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Osteoblastic sclerostin loop3-LRP4 interaction required by sclerostin to inhibit bone formation 认领 引用
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作者 Luyao Wang Xiaohui Tao +23 位作者 Hewen Jiang Shijian Ding Ning Zhang Xin Yang Shenghang Wang Yihao Zhang Nanxi Li Haitian Li Zhanghao Li Xiaoxin Wen Meiheng Sun Chuanxin Zhong Heiwa So Jin Liu Yuanyuan Yu Hua Yue Xianghang Luo Péter Ferdinandy Tao Zhang Shu Zhang Zhenlin Zhang Aiping Lu Baoting Zhang Ge Zhang 《Bone Research》 SCIE CAS CSCD 2026年第3期949-962,共14页
Sclerostin negatively regulates bone formation.The marketed antibody against sclerostin loop2 promoted bone formation but may have caused severe cardiovascular events in clinical use.In our published studies,sclerosti... Sclerostin negatively regulates bone formation.The marketed antibody against sclerostin loop2 promoted bone formation but may have caused severe cardiovascular events in clinical use.In our published studies,sclerostin loop3 was found to be involved in inhibitory effects of sclerostin on bone formation,whereas cardiovascular protective effects of sclerostin in mice were independent of loop3.It is necessary to investigate how sclerostin loop3 participates in the inhibitory effects of sclerostin on bone formation to facilitate developing precise strategies that promote bone formation without increasing cardiovascular risk.In this study,sclerostin loop3 was identified to bind to LRP4,thereby facilitating binding of sclerostin to LRP6 in osteoblasts.Blockade of sclerostin loop3-LRP4 interaction by both Lrp4 mutation(Lrp4m)and blocking peptide(LRP4-Pep)diminished the antagonistic effect of sclerostin on Wnt/β-catenin signaling in osteoblasts in vitro.Consistently,Lrp4m promoted bone formation in Lrp4m mice in vivo.Mechanistically,osteoblast-conditional correction of Lrp4m to wild-type Lrp4 resulted in significantly lower bone formation than Lrp4m mice,indicating that the promotive effects of Lrp4m on bone formation acted in osteoblasts in vivo.Moreover,re-expression of sclerostin dramatically inhibited bone formation in sost−/−mice,whilst the inhibitory effects of sclerostin were significantly weaker in sost−/−.Lrp4m mice.Pharmacologically,LRP4-Pep diminished the inhibitory effects of sclerostin on bone formation in SOSTki mice.Taken together,osteoblastic sclerostin loop3-LRP4 interaction,as an anchor,was required by sclerostin to bind to LRP6,thereby inhibiting bone formation.Translationally,blockade of sclerostin loop3-LRP4 interaction in osteoblasts would provide precise therapeutic strategies to promote bone formation without increasing cardiovascular risk. 展开更多
关键词 Wnt catenin signaling osteoblastic interaction sclerostin loop bone formation LRP cardiovascular risk
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Value of pre-treatment biomarkers in prediction of response to neoadjuvant endocrine therapy for hormone receptor-positive postmenopausal breast cancer 认领 引用 被引量：2
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作者 Min Ying Yingjian He +7 位作者 Meng Qi Bin Dong Aiping Lu Jinfeng Li Yuntao Xie Tianfeng Wang Benyao Lin Tao Ouyang 《Chinese Journal of Cancer Research》 SCIE CAS CSCD 2013年第4期397-404,共8页
Objective： To determine the predictive ability of biomarkers for responses to neoadjuvant endocrine therapy （NET） in postmenopausal breast cancer. Methods： Consecutive 160 postmenopausal women with T 1-3 N 0-1 M 0... Objective： To determine the predictive ability of biomarkers for responses to neoadjuvant endocrine therapy （NET） in postmenopausal breast cancer. Methods： Consecutive 160 postmenopausal women with T 1-3 N 0-1 M 0 hormone receptor （HR）-positive invasive breast cancer were treated with anastrozole for 16 weeks before surgery. New slides of tumor specimens taken before and after treatment were conducted centrally for biomarker analysis and classified using the Applied Imaging Ariol MB-8 system. The pathological response was evaluated using the Miller ＆ Payne classification. The cell cycle response was classified according to the change in the Ki67 index after treatment. Multivariable logistic regression analysis was used to calculate the combined index of the biomarkers. Receiver operating characteristic （ROC） curves were used to determine whether parameters may predict response. Results： The correlation between the pathological and cell cycle responses was low （Spearman correlation coefficient =0.241, P〈0.001; Kappa value =0.119, P=0.032）. The cell cycle response was significantly associated with pre-treatment estrogen receptor （ER） status （P=0.001）, progesterone receptor （PgR） status （P〈0.001）, human epidermal growth factor receptor 2 （Her-2） status （P=0.050） and the Ki67 index （P〈0.001）, but the pathological response was not correlated with these factors. Pre-treatment ER levels [area under the curve （AUC） =0.634, 95% confidence interval （95% CI）, 0.534-0.735, P=0.008] and combined index of pre-treatment ER and PgR levels （AUC =0.684, 95% CI, 0.591-0.776, P〈0.001） could not predict the cell cycle response, but combined index including per-treatment ER/PR/Her-2/Ki67 expression levels could （AUC =0.830, 95% CI, 0.759-0.902, P〈0.001）. Conclusions： The combined use of pre-treatment ER/PgR/Her-2/Ki67 expression levels, instead of HR expression levels, may predict the cell cycle response to NET. 展开更多
