Excessive and persistent inflammatory responses are a potential pathological condition that can lead to diseases of various systems, including nervous, respiratory, digestive, circulatory, and endocrine systems. Cannabinoid type 2 receptor(CB2R) belongs to the G protein-coupled receptor family and is widely distributed in immune cells, peripheral tissues, and the central nervous system. It plays a role in inflammatory responses under various pathological conditions. The down-regulation of CB2R activity is an important marker of inflammation and and CB2R modulators have been shown to have anti-inflammatory effects. This study explored the relationship between CB2R and inflammatory responses, delved into its regulatory mechanisms in inflammatory diseases, and summarized the research progress on CB2R modulators from plants other than cannabis, including plant extracts and monomeric compounds, in exerting anti-inflammatory effects. The aim is to provide new insights into the prevention and treatment of inflammatory diseases.
Cannabinoid Receptor Modulators/pharmacology* ; Cannabinoid Receptor Agonists/pharmacology* ; Receptors, Cannabinoid ; Cannabinoids/pharmacology* ; Anti-Inflammatory Agents/pharmacology*

Being a great threaten for human health, obesity has become a pandemic chronic disease. There have been several therapeutic treatments for this social health issue, including diet and exercise therapy, medication and surgery, among which the diet is still the most common way. However, none of these therapeutic measures available is ideal, making it necessary to find an effective medical treatment. The endocannabinoid system, which is well known for its contributions in certain mental processes such as relaxation, amelioration of pain and anxiety, and sedation initiation, has been recently reported to play an essential role in regulating appetite and metabolism to maintain energy balance, leading to the belief that endocannabinoid system is closely related to obesity. This new discovery deepens our understanding of obesity, and provides us with a new direction for clinical obesity treatment. Rimonabant is an antagonist for CB1, and has entered the market in some countries. However, although effective as an anti-obesity drug, rimonabant also causes obviously adverse side-effects, thus is being doubted and denied for medical usage.
Animals ; Anti-Obesity Agents ; therapeutic use ; Cannabinoid Receptor Modulators ; antagonists & inhibitors ; metabolism ; Endocannabinoids ; Humans ; Obesity ; drug therapy ; metabolism ; Piperidines ; therapeutic use ; Pyrazoles ; therapeutic use ; Receptors, Cannabinoid ; metabolism

Cannabinoid Receptor Modulators ; Endocannabinoids ; Humans ; Metabolic Syndrome ; metabolism

OBJECTIVETo study the influences of endocannabinoid-anandamide (AEA) on the proliferation and apoptosis of the colorectal cancer cell line (CaCo-2) and to elucidate the effects of CB1 and lipid rafts, and to further elucidate the molecular mechanism and the effect of AEA on the generation and development of colorectal cancer.

METHODSHuman colorectal cancer cell line CaCo-2 was cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum in 5% CO(2) atmosphere at 37°C. CaCo-2 cells were divided into different groups and treated with different concentrations of AEA, AEA + SR141716A, AEA + AM630 and AEA + methyl-β-cyclodextrin (MCD). MTT assay was used to determine the effects of AEA, its putative CB1, CB2 receptor antagonists (SR141716A and AM630) and MCD on the proliferation of CaCo-2 cells. Annexin V-PE/7AAD binding assay was used to detect apoptosis in the CaCo-2 cells. Western-blot was applied to check the expressions of CB1, CB2, p-AKT and caspase-3 proteins in different groups of CaCo-2 cells.

RESULTSAEA inhibited the proliferation of CaCo-2 cells in a concentration-dependent manner and the effect could be antagonized by SR141716A and MCD. The inhibiting rates were (21.52 ± 0.45)%, (42.16 ± 0.21)%, (73.64 ± 0.73)% and (83.28 ± 0.71)%, respectively, at different concentrations of AEA (5, 10, 20 and 40 µmol/L). The three groups (20 µmol/L AEA, 20 µmol/L AEA + 10 µmol/L SR141716A and 20 µmol/L AEA + 1 mmol/L MCD) showed different inhibiting rates [(73.64 ± 0.73)%, (16.15 ± 0.75)% and (12.58 ± 0.63)%], respectively. Annexin V-PE/7AAD binding assay showed that AEA induced apoptosis in the CaCo-2 cells and MCD could antagonize this effect. The apoptosis rates of the three groups (control, 20 µmol/L AEA and 20 µmol/L AEA + 1 mmol/L MCD) were (2.95 ± 0.73)%, (39.61 ± 0.73)% and (14.10 ± 0.64)%, respectively. The expressions of CB1, CB2, p-AKT and Caspase-3 proteins were all observed in the CaCo-2 cells. AEA inhibited p-AKT protein expression and induced caspase-3 protein expression. The two actions were also antagonized by MCD.

