860-7314, Vol. 17, no 1, article id 2100417Article in journal (Refereed)
    Abstract [en]

    The use of anticancer peptides (ACPs) as an alternative/complementary strategy to conventional chemotherapy treatments has been shown to decrease drug resistance and/or severe side effects. However, the efficacy of the positively-charged ACP is inhibited by elevated levels of negatively-charged cell-surface components which trap the peptides and prevent their contact with the cell membrane. Consequently, this decreases ACP-mediated membrane pore formation and cell lysis. Negatively-charged heparan sulphate (HS) and chondroitin sulphate (CS) have been shown to inhibit the cytotoxic effect of ACPs.

    In this study, we propose a strategy to promote the broad utilization of ACPs. In this context, we developed a drug repositioning pipeline to analyse transcriptomics data generated for four different cancer cell lines (A549, HEPG2, HT29, and MCF7) treated with hundreds of drugs in the LINCS L1000 project. Based on previous studies identifying genes modulating levels of the glycosaminoglycans (GAGs) HS and CS at the cell surface, our analysis aimed at identifying drugs inhibiting genes correlated with high HS and CS levels. As a result, we identified six chemicals as likely repositionable drugs with the potential to enhance the performance of ACPs. The codes in R and Python programming languages are publicly available in https://github.com/ElyasMo/ACPs_HS_HSPGs_CS.

    As a conclusion, these six drugs are highlighted as excellent targets for synergistic studies with ACPs aimed at lowering the costs associated with ACP-treatment.

  • 15. Neogi, Ujjwal
    et al.
    Elaldi, Nazif
    Appelberg, Sofia
    Ambikan, Anoop
    Kennedy, Emma
    Dowall, Stuart
    Bagci, Binnur K.
    Gupta, Soham
    Rodriguez, Jimmy E.
    Svensson-Akusjärvi, Sara
    Monteil, Vanessa
    Vegvari, Akos
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Banerjea, Akhil
    Weber, Friedemann
    Hewson, Roger
    Mirazimi, Ali
    Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target2022In: eLIFE, E-ISSN 2050-084X, Vol. 11, article id e76071Article in journal (Refereed)
    Abstract [en]

    The pathogenesis and host-viral interactions of the Crimean–Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches, including biological network analysis in elucidating the complex host-viral response, interrogates the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) followed by untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host’s metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and concordant with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at the system level and during progressive replication.

  • 16. Olund Villumsen, Sofie
    et al.
    Benfeitas, Rui
    Stockholm University, Science for Life Laboratory (SciLifeLab). Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Dehlbaek Knudsen, Andreas
    Gelpi, Marco
    Høgh, Julie
    Thomsen, Magda Teresa
    Murray, Daniel
    Ullum, Henrik
    Neogi, Ujjwal
    Nielsen, Susanne Dam
    Integrative Lipidomics and Metabolomics for System-Level Understanding of the Metabolic Syndrome in Long-Term Treated HIV-Infected Individuals2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 742736Article in journal (Refereed)
    Abstract [en]

    People living with HIV (PLWH) require life-long anti-retroviral treatment and often present with comorbidities such as metabolic syndrome (MetS). Systematic lipidomic characterization and its association with the metabolism are currently missing. We included 100 PLWH with MetS and 100 without MetS from the Copenhagen Comorbidity in HIV Infection (COCOMO) cohort to examine whether and how lipidome profiles are associated with MetS in PLWH. We combined several standard biostatistical, machine learning, and network analysis techniques to investigate the lipidome systematically and comprehensively and its association with clinical parameters. Additionally, we generated weighted lipid-metabolite networks to understand the relationship between lipidomic profiles with those metabolites associated with MetS in PLWH. The lipidomic dataset consisted of 917 lipid species including 602 glycerolipids, 228 glycerophospholipids, 61 sphingolipids, and 26 steroids. With a consensus approach using four different statistical and machine learning methods, we observed 13 differentially abundant lipids between PLWH without MetS and PLWH with MetS, which mainly belongs to diacylglyceride (DAG, n = 2) and triacylglyceride (TAG, n = 11). The comprehensive network integration of the lipidomics and metabolomics data suggested interactions between specific glycerolipids' structural composition patterns and key metabolites involved in glutamate metabolism. Further integration of the clinical data with metabolomics and lipidomics resulted in the association of visceral adipose tissue (VAT) and exposure to earlier generations of antiretroviral therapy (ART). Our integrative omics data indicated disruption of glutamate and fatty acid metabolism, suggesting their involvement in the pathogenesis of PLWH with MetS. Alterations in the lipid homeostasis and glutaminolysis need clinical interventions to prevent accelerated aging in PLWH with MetS.

  • 17. Song, Byong-Sop
    et al.
    Moon, Ji Sun
    Tian, Jingwen
    Lee, Ho Yeop
    Sim, Byeong Chang
    Kim, Seok-Hwan
    Kang, Seul Gi
    Kim, Jung Tae
    Ha, Thi
    Benfeitas, Rui
    Stockholm University, Science for Life Laboratory (SciLifeLab).
    Kim, Yeongmin
    Park, Sanghee
    Wolfe, Robert R.
    Eun, Hyuk Soo
    Shong, Minho
    Lee, Sunjae
    Kim, Il-Young
    Yi, Hyon-Seung
    Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion2022In: Journal for ImmunoTherapy of Cancer, E-ISSN 2051-1426, Vol. 10, no 5, article id e004337Article in journal (Refereed)
    Abstract [en]

    Background Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer.

    Methods We used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively.

    Results Single-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression. Crif1 deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U-13C6]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells. Crif1 deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production.

    Conclusions Hepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression.

  • 18. Zhang, Cheng
    et al.
    Bjornson, Elias
    Arif, Muhammad
    Tebani, Abdellah
    Lovric, Alen
    Benfeitas, Rui
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Ozcan, Mehmet
    Juszczak, Kajetan
    Kim, Woonghee
    Kim, Jung Tae
    Bidkhori, Gholamreza
    Stahlman, Marcus
    Bergh, Per-Olof
    Adiels, Martin
    Turkez, Hasan
    Taskinen, Marja-Riitta
    Bosley, Jim
    Marschall, Hanns-Ulrich
    Nielsen, Jens
    Uhlen, Mathias
    Boren, Jan
    Mardinoglu, Adil
    The acute effect of metabolic cofactor supplementation: a potential therapeutic strategy against non-alc33oholic fatty liver disease2020In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 16, no 4, article id e9495Article in journal (Refereed)
    Abstract [en]

    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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