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ABSTRACT Objective To verify the involvement of the endocannabinoid system in the immunomodulatory profile of stem cells from human exfoliated deciduous teeth, in the presence or absence of TNF-α, and agonist and antagonists of CB1 and CB2. Methods Stem cells from human exfoliated deciduous teeth were cultured in the presence or absence of an agonist, anandamide, and two antagonists, AM251 and SR144528, of CB1 and CB2 receptors, with or without TNF-α stimulation. For analysis of immunomodulation, surface molecules linked to immunomodulation, namely human leukocyte antigen-DR isotype (HLA-DR), and programmed death ligands 1 (PD-L1) and 2 (PD-L2) were measured using flow cytometry. Results The inhibition of endocannabinoid receptors together with the proinflammatory effect of TNF-α resulted in increased HLA-DR expression in stem cells from human exfoliated deciduous teeth, as well as, in these cells acquiring an anti-inflammatory profile by enhancing the expression of PD-L1 and PD-L2. Conclusion Stem cells from human exfoliated deciduous teeth respond to the endocannabinoid system and TNF-α by altering key immune response molecules.
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Epilepsy,a group of chronic neurological disorders characterized by spontaneous and recurrent seizures and learning and memory impairments,results in transient brain dysfunction due to sudden abnormal discharge of brain neurons.The pathogenesis of epilepsy is very complicated and has not yet been fully elucidated.The imbalance between excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) neurotransmitters in the central nervous system and changes in ionic functions of N-methyl-D-aspartate receptors directly induce epileptic seizures.The endocannabinoid system plays an important role in retrograde synaptic transmission and exerts the anti-epileptic effect in cannabinoid receptor 1 (CBR1) dependent manner by regulating the synaptic transmission of glutamatergic and GABAergic neurons and homeostatsis of ionic channel function.Elucidating the specific mechanism of action of CBR1 signaling pathway in epilepsy,can provide an effective theoretical basis and novel drug's target for clinical treatment of epilepsy.
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Epigenetic studies have led to a more profound understanding of the mechanisms involved in chronic conditions. In the case of alcohol addiction, according to the National Institute on Alcohol Abuse and Alcoholism, 16 million adults suffer from Alcohol Use Disorders (AUDs). Even though therapeutic interventions like behavioral therapy and medications to prevent relapse are currently available, no robust cure exists, which stems from the lack of understanding the mechanisms of action of alcohol and the lack of development of precision medicine approaches to treat AUDs. Another common group of addictive substance, cannabinoids, have been studied extensively to reveal they work through cannabinoid receptors. Therapeutic applications have been found for the cannabinoids and a deeper understanding of the endocannabinoid system has been gained over the years. Recent reports of cannabinergic mechanisms in AUDs has opened an exciting realm of research that seeks to elucidate the molecular mechanisms of alcohol-induced end organ diseases and hopefully provide insight into new therapeutic strategies for the treatment of AUDs. To date, several epigenetic mechanisms have been associated with alcohol and cannabinoids independently. Therefore, the scope of this review is to compile the most recent literature regarding alcohol and cannabinoids in terms of a possible epigenetic connection between the endocannabinoid system and alcohol effects. First, we will provide an overview of epigenetics, followed by an overview of alcohol and epigenetic mechanisms with an emphasis on histone modifications and DNA methylations. Then, we will provide an overview of cannabinoids and epigenetic mechanisms. Lastly, we will discuss evidence of interactions between alcohol and cannabinergic pathways and possible insights into the novel epigenetic mechanisms underlying alcohol-cannabinergic pathway activity. Finalizing the review will be a discussion of future directions and therapeutic applications.
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Objective To study the effect of rimonabant, cannabinoid receptor 1(CB1) antagonist, on the expressions of CB1 andα-smooth muscle actin (α-SMA) in C57 mice with experimental hepatic fibrosis, and their mechanisms in liver fibrosis progression thereof. Methods Thirty C57 mice were randomly divided into three groups, normal control group, mod-el control group and model+rimonabant group, 10 mice for each group. The mouse model of experimental hepatic fibrosis was induced by intraperitoneal injection with 10%CCl4 for two weeks. The normal saline was delivered by gavage daily in normal control group and model control group. Rimonabant was given to mice in model+rimonabant group. Mice were sacri-ficed at the end of eight weeks. Samples of liver tissue were collected. The expressions of CB1 andα-SMA in liver tissue of mice were observed by immunohistochemical staining. The score of fibrosis stage (S) in liver tissue was also analyzed. Re-sults The positive expressions of CB1 andα-SMA and the score S were significantly higher in model control group and model+rimonabant group than those in normal control group (P<0.05). The positive expressions of CB1 andα-SMA and the score S were significantly lower in rimonabant group than those in model control group (P<0.05). There were positive corre-lations in CB1,α-SMA and S scores between normal control group, model control group and model+rimonabant group (P<0.05). Conclusion The activation of CB1 can promote the formation of liver fibrosis. The anti-fibrotic effect of rimonabant, CB1 antagonist, related with the inhibiting of the proliferation and activation of hepatic stellate cells (HSC), and the inhibit-ing of the expression of CB1.
