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Eliciting Mechanistic Insight with Multi-Omic Approaches in Diabetes, Cancer, and Aging

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 8960

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Special Issue Editor

Dr. Yury O. Nunez Lopez

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Guest Editor

Advent Health, Translational Research Institute for Metabolism and Diabetes, Orlando, FL 32804, USA
Interests: extracellular vesicles; multi-omics; diabetes; cancer; aging

Special Issue Information

Dear Colleagues,

Omic approaches have commonly been used for the discovery of disease biomarkers. However, their powers to provide mechanistic insights into and uncover the novel pathobiology of diseases have been largely overlooked. Complex natural processes such as aging and complex diseases such as diabetes and cancer are characterized by high heterogeneity. Therefore, understanding their underlying biology becomes a difficult and lengthy task. Integrating multi-omic profiling data at the system level with the vast array of biological knowledge accessible in public and private databases has facilitated the generation of testable hypotheses and the discovery of novel mechanisms affecting such complex processes. With this Special Issue, we aim to promote novel integrative systems biology approaches based on high-throughput technologies and data analyses that advance our understanding of diabetes, cancer, and aging, individually and as an age-related interacting system.

Subtopics:

Multi-omics and systems biology;
Multi-omics of extracellular vesicles;
Multi-omics in diabetes;
Multi-omics in cancer;
Multi-omics in aging;
Diabetes and cancer interactions;
Diabetes and aging interactions;
Cancer and aging interactions;
The deadliest triangle: diabetes, cancer, and aging.

Dr. Yury O. Nunez Lopez
Guest Editor

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Keywords

multi-omics
systems biology
extracellular vesicles
diabetes
cancer
aging

Published Papers (3 papers)

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Research

20 pages, 4390 KiB

Open AccessArticle

Biliary Metabolome Profiling for Evaluation of Liver Metabolism and Biliary Tract Function Related to Organ Preservation Method and Degree of Ischemia in a Porcine Model

by Kamil Łuczykowski, Natalia Warmuzińska, Dagmar Kollmann, Markus Selzner and Barbara Bojko

Int. J. Mol. Sci. 2023, 24(3), 2127; https://doi.org/10.3390/ijms24032127 - 21 Jan 2023

Cited by 2 | Viewed by 1884

Abstract

The development of surgical techniques, immunosuppressive strategies and new organ preservation methods have meant that transplant centers have to face the problem of an insufficient number of organs for transplantation concerning the constantly growing demand. Therefore, using organs from expanded criteria donors and developing new analytical solutions to find parameters or compounds that would allow a more efficient assessment of organ quality before transplantation are options for meeting this challenge. This study proposed bile metabolomic analysis to evaluate liver metabolism and biliary tract function depending on the organ preservation method and degree of warm ischemia time. The analyses were performed on solid-phase microextraction-prepared bile samples from porcine model donors with mild (heart beating donor [HBD]) and moderate warm ischemia (donation after circulatory death [DCD]) grafts subjected to static cold storage (SCS) or normothermic ex vivo liver perfusion (NEVLP) before transplantation. Bile produced in the SCS-preserved livers was characterized by increased levels of metabolites such as chenodeoxycholic acid, arachidonic acid and 5S-hydroxyeicosatetraeonic acid, as well as saturated and monounsaturated lysophosphatidylcholines (LPC). Such changes may be associated with differences in the bile acid synthesis pathways and organ inflammation. Moreover, it has been shown that NEVLP reduced the negative effect of ischemia on organ function. A linear relationship was observed between levels of lipids from the LPC group and the time of organ ischemia. This study identified metabolites worth considering as potential markers of changes occurring in preserved grafts. Full article

(This article belongs to the Special Issue Eliciting Mechanistic Insight with Multi-Omic Approaches in Diabetes, Cancer, and Aging)

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20 pages, 2646 KiB

Open AccessArticle

Detectable Lipidomes and Metabolomes by Different Plasma Exosome Isolation Methods in Healthy Controls and Patients with Advanced Prostate and Lung Cancer

by Alex C. Soupir, Yijun Tian, Paul A. Stewart, Yury O. Nunez-Lopez, Brandon J. Manley, Bruna Pellini, Amanda M. Bloomer, Jingsong Zhang, Qianxing Mo, Douglas C. Marchion, Min Liu, John M. Koomen, Erin M. Siegel and Liang Wang

Int. J. Mol. Sci. 2023, 24(3), 1830; https://doi.org/10.3390/ijms24031830 - 17 Jan 2023

