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Open AccessArticle

Targeting 7KCh-Induced Cell Death Response Mediated by p38, P2X7 and GSDME in Retinal Pigment Epithelium Cells with Sterculic Acid

by Ana Pariente, Rafael Peláez, Rodrigo Ochoa, Álvaro Pérez-Sala, Ángela Villanueva-Martínez, Miriam Bobadilla and Ignacio M. Larráyoz

Pharmaceutics 2023, 15(11), 2590; https://doi.org/10.3390/pharmaceutics15112590 - 5 Nov 2023

Cited by 2 | Viewed by 1847

Abstract

Age-related macular degeneration (AMD) is the main cause of blindness in developed countries. AMD is characterized by the formation of drusen, which are lipidic deposits, between retinal pigment epithelium (RPE) and the choroid. One of the main molecules accumulated in drusen is 7-Ketocholesterol [...] Read more.

Age-related macular degeneration (AMD) is the main cause of blindness in developed countries. AMD is characterized by the formation of drusen, which are lipidic deposits, between retinal pigment epithelium (RPE) and the choroid. One of the main molecules accumulated in drusen is 7-Ketocholesterol (7KCh), an oxidized-cholesterol derivative. It is known that 7KCh induces inflammatory and cytotoxic responses in different cell types and the study of its mechanism of action is interesting in order to understand the development of AMD. Sterculic acid (SA) counteracts 7KCh response in RPE cells and could represent an alternative to improve currently used AMD treatments, which are not efficient enough. In the present study, we determine that 7KCh induces a complex cell death signaling characterized by the activation of necrosis and an alternative pyroptosis mediated by P2X7, p38 and GSDME, a new mechanism not yet related to the response to 7KCh until now. On the other hand, SA treatment can successfully attenuate the activation of both necrosis and pyroptosis, highlighting its therapeutic potential for the treatment of AMD. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

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22 pages, 4226 KB

Open AccessArticle

Identification of 7-Ketocholesterol-Modulated Pathways and Sterculic Acid Protective Effect in Retinal Pigmented Epithelium Cells by Using Genome-Wide Transcriptomic Analysis

by Ana Pariente, Álvaro Pérez-Sala, Rodrigo Ochoa, Miriam Bobadilla, Ángela Villanueva-Martínez, Rafael Peláez and Ignacio M. Larráyoz

Int. J. Mol. Sci. 2023, 24(8), 7459; https://doi.org/10.3390/ijms24087459 - 18 Apr 2023

Cited by 5 | Viewed by 2597

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. AMD is characterized by the formation of lipidic deposits between the retinal pigment epithelium (RPE) and the choroid called drusen. 7-Ketocholesterol (7KCh), an oxidized-cholesterol derivative, is closely related to AMD [...] Read more.

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. AMD is characterized by the formation of lipidic deposits between the retinal pigment epithelium (RPE) and the choroid called drusen. 7-Ketocholesterol (7KCh), an oxidized-cholesterol derivative, is closely related to AMD as it is one of the main molecules accumulated in drusen. 7KCh induces inflammatory and cytotoxic responses in different cell types, and a better knowledge of the signaling pathways involved in its response would provide a new perspective on the molecular mechanisms that lead to the development of AMD. Furthermore, currently used therapies for AMD are not efficient enough. Sterculic acid (SA) attenuates the 7KCh response in RPE cells and is presented as an alternative to improve these therapies. By using genome-wide transcriptomic analysis in monkey RPE cells, we have provided new insight into 7KCh-induced signaling in RPE cells, as well as the protective capacity of SA. 7KCh modulates the expression of several genes associated with lipid metabolism, endoplasmic reticulum stress, inflammation and cell death and induces a complex response in RPE cells. The addition of SA successfully attenuates the deleterious effect of 7KCh and highlights its potential for the treatment of AMD. Full article

(This article belongs to the Special Issue Neurodegenerative Retinal Diseases and Other Neurodegenerative Pathologies)

