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Article ; Online: High-Throughput Metabolomics Platform for the Rapid Data-Driven Development of Novel Additive Solutions for Blood Storage

Travis Nemkov / Tatsuro Yoshida / Maria Nikulina / Angelo D’Alessandro

Frontiers in Physiology, Vol

2022 Volume 13

Abstract: Red blood cell transfusion is a life-saving intervention, and storage is a logistic necessity to make ~110 million units available for transfusion every year worldwide. However, storage in the blood bank is associated with a progressive metabolic decline, ...

Abstract	Red blood cell transfusion is a life-saving intervention, and storage is a logistic necessity to make ~110 million units available for transfusion every year worldwide. However, storage in the blood bank is associated with a progressive metabolic decline, which correlates with the accumulation of morphological lesions, increased intra- and extra-vascular hemolysis upon transfusion, and altered oxygen binding/off-loading kinetics. Prior to storage, red blood cells are suspended in nutrient formulations known as additive solutions to prolong cellular viability. Despite a thorough expansion of knowledge regarding red blood cell biology over the past few decades, only a single new additive solution has been approved by the Food and Drug Administration this century, owing in part to the limited capacity for development of novel formulations. As a proof of principle, we leveraged a novel high-throughput metabolomics technology as a platform for rapid data-driven development and screening of novel additive solutions for blood storage under both normoxic and hypoxic conditions. To this end, we obtained leukocyte-filtered red blood cells (RBCs) and stored them under normoxic or hypoxic conditions in 96 well plates (containing polyvinylchloride plasticized with diethylhexylphthalate to concentrations comparable to full size storage units) in the presence of an additive solution supplemented with six different compounds. To inform this data-driven strategy, we relied on previously identified metabolic markers of the RBC storage lesion that associates with measures of hemolysis and post-transfusion recovery, which are the FDA gold standards to predict stored blood quality, as well as and metabolic predictors of oxygen binding/off-loading parameters. Direct quantitation of these predictors of RBC storage quality were used here—along with detailed pathway analysis of central energy and redox metabolism—as a decision-making tool to screen novel additive formulations in a multiplexed fashion. Candidate supplements are shown ...
Keywords	transfusion medicine ; storage ; red blood cell ; metabolism ; methionine ; high-throughput screening ; Physiology ; QP1-981
Subject code	670
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: In Sickness and in Health

Marianna H. Antonelou / Angelo D’Alessandro / Anastasios G. Kriebardis

International Journal of Molecular Sciences, Vol 23, Iss 6957, p

Erythrocyte Responses to Stress and Aging

2022 Volume 6957

Abstract: Mature red blood cells (RBC) are the most abundant host cell in our body [.] ...

Abstract	Mature red blood cells (RBC) are the most abundant host cell in our body [.]
Keywords	n/a ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Induction of Drug-Resistance and Production of a Culture Medium Able to Induce Drug-Resistance in Vinblastine Untreated Murine Myeloma Cells

Valentina Laghezza Masci / Davide Stefanoni / Angelo D’Alessandro / Marta Zambelli / Lorenzo Modesti / Daniele Pollini / Elisa Ovidi / Antonio Tiezzi

Molecules, Vol 28, Iss 2051, p

2023 Volume 2051

Abstract: Cancer therapies use different compounds of synthetic and natural origin. However, despite some positive results, relapses are common, as standard chemotherapy regimens are not fully capable of completely eradicating cancer stem cells. While vinblastine ... ...

