RESUMO
Oral health is crucial to overall health, and periodontal disease (PDD) is a chronic inflammatory disease. Over the past decade, PDD has been recognized as a significant contributor to systemic inflammation. Here, we relate our seminal work defining the role of lysophosphatidic acid (LPA) and its receptors (LPARs) in the oral system with findings and parallels relevant to cancer. We discuss the largely unexplored fine-tuning potential of LPA species for biological control of complex immune responses and suggest approaches for the areas where we believe more research should be undertaken to advance our understanding of signaling at the level of the cellular microenvironment in biological processes where LPA is a key player so we can better treat diseases such as PDD, cancer, and emerging diseases.
Assuntos
Neoplasias , Receptores de Ácidos Lisofosfatídicos , Humanos , Lisofosfolipídeos/fisiologia , Transdução de Sinais , Inflamação , Microambiente TumoralRESUMO
Mast cells (MCs) are the main participants in the control of immune reactions associated with inflammation, allergies, defense against pathogens, and tumor growth. Bioactive lipids are lipophilic compounds able to modulate MC activation. Here, we explored some of the effects of the bioactive lipid lysophosphatidylinositol (LPI) on MCs. Utilizing murine bone marrow-derived mast cells (BMMCs), we found that LPI did not cause degranulation, but slightly increased FcεRI-dependent ß-hexosaminidase release. However, LPI induced strong chemotaxis together with changes in LIM kinase (LIMK) and cofilin phosphorylation. LPI also promoted modifications to actin cytoskeleton dynamics that were detected by an increase in cell size and interruptions in the continuity of the cortical actin ring. The chemotaxis and cortical actin ring changes were dependent on GPR55 receptor activation, since the specific agonist O1602 mimicked the effects of LPI and the selective antagonist ML193 prevented them. The LPI and O1602-dependent stimulation of BMMC also led to VEGF, TNF, IL-1α, and IL-1ß mRNA accumulation, but, in contrast with chemotaxis-related processes, the effects on cytokine transcription were dependent on GPR55 and cannabinoid (CB) 2 receptors, since they were sensitive to ML193 and to the specific CB2 receptor antagonist AM630. Remarkably, GPR55-dependent BMMC chemotaxis was observed towards conditioned media from distinct mouse and human cancer cells. Our data suggest that LPI induces the chemotaxis of MCs and leads to cytokine production in MC in vitro with the differential participation of GPR55 and CB2 receptors. These effects could play a significant role in the recruitment of MCs to tumors and the production of MC-derived pro-angiogenic factors in the tumor microenvironment.
Assuntos
Receptor CB2 de Canabinoide , Receptores Acoplados a Proteínas G , Camundongos , Humanos , Animais , Receptores Acoplados a Proteínas G/genética , Receptor CB2 de Canabinoide/genética , Quimiotaxia , Mastócitos , Citocinas , Actinas , Receptores de Canabinoides/genética , Lisofosfolipídeos/farmacologia , Lisofosfolipídeos/fisiologiaRESUMO
Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that regulates fundamental cellular processes such as proliferation, migration, apoptosis, and differentiation through 5 cognate G protein-coupled receptors (S1P1-S1P5). We previously demonstrated that blockade of S1P2 signaling in S1P2-deficient mice attenuates high-fat diet-induced adipocyte hypertrophy and glucose intolerance and an S1P2-specific antagonist JTE-013 inhibits, whereas an S1P1/S1P3 dual antagonist (VPC23019) activates, adipogenic differentiation of preadipocytes. Based on those observations, this study examined whether an S1P1-specific agonist, SEW-2871, VPC23019, or their combination acts on obesity and glucose intolerance in leptin-deficient ob/ob mice. The oral administration of SEW-2871 or JTE-013 induced significant reductions in body/epididymal fat weight gains and epididymal/inguinal fat adipocyte sizes and improved glucose intolerance and adipocyte inflammation in ob/ob mice but not in their control C57BL/6J mice. Both SEW-2871 and JTE-013 decreased messenger RNA levels of tumor necrosis factor-α and CD11c, whereas they increased those of CD206 and adiponectin in the epididymal fats isolated from ob/ob mice with no changes in the levels of peroxisome proliferator activated receptor γ and its regulated genes. By contrast, VPC23019 did not cause any such alterations but counteracted with all those SEW-2871 actions in these mice. In conclusion, the S1P1 agonist SEW-2871 acted like the S1P2 antagonist JTE-013 to reduce body/epididymal fats and improve glucose tolerance in obese mice. Therefore, this study raises the possibility that endogenous S1P could promote obesity/type 2 diabetes through the S1P2, whereas exogenous S1P could act against them through the S1P1.
Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Animais , Masculino , Camundongos , Glucose , Lisofosfolipídeos/farmacologia , Lisofosfolipídeos/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade , Receptores de Lisoesfingolipídeo/genética , Esfingosina/farmacologia , Esfingosina/fisiologia , Receptores de Esfingosina-1-FosfatoRESUMO
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonias. Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are signaling lipids that evoke growth factor-like responses to many cells. Recent studies revealed the involvement of LPA and S1P in the pathology of IPF. In this study, we determined LPA, S1P and ceramide 1-phosphate (C1P) in peripheral blood plasma of IPF patients, and examined correlation to the vital capacity of lung (VC), an indicator of development of fibrosis. Blood plasma samples were taken from eleven patients with IPF and seven healthy volunteers. The lipids of the sample were extracted and subjected to liquid chromatography-tandem mass spectrometry for analysis. Results showed that there is a significant negative correlation between VC and plasma LPA levels, indicating that IPF patients with advanced fibrosis had higher concentration of LPA in their plasma. Average of S1P levels were significantly higher in IPF patients than those in healthy subjects. Although it is not statistically significant, a similar correlation trend that observed in LPA levels also found between VC and S1P levels. These results indicated that plasma LPA and S1P may be associated with deterioration of pulmonary function of IPF patients. J. Med. Invest. 69 : 196-203, August, 2022.
Assuntos
Fibrose Pulmonar Idiopática , Ceramidas , Fibrose , Humanos , Lisofosfolipídeos/análise , Lisofosfolipídeos/fisiologia , Esfingosina/análogos & derivadosRESUMO
Sunitinib resistance is a major challenge in systemic therapy for renal cell carcinoma (RCC). The role of circular RNAs (circRNAs) in regulating sunitinib resistance of RCC is largely unknown. We established sunitinib-resistant RCC cell lines in vivo. Through RNA-sequencing, we identified circSNX6, whose expression is upregulated in sunitinib-resistant cells compared with their parental cells. High circSNX6 expression was correlated with sunitinib resistance and worse oncologic outcomes in a cohort of 81 RCC patients. In vitro and in vivo experiments confirmed that circSNX6 could promote sunitinib resistance in RCC. circSNX6 acts as a molecular "sponge" to relieve the suppressive effect of microRNA (miR)-1184 on its target gene, glycerophosphocholine phosphodiesterase 1 (GPCPD1), which increases intracellular lysophosphatidic acid (LPA) levels and, ultimately, promotes sunitinib resistance in RCC cells. Our findings demonstrated that the circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular LPA levels and sunitinib resistance in RCC; they also provide a novel prognostic indicator and promising therapeutic targets.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Lisofosfolipídeos/fisiologia , MicroRNAs/fisiologia , Fosfolipases/fisiologia , RNA Circular/fisiologia , Sunitinibe/farmacologia , Adulto , Idoso , Animais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Renais/genética , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-IdadeRESUMO
Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1α regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Cicatrização/fisiologia , Animais , Diferenciação Celular/genética , Movimento Celular/fisiologia , Citocinas/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Inflamação/metabolismo , Lisofosfolipídeos/fisiologia , Ativação de Macrófagos/fisiologia , Macrófagos/metabolismo , Macrófagos/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/fisiologia , Esfingosina/metabolismo , Esfingosina/fisiologiaRESUMO
For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.
