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Article ; Online: Cancer evaluation in dogs using cerumen as a source for volatile biomarker prospection.

Barbosa, João Marcos G / Shokry, Engy / Caetano David, Lurian / Pereira, Naiara Z / da Silva, Adriana R / de Oliveira, Vilma F / Fioravanti, Maria Clorinda S / da Cunha, Paulo H Jorge / de Oliveira, Anselmo E / Antoniosi Filho, Nelson Roberto

Molecular omics

2024 Volume 20, Issue 1, Page(s) 27–36

Abstract: Cancer is one of the deadliest diseases in humans and dogs. Nevertheless, most tumor types spread faster in canines, and early cancer detection methods are necessary to enhance animal survival. Here, cerumen (earwax) was tested as a source of potential ... ...

Abstract	Cancer is one of the deadliest diseases in humans and dogs. Nevertheless, most tumor types spread faster in canines, and early cancer detection methods are necessary to enhance animal survival. Here, cerumen (earwax) was tested as a source of potential biomarkers for cancer evaluation in dogs. Earwax samples from dogs were collected from tumor-bearing and clinically healthy dogs, followed by Headspace/Gas Chromatography-Mass Spectrometry (HS/GC-MS) analyses and multivariate statistical workflow. An evolutionary-based multivariate algorithm selected 18 out of 128 volatile metabolites as a potential cancer biomarker panel in dogs. The candidate biomarkers showed a full discrimination pattern between tumor-bearing dogs and cancer-free canines with high accuracy in the test dataset: an accuracy of 95.0% (75.1-99.9), and sensitivity and specificity of 100.0% and 92.9%, respectively. In summary, this work raises a new perspective on cancer diagnosis in dogs, being carried out painlessly and non-invasive, facilitating sample collection and periodic application in a veterinary routine.
MeSH term(s)	Humans ; Dogs ; Animals ; Cerumen/chemistry ; Cerumen/metabolism ; Volatile Organic Compounds/analysis ; Volatile Organic Compounds/chemistry ; Volatile Organic Compounds/metabolism ; Neoplasms/diagnosis ; Neoplasms/veterinary ; Neoplasms/metabolism ; Biomarkers, Tumor/metabolism ; Gas Chromatography-Mass Spectrometry/methods
Chemical Substances	Volatile Organic Compounds ; Biomarkers, Tumor
Language	English
Publishing date	2024-01-15
Publishing country	England
Document type	Journal Article
ISSN	2515-4184
ISSN (online)	2515-4184
DOI	10.1039/d3mo00147d
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Article ; Online: Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing.

Zarou, Martha M / Rattigan, Kevin M / Sarnello, Daniele / Shokry, Engy / Dawson, Amy / Ianniciello, Angela / Dunn, Karen / Copland, Mhairi / Sumpton, David / Vazquez, Alexei / Helgason, G Vignir

Nature communications

2024 Volume 15, Issue 1, Page(s) 1931

Abstract: Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in ... ...

Abstract	Supporting cell proliferation through nucleotide biosynthesis is an essential requirement for cancer cells. Hence, inhibition of folate-mediated one carbon (1C) metabolism, which is required for nucleotide synthesis, has been successfully exploited in anti-cancer therapy. Here, we reveal that mitochondrial folate metabolism is upregulated in patient-derived leukaemic stem cells (LSCs). We demonstrate that inhibition of mitochondrial 1C metabolism through impairment of de novo purine synthesis has a cytostatic effect on chronic myeloid leukaemia (CML) cells. Consequently, changes in purine nucleotide levels lead to activation of AMPK signalling and suppression of mTORC1 activity. Notably, suppression of mitochondrial 1C metabolism increases expression of erythroid differentiation markers. Moreover, we find that increased differentiation occurs independently of AMPK signalling and can be reversed through reconstitution of purine levels and reactivation of mTORC1. Of clinical relevance, we identify that combination of 1C metabolism inhibition with imatinib, a frontline treatment for CML patients, decreases the number of therapy-resistant CML LSCs in a patient-derived xenograft model. Our results highlight a role for folate metabolism and purine sensing in stem cell fate decisions and leukaemogenesis.
MeSH term(s)	Humans ; Mechanistic Target of Rapamycin Complex 1 ; AMP-Activated Protein Kinases ; Purines/therapeutic use ; Purine Nucleotides ; Leukemia, Myeloid ; Folic Acid/metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
Chemical Substances	Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; AMP-Activated Protein Kinases (EC 2.7.11.31) ; Purines ; Purine Nucleotides ; Folic Acid (935E97BOY8)
Language	English
Publishing date	2024-03-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-46114-0
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Article ; Online: Sarcopenia: investigation of metabolic changes and its associated mechanisms.

