RESUMO
Acute lung injury (ALI) is a life threatening disease in critically ill patients, and characterized by excessive reactive oxygen species (ROS) and inflammatory factors levels in the lung. Multiple evidences suggest that nanozyme with diversified catalytic capabilities plays a vital role in this fatal lung injury. At present, we developed a novel class of polydopamine (PDA) coated cerium dioxide (CeO2) nanozyme (Ce@P) that acts as the potent ROS scavenger for scavenging intracellular ROS and suppressing inflammatory responses against ALI. Herein, we aimed to identify that Ce@P combining with NIR irradiation could further strengthen its ROS scavenging capacity. Specifically, NIR triggered Ce@P exhibited the most potent antioxidant and anti-inflammatory behaviors in lipopolysaccharide (LPS) induced macrophages through decreasing the intracellular ROS levels, down-regulating the levels of TNF-α, IL-1ß and IL-6, up-regulating the level of antioxidant cytokine (SOD-2), inducing M2 directional polarization (CD206 up-regulation), and increasing the expression level of HSP70. Besides, we performed intravenous (IV) injection of Ce@P in LPS induced ALI rat model, and found that it significantly accumulated in the lung tissue for 6 h after injection. It was also observed that Ce@P + NIR presented the superior behaviors of decreasing lung inflammation, alleviating diffuse alveolar damage, as well as promoting lung tissue repair. All in all, it has developed the strategy of using Ce@P combining with NIR irradiation for the synergistic enhanced treatment of ALI, which can serve as a promising therapeutic strategy for the clinical treatment of ROS derived diseases as well.
Assuntos
Lesão Pulmonar Aguda , Cério , Indóis , Polímeros , Espécies Reativas de Oxigênio , Cério/química , Cério/farmacologia , Animais , Lesão Pulmonar Aguda/tratamento farmacológico , Polímeros/química , Polímeros/farmacologia , Indóis/química , Indóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ratos , Camundongos , Masculino , Células RAW 264.7 , Pulmão/efeitos dos fármacos , Pulmão/patologia , Antioxidantes/farmacologia , Antioxidantes/química , Ratos Sprague-Dawley , Lipopolissacarídeos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Raios Infravermelhos , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/uso terapêutico , Nanopartículas/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Citocinas/metabolismoRESUMO
Excessive hepatic lipid droplets (LDs) accumulation-induced lipid metabolism disorder contributes to the development of non-alcoholic fatty liver disease (NAFLD). Exercise is a promising therapeutic strategy for NAFLD. However, the mechanism by which exercise ameliorates NAFLD through regulating the catabolism of hepatic LDs remains unclear. In the present study, we investigated the effect of perilipin2 (PLIN2)-lysosomal acid lipase (LIPA) axis mediating exercise-triggered lipophagy in a high-fat diet (HFD)-induced NAFLD mouse model. Our results showed that exercise could reduce HFD-induced hepatic LDs accumulation and change the expression of lipolysis-related enzymes. Moreover, exercise upregulated the expression of microtubule associated protein 1 light chain 3 (LC3) and autophagy-related proteins, and downregulated sequestosome 1 (P62) expression and promoted autophagosomes formation. Interestingly, exercise downregulated PLIN2 expression, upregulated LIPA expression, and increased the activity of hepatic LIPA and serum levels of LIPA in the NAFLD mouse model. Further mechanistic studies demonstrated that adenosine monophosphate-activated protein kinase (AMPK) activator-5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr) treatment significantly increased mRNA levels and protein expression of LIPA and LC3II and decreased levels of PLIN2 and P62 in palmitic acid (PA)-treated HepG2 cells. PLIN2 silencing and LIPA overexpression notably increased the mRNA level and protein expression of LC3II and decreased the mRNA level and protein expression of p62, respectively. In summary, our findings reveal novel insights into the effect of exercise on improving lipid droplet metabolism disorder in NAFLD. Enhancing the PLIN2-LIPA axis-mediated lipophagy may be one of the key mechanisms involved in NAFLD alleviation by exercise.
