摘要：
(1) Background: Chemokine-like factor 1 (CKLF1) is a chemokine with potential to be a target for stroke therapy. Compound IMM-H004 is a novel coumarin derivative screened from a CKLF1/C-C chemokine receptor type 4 (CCR4) system and has been reported to improve cerebral ischemia/reperfusion injury. This study aims to investigate the protective effects of IMM-H004 on cerebral ischemia injury and its infectious cardiopulmonary complications in adult and aged rats from the CKLF1 perspective. (2) Methods: The effects of IMM-H004 on the protection was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, behavior tests, magnetic resonance imaging (MRI) scans, enzyme-linked immunosorbent assay (ELISA), Nissl staining, histo-pathological examination, and cardiopulmonary function detection. Immunohistological staining, immunofluorescence staining, quantitative real-time PCR (qPCR), and western blotting were used to elucidate the underlying mechanisms. (3) Results: IMM-H004 protects against cerebral ischemia induced brain injury and its cardiopulmonary complications, inhibiting injury, and inflammation through CKLF1-dependent anti-inflammation pathway in adult and aged rats. IMM-H004 downregulates the amount of CKLF1, suppressing the followed inflammatory response, and further protects the damaged organs from ischemic injury. (4) Conclusions: The present study suggested that the protective mechanism of IMM-H004 is dependent on CKLF1, which will lead to excessive inflammatory response in cerebral ischemia. IMM-H004 could also be a therapeutic agent in therapy for ischemic stroke and cardiopulmonary complications in the aged population.
作者机构：
[Wang, Zhen-zhen; Mou, Zheng; Chen, Nai-hong; Zhang, Shuai; Chen, Jiao; Chu, Shi-feng] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China.;[Wang, Zhen-zhen; Mou, Zheng; Chen, Nai-hong; Zhang, Shuai; Chen, Jiao; Chu, Shi-feng] Chinese Acad Med Sci, Neurosci Ctr, Beijing 100050, Peoples R China.;[Wang, Zhen-zhen; Mou, Zheng; Chen, Nai-hong; Zhang, Shuai; Chen, Jiao; Chu, Shi-feng] Peking Union Med Coll, Beijing 100050, Peoples R China.;[Chen, Nai-hong; Chu, Shi-feng] Hunan Univ Chinese Med, Changsha 410208, Hunan, Peoples R China.;[Chen, Nai-hong] Guangzhou Univ Chinese Med, Guangzhou 510000, Guangdong, Peoples R China.
通讯机构：
[Chen, Nai-hong] C;[Chen, Nai-hong] P;Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China.;Chinese Acad Med Sci, Neurosci Ctr, Beijing 100050, Peoples R China.;Peking Union Med Coll, Beijing 100050, Peoples R China.
摘要：
Glucocorticoids are vital stress response hormones and facilitate stress coping. However, sustained glucocorticoid exposure is associated with negative effects on brain. The precise role of glucocorticoids in depression and anxiety remains unclear. In the present study, we found that rats exposed to chronic unpredictable stress (CUS) showed anxiety-like behavior but not depressive-like behavior in the absence of glucocorticoid production. It was interesting to find that the level of serotonin (5-HT) and the expression of tryptophan hydroxylase-2 (TPH2) were decreased after CUS in the hippocampus in sham rats, while adrenalectomy (ADX) prevented such decreases. In addition, the neurogenesis in hippocampus decreased in both sham and ADX rats after stress exposure. Furthermore, inhibition of mineralocorticoid receptor (MR) with spironolactone induced anxiety like behavior in sham rats but not ADX rats. The proliferation of cells was blocked by spironolactone. In conclusion, our results indicate that MR-dependent neurogenesis was closely related with anxiety-like behavior.