Abstract	Cancer therapies use different compounds of synthetic and natural origin. However, despite some positive results, relapses are common, as standard chemotherapy regimens are not fully capable of completely eradicating cancer stem cells. While vinblastine is a common chemotherapeutic agent in the treatment of blood cancers, the development of vinblastine resistance is often observed. Here, we performed cell biology and metabolomics studies to investigate the mechanisms of vinblastine resistance in P3X63Ag8.653 murine myeloma cells. Treatment with low doses of vinblastine in cell media led to the selection of vinblastine-resistant cells and the acquisition of such resistance in previously untreated, murine myeloma cells in culture. To determine the mechanistic basis of this observation, we performed metabolomic analyses of resistant cells and resistant drug-induced cells in a steady state, or incubation with stable isotope-labeled tracers, namely, 13 C 15 N-amino acids. Taken together, these results indicate that altered amino acid uptake and metabolism could contribute to the acquisition of vinblastine resistance in blood cancer cells. These results will be useful for further research on human cell models.
Keywords	vinblastine ; drug resistance ; vinblastine-resistant cells ; metabolomic analyses ; murine myeloma cells ; Organic chemistry ; QD241-441
Subject code	610
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Auxin exposure disrupts feeding behavior and fatty acid metabolism in adult Drosophila

Sophie A Fleck / Puja Biswas / Emily D DeWitt / Rebecca L Knuteson / Robert C Eisman / Travis Nemkov / Angelo D'Alessandro / Jason M Tennessen / Elizabeth Rideout / Lesley N Weaver

eLife, Vol

2024 Volume 12

Abstract: The ease of genetic manipulation in Drosophila melanogaster using the Gal4/UAS system has been beneficial in addressing key biological questions. Current modifications of this methodology to temporally induce transgene expression require temperature ... ...

Abstract	The ease of genetic manipulation in Drosophila melanogaster using the Gal4/UAS system has been beneficial in addressing key biological questions. Current modifications of this methodology to temporally induce transgene expression require temperature changes or exposure to exogenous compounds, both of which have been shown to have detrimental effects on physiological processes. The recently described auxin-inducible gene expression system (AGES) utilizes the plant hormone auxin to induce transgene expression and is proposed to be the least toxic compound for genetic manipulation, with no obvious effects on Drosophila development and survival in one wild-type strain. Here, we show that auxin delays larval development in another widely used fly strain, and that short- and long-term auxin exposure in adult Drosophila induces observable changes in physiology and feeding behavior. We further reveal a dosage response to adult survival upon auxin exposure, and that the recommended auxin concentration for AGES alters feeding activity. Furthermore, auxin-fed male and female flies exhibit a significant decrease in triglyceride levels and display altered transcription of fatty acid metabolism genes. Although fatty acid metabolism is disrupted, auxin does not significantly impact adult female fecundity or progeny survival, suggesting AGES may be an ideal methodology for studying limited biological processes. These results emphasize that experiments using temporal binary systems must be carefully designed and controlled to avoid confounding effects and misinterpretation of results.
Keywords	auxin ; toxicology ; metabolism ; triglyceride ; oogenesis ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	590
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Metabolism navigates neural cell fate in development, aging and neurodegeneration

Larissa Traxler / Jessica Lagerwall / Sophie Eichhorner / Davide Stefanoni / Angelo D'Alessandro / Jerome Mertens

Disease Models & Mechanisms, Vol 14, Iss

2021 Volume 8

Abstract: An uninterrupted energy supply is critical for the optimal functioning of all our organs, and in this regard the human brain is particularly energy dependent. The study of energy metabolic pathways is a major focus within neuroscience research, which is ... ...

Abstract	An uninterrupted energy supply is critical for the optimal functioning of all our organs, and in this regard the human brain is particularly energy dependent. The study of energy metabolic pathways is a major focus within neuroscience research, which is supported by genetic defects in the oxidative phosphorylation mechanism often contributing towards neurodevelopmental disorders and changes in glucose metabolism presenting as a hallmark feature in age-dependent neurodegenerative disorders. However, as recent studies have illuminated roles of cellular metabolism that span far beyond mere energetics, it would be valuable to first comprehend the physiological involvement of metabolic pathways in neural cell fate and function, and to subsequently reconstruct their impact on diseases of the brain. In this Review, we first discuss recent evidence that implies metabolism as a master regulator of cell identity during neural development. Additionally, we examine the cell type-dependent metabolic states present in the adult brain. As metabolic states have been studied extensively as crucial regulators of malignant transformation in cancer, we reveal how knowledge gained from the field of cancer has aided our understanding in how metabolism likewise controls neural fate determination and stability by directly wiring into the cellular epigenetic landscape. We further summarize research pertaining to the interplay between metabolic alterations and neurodevelopmental and psychiatric disorders, and expose how an improved understanding of metabolic cell fate control might assist in the development of new concepts to combat age-dependent neurodegenerative diseases, particularly Alzheimer's disease.
Keywords	brain aging ; epigenetics ; metabolic state ; neural development ; psychiatric disorder ; Medicine ; R ; Pathology ; RB1-214
Subject code	570
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Maternal Pyrroloquinoline Quinone Supplementation Improves Offspring Liver Bioactive Lipid Profiles throughout the Lifespan and Protects against the Development of Adult NAFLD

