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| 1 | Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion显示文摘The recent outbreak of coronavirus disease(COVID-19)caused by SARS-CoV-2 infection in Wuhan,China has posed a serious threat to global public health.To develop specific anti-coronavirus therapeutics and prophylactics,the molecular mechanism that underlies viral infection must first be defined.Therefore,we herein established a SARS-CoV-2 spike(S)protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed a superior plasma membrane fusion capacity compared to that of SARS-CoV.We solved the X-ray crystal structure of six-helical bundle(6-HB)core of the HR1 and HR2 domains in the SARS-CoV-2 S protein S2 subunit revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with the HR2 domain.We previously developed a pan-coronavirus fusion inhibitor,EK1,which targeted the HR!domain and could inhibit infection by divergent human coronaviruses tested,including SARS-CoV and MERS-CoV.Here we generated a series of lipopeptides derived from EK1 and found that EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM,about 241-and 149-fold more potent than the original EK1 peptide,respectively.EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested,including SARS-CoV and MERS-CoV,as well as SARSr-CoVs,and potently inhibited the replication of 5 live human coronaviruses examined,including SARS-CoV-2.Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection,suggesting that EK1C4 could be used for prevention and treatment of infection by the currently circulating SARS-CoV-2 and other emerging SARSr-CoVs. | Shuai Xia Meiqin Liu Chao Wang Wei Xu Qiaoshuai Lan Siliang Feng Feifei Qi Linlin Bao Lanying Du Shuwen Liu Chuan Qin Fei Sun Zhengli Shi Yun Zhu Shibo Jiang Lu Lu | 2020 | Cell Research2020，30，4： | 81 |
| 2 | HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation显示文摘N6-methyladenosine(m6A),and its reader protein YTHDF1,play a pivotal role in human tumorigenesis by affecting nearly everystage of RNA metabolism.Autophagy activation is one of the ways by which cancer cells survive hypoxia.However,the possibleinvolvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma(HCO).In this study,specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing,knockout,and-knockdownHCC cells,HCC organoids,and HCC patient-derived xenograft(PDX)murine models.YTHDF1 expression and hypoxia inducedautophagy were significantly correlated in vitro;signifhcant overexpression of YTHDF1 in HCC tissues was associated with poorprognosis,Multivariate cox regression analysis identihed YTHDF1 expression as an independent prognostic factor in patients withHCC.Multiple HC models conhrmed that YTHDF1 deficiency inhibited HCC autophagy,growth,and metastasis.Luciferase reporterassays and chromatin immunoprecipitation demonstrated that HlIF-1a regulated YTHDF1 transcription by directly binding to itspromoter region under hypoxia.The results of methylated RNA immunoprecipitation sequencing,proteomics,and polysomeprofling indicated that YTHDF1 contibuted to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modifhed ATG2A and ATG14 mRNA,thus facilitating autophagy and autophagy-related malignancy of HCC.Taken together,HlE-1d-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner.Our fndings suggest thatYTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC. | Qing Li Yong Ni Liren Zhang Runqiu Jiang Jing Xu Hong Yang Yuanchang Hu Jiannan Qiu Liyong Pu Jinhai Tang Xuehao Wang | 2021 | Signal Transduction and Targeted Therapy2021，6，3： | 24 |
