The major aim of stroke therapy is to stimulate brain repair and improve behavioral recovery after cerebral ischemia.One option is to stimulate endogenous neurogenesis in the subventricular zone and direct the newly f...The major aim of stroke therapy is to stimulate brain repair and improve behavioral recovery after cerebral ischemia.One option is to stimulate endogenous neurogenesis in the subventricular zone and direct the newly formed neurons to the damaged area.However,only a small percentage of these neurons survive,and many do not reach the damaged area,possibly because the corpus callosum impedes the migration of subventricular zone-derived stem cells into the lesioned cortex.A second major obstacle to stem cell therapy is the strong inflammatory reaction induced by cerebral ischemia,whereby the associated phagocytic activity of brain macrophages removes both therapeutic cells and/or cell-based drug carriers.To address these issues,neurogenesis was electrically stimulated in the subventricular zone,followed by isolation of proliferating cells,including newly formed neurons,which were subsequently mixed with a nutritional hydrogel.This mixture was then transferred to the stroke cavity of day 14 post-stroke mice.We found that the performance of the treated animals improved in behavioral tests,including novel object,open field,hole board,grooming,and“time-to-feel”adhesive tape tests.Furthermore,immunostaining revealed that the stem cell marker nestin,the neuroepithelial marker Mash1,and the immature neuronal marker doublecortin-positive cells survived in the transplanted area for 2 weeks,possibly due to reduced phagocytic activity and supportive angiogenesis.These results clearly indicate that the transplantation of committed subventricular zone stem cells combined with a protective nutritional gel directly into the infarct cavity after the peak of stroke-induced neuroinflammation represents a feasible approach to improve neurorestoration after cerebral ischemia.展开更多
Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression w...Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.展开更多
基金supported by European Union Funding Programme,PNRR,No. 760058(to DMH)the UEFISCDI Project,No. PN-III-P4-IDPCE-2020-059(to APW)
文摘The major aim of stroke therapy is to stimulate brain repair and improve behavioral recovery after cerebral ischemia.One option is to stimulate endogenous neurogenesis in the subventricular zone and direct the newly formed neurons to the damaged area.However,only a small percentage of these neurons survive,and many do not reach the damaged area,possibly because the corpus callosum impedes the migration of subventricular zone-derived stem cells into the lesioned cortex.A second major obstacle to stem cell therapy is the strong inflammatory reaction induced by cerebral ischemia,whereby the associated phagocytic activity of brain macrophages removes both therapeutic cells and/or cell-based drug carriers.To address these issues,neurogenesis was electrically stimulated in the subventricular zone,followed by isolation of proliferating cells,including newly formed neurons,which were subsequently mixed with a nutritional hydrogel.This mixture was then transferred to the stroke cavity of day 14 post-stroke mice.We found that the performance of the treated animals improved in behavioral tests,including novel object,open field,hole board,grooming,and“time-to-feel”adhesive tape tests.Furthermore,immunostaining revealed that the stem cell marker nestin,the neuroepithelial marker Mash1,and the immature neuronal marker doublecortin-positive cells survived in the transplanted area for 2 weeks,possibly due to reduced phagocytic activity and supportive angiogenesis.These results clearly indicate that the transplantation of committed subventricular zone stem cells combined with a protective nutritional gel directly into the infarct cavity after the peak of stroke-induced neuroinflammation represents a feasible approach to improve neurorestoration after cerebral ischemia.
基金supported by the National Natural Science Foundation of China(Nos.82073688,82103971 and 81930075)Shanghai Science and Technology Development Fund from Central Leading Local Government(No.YDZX20223100001004,China)+1 种基金Science and Technology Commission of Shanghai Municipality(No.21S11907300,China)Program of Shanghai Academic/Technology Research Leader(No.20XD1400700,China)。
文摘Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.
