AIM:To investigate whether nintedanib can inhibit pterygium cells through the fibroblast growth factor receptor 2(FGFR2)/extracellular-signal-regulated kinase(ERK)pathway.METHODS:Human primary pterygium cells were cul...AIM:To investigate whether nintedanib can inhibit pterygium cells through the fibroblast growth factor receptor 2(FGFR2)/extracellular-signal-regulated kinase(ERK)pathway.METHODS:Human primary pterygium cells were cultured in vitro.After treatment with nintedanib,the cell morphology was observed under microscopy,the morphological changes of the nucleus were observed after DAPI staining,apoptosis was analyzed by Annexin-V FITC/PI double staining,and the changes of apoptosis-associated proteins were detected by Western blot.The binding ability of nintedanib to FGFR2 was predicted by molecular docking.Finally,by silencing FGFR2,we explored whether nintedanib inhibited FGFR2/ERK pathway.RESULTS:The results showed that nintedanib inhibited the growth of pterygium cells and caused nuclear pyknosis.The results of Annexin-VFITC/PI double staining showed that nintedanib was able to induce early and late apoptosis of pterygium cells,significantly increasing the expression of apoptosis-associated proteins Bax and cleaved-Caspase3(P<0.05),and reducing the expression of Bcl-2(P<0.05).In addition,nintedanib significantly inhibited ERK1/2 phosphorylation through FGFR2(P<0.05).After silencing the expression of FGFR2,there was no significant difference in the inhibition of ERK1/2 phosphorylation by nintedanib(P>0.05).CONCLUSION:Nintedanib induces apoptosis of pterygium cells by inhibiting FGFR2/ERK pathway.展开更多
AIM:To evaluate whether a novel tyrosine kinase inhibitor nintedanib could inhibit basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)simultaneously for retinal vascular disease in vivo.ME...AIM:To evaluate whether a novel tyrosine kinase inhibitor nintedanib could inhibit basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)simultaneously for retinal vascular disease in vivo.METHODS:After a laser induced rabbit retinal vein occlusion(RVO)model was made,0.5 mg of nintedanib was injected intravitreally in the left eye on the third day while the right eye was as a control.Intracameral samples were taken on the day before laser treatment and days 1,3,7,14,21,and 28 after treatment.Enzyme-linked immunosorbent assay(ELISA)was used to test the bFGF and VEGF-A concentrations in the aqueous humor.RESULTS:Both bFGF and VEGF-A rose significantly on the third day after laser treatment in both eyes.In the control eye the bFGF concentration peaked on the 14th day while the VEGF-A concentration dropped rapidly soon after the third day.After nintadanib injection in the study eye,both bFGF and VEGF-A showed a significant reduction on the 4th day(7th day after laser treatment)when compared to the control eye,and kept on low level in the following several weeks.CONCLUSION:Intravitreal injection of nintedanib can inhibit the expression of bFGF and VEGF in the process of RVO model to a certain extent,which is expected to become a new method for the treatment of retinal vascular diseases or fibrotic diseases.展开更多
AIM:To investigate the effects of nintedanib thermo-sensitive hydrogel(NTH)on neovascularization and related markers in corneal alkali burns of Wistar rats.METHODS:NTH was prepared by grinding,and its phase-transition...AIM:To investigate the effects of nintedanib thermo-sensitive hydrogel(NTH)on neovascularization and related markers in corneal alkali burns of Wistar rats.METHODS:NTH was prepared by grinding,and its phase-transition temperature was determined.Thirty specific-pathogen-free Wistar rats served as a model of corneal alkali burn in the right eye were randomly divided into 3 groups(n=10,each):model group treated with 0.9%saline once a day,NTH group with 0.2%nintedanib b.i.d,and dexamethasone group with dexamethasone ointment once a day.The left eye of rats served as the controls.The corneal transparency was observed under a slit-lamp microscope,and the area of neovascularization was calculated.On day 7,the rats were sacrificed,and the cornea was removed and embedded with paraffin,then stained with hematoxylin一eosin,and the expression of vascular endothelial growth factor receptor 2(VEGFR-2)and CD31 in the corneal tissues of each group was detected by immunofluorescence.RESULTS:The phase-transition temperature ofnintedanib obtained by grinding was 37℃after adding artificial tears.The results of the alkali burn model indicated that the growth rate of neovascularization in the NTH group was slower than that in the model group,and the neovascularization area was significantly smaller than that in the model group(P<0.05).Moreover,CD31 and VEGFR-2 expression levels in the NTH group were significantly lower than those in the model group.CONCLUSION:NTH becomes colloidal at body temperature,which is beneficial for releasing the drug slowly and can significantly inhibit the neovascularization of corneal induced by alkali burn in rats.展开更多