| 3 | LncRNA Nron regulates osteoclastogenesis during orthodontic bone resorption显示文摘Activation of osteoclasts during orthodontic tooth treatment is a prerequisite for alveolar bone resorption and tooth movement.However,the key regulatory molecules involved in osteoclastogenesis during this process remain unclear.Long noncoding RNAs(lnc RNAs)are a newly identified class of functional RNAs that regulate cellular processes,such as gene expression and translation regulation.Recently,lnc RNAs have been reported to be involved in osteogenesis and bone formation.However,as the most abundant noncoding RNAs in vivo,the potential regulatory role of lnc RNAs in osteoclast formation and bone resorption urgently needs to be clarified.We recently found that the lnc RNA Nron(long noncoding RNA repressor of the nuclear factor of activated T cells)is highly expressed in osteoclast precursors.Nron is downregulated during osteoclastogenesis and bone ageing.To further determine whether Nron regulates osteoclast activity during orthodontic treatment,osteoclastic Nron transgenic(Nron c TG)and osteoclastic knockout(Nron CKO)mouse models were generated.When Nron was overexpressed,the orthodontic tooth movement rate was reduced.In addition,the number of osteoclasts decreased,and the activity of osteoclasts was inhibited.Mechanistically,Nron controlled the maturation of osteoclasts by regulating NFATc1 nuclear translocation.In contrast,by deleting Nron specifically in osteoclasts,tooth movement speed increased in Nron CKO mice.These results indicate that lnc RNAs could be potential targets to regulate osteoclastogenesis and orthodontic tooth movement speed in the clinic in the future. | Ruilin Zhang Junhui Li Gongchen Li Fujun Jin Zuolin Wang Rui Yue Yibin Wang Xiaogang Wang Yao Sun | 2020 | International Journal of Oral Science2020，12，2： | 9 |
| 4 | ZBP1(DAI/DLM-1) promotes osteogenic differentiation while inhibiting adipogenic differentiation in mesenchymal stem cells through a positive feedback loop of Wnt/β-catenin signaling显示文摘The lineage specification of mesenchymal stem/stromal cells(MSCs) is tightly regulated by a wide range of factors. Recently, the versatile functions of ZBP1(also known as DAI or DLM-1) have been reported in the blood circulation and immune systems.However, the biological function of ZBP1 during the lineage specification of MSCs is still unknown. In the present study, we found that ZBP1 was upregulated during osteogenesis but downregulated during adipogenesis in mouse bone marrow-derived MSCs(m BMSCs). ZBP1 was highly expressed in osteoblasts but expressed at a relatively low level in marrow adipocytes. Knockdown of ZBP1 inhibited alkaline phosphataseactivity, extracellular matrix mineralization, and osteogenesis-related gene expression in vitro and reduced ectopic bone formation in vivo. Knockdown of ZBP1 also promoted adipogenesis in MSCs in vitro. Conversely, the overexpression of ZBP1 increased the osteogenesis but suppressed the adipogenesis of MSCs. When the expression of ZBP1 was rescued, the osteogenic capacity of ZBP1-depleted m BMSCs was restored at both the molecular and phenotypic levels.Furthermore, we demonstrated that ZBP1, a newly identified target of Wnt/β-catenin signaling, was required for β-catenin translocation into nuclei. Collectively, our results indicate that ZBP1 is a novel regulator of bone and fat transdifferentiation via Wnt/β-catenin signaling. | Xuefeng Zhao Liang Xie Zhiyong Wang Jiongke Wang Hao Xu Xianglong Han Ding Bai Peng Deng | 2020 | Bone Research2020，8，2： | 8 |
| 5 | Curcumin inhibition of JNKs prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease through suppressing mitochondria dysfunction显示文摘Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood.The results of our recent experiments indicated that curcumin could protect dopaminergic neurons from apoptosis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)mouse model of Parkinson’s disease(PD).The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by curcumin in MPTP mouse model.Further studies showed that curcumin inhibited JNKs hyperphosphorylation induced by MPTP treatment.JNKs phosphorylation can cause translocation of Bax to mitochondria and the release of cytochrome c which both ultimately contribute to mitochondria-mediated apoptosis.These pro-apoptosis effect can be diminished by curcumin.Our experiments demonstrated that curcumin can prevent nigrostriatal degeneration by inhibiting the dysfunction of mitochondrial through suppressing hyperphosphorylation of JNKs induced by MPTP.Our results suggested that JNKs/mitochondria pathway may be a novel target in the treatment of PD patients. | Jing Pan Hui Li Jian-Fang Ma Yu-Yan Tan Qin Xiao Jian-Qing Ding Sheng-Di Chen | 2012 | Translational Neurodegeneration2012，1，1： | 7 |
