Cannabinoids are a group of compounds acting pri-marily via CB1 and CB2 receptors.The expression of cannabinoid receptors in normal liver is low or absent.However,many reports have proven up-regulation of the expressi...Cannabinoids are a group of compounds acting pri-marily via CB1 and CB2 receptors.The expression of cannabinoid receptors in normal liver is low or absent.However,many reports have proven up-regulation of the expression of CB1 and CB2 receptors in hepatic myofibroblasts and vascular endothelial cells,as well as increased concentration of endocannabinoids in liver in the course of chronic progressive liver diseases.It has been shown that CB1 receptor signalling exerts profibrogenic and proinflammatory effects in liver tis-sue,primarily due to the stimulation of hepatic stellate cells,whereas the activation of CB2 receptors inhibits or even reverses liver fibrogenesis.Similarly,CB1 re-ceptor stimulation contributes to progression of liver steatosis.In end-stage liver disease,the endocannabi-noid system has been shown to contribute to hepatic encephalopathy and vascular effects,such as portal hypertension,splanchnic vasodilatation,relative pe-ripheral hypotension and probably cirrhotic cardiomy-opathy.So far,available evidence is based on cellular cultures or animal models.Clinical data on the effects of cannabinoids in chronic liver diseases are limited.However,recent studies have shown the contribution of cannabis smoking to the progression of liver fibrosis and steatosis.Moreover,controlling CB1 or CB2 signal-ling appears to be an attractive target in managing liver diseases.展开更多
The endocannabinoid system(ECS),particularly its signaling pathways and ligands,has garnered considerable interest in recent years.Along with clinical work investigating the ECS’functions,including its role in the de...The endocannabinoid system(ECS),particularly its signaling pathways and ligands,has garnered considerable interest in recent years.Along with clinical work investigating the ECS’functions,including its role in the development of neurological and inflammatory conditions,much research has focused on developing analytical protocols enabling the precise monitoring of the levels and metabolism of the most potent ECS ligands:exogenous phytocannabinoids(PCs)and endogenous cannabinoids(endocannabinoids,ECs).Solid-phase microextraction(SPME)is an advanced,non-exhaustive sample-preparation technique that facilitates the precise and efficient isolation of trace amounts of analytes,thus making it appealing for the analysis of PCs and ECs in complex matrices of plant and animal/human origin.In this paper,we review recent forensic medicine and toxicological studies wherein SPME has been applied to monitor levels of PCs and ECs in complex matrices,determine their effects on organism physiology,and assess their role in the development of several diseases.展开更多
Globally,it is evident that glioblastoma multiforme(GBM)is an aggressive malignant cancer with a high mortality rate and no effective treatment options.Glioblastoma is classified as the stage-four progression of a gli...Globally,it is evident that glioblastoma multiforme(GBM)is an aggressive malignant cancer with a high mortality rate and no effective treatment options.Glioblastoma is classified as the stage-four progression of a glioma tumor,and its diagnosis results in a shortened life expectancy.Treatment options for GBM include chemotherapy,immunotherapy,surgical intervention,and conventional pharmacotherapy;however,at best,they extend the patient’s life by a maximum of 5 years.GBMs are considered incurable due to their high recurrence rate,despite various aggressive therapeutic approaches which can have many serious adverse effects.Ceramides,classified as endocannabinoids,offer a promising novel therapeutic approach for GBM.Endocannabinoids may enhance the apoptosis of GBM cells but have no effect on normal healthy neural cells.Cannabinoids promote atypical protein kinase C,deactivate fatty acid amide hydrolase enzymes,and activate transient receptor potential vanilloid 1(TRPV1)and TRPV2 to induce pro-apoptotic signaling pathways without increasing endogenous cannabinoids.In previous in vivo studies,endocannabinoids,chemically classified as amide formations of oleic and palmitic acids,have been shown to increase the pro-apoptotic activity of human cancer cells and inhibit cell migration and angiogenesis.This review focuses on the biological synthesis and pharmacology of endogenous cannabinoids for the enhancement of cancer cell apoptosis,which have potential as a novel therapy for GBM.展开更多
