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
Morinda citrifolia (noni) fruit juice has been shown to have a wide variety of potential health benefits in human clinical trials. It may also influence the endocannabinoid system of the body. Since the main ingredien...Morinda citrifolia (noni) fruit juice has been shown to have a wide variety of potential health benefits in human clinical trials. It may also influence the endocannabinoid system of the body. Since the main ingredient of the product studied in these clinical trials was juice made from noni fruit puree from French Polynesia, it was evaluated for its ability to inhibit the two major endocannabinoid degradation enzymes in vitro. Noni fruit juice inhibited both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) in a concentration-dependent manner, suggesting that it may help maintain anandamide and 2-arachidonoylglycerol levels. Samples of the puree were also analyzed for the presence of characteristic phytochemical markers of authentic noni fruit such as scopoletin, rutin, quercetin, deacetylasperulosidic acid and asperulosidic acid, all of which were present. Also present was scandoside, which is reported for the first time as being identified in noni fruit or its juice. Some of these compounds may contribute to the FAAH and MAGL inhibiting activity of noni juice. These results reveal another set of mechanisms by which noni juice possibly supports mental health, maintains joint health, relieves discomfort and modulates the immune system.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
目的:研究JZL184对结直肠癌细胞系细胞凋亡的影响及其可能的机制.方法:分别用JZL184,JZL184联合不同浓度5-氟尿嘧啶(5-fluorouracil,5-Fu)及单用5-Fu干预SW480和Lovo 48 h,流式细胞仪检测结直肠癌细胞系SW480和Lovo细胞凋亡率变化.Weste...目的:研究JZL184对结直肠癌细胞系细胞凋亡的影响及其可能的机制.方法:分别用JZL184,JZL184联合不同浓度5-氟尿嘧啶(5-fluorouracil,5-Fu)及单用5-Fu干预SW480和Lovo 48 h,流式细胞仪检测结直肠癌细胞系SW480和Lovo细胞凋亡率变化.Western blot检测JZL184干预SW480及Lovo 48 h后p-AKT、p-m TOR、proCaspase3和pro-Caspase8蛋白水平的变化.结果:在结直肠癌细胞系SW480及Lovo中,J Z L184联合5-F u与单用5-F u组相比细胞凋亡不同程度增加(在SW480中凋亡率提升分别为:JZL184+500μmol/L 5-Fu 13.91%±9.13%,JZL184+200μmol/L 5-Fu 26.34%±13.32%,JZL184+100μmol/L 5-Fu 43.32%±8.04%,JZL184+10μmol/L 5-Fu 31.4%±5.82%;在L o v o中凋亡率提升分别为:JZL184+500μmol/L 5-Fu 17.56%±8.14%,JZL184+200μmol/L 5-Fu 33.04%±9.49%,JZL184+100μmol/L 5-Fu 36.91%±16.63%,JZL184+10μmol/L 5-Fu 21.26%±11.03%.与对照组相比,10μmol/L JZL184可不同程度抑制结直肠癌细胞系SW480及Lovo p-A K T、p-m T O R、p r o-C a s p a s e3、p r oCaspase8蛋白水平(P<0.05).结论:JZL184抑制AKT-m TOR通路及促进p r o-C a s p a s e8和p r o-C a s p a s e3裂解活化从而增强5-Fu诱导结直肠癌细胞系SW480,L o v o细胞凋亡,提高结直肠癌细胞系对5-Fu敏感性.展开更多
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
文摘Morinda citrifolia (noni) fruit juice has been shown to have a wide variety of potential health benefits in human clinical trials. It may also influence the endocannabinoid system of the body. Since the main ingredient of the product studied in these clinical trials was juice made from noni fruit puree from French Polynesia, it was evaluated for its ability to inhibit the two major endocannabinoid degradation enzymes in vitro. Noni fruit juice inhibited both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) in a concentration-dependent manner, suggesting that it may help maintain anandamide and 2-arachidonoylglycerol levels. Samples of the puree were also analyzed for the presence of characteristic phytochemical markers of authentic noni fruit such as scopoletin, rutin, quercetin, deacetylasperulosidic acid and asperulosidic acid, all of which were present. Also present was scandoside, which is reported for the first time as being identified in noni fruit or its juice. Some of these compounds may contribute to the FAAH and MAGL inhibiting activity of noni juice. These results reveal another set of mechanisms by which noni juice possibly supports mental health, maintains joint health, relieves discomfort and modulates the immune system.
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.
文摘目的:研究JZL184对结直肠癌细胞系细胞凋亡的影响及其可能的机制.方法:分别用JZL184,JZL184联合不同浓度5-氟尿嘧啶(5-fluorouracil,5-Fu)及单用5-Fu干预SW480和Lovo 48 h,流式细胞仪检测结直肠癌细胞系SW480和Lovo细胞凋亡率变化.Western blot检测JZL184干预SW480及Lovo 48 h后p-AKT、p-m TOR、proCaspase3和pro-Caspase8蛋白水平的变化.结果:在结直肠癌细胞系SW480及Lovo中,J Z L184联合5-F u与单用5-F u组相比细胞凋亡不同程度增加(在SW480中凋亡率提升分别为:JZL184+500μmol/L 5-Fu 13.91%±9.13%,JZL184+200μmol/L 5-Fu 26.34%±13.32%,JZL184+100μmol/L 5-Fu 43.32%±8.04%,JZL184+10μmol/L 5-Fu 31.4%±5.82%;在L o v o中凋亡率提升分别为:JZL184+500μmol/L 5-Fu 17.56%±8.14%,JZL184+200μmol/L 5-Fu 33.04%±9.49%,JZL184+100μmol/L 5-Fu 36.91%±16.63%,JZL184+10μmol/L 5-Fu 21.26%±11.03%.与对照组相比,10μmol/L JZL184可不同程度抑制结直肠癌细胞系SW480及Lovo p-A K T、p-m T O R、p r o-C a s p a s e3、p r oCaspase8蛋白水平(P<0.05).结论:JZL184抑制AKT-m TOR通路及促进p r o-C a s p a s e8和p r o-C a s p a s e3裂解活化从而增强5-Fu诱导结直肠癌细胞系SW480,L o v o细胞凋亡,提高结直肠癌细胞系对5-Fu敏感性.
