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Article ; Online: Systems biology perspective for studying the gut microbiota in human physiology and liver diseases

Ozlem Altay / Jens Nielsen / Mathias Uhlen / Jan Boren / Adil Mardinoglu

EBioMedicine, Vol 49, Iss , Pp 364-

2019 Volume 373

Abstract: The advancement in high-throughput sequencing technologies and systems biology approaches have revolutionized our understanding of biological systems and opened a new path to investigate unacknowledged biological phenomena. In parallel, the field of ... ...

Abstract	The advancement in high-throughput sequencing technologies and systems biology approaches have revolutionized our understanding of biological systems and opened a new path to investigate unacknowledged biological phenomena. In parallel, the field of human microbiome research has greatly evolved and the relative contribution of the gut microbiome to health and disease have been systematically explored. This review provides an overview of the network-based and translational systems biology-based studies focusing on the function and composition of gut microbiota. We also discussed the association between the gut microbiome and the overall human physiology, as well as hepatic diseases and other metabolic disorders. Keywords: Gut microbiome, Liver diseases, Host-microbiome interactions, Systems biology, Personalized medicine, Meta-omics, Biomarker, Metabolic models
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Next generation plasma proteome profiling of COVID-19 patients with mild to moderate symptoms

Wen Zhong / Ozlem Altay / Muhammad Arif / Fredrik Edfors / Levent Doganay / Adil Mardinoglu / Mathias Uhlen / Linn Fagerberg

EBioMedicine, Vol 74, Iss , Pp 103723- (2021)

2021

Abstract: Background: COVID-19 has caused millions of deaths globally, yet the cellular mechanisms underlying the various effects of the disease remain poorly understood. Recently, a new analytical platform for comprehensive analysis of plasma protein profiles ... ...

Abstract	Background: COVID-19 has caused millions of deaths globally, yet the cellular mechanisms underlying the various effects of the disease remain poorly understood. Recently, a new analytical platform for comprehensive analysis of plasma protein profiles using proximity extension assays combined with next generation sequencing has been developed, which allows for multiple proteins to be analyzed simultaneously without sacrifice on accuracy or sensitivity. Methods: We analyzed the plasma protein profiles of COVID-19 patients (n = 50) with mild and moderate symptoms by comparing the protein levels in newly diagnosed patients with the protein levels in the same individuals after 14 days. Findings: The study has identified more than 200 proteins that are significantly elevated during infection and many of these are related to cytokine response and other immune-related functions. In addition, several other proteins are shown to be elevated, including SCARB2, a host cell receptor protein involved in virus entry. A comparison with the plasma protein response in patients with severe symptoms shows a highly similar pattern, but with some interesting differences. Interpretation: The study presented here demonstrates the usefulness of “next generation plasma protein profiling” to identify molecular signatures of importance for disease progression and to allow monitoring of disease during recovery from the infection. The results will facilitate further studies to understand the molecular mechanism of the immune-related response of the SARS-CoV-2 virus. Funding: This work was financially supported by Knut and Alice Wallenberg Foundation.
Keywords	COVID-19 ; Protein profiling ; Plasma proteome ; Immune response ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Systems Biology Approaches to Decipher the Underlying Molecular Mechanisms of Glioblastoma Multiforme

Ali Kaynar / Ozlem Altay / Xiangyu Li / Cheng Zhang / Hasan Turkez / Mathias Uhlén / Saeed Shoaie / Adil Mardinoglu

International Journal of Molecular Sciences, Vol 22, Iss 13213, p

2021 Volume 13213

Abstract: Glioblastoma multiforme (GBM) is one of the most malignant central nervous system tumors, showing a poor prognosis and low survival rate. Therefore, deciphering the underlying molecular mechanisms involved in the progression of the GBM and identifying ... ...

