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Cannabidiol prevents depressive-like behaviors through the modulation of neural stem cell differentiation

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Frontiers of Medicine 2022年第2期16卷 227-239页

作者： Ming Hou Suji Wang Dandan Yu Xinyi Lu Xiansen Zhao Zhangpeng Chen Chao Yan State Key Laboratory of Pharmaceutical Biotechnology School of Life SciencesNanjing UniversityNanjing 210023China Institute of Artificial Intelligence Biomedicine Nanjing UniversityNanjing 210023China Chemistry and Biomedicine Innovation Center Nanjing UniversityNanjing 210023China Engineering Research Center of Protein and Peptide Medicine Ministry of EducationNanjing 210023China

Chronic stress impairs radial neural stem cell(rNSC)differentiation and adult hippocampal neurogenesis(AHN),whereas promoting AHN can increase stress resilience against depression.Therefore,investigating the mechanism of neural differentiation and AHN is of great importance for developing antidepressant drugs.The nonpsychoactive phytocannabinoid Cannabidiol(CBD)has been shown to be effective against depression.However,whether CBD can modulate rNSC differentiation and hippocampal neurogenesis is unknown.Here,by using the chronic restraint stress(CRS)mouse model,we showed that hippocampal rNSCs mostly differentiated into astrocytes under stress conditions.Moreover,transcriptome analysis revealed that the FoxO signaling pathway was involved in the regulation of this process.The administration of CBD rescued depressive-like symptoms in CRS mice and prevented rNSCs overactivation and differentiation into astrocyte,which was partly mediated by the modulation of the FoxO signaling pathway.These results revealed a previously unknown neural mechanism for neural differentiation and AHN in depression and provided mechanistic insights into the antidepressive effects of CBD.

关键词： Cannabidiol depression radial neural stem cells neurogenesis

Intranasal temperature-sensitive hydrogels of Cannabidiol inclusion complex for the treatment of post-traumatic stress disorder

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Acta Pharmaceutica Sinica B 2021年第7期11卷 2031-2047页

作者： Lulu Pang Siqing Zhu Jinqiu Ma Lin Zhu Yijing Liu Ge Ou Ruiteng Li Yaxin Wang Yi Liang Xu Jin Lina Du Yiguang Jin Department of Pharmaceutical Sciences Beijing Institute of Radiation MedicineBeijing 100850China College of Pharmacy Shandong University of Traditional Chinese MedicineJinan 250355China College of Pharmacy Anhui Medical UniversityHefei 230001China Pharmacy Department Chinese PLA General HospitalBeijing 100853China Department of Anesthesiology Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China

Post-traumatic stress disorder(PTSD)is a psychiatric disease that seriously affects brain function.Currently,selective serotonin reuptake inhibitors(SSRIs)are used to treat PTSD clinically but have decreased efficiency and increased side effects.In this study,nasal Cannabidiol inclusion complex temperature-sensitive hydrogels(CBD TSGs)were prepared and evaluated to treat PTSD.Mice model of PTSD was established with conditional fear box.CBD TSGs could significantly improve the spontaneous behavior,exploratory spirit and alleviate tension in open field box,relieve anxiety and tension in elevated plus maze,and reduce the freezing time.Hematoxylin and eosin and c-FOS immunohistochemistry slides showed that the main injured brain areas in PTSD were the prefrontal cortex,amygdala,and hippocampus CA1.CBD TSGs could reduce the level of tumor necrosis factor-a caused by PTSD.Western blot analysis showed that CBD TSGs increased the expression of the 5-HT1 A receptor.Intranasal administration of CBD TSGs was more efficient and had more obvious brain targeting effects than oral administration,as evidenced by the pharmacokinetics and brain tissue distribution of CBD TSGs.Overall,nasal CBD TSGs are safe and effective and have controlled release.There are a novel promising option for the clinical treatment of PTSD.

