Metabolismo de los esfingolípidos y su relación con las enfermedades cardiovasculares, renales y metabólicas / Sphingolipid metabolism and its relationship with cardiovascular, renal and metabolic diseases

Resumen Los esfingolípidos (esfingomielina, glucolípidos y gangliósidos) se localizan en las membranas celulares, el plasma y las lipoproteínas. En pacientes con enfermedades cardiovasculares, renales y metabólicas, el perfil de los esfingolípidos y sus metabolitos (ceramida, esfingosina y esfingosina-1-fosfato) se modifica, y estos cambios pueden explicar las alteraciones en algunas respuestas celulares, como la apoptosis. Además, se ha sugerido que la esfingosina y la esfingosina-1-fosfato previenen la COVID-19. En esta revisión también se mencionan brevemente las técnicas que permiten el estudio de los esfingolípidos y sus metabolitos.

Abstract Sphingolipids (sphingomyelin, glycolipids, gangliosides) are located in cell membranes, plasma, and lipoproteins. In patients with cardiovascular, renal, and metabolic diseases, the profile of sphingolipids and their metabolites (ceramide, sphingosine, and sphingosine-1-phosphate) is modified, and these changes may explain the alterations in some cellular responses such as apoptosis. Furthermore, sphingosine and sphingosine-1-phosphate have been suggested to prevent COVID-19. This review also briefly mentions the techniques that allow us to study sphingolipids and their metabolites.

Role of sphingomyelinases in hepatocellular carcinoma / 临床肝胆病杂志

Sphingomyelinases (SMase) are the main enzymes that regulate the signaling pathway of sphingomyelin and the metabolism of related products, and they are involved in the key steps of the complex metabolic process of sphingomyelin. In recent years, many studies have shown that SMase is involved in the biological processes such as cell cycle arrest, cell migration, and inflammation and promotes the development and progression of hepatocellular carcinoma by regulating the apoptosis and proliferation of tumor stem cells. SMase has an important potential biological value in the development, progression, diagnosis, and treatment of hepatocellular carcinoma. This article summarizes the exact role of SMase in the development and progression of hepatocellular carcinoma, in order to provide new ideas and strategies for the clinical treatment of hepatocellular carcinoma and the development of new drugs.

Sphingolipid Mediators of Myocardial Pathology

Cardiomyopathy is the leading cause of mortality worldwide. While the causes of cardiomyopathy continue to be elucidated, current evidence suggests that aberrant bioactive lipid signaling plays a crucial role as a component of cardiac pathophysiology. Sphingolipids have been implicated in the pathophysiology of cardiovascular disease, as they regulate numerous cellular processes that occur in primary and secondary cardiomyopathies. Experimental evidence gathered over the last few decades from both in vitro and in vivo model systems indicates that inhibitors of sphingolipid synthesis attenuate a variety of cardiomyopathic symptoms. In this review, we focus on various cardiomyopathies in which sphingolipids have been implicated and the potential therapeutic benefits that could be gained by targeting sphingolipid metabolism.

Role of sphingolipids signaling in pathogenesis of pulmonary fibrosis / 中国药理学与毒理学杂志

Pulmonary fibrosis is a group of chronic lung diseases caused by various factors and characterized by chronic inflammations,lung tissue structure damage,increase of pulmonary interstitial collagen and massive deposition of extracellular matrix (ECM). Because of its complicated etiology, there is no effective treatment currently. Recent studies showed that the activation of sphingolipids signaling and pulmonary fibrosis were closely related. This paper describes the composition and function of sphingolipids signaling pathway and its effect on fibrosis in order to provide new ideas about further study of the pathogenesis of pulmonary fibrosis and methods of prevention.

Promoting proliferation and inhibiting apoptosis effects of sphingosine-1-phospate on human retinal pigment epithelium cells under the hypoxic condition / 中华实验眼科杂志

