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ABSTRACT BACKGROUND AND OBJECTIVES: Pharmaceutical preparations of cannabis have been used by mankind since long time ago, and recently they have been the pharmaceutical industry's focus. However, for proper therapeutic application, in-depth knowledge of the endocannabinoid system, which is made mainly by lipid signaling, is needed. The purpose of this study was to explore the current understanding of the players in this system, paying special attention to the molecular machinery required to process it. CONTENTS: This is a narrative review of the current literature regarding major components of the endocannabinoid system, in particular: the receptors, main endogenous ligands, and the enzymes responsible for its components processing. The pharmacological and preclinical aspects were emphasized. CONCLUSION: The better comprehension of the molecular structure of receptors and enzymes will be crucial to developing new pharmacological strategies. A detailed description of the machinery responsible for endocannabinoid lipid metabolization will pave the way for the discovery of new drugs that act on the endogenous system and that can be applied effectively in clinical practice.
RESUMO JUSTIFICATIVA E OBJETIVOS: Os preparados medicinais canabinoides são há muito utilizados pela humanidade e têm sido objeto de interesse da indústria farmacológica recente. Para a aplicação terapêutica adequada é necessário, no entanto, o conhecimento aprofundado do sistema canabinoide endógeno, o qual em sua grande parte é constituído por mensageiros lipídicos. O objetivo deste estudo foi explorar o conhecimento vigente a respeito dos constituintes desse sistema, com especial atenção à maquinaria molecular necessária para processá-los. CONTEÚDO: Trata-se de uma revisão narrativa da literatura atual acerca dos integrantes do sistema canabinoide endógeno, notadamente: seus receptores, os principais ligantes endógenos e as enzimas responsáveis pelo processamento de seus componentes. Os aspectos farmacológicos e pré-clínicos foram enfatizados. CONCLUSÃO: O melhor entendimento da ultraestrutura de receptores e enzimas contribuirá de forma decisiva para o desenvolvimento de novas estratégias farmacológicas. A partir da descrição pormenorizada da maquinaria responsável pela metabolização lipídica endocanabinoide é que se pavimentará o caminho para a descoberta de novos fármacos que atuem no sistema endógeno e que possam ser aplicados de forma eficaz na prática clínica.
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BACKGROUND: Metabolic dysfunctions characteristic of overt hypothyroidism (OH) start at the early stage of subclinical hypothyroidism (SCH). Na⁺/K⁺-ATPase (the sodium pump) is a transmembrane enzyme that plays a vital role in cellular activities in combination with membrane lipids. We evaluated the effects of early changes in thyroid hormone and membrane cholesterol on sodium pump activity in SCH and OH patients. METHODS: In 32 SCH patients, 35 OH patients, and 34 euthyroid patients, sodium pump activity and cholesterol levels in red blood cell membranes were measured. Serum thyroxine (T₄) and thyroid stimulating hormone (TSH) levels were measured using enzyme-linked immunosorbent assays. Differences in their mean values were analysed using post hoc analysis of variance. We assessed the dependence of the sodium pump on other metabolites by multiple regression analysis. RESULTS: Sodium pump activity and membrane cholesterol were lower in both hypothyroid groups than in control group, OH group exhibiting lower values than SCH group. In SCH group, sodium pump activity showed a significant direct dependence on membrane cholesterol with an inverse relationship with serum TSH levels. In OH group, sodium pump activity depended directly on membrane cholesterol and serum T4 levels. No dependence on serum cholesterol was observed in either case. CONCLUSION: Despite the presence of elevated serum cholesterol in hypothyroidism, membrane cholesterol contributed significantly to maintain sodium pump activity in the cells. A critical reduction in membrane cholesterol levels heralds compromised enzyme activity, even in the early stage of hypothyroidism, and this can be predicted by elevated TSH levels alone, without any evident clinical manifestations.
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Humans , Cholesterol , Enzyme-Linked Immunosorbent Assay , Erythrocytes , Hypothyroidism , Membrane Lipids , Membranes , Sodium , Sodium-Potassium-Exchanging ATPase , Thyroid Gland , Thyrotropin , ThyroxineABSTRACT
Objective To investigate the expression of flotillin-1 in cervical cancer,and molecular mechanism and relationship between flotillin-1 and lymph node metastasis.Methods Real-time polymerase chain reaction (RT-PCR),Western blot and immunohistochemistry were used to detect the expression of flotillin-1 in cervical cancer cells and tissues,and detect the role of flotillin-1 in cervical cancer metastasis and the possible mechanism by over-expression and interference.Results The protein and mRNA expression of Flotillin-1 were significantly upregnlated in cervical cancer cell lines and cancer tissues.The elevated expression of flotillin-1 protein in early-stage cervical cancers was significantly associated with pelvic lymph node metastasis (P ＜0.01).Moreover,flotillin-1 up-and down-regulations remarkably affected the motility and invasion of cervical cancer cells through epithelial-mesenchymal transition (EMT) regulated by the Wnt//β-catenin and nuclear factor-κB (NF-κB) pathways.Conclusions Flotillin-1 regulates the EMT process through the catenin beta Wnt and NF-κB signaling pathway,and promotes the metastasis of cervical cancers.The flotillin-1 expression profile serves as novel independent predictor of lymph node metastasis in early-stage cervical cancers.
