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Low corticosterone levels attenuate late life depression and enhance glutamatergic neurotransmission in female rats

中国药理学报（英文版） 2021年第6期42卷 848-860页

作者： Shi-feng Chu Zhao Zhang Xin Zhou Wen-bin He Bo Yang Li-yuan Cui Hong-yuan He Zhen-zhen Wang Nai-hong Chen State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica and Neuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Shanxi Key Laboratory of Chinese Medicine Encephalopathy Shanxi University of Chinese MedicineJinzhong 030619China Department of Pharmacy Characteristic Medical Center of the Chinese People's Armed Police ForceTianjin 300300China Tianjin University of Traditional Chinese Medicine Tianjin 301617China

Sustained elevation of corticosterone(CORT)is one of the common causes of aging and major depression ***,the role of elevated CORT in late life depression(LLD)has not been *** this study,18-month-old female rats were subjected to bilateral adrenalectomy or sham *** CORT levels in plasma were adjusted by CORT replacement and the rats were divided into high-level CORT(H-CORT),low-level CORT(L-CORT),and Sham *** showed that L-CORT rats displayed attenuated depressive symptoms and memory defects in behavioral tests as compared with Sham or H-CORT ***,we showed that glutamatergic transmission was enhanced in L-CORT rats,evidenced by enhanced population spike amplitude(PSA)recorded from the dentate gyrus of hippocampus in vivo and increased glutamate release from hippocampal synaptosomes caused by high frequency stimulation or CORT *** injection of an enzymatic glutamate scavenger system,glutamic-pyruvic transmine(GPT,1 μM),significantly increased the PSA in Sham rats,suggesting that extracelluar accumulation of glutamate might be the culprit of impaired glutamatergic transmission,which was dependent on the uptake by Glt-1 in *** revealed that hippocampal Glt-1 expression level in the L-CORT rats was much higher than in Sham and H-CORT *** a gradient neuron-astrocyte coculture,we found that the expression of Glt-1 was decreased with the increase of neural percentage,suggesting that impairment of Glt-1 might result from the high level of CORT contributed neural *** sham rats,administration of DHK that inhibited Glt-1 activity induced significant LLD symptoms,whereas administration of RIL that promoted glutamate uptake significantly attenuated *** of these results suggest that glutamatergic transmission impairment is one of important pathogenesis in LLD induced by high level of CORT,which provide promising clues for the treatment of LLD.

关键词： major depression disorder late life depression corticosterone hippocampus glutamatergic transmission glutamate/glutamine cycle glutamate transporter 1

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The Combination of a Novel Pleuromutilin Derivative and Polymyxin B Nonapeptide: An Example of Converting Pleuromutilin from Gram-Positive-Only to Broad-Spectrum

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SSRN 2025年

作者： Luo, Xinyu Fu, Hengjian Zhang, Jie Han, Zunsheng Pan, Weidong Zhang, Wenxuan Xia, Jie Wu, Song State Key Laboratory of Bioactive Substance and Function of Natural Medicines Department of New Drug Research and Development Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China State Key Laboratory of Functions and Applications of Medicinal Plants Guizhou Medical University Guiyang550014 China

To alleviate the difficulties in developing antibiotics for Gram-negative bacteria (GNB), our study focuses on expanding the utility of pleuromutilin derivatives, known as Gram-positive-only antibiotics, in battling against GNB. A series of pleuromutilin derivatives were designed and synthesized, which contributed to a promising compound 15b. It exhibited upgrading activity against both Gram-positive bacteria (GPB) and GNB, as well as promising druglike properties. Combined with the outer membrane disruptor polymyxin B nonapeptide (PMBN, 6), 15b showed further enhanced activities against various GNB, less induced resistance, low impact on polymyxin-related resistance, and in vivo efficacy in Galleria mellonella model. Our results indicate the potential of pleuromutilin derivatives as viable broad-spectrum treatment options. © 2025, The Authors. All rights reserved.

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AD-16 Protects Against Hypoxic-Ischemic Brain Injury by Inhibiting Neuroinflammation

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Neuroscience Bulletin 2022年第8期38卷 857-870页

作者： Zhihua Huang Zhengwei Luo Andrea Ovcjak Jiangfan Wan Nai-hong Chen Wenhui Hu Hong-Shuo Sun Zhong-Ping Feng Department of Physiology Temerty Faculty of MedicineUniversity of TorontoTorontoONM5S 1A8Canada Department of Surgery Temerty Faculty of MedicineUniversity of TorontoTorontoONM5S 1A8Canada State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaNeuroscience CenterChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100050China Key Laboratory of Molecular Target and Clinical Pharmacology State Key Laboratory of Respiratory DiseaseSchool of Pharmaceutical Sciences and the Fifth Affiliated HospitalGuangzhou Medical UniversityGuangzhou511436GuangdongChina Leslie Dan Faculty of Pharmacy University of TorontoTorontoONM5S 3M2Canada

