Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchyma...Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241(EVs-AM1241)to protect against neurodegenerative progression and neuronal function in AD model mice.According to the results,EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241.The Morris water maze(MWM)and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved.In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning.Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloidβ(Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241.Moreover,EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton,indicating that they enhanced neuronal regeneration.RNA sequencing revealed that EVs-AM1241 facilitated Aβphagocytosis,promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway.Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in modelmice,indicating that they are very promising particles for treating AD.展开更多
In recent times there has been an intensification of interest in the pathological role of neuroinflammation in neurodegenerative disease. Neuroprotective strategies to slow, halt or reverse neuro- degeneration have no...In recent times there has been an intensification of interest in the pathological role of neuroinflammation in neurodegenerative disease. Neuroprotective strategies to slow, halt or reverse neuro- degeneration have not proven fruitful clinically, and the notion of a multi-hit hypothesis in the progression of neurodegenerative disease has steered focus towards other contributory pathological factors, particularly neuroinflammation. Neuroinflammation is believed to sustain the neurodegenerative pathology, forming a cy- clical and self-sustaining pathological process, with dying neurons activating microglia, which, once activated, can release several fac- tors that kill further neurons （reviewed in Blandini, 2013）.展开更多
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...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.展开更多
This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique...This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3–300 μmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 μmol/L), a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01–1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners. The concentra-tion-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC50 values of two curves were very close (17.5±4.5) mmol/L vs. (15.2±4.5) mmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HT3 by (48.65±4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I5-HT3 by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I5-HT3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor. WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner. The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2, but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.展开更多
目的研究大麻素Ⅱ型(CB2)受体激活对1-甲基-4-苯基吡啶离子(MPP +)致SH-SY5Y细胞损伤的保护作用。方法 根据药物处理的不同将细胞分为正常对照组(C组)、MPP +组(M组)、JWH-133/MPP +组(J+M组)以及JWH-133/AM630/MPP +组(J+A+M组)。用免...目的研究大麻素Ⅱ型(CB2)受体激活对1-甲基-4-苯基吡啶离子(MPP +)致SH-SY5Y细胞损伤的保护作用。方法 根据药物处理的不同将细胞分为正常对照组(C组)、MPP +组(M组)、JWH-133/MPP +组(J+M组)以及JWH-133/AM630/MPP +组(J+A+M组)。用免疫印迹法检测各组细胞CB2受体和酪氨酸羟化酶(TH)蛋白的表达,用流式细胞仪检测细胞线粒体膜电位(ΔΨm)的变化。结果 与C组相比,M组的CB2受体蛋白表达下降( P <0.01);经JWH-133预处理后,CB2受体蛋白表达高于M组( P <0.01),此作用可被AM630所阻断;与C组相比,M组的TH表达降低( P <0.05),经JWH-133预处理后,TH表达高于M组( P <0.05),AM630预处理可抑制此作用;与C组相比,M组细胞的ΔΨm明显下降( P <0.01),经JWH-133预处理后,细胞ΔΨm下降幅度变小( P <0.01),此作用可被AM630所阻断。结论 CB2受体激活可以抑制MPP +对SH-SY5Y细胞的损伤作用。展开更多
背景:大麻素受体通过与配体结合,调控牙周炎的炎症和骨量,促进牙周组织的愈合,在临床上牙周炎的预防和治疗方面具有重要意义。目的:综述大麻素受体与牙周炎的关系,主要为大麻素Ⅰ型(CB1)受体、大麻素Ⅱ型(CB2)受体与炎症和牙槽骨骨改建...背景:大麻素受体通过与配体结合,调控牙周炎的炎症和骨量,促进牙周组织的愈合,在临床上牙周炎的预防和治疗方面具有重要意义。目的:综述大麻素受体与牙周炎的关系,主要为大麻素Ⅰ型(CB1)受体、大麻素Ⅱ型(CB2)受体与炎症和牙槽骨骨改建的关系,以及涉及的常见细胞信号传导通路,为牙周炎预防和治疗及其在临床其他领域的应用提供思路。方法:检索PubMed、万方数据库、CNKI中国期刊全文数据库1985年7月至2022年7月收录的相关文献。英文检索词为“cannabinoids receptor,CB1 receptor and periodontitis,CB2 receptor and periodontitis,CB1 receptors and bone remodeling,CB2 receptors and bone remodeling,CB1 receptors and signaling pathways,CB2 receptors and signaling pathways”,中文检索词为“大麻素受体,CB1受体和牙周炎,CB2受体和牙周炎,CB1受体和骨改建,CB2受体和骨改建,CB1受体和信号通路、CB2受体和信号通路”,最终纳入107篇文献进行归纳总结。结果与结论:①内源性大麻素系统包含多种受体,其中最具有代表性的为CB1和CB2受体,均属于G蛋白偶联超家族成员;二者在牙周组织中均存在表达;②在天然配体或人工合成激动剂的作用下,大麻素受体可通过不同的代谢通路在体内外产生特定的生理效应,从而调控牙周炎局部的炎症和骨细胞的生成和分化,最终影响炎症和骨量;③进一步研究大麻素受体与牙周炎炎症和牙槽骨骨形成、骨吸收的关系,以及涉及到的常见信号通路——丝裂原活化蛋白激酶(MAPK)信号通路、NF-κB信号通路,为临床上牙周炎的预防和治疗提供新的思路成为目前研究的重点。展开更多
基金supported by the National Key Research and Development Program (grant no. 2021YFA1101301)the National Natural Science Foundation of China (grant no. 82225027, 82271419, 81820108013, 62127810, 81901902)+1 种基金Shanghai Rising-Star Program (grant no. 22QA1408200)the Fundamental Research Funds for the Central Universities(no. 22120220555, no. 22120230292, no. 22120230138)
文摘Alzheimer’s disease(AD)is a typical neurodegenerative disease that leads to irreversible neuronal degeneration,and effective treatment remains elusive due to the unclear mechanism.We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241(EVs-AM1241)to protect against neurodegenerative progression and neuronal function in AD model mice.According to the results,EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241.The Morris water maze(MWM)and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved.In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning.Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloidβ(Aβ)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241.Moreover,EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton,indicating that they enhanced neuronal regeneration.RNA sequencing revealed that EVs-AM1241 facilitated Aβphagocytosis,promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway.Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in modelmice,indicating that they are very promising particles for treating AD.
