Signal Peptide and Denaturing Temperature are Critical Factors for Efficient Mammalian Expression and Immunoblotting of Cannabinoid Receptors

Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide. In addition, the artificially synthesized cannabinoid receptor was found to aggregate under routine sample denaturing temperatures (i.e.,≥95°C), forming a large molecular weight band when analyzed by immuno-blotting. Only denaturing temperatures ≤75°C yielded a clear band at the predicted molecular weight. Collectively, we showed that efficient mammalian expression of cannabinoid receptors need a signal peptide sequence, and described the requirement for a low sample denaturing temperature in immuno-blot analysis. These findings provide very useful information for efficient mammalian expression and immuno-blotting of membrane receptors.

No changes in densities of cannabinoid receptors in the superior temporal gyrus in schizophrenia

Objective In 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.Methods Quantitative autoradiography was used to investigate the binding densities of[^3H]SR141716A（a selective antagonist）and[^3H]CP-55940（an agonist）to the CB1 receptors in the STG.Post-mortem brain tissue was obtained from the NSW Tissue Resource Centre（Australia）.Results Contrasting 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[^3H]SR141716A and[^3H]CP-55940 binding. Conclusion We suggest that CB1 receptors in the STG are not involved in the pathology of schizophrenia and the auditory hallucination symptom of this disease.

Endocannabinoids Anandamide and Its Cannabinoid Receptors in Liver Fibrosis after Murine Schistosomiasis

This study examined endogenous carmabinoid （ECB）-anandamide （AEA） and its cannabinoid receptors （CBR） in mice liver with the development ofschistosomajaponicum. Mice were infected with schistosoma by means of pasting the cercaria onto their abdomens. Liver fibrosis was pathologically confirmed nine weeks after the infection. High performance liquid chromatography （HPLC） was employed to determine the concentration of AEA in the plasma of mice. Immunofluo-rescence was used to detect the expression of CBR1 and CBR2 in liver tissue. Morphological examination showed typical pathological changes, with worm tubercles of schistosoma deposited in the liver tissue, fibrosis around the worm tubercles and infiltration or soakage of inflammatory cells. Also, CBR1 and CBR2 were present in hepatocytes and hepatic sinusoids of the two groups, but they were obviously enhanced in the schistosoma-infected mice. However, the average optical density of CBR1 in the negative control and fibrosis group was 13.28±7.32 and 30.55±7.78, and CBR2 were 28.13±6.42 and 52.29±4.24 （P〈0.05）. The levels of AEA in the fibrosis group were significantly increased as compared with those of the control group. The concentrations of AEA were （0.37±0.07） and （5.67±1.34） ng/mL （P〈0.05）. It is concluded that the expression of endocannabinoids AEA and its cannabinoid receptor CBR were significantly increased in schistosoma-infected mice. Endogenous endocannabinoids may be involved in the development of schistosoma-induced liver fibrosis.

Pharmacological inhibition of cannabinoid receptor 1 stimulates gastric release of nesfatin-1 via the mTOR pathway

AIM To determine whether Nucb2/nesfatin1 production is regulated by the cannabinoid system through the intracellular m TOR pathway in the stomach.METHODS Sprague Dawley rats were treated with vehicle, rimonabant, rapamycin or rapamycin+rimonabant. Gastric tissue obtained from the animals was used for biochemical assays: Nucb2 m RNA measurement by real time PCR, gastric Nucb2/nesfatin protein content by western blot, and gastric explants to obtain gastric secretomes. Nucb2/nesfatin levels were measured in gastric secretomes and plasma using enzyme-linked immunosorbent assay. RESULTS The inhibition of cannabinoid receptor 1(CB1) by the peripheral injection of an inverse agonist, namely rimonabant, decreases food intake and increases the gastric secretion and circulating levels of Nucb2/nesfatin-1. In addition, rimonabant treatment activates m TOR pathway in the stomach as showed by the increase in pm TOR/m TOR expression in gastric tissue obtained from rimonabant treated animals. These effects were confirmed by the use of a CB1 antagonist, AM281. When the intracellular pathway m TOR/S6 k was inactivated by chronic treatment with rapamycin, rimonabant treatment was no longer able to stimulate the gastric secretion of Nucb2/nesfatin-1.CONCLUSION The peripheral cannabinoid system regulates food intake through a mechanism that implies gastric production and release of Nucb2/Nesfatin-1, which is mediated by the m TOR/S6 k pathway.