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20 pages, 3455 KB

Open AccessArticle

Sterculic Acid Alters Adhesion Molecules Expression and Extracellular Matrix Compounds to Regulate Migration of Lung Cancer Cells

by Rafael Peláez, Rodrigo Ochoa, Ana Pariente, Ángela Villanueva-Martínez, Álvaro Pérez-Sala and Ignacio M. Larráyoz

Cancers 2021, 13(17), 4370; https://doi.org/10.3390/cancers13174370 - 29 Aug 2021

Cited by 7 | Viewed by 3434

Abstract

Sterculic acid (SA) is a cyclopropenoid fatty acid isolated from Sterculia foetida seeds. This molecule is a well-known inhibitor of SCD1 enzyme, also known as ∆9-desaturase, which main function is related to lipid metabolism. However, recent studies have demonstrated that it also modifies [...] Read more.

Sterculic acid (SA) is a cyclopropenoid fatty acid isolated from Sterculia foetida seeds. This molecule is a well-known inhibitor of SCD1 enzyme, also known as ∆9-desaturase, which main function is related to lipid metabolism. However, recent studies have demonstrated that it also modifies many other pathways and the underlying gene expression. SCD overexpression, or up-regulated activity, has been associated with tumor aggressiveness and poor prognosis in many cancer types. Scd1 down-regulation, with different inhibitors or molecular strategies, reduces tumor cell survival and cell proliferation, as well as the chemoresistance associated with cancer stem cell presence. However, SA effects over cancer cell migration and extracellular matrix or adhesion molecules have not been described in cancer cells up to now. We used different migration assays and qPCR gene expression analysis to evaluate the effects of SA treatment in cancer cells. The results reveal that SA induces tumoral cell death at high doses, but we also observed that lower SA-treatments induce cell adhesion-migration capacity reduction as a result of modifications in the expression of genes related to integrins and extracellular matrix compounds. Overall, the functional and transcriptomic findings suggest that SA could represent a new inhibitor activity of epithelial to mesenchymal transition. Full article

(This article belongs to the Special Issue Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets)

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10 pages, 2174 KB

Open AccessArticle

Tilia sp. Seed Oil—Composition, Antioxidant Activity and Potential Use

by Nina Poljšak and Nina Kočevar Glavač

Appl. Sci. 2021, 11(11), 4932; https://doi.org/10.3390/app11114932 - 27 May 2021

Cited by 16 | Viewed by 4993

Abstract

Research on new, untapped seed oil sources is receiving increased attention. In this study, 18 different seed samples of Tilia cordata and Tilia platyphyllos from various locations in Slovenia were collected and oil was extracted. The compositions of triglyceride fatty acids and unsaponifiable [...] Read more.

Research on new, untapped seed oil sources is receiving increased attention. In this study, 18 different seed samples of Tilia cordata and Tilia platyphyllos from various locations in Slovenia were collected and oil was extracted. The compositions of triglyceride fatty acids and unsaponifiable compounds were determined using GC-MS, while antioxidant activity was evaluated using the DPPH method. The oil content in the seeds varied significantly, from 9.1% to 21.7%. Linoleic acid (50–60%) was found to be the predominant fatty acid, followed by oleic acid (18–22%) and palmitic acid (8–9%). Characteristic cyclopropene fatty acids (sterculic, dihydrosterculic and malvalic acids) were present in the average range of 4–8.4%. Antioxidant activity ranged from 8.9% to 65.5%, and was higher, on average, for T. platyphyllos. Higher antioxidant activity was closely correlated with higher γ-tocopherol contents. Statistically significant correlations were confirmed between antioxidant activity and γ-tocopherol, between Δ-tocopherol and phytol, between stigmasterol and β-sitosterol and between squalene and malvalic acid. Tilia oil may be of great interest for cosmetic and dermal preparations. It is, however, not considered a good source of dietary fatty acids due to the undesired, significant content of omega-6 fatty acids. Full article

(This article belongs to the Special Issue Plants: From Farm to Food and Biomedical Applications)

