Research

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25 pages, 13769 KiB

Open AccessArticle

Screening for Lipid-Metabolism-Related Genes and Identifying the Diagnostic Potential of ANGPTL6 for HBV-Related Early-Stage Hepatocellular Carcinoma

by Duo Zuo, Jiawei Xiao, Haohua An, Yongzi Chen, Jianhua Li, Xiaohui Yang, Xia Wang and Li Ren

Biomolecules 2022, 12(11), 1700; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12111700 - 17 Nov 2022

Cited by 1 | Viewed by 2016

Abstract

Lipid metabolic reprogramming is one of the hallmarks of hepatocarcinogenesis and development. Therefore, lipid-metabolism-related genes may be used as potential biomarkers for hepatocellular carcinoma (HCC). This study aimed to screen for genes with dysregulated expression related to lipid metabolism in HCC and explored [...] Read more.

Lipid metabolic reprogramming is one of the hallmarks of hepatocarcinogenesis and development. Therefore, lipid-metabolism-related genes may be used as potential biomarkers for hepatocellular carcinoma (HCC). This study aimed to screen for genes with dysregulated expression related to lipid metabolism in HCC and explored the clinical value of these genes. We screened differentially expressed proteins between tumorous and adjacent nontumorous tissues of hepatitis B virus (HBV)-related HCC patients using a Nanoscale Liquid Chromatography–Tandem Mass Spectrometry platform and combined it with transcriptomic data of lipid-metabolism-related genes from the GEO and HPA databases to identify dysregulated genes that may be involved in lipid metabolic processes. The potential clinical values of these genes were explored by bioinformatics online analysis tools (GEPIA, cBioPortal, SurvivalMeth, and TIMER). The expression levels of the secreted protein (angiopoietin-like protein 6, ANGPTL6) in serum were analyzed by ELISA. The ability of serum ANGPTL6 to diagnose early HCC was assessed by ROC curves. The results showed that serum ANGPTL6 could effectively differentiate between HBV-related early HCC patients with normal serum alpha-fetoprotein (AFP) levels and the noncancer group (healthy participants and chronic hepatitis B patients) (AUC = 0.717, 95% CI: from 0.614 to 0.805). Serum ANGPTL6 can be used as a potential second-line biomarker to supplement serum AFP in the early diagnosis of HBV-related HCC. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease)

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17 pages, 2872 KiB

Open AccessArticle

Influence of Inhibition of COX-2-Dependent Lipid Metabolism on Regulation of UVB-Induced Keratinocytes Apoptosis by Cannabinoids

by Piotr Wójcik, Michał Biernacki, Natalia Domian, Neven Žarković and Elżbieta Skrzydlewska

Biomolecules 2022, 12(6), 842; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12060842 - 17 Jun 2022

Cited by 5 | Viewed by 2279

Abstract

Inflammation and apoptosis are regulated by similar factors, including ultraviolet B (UVB) radiation and cannabinoids, which are metabolized by cyclooxygenase-2 (COX-2) into pro-apoptotic prostaglandin derivatives. Thus, the aim of this study was to evaluate the impact of cyclooxygenase-2 inhibition by celecoxib on the [...] Read more.

Inflammation and apoptosis are regulated by similar factors, including ultraviolet B (UVB) radiation and cannabinoids, which are metabolized by cyclooxygenase-2 (COX-2) into pro-apoptotic prostaglandin derivatives. Thus, the aim of this study was to evaluate the impact of cyclooxygenase-2 inhibition by celecoxib on the apoptosis of keratinocytes modulated by UVB, anandamide (AEA) and cannabidiol (CBD). For this purpose, keratinocytes were non-treated/treated with celecoxib and/or with UVB and CBD and AEA. Apoptosis was evaluated using microscopy, gene expressions using quantitate reverse-transcriptase polymerase chain reaction; prostaglandins using liquid chromatography tandem mass spectrometry and cyclooxygenase activity using spectrophotometry. UVB enhances the percentage of apoptotic keratinocytes, which can be caused by the increased prostaglandin generation by cyclooxygenase-2, or/and induced cannabinoid receptor 1/2 (CB1/2) expression. AEA used alone intensifies apoptosis by affecting caspase expression, and in UVB-irradiated keratinocytes, cyclooxygenase-2 activity is increased, while CBD acts as a cytoprotective when used with or without UVB. After COX-2 inhibition, UVB-induced changes are partially ameliorated, when anandamide becomes an anti-apoptotic agent. It can be caused by observed reduced generation of anandamide pro-apoptotic derivative prostaglandin-ethanolamide by COX. Therefore, products of cyclooxygenase-dependent lipid metabolism seem to play an important role in the modulation of UVB-induced apoptosis by cannabinoids, which is particularly significant in case of AEA as inhibition of cyclooxygenase reduces the generation of pro-apoptotic lipid mediators and thus prevents apoptosis. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease)