Ashok Mandala / Evgenia Dobrinskikh / Rachel C. Janssen / Oliver Fiehn / Angelo D’Alessandro / Jacob E. Friedman / Karen R. Jonscher

International Journal of Molecular Sciences, Vol 23, Iss 6043, p

2022 Volume 6043

Abstract: Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric nonalcoholic fatty liver disease (NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with nonalcoholic steatohepatitis ( ... ...

Abstract	Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric nonalcoholic fatty liver disease (NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with nonalcoholic steatohepatitis (NASH), a leading etiology for liver transplant. Animal models show that signs of liver injury and perturbed lipid metabolism associated with NAFLD begin in utero; however, safe dietary therapeutics to blunt developmental programming of NAFLD are unavailable. Using a mouse model of maternal Western-style diet (WD), we previously showed that pyrroloquinoline quinone (PQQ), a potent dietary antioxidant, protected offspring of WD-fed dams from development of NAFLD and NASH. Here, we used untargeted mass spectrometry-based lipidomics to delineate lipotoxic effects of WD on offspring liver and identify lipid targets of PQQ. PQQ exposure during pregnancy altered hepatic lipid profiles of WD-exposed offspring, upregulating peroxisome proliferator-activated receptor (PPAR) α signaling and mitochondrial fatty acid oxidation to markedly attenuate triglyceride accumulation beginning in utero. Surprisingly, the abundance of very long-chain ceramides, important in promoting gut barrier and hepatic function, was significantly elevated in PQQ-treated offspring. PQQ exposure reduced the hepatic phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio in WD-fed offspring and improved glucose tolerance. Notably, levels of protective n − 3 polyunsaturated fatty acids (PUFAs) were elevated in offspring exposed to PQQ, beginning in utero, and the increase in n − 3 PUFAs persisted into adulthood. Our findings suggest that PQQ supplementation during gestation and lactation augments pathways involved in the biosynthesis of long-chain fatty acids and plays a unique role in modifying specific bioactive lipid species critical for protection against NAFLD risk in later life.
Keywords	pyrroloquinoline quinone ; pediatric NAFLD ; untargeted lipidomics ; very long-chain ceramides ; hepatic PC/PE ratio ; fatty acid oxidation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610 ; 571
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: p53-driven lipidome influences non-cell-autonomous lysophospholipids in pancreatic cancer

Alessio Butera / Micaela Roy / Carlotta Zampieri / Eleonora Mammarella / Emanuele Panatta / Gerry Melino / Angelo D’Alessandro / Ivano Amelio

Biology Direct, Vol 17, Iss 1, Pp 1-

2022 Volume 11

Abstract: Abstract Adaptation of the lipid metabolism participates in cancer pathogenesis, facilitating energy storage and influencing cell fate and control of molecular signalling. The tumour suppressor protein p53 is a molecular hub of cell metabolism, ... ...