关键词 Breast cancer neoadjuvant endocrine therapy （NET） responsiveness predictive value
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Gut microbial metabolite targets HDAC3-FOXK1-interferon axis in fibroblast-like synoviocytes to ameliorate rheumatoid arthritis 认领 引用 被引量：11
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作者 Hongzhen Chen Xuekun Fu +15 位作者 Xiaohao Wu Junyi Zhao Fang Qiu Zhenghong Wang Zhuqian Wang Xinxin Chen Duoli Xie Jie Huang Junyu Fan Xu Yang Yi Song Jie Li Dongyi He Guozhi Xiao Aiping Lu Chao Liang 《Bone Research》 SCIE CAS CSCD 2024年第2期421-437,共17页
Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that gene... Rheumatoid arthritis(RA)is an autoimmune disease.Early studies hold an opinion that gut microbiota is environmentally acquired and associated with RA susceptibility.However,accumulating evidence demonstrates that genetics also shape the gut microbiota.It is known that some strains of inbred laboratory mice are highly susceptible to collagen-induced arthritis(CIA),while the others are resistant to CIA.Here,we show that transplantation of fecal microbiota of CIA-resistant C57BL/6J mice to CIA-susceptible DBA/1J mice confer CIA resistance in DBA/1J mice.C57BL/6J mice and healthy human individuals have enriched B.fragilis than DBA/1J mice and RA patients.Transplantation of B.fragilis prevents CIA in DBA/1J mice.We identify that B.fragilis mainly produces propionate and C57BL/6J mice and healthy human individuals have higher level of propionate.Fibroblast-like synoviocytes(FLSs)in RA are activated to undergo tumor-like transformation.Propionate disrupts HDAC3-FOXK1 interaction to increase acetylation of FOXK1,resulting in reduced FOXK1 stability,blocked interferon signaling and deactivation of RA-FLSs.We treat CIA mice with propionate and show that propionate attenuates CIA.Moreover,a combination of propionate with anti-TNF etanercept synergistically relieves CIA.These results suggest that B.fragilis or propionate could be an alternative or complementary approach to the current therapies. 展开更多
关键词 HDAC3 cytes interferon
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One-pot synthesis of silver colloid with body-heat for surface-enhanced Raman spectroscopy detections 认领 引用 被引量：3
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作者 Wanchao Chen Yan Kang +4 位作者 Han Zhang Tianxiong Huang Xin Tao Aiping Lu Yiping Du 《Chinese Chemical Letters》 SCIE CAS CSCD 2019年第5期1027-1030,共4页
In this study,a convenient method of preparing the substrate is proposed with one-pot synthesis of silver colloid under body heat,and the SERS detection uses the fresh substrate to avoid the drawback of substrates’sh... In this study,a convenient method of preparing the substrate is proposed with one-pot synthesis of silver colloid under body heat,and the SERS detection uses the fresh substrate to avoid the drawback of substrates’short life of use.The synthesis of silver colloid is carried out in a 10 mL vial by using ascorbic acid as a reductant and trisodium citrate as a stabilizer.The vial is grasped with the palm of the experimenter for several minutes without shaking.The proposed method is simple,rapid,green energy and cost-effective.By adjusting the concentration of trisodium citrate,not only the particle size can be controlled from about 110 nm to 50 nm but also the homogeneity of nanoparticles can be improved.As a SERS substrate,the silver colloid has high batch reproducibility and showed good SERS activity.The relative standard deviation between different manufacturers is 5.51%when the substrate of silver colloid is used for the detection of rhodamine 6 G.Using the substrate,the lowest detection concentrations of rhodamine 6 G,crystal violet,enrofloxacin,melamine and leucomalachite green are 1.0×10-8,6.1×10-8,1.4×10-6,7.1×10-5 and 5.1×10-8 mol/L,respectively.Results demonstrate that the developed method has the advantage of convenience and high efficiency in the field preparation of reliable SERS substrate. 展开更多
关键词 One-pot synthesis Silver colloid Substrate Surface-enhanced Raman spectroscopy (SERS)
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Treatment Principles of Obesity with Chinese Herbal Medicine: Literature Analysis by Text Mining 认领 引用
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作者 Yunyu Huang Lianjie Wang +5 位作者 Shidong Wang Feng Cai Guang Zheng Aiping Lu Xiuchen Yu Miao Jiang 《Engineering（科研）》 2013年第10期7-11,共5页