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14 pages, 1751 KiB

Open AccessArticle

The FAAH Inhibitor URB597 Modulates Lipid Mediators in the Brain of Rats with Spontaneous Hypertension

by Michał Biernacki, Marta Baranowska-Kuczko, Gabriella N. Niklińska and Elżbieta Skrzydlewska

Biomolecules 2020, 10(7), 1022; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10071022 - 10 Jul 2020

Cited by 8 | Viewed by 3033

Abstract

Hypertension is accompanied by oxidative stress, which can be modified by the functioning of the endocannabinoid system playing a prominent modulatory role in the brain. The present study tested whether chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl) phenyl]N-cyclohexylcarbamate (URB597) [...] Read more.

Hypertension is accompanied by oxidative stress, which can be modified by the functioning of the endocannabinoid system playing a prominent modulatory role in the brain. The present study tested whether chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl) phenyl]N-cyclohexylcarbamate (URB597) to rats with primary hypertension (SHR) can modify redox balance and consequently brain phospholipid metabolism. Experiments were conducted using SHRs and normotensive control Wistar–Kyoto rats treated by intraperitoneal injection with URB597 for 14 days. The biochemical parameters were assayed in the rats’ brains. Inhibition of FAAH activity by URB597 resulted in an increase in anandamide and GPR55 receptor levels, as well as a decrease in CB₂ receptor expression. However, there was a simultaneous increase in Nrf2 expression, as well as Cu, Zn-SOD, GSH-Px, glutathione reductase activity, and vitamin E levels in brain tissue of SHR rats. Consequently, URB597 caused a decrease in levels of phospholipid fatty acids and MDA, and an increase in free fatty acids. Given the importance of maintaining redox balance for brain function, the results of this study point to endocannabinoids as a potential therapeutic target for preventing brain metabolic disorders in hypertension. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease)

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21 pages, 8074 KiB

Open AccessArticle

Proeryptotic Activity of 4-Hydroxynonenal: A New Potential Physiopathological Role for Lipid Peroxidation Products

by Mario Allegra, Ignazio Restivo, Alberto Fucarino, Alessandro Pitruzzella, Sonya Vasto, Maria Antonia Livrea, Luisa Tesoriere and Alessandro Attanzio

Biomolecules 2020, 10(5), 770; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10050770 - 16 May 2020

Cited by 19 | Viewed by 2349

Abstract

Background: Eryptosis is a physiological, apoptosis-like death of injured erythrocytes crucial to prevent premature haemolysis and the pathological sequalae generated by cell-free haemoglobin. When dysregulated, the process is associated to several inflammatory-based pathologies. 4-Hydroxy-trans-2-nonenal (HNE) is an endogenous signalling molecule at physiological levels [...] Read more.

Background: Eryptosis is a physiological, apoptosis-like death of injured erythrocytes crucial to prevent premature haemolysis and the pathological sequalae generated by cell-free haemoglobin. When dysregulated, the process is associated to several inflammatory-based pathologies. 4-Hydroxy-trans-2-nonenal (HNE) is an endogenous signalling molecule at physiological levels and, at higher concentrations, is involved in the pathogenesis of several inflammatory-based diseases. This work evaluated whether HNE could induce eryptosis in human erythrocytes. Methods: Measurements of phosphatidylserine, cell volume, intracellular oxidants, Ca⁺⁺, glutathione, ICAM-1, and ceramide were assessed by flow cytometry. Scanning electron microscopy evaluated morphological alterations of erythrocytes. Western blotting assessed caspases. PGE₂ was measured by ELISA. Adhesion of erythrocytes on endothelial cells was evaluated by gravity adherence assay. Results: HNE in the concentration range between 10–100 µM induces eryptosis, morphological alterations correlated to caspase-3 activation, and increased Ca⁺⁺ levels. The process is not mediated by redox-dependent mechanisms; rather, it strongly depends on PGE₂ and ceramide. Interestingly, HNE induces significant increase of erythrocytes adhesion to endothelial cells (ECs) that are in turn dysfunctionated as evident by overexpression of ICAM-1. Conclusions: Our results unveil a new physiopathological role for HNE, provide mechanistic details of the HNE-induced eryptosis, and suggest a novel mechanism through which HNE could exert pro-inflammatory effects. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease)

