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TCP-1,a novel peptide to diagnose early colon cancer

Chinese Chemical Letters 2024年第3期35卷 226-233页

作者： Hang Yu Baoying Wen Min Huang Ru Feng Libin Pan Manyi Xu Hao Lin Lin Cong Sen Zhang Yan Li Chi-Hin Cho Chongjing Zhang Xiaoguang Chen Yan Wang State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical SciencesBeijing 100050China School of Biomedical Sciences Faculty of MedicineThe Chinese University of Hong KongHong KongChina

A nine cyclic peptide(TCP-1)showed excellent specificity for colon ***-1 binds with human tumor tissues at early stages and mice tumor with diameters of 1-4 mm,suggesting that TCP-1 may be used for early diagnosis of colon *** mechanism of the targeted binding of TCP-1 to colon cancer was also studied using immunoprecipitation,LC-MS and *** screening and identifying of the possible binding target proteins of TCP-1,keratin,typeⅡcytoskeletal 5 was speculated to be the specific binding target protein of TCP-1 in human tumor *** studies were conducted to investigate the target-mediated drug disposition of the new tumor-specific peptide by LC-MS/*** tissue distribution study showed that TCP-1 was found only in colon tumors(the target site)in tumor mice did not bind to any other *** TCP-1 to tumor markedly increased its removal rate from blood circulation but mildly extended its staying time in *** tumor mice,a lower AUC of TCP-1(reduced by almost 35%)and 2-fold higher clearance were found compared to that of normal *** proposed metabolic pathway of TCP-1 in the kidney was also determined using LC-MS^(n)-*** high specificity and low toxicity of the peptide may be caused by its extremely tight binding to the *** applications for future clinical use,including MRI and PET/CT were also explored,and this research may promote the development of colon cancer diagnostic technology research and provide new ideas and technical routes for tumor diagnostic technology.

关键词： Colon cancer TCP-1 Peptide Cytokeratin 5 Pharmacokinetics/pharmacodynamics(PK/PD)

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Thermal proteome profiling (TPP) reveals NAMPT as the anti-glioma target of phenanthroindolizidine alkaloid PF403

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Acta Pharmaceutica Sinica B 2025年第4期15卷 2008-2023页

作者： Li, Fangfei Zhang, Zhaoxin Shi, Qinyan Wang, Rubing Ji, Ming Chen, Xiaoguang Li, Yong Liu, Yunbao Yu, Shishan State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100050 China

Glioma is difficult to treat due to the unique tumor microenvironment and blood–brain barrier. (13aS)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b] indolizidine (PF403), a phenanthroindolizidine alkaloid, has been identified as a promising therapeutic agent for the treatment of glioma. However, the anti-glioma mechanism of PF403 in vivo has not been conclusively verified and must be further elucidated. Hence, a strategy without chemical modification was applied to identify the target of PF403. In this study, we identified nicotinamide phosphoribosyl transferase (NAMPT) as the target of PF403 by using thermal proteome profiling (TPP). Moreover, microscale thermophoresis (MST), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) experiments confirmed that NAMPT exhibits good affinity for PF403. Direct and indirect enzyme activity assays revealed that PF403 inhibited the catalytic activity of NAMPT, leading to a decrease in the concentration of nicotinamide adenine dinucleotide (NAD⁺) in U87 cells. X-ray diffraction and amino acid spot mutation experiments revealed that PF403 primarily relies on the formation of pi–pi interactions with residue Tyr188 to maintain binding with NAMPT (PDB code 8Y55). After NAMPT was knocked down with lentivirus, PF403 lost or partially lost its antitumor activity at the cellular and animal levels. These findings suggest that PF403 exerts antitumor activity by directly targeting NAMPT. © 2025 The Authors

关键词： CETSA Chemical biology Glioma NAMPT PF403 Phenanthroindolizidine alkaloid Target identification Thermal proteome profiling

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Albizzia chinensis(Osbeck)Merr extract YS ameliorates ethanol-induced acute gastric ulcer injury in rats by regulating NRF2 signaling pathway

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Animal Models and Experimental Medicine 2024年第3期7卷 275-282页

作者： Bo Tang Liangning Li Yuanzhi Yu Guibin Wang Shuanggang Ma Shishan Yu Jianjun Zhang Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina State Key Laboratory of Digestive Health BeijingChina State Key Laboratory of Bioactive Substance and Function of Natural Medicines BeijingChina