AIM:To evaluate the potential efficacy and mechanisms of nintedanib in corneal neovascularization(NV)in rabbit models.METHODS:Corneal NV was induced using 1 mol/L Na OH.Rabbits(n=21)were randomized to 3 groups:Group 1...AIM:To evaluate the potential efficacy and mechanisms of nintedanib in corneal neovascularization(NV)in rabbit models.METHODS:Corneal NV was induced using 1 mol/L Na OH.Rabbits(n=21)were randomized to 3 groups:Group 1 were treated with 0.9%NaCl,Group 2 with Avastin(5 mg/mL),and Group 3 with nintedanib(1 mg/mL).All treatments star ted 1 d af ter alkaline burns and were topically performed 3 times a day for 2 wk.Photographs were taken on a slit lamp microscope on day 7 and 14.The NV area,the length of the vascularization and angiogenesis index(AI)were used to evaluate the corneal NV.On day 14,the immunohistochemical(IHC)studies of the cornea were examined.Western blot was performed to test the expression levels of vascular endothelial growth factor(VEGF),Akt,p-Akt,P38,p-P38,MMP-2 and MMP-9.RESULTS:The corneal NV area,vessel length and AI in Group 3 were significantly lower than Group 2,with both being lower than Group 1.IHC staining showed that VEGF was significantly overexpressed in the epithelium and stroma of cornea following alkaline burns.In contrast,the level of VEGF was significantly suppressed in both Group 2 and Group 3.Western blot results further confirmed that,compared with Group 1,Group 3 had significantly reduced expressions of VEGF,Akt,p-Akt,p-P38,MMP-2,and MMP-9 in corneal tissues.Trends of lower levels of MMP-2,AKT,and p-AKT in Group 3 than Group 2 were identified.CONCLUSION:Nintedanib and Avastin can effectively inhibit corneal NV,with P38 MAPK and AKT signaling pathways being possibly involved.Nintedanib seems more effective than Avastin and has the potential to be a novel therapy for preventing corneal NV.展开更多
AIM:To investigate the efficacy of nintedanib on reducing postoperative inflammation,fibrosis and adhesion formation following extraocular muscle surgery in rabbits in comparison with triamcinolone acetonide(TA).METHO...AIM:To investigate the efficacy of nintedanib on reducing postoperative inflammation,fibrosis and adhesion formation following extraocular muscle surgery in rabbits in comparison with triamcinolone acetonide(TA).METHODS:Reinsertion of superior rectus muscle in right eyes of 30 New Zealand white rabbits were performed.They were randomized to receive one of the following treatments:0.9%normal saline,one of 1-,5-,and 10μmol doses of nintedanib subconjunctivally immediately after surgery and on postoperative day 1,2,3,5,and 7,and TA immediately after surgery.As a control group,unoperated left eyes(n=6)were used.On the 28 th day,six eyes from each group were enucleated and histopathologically and immunohistochemically analyzed to assess the postoperative inflammatory changes,fibrosis and adhesion.Transforming growth factor beta,matrix metalloproteinase-2 and alpha smooth muscle actin expressions were evaluated.RESULTS:Conjunctival and scleral inflammation in TA and nintedanib groups were significantly reduced compared to saline(sham)group.Conjunctival vascularity and rectus muscle fibrosis were significantly reduced in 10μmol nintedanib group.Nintedanib groups were the most effective groups in reduction of perimuscular fibrosis.Neither three nintedanib groups nor TA group differed statistically from sham group with regard to adhesion.The expressions of transforming growth factor beta,alpha smooth muscle actin and matrix metalloproteinase-2 were reduced in nintedanib groups compared to saline group.CONCLUSION:Nintedanib appears to attenuate postoperative inflammation and fibrosis after extraocular muscle surgery.Nintedanib may be a safer and stronger alternative agent in extraocular muscle surgery when compared to steroids.Further investigation is needed to prove antiadhesive effect of nintedanib.展开更多
文摘AIM:To investigate whether nintedanib can inhibit pterygium cells through the fibroblast growth factor receptor 2(FGFR2)/extracellular-signal-regulated kinase(ERK)pathway.METHODS:Human primary pterygium cells were cultured in vitro.After treatment with nintedanib,the cell morphology was observed under microscopy,the morphological changes of the nucleus were observed after DAPI staining,apoptosis was analyzed by Annexin-V FITC/PI double staining,and the changes of apoptosis-associated proteins were detected by Western blot.The binding ability of nintedanib to FGFR2 was predicted by molecular docking.Finally,by silencing FGFR2,we explored whether nintedanib inhibited FGFR2/ERK pathway.RESULTS:The results showed that nintedanib inhibited the growth of pterygium cells and caused nuclear pyknosis.The results of Annexin-VFITC/PI double staining showed that nintedanib was able to induce early and late apoptosis of pterygium cells,significantly increasing the expression of apoptosis-associated proteins Bax and cleaved-Caspase3(P<0.05),and reducing the expression of Bcl-2(P<0.05).In addition,nintedanib significantly inhibited ERK1/2 phosphorylation through FGFR2(P<0.05).After silencing the expression of FGFR2,there was no significant difference in the inhibition of ERK1/2 phosphorylation by nintedanib(P>0.05).CONCLUSION:Nintedanib induces apoptosis of pterygium cells by inhibiting FGFR2/ERK pathway.
