Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation.Nevertheless,current therapeutic regimens are inadequate to promptly address the vast diversity...Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation.Nevertheless,current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens.Omiganan,an antimicrobial peptide,has shown promise for neutralizing endotoxins and eliminating diverse pathogens.However,its clinical application is hindered by safety and stability concerns.Herein,we present a nanoscale drug delivery system(Omi-hyd-Dex@HA NPs)that selectively targets infectious microenvironments(IMEs)and responds to specific stimuli for efficient intervention in sepsis.The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid(HA).The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes,but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase.The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation.In multiple tissue infection and sepsis animal models,Omi-hyd-Dex@HA NPs exhibited rapid source control and comprehensive inflammation reduction,thereby preventing subsequent fatal complications and significantly improving survival outcomes.The bio-responsive and self-delivering nanosystem offers a promising strategy for systemic sepsis treatment in emergencies.展开更多
TRIM28(Tripartite motif-containing protein 28), a member of TRIM family, is aberrantly expressed and reportedly has different functions in many types of human cancer. However, the biological roles of TRIM28 and relate...TRIM28(Tripartite motif-containing protein 28), a member of TRIM family, is aberrantly expressed and reportedly has different functions in many types of human cancer. However, the biological roles of TRIM28 and related mechanism in colorectal cancer(CRC) remain unclear. Here, we showed that TRIM28 was downregulated in colorectal cancer compared with normal mucosa, especially at advanced stages, and acted as an independent prognostic factor of favorable outcome. Functional studies demonstrated that TRIM28 restrained CRC migration and invasion in vitro and in vivo. Mechanistically, we reported that CARM1(co-activator-associated arginine methyltransferase1) was a critical player downstream of TRIM28. TRIM28 interacted with CARM1, and protected CARM1 from proteasome-mediated degradation through physical protein-protein interaction to suppress CRC metastasis. Further, TRIM28 suppressed the migration and invasion of CRC cells through inhibiting WNT/b-catenin signaling in a CARM1-dependent manner, but independent of CARM10 s methyltransferase activity. The protein expression of CARM1 was positively correlated with TRIM28 in CRC tissues. Patients with high levels of TRIM28 and CARM1 had improved prognosis, whereas patients with low TRIM28 and CARM1 expression had the poor outcomes. Thus, our study reveals an inhibitory role of TRIM28 in CRC metastasis, which was achieved through a TRIM28-CARM1-WNT/b-catenin axis. This work provides potential prognostic and therapeutic targets for CRC treatment.展开更多
基金supported by the Program of the Scientific and Technological in Guiyang City(Grant No.Zhu Ke He[2020]-16-5)Program of Scientific and Technological Project in Guizhou Province(Grant No.[2020]4Y197,Qian Ke He Ji Chu ZK[2022]Yi Ban 516,Qian Ke He Ji Chu ZK[2021]Yi Ban 559)+3 种基金the Science and Technology Talents Growth Project in Education Department of Guizhou Province(Grant No.Qian Jiao He KY Zi[2021]4Y211)the Program of Science and Technology of Guizhou Provincial Health Commission(Grant No.gzwjkj2020-1-215)the Knowledge Innovation Special Project for Fundamental Research of Wuhan(Grant No.2022020801010461)the Sichuan Science and Technology Program(Grant No.2022NSFSC1420).
文摘Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation.Nevertheless,current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens.Omiganan,an antimicrobial peptide,has shown promise for neutralizing endotoxins and eliminating diverse pathogens.However,its clinical application is hindered by safety and stability concerns.Herein,we present a nanoscale drug delivery system(Omi-hyd-Dex@HA NPs)that selectively targets infectious microenvironments(IMEs)and responds to specific stimuli for efficient intervention in sepsis.The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid(HA).The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes,but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase.The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation.In multiple tissue infection and sepsis animal models,Omi-hyd-Dex@HA NPs exhibited rapid source control and comprehensive inflammation reduction,thereby preventing subsequent fatal complications and significantly improving survival outcomes.The bio-responsive and self-delivering nanosystem offers a promising strategy for systemic sepsis treatment in emergencies.
基金supported by the Major State Basic Research Development Program of China (2015CB554007)the National Natural Science Foundation of China (81572866, 81773263 81773104, 31701202)+5 种基金the International Science and Technology Corporation Program of Chinese Ministry of Science and Technology (2014DFA32920)the Science and Technology Program of Chinese Ministry of Education (113044A)the Frontier Exploration Program of Huazhong University of Science and Technology (2015TS153)the Natural Science Foundation Program of Hubei Province (2015CFA049)the Research Fund of Public Welfare in Health Industry (201402015)the Research Fund of Public Welfare in Health Industry (201402015) from the Health and Family Plan Committee of China
文摘TRIM28(Tripartite motif-containing protein 28), a member of TRIM family, is aberrantly expressed and reportedly has different functions in many types of human cancer. However, the biological roles of TRIM28 and related mechanism in colorectal cancer(CRC) remain unclear. Here, we showed that TRIM28 was downregulated in colorectal cancer compared with normal mucosa, especially at advanced stages, and acted as an independent prognostic factor of favorable outcome. Functional studies demonstrated that TRIM28 restrained CRC migration and invasion in vitro and in vivo. Mechanistically, we reported that CARM1(co-activator-associated arginine methyltransferase1) was a critical player downstream of TRIM28. TRIM28 interacted with CARM1, and protected CARM1 from proteasome-mediated degradation through physical protein-protein interaction to suppress CRC metastasis. Further, TRIM28 suppressed the migration and invasion of CRC cells through inhibiting WNT/b-catenin signaling in a CARM1-dependent manner, but independent of CARM10 s methyltransferase activity. The protein expression of CARM1 was positively correlated with TRIM28 in CRC tissues. Patients with high levels of TRIM28 and CARM1 had improved prognosis, whereas patients with low TRIM28 and CARM1 expression had the poor outcomes. Thus, our study reveals an inhibitory role of TRIM28 in CRC metastasis, which was achieved through a TRIM28-CARM1-WNT/b-catenin axis. This work provides potential prognostic and therapeutic targets for CRC treatment.