Metabolic and inflammatory functions of cannabinoid receptor type 1 are differentially modulated by adiponectin

BACKGROUND Antagonists of cannabinoid type 1 receptor(CB1)have been shown to promote body weight loss and improve insulin sensitivity.Cannabinoids decrease adiponectin,and CB1 blocker increase adiponectin.However,the mediators of CB1 actions are not well defined.AIM To investigate whether the beneficial effects of CB1 inhibition are,at least in part,mediated by adiponectin.METHODS We compared metabolic and inflammatory phenotypes of wild-type(WT)mice,CB1-null(CB1^(-/-))and CB1/adiponectin double-knockout(DKO)mice.We assessed the insulin sensitivity using insulin tolerance test and glucose tolerance test,and inflammation using flow cytometry analysis of macrophages.RESULTS CB1^(-/-)mice exhibited significantly reduced body weight and fat mass when compared to WT mice.While no significance was found in total daily food intake and locomotor activity,CB1^(-/-)mice showed increased energy expenditure,enhanced thermogenesis in brown adipose tissue(BAT),and improved insulin sensitivity compared to WT mice.DKO showed no difference in body weight,adiposity,nor insulin sensitivity;only showed a modestly elevated thermogenesis in BAT compared to CB1^(-/-)mice.The metabolic phenotype of DKO is largely similar to CB1^(-/-)mice,suggesting that adiponectin is not a key mediator of the metabolic effects of CB1.Interestingly,CB1^(-/-)mice showed reduced pro-inflammatory macrophage polarization in both peritoneal macrophages and adipose tissue macrophages compared to WT mice;in contrast,DKO mice exhibited increased pro-inflammatory macrophage polarization in these macrophages compared to CB1^(-/-)mice,suggesting that adiponectin is an important mediator of the inflammatory effect of CB1.CONCLUSION Our findings reveal that CB1 functions through both adiponectin-dependent and adiponectin-independent mechanisms:CB1 regulates energy metabolism in an adiponectin-independent manner,and inflammation in an adiponectin-dependent manner.The differential effects of adiponectin on CB1-mediated metabolic and inflammatory functions should be taken into consideration in CB1 antagonist utilization.

Distribution and Possible Function of Cannabinoid Receptor Subtype 1 in the Human Prostate

Background: Cannabinoid receptor subtype 1 (CB1) has a relationship to the proliferation of various cells including malignant tumoral cells. We investigated and compared the expression of CB1 in benign and malignant human prostate tissues and in benign and malignant human prostate cell lines, as well as its function for the proliferation of human prostate cancer cells. Methods: Real-time quantitative PCR was performed to compare its expressions in human prostate tissues (normal, benign hyperplasia, and cancer) and prostate cell lines (3 normal and 3 malignant). For localization of CB1, immunofluorescent staining with rabbit anti-CB1 polyclonal antibodies and tetramethyl isothiocyanate (TRITC)-labeled swine anti-rabbit immunoglobulin (DAKO) were used under fluorescence microscope. To further analyze whether cell death was induced by anandamide (non-selective agonist for CB1/CB2) via a receptor dependent mechanism, the viability of DU145 cells, which is known as androgen-insensitive prostate cancer cell, was measured using MTT assay. Results: CB1mRNA was found to be expressed in the all 3 human prostate tissues, however, CB1 protein was expressed in BPH and low grade malignant PC tissues, but not in high grade malignant PC tissues. CB1 as for cell lines, the expression of CB1 was low in malignant cell lines except for DU145. Anandamide elicited cell death, which was significantly inhibited by AM251 (selective antagonist for CB1), indicating that cell death induced by anandamide in DU145 cells was mediated by CB1. Anandamide time-dependently elicits up-regulation of CB1 in DU145 cells. Conclusions: CB1 may be an inhibitory regulator of androgen-insensitive human prostate cancer epithelial cell growth.

