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Article ; Online: Genome-scale metabolic models for natural and long-term drug-induced viral control in HIV infection.

Ambikan, Anoop T / Svensson-Akusjärvi, Sara / Krishnan, Shuba / Sperk, Maike / Nowak, Piotr / Vesterbacka, Jan / Sönnerborg, Anders / Benfeitas, Rui / Neogi, Ujjwal

Life science alliance

2022 Volume 5, Issue 9

Abstract: 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 ... ...

Abstract	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, PLWH
MeSH term(s)	Genome ; HIV Infections/genetics ; HIV-1 ; Humans ; Oxidative Phosphorylation
Language	English
Publishing date	2022-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202201405
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Interplay Between Thiamine and p53/p21 Axes Affects Antiproliferative Action of Cisplatin in Lung Adenocarcinoma Cells by Changing Metabolism of 2-Oxoglutarate/Glutamate.

Aleshin, Vasily A / Zhou, Xiaoshan / Krishnan, Shuba / Karlsson, Anna / Bunik, Victoria I

Frontiers in genetics

2021 Volume 12, Page(s) 658446

Abstract: Thiamine (vitamin B1) is often deficient in oncopatients, particularly those undergoing chemotherapy. However, interaction between the thiamine deficiency and anticancer action of drugs has not been characterized. A major natural thiamine derivative, ... ...

Abstract	Thiamine (vitamin B1) is often deficient in oncopatients, particularly those undergoing chemotherapy. However, interaction between the thiamine deficiency and anticancer action of drugs has not been characterized. A major natural thiamine derivative, thiamine diphosphate (ThDP), is a coenzyme of central metabolism, also known to affect transcriptional activity of the master metabolic regulator and genome guardian p53. A direct transcriptional target of p53, p21, regulates cell cycle dynamics and DNA damage response. Our work focuses on dependence of the action of the DNA damaging anticancer drug cisplatin on metabolic regulation through p53/p21 axes and cellular thiamine status in human lung adenocarcinoma cells A549. These cells are used as a model of a hardly curable cancer, known to develop chemoresistance to platinum drugs, such as cisplatin. Compared to wild type (A549
Language	English
Publishing date	2021-04-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2021.658446
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Article ; Online: Role of myeloid cells in system-level immunometabolic dysregulation during prolonged successful HIV-1 treatment.

Svensson Akusjärvi, Sara / Krishnan, Shuba / Ambikan, Anoop T / Mikaeloff, Flora / Munusamy Ponnan, Sivasankaran / Vesterbacka, Jan / Lourda, Magda / Nowak, Piotr / Sönnerborg, Anders / Neogi, Ujjwal

AIDS (London, England)

2023 Volume 37, Issue 7, Page(s) 1023–1033

Abstract: Objective: Why people with HIV-1 on ART (PWH ART ) display convoluted metabolism and immune cell functions during prolonged suppressive therapy is not well evaluated. In this study, we aimed to address this question using multiomics methodologies to ... ...

Abstract	Objective: Why people with HIV-1 on ART (PWH ART ) display convoluted metabolism and immune cell functions during prolonged suppressive therapy is not well evaluated. In this study, we aimed to address this question using multiomics methodologies to investigate immunological and metabolic differences between PWH ART and HIV-1 negative individuals (HC). Design: Cross-sectional study. Methods: Untargeted and targeted metabolomics was performed using gas and liquid chromatography/mass spectrometry, and targeted proteomics using Olink inflammation panel on plasma samples. The cellular metabolic state was further investigated using flow cytometry and intracellular metabolic measurement in single-cell populations isolated by EasySep cell isolation. Finally, flow cytometry was performed for deep-immunophenotyping of mononuclear phagocytes. Results: We detected increased levels of glutamate, lactate, and pyruvate by plasma metabolomics and increased inflammatory markers (e.g. CCL20 and CCL7) in PWH ART compared to HC. The metabolite transporter detection by flow cytometry in T cells and monocytes indicated an increased expression of glucose transporter 1 (Glut1) and monocarboxylate transporter 1 (MCT-1) in PWH ART . Single cell-type metabolite measurement identified decreased glucose, glutamate, and lactate in monocytic cell populations in PWH ART . Deep-immunophenotyping of myeloid cell lineages subpopulations showed no difference in cell frequency, but expression levels of CCR5 were increased on classical monocytes and some dendritic cells. Conclusions: Our data thus suggest that the myeloid cell populations potentially contribute significantly to the modulated metabolic environment during suppressive HIV-1 infection.
MeSH term(s)	Humans ; HIV Infections ; HIV-1 ; Cross-Sectional Studies ; HIV Seropositivity ; Myeloid Cells ; Glutamates ; Lactates
Chemical Substances	Glutamates ; Lactates
Language	English
Publishing date	2023-03-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639076-6
ISSN	1473-5571 ; 0269-9370 ; 1350-2840
ISSN (online)	1473-5571
ISSN	0269-9370 ; 1350-2840
DOI	10.1097/QAD.0000000000003512
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Article ; Online: Peripheral blood CD4

