Metabolomics techniques are increasingly being applied in the field of biomedicine for purposes such as exploring drug targets, drug development, and the formulation of treatment guidelines. With continuous innovation in metabolomics technologies, researchers in the field of biomedicine are constantly developing efficient new metabolomics techniques that will drive the high-quality development of precision medicine. In past explorations, many researchers have proposed new tools and approaches in metabolomics research, such as stable isotope tracing metabolomics, mass spectrometry imaging spatial metabolomics, and functional metabolomics, which effectively address the limitations of conventional metabolomics in the precise identification of biomarkers.
In conventional metabolomics research, liquid chromatography (LC) and gas chromatography (GC) are the most commonly used tools for metabolite separation, while nuclear magnetic resonance (NMR) and mass spectrometry (MS) dominate in the detection part. LC and GC are often coupled with MS for metabolomics analysis (LC-MS and GC-MS), while NMR is typically used as a standalone metabolomics analysis tool. Among these, LC-MS and GC-MS offer high sensitivity, with LC-MS covering a broader range of substances, while GC-MS is more suitable for volatile and thermally stable substances, often requiring derivatization of samples, which limits its applicability. NMR has fewer sample limitations, does not cause sample destruction, but has lower sensitivity, larger instrument footprint, and higher costs. Metabolomics research targets both endogenous and exogenous metabolites, which are substrates or products of chemical reactions and typically have molecular weights smaller than 1800 Da.
There are primarily two types of metabolomics research methods: untargeted metabolomics and targeted metabolomics. Untargeted metabolomics is mainly used to identify differential metabolites, with a wide range of metabolite detection, but it cannot accurately reflect changes in metabolite levels, making it semi-quantitative. It can be used to identify new metabolites. Conversely, targeted metabolomics focuses more on specific metabolites and generally only analyzes the same type of metabolites, with a limited detection range. However, it can provide accurate quantification of target metabolites by using metabolite standards and can also reflect the interactions between metabolites. The workflow of metabolomics research typically consists of six steps: sample preparation, metabolite measurement and data acquisition, data processing, multivariate analysis, metabolite identification, and biological function exploration (interpreting biological significance). Metabolomics research encompasses a variety of biological sample types, including cells, tissues, and biological fluids, which can all be analyzed.
Metabolomics New Technologies Based on Novel Tools
Stable Isotope Tracing Metabolomics
Stable Isotope Tracing (SIT) Metabolomics is an advanced analytical approach that combines stable isotope labeling techniques with mass spectrometry. It allows researchers to track specific atoms within molecules and gain insights into metabolic pathways, cellular functions, and disease mechanisms. Common stable isotopes like ¹³C, ¹⁵N, or ²H are introduced into molecules of interest during experiments, enabling the quantification of metabolic fluxes, substrate utilization, protein kinetics, lipid metabolism, and more. SIT metabolomics finds applications in biochemistry, nutrition, pharmacology, disease research, and drug development, providing a comprehensive understanding of metabolic processes in biological systems.
Global stable-isotope tracing metabolomics (Wang et al., 2022)
Mass Spectrometry Imaging Spatial Metabolomics
Mass spectrometry imaging spatial metabolomics is an advanced analytical technique that integrates mass spectrometry imaging with metabolomics to study the spatial distribution and metabolic profiles of molecules within biological samples. This approach enables high-resolution spatial localization and quantification of various metabolites, revealing metabolic heterogeneity within tissues, cells, and biological specimens. Mass spectrometry imaging spatial metabolomics finds broad applications in biomedical research, drug development, and clinical diagnostics. It can be employed to analyze tissue samples, cell cultures, and in vivo metabolic processes, providing researchers with a powerful tool to gain deeper insights into metabolic activities within biological systems, thus advancing research in the fields of medicine and life sciences.