Activation of cannabinoid receptor CB2 regulates LPS-induced pro-inflammatory cytokine production and osteoclastogenic gene expression in human periodontal ligament cells

Background and Objective: It has been found that human periodontal ligament (hPDL) cells express cannabinoid receptor CB2. However, the functional importance of CB2 in hPDL cells exposed to bacterial endotoxins is not known. Here we investigate if the inflammation promoter lipopolysaccharide (LPS) affects CB2 expression and if activation of CB2 regulates LPS-induced pro-inflammatory cytokine production and osteoclastogenic gene expression in hPDL cells. Methods: The hPDL cells were obtained from extracted teeth of periodontally healthy subjects. CB2 expression in hPDL cells exposed to LPS was deter- mined by quantitative real-time PCR analysis. Then, the cells were incubated with or without CB2-specific agonist HU-308 before further stimulation with LPS. In some experiments, the cells were pre-treated with CB2-specific antagonist SR144528. The production of pro-inflammatory cytokines interleukin-1 beta (IL- 1β), interleukin-6 (IL-6) and tumor necrosis factoralpha (TNF-α) was assessed by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of osteoclastogenic genes osteoprotegerin (OPG) and receptor activator of NF-κB ligand (RANKL) was examined using quantitative real-time PCR analysis. Results: CB2 expression in hPDL cells was markedly enhanced by LPS. HU-308 significantly suppressed the production of IL-1β, IL-6 and TNF-α exposed to LPS, whereas SR144528 attenuated this effect. The OPG/RANKL ratio decreased when exposed to LPS, furthermore increased significantly with the addition of HU-308 and finally decreased markedly after pretreatment with SR144528. Conclusion: Our study demonstrated that activation of CB2 had anti-inflammatory and anti-resorptive effects on LPS-stimulated hPDL cells. These findings suggest that activation of CB2 might be an effective therapeutic strategy for the treatment of inflammation and alveolar bone resorption in periodontitis.

CB_1 Cannabinoid Receptor-Dependent and-Independent Inhibition of Depolarization-Induced Calcium Influx in Oligodendrocytes

Ca2+稳态平衡的调节在少突胶质细胞功能和存活中起重要作用。大麻素CB1和CB2受体在许多细胞中调节Ca2+水平和/或K+电流。本文利用培养的少突胶质细胞中,通过增高细胞外K+浓度(50 mM诱导膜去极化,研究大麻素复合物在此过程引发钙内流中的作用。CB2受体激动剂ACEA导致去极化诱导的少突胶质细胞胞浆的Ca2+瞬变表达浓度依赖性抑制,最大效应为(94±3)%,半效应浓度(EC50)为(1.3±0.03)μM。这种作用可被CB2/CB2激动剂CP55、940、内源性大麻素类AEA和2-AG所模拟,但是CB2受体选择性激动剂J WH133没有作用。CB2受体拮抗剂AM251(1μM)也可减少细胞外高K+诱导的Ca2+反应,但不能防止ACEA(3μM)诱发的抑制效应。然而,ACEA和AEA减少去极化诱导的Ca2+瞬变的能力在CB2受体敲除小鼠和经百日咳毒素预处理的少突胶质细胞中明显降低。内流性K+通道阻断剂BaCl2(300μM)和CsCl2(1 mM)降低电压诱导的Ca2+内流并部分阻断ACEA的抑制效应。本文表明,大麻素抑制少突胶质细胞中去极化诱导的Ca2+瞬变是通过包括PTX-敏感的Gi/o蛋白和阻断K+内流通道的CB2受体依赖性和非依赖性机制。

Activation of Cannabinoid Receptor 1 in GABAergic Neurons in the Rostral Anterior Insular Cortex Contributes to the Analgesia Following Common Peroneal Nerve Ligation

The rostral agranular insular cortex(RAIC)has been associated with pain modulation.Although the endogenous cannabinoid system(eCB)has been shown to regulate chronic pain,the roles of eCBs in the RAIC remain elusive under the neuropathic pain state.Neuropathic pain was induced in C57BL/6 mice by common peroneal nerve(CPN)ligation.The roles of the eCB were tested in the RAIC of ligated CPN C57BL/6J mice,glutamatergic,or GABAergic neuron cannabinoid receptor 1(CB1R)knockdown mice with the whole-cell patch-clamp and pain behavioral methods.The E/I ratio(amplitude ratio between mEPSCs and mIPSCs)was significantly increased in layer V pyramidal neurons of the RAIC in CPN-ligated mice.Depolarization-induced suppression of inhibition but not depolarization-induced suppression of excitation in RAIC layer V pyramidal neurons were significantly increased in CPN-ligated mice.The analgesic effect of ACEA(a CB1R agonist)was alleviated along with bilateral dorsolateral funiculus lesions,with the administration of AM251(a CB1R antagonist),and in CB1R knockdown mice in GABAergic neurons,but not glutamatergic neurons of the RAIC.Our results suggest that CB1R activation reinforces the function of the descending pain inhibitory pathway via reducing the inhibition of glutamatergic layer V neurons by GABAergic neurons in the RAIC to induce an analgesic effect in neuropathic pain.