Abstract	Glioblastoma multiforme (GBM) is one of the most malignant central nervous system tumors, showing a poor prognosis and low survival rate. Therefore, deciphering the underlying molecular mechanisms involved in the progression of the GBM and identifying the key driver genes responsible for the disease progression is crucial for discovering potential diagnostic markers and therapeutic targets. In this context, access to various biological data, development of new methodologies, and generation of biological networks for the integration of multi-omics data are necessary for gaining insights into the appearance and progression of GBM. Systems biology approaches have become indispensable in analyzing heterogeneous high-throughput omics data, extracting essential information, and generating new hypotheses from biomedical data. This review provides current knowledge regarding GBM and discusses the multi-omics data and recent systems analysis in GBM to identify key biological functions and genes. This knowledge can be used to develop efficient diagnostic and treatment strategies and can also be used to achieve personalized medicine for GBM.
Keywords	glioblastoma ; genome-scale metabolic models ; multi-omics data ; systems biology ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	004
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Current Status of COVID-19 Therapies and Drug Repositioning Applications

Ozlem Altay / Elyas Mohammadi / Simon Lam / Hasan Turkez / Jan Boren / Jens Nielsen / Mathias Uhlen / Adil Mardinoglu

iScience, Vol 23, Iss 7, Pp 101303- (2020)

2020

Abstract: 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 ...

Abstract	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.
Keywords	Health Sciences ; Medicine ; Science ; Q ; covid19
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Multiomics Analysis Reveals the Impact of Microbiota on Host Metabolism in Hepatic Steatosis

Mujdat Zeybel / Muhammad Arif / Xiangyu Li / Ozlem Altay / Hong Yang / Mengnan Shi / Murat Akyildiz / Burcin Saglam / Mehmet Gokhan Gonenli / Buket Yigit / Burge Ulukan / Dilek Ural / Saeed Shoaie / Hasan Turkez / Jens Nielsen / Cheng Zhang / Mathias Uhlén / Jan Borén / Adil Mardinoglu

Advanced Science, Vol 9, Iss 11, Pp n/a-n/a (2022)

2022

Abstract: Abstract Metabolic dysfunction‐associated fatty liver disease (MAFLD) is a complex disease involving alterations in multiple biological processes regulated by the interactions between obesity, genetic background, and environmental factors including the ... ...

Abstract	Abstract Metabolic dysfunction‐associated fatty liver disease (MAFLD) is a complex disease involving alterations in multiple biological processes regulated by the interactions between obesity, genetic background, and environmental factors including the microbiome. To decipher hepatic steatosis (HS) pathogenesis by excluding critical confounding factors including genetic variants and diabetes, 56 heterogenous MAFLD patients are characterized by generating multiomics data including oral and gut metagenomics as well as plasma metabolomics and inflammatory proteomics data. The dysbiosis in the oral and gut microbiome is explored and the host–microbiome interactions based on global metabolic and inflammatory processes are revealed. These multiomics data are integrated using the biological network and HS's key features are identified using multiomics data. HS is finally predicted using these key features and findings are validated in a follow‐up cohort, where 22 subjects with varying degree of HS are characterized.
Keywords	gut and oral metagenomics ; metabolic dysfunction‐associated fatty liver disease ; metabolomics ; multiomics analysis ; proteomics ; systems biology ; Science ; Q
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Revealing the Molecular Mechanisms of Alzheimer’s Disease Based on Network Analysis

Abdulahad Bayraktar / Simon Lam / Ozlem Altay / Xiangyu Li / Meng Yuan / Cheng Zhang / Muhammad Arif / Hasan Turkez / Mathias Uhlén / Saeed Shoaie / Adil Mardinoglu

International Journal of Molecular Sciences, Vol 22, Iss 11556, p

2021 Volume 11556

Abstract: The complex pathology of Alzheimer’s disease (AD) emphasises the need for comprehensive modelling of the disease, which may lead to the development of efficient treatment strategies. To address this challenge, we analysed transcriptome data of post- ... ...