Assuntos
Sistema Nervoso Central/fisiopatologia , Inflamação/fisiopatologia , Lipídeos de Membrana/fisiologia , Modelos Biológicos , Degeneração Neural/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Esfingolipídeos/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Ceramidas/fisiologia , Eicosanoides/fisiologia , Previsões , Homeostase , Humanos , Inflamação/patologia , Lipoxigenase/fisiologia , Lisofosfolipídeos/fisiologia , Degeneração Neural/patologia , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Prostaglandina-Endoperóxido Sintases/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologiaRESUMO
Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. The regulatory mechanisms of BCSC interactions with the vascular niche within the tumor microenvironment (TME) and their self-renewal are currently under extensive investigation. We have demonstrated the existence of an arteriolar niche in the TME of human BC tissues. Intriguingly, BCSCs tend to be enriched within the arteriolar niche in human estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the lysophosphatidic acid (LPA)/protein kinase D (PKD-1) signaling pathway, which promotes both arteriolar differentiation of ECs and self-renewal of CSCs likely via differential regulation of CD36 transcription. This study indicates that CSCs may enjoy blood perfusion to maintain their stemness features. Targeting the LPA/PKD-1 -CD36 signaling pathway may have therapeutic potential to curb tumor progression by disrupting the arteriolar niche and effectively eliminating CSCs.
Assuntos
Neoplasias da Mama/patologia , Lisofosfolipídeos/fisiologia , Células-Tronco Neoplásicas/fisiologia , Proteína Quinase C/fisiologia , Nicho de Células-Tronco/fisiologia , Antígenos CD36/análise , Comunicação Celular , Diferenciação Celular , Células Endoteliais/citologia , Feminino , Humanos , Proteína Quinase C/análise , Transdução de Sinais/fisiologia , Microambiente TumoralRESUMO
OBJECTIVES: This study was designed to explore the intellectual landscape of research into the application of sphingosine 1 phosphate (S1P) in age-related diseases and to identify thematic development trends and research frontiers in this area. METHODS: Scientometric research was conducted by analyzing bibliographic records retrieved from the Web of Science (WOS) Sci-Expanded Database dated between 1900 and 2020. Countries, institutions, authors, keyword occurrence analysis, and cooperation network analysis were performed using the CiteSpace and VOSviewer software. RESULTS: A total of 348 valid records were included in the final dataset, and the number of publications and the frequency of citations have grown rapidly over the last ten years. The USA (n = 175), China (n = 42), and Germany (n = 37) were the three largest contributors to the global publications on S1P and aging, while the Medical University of South Carolina (n = 15), University of California, San Francisco (n = 13), and University of Toronto (n = 13) were the leading institutions in this field. Analysis showed that early studies primarily focused on the mechanism of S1P intervention in AD. While S1P and its relevant metabolites have remained a long-term active area of research, recent studies have focused more on interventions aimed at improving retinal degeneration, cardiomyopathy, multiple sclerosis, and diabetes, among others. CONCLUSIONS: It is worth mentioning that this manuscript is the first to describe any bibliometric analysis of S1P and its application in age-related interventions. This study includes a discussion of the (1) historical overview of the topic; (2) main contributors: journals, countries, institutes, funding agencies, and authors; (3) collaboration between institutes and authors; (4) research hot spots and zones; and 5) research trends and frontiers. This will enable scholars to understand the current status of S1P research in age-related diseases.
Assuntos
Envelhecimento , Pesquisa Biomédica/tendências , Lisofosfolipídeos/fisiologia , Esfingosina/análogos & derivados , Humanos , Esfingosina/fisiologiaRESUMO
In malaria-endemic countries, the burden of hypertension is on the rise. Although malaria and hypertension seem to have no direct link, several studies in recent years support their possible link. Three bioactive molecules such as angiotensin II (Ang II), bradykinin (BK) and sphingosine 1-phosphate (S1P) are crucial in regulating blood pressure. While the increased level of Ang II and S1P are responsible for inducing hypertension, BK is arthero-protective and anti-hypertensive. Therefore, in the present review, based on available literatures we highlight the present knowledge on the production and bioavailability of these molecules, the mechanism of their regulation of hypertension, and patho-physiological role in malaria. Further, a possible link between malaria and hypertension is hypothesized through various arguments based on experimental evidence. Understanding of their mechanisms of blood pressure regulation during malaria infection may open up avenues for drug therapeutics and management of malaria in co-morbidity with hypertension.