Obesity represents a social health problem worldwide, associated with serious health risks and increased mortality. The prevalence of obesity is reported to be increasing in both developed and developing countries. Ob... Obesity represents a social health problem worldwide, associated with serious health risks and increased mortality. The prevalence of obesity is reported to be increasing in both developed and developing countries. Obesity is associated with a significant range of comorbidities and is linked with increases in mortality, thus the treatment of obesity is very important. Chinese herbal medicine (CHM) has been used for weight management both in China and in western countries for many years, the effectiveness and safety of CHMs in obesity have been proved. Yet the principles of treating obesity with CHMs are hard to manage due to the complexity of TCM theory. In this study, a novel text mining method was developed based on a comprehensive collection of literatures in order to explore the treatment principles more intuitively. Networks of TCM patterns and CHMs which are most frequently used in obesity treatment are built-up and analyzed, two major principles are explored in treating obesity: one is resolving phlegm and dampness, the other is clearing heat and reinforcing deficiency. These findings might guide the clinicians in treatment of obesity. 展开更多
关键词 Obesity Chinese Herbal Medicine Pattern Traditional Chinese Medicine Text Mining
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Elevating traditional Chinese medicine in global health research: The case for Chinese herbal medicine formulas in mainstream therapeutics 认领 引用 被引量：1
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作者 Aiping Lu 《The Innovation》 EI 2025年第4期11-12,共2页
In recent years,there has been a notable increase in the publication of clinical research on traditional Chinese medicine(TCM)in internationally renowned journals.Historically,publications on TCM in top medical journa... In recent years,there has been a notable increase in the publication of clinical research on traditional Chinese medicine(TCM)in internationally renowned journals.Historically,publications on TCM in top medical journals such as the Annals of Internal Medicine,the British Medical Journal,The Lancet,the Journal of the American Medical Association,and the New England Journal of Medicine have predominantly focused on acupuncture,with over 46 randomized controlled trials(RCTs)published on this topic.In contrast,only three RCTs on Chinese herbal medicine(CHM)formulas have been published in these five journals.However,there have been nearly 200 RCTs on CHMformulas published in Q1 journals,indicating a significant body of research in this area within the top-tier scientific community.A prime example of this is the recent publication of“Traditional Chinese medicine FYTF-919(Zhongfeng Xingnao oral prescription)for the treatment of acute intracerebral haemorrhage:a multicentre,randomised,placebo-controlled,double-blind,clinical trial”in The Lancet on November 12,2024.1 This publication underscores the growing recognition of CHMformulas in mainstream therapeutics and presents significant opportunities for further investigation and reflection in this field. 展开更多
关键词 Annals Internal Medicine chinese herbal medicine formulas top medical journals acupuncture clinical research traditional chinese medicine tcm randomized controlled trials traditional chinese medicine
Comparison of 5 BMPs for their chondrogenic potentials and microfracture-mediated cartilage repair using heparin/PEAD coacervate sustained release polymer 认领 引用
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作者 Xueqin Gao Nathaniel Wright +8 位作者 Matthieu Huard Jian Tan Joseph Ruzbarsky Aiping Lu Laura Chubb Rocky Tuan Marc J.Philippon Yadong Wang Johnny Huard 《Bioactive Materials》 SCIE CSCD 2025年第10期588-603,共16页
Cartilage defect repair and osteoarthritis treatments remain clinical challenges.Microfracture is a commonly used surgical procedure for the treatment of cartilage defects but often leads to fibrocartilage repair.The ... Cartilage defect repair and osteoarthritis treatments remain clinical challenges.Microfracture is a commonly used surgical procedure for the treatment of cartilage defects but often leads to fibrocartilage repair.The aim of this study is to compare the effects of 5 bone morphogenetic proteins(BMPs)on chondrogenic differentiation of human bone marrow mesenchymal stem cells,as well as to investigate the use of the heparin/poly(ethylene arginine aspartate diglyceride(PEAD)coacervate sustained release system to deliver these BMPs for microfracture-mediated cartilage repair.Our results indicate that all 5 human BMPs significantly enhance the chondrogenic differentiation of human bone marrow mesenchymal stem cells(hBMMSCs)with BMPs 2,4 and 9 being more potent than BMP6 or BMP7,as revealed by Alcian blue,SO staining,and immunohistochemistry of COL2.Coacervate-BMPs are biocompatible for both hBMMSCs and rat muscle-derived stem cells(MDSCs)and promote their proliferation.In vivo,sustained release of human BMPs 2,4,6,7,9 with heparin/PEAD coacervate significantly enhances microfracture-mediated cartilage repair in a rat osteochondral defect model,as demon-strated by ICRS macroscopic score,Seller’s histology score,and COL2 staining.These effects are mediated by increasing SOX9 expression in the regenerated cartilage.In conclusion,BMPs 2,4,9 are the most potent BMPS to promote chondrogenic differentiation,while all BMPs enhanced microfracture-mediated cartilage repair when delivered with heparin/PEAD coacervate without a significant difference between the different BMPs. 展开更多