CONCLUSIONSAEA can strongly suppress the proliferation of colorectal cancer CaCo-2 cells via the CB1 receptor and membrane cholesterol-LRs and induce apoptosis via lipid rafts. Anandamide plays a very important role in the carcinogenesis and development of colorectal cancer. MCD is a critical member in this system.

Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Arachidonic Acids ; antagonists & inhibitors ; pharmacology ; Caco-2 Cells ; Cannabinoid Receptor Modulators ; antagonists & inhibitors ; pharmacology ; Caspase 3 ; metabolism ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Endocannabinoids ; Humans ; Indoles ; pharmacology ; Membrane Microdomains ; metabolism ; Piperidines ; pharmacology ; Polyunsaturated Alkamides ; antagonists & inhibitors ; pharmacology ; Proto-Oncogene Proteins c-akt ; metabolism ; Pyrazoles ; pharmacology ; Receptor, Cannabinoid, CB1 ; antagonists & inhibitors ; metabolism ; Receptor, Cannabinoid, CB2 ; antagonists & inhibitors ; metabolism ; beta-Cyclodextrins ; metabolism

The plant Cannabis has been used in clinic for centuries, and has been known to be beneficial in a variety of gastrointestinal diseases, such as emesis, diarrhea, inflammatory bowel disease and intestinal pain. In this text, we'll review the components of the endogenous cannabinoid system as well as its role in the regulation of gastrointestinal activities, thus providing relative information for further study. Moreover, modulation of the endogenous cannabinoid system in gastrointestinal tract may provide a useful therapeutic target for gastrointestinal disorders.
Animals ; Cannabinoid Receptor Modulators ; pharmacology ; Endocannabinoids ; physiology ; Gastrointestinal Diseases ; physiopathology ; Gastrointestinal Tract ; physiology ; Humans

Animals ; Cannabinoid Receptor Modulators ; Liver ; metabolism ; Liver Cirrhosis, Experimental ; metabolism ; parasitology ; Male ; Mice ; Mice, Inbred Strains ; Receptor, Cannabinoid, CB1 ; metabolism ; Schistosoma mansoni ; Schistosomiasis mansoni ; metabolism

OBJECTIVETo study the effects of endogenous cannabinoid anandamide (AEA) and its putative endocannabinoid receptors (CBR) on the activation and proliferation of hepatic stellate cells (HSC) and to study the role played by AEA during liver fibrosis.

METHODSBy using immunofluorescence and cell culture, the expression of CBR 1 and 2 in the PDGF-stimulated HSCs was investigated. By using PCR and Western-blot, the effects of 10, 20mumol/L AEA and CBR2 antagonist AM630 on the cultured and activated HSC were observed. Methyl thiazolyl tetrazolium and flow cytometry were used to investigate whether AEA induces growth inhibition or apoptosis in the activated HSCs.

RESULTSBoth CBR1 and CBR2 receptors were detectable in cultured HSCs with a higher level of CBR2 than CBR1 (F = 116.797, P less than 0.01). When HSCs were stimulated by PDGF, the expression of CBR2 receptors was significantly enhanced (F = 7.878, P less than 0.05). HSC proliferation was dose-dependently inhibited by 10, 20, and 50micromol/L AEA, with the rates of 7.12%+/-0.34%, 12.52%+/-0.78%, 80.13%+/-1.57% respectively (F = 533.41, P less than 0.01). However, it did not induce apoptosis, but necrosis. The expressions of alpha-SMA, TGFb1, a1(I), a1(III) and TIMP-1 were significantly suppressed by 20micromol/L AEA, but CBR2 antagonist AM630 reversed this suppressor action of AEA.

CONCLUSIONSAEA may inhibit activation and proliferation of HSCs; CBR2 receptors mediate AEA-induced inhibitory action on the activation of HSCs. This CBR2 receptor-mediated action and AEA on HSCs could be used as a therapeutic target against liver fibrosis.

Animals ; Arachidonic Acids ; pharmacology ; Cannabinoid Receptor Modulators ; pharmacology ; Cell Proliferation ; drug effects ; Cells, Cultured ; Endocannabinoids ; Hepatic Stellate Cells ; cytology ; drug effects ; metabolism ; Indoles ; pharmacology ; Polyunsaturated Alkamides ; pharmacology ; Rats ; Receptor, Cannabinoid, CB2 ; metabolism

OBJECTIVETo study the effect of anandamide (AEA) on necrosis in HepG2 cells and to explore the role of AEA in progression of liver cancer.

METHODSLocalization of the fatty acid hydrolytic enzyme (FAAH), cannabinoid receptors 1(CB1) and cannabinoid receptors 2 (CB2) proteins was detected in L02 and HepG2 cells using immunofluorescence. L02 and HepG2 cells were treated with different concentrations of AEA and methyl-beta-cyclodextrin, and the rates of cells necrosis were examined by PI stain. Meanwhile, the expression levels of FAAH, CB1 and CB2 receptor proteins, as well as P38 mitogen-activated protein kinase (p-P38 MAPK) and c-Jun-NH2-terminal kinase (p-JNK) proteins, were analyzed by Western blot.