Assuntos
Angiotensina II/fisiologia , Bradicinina/fisiologia , Hipertensão/etiologia , Lisofosfolipídeos/fisiologia , Malária/complicações , Esfingosina/análogos & derivados , Pressão Sanguínea , Comorbidade , Feminino , Humanos , Hipertensão/epidemiologia , Malária/epidemiologia , Masculino , Gravidez , Esfingosina/fisiologiaRESUMO
Lipidomics is a lipid-targeted metabolomics approach that aims to the comprehensive analysis of lipids in biological systems in order to highlight the specific functions of lipid species in health and disease. Lipids play pivotal roles as they are major structural components of the cellular membranes and energy storage molecules but also, as most recently shown, they act as functional and regulatory components of intra- and intercellular signaling. Herein, emphasis is given to the recently highlighted roles of specific bioactive lipids species, as polyunsaturated fatty acids (PUFA)-derived mediators (generally known as eicosanoids), endocannabinoids (eCBs), and lysophospholipids (LPLs), and their involvement in the mesenchymal stem cells (MSCs)-related inflammatory scenario. Indeed, MSCs are a heterogenous population of multipotent cells that have attracted much attention for their potential in regulating inflammation, immunomodulatory capabilities, and reparative roles. The lipidomics of the inflammatory disease osteoarthritis (OA) and the influence of MSCs-derived lipids have also been addressed.
Assuntos
Inflamação/metabolismo , Lipídeos/fisiologia , Células-Tronco Mesenquimais/metabolismo , Imunidade Adaptativa , Animais , Diferenciação Celular , Eicosanoides/fisiologia , Endocanabinoides/fisiologia , Vesículas Extracelulares , Ácidos Graxos Insaturados/farmacologia , Humanos , Imunidade Inata , Inflamação/imunologia , Lipídeos/classificação , Lisofosfolipídeos/fisiologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteoartrite/metabolismo , Osteoartrite/terapiaRESUMO
Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P1-S1P5. Scrutiny of S1P-regulated pathways over the past three decades has identified important and occasionally counteracting functions in the brain and cerebrovascular system. For example, while S1P1 and S1P3 mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S1P2 is anti-inflammatory but disrupts barrier integrity. Cumulatively, there is significant preclinical evidence implicating critical roles for this pathway in regulating processes that drive cerebrovascular disease and vascular dementia, both being part of the continuum of vascular cognitive impairment (VCI). This is supported by clinical studies that have identified correlations between alterations of S1P and cognitive deficits. We review studies which proposed and evaluated potential mechanisms by which such alterations contribute to pathological S1P signaling that leads to VCI-associated chronic neuroinflammation and neurodegeneration. Notably, S1P receptors have divergent but overlapping expression patterns and demonstrate complex interactions. Therefore, the net effect produced by S1P represents the cumulative contributions of S1P receptors acting additively, synergistically, or antagonistically on the neural, vascular, and immune cells of the brain. Ultimately, an optimized therapeutic strategy that targets S1P signaling will have to consider these complex interactions.