Role of Cannabinoid CB1 Receptor in Object Recognition Memory Impairment in Chronically Rapid Eye Movement Sleep-deprived Rats

Objective We aimed to investigate whether antagonism of the cannabinoid CB1 receptor(CB1R)could affect novel object recognition(NOR)memory in chronically rapid eye movement sleep-deprived(RSD)rats.Methods The animals were examined for recognition memory following a 7-day chronic partial RSD paradigm using the multiple platform technique.The CB1R antagonist rimonabant(1 or 3 mg/kg,i.p.)was administered either at one hour prior to the sample phase for acquisition,or immediately after the sample phase for consolidation,or at one hour before the test phase for retrieval of NOR memory.For the reconsolidation task,rimonabant was administered immediately after the second sample phase.Results The RSD episode impaired acquisition,consolidation,and retrieval,but it did not affect the reconsolidation of NOR memory.Rimonabant administration did not affect acquisition,consolidation,and reconsolidation;however,it attenuated impairment of the retrieval of NOR memory induced by chronic RSD.Conclusions These findings,along with our previous report,would seem to suggest that RSD may affect different phases of recognition memory based on its duration.Importantly,it seems that the CB1R may,at least in part,be involved in the adverse effects of chronic RSD on the retrieval,but not in the acquisition,consolidation,and reconsolidation,of NOR memory.

CB 1 cannabinoid receptor participates in the vascular hyporeactivity resulting from hemorrhagic shock in rats

Background Vascular hyporeactivity, which occurs in the terminal stage of hemorrhagic shock, is believed to be critical for treating hemorrhagic shock. The present study was designed to examine whether the CB1 cannabinoid receptor （CB1 R） was involved in the development of vascular hyporeactivity in rats suffering from hemorrhagic shock. Methods Sixteen animals were randomly divided into two groups （n=8 in each group）： sham-operated （Sham） and hemorrhagic shock （HS） groups. Hemorrhagic shock was induced by bleeding. The mean arterial pressure （MAP） was reduced to and stabilized at （25±5） mmHg for 2 hours. The vascular reactivity was determined by the response of MAP to norepinephrine （NE）. In later experiments another twelve animals were used in which the changes of CB1R mRNA and protein in aorta and superior mesenteric artery （SMA） were analyzed by RT-PCR and Western blotting. In addition, we investigated the effects of a CB1R antagonist on the vascular hyporeactivity and survival rates in rats with hemorrhagic shock. Survival rates were analyzed by the Fisher＇s exact probability test. The MAP response was analyzed by one-way analysis of variance （ANOVA）. Results Vascular hyporeactivity developed in all animals suffering from hemorrhagic shock. The expression of CBIR mRNA and protein in aorta and 2-3 branches of the SMA were significantly increased in the HS group after the development of vascular hyporeactivity when compared to those in Sham group. When SR141716A or AM251 was administered, the MAP response to NE was （41.75±4.08） mmHg or （44.78±1.80） mmHg respectively, which was higher than that in saline groups with （4.31±0.36） mmHg （P 〈0.01）. We also showed an increased 4-hour survival rate in the SR141716A or AM251-treated group with 20% or 30%, but with a statistically significant difference present between the AM251-treated and saline groups （P 〈0.05）. Conclusions CBIR is involved in vascular hyporeactivity resulting from hemorrhagic shock in rats, and CB1R antagonist may be useful in treating patients with traumatic, hemorrhagic shock who need field-rescue or initial treatment.

Cannabinoid receptor-2 selective antagonist negatively regulates receptor activator of nuclear factor kappa B ligand mediated osteoclastogenesis

