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Article ; Online: Multiomics Signatures of Coagulopathy in a Polytrauma Swine Model Contrasted with Severe Multisystem Injured Patients.

LaCroix, Ian S / Moore, Ernest E / Cralley, Alexis / Cendali, Francesca I / Dzieciatkowska, Monika / Hom, Patrick / Mitra, Sanchayita / Cohen, Mitchell / Silliman, Christopher / Hansen, Kirk C / D'Alessandro, Angelo

Journal of proteome research

2024 Volume 23, Issue 4, Page(s) 1163–1173

Abstract: Trauma-induced coagulopathy (TIC) is a leading contributor to preventable mortality in severely injured patients. Understanding the molecular drivers of TIC is an essential step in identifying novel therapeutics to reduce morbidity and mortality. This ... ...

Abstract	Trauma-induced coagulopathy (TIC) is a leading contributor to preventable mortality in severely injured patients. Understanding the molecular drivers of TIC is an essential step in identifying novel therapeutics to reduce morbidity and mortality. This study investigated multiomics and viscoelastic responses to polytrauma using our novel swine model and compared these findings with severely injured patients. Molecular signatures of TIC were significantly associated with perturbed coagulation and inflammation systems as well as extensive hemolysis. These results were consistent with patterns observed in trauma patients who had multisystem injuries. Here, intervention using resuscitative endovascular balloon occlusion of the aorta following polytrauma in our swine model revealed distinct multiomics alterations as a function of placement location. Aortic balloon placement in zone-1 worsened ischemic damage and mitochondrial dysfunction, patterns that continued throughout the monitored time course. While placement in zone-III showed a beneficial effect on TIC, it showed an improvement in effective coagulation. Taken together, this study highlights the translational relevance of our polytrauma swine model for investigating therapeutic interventions to correct TIC in patients.
MeSH term(s)	Humans ; Animals ; Swine ; Multiomics ; Multiple Trauma/complications ; Multiple Trauma/therapy ; Aorta ; Blood Coagulation ; Balloon Occlusion/methods
Language	English
Publishing date	2024-02-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.3c00581
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Article: Metabolic correlates to critical speed in murine models of sickle cell disease.

Cendali, Francesca I / Nemkov, Travis / Lisk, Christina / Lacroix, Ian S / Nouraie, Seyed-Mehdi / Zhang, Yingze / Gordeuk, Victor R / Buehler, Paul W / Irwin, David / D'Alessandro, Angelo

Frontiers in physiology

2023 Volume 14, Page(s) 1151268

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2023-03-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2023.1151268
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Article ; Online: Omics Signatures of Tissue Injury and Hemorrhagic Shock in Swine.

LaCroix, Ian S / Cralley, Alexis / Moore, Ernest E / Cendali, Francesca I / Dzieciatkowska, Monika / Hom, Patrick / Mitra, Sanchayita / Cohen, Mitchell / Silliman, Christopher / Sauaia, Angela / Hansen, Kirk C / D'Alessandro, Angelo

Annals of surgery

2023 Volume 278, Issue 6, Page(s) e1299–e1312

Abstract: Objective: Advanced mass spectrometry methods were leveraged to analyze both proteomics and metabolomics signatures in plasma upon controlled tissue injury (TI) and hemorrhagic shock (HS)-isolated or combined-in a swine model, followed by correlation to ...