Background Sphingosine-l-phospate (S1P) is a bioactive lipid and important messenger molecule in cells.It participates in the regulation of many biological processes,such as cell proliferation,migration,survival,differentiation,apoptosis,etc.Hypoxia is a trigger factor of choriod neovascularization (CNV) and pathological basis of many diseases,and retinal pigment epithelial (RPE) cells are involved in formation of CNV.However,the effects of S1P on proliferation and apoptosis of RPE cells are below understood.Objective This study was to investigate the influence of S1P on proliferation and apoptosis of human RPE cells under hypoxic conditions.Methods Human RPE cells line-D407 cells were cultured and passaged and generation 3-5 cells were used and divided into 6 groups.The cells were regularly cultured in the blank control group using DMEM containing 10％ fetal bovine serum.CoCl2(200.00 μmol/L) was added into the colture medium for 2 hours in the hypooxic group.S1P of different concentrations (0.01,0.10,1.00,10.00 μmol/L) were added in culture medium 2 hours after the affection of 200.00 μmol/L CoCl2.The proliferative values of the cells were detected using WST-1 method as the absorbance (A value) and the proliferative rate of different groups were calculated.The apoptosis of the cells was assayed by Hoechst staining.The results were compared among different groups.Results Cultured cells showed the round-like in shape with clear nuclei and pigment.The proliferative values (A value) was 0.91 ±0.08,0.37±0.09,0.46±0.08,0.52±0.09,0.61 ±0.06,0.70±0.10 in the blank control group,hypoxic group and 0.01,0.10,1.00,10.00 μmol/L S1P groups,respectively,with a significant difference among the groups (F=21.104,P=0.000),and A values in various S1P groups were higher than those in the hypoxiac group (all at P＜0.05).The proliferative rate was gradually raised with the increase of dose of S1P.Hoechst staining exhibited a few apoptosis cells in the blank control group,but in the hypoxic group,a lots of apoptosis cells were seen with the light-blue nuclei and condensable chromatin.However,the number of apoptosis cells was significantly decreased in various concentrations of S 1 P groups.The apoptosis rates were (1.21 ±0.08) ％,(8.99 ±0.09) ％,(6.60 ±0.08) ％,(5.95 ±0.09) ％,(4.81 ± 0.06)％ and (3.96±0.10)％ in the blank control group,hypoxic group and the 0.01,0.10,1.00,10.00 μmol/L S1P groups,respectively,with a significant difference among the groups (F =25.070,P =0.000).Compared with the hypoxia group,the cellular apoptosis rates of various S1P groups were lower (all at P＜0.05).Conclusions Under the hypoxia condition,S1P can promote the proliferation of human RPE cells and inhibit apoptosis.

Modulación del metabolismo de esfingolípidos en cáncer de vejiga como una potencial estrategia para optimizar resultados de terapias intravesicales para tumores de vejiga no musculoinvasores / Modulation of sphingolipid metabolism in bladder cancer as a potential strategy to optimize outcomes of intravesical therapies for non-muscle invasive bladder cancers

El cáncer de vejiga representa un problema de salud pública importante a nivel mundial. En Chile su relevancia es aún mayor en la región de Antofagasta. Este cáncer se caracteriza por una alta tasa de recurrencia, por lo que los pacientes requieren un seguimiento estricto que afecta su calidad de vida e implica elevados costos para los sistemas de salud. Esto explica la necesidad de optimizar los tratamientos actuales (quimioterapia e inmunoterapia con BCG intravesical) para reducir las tasas de recurrencia y progresión. Los esfingolípidos son lípidos bioactivos que a nivel celular cumplen funciones relacionadas con la regulación del crecimiento, proliferación, migración, invasión, resistencia a drogas y apoptosis. La evidencia disponible a la fecha sobre el rol de los esfingolípidos en cáncer de vejiga es escasa, pero sugiere que en este cáncer existe un metabolismo esfingolipídico desplazado hacia la reducción de los niveles intracelulares de ceramida y esfingosina (esfingolípidos pro-apoptóticos) y aumento de esfingosina 1-fosfato (esfingolípido anti-apoptótico). La manipulación del metabolismo esfingolipídico para invertir esta relación se propone en esta revisión como una estrategia que podría ayudar a optimizar el efecto de las terapias disponibles actualmente para reducir las recurrencias y progresiones de los tumores de vejiga no músculo-invasores...

Bladder cancer is an important health problem worldwide. In Chile it has particular relevance in the region of Antofagasta. This cancer is characterized by a high recurrence rate, for which patients need a strict follow up that impairs their quality of life and determines increased costs for health care systems. These facts explain the necessity of optimizing the actual treatments (chemotherapy and BCG immunotherapy) for reducing the rates of recurrence and progression. Sphingolipids are bioactive lipids that at a cellular level have roles related to the regulation of growth, proliferation, migration, invasiveness, drug resistance and apoptosis. To date, the available evidence about the role of sphingolipids in bladder cancer is scarce, but suggests that in this cancer there is a sphingolipid metabolism shifted towards a reduction of the intracellular levels of ceramide and sphingosine (pro-apoptotic sphingolipids) and an increase of sphingosine 1-phosphate (anti-apoptotic sphingolipid). In this review we propose that the manipulation of the sphingolipid metabolism to invert this balance can contribute to optimize the effect of the actual therapies to reduce the rates of recurrence and progression of non-muscle invasive bladder cancers...