Marques, Jair / Shokry, Engy / Uhl, Olaf / Baber, Lisa / Hofmeister, Fabian / Jarmusch, Stefanie / Bidlingmaier, Martin / Ferrari, Uta / Koletzko, Berthold / Drey, Michael

Skeletal muscle

2023 Volume 13, Issue 1, Page(s) 2

Abstract: Background: Sarcopenia is one of the most predominant musculoskeletal diseases of the elderly, defined as age-related progressive and generalized loss of muscle mass with a simultaneous reduction in muscle strength and/or function. Using metabolomics, ... ...

Abstract	Background: Sarcopenia is one of the most predominant musculoskeletal diseases of the elderly, defined as age-related progressive and generalized loss of muscle mass with a simultaneous reduction in muscle strength and/or function. Using metabolomics, we aimed to examine the association between sarcopenia and the plasma metabolic profile of sarcopenic patients, measured using a targeted HPLC-MS/MS platform. Methods: Plasma samples from 22 (17 men) hip fracture patients undergoing surgery (8 sarcopenic, age 81.4+6.3, and 14 non-sarcopenic, age 78.4±8.1) were analyzed. T test, fold change, orthogonal partial least squares discriminant analysis, and sparse partial least squares discriminant analysis were used for mining significant features. Metabolite set enrichment analysis and mediation analysis by PLSSEM were thereafter performed. Results: Using a univariate analysis for sarcopenia z score, the amino acid citrulline was the only metabolite with a significant group difference after FDR correction. Positive trends were observed between the sarcopenia z score and very long-chain fatty acids as well as dicarboxylic acid carnitines. Multivariate analysis showed citrulline, non-esterified fatty acid 26:2, and decanedioyl carnitine as the top three metabolites according to the variable importance in projection using oPLS-DA and loadings weight by sPLS-DA. Metabolite set enrichment analysis showed carnitine palmitoyltransferase deficiency (II) as the highest condition related to the metabolome. Conclusions: We observed a difference in the plasma metabolic profile in association with different measures of sarcopenia, which identifies very long-chain fatty acids, Carn.DC and citrulline as key variables associated with the disease severity. These findings point to a potential link between sarcopenia and mitochondrial dysfunction and portraits a number of possible biochemical pathways which might be involved in the disease pathogenesis.
MeSH term(s)	Male ; Humans ; Aged ; Aged, 80 and over ; Sarcopenia ; Citrulline ; Tandem Mass Spectrometry ; Metabolomics ; Fatty Acids/metabolism
Chemical Substances	Citrulline (29VT07BGDA) ; Fatty Acids
Language	English
Publishing date	2023-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2595637-1
ISSN	2044-5040 ; 2044-5040
ISSN (online)	2044-5040
ISSN	2044-5040
DOI	10.1186/s13395-022-00312-w
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Article: Insights into cerumen and application in diagnostics: past, present and future prospective.

Shokry, Engy / Filho, Nelson Roberto Antoniosi

Biochemia medica

2017 Volume 27, Issue 3, Page(s) 30503

Abstract: Cerumen or earwax is an emerging bio-fluid in clinical diagnosis that has been very little exploited during the past decades in spite of its high diagnostic potential. It is highly abundant in diagnostic biomarkers such as genetic material, lipids, ... ...

Abstract	Cerumen or earwax is an emerging bio-fluid in clinical diagnosis that has been very little exploited during the past decades in spite of its high diagnostic potential. It is highly abundant in diagnostic biomarkers such as genetic material, lipids, proteins, chemical elements, internal and external metabolites (
MeSH term(s)	Biomarkers/chemistry ; Biomarkers/metabolism ; Cerumen/chemistry ; Cerumen/metabolism ; Diabetes Mellitus/diagnosis ; Diabetes Mellitus/metabolism ; Humans ; Metabolomics ; Parkinson Disease/diagnosis ; Parkinson Disease/metabolism ; Proteomics
Chemical Substances	Biomarkers
Language	English
Publishing date	2017-11-27
Publishing country	Croatia
Document type	Journal Article ; Review
ZDB-ID	1208725-7
ISSN	1846-7482 ; 1330-0962
ISSN (online)	1846-7482
ISSN	1330-0962
DOI	10.11613/BM.2017.030503
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Article ; Online: ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota.