Abstract	Objective: Advanced mass spectrometry methods were leveraged to analyze both proteomics and metabolomics signatures in plasma upon controlled tissue injury (TI) and hemorrhagic shock (HS)-isolated or combined-in a swine model, followed by correlation to viscoelastic measurements of coagulopathy via thrombelastography. Background: TI and HS cause distinct molecular changes in plasma in both animal models and trauma patients. However, the contribution to coagulopathy of trauma, the leading cause of preventable mortality in this patient population remains unclear. The recent development of a swine model for isolated or combined TI+HS facilitated the current study. Methods: Male swine (n=17) were randomized to either isolated or combined TI and HS. Coagulation status was analyzed by thrombelastography during the monitored time course. The plasma fractions of the blood draws (at baseline; end of shock; and at 30 minutes, 1, 2, and 4 hours after shock) were analyzed by mass spectrometry-based proteomics and metabolomics workflows. Results: HS-isolated or combined with TI-caused the most severe omic alterations during the monitored time course. While isolated TI delayed the activation of coagulation cascades. Correlation to thrombelastography parameters of clot strength (maximum amplitude) and breakdown (LY30) revealed signatures of coagulopathy which were supported by analysis of gene ontology-enriched biological pathways. Conclusion: The current study provides a comprehensive characterization of proteomic and metabolomic alterations to combined or isolated TI and HS in a swine model and identifies early and late omics correlates to viscoelastic measurements in this system.
MeSH term(s)	Animals ; Male ; Blood Coagulation ; Blood Coagulation Disorders/etiology ; Disease Models, Animal ; Proteomics ; Shock, Hemorrhagic/complications ; Swine ; Thrombelastography ; Random Allocation
Language	English
Publishing date	2023-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	340-2
ISSN	1528-1140 ; 0003-4932
ISSN (online)	1528-1140
ISSN	0003-4932
DOI	10.1097/SLA.0000000000005944
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Article: Prevalence and Clinical Implications of Heightened Plastic Chemical Exposure in Pediatric Patients Undergoing Cardiopulmonary Bypass.

Guerrelli, Devon / Desai, Manan / Semaan, Youssef / Essa, Yasin / Zurakowski, David / Cendali, Francesca I / Reisz, Julie A / D'Alessandro, Angelo / Luban, Naomi C / Posnack, Nikki Gillum

medRxiv : the preprint server for health sciences

2023

Abstract: Importance: Phthalate chemicals are used to manufacture disposable plastic medical products, including blood storage bags and components of cardiopulmonary bypass (CPB) circuits. During cardiac surgery, patients can be inadvertently exposed to phthalate ...

Abstract	Importance: Phthalate chemicals are used to manufacture disposable plastic medical products, including blood storage bags and components of cardiopulmonary bypass (CPB) circuits. During cardiac surgery, patients can be inadvertently exposed to phthalate chemicals that are released from these plastic products. Objective: To quantify iatrogenic phthalate chemical exposure in pediatric patients undergoing cardiac surgery, and examine the link between phthalate exposure and post-operative outcomes. Design setting and participants: The study cohort included 122 pediatric patients undergoing cardiac surgery at Children's National Hospital. For each patient, a single plasma sample was collected pre-operatively and two additional samples were collected post-operatively upon return from the operating room (post-operative day 0) and the morning after surgery (post-operative day 1). Exposures: Concentrations of di(2-ethylhexyl)phthalate (DEHP) and its metabolites were quantified using ultra high-pressure liquid chromatography coupled to mass spectrometry. Main outcomes and measures: Plasma concentrations of phthalates, post-operative blood gas measurements, and post-operative complications. Results: Study subjects were subdivided into three groups, according to surgical procedure: 1) cardiac surgery not requiring CPB support, 2) cardiac surgery requiring CPB with crystalloid prime, and 3) cardiac surgery requiring CPB with red blood cells (RBCs) to prime the circuit. Phthalate metabolites were detected in all patients, and postoperative phthalate levels were highest in patients undergoing CPB with RBC-based prime. Age-matched (<1 year) CPB patients with elevated phthalate exposure were more likely to experience post-operative complications, including arrhythmias, low cardiac output syndrome, and additional post-operative interventions. RBC washing was an effective strategy to reduce DEHP levels in CPB prime. Conclusions and relevance: Pediatric cardiac surgery patients are exposed to phthalate chemicals from plastic medical products, and the degree of exposure increases in the context of CPB with RBC-based prime. Additional studies are warranted to measure the direct effect of phthalates on patient health outcomes and investigate mitigation strategies to reduce exposure. Key points: Question:
Language	English
Publishing date	2023-05-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.02.23289379
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Article ; Online: The solute carrier family 7 member 11 (SLC7A11) is regulated by LH/androgen and required for cystine/glutathione homeostasis in mouse Sertoli cells.

Liu, Zhenghui / Wang, Huizen / Larsen, Mark / Gunewardana, Sumedha / Cendali, Francesca I / Reisz, Julie A / Akiyama, Haruhiko / Behringer, Richard R / Ma, Qianyi / Hammoud, S Sue / Kumar, T Rajendra

Molecular and cellular endocrinology

2022 Volume 549, Page(s) 111641

Abstract: Luteinizing hormone (LH) stimulates testosterone production from Leydig cells. Both LH and testosterone play important roles in spermatogenesis and male fertility. To identify LH - and testosterone - responsive transporter genes that play key roles in ... ...