Background The cannabinoid receptor-2 （CB2） is important for bone remodeling. In this study, we investigated the effects of CB2 selective antagonist （AM630） on receptor activator of nuclear factor kappa B （RANK） ligand （RANKL）induced osteoclast differentiation and the underlying signaling pathway using a monocyte-macrophage cell line-RAW264.7.Methods RAW264.7 was cultured with RANKL for 6 days and then treated with AM630 for 24 hours. Mature osteoclasts were measured by tartrate-resistant acid phosphatase （TRAP） staining using a commercial kit. Total ribonucleic acid （RNA）was isolated and real-time reverse transcriptase-polymerase chain reaction （RT-PCR） was done to examine the expression of RANK, cathepsin K （CPK） and nuclear factor kappa B （NF-κB）. The extracellular signal-regulated kinase （ERK）,phosphorylation of ERK （P-ERK） and NF-κB production were tested by Western blotting. The effect of AM630 on RAW264.7 viability was determined using the 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazoliumbromide （MTT） assay.Results AM630 did not affect the viability of RAW264.7. However, this CB2 selective antagonist markedly inhibited osteoclast formation and the inhibition rate was dose-dependent. The dose of 〉100 nmol/L could reduce TRAP positive cells to the levels that were significantly lower than the control. AM630 suppressed the expression of genes associated with osteoclast differentiation and activation, such as RANK and CPK. An analysis of a signaling pathway showed that AM630 inhibited the RANKL-induced activation of ERK, but not NF-κB.Conclusion AM630 could inhibit the osteoclastogenesis from RAW264.7 induced with RANKL.

Cannabinoid CB_(2) receptors and spinal microglia are implicated in tingenone-mediated antinociception in mice

Objective:To investigate the antinociceptive effect of tingenone on inflammatory pain,as well as and the involvement of the cannabinoid receptors type 2(CB2)and spinal microglia in this process.Methods:Male Swiss mice were subjected to inflammatory pain induced by intraplantar injection of carrageenan.The nociceptive threshold was measured by von Frey filaments test.Tingenone was administered orally 60 min before carrageenan injection.To evaluate the involvement of CB2 receptor,endocannabinoids,and microglia,AM630(a CB2 receptor antagonist),MAFP(an inhibitor of an enzyme that hydrolyses endocannabinoids),and minocycline(a microglial inhibitor)were given intrathecally 20 min before tingenone administration.In addition,an immunofluorescence assay was used to evaluate CB2 receptor and CD11 B(a microglial marker)expression in the spinal cord dorsal horn.Results:Tingenone significantly reduced carrageenan-induced hyperalgesia,which was reversed by pretreatment with AM630.MAFP and minocycline potentiated and prolonged the tingenoneinduced antinociception.CD11 B expression was increased in the spinal cord dorsal horn of mice with inflammatory pain pretreated with tingenone,which was reduced by AM630,MAFP,and minocycline.Conclusions:CB2 receptors and endocannabinoids participate in the tingenone-induced antinociception which may involve the inhibition of microglia at spinal level.

Endocannabinoid 2-arachidonoylglycerol protects inflammatory insults from sulfur dioxide inhalation via cannabinoid receptors in the brain

Sulfur dioxide（SO_2） pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction.However,there are currently no effective medications targeting the harmful outcomes from chemical inhalation.Endocannabinoids（eCBs） are involved in neuronal protection against inflammation-induced neuronal injury.The 2-arachidonoylglycerol（2-AG）,the most abundant eCBs and a full agonist for cannabinoid receptors（CB1 and CB2）,is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction.Here,we indicated that endogenous 2-AG protected against neuroinflammation in response to SO_2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines,including tumor necrosis factor alpha（TNF-a）,interleukin（IL）-1β,and inducible nitric oxide synthase（iNOS）.In addition,endogenous 2-AG prevented cerebral vasculature dysfunction following SO_2 inhalation by inhibiting endothelin 1（ET-1）,vascular cell adhesion molecule-1（VCAM-1） and intercellular adhesion molecule 1（ICAM-1） expression,elevating endothelial nitric oxide synthase（eNOS） level,and restoring the imbalance between thromboxane A2（TXA2） and prostaglandin 12（PGI2）.In addition,the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors.Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO_2 inhalation.

Novel Method for Synthesis of Diarylpyrazole Derivatives as Cannabinoid CB_1 Receptor Antagonists

A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, which involved initial condensation of the sodium salt of compound 12 with diazonium compounds, and further cyclization by heating at reflux in acetic acid. Eight diarylpyrazole derivatives and nine new synthesized compounds were characterized by 1H NMR, IR, MS, and elemental analysis. The reaction conditions were mild and the overall yields of the target compounds ranged from 26% to 44%.

