ABSTRACT
Pyrogallol, a natural polyphenol compound (1,2,3-trihydroxybenzene), has shown efficacy in the therapeutic treatment of disorders associated with inflammation. Nevertheless, the mechanisms underlying the protective properties of pyrogallol against influenza A virus infection are not yet established. We established in this study that pyrogallol effectively alleviated H1N1 influenza A virus-induced lung injury and reduced mortality. Treatment with pyrogallol was found to promote the expression and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor gamma (PPAR-γ). Notably, the activation of Nrf2 by pyrogallol was involved in elevating the expression of PPAR-γ, both of which act synergistically to enhance heme oxygenase-1 (HO-1) synthesis. Blocking HO-1 by zinc protoporphyrin (ZnPP) reduced the suppressive impact of pyrogallol on H1N1 virus-mediated aberrant retinoic acid-inducible gene-I-nuclear factor kappa B (RIG-I-NF-κB) signaling, which thus abolished the dampening effects of pyrogallol on excessive proinflammatory mediators and cell death (including apoptosis, necrosis, and ferroptosis). Furthermore, the HO-1-independent inactivation of janus kinase 1/signal transducers and activators of transcription (JAK1/STATs) and the HO-1-dependent RIG-I-augmented STAT1/2 activation were both abrogated by pyrogallol, resulting in suppression of the enhanced transcriptional activity of interferon-stimulated gene factor 3 (ISGF3) complexes, thus prominently inhibiting the amplification of the H1N1 virus-induced proinflammatory reaction and apoptosis in interferon-beta (IFN-ß)-sensitized cells. The study provides evidence that pyrogallol alleviates excessive proinflammatory responses and abnormal cell death via HO-1 induction, suggesting it could be a potential agent for treating influenza.
ABSTRACT
BACKGROUND: Severe respiratory system illness caused by influenza A virus infection is associated with excessive inflammation and abnormal apoptosis in alveolar epithelial cells (AEC). However, there are limited therapeutic options for influenza-associated lung inflammation and apoptosis. Pterostilbene (PTE, trans-3,5-dimethoxy-4-hydroxystilbene) is a dimethylated analog of resveratrol that has been reported to limit influenza A virus infection by promoting antiviral innate immunity, but has not been studied for its protective effects on virus-associated inflammation and injury in AEC. PURPOSE: Our study aimed to investigate the protective effects and underlying mechanisms of PTE in modulating inflammation and apoptosis in AEC, as well as its effects on macrophage polarization during influenza virus infection. STUDY DESIGN AND METHODS: A murine model of influenza A virus-mediated acute lung injury was established by intranasal inoculation with 5LD50 of mouse-adapted H1N1 viruses. Hematoxylin and eosin staining, immunofluorescence, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, Luminex and flow cytometry were performed. RESULTS: PTE effectively mitigated lung histopathological changes and injury induced by H1N1 viruses in vivo. These beneficial effects of PTE were attributed to the suppression of inflammation and apoptosis in AEC, as well as the modulation of M1 macrophage polarization. Mechanistic investigations revealed that PTE activated the phosphorylated AMP-activated protein kinase alpha (P-AMPKα)/sirtui1 (Sirt1)/PPARγ coactivator 1-alpha (PGC1α) signal axis, leading to the inhibition of nuclear factor kappa-B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling induced by H1N1 viruses, thereby attenuating inflammation and apoptosis in AEC. PTE also forced activation of the P-AMPKα/Sirt1/PGC1α signal axis in RAW264.7 cells, counteracting the activation of phosphorylated signal transducer and activator of transcription 1 (P-STAT1) induced by H1N1 viruses and the augment of P-STAT1 activation in RAW264.7 cells with interferon-gamma (IFN-γ) pretreatment before viral infection, thereby reducing H1N1 virus-mediated M1 macrophage polarization as well as the enhancement of macrophages into M1 phenotypes elicited by IFN-γ pretreatment. Additionally, the promotion of the transition of macrophages towards the M2 phenotype by PTE was also related to activation of the P-AMPKα/Sirt1/PGC1α signal axis. Moreover, co-culturing non-infected AEC with H1N1 virus-infected RAW264.7 cells in the presence of PTE inhibited apoptosis and tight junction disruption, which was attributed to the suppression of pro-inflammatory mediators and pro-apoptotic factors in an AMPKα-dependent manner. CONCLUSION: In conclusion, our findings suggest that PTE may serve as a promising novel therapeutic option for treating influenza-associated lung injury. Its ability to suppress inflammation and apoptosis in AEC, modulate macrophage polarization, and preserve alveolar epithelial cell integrity highlights its potential as a therapeutic agent in influenza diseases.
