| 1. |
- Balgoma, David, et al.
(författare)
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Orthogonality in Principal Component Analysis Allows the Discovery of Lipids in the Jejunum That Are Independent of Ad Libitum Feeding
- 2022
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Ingår i: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 12:9
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Tidskriftsartikel (refereegranskat)abstract
- Ad libitum feeding of experimental animals is preferred because of medical relevance together with technical and practical considerations. In addition, ethical committees may require ad libitum feeding. However, feeding affects the metabolism so ad libitum feeding may mask the effects of drugs on tissues directly involved in the digestion process (e.g., jejunum and liver). Despite this effect, principal component analysis has the potential of identifying metabolic traits that are statistically independent (orthogonal) to ad libitum feeding. Consequently, we used principal component analysis to discover the metabolic effects of doxorubicin independent of ad libitum feeding. First, we analyzed the lipidome of the jejunum and the liver of rats treated with vehicle or doxorubicin. Subsequently, we performed principal component analysis. We could identify a principal component associated to the hydrolysis of lipids during digestion and a group of lipids that were orthogonal. These lipids in the jejunum increased with the treatment time and presented a polyunsaturated fatty acid as common structural trait. This characteristic suggests that doxorubicin increases polyunsaturated fatty acids. This behavior agrees with our previous in vitro results and suggests that doxorubicin sensitized the jejunum to ferroptosis, which may partially explain the toxicity of doxorubicin in the intestines.
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| 2. |
- Balgoma, David, et al.
(författare)
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Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver
- 2020
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Ingår i: Metabolomics. - : SPRINGER. - 1573-3882 .- 1573-3890. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The abuse of anabolic androgenic steroids (AASs) is a source of public concern because of their adverse effects. Supratherapeutic doses of AASs are known to be hepatotoxic and regulate the lipoproteins in plasma by modifying the metabolism of lipids in the liver, which is associated with metabolic diseases. However, the effect of AASs on the profile of lipids in plasma is unknown.Objectives: To describe the changes in the plasma lipidome exerted by AASs and to discuss these changes in the light of previous research about AASs and de novo lipogenesis in the liver.Methods: We treated male Wistar rats with supratherapeutic doses of nandrolone decanoate and testosterone undecanoate. Subsequently, we isolated the blood plasma and performed lipidomics analysis by liquid chromatography-high resolution mass spectrometry.Results: Lipid profiling revealed a decrease of sphingolipids and glycerolipids with palmitic, palmitoleic, stearic, and oleic acids. In addition, lipid profiling revealed an increase in free fatty acids and glycerophospholipids with odd-numbered chain fatty acids and/or arachidonic acid.Conclusion: The lipid profile presented herein reports the imprint of AASs on the plasma lipidome, which mirrors the downregulation of de novo lipogenesis in the liver. In a broader perspective, this profile will help to understand the influence of androgens on the lipid metabolism in future studies of diseases with dysregulated lipogenesis (e.g. type 2 diabetes, fatty liver disease, and hepatocellular carcinoma).
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| 3. |
- Balgoma, David, et al.
(författare)
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Anthracyclins Increase PUFAs : Potential Implications in ER Stress and Cell Death
- 2021
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Ingår i: Cells. - : MDPI. - 2073-4409. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic and personalized interventions in cancer treatment require a better understanding of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes in the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethanolamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggest supplementation with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depending on the type of tumor and the individual. Finally, in agreement with previous research, we found a relationship across the different cell types between: (i) the change in endoplasmic reticulum (ER) stress, and (ii) the imbalance between PUFAs and cholesterol and saturated lipids. In the light of previous research, this imbalance partially explains the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies.
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| 4. |
- Balgoma, David, et al.
(författare)
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Common Fatty Markers in Diseases with Dysregulated Lipogenesis
- 2019
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Ingår i: Trends in endocrinology and metabolism. - : ELSEVIER SCIENCE LONDON. - 1043-2760 .- 1879-3061. ; 30:5, s. 283-285
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have reported the upregulation of a subgroup of triacylglycerides as markers of different diseases with dysregulated lipogenesis, which means that these markers are not selective. This observation has a deep impact on their use as diagnostic tools in clinical practice (e.g., markers of risk of type 2 diabetes).
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| 5. |
- Balgoma, David, et al.
(författare)
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Etherglycerophospholipids and ferroptosis : structure, regulation, and location
- 2021
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Ingår i: Trends in endocrinology and metabolism. - : Elsevier. - 1043-2760 .- 1879-3061. ; 32:12, s. 960-962
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Two pioneering studies by Zou et al. and Cui et al. have reported that the synthesis of etherglycerophospholipids (etherPLs) sensitizes cells to ferroptosis. The location and regulation of etherPLs suggest that: (i) lipid peroxidation in the inner leaflet of the plasma membrane might be of importance in ferroptosis, and (ii) different etherPLs may differently sensitize cells to ferroptosis.
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| 6. |
- Balgoma, David, et al.
(författare)
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Lipidomics Issues on Human Positive ssRNA Virus Infection : An Update
- 2020
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Ingår i: Metabolites. - : MDPI AG. - 2218-1989 .- 2218-1989. ; 10:9
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Forskningsöversikt (refereegranskat)abstract
- The pathogenic mechanisms underlying the Biology and Biochemistry of viral infections are known to depend on the lipid metabolism of infected cells. From a lipidomics viewpoint, there are a variety of mechanisms involving virus infection that encompass virus entry, the disturbance of host cell lipid metabolism, and the role played by diverse lipids in regard to the infection effectiveness. All these aspects have currently been tackled separately as independent issues and focused on the function of proteins. Here, we review the role of cholesterol and other lipids in ssRNA+ infection.
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| 7. |
- Balgoma, David, et al.