Neuroinflammation is a key contributor to the pathogenic cascades induced by hypoxic-ischemic(HI)insult in the neonatal ***-16 is a novel anti-inflammatory compound,recently found to exert potent inhibition of the lipopolysaccharide-induced production of pro-inflammatory and neurotoxic *** this study,we evaluated the effect of AD-16 on primary astrocytes and neurons under oxygen-glucose deprivation(OGD)in vitro and in mice with neonatal HI brain injury in *** demonstrated that AD-16 protected against OGD-induced astrocytic and neuronal cell *** dose post-treatment with AD-16(1 mg/kg)improved the neurobehavioral outcome and reduced the infarct volume with a therapeutic window of up to 6 *** administration reduced the mortality rate and preserved whole-brain morphology following neonatal *** in vitro and in vivo effects suggest that AD-16 offers promising therapeutic efficacy in attenuating the progression of HI brain injury and protecting against the associated mortality and morbidity.

关键词： Neuroinflammation Neonatal hypoxic-ischemic brain injury Neuroprotection AD-16

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The Combination of a Novel Pleuromutilin Derivative and Polymyxin B Nonapeptide: An Example of Converting Pleuromutilin from Gram-Positive-Only to Broad-Spectrum

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SSRN 2024年

作者： Luo, Xinyu Fu, Hengjian Zhang, Jie Han, Zunsheng Pan, Weidong Xia, Jie Zhang, Wenxuan Wu, Song State Key Laboratory of Bioactive Substance and Function of Natural Medicines Department of New Drug Research and Development Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China State Key Laboratory of Functions and Applications of Medicinal Plants Guizhou Medical University Guiyang550014 China

Abstract:To alleviate the difficulties in developing antibiotics for Gram-negative bacteria (GNB), our study focuses on expanding the utility of pleuromutilin derivatives, known as gram-positive-only antibiotics, in battling against GNB. A series of pleuromutilin derivatives were designed and synthesized, which contributed to a promising compound 15b. It exhibited upgrading activity against both Gram-positive bacteria (GPB) and GNB, as well as promising druglike properties. Combined with the outer membrane disruptor polymyxin B nonapeptide (PMBN, 6), 15b showed further enhanced activities against various GNB, less induced resistance, and low impact on polymyxin-related resistance. Our results indicate the potential of pleuromutilin derivatives as viable broad-spectrum treatment options. © 2024, The Authors. All rights reserved.

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Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy

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Virologica Sinica 2024年第6期39卷 892-908页

作者： Lihong Huang Lele Liu Junhai Zhu Nanjun Chen Jie Chen Chuen-Fuk Chan Fei Gao Youqin Yin Jiufeng Sun Rongxin Zhang Kehui Zhang Wenbao Qi Jianbo Yue State Key Laboratory for Animal Disease Control and Prevention South China Agricultural UniversityGuangzhou510642China Key Laboratory of Zoonoses Ministry of Agriculture and Rural AffairsSouth China Agricultural UniversityGuangzhou510642China National and Regional Joint Engineering Laboratory for Medicament of Zoonoses Prevention and Control Guangzhou510642China Key Laboratory of Zoonoses Prevention and Control of Guangdong Province GuangzhouChina Department of Computer Science City University of Hong KongHong Kong999077China Department of Biomedical Sciences City University of Hong KongHong Kong999077China Guangdong Workstation for Emerging Infectious Disease Control and Prevention Guangdong Provincial Key Laboratory of Pathogen Detection for Emerging Infectious Disease ResponseGuangdong Provincial Center for Disease Control and PreventionGuangzhou511430China Laboratory of Immunology and Inflammation Institute of Basic Medical Sciences and Department of BiotechnologySchool of Life Sciences and BiopharmaceuticsGuangdong Pharmaceutical UniversityGuangzhou510006China State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100730China Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing100730China City University of Hong Kong Shenzhen Research Institute Shenzhen518057China Division of Natural and Applied Sciences Synear Molecular Biology LabGlobal Health Research CenterDuke Kunshan UniversityKunshan215316China College of Life Sciences Wuhan UniversityWuhan430072China

