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Chinese Chemical Letters 2024年第8期35卷 187-200页

作者： Si Ha Jiacheng Zhu Hua Xiang Guoshun Luo State Key Laboratory of Natural medicines and department of Medicinal Chemistry China Pharmaceutical UniversityNanjing 211198China

Small molecule inhibitors have dominated the pharmaceutical landscape for a long time as the primary therapeutic paradigm targeting pathogenic ***,their efficacy heavily relies on the amino acid composition and spatial constitution of proteins,rendering them susceptible to drug resistance and failing to target undruggable *** recent years,the advent of targeted protein degradation(TPD)technology has captured substantial attention from both industry and *** an event-driven mode,TPD offers a novel approach to eliminate pathogenic proteins by promoting their degrada-tion,thus circumventing the limitations associated with traditional small molecule ***-bic tag tethering degrader(HyTTD)technology represents one such TPD approach that is currently in the burgeoning *** employ endogenous protein degradation systems to induce the degrada-tion of target proteins through the proteasome pathway,which displays significant potential for medical *** this review,we provide a comprehensive overview of the development history and the reported mechanism of action of ***,we delve into the physiological roles,structure-activity re-lationships,and medical implications of HyTTDs targeting various disease-associated ***,we propose insights into the challenges that necessitate resolution for the successful development of HyTTDs,with the ultimate goal of initiating a new age of clinical treatment leveraging the immense po-tential of HyTTDs.

关键词： Targeted protein degradation(TPD) Hydrophobic tag Degrader Hydrophobic tag tethering degrader(HyTTD) Targeted therapy

The Wnt-dependent and Wnt-independent functions of BCL9 in development,tumorigenesis,and immunity:Implications in therapeutic opportunities

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Genes & Diseases 2024年第2期11卷 701-710页

作者： Minjie Wu Heng Dong Chao Xu Mengqing Sun Haojin Gao Fangtian Bu Jianxiang Chen College of Pharmacy and department of Hepatology Institute of Hepatology and Metabolic DiseasesThe Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhouZhejiang 311121China Laboratory of Cancer Genomics Division of Cellular and Molecular ResearchNational Cancer CentreSingapore 169610Singapore Key Laboratory of Elemene Class Anti-Cancer Chinese medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhouZhejiang 311121China

B-cell CLL/lymphoma 9(BCL9)is considered a key developmental regulator and a well-established oncogenic driver in multiple cancer types,mainly through potentiating the Wnt/β-catenin ***,increasing evidences indicate that BCL9 also plays multiple Wnt-independent ***,we summarized the updates of the canonical and non-canonical functions of BCL9 in cellular,physiological,or pathological ***,we also concluded that the targeted inhibitors disrupt the interaction ofβ-catenin with BCL9 reported recently.

关键词： BCL9 Development Immunity Multifaceted functions Therapeutic target Tumorigenesis

Two types of coumarins-specific enzymes complete the last missing steps in pyran- and furanocoumarins biosynthesis

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Acta Pharmaceutica Sinica B 2024年第2期14卷 869-880页

作者： Yucheng Zhao Yuedong He Liangliang Han Libo Zhang Yuanzheng Xia Fucheng Yin Xiaobing Wang Deqing Zhao Sheng Xu Fei Qiao Yibei Xiao Lingyi Kong department of Resources Science of Traditional Chinese medicines School of Traditional Chinese Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China College of Bioscience and Biotechnology Hunan Agricultural UniversityChangsha 410128China Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural medicines Department of Natural Medicinal ChemistryChina Pharmaceutical UniversityNanjing 210009China Key Laboratory of Crop Gene Resources and Germplasm Enhancement in Southern China Ministry of AgricultureTropical Crops Genetic Resources InstituteChinese Academy of Tropical Agricultural SciencesHaikou 517317China Institute of Botany Jiangsu Province and Chinese Academy of SciencesNanjing 210014China department of Pharmacology School of Pharmacyand State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Pyran-and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofurans,respectively,exhibiting diverse physiological and medical ***,the biosynthetic mechanisms for their core structures remain poorly *** we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in *** included three distinct *** prenyltransferases(PpPT1e3)responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors,and two novel CYP450 cyclases(PpDC and PpOC)crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran *** analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring *** possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and assessed using site-specific *** identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic *** study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chemically diverse in terms of enzyme function and catalytic process.

