ABSTRACT
Monoacylglycerol lipase (MGL) is a serine hydrolase that plays a major role in the degradation of endogenous cannabinoid 2-arachidonoylglycerol. The role of MGL in some cancer cells has been confirmed, where inhibition of the MGL activity shows inhibition on cell proliferation. This makes MGL a promising drug target for the treatment of cancer. Recently, the development of covalent inhibitors of MGL has developed rapidly. These drugs have strong covalent binding ability, high affinity, long duration, low dose and low risk of drug resistance, so they have received increasing attention. This article introduces the structure and function of MGL, the characteristics, mechanisms and progress of covalent MGL inhibitors, providing reference for the development of novel covalent small molecule inhibitors of MGL.
Subject(s)
Monoacylglycerol Lipases/metabolism , Endocannabinoids/metabolismABSTRACT
Tumorigenesis involves metabolic reprogramming and abnormal lipid metabolism, which is manifested by increased endogenous fat mobilization, hypertriglyceridemia, and increased fatty acid synthesis. Fatty acid synthase (FASN) is a key enzyme for the de novo synthesis of fatty acids, and monoacylglycerol esterase (MGLL) is an important metabolic enzyme that converts triglycerides into free fatty acids. Both enzymes play an important role in lipid metabolism and are associated with tumor-related signaling pathways, the most common of which is the PI3K-AKT signaling pathway. They can also regulate the immune microenvironment, participate in epithelial-mesenchymal transition, and then regulate tumor invasion and metastasis. Current literature have shown that these two genes are abnormally expressed in many types of tumors and are highly correlated with tumor migration and invasion. This article introduces the structures and functions of FASN and MGLL, their relationship with abnormal lipid metabolism, and the mechanism of the regulation of tumor invasion and metastasis and reviews the research progress of the relationship of FASN and MGLL with tumor invasion and metastasis.
Subject(s)
Humans , Cell Line, Tumor , Fatty Acid Synthase, Type I/metabolism , Lipid Metabolism , Monoacylglycerol Lipases/metabolism , Neoplasms , Phosphatidylinositol 3-Kinases , Signal Transduction , Tumor MicroenvironmentABSTRACT
Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC 120 nmol·L) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.
Subject(s)
Animals , Female , Humans , Male , Mice , Analgesics , Chemistry , Chronic Pain , Drug Therapy , Abietanes , Chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors , Chemistry , Mice, Inbred ICR , Monoacylglycerol Lipases , Metabolism , Structure-Activity RelationshipABSTRACT
Due to ineffectiveness and side effects of existing analgesics, chronic pain has become one of the most complex and difficult problems in the clinic. Monoacylglycerol lipase (MAGL) is an essential hydrolase in the endocannabinoid system and has been identified as a potential target for the treatment of pain. In the present study, we designed and synthesized twelve tanshinone IIA analogs and screened their activity against MAGL. Selected compounds were tested for analgesic activity in vivo, with the acetic acid writhing test model. Among the test compounds, compound III-3 (IC 120 nmol·L) showed significant activity against MAGL and ameliorated the clinical progression in the mouse pain model. Additionally, compound III-3, substitution with N-methyl-2-morpholinoacetamide, demonstrated improved solubility relative to tanshinone IIA.
Subject(s)
Animals , Female , Humans , Male , Mice , Abietanes , Chemistry , Analgesics , Chemistry , Chronic Pain , Drug Therapy , Drug Evaluation, Preclinical , Enzyme Inhibitors , Chemistry , Mice, Inbred ICR , Monoacylglycerol Lipases , Metabolism , Structure-Activity RelationshipABSTRACT
Las lipasas son enzimas con propiedades funcionales muy interesantes que permiten su utilización práctica en diversos campos de las industrias agroquímica, farmacéutica, de detergentes y alimentaria, así como en química fina. Entre las aplicaciones más importantes de estas moléculas se encuentran: la resolución de mezclas racémicas, la obtención de compuestos ópticamente puros y la bioconversión de principios activos. En este trabajo se presenta una amplia revisión del tema, que abarca desde aspectos estructurales y funcionales de las lipasas, hasta la inmovilización de estas enzimas mediante adsorción interfacial y su empleo en biotecnología.