Abstract	The complex pathology of Alzheimer’s disease (AD) emphasises the need for comprehensive modelling of the disease, which may lead to the development of efficient treatment strategies. To address this challenge, we analysed transcriptome data of post-mortem human brain samples of healthy elders and individuals with late-onset AD from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and Mayo Clinic (MayoRNAseq) studies in the AMP-AD consortium. In this context, we conducted several bioinformatics and systems medicine analyses including the construction of AD-specific co-expression networks and genome-scale metabolic modelling of the brain in AD patients to identify key genes, metabolites and pathways involved in the progression of AD. We identified AMIGO1 and GRPRASP2 as examples of commonly altered marker genes in AD patients. Moreover, we found alterations in energy metabolism, represented by reduced oxidative phosphorylation and ATPase activity, as well as the depletion of hexanoyl-CoA, pentanoyl-CoA, (2E)-hexenoyl-CoA and numerous other unsaturated fatty acids in the brain. We also observed that neuroprotective metabolites (e.g., vitamins, retinoids and unsaturated fatty acids) tend to be depleted in the AD brain, while neurotoxic metabolites (e.g., β-alanine, bilirubin) were more abundant. In summary, we systematically revealed the key genes and pathways related to the progression of AD, gained insight into the crucial mechanisms of AD and identified some possible targets that could be used in the treatment of AD.
Keywords	Alzheimer’s disease ; gene co-expression network ; genome-scale metabolic model ; reporter metabolite analysis ; energy metabolism ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Combined Metabolic Activators Accelerates Recovery in Mild‐to‐Moderate COVID‐19

Ozlem Altay / Muhammad Arif / Xiangyu Li / Hong Yang / Mehtap Aydın / Gizem Alkurt / Woonghee Kim / Dogukan Akyol / Cheng Zhang / Gizem Dinler‐Doganay / Hasan Turkez / Saeed Shoaie / Jens Nielsen / Jan Borén / Oktay Olmuscelik / Levent Doganay / Mathias Uhlén / Adil Mardinoglu

Advanced Science, Vol 8, Iss 17, Pp n/a-n/a (2021)

2021

Abstract: Abstract COVID‐19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+) and glutathione metabolism. Here it is investigated if administration of a mixture of ... ...

Abstract	Abstract COVID‐19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID‐19 patients. CMAs include l‐serine, N‐acetyl‐l‐cysteine, nicotinamide riboside, and l‐carnitine tartrate, salt form of l‐carnitine. Placebo‐controlled, open‐label phase 2 study and double‐blinded phase 3 clinical trials are conducted to investigate the time of symptom‐free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID‐19 with CMAs lead to a more rapid symptom‐free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.
Keywords	combined metabolic activators ; COVID‐19 ; metabolomics ; omics data ; proteomics ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients

Mujdat Zeybel / Ozlem Altay / Muhammad Arif / Xiangyu Li / Hong Yang / Claudia Fredolini / Murat Akyildiz / Burcin Saglam / Mehmet Gokhan Gonenli / Dilek Ural / Woonghee Kim / Jochen M Schwenk / Cheng Zhang / Saeed Shoaie / Jens Nielsen / Mathias Uhlén / Jan Borén / Adil Mardinoglu

Molecular Systems Biology, Vol 17, Iss 10, Pp n/a-n/a (2021)

2021

Abstract: Abstract Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, ... ...

Abstract	Abstract Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo‐controlled 10‐week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host–microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.
Keywords	CMA ; multi‐omics ; NAFLD ; systems biology ; Biology (General) ; QH301-705.5 ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients

Burak Yulug / Ozlem Altay / Xiangyu Li / Lutfu Hanoglu / Seyda Cankaya / Simon Lam / Halil Aziz Velioglu / Hong Yang / Ebru Coskun / Ezgi Idil / Rahim Nogaylar / Ahmet Ozsimsek / Cemil Bayram / Ismail Bolat / Sena Oner / Ozlem Ozdemir Tozlu / Mehmet Enes Arslan / Ahmet Hacimuftuoglu / Serkan Yildirim /

Muhammad Arif / Saeed Shoaie / Cheng Zhang / Jens Nielsen / Hasan Turkez / Jan Borén / Mathias Uhlén / Adil Mardinoglu

Translational Neurodegeneration, Vol 12, Iss 1, Pp 1-

a randomised, double-blinded, placebo-controlled phase-II trial

2023 Volume 23

Abstract: Abstract Background Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the ... ...

Abstract	Abstract Background Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. Methods Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. Results We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Conclusion Our results indicate that treatment of AD patients with CMA can lead to ...
Keywords	Alzheimer’s disease ; Combined metabolic activators ; Multi-omics ; Systems biology ; Systems medicine ; Neurology. Diseases of the nervous system ; RC346-429
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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