Abstract	Abstract Adaptation of the lipid metabolism participates in cancer pathogenesis, facilitating energy storage and influencing cell fate and control of molecular signalling. The tumour suppressor protein p53 is a molecular hub of cell metabolism, supporting antioxidant capabilities and counteracting oncogene-induced metabolic switch. Despite extensive work has described the p53-dependent metabolic pathways, a global profiling of p53 lipidome is still missing. By high-throughput untargeted lipidomic analysis of pancreatic ductal adenocarcinoma (PDAC) cells, we profile the p53-dependent lipidome, revealing intracellular and secreted lysophospholipids as one of the most affected class. Lysophospholipids are hydrolysed forms of phospholipids that results from phospholipase activity, which can function as signalling molecules, exerting non-cell-autonomous effects and instructing cancer microenvironment and immunity. Here, we reveal that p53 depletion reduces abundance of intracellular lysophosphatidyl-choline, -ethanolamine and -serine and their secretion in the extracellular environment. By integrating this with genomic and transcriptomic studies from in vitro models and human PDAC patients, we identified potential clinically relevant candidate p53-dependent phospholipases. In particular PLD3, PLCB4 and PLCD4 expression is regulated by p53 and chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) indicates a direct transcriptional control on their chromatin accessible genomic loci. Consistently, PLD3, PLCB4 and PLCD4 expression correlates with p53 mutational status in PDAC patients, and these genes display prognostic significance. Overall, our data provide insights into lipidome rewiring driven by p53 loss and identify alterations of lysophospholipids as a potential molecular mechanism for p53-mediated non-cell-autonomous molecular signalling that instructs cancer microenvironment and immunity during PDAC pathogenesis.
Keywords	p53 ; Pancreatic cancer ; Lipid metabolism ; Phospholipase ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: ZOOMICS

Lorenzo Bertolone / Hye Kyung H. Shin / Jin Hyen Baek / Yamei Gao / Steven L. Spitalnik / Paul W. Buehler / Angelo D’Alessandro

Frontiers in Physiology, Vol

Comparative Metabolomics of Red Blood Cells From Guinea Pigs, Humans, and Non-human Primates During Refrigerated Storage for Up to 42 Days

2022 Volume 13

Abstract: Unlike other rodents, guinea pigs (Cavia porcellus) have evolutionarily lost their capacity to synthesize vitamin C (ascorbate) de novo and, like several non-human primates and humans, rely on dietary intake and glutathione-dependent recycling to cope ... ...

Abstract	Unlike other rodents, guinea pigs (Cavia porcellus) have evolutionarily lost their capacity to synthesize vitamin C (ascorbate) de novo and, like several non-human primates and humans, rely on dietary intake and glutathione-dependent recycling to cope with oxidant stress. This is particularly relevant in red blood cell physiology, and especially when modeling blood storage, which exacerbates erythrocyte oxidant stress. Herein we provide a comprehensive metabolomics analysis of fresh and stored guinea pig red blood cell concentrates (n = 20), with weekly sampling from storage day 0 through 42. Results were compared to previously published ZOOMICS studies on red blood cells from three additional species with genetic loss of L-gulonolactone oxidase function, including humans (n = 21), olive baboons (n = 20), and rhesus macaques (n = 20). While metabolic trends were comparable across all species, guinea pig red blood cells demonstrated accelerated alterations of the metabolic markers of the storage lesion that are consistent with oxidative stress. Compared to the other species, guinea pig red blood cells showed aberrant glycolysis, pentose phosphate pathway end product metabolites, purine breakdown products, methylation, glutaminolysis, and markers of membrane lipid remodeling. Consistently, guinea pig red blood cells demonstrated higher end storage hemolysis, and scanning electron microscopy confirmed a higher degree of morphological alterations of their red blood cells, as compared to the other species. Despite a genetic inability to produce ascorbate that is common to the species evaluated, guinea pig red blood cells demonstrate accelerated oxidant stress under standard storage conditions. These data may offer relevant insights into the basal and cold storage metabolism of red blood cells from species that cannot synthesize endogenous ascorbate.
Keywords	comparative biology ; erythrocyte ; rodent ; hemolysis ; metabolomics ; ascorbate ; Physiology ; QP1-981
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Moderate hypoxia induces metabolic divergence in circulating monocytes and tissue resident macrophages from Berkeley sickle cell anemia mice

