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Chinese Journal of natural medicines 2024年第5期22卷 441-454页

作者： SHAO Siyuan SUN Mohan MA Xianjie JIANG Jianwei TIAN Jinying ZHANG Jianjun YE Fei LI Shuai 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

Five novel(9,10-dihydro)phenanthrene and bibenzyl trimers,as well as two previously identified biphenanthrenes and bibenzyls,were isolated from the tubers of Bletilla striata.Their structures were elucidated through comprehensive analyses of NMR and HRESIMS spectroscopic data.The absolute configurations of these compounds were determined by calculating rotational energy barriers and comparison of experimental and calculated ECD curves.Compounds 5b and 6 exhibited inhibitory effects on LPS-induced NO production in BV-2 cells,with IC_(50) values of 12.59±0.40 and 15.59±0.83μmol·L^(-1),respectively.A mechanistic study suggested that these compounds may attenuate neuroinflammation by reducing the activation of the AKT/IκB/NF-κB signaling pathway.Additionally,compounds 3a,6,and 7 demonstrated significant PTP1B inhibitory activities,with IC_(50) values of 1.52±0.34,1.39±0.11,and 1.78±0.01μmol·L^(-1),respectively.Further investigation revealed that compound 3a might inhibit LPS-induced PTP1B overexpression and NF-κB activation,thereby mitigating the neuroinflammatory response in BV-2 cells.

关键词： Bletilla striata Phenanthrene/bibenzyl trimer NO inhibition AKT/IκB/NF-κB signaling pathway PTP1B inhibitory effect

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 ulcers.YS,an extract from the Chinese herb Albizzia chinensis(Osbeck)Merr,has potential therapeutic applications for gastrointestinal diseases.Here we elucidated the protective effect and underlying mechanism of action of YS on gastric ulcer in rats injured by ethanol.Methods: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 staining.GES-1 cells damaged by hydrogen peroxide were used to simulate oxidative damage in gastric mucosal epithelial cells.Endogenous NRF2 was knocked down using small interfering RNA.Immunoprecipitation was used to detect ubiquitination of NRF2.Co-i mmunoprecipitation was used to detect the NRF2-Keap1 interaction.Results: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 ethanol.YS promoted NRF2 translocation from cytoplasm to nucleus and enhanced the NQO1 and HO-1 expression levels in injured rat gastric tissue.In addition,YS regulated NQO1 and HO-1 via NRF2 in H_(2)O_(2)-i nduced oxidative injured GES-1 cells.Further 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 factors.NRF2 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

A multi-enzymatic cascade reaction for the synthesis of bioactive C-oligosaccharides

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Chinese Chemical Letters 2024年第6期35卷 451-455页

作者： Kebo Xie Qian Zhang Fei Ye Jungui Dai state key laboratory of bioactive Substance and function of natural medicines CAMS Key Laboratory of Enzyme and Biocatalysis of Natural Drugs and NHC Key Laboratory of Biosynthesis of Natural ProductsInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

C-Oligosaccharides are rare in nature and possess diverse bioactivities.However,their chemical synthesis faces many challenges.In this work,enzymatic introduction of C-linked sugar chains to target aglycones was successfully achieved by multi-enzymatic cascade reactions.A C-glycosyltransferase from Aloe barbadensis was employed to introduce the first C-linked glucose and then a cyclomaltodextrin glucanotransferase from Bacillus licheniformis was used to extend the sugar chain.A total of twenty C-oligosaccharides with 2-6 sugars were synthesized from scale-up reactions and exhibited good water solubility and sodium-dependent glucose transporter 2(SGLT2)inhibitory activity.Furthermore,a glucoamylase was used to control the length of the sugar chain and the C-maltosides were efficiently synthesized.These findings not only expanded the structural diversity of C-oligosaccharides,but also provided a strategy for the modification of C-glycoside drugs to improve the druggability.