Eberhart, Tanja / Stanley, Federico Uchenna / Ricci, Luisa / Chirico, Tiziana / Ferrarese, Roberto / Sisti, Sofia / Scagliola, Alessandra / Baj, Andreina / Badurek, Sylvia / Sommer, Andreas / Culp-Hill, Rachel / Dzieciatkowska, Monika / Shokry, Engy / Sumpton, David / D'Alessandro, Angelo / Clementi, Nicola / Mancini, Nicasio / Cardaci, Simone

Cell death & disease

2024 Volume 15, Issue 2, Page(s) 105

Abstract: Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, ... ...

Abstract	Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.
MeSH term(s)	Animals ; Mice ; Diet, High-Fat/adverse effects ; Gastrointestinal Microbiome ; Mice, Inbred C57BL ; Obesity/metabolism ; Succinates
Chemical Substances	itaconic acid (Q4516562YH) ; Succinates ; Irg1 protein, mouse (EC 4.2.1.79)
Language	English
Publishing date	2024-02-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-024-06483-2
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Article ; Online: Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.

Mahmood, Mahnoor / Liu, Eric Minwei / Shergold, Amy L / Tolla, Elisabetta / Tait-Mulder, Jacqueline / Huerta-Uribe, Alejandro / Shokry, Engy / Young, Alex L / Lilla, Sergio / Kim, Minsoo / Park, Tricia / Boscenco, Sonia / Manchon, Javier L / Rodríguez-Antona, Crístina / Walters, Rowan C / Springett, Roger J / Blaza, James N / Mitchell, Louise / Blyth, Karen /

Zanivan, Sara / Sumpton, David / Roberts, Edward W / Reznik, Ed / Gammage, Payam A

Nature cancer

2024 Volume 5, Issue 4, Page(s) 659–672

Abstract: The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is ... ...

Abstract	The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.
MeSH term(s)	DNA, Mitochondrial/genetics ; Animals ; Melanoma/genetics ; Melanoma/drug therapy ; Mutation ; Mice ; Humans ; Immune Checkpoint Inhibitors/therapeutic use ; Immune Checkpoint Inhibitors/pharmacology ; Glycolysis/genetics ; Tumor Microenvironment ; Cell Line, Tumor ; Electron Transport Complex I/genetics ; Electron Transport Complex I/metabolism ; Neutrophils/metabolism ; Neutrophils/immunology ; Mitochondria/metabolism ; Mitochondria/genetics ; Oxidative Phosphorylation/drug effects
Chemical Substances	DNA, Mitochondrial ; Immune Checkpoint Inhibitors ; Electron Transport Complex I (EC 7.1.1.2)
Language	English
Publishing date	2024-01-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-023-00721-w
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Article ; Online: Arginine dependency is a therapeutically exploitable vulnerability in chronic myeloid leukaemic stem cells.

Rattigan, Kevin M / Zarou, Martha M / Brabcova, Zuzana / Prasad, Bodhayan / Zerbst, Désirée / Sarnello, Daniele / Kalkman, Eric R / Ianniciello, Angela / Scott, Mary T / Dunn, Karen / Shokry, Engy / Sumpton, David / Copland, Mhairi / Tardito, Saverio / Vande Voorde, Johan / Mussai, Francis / Cheng, Paul / Helgason, G Vignir

EMBO reports

2023 Volume 24, Issue 10, Page(s) e56279

Abstract: To fuel accelerated proliferation, leukaemic cells undergo metabolic deregulation, which can result in specific nutrient dependencies. Here, we perform an amino acid drop-out screen and apply pre-clinical models of chronic phase chronic myeloid leukaemia ...

Abstract	To fuel accelerated proliferation, leukaemic cells undergo metabolic deregulation, which can result in specific nutrient dependencies. Here, we perform an amino acid drop-out screen and apply pre-clinical models of chronic phase chronic myeloid leukaemia (CML) to identify arginine as a nutrient essential for primary human CML cells. Analysis of the Microarray Innovations in Leukaemia (MILE) dataset uncovers reduced ASS1 levels in CML compared to most other leukaemia types. Stable isotope tracing reveals repressed activity of all urea cycle enzymes in patient-derived CML CD34
MeSH term(s)	Humans ; Arginine/metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism ; Apoptosis ; Stem Cells/metabolism ; Neoplastic Stem Cells/metabolism
Chemical Substances	Arginine (94ZLA3W45F)
Language	English
Publishing date	2023-07-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.202256279
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Zs.A 5433: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 41: Show issues

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Article ; Online: Associations of maternal and infant metabolite profiles with foetal growth and the odds of adverse birth outcomes.