Activation of cannabinoid receptor type 1 on presynaptic neurons is postulated to suppress neu- ~ ~ ~ 2＋ ~ ~ 2＋ rotransmlsslon by decreasing Ca reflux through high voltage-gated Ca channels. However, recent studies...Activation of cannabinoid receptor type 1 on presynaptic neurons is postulated to suppress neu- ~ ~ ~ 2＋ ~ ~ 2＋ rotransmlsslon by decreasing Ca reflux through high voltage-gated Ca channels. However, recent studies suggest that cannabinoids which activate cannabinoid receptor type 1 can increase neurotransmitter release by enhancing Ca2＋ influx in vitro. The aim of the present study was to investigate the modulation of intracellular Ca2＋ concentration by the cannabinoid receptor type 1 agonist anandamide, and its underlying mechanisms. Using whole cell voltage-damp and calcium imaging in cultured trigeminal ganglion neurons, we found that anandamide directly caused Ca2＋ influx in a dose-dependent manner, which then triggered an increase of intracellular Ca2＋ concentration. The cyclic adenosine and guanosine monophosphate-dependent protein kinase systems, but not the protein kinase C system, were involved in the increased intracellular Ca2＋concentration by anandamide. This result showed that anandamide increased intracellu- lar Ca2＋ concentration and inhibited high voltage-gated Ca2＋ channels through different signal transduction pathways.展开更多
Irritable bowel syndrome (IBS) is a complex symptom-based disorder without established biomarkers or putative pathophysiology. IBS is a common functional gastrointestinal disorder which is defined as recurrent abdomin...Irritable bowel syndrome (IBS) is a complex symptom-based disorder without established biomarkers or putative pathophysiology. IBS is a common functional gastrointestinal disorder which is defined as recurrent abdominal pain or discomfort that has at least two of the following symptoms for 3 d per month in the past 3 mo according to ROME III: relief by defecation, onset associated with a change in stool frequency or onset with change in appearance or form of stool. Recent discoveries revealed genetic polymorphisms in specific cytokines and neuropeptides may possibly influence the frequencies and severity of symptoms, as well as the therapeutic responses in treating IBS patients. This review gives new insights on how genetic determinations influence in clinical manifestations, treatment responses and potential biomarkers of IBS.展开更多
Objective:Bushen Tiansui formula(BSTSF),a traditional Chinese medicine prescription,has been widely used to treat Alzheimer’s disease(AD).However,the mechanisms underlying its effects remain largely unknown.In this s...Objective:Bushen Tiansui formula(BSTSF),a traditional Chinese medicine prescription,has been widely used to treat Alzheimer’s disease(AD).However,the mechanisms underlying its effects remain largely unknown.In this study,a rat AD model was used to study the effects of BSTSF on cognitive performance and expression of transfer RNA-derived small RNAs(tsRNAs)in the hippocampus,to determine whether treatment of AD with BSTSF could regulate the expression of tsRNAs,a novel small non-coding RNA.Methods:To generate a validated AD model,oligomeric amyloid-β_(1-42)(Aβ_(1-42))was injected intracerebroventricularly into rats.The Morris water maze(MWM)test was used to evaluate rat cognitive performance,and tsRNA-sequencing was conducted to examine tsRNA expression in the rat hippocampus.Potential targets were validated by quantitative real-time polymerase chain reaction(qRT-PCR).Bioinformatic analyses were conducted to investigate the biological function of candidate tsRNAs.Results:The learning and memory deficits of Aβ_(1-42)-induced AD rats,assessed by MWM tests,were clearly ameliorated by BSTSF treatment.A total of 387 tsRNAs were detected in the rat hippocampus.Among them,13 were significantly dysregulated in AD rats compared with sham control rats,while 57 were markedly altered by BSTSF treatment,relative to untreated AD rats(fold change>2 and P<0.05).Moreover,six BSTSF treatment-related tsRNAs were identified and validated by qRT-PCR.Bioinformatic analyses indicated that the six treatment-related tsRNAs had potential therapeutic roles,via multiple signaling pathways and Gene Ontology biological functions,including cyclic adenosine monophosphate and retrograde endocannabinoid signaling.Conclusion:This study identified a previously uncharacterized mechanism underlying the effects of BSTSF in alleviating the learning and memory deficits in Aβ_(1-42)-induced AD rats,demonstrating that tsRNAs are potential therapeutic targets of BSTSF in the treatment of AD.展开更多