Background:Around the world,there is a high incidence of gastric ***,an extract from the Chinese herb Albizzia chinensis(Osbeck)Merr,has potential therapeutic applications for gastrointestinal *** we elucidated the protective effect and underlying mechanism of action of YS on gastric ulcer in rats injured by ***:The ethanol-i nduced gastric ulcer rat model was used to assess the protective effect of YS.A pathological examination of gastric tissue was performed by H&E ***-1 cells damaged by hydrogen peroxide were used to simulate oxidative damage in gastric mucosal epithelial *** NRF2 was knocked down using small interfering *** was used to detect ubiquitination of ***-i mmunoprecipitation was used to detect the NRF2-Keap1 ***:YS(10 and 30 mg/kg,i.g.)significantly reduced the ulcer index,decreased MDA level,and increased SOD and GSH levels in gastric tissues damaged by *** promoted NRF2 translocation from cytoplasm to nucleus and enhanced the NQO1 and HO-1 expression levels in injured rat gastric *** addition,YS regulated NQO1 and HO-1 via NRF2 in H_(2)O_(2)-i nduced oxidative injured GES-1 *** studies on the underlying mechanism indicated that YS reduced the interaction between NRF2 and Keap1 and decreased ubiquitylation of NRF2,thereby increasing its stability and expression of downstream ***2 knockdown abolished the effect of YS on MDA and SOD in GES-1 cells treated with H_(2)O_(2).Conclusion:YS reduced the NRF2-Keap1 interaction,promoting NRF2 translocation into the nucleus,which increasing the transcription and translation of NQO1 and HO-1 and improved the antioxidant capacity of rat stomach.

关键词： antioxidative ethanol gastric ulcer NRF2 YS

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Three-step synthesis of flavanostilbenes with a 2-cyclohepten-1-one core by Cu-mediated[5+2]cycloaddition/decarboxylation cascade

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Chinese Chemical Letters 2025年第2期36卷 350-355页

作者： Gangsheng Li Xiang Yuan Fu Liu Zhihua Liu Xujie Wang Yuanyuan Liu Yanmin Chen Tingting Wang Yanan Yang Peicheng Zhang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Beijing Wehand-Bio Pharmaceutical Co. Ltd.Beijing 100500China

The first synthesis of flavanostilbenes with a 2-cyclohepten-1-one core was carried out by applying an effective strategy in three steps from abundant polymerized flavanol resources.A key regio-and stereoselective Cu-mediated[5+2]cycloaddition/decarboxylation cascade was explored and applied without the use of protecting groups,and water as an environmentally friendly solvent contributed to the *** intramolecular[5+2]cycloaddition mechanism,involving oxidation and dearomatization of the flavanol unit as a diene,was proposed and supported by the synthesis of the *** regioselectivity of the cyclization was found to be dependent on the substitution effects of the stilbene units by the exploration of substrate scope.

关键词： [5+2]Cycloaddition Biomimetic synthesis Copper natural products Substrate

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A novel small-molecule PCSK9 inhibitor E28362 ameliorates hyperlipidemia and atherosclerosis

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中国药理学报（英文版） 2024年第10期45卷 2119-2133页

作者： Wei-zhi Wang Chao Liu Jin-que Luo Li-juan Lei Ming-hua Chen Yu-yan Zhang Ren Sheng Yi-ning Li Li Wang Xin-hai Jiang Tong-mei Xiao Yu-hao Zhang Shun-wang Li Ye-xiang Wu Yang Xu Yan-ni Xu Shu-yi Si State Key Laboratory of Bioactive Substances and Functions of Natural Medicines NHC Key Laboratory of Biotechnology for Microbial DrugsNational Center for New Microbial Drug ScreeningInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical College(CAMS & PUMC)Beijing 100050China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines NHC Key Laboratory of Biotechnology for Microbial DrugsNational Center for New Microbial Drug ScreeningInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical College(CAMS & PUMC)Beijing 100050China Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations Changsha Medical UniversityChangsha 410219China State Key Laboratory of Bioactive Substances and Functions of Natural Medicines NHC Key Laboratory of Biotechnology for Microbial DrugsNational Center for New Microbial Drug ScreeningInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical College(CAMS & PUMC)Beijing 100050China Xinjiang Key Laboratory of Uighur Medicine Xinjiang Institute of Materia MedicaUrumqi 830002China

