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Article ; Online: Modified lipid metabolism and cytosolic phospholipase A2 activation in mesangial cells under pro-inflammatory conditions

Roberto Boi / Kerstin Ebefors / Marcus Henricsson / Jan Borén / Jenny Nyström

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 13

Abstract: Abstract Diabetic kidney disease is a consequence of hyperglycemia and other complex events driven by early glomerular hemodynamic changes and a progressive expansion of the mesangium. The molecular mechanisms behind the pathophysiological alterations of ...

Abstract	Abstract Diabetic kidney disease is a consequence of hyperglycemia and other complex events driven by early glomerular hemodynamic changes and a progressive expansion of the mesangium. The molecular mechanisms behind the pathophysiological alterations of the mesangium are yet to be elucidated. This study aimed at investigating whether lipid signaling might be the missing link. Stimulation of human mesangial cells with high glucose primed the inflammasome-driven interleukin 1 beta (IL-1β) secretion, which in turn stimulated platelet-derived growth factor (PDGF-BB) release. Finally, PDGF-BB increased IL-1β secretion synergistically. Both IL-1β and PDGF-BB stimulation triggered the formation of phosphorylated sphingoid bases, as shown by lipidomics, and activated cytosolic phospholipase cPLA2, sphingosine kinase 1, cyclooxygenase 2, and autotaxin. This led to the release of arachidonic acid and lysophosphatidylcholine, activating the secretion of vasodilatory prostaglandins and proliferative lysophosphatidic acids. Blocking cPLA2 release of arachidonic acid reduced mesangial cells proliferation and prostaglandin secretion. Validation was performed in silico using the Nephroseq database and a glomerular transcriptomic database. In conclusion, hyperglycemia primes glomerular inflammatory and proliferative stimuli triggering lipid metabolism modifications in human mesangial cells. The upregulation of cPLA2 was critical in this setting. Its inhibition reduced mesangial secretion of prostaglandins and proliferation, making it a potential therapeutical target.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: 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: Systems Biology Approaches to Understand the Host–Microbiome Interactions in Neurodegenerative Diseases

Dorines Rosario / Jan Boren / Mathias Uhlen / Gordon Proctor / Dag Aarsland / Adil Mardinoglu / Saeed Shoaie

Frontiers in Neuroscience, Vol

2020 Volume 14

Abstract: 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 ... ...

Abstract	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.
Keywords	systems biology ; microbiota-gut-brain axis ; neurodegenerative diseases ; Parkinson’s disease ; Alzheimer’s disease ; biologic network ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Applications of Genome-Wide Screening and Systems Biology Approaches in Drug Repositioning

Elyas Mohammadi / Rui Benfeitas / Hasan Turkez / Jan Boren / Jens Nielsen / Mathias Uhlen / Adil Mardinoglu

Cancers, Vol 12, Iss 2694, p

2020 Volume 2694

Abstract: 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 ... ...

Abstract	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.
Keywords	drug repositioning ; genomic screens ; machine learning ; systems pharmacology ; systems medicine ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282
Subject code	006
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Antibodies against apoB100 peptide 210 inhibit atherosclerosis in apoE-/- mice

Pontus Dunér / Ingrid Yao Mattisson / Per Fogelstrand / Lars Glise / Stacey Ruiz / Christopher Farina / Jan Borén / Jan Nilsson / Eva Bengtsson

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 10

Abstract: Abstract Atherosclerotic plaques are characterized by an accumulation and subsequent oxidation of LDL, resulting in adaptive immune responses against formed or exposed neoepitopes of the LDL particle. Autoantibodies against native p210, the 3136–3155 ... ...