Aspirin-exacerbated respiratory disease(AERD)is characterized by the triad of chronic rhinosinusitis with nasal polyposis,adult-onset asthma and non-IgE mediated reactions to aspirin and other cyclooxygenase-1(COX-1)i...Aspirin-exacerbated respiratory disease(AERD)is characterized by the triad of chronic rhinosinusitis with nasal polyposis,adult-onset asthma and non-IgE mediated reactions to aspirin and other cyclooxygenase-1(COX-1)inhibitors.Patients with AERD are dependent on COX-1 activity to maintain production of prostaglandin(PG)species,such as PGE2,which maintain physiologic levels of inflammation and limit the production of pro-inflammatory cysteinyl leukotrienes.The endogenous cannabinoid system is a family of immunomodulatory lipids and their innate g-protein coupled receptors that are closely related to arachidonic acid and may modulate inflammation via several pathways,including the direct production of metabolically active prostaglandin glycerol-esters.A recent pilot study has identified the significant up-regulation of the peripherally expressed,type-2 cannabinoid receptor(CB2)in AERD nasal polyps versus control tissues from patients with either allergic fungal rhinosinusitis or no history of chronic sinonasal inflammation.These early findings suggest the involvement of increased endogenous cannabinoid activity in prostaglandin deficient states such as AERD.Future study is needed to explore the significance of these findings,with specific investigation of the impact of CB2 activation on markers of airway inflammation,as well as the potential to measure CB2 expression as a screening biomarker for the evaluation of unrecognized disease.展开更多
To sustain the nutrient demands of rapid fetal growth,parturition,and milk synthesis,periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis.This process induces an inflammatory response ...To sustain the nutrient demands of rapid fetal growth,parturition,and milk synthesis,periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis.This process induces an inflammatory response within AT that is resolved as lactation progresses;however,excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases.The suppression of lipolytic action and inflammation,along with amplification of adipogenesis and lipogenesis,serve as prospective therapeutic targets for improving the health of periparturient dairy cows.Generally,the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis,suppresses lipolysis,and increases appetite in mammals.These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows’health,although much is still to be revealed in this context.This review summarizes the current knowledge surrounding the components of the endocannabinoid system,elaborates on the metabolic effects of its activation,and explores the potential to modulate its activity in periparturient dairy cows.展开更多
文摘Cannabinoids are a group of compounds acting pri-marily via CB1 and CB2 receptors.The expression of cannabinoid receptors in normal liver is low or absent.However,many reports have proven up-regulation of the expression of CB1 and CB2 receptors in hepatic myofibroblasts and vascular endothelial cells,as well as increased concentration of endocannabinoids in liver in the course of chronic progressive liver diseases.It has been shown that CB1 receptor signalling exerts profibrogenic and proinflammatory effects in liver tis-sue,primarily due to the stimulation of hepatic stellate cells,whereas the activation of CB2 receptors inhibits or even reverses liver fibrogenesis.Similarly,CB1 re-ceptor stimulation contributes to progression of liver steatosis.In end-stage liver disease,the endocannabi-noid system has been shown to contribute to hepatic encephalopathy and vascular effects,such as portal hypertension,splanchnic vasodilatation,relative pe-ripheral hypotension and probably cirrhotic cardiomy-opathy.So far,available evidence is based on cellular cultures or animal models.Clinical data on the effects of cannabinoids in chronic liver diseases are limited.However,recent studies have shown the contribution of cannabis smoking to the progression of liver fibrosis and steatosis.Moreover,controlling CB1 or CB2 signal-ling appears to be an attractive target in managing liver diseases.
文摘The endocannabinoid system(ECS),particularly its signaling pathways and ligands,has garnered considerable interest in recent years.Along with clinical work investigating the ECS’functions,including its role in the development of neurological and inflammatory conditions,much research has focused on developing analytical protocols enabling the precise monitoring of the levels and metabolism of the most potent ECS ligands:exogenous phytocannabinoids(PCs)and endogenous cannabinoids(endocannabinoids,ECs).Solid-phase microextraction(SPME)is an advanced,non-exhaustive sample-preparation technique that facilitates the precise and efficient isolation of trace amounts of analytes,thus making it appealing for the analysis of PCs and ECs in complex matrices of plant and animal/human origin.In this paper,we review recent forensic medicine and toxicological studies wherein SPME has been applied to monitor levels of PCs and ECs in complex matrices,determine their effects on organism physiology,and assess their role in the development of several diseases.
