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Metabolomics Approach to Tackle Toxicological and Pharmacological Issues

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

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 14041

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Dr. Nuno G. Oliveira

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Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal
Interests: mechanisms of toxicity; genotoxicity; DNA damage; oxidative stress inducers; antioxidants; SOD mimics; chemotherapeutic drugs; DNA repair inhibitors; cytotoxicity
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Prof. Dr. Paula Guedes de Pinho

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UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Interests: metabolomics; urological cancers; toxicology; toxicometabolomics; drugs of abuse
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Dear Colleagues,

The identification and quantification of metabolites responding to a specific stimulus is of the utmost importance in tackling toxicological and pharmacological issues. In fact, in the field of metabolomics, information concerning the pattern of the low-molecular-weight compounds generated in a biological system upon exposure to xenobiotics provides new insights into the cellular and organ-specific pathways involved.

Metabolomics thus represents a powerful tool to evaluate the mode of action of drugs and chemical contaminants. Moreover, toxicometabolomics and pharmacometabolomics data may clarify the differences observed in drug responses (i.e., responders vs. non-responders) and help identify biomarkers related to drug efficacy or toxicity. These approaches are also critical to providing pharmacokinetics (PK) and pharmacodynamics (PD) data for use in precision medicine.

In view of this, we are inviting you to submit your experimental work or a review article on a pertinent subject within the scope of this Special Issue. This is an excellent opportunity for researchers from different fields of expertise to disseminate their recent findings and keep themselves up to date on this emerging topic.

Dr. Nuno G. Oliveira
Prof. Dr. Paula Guedes De Pinho
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

metabolomics
metabolites
drugs
contaminants
xenobiotics
toxicity
pharmacology
toxicology

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Published Papers (8 papers)

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Research

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23 pages, 5545 KiB

Open AccessArticle

Metabonomics and Transcriptomics Analyses Reveal the Development Process of the Auditory System in the Embryonic Development Period of the Small Yellow Croaker under Background Noise

by Qinghua Jiang, Xiao Liang, Ting Ye, Yu Zhang and Bao Lou

Int. J. Mol. Sci. 2024, 25(4), 1954; https://doi.org/10.3390/ijms25041954 - 6 Feb 2024

Viewed by 1283

Abstract

Underwater noise pollution has become a potential threat to aquatic animals in the natural environment. The main causes of such pollution are frequent human activities creating underwater environmental noise, including commercial shipping, offshore energy platforms, scientific exploration activities, etc. However, in aquaculture environments, underwater noise pollution has also become an unavoidable problem due to background noise created by aquaculture equipment. Some research has shown that certain fish show adaptability to noise over a period of time. This could be due to fish’s special auditory organ, i.e., their “inner ear”; meanwhile, otoliths and sensory hair cells are the important components of the inner ear and are also essential for the function of the auditory system. Recently, research in respect of underwater noise pollution has mainly focused on adult fish, and there is a lack of the research on the effects of underwater noise pollution on the development process of the auditory system in the embryonic development period. Thus, in this study, we collected embryo–larval samples of the small yellow croaker (Larimichthys polyactis) in four important stages of otic vesicle development through artificial breeding. Then, we used metabonomics and transcriptomics analyses to reveal the development process of the auditory system in the embryonic development period under background noise (indoor and underwater environment sound). Finally, we identified 4026 differentially expressed genes (DEGs) and 672 differential metabolites (DMs), including 37 DEGs associated with the auditory system, and many differences mainly existed in the neurula stage (20 h of post-fertilization/20 HPF). We also inferred the regulatory mode and process of some important DEGs (Dnmt1, CPS1, and endothelin-1) in the early development of the auditory system. In conclusion, we suggest that the auditory system development of L. polyactis begins at least in the neurula stage or earlier; the other three stages (tail bud stage, caudal fin fold stage, and heart pulsation stage, 28–35 HPF) mark the rapid development period. We speculate that the effect of underwater noise pollution on the embryo–larval stage probably begins even earlier. Full article

(This article belongs to the Special Issue Metabolomics Approach to Tackle Toxicological and Pharmacological Issues)

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14 pages, 2506 KiB

Open AccessArticle

Biological Impact of Organic Extracts from Urban-Air Particulate Matter: An In Vitro Study of Cytotoxic and Metabolic Effects in Lung Cells

by Tatiana D. Silva, Célia Alves, Helena Oliveira and Iola F. Duarte

Int. J. Mol. Sci. 2023, 24(23), 16896; https://doi.org/10.3390/ijms242316896 - 29 Nov 2023