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12 pages, 2052 KB

Open AccessArticle

Determination of Cyclopropenoid Fatty Acids in Ewe Milk Fat by GC-MS after Intravenous Administration of Sterculic Acid

by Veronica Lolli, Pablo G. Toral, Augusta Caligiani and Pilar Gómez-Cortés

Foods 2020, 9(7), 901; https://doi.org/10.3390/foods9070901 - 8 Jul 2020

Cited by 4 | Viewed by 3746

Abstract

Cyclopropenoid fatty acids (CPEFA), found in oilseeds from Malvaceae and Sterculiaceae, have been shown to interfere with the endogenous synthesis of several bioactive lipids of dairy fat, such as cis-9, trans-11 18:2 and cis-9 18:1, by inhibiting Δ9-desaturase. No previous [...] Read more.

Cyclopropenoid fatty acids (CPEFA), found in oilseeds from Malvaceae and Sterculiaceae, have been shown to interfere with the endogenous synthesis of several bioactive lipids of dairy fat, such as cis-9, trans-11 18:2 and cis-9 18:1, by inhibiting Δ9-desaturase. No previous study has reported the presence of sterculic acid in animal fat and its incorporation in tissues after its administration, due to the lack of a proper methodology. In the present research, a GC-MS method based on cold base derivatization to fatty acids methylesters was developed to determine CPEFA in ewe milk triglycerides, after infusing sterculic acid (0.5 g/day) to six lactating ewes. An alternative derivatization based on silanyzation followed by GC-MS analysis was also tested, showing its possible applicability when CPEFA are present in the form of free fatty acids. Sterculic acid was detected in ewe milk triglycerides, demonstrating its incorporation from the bloodstream into milk by the mammary gland. The mean transfer rate represented 8.0 ± 1.0% of the daily dose. This study provides, for the first time, the presence of sterculic acid in milk fat, supporting the importance of understanding its occurrence in vivo and encouraging further research to determine whether it can be present in foods, such as dairy products, obtained under practical farming conditions. Full article

(This article belongs to the Special Issue Characterization and Detection of Lipid Substances in Food)

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18 pages, 2013 KB

Open AccessArticle

Genome-Wide Transcriptomic Analysis Identifies Pathways Regulated by Sterculic Acid in Retinal Pigmented Epithelium Cells

by Ana Pariente, Álvaro Pérez-Sala, Rodrigo Ochoa, Rafael Peláez and Ignacio M. Larráyoz

Cells 2020, 9(5), 1187; https://doi.org/10.3390/cells9051187 - 11 May 2020

Cited by 13 | Viewed by 3100

Abstract

In addition to its predominant role in lipid metabolism and body weight control, SCD1 has emerged recently as a potential new target for the treatment of various diseases. Sterculic acid (SA) is a cyclopropene fatty acid with numerous biological activities, generally attributed to [...] Read more.

In addition to its predominant role in lipid metabolism and body weight control, SCD1 has emerged recently as a potential new target for the treatment of various diseases. Sterculic acid (SA) is a cyclopropene fatty acid with numerous biological activities, generally attributed to its Stearoyl-CoA desaturase (SCD) inhibitory properties. Additional effects exerted by SA, independently of SCD inhibition, may be mediating anti-inflammatory and protective roles in retinal diseases such as age-related macular degeneration (AMD), but the mechanisms involved are poorly understood. In order to provide insights into those mechanisms, genome-wide transcriptomic analyses were carried out in mRPE cells exposed to SA for 24 h. Integrative functional enrichment analysis of genome-wide expression data provided biological insight about the protective mechanisms induced by SA. On the one hand, pivotal genes related to fatty acid biosynthesis, steroid biosynthesis, cell death, actin-cytoskeleton reorganization and extracellular matrix-receptor interaction were significantly downregulated by exposition to SA. On the other hand, genes related to fatty acid degradation and beta-oxidation were significantly upregulated. In conclusion, SA administration to RPE cells regulates crucial pathways related to cell proliferation, inflammation and cell death that may be of interest for the treatment of ocular diseases. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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12 pages, 1360 KB