文摘Globally,it is evident that glioblastoma multiforme(GBM)is an aggressive malignant cancer with a high mortality rate and no effective treatment options.Glioblastoma is classified as the stage-four progression of a glioma tumor,and its diagnosis results in a shortened life expectancy.Treatment options for GBM include chemotherapy,immunotherapy,surgical intervention,and conventional pharmacotherapy;however,at best,they extend the patient’s life by a maximum of 5 years.GBMs are considered incurable due to their high recurrence rate,despite various aggressive therapeutic approaches which can have many serious adverse effects.Ceramides,classified as endocannabinoids,offer a promising novel therapeutic approach for GBM.Endocannabinoids may enhance the apoptosis of GBM cells but have no effect on normal healthy neural cells.Cannabinoids promote atypical protein kinase C,deactivate fatty acid amide hydrolase enzymes,and activate transient receptor potential vanilloid 1(TRPV1)and TRPV2 to induce pro-apoptotic signaling pathways without increasing endogenous cannabinoids.In previous in vivo studies,endocannabinoids,chemically classified as amide formations of oleic and palmitic acids,have been shown to increase the pro-apoptotic activity of human cancer cells and inhibit cell migration and angiogenesis.This review focuses on the biological synthesis and pharmacology of endogenous cannabinoids for the enhancement of cancer cell apoptosis,which have potential as a novel therapy for GBM.
基金supported by NIH,grant No.GM-63577NNSF,grant No.30571537,No.30271500+1 种基金the National Natural Science Foundation of China,No.30271500,30571537 and 813702462010 National Clinical Key Disciplines Construction Grant from the Ministry of Health of the People’s Republic of China
文摘Activation of cannabinoid receptor type 1 on presynaptic neurons is postulated to suppress neu- ~ ~ ~ 2＋ ~ ~ 2＋ rotransmlsslon by decreasing Ca reflux through high voltage-gated Ca channels. However, recent studies suggest that cannabinoids which activate cannabinoid receptor type 1 can increase neurotransmitter release by enhancing Ca2＋ influx in vitro. The aim of the present study was to investigate the modulation of intracellular Ca2＋ concentration by the cannabinoid receptor type 1 agonist anandamide, and its underlying mechanisms. Using whole cell voltage-damp and calcium imaging in cultured trigeminal ganglion neurons, we found that anandamide directly caused Ca2＋ influx in a dose-dependent manner, which then triggered an increase of intracellular Ca2＋ concentration. The cyclic adenosine and guanosine monophosphate-dependent protein kinase systems, but not the protein kinase C system, were involved in the increased intracellular Ca2＋concentration by anandamide. This result showed that anandamide increased intracellu- lar Ca2＋ concentration and inhibited high voltage-gated Ca2＋ channels through different signal transduction pathways.
文摘Irritable bowel syndrome (IBS) is a complex symptom-based disorder without established biomarkers or putative pathophysiology. IBS is a common functional gastrointestinal disorder which is defined as recurrent abdominal pain or discomfort that has at least two of the following symptoms for 3 d per month in the past 3 mo according to ROME III: relief by defecation, onset associated with a change in stool frequency or onset with change in appearance or form of stool. Recent discoveries revealed genetic polymorphisms in specific cytokines and neuropeptides may possibly influence the frequencies and severity of symptoms, as well as the therapeutic responses in treating IBS patients. This review gives new insights on how genetic determinations influence in clinical manifestations, treatment responses and potential biomarkers of IBS.