Assuntos
Demência Vascular/fisiopatologia , Lisofosfolipídeos/fisiologia , Receptores de Esfingosina-1-Fosfato/fisiologia , Esfingosina/análogos & derivados , Aldeído Liases/antagonistas & inibidores , Aldeído Liases/fisiologia , Doença de Alzheimer/fisiopatologia , Animais , Transtornos Cerebrovasculares/fisiopatologia , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Cloridrato de Fingolimode/uso terapêutico , Humanos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/fisiopatologia , Inflamação , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/fisiopatologia , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/fisiopatologia , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Transdução de Sinais , Esfingosina/fisiologia , Receptores de Esfingosina-1-Fosfato/efeitos dos fármacosRESUMO
Transfusion-related acute lung injury (TRALI) is a hazardous transfusion complication with an associated mortality of 5% to 15%. We previously showed that stored (5 days) but not fresh platelets (1 day) cause TRALI via ceramide-mediated endothelial barrier dysfunction. As biological ceramides are hydrophobic, extracellular vesicles (EVs) may be required to shuttle these sphingolipids from platelets to endothelial cells. Adding to complexity, EV formation in turn requires ceramide. We hypothesized that ceramide-dependent EV formation from stored platelets and EV-dependent sphingolipid shuttling induces TRALI. EVs formed during storage of murine platelets were enumerated, characterized for sphingolipids, and applied in a murine TRALI model in vivo and for endothelial barrier assessment in vitro. Five-day EVs were more abundant, had higher long-chain ceramide (C16:0, C18:0, C20:0), and lower sphingosine-1-phosphate (S1P) content than 1-day EVs. Transfusion of 5-day, but not 1-day, EVs induced characteristic signs of lung injury in vivo and endothelial barrier disruption in vitro. Inhibition or supplementation of ceramide-forming sphingomyelinase reduced or enhanced the formation of EVs, respectively, but did not alter the injuriousness per individual EV. Barrier failure was attenuated when EVs were abundant in or supplemented with S1P. Stored human platelet 4-day EVs were more numerous compared with 2-day EVs, contained more long-chain ceramide and less S1P, and caused more endothelial cell barrier leak. Hence, platelet-derived EVs become more numerous and more injurious (more long-chain ceramide, less S1P) during storage. Blockade of sphingomyelinase, EV elimination, or supplementation of S1P during platelet storage may present promising strategies for TRALI prevention.
Assuntos
Vesículas Extracelulares/fisiologia , Transfusão de Plaquetas/efeitos adversos , Esfingolipídeos/metabolismo , Lesão Pulmonar Aguda Relacionada à Transfusão/etiologia , Animais , Plaquetas/ultraestrutura , Preservação de Sangue , Ceramidas/metabolismo , Células Endoteliais/fisiologia , Endotoxinas/toxicidade , Humanos , Lisofosfolipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Biológicos , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielina Fosfodiesterase/deficiência , Esfingomielina Fosfodiesterase/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia , Lesão Pulmonar Aguda Relacionada à Transfusão/metabolismo , Lesão Pulmonar Aguda Relacionada à Transfusão/prevenção & controleRESUMO
Sphingosine 1-phosphate (S1P) is an important lipid biomolecule that exerts pleiotropic cellular actions as it binds to and activates its five G-protein-coupled receptors, S1P1-5. Through these receptors, S1P can mediate diverse biological activities in both healthy and diseased conditions. S1P is produced by S1P-producing enzymes, sphingosine kinases (SphK1 and SphK2), and is abundantly present in different organs, including the brain. The medically important roles of receptor-mediated S1P signaling are well characterized in multiple sclerosis because FTY720 (Gilenya™, Novartis), a non-selective S1P receptor modulator, is currently used as a treatment for this disease. In cerebral ischemia, its role is also notable because of FTY720's efficacy in both rodent models and human patients with cerebral ischemia. In particular, some of the S1P receptors, including S1P1, S1P2, and S1P3, have been identified as pathogenic players in cerebral ischemia. Other than these receptors, S1P itself and S1P-producing enzymes have been shown to play certain roles in cerebral ischemia. This review aims to compile the current updates and overviews about the roles of S1P signaling, along with a focus on S1P receptors in cerebral ischemia, based on recent studies that used in vivo rodent models of cerebral ischemia.
