Psoriasis is a common chronic inflammatory skin disease characterized by inflammatory cell infiltration and epidermal hyperplasia.However,the regulatory complexity of cytokine and cellular networks still needs to be i...Psoriasis is a common chronic inflammatory skin disease characterized by inflammatory cell infiltration and epidermal hyperplasia.However,the regulatory complexity of cytokine and cellular networks still needs to be investigated.Here,we show that the expression of FXYD3,a member of the FXYD domain-containing regulators of Na+/K+ATPases family,is significantly increased in the lesional skin of psoriasis patients and mice with imiquimod(IMQ)-induced psoriasis.IL-17A,a cytokine important for the development of psoriatic lesions,contributes to FXYD3 expression in human primary keratinocytes.FXYD3 deletion in keratinocytes attenuated the psoriasis-like phenotype and inflammation in an IMQ-induced psoriasis model.Importantly,FXYD3 promotes the formation of the IL-17R-ACT1 complex by competing with IL-17R for binding to TRAF3 and then enhances IL-17A signaling in keratinocytes.This promotes the activation of the NF-κB and MAPK signaling pathways and leads to the expression of proinflammatory factors.Our results clarify the mechanism by which FXYD3 serves as a mediator of IL-17A signaling in keratinocytes to form a positive regulatory loop to promote psoriasis exacerbation.Targeting FXYD3 may serve as a potential therapeutic approach in the treatment of psoriasis.展开更多
Urothelial carcinoma(UC)is a common malignant tumor in the urinary system with high recurrence rate and low survival rate 5 years after surgery.At present,imaging examination and other diagnostic methods have some sho...Urothelial carcinoma(UC)is a common malignant tumor in the urinary system with high recurrence rate and low survival rate 5 years after surgery.At present,imaging examination and other diagnostic methods have some shortcomings such as invasiveness and non-specificity.Therefore,it is urgent to develop a simple,rapid,noninvasive,highly sensitive and highly specific strategy to diagnose UC.Herein,a high-performance fluorescence sensor was constructed by the plasmonic gold nanorods(AuNRs)-enhanced near-infrared(NIR)fluorescence of silver sulfide quantum dots(Ag_(2)S QDs).The designed sensor can be used for the fast and accurate detection of small molecule single-transmembrane protein(FXYD3),which is overexpressed in 90%of ureteral cancers and 84%of high-grade bladder cancers.Due to its high specificity,the NIR fluorescence sensor achieves the detection of FXYD3 in the range of 0.25-150 ng·ml^(-1)with a detection limit of 0.2 ng·ml^(-1).Importantly,it also can be used for accurate diagnosis of FXYD3 in the urine of patients with relevant cancers,and the results are consistent with clinical cystoscopy and pathological analysis.The proposed fluorescence sensor provides a simple,ultrasensitive,reliable method for UC screening,tumor-grade classification and postoperative monitoring and will have great potential for clinical applications.展开更多
基金the National Natural Science Foundation of China(91842103,31870907,81930041)the Natural Science Foundation of Zhejiang Province(Z19H100001).
文摘Psoriasis is a common chronic inflammatory skin disease characterized by inflammatory cell infiltration and epidermal hyperplasia.However,the regulatory complexity of cytokine and cellular networks still needs to be investigated.Here,we show that the expression of FXYD3,a member of the FXYD domain-containing regulators of Na+/K+ATPases family,is significantly increased in the lesional skin of psoriasis patients and mice with imiquimod(IMQ)-induced psoriasis.IL-17A,a cytokine important for the development of psoriatic lesions,contributes to FXYD3 expression in human primary keratinocytes.FXYD3 deletion in keratinocytes attenuated the psoriasis-like phenotype and inflammation in an IMQ-induced psoriasis model.Importantly,FXYD3 promotes the formation of the IL-17R-ACT1 complex by competing with IL-17R for binding to TRAF3 and then enhances IL-17A signaling in keratinocytes.This promotes the activation of the NF-κB and MAPK signaling pathways and leads to the expression of proinflammatory factors.Our results clarify the mechanism by which FXYD3 serves as a mediator of IL-17A signaling in keratinocytes to form a positive regulatory loop to promote psoriasis exacerbation.Targeting FXYD3 may serve as a potential therapeutic approach in the treatment of psoriasis.
基金financially supported in part by the National Natural Science Foundation of China(Nos.22005081,51873222 and 52111530128)Zhejiang Provincial Natural Science Foundation of China(Nos.LY22B050003 and LZ22B050001)+1 种基金the Funding for the Scientific Research Foundation for Scholars of Hangzhou Normal University(Nos.4095C5021920467 and 4095C5021920452)the Key Research and Development Projects of Anhui Province(Nos.202004g01020016 and 202104g01020009)。
文摘Urothelial carcinoma(UC)is a common malignant tumor in the urinary system with high recurrence rate and low survival rate 5 years after surgery.At present,imaging examination and other diagnostic methods have some shortcomings such as invasiveness and non-specificity.Therefore,it is urgent to develop a simple,rapid,noninvasive,highly sensitive and highly specific strategy to diagnose UC.Herein,a high-performance fluorescence sensor was constructed by the plasmonic gold nanorods(AuNRs)-enhanced near-infrared(NIR)fluorescence of silver sulfide quantum dots(Ag_(2)S QDs).The designed sensor can be used for the fast and accurate detection of small molecule single-transmembrane protein(FXYD3),which is overexpressed in 90%of ureteral cancers and 84%of high-grade bladder cancers.Due to its high specificity,the NIR fluorescence sensor achieves the detection of FXYD3 in the range of 0.25-150 ng·ml^(-1)with a detection limit of 0.2 ng·ml^(-1).Importantly,it also can be used for accurate diagnosis of FXYD3 in the urine of patients with relevant cancers,and the results are consistent with clinical cystoscopy and pathological analysis.The proposed fluorescence sensor provides a simple,ultrasensitive,reliable method for UC screening,tumor-grade classification and postoperative monitoring and will have great potential for clinical applications.