Viewed by 1277

Abstract

Atmospheric particulate matter (PM) with diameters below 10 µm (PM₁₀) may enter the lungs through inhalation and are linked to various negative health consequences. Emergent evidence emphasizes the significance of cell metabolism as a sensitive target of PM exposure. However, the current understanding of the relationship between PM composition, conventional toxicity measures, and the rewiring of intracellular metabolic processes remains limited. In this work, PM₁₀ sampled at a residential area (urban background, UB) and a traffic-impacted location (roadside, RS) of a Portuguese city was comprehensively characterized in terms of polycyclic aromatic hydrocarbons and plasticizers. Epithelial lung cells (A549) were then exposed for 72 h to PM₁₀ organic extracts and different biological outcomes were assessed. UB and RS PM₁₀ extracts dose-dependently decreased cell viability, induced reactive oxygen species (ROS), decreased mitochondrial membrane potential, caused cell cycle arrest at the G0/G1 phase, and modulated the intracellular metabolic profile. Interestingly, the RS sample, richer in particularly toxic PAHs and plasticizers, had a greater metabolic impact than the UB extract. Changes comprised significant increases in glutathione, reflecting activation of antioxidant defences to counterbalance ROS production, together with increases in lactate, NAD⁺, and ATP, which suggest stimulation of glycolytic energy production, possibly to compensate for reduced mitochondrial activity. Furthermore, a number of other metabolic variations hinted at changes in membrane turnover and TCA cycle dynamics, which represent novel clues on potential PM₁₀ biological effects. Full article

(This article belongs to the Special Issue Metabolomics Approach to Tackle Toxicological and Pharmacological Issues)

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19 pages, 3202 KiB

Open AccessArticle

Multi-Omics Analysis of NCI-60 Cell Line Data Reveals Novel Metabolic Processes Linked with Resistance to Alkylating Anti-Cancer Agents

by Blake R. Rushing

Int. J. Mol. Sci. 2023, 24(17), 13242; https://doi.org/10.3390/ijms241713242 - 26 Aug 2023

Cited by 1 | Viewed by 2015

Abstract

This study aimed to elucidate the molecular determinants influencing the response of cancer cells to alkylating agents, a major class of chemotherapeutic drugs used in cancer treatment. The study utilized data from the National Cancer Institute (NCI)-60 cell line screening program and employed a comprehensive multi-omics approach integrating transcriptomic, proteomic, metabolomic, and SNP data. Through integrated pathway analysis, the study identified key metabolic pathways, such as cysteine and methionine metabolism, starch and sucrose metabolism, pyrimidine metabolism, and purine metabolism, that differentiate drug-sensitive and drug-resistant cancer cells. The analysis also revealed potential druggable targets within these pathways. Furthermore, copy number variant (CNV) analysis, derived from SNP data, between sensitive and resistant cells identified notable differences in genes associated with metabolic changes (WWOX, CNTN5, DDAH1, PGR), protein trafficking (ARL17B, VAT1L), and miRNAs (MIR1302-2, MIR3163, MIR1244-3, MIR1302-9). The findings of this study provide a holistic view of the molecular landscape and dysregulated pathways underlying the response of cancer cells to alkylating agents. The insights gained from this research can contribute to the development of more effective therapeutic strategies and personalized treatment approaches, ultimately improving patient outcomes in cancer treatment. Full article

(This article belongs to the Special Issue Metabolomics Approach to Tackle Toxicological and Pharmacological Issues)

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15 pages, 1080 KiB

Open AccessArticle

A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study

by Ana Dias-Carvalho, Ana Margarida-Araújo, Ana Reis-Mendes, Catarina Oliveira Sequeira, Sofia Azeredo Pereira, Paula Guedes de Pinho, Félix Carvalho, Susana Isabel Sá, Eduarda Fernandes and Vera Marisa Costa

Int. J. Mol. Sci. 2023, 24(17), 13126; https://doi.org/10.3390/ijms241713126 - 23 Aug 2023