Svensson Akusjärvi, Sara / Krishnan, Shuba / Jütte, Bianca B / Ambikan, Anoop T / Gupta, Soham / Rodriguez, Jimmy Esneider / Végvári, Ákos / Sperk, Maike / Nowak, Piotr / Vesterbacka, Jan / Svensson, J Peter / Sönnerborg, Anders / Neogi, Ujjwal

Communications biology

2022 Volume 5, Issue 1, Page(s) 357

Abstract: HIV-1 infection induces a chronic inflammatory environment not restored by suppressive antiretroviral therapy (ART). As of today, the effect of viral suppression and immune reconstitution in people living with HIV-1 (PLWH) has been well described but not ...

Abstract	HIV-1 infection induces a chronic inflammatory environment not restored by suppressive antiretroviral therapy (ART). As of today, the effect of viral suppression and immune reconstitution in people living with HIV-1 (PLWH) has been well described but not completely understood. Herein, we show how PLWH who naturally control the virus (PLWH
MeSH term(s)	CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; Elite Controllers ; HIV Infections/drug therapy ; HIV-1 ; Humans ; Proteomics ; Receptors, CCR6/metabolism
Chemical Substances	CCR6 protein, human ; Receptors, CCR6
Language	English
Publishing date	2022-04-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-03315-x
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Article ; Online: Distinct lipid profile, low-level inflammation, and increased antioxidant defense signature in HIV-1 elite control status.

Sperk, Maike / Mikaeloff, Flora / Svensson-Akusjärvi, Sara / Krishnan, Shuba / Ponnan, Sivasankaran Munusamy / Ambikan, Anoop T / Nowak, Piotr / Sönnerborg, Anders / Neogi, Ujjwal

iScience

2021 Volume 24, Issue 2, Page(s) 102111

Abstract: HIV-1 elite controllers (EC) are a rare but heterogeneous group of HIV-1-infected individuals who can suppress viral replication in the absence of antiretroviral therapy. The mechanisms of how EC achieve undetectable viral loads remain unclear. This ... ...

Abstract	HIV-1 elite controllers (EC) are a rare but heterogeneous group of HIV-1-infected individuals who can suppress viral replication in the absence of antiretroviral therapy. The mechanisms of how EC achieve undetectable viral loads remain unclear. This study aimed to investigate host plasma metabolomics and targeted plasma proteomics in a Swedish HIV-1 cohort including EC and treatment-naïve viremic progressors (VP) as well as HIV-negative individuals (HC) to get insights into EC phenotype. Metabolites belonging to antioxidant defense had higher levels in EC relative to VP, whereas inflammation markers were increased in VP compared with EC. Only four plasma proteins (CCL4, CCL7, CCL20, and NOS3) were increased in EC compared with HC, and CCL20/CCR6 axis can play an essential role in EC status. Our study suggests that low-level inflammation and oxidative stress at physiological levels could be important factors contributing to elite control phenotype.
Language	English
Publishing date	2021-01-28
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.102111
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Article ; Online: Peripheral blood CD4+CCR6+ compartment differentiates HIV-1 infected or seropositive elite controllers from long-term successfully treated individuals

Sara Svensson Akusjärvi / Shuba Krishnan / Bianca B. Jütte / Anoop T. Ambikan / Soham Gupta / Jimmy Esneider Rodriguez / Ákos Végvári / Maike Sperk / Piotr Nowak / Jan Vesterbacka / J. Peter Svensson / Anders Sönnerborg / Ujjwal Neogi

Communications Biology, Vol 5, Iss 1, Pp 1-

2022 Volume 13

Abstract: The expression profiles dynamics of several chemokine receptors are lower for people living with HIV-1 who naturally control the virus compared to those on suppressive antiretroviral therapy and HIV-negative controls, shedding light on the mechanisms of ... ...

