International Journal of Molecular Sciences

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Lipid Metabolism and Signaling in Tumors and Cerebrovascular Diseases

by Laura Gatti

Int. J. Mol. Sci. 2022, 23(11), 6280; https://doi.org/10.3390/ijms23116280 - 3 Jun 2022

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Abstract

The aim of this Special Issue was to update readers regarding state-of-the-art research into lipid metabolism and signaling in tumors and cerebrovascular diseases [...] Full article

(This article belongs to the Special Issue Lipid Metabolism and Signaling in Tumors and Cerebrovascular Diseases)

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12 pages, 1728 KiB

Open AccessArticle

The Lipid Asset Is Unbalanced in Peripheral Nerve Sheath Tumors

by Ignazio G. Vetrano, Michele Dei Cas, Vittoria Nazzi, Marica Eoli, Niccolò Innocenti, Veronica Saletti, Antonella Potenza, Tatiana Carrozzini, Giuliana Pollaci, Gemma Gorla, Rita Paroni, Riccardo Ghidoni and Laura Gatti

Int. J. Mol. Sci. 2022, 23(1), 61; https://doi.org/10.3390/ijms23010061 - 22 Dec 2021

Cited by 4 | Viewed by 3337

Abstract

Peripheral nerve sheath tumors (PNSTs) include schwannomas, neurofibromas (NFs), and plexiform neurofibromas (PNFs), among others. While they are benign tumors, according to their biological behavior, some have the potential for malignant degeneration, mainly PNFs. The specific factors contributing to the more aggressive behavior [...] Read more.

Peripheral nerve sheath tumors (PNSTs) include schwannomas, neurofibromas (NFs), and plexiform neurofibromas (PNFs), among others. While they are benign tumors, according to their biological behavior, some have the potential for malignant degeneration, mainly PNFs. The specific factors contributing to the more aggressive behavior of some PNSTs compared to others are not precisely known. Considering that lipid homeostasis plays a crucial role in fibrotic/inflammatory processes and in several cancers, we hypothesized that the lipid asset was also unbalanced in this group of nerve tumors. Through untargeted lipidomics, NFs presented a significant increase in ceramide, phosphatidylcholine, and Vitamin A ester. PNFs displayed a marked decrease in 34 out of 50 lipid class analyzed. An increased level of ether- and oxidized-triacylglycerols was observed; phosphatidylcholines were reduced. After sphingolipidomic analysis, we observed six sphingolipid classes. Ceramide and dihydroceramides were statistically increased in NFs. All the glycosylated species appeared reduced in NFs, but increased in PNFs. Our findings suggested that different subtypes of PNSTs presented a specific modulation in the lipidic profile. The untargeted and targeted lipidomic approaches, which were not applied until now, contribute to better clarifying bioactive lipid roles in PNS natural history to highlight disease molecular features and pathogenesis. Full article

(This article belongs to the Special Issue Lipid Metabolism and Signaling in Tumors and Cerebrovascular Diseases)

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16 pages, 2419 KiB

Open AccessArticle

Plasma Lipid Profiling Contributes to Untangle the Complexity of Moyamoya Arteriopathy

by Michele Dei Cas, Tatiana Carrozzini, Giuliana Pollaci, Antonella Potenza, Sara Nava, Isabella Canavero, Francesca Tinelli, Gemma Gorla, Ignazio G. Vetrano, Francesco Acerbi, Paolo Ferroli, Elisa F. Ciceri, Silvia Esposito, Veronica Saletti, Emilio Ciusani, Aida Zulueta, Rita Paroni, Eugenio A. Parati, Riccardo Ghidoni, Anna Bersano and Laura Gatti Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(24), 13410; https://doi.org/10.3390/ijms222413410 - 14 Dec 2021

Cited by 12 | Viewed by 3145

Abstract

Moyamoya arteriopathy (MA) is a rare cerebrovascular disorder characterized by ischemic/hemorrhagic strokes. The pathophysiology is unknown. A deregulation of vasculogenic/angiogenic/inflammatory pathways has been hypothesized as a possible pathophysiological mechanism. Since lipids are implicated in modulating neo-vascularization/angiogenesis and inflammation, their deregulation is potentially involved [...] Read more.