关键词： Tetrahydropyrans Tetrahydrofurans Baldwin rules Coumarins CYP450cyclase

Tanshinone IIA ameliorates energy metabolism dysfunction of pulmonary fibrosis using 13C metabolic flux analysis

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Journal of Pharmaceutical Analysis 2024年第2期14卷 244-258页

作者： Baixi Shan Haoyan Zhou Congying Guo Xiaolu Liu Mingyu Wu Rao Zhai Jun Chen State Key Laboratory of Natural medicines China Pharmaceutical UniversityNanjing210009China department of Pharmacognosy School of Traditional Chinese PharmacyChina Pharmaceutical UniversityNanjing210009China

Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic target anti-PF. The well-documented against PF properties of Tanshinone IIA (Tan IIA) have been primarily attributed to its antioxidant and anti-inflammatory potency. Emerging evidence suggests that Tan IIA may target energy metabolism pathways, including glycolysis and tricarboxylic acid (TCA) cycle. However, the detailed and advanced mechanisms underlying the anti-PF activities remain obscure. In this study, we applied [U-13C]-glucose metabolic flux analysis (MFA) to examine metabolism flux disruption and modulation nodes of Tan IIA in PF. We identified that Tan IIA inhibited the glycolysis and TCA flux, thereby suppressing the production of transforming growth factor-β1 (TGF-β1)-dependent extracellular matrix and the differentiation and proliferation of myofibroblasts in vitro. We further revealed that Tan IIA inhibited the expression of key metabolic enzyme hexokinase 2 (HK2) by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α) pathway activities, which decreased the accumulation of abnormal metabolites. Notably, we demonstrated that Tan IIA inhibited ATP citrate lyase (ACLY) activity, which reduced the collagen synthesis pathway caused by cytosol citrate consumption. Further, these results were validated in a mouse model of bleomycin-induced PF. This study was novel in exploring the mechanism of the occurrence and development of Tan IIA in treating PF using 13C-MFA technology. It provided a novel understanding of the mechanism of Tan IIA against PF from the perspective of metabolic reprogramming.

关键词： Pulmonary fibrosis Tanshinone IIA 13C-metabolic flux analysis Metabolic reprogramming

A PDGFRβ-targeting nanodrill system for pancreatic fibrosis therapy

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Chinese Chemical Letters 2024年第10期35卷 379-385页

作者： Han Han Bi-Te Chen Jia-Rong Ding Jin-Ming Si Tian-Jiao Zhou Yi Wang Lei Xing Hu-Lin Jiang State Key Laboratory of Natural medicines Department of Pharmaceutics China Pharmaceutical University department of Nephrology Changhai Hospital Naval Medical University College of Pharmacy Yanbian University

Activated pancreatic stellate cells(PSCs) are the main source of collagen layer deposition and the key target in pancreatic fibrosis. However, no effective treatment specific to pancreatic fibrosis clinically, owing to the drug accumulation blocked by the collagen barrier and thus it is difficult to inhibit activated PSCs precisely. Herein, a PSCs-targeting nano-system based on “nanodrill” strategy(LA-PC) was designed to enhance the accumulation of all-trans retinoic acid(ATRA) in PSCs, relying on the platelet-derived growth factor receptor beta(PDGFRβ)-targeting peptide(p PB: C*SRNLIDC*) and collagenase(Col). After being injected into fibrotic mice via tail vein, the Col modified on LA-PC can remove the excess collagen layer,and the drug delivery efficiency through pPB targeting peptide was more than 5 times higher than that of free ATRA, as well as the degree of fibrosis significantly reduced. Notably, this nano-system effectively inhibited platelet-derived growth factor subunit B(PDGF-BB)/PDGFRβ axis on PSCs via a down-regulated extracellular signal-regulated protein kinase(ERK) pathway, and accordingly reduced the level of PDGFBB. Thus, the smart platform provided a promising strategy for the treatment of pancreatic fibrosis to achieve the precise regulation of PSCs.