Subject(s)
Acute Lung Injury , Apoptosis , Influenza A Virus, H1N1 Subtype , Orthomyxoviridae Infections , Sirtuin 1 , Stilbenes , Animals , Stilbenes/pharmacology , Acute Lung Injury/drug therapy , Acute Lung Injury/virology , Mice , Influenza A Virus, H1N1 Subtype/drug effects , Apoptosis/drug effects , Sirtuin 1/metabolism , Orthomyxoviridae Infections/drug therapy , RAW 264.7 Cells , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Macrophages/drug effects , Disease Models, Animal , Mice, Inbred C57BL , AMP-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Alveolar Epithelial Cells/drug effects , Alveolar Epithelial Cells/virology , Lung/drug effects , Lung/virology , Lung/pathology , FemaleABSTRACT
Pyrogallol (1,2,3-trihydroxybenzene), a polyphenolic natural compound, has attracted considerable attention with regard to its potential anticancer activity. However, further study is needed to elucidate the underlying mechanism related to the antiNSCLC activity of pyrogallol and provide a comprehensive theoretical basis for better clinical utilization of pyrogallol. Our current study aims to investigate the effects and potential underlying mechanisms of pyrogallol on the inhibition of NSCLC growth. Our results showed that pyrogallol treatment induced cell cycle arrest at the G2/M phase and apoptosis in two different NSCLC cell lines. Mechanistically, we found that the induction of cell cycle arrest in NSCLC cells at the G2/M phase by pyrogallol was due to the upregulation of p21 in a p53-dependent manner. And blockade of p53 and p21 effectively abolished the cell cycle arrest at the G2/M phase. Meanwhile, p53 inhibition has been found to abrogate the pyrogallol-induced apoptosis of the two NSCLC cells. Moreover, we revealed that the inhibitory effects of pyrogallol on ß-catenin signaling resulted from autophagy initiation depending on p53 activation, accompanied by an increase in p62/SQSTM1 expression, thus p62 subsequently interacting with ubiquitinated ß-catenin and facilitating autophagic destruction of ß-catenin. Furthermore, in vivo experiments demonstrated that pyrogallol exerted growth inhibition on NSCLC with low toxicity through the same molecular mechanism as observed in vitro. Our findings could contribute to the understanding of the mechanism by which pyrogallol negatively regulates NSCLC growth, which could be effective in treating NSCLC.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Pyrogallol/pharmacology , Pyrogallol/therapeutic use , Up-Regulation , Tumor Suppressor Protein p53/metabolism , Sequestosome-1 Protein/genetics , Sequestosome-1 Protein/metabolism , Lung Neoplasms/drug therapy , beta Catenin/metabolism , Cell Line, Tumor , Apoptosis , Cell ProliferationABSTRACT
BACKGROUND: Rosmarinic acid (RosA) is a natural phenolic compound that possesses a wide-range of pharmacological properties. However, the effects of RosA on influenza A virus-mediated acute lung injury remain unknown. In this study, we aimed to explore whether RosA could protect against H1N1 virus-mediated lung injury and elucidate the underlying mechanisms. METHODS: Mice were intragastrically administered with RosA for 2 days before intranasal inoculation of the H1N1 virus (5LD50) for the establishment of an acute lung injury model. At day 7 post-infection (p.i.), gross anatomic lung pathology, lung histopathologic, and lung index (lung weight/body weight) were examined. Luminex assay, multiple immunofluorescence and flow cytometry were performed to detect the levels of pro-inflammatory cytokines and apoptosis, respectively. Western blotting and plasmid transfection with hematopoietic-type PGD2 synthase (h-PGDS) overexpression were conducted to elucidate the mechanisms. RESULTS: RosA effectively attenuated H1N1 virus-triggered deterioration of gross anatomical morphology, worsened lung histopathology, and elevated lung index. Excessive pro-inflammatory reactions, aberrant alveolar epithelial cell apoptosis, and cytotoxic CD8+ T lung recruitment in the lung tissues induced by H1N1 virus infection were observed to be reduced by RosA treatment. In vitro experiments demonstrated that RosA treatment dose-dependently suppressed the increased levels of pro-inflammatory mediators and apoptosis through inhibition of nuclear factor kappa B (NF-κB) and P38 MAPK signaling pathways in H1N1 virus-infected A549 cells, which was accompanied by promoting activation of the h-PGDS-PGD2-HO-1 signal axis. Furthermore, we strikingly found that h-PGDS inhibition significantly abrogated the inhibitory effects of RosA on H1N1 virus-mediated activation of NF-κB and P38 MAPK signaling pathways, resulting in diminishing the suppressive effects on the increased levels of pro-inflammatory cytokines and chemokines as well as apoptosis. Finally, suppressing h-PGDS prominently abolished the protective effects of RosA on H1N1 virus-mediated severe pneumonia and lung injury. CONCLUSIONS: Taken together, our study demonstrates that RosA is a promising compound to alleviate H1N1 virus-induced severe lung injury through prompting the h-PGDS-PGD2-HO-1 signal axis.