Assuntos
Isquemia Encefálica/metabolismo , Lisofosfolipídeos/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Receptores de Esfingosina-1-Fosfato/fisiologia , Esfingosina/análogos & derivados , Animais , Dano Encefálico Crônico/etiologia , Dano Encefálico Crônico/metabolismo , Isquemia Encefálica/complicações , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Cloridrato de Fingolimode/uso terapêutico , Humanos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Inflamação , AVC Isquêmico/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Ratos , Transdução de Sinais/fisiologia , Esfingosina/fisiologiaRESUMO
Breast cancer is one of the most common female malignant cancers. Biorhythm disorder largely increases the risk of breast cancer. We aimed to investigate the biological functions and molecular mechanisms of circadian gene TIMELESS circadian regulator (TIM) in estrogen receptor (ER)-positive breast cancer and provide a new therapeutic target for breast cancer patients. Here, we explored that the expression of TIM was elevated in breast cancer, and high expression of TIM in cancer tissues was associated with poor prognosis, especially in the ER-positive breast cancer patients. In addition, we found that TIM promoted cell proliferation and enhanced mitochondrial respiration. TIM interacted with specificity protein 1 (Sp1) which contributes to upregulate the expression of alkaline ceramidase 2 (ACER2). Moreover, ACER2 is responsible for TIM-mediated promotive effects of cell growth and mitochondrial respiration. Collectively, our research unveiled a novel function of TIM in sphingolipid metabolism through interaction with Sp1. It provides a new theoretical explanation for the pathogenesis of breast cancer, and targeting TIM may serve as a potential therapeutic target for ER-positive breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Esfingolipídeos/metabolismo , Ceramidase Alcalina/fisiologia , Animais , Biópsia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Lisofosfolipídeos/fisiologia , Camundongos , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Fator de Transcrição Sp1/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Lipids are abundant and play essential roles in human health and disease. The main functions of lipids are building blocks for membrane biogenesis. However, lipids are also metabolized to produce signaling molecules. Here, we discuss the emerging roles of circulating lysophospholipids. These lysophospholipids consist of lysoglycerophospholipids and lysosphingolipids. They are both present in cells at low concentration, but their concentrations in extracellular fluids are significantly higher. The biological functions of some of these lysophospholipids have been recently revealed. Remarkably, some of the lysophospholipids play pivotal signaling roles as well as being precursors for membrane biogenesis. Revealing how circulating lysophospholipids are produced, released, transported, and utilized in multi-organ systems is critical to understand their functions. The discovery of enzymes, carriers, transporters, and membrane receptors for these lysophospholipids has shed light on their physiological significance. In this review, we summarize the biological roles of these lysophospholipids via discussing about the proteins regulating their functions. We also discuss about their potential impacts to human health and diseases.
Assuntos
Proteínas de Transporte/metabolismo , Lisofosfolipídeos/fisiologia , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Proteínas de Transporte/genética , Humanos , Lisofosfolipídeos/química , Transdução de SinaisRESUMO
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks synovial joint tissues. Interleukin (IL)-1ß is a critical proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we investigated how S1P mediates IL-1ß expression in osteoblasts. Our analysis of records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-1ß in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P concentration dependently increased mRNA and protein expression of IL-1ß. Elevations in IL-1ß mRNA expression induced by S1P were reduced by the small interfering RNA (siRNA) against the S1P1 receptor. S1P also augmented JAK and STAT3 molecular cascades. We also found that JAK and STAT3 inhibitors and their siRNAs antagonized S1P-promoted IL-1ß expression. Our results indicate that S1P promotes the expression of IL-1ß in osteoblasts via the S1P1 receptor and the JAK and STAT3 signaling pathways.
