Glutamate excitotoxicity has been shown to play an important role in glaucoma, and glutamate can induce ferroptosis. The p38 mitogenactivated protein kinase(MAPK) pathway inhibitor SB202190 has a potential ability to ...Glutamate excitotoxicity has been shown to play an important role in glaucoma, and glutamate can induce ferroptosis. The p38 mitogenactivated protein kinase(MAPK) pathway inhibitor SB202190 has a potential ability to suppress ferroptosis, and its downstream targets, such as p53, have been shown to be associated with ferroptosis. However, whether ferroptosis also occurs in retinal ganglion cells in response to glutamate excitotoxicity and whether inhibition of ferroptosis reduces the loss of retinal ganglion cells induced by glutamate excitotoxicity remain unclear. This study investigated ferroptosis in a glutamate-induced glaucoma rat model and explored the effects and molecular mechanisms of SB202190 on retinal ganglion cells. A glutamate-induced excitotoxicity model in R28 cells and an N-methyl-D-aspartate-induced glaucoma model in rats were used. In vitro experiments showed that glutamate induced the accumulation of iron and lipid peroxide and morphological changes of mitochondria in R28 cells, and SB202190 inhibited these changes. Glutamate induced the levels of p-p38 MAPK/p38 MAPK and SAT1 and decreased the expression levels of ferritin light chain, SLC7A11, and GPX4. SB202190 inhibited the expression of iron death-related proteins induced by glutamate. In vivo experiments showed that SB202190 attenuated N-methyl-D-aspartate-induced damage to rat retinal ganglion cells and improved visual function. These results suggest that SB202190 can inhibit ferroptosis and protect retinal ganglion cells by regulating ferritin light chain, SAT1, and SLC7A11/Gpx4 pathways and may represent a potential retina protectant.展开更多
Immunotherapy assays using immunoadjuvants and tumor antigens could greatly increase the survival rates of patients with malignant tumors.As effective carriers,metal-organic frameworks(MOFs)have been widely utilized i...Immunotherapy assays using immunoadjuvants and tumor antigens could greatly increase the survival rates of patients with malignant tumors.As effective carriers,metal-organic frameworks(MOFs)have been widely utilized in cancer therapy due to their remarkable histocompatibility and low toxicity.Herein,we constructed a multimodal imaging-guided synergistic cancer photoimmunotherapy by employing a specific MOF(MIL101-NH2)as the core carrier;the MOF was dual-dressed with photoacoustic and fluorescent signal donors(indocyanine green,ICG)and immune adjuvants(cytosine-phosphate-guanine sequence,CpG)and named ICGCpG@MOF.This nanocarrier could passively target the tumor site through the EPR effect and achieve multimodal imaging(fluorescence,photoacoustic,photothermal and magnetic resonance imaging)of the tumor.Synergistic cancer photoimmunotherapy was achieved via simultaneous photodynamic and photothermal methods with 808 nm laser irradiation.ICG-CpG@MOF achieved the GSH-controlled release of immunoadjuvant into the tumor microenvironment.Furthermore,the released tumor-associated antigen along with CpG could induce the transformation of tumor cells from cold to hot by activating the immune system,which significantly enhanced tumor cytotoxicity and achieved high cure rates with minimal side-effects.This strategy utilizing multimodal imaging and synergistic cancer photoimmunotherapy provides a promising approach for the diagnosis and treatment of cancer.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81974132,81770927Hunan Provincial Health Commission,No.20220702839+1 种基金the Natural Science Foundation of Hunan Province of China,No.2022JJ30076National Key R&D Program of China,No.2021YFA1101202(all to WS)。
文摘Glutamate excitotoxicity has been shown to play an important role in glaucoma, and glutamate can induce ferroptosis. The p38 mitogenactivated protein kinase(MAPK) pathway inhibitor SB202190 has a potential ability to suppress ferroptosis, and its downstream targets, such as p53, have been shown to be associated with ferroptosis. However, whether ferroptosis also occurs in retinal ganglion cells in response to glutamate excitotoxicity and whether inhibition of ferroptosis reduces the loss of retinal ganglion cells induced by glutamate excitotoxicity remain unclear. This study investigated ferroptosis in a glutamate-induced glaucoma rat model and explored the effects and molecular mechanisms of SB202190 on retinal ganglion cells. A glutamate-induced excitotoxicity model in R28 cells and an N-methyl-D-aspartate-induced glaucoma model in rats were used. In vitro experiments showed that glutamate induced the accumulation of iron and lipid peroxide and morphological changes of mitochondria in R28 cells, and SB202190 inhibited these changes. Glutamate induced the levels of p-p38 MAPK/p38 MAPK and SAT1 and decreased the expression levels of ferritin light chain, SLC7A11, and GPX4. SB202190 inhibited the expression of iron death-related proteins induced by glutamate. In vivo experiments showed that SB202190 attenuated N-methyl-D-aspartate-induced damage to rat retinal ganglion cells and improved visual function. These results suggest that SB202190 can inhibit ferroptosis and protect retinal ganglion cells by regulating ferritin light chain, SAT1, and SLC7A11/Gpx4 pathways and may represent a potential retina protectant.
基金This work was supported by grants from the National Natural Science Foundation of China,China(21904145,81972019 and 31700150)China Postdoctoral Science Foundation,China(2018M633273)+1 种基金Chen Jingyu team of Sanming Project of Medicine in Shenzhen,China(SZSM201812058)Guangdong Provincial Science and Technology Plan project,China(No.2017B030314108).
文摘Immunotherapy assays using immunoadjuvants and tumor antigens could greatly increase the survival rates of patients with malignant tumors.As effective carriers,metal-organic frameworks(MOFs)have been widely utilized in cancer therapy due to their remarkable histocompatibility and low toxicity.Herein,we constructed a multimodal imaging-guided synergistic cancer photoimmunotherapy by employing a specific MOF(MIL101-NH2)as the core carrier;the MOF was dual-dressed with photoacoustic and fluorescent signal donors(indocyanine green,ICG)and immune adjuvants(cytosine-phosphate-guanine sequence,CpG)and named ICGCpG@MOF.This nanocarrier could passively target the tumor site through the EPR effect and achieve multimodal imaging(fluorescence,photoacoustic,photothermal and magnetic resonance imaging)of the tumor.Synergistic cancer photoimmunotherapy was achieved via simultaneous photodynamic and photothermal methods with 808 nm laser irradiation.ICG-CpG@MOF achieved the GSH-controlled release of immunoadjuvant into the tumor microenvironment.Furthermore,the released tumor-associated antigen along with CpG could induce the transformation of tumor cells from cold to hot by activating the immune system,which significantly enhanced tumor cytotoxicity and achieved high cure rates with minimal side-effects.This strategy utilizing multimodal imaging and synergistic cancer photoimmunotherapy provides a promising approach for the diagnosis and treatment of cancer.
