Cannabinoids have long been suspected associating with abnormal fetal growth and outcome. However, the molecular mechanisms in which they are involved had long been obscure for several decades. Only recently, after th...Cannabinoids have long been suspected associating with abnormal fetal growth and outcome. However, the molecular mechanisms in which they are involved had long been obscure for several decades. Only recently, after the identification of two types of cannabinoid receptors （CB1-R and CB2-R） and the following discoveries of their corresponding endogenous ligands, the mystery behind those seemingly facts began gradually unveiled. Through a series of landmark research, it is now indicated that the endocannabinoid signaling via the ligand-receptor interaction plays an important role in modulating early development of preimplantation embryo and synchronizing embryo development with uterine receptivity for implantation. Current data suggest that the physiological functions their metabolic pathways are potentially very of endocannabinoid signaling as well as exited areas to be explored further. This review will first introduce the reproductive functions of endocannabinoid signaling from epidemiological and molecular background, then focus on its reciprocal interactions between the embryo and maternal tissues, as well as related metabolic aspects in regards to implantation. It is hoped that further investigation of this physiologically fundamental signaling will generate more exciting information elucidating the complexity of implantation thus lead to a better control of human reproduction.展开更多
Background:The expression,localization,and function of the endocannabinoid system has been well characterized in recent years in the monkey retina and in the primary thalamic relay,the lateral geniculate nucleus(dLGN)...Background:The expression,localization,and function of the endocannabinoid system has been well characterized in recent years in the monkey retina and in the primary thalamic relay,the lateral geniculate nucleus(dLGN).Few data are available on cortical recipients’structures of the dLGN,namely the primary visual cortex(V1).The goal of this study is to characterize the expression and localization of the metabotropic cannabinoid receptor type 1(CB1R),the synthesizing enzyme N-acyl phosphatidyl-ethanolamine phospholipase D(NAPE-PLD),and the degradation enzyme fatty acid amide hydrolase(FAAH)in the vervet monkey area V1.Methods:Using Western blots and immunohistochemistry,we investigated the expression patterns of CB1R,NAPE-PLD,and FAAH in the vervet monkey primary visual cortex.Results:CB1R,NAPE-PLD,and FAAH were expressed in the primary visual cortex throughout the rostro-caudal axis.CB1R showed very low levels of staining in cortical layer 4,with higher expressions in all other cortical layers,especially layer 1.NAPE-PLD and FAAH expressions were highest in layers 1,2 and 3,and lowest in layer 4.Conclusions:Interestingly enough,CB1R was very low in layer 4 of V1 in comparison to the other cortical layers.The visual information coming from the dLGN and entering layer 4Calpha(magno cells)and 4Cbeta(parvo cells)may be therefore modulated by the higher expression levels of CB1R in cortical layers 2 and 3 on the way to the dorsal and ventral visual streams.This is further supported by the higher expression of NAPE-PLD and FAAH in the outer cortical layers.These data indicate that CB1R system can influence the network of activity patterns in the visual stream after the visual information has reached area V1.These novel results provide insights for understanding the role of the endocannabinoids in the modulation of cortical visual inputs,and hence,visual perception.展开更多
Background:The goal of this study is to determine the expression and localization of the cannabinoid receptor type 1(CB1R),the synthesizing enzyme N-acyl phosphatidyl-ethanolamine phospholipase D(NAPE-PLD),and the deg...Background:The goal of this study is to determine the expression and localization of the cannabinoid receptor type 1(CB1R),the synthesizing enzyme N-acyl phosphatidyl-ethanolamine phospholipase D(NAPE-PLD),and the degradation enzyme fatty acid amide hydrolase(FAAH)in the vervet monkey area V1 to better understand the mechanisms underlying the effects of eCB system modulation on cortical visual processing.Methods:Using Western blots and immunohistochemistry,we investigated the laminar and cellular expression patterns of CB1R,NAPE-PLD,and FAAH across the rostrocaudal axis of the vervet monkey(Chlorocebus sabaeus)primary visual cortex.Results:CB1R,NAPE-PLD,and FAAH were expressed in V1 throughout the rostrocaudal axis.CB1R showed very low staining in layer(L)4,with higher expression in all other layers,especially L1,followed by L2 and L3.NAPE-PLD and FAAH expression patterns were similar,but not quite as low in L4.CB1R,NAPE-PLD,and FAAH were localized in vGlut2-positive cells,representing glutamatergic projection neurons,and in somatostatin(SST)-positive cells,a class of GABAergic interneurons.Conclusions:The low level of CB1R in L4 indicates less direct endocannabinoid modulation of V1 afferents from the dLGN,but that greater modulation may occur via the higher expression of CB1R in L2 and L3 on the way to the dorsal and ventral visual streams.This is further supported by the higher expression of NAPE-PLD and FAAH in these layers.Expression in vGlut2-positive and SST-positive cells represents a role at both glutamatergic and GABAergic neurons.These data indicate that CB1R may influence the network of activity patterns in the visual streams after the visual information has reached V1,and thus may influence visual perception.展开更多
