Purpose:Monoacylglycerol O-acyltransferase 1(MGAT1)is reported to play a key role in the development of diet-induced nonalcoholic fatty liver disease(NAFLD).Thus,this study investigated the effect of exercise on suppr...Purpose:Monoacylglycerol O-acyltransferase 1(MGAT1)is reported to play a key role in the development of diet-induced nonalcoholic fatty liver disease(NAFLD).Thus,this study investigated the effect of exercise on suppression of the MGAT1 pathway in NAFLD tissue of high-fat diet(HFD)-induced obese rats.Methods:Male Sprague-Dawley rats were fed an HFD containing 45%fat for 6 weeks.Upon confirmation that NAFLD had been induced in the obese animals,they were divided into HFD-fed groups provided with exercise(HFD+EXE)or without exercise(HFD)and a group given dietary adjustment(DA)only,for a further 6 weeks of intervention treatment.The 6-week regular moderate aerobic exercise consisted of an accommodation phase with increasing exercise.Lipid accumulation in the liver tissue was determined by Oil Red O staining.The MGAT1 and liver lipogenic gene mRNA levels were measured by qPCR,and their protein levels by western blot assay.Results:Oil Red O staining showed that NAFLD was successfully induced by HFD-fed.The gene expression of MGAT1 was significantly lower in HFD+EXE than HFD.However,there was no significant difference between HFD+EXE and DA.The protein expression of MGAT1 was significantly lower in HFD+EXE than both HFD and DA.Messenger RNA and protein expression of other lipogenic genes were not different among groups.These data indicate that exercise suppresses MGAT1 pathway regardless of HFD feeding;in part,this effect could be greater than DA.Conclusion:Our data suggest that exercise can improve NAFLD,which is probably due to suppression of MGAT1 pathway.展开更多
Dietary oversupply of triglycerides represent the hallmark of obesity and connected complications in the liver such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis,which eventually progress to c...Dietary oversupply of triglycerides represent the hallmark of obesity and connected complications in the liver such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis,which eventually progress to cirrhosis and hepatocellular carcinoma.Monoacylglycerol lipase is the last enzymatic step in the hydrolysis of triglycerides,generating glycerol and fatty acids(FAs),which are signaling precursors in physiology and disease.Notably,monoacylglycerol lipase(MGL)also hydrolyzes 2-arachidonoylglycerol,which is a potent ligand within the endocannabinoid system,into arachidonic acid-a precursor for prostaglandin synthesis;thus representing a pivotal substrates provider in multiple organs for several intersecting biological pathways ranging from FA metabolism to inflammation,pain and appetite.MGL inhibition has been shown protective in limiting several liver diseases as FAs may drive hepatocyte injury,fibrogenesis and de-activate immune cells,however the complexity of MGL network system still needs further and deeper understanding.The present review will focus on MGL function and FA partitioning in the horizons of liver disease.展开更多
Morinda citrifolia (noni) fruit juice has exhibited a variety of biological activities in human clinical trials, indicating that it influences multiple systems of the body. Since the 1990s, the endocannabinoid system ...Morinda citrifolia (noni) fruit juice has exhibited a variety of biological activities in human clinical trials, indicating that it influences multiple systems of the body. Since the 1990s, the endocannabinoid system (ECS) has been found to modulate the activity of other organ systems. To investigate noni’s potential impact on the ECS, extracts from freeze-dried noni fruit were evaluated in fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition assays. The ethyl acetate extract demonstrated the greatest activity against both enzymes. Lignans in this extract also inhibited enzyme activities, with americanin A being the most active in both assays. Americanoic acid and 3,3’-bisdemethylpinoresinol were the next most active compounds. These results suggest that lignans in noni fruit may influence endocannabinoid levels within the body via FAAH and MAGL inhibition. This reveals another set of probable mechanisms of action by which noni juice affects human health.展开更多
The arachidonic acid (AA) pathway produces several essential proinflammatory eicosanoids. However, in many neurodegenerative diseases, e.g. Alzheimer’s disease (AD), this pathway is chronically hyperactivated. In bra...The arachidonic acid (AA) pathway produces several essential proinflammatory eicosanoids. However, in many neurodegenerative diseases, e.g. Alzheimer’s disease (AD), this pathway is chronically hyperactivated. In brain, primarily monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to AA, which is further metabolized to generate many proinflammatory eicosanoids. MAGL inhibition, simultaneously reducing the level of eicosanoids and increasing those of neuroprotective endocannabinoids, has proved efficacious in some AD models, reducing neurotoxic β-amyloid (Aβ) levels and improving memory functions. Here, a MAGL inhibitor, JZL184 was chronically administered (16 mg/kg, i.p., 3 x/wk for 5 mo) for 1 - 1.5 mo and 7 - 8 mo old transgenic (TG) and wild-type (WT) APP/PS1-21 mice modelling cerebral amyloidosis. According to immunohistochemistry, JZL184 significantly increased the expression levels of cannabinoid receptor 1 in older WT and younger TG and WT mice, decreased cannabinoid receptor 2 and oligomeric Aβ in older and younger TG mice and decreased microglia-specific marker Iba1 in younger TG mice, compared to TG mice treated with vehicle only. However, in the Morris Water Maze test, spatial memory functions improved significantly only in younger TG and WT mice, compared to vehicle-treated littermates. These tentative results suggest that chronic, rather long-term MAGL inhibition can decelerate pathological changes in TG APP/PS1-21 mice but it improves memory functions only when administered at an early stage of the展开更多
Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders...Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders.While MAGL inhibitors have entered the clinical arena,a highly selective and MAGL-specific positron emission tomography(PET)ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients.Accordingly,this study aimed to develop a new series of reversible MAGL inhibitor candidates,based on a piperazinyl azetidine diamide scaffold.Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates.Subsequently,it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging,as well as ex vivo biodistribution and metabolite analysis experiments in rodents.Compound 3 exhibited a heterogeneous radioactivity distribution,favorable brain uptake,and excellent in vivo binding specificity.Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of[^(18)F]3 in rat brains.In conclusion,[^(18)F]3([^(18)F]MAGL-2011)has the potential to serve as an effective MAGL PET ligand.展开更多
Monoacylglycerol lipase(MAGL)is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids.It links the endocannabinoid and eicosanoid systems together by de...Monoacylglycerol lipase(MAGL)is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids.It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid,the precursor of prostaglandins and other inflammatory mediators.MAGL inhibitors have been considered as important agents in many therapeutic fields,including anti-nociceptive,anxiolytic,antiinflammatory,and even anti-cancer.Currently,ABX-1431,a first-in-class inhibitor of MAGL,is entering clinical phase 2 studies for neurological disorders and other diseases.This review summarizes the diverse(patho)physiological roles of MAGL and will provide an overview on the development of MAGL inhibitors.Although a large number of MAGL inhibitors have been reported,novel inhibitors are still required,particularly reversible ones.展开更多
As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dys...As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms,including neuroinflammation,cognitive impairment,epileptogenesis,nociception and neurodegenerative diseases.Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions,and a MAGL positron emission tomography(PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors.Herein,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates.Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[^(18)F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [^(18)F]14(also named as [^(18)F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.展开更多
文摘Purpose:Monoacylglycerol O-acyltransferase 1(MGAT1)is reported to play a key role in the development of diet-induced nonalcoholic fatty liver disease(NAFLD).Thus,this study investigated the effect of exercise on suppression of the MGAT1 pathway in NAFLD tissue of high-fat diet(HFD)-induced obese rats.Methods:Male Sprague-Dawley rats were fed an HFD containing 45%fat for 6 weeks.Upon confirmation that NAFLD had been induced in the obese animals,they were divided into HFD-fed groups provided with exercise(HFD+EXE)or without exercise(HFD)and a group given dietary adjustment(DA)only,for a further 6 weeks of intervention treatment.The 6-week regular moderate aerobic exercise consisted of an accommodation phase with increasing exercise.Lipid accumulation in the liver tissue was determined by Oil Red O staining.The MGAT1 and liver lipogenic gene mRNA levels were measured by qPCR,and their protein levels by western blot assay.Results:Oil Red O staining showed that NAFLD was successfully induced by HFD-fed.The gene expression of MGAT1 was significantly lower in HFD+EXE than HFD.However,there was no significant difference between HFD+EXE and DA.The protein expression of MGAT1 was significantly lower in HFD+EXE than both HFD and DA.Messenger RNA and protein expression of other lipogenic genes were not different among groups.These data indicate that exercise suppresses MGAT1 pathway regardless of HFD feeding;in part,this effect could be greater than DA.Conclusion:Our data suggest that exercise can improve NAFLD,which is probably due to suppression of MGAT1 pathway.
文摘Dietary oversupply of triglycerides represent the hallmark of obesity and connected complications in the liver such as non-alcoholic fatty liver disease and non-alcoholic steatohepatitis,which eventually progress to cirrhosis and hepatocellular carcinoma.Monoacylglycerol lipase is the last enzymatic step in the hydrolysis of triglycerides,generating glycerol and fatty acids(FAs),which are signaling precursors in physiology and disease.Notably,monoacylglycerol lipase(MGL)also hydrolyzes 2-arachidonoylglycerol,which is a potent ligand within the endocannabinoid system,into arachidonic acid-a precursor for prostaglandin synthesis;thus representing a pivotal substrates provider in multiple organs for several intersecting biological pathways ranging from FA metabolism to inflammation,pain and appetite.MGL inhibition has been shown protective in limiting several liver diseases as FAs may drive hepatocyte injury,fibrogenesis and de-activate immune cells,however the complexity of MGL network system still needs further and deeper understanding.The present review will focus on MGL function and FA partitioning in the horizons of liver disease.
文摘Morinda citrifolia (noni) fruit juice has exhibited a variety of biological activities in human clinical trials, indicating that it influences multiple systems of the body. Since the 1990s, the endocannabinoid system (ECS) has been found to modulate the activity of other organ systems. To investigate noni’s potential impact on the ECS, extracts from freeze-dried noni fruit were evaluated in fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition assays. The ethyl acetate extract demonstrated the greatest activity against both enzymes. Lignans in this extract also inhibited enzyme activities, with americanin A being the most active in both assays. Americanoic acid and 3,3’-bisdemethylpinoresinol were the next most active compounds. These results suggest that lignans in noni fruit may influence endocannabinoid levels within the body via FAAH and MAGL inhibition. This reveals another set of probable mechanisms of action by which noni juice affects human health.