关键词： Post-traumatic stress disorder Cannabidiol Hydroxypropyl-β-cyclodextrin Inclusion complex Hydrogels Brain targeting Blood-brain barrier Intranasal administration

Impact of smoking Cannabidiol (CBD)-rich marijuana on driving ability

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Forensic Sciences Research 2021年第4期6卷 195-207页

作者： Tim J.Gelmi Wolfgang Weinmann Matthias Pfäffli Department of Forensic Toxicology and chemistry institute of Forensic MedicineUniversity of BernBernswitzerland Graduate school for cellular and Biomedical sciences(GcB) University of BernBernswitzerland Department of Traffic sciences institute of Forensic MedicineUniversity of BernBernswitzerland

To investigate effects of smoking Cannabidiol(CBD)-rich marijuana on driving ability and determine free CBD andΔ9-tetrahydrocannabinol(THC)concentrations in capillary blood samples,a randomised,double-blind,placebo-controlled,two-way crossover pilot study was conducted with 33 participants.Participants smoked a joint containing 500 mg of tobacco and either 500 mg of CBD-rich marijuana(16.6%total CBD;0.9%total THC)or 500 mg of a placebo substance,then performed three different dimensions of the Vienna Test System TRAFFIC examining reaction time,behaviour under stress,and concentration performance.For further assessment of participants’fitness to drive,three tests of balance and coordination were evaluated and vital signs(blood pressure and pulse)were measured.Dried blood spot samples of capillary blood were taken after smoking and after completion of the tests to determine the cannabinoid concentrations(CBD,THC and THC-metabolites).The results revealed no significant differences between the effects of smoking CBD-rich marijuana and placebo on reaction time,motor time,behaviour under stress,or concentration performance.Maximum free CBD and THC concentrations in capillary blood were detected shortly after smoking,ranging between 2.6-440.0 ng/mL and 6.7-102.0 ng/mL,respectively.After 45 min,capillary blood concentrations had already declined and were in the range of 1.9-135.0 ng/mL(free CBD)and 0.9-38.0 ng/mL(free THC).Although the observed levels of free THC concentrations have been reported to cause symptoms of impairment in previous studies in which THC-rich marijuana was smoked,no signs of impairment were found in the current study.This finding suggests that higher CBD concentrations cause a negative allosteric effect in the endocannabinoid system,preventing the formation of such symptoms.Nevertheless,it is recommended that consumers refrain from driving for several hours after smoking CBD-rich marijuana,as legal THC concentration limits may be exceeded.

关键词： Forensic sciences forensic toxicology Cannabidiol driving while impaired road safety driving assessment

Δ 9-Tetrahydrocannabinol Toxicity and Validation of Cannabidiol on Brain Dopamine Levels: An Assessment on Cannabis Duplicity

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Natural Products and Bioprospecting 2020年第5期10卷 285-296页

作者： Swapnali Chetia Gaurab Borah Department of Zoology Rajiv Gandhi UniversityRono HillsDoimukhArunachal Pradesh 791112India

Δ9-tetrahydrocannabinol(THC)of cannabis is the main psychoactive component which is a global significant concern to human health.Evaluation on THC reported its drastic effect on the brain dopaminergic(DAergic)system stimulating mesolimbic DA containing neurons thereby increasing the level of striatal DA.Cannabidiol(CBD),with its anxiolytic and anti-psychotic property,is potent to ameliorate the THC-induced DAergic variations.Legal authorization of cannabis use and its analogs in most countries led to a drastic dispute in the elicitation of cannabis products.With a recent increase in cannabis-induced disorder rates,the present review highlighted the detrimental effects of THC and the effects of CBD on THC induced alterations in DA synthesis and release.Alongside the reported data,uses of cannabis as a therapeutic medium in a number of health complications are also being briefly reviewed.These evaluated reports led to an anticipation of additional research contradictory to the findings of THC and CBD activity in the brain DAergic system and their medical implementations as therapeutics.