基金supported by the Irish Health Research Board(HRA_POR/2012/12)
文摘In recent times there has been an intensification of interest in the pathological role of neuroinflammation in neurodegenerative disease. Neuroprotective strategies to slow, halt or reverse neuro- degeneration have not proven fruitful clinically, and the notion of a multi-hit hypothesis in the progression of neurodegenerative disease has steered focus towards other contributory pathological factors, particularly neuroinflammation. Neuroinflammation is believed to sustain the neurodegenerative pathology, forming a cy- clical and self-sustaining pathological process, with dying neurons activating microglia, which, once activated, can release several fac- tors that kill further neurons （reviewed in Blandini, 2013）.
文摘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.
基金supported by National Natural Science Foundation of China(No.30271500)Science and Tech-nology Research Project Fund from the Department of Edu-cation of Hubei Province of China(No.B20115101)
文摘This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3–300 μmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 μmol/L), a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01–1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners. The concentra-tion-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC50 values of two curves were very close (17.5±4.5) mmol/L vs. (15.2±4.5) mmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HT3 by (48.65±4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I5-HT3 by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I5-HT3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor. WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner. The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2, but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.
文摘目的研究大麻素Ⅱ型(CB2)受体激活对1-甲基-4-苯基吡啶离子(MPP +)致SH-SY5Y细胞损伤的保护作用。方法 根据药物处理的不同将细胞分为正常对照组(C组)、MPP +组(M组)、JWH-133/MPP +组(J+M组)以及JWH-133/AM630/MPP +组(J+A+M组)。用免疫印迹法检测各组细胞CB2受体和酪氨酸羟化酶(TH)蛋白的表达,用流式细胞仪检测细胞线粒体膜电位(ΔΨm)的变化。结果 与C组相比,M组的CB2受体蛋白表达下降( P <0.01);经JWH-133预处理后,CB2受体蛋白表达高于M组( P <0.01),此作用可被AM630所阻断;与C组相比,M组的TH表达降低( P <0.05),经JWH-133预处理后,TH表达高于M组( P <0.05),AM630预处理可抑制此作用;与C组相比,M组细胞的ΔΨm明显下降( P <0.01),经JWH-133预处理后,细胞ΔΨm下降幅度变小( P <0.01),此作用可被AM630所阻断。结论 CB2受体激活可以抑制MPP +对SH-SY5Y细胞的损伤作用。
文摘背景:大麻素受体通过与配体结合,调控牙周炎的炎症和骨量,促进牙周组织的愈合,在临床上牙周炎的预防和治疗方面具有重要意义。目的:综述大麻素受体与牙周炎的关系,主要为大麻素Ⅰ型(CB1)受体、大麻素Ⅱ型(CB2)受体与炎症和牙槽骨骨改建的关系,以及涉及的常见细胞信号传导通路,为牙周炎预防和治疗及其在临床其他领域的应用提供思路。方法:检索PubMed、万方数据库、CNKI中国期刊全文数据库1985年7月至2022年7月收录的相关文献。英文检索词为“cannabinoids receptor,CB1 receptor and periodontitis,CB2 receptor and periodontitis,CB1 receptors and bone remodeling,CB2 receptors and bone remodeling,CB1 receptors and signaling pathways,CB2 receptors and signaling pathways”,中文检索词为“大麻素受体,CB1受体和牙周炎,CB2受体和牙周炎,CB1受体和骨改建,CB2受体和骨改建,CB1受体和信号通路、CB2受体和信号通路”,最终纳入107篇文献进行归纳总结。结果与结论:①内源性大麻素系统包含多种受体,其中最具有代表性的为CB1和CB2受体,均属于G蛋白偶联超家族成员;二者在牙周组织中均存在表达;②在天然配体或人工合成激动剂的作用下,大麻素受体可通过不同的代谢通路在体内外产生特定的生理效应,从而调控牙周炎局部的炎症和骨细胞的生成和分化,最终影响炎症和骨量;③进一步研究大麻素受体与牙周炎炎症和牙槽骨骨形成、骨吸收的关系,以及涉及到的常见信号通路——丝裂原活化蛋白激酶(MAPK)信号通路、NF-κB信号通路,为临床上牙周炎的预防和治疗提供新的思路成为目前研究的重点。