RESULTSThe FAAH, CB1 and CB2 receptor proteins were observed both in cytoplasm and on membrane in L02 and HepG2 cells. The expression level of FAAH protein was higher in HepG2 than in L02 cells. The expression level of CB1 receptor protein was very low in both L02 and HepG2 cells. The expression level of CB2 receptor protein was high in both L02 and HepG2 cells. AEA treatment induced necrosis in HepG2 cells but not in L02 cells. Methyl-beta-cyclodextrin treatment prevented necrosis in HepG2 cells (t = 3.702; 5.274; 3.503, P less than 0.05). The expression patterns of FAAH, CB1 and CB2 receptor protein in L02 and HepG2 cells were confirmed by western blot, which were consistent with the immunofluorescence results. AEA treatment increased the levels of p-P38MAPK and p-JNK proteins in a dose-dependent manner in HepG2 cells (F = 11.908; 26.054, P less than 0.05) and the increase can be partially by prevented by MCD (t = 2.801; t = 12.829, P less than 0.05).

CONCLUSIONAEA treatment induces necrosis in HepG2 cells via CB1 and CB2 receptors and lipid rafts.

Amidohydrolases ; metabolism ; Arachidonic Acids ; pharmacology ; Cannabinoid Receptor Modulators ; pharmacology ; Cholesterol ; metabolism ; Endocannabinoids ; Hep G2 Cells ; Humans ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Necrosis ; Polyunsaturated Alkamides ; pharmacology ; Receptor, Cannabinoid, CB1 ; metabolism ; Receptor, Cannabinoid, CB2 ; metabolism ; Signal Transduction ; beta-Cyclodextrins ; pharmacology ; p38 Mitogen-Activated Protein Kinases ; metabolism

OBJECTIVEIn recent years, abnormal changes in the endocannabinoid system have been found in schizophrenia. The superior temporal gyrus (STG) is strongly implicated in the pathophysiology of schizophrenia, particularly with regards to auditory hallucinations. In this study, we investigated the binding density of cannabinoid CB1 receptors in the STG of schizophrenia patients compared to control subjects.

METHODSQuantitative autoradiography was used to investigate the binding densities of [(3)H]SR141716A (a selective antagonist) and [(3)H]CP-55940 (an agonist) to the CB1 receptors in the STG. Post-mortem brain tissue was obtained from the NSW Tissue Resource Centre (Australia).

RESULTSContrasting to previous findings in the alterations of CB1 receptor densities in the prefrontal, anterior and posterior cingulate cortex of schizophrenia, which were suggested to be associated to impairment of cognition function, no significant difference was found between the schizophrenia and control cases in both [(3)H]SR141716A and [(3)H]CP-55940 binding.

CONCLUSIONWe suggest that CB1 receptors in the STG are not involved in the pathology of schizophrenia and the auditory hallucination symptom of this disease.

Adult ; Aged ; Autoradiography ; Case-Control Studies ; Humans ; Middle Aged ; Receptor, Cannabinoid, CB1 ; agonists ; antagonists & inhibitors ; metabolism ; Reference Values ; Schizophrenia ; metabolism ; physiopathology ; Temporal Lobe ; metabolism

It is now well established that several G protein- coupled receptors can signal without agonist stimulation (constitutive receptors). Inverse agonists have been shown to inhibit the activity of such constitutive G protein-coupled receptor signaling. Agonist activation of the Gi/o-coupled peripheral cannabinoid receptor CB2 normally inhibits adenylyl cyclase type V and stimulates adenylyl cyclase type II. Using transfected COS cells, we show here that application of SR144528, an inverse agonist of CB2, leads to a reverse action (stimulation of adenylyl cyclase V and inhibition of adenylyl cyclase II). This inverse agonism of SR144528 is dependent on the temperature, as well as on the concentration of the cDNA of CB2 transfected. Pertussis toxin blocked the regulation of adenylyl cyclase activity by SR 144528.
Adenylate Cyclase/antagonists&inhibitors/genetics/metabolism ; Animals ; Binding, Competitive ; Bornanes/metabolism/*pharmacology ; COS Cells ; Cannabinoids/metabolism ; Cercopithecus aethiops ; Isoenzymes/antagonists&inhibitors/genetics/metabolism ; Pyrazoles/metabolism/*pharmacology ; Rats ; *Receptor, Cannabinoid, CB2 ; Receptors, Cannabinoid ; Receptors, Drug/agonists/*antagonists&inhibitors/genetics/metabolism ; Signal Transduction/drug effects/physiology ; Transfection