Lipases are enzymes with very interesting functional properties that allow their practical use in different fields of Agro-Chemical, Pharmaceutical and Food industries, as well as in Fine Chemistry. Among the most relevant applications of these molecules are: racemic mixtures resolution, obtainment of optically pure compounds and bioconversion of active principles. In this work a broad review of this topic is presented. This includes since structural and functional features of lipases until the immobilization of these enzymes by interfacial adsorption and their employment in biotechnology.
Subject(s)
Monoacylglycerol Lipases/biosynthesis , Monoacylglycerol Lipases/physiology , Monoacylglycerol Lipases/genetics , Monoacylglycerol Lipases/chemistry , Monoacylglycerol Lipases/chemical synthesis , Monoacylglycerol Lipases , Esterases/biosynthesis , Esterases/genetics , Esterases/chemistry , EsterasesABSTRACT
En el presente trabajo se optimizaron las condiciones de extracción de esterasas con actividad en interfaces, a partir de la anémona marina Stichodactyla helianthus y del camarón peneido Litopenaeus vannamei Las esterasas interfaciales, cuya presencia en estas especies había sido informada previamente, presentan características funcionales que las hacen muy atractivas para su empleo industrial. Los homogenados de los animales se trataron con los detergentes Tritón X-100, Tween 20 y Tween 80 en dos concentraciones cada uno: la Concentración Micelar Crítica (CMC) y la mitad de ésta. Además se empleó NaCl 0,5 mol/L y n-butanol a las proporciones 5, 10 y 20%. Cada variante fue comparada con el método tradicional de extracción con agua destilada, que fue tomado como control. Los mejores resultados se obtuvieron empleando n-butanol al 20%, para recuperar las actividades esterasa y fosfolipasa, y al 10%, en el aislamiento de la actividad lipasa. La efectividad de este solvente en el aislamiento de estas enzimas con afinidad por las interfaces lípido/agua, pudiera estar dada por su capacidad para romper los agregados entre estas moléculas y causar la desorción de las mismas a los restos de membrana y tejidos presentes en la preparación.
Interfacial esterases present great functional versatility, making them very attractive molecules for industrial applications. The conditions for extracting interfacial esterases previously detected in the sea anemone Stichodactyla helianthus and the shrimp Litopenaeus vannamei were optimised in this work. Animal homogenates were treated with Triton X-100, Tween 20 and Tween 80 detergents at two different concentrations: critical micellar concentration (CMC) and half of that concentration; 0.5 mol/L NaCl and n-butanol at 5%, 10% and 20% v/v ratios were also tested. Each procedure was compared to the control extraction method using distilled water. The best results were obtained with 20% n-butanol for recovering esterase and phospholipase activity whilst 10% n-butanol extraction was the most effective for lipase activity isolation. This solventâs suitability for isolating interface-activated enzymes could be explained by its ability to dissociate biomolecule aggregates and cause enzyme desorption from the membranes and tissues remaining in the preparation.