| 6 | Studies of the Genotoxicity of Glycidyl Methacrylate (GMA)显示文摘The following experiments were conducted to evaluate the genotoxic effects of GMA (glycidyl methacrylale) on mammalian and human cells.(1) Using the absorption spectrum shift method in vitro, we observed that the maximums of calf thymus DNA and GMA were shifted toward longer wavelengths (a change of more than 15nm) and the absorbance decreased after incubation at room temperature for 15min or more.The result indicates that binding of DNA and GMA had occurred.The binding force is strong, not affected by the addition of concentrated sodium chloride solution, and only slightly decreased by the addition of 8 M urea solution.Therefore the bond between DNA and GMA might be covalent.(2) In cell cultures, unscheduled DNA synthesis (UDS) in human and/or rat lymphocyte was induced and DNA semiconserva-tive replication was inhibited by GMA at concentrations of less than 5.2 mM.(3) Sperm abnormality tests and assays of UDS in germ cells of male mice were conducted to study the in vivo genotoxicity of GMA.The results revealed that GMA could damage DNA, increase sperm abnormality frequency, and reduce the number of sperm cells, 1990 Academic Press.Inc. | DAYING XIE, WEI ZHANG, LAIFU CAO, WENQING SUN, ZHONGSHENG LI, QING GAO, YILI WU, HUILAN GAO, HUIFANG YANG, JIM ZUO,~* AND FUDE FANG~* Institute oF Occupational Medicine. Chinese Academy ol Preventive Medicine. Beijing 100050. and *Institute of Basic Medical Sciences, Chinese Academy ol Medical Sciences. Beijing 100730, China | 1990 | Biomedical and Environmental Sciences1990，3，3： | 7 |
| 7 | The interaction of CpEBF1 with CpMADSs is involved in cell wall degradation during papaya fruit ripening显示文摘Ethylene plays a pivotal role in climacteric fruit ripening;whereas 1-MCP,a non-toxic antagonist of ethylene,prevents ethylene-dependent responses and fruit ripening.In this study,a short-term treatment(1 h)with 400 nL L^(−1)1-MCP delayed the ripening of harvested papaya.However,long-term application of 1-MCP(400 nL L^(−1),16 h)resulted in abnormal fruit ripening,with the fruits exhibiting normal yellowing without softening,significantly higher cellulose and lignin contents,and intact cell walls(CW).Furthermore,we found that long-term treatment with 1-MCP significantly inhibited the expression of CpEBF1,an EIN3-binding F-box-1 gene.A protein interaction analysis using yeast two-hybrid,BiFC and GST pull-down assays showed that CpEBF1 interacts with the CpMADS1/3 and CpEIL1 proteins.The interaction of CpEBF1 with CpMADS1/3 further activated the activities of CW-degradation gene promoters.Subcellular localization showed that these proteins were localized in the nucleus.Additionally,the expression levels of CpMADS1/3,CpEIL1,and several CW-degradation-related genes were significantly downregulated by long-term 1-MCP treatment.Therefore,we propose that the inhibited expression of CpEBF1 and CpMADS1/3 resulted in the repressed activation of CW-degradation-related genes via their interaction,thereby resulting in fruit softening disorders. | Xiaochun Ding Xiaoyang Zhu Lanlan Ye Shuangling Xiao Zhenxian Wu Weixin Chen Xueping Li | 2019 | Horticulture Research2019，6，1： | 7 |
| 8 | Regulation of FN1 degradation by the p62/SQSTM1-dependent autophagy-lysosome pathway in HNSCC显示文摘Epithelial–mesenchymal transition(EMT)is involved in both physiological and pathological processes.EMT plays an essential role in the invasion,migration and metastasis of tumours.Autophagy has been shown to regulate EMT in a variety of cancers but not in head and neck squamous cell carcinoma(HNSCC).Herein,we investigated whether autophagy also regulates EMT in HNSCC.Analyses of clinical data from three public databases revealed that higher expression of fibronectin-1(FN1)correlated with poorer prognosis and higher tumour pathological grade in HNSCC.Data from SCC-25 