Abstract	The expression profiles dynamics of several chemokine receptors are lower for people living with HIV-1 who naturally control the virus compared to those on suppressive antiretroviral therapy and HIV-negative controls, shedding light on the mechanisms of natural control of HIV-1 infection.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Inhibition of glutamate oxaloacetate transaminase 1 in cancer cell lines results in altered metabolism with increased dependency of glucose.

Zhou, Xiaoshan / Curbo, Sophie / Li, Fuqiang / Krishnan, Shuba / Karlsson, Anna

BMC cancer

2018 Volume 18, Issue 1, Page(s) 559

Abstract: Background: Glutamate oxaloacetate transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements. KRAS mutated cancer cells were recently shown to rely on GOT1 to ... ...

Abstract	Background: Glutamate oxaloacetate transaminase 1 (GOT1) regulates cellular metabolism through coordinating the utilization of carbohydrates and amino acids to meet nutrient requirements. KRAS mutated cancer cells were recently shown to rely on GOT1 to support long-term cell proliferation. The aim of the present study was to address the role of GOT1 in the metabolic adaption of cancer cells. Methods: GOT1-null and knockdown cell lines were established through CRISPR/Cas9 and shRNA techniques. The growth properties, colony formation ability, autophagy and selected gene expression profiles were analysed. Glucose deprivation decreased the viability of the GOT1-null cells and rescue experiments were conducted with selected intermediates. The redox NADH/NAD Results: Inhibition of GOT1 sensitized the cancer cells to glucose deprivation, which was partially counteracted by oxaloacetate and phosphoenol pyruvate, metabolic intermediates downstream of GOT1. Moreover, GOT1-null cells accumulated NADH and displayed a decreased ratio of NADH/NAD Conclusions: Our study suggests an important role of GOT1 to coordinate the glycolytic and the oxidative phosphorylation pathways in KRAS mutated cancer cells. GOT1 is crucial to provide oxaloacetate at low glucose levels, likely to maintain the redox homeostasis. Our data suggest GOT1 as a possible target in cancer therapy.
MeSH term(s)	A549 Cells ; Aspartate Aminotransferase, Cytoplasmic/genetics ; Aspartate Aminotransferase, Cytoplasmic/metabolism ; Cell Line, Tumor ; Cellular Reprogramming ; Datasets as Topic ; Gene Expression Profiling ; Gene Knockout Techniques ; Glucose/metabolism ; Humans ; Lactic Acid/metabolism ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/mortality ; Oxaloacetic Acid/metabolism ; Oxidative Phosphorylation ; Proto-Oncogene Proteins p21(ras)/genetics ; Survival Rate ; Up-Regulation
Chemical Substances	KRAS protein, human ; Oxaloacetic Acid (2F399MM81J) ; Lactic Acid (33X04XA5AT) ; Aspartate Aminotransferase, Cytoplasmic (EC 2.6.1.-) ; GOT1 protein, human (EC 2.6.1.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2018-05-11
Publishing country	England
Document type	Journal Article
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/s12885-018-4443-1
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Article ; Online: Integrative proteo-transcriptomic and immunophenotyping signatures of HIV-1 elite control phenotype

Sara Svensson Akusjärvi / Anoop T. Ambikan / Shuba Krishnan / Soham Gupta / Maike Sperk / Ákos Végvári / Flora Mikaeloff / Katie Healy / Jan Vesterbacka / Piotr Nowak / Anders Sönnerborg / Ujjwal Neogi

iScience, Vol 25, Iss 1, Pp 103607- (2022)

A cross-talk between glycolysis and HIF signaling

2022

Abstract: Summary: Natural control of HIV-1 is a characteristic of <1% of HIV-1-infected individuals, so called elite controllers (EC). In this study, we sought to identify signaling pathways associated with the EC phenotype using integrative proteo-transcriptomic ...

Abstract	Summary: Natural control of HIV-1 is a characteristic of <1% of HIV-1-infected individuals, so called elite controllers (EC). In this study, we sought to identify signaling pathways associated with the EC phenotype using integrative proteo-transcriptomic analysis and immunophenotyping. We found HIF signaling and glycolysis as specific traits of the EC phenotype together with dysregulation of HIF target gene transcription. A higher proportion of HIF-1α and HIF-1β in the nuclei of CD4+ and CD8+ T cells in the male EC were observed, indicating a potential increased activation of the HIF signaling pathway. Furthermore, intracellular glucose levels were elevated in EC even as the surface expression of the metabolite transporters Glut1 and MCT-1 were decreased on lymphocytes indicative of unique metabolic uptake and flux profile. Combined, our data show that glycolytic modulation and altered HIF signaling is a unique feature of the male EC phenotype that may contribute to natural control of HIV-1.
Keywords	Glycobiology ; Molecular biology ; Immunology ; Virology ; Omics ; Science ; Q
Subject code	570
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Severe mtDNA depletion and dependency on catabolic lipid metabolism in DGUOK knockout mice.