关键词： Liposome Pancreatic fibrosis Pancreatic stellate cells PDGFRβ pPB peptide

Monotropein Induced Apoptosis and Suppressed Cell Cycle Progression in Colorectal Cancer Cells

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Chinese Journal of Integrative Medicine 2024年第1期30卷 25-33页

作者： GAO Quan LI Lin ZHANG Qi-man SHENG Qin-song ZHANG Ji-liang JIN Li-jun SHANG Rui-yan School of Pharmacy and department of Medical Oncology the Affiliated Hospital of Hangzhou Normal UniversityHangzhou Normal UniversityHangzhou(311121)China Key Laboratory of Elemene Class Anti-Cancer Chinese medicines Engineering Laboratory of Development and Application of Traditional Chinese MedicinesCollaborative Innovation Center of Traditional Chinese Medicines of Zhejiang ProvinceHangzhou Normal UniversityHangzhou(311121)China department of Colorectal Surgery the First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina Beijing Tong Ren Tang Chinese Medicine Co. Ltd.Beijing(100000)China department of Traditional Chinese Medicine Hangzhou Shangcheng District People's HospitalHangzhou(310006)China department of Gynecology Hangzhou Women's HospitalHangzhou(310008)China

Objective: To determine whether monotropein has an anticancer effect and explore its potential mechanisms against colorectal cancer(CRC) through network pharmacology and molecular docking combined with experimental verification. Methods: Network pharmacology and molecular docking were used to predict potential targets of monotropein against CRC. Cell counting kit assay, plate monoclonal assay and microscopic observation were used to investigate the antiproliferative effects of monotropein on CRC cells HCT116, HT29 and LoVo. Flow cytometry and scratch assay were used to analyze apoptosis and cell cycle, as well as cell migration, respectively in HCT116, HT29, and LoVo cells. Western blotting was used to detect the expression of proteins related to apoptosis, cell cycle, and cell migration, and the expression of proteins key to the Akt pathway. Results: The Gene Ontology and Reactome enrichment analyses indicated that the anticancer potential of monotropein against CRC might be involved in multiple cancer-related signaling pathways. Among these pathways, RAC-beta serine/threonine-protein kinase(Akt1, Akt2), cyclin-dependent kinase 6(CDK6), matrix metalloproteinase-9(MMP9), epidermal growth factor receptor(EGFR), cell division control protein 42 homolog(CDC42) were shown as the potential anticancer targets of monotropein against CRC. Molecular docking suggested that monotropein may interact with the 6 targets(Akt1, Akt2, CDK6, MMP9, EGFR, CDC42). Subsequently, cell activity of HCT116, HT29 and LoVo cell lines were significantly suppressed by monotropein(P<0.05). Furthermore, our research revealed that monotropein induced cell apoptosis by inhibiting Bcl-2 and increasing Bax, induced G_1–S cycle arrest in colorectal cancer by decreasing the expressions of CyclinD1, CDK4 and CDK6, inhibited cell migration by suppressing the expressions of CDC42 and MMP9(P<0.05), and might play an anticancer role through Akt signaling pathway. Conclusions: Monotropein exerts its antitumor

关键词： monotropein Chinese medicine anticancer activity colorectal cancer cells network pharmacology

Ultra-warm artificial aerogel fibers:a biomimetic material based on polar bear hair

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Chinese Journal of Natural medicines 2024年第6期22卷 481-482页

作者： LI Yu LI Siwen State Key Laboratory of Natural medicines Jiangsu Key Laboratory of Drug ScreeningDepartment of Biomedical EngineeringSchool of EngineeringChina Pharmaceutical UniversityNanjing 211198China

Aerogels are widely recognized as the premier thermal insulation materials due to their high porosity and exception-ally low thermal conductivity^([1,2]).Regrettably,their wide-spread application in thermal insulation textiles is signific-antly limited by their fragility and poor ***-though many aerogel fibers made with silica^([3]),graphene^([4,5]),carbon nanotube^([6]),titanium oxide^([7]),and cellulose^([8])have been prepared through various methods.