cells demonstrated that rapamycin and Earle’s balanced salt solution(EBSS)promoted autophagy,leading to increased FN1 degradation,while 3-methyladenine(3-MA),bafilomycin A1(Baf A1)and chloroquine(CQ)inhibited autophagy,leading to decreased FN1 degradation.On the other hand,autophagic flux was blocked in BECN1 mutant HNSCC Cal-27 cells,and rapamycin did not promote autophagy in Cal-27 cells;also in addition,FN1 degradation was inhibited.Further,we identified FN1 degradation through the lysosome-dependent degradation pathway using the proteasome inhibitor MG132.Data from immunoprecipitation assays also showed that p62/SQSTM1 participated as an autophagy adapter in the autophagy–lysosome pathway of FN1 degradation.Finally,data from immunoprecipitation assays demonstrated that the interaction between p62 and FN1 was abolished in p62 mutant MCF-7 and A2780 cell lines.These results indicate that autophagy significantly promotes the degradation of FN1.Collectively,our findings clearly suggest that FN1,as a marker of EMT,has adverse effects on HNSCC and elucidate the autophagy–lysosome degradation mechanism of FN1. | Xinchen Liu Lin Meng Xing Li Daowei Li Qilin Liu Yumeng Chen Xiangwei Li Wenhuan Bu Hongchen Sun | 2020 | International Journal of Oral Science2020，12，4： | 7 |
| 9 | TAZ inhibits osteoclastogenesis by attenuating TAK1/NF-κB signaling显示文摘Osteoporosis is an osteolytic disorder commonly associated with excessive osteoclast formation.Transcriptional coactivator with PDZ-binding motif(TAZ)is a key downstream effector of the Hippo signaling pathway;it was suggested to be involved in the regulation of bone homeostasis.However,the exact role of TAZ in osteoclasts has not yet been established.In this study,we demonstrated that global knockout and osteoclast-specific knockout of TAZ led to a low-bone mass phenotype due to elevated osteoclast formation,which was further evidenced by in vitro osteoclast formation assays.Moreover,the overexpression of TAZ inhibited RANKL-induced osteoclast formation,whereas silencing of TAZ reduced it.Mechanistically,TAZ bound to TGF-activated kinase 1(TAK1)and reciprocally inhibited NF-κB signaling,suppressing osteoclast differentiation.Collectively,our findings highlight an essential role of TAZ in the regulation of osteoclastogenesis in osteoporosis and its underlying mechanism. | Wanlei Yang Xuanyuan Lu Tan Zhang Weiqi Han Jianlei Li Wei He Yewei Jia Kangxian Zhao An Qin Yu Qian | 2021 | Bone Research2021，9，3： | 6 |
| 10 | An antibody against Siglec-15 promotes bone formation and fracture healing by increasing TRAP^(+)mononuclear cells and PDGF-BB secretion显示文摘Osteoporosis(OP)is a common age-related disease characterized by a deterioration of bone mass and structure that predisposes patients to fragility fractures.Pharmaceutical therapies that promote anabolic bone formation in OP patients and OP-induced fracture are needed.We investigated whether a neutralizing antibody against Siglec-15 can simultaneously inhibit bone resorption and stimulate bone formation.We found that the multinucleation of osteoclasts was inhibited in SIGLEC-15 conditional knockout mice and mice undergoing Siglec-15 neutralizing antibody treatment.The secretion of platelet-derived growth factor-BB(PDGF-BB),the number of tartrate-resistant acid phosphatase-positive(TRAP+)mononuclear cells,and bone formation were significantly increased in the SIGLEC-15 conditional knockout mice and antibody-treated mice.The anabolic effect of the Siglec-15 neutralizing antibody on bone formation was blunted in mice with Pdgfb deleted in TRAP-1'cells.These findings showed that the anabolic effect of the Siglec-15 neutralizing antibody was mediated by elevating PDGF-BB production of TRAP4 mononuclear cells.To test the therapeutic potential of the Siglec-15 neutralizing antibody,we injected the antibody in an ovariectomy-induced osteoporotic mouse model,which mimics postmenopausal osteoporosis in women,and in two fracture healing models because fracture is the most serious health consequence of osteoporosis.The Siglec-15 neutralizing antibody effectively reduced bone resorption and stimulated bone formation in estrogen deficiency-induced osteoporosis.Of note,the Siglec-15 neutralizing antibody promoted intramembranous and endochondral ossification at the damaged area of cortical bone in fracture healing mouse models.Thus,the Siglec-15 neutralizing antibody shows significant translational potential as a novel therapy for OP and bone fracture. | Gehua Zhen Yang Dan Ruomei Wang Ce Dou Qiaoyue Guo Melissa Zarr Linda N.Liu Lieping Chen Ruoxian Deng Yusheng Li Zengwu Shao Xu Cao | 2021 | Bone Research2021，9，4： | 6 |
