RESUMEN
Compared with traditional technological innovation modes, green technology innovation is more targeted for low carbon development and critical support for countries worldwide to combat climate change. The impact of green technology innovation on carbon emissions is considered in terms of fixed effect and mediating effect models through industrial structure upgrading. For this purpose, the sample dataset of 30 provincial administrative areas in China from 2008 to 2020 is employed. The results demonstrate that green technology innovation exerts significantly inhibitory effects on carbon emissions, whose conclusion still holds after removing municipalities and replacing the dependent variable. Industrial structure upgrading is vital for green technology innovation to diminish carbon emissions. There is significant regional heterogeneity in the effects of green technology innovation on carbon emissions, i.e., the direct and indirect impact of green technology innovation on carbon emission reduction is significant in the eastern-central area, but its effect is insignificant in the western region. Therefore, it is essential to realize carbon emission reduction by further bolstering green technology innovation and accelerating industrial structure upgrading to fulfill the synergy of technology and structure.
RESUMEN
Glioblastoma (GBM) is a deadly cancer in which cancer stem cells (CSCs) sustain tumor growth and contribute to therapeutic resistance. Protein arginine methyltransferase 5 (PRMT5) has recently emerged as a promising target in GBM. Using two orthogonal-acting inhibitors of PRMT5 (GSK591 or LLY-283), we show that pharmacological inhibition of PRMT5 suppresses the growth of a cohort of 46 patient-derived GBM stem cell cultures, with the proneural subtype showing greater sensitivity. We show that PRMT5 inhibition causes widespread disruption of splicing across the transcriptome, particularly affecting cell cycle gene products. We identify a GBM splicing signature that correlates with the degree of response to PRMT5 inhibition. Importantly, we demonstrate that LLY-283 is brain-penetrant and significantly prolongs the survival of mice with orthotopic patient-derived xenografts. Collectively, our findings provide a rationale for the clinical development of brain penetrant PRMT5 inhibitors as treatment for GBM.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Animales , Apoptosis , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Epigenómica , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones , Células Madre Neoplásicas/metabolismo , Proteína-Arginina N-Metiltransferasas/efectos de los fármacos , Proteína-Arginina N-Metiltransferasas/genética , Empalme del ARN , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Omega-3 polyunsaturated fatty acids (ω3 PUFAs) suppress inflammation through activation of free fatty acid receptor 4 (FFAR4), but this pathway has not been explored in the context of cardiovascular disease. We aimed to elucidate the involvement of FFAR4 activation by ω3 PUFAs in the process of vascular inflammation and neointimal hyperplasia in mice. METHODS AND RESULTS: We used mice with disruption of FFAR4 (Ffar4(-/-)), along with a strain that synthesizes high levels of ω3 PUFAs (fat-1) and a group of crossed mice (Ffar4(-/-)/fat-1), to elucidate the role of FFAR4 in vascular dysfunction using acute and chronic thrombosis/vascular remodeling models. The presence of FFAR4 in vascular-associated cells including perivascular adipocytes and macrophages, but not platelets, was demonstrated. ω3 PUFAs endogenously generated in fat-1 mice (n=9), but not in compound Ffar4(-/-)/fat-1 mice (n=9), attenuated femoral arterial thrombosis induced by FeCl3. Neointimal hyperplasia and vascular inflammation in the common carotid artery were significantly curtailed 4 weeks after FeCl3 injury in fat-1 mice (n=6). This included greater luminal diameter and enhanced blood flow, reduced intima:media ratio, and diminished macrophage infiltration in the vasculature and perivascular adipose tissue compared with control mice. These effects were attenuated in the Ffar4(-/-)/fat-1 mice. CONCLUSIONS: These results indicate that ω3 PUFAs mitigate vascular inflammation, arterial thrombus formation, and neointimal hyperplasia by interaction with FFAR4 in mice. Moreover, the ω3 PUFA-FFAR4 pathway decreases inflammatory responses with dampened macrophage transmigration and infiltration.