ABSTRACT
The severity of a viral respiratory illness was greatly exacerbated after exposure to a contaminant containing benzo[a]pyrene (B[a]P). Flavonoid-rich fruit intake has gained intense interest due to their health-promoting benefits for viral respiratory diseases, including influenza viruses. In our study, diosmetin (3',5,7-trihydroxy-4'-methoxyflavone), a naturally occurring hydroxylated methoxyflavone that is abundant in Citrus fruits, was explored for its effects on B[a]P-exacerbated H1N1 influenza virus-mediated inflammation and lung injury. Initially, in vivo results demonstrated that diosmetin protected against H1N1 virus-elicited acute lung injury. Simultaneously, H1N1 virus or B[a]P-stimulated A549 cells treated with diosmetin inhibited NF-κB and P-P38 activation, resulting in suppression of pro-inflammatory cytokines and apoptosis. Interestingly, diosmetin obviously promoted the expression of PPAR-γ as well as nuclear translocation of PPAR-γ, whereas, PPAR-γ inhibition by GW9662 weakened the inhibitory effects of diosmetin on H1N1 virus or B[a]P-mediated activation of NF-κB and P-P38, elevated expression of pro-inflammatory mediators as well as apoptosis. Furthermore, it was surprising to discover that mice exposed to both B[a]P and H1N1 viruses contributed to exacerbated acute lung injury, which were significantly ameliorated by diosmetin administration. In vitro studies showed that A549 cells with the combination of B[a]P and H1N1 virus augmented NF-κB and P-P38 activation, accompanied by higher levels of pro-inflammatory mediators and apoptosis, all of which were also significantly reduced by diosmetin treatment. Repressing PPAR-γ abrogated the inhibitory effects of diosmetin on B[a]P-exacerbated H1N1 virus-mediated NF-κB and P-P38 activation, inflammation, and apoptosis in A549 cells. Our findings suggest that diosmetin protected against B[a]P-exacerbated H1N1 virus-mediated lung injury by suppressing the exacerbation of NF-κB and P38 kinase activation in a PPAR-γ-dependent manner, suggesting potential benefits for B[a]P-exacerbated influenza-related illness therapeutics.
Subject(s)
Acute Lung Injury , Influenza A Virus, H1N1 Subtype , Influenza, Human , Animals , Mice , Humans , NF-kappa B/metabolism , Benzo(a)pyrene , PPAR gamma/genetics , PPAR gamma/metabolism , Inflammation/drug therapy , Flavonoids/pharmacology , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Influenza, Human/drug therapy , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism , Inflammation MediatorsABSTRACT
BACKGROUND: Acute lung injury (ALI) arises from sepsis or bacterial infection, which are life-threatening respiratory disorders that cause the leading cause of death worldwide. 5-Methoxyflavone, a methylated flavonoid, is gaining increased attention for its various health benefits. In the current study, we investigated the potential effects of 5-methoxyflavone against LPS-mediated ALI and elucidated the corresponding possible mechanism. METHODS: A mouse model with ALI was established by intratracheal instillation of LPS, and lung pathological changes, signaling pathway related proteins and apoptosis in lung tissues were estimated by H&E staining, immunofluorescence and TUNEL assay, respectively. Cell viability was evaluated by MTT assay; protein levels of pro-inflammatory mediators were measured by ELISA assay; levels of ROS and M1 macrophage polarization were assayed by flow cytometry; the expression of Nrf2 signaling, NOX4/TLR4 axis and P-STAT1 were detected by western blotting. RESULTS: Our results showed that 5-methoxyflavone treatment inhibited LPS-induced expression of NOX4 and TLR4 as well as the activation of downstream signaling (NF-κB and P38 MAPK), which was accompanied by markedly decreased ROS levels and pro-inflammatory cytokines (IL-6, TNF-α, MCP-1, and IL-8) in BEAS-2B cells. Moreover, we revealed that these effects of 5-methoxyflavone were related to its Nrf2 activating property, and blockade of Nrf2 prevented its inhibitory effects on NOX4/TLR4/NF-κB/P38 MAPK signaling, thus abrogating the anti-inflammatory effects of 5-methoxyflavone. Besides, the Nrf2 activating property of 5-methoxyflavone in RAW264.7 cells led to inhibition of LPS/IFN-γ-mediated STAT1 signaling, resulting in suppression of LPS/IFN-γ-induced M1 macrophage polarization and the repolarization of M2 macrophages to M1. In a mouse model of LPS-induced ALI, 5-methoxyflavone administration ameliorated LPS-mediated lung pathological changes, the increased lung index (lung/body weight ratio), and epithelial cell apoptosis. Meanwhile, we found 5-methoxyflavone effectively suppressed the hyperactive signaling pathways and the production of excessive pro-inflammatory mediators. Moreover, 5-methoxyflavone reduced LPS-mediated M1 macrophage polarization associated with elevated P-STAT1 activation in the lung tissues. In addition, 5-methoxyflavone improved the survival of LPS-challenged mice. CONCLUSION: These results indicated that 5-methoxyflavone might be suitable for the development of a novel drug for ALI therapeutic.
ABSTRACT
Influenza-related acute lung injury (ALI) is a life-threatening condition that results mostly from uncontrolled replication of influenza virus (IV) and severe proinflammatory responses. The methoxy flavonoid compound 5-methoxyflavone (5-MF) is believed to have superior biological activity in the treatment of cancer. However, the effects and underlying mechanism of 5-MF on IV-mediated ALI are still unclear. Here, we showed that 5-MF significantly improved the survival of mice with lethal IV infection and ameliorated IV-mediated lung edema, lung histological changes, and inflammatory cell lung recruitment. We found that 5-MