Cannabinoids and endocannabinoids as therapeutics for nervous system disorders:preclinical models and clinical studies

Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body.They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.Some of these include central nervous system(CNS)diseases and dysfunctions such as forms of epilepsy,multiple sclerosis,Parkinson’s disease,pain and neuropsychiatric disorders.In addition,the endogenously produced cannabinoid lipids,endocannabinoids,are critical for normal CNS function,and if controlled or modified,may represent an additional therapeutic avenue for CNS diseases.This review discusses in vitro cellular,ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies.In addition,the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.

Maternal supplementation with n-3 fatty acids affects placental lipid metabolism, inflammation, oxidative stress, the endocannabinoid system, and the neonate cytokine concentrations in dairy cows

Background The placenta plays a crucial role in supporting and influencing fetal development.We compared the effects of prepartum supplementation with omega-3(n-3)fatty acid(FA)sources,flaxseed oil(FLX)and fish oil(FO),on the expression of genes and proteins related to lipid metabolism,inflammation,oxidative stress,and the endocannabinoid system(ECS)in the expelled placenta,as well as on FA profile and inflammatory response of neonates.Late-pregnant Holstein dairy cows were supplemented with saturated fat(CTL),FLX,or FO.Placental cotyledons(n=5)were collected immediately after expulsion,and extracted RNA and proteins were analyzed by RTPCR and proteomic analysis.Neonatal blood was assessed for FA composition and concentrations of inflammatory markers.Results FO increased the gene expression of fatty acid binding protein 4(FABP4),interleukin 10(IL-10),catalase(CAT),cannabinoid receptor 1(CNR1),and cannabinoid receptor 2(CNR2)compared with CTL placenta.Gene expression of ECS-enzyme FA-amide hydrolase(FAAH)was lower in FLX and FO than in CTL.Proteomic analysis identified 3,974 proteins;of these,51–59 were differentially abundant between treatments(P≤0.05,|fold change|≥1.5).Top canonical pathways enriched in FLX vs.CTL and in FO vs.CTL were triglyceride metabolism and inflammatory processes.Both n-3 FA increased the placental abundance of FA binding proteins(FABPs)3 and 7.The abundance of CNR1 cannabinoid-receptor-interacting-protein-1(CNRIP1)was reduced in FO vs.FLX.In silico modeling affirmed that bovine FABPs bind to endocannabinoids.The FLX increased the abundance of inflammatory CD44-antigen and secreted-phosphoprotein-1,whereas prostaglandin-endoperoxide synthase 2 was decreased in FO vs.CTL placenta.Maternal FO enriched neonatal plasma with n-3 FAs,and both FLX and FO reduced interleukin-6 concentrations compared with CTL.Conclusion Maternal n-3 FA from FLX and FO differentially affected the bovine placenta;both enhanced lipid metabolism and modulated oxidative stress,however,FO increased some transcriptional ECS components,possibly related to the increased FABPs.Maternal FO induced a unique balance of pro-and anti-inflammatory components in the placenta.Taken together,different sources of n-3 FA during late pregnancy enhanced placental immune and metabolic processes,which may affect the neonatal immune system.

A proposed modulatory role of the endocannabinoid system on adipose tissue metabolism and appetite in periparturient dairy cows

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.

Effects of omega-3 supplementation on components of the endocannabinoid system and metabolic and inflammatory responses in adipose and liver of peripartum dairy cows

Background:Dietary supplementation of omega-3 fatty acids can reduce the activation of the endocannabinoid system(ECS)by decreasing the availability of arachidonic acid,thus lowering endocannabinoids(e CBs)levels.The ECS is a modulator of energy metabolism,stress response and inflammation in mammals,yet there is little information on the roles of the ECS in transition dairy cows.During the periparturient period,the adipose tissue and liver are the main metabolic organs that participate in the adaptations of dairy cows to onset of lactation;however,exceeded adipose tissue lipolysis and accumulation of lipids in the liver have adverse effects on cows'physiology.Here we aimed to examine whether omega-3 supplementation during the transition period will modulate ECS activation and affect metabolic and inflammatory indices in postpartum dairy cows,by supplementing twenty-eight transition Holstein dairy cows with either saturated fat(CTL)or encapsulated flaxseed oil(FLX).Components of the ECS,metabolic and inflammatory markers were measured in blood,liver,and subcutaneous adipose tissue.Results:FLX supplementation reduced feed intake by 8.1%(P<0.01)and reduced plasma levels of arachidonic acid(by 44.2%;P=0.02)and anandamide(by 49.7%;P=0.03)postpartum compared to CTL.The m RNA transcription levels of the cannabinoid receptor 1(CNR1/CB1)tended to be lower(2.5 folds)in white blood cells of FLX than in CTL(P=0.10),and protein abundance of ECS enzyme monoacylglycerol lipase was higher in peripheral blood mononuclear cells of FLX than in CTL(P=0.04).In adipose tissue,palmitoylethanolamide levels were lower in FLX than in CTL(by 61.5%;P=0.02),relative m RNA transcription of lipogenic genes were higher,and the protein abundance of cannabinoid receptor 2(P=0.08)and monoacylglycerol lipase(P=0.10)tended to be higher in FLX compared to CTL.Hepatic 2-arachidonoylglycerol tended to be higher(by 73.1%;P=0.07),and interlukin-6 m RNA transcription level was 1.5 folds lower in liver of FLX than in CTL(P=0.03).Conclusions:Nutritional supplementation of omega-3 fatty acids seems to partly modulate ECS activation,which could be related to lower feed intake.The altered ECS components in blood,adipose tissue and liver are associated with moderate modulations in lipid metabolism in the adipose and inflammation in liver of peripartum dairy cows.

