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Eur J Pharmacol ; 911: 174559, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34637700


OBJECTIVE: In this study, it was hypothesized that klotho deficiency plays an essential role in cardiac ageing in vivo and demonstrated that supplementation with exogenous klotho protects against cardiomyocyte ageing in vitro. METHODS: We measured the lifespan of wild-type (WT) and klotho-hypomorphic mutant (KL-/-) mice and recorded the cardiac function of the mice through echocardiography. We used immunofluorescence staining to detect the LC3B (microtubule-associated protein light chain 3 B), Beclin 1, Bax and Bcl 2 proteins. In vitro, H9c2 cells were incubated with different levels of D-galactose (D-gal) with or without klotho. SA-ß-galactosidase staining and western blotting were performed to detect ageing-associated proteins (P53, P21 and P16), autophagy-associated proteins (LC3 II/LC3 I and Beclin 1) and apoptosis-associated proteins (Bax and Bcl 2). Moreover, one-step TUNEL apoptosis, CCK-8, cell morphology, Hoechst 33258 staining, lactate dehydrogenase (LDH) release, and caspase-3 activity assays were performed, and intracellular reactive oxygen species (ROS) levels were measured. RESULTS: Genetic klotho deficiency decreased lifespan and cardiac function in mice, impaired autophagic activity and increased apoptotic activity. Exogenous klotho attenuated cardiomyocyte ageing and reversed changes in autophagic and apoptotic activity caused by D-gal. Moreover, klotho supplementation prevented D-gal-induced oxidative stress and cytotoxicity. CONCLUSIONS: Klotho might have a protective effect on cardiac ageing via autophagy activation and apoptosis inhibition.

Aging (Albany NY) ; 13(16): 20534-20551, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34432650


OBJECTIVE: The NOD-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) inflammasome is associated with many physiological processes related to aging. We investigated whether NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging dissected the underlying mechanism. METHODS: H9c2 cells were treated with different concentrations of D-galactose (D-gal, 0, 2, 10 and 50 g/L) for 24 hours. The cytochemical staining, flow cytometry and fluorescence microscope analysis were employed to detect the ß-galactosidase (ß-gal) activity. Western blot analysis was used to detect the age-associated proteins (P53, P21) and NLRP3 inflammasome proteins [NLRP3, apoptosis-associated speck-like protein (ASC)]. Confocal fluorescent images were applied to capture the colocalization of NLRP3 and caspase-1. Intracellular reactive oxygen species (ROS) was measured using 2'7'-dichlorodihydrofluorescein diacetate (DCFH-DA) by flow cytometry and visualized using a fluorescence microscope. The IL-1ß, IL-18 and lactate dehydrogenase (LDH) release were also detected. RESULTS: D-gal induced-H9c2 cells caused cardiocytes' aging changes (ß-gal staining, CellEvent™ Senescence Green staining, P53, P21) in a concentration-dependent manner. NLRP3 inflammasomes were activated, IL-1ß, IL-18 and LDH release and ROS generation were increased in the cardiocytes aging progress. When MCC950 inhibited NLRP3 inflammasomes, it attenuated the cardiocytes aging, yet the ROS generation was similar. Inhibition of ROS by NAC attenuated cardiocytes aging and inhibited the NLRP3 inflammasome activation at the same time. NLRP3 inflammasome activation by nigericin-induced cardiocytes cells aging progress. CONCLUSIONS: NLRP3 inflammasome activation contributes to the pathogenesis of cardiocytes aging, and ROS generation may serve as a potential mechanism by which NLRP3 inflammasome is activated.

Hepatobiliary Pancreat Dis Int ; 17(6): 517-523, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30262421


BACKGROUND: Treatment options for patients with cavernous transformation of portal vein (CTPV) are limited. This study aimed to evaluate the feasibility, efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) to prevent recurrent esophageal variceal bleeding in patients with CTPV. METHODS: We retrospectively analyzed 67 consecutive patients undergone TIPS from January 2011 to December 2016. All patients were diagnosed with CTPV. The indication for TIPS was a previous episode of variceal bleeding. The data on recurrent bleeding, stent patency, hepatic encephalopathy and survival were retrieved and analyzed. RESULTS: TIPS procedure was successfully performed in 56 out of 67 (83.6%) patients with CTPV. TIPS was performed via a transjugular approach alone (n = 15), a combined transjugular/transhepatic approach (n = 33) and a combined transjugular/transsplenic approach (n = 8). Mean portosystemic pressure gradient (PSG) decreased from 28.09 ±â€¯7.28 mmHg to 17.53 ±â€¯6.12 mmHg after TIPS (P < 0.01). The probability of the remaining free recurrent variceal bleeding was 87.0%. The probability of TIPS patency reached 81.5%. Hepatic encephalopathy occurrence was 27.8%, and survival rate was 88.9% until the end of follow-up. Four out of 11 patients who failed TIPS died, and 4 had recurrent bleeding. CONCLUSIONS: TIPS should be considered a safe and feasible alternative therapy to prevent recurrent esophageal variceal bleeding in patients with CTPV, and to achieve clinical improvement.

Varizes Esofágicas e Gástricas/prevenção & controle , Hemorragia Gastrointestinal/prevenção & controle , Hipertensão Portal/cirurgia , Veia Porta/anormalidades , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Adulto , Idoso , Feminino , Encefalopatia Hepática/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Veia Porta/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Derivação Portossistêmica Transjugular Intra-Hepática/mortalidade , Recidiva , Estudos Retrospectivos