Abstract	Luteinizing hormone (LH) stimulates testosterone production from Leydig cells. Both LH and testosterone play important roles in spermatogenesis and male fertility. To identify LH - and testosterone - responsive transporter genes that play key roles in spermatogenesis, we performed large-scale gene expression analyses on testes obtained from adult control and Lhb knockout mice. We found a significant reduction in cystine/glutamate transporter encoding Slc7a11 mRNA in testes of Lhb null mice. We observed that Slc7a11/SLC7A11 expression was initiated pre-pubertally and developmentally regulated in mouse testis. Immunolocalization studies confirmed that SLC7A11 was mostly expressed in Sertoli cells in testes of control and germ cell-deficient mice. Western blot analyses indicated that SLC7A11 was significantly reduced in testes of mutant mice lacking either LH or androgen receptor selectively in Sertoli cells. Genetic and pharmacological rescue of Lhb knockout mice restored the testicular expression of Slc7a11 comparable to that observed in controls. Additionally, Slc7a11 mRNA was significantly suppressed upon Sertoli cell/testicular damage induced in mice by cadmium treatment. Knockdown of Slc7a11 in vitro in TM4 Sertoli cells or treatment of mice with sulfasalazine, a SLC7A11 inhibitor caused a significant reduction in intracellular cysteine and glutathione levels but glutamate content remained unchanged as determined by metabolomic analysis. Knockdown of Slc7a11 resulted in compensatory upregulation of other glutamate transporters belonging to the Slc1a family presumably to maintain intracellular glutamate levels. Collectively, our studies identified that SLC7A11 is an LH/testosterone-regulated transporter that is required for cysteine/glutathione but not glutamate homeostasis in mouse Sertoli cells.
MeSH term(s)	Amino Acid Transport System y+/metabolism ; Androgens/metabolism ; Animals ; Cysteine/metabolism ; Cystine/metabolism ; Glutamates/metabolism ; Glutathione/metabolism ; Homeostasis ; Leydig Cells/metabolism ; Luteinizing Hormone/pharmacology ; Male ; Mice ; Mice, Knockout ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Sertoli Cells/metabolism ; Spermatogenesis ; Testis/metabolism ; Testosterone/pharmacology
Chemical Substances	Amino Acid Transport System y+ ; Androgens ; Glutamates ; RNA, Messenger ; Slc7a11 protein, mouse ; Testosterone (3XMK78S47O) ; Cystine (48TCX9A1VT) ; Luteinizing Hormone (9002-67-9) ; Glutathione (GAN16C9B8O) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2022-04-06
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2022.111641
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Article: Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC).

Guntur, Vamsi P / Nemkov, Travis / de Boer, Esther / Mohning, Michael P / Baraghoshi, David / Cendali, Francesca I / San-Millán, Inigo / Petrache, Irina / D'Alessandro, Angelo

Metabolites

2022 Volume 12, Issue 11

Abstract: Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower ... ...

Abstract	Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan-a hallmark of disease severity in COVID-19-is not normalized in PASC patients, despite normalization of kynurenine levels-a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.
Language	English
Publishing date	2022-10-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo12111026
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Article: The solute carrier family 7 member 11 (SLC7A11) is regulated by LH/androgen and required for cystine/glutathione homeostasis in mouse Sertoli cells

Liu, Zhenghui / Wang, Huizen / Larsen, Mark / Gunewardana, Sumedha / Cendali, Francesca I. / Reisz, Julie R. / Akiyama, Haruhiko / Behringer, Richard R. / Ma, Qianyi / Hammoud, S. Sue / Kumar, T. Rajendra