Metabolism of Very Long-Chain Fatty Acids: Genes and Pathophysiology

Fatty acids (FAs) are highly diverse in terms of carbon (C) chain-length and number of double bonds. FAs with C>20 are called very long-chain fatty acids (VLCFAs). VLCFAs are found not only as constituents of cellular lipids such as sphingolipids and glycerophospholipids but also as precursors of lipid mediators. Our understanding on the function of VLCFAs is growing in parallel with the identification of enzymes involved in VLCFA synthesis or degradation. A variety of inherited diseases, such as ichthyosis, macular degeneration, myopathy, mental retardation, and demyelination, are caused by mutations in the genes encoding VLCFA metabolizing enzymes. In this review, we describe mammalian VLCFAs by highlighting their tissue distribution and metabolic pathways, and we discuss responsible genes and enzymes with reference to their roles in pathophysiology.

El Ca2+ y los esfingolípidos como moduladores de la apoptosis y el cáncer / Ca2+ and sphingolipids as modulators for apoptosis and cancer

El Ca2+ es un segundo mensajero que regula funciones directamente relacionadas con el cáncer como la proliferación, diferenciación y la apoptosis. La concentración intracelular de Ca2+ ([Ca2+]i) está altamente regulada por diversos mecanismos entre los que destacan canales iónicos, la Ca2+-ATPasa del retículo endoplasmático (SERCA) y de la membrana plasmática (PMCA), y el transporte de Ca2+ mitocondrial. En el cáncer, la célula tumoral prolifera sin control tras su incapacidad de reconocer señales apoptóticas. La apoptosis es mediada a través de cambios en la actividad de ciertas proteínas como las caspasas y miembros de la familia Bcl-2. Adicionalmente, el “estrés del retículo”, promovido por la acumulación y agregación de proteínas mal plegadas en el interior del retículo endoplasmático (RE), puede desencadenar la apoptosis. El “estrés del retículo” es inducido por una variedad de agentes, entre los que destaca la tapsigargina, inhibidor específico de la SERCA, la cual promueve un notable aumento en la [Ca2+]i, induciendo además apoptosis. En consecuencia, actualmente se están ensayando exitosamente derivados de la tapsigargina como agentes antineoplásicos. El Ca2+ es transferido a la mitocondria desencadenando señales apoptóticas. Por otra parte, los esfingolípidos, como la ceramida y la esfingosina, y sus derivados fosforilados, la ceramida-1-fosfato y la esfingosina-1-fosfato, los cuales regulan la [Ca2+]i, también están estrechamente vinculados con la señalización intracelular en procesos relacionados con el cáncer. Esta revisión discute nuevas evidencias sobre el efecto de estos esfingolípidos en la homeostasis de Ca+2 intracelular y su conexión con la apoptosis y el cáncer.

Ca2+ is a second messenger which regulates many functions directly related with cancer such as proliferation, differentiation and apoptosis. The intracellular Ca2+ concentration ([Ca2+]i) is finely regulated by several mechanisms, among them ionic channels, the endoplasmic reticulum Ca2+-ATPase (SERCA), the plasma membrane calcium pump (PMCA) and the mitochondrial Ca2+ transport. In cancer, the tumour cell proliferates without control since the capacity to recognize apoptotic signals has been lost. The apoptosis is regulated by changes in several proteins, as caspases and the Bcl-2 family members, among others. Additionally, the “reticulum stress”, promoted by the accumulation and aggregation of unfolded proteins in the interior of the endoplasmic reticulum (ER), ussually leads to apoptosis. The “reticulum stress” can be induced by several agents, remarkably with thapsigargin, a selective inhibitor of the SERCA, which in turn induces a large increment in [Ca2+]I, leading to apoptosis. As a consequence, currently, derivatives of thapsigargin are successfully been assayed as anti-neoplastic agents. Ca2+ is then transferred to the mitochondria, where it is known to constitute a main apoptotic signal. On the other hand, several sphingolipids, such as ceramide and sphingosine, and their phosphorylated derivatives ceramide-1-phosphate and sphingosine-1-phosphate, directly involved in the [Ca2+]I regulation, are also recognized as signal messengers related with cancer processes. In this review we discuss new evidences on the effect of several sphingolipids in the intracellular Ca2+ homeostasis and its relationship with apoptosis and cancer.

Overview of P-glycoprotein inhibitors: a rational outlook

P-glycoprotein (P-gp), a transmembrane permeability glycoprotein, is a member of ATP binding cassette (ABC) super family that functions specifically as a carrier mediated primary active efflux transporter. It is widely distributed throughout the body and has a diverse range of substrates. Several vital therapeutic agents are substrates to P-gp and their bioavailability is lowered or a resistance is induced because of the protein efflux. Hence P-gp inhibitors were explored for overcoming multidrug resistance and poor bioavailability problems of the therapeutic P-gp substrates. The sensitivity of drug moieties to P-gp and vice versa can be established by various experimental models in silico, in vitro and in vivo. Ever since the discovery of P-gp, the research plethora identified several chemical structures as P-gp inhibitors. The aim of this review was to emphasize on the discovery and development of newer, inert, non-toxic, and more efficient, specifically targeting P-gp inhibitors, like those among the natural herb extracts, pharmaceutical excipients and formulations, and other rational drug moieties. The applications of cellular and molecular biology knowledge, in silico designed structural databases, molecular modeling studies and quantitative structure-activity relationship (QSAR) analyses in the development of novel rational P-gp inhibitors have also been mentioned.

Glicoproteína-p (P-gp), uma glicoproteína de transmembrana permeável, é um membro da superfamília (ABC) de cassete de gene de ligação de ATP que funciona especificamente como um carreador mediado pelo transportador de efluxo ativo primário. É amplamente distribuído por todo o corpo e apresenta uma gama diversificada de substratos. Diversos agentes terapêuticos vitais são substratos para P-gp e sua biodisponibilidade é reduzida ou a resistência é induzida devido ao efluxo de proteínas. Portanto, os inibidores da P-gp foram explorados para a superação da resistência a múltiplas drogas e problemas de biodisponibilidade deficiente dos substratos terapêuticos da P-gp. A sensibilidade das moléculas da droga à P-gp e vice-versa, pode ser estabelecida por vários modelos experimentais in silico, in vitro e in vivo. Desde a descoberta da P-gp, diversas pesquisas identificaram várias estruturas químicas como inibidores da P-gp. O objetivo deste presente estudo foi o de enfatizar a descoberta e desenvolvimento de inibidores mais novos, inertes, atóxicos e mais eficazes, visando especificamente os da P-gp, como aqueles entre os extratos vegetais, excipientes e formulações farmacêuticas, e outras moléculas racionais de droga. As aplicações do conhecimento de biologia celular e molecular, bancos de dados estruturais in silico, estudos de modelagem molecular e análises da relação quantitativa estrutura-atividade (QSAR) no desenvolvimento de novos inibidores racionais da P-gp também foram mencionados.

Identification and Characterization of The Arabidopsis fumonisin B_1 resistant fbr136 / 生物化学与生物物理进展

Plant programmed cell death (PCD) plays an important role in plant growth and development as well as defensive response against biotic and abiotic stresses. Fumonisin B1 (FB1) is a fungi toxin, which is a competitive inhibitor of ceramide synthase in de novo sphingolipid biosynthesis. FB1 can induce PCD in both animal and plant cells. To dissect this pathway, a genetic screen for fumonisin B1 resistant (fbr) mutants, and identified 11 fbr mutants was carried out. Genetic analysis showed that these 11 mutants belonged to 9 complementary groups or genetic loci. Here a detailed phenotypic analysis of fbr136 was reported. In addition to the resistance to FB1, fbr136 also showed resistance other PCD-inducing compounds, including H2O2 and paraquat. Furthermore, FB1-induced PR1 expression was reduced in fbr136, suggesting that a PCD pathway is likely impaired in the mutant. When stained with nitroblue tetrazolium (NBT), fbr136 showed a reduced accumulation of reactive oxygen species (ROS) induced by FB1. The fbr136 mutation was roughly mapped onto chromosome Ⅲ, where no other fbr mutants have been previously identified. It is proposed that FBR136 may act as an important regulator in a sphingolipid-mediated PCD pathway, involved in the generation of ROS.

Modulation of multidrug resistance by 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol in SKOV3-adriamycin-resistant cell line / 中华妇产科杂志

Objective To study the modulation of mdr1 and P glycoprotein (P gp) by 1 phenyl 2 palmitoylamino 3 morpholino 1 propanol (PPMP) in SKOV3 adriamycin resistant (SKOV3/AdrR) cell line Methods SKOV3/AdrR cells were treated with PPMP, mRNA expression of multidrug resistant (mdr1) gene was analyzed by reverse transcriptase polymerase chain reaction Intracellular rhodamine (Rh123) concentration was measured by flow cytometry Results PPMP was found to inhibit mdr1 expression of SKOV3/AdrR at the mRNA level This modulation of gene expression was content dependent and complete inhibition appeared at 25 ?mol/L PPMP treatment PPMP could increase intracellular Rh123 accumulation in SKOV3/AdrR cells After 15, 25 ?mol/L PPMP treatment, Rh123 accumulation in SKOV3/AdrR was markedly enhanced Rh123 fluorescence intensity were 389 98,426 08 respectively ( P