关键词： Cannabis Tetrahydrocannabinol Cannabidiol Dopamine Medicinal uses

Single-cell analyses reveal Cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer

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药物分析学报:英文版 2023年第7期13卷 726-744页

作者： Xiaofan Sun Lisha Zhou Yi Wang Guoliang Deng Xinran Cao Bowen Ke Xiaoqi Wu Yanhong Gu Haibo Cheng Qiang Xu Qianming Du Hongqi Chen Yang Sun Department of Rheumatology and Immunology Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing210008China State Key Laboratory of Pharmaceutical Biotechnology School of Life SciencesNanjing UniversityNanjing210023China Colon and Rectal Surgery Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese MedicineNanjing210001China Laboratory of Anesthesia and Critical Care Medicine Department of AnesthesiologyTranslational Neuroscience CenterWest China Hospital and State Key Laboratory of BiotherapySichuan UniversityChengdu610044China Genergy Bio-technology(Shanghai)Co. LtdShanghai200241China The First Affiliated Hospital of Nanjing Medical University Jiangsu Province HospitalNanjing210029China Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor The First Clinical College of Nanjing University of Chinese MedicineNanjing210023China General Clinical Research Center Nanjing First HospitalNanjing Medical UniversityNanjing210006China School of Basic Medicine&Clinical Pharmacy China Pharmaceutical UniversityNanjing210009China Department of General Surgery Shanghai Jiao Tong University Affiliated Sixth People's HospitalShanghai200030China Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy Xuzhou Medical UniversityXuzhouJiangsu221004China

Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.

关键词： scRNA-seq scATAC-seq Cannabidiol Colorectal cancer Tumor microenvironment Macrophage

Engineering Cannabidiol synergistic carbon monoxide nanocomplexes to enhance cancer therapy via excessive autophagy

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Acta Pharmaceutica Sinica B 2023年第11期13卷 4591-4606页

作者： Chang Xiao Yue Sun Jialong Fan William Nguyen Simin Chen Ying Long Wei Chen Aiguo Zhu Bin Liu College of Biology Hunan UniversityChangsha 410082China General Hospital of Ningxia Medical University School of Public Health and ManagementNingxia Medical UniversityYinchuan 750004China Institute of Bast Fiber Crops Chinese Academy of Agricultural SciencesChangsha 410205China Department of Physics the University of Texas at ArlingtonArlingtonTX 76019USA

Although carbon monoxide(CO)-based treatments have demonstrated the high cancer efficacy by promoting mitochondrial damage and core-region penetrating ability,the efficiency was often compromised by protective autophagy(mitophagy).Herein,Cannabidiol(CBD)is integrated into biomimetic carbon monoxide nanocomplexes(HMPOC@M)to address this issue by inducing excessive autophagy.The biomimetic membrane not only prevents premature drugs leakage,but also prolongs blood circulation for tumor enrichment.After entering the acidic tumor microenvironment,carbon monoxide(CO)donors are stimulated by hydrogen oxide(H_(2)O_(2))to disintegrate into CO and Mn^(2+).The comprehensive effect of CO/Mn^(2+)and CBD can induce ROS-mediated cell apoptosis.In addition,HMPOC@Mmediated excessive autophagy can promote cancer cell death by increasing autophagic flux via classⅢPI3K/BECN1 complex activation and blocking autolysosome degradation via LAMP1 downregulation.Furthermore,in vivo experiments showed that HMPOC@M+laser strongly inhibited tumor growth and attenuated liver and lung metastases by downregulating VEGF and MMP9 proteins.This strategy may highlight the pro-death role of excessive autophagy in TNBC treatment,providing a novel yet versatile avenue to enhance the efficacy of CO treatments.Importantly,this work also indicated the applicability of CBD for triple-negative breast cancer(TNBC)therapy through excessive autophagy.

关键词： Carbon monoxide therapy Cannabidiol Reactive oxygen species Excessive autophagy Autophagic flux Autolysosome degradation Metastases Triple-negative breast cancer

Long-Term Impact in the Quality of Life of Patients with Drug-Resistant Epilepsy That Use Cannabidiol

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Neuroscience & Medicine 2021年第4期12卷 103-113页

作者： Gabriela Pesántez Ríos Ignacio Pascual Pascual Ximena Pesántez Ríos Luciana Armijos Estefanía Chediak Hugo Navarrete Zambrano Ruth Jimbo Galo Pesantez Cuesta Servicio de Neurología Pediátrica Centro Nacional de Epilepsia Quito Ecuador Universidad Autónoma de Madrid Madrid Espa&#241 a Servicio de Neurología Pediátrica Hospital Universitario La Paz Madrid Espa&#241 a Centro de Investigación para la Salud en América Latina (CISeAL) Quito Ecuador Facultad de Medicina Pontificia Universidad Católica del Ecuador Quito Ecuador