Abstract	Abstract Atherosclerotic plaques are characterized by an accumulation and subsequent oxidation of LDL, resulting in adaptive immune responses against formed or exposed neoepitopes of the LDL particle. Autoantibodies against native p210, the 3136–3155 amino acid sequence of the LDL protein apolipoprotein B-100 (apoB100) are common in humans and have been associated with less severe atherosclerosis and decreased risk for cardiovascular events in clinical studies. However, whether apoB100 native p210 autoantibodies play a functional role in atherosclerosis is not known. In the present study we immunized apoE-/- mice with p210-PADRE peptide to induce an antibody response against native p210. We also injected mice with murine monoclonal IgG against native p210. Control groups were immunized with PADRE peptide alone or with control murine monoclonal IgG. Immunization with p210-PADRE induced an IgG1 antibody response against p210 that was associated with reduced atherosclerotic plaque formation in the aorta and reduced MDA-LDL content in the lesions. Treatment with monoclonal p210 IgG produced a similar reduction in atherosclerosis as immunization with p210-PADRE. Our findings support an atheroprotective role of antibodies against the apoB100 native p210 and suggest that vaccines that induce the expression of native p210 IgG represent a potential therapeutic strategy for lowering cardiovascular risk.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Informing Pharmacokinetic Models With Physiological Data

J. R. Bosley / Elias Björnson / Cheng Zhang / Hasan Turkez / Jens Nielsen / Mathias Uhlen / Jan Borén / Adil Mardinoglu

Frontiers in Pharmacology, Vol

Oral Population Modeling of L-Serine in Humans

2021 Volume 12

Abstract: To determine how to set optimal oral L-serine (serine) dose levels for a clinical trial, existing literature was surveyed. Data sufficient to set the dose was inadequate, and so an (n = 10) phase I-A calibration trial was performed, administering serine ... ...

Abstract	To determine how to set optimal oral L-serine (serine) dose levels for a clinical trial, existing literature was surveyed. Data sufficient to set the dose was inadequate, and so an (n = 10) phase I-A calibration trial was performed, administering serine with and without other oral agents. We analyzed the trial and the literature data using pharmacokinetic (PK) modeling and statistical analysis. The therapeutic goal is to modulate specific serine-related metabolic pathways in the liver using the lowest possible dose which gives the desired effect since the upper bound was expected to be limited by toxicity. A standard PK approach, in which a common model structure was selected using a fit to data, yielded a model with a single central compartment corresponding to plasma, clearance from that compartment, and an endogenous source of serine. To improve conditioning, a parametric structure was changed to estimate ratios (bioavailability over volume, for example). Model fit quality was improved and the uncertainty in estimated parameters was reduced. Because of the particular interest in the fate of serine, the model was used to estimate whether serine is consumed in the gut, absorbed by the liver, or entered the blood in either a free state, or in a protein- or tissue-bound state that is not measured by our assay. The PK model structure was set up to represent relevant physiology, and this quantitative systems biology approach allowed a broader set of physiological data to be used to narrow parameter and prediction confidence intervals, and to better understand the biological meaning of the data. The model results allowed us to determine the optimal human dose for future trials, including a trial design component including IV and tracer studies. A key contribution is that we were able to use human physiological data from the literature to inform the PK model and to set reasonable bounds on parameters, and to improve model conditioning. Leveraging literature data produced a more predictive, useful model.
Keywords	Pharmacokinectics ; L-Serine (ser) ; systems biology ; NAFLD (non alcoholic fatty liver disease) ; oral supplementation ; Therapeutics. Pharmacology ; RM1-950
Subject code	310
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis

Mario Ruiz / Ranjan Devkota / Dimitra Panagaki / Per-Olof Bergh / Delaney Kaper / Marcus Henricsson / Ali Nik / Kasparas Petkevicius / Johanna L. Höög / Mohammad Bohlooly-Y / Peter Carlsson / Jan Borén / Marc Pilon

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 19

Abstract: Cells and organisms requires proper membrane composition, which the cell must modulate as membrane lipids are primary acquired from the diet. Here, Ruiz et al. identify a conserved pathway connecting the fluidity regulators AdipoR1/2 with fatty acid ... ...

Abstract	Cells and organisms requires proper membrane composition, which the cell must modulate as membrane lipids are primary acquired from the diet. Here, Ruiz et al. identify a conserved pathway connecting the fluidity regulators AdipoR1/2 with fatty acid desaturase SCD to mediate membrane homeostasis.
Keywords	Science ; Q
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: De novo lipogenesis in metabolic homeostasis

Giovanni Solinas / Jan Borén / Abdul G. Dulloo

Molecular Metabolism, Vol 4, Iss 5, Pp 367-

More friend than foe?