基金supported by the National Natural Science Foundation of China(No.81603670,81873169)the Hunan Provincial Natural Science Foundation of China(No.2017JJ3459,2020JJ4803)。
文摘Objective:Bushen Tiansui formula(BSTSF),a traditional Chinese medicine prescription,has been widely used to treat Alzheimer’s disease(AD).However,the mechanisms underlying its effects remain largely unknown.In this study,a rat AD model was used to study the effects of BSTSF on cognitive performance and expression of transfer RNA-derived small RNAs(tsRNAs)in the hippocampus,to determine whether treatment of AD with BSTSF could regulate the expression of tsRNAs,a novel small non-coding RNA.Methods:To generate a validated AD model,oligomeric amyloid-β_(1-42)(Aβ_(1-42))was injected intracerebroventricularly into rats.The Morris water maze(MWM)test was used to evaluate rat cognitive performance,and tsRNA-sequencing was conducted to examine tsRNA expression in the rat hippocampus.Potential targets were validated by quantitative real-time polymerase chain reaction(qRT-PCR).Bioinformatic analyses were conducted to investigate the biological function of candidate tsRNAs.Results:The learning and memory deficits of Aβ_(1-42)-induced AD rats,assessed by MWM tests,were clearly ameliorated by BSTSF treatment.A total of 387 tsRNAs were detected in the rat hippocampus.Among them,13 were significantly dysregulated in AD rats compared with sham control rats,while 57 were markedly altered by BSTSF treatment,relative to untreated AD rats(fold change>2 and P<0.05).Moreover,six BSTSF treatment-related tsRNAs were identified and validated by qRT-PCR.Bioinformatic analyses indicated that the six treatment-related tsRNAs had potential therapeutic roles,via multiple signaling pathways and Gene Ontology biological functions,including cyclic adenosine monophosphate and retrograde endocannabinoid signaling.Conclusion:This study identified a previously uncharacterized mechanism underlying the effects of BSTSF in alleviating the learning and memory deficits in Aβ_(1-42)-induced AD rats,demonstrating that tsRNAs are potential therapeutic targets of BSTSF in the treatment of AD.
基金The National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378 and KL2TR002381.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
文摘Aspirin-exacerbated respiratory disease(AERD)is characterized by the triad of chronic rhinosinusitis with nasal polyposis,adult-onset asthma and non-IgE mediated reactions to aspirin and other cyclooxygenase-1(COX-1)inhibitors.Patients with AERD are dependent on COX-1 activity to maintain production of prostaglandin(PG)species,such as PGE2,which maintain physiologic levels of inflammation and limit the production of pro-inflammatory cysteinyl leukotrienes.The endogenous cannabinoid system is a family of immunomodulatory lipids and their innate g-protein coupled receptors that are closely related to arachidonic acid and may modulate inflammation via several pathways,including the direct production of metabolically active prostaglandin glycerol-esters.A recent pilot study has identified the significant up-regulation of the peripherally expressed,type-2 cannabinoid receptor(CB2)in AERD nasal polyps versus control tissues from patients with either allergic fungal rhinosinusitis or no history of chronic sinonasal inflammation.These early findings suggest the involvement of increased endogenous cannabinoid activity in prostaglandin deficient states such as AERD.Future study is needed to explore the significance of these findings,with specific investigation of the impact of CB2 activation on markers of airway inflammation,as well as the potential to measure CB2 expression as a screening biomarker for the evaluation of unrecognized disease.
基金This project was funded by the US-Israel Binational Agricultural Research and Development Fund(Grant IS-5167-19)MNS was supported in part by the USDA National Institute for Food and Agriculture(Washington,DC,USA)competitive project 2019-67015-29443.
文摘To sustain the nutrient demands of rapid fetal growth,parturition,and milk synthesis,periparturient dairy cows mobilize adipose tissue fatty acid stores through lipolysis.This process induces an inflammatory response within AT that is resolved as lactation progresses;however,excessive and protracted lipolysis compounds the risk for metabolic and inflammatory diseases.The suppression of lipolytic action and inflammation,along with amplification of adipogenesis and lipogenesis,serve as prospective therapeutic targets for improving the health of periparturient dairy cows.Generally,the activation of cannabinoid receptors by endocannabinoids enhances adipogenesis and lipogenesis,suppresses lipolysis,and increases appetite in mammals.These biological effects of activating the endocannabinoid system open the possibility of harnessing the endocannabinoid system through nutritional intervention in dairy herds as a potential tool to improve dairy cows’health,although much is still to be revealed in this context.This review summarizes the current knowledge surrounding the components of the endocannabinoid system,elaborates on the metabolic effects of its activation,and explores the potential to modulate its activity in periparturient dairy cows.