Open AccessFeature PaperArticle

Ceiba speciosa (A. St.-Hil.) Seeds Oil: Fatty Acids Profiling by GC-MS and NMR and Bioactivity

by Sergio Rosselli, Rosa Tundis, Maurizio Bruno, Mariarosaria Leporini, Tiziana Falco, Rossella Gagliano Candela, Natale Badalamenti and Monica R. Loizzo

Molecules 2020, 25(5), 1037; https://doi.org/10.3390/molecules25051037 - 25 Feb 2020

Cited by 27 | Viewed by 5106

Abstract

This study aimed to evaluate the chemical composition by gas chromatography-mass spectrometry (GC-MS) and Nuclear Magnetic Resonance (NMR) analyses, the antioxidant activities evaluated by different in vitro assays namely 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), Ferric Reducing Ability Power (FRAP), and β-carotene bleaching tests, [...] Read more.

This study aimed to evaluate the chemical composition by gas chromatography-mass spectrometry (GC-MS) and Nuclear Magnetic Resonance (NMR) analyses, the antioxidant activities evaluated by different in vitro assays namely 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), Ferric Reducing Ability Power (FRAP), and β-carotene bleaching tests, and the inhibitory effects of enzymes linked to obesity (lipase, α-amylase, and α-glucosidase) of fixed seed oil of Ceiba speciosa (A. St.-Hil.). Fourteen compounds were identified. Linoleic acid (28.22%) was the most abundant followed by palmitic acid (19.56%). Malvalic acid (16.15%), sterculic acid (11.11%), and dihydrosterculic acid (2.74%) were also detected. C. speciosa fixed oil exerted a promising ABTS radicals scavenging activity with an IC₅₀ value of 10.21 µg/mL, whereas an IC₅₀ of 77.44 µg/mL against DPPH⁺ radicals was found. C. speciosa fixed oil inhibited lipase with an IC₅₀ value of 127.57 µg/mL. The present investigation confirmed the functional properties of C. speciosa fixed oil, and proposes its use as valuable source of bioactive constituents. Full article

(This article belongs to the Special Issue Bioproducts for Health)

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20 pages, 1857 KB

Open AccessFeature PaperReview

Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases

by Rafael Peláez, Ana Pariente, Álvaro Pérez-Sala and Ignacio M. Larráyoz

Cells 2020, 9(1), 140; https://doi.org/10.3390/cells9010140 - 7 Jan 2020

Cited by 45 | Viewed by 9635

Abstract

In many tissues, stearoyl-CoA desaturase 1 (SCD1) catalyzes the biosynthesis of monounsaturated fatty acids (MUFAS), (i.e., palmitoleate and oleate) from their saturated fatty acid (SFA) precursors (i.e., palmitate and stearate), influencing cellular membrane physiology and signaling, leading to broad effects on human physiology. [...] Read more.

In many tissues, stearoyl-CoA desaturase 1 (SCD1) catalyzes the biosynthesis of monounsaturated fatty acids (MUFAS), (i.e., palmitoleate and oleate) from their saturated fatty acid (SFA) precursors (i.e., palmitate and stearate), influencing cellular membrane physiology and signaling, leading to broad effects on human physiology. In addition to its predominant role in lipid metabolism and body weight control, SCD1 has emerged recently as a potential new target for the treatment for various diseases, such as nonalcoholic steatohepatitis, Alzheimer’s disease, cancer, and skin disorders. Sterculic acid (SA) is a cyclopropene fatty acid originally found in the seeds of the plant Sterculia foetida with numerous biological activities. On the one hand, its ability to inhibit stearoyl-CoA desaturase (SCD) allows its use as a coadjuvant of several pathologies where this enzyme has been associated. On the other hand, additional effects independently of its SCD inhibitory properties, involve anti-inflammatory and protective roles in retinal diseases such as age-related macular degeneration (AMD). This review aims to summarize the mechanisms by which SA exerts its actions and to highlight the emerging areas where this natural compound may be of help for the development of new therapies for human diseases. Full article

(This article belongs to the Special Issue Rejuvenating, Geroprotective and Cytoprotective Activities of Natural and Synthetic Compounds: Proofs of Concept, Associated Mechanims and Applications)

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