Voerman, Ellis / Jaddoe, Vincent W V / Shokry, Engy / Ruijter, George J G / Felix, Janine F / Koletzko, Berthold / Gaillard, Romy

Pediatric obesity

2021 Volume 17, Issue 2, Page(s) e12844

Abstract: Background: Adaptations in maternal and foetal metabolic pathways may predispose to altered foetal growth and adverse birth outcomes.: Objective: To assess the associations of maternal early-pregnancy metabolite profiles and infant metabolite ... ...

Abstract	Background: Adaptations in maternal and foetal metabolic pathways may predispose to altered foetal growth and adverse birth outcomes. Objective: To assess the associations of maternal early-pregnancy metabolite profiles and infant metabolite profiles at birth with foetal growth from first trimester onwards and the odds of adverse birth outcomes. Methods: In a prospective population-based cohort among 976 Dutch pregnant women and their children, serum concentrations of amino acids, non-esterified fatty acids (NEFA), phospholipids (PL) and carnitines in maternal early-pregnancy blood and in cord blood were obtained by liquid-chromatography tandem mass spectrometry. Information on foetal growth was available from first trimester onwards. Results: After false discovery rate correction for multiple testing, higher infant total and individual NEFA concentrations were associated with a lower weight, length, and head circumference at birth. Higher infant total and individual acyl-lysophosphatidylcholine (lyso.PC.a) and alkyl-lysophosphatidylcholine concentrations were associated with higher weight and head circumference (lyso.PC.a only) at birth, higher odds of LGA and lower odds of SGA. Few individual maternal metabolites were associated with foetal growth measures in third trimester and at birth, but not with the odds of adverse birth outcomes. Conclusions: Our results suggest that infant metabolite profiles, particularly total and individual lyso.PC.a and NEFA concentrations, were strongly related to growth measures at birth and the odds of adverse birth outcomes. Few individual maternal early-pregnancy metabolites, but not total metabolite concentrations, are associated with foetal growth measures in third trimester and at birth.
MeSH term(s)	Birth Weight ; Child ; Chromatography, Liquid ; Cohort Studies ; Female ; Fetal Development ; Humans ; Infant ; Infant, Newborn ; Pregnancy ; Pregnancy Complications ; Prospective Studies
Language	English
Publishing date	2021-08-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2655527-X
ISSN	2047-6310 ; 2047-6302
ISSN (online)	2047-6310
ISSN	2047-6302
DOI	10.1111/ijpo.12844
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Zs.A 6619: Show issues

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Article ; Online: Mesenchymal stromal cells cultured in physiological conditions sustain citrate secretion with glutamate anaplerosis.

Taurino, Giuseppe / Deshmukh, Ruhi / Villar, Victor H / Chiu, Martina / Shaw, Robin / Hedley, Ann / Shokry, Engy / Sumpton, David / Dander, Erica / D'Amico, Giovanna / Bussolati, Ovidio / Tardito, Saverio

Molecular metabolism

2022 Volume 63, Page(s) 101532

Abstract: Bone marrow mesenchymal stromal cells (MSCs) have immunomodulatory and regenerative potential. However, culture conditions govern their metabolic processes and therapeutic efficacy. Here we show that culturing donor-derived MSCs in Plasmax™, a ... ...

Abstract	Bone marrow mesenchymal stromal cells (MSCs) have immunomodulatory and regenerative potential. However, culture conditions govern their metabolic processes and therapeutic efficacy. Here we show that culturing donor-derived MSCs in Plasmax™, a physiological medium with the concentrations of nutrients found in human plasma, supports their proliferation and stemness, and prevents the nutritional stress induced by the conventional medium DMEM. The quantification of the exchange rates of metabolites between cells and medium, untargeted metabolomics, stable isotope tracing and transcriptomic analysis, performed at physiologically relevant oxygen concentrations (1%O
MeSH term(s)	Bone Marrow Cells ; Citrates/metabolism ; Glucose/metabolism ; Glutamic Acid/metabolism ; Humans ; Mesenchymal Stem Cells/metabolism
Chemical Substances	Citrates ; Glutamic Acid (3KX376GY7L) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-06-22
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2022.101532
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Article: Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade.

bioRxiv : the preprint server for biology

2023

Abstract: The mitochondrial genome encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutation in the cancer genome, with truncating mutations in respiratory complex I genes being ... ...

Abstract	The mitochondrial genome encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutation in the cancer genome, with truncating mutations in respiratory complex I genes being most over-represented
Language	English
Publishing date	2023-03-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.21.533091
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