Moyamoya arteriopathy (MA) is a rare cerebrovascular disorder characterized by ischemic/hemorrhagic strokes. The pathophysiology is unknown. A deregulation of vasculogenic/angiogenic/inflammatory pathways has been hypothesized as a possible pathophysiological mechanism. Since lipids are implicated in modulating neo-vascularization/angiogenesis and inflammation, their deregulation is potentially involved in MA. Our aim is to evaluate angiogenic/vasculogenic/inflammatory proteins and lipid profile in plasma of MA patients and control subjects (healthy donors HD or subjects with atherosclerotic cerebrovascular disease ACVD). Angiogenic and inflammatory protein levels were measured by ELISA and a complete lipidomic analysis was performed on plasma by mass spectrometry. ELISA showed a significant decrease for MMP-9 released in plasma of MA. The untargeted lipidomic analysis showed a cumulative depletion of lipid asset in plasma of MA as compared to HD. Specifically, a decrease in membrane complex glycosphingolipids peripherally circulating in MA plasma with respect to HD was observed, likely suggestive of cerebral cellular recruitment. The quantitative targeted approach demonstrated an increase in free sphingoid bases, likely associated with a deregulated angiogenesis. Our findings indicate that lipid signature could play a central role in MA and that a detailed biomarker profile may contribute to untangle the complex, and still obscure, pathogenesis of MA. Full article

(This article belongs to the Special Issue Lipid Metabolism and Signaling in Tumors and Cerebrovascular Diseases)

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18 pages, 2406 KiB

Open AccessArticle

Ganglioside Composition Distinguishes Anaplastic Ganglioglioma Tumor Tissue from Peritumoral Brain Tissue: Complementary Mass Spectrometry and Thin-Layer Chromatography Evidence

by Dragana Fabris, Ivana Karmelić, Hasan Muharemović, Tomislav Sajko, Mia Jurilj, Slavica Potočki, Ruđer Novak and Željka Vukelić

Int. J. Mol. Sci. 2021, 22(16), 8844; https://doi.org/10.3390/ijms22168844 - 17 Aug 2021

Cited by 6 | Viewed by 3218

Abstract

Gangliosides serve as antitumor therapy targets and aberrations in their composition strongly correlate with tumor growth and invasiveness. Anaplastic ganglioglioma is a rare, poorly characterized, malignant neuronal–glial tumor type. We present the first comparative characterization of ganglioside composition in anaplastic ganglioglioma vs. peritumoral [...] Read more.

Gangliosides serve as antitumor therapy targets and aberrations in their composition strongly correlate with tumor growth and invasiveness. Anaplastic ganglioglioma is a rare, poorly characterized, malignant neuronal–glial tumor type. We present the first comparative characterization of ganglioside composition in anaplastic ganglioglioma vs. peritumoral and healthy brain tissues by combining mass spectrometry and thin-layer chromatography. Anaplastic ganglioglioma ganglioside composition was highly distinguishable from both peritumoral and healthy tissue despite having five to six times lower total content. Ten out of twelve MS-identified ganglioside classes, defined by unique glycan residues, were represented by a large number and considerable abundance of individual species with different fatty acid residues (C16–C24) in ceramide portions. The major structurally identified class was tumor-associated GD3 (>50%) with 11 species; GD3 (d18:1/24:0) being the most abundant. The dominant sphingoid base residue in ganglioside ceramides was sphingosine (d18:1), followed by eicosasphingosine (d20:1). The peritumoral tissue ganglioside composition was estimated as normal. Specific ganglioside composition and large variability of ganglioside ceramide structures determined in anaplastic ganglioglioma demonstrate realistic ganglioside expression patterns and correspond to the profile of high-grade malignancy brain tumors. Full article