关键词： C-Oligosaccharides C-Glycosyltransferase Cyclomaltodextrin glucanotransferase Glucoamylase Enzymatic synthesis SGLT2 inhibitory activity

A fungal CYP from Beauveria bassiana with promiscuous steroid hydroxylation capabilities

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Chinese Chemical Letters 2024年第5期35卷 218-222页

作者： Yu Peng Yue Wang Tian-Jiao Chen Jing-Jing Chen Jin-Ling Yang Ting Gong Ping Zhu state key laboratory of bioactive Substance and function of natural medicines NHC Key Laboratory of Biosynthesis of Natural ProductsCAMS Key Laboratory of Enzyme and Biocatalysis of Natural DrugsInstitute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Hydroxylation of steroid core is critical to the synthesis of steroid drugs.Direct sp^(3) C-H hydroxylation is challenging through chemical catalysis,alternatively,fungal biotransformation offers a possible solution to this problem.However,mining and metabolic engineering of cytochrome P450 monooxygenases(CYPs)is usually regarded as a more eco-friendly and efficient strategy.Herein,we report the mining and identification of a new steroid CYP(CYP68BE1)from Beauveria bassiana by transcriptomics,heterologous expression,in vivo and in vitro functional characterization.The catalytic promiscuity of CYP68BE1 was explored,and CYP68BE1 showed promiscuously and catalytically versatile,which is qualified for monohydroxylation on C11α,C1α,C6βand dihydroxylation on C1β,11αand C6β,11αof six steroids,leading to the production of key steroid intermediates required in the industrial synthesis of some indispensable steroid drugs.Molecular dynamics simulations were performed,revealing the molecular basis of different binding orientations of CYP68BE1 with different substrates.The discovery of CYP68BE1 offers a promising biocatalyst for enriching the steroid structural and functional diversity,which also can be applied to biosynthesize valuable steroid drug intermediates.

关键词： Fungal CYPs Steroid hydroxylase Beauveria bassiana Promiscuous biocatalyst Molecular dynamics

The raphe nuclei are the early lesion site of gastric α-synuclein propagation to the substantia nigra

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2057-2076页

作者： Chenglu Zhang Ruxue Bo Tiantian Zhou Naihong Chen Yuhe Yuan state key laboratory of bioactive substances and functions of natural medicines Chinese Academy of Medical Sciences&Peking Union Medical College Institute of Materia MedicaBeijing 100050China

Parkinson's disease(PD)is a neurodegeneration disease withα-synuclein accumulated in the substantia nigra pars compacta(SNpc)and most of the dopaminergic neurons are lost in SNpc while patients are diagnosed with PD.Exploring the pathology at an early stage contributes to the development of the disease-modifying strategy.Although the“gut–brain”hypothesis is proposed to explain the underlying mechanism,where the earlier lesioned site in the brain of gastricα-synuclein and howα-synuclein further spreads are not fully understood.Here we report that caudal raphe nuclei(CRN)are the early lesion site of gastricα-synuclein propagating through the spinal cord,while locus coeruleus(LC)and substantia nigra pars compacta(SNpc)were further affected over a time frame of 7 months.Pathologicalα-synuclein propagation via CRN leads to neuron loss and disordered neuron activity,accompanied by abnormal motor and non-motor behavior.Potential neuron circuits are observed among CRN,LC,and SNpc,which contribute to the venerability of dopaminergic neurons in SNpc.These results show that CRN is the key region for the gastricα-synuclein spread to the midbrain.Our study provides valuable details for the“gut–brain”hypothesis and proposes a valuable PD model for future research on early PD intervention.