基金Supported by Medical Health Science and Technology Project of Zhejiang Province(No.2020KY654).
文摘AIM:To evaluate whether a novel tyrosine kinase inhibitor nintedanib could inhibit basic fibroblast growth factor(bFGF)and vascular endothelial growth factor(VEGF)simultaneously for retinal vascular disease in vivo.METHODS:After a laser induced rabbit retinal vein occlusion(RVO)model was made,0.5 mg of nintedanib was injected intravitreally in the left eye on the third day while the right eye was as a control.Intracameral samples were taken on the day before laser treatment and days 1,3,7,14,21,and 28 after treatment.Enzyme-linked immunosorbent assay(ELISA)was used to test the bFGF and VEGF-A concentrations in the aqueous humor.RESULTS:Both bFGF and VEGF-A rose significantly on the third day after laser treatment in both eyes.In the control eye the bFGF concentration peaked on the 14th day while the VEGF-A concentration dropped rapidly soon after the third day.After nintadanib injection in the study eye,both bFGF and VEGF-A showed a significant reduction on the 4th day(7th day after laser treatment)when compared to the control eye,and kept on low level in the following several weeks.CONCLUSION:Intravitreal injection of nintedanib can inhibit the expression of bFGF and VEGF in the process of RVO model to a certain extent,which is expected to become a new method for the treatment of retinal vascular diseases or fibrotic diseases.
基金Supported by Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project(No.2018ZA111)Natural Science Foundation of Zhejiang Province(No.LY19H120001)+4 种基金Zhejiang Provincial Medicine and Health Science and Technology Project(No.2020KY288)Ningbo Natural Science Foundation(No.2019A610353)Ningbo Leading and Outstanding Talents Cultivation Project Selects and Supports Scientific Research Projects(No.NBLJ201801037)Ningbo Public Welfare Science and Technology Plan Project(No.2019C50059)Ningbo Yinzhou District Science and Technology Bureau Agricultural and Social Science and Technology Plan Project(Yanke[2017]No.110)。
文摘AIM:To investigate the effects of nintedanib thermo-sensitive hydrogel(NTH)on neovascularization and related markers in corneal alkali burns of Wistar rats.METHODS:NTH was prepared by grinding,and its phase-transition temperature was determined.Thirty specific-pathogen-free Wistar rats served as a model of corneal alkali burn in the right eye were randomly divided into 3 groups(n=10,each):model group treated with 0.9%saline once a day,NTH group with 0.2%nintedanib b.i.d,and dexamethasone group with dexamethasone ointment once a day.The left eye of rats served as the controls.The corneal transparency was observed under a slit-lamp microscope,and the area of neovascularization was calculated.On day 7,the rats were sacrificed,and the cornea was removed and embedded with paraffin,then stained with hematoxylin一eosin,and the expression of vascular endothelial growth factor receptor 2(VEGFR-2)and CD31 in the corneal tissues of each group was detected by immunofluorescence.RESULTS:The phase-transition temperature ofnintedanib obtained by grinding was 37℃after adding artificial tears.The results of the alkali burn model indicated that the growth rate of neovascularization in the NTH group was slower than that in the model group,and the neovascularization area was significantly smaller than that in the model group(P<0.05).Moreover,CD31 and VEGFR-2 expression levels in the NTH group were significantly lower than those in the model group.CONCLUSION:NTH becomes colloidal at body temperature,which is beneficial for releasing the drug slowly and can significantly inhibit the neovascularization of corneal induced by alkali burn in rats.
