RESUMEN
BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with a greater risk of developing cardiovascular disease and have adverse impacts on the cardiac structure and function. Little is known about the effect of non-obese NAFLD upon cardiac function. We aimed to compare the echocardiographic parameters of left ventricle (LV) between non-obese NAFLD group and control group, and explore the correlation of non-obese NAFLD with LV diastolic dysfunction. METHODS AND RESULTS: In this cross-sectional study, 316 non-obese inpatients were enrolled, including 72 participants with NAFLD (non-obese NAFLD group) and 244 participants without NAFLD (control group). LV structural and functional indices of two groups were comparatively analyzed. LV diastolic disfunction was diagnosed and graded using the ratio of the peak velocity of the early filling (E) wave to the atrial contraction (A) wave and E value. Compared with control group, the non-obese NAFLD group had the lower E/Aã(0.80 ± 0.22) vs (0.88 ± 0.35), t = 2.528, p = 0.012ãand the smaller LV end-diastolic diameterã(4.51 ± 0.42)cm vs (4.64 ± 0.43)cm, t = 2.182, p = 0.030ã. And the non-obese NAFLD group had a higher prevalence of E/A < 1 than control group (83.3% vs 68.9%, X2 = 5.802, p = 0.016) while two groups had similar proportions of LV diastolic dysfunction (58.3% vs 53.7%, X2 = 0.484, p = 0.487). Multivariate logistic regression analysis showed that non-obese NAFLD was associated with an increase in E/A < 1 (OR = 6.562, 95%CI 2.014, 21.373, p = 0.002). CONCLUSIONS: Non-obese NAFLD was associated with decrease of E/A, while more research will be necessary to evaluate risk of non-obese NAFLD for LV diastolic dysfunction in future.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Disfunción Ventricular Izquierda , Humanos , Adulto , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Estudios Transversales , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/epidemiología , EcocardiografíaRESUMEN
Claudins (CLDN) are a family of proteins that represent the most important components of tight junctions, where they establish the paracellular barrier that controls the flow of molecules in the intercellular space between epithelial cells. Several types of viruses make full use of CLDN to facilitate entry into cells. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important pathogens in the swine industry. In this study, we found that CLDN4 functions as an anti-PRRSV factor by blocking its absorption during the early stages of infection. The small extracellular loop (ECL2) of CLDN4 restricted the viral particles outside cells by binding to GP3. A novel function of GP3-mediated regulation of CLDN4 transcription was suggested. CLDN4 can be decreased through downregulating the level of CLDN4 transcription by ubiquitinating the transcription factor, SP1. The mechanism by which highly pathogenic PRRSV infects the epithelium was proposed. Importantly, ECL2 was found to block PRRSV absorption and infection and neutralize the virus. A more in-depth understanding of PRRSV infection is described, and novel therapeutic antiviral strategies are discussed.IMPORTANCE In the present study, the role of CLDN4 in PRRSV infection was studied. The results showed that CLDN4 blocked absorption into cells and restricted extracellular viral particles via the interaction between the CLDN4 small extracellular loop, ECL2, and the viral surface protein GP3. GP3 was found to downregulate CLDN4 through ubiquitination of the transcription factor SP1 to facilitate viral entry. The mechanism by which highly pathogenic PRRSV infects the epithelium is suggested. A novel function of GP3 in regulating gene transcription was discovered. Moreover, ECL2 could block PRRSV absorption and infection, as well as neutralizing the virus in the supernatant, which may lead to the development of novel therapeutic antiviral strategies.
Asunto(s)
Claudina-4/biosíntesis , Síndrome Respiratorio y de la Reproducción Porcina/metabolismo , Virus del Síndrome Respiratorio y Reproductivo Porcino/metabolismo , Proteínas Estructurales Virales/metabolismo , Animales , Chlorocebus aethiops , Claudina-4/genética , Células HEK293 , Humanos , Síndrome Respiratorio y de la Reproducción Porcina/genética , Virus del Síndrome Respiratorio y Reproductivo Porcino/genética , Estructura Secundaria de Proteína , Factor de Transcripción Sp1/genética , Factor de Transcripción Sp1/metabolismo , Porcinos , Transcripción Genética , Ubiquitinación , Células Vero , Proteínas Estructurales Virales/genéticaRESUMEN
The highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) emerged in 2006 in China and caused great economic losses for the swine industry because of the lack of an effective vaccine. 14-3-3 proteins are generating significant interest as potential drug targets by allowing the targeting of specific pathways to elicit therapeutic effects in human diseases. In a previous study, 14-3-3s were identified to interact with non-structural protein 2 (NSP2) of PRRSV. In the present study, the specific subtype 14-3-3ε was confirmed to interact with NSP2 and play a role in the replication of the HP-PRRSV TA-12 strain. Knockdown of 14-3-3ε in Marc-145 cells and porcine alveolar macrophages (PAMs) caused a significant decrease in TA-12 replication, while stable overexpression of 14-3-3ε caused a significant increase in the replication of TA-12 and low pathogenic PRRSV (LP-PRRSV) CH-1R. The 14-3-3 inhibitor difopein also decreased TA-12 and CH-1R replication in Marc-145 cells and PAMs. These findings are consistent with 14-3-3ε acting as a proviral factor and suggest that 14-3-3ε siRNA and difopein are therapeutic candidates against PRRSV infection.
Asunto(s)
Proteínas 14-3-3/metabolismo , Síndrome Respiratorio y de la Reproducción Porcina/virología , Virus del Síndrome Respiratorio y Reproductivo Porcino/metabolismo , Proteínas no Estructurales Virales/metabolismo , Proteínas 14-3-3/fisiología , Animales , Antivirales/uso terapéutico , Western Blotting , Técnicas de Silenciamiento del Gen/veterinaria , Microscopía Confocal , Síndrome Respiratorio y de la Reproducción Porcina/tratamiento farmacológico , Síndrome Respiratorio y de la Reproducción Porcina/metabolismo , Virus del Síndrome Respiratorio y Reproductivo Porcino/fisiología , Proteínas/uso terapéutico , ARN Interferente Pequeño/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Porcinos , Proteínas no Estructurales Virales/fisiología , Replicación ViralRESUMEN
Pigs are considered a "mixing vessel" that can produce new influenza strains through genetic reassortments, which pose a threat to public health and cause economic losses worldwide. The timely surveillance of the epidemiology of the swine influenza virus is of importance for prophylactic action. In this study, 15 H1N1, one H1N2, and four H3N2 strains were isolated from a total of 4080 nasal swabs which were collected from 20 pig farms in three provinces in China between 2016 and 2019. All the isolates were clustered into four genotypes. A new genotype represented by the H1N2 strain was found, whose fragments came from the triple reassortant H1N2 lineage, classical swine influenza virus (cs-H1N1) lineage, and 2009 H1N1 pandemic virus lineage. A/Sw/HB/HG394/2018(H1N1), which was clustered into the cs-H1N1 lineage, showed a close relationship with the 1918 pandemic virus. Mutations determining the host range specificity were found in the hemagglutinin of all isolates, which indicated that all the isolates had the potential for interspecies transmission. To examine pathogenicity, eight isolates were inoculated into 6-week-old female BALB/c mice. The isolates replicated differently, producing different viral loadings in the mice; A/Swine/HB/HG394/2018(H1N1) replicated the most efficiently. This suggested that the cs-H1N1 reappeared, and more attention should be given to the new pandemic to pigs. These results indicated that new reassortments between the different strains occurred, which may increase potential risks to human health. Continuing surveillance is imperative to monitor swine influenza A virus evolution.