RESUMEN
Emphysema is a chronic obstructive lung disease characterized by inflammation and enlargement of the air spaces. Regorafenib, a potential senomorphic drug, exhibited a therapeutic effect in porcine pancreatic elastase (PPE)-induced emphysema in mice. In the current study we examined the preventive role of regorafenib in development of emphysema. Lung function tests and morphometry showed that oral administration of regorafenib (5 mg/kg/day) for seven days after instillation of PPE resulted in attenuation of emphysema. Mechanistically, regorafenib reduced the recruitment of inflammatory cells, particularly macrophages and neutrophils, in bronchoalveolar lavage fluid. In agreement with these findings, measurements using a cytokine array and ELISA showed that expression of inflammatory mediators including interleukin (IL)-1ß, IL-6, and CXCL1/KC, and tissue inhibitor of matrix metalloprotease-1 (TIMP-1), was downregulated. The results of immunohistochemical analysis confirmed that expression of IL-6, CXCL1/KC, and TIMP-1 was reduced in the lung parenchyma. Collectively, the results support the preventive role of regorafenib in development of emphysema in mice and provide mechanistic insights into prevention strategies. [BMB Reports 2023; 56(8): 439-444].
Asunto(s)
Enfisema , Enfisema Pulmonar , Animales , Ratones , Modelos Animales de Enfermedad , Enfisema/tratamiento farmacológico , Interleucina-6 , Pulmón/metabolismo , Ratones Endogámicos C57BL , Elastasa Pancreática , Enfisema Pulmonar/inducido químicamente , Enfisema Pulmonar/tratamiento farmacológico , Enfisema Pulmonar/metabolismo , Porcinos , Inhibidor Tisular de Metaloproteinasa-1/farmacología , Inhibidor Tisular de Metaloproteinasa-1/uso terapéuticoRESUMEN
Senescence, a hallmark of aging, is a factor in age-related diseases (ARDs). Therefore, targeting senescence is widely regarded as a practicable method for modulating the effects of aging and ARDs. Here, we report the identification of regorafenib, an inhibitor of multiple receptor tyrosine kinases, as a senescence-attenuating drug. We identified regorafenib by screening an FDA-approved drug library. Treatment with regorafenib at a sublethal dose resulted in effective attenuation of the phenotypes of ßPIX knockdown- and doxorubicin-induced senescence and replicative senescence in IMR-90 cells; cell cycle arrest, and increased SA-ß-Gal staining and senescence-associated secretory phenotypes, particularly increasing the secretion of interleukin 6 (IL-6) and IL-8. Consistent with this result, slower progression of ßPIX depletion-induced senescence was observed in the lungs of mice after treatment with regorafenib. Mechanistically, the results of proteomics analysis in diverse types of senescence indicated that growth differentiation factor 15 and plasminogen activator inhibitor-1 are shared targets of regorafenib. Analysis of arrays for phospho-receptors and kinases identified several receptor tyrosine kinases, including platelet-derived growth factor receptor α and discoidin domain receptor 2, as additional targets of regorafenib and revealed AKT/mTOR, ERK/RSK, and JAK/STAT3 signaling as the major effector pathways. Finally, treatment with regorafenib resulted in attenuation of senescence and amelioration of porcine pancreatic elastase-induced emphysema in mice. Based on these results, regorafenib can be defined as a novel senomorphic drug, suggesting its therapeutic potential in pulmonary emphysema.
Asunto(s)
Enfisema , Enfisema Pulmonar , Síndrome de Dificultad Respiratoria , Ratones , Animales , Porcinos , Senoterapéuticos , Tirosina , Senescencia Celular/genéticaRESUMEN
Proper targeting of the ßPAK-interacting exchange factor (ßPIX)/G protein-coupled receptor kinase-interacting target protein (GIT) complex into distinct cellular compartments is essential for its diverse functions including neurite extension and synaptogenesis. However, the mechanism for translocation of this complex is still unknown. In the present study, we reported that the conventional kinesin, called kinesin-1, can transport the ßPIX/GIT complex. Additionally, ßPIX bind to KIF5A, a neuronal isoform of kinesin-1 heavy chain, but not KIF1 and KIF3. Mapping analysis revealed that the tail of KIF5s and LZ domain of ßPIX were the respective binding domains. Silencing KIF5A or the expression of a variety of mutant forms of KIF5A inhibited ßPIX targeting the neurite tips in PC12 cells. Furthermore, truncated mutants of ßPIX without LZ domain did not interact with KIF5A, and were unable to target the neurite tips in PC12 cells. These results defined kinesin-1 as a motor protein of ßPIX, and may provide new insights into ßPIX/GIT complex-dependent neuronal pathophysiology. [BMB Reports 2021; 54(7): 380-385].