| 11 | Melatonin enhances radiofrequency-induced NK antitumor immunity,causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development显示文摘Surgery is the comm on treatme nt for early lung cancer with multiple pulm onary no dules,but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas.In this study,we found that a combined treatment of local rad iofreq ue ncy ablati on(RFA)and melatonin(MLT)greatly improved clinical outcomes for early lung cancer patie nts with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas.Mechanically,as demonstrated in an associated mouse lung tumor model,RFA not only effectively remove treated tumors but also stimulate antitumor immunity,which could inhibit tumor growth in non-ablated areas.MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA.Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment,which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT.Analysis of residual tumor further revealed the depressed activity of MAPK,NF-kappa B,Wnt,and Hedgehog pathways and upregulated P53 pathway in tumors,which was in line with the inhibited tumor growth.Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy.These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules.Trial registration:www.chictr.org.cn,identifier ChiCTR2100042695,http://gffzz62a03ee25e6f4a77h9vkovuk69w656v95.ffgz.tsg.suse.edu.cn/showproj.aspx?proj=120931. | Ming Li Bingjie Hao Menghuan Zhang Russel J.Reiter Shumeng Lin Tiansheng Zheng Xiangyun Chen Yanbei Ren Liduo Yue Baigenzhin Abay Guojie Chen Xiao Xu Yufeng Shi Lihong Fan | 2021 | Signal Transduction and Targeted Therapy2021，6，10： | 6 |
| 12 | In vitro antioxidant,antimicrobial and anti-diabetic properties of polyphenols of Passiflora ligularis Juss.fruit pulp显示文摘In the present study,anti-radical,anti-diabetic and antimicrobial activities of different solvent extracts of Passiflora ligularis fruits were investigated.Among the various solvents,acetone extract displayed maximum total phenolic(640.70 mg GAE/g extract),tannin(214.30 mg GAE/g extract)and flavonoid contents(387.33 mg RE/g extract).Results of antioxidant studies revealed that the acetone extract of fruits possessed an efficient 2,2-diphenyl-1-picryl-hydrazyl(DPPH•)(IC5019.13g/mL),2,2-azinobis(3-ethylbenzothiozoline-6-sulfonic acid)(ABTS•+)(9800.94mol/L trolox equi/g extract),superoxide(78.27%)and nitric oxide(79.95%)radical scavenging activities,ferric reducing antioxidant power(43.06 mmol Fe(II)/mg extract),metal chelating(134.53 mg EDTA/g extract)ability.The acetone extract of P.ligularis fruits also exhibited significant(P<0.005)inhibition activities onα-amylase(82.56%)andα-glucosidase(75.36%)enzymes.Furthermore,the fruits of P.ligularis also demonstrated antibacterial activities against Gram(+)and Gram(−)bacteria and inhibited the fungal strains Candida albicans(14.85 mm)and Aspergillus niger(13.91 mm)in the disc diffusion method.Quantification of polyphenolics by HPLC showed the presence of ellagic acid,gallic acid,and rutin.Therefore,the results indicate that the fruit pulp of P.ligularis can serve as a potential antioxidative and antimicrobial agent in food and pharmaceutical industries. | Shanmugam Saravanan Thangaraj Parimelazhagan | 2014 | Food Science and Human Wellness2014，3，2： | 6 |