Zhou, Xiaoshan / Curbo, Sophie / Zhao, Qian / Krishnan, Shuba / Kuiper, Raoul / Karlsson, Anna

Human molecular genetics

2019 Volume 28, Issue 17, Page(s) 2874–2884

Abstract: Deoxyguanosine kinase (DGUOK) provides guanosine and adenosine nucleotides for mitochondrial DNA (mtDNA) replication, and its deficiency in humans leads to hepatocerebral mtDNA depletion syndrome or to isolated hepatic disease. There are poor treatment ... ...

Abstract	Deoxyguanosine kinase (DGUOK) provides guanosine and adenosine nucleotides for mitochondrial DNA (mtDNA) replication, and its deficiency in humans leads to hepatocerebral mtDNA depletion syndrome or to isolated hepatic disease. There are poor treatment options for DGUOK deficiency and the aim of this study was to generate a model for further studies of the disease that could reveal novel treatment strategies. We report a Dguok-deficient mouse strain that, similar to humans, is most severely affected in the liver. The Dguok complete knockout mice (Dguok-/-) were born normal, but began to lose weight at week 6. A change of fur color from black to blueish grey started at week 16 and was complete at week 20. The movements and behavior were indistinguishable compared to wild-type (wt) mice. A decrease of mtDNA copy number occurred in multiple tissues, with the liver being the most severely affected. The mtDNA-encoded protein cytochrome c oxidase was much lower in Dguok-/- liver tissue than in the wt, whereas the expression of the nuclear-encoded succinate dehydrogenase complex subunit A was unaffected. Histopathology showed severe alterations and immunohistochemistry showed signs of both oxidative stress and regeneration in Dguok-/- liver. The subcutaneous fat layer was undetectable in Dguok-/-, which, in addition to gene expression analysis, indicated an altered lipid metabolism. We conclude that Dguok has a major role for the synthesis of deoxyribonucleotides for mtDNA replication particularly in the liver, similar to the human disorder. Our data also show a catabolic lipid metabolism in liver tissue of Dguok-/-.
MeSH term(s)	Animals ; Biomarkers ; DNA, Mitochondrial ; Disease Models, Animal ; Female ; Gene Dosage ; Gene Expression Profiling ; Gene Targeting ; Genetic Loci ; Lipid Metabolism ; Liver/metabolism ; Liver/pathology ; Male ; Mice ; Mice, Knockout ; Mitochondria/genetics ; Mitochondria/metabolism ; Mitochondria/ultrastructure ; Mitochondrial Diseases/genetics ; Mitochondrial Diseases/metabolism ; Phenotype ; Subcutaneous Fat/metabolism ; Transcriptome
Chemical Substances	Biomarkers ; DNA, Mitochondrial
Language	English
Publishing date	2019-07-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddz103
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Zs.A 3469: Show issues

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Article ; Online: Integrative proteo-transcriptomic and immunophenotyping signatures of HIV-1 elite control phenotype: A cross-talk between glycolysis and HIF signaling.

Akusjärvi, Sara Svensson / Ambikan, Anoop T / Krishnan, Shuba / Gupta, Soham / Sperk, Maike / Végvári, Ákos / Mikaeloff, Flora / Healy, Katie / Vesterbacka, Jan / Nowak, Piotr / Sönnerborg, Anders / Neogi, Ujjwal

iScience

2021 Volume 25, Issue 1, Page(s) 103607

Abstract: Natural control of HIV-1 is a characteristic of <1% of HIV-1-infected individuals, so called elite controllers (EC). In this study, we sought to identify signaling pathways associated with the EC phenotype using integrative proteo-transcriptomic analysis ...

Abstract	Natural control of HIV-1 is a characteristic of <1% of HIV-1-infected individuals, so called elite controllers (EC). In this study, we sought to identify signaling pathways associated with the EC phenotype using integrative proteo-transcriptomic analysis and immunophenotyping. We found HIF signaling and glycolysis as specific traits of the EC phenotype together with dysregulation of HIF target gene transcription. A higher proportion of HIF-1α and HIF-1β in the nuclei of CD4
Language	English
Publishing date	2021-12-10
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.103607
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