基金Supported by the Natural Science Foundation of Tianjin City(No.2150000045)。
文摘AIM:To evaluate the potential efficacy and mechanisms of nintedanib in corneal neovascularization(NV)in rabbit models.METHODS:Corneal NV was induced using 1 mol/L Na OH.Rabbits(n=21)were randomized to 3 groups:Group 1 were treated with 0.9%NaCl,Group 2 with Avastin(5 mg/mL),and Group 3 with nintedanib(1 mg/mL).All treatments star ted 1 d af ter alkaline burns and were topically performed 3 times a day for 2 wk.Photographs were taken on a slit lamp microscope on day 7 and 14.The NV area,the length of the vascularization and angiogenesis index(AI)were used to evaluate the corneal NV.On day 14,the immunohistochemical(IHC)studies of the cornea were examined.Western blot was performed to test the expression levels of vascular endothelial growth factor(VEGF),Akt,p-Akt,P38,p-P38,MMP-2 and MMP-9.RESULTS:The corneal NV area,vessel length and AI in Group 3 were significantly lower than Group 2,with both being lower than Group 1.IHC staining showed that VEGF was significantly overexpressed in the epithelium and stroma of cornea following alkaline burns.In contrast,the level of VEGF was significantly suppressed in both Group 2 and Group 3.Western blot results further confirmed that,compared with Group 1,Group 3 had significantly reduced expressions of VEGF,Akt,p-Akt,p-P38,MMP-2,and MMP-9 in corneal tissues.Trends of lower levels of MMP-2,AKT,and p-AKT in Group 3 than Group 2 were identified.CONCLUSION:Nintedanib and Avastin can effectively inhibit corneal NV,with P38 MAPK and AKT signaling pathways being possibly involved.Nintedanib seems more effective than Avastin and has the potential to be a novel therapy for preventing corneal NV.
基金Supported by Kocaeli University Scientific Research Projects Unit Fund(No.2019/029)。
文摘AIM:To investigate the efficacy of nintedanib on reducing postoperative inflammation,fibrosis and adhesion formation following extraocular muscle surgery in rabbits in comparison with triamcinolone acetonide(TA).METHODS:Reinsertion of superior rectus muscle in right eyes of 30 New Zealand white rabbits were performed.They were randomized to receive one of the following treatments:0.9%normal saline,one of 1-,5-,and 10μmol doses of nintedanib subconjunctivally immediately after surgery and on postoperative day 1,2,3,5,and 7,and TA immediately after surgery.As a control group,unoperated left eyes(n=6)were used.On the 28 th day,six eyes from each group were enucleated and histopathologically and immunohistochemically analyzed to assess the postoperative inflammatory changes,fibrosis and adhesion.Transforming growth factor beta,matrix metalloproteinase-2 and alpha smooth muscle actin expressions were evaluated.RESULTS:Conjunctival and scleral inflammation in TA and nintedanib groups were significantly reduced compared to saline(sham)group.Conjunctival vascularity and rectus muscle fibrosis were significantly reduced in 10μmol nintedanib group.Nintedanib groups were the most effective groups in reduction of perimuscular fibrosis.Neither three nintedanib groups nor TA group differed statistically from sham group with regard to adhesion.The expressions of transforming growth factor beta,alpha smooth muscle actin and matrix metalloproteinase-2 were reduced in nintedanib groups compared to saline group.CONCLUSION:Nintedanib appears to attenuate postoperative inflammation and fibrosis after extraocular muscle surgery.Nintedanib may be a safer and stronger alternative agent in extraocular muscle surgery when compared to steroids.Further investigation is needed to prove antiadhesive effect of nintedanib.
文摘总结nintedanib(尼达尼布,商品名Ofev)胶囊治疗特发性肺间质纤维化(Idiopathic pulmonary fibrosis IPF)的最新研究结果,为临床提供参考。共检索中国知网、万方、维普等中文数据库及PubMed、EMbase、Cochrane等外文数据库。筛选文献包括尼达尼布治疗IPF的随机对照试验(RCT)、相关文献、2016年最新的会议信息及报道资料。结果其中包括有3项RCT相关文献以及2016年最新的会议信息及报道资料。尼达尼布是继大家熟知的吡非尼酮之后,又一治疗IPF的新药[7]。美国食品药品管理局(Food and Drug Administration FDA)及欧盟药品管理局(EMA)分别于2014年10月15日及2015年1月15日,批准尼达尼布正式在美国及欧盟上市用于治疗IPF[6]。给IPF的治疗带来希望,值得临床医师关注。
