Neurons are the most extensive and polarized cells that display a unique single long axon and multiple dendrites, which are compartments exhibiting structural and functional differences. Polarity occurs early in neuro...Neurons are the most extensive and polarized cells that display a unique single long axon and multiple dendrites, which are compartments exhibiting structural and functional differences. Polarity occurs early in neuronal development and it is maintained by complex subcellular mechanisms throughout cell life. A well-defined and controlled spatio-temporal program of cellular and molecular events strictly regulates the formation of the axon and dendrites from a non-polarized cell. This event is critical for an adequate neuronal wiring and therefore for the normal functioning of the nervous system. Neuronal polarity is very sensitive to the harmful effects of different factors present in the environment. In this regard, rotenone is a crystalline, colorless and odorless isoflavone used as insecticide, piscicide and broad spectrum pesticide commonly used earlier in agriculture. In the present review we will summarize the toxicity mechanism caused by this pesticide in different neuronal cell types, focusing on a particular biological mechanism whereby rotenone could impair neuronal polarization in cultured hippocampal neurons. Recent advances suggest that the inhibition of axonogenesis produced by rotenone could be related with its effect on microtubule dynamics, the actin cytoskeleton and their regulatory pathways, particularly affecting the small RhoGTPase RhoA. Unveiling the mechanism by which rotenone produces neurotoxicity will be instrumental to understand the cellular mechanisms involved in neurodegenerative diseases influenced by this environmental pollutant, which may lead to research focused on the design of new therapeutic strategies.展开更多
Acute kidney injury(AKI)has high morbidity and mortality,but effective clinical drugs and management are lacking.Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI...Acute kidney injury(AKI)has high morbidity and mortality,but effective clinical drugs and management are lacking.Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets.Emerging evidence has highlighted the importance of forkhead box protein O1(FoxO1)in mediating macrophage activation and polarization in various diseases,but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear.The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI.We observed a significant upregulation of FoxO1 in kidney macrophages following ischemiaereperfusion(I/R)injury.Additionally,our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome(AS-Lipo),mainly acting on macrophages,effectively mitigated renal injury induced by I/R injury in mice.By generating myeloid-specific FoxO1-knockout mice,we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI.Furthermore,our study provided evidence of FoxO1’s pivotal role in macrophage chemotaxis,inflammation,and migration.Moreover,the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1(ARHGEF1),indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway.Consequently,our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI.Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.展开更多
文摘Neurons are the most extensive and polarized cells that display a unique single long axon and multiple dendrites, which are compartments exhibiting structural and functional differences. Polarity occurs early in neuronal development and it is maintained by complex subcellular mechanisms throughout cell life. A well-defined and controlled spatio-temporal program of cellular and molecular events strictly regulates the formation of the axon and dendrites from a non-polarized cell. This event is critical for an adequate neuronal wiring and therefore for the normal functioning of the nervous system. Neuronal polarity is very sensitive to the harmful effects of different factors present in the environment. In this regard, rotenone is a crystalline, colorless and odorless isoflavone used as insecticide, piscicide and broad spectrum pesticide commonly used earlier in agriculture. In the present review we will summarize the toxicity mechanism caused by this pesticide in different neuronal cell types, focusing on a particular biological mechanism whereby rotenone could impair neuronal polarization in cultured hippocampal neurons. Recent advances suggest that the inhibition of axonogenesis produced by rotenone could be related with its effect on microtubule dynamics, the actin cytoskeleton and their regulatory pathways, particularly affecting the small RhoGTPase RhoA. Unveiling the mechanism by which rotenone produces neurotoxicity will be instrumental to understand the cellular mechanisms involved in neurodegenerative diseases influenced by this environmental pollutant, which may lead to research focused on the design of new therapeutic strategies.
基金supported by grants from the National Natural Science Foundation of China(No.92168120 to Lu Tie)the Key Research and Development Project of Xinjiang Uygur Autonomous Region(2023B02010-5 to Lu Tie and Linlin Li,China)+1 种基金the Beijing Natural Science Foundation(No.Z200019 to Lu Tie,China)grants from the National Natural Science Foundation of China(82073878,81874318,81473235 to Xuejun Li).
文摘Acute kidney injury(AKI)has high morbidity and mortality,but effective clinical drugs and management are lacking.Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets.Emerging evidence has highlighted the importance of forkhead box protein O1(FoxO1)in mediating macrophage activation and polarization in various diseases,but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear.The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI.We observed a significant upregulation of FoxO1 in kidney macrophages following ischemiaereperfusion(I/R)injury.Additionally,our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome(AS-Lipo),mainly acting on macrophages,effectively mitigated renal injury induced by I/R injury in mice.By generating myeloid-specific FoxO1-knockout mice,we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI.Furthermore,our study provided evidence of FoxO1’s pivotal role in macrophage chemotaxis,inflammation,and migration.Moreover,the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1(ARHGEF1),indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway.Consequently,our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI.Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.