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The hallmark lesions of age-related macular degeneration (AMD) are drusen and basal linear deposit which are lipid substances deposited in Bruch membrane or the compartment on the Bruch membrane.There is a prevailing hypothesis that lipid and its oxidized derivant deposited in retina may have important roles in the pathogenesis of AMD.Lipid oxidation products are toxic,may affect the adjacent cells,induce inflammation,and trigger neovascularization.7-ketocholestoral (7KCh),a naturally occurring oxidized form of cholesterol,had been found to be toxic to retinal cells and able to induce chronic inflammation,which may play a critical role in the development of AMD.However the precise mechanism remains to be elucidated.Thus we will make a brief review of 7KCh and its association with AMD.
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Introdução: Devido a diversos fatores, recém-nascidos prematuros, em sua maioria, necessitam de nutrição parenteral e uma fonte lipídica que possua um equilíbrio entre os variados tipos de ácidos graxos. SMOFlipid® 20%, uma nova emulsão lipídica pode ser mais adequada para esse equilíbrio. Objetivo: Avaliar o perfil de incorporação de ácidos graxos em eritrócitos de prematuros recebendo essa nova emulsão lipídica, comparada com outra emulsão baseada em óleo de soja. Métodos: Em um ensaio clinico controlado randomizado duplo cego avaliou-se 47 recém-nascidos pré-termo que receberam nutrição parenteral SMOFlipid® 20% (n=25) ou LIPOVENOS® MCT 20% (n=22). Foram avaliados parâmetros laboratoriais, clínicos, demográficos e o perfil de incorporação de ácidos graxos na membrana de eritrócitos. Resultados: Os parâmetros clínicos e demográficos como peso, perímetro cefálico, comprimento, idade gestacional e índice de Apgar não diferiram entre os grupos. Os valores de triglicerídeos e da lipoproteína de muito baixa densidade (VLDL) foram estatisticamente maiores no grupo SMOFLIPID® 20%. Níveis de Aspartato aminotransferase (AST) foram menores em ambos os grupos e os níveis de bilirrubina total e frações não tiveram diferenças. A emulsão SMOFlipid® 20% aumentou os níveis dos ácidos docosa-hexaenoico DHA (C 22:6 w3) e Eicosapentaenoico EPA (C 20:5 w3) na membrana dos eritrócitos. Conclusões: Neste grupo de recém-nascidos pré-termos, essa nova emulsão lipídica, além de mostrar segurança, contribuiu para uma mudança benéfica no perfil de incorporação de ácidos graxos nas membranas celulares, principalmente DHA e EPA.
Introduction: Due to several factors, premature newborn infants, in most cases, require parenteral nutrition and a lipid source with balance among the different types of fatty acids. SMOFlipid® 20%, a new lipid emulsion may be more appropriate for this balance. Objectives: To evaluate the profile of fatty acids incorporation in erythrocytes of premature newborn infants receiving this new lipid emulsion compared with an emulsion based on soybean oil. Methods: In a randomized, controlled, double-blind clinical trial, 47 preterm newborn who received parenteral nutrition SMOFlipid® 20% (n=25) or Lipovenos MCT® 20% (n=22) were evaluated. Laboratorial, clinical and demographic parameters and the profile of incorporation of fatty acids in the erythrocyte membrane were evaluated. Results: The clinical and demographic parameters such as weight, head circumference, length, gestational age, and Apgar scores did not differ between the groups. The values of triglycerides and lipoprotein of very low density (VLDL) were statistically higher in the SMOFlipid® 20% group. Levels of aspartate aminotransferase (AST) were lower in both groups and levels of total bilirubin and fractions had no differences. The SMOFlipid® 20% emulsion increased the levels of the docosahexaenoic acid (DHA) and eicosapentaenoic (EPA) acid in the erythrocytes membrane. Conclusions: In this group of preterm newborn infants, this new lipid emulsion, besides showing security, contributed to a beneficial change in the incorporation profile of fatty acids cell membranes, especially DHA and EPA.