Metabolomics for Novel Samples in Biomedicine
Peripheral Blood Mononuclear Cells (PBMCs) Metabolomics
PBMCs are peripheral blood cells with a single-cell nucleus, primarily composed of lymphocytes (T cells, B cells, NK cells) and monocytes, collectively referred to as various immune cells. PBMCs play a crucial role in immune responses, metabolism, and cell communication in the body, and they can also reflect biological processes in the central nervous system. Therefore, they can serve as subjects for the study of immune-related, metabolic disorders, and neurodegenerative diseases.
One significant application of PBMCs metabolomics is in the discovery of disease biomarkers. By examining the distinct metabolic signatures associated with different diseases, such as cancer, autoimmune disorders, and infectious diseases, researchers can identify potential biomarkers for early disease detection, disease staging, and monitoring the response to treatments. This has the potential to revolutionize diagnostics and improve patient outcomes.
In drug development and toxicity assessment, PBMCs metabolomics plays a crucial role. It enables the assessment of how pharmaceutical compounds affect metabolic pathways within immune cells. By monitoring metabolic changes in PBMCs, researchers can identify promising drug candidates and evaluate potential toxicities, thereby aiding in the development of safer and more effective medications.
Another compelling application of PBMCs metabolomics is in the field of immunometabolism. This area of study investigates how the metabolic status of PBMCs influences immune cell function and responses to pathogens. Understanding immunometabolism can lead to the development of innovative immunotherapies and vaccines, with the potential to enhance our ability to combat infections and immune-related disorders.
In the era of personalized medicine, PBMCs metabolomics contributes by providing insights into individual metabolic profiles. By tailoring treatment plans based on PBMC metabolic data, healthcare providers can optimize therapeutic interventions, leading to more effective treatments and improved patient outcomes. This approach holds promise for a wide range of diseases, from metabolic disorders to cancer.
Furthermore, PBMCs metabolomics is instrumental in studying the effects of nutrition, exercise, and lifestyle on immune cell metabolism. This research informs strategies for disease prevention and management, as well as personalized dietary and lifestyle recommendations. It offers a bridge between clinical medicine and lifestyle interventions, fostering a holistic approach to healthcare.
In the realm of inflammation and immune response research, PBMCs metabolomics allows researchers to delve into the metabolic changes that occur in response to inflammation and immune challenges. These insights provide a deeper understanding of inflammatory diseases and immune system dysregulation, potentially leading to novel therapeutic interventions.
Longitudinal studies employing PBMCs metabolomics can track metabolic changes over time, enabling the monitoring of disease progression and treatment effectiveness. This longitudinal data is invaluable for developing predictive models for disease outcomes and tailoring treatments to individual patient needs.
Metabolomics Based on Peripheral Blood Mononuclear Cells (Huang et al., 2022)
Single-Cell Metabolomics
Single-cell metabolomics is a revolutionary analytical technique that has found diverse applications in the field of biomedicine. By enabling the study of cellular metabolism at the individual cell level, it offers unprecedented insights into cellular heterogeneity, disease mechanisms, drug development, and personalized medicine.
In cancer research, single-cell metabolomics plays a pivotal role. It elucidates the metabolic reprogramming that occurs in cancer cells, helping identify novel therapeutic targets. Moreover, it facilitates the study of tumor heterogeneity, offering insights into metabolic vulnerabilities that can be exploited for precision oncology treatments.
Neuroscience benefits from single-cell metabolomics as it provides insights into neurotransmitter metabolism and neurodegenerative diseases. By studying the metabolic profiles of neurons and glial cells, researchers gain a deeper understanding of brain metabolism and the effects of neuroactive compounds.
In stem cell biology, single-cell metabolomics helps characterize the metabolic states of stem cells during differentiation and reprogramming. This knowledge aids in optimizing culture conditions for stem cell therapies and regenerative medicine, paving the way for innovative treatments.
In the context of infectious diseases, single-cell metabolomics allows for the study of metabolic responses in host cells and pathogens during infection. It helps identify critical metabolic pathways for pathogen survival, offering potential targets for antimicrobial therapies.