Proprotein convertase subtilisin/kexin type 9(PCSK9)binds to the epidermal growth factor precursor homologous domain A(EGF-A)of low-density lipoprotein receptor(LDLR)in the liver and triggers the degradation of LDLR via the lysosomal pathway,consequently leading to an elevation in plasma LDL-C *** PCSK9 prolongs the lifespan of LDLR and maintains cholesterol homeostasis in the ***,PCSK9 is an innovative pharmacological target for treating hypercholesterolemia and *** this study,we discovered that E28362 was a novel small-molecule PCSK9 inhibitor by conducting a virtual screening of a library containing 40,000 compounds.E28362(5,10,20 μM)dose-dependently increased the protein levels of LDLR in both total protein and the membrane fraction in both HepG2 and AML12 cells,and enhanced the uptake of Dil-LDL in AML12 *** assay showed that E28362 up to 80 μM had no obvious toxicity in HepG2,AML12,and HEK293a *** effects of E28362 on hyperlipidemia and atherosclerosis were evaluated in three different animal *** high-fat diet-fed golden hamsters,administration of E28362(6.7,20,60 mg·kg-1·d-1,i.g.)for 4 weeks significantly reduced plasma total cholesterol(TC),triglyceride(TG),low-density lipoprotein-cholesterol(LDL-C)and PCSK9 levels,and reduced liver TC and TG *** Western diet-fed ApoE-/-mice(20,60 mg·kg-1·d-1,i.g.)and human PCSK9 D374Y overexpression mice(60 mg·kg-1·d-1,i.g.),administration of E28362 for 12 weeks significantly decreased plasma LDL-C levels and the area of atherosclerotic lesions in en face aortas and aortic ***,E28362 significantly increased the protein expression level of LDLR in the *** revealed that E28362 selectively bound to PCSK9 in HepG2 and AML12 cells,blocked the interaction between LDLR and PCSK9,and induced the degradation of PCSK9 through the ubiquitin-proteasome pathway,which finally resulted in increased LDLR protein *** conclusion,E28362 can block the interactio

关键词： atherosclerosis hyperlipidemia PCSK9 inhibitor E28362 LDLR

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Manipulation of IME4 expression, a global regulation strategy for metabolic engineering in Saccharomyces cerevisiae

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Acta Pharmaceutica Sinica B 2023年第6期13卷 2795-2806页

作者： Jianxun Zhu Tianyue An Wenlong Zha Ke Gao Ting Li Jiachen Zi State Key Laboratory of Bioactive Substance and Function of Natural Medicines CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugsand NHC Key Laboratory of Biosynthesis of Natural ProductsInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China College of Pharmacy Jinan UniversityGuangzhou 510632China

Metabolic engineering has been widely used for production of natural medicinal ***, engineering high-yield platforms is hindered in large part by limited knowledge of complex regulatory machinery of metabolic network. N~6-Methyladenosine(m^(6)A) modification of RNA plays critical roles in regulation of gene expression. Herein, we identify 1470 putatively m^(6)A peaks within 1151 genes from the haploid Saccharomyces cerevisiae strain. Among them, the transcript levels of 94 genes falling into the pathways which are frequently optimized for chemical production, are remarkably altered upon overexpression of IME4(the yeast m^(6)A methyltransferase). In particular, IME4 overexpression elevates the mRNA levels of the methylated genes in the glycolysis, acetyl-CoA synthesis and shikimate/aromatic amino acid synthesis modules. Furthermore, ACS1 and ADH2, two key genes responsible for acetyl-CoA synthesis, are induced by IME4 overexpression in a transcription factor-mediated ***, we show IME4 overexpression can significantly increase the titers of isoprenoids and aromatic compounds. Manipulation of m^(6)A therefore adds a new layer of metabolic regulatory machinery and may be broadly used in bioproduction of various medicinal molecules of terpenoid and phenol classes.

关键词： RNA m^(6)A modification Metabolic engineering Saccharomyces cerevisiae Isoprenoids Aromatic compounds

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Berberine ameliorates chronic kidney disease through inhibiting the production of gut-derived uremic toxins in the gut microbiota

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Acta Pharmaceutica Sinica B 2023年第4期13卷 1537-1553页

作者： Libin Pan Hang Yu Jie Fu Jiachun Hu Hui Xu Zhengwei Zhang Mengmeng Bu Xinyu Yang Haojian Zhang Jinyue Lu Jiandong Jiang Yan Wang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences/Peking Union Medical CollegeBeijing 100050China Received 5 September 2022Revised 8 November