Assuntos
Interleucina-1beta/genética , Janus Quinases/metabolismo , Lisofosfolipídeos/fisiologia , Osteoblastos/metabolismo , Fator de Transcrição STAT3/metabolismo , Esfingosina/análogos & derivados , Artrite Reumatoide/metabolismo , Células Cultivadas , Humanos , Lisofosfolipídeos/farmacologia , Masculino , Osteoartrite/metabolismo , Osteoblastos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Esfingosina/farmacologia , Esfingosina/fisiologia , Receptores de Esfingosina-1-Fosfato/genéticaRESUMO
BACKGROUND: Baicalein has been shown to have anti-inflammatory and anti-tumor activities. However, the mechanisms underlying its anti-inflammatory effect on colitis remain unclear. METHODS: A dextran sodium sulfate (DSS)-induced model of acute colitis was established in BALB/c mice (6-8 weeks old, weighing 18-22âg). Six groups of mice received: (1) water for 10 days (control), nâ=â6; (2) DSS 4% solution in the drinking water for 7 days, followed by normal water for 3 days, nâ=â7; (3), (4), and (5) as for group 2 plus baicalein (10, 20, 40âmg/kg) administered once daily starting on day 1, nâ=â6; and (6) as for (2) plus 5-aminosalicylic acid (50âmg/kg) administered once daily starting on day 1, nâ=â6. Body weights, stool consistency, and hematochezia were recorded, and the severity of colitis was evaluated using a disease activity index. On day 11, the mice were euthanized, and organs and blood were collected for analysis. Serum inflammatory factors were detected by enzyme-linked immunosorbent assay; CD11b-positive cells were analyzed by immunofluorescence microscopy; expression of retinoic-acid-receptor-related orphan nuclear receptor gamma, sphingosine kinase 1 (SPHK1), and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) was detected by immunohistochemistry; and expression of nucleotide-binding oligomerization domain 2 (NOD2), SPHK1, sphingosine 1-phosphate receptor 1 (S1PR1), total STAT3, and p-STAT3 were detected by western blotting analysis. Inter-group differences were compared using Student's t test. RESULTS: Baicalein treatment dose-dependently reduced DSS-induced weight loss (Pâ<â0.01 or Pâ<â0.05), splenomegaly (Pâ<â0.01), and colonic damage, as reflected by amelioration of diarrhea, rectal bleeding, and colonic ulceration, congestion, edema (shown as colon length, Pâ<â0.05 or Pâ<â0.01), and inflammatory cell infiltration. Baicalein also significantly decreased the levels of inflammatory mediators in the serum (Pâ<â0.01) and colon, and significantly inhibited expression of NOD2 SPHK1, S1PR1, and p-STAT3 in the colon (Pâ<â0.05). CONCLUSIONS: Baicalein treatment ameliorated colitis in mice by inhibiting S1P-STAT3 signaling, suggesting that this flavonoid might be beneficial in the treatment of colitis.
Assuntos
Colite/prevenção & controle , Flavanonas/uso terapêutico , Lisofosfolipídeos/fisiologia , Fator de Transcrição STAT3/fisiologia , Esfingosina/análogos & derivados , Animais , Colite/induzido quimicamente , Sulfato de Dextrana/farmacologia , Feminino , Flavanonas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína Adaptadora de Sinalização NOD2/análise , Fosfotransferases (Aceptor do Grupo Álcool)/análise , Fator de Transcrição STAT3/análise , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Esfingosina/fisiologia , Receptores de Esfingosina-1-Fosfato/análiseRESUMO
Alzheimer's disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients' lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.
Assuntos
Doença de Alzheimer/metabolismo , Ácidos Graxos Ômega-3/fisiologia , Ácidos Graxos Ômega-6/fisiologia , Esfingolipídeos/fisiologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Sistema Nervoso Central/metabolismo , Ceramidas/antagonistas & inibidores , Ceramidas/fisiologia , Modelos Animais de Doenças , Ácidos Graxos Insaturados/metabolismo , Previsões , Humanos , Inflamação , Lipoxigenases/metabolismo , Lisofosfolipídeos/fisiologia , Camundongos , Microglia/patologia , Modelos Biológicos , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores de Reconhecimento de Padrão/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêuticoRESUMO
Sphingosine-1-phoshate (S1P) is a membrane sphingolipid involved in several physiological processes, including cell proliferation, tissue growth, cell survival and migration, inflammation, vasculogenesis, and angiogenesis. Herein, we review the most critical effects of S1P on ovarian function, including its physiological and pathophysiological effects. Based on the available evidence, S1P plays an important role in ovarian physiology, participating as an essential stimulator of follicular development in both the preantral and antral phases, as well as in ovulation and corpus luteum development. Moreover, S1P may be a good cytoprotective agent against cancer treatment side-effects (chemotherapy with or without radiation therapy). In the future, this compound may be given for fertility preservation to women undergoing cancer treatment. However, further studies are required to confirm its efficacy in ovarian protection and also its safety in terms of cancer prognosis, given the biological action of the compound. Under- or over-production of S1P may be related to ovarian pathologies.