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BACKGROUND/AIMS: This study was designed to investigate the possibility that the enhanced nociceptive responsiveness associated with canabonoid type 1 receptors (CB1Rs) and identify its role in mediating visceral hypersensitivity induced by chronic restraint stress. METHODS: Rats were exposed to daily partial restraint stress or sham partial restraint stress with intraperitoneal injection of the vehicle, CB1R agonist or antagonist for 4 consecutive days. We tested the visceromotor reflex to colorectal distention at day 0 and 5. Reverse-transcription polymerase chain reaction and Western blot were used to assess the expression of CB1Rs. RESULTS: Intraperitoneal CB1 agonist (ACEA) injection significantly diminished (p < 0.05) the enhanced visceromotor reflex to colorectal distention at day 5 in stressed rats. Change in electromyogram response after ACEA over baseline, at pressure of 40 mmHg (+13.3 +/- 2.2), 60 mmHg (+15.3 +/- 2.8) and 80 mmHg (+17.0 +/- 4.0) were much lower than in the control animals, which were +35.9 +/- 5.1, +41.1 +/- 6.3 and +54.1 +/- 9.6, respectively. Whereas, CB1 antagonist (SR141716A) had an opposite effect. Compared with control group, the change in electromyogram response after SR141716A over baseline was significantly enhanced (p < 0.05) for the distending pressure of 40 mmHg (+56.0 +/- 10.3), 60 mmHg (+74.6 +/- 12.3) and 80 mmHg (+82.9 +/- 11.0), respectively. Reverse-transcription polymerase chain reaction and Western blotting demonstrated the stress-induced up-regulation of colon CB1Rs (p < 0.05). CONCLUSIONS: Our results suggest there is a key contribution of peripheral CB1Rs involved in the maintenance of visceral hyperalgesia after repeated restraint stress, providing a novel mechanism for development of peripheral visceral sensitization.
ABSTRACT
BACKGROUND/AIMS: This study was designed to investigate the possibility that the enhanced nociceptive responsiveness associated with canabonoid type 1 receptors (CB1Rs) and identify its role in mediating visceral hypersensitivity induced by chronic restraint stress. METHODS: Rats were exposed to daily partial restraint stress or sham partial restraint stress with intraperitoneal injection of the vehicle, CB1R agonist or antagonist for 4 consecutive days. We tested the visceromotor reflex to colorectal distention at day 0 and 5. Reverse-transcription polymerase chain reaction and Western blot were used to assess the expression of CB1Rs. RESULTS: Intraperitoneal CB1 agonist (ACEA) injection significantly diminished (p < 0.05) the enhanced visceromotor reflex to colorectal distention at day 5 in stressed rats. Change in electromyogram response after ACEA over baseline, at pressure of 40 mmHg (+13.3 +/- 2.2), 60 mmHg (+15.3 +/- 2.8) and 80 mmHg (+17.0 +/- 4.0) were much lower than in the control animals, which were +35.9 +/- 5.1, +41.1 +/- 6.3 and +54.1 +/- 9.6, respectively. Whereas, CB1 antagonist (SR141716A) had an opposite effect. Compared with control group, the change in electromyogram response after SR141716A over baseline was significantly enhanced (p < 0.05) for the distending pressure of 40 mmHg (+56.0 +/- 10.3), 60 mmHg (+74.6 +/- 12.3) and 80 mmHg (+82.9 +/- 11.0), respectively. Reverse-transcription polymerase chain reaction and Western blotting demonstrated the stress-induced up-regulation of colon CB1Rs (p < 0.05). CONCLUSIONS: Our results suggest there is a key contribution of peripheral CB1Rs involved in the maintenance of visceral hyperalgesia after repeated restraint stress, providing a novel mechanism for development of peripheral visceral sensitization.
