RESUMO
PURPOSE: Type 1 diabetes (T1DM) is a chronic metabolic disorder that can cause damage to multiple organs including the spleen. Sole insulin therapy is not satisfactory. This study aims to investigate the effects and mechanisms of combined treatment with insulin and N-acetylcysteine (NAC) on spleen damage in T1DM canines, in order to identify drugs that may better assist patients in the management of diabetes and its complications. METHODS: The canine model of T1DM was established by intravenous injection of alloxan (ALX) and streptozotocin (STZ). The therapeutic effects of insulin and NAC were evaluated by clinical manifestations, spleen protein and mRNA expression. RESULTS: The results indicate that the combined treatment of insulin and NAC can alleviate hyperglycemia and hematologic abnormalities, improve splenic histopathological changes, prevent fibrous tissue proliferation, and glycogen deposition. In addition, we observed that this combination treatment significantly suppressed the protein expression of p-P65/P65 (17.6 %, P < 0.05), NLRP3 (46.8 %, P < 0.05), and p-P38/P38 (37.1 %, P < 0.05) induced by T1DM when compared to insulin treatment alone. Moreover, it also significantly decreased the mRNA expression of TLR4 (45.0 %, P < 0.01), TNF-α (30.3 %, P < 0.05), and NLRP3 (43.3 %, P < 0.05). CONCLUSIONS: This combination has the potential to mitigate splenic inflammatory injury in T1DM canines by suppressing the activation of MAPKs-NF-κB pathway and pyroptosis. These findings provide a reference for the treatment strategies of diabetes and its complications.
Assuntos
Acetilcisteína , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Quimioterapia Combinada , Insulina , NF-kappa B , Piroptose , Transdução de Sinais , Baço , Animais , Cães , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , NF-kappa B/metabolismo , Piroptose/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Masculino , Baço/efeitos dos fármacos , Baço/patologia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Esplenopatias/tratamento farmacológico , Esplenopatias/etiologia , Esplenopatias/complicações , Sistema de Sinalização das MAP Quinases/efeitos dos fármacosRESUMO
Micro/nanoplastics (M/NPs) are the novel contaminants ubiquitous in the environment. Cadmium (Cd), a kind of heavy metal pollutant widely distributed, could potentially co-exist with PS-NPs in the environment. However, their combined effects on cardiomyocyte and its molecular mechanism in mammals remained ambiguous. Here, we examined whether PANoptosis, an emerging and complicated kind of programmed cell death, was involved in PS-NPs and Cd co-exposure-elicited cardiac injury. In this study, 60 male mice were orally subjected to environmentally relevant concentrations of PS-NPs (1 mg/kg) and/or CdCl2 (1.5 mg/kg) for 35 days. As we speculated, PS-NPs and Cd co-exposure affected the expression of pyroptosis(Caspase-1, Cleaved-Caspase-1, GSDMD, N-GSDMD, AIM2, Pyrin, NLRP3, IL-18, IL-1ß)-, apoptosis(Caspase-3, Cleaved-Caspase-3, Caspase-8, Cleaved-Caspase-8, Caspase-7, BAX)- and necroptosis (t-RIPK3, p-RIPK3, t-RIPK1, p-RIPK1, t-MLKL, p-MLKL, ZBP1)-related genes and protein, resulting in growth restriction and damaged myocardial microstructure in mice. Notably, the combined effects on Cd and PS-NPs even predominantly aggravated the toxic damage. Intriguingly, we fortuitously discovered PS-NPs and/or Cd exposure facilitated linear ubiquitination of certain proteins in mice myocardium. In summation, this study shed light toward the effects of Cd and PS-NPs on cardiotoxicity, advanced the understanding of myocardial PANoptosis and provided a scientific foundation for further exploration of the combined toxicological effects of PS-NPs and heavy metals.
Assuntos
Cádmio , Miócitos Cardíacos , Masculino , Animais , Camundongos , Cádmio/toxicidade , Caspase 3 , Caspase 8 , Microplásticos , Poliestirenos , MamíferosRESUMO
Nanoplastics (NPs) are defined as a group of emerging pollutants. However, the adverse effect of NPs and/or heavy metals on mammals is still largely unclear. Therefore, we performed a 35-day chronic toxicity experiment with mice to observe the impacts of exposure to Cadmium (Cd) and/or polystyrene nanoplastics (PSNPs). This study revealed that combined exposure to Cd and PSNPs added to the mice's growth toxicity and kidney damage. Moreover, Cd and PSNPs co-exposure obviously increased the MDA level and expressions of 4-HNE and 8-OHDG while decreasing the activity of antioxidase in kidneys via inhibiting the Nrf2 pathway and its downstream genes and proteins expression. More importantly, the results suggested for the first time that Cd and PSNPs co-exposure synergistically increased iron concentration in kidneys, and induced ferroptosis through regulating expression levels of SLC7A11, GPX4, PTGS2, HMGB1, FTH1 and FTL. Simultaneously, Cd and PSNPs co-exposure further increased the expression levels of Pink, Parkin, ATG5, Beclin1, and LC3 while significantly reducing the P62 expression level. In brief, this study found that combined exposure to Cd and PSNPs synergistically caused oxidative stress, ferroptosis and excessive mitophagy ultimately aggravating kidney damage in mice, which provided new insight into the combined toxic effect between heavy metals and PSNPs on mammals.