| 13 | Sodium cantharidinate,a novel anti-pancreatic cancer agent that activates functional p53显示文摘Despite the use of many types of chemotherapies for pancreatic cancer, optimal efficacy has not been obtained so far. Pancreatic cancer shows a high incidence of TP53 mutations, inactivating its tumor suppressor activity. In this study, we identified sodium cantharidinate as a novel, potential anti-pancreatic cancer agent that activates p53 function. Sodium cantharidinate reduced the viability of pancreatic cancer cells, including the human primary pancreatic cancer cells, PANC-1, As PC-1, SW1990 and BXPC-3, in a dose-dependent manner. Sodium cantharidinate induced apoptosis and DNA damage of pancreatic cancer cells. Furthermore, proteome-wide sequencing analysis detected a marked perturbation in p53 signaling pathway on PANC-1 cells upon sodium cantharidinate. Consistent with the previous results, sodium cantharidinate treatment decreased Bcl-2 and mitochondrial cytochrome-c protein expression, as well as phosphorylation of MDM2;meanwhile, it increased the levels of cleaved-caspase-3,cleaved-caspase-9, cleaved-PARP, Bax, and phosphorylated p53, thus inducing the apoptosis of pancreatic cancer cells. The p53-activating effect of sodium cantharidinate was strongly abrogated by treatment with TP53-targeting sh RNA. Moreover, sodium cantharidinate inhibited neoplasm growth via the JAK2-STAT3 pathway, which was inhibited by sh RNA-TP53 and triggered by combination with gemcitabine. Combination therapy indicated that sodium cantharidinate and gemcitabine synergistically reduced ex vivo and in vivo growth of pancreatic neoplasm. Further docking studies revealed the different binding fates of sodium cantharidinate to activate wild-type p53 function. Thus, sodium cantharidinate could be a potential agent with promising anti-pancreatic cancer efficacy. | Xiaoxiao Liu Li Zhang Pyone Myat Thu Wenjian Min Peng Yang Ji Li Ping Li Xiaojun Xu | 2021 | Science China(Life Sciences)2021，64，8： | 5 |
| 14 | FABP4 secreted by M1-polarized macrophages promotes synovitis and angiogenesis to exacerbate rheumatoid arthritis显示文摘Increasing evidence shows that adipokines play a vital role in the development of rheumatoid arthritis(RA).Fatty acid-binding protein 4(FABP4),a novel adipokine that regulates inflammation and angiogenesis,has been extensively studied in a variety of organs and diseases.However,the effect of FABP4 on RA remains unclear.Here,we found that FABP4 expression was upregulated in synovial M1-polarized macrophages in RA.The increase in FABP4 promoted synovitis,angiogenesis,and cartilage degradation to exacerbate RA progression in vivo and in vitro,whereas BMS309403(a FABP4 inhibitor)and anagliptin(dipeptidyl peptidase 4 inhibitor)inhibited FABP4 expression in serum and synovial M1-polarized macrophages in mice to alleviate RA progression.Further studies showed that constitutive activation of mammalian target of rapamycin complex 1(mTORC1)by TSC1 deletion specifically in the myeloid lineage regulated FABP4 expression in macrophages to exacerbate RA progression in mice.In contrast,inhibition of mTORC1 by ras homolog enriched in brain(Rheb1)disruption specifically in the myeloid lineage reduced FABP4 expression in macrophages to attenuate RA development in mice.Our findings established an essential role of FABP4 that is secreted by M1-polarized macrophages in synovitis,angiogenesis,and cartilage degradation in RA.BMS309403 and anagliptin inhibited FABP4 expression in synovial M1-polarized macrophages to alleviate RA development.Hence,FABP4 may represent a potential target for RA therapy. | Dong Guo Chuangxin Lin Yuheng Lu Hong Guan Weizhong Qi Hongbo Zhang Yan Shao Chun Zeng Rongkai Zhang Haiyan Zhang Xiaochun Bai Daozhang Cai | 2022 | Bone Research2022，10，4： | 5 |
| 15 | Preface显示文摘Kaschin-Beck disease (KBD) is regarded as an endemic, chronic, high incidence and degenerative osteoarthropathie disease. The areas of endemic KBD are relatively stable and are correlated with specific geographical environments. In China, estimation of KBD patients in 1985 indicated more than 2 million people were severely affected in a broad region inhibited by over 30 million people. KBD endemic areas form a broad belt extending from northeast to southwest. The disease mostly appears in mountainous and hilly regions, and farmers are the major potentially affected ones. Hence KBD has been designated a national health priori-ty problem in China since 60’s. | Peng AnProfessor Research Center for Eco-Environmental Sciences,Chinese Academy o Sciences | 1991 | Journal of Environmental Sciences1991，3，4： | 5 |