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.

Function of the Endocannabinoid System in Neurodegenerative Diseases and Cancers

Neurodegenerative diseases are characterized by progressive degeneration and/or death of neuronal cells and results in a wide array of cognitive impairments and other serious neurological defects. The signaling pathways and definite cause underlying the development of neurodegenerative nerve diseases have not been well defined. There is evidence of mechanisms within the endocannabinoid system that may suggest important pathways involved the progression of neurodegenerative diseases as well as some cancers. The endocannabinoid system is an endogenous ubiquitous neuromodulatory system that plays a critical in the development of the central nervous system (CNS), synaptic plasticity, as well as other primary neuronal functions. The recent identification of various cannabinoid receptors and their endogenous lipid ligands has generated an interest and significant increase in research of the endocannabinoid system and its role in human health and diseases. The Endocannabinoid system possesses essential endogenous receptors—cannabinoid receptors type 1 (CB1R) and type 2 (CB2R)—which are involved in mechanisms that contribute to the progression of neurodegenerative diseases and some cancers. In this review, we discuss the role of the endocannabinoid system in various neurodegenerative diseases as well as some cancers, and its promise as a targeted pharmacological therapy for patients of neurodegenerative diseases.

Endocannabinoid system: A newer molecular target for the treatment of alcohol-related behaviors

The cannabinoid （CB） receptors, endocannabinoids （eCB） and their synthesizing and catabolizing enzymes and the proteins involved in their transport, constitute what is now recognized as the eCB system. The eCBs are a class of lipids that have been identifed as retro-grade messengers and produce their effects via presyn-aptic CB receptors. The major function of the eCBs has been suggested to be that of modulating the release of several neurotransmitters implicated in a number of biological functions that include reward and reinforce-ment. There is now significant evidence to suggest that the eCB system plays an important role in the development of alcohol tolerance, dependence and relapse. Recent studies suggest that the pharmacological manipulation of the eCB system has the potential not only to block the direct reinforcing properties of alcohol but also alleviate behavioral abnormalities associated with relapse. There is also accumulating evidence that points to the possible utility of the eCB system targeted drugs in the treatment of alcoholism-related behavioral disorders. The agents that block CB1 receptor function or inhibit the synthesis of eCBs are attractive candidate drugs that need to be explored. Further understanding of the role of the eCB system in molecular mechanism/s that underlies alcoholism-related behaviors should lead to a better treatment of this devastating disorder.

基于ECS-700系统宽融合多支持智能控制应用研究

通过分析ECS-700系统优势,得出ECS-700系统是能满足监控与管理、提高仪表控制系统可靠性,保障生产工艺安全的大型高端集散控制系统;针对兰州某公司水性科技产业园项目水性树脂标段中的电气自控工程实际情况,提出基于ECS-700系统的宽融合多支持智能控制应用方案,设计预处理车间和关键设备智能控制流程。结果表明该应用方案满足了生产和实际工程要求,系统安全可靠,极大地提高了维修效率和控制处理效率。

中国工程建设标准化协会标准《智能化碳纤雨水收集模块系统技术规程》T/CECS 1272-2023的勘误

中国工程建设标准化协会标准《智能化碳纤雨水收集模块系统技术规程》T/CECS 1272-2023中“表3.2.2碳纤雨水收集模块芯材技术参数表”更正如下。

基于ECS的内河船舶引航操作适任实操评估方法研究

重庆内河船员适任评估示范中心建成以后,内河船员实操考试将由现有的实船评估向模拟器评估逐步转变。通过分析重庆海事局当前内河船员实操考试的现状及存在的问题,结合现实问题,提出了利用电子海图系统(ECS)开展内河船舶引航操作项目实操评估的可行性方案。

元素俘获谱测井(ECS)结合QAPF法识别火成岩岩性

应用元素俘获谱测井(ECS)得到的元素含量,再结合火成岩定量矿物成分分类法(CIPW)标准矿物法计算得到中酸性火成岩的标准矿物体积含量,与矿物密度加权得到骨架密度和岩心颗粒密度对比,现场应用证明计算得到的矿物含量可靠。应用ECS数据进行岩性判别的TAS图版法和常规曲线图版岩性法,结合火成岩定量矿物成分分类法按标准矿物进行岩性划分,得到综合岩性与薄片对比效果较好。该方法为测井岩性评价提供了岩性识别的新手段。