4,4-Dimethylsterols constitute a unique class of phytosterols responsible for regulating endogenous cannabinoid system(ECS)functions.However,precise mechanism through which 4,4-dimethylsterols affect fat metabolism an...4,4-Dimethylsterols constitute a unique class of phytosterols responsible for regulating endogenous cannabinoid system(ECS)functions.However,precise mechanism through which 4,4-dimethylsterols affect fat metabolism and the linkage to the ECS remain unresolved.In this study,we identified that 4,4-dimethylsterols,distinct from 4-demethseterols,act as inhibitors of fatty acid amide hydrolases(FAAHs)both in vivo and in vitro.Genetic ablation of FAAHs(faah-1)abolishes the effects of 4,4-dimethylsterols on fat accumulation and locomotion behavior in a Caenorhabditis elegans model.We confirmed that dietary intervention with 4,4-dimethylsterols in a high-fat diet(HFD)mouse model leads to a significant reduction in body weight(>11.28%)with improved lipid profiles in the liver and adipose tissues and increased fecal triacylglycerol excretion.Untargeted and targeted metabolomics further verified that 4,4-dimethylsterols influence unsaturated fatty acid biosynthesis and elevate oleoyl ethanolamine levels in the intestine.We propose a potential molecular mechanism in which 4,4-dimethylsterols engage in binding interactions with the catalytic pocket(Ser241)of FAAH-1 protein due to the shielded polarity,arising from the presence of 2 additional methyl groups(CH3).Consequently,4,4-dimethylsterols represent an unexplored class of beneficial phytosterols that coordinate with FAAH-1 activity to reduce fat accumulation,which offers new insight into intervention strategies for treating diet-induced obesity.展开更多
A predictive pharmacophore model has been generated from a series of diverse fatty acid amide hydrolase(FAAH)inhibitors and the optimal pharmacophore model applied in virtual screening.The pharmacophore model was base...A predictive pharmacophore model has been generated from a series of diverse fatty acid amide hydrolase(FAAH)inhibitors and the optimal pharmacophore model applied in virtual screening.The pharmacophore model was based on a training set of 21 compounds carefully selected from the published literatures.The optimal model Hypo-1 included four features(two hydrogen-bond acceptor units,one aromatic hydrophobic unit and one aromatic ring unit)and two excluded volumes.Cross-validation of the model confirmed that Hypo-1 was not generated by chance correlation.A large test set of 55 compounds showed that Hypo-1 performed well in classifying highly active and less active FAAH inhibitors.Superimposition analysis of the FAAH X-ray crystal structure and the pharmacophore Hypo-1 further validated the adequacy of the model.Virtual screening generated a total of 976 hits from the Zinc Natural Products database,a hit rate of 1.04%and enrichment of 83.89.The acceptable hit rate further supports the use of Hypo-1 as a 3D query tool for virtual screening.展开更多
基金This study was supported by grants from National Natural Science Fundation of China(No.30470654)
文摘Cannabinoids have long been suspected associating with abnormal fetal growth and outcome. However, the molecular mechanisms in which they are involved had long been obscure for several decades. Only recently, after the identification of two types of cannabinoid receptors （CB1-R and CB2-R） and the following discoveries of their corresponding endogenous ligands, the mystery behind those seemingly facts began gradually unveiled. Through a series of landmark research, it is now indicated that the endocannabinoid signaling via the ligand-receptor interaction plays an important role in modulating early development of preimplantation embryo and synchronizing embryo development with uterine receptivity for implantation. Current data suggest that the physiological functions their metabolic pathways are potentially very of endocannabinoid signaling as well as exited areas to be explored further. This review will first introduce the reproductive functions of endocannabinoid signaling from epidemiological and molecular background, then focus on its reciprocal interactions between the embryo and maternal tissues, as well as related metabolic aspects in regards to implantation. It is hoped that further investigation of this physiologically fundamental signaling will generate more exciting information elucidating the complexity of implantation thus lead to a better control of human reproduction.
文摘Background:The expression,localization,and function of the endocannabinoid system has been well characterized in recent years in the monkey retina and in the primary thalamic relay,the lateral geniculate nucleus(dLGN).Few data are available on cortical recipients’structures of the dLGN,namely the primary visual cortex(V1).The goal of this study is to characterize the expression and localization of the metabotropic cannabinoid receptor type 1(CB1R),the synthesizing enzyme N-acyl phosphatidyl-ethanolamine phospholipase D(NAPE-PLD),and the degradation enzyme fatty acid amide hydrolase(FAAH)in the vervet monkey area V1.Methods:Using Western blots and immunohistochemistry,we investigated the expression patterns of CB1R,NAPE-PLD,and FAAH in the vervet monkey primary visual cortex.Results:CB1R,NAPE-PLD,and FAAH were expressed in the primary visual cortex throughout the rostro-caudal axis.CB1R showed very low levels of staining in cortical layer 4,with higher expressions in all other cortical layers,especially layer 1.NAPE-PLD and FAAH expressions were highest in layers 1,2 and 3,and lowest in layer 4.Conclusions:Interestingly enough,CB1R was very low in layer 4 of V1 in comparison to the other cortical layers.The visual information coming from the dLGN and entering layer 4Calpha(magno cells)and 4Cbeta(parvo cells)may be therefore modulated by the higher expression levels of CB1R in cortical layers 2 and 3 on the way to the dorsal and ventral visual streams.This is further supported by the higher expression of NAPE-PLD and FAAH in the outer cortical layers.These data indicate that CB1R system can influence the network of activity patterns in the visual stream after the visual information has reached area V1.These novel results provide insights for understanding the role of the endocannabinoids in the modulation of cortical visual inputs,and hence,visual perception.