Cited by 3 | Viewed by 1883

Abstract

Long-term cognitive dysfunction, or “chemobrain”, has been observed in cancer patients treated with chemotherapy. Mitoxantrone (MTX) is a topoisomerase II inhibitor that binds and intercalates with DNA, being used in the treatment of several cancers and multiple sclerosis. Although MTX can induce chemobrain, its neurotoxic mechanisms are poorly studied. This work aimed to identify the adverse outcome pathways (AOPs) activated in the brain upon the use of a clinically relevant cumulative dose of MTX. Three-month-old male CD-1 mice were given a biweekly intraperitoneal administration of MTX over the course of three weeks until reaching a total cumulative dose of 6 mg/kg. Controls were given sterile saline in the same schedule. Two weeks after the last administration, the mice were euthanized and their brains removed. The left brain hemisphere was used for targeted profiling of the metabolism of glutathione and the right hemisphere for an untargeted metabolomics approach. The obtained results revealed that MTX treatment reduced the availability of cysteine (Cys), cysteinylglycine (CysGly), and reduced glutathione (GSH) suggesting that MTX disrupts glutathione metabolism. The untargeted approach revealed metabolic circuits of phosphatidylethanolamine, catecholamines, unsaturated fatty acids biosynthesis, and glycerolipids as relevant players in AOPs of MTX in our in vivo model. As far as we know, our study was the first to perform such a broad profiling study on pathways that could put patients given MTX at risk of cognitive deficits. Full article

(This article belongs to the Special Issue Metabolomics Approach to Tackle Toxicological and Pharmacological Issues)

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13 pages, 3313 KiB

Open AccessArticle

Purine Metabolism and Pyrimidine Metabolism Alteration Is a Potential Mechanism of BDE-47-Induced Apoptosis in Marine Rotifer Brachionus plicatilis

by Sai Cao, Jiayi Wang, Xinye You, Bin Zhou, You Wang and Zhongyuan Zhou

Int. J. Mol. Sci. 2023, 24(16), 12726; https://doi.org/10.3390/ijms241612726 - 12 Aug 2023

Cited by 6 | Viewed by 1440

Abstract

This present study was conducted to provide evidence and an explanation for the apoptosis that occurs in the marine rotifer Brachionus plicatilis when facing 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) stress. Metabolomics analysis showed that aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, and arginine biosynthesis were the top three sensitive pathways to BDE-47 exposure, which resulted in the reduction in the amino acid pool level. Pyrimidine metabolism and purine metabolism pathways were also significantly influenced, and the purine and pyrimidine content were obviously reduced in the low (0.02 mg/L) and middle (0.1 mg/L) concentration groups while increased in the high (0.5 mg/L) concentration group, evidencing the disorder of nucleotide synthesis and decomposition in B. plicatilis. The biochemical detection of the key enzymes in purine metabolism and pyrimidine metabolism showed the downregulation of Glutamine Synthetase (GS) protein expression and the elevation of Xanthine Oxidase (XOD) activity, which suggested the impaired DNA repair and ROS overproduction. The content of DNA damage biomarker (8-OHdG) increased in treatment groups, and the p53 signaling pathway was found to be activated, as indicated by the elevation of the p53 protein expression and Bax/Bcl-2 ratio. The ROS scavenger (N-acetyl-L-cysteine, NAC) addition effectively alleviated not only ROS overproduction but also DNA damage as well as the activation of apoptosis. The combined results backed up the speculation that purine metabolism and pyrimidine metabolism alteration play a pivotal role in BDE-47-induced ROS overproduction and DNA damage, and the consequent activation of the p53 signaling pathway led to the observed apoptosis in B. plicatilis. Full article

(This article belongs to the Special Issue Metabolomics Approach to Tackle Toxicological and Pharmacological Issues)

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13 pages, 3017 KiB

Open AccessArticle

Integration of Metabolomic and Transcriptomic Provides Insights into Anti-Inflammatory Response to trans-10-Hydroxy-2-decenoic Acid on LPS-Stimulated RAW 264.7 Cells

by Minjie Huang, Jie Dong, Xiaodong Tan, Shuyuan Yang, Minghui Xiao and Deqian Wang

Int. J. Mol. Sci. 2023, 24(16), 12666; https://doi.org/10.3390/ijms241612666 - 11 Aug 2023

Viewed by 1662

Abstract

Trans-10-hydroxy-2-decenoic acid (10-HDA) is a unique fatty acid found in royal jelly that possesses potential health benefits such as anti-inflammatory. However, further research is needed to fully understand its mechanisms of action and therapeutic potential for inflammation-associated diseases. In this present study, liquid chromatography–tandem mass spectrometry (LC-MS/MS) and RNA-seq analyses were conducted to comprehensively analyze the in vitro anti-inflammatory effects of 10-HDA on lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Our results demonstrated that 128 differentially expressed metabolites and 1721 differentially expressed genes were identified in the 10-HDA-treated groups compared to the LPS groups. Metabolites were significantly enriched in amino acid metabolism pathways, including methionine metabolism, glycine and serine metabolism, and tryptophan metabolism. The differentially expressed genes enrichment analysis indicated that antigen processing and presentation, NOD-like receptor signaling pathway, and arginine biosynthesis were enriched with the administration of 10-had. The correlation analysis revealed that glycerophospholipid metabolism and s-adenosylmethionine-dependent methylation processes might be involved in the response to the 10-HDA treatment. Overall, the findings from this study showed that 10-HDA might involve the modulation of certain signaling pathways involved in the inflammatory response, but further research is needed to determine the safety and efficacy as a therapeutic agent. Full article