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Humans , Male , Female , Infant, Newborn , Docosahexaenoic Acids , Fatty Acids , Fish Oils , Infant, Premature , Membrane Lipids , Parenteral NutritionABSTRACT
Objective To verify the validity of the sucrose density gradient ultracentrifugation method for lipid rafts from cerebral cortex. Methods Extract lipid rafts from cerebral cortex in mouse were extracted by the sucrose density gradi-ent ultracentrifugation method. The properties of lipid rafts were detected by Western blotting method, double enzyme and light scattering methods. HPLC MS/MS proteomics and bioinformatics were used to locate proteins of lipid rafts in cells. Re-sults Lipid rafts from cerebral cortex were provided with the model properties of lipid rafts such as high light scattering and cholesterol and high expression of Flotillin-1. HPLC MS/MS proteomics identified total 647 proteins. Most of these pro-teins were from plasma membrane, endoplasmic reticulum, cytoskeleton and cytosol, however, there were 21% proteins among total 647 proteins were from nucleus, mitochondria and ribosomes. Conclusion The sucrose density gradient ultra-centrifugation method is a effective method to extract lipid rafts from cerebral cortex, however, the properties of mixture should be considered.
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Objective To explore the effects of blood-circulation promoting and phlegm removing treatment on the structure, activity of Ca 2+ -Mg 2+ ATPase and malondialdehyde(MDA) content of mitochondria membrane in spontaneous hypertensive rats (SHR). Methods Spontaneous hypertensive rats (SHR) were classified into 14-week-old model group(Group C),28-week-old model group(Group D) and treatment group (treated with blood-circulation promoting and phlegm removing Chinese herbal medicine,Group E).Normal Wistar rats 14 weeks old (Group A)and 28 weeks old(Group B) served as the controls.The structure of myocardial mitochondria membrane were analyzed quantitatively by transmission electron microscope,and the activity of Ca 2+ -Mg 2+ ATPase and MDA content were also detected. Results Specific surface area of mitochondria was smaller, the activity of Ca 2+ -Mg 2+ ATPase was lower and MDA content was higher in SHR than the controls.MDA content increased as the duration of disease prolonged. Chinese herbal medicine could counteract the above changes. Conclusion Blood-circulation promoting and phlegm removing herbs can partially counteract the progress of left ventricular hypertrophy in SHR.
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Objective To further confirm the role of lipid-peroxidation caused by oxygen free radicals injury played in the pathogenesis of dilsted cardiomypathy. Methods The superoxide dismutase activities and lipids composi tion of erythrocytes in 18 patients with dilated cardiomyopathy and 16 healthy controls were measured. Results ① Su peroxide dismutase(SOD) activites of erythrocytes were lower in dilated cardiomyopathy(DCM) patients than that in healthy controls (P ＜0. 001). ②The lipids composition of erythrocytes has changed in the DCM patients compared with healthy controls: total lipids changed little (P＞0. 05); total phospholipids were lower, but not significantly (P ＞0.05); total cholesterol increased significantly (P ＜0. 05). The cholesterol to phospholipids molecular ratio of erythrocyte membrane has increased remarkably (P＞0. 05). Conclusion It can be supposed that decreased SOD ac tivities play an important role in the damage of membrane system and the pathogensis of DCM.
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Aim To study the protective effects of puerarin on the neurons damaged by glutamic acid.Method The rat primary cultured neurons were damaged by glutamic acid,the membrane lipids fluidity was studied with fluorescence polarization(P) and mean microviscosity(?) with DPH as a probe;the protective effects of puerarin on this model were evaluated by lactate dehydrogenase(LDH) efflux assay and colormetric MTT assay.Results The fluorescence polarizating and mean microviscosity of puerarin were lower than glutamic acid model group in a dose-depended manner.Treatment of puerarin resulted in the decrease of LDH release from primary cultured neurons damaged by glutamic acid and increase in the optical density(A) at 540 nm tested by colorimetric MTT assay.No proliferating effects on normal primary cultured neurons were observed.Conclusion The results suggested that puerarin had a protective effect on rat primary cultured neurons damaged by glutamic acid,it might be relative to the improvement of membrane lipids fluidity
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The carbohydrate and lipid contents and Ca2+-Mg2+ ATPase activity of erythrocyte membrane were studied in 10 patients with DMD. The results demonstrated that the sialic acid content was markedly decreased, and the neutral sugar content normal. The cholesterol was significantly increased, but the phospholipids unchanged, resulting in a significantly reduced P/C ratio. The activity of Ca2+-Mg2+ ATPase elevated markedly. The study suggests that the erythrocyte membranes with DMD are altered both in composition and function.