大麻素1型受体参与疼痛调节机制的研究进展

大麻素1型受体(CB1R)是近年来研究较为广泛的内源性大麻素受体之一,在中枢和外周神经系统均有表达。CB1R位于突触前膜,通过逆行抑制性突触传递调节神经递质的释放,是治疗疼痛的有效靶点。激活CB1R对伤害性、病理性和炎性疼痛均具有镇痛效应,拮抗CB1R可引起疼痛敏化。本文通过对CB1R结构功能、信号转导、镇痛机制方面进行综述,为进一步了解疼痛的病理生理学机制及探索更优疼痛治疗方法提供参考。

大麻素2型受体在加速正畸牙移动中的作用

目的 探讨大麻素2型受体(CB2)在正畸过程中对小鼠正畸牙移动(OTM)速率和压力侧牙周组织改建的作用。方法 筛选CB2^(-/-)和同窝WT型各30只雄性小鼠,6周龄时建立牙齿移动模型,建模时间分别为0、3、7、14、21 d(n=6)后取材,经体视显微镜测量牙移动距离;HE染色观察根压力区牙周组织变化;TRAP染色统计根压力区破骨细胞数量;免疫组织化学染色观察根压力区基质金属蛋白酶-9(MMP-9)阳性单核细胞和多核细胞的数量变化。结果 正畸牙移动距离测量结果显示,在21 d内,随着时间延长,牙齿移动距离逐渐增加,且3、7、14、21 d时CB2^(-/-)组牙齿移动距离均较WT小鼠增加;HE染色显示OTM第14天时CB2^(-/-)小鼠压力区牙周膜间隙宽度大于WT小鼠(P<0.000 1);TRAP染色显示14 d时,在第一磨牙远中根压力区硬骨板处,CB2^(-/-)小鼠的破骨细胞数量大于WT小鼠(P<0.001);MMP-9免疫组织化学染色显示OTM 14 d时,在压力区牙周膜区域,CB2^(-/-)小鼠的MMP-9(+)单核细胞和MMP-9(+)多核细胞数量均大于WT小鼠(P<0.05)。结论 CB2可加速正畸力作用下牙齿移动速率。CB2缺失加速正畸牙移动是通过加速牙移动过程中压力侧骨吸收实现的。

新精神活性物质药理作用研究进展

新精神活性物质是近几年开始流行的新型滥用物质,比起传统毒品来说其种类更丰富、化学结构更复杂。新精神活性物质按照药理学作用可分为七大类,除了效果未知的类别,其余的兴奋剂类、合成大麻素受体激动剂类、经典致幻剂类、合成阿片类、身心分离剂类和镇静催眠类都可通过与特异性受体结合从而发挥作用。该文对新精神活性物质的药理作用及其机制进行综述,以期为新精神活性物质的研究提供参考。

Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy

Diabetic complications,chiefly seen in long-term situations,are persistently deleterious to a large extent,requiring multi-factorial risk reduction strategies beyond glycemic control.Diabetic cardiomyopathy is one of the most common deleterious diabetic complications,being the leading cause of mortality among diabetic patients.The mechanisms of diabetic cardiomyopathy are multi-factorial,involving increased oxidative stress,accumulation of advanced glycation end products(AGEs),activation of various pro-inflammatory and cell death signaling pathways,and changes in the composition of extracellular matrix with enhanced cardiac fibrosis.The novel lipid signaling system,the endocannabinoid system,has been implicated in the pathogenesis of diabetes and its complications through its two main receptors:Cannabinoid receptor type 1 and cannabinoid receptor type 2,alongside other components.However,the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated.This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy.These mechanisms include oxidative/nitrative stress,inflammation,accumulation of AGEs,cardiac remodeling,and autophagy.A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.

大麻素受体1在阻塞性睡眠呼吸暂停低通气综合征炎症反应中的神经免疫调节作用研究进展

阻塞性睡眠呼吸暂停低通气综合征(OSA)是一种全身性炎症性疾病,OSA病人睡眠结构的紊乱与下丘脑-垂体-肾上腺(HPA)轴的失调相互作用,持续激活HPA轴可诱导免疫细胞的糖皮质激素抵抗,使免疫系统反应转向促炎,导致并发症的加重,其特征性的慢性间歇低氧(CIH)也可通过多种途径激活糖皮质激素抑制核因子-κB(NF-κB)和相关炎症因子的表达,导致氧化应激、炎症、内皮功能障碍。内源性大麻素系统(ECS)在HPA轴活动以及对应激的神经内分泌反应中发挥主要调节作用,为机体提供重要的免疫防御。CIH可引起大麻素受体1(CB1R)表达增加,而CB1R拮抗剂可发挥抗炎作用,减轻CIH引起的器官损伤。CB1R拮抗剂已被证明可作为免疫抑制剂和抗炎剂,通过下调NF-κB信号发挥有益作用。现就CB1R拮抗剂调节OSA炎症反应潜在机制的研究进展进行综述。