关键词： Raphe nuclei α-Synuclein Gastrointestinal tract Electrophysiology Locus coeruleus Substantia nigra pars compacta Parkinson's disease Spinal cord

Effective assignment of positional isomers in dimeric shikonin and its analogs by ^(1)H NMR spectroscopy

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Chinese Chemical Letters 2024年第5期35卷 223-226页

作者： Ling-Hao Zhao Hai-Wei Yan Jian-Shuang Jiang Xu Zhang Xiang Yuan Ya-Nan Yang Pei-Cheng 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

An approach for distinguishing two types of positional isomers of dimeric shikonin and its analogs was explored with ^(4)JC,H long-range correlation by prolonging the acquisition time at ^(2,3)JC,H values of 2.0 and 8.0Hz.Furthermore,the ^(1)H(proton)nuclear magnetic resonance(NMR)pattern of phenolic hydroxyl protons was developed as a“diagnosis signal”to ascertain the relative location of each side chain in DMSO-d_(6) at sample concentrations of 0.022-0.034 mol/L.The chemical shift differences of 0.6ppm between OH-5' and OH-1 and between OH-8'and OH-4 are assigned to Type A and Type B,respectively.All reported ambiguous structures were corrected by this pattern.Additionally,the steric structures of isolated compounds were elucidated by quantum chemical calculations of electronic circular dichroism(ECD)spectra.

关键词： Arnebia euchroma Dimeric hydroxyl naphthoquinones Positional isomers ^(1)H NMR spectroscopy Chemical shift difference

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

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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 cancer.TCP-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 cancer.The mechanism of the targeted binding of TCP-1 to colon cancer was also studied using immunoprecipitation,LC-MS and bioinformatics.After 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 tissue.Pharmacokinetics studies were conducted to investigate the target-mediated drug disposition of the new tumor-specific peptide by LC-MS/MS.The 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 tissues.Conjugating TCP-1 to tumor markedly increased its removal rate from blood circulation but mildly extended its staying time in vivo.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 mice.The proposed metabolic pathway of TCP-1 in the kidney was also determined using LC-MS^(n)-IT-TOF.The high specificity and low toxicity of the peptide may be caused by its extremely tight binding to the targets.Potential 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)

Heavy-atom engineered hypoxia-responsive probes for precisive photoacoustic imaging and cancer therapy

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Chinese Chemical Letters 2024年第4期35卷 316-320页

作者： Ling-Ling Wu Xiangchuan Meng Qingyang Zhang Xiaowan Han Feiya Yang Qinghua Wang Hai-Yu Hu Nianzeng Xing Department of Urology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China state key laboratory of bioactive substances and function of natural medicine Institute of Materia MedicaPeking Union Medical College and Chinese Academy of Medical SciencesBeijing 100050China

Photoacoustic agents combining photodynamic therapy(PDT) and photothermal therapy(PTT) functions have emerged as potent theranostic agents for combating cancer. The molecular approaches for enhancing the near-infrared(NIR)-absorption and maximizing non-radiative energy transfer are essential for effective photoacoustic imaging(PAI) and therapy applications. In addition, such molecules with high specificity and affinity to cancer cells are urgently needed, which would further decrease the side effect during treatments. In this study, we applied a heavy-atom engineering strategy and introduced p-aminophenol,-thio, and-seleno moieties into NIR heptamethine cyanine(Cy7) skeleton(Cy7-X-NH_(2), X = O, S, Se) to significantly increase photothermal conversion efficiency for PTT and promote intersystem crossing for PDT.Additionally, we designed a series of nitroreductase(NTR)-activated photoacoustic probes(Cy7-X-NO_(2),X = O, S, Se), and target hypoxic tumors with NTR overexpression. Our prostate cancer targeting probe,Cy7-Se-NO_(2)-KUE, exhibited specific tumor photoacoustic signals and effective tumor killing through outstanding synergistic PTT/PDT in vivo. These findings highlighted a versatile strategy for cancer photoacoustic diagnosis and enhanced phototherapy.