关键词 BMP2,4,6,7,9 In vitro chondrogenesis Microfracture Cartilage repair Human bone marrow mesenchymal stem cells
Drug discovery of sclerostin inhibitors 认领 引用 被引量：7
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作者 Sifan Yu Dijie Li +14 位作者 Ning Zhang Shuaijian Ni Meiheng Sun Luyao Wang Huan Xiao Dingdong Liu Jin Liu Yuanyuan Yu Zongkang Zhang Samuel Tin Yui Yeung Shu Zhang Aiping Lu Zhenlin Zhang Baoting Zhang Ge Zhang 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2022年第5期2150-2170,共21页
Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contrib... Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA,the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis;however, it conferred high cardiovascular risk in clinical trials. Furthermore,romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy. 展开更多
关键词 Sclerostin WNT signalling pathway Sclerostin inhibitors Antibody Bone diseases Aptamer Small molecule inhibitors Artificial intelligence
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Natural products for infectious microbes and diseases:an overview of sources,compounds,and chemical diversities 认领 引用 被引量：6
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作者 Lu Luo Jun Yang +8 位作者 Cheng Wang Jie Wu Yafang Li Xu Zhang Hui Li Hui Zhang Yumei Zhou Aiping Lu Shilin Chen 《Science China(Life Sciences)》 SCIE CAS CSCD 2022年第6期1123-1145,共23页
As coronavirus disease 2019(COVID-19) threatens human health globally,infectious disorders have become one of the most challenging problem for the medical community.Natural products(NP) have been a prolific source of ... As coronavirus disease 2019(COVID-19) threatens human health globally,infectious disorders have become one of the most challenging problem for the medical community.Natural products(NP) have been a prolific source of antimicrobial agents with widely divergent structures and a range of vast biological activities.A dataset comprising 618 articles,including 646 NP-based compounds from 672 species of natural sources with biological activities against 21 infectious pathogens from five categories,was assembled through manual selection of published articles.These data were used to identify 268 NP-based compounds classified into ten groups,which were used for network pharmacology analysis to capture the most promising lead-compounds such as agelasine D,dicumarol,dihydroartemisinin and pyridomycin.The distribution of maximum Tanimoto scores indicated that compounds which inhibited parasites exhibited low diversity,whereas the chemistries inhibiting bacteria,fungi,and viruses showed more structural diversity.A total of 331 species of medicinal plants with compounds exhibiting antimicrobial activities were selected to classify the family sources.The family Asteraceae possesses various compounds against C.neoformans,the family Anacardiaceae has compounds against Salmonella typhi,the family Cucurbitacea against the human immunodeficiency virus(HIV),and the family Ancistrocladaceae against Plasmodium.This review summarizes currently available data on NPbased antimicrobials against refractory infections to provide information for further discovery of drugs and synthetic strategies for anti-infectious agents. 展开更多
关键词 natural product infectious pathogen drug discovery drug development in silico analysis
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Virtual screening of the inhibitors targeting at the viral protein 40 of Ebola virus 认领 引用 被引量：1
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作者 V.Karthick N.Nagasundaram +5 位作者 C.George Priya Doss Chiranjib Chakraborty R.Siva Aiping Lu Ge Zhang Hailong Zhu 《Infectious Diseases of Poverty》 SCIE CAS 2016年第1期97-106,共10页