Introduction: Epilepsy is considered a chronic neurological condition that manifests itself with seizures, where 30% - 40% of patients do not achieve control of their seizures despite proper management. Seizures represent a significant limitation in the patient’s daily activities and are often accompanied by emotional and relational difficulties that have a great impact on the quality of life of the patient and their families. Cannabidiol (CBD) has been found to be effective in controlling seizures and may also improve cognitive and behavioral abilities. Material and Methods: The Quality of Life of the Patient with Epilepsy (CAVE) scale was applied to patients with refractory epilepsies who use Cannabidiol (CBD) added to their base therapy, before the use of CBD and after 12 months of follow-up. The presentation of collateral effects was also evaluated. Results: Out of 34 patients, 26 (76.5%) increased their CAVE value at the end of the study and only 1 (2.9%) decreased. 19 (55.9%) improved in learning and behavior, 55.8% in the frequency of seizures and 79.4% reported a decrease in the intensity of seizures. There were other positive side effects such as improvement in alertness, language, sleep and behavior. The main side effects were mild and transitory, including drowsiness, and constipation. There was a correlation between the global perception of improvement and seizure control. Conclusions: This study shows that in the long term CBD improves the quality of life of patients with refractory epilepsies, through the control of seizures and the improvement of cognitive and behavioral functions.

关键词： Quality of Life Refractory Epilepsy Cannabidiol

Preparation of Cannabidiol and its application in daily chemical industry

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China Detergent & Cosmetics 2020年第4期5卷 14-18页

作者： Yang Jiarui The Affiliated High School of Peking University China

Cannabidiol(CBD)is a physiologically active natural substance,usually extracted from the flowers and leaves of hemp.CBD not only has the function of alleviating the symptoms of many mental disorders,but also has the function of anti-inflammation,anti-oxidation and treatment of skin diseases.Because of its beneficial effects,CBD has been used as an important raw material in the production of health care products and skin care products,which have already been sold on the market.This paper reviewed the main preparation techniques of CBD.The author developed a new refining process for CBD purification combining molecular distillation and crystallization.This new process is both environmental friendly and economical.The obtained samples meet the requirements of the cosmetic industry.The paper also introduces the application prospect of CBD products in daily Chemical Industry,especially in skin care.

关键词： Cannabidiol CBD tetrahydrocannabinol THC skin care

Cannabidiol and terpenes from hemp-ingredients for future foods and processing technologies

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Journal of Future Foods

Journal of Future Foods 2021年第2期1卷 113-127页

作者： Chang Chen Zhongli Pan Department of Biological and Agricultural Engineering University of CaliforniaDavisCA 95616USA

Hemp(Cannabis Sativa L.)is a broadly grown plant worldwide.In recent years,the Cannabidiol(CBD)and terpene species in hemp have drawn increasing research interests due to their human health benefits and pharmaceutical values such as anti-anxiety,pain-relief,relaxation promotion,anti-inflammation and antimicrobial activities.However,the research and application of hemp CBD and terpenes in food systems are scarcely reported,because of various legal regulations,consumer basis and technological challenges.In addition,processing technologies of hemp such as drying,extraction and purifi cation for stable productions of high quality and food-safe CBD and terpene for food purposes have not been extensively studied,lacking thorough reviews.Therefore,in this comprehensive review,the basic characteristics of hemp CBD and terpenes,and their related legal regulations around the world are summarized;the status and technological challenges in the incorporation of hemp CBD and terpenes in food products,and in processing technologies of hemp biomass are identified and discussed;potential solutions,future trends,and research needs are highlighted.The fi ndings from this review may excite more food-related research on hemp processing and CBD/terpenes applications in foods.It can also help the hemp industry to improve the processing effi ciency of hemp as a valuable bioresource,and for food manufacturers to shape their paths to use hemp CBD and terpenes as future functional food ingredients.

关键词： Hemp Cannabidiol Terpene Functional foods Ingredients Drying Extraction