(This article belongs to the Special Issue Lipid Metabolism and Signaling in Tumors and Cerebrovascular Diseases)

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14 pages, 19185 KiB

Open AccessArticle

Ablation of Acid Ceramidase Impairs Autophagy and Mitochondria Activity in Melanoma Cells

by Michele Lai, Veronica La Rocca, Rachele Amato, Giulia Freer, Mario Costa, Pietro Giorgio Spezia, Paola Quaranta, Giuseppe Lombardo, Daniele Piomelli and Mauro Pistello

Int. J. Mol. Sci. 2021, 22(6), 3247; https://doi.org/10.3390/ijms22063247 - 23 Mar 2021

Cited by 14 | Viewed by 3804

Abstract

Cutaneous melanoma is often resistant to therapy due to its high plasticity, as well as its ability to metabolise chemotherapeutic drugs. Sphingolipid signalling plays a pivotal role in its progression and metastasis. One of the ways melanoma alters sphingolipid rheostat is via over-expression [...] Read more.

Cutaneous melanoma is often resistant to therapy due to its high plasticity, as well as its ability to metabolise chemotherapeutic drugs. Sphingolipid signalling plays a pivotal role in its progression and metastasis. One of the ways melanoma alters sphingolipid rheostat is via over-expression of lysosomal acid ceramidase (AC), which catalyses the hydrolysis of pro-apoptotic long-chain ceramides into sphingosine and fatty acid. In this report, we examine the role of acid ceramidase in maintaining cellular homeostasis through the regulation of autophagy and mitochondrial activity in melanoma cell lines. We show that under baseline conditions, wild-type melanoma cells had 3-fold higher levels of the autophagy marker, microtubule-associated proteins 1A/1B light chain 3B (LC3 II), compared to AC-null cells. This difference was further magnified after cell starvation. Moreover, we noticed autophagy impairment in A375 AC-null cells, possibly due to local accumulation of non-metabolized ceramides. Nonetheless, we observed that AC-null cells exhibited a significant increase in mitochondrial membrane potential compared to control cells. Consistent with this observation, we found that, after total starvation, ~30% of AC-null cells undergo apoptosis compared to ~6% of wild-type cells. As expected, AC transfection restored viability in A375 AC-null cells. Together, these findings suggest that AC-null melanoma cells change and adapt their metabolism to survive in the absence of AC, although in a way that does not allow them to cope with the stress of nutrient deprivation. Full article

(This article belongs to the Special Issue Lipid Metabolism and Signaling in Tumors and Cerebrovascular Diseases)

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Review

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15 pages, 952 KiB

Open AccessReview

The Role of Thromboxane in the Course and Treatment of Ischemic Stroke: Review

by Małgorzata Szczuko, Igor Kozioł, Dariusz Kotlęga, Jacek Brodowski and Arleta Drozd

Int. J. Mol. Sci. 2021, 22(21), 11644; https://doi.org/10.3390/ijms222111644 - 28 Oct 2021

Cited by 40 | Viewed by 11934

Abstract

Cardiovascular diseases are currently among the leading causes of morbidity and mortality in many developed countries. They are distinguished by chronic and latent development, a course with stages of worsening of symptoms and a period of improvement, and a constant potential threat to [...] Read more.