关键词： Aerogel fibers Biomimetic materials Green technologies

Glutathione-depleted cyclodextrin pseudo-polyrotaxane nanoparticles for anti-inflammatory oxaliplatin(Ⅳ) prodrug delivery and enhanced colorectal cancer therapy

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Chinese Chemical Letters 2024年第4期35卷 280-286页

作者： Wenjia Wang Xingyue He Xiaojie Wang Tiantian Zhao Osamu Muraoka Genzoh Tanabe Weijia Xie Tianjiao Zhou Lei Xing Qingri Jin Hulin Jiang State Key Laboratory of Natural medicines China Pharmaceutical UniversityNanjing 210009China Faculty of Pharmacy Kinki University HigashiosakaOsaka 577-8502Japan State Key Laboratory of Natural medicines(SKLNM)and department of Medicinal Chemistry School of PharmacyChina Pharmaceutical UniversityNanjing 210009China School of Pharmacy Hangzhou Medical CollegeHangzhou 311399China College of Pharmacy Yanbian UniversityYanji 133002China

Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and prostaglandin E2(PGE2), which can promote tumor metastasis. Moreover,high glutathione(GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties(desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles(designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein,and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.

关键词： Oxaliplatin Glutathione depletion Tetravalent platinum prodrug Synergistic therapy Colorectal cancer

Eubacterium coprostanoligenes alleviates chemotherapy-induced intestinal mucositis by enhancing intestinal mucus barrier

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1677-1692页

作者： Dongsheng Bai Jiawei Zhao Runde Wang Jiaying Du Chen Zhou Chunyang Gu Yuxiang Wang Lulu Zhang Yue Zhao Na Lu State Key Laboratory of Natural medicines Jiangsu Key Laboratory of Carcinogenesis and InterventionDepartment of PhysiologySchool of Basic Medicine and Clinical PharmacyChina Pharmaceutical UniversityNanjing 210009China department of Clinical Pharmacology School of PharmacyNanjing Medical UniversityNanjing 211166China

Chemotherapy-induced mucositis represents a severe adverse outcome of cancer treatment,significantly curtailing the efficacy of these treatments and,in some cases,resulting in fatal *** identifying intestinal epithelial cell damage as a key factor in chemotherapy-induced mucositis,the paucity of effective treatments for such damage is *** our study,we discovered that Eubacterium coprostanoligenes promotes mucin secretion by goblet cells,thereby fortifying the integrity of the intestinal mucus *** enhanced barrier function serves to resist microbial invasion and sub-sequently reduces the inflammatory ***,this effect remains unobtrusive to the anti-tumor efficacy of chemotherapy ***,*** up-regulates the expression of AUF1,leading to the stabilization of Muc2 mRNA and an increase in mucin synthesis in goblet *** espe-cially significant finding is that *** activates the AhR pathway,thereby promoting the expression of *** summary,our results strongly indicate that *** enhances the intestinal mucus barrier,effec-tively alleviating chemotherapy-induced intestinal mucositis by activating the AhR/AUFl pathway,consequently enhancing Muc2 mRNA stability.

关键词： Chemotherapy Mucositis Eubacterium coprostanoligenes MUC2 AUF1

Natural polysaccharide-based smart CXCR4-targeted nano-system for magnified liver fibrosis therapy

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Chinese Chemical Letters 2024年第2期35卷 341-346页

作者： Liqiong Sun Xinping Luo Chenxi Zhou Zhanwei Zhou Minjie Sun College of Horticulture Nanjing Agricultural UniversityNanjing 210095China NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients State Key Laboratory of Natural MedicinesDepartment of PharmaceuticsChina Pharmaceutical UniversityNanjing 210009China

Activated hepatic stellate cells(aHSCs),the main source of extracellular matrix deposition,are key targets in liver ***,no effective drug specific to aHSCs has been clinically applied due to poor drug delivery ***,we designed a CXC chemokine receptor 4(CXCR4)-targeted reactive oxygen species(ROS)-responsive platform AMD-Dex-ROS-responsive-sorafenib(ARS)based on natural polysaccharide and thioctic acid frame,which can deliver anti-fibrosis drug represented by sorafenib specifically to aHSCs on account of CXCR4 over-expression on aHSCs,and smartly disassemble via ROS-responsive thioketal rupture relying on high intracellular ROS in HSCs,realized on-demand drug release and effective liver fibrosis ***,in this platform,the CXCR4 antagonist AMD3100 not only enhanced aHSCs targeting efficiency of sorafenib but also effectively magnified the aHSCs elimination of sorafenib by blocking stroma cell derived factor-1(SDF-1)/CXCR4-induced aHSCs protection,resulting in synergistic anti-fibrosis *** platform provided a new approach for drug delivery system design and liver fibrosis treatment.

关键词： Nanoparticle CXCR4 antagonism ROS-responsive Hepatic stellate cells Liver fibrosis