(This article belongs to the Special Issue Metabolomics Approach to Tackle Toxicological and Pharmacological Issues)

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18 pages, 3373 KiB

Open AccessArticle

Impact of Sea Warming and 17-α-Ethinylestradiol Exposure on the Lipid Metabolism of Ruditapes philippinarum Clams

by João A. Rodrigues, Daniela S. C. Bispo, Mónica G. Silva, Rita Araújo, Amadeu M. V. M. Soares, Rosa Freitas and Ana M. Gil

Int. J. Mol. Sci. 2023, 24(11), 9485; https://doi.org/10.3390/ijms24119485 - 30 May 2023

Cited by 1 | Viewed by 1804

Abstract

This paper reports on an NMR metabolomics study of lipophilic extracts of Ruditapes philippinarum clams exposed to the hormonal contaminant 17-α-ethinylestradiol (EE2), at 17 °C and 21 °C. The results reveal that exposure at 17 °C triggers a weak response at low EE2 concentrations, suggestive of a slight increase in membrane rigidity, followed by lipid metabolic stability at higher EE2 concentrations. On the other hand, at 21 °C, lipid metabolism begins to respond at 125 ng/L EE2, with antioxidant docosahexaenoic acid (DHA) helping to tackle high-oxidative-stress conditions, in tandem with enhanced storage of triglycerides. Exposure to 625 ng/L EE2 (highest concentration) enhances phosphatidylcholine (PtdCho) and polyunsaturated fatty acid (PUFA) levels, their direct intercorrelation suggesting PUFA incorporation in new membrane phospholipids. This should lead to increased membrane fluidity, probably aided by a decrease in cholesterol. PUFA levels, considered a measure of membrane fluidity, were strongly (and positively) correlated to intracellular glycine levels, thus identifying glycine as the main osmolyte entering the cells under high stress. Membrane fluidity also seems to elicit the loss of taurine. This work contributes to the understanding of the mechanisms of response of R. philippinarum clams to EE2 in tandem with warming while unveiling novel potential markers of stress mitigation, namely high levels of PtdCho, PUFAs (or PtdCho/glycerophosphocholine and PtdCho/acetylcholine ratios) and linoleic acid and low PUFA/glycine ratios. Full article

(This article belongs to the Special Issue Metabolomics Approach to Tackle Toxicological and Pharmacological Issues)

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Review

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20 pages, 1001 KiB

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Metabolomic Signatures of Treatment Response in Bladder Cancer

by Tiago Vieira de Sousa, Paula Guedes de Pinho and Joana Pinto

Int. J. Mol. Sci. 2023, 24(24), 17543; https://doi.org/10.3390/ijms242417543 - 16 Dec 2023

Cited by 1 | Viewed by 1919

Abstract

Bladder cancer (BC) stands as one of the most prevalent urological malignancies, with over 500 thousand newly diagnosed cases annually. Treatment decisions in BC depend on factors like the risk of recurrence, the type of tumor, and the stage of the disease. While standard therapeutic approaches encompass transurethral resection of the bladder tumor, radical cystectomy, and chemo- or immunotherapy, these methods exhibit limited efficacy in mitigating the aggressive and recurrent nature of bladder tumors. To overcome this challenge, it is crucial to develop innovative methods for monitoring and predicting treatment responses among patients with BC. Metabolomics is gaining recognition as a promising approach for discovering biomarkers. It has the potential to reveal metabolic disruptions that precisely reflect how BC patients respond to particular treatments, providing a revolutionary method to improve accuracy in monitoring and predicting outcomes. In this article, we present a comprehensive review of studies employing metabolomics approaches to investigate the metabolic responses associated with different treatment modalities for BC. The review encompasses an exploration of various models, samples, and analytical techniques applied in this context. Special emphasis is placed on the reported changes in metabolite levels derived from these studies, highlighting their potential as biomarkers for personalized medicine in BC. Full article

(This article belongs to the Special Issue Metabolomics Approach to Tackle Toxicological and Pharmacological Issues)

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