At present,clinical interventions for chronic kidney disease are very limited,and most patients rely on dialysis to sustain their lives for a long ***,studies on the gut—kidney axis have shown that the gut microbiota is a potentially effective target for correcting or controlling chronic kidney *** study showed that berberine,a natural drug with low oral availability,significantly ameliorated chronic kidney disease by altering the composition of the gut microbiota and inhibiting the production of gut-derived uremic toxins,including ***,berberine reduced the content of pcresol sulfate in plasma mainly by lowering the abundance of g_Clostridium_sensu_stricto_1 and inhibiting the tyrosine—p-cresol pathway of the intestinal ***,berberine increased the butyric acid producing bacteria and the butyric acid content in feces,while decreased the renal toxic trimethylamine *** findings suggest that berberine may be a therapeutic drug with significant potential to ameliorate chronic kidney disease through the gut—kidney axis.

关键词： Chronic kidney disease Gut microbiota Berberine Gut—kidney axis Clostridium p-Cresol Uremic toxins p-Cresol sulfate

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Author correction to‘Protective effects of VMY-2-95 on corticosterone-induced injuries in mice and cellular models’[Acta Pharmaceutica Sinica B 11(2021)1903-1913]

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Acta Pharmaceutica Sinica B 2023年第8期13卷 899-901页

作者： Ziru Yu Dewen Kong Yu Liang Xiaoyue Zhao Guanhua Du State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Beijing Key Laboratory of Drug Target and Screening ResearchInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

The authors regret that there was a picture error in Fig.5F owing to the inappropriate data statistics—forgetting gating when data collecting and a picture error in Fig.6F owing to the data copy mistake when drawing ... 详细信息

关键词： correction injuries getting

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PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway

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中国药理学报（英文版） 2024年第6期45卷 1142-1159页

作者： Nian-ying Shang Long-jian Huang Jia-qi Lan Yu-ying Kang Jing-shu Tang Hong-yue Wang Xin-nan Li Zhuo Sun Qiu-yu Chen Meng-yao Liu Zi-peng Wen Xin-hong Feng Lei Wu Ying Peng State Key Laboratory of Bioactive Substances and Functions of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing 100050China Department of Neurology Beijing Tsinghua Changgung HospitalSchool of Clinical MedicineTsinghua UniversityBeijing 102218China

Alzheimer's disease(AD),a progressive neurodegenerative disorder,is the most common cause of dementia in elderly people and substantially affects patient quality of *** stress is considered a key factor in the development of ***2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in *** studies show that potassium 2-(1-hydroxypentyl)-benzoate(PHPB)exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic *** this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress(OS)*** 5-and 13-month-old APP/PS1 mice were administered PHPB(100mg·kg-1-d-1,i.g.)for 10 *** the cognition assessment,the mice were euthanized,and the left hemisphere of the brain was harvested for *** showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test,and knockdown of Nrf2 gene only slightly increased the impairment,while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse *** administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 *** addition,PHPB administration significantly increased the p-AKT/AKT and p-GSK3β/GSK3βratios and the expression levels of Nrf2,HO-1 and NQO-1 in APP/PS1 mice,but these changes were abolished by knockdown of Nrf2 *** SK-N-SH APPwt cells and primary mouse neurons,PHPB(10 μM)significantly increased the p-AKT/AKT and p-GSK3β/GSK3βratios and the level of Nrf2,which were blocked by knockdown of Nrf2 *** summary,this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3β/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

关键词： Alzheimer disease potassium 2-(1-hydroxypentyl)-benzoate(PHPB) cognition oxidative stress NF-E2-related factor 2

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Selectively T cell phosphorylation activation of azvudine in the thymus tissue with immune protection effect

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3140-3154页

作者： Ning Sheng Rui Li Yang Li Zhe Wang Lulu Wang Yuhuan Li Jinlan Zhang Jiandong Jiang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

Thymus is the important immune organ,responsible for T cell development and *** lower circulating T counts have been observed in patients who died from COVID-19 compared with ***,also known as FNC,is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 *** this study,single-cell transcriptome,proteomics,and parallel reaction monitoring(PRM)were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey *** results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as *** enzymes involved in the FNC phosphorylation process,such as Dck,Cmpk1,and Nme2,were highly expressed in CD4+ T cells,CD8+ T cells,and DP(CD4+ CD8+)***,FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases,phosphoribosyl transferases,and deaminases,*** robust phosphorylation capacity of the thymus for cytidine analogue drug FNC,and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection *** suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties,as an important factor during antiviral drug design.

关键词： Azvudine T cell Thymus Phosphorylation activation Nucleoside analogue

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