文摘Background:The goal of this study is to determine the expression and localization of the cannabinoid receptor type 1(CB1R),the synthesizing enzyme N-acyl phosphatidyl-ethanolamine phospholipase D(NAPE-PLD),and the degradation enzyme fatty acid amide hydrolase(FAAH)in the vervet monkey area V1 to better understand the mechanisms underlying the effects of eCB system modulation on cortical visual processing.Methods:Using Western blots and immunohistochemistry,we investigated the laminar and cellular expression patterns of CB1R,NAPE-PLD,and FAAH across the rostrocaudal axis of the vervet monkey(Chlorocebus sabaeus)primary visual cortex.Results:CB1R,NAPE-PLD,and FAAH were expressed in V1 throughout the rostrocaudal axis.CB1R showed very low staining in layer(L)4,with higher expression in all other layers,especially L1,followed by L2 and L3.NAPE-PLD and FAAH expression patterns were similar,but not quite as low in L4.CB1R,NAPE-PLD,and FAAH were localized in vGlut2-positive cells,representing glutamatergic projection neurons,and in somatostatin(SST)-positive cells,a class of GABAergic interneurons.Conclusions:The low level of CB1R in L4 indicates less direct endocannabinoid modulation of V1 afferents from the dLGN,but that greater modulation may occur via the higher expression of CB1R in L2 and L3 on the way to the dorsal and ventral visual streams.This is further supported by the higher expression of NAPE-PLD and FAAH in these layers.Expression in vGlut2-positive and SST-positive cells represents a role at both glutamatergic and GABAergic neurons.These data indicate that CB1R may influence the network of activity patterns in the visual streams after the visual information has reached V1,and thus may influence visual perception.
基金support from the National Natural Science Foundation of China(no.32272302)the Jiangsu Province Key National Industry Technology Research and Development Cooperation Project(BZ2022041).
文摘4,4-Dimethylsterols constitute a unique class of phytosterols responsible for regulating endogenous cannabinoid system(ECS)functions.However,precise mechanism through which 4,4-dimethylsterols affect fat metabolism and the linkage to the ECS remain unresolved.In this study,we identified that 4,4-dimethylsterols,distinct from 4-demethseterols,act as inhibitors of fatty acid amide hydrolases(FAAHs)both in vivo and in vitro.Genetic ablation of FAAHs(faah-1)abolishes the effects of 4,4-dimethylsterols on fat accumulation and locomotion behavior in a Caenorhabditis elegans model.We confirmed that dietary intervention with 4,4-dimethylsterols in a high-fat diet(HFD)mouse model leads to a significant reduction in body weight(>11.28%)with improved lipid profiles in the liver and adipose tissues and increased fecal triacylglycerol excretion.Untargeted and targeted metabolomics further verified that 4,4-dimethylsterols influence unsaturated fatty acid biosynthesis and elevate oleoyl ethanolamine levels in the intestine.We propose a potential molecular mechanism in which 4,4-dimethylsterols engage in binding interactions with the catalytic pocket(Ser241)of FAAH-1 protein due to the shielded polarity,arising from the presence of 2 additional methyl groups(CH3).Consequently,4,4-dimethylsterols represent an unexplored class of beneficial phytosterols that coordinate with FAAH-1 activity to reduce fat accumulation,which offers new insight into intervention strategies for treating diet-induced obesity.
基金supported by the National Science Foundation of China(Grant No.40976050)。
文摘A predictive pharmacophore model has been generated from a series of diverse fatty acid amide hydrolase(FAAH)inhibitors and the optimal pharmacophore model applied in virtual screening.The pharmacophore model was based on a training set of 21 compounds carefully selected from the published literatures.The optimal model Hypo-1 included four features(two hydrogen-bond acceptor units,one aromatic hydrophobic unit and one aromatic ring unit)and two excluded volumes.Cross-validation of the model confirmed that Hypo-1 was not generated by chance correlation.A large test set of 55 compounds showed that Hypo-1 performed well in classifying highly active and less active FAAH inhibitors.Superimposition analysis of the FAAH X-ray crystal structure and the pharmacophore Hypo-1 further validated the adequacy of the model.Virtual screening generated a total of 976 hits from the Zinc Natural Products database,a hit rate of 1.04%and enrichment of 83.89.The acceptable hit rate further supports the use of Hypo-1 as a 3D query tool for virtual screening.