Subject(s)
Monoacylglycerol Lipases/administration & dosage , Monoacylglycerol Lipases/toxicity , Esterases/chemistry , Esterases/toxicityABSTRACT
Leptin, a cytokine predominantly secreted from fat tissue, plays an important role in regulating organism energy balance. Leptin can stimulate lipolysis, but the mechanism is unclear. In order to study the molecular mechanism of leptin stimulating lipolysis, we systemically studied the mRNA expression of key lipolytic enzymes. Morphological observation, Oil Red O staining and RT-PCR were used to identify pig primary adipocytes; commercial kits were used to measure the glycerol and FFA release; Semiquantitative RT-PCR was used to detect the mRNA expression of key lipolytic enzymes. The results showed that 100 nmol/L leptin up-regulated the mRNA expression of ATGL, TGH-2, HSL, MGL and LPL (P<0.01), but down-regulated the Perilipin mRNA expression (P<0.01). At the same time, leptin promoted the glycerol release in a dose dependent manner (P<0.01), but had no effect on the FFA release (P>0.05). These indicate that leptin may mainly stimulate lipolysis in pig primary adipocytes by up-regulating the expression of ATGL, MGL, LPL and down-regulating the expression of Perilipin. The unchanged FFA release may be resulted from Leptin promoting UCPs mRNA expression and increasing FFA expenditure.
Subject(s)
Animals , Male , Adipocytes , Cell Biology , Metabolism , Animals, Newborn , Cells, Cultured , Leptin , Pharmacology , Lipase , Genetics , Metabolism , Lipolysis , Monoacylglycerol Lipases , Genetics , Metabolism , RNA, Messenger , Genetics , Metabolism , SwineABSTRACT
La obesidad es un trastorno metabólico crónico que se caracteriza por la acumulación de tejido adiposo. El tratamiento basado en la dieta y el ejercicio es la indicación de elección; sin embargo, esto no es suficiente, dado que la cantidad de personas con sobrepeso y obesidad en las sociedades industriales aumenta constantemente, lo cual le confiere características de epidemia. Aún grados menores de obesidad producen un aumento de la morbimortalidad cardiovascular, con un gran costo sanitario y económico. En aquellos pacientes en los que el tratamiento no farmacológico haya fracasado y que presenten un IMC mayor menor 30 o mayor menor 27 kg/m² más dos factores de riesgo se debería contemplar el uso de fármacos antiobesidad. En la actualidad contamos con dos fármacos, el orlistat y la sibutramina, que están autorizados para el uso crónico en esta patología, asociados con la dieta y el ejercicio. Además, numerosas moléculas se encuentran en diferentes fases de investigación. El conocimiento de los múltiples y diferentes mecanismos que intervienen en la regulación del metabolismo nos permitirá no sólo conocer esta "enfermedad" sino tratarla adecuadamente.
Subject(s)
Humans , Obesity/complications , Obesity/drug therapy , Obesity/therapy , Cyclobutanes/therapeutic use , Monoacylglycerol Lipases/therapeutic use , Body WeightABSTRACT
A presente revisäo trata-se de um estudo químico-farmacêutico e aspectos bioquímicos do orlistat, descrevendo o metabolismo lipidicos e aspectos relevantes a respeito deste fármaco, como, por exemplo, mecanismo de açäo, relaçäo estrutura-atividade, farmacocinética, posologia, efeitos adversos, entre outros.(au)
Subject(s)
Humans , Adult , Monoacylglycerol Lipases , ObesityABSTRACT
Óleo da castanha do Pará (Bertholletia excelsa), extraído por prensagem das sementes a frio, foi submetido às modificações de fracionamento, hidrogenação, interesterificação e misturas com as gorduras obtidas na hidrogenação. Na hidrogenação o óleo foi submetido a três reações em reator Parr de 1 L, catalisador de níquel (Pricatt 9920-06 - Unichema), e sob as seguintes condições: 175ºC, 3 atm, 60 min (GH1), 150ºC, 1 atm, 30 min (GH2) e 125ºC, 1 atm, 30 min (GH3). O teor de acido esteárico aumentou de 11,6 por cento (óleo original) a 56,7 por cento, 16,3 por cento e 15,3 por cento em GH1, GH2 e GH3, respectivamente. O ácido oléico, representando 34,5 por cento no óleo original descresceu em GH1 a 25,9 por cento e aumentou em GH2 e GH3 a 59,9 por cento e 53,8 por cento, respectivamente...