文摘The arachidonic acid (AA) pathway produces several essential proinflammatory eicosanoids. However, in many neurodegenerative diseases, e.g. Alzheimer’s disease (AD), this pathway is chronically hyperactivated. In brain, primarily monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to AA, which is further metabolized to generate many proinflammatory eicosanoids. MAGL inhibition, simultaneously reducing the level of eicosanoids and increasing those of neuroprotective endocannabinoids, has proved efficacious in some AD models, reducing neurotoxic β-amyloid (Aβ) levels and improving memory functions. Here, a MAGL inhibitor, JZL184 was chronically administered (16 mg/kg, i.p., 3 x/wk for 5 mo) for 1 - 1.5 mo and 7 - 8 mo old transgenic (TG) and wild-type (WT) APP/PS1-21 mice modelling cerebral amyloidosis. According to immunohistochemistry, JZL184 significantly increased the expression levels of cannabinoid receptor 1 in older WT and younger TG and WT mice, decreased cannabinoid receptor 2 and oligomeric Aβ in older and younger TG mice and decreased microglia-specific marker Iba1 in younger TG mice, compared to TG mice treated with vehicle only. However, in the Morris Water Maze test, spatial memory functions improved significantly only in younger TG and WT mice, compared to vehicle-treated littermates. These tentative results suggest that chronic, rather long-term MAGL inhibition can decelerate pathological changes in TG APP/PS1-21 mice but it improves memory functions only when administered at an early stage of the
基金supported by NCI T32CA275777support provided,in part,by the NIH grants(S10OD034326,DA038000 and DA043507,USA)+1 种基金Emory Radiology Startup and Chair FundEmory School of Medicine Endowed Directorship.
文摘Monoacylglycerol lipase(MAGL)constitutes a crucial serine hydrolase within the endocannabinoid system,which has been suggested as a potential therapeutic target for the treatment of various neurodegenerative disorders.While MAGL inhibitors have entered the clinical arena,a highly selective and MAGL-specific positron emission tomography(PET)ligand holds promise to significantly facilitate clinical drug development by allowing the quantification of MAGL levels and the assessment of target occupancy in patients.Accordingly,this study aimed to develop a new series of reversible MAGL inhibitor candidates,based on a piperazinyl azetidine diamide scaffold.Compound 3 demonstrated the most promising performance characteristics in pharmacological evaluations compared to other MAGL inhibitor candidates.Subsequently,it was labeled with fluorine-18 and further assessed through autoradiography and PET imaging,as well as ex vivo biodistribution and metabolite analysis experiments in rodents.Compound 3 exhibited a heterogeneous radioactivity distribution,favorable brain uptake,and excellent in vivo binding specificity.Target occupancy studies with a therapeutic MAGL inhibitor demonstrated a dose-dependent PET signal reduction of[^(18)F]3 in rat brains.In conclusion,[^(18)F]3([^(18)F]MAGL-2011)has the potential to serve as an effective MAGL PET ligand.
基金supported by the National Natural Science Foundation of China(No.21807076)the Sichuan Natural Science Foundation,China(No.2019YJ0112).
文摘Monoacylglycerol lipase(MAGL)is a serine hydrolase that plays a crucial role catalysing the hydrolysis of monoglycerides into glycerol and fatty acids.It links the endocannabinoid and eicosanoid systems together by degradation of the abundant endocannabinoid 2-arachidaoylglycerol into arachidonic acid,the precursor of prostaglandins and other inflammatory mediators.MAGL inhibitors have been considered as important agents in many therapeutic fields,including anti-nociceptive,anxiolytic,antiinflammatory,and even anti-cancer.Currently,ABX-1431,a first-in-class inhibitor of MAGL,is entering clinical phase 2 studies for neurological disorders and other diseases.This review summarizes the diverse(patho)physiological roles of MAGL and will provide an overview on the development of MAGL inhibitors.Although a large number of MAGL inhibitors have been reported,novel inhibitors are still required,particularly reversible ones.
基金the financial support from the NIH grants (DA038000 and DA043507 to S. H. L. and DA033760 to B. F. C.)the Swiss National Science Foundation for a postdoctoral fellowship to Michael A. Schafroth (Grant No. P2EZP3_175137, Switzerland)。
文摘As a serine hydrolase,monoacylglycerol lipase(MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol(2-AG) in the central nervous system(CNS),leading to the formation of arachidonic acid(AA).Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms,including neuroinflammation,cognitive impairment,epileptogenesis,nociception and neurodegenerative diseases.Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions,and a MAGL positron emission tomography(PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors.Herein,we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates.Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound,which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[^(18)F]fluoropyridine scaffold.Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [^(18)F]14(also named as [^(18)F]MAGL-1902).This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.