Christina Lisk / Francesca Cendali / David I. Pak / Delaney Swindle / Kathryn Hassell / Rachelle Nuss / Gemlyn George / Pavel Davizon-Castillo / Paul W. Buehler / Angelo D’Alessandro / David C. Irwin

Frontiers in Medicine, Vol

2023 Volume 10

Abstract: IntroductionHuman and murine sickle cell disease (SCD) associated pulmonary hypertension (PH) is defined by hemolysis, nitric oxide depletion, inflammation, and thrombosis. Further, hemoglobin (Hb), heme, and iron accumulation are consistently observed ... ...

Abstract	IntroductionHuman and murine sickle cell disease (SCD) associated pulmonary hypertension (PH) is defined by hemolysis, nitric oxide depletion, inflammation, and thrombosis. Further, hemoglobin (Hb), heme, and iron accumulation are consistently observed in pulmonary adventitial macrophages at autopsy and in hypoxia driven rodent models of SCD, which show distribution of ferric and ferrous Hb as well as HO-1 and ferritin heavy chain. The anatomic localization of these macrophages is consistent with areas of significant vascular remodeling. However, their contributions toward progressive disease may include unique, but also common mechanisms, that overlap with idiopathic and other forms of pulmonary hypertension. These processes likely extend to the vasculature of other organs that are consistently impaired in advanced SCD.MethodsTo date, limited information is available on the metabolism of macrophages or monocytes isolated from lung, spleen, and peripheral blood in humans or murine models of SCD.ResultsHere we hypothesize that metabolism of macrophages and monocytes isolated from this triad of tissue differs between Berkley SCD mice exposed for ten weeks to moderate hypobaric hypoxia (simulated 8,000 ft, 15.4% O2) or normoxia (Denver altitude, 5000 ft) with normoxia exposed wild type mice evaluated as controls.DiscussionThis study represents an initial set of data that describes the metabolism in monocytes and macrophages isolated from moderately hypoxic SCD mice peripheral lung, spleen, and blood mononuclear cells.
Keywords	sickle cell disease ; hypoxia ; spleen ; pulmonary hypertension ; metabolic disease ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Blood bank storage of red blood cells increases RBC cytoplasmic membrane order and bending rigidity.

Sebastian Himbert / Syed M Qadri / William P Sheffield / Peter Schubert / Angelo D'Alessandro / Maikel C Rheinstädter

PLoS ONE, Vol 16, Iss 11, p e

2021 Volume 0259267

Abstract: Blood banks around the world store blood components for several weeks ensuring its availability for transfusion medicine. Red blood cells (RBCs) are known to undergo compositional changes during storage, which may impact the cells' function and ... ...

Abstract	Blood banks around the world store blood components for several weeks ensuring its availability for transfusion medicine. Red blood cells (RBCs) are known to undergo compositional changes during storage, which may impact the cells' function and eventually the recipients' health. We extracted the RBC's cytoplasmic membrane (RBCcm) to study the effect of storage on the membranes' molecular structure and bending rigidity by a combination of X-ray diffraction (XRD), X-ray diffuse scattering (XDS) and coarse grained Molecular Dynamics (MD) simulations. Blood was stored in commercial blood bags for 2 and 5 weeks, respectively and compared to freshly drawn blood. Using mass spectrometry, we measured an increase of fatty acids together with a slight shift towards shorter tail lengths. We observe an increased fraction (6%) of liquid ordered (lo) domains in the RBCcms with storage time, and an increased lipid packing in these domains, leading to an increased membrane thickness and membrane order. The size of both, lo and liquid disordered (ld) lipid domains was found to decrease with increased storage time by up to 25%. XDS experiments reveal a storage dependent increase in the RBCcm's bending modulus κ by a factor of 2.8, from 1.9 kBT to 5.3 kBT. MD simulations were conducted in the absence of proteins. The results show that the membrane composition has a small contribution to the increased bending rigidity and suggests additional protein-driven mechanisms.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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