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20 pages, 6306 KiB

Open AccessArticle

The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

by Teresa Martínez-Sena, Polina Soluyanova, Carla Guzmán, José Manuel Valdivielso, José Vicente Castell and Ramiro Jover

Biomolecules 2020, 10(3), 493; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030493 - 24 Mar 2020

Cited by 22 | Viewed by 4823

Abstract

The vitamin D receptor (VDR) must be relevant to liver lipid metabolism because VDR deficient mice are protected from hepatosteatosis. Therefore, our objective was to define the role of VDR on the overall lipid metabolism in human hepatocytes. We developed an adenoviral vector [...] Read more.

The vitamin D receptor (VDR) must be relevant to liver lipid metabolism because VDR deficient mice are protected from hepatosteatosis. Therefore, our objective was to define the role of VDR on the overall lipid metabolism in human hepatocytes. We developed an adenoviral vector for human VDR and performed transcriptomic and metabolomic analyses of cultured human hepatocytes upon VDR activation by vitamin D (VitD). Twenty percent of the VDR responsive genes were related to lipid metabolism, including MOGAT1, LPGAT1, AGPAT2, and DGAT1 (glycerolipid metabolism); CDS1, PCTP, and MAT1A (phospholipid metabolism); and FATP2, SLC6A12, and AQP3 (uptake of fatty acids, betaine, and glycerol, respectively). They were rapidly induced (4–6 h) upon VDR activation by 10 nM VitD or 100 µM lithocholic acid (LCA). Most of these genes were also upregulated by VDR/VitD in mouse livers in vivo. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) metabolomics demonstrated intracellular accumulation of triglycerides, with concomitant decreases in diglycerides and phosphatidates, at 8 and 24 h upon VDR activation. Significant alterations in phosphatidylcholines, increases in lyso-phosphatidylcholines and decreases in phosphatidylethanolamines and phosphatidylethanolamine plasmalogens were also observed. In conclusion, active VitD/VDR signaling in hepatocytes triggers an unanticipated coordinated gene response leading to triglyceride synthesis and to important perturbations in glycerolipids and phospholipids. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease)

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20 pages, 2524 KiB

Open AccessArticle

Cannabidiol Effects on Phospholipid Metabolism in Keratinocytes from Patients with Psoriasis Vulgaris

by Iwona Jarocka-Karpowicz, Michał Biernacki, Adam Wroński, Agnieszka Gęgotek and Elżbieta Skrzydlewska

Biomolecules 2020, 10(3), 367; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030367 - 28 Feb 2020

Cited by 53 | Viewed by 7935

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by dysregulated keratinocyte differentiation, but oxidative stress also plays an important role in the pathogenesis of this disease. Here, we examined the effect of cannabidiol (CBD), a phytocannabinoid with antioxidant and anti-inflammatory properties, on the [...] Read more.

Psoriasis is a chronic inflammatory skin disease characterized by dysregulated keratinocyte differentiation, but oxidative stress also plays an important role in the pathogenesis of this disease. Here, we examined the effect of cannabidiol (CBD), a phytocannabinoid with antioxidant and anti-inflammatory properties, on the redox balance and phospholipid metabolism in UVA/UVB-irradiated keratinocytes isolated from the skin of psoriatic patients or healthy volunteers. CBD accumulates mainly in membrane keratinocytes, especially from patients with psoriasis. This phytocannabinoid reduces the redox imbalance observed in the UV-irradiated keratinocytes of healthy subjects. It does so by decreasing reactive oxygen species (ROS) generation, increasing the Trx-dependent system efficiency, and increasing vitamin A and E levels. Consequently, a reduction in lipid peroxidation products, such as 8-isoprostanes and 4-hydroxynonenal, was also observed. Moreover, CBD modifies redox balance and lipid peroxidation in psoriatic patient keratinocytes following UV-irradiation. Interestingly, these changes are largely in the opposite direction to the case of keratinocytes from healthy subjects. CBD also regulates metabolic changes by modulating the endocannabinoid system that is disturbed by psoriasis development and UV irradiation. We observed a decrease in anandamide level in the UV-irradiated keratinocytes of healthy controls following CBD treatment, while in keratinocytes from patients treated with CBD, anandamide level was increased. However, the level of palmitoylethanolamide (PEA) was decreased in both groups treated with CBD. We further demonstrate that CBD increases CB1 receptor expression, primarily in the keratinocytes of patients, and increases CB2 receptor expression in both the psoriatic and control groups. However, CBD decreases CB2 receptor expression in UV-irradiated keratinocytes taken from patients. The UV- and psoriasis-induced activity of transmembrane transporters (Multidrug-Resistance (MDR) and breast cancer resistance protein (BCRP)) is normalized after CBD treatment. We conclude that CBD partially reduces oxidative stress in the keratinocytes of healthy individuals, while showing a tendency to increase the oxidative and inflammatory state in the keratinocytes of patients with psoriasis, especially following UV-irradiation. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease)