Flaviviruses,such as dengue virus(DENV),Zika virus(ZIKV),and Japanese encephalitis virus(JEV),represent a substantial public health challenge as there are currently no approved treatments ***,we investigated the antiviral effects of bis-benzylisoquinoline alkaloids(BBAs)on flavivirus *** evaluated five specific BBAs—berbamine,tetrandrine,iso-tetrandrine,fangchinoline,and cepharanthine—and found that they effectively inhibited infections by ZIKV,DENV,or JEV by blocking virus entry and genome replication stages in the flavivirus life ***,we synthesized a fluorophore-conjugated BBA and showed that BBAs targeted endolysosomes,causing lysosomal pH *** studies on inhibiting ZIKV infection by BBAs revealed that these compounds blocked TRPML channels,leading to lysosomal dysfunction and reducing the expression of NCAM1,a key receptor for the entry of ZIKV into cells,thereby decreasing cells susceptibility to ZIKV ***,BBAs inhibited the fusion of autophagosomes and lysosomes,significantly reducing viral RNA ***,our results suggest that BBAs inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy,respectively,underscoring the potential of BBAs as therapeutic agents against flavivirus infections.

关键词： Bis-benzylisoquinoline alkaloids(BBAs) Flavivirus Zika virus(ZIKV) Endolysosomes TRPML channels Autophagy

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Evaluating the neuroprotective effects of the novel Kv2.1 blocker Zj7923 against ischemic stroke in vitro and in vivo

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Neuropharmacology 2025年 278卷 110537页

作者： Tianjiao Yang Weiping Wang Zhuo Li Jie Cai Nan Feng Shaofeng Xu Ling Wang Xiaoliang Wang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China. Electronic address: wangxl@***.

The voltage-dependent potassium channel Kv2.1 correlates closely to the regulation of neuronal excitability and cellular apoptosis. Ischemia or oxidative treatment were known to stimulate the surge of Kv2.1-mediated current to activate neuronal apoptosis pathways, while inhibiting excessive Kv2.1 K current efflux could reduce neuronal apoptosis and exhibit neuroprotective effects. Here, we found a novel Kv2.1 selective blocker Zj7923 and investigated whether it produces neuroprotective function after ischemic stroke animal model. We demonstrate that Zj7923 potently inhibits Kv2.1 current with an IC of 0.12 μM. Zj7923 had no obvious effect on the activation process of Kv2.1 channels, but could significantly accelerate the inactivation process of Kv2.1 channels. The mutations at Y380 and K356 in the outer vestibule of Kv2.1 channels weakened the inhibitory effect of Zj7923, and the IC value of Zj7923 on the mutation channels increased to 3.66 μM and 3.20 μM, respectively, indicating that the compound may act on the above two positions. Zj7923 could increase the spontaneous firing rate of normal hippocampal pyramidal neurons and ameliorate OGD-induced impairment of neuronal excitability. Kv2.1 channel inhibition by Zj7923 provides protection against DTDP-induced apoptosis and its mechanism might be related to the modulation of the expression of apoptosis-related proteins, such as Bcl-2, Bax and cleaved caspase-3 proteins. In vivo pharmacodynamics evaluation, intravenous administration of Zj7923 in rats following transient middle cerebral artery occlusion significantly reduced infarct volume and improved neurological deficits. Our results indicate that Zj7923 exerts a neuronal protection from cerebral ischemia in vitro and in vivo by inhibiting Kv2.1 current and validate the potential value of developing drugs targeting Kv2.1 for ischemic stroke.

关键词： Kv2.1 apoptosis cerebral ischemia neuronal excitability neuroprotection potassium channel blocker

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Synthesis of tetrahydroisoquinolines through TiCl4-mediated cyclization and Et3SiH reduction

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Chinese Chemical Letters 2020年第3期31卷 729-732页

作者： Zeyu Shi Qiong Xiao Dali Yin State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China Department of Medicinal Chemistry Beijing Key Laboratory of Active Substances Discovery and Drugability EvaluationInstitute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China

A versatile and efficient telescoped reaction sequence for the synthesis of tetrahydroisoquinolines(THIQs)is reported that uses TiCl4 to promote cyclization of a benzylaminoacetal derivative and Et3SiH for reduction of the intermediate *** method is complimentary to the classical Pomeranz-Fritsch and related reactions since it tolerates electron-withdrawing substituents and allows access to 8-substituted THIQs.