Background:The Ebola virus is highly pathogenic and destructive to humans and other primates.The Ebola virus encodes viral protein 40(VP40),which is highly expressed and regulates the assembly and release of viral par... Background:The Ebola virus is highly pathogenic and destructive to humans and other primates.The Ebola virus encodes viral protein 40(VP40),which is highly expressed and regulates the assembly and release of viral particles in the host cell.Because VP40 plays a prominent role in the life cycle of the Ebola virus,it is considered as a key target for antiviral treatment.However,there is currently no FDA-approved drug for treating Ebola virus infection,resulting in an urgent need to develop effective antiviral inhibitors that display good safety profiles in a short duration.Methods:This study aimed to screen the effective lead candidate against Ebola infection.First,the lead molecules were filtered based on the docking score.Second,Lipinski rule of five and the other drug likeliness properties are predicted to assess the safety profile of the lead candidates.Finally,molecular dynamics simulations was performed to validate the lead compound.Results:Our results revealed that emodin-8-beta-D-glucoside from the Traditional Chinese Medicine Database(TCMD)represents an active lead candidate that targets the Ebola virus by inhibiting the activity of VP40,and displays good pharmacokinetic properties.Conclusion:This report will considerably assist in the development of the competitive and robust antiviral agents against Ebola infection. 展开更多
关键词 Ebola VP40 Traditional Chinese Medicine Database Molecular docking Molecular dynamics
Targeted protein degradation in cancers:Orthodox PROTACs and beyond 认领 引用 被引量：5
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作者 Jin Li Xinxin Chen +1 位作者 Aiping Lu Chao Liang 《The Innovation》 EI 2023年第3期5-19,共15页
Targeted protein degradation(TPD)is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors.Proteolysis-targeting chimera(PROTAC)technology can be used to target proteins by hijacki... Targeted protein degradation(TPD)is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors.Proteolysis-targeting chimera(PROTAC)technology can be used to target proteins by hijacking the ubiquitin-proteasome system.Conceptually,PROTAC aims to target the“undruggable”majority of proteins in the human proteome.Through constant exploration and optimization of PROTACs and the exploitation of other TPD strategies over two decades,TPD has expanded from theoretical studies to clinical strategies,with practical applications in oncological,immunological,and other diseases.In this review,we introduce the mechanisms,features,and molecular targets of orthodox PROTACs and summarize the PROTAC drugs under study as cancer therapeutics in clinical trials.We also discuss PROTAC derivatives and other TPD strategies,such as lysosome-targeting chimeras,autophagy-targeting chimeras,and molecular glue strategies.Collectively,the studies summarized herein support the full potential of TPD in the biomedical industry. 展开更多
关键词 overcome summarized herein
Correlation between cold and hot pattern in traditional Chinese medicine and gene expression profiles in rheumatoid arthritis 认领 引用 被引量：8
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作者 Miao Jiang Cheng Xiao +9 位作者 Gao Chen Cheng Lu Qinglin Zha Xiaoping Yan Weiping Kong Shijie Xu Dahong Ju Pu Xu Youwen Zou Aiping Lu 《Frontiers of Medicine》 CSCD 2011年第2期219-228,共10页
Clinical manifestations of rheumatoid arthritis(RA)are diversified,and based on the manifestations,the patients with RA could be classified into different patterns under traditional Chinese medicine.These patterns dec... Clinical manifestations of rheumatoid arthritis(RA)are diversified,and based on the manifestations,the patients with RA could be classified into different patterns under traditional Chinese medicine.These patterns decide the selection of herbal prescription,and thus they can help find a subset of rheumatoid arthritis patients for a type of therapy.In the present study,we combine genome-wide expression analysis with methods of systems biology to identify the functional gene networks for the sets of clinical symptoms that comprise the major information for pattern classification.Clinical manifestations in rheumatoid arthritis were clustered with factor analysis,and two factors(similar to cold and hot patterns in traditional Chinese medicine)were found.Microarray technology was used to reveal gene expression profiles in CD4+T cells from 21 rheumatoid arthritis patients.Protein-protein interaction information for these genes from databases and literature data was searched.The highly-connected regions were detected to infer significant complexes or pathways in this protein-protein interaction network.The significant pathways and function were extracted from these subnetworks using the Biological Network Gene Ontology tool.The genes significantly related to hot and cold patterns were identified by correlations analysis.MAPK signalling pathway,Wnt signaling pathway,and insulin signaling pathway were found to be related to hot pattern.Purine metabolism was related to both hot and cold patterns.Alanine,aspartate,and tyrosine metabolism were related to cold pattern,and histindine metabolism and lysine degradation were related to hot pattern.The results suggest that cold and hot patterns in traditional Chinese medicine were related to different pathways,and the network analysis might be used for identifying the pattern classification in other diseases. 展开更多
关键词 gene expression profile pathway rheumatoid arthritis traditional Chinese medicine systems biology
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