作者机构：
College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China;[张钊] Institute of Materia Mediea and Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100050, China;[朱天碧; 陈乃宏; 彭也] College of Pharmacy, Hunan University of Chinese Medicine, Changsha, 410208, China, Institute of Materia Mediea and Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, 100050, China
作者机构：
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica &Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College;Department of Pharmacy, Xuanwu Hospital of Capital Medical University;[CHEN Nai-hong; ZHANG Zhao; CHU Shi-feng; GAO Yan] 中国医学科学院神经科学研究所;[ZHANG Lan] 首都医科大学宣武医院
摘要：
Panax Ginseng has been used for thousands of years in traditional Chinese medicine（TCM） as a tonic to improver stamina and vitality. Ginsenoside Rg1（Rg1）, a saponin extracted from Panax ginseng, is considered one of the most potent pharmacological candidates among TCM. In various diseases related to nervous system, Rg1 has shown excellent pharmacological activities.（1） Stroke: Rg1 has been well documented to be effective against ischemic/reperfusion（I/R） neuronal injury. A systematic review and meta-analysis revealed a marked efficacy of Rg1 in experimental acute ischemic stroke, as manifested by its ability to reduce infract volume and improve neurological score. The protective effects of Rg1 were abolished by injecting of AAV-HIF-mi R-144-sh RNA into the predicted ischemic penumbra.（2） Depression: In addition, Rg1 showed antidepressive effects in chronic unpredictable mild stress（CUMS） model of depression and in gonadectomized（GDX） model of neuroendocrine disturbance. Rg1 displayed antidepressant activity through the modulation of HPA and HPG axis, markedly alleviated depression-like behavior in rats. Long-term Rg1 treatment of CUS-exposed rats also significantly prevented the decrease in dye diffusion and improved the ultrastructure of astrocyte gap junctions in the PFC. Rg1 upregulated Cx43 expression in PFC reduced by CUS exposure, indicating beneficial effects on the functional activity of gap junction channels in the brain.（3） Parkinson disease（PD）: Oral treatment with Rg1 significantly attenuated high MPTP-induced mortality, behavior defects, loss of dopamine neurons and abnormal unltrastructure changes in SNpc. It regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as TNF-alpha and IL-1β in SNpc. Rg1 also alleviated the unusual MPTP-induced increase in oligomeric, phosphorylated and disease-related α-synuclein in SNpc.（4） Alzheimer disease（AD）: Okadaic acid（OKA）intracerebroventricular injection induced memory impairment, including changes in the ability of orientation navigate, spatial probe and relearning memory in behavioral test of Morris water maze（MWM）. OKA treated rats showed memory impairment including increasing of phospho-tau, decreasing of phospho-GSK3β and the formation of β-amyloid in special brain regions, which were reversed by Rg1. The possible neuroprotective mechanism might be that Rg1 decreases OKAinduced memory impairment through GSK3β/tau signaling pathway and/or attenuating Aβ formation. Meanwhile, Rg1 activated ERK/MAPK pathway by Ca MKIIα, and the activation of CREB was not only dependent on ERK induced by Rg1. Additionally, Rg1 inhibited microglial activation by suppressing Iba1 expression. Rg1 inhibited the inflammation mediated by LPS through suppressing NF-κB and MAPK pathway, which provided the explanation for its therapeutic effect on neurodegenerative diseases.
作者机构：
[Chen, Chen; Chen, Nai-Hong; Zhang, Zhao; Chu, Shi-Feng] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China.;[Chen, Chen; Chen, Nai-Hong; Zhang, Zhao; Chu, Shi-Feng] Chinese Acad Med Sci, Neurosci Ctr, Beijing 100050, Peoples R China.;[Chen, Chen; Chen, Nai-Hong; Zhang, Zhao; Chu, Shi-Feng] Peking Union Med Coll, 1 Xiannongtan St, Beijing 100050, Peoples R China.;[Ai, Qi-Di; Chen, Nai-Hong] Hunan Univ Tradit Chinese Med, Changsha 410208, Hunan, Peoples R China.;[Chen, Nai-Hong] Chinese Acad Med Sci, Inst Mat Med, Neurosci Ctr, State Key Lab Bioact Subst & Funct Nat Med, 1 Xiannongtan St, Beijing 100050, Peoples R China.
通讯机构：
[Chen, Nai-Hong] P;[Chen, Nai-Hong] C;Peking Union Med Coll, 1 Xiannongtan St, Beijing 100050, Peoples R China.;Chinese Acad Med Sci, Inst Mat Med, Neurosci Ctr, State Key Lab Bioact Subst & Funct Nat Med, 1 Xiannongtan St, Beijing 100050, Peoples R China.
关键词：
NK cells;Cerebral ischemia;Inflammation;Immunodpression;Infection
摘要：
As a vital cell type in immune system and infiltrating cells in ischemic brain, NK cells can bridge the crosstalk between immune system and nervous system in stroke setting. The mechanism of action of NK cells is complicated, involving direct and indirect actions. NK cells are closely associated with poststroke inflammation, immunodepression and infections. The excessive inflammatory response in ischemic brain is one of the important causes for aggravating cerebral ischemic injury. Besides the inflammation induced by ischemia itself, thrombolytic drug tissue plasminogen activator (tPA) administration could also induce deteriorative inflammation, which is unfavorable for stroke control and recovery. Regulating NK cells may has the potential to modulate the immune response, limiting the development of ischemic damage and getting better outcome. In addition, post-stroke immunosuppression may lead to infections which contribute to higher severity and mortality of ischemic stroke (IS). Targeting NK cells may help to find novel pathways for IS therapy, which can both ameliorate the infarction itself, but also reduce the infectious complications. NK cells may also link IS and related diseases, suggesting NK cells can be used as a diagnostic or prognostic biomarker for IS prevention and treatment.
作者机构：
[刘芳; 韩晓蕾; 赵春媛] School of Pharmacy, Hunan University of Traditional Chinese Medicine, Changsha, 410208, China;School of Chinese Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China;Hunan TCM Decoction Standardization and Functional Engineering Technology Research Center, Changsha, 410208, China;Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, 100050, China;[俞婷] School of Pharmacy, Hunan University of Traditional Chinese Medicine, Changsha, 410208, China, School of Chinese Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