(författare)
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Modeling the fragmentation patterns of triacylglycerides in mass spectrometry allows the quantification of the regioisomers with a minimal number of standards
- 2019
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Ingår i: Analytica Chimica Acta. - : Elsevier BV. - 0003-2670 .- 1873-4324. ; 1057, s. 60-69
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Tidskriftsartikel (refereegranskat)abstract
- Mass spectrometry allows the relative quantification of the regioisomers of triacylglycerides by the calibration of their fragmentation patterns. However, due to the plethora of regioisomers of triacylglycerides, calibration with every standard is not feasible. An analytical challenge in the field is the prediction of the fragmentation patterns of triacylglycerides to quantify their regioisomers. Thus, we aimed to model these fragmentation patterns to quantify the regioisomeric composition, even for those without commercially available standards. In a first step, we modeled the fragmentation patterns of the regioisomers of triacylglycerides obtained from different published datasets. We found the same qualitative trends of fragmentation beyond differences in the type of adduct in these datasets (both [M+NH4]+ and [M+H]+), and the type of instrument (orbitrap, Q-ToF, ion-trap, single quadrupole, and triple quadrupole). However, the quantitative trends of fragmentation were adduct and instrument specific. From these observations, we modeled quantitatively the common trends of fragmentation of triacylglycerides in every dataset. In a second step, we applied this methodology on a Synapt G2S Q-ToF to quantify the regioisomers of triacylglycerides in sunflower and olive oils. The results of our quantification were in good agreement with previous published quantifications of triacylglycerides, even for regioisomers that were not present in the training dataset. The species with more than two highly unsaturated fatty acids (arachidonic, eicosapentaenoic, and docosahexaenoic acids) showed a complex behavior and lower predictability of their fragmentation patterns. However, this framework presents the capacity to model this behavior when more data are available. It would be also applicable to standardize the quantification of the regioisomers of triacylglycerides in an inter-laboratory ring study.
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| 8. |
- Gil-de-Gomez, Luis, et al.
(författare)
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Lipidomic-Based Advances in Diagnosis and Modulation of Immune Response to Cancer
- 2020
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Ingår i: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 10:8
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Forskningsöversikt (refereegranskat)abstract
- While immunotherapies for diverse types of cancer are effective in many cases, relapse is still a lingering problem. Like tumor cells, activated immune cells have an anabolic metabolic profile, relying on glycolysis and the increased uptake and synthesis of fatty acids. In contrast, immature antigen-presenting cells, as well as anergic and exhausted T-cells have a catabolic metabolic profile that uses oxidative phosphorylation to provide energy for cellular processes. One goal for enhancing current immunotherapies is to identify metabolic pathways supporting the immune response to tumor antigens. A robust cell expansion and an active modulation via immune checkpoints and cytokine release are required for effective immunity. Lipids, as one of the main components of the cell membrane, are the key regulators of cell signaling and proliferation. Therefore, lipid metabolism reprogramming may impact proliferation and generate dysfunctional immune cells promoting tumor growth. Based on lipid-driven signatures, the discrimination between responsiveness and tolerance to tumor cells will support the development of accurate biomarkers and the identification of potential therapeutic targets. These findings may improve existing immunotherapies and ultimately prevent immune escape in patients for whom existing treatments have failed.
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| 9. |
- Kolmert, Johan, et al.
(författare)
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Urinary Leukotriene E-4 and Prostaglandin D-2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation A Clinical Observational Study
- 2021
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - NEW YORK, USA : AMER THORACIC SOC. - 1073-449X .- 1535-4970. ; 203:1, s. 37-53
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE(2) pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE(2) metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD(2) metabolite 2,3-dinor-11 beta-PGF(2 alpha). High concentrations of LTE4 and PGD(2) metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOARED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.
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| 10. |
- Kopsida, Maria, et al.
(författare)
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Inhibiting the endoplasmic reticulum stress response enhances the effect of doxorubicin by altering the lipid metabolism of liver cancer cells
- 2024
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Ingår i: Molecular Metabolism. - : Elsevier. - 2212-8778. ; 79
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) is characterized by a low and variable response to chemotherapeutic treatments. One contributing factor to the overall pharmacodynamics is the activation of endoplasmic reticulum (ER) stress pathways. This is a cellular stress mechanism that becomes activated when the cell's need for protein synthesis surpasses the ER's capacity to maintain accurate protein folding, and has been implicated in creating drug-resistance in several solid tumors. Objective: To identify the role of ER-stress and lipid metabolism in mediating drug response in HCC. Methods: By using a chemically-induced mouse model for HCC, we administered the ER-stress inhibitor 4m8C and/or doxorubicin (DOX) twice weekly for three weeks post-tumor initiation. Histological analyses were performed alongside comprehensive molecular biology and lipidomics assessments of isolated liver samples. In vitro models, including HCC cells, spheroids, and patient-derived liver organoids were subjected to 4m8C and/or DOX, enabling us to assess their synergistic effects on cellular viability, lipid metabolism, and oxygen consumption rate. Results: We reveal a pivotal synergy between ER-stress modulation and drug response in HCC. The inhibition of ER-stress using 4m8C not only enhances the cytotoxic effect of DOX, but also significantly reduces cellular lipid metabolism. This intricate interplay culminates in the deprivation of energy reserves essential for the sustenance of tumor cells. Conclusions: This study elucidates the interplay between lipid metabolism and ER-stress modulation in enhancing doxorubicin efficacy in HCC. This novel approach not only deepens our understanding of the disease, but also uncovers a promising avenue for therapeutic innovation. The long-term impact of our study could open the possibility of ER-stress inhibitors and/or lipase inhibitors as adjuvant treatments for HCC-patients. (c) 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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