Cited by 3 | Viewed by 3312

Abstract

Circulating exosomes in the blood are promising tools for biomarker discovery in cancer. Due to their heterogeneity, different isolation methods may enrich distinct exosome cargos generating different omic profiles. In this study, we evaluated the effects of plasma exosome isolation methods on detectable multi-omic profiles in patients with non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and healthy controls, and developed an algorithm to quantify exosome enrichment. Plasma exosomes were isolated from CRPC (n = 10), NSCLC (n = 14), and healthy controls (n = 10) using three different methods: size exclusion chromatography (SEC), lectin binding, and T-cell immunoglobulin domain and mucin domain-containing protein 4 (TIM4) binding. Molecular profiles were determined by mass spectrometry of extracted exosome fractions. Enrichment analysis of uniquely detected molecules was performed for each method with MetaboAnalyst. The exosome enrichment index (EEI) scores methods based on top differential molecules between patient groups. The lipidomic analysis detected 949 lipids using exosomes from SEC, followed by 246 from lectin binding and 226 from TIM4 binding. The detectable metabolites showed SEC identifying 191 while lectin binding and TIM4 binding identified 100 and 107, respectively. When comparing uniquely detected molecules, different methods showed preferential enrichment of different sets of molecules with SEC enriching the greatest diversity. Compared to controls, SEC identified 28 lipids showing significant difference in NSCLC, while only 1 metabolite in NSCLC and 5 metabolites in CRPC were considered statistically significant (FDR < 0.1). Neither lectin-binding- nor TIM4-binding-derived exosome lipids or metabolites demonstrated significant differences between patient groups. We observed the highest EEI from SEC in lipids (NSCLC: 871.33) which was also noted in metabolites. These results support that the size exclusion method of exosome extraction implemented by SBI captures more heterogeneous exosome populations. In contrast, lectin-binding and TIM4-binding methods bind surface glycans or phosphatidylserine moieties of the exosomes. Overall, these findings suggest that specific isolation methods select subpopulations which may significantly impact cancer biomarker discovery. Full article

(This article belongs to the Special Issue Eliciting Mechanistic Insight with Multi-Omic Approaches in Diabetes, Cancer, and Aging)

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25 pages, 4320 KiB

Open AccessArticle

Proteomics and Phosphoproteomics of Circulating Extracellular Vesicles Provide New Insights into Diabetes Pathobiology

by Yury O. Nunez Lopez, Anton Iliuk, Alejandra M. Petrilli, Carley Glass, Anna Casu and Richard E. Pratley

Int. J. Mol. Sci. 2022, 23(10), 5779; https://doi.org/10.3390/ijms23105779 - 21 May 2022

Cited by 18 | Viewed by 3154

Abstract

The purpose of this study was to define the proteomic and phosphoproteomic landscape of circulating extracellular vesicles (EVs) in people with normal glucose tolerance (NGT), prediabetes (PDM), and diabetes (T2DM). Archived serum samples from 30 human subjects (n = 10 per group, ORIGINS study, NCT02226640) were used. EVs were isolated using EVtrap^®. Mass spectrometry-based methods were used to detect the global EV proteome and phosphoproteome. Differentially expressed features, correlation, enriched pathways, and enriched tissue-specific protein sets were identified using custom R scripts. Phosphosite-centric analyses were conducted using directPA and PhosR software packages. A total of 2372 unique EV proteins and 716 unique EV phosphoproteins were identified among all samples. Unsupervised clustering of the differentially expressed (fold change ≥ 2, p < 0.05, FDR < 0.05) proteins and, particularly, phosphoproteins showed excellent discrimination among the three groups. CDK1 and PKCδ appear to drive key upstream phosphorylation events that define the phosphoproteomic signatures of PDM and T2DM. Circulating EVs from people with diabetes carry increased levels of specific phosphorylated kinases (i.e., AKT1, GSK3B, LYN, MAP2K2, MYLK, and PRKCD) and could potentially distribute activated kinases systemically. Among characteristic changes in the PDM and T2DM EVs, “integrin switching” appeared to be a central feature. Proteins involved in oxidative phosphorylation (OXPHOS), known to be reduced in various tissues in diabetes, were significantly increased in EVs from PDM and T2DM, which suggests that an abnormally elevated EV-mediated secretion of OXPHOS components may underlie the development of diabetes. A highly enriched signature of liver-specific markers among the downregulated EV proteins and phosphoproteins in both PDM and T2DM groups was also detected. This suggests that an alteration in liver EV composition and/or secretion may occur early in prediabetes. This study identified EV proteomic and phosphoproteomic signatures in people with prediabetes and T2DM and provides novel insight into the pathobiology of diabetes. Full article

(This article belongs to the Special Issue Eliciting Mechanistic Insight with Multi-Omic Approaches in Diabetes, Cancer, and Aging)

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Eliciting Mechanistic Insight with Multi-Omic Approaches in Diabetes, Cancer, and Aging

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