Assuntos
Transtornos do Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/genética , Gotículas Lipídicas/metabolismo , Autofagia , Modelos Animais de Doenças , Transtornos do Metabolismo dos Lipídeos/metabolismo , RNA Mensageiro/metabolismoRESUMO
Alanine-serine-cysteine transporter 2 (ASCT2) is up-regulated in lung cancers, and inhibiting it could potentially lead to nutrient deprivation, making it a viable strategy for cancer treatment. In this study, we present a series of ASCT2 inhibitors based on aminobutanoic acids, which exhibit potent inhibitory activity. Two compounds, 20k and 25e, were identified as novel and potent ASCT2 inhibitors, with IC50 values at the micromolar level in both A549 and HEK293 cells, effectively blocking glutamine (Gln) uptake. Additionally, these compounds regulated amino acid metabolism, suppressed mTOR signaling, inhibited non-small-cell lung cancer (NSCLC) growth, and induced apoptosis. In vivo, experiments showed that 20k and 25e suppressed tumor growth in an A549 xenograft model, with tumor growth inhibition (TGI) values of 65 and 70% at 25 mg/kg, respectively, while V9302 only achieved a TGI value of 29%. Furthermore, both compounds demonstrated promising therapeutic potential in patient-derived organoids. Therefore, these ASCT2 inhibitors based on aminobutanoic acids are promising therapeutic agents for treating NSCLC by targeting cancer Gln metabolism.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Cisteína , Serina , Alanina , Células HEK293 , Glutamina , Antígenos de Histocompatibilidade Menor/metabolismo , Linhagem Celular TumoralRESUMO
CONTEXT AND OBJECTIVE: Dimethylarginine dimethylaminohydrolase enzymes (DDAH), which are encoded by the genes DDAH1 and DDAH2, play a fundamental role in maintaining endothelial function. We conducted a case-control study on a Chinese population that included three ethnic groups (Han, Kazakh and Uygur), to systemically investigate associations between variations in the genes DDAH1 and DDAH2 and hypertension. DESIGN AND SETTING: Experimental study at the Department of Internal Medicine and Genetic Diagnosis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. METHODS: This case-control study included 1,224 patients with hypertension and 967 healthy unrelated individuals as controls. DDAH1 -396 4N (GCGT) del>ins, rs3087894, rs805304 and rs9267551 were genotyped using the TaqMan 5' nuclease assay. RESULTS: The G/C genotype of rs3087894 in DDAH1 was a risk factor for hypertension in the Kazakh group in the co-dominant model (G/C versus G/G) (OR 1.39; 95% CI: 1.02-1.88; P < 0.05), with the same result in the dominant model (G/C + C/C versus G/G) (OR 1.38; 95% CI: 1.03-1.84; P < 0.05). In contrast, the C/C genotype of rs3087894 seemed to be a protective factor against hypertension in the Uygur group in the recessive model (C/C versus G/G + G/C) (OR 0.62; 95% CI: 0.39- 0.97; P < 0.05). Similar findings for rs3087894 were also observed after adjusting the variable for the age covariate. CONCLUSION: Our results indicated that the C-allele of rs3087894 in DDAH1 was a risk factor for hypertension in the Kazakh group but a protective factor in the Uygur group.
RESUMO CONTEXTO E OBJETIVO: Enzimas dimetilarginina dimetilaminohidrolase (DDAH), codificadas por genes DDAH1 e DDAH2, desempenham papel fundamental na manutenção da função endotelial. Realizamos estudo tipo caso-controle na população chinesa, com três grupos étnicos (han, kazakh e uygur) para investigar sistematicamente a associação entre a variação de genes DDAH1 e DDAH2 e a hipertensão. DESENHO E LOCAL: Estudo tipo caso-controle no Departamento de Medicina Interna e Diagnóstico Genético, Hospital de Tongji, Tongji Medical College, Universidade de Ciência e Tecnologia de Huazhong. MÉTODOS: Este estudo incluiu 1.224 pacientes com hipertensão e 967 indivíduos saudáveis, sem parentesco, como controles. DDAH1 -396 4 N (GCGT) del > ins, rs3087894, rs805304 and rs9267551 foram genotipados usando o ensaio nuclease TaqMan 5'. RESULTADOS: O genótipo G/C de rs3087894 no DDAH1 foi um fator de risco para a hipertensão arterial no grupo kazakh em modelo codominante (G/C versus G/G; OR 1,39; IC 95%: 1,02-1,88; P < 0,05), com o mesmo resultado no modelo dominante (G/C + C/C versus G/G; OR 1,38; IC 95%: 1,03-1,84; P < 0,05). Em contraste, o genótipo C/C de rs3087894 parecia ser um fator de proteção para a hipertensão no grupo uygur no modelo recessivo (C/C versus G/G + G/C; OR 0,62; IC 95%: 0,39-0,97; P < 0,05). Achado semelhante para rs3087894 também foi observado depois de se ajustar a variante à covariante idade. CONCLUSÃO: Os nossos resultados indicaram que o C-alelo de rs3087894 no DDAH1 foi fator de risco para a hipertensão no grupo de kazakh, mas fator de proteção no grupo de uygur.