Molecular and cellular endocrinology. 2022 Apr. 02,

2022

Abstract	Luteinizing hormone (LH) stimulates testosterone production from Leydig cells. Both LH and testosterone play important roles in spermatogenesis and male fertility. To identify LH - and testosterone - responsive transporter genes that play key roles in spermatogenesis, we performed large-scale gene expression analyses on testes obtained from adult control and Lhb knockout mice. We found a significant reduction in cystine/glutamate transporter encoding Slc7a11 mRNA in testes of Lhb null mice. We observed that Slc7a11/SLC7A11 expression was initiated pre-pubertally and developmentally regulated in mouse testis. Immunolocalization studies confirmed that SLC7A11 was mostly expressed in Sertoli cells in testes of control and germ cell-deficient mice. Western blot analyses indicated that SLC7A11 was significantly reduced in testes of mutant mice lacking either LH or androgen receptor selectively in Sertoli cells. Genetic and pharmacological rescue of Lhb knockout mice restored the testicular expression of Slc7a11 comparable to that observed in controls. Additionally, Slc7a11 mRNA was significantly suppressed upon Sertoli cell/testicular damage induced in mice by cadmium treatment. Knockdown of Slc7a11 in vitro in TM4 Sertoli cells or treatment of mice with sulfasalazine, a SLC7A11 inhibitor caused a significant reduction in intracellular cysteine and glutathione levels but glutamate content remained unchanged as determined by metabolomic analysis. Knockdown of Slc7a11 resulted in compensatory upregulation of other glutamate transporters belonging to the Slc1a family presumably to maintain intracellular glutamate levels. Collectively, our studies identified that SLC7A11 is an LH/testosterone-regulated transporter that is required for cysteine/glutathione but not glutamate homeostasis in mouse Sertoli cells.
Keywords	Sertoli cells ; Western blotting ; adults ; androgen receptors ; cadmium ; cysteine ; cystine ; gene expression ; glutamic acid ; glutathione ; homeostasis ; luteinizing hormone ; male fertility ; metabolomics ; mice ; solutes ; spermatogenesis ; sulfasalazine ; testosterone
Language	English
Dates of publication	2022-0402
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2022.111641
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19.

Cells

2021 Volume 10, Issue 9

Abstract: The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. The present large study sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831) that tested positive ( ... ...

Abstract	The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. The present large study sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831) that tested positive (n = 543) or negative (n = 288) for COVID-19. High-throughput metabolomics analyses were complemented with antigen and enzymatic activity assays on plasma from acutely ill patients collected while in the emergency department, at admission, or during hospitalization. Lipidomics analyses were also performed on COVID-19-positive or -negative subjects with the lowest and highest body mass index (n = 60/group). Significant changes in amino acid and fatty acid/acylcarnitine metabolism emerged as highly relevant markers of disease severity, progression, and prognosis as a function of biological and clinical variables in these patients. Further, machine learning models were trained by entering all metabolomics and clinical data from half of the COVID-19 patient cohort and then tested on the other half, yielding ~78% prediction accuracy. Finally, the extensive amount of information accumulated in this large, prospective, observational study provides a foundation for mechanistic follow-up studies and data sharing opportunities, which will advance our understanding of the characteristics of the plasma metabolism in COVID-19 and other acute critical illnesses.
MeSH term(s)	Acute Disease ; Adult ; Amino Acids/blood ; Body Mass Index ; COVID-19/metabolism ; Carnitine/analogs & derivatives ; Carnitine/blood ; Cohort Studies ; Fatty Acids/blood ; Female ; Humans ; Kynurenine/blood ; Machine Learning ; Metabolomics ; Middle Aged ; Prognosis ; Prospective Studies ; SARS-CoV-2/isolation & purification ; Severity of Illness Index ; Tryptophan/blood
Chemical Substances	Amino Acids ; Fatty Acids ; acylcarnitine ; Kynurenine (343-65-7) ; Tryptophan (8DUH1N11BX) ; Carnitine (S7UI8SM58A)
Language	English
Publishing date	2021-09-02
Publishing country	Switzerland
Document type	Journal Article ; Observational Study ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10092293
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Article ; Online: Multiomics Signatures of Coagulopathy in a Polytrauma Swine Model Contrasted with Severe Multisystem Injured Patients.

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Article: Metabolic correlates to critical speed in murine models of sickle cell disease.

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Article ; Online: Omics Signatures of Tissue Injury and Hemorrhagic Shock in Swine.

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Article: Prevalence and Clinical Implications of Heightened Plastic Chemical Exposure in Pediatric Patients Undergoing Cardiopulmonary Bypass.

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Article ; Online: The solute carrier family 7 member 11 (SLC7A11) is regulated by LH/androgen and required for cystine/glutathione homeostasis in mouse Sertoli cells.

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Article: Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC).

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Article: The solute carrier family 7 member 11 (SLC7A11) is regulated by LH/androgen and required for cystine/glutathione homeostasis in mouse Sertoli cells

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Article ; Online: Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19.

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