关键词： Tetrahydroisoquinoline TiCl4 Cyclization Et3SiH Telescoped reaction

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Design, Synthesis, and Structure-Activity Relationships of Xanthine Derivatives as Broad-Spectrum Inhibitors of Coronavirus Replication

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SSRN 2024年

作者： Chen, Xiaofang Ding, Xiaotian Bian, Cong Wang, Kun Zheng, Xiao Yan, Haiyan Qiao, Mengqian Wu, Shuo Li, Yihua Wang, Li Wang, Lifei Du, Yu Li, Yuhuan Hong, Bin CAMS Key Laboratory of Synthetic Biology for Drug Innovation NHC Key Laboratory of Biotechnology for Microbial Drugs State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China CAMS Key Laboratory of Antiviral Drug Research NHC Key Laboratory of Biotechnology for Microbial Drugs State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China NHC Key Laboratory of Biotechnology for Microbial Drugs Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China CAMS Key Laboratory of Antiviral Drug Research Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China CAMS Key Laboratory of Synthetic Biology for Drug Innovation NHC Key Laboratory of Biotechnology for Microbial Drugs Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China

Illuminated by insights into the hijacking of host cellular metabolism by coronaviruses, we identified an initial hit compound 7030B-C5, characterized by a xanthine scaffold, via a cellular-level phenotypic screening from a domestic repertoire of lipid-modulating agents. A series of derivatives were synthesized and optimized through comprehensive structure-activity relationship (SAR) studies focusing on the N-1, C-8, and N-7 positions of xanthine and preliminary exploration on the N-3 position and parent nucleus. Compounds 10e, 10f and 10o, featuring modifications at the N-7 position, showed inhibitory activity with EC50 values in the three-digit nanomolar range against HCoV-229E. In particular, compound 10o exerted superior potency across various coronavirus strains, including HCoV-229E, HCoV-OC43, and the Omicron variants of SARS-CoV-2. Further investigations revealed that 10o acted on the post-entry stages of virus replication and exhibited a distinctive antiviral mechanism from that of clinically approved nirmatrelvir and molnupiravir. Moreover, drug combination study indicates that 10o operates additively with nirmatrelvir, molnupiravir or omicsynin B4, a dual inhibitor of host proteases for S protein priming. Additionally, in vivo assessments show that 10o has favorable pharmacokinetic and safety profiles compared to its parent compound 7030B-C5. These findings underscore the potential of 10o as a promising antiviral candidate for the treatment of current and potential future coronavirus infections. © 2024, The Authors. All rights reserved.

关键词： Coronavirus

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A concise total synthesis of monoterpenoid indole alkaloid (-)-voacafricine A

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Chinese Chemical Letters 2025年

作者： Xuan Pan Tao Sheng Zhanzhu Liu State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia Medica Peking Union Medical College and Chinese Academy of Medical Sciences Beijing 100050 China

A concise total synthesis of novel monoterpenoid indole alkaloid (-)-voacafricine A is described, which proceeded in 14 longest linear steps and 5.2% overall yield. key transformations comprised of (a) an organocatalytically asymmetric Pictet-Spengler cyclization/lactamization cascade reaction generating the key tetracyclic lactam skeleton; (b) asymmetric α -alkylation of carbonyl group induced by Evans’ chiral auxiliary with excellent diastereoselectivity; (c) a highly efficient one-pot desulfurization/hydrogenation/debenzylation transformation using Raney Ni under hydrogen atmosphere; as well as (d) an intramolecular Vorbürggen reaction constructing the quaternary ammonium motif and the final cagelike skeleton.

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Novel Pleuromutilin Derivatives Conjugated with Phenyl-Sulfide and Boron-Containing Moieties as Potent Antibacterial Agents Against Antibiotic-Resistant Bacteria

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SSRN 2024年

作者： Luo, Xinyu Wu, Guangxu Feng, Jing Zhang, Jie Fu, Hengjian Yu, Hang Han, Zunsheng Nie, Wansen Zhu, Zihao Liu, Bo Pan, Weidong Li, Beibei Wang, Yan Li, Tianlei Zhang, Wenxuan Wu, Song State Key Laboratory of Bioactive Substance and Function of Natural Medicines Department of New Drug Research and Development Institute of Materia Medica Chinese Academy of Medical Sciences Peking Union Medical College Beijing100050 China State Key Laboratory of Functions and Applications of Medicinal Plants Guizhou Medical University Guiyang550014 China Shanghai Veterinary Research Institute Chinese Academy of Agricultural Science Shanghai200241 China Guizhou University China

In response to the escalating threat of microbial resistance, a series of novel pleuromutilin derivatives, conjugated with phenyl-sulfide and boron-containing moieties, were designed and synthesized. Most derivatives, especially 14b and 16b, demonstrated significant efficacy against Gram-positive bacteria, including multidrug-resistant strains, as well as pleuromutilin-resistant strains. Compound 16b displayed significantly bactericidal activity and low spontaneous resistance frequency as well as high stability in liver microsomes of rats and humans. Compound 16b also exhibited promising antibacterial activities and tolerance in mouse models. Our data highlight the potential of conjugated pleuromutilin derivatives as valuable agents against drug-resistant bacteria. © 2024, The Authors. All rights reserved.

关键词： Sulfur compounds

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