Cardiovascular diseases are currently among the leading causes of morbidity and mortality in many developed countries. They are distinguished by chronic and latent development, a course with stages of worsening of symptoms and a period of improvement, and a constant potential threat to life. One of the most important disorders in cardiovascular disease is ischemic stroke. The causes of ischemic stroke can be divided into non-modifiable and modifiable causes. One treatment modality from a neurological point of view is acetylsalicylic acid (ASA), which blocks cyclooxygenase and, thus, thromboxane synthesis. The legitimacy of its administration does not raise any doubts in the case of the acute phase of stroke in patients in whom thrombolytic treatment cannot be initiated. The measurement of thromboxane B2 (TxB2) in serum (a stable metabolic product of TxA2) is the only test that measures the effect of aspirin on the activity of COX-1 in platelets. Measurement of thromboxane B2 may be a potential biomarker of vascular disease risk in patients treated with aspirin. The aim of this study is to present the role of thromboxane B2 in ischemic stroke and to present effective therapies for the treatment of ischemic stroke. Scientific articles from the PubMed database were used for the work, which were selected on the basis of a search for “thromboxane and stroke”. Subsequently, a restriction was introduced for works older than 10 years, those concerning animals, and those without full text access. Ultimately, 58 articles were selected. It was shown that a high concentration of TXB2 may be a risk factor for ischemic stroke or ischemic heart disease. However, there is insufficient evidence to suggest that thromboxane could be used in clinical practice as a marker of ischemic stroke. The inclusion of ASA in the prevention of stroke has a beneficial effect that is associated with the effect on thromboxane. However, its insufficient power in 25% or even 50% of the population should be taken into account. An alternative and/or additional therapy could be a selective antagonist of the thromboxane receptor. Thromboxane A2 production is inhibited by estrogen; therefore, the risk of CVD after the menopause and among men is higher. More research is needed in this area. Full article

(This article belongs to the Special Issue Lipid Metabolism and Signaling in Tumors and Cerebrovascular Diseases)

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18 pages, 3928 KiB

Open AccessReview

The Role of Sphingolipids in Cancer Immunotherapy

by Paola Giussani, Alessandro Prinetti and Cristina Tringali

Int. J. Mol. Sci. 2021, 22(12), 6492; https://doi.org/10.3390/ijms22126492 - 17 Jun 2021

Cited by 13 | Viewed by 4237

Abstract

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance [...] Read more.

Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets. Full article

(This article belongs to the Special Issue Lipid Metabolism and Signaling in Tumors and Cerebrovascular Diseases)

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13 pages, 1071 KiB

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Altered Metabolism in Glioblastoma: Myeloid-Derived Suppressor Cell (MDSC) Fitness and Tumor-Infiltrating Lymphocyte (TIL) Dysfunction

by Natalia Di Ianni, Silvia Musio and Serena Pellegatta

Int. J. Mol. Sci. 2021, 22(9), 4460; https://doi.org/10.3390/ijms22094460 - 24 Apr 2021

Cited by 16 | Viewed by 4181

Abstract

The metabolism of glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is flexible and adaptable to different adverse conditions, such as nutrient deprivation. Beyond glycolysis, altered lipid metabolism is implicated in GBM progression. Indeed, metabolic subtypes were recently identified based on [...] Read more.

The metabolism of glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is flexible and adaptable to different adverse conditions, such as nutrient deprivation. Beyond glycolysis, altered lipid metabolism is implicated in GBM progression. Indeed, metabolic subtypes were recently identified based on divergent glucose and lipid metabolism. GBM is also characterized by an immunosuppressive microenvironment in which myeloid-derived suppressor cells (MDSCs) are a powerful ally of tumor cells. Increasing evidence supports the interconnection between GBM and MDSC metabolic pathways. GBM cells exert a crucial contribution to MDSC recruitment and maturation within the tumor microenvironment, where the needs of tumor-infiltrating lymphocytes (TILs) with antitumor function are completely neglected. In this review, we will discuss the unique or alternative source of energy exploited by GBM and MDSCs, exploring how deprivation of specific nutrients and accumulation of toxic byproducts can induce T-cell dysfunction. Understanding the metabolic programs of these cell components and how they impact fitness or dysfunction will be useful to improve treatment modalities, including immunotherapeutic strategies. Full article

(This article belongs to the Special Issue Lipid Metabolism and Signaling in Tumors and Cerebrovascular Diseases)

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