| 16 | Carbamylated erythropoietin regulates immune responses and promotes long-term kidney allograft survival through activation of PI3K/AKT signaling显示文摘Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival.To determine mechanisms by which a nonhematopoietic erythropoietin(EPO)derivative,carbamylated EPO(CEPO),regulates innate and adaptive immune cells and affects renal allograft survival,we utilized a rat model of fully MHC-mismatched kidney transplantation.CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group.This therapeutic effect was inhibited when the recipients were given LY294002,a selective inhibitor of the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway or anti-EPO receptor(EPOR)antibody,in addition to CEPO.In vitro,CEPO inhibited the differentiation and function of dendritic cells and modulated their production of proinflammatory and anti-inflammatory cytokines,along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells.Moreover,after CD4^(+)T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell(Treg)/Th17 ratio increased.These effects were abolished by LY294002 or anti-EPOR antibody,suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner.The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival. | Ning Na Daqiang Zhao Jinhua Zhang Jiaqing Wu Bin Miao Heng Li Yingxun Luo Zuofu Tang Wensheng Zhang Joseph A.Bellanti Song Guo Zheng | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 4 |
| 17 | Hydrogen sulfide inhibits ethylene-induced petiole abscission in tomato(Solanum lycopersicum L.)显示文摘Abscission is a dynamic physiological process that is ubiquitous in plants and can also be an essential agronomic trait in crops,thus attracting attention from plant growers and breeders.In general,the process of plant organ abscission can be divided into four steps,among which the step to obtain the competence to respond to abscission signals(step 2)is the most complex;however,the molecular mechanism underlying this process remains unclear.In this study,we found that hydrogen sulfide(H_(2)S)inhibited the abscission of the tomato petiole in a dose-dependent manner,and the abscission of the petiole was accelerated when an H_(2)S scavenger was applied.Further enzymatic activity and gene expression analyses showed that H_(2)S suppressed the activity of enzymes capable of modifying the cell wall by inhibiting the usual upregulation of the transcription of the corresponding genes during the abscission process but not by affecting the activities of these enzymes by direct posttranslational modification.H_(2)S treatment upregulated the expression levels of SlIAA3 and SlIAA4 but downregulated the transcription of ILR-L3 and ILR-L4 in the earlier stages of the abscission process,indicating that H_(2)S probably functioned in the second step of the abscission process by preventing the abscission zone cells from obtaining the competence to respond to abscission signals by modulating the content of the bioactive-free auxin in these cells.Moreover,similar H_(2)S inhibitory effects were also demonstrated in the process of floral organ abscission and anther dehiscence in other plant species,suggesting a ubiquitous role for H_(2)S in cell separation processes. | Danmei Liu Jianing Li Zhuowen Li Yanxi Pei | 2020 | Horticulture Research2020，7，1： | 4 |