关键词： Heavy-atom effect Phototherapy Photoacoustic imaging Hypoxia-responsive Prostate cancer

Unlocking the potential of amorphous calcium carbonate: A star ascending in the realm of biomedical application

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Acta Pharmaceutica Sinica B 2024年第2期14卷 602-622页

作者： Han Liu Zhiyang Wen Zihan Liu Yanfang Yang Hongliang Wang Xuejun Xia Jun Ye Yuling Liu state key laboratory of bioactive Substance and function of natural medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Beijing key laboratory of Drug Delivery Technology and Novel Formulation Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China

Calcium-based biomaterials have been intensively studied in the field of drug delivery owing to their excellent biocompatibility and biodegradability.Calcium-based materials can also deliver contrast agents,which can enhance real-time imaging and exert a Ca^(2+)-interfering therapeutic effect.Based on these characteristics,amorphous calcium carbonate(ACC),as a brunch of calcium-based biomaterials,has the potential to become a widely used biomaterial.Highly functional ACC can be either discovered in natural organisms or obtained by chemical synthesis However,the standalone presence of ACC is unstable in vivo.Additives are required to be used as stabilizers or core-shell structures formed by permeable layers or lipids with modified molecules constructed to maintain the stability of ACC until the ACC carrier reaches its destination.ACC has high chemical instability and can produce biocompatible products when exposed to an acidic condition in vivo,such as Ca^(2+) with an immune-regulating ability and CO_(2) with an imaging-enhancing ability.Owing to these characteristics,ACC has been studied for selfsacrificing templates of carrier construction,targeted delivery of oncology drugs,immunomodulation,tumor imaging,tissue engineering,and calcium supplementation.Emphasis in this paper has been placed on the origin,structural features,and multiple applications of ACC.Meanwhile,ACC faces many challenges in clinical translation,and long-term basic research is required to overcome these challenges.We hope that this study will contribute to future innovative research on ACC.

关键词： Amorphous calcium carbonate Drugdelivery system Nanoparticle Acid sensitivity Water instability,Tumortherapy Tissue engineering Calcium supplement

Concise Synthesis of Lactococcus garvieae Lipoteichoic Acids Through an Additive-Modulated Preactivation Protocol and the Immunological Studies

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CCS Chemistry 2024年第2期6卷 403-414页

作者： Tianlu Li Tong Li Yue Yang Haoru Zhuang Jianwu Lv Ning Zhou Miaomiao Zhang Fengshan Wang Yiqun Geng Richard R.Schmidt Peng Peng National Glycoengineering Research Center Shandong Key Laboratory of Carbohydrate Chemistry and GlycobiologyNMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based MedicineShandong UniversityQingdao 266237 state key laboratory of bioactive Substance and function of natural medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050 Department of Chemistry University of KonstanzD-78457 Konstanz

Lipoteichoic acids(LTAs)are macroamphiphiles composed of alditol,lipid,phosphate,and carbohydrate units.Due to their inherent complexity,it is a severe challenge to access LTAs with structural integrity from natural sources for biological or immunological evaluation.Here,we describe the first total synthesis of Lactococcus garvieae LTA(type II LTA),containing five distinct 1,2-cis gluco/galactopyranosidic linkages,via a novel additive-modulated O-glycosyl trichloroacetimidate preactivation glycosidation strategy.This strategy features(1)high glycosidation yields and excellent 1,2-cis stereoselectivities independent of the donor anomeric configuration,(2)common and inexpensive reagents as promoters and additives,(3)application to standard glycosyl imidate donors without resorting to participating protection,and(4)general application to reactive and less reactive glycosyl acceptors.Thus,via the precise stereocontrolled construction of three galactopyranosidic and two glucopyranosidic bonds on a multigram scale,a series of structurally well-defined LTA molecules were successfully assembled.Immunological evaluation of these type II synthetic LTAs showed a structure–activity relationship in the stimulation of a proinflammatory response.

关键词： 1,2-cis glycosidation stereoselectivity lipoteichoic acid total synthesis additive-modulated trichloroacetimidate glycosidation immune response