The field of drug development and toxicology benefits greatly from single-cell metabolomics. It enables the assessment of how drugs and toxins affect the metabolic profiles of individual cells, leading to a deeper understanding of drug mechanisms of action and potential cellular toxicities.
Immunology is another area where single-cell metabolomics makes significant contributions. It helps unravel immune cell heterogeneity and their metabolic responses during infections and autoimmune diseases. This knowledge is instrumental in developing immunotherapies and vaccines.
Personalized medicine is enhanced by single-cell metabolomics, as it allows for the profiling of individual cells from patient samples. This data can be used to tailor treatment strategies, resulting in more personalized and effective therapies.
Developmental biology benefits from single-cell metabolomics by providing insights into metabolic changes during embryonic development and tissue regeneration. Researchers can better understand how metabolic processes contribute to organ formation and regeneration.
Organelle Metabolomics
Organelle metabolomics, a burgeoning field in cell biology, focuses on the systematic study of metabolites within specific subcellular organelles. This approach provides unique insights into the metabolic processes taking place in distinct cellular compartments, paving the way for a deeper understanding of cellular function, disease mechanisms, and drug development.
Mitochondrial Metabolomics: The analysis of mitochondrial metabolites is pivotal in elucidating the energy production, redox balance, and cellular signaling orchestrated by these organelles. By examining mitochondrial metabolomics, researchers gain crucial insights into the mechanisms underlying diseases such as cancer, neurodegenerative disorders, and metabolic syndromes.
Endoplasmic Reticulum (ER) Metabolomics: ER metabolomics offers a comprehensive view of lipid synthesis, protein folding, and calcium signaling. Dysregulation in ER metabolism is implicated in diseases such as diabetes and neurodegenerative disorders, making this area of research indispensable for understanding these conditions.
Lysosomal Metabolomics: The study of lysosomal metabolites is paramount for unravelling the intricacies of autophagy, lysosomal storage disorders, and drug targets related to lysosomes. By examining lysosomal metabolism, researchers gain insights into cellular waste disposal and its implications for health and disease.
Peroxisomal Metabolomics: Peroxisomes play a pivotal role in lipid metabolism and detoxification. Investigating peroxisomal metabolites deepens our understanding of peroxisomal disorders and their impact on cellular homeostasis, particularly in relation to fatty acid oxidation.
Golgi Apparatus Metabolomics: Metabolomics of the Golgi apparatus sheds light on glycosylation, lipid metabolism, and protein trafficking. This research is instrumental in deciphering diseases associated with protein secretion and glycosylation defects.
Drug Development: Organelle metabolomics plays a pivotal role in evaluating the effects of pharmaceutical compounds on the metabolism of specific organelles. It contributes to drug discovery by elucidating mechanisms of action and assessing potential toxicities, offering insights into novel drug targets.
Cellular Physiology: The study of organelle metabolomics enhances our comprehension of how various organelles collaborate in maintaining cellular functions such as energy production, signaling, and macromolecule synthesis. This research contributes to our knowledge of cellular homeostasis.
Disease Mechanisms: Organelle metabolomics provides invaluable insights into the metabolic changes associated with a plethora of diseases. By understanding the metabolic shifts occurring within organelles, researchers can identify diagnostic biomarkers and potential therapeutic targets.
Cellular Responses to Stress: Investigating organelle-specific responses to stressors, including oxidative stress, nutrient deprivation, and pathogen invasion, provides crucial insights into cellular adaptation and survival mechanisms. This research informs our understanding of cellular resilience and vulnerability.
References
- Wang, Ruohong, et al. "Global stable-isotope tracing metabolomics reveals system-wide metabolic alternations in aging Drosophila." Nature Communications 13.1 (2022): 3518
- Huang, Dehua, et al. "Metabolomics based on peripheral blood mononuclear cells to dissect the mechanisms of Chaigui granules for treating depression." ACS omega 7.10 (2022): 8466-8482.
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