| 18 | Targeting folate receptorβpositive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex显示文摘Tumor-associated macrophages(TAMs)facilitate cancer progression by promoting tumor invasion,angiogenesis,metastasis,inflammatory responses,and immunosuppression.Folate receptorβ(FRβ)is overexpressed in TAMs.However,the clinical significance of FRβ-positive macrophages in lung cancer remains poorly understood.In this study,we verified that FRβoverexpression in lung cancer TAMs was associated with poor prognosis.We utilized a folate-modified lipoplex comprising a folatemodified liposome(F-PLP)delivering a BIM-S plasmid to target both lung cancer cells and FRβ-positive macrophages in the tumor microenvironment.Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis.Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRβ-positive macrophages and reduced tumor growth.Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis,reducing tumor proliferation,and inhibiting tumor angiogenesis.In addition,a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously.This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs. | Yan Tie Heng Zheng Zhiyao He Jingyun Yang Bin Shao Li Liu Min Luo Xia Yuan Yu Liu Xiangxian Zhang Hongyi Li Min Wu Xiawei Wei | 2020 | Signal Transduction and Targeted Therapy2020，5，1： | 4 |
| 19 | Molecular dynamics simulation of aluminum inhibited leaching during ion-adsorbed type rare earth ore leaching process显示文摘Molecular dynamics simulation was adopted to study the interaction between sulfosalicylic acid and aluminum,lanthanum and yttrium,and adsorption on kaolinite surfaces.A complexation reaction occurs between sulfosalicylic acid and aluminum,with an interaction energy of-10472.05 kJ/mol.O—Al covalent bonds are formed with a peak value of 7.93,while there is only weak adsorption between sulfosalicylic acid and rare earth ions.A hydrogen bonding reaction with 13605.82 kJ/mol energy occurs between sulfosalicylic acid and the surface of kaolinite(100).Thus,sulfosalicylic acid can form a complex with free aluminum ions,and can also be adsorbed on kaolinite by hydrogen bonding with aluminum in kaolinite(100)surfaces.Leaching of ion-adsorbed type rare earth ore was performed with aluminum inhibited,results show that when sulfosalicylic acid dosage increases from 0 to 0.15 wt%,aluminum ion concentration in the leaching solution decreases from 273.23 to 47.19 mg/L.And the effect of leaching pH value on the effect of sulfosalicylic acid on aluminum inhibition was studied,the result shows that,when the leaching pH value is 4.0—5.0,the rare earth leaching rate and the aluminum ion concentration basically remain unchanged.The molecular dynamics simulation results were verified by detection and analysis of XPS and SEM. | Dongmei Zhu Tingsheng Qiu Jianfeng Zhong Qinghua Zeng Xihui Fang | 2019 | Journal of Rare Earths2019，37，12： | 4 |
| 20 | Distinct contribution of PD-L1 suppression by spatial expression of PD-L1 on tumor and non-tumor cells显示文摘Programmed cell death receptor 1(PD-1)and its ligand,PD-L1,are important immune checkpoint proteins.Although antibodies that block PD-1/PD-L1 have shown promising clinical efficacy in a subset of cancer patients,the detailed cellular and molecular mechanisms behind anti-PD-1 and anti-PD-L1 immunotherapy are not well defined.Specifically,the way in which PD-L1 contributes to immune suppression on tumor and non-tumor cells remains controversial.By selectively blocking PD-L1 on either tumor or non-tumor cells,we demonstrated that PD-L1 from both sources suppressed the anti-tumor T-cell response.Blocking PD-L1 on either tumor cells or non-tumor cells inhibited tumor growth and enhanced immune cell infiltration,as well as the tumor-specific T-cell response.Further,simultaneously blocking tumor-and non-tumor-derived PD-L1 maximized anti-tumor T-cell responses and demonstrated synergy.In addition,the relative contribution of PD-L1 on tumor and non-tumor cells to immune suppression depended on the PD-L1 expression level.Lastly,we found that the F4/80 receptor was involved in the anti-tumor effect of PD-L1 blockade.Taken together,our data indicate that PD-L1 on both tumor and non-tumor cells is critical for T-cell inhibition,which provides new directions for the optimization of PD-L1-blocking antibodies and the development of clinical biomarker strategies. | Xiaoqing Zhang Chen Cheng Jiyan Hou Xinyue Qi Xin Wang Ping Han Xuanming Yang | 2019 | Cellular & Molecular Immunology2019，16，4： | 3 |
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