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Review

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24 pages, 386 KiB

Open AccessReview

The Short Overview on the Relevance of Fatty Acids for Human Cardiovascular Disorders

by Viktoriya S. Shramko, Yana V. Polonskaya, Elena V. Kashtanova, Ekaterina M. Stakhneva and Yuliya I. Ragino

Biomolecules 2020, 10(8), 1127; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10081127 - 30 Jul 2020

Cited by 76 | Viewed by 6335

Abstract

This review presents existing evidence of the influence of saturated and unsaturated fatty acids on cardiovascular diseases (CVD). Data are discussed regarding the roles of the most relevant fatty acids, such as myristic (C14:0), palmitic (C16:0), stearic (C18:0), palmitoleic (C16:1), oleic (C18:1), linoleic [...] Read more.

This review presents existing evidence of the influence of saturated and unsaturated fatty acids on cardiovascular diseases (CVD). Data are discussed regarding the roles of the most relevant fatty acids, such as myristic (C14:0), palmitic (C16:0), stearic (C18:0), palmitoleic (C16:1), oleic (C18:1), linoleic (C18:2), α-linolenic (C18:3, ω-3), γ-linolenic (C18:3, ω-6), arachidonic (C20:4), eicosapentaenoic (C20:5), docosahexaenoic (C22:6), and docosapentaenoic (C22:5) acid. The accumulated knowledge has expanded the understanding of the involvement of fatty acids in metabolic processes, thereby enabling the transition from basic exploratory studies to practical issues of application of these biomolecules to CVD treatment. In the future, these findings are expected to facilitate the interpretation and prognosis of changes in metabolic lipid aberrations in CVD. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease)

23 pages, 2446 KiB

Open AccessReview

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

by Piotr Wójcik, Neven Žarković, Agnieszka Gęgotek and Elżbieta Skrzydlewska

Biomolecules 2020, 10(3), 402; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10030402 - 05 Mar 2020

Cited by 30 | Viewed by 3979

Abstract

Apoptosis is the physiological mechanism of cell death and can be modulated by endogenous and exogenous factors, including stress and metabolic alterations. Reactive oxygen species (ROS), as well as ROS-dependent lipid peroxidation products (including isoprostanes and reactive aldehydes including 4-hydroxynonenal) are proapoptotic factors. [...] Read more.

Apoptosis is the physiological mechanism of cell death and can be modulated by endogenous and exogenous factors, including stress and metabolic alterations. Reactive oxygen species (ROS), as well as ROS-dependent lipid peroxidation products (including isoprostanes and reactive aldehydes including 4-hydroxynonenal) are proapoptotic factors. These mediators can activate apoptosis via mitochondrial-, receptor-, or ER stress-dependent pathways. Phospholipid metabolism is also an essential regulator of apoptosis, producing the proapoptotic prostaglandins of the PGD and PGJ series, as well as the antiapoptotic prostaglandins of the PGE series, but also 12-HETE and 20-HETE. The effect of endocannabinoids and phytocannabinoids on apoptosis depends on cell type-specific differences. Cells where cannabinoid receptor type 1 (CB1) is the dominant cannabinoid receptor, as well as cells with high cyclooxygenase (COX) activity, undergo apoptosis after the administration of cannabinoids. In contrast, in cells where CB2 receptors dominate, and cells with low COX activity, cannabinoids act in a cytoprotective manner. Therefore, cell type-specific differences in the pro- and antiapoptotic effects of lipids and their (oxidative) products might reveal new options for differential bioanalysis between normal, functional, and degenerating or malignant cells, and better integrative biomedical treatments of major stress-associated diseases. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease)

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