2015 Volume 377

Abstract: Background: An acute surplus of carbohydrates, and other substrates, can be converted and safely stored as lipids in adipocytes via de novo lipogenesis (DNL). However, in obesity, a condition characterized by chronic positive energy balance, DNL in non- ... ...

Abstract	Background: An acute surplus of carbohydrates, and other substrates, can be converted and safely stored as lipids in adipocytes via de novo lipogenesis (DNL). However, in obesity, a condition characterized by chronic positive energy balance, DNL in non-adipose tissues may lead to ectopic lipid accumulation leading to lipotoxicity and metabolic stress. Indeed, DNL is dynamically recruited in liver during the development of fatty liver disease, where DNL is an important source of lipids. Nonetheless, a number of evidences indicates that DNL is an inefficient road for calorie to lipid conversion and that DNL may play an important role in sustaining metabolic homeostasis. Scope of review: In this manuscript, we discuss the role of DNL as source of lipids during obesity, the energetic efficiency of this pathway in converting extra calories to lipids, and the function of DNL as a pathway supporting metabolic homeostasis. Major conclusion: We conclude that inhibition of DNL in obese subjects, unless coupled with a correction of the chronic positive energy balance, may further promote lipotoxicity and metabolic stress. On the contrary, strategies aimed at specifically activating DNL in adipose tissue could support metabolic homeostasis in obese subjects by a number of mechanisms, which are discussed in this manuscript.
Keywords	Ectopic lipids ; Glucose disposal ; Thermogenesis ; Lipokines ; Obesity ; Metabolic flexibility ; Internal medicine ; RC31-1245
Language	English
Publishing date	2015-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prediction of drug candidates for clear cell renal cell carcinoma using a systems biology-based drug repositioning approach

Xiangyu Li / Koeun Shong / Woonghee Kim / Meng Yuan / Hong Yang / Yusuke Sato / Haruki Kume / Seishi Ogawa / Hasan Turkez / Saeed Shoaie / Jan Boren / Jens Nielsen / Mathias Uhlen / Cheng Zhang / Adil Mardinoglu

EBioMedicine, Vol 78, Iss , Pp 103963- (2022)

2022

Abstract: Summary: Background: The response rates of the clinical chemotherapies are still low in clear cell renal cell carcinoma (ccRCC). Computational drug repositioning is a promising strategy to discover new uses for existing drugs to treat patients who cannot ...

Abstract	Summary: Background: The response rates of the clinical chemotherapies are still low in clear cell renal cell carcinoma (ccRCC). Computational drug repositioning is a promising strategy to discover new uses for existing drugs to treat patients who cannot get benefits from clinical drugs. Methods: We proposed a systematic approach which included the target prediction based on the co-expression network analysis of transcriptomics profiles of ccRCC patients and drug repositioning for cancer treatment based on the analysis of shRNA- and drug-perturbed signature profiles of human kidney cell line. Findings: First, based on the gene co-expression network analysis, we identified two types of gene modules in ccRCC, which significantly enriched with unfavorable and favorable signatures indicating poor and good survival outcomes of patients, respectively. Then, we selected four genes, BUB1B, RRM2, ASF1B and CCNB2, as the potential drug targets based on the topology analysis of modules. Further, we repurposed three most effective drugs for each target by applying the proposed drug repositioning approach. Finally, we evaluated the effects of repurposed drugs using an in vitro model and observed that these drugs inhibited the protein levels of their corresponding target genes and cell viability. Interpretation: These findings proved the usefulness and efficiency of our approach to improve the drug repositioning researches for cancer treatment and precision medicine. Funding: This study was funded by Knut and Alice Wallenberg Foundation and Bash Biotech Inc., San Diego, CA, USA.
Keywords	Systems biology ; Co-expression network ; Target chemotherapy ; Drug repositioning ; ccRCC ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Elsevier
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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