HPS和ECS在危重病例抢救技能培训中的应用

危重病例抢救是医学临床技能重要的组成部分,也是临床医生必须掌握的重要技能,危重病例抢救技能是各种基本临床技能的综合,也是培养医学生科学诊断思维和良好心理素质的重要手段。为了探讨临床危重病例抢救技能培训的新方法。将HPS和ECS应用在危重病例抢救技能培训中,重现了危重症抢救现场,缓解了临床教学资源不足的矛盾,提高了医学生的临床技能、沟通技巧和综合诊断技能。HPS和ECS应用于危重病例抢救技能培训顺应现代医学教育的趋势,必将成为培养医学创新型人才所必不可少的手段。

角色体验法融入戴明循环在ECS模拟教学中的应用

为探索角色体验法融人戴明循环在高级综合模拟人(emergency care simulator,ECS)模拟教学的应用及其效果,在武汉科技大学医学院10级225名医学生临床实习前的技能强化训练中,使用ECS综合模拟人通过角色体验案例设计教学进行模拟培训和试卷问答,应用戴明循环发现问题并解决。经过第2个、第3个戴明循环后学生的病史采集、体格检查、初步诊断及鉴别等临床技能明显提高(P<0.05),94%的学生愿意接收这种新形式的临床培训,并对这样的教学形式表示满意。角色体验法融入戴明循环应用于ECS实践教学可激发学生学习兴趣,提高其技能操作水平,从而为以后的临床工作打下坚实的基础。

ECS模拟教学在外科休克临床教学中的应用

探讨智能型高级综合模拟人(ECS)模拟教学在外科休克临床教学中的教学方式和效果。将56名国际学院临床医学本科学生随机分为2组,一组采用ECS模拟教学,一组用传统教学法,学习结束综合评价两组学生的学习成绩和效果。结果显示ECS组的综合考试成绩、临床理论知识及临床技能明显优于传统教学组。

运用ECS评价护理本科生临床综合能力指标体系的研究

目的:探讨以团队合作为基础、运用ECS设置临床模拟病例(emergency care simulator生理驱动高仿真模拟人)对护理本科生临床综合能力进行考核的新模式下,构建出一套客观、全面的护理本科生临床综合能力评价指标体系。方法:将护理程序和护理管理学有效结合为理论框架,形成初步专家咨询问卷,选取山西省内两所高等医学院校及五所三级甲等医院具有副高级职称以上的护理教育、护理管理、临床带教、医学教育等相关领域的资深、权威专家运用德尔菲法进行3轮专家咨询,对特殊问题进行深度访谈。参与三轮专家咨询的人数为31名、30名、30名。结果:构建出由专业综合知识、护理综合技能操作质量、人文素质、终末质量4项一级指标、14项二级指标、26项三级指标构成的临床综合能力评价指标,并用统计学方法确定了各项指标的权重。结论:研究构建出的指标体系对今后国内规范、统一ECS评价护理本科临床综合能力的指标构建有很好的借鉴意义。

应用ECS测井资料丰富岩性识别图版信息

在火山岩储层研究中,岩性识别显得越来越重要。利用常规测井曲线识别岩性简单有效的方法是交会图版法。以松辽盆地北部深层火山岩为对象,利用岩心薄片和对应的ECS测井资料双向定名绘制了该区的岩性识别图版。薄片毕竟是有限的,利用其他井的ECS资料对未有薄片样点的图版区域进行划分,丰富了图版信息。

斜视滑动聚束SAR成像的ECS算法

建立典型滑动聚束SAR(合成孔径雷达)斜视成像模型.在考虑不同方位目标回波信号多普勒空变性的情况下,详细分析两步算法方位滤波恢复滑动聚束SAR方位欠采样信号的原理.对结合两步算法和传统CS算法的ECS算法进行了在斜视成像模型下的修正.针对滑动聚束工作模式的特点,讨论其中关键处理参数的选择问题,给出算法的处理流程.最后,用计算机仿真实验验证了方法的有效性.

基于ECS+FIR的星载SAR快视成像算法

常用的快视成像算法 (SPECAN算法、RD +FIR算法等 )无法满足大距离徙动条件下星载SAR成像处理的精度要求 .针对以上问题 ,本文提出了一种基于等效斜视模型的ECS +FIR滤波的快视成像算法 .该算法的运算量不随距离徙动量的增大而增加 ,适合于大距离徙动量的星载SAR数据快视成像 .该算法在距离向采用FIR滤波来降低信号采样率 ,在方位向利用SCANSAR原理采用部分孔径数据进行成像 ,从而有效地减小了成像处理的运算量 .论文详细地给出了ECS +FIR快视算法的原理和流程 ,并将该算法同SPECAN算法、RD +FIR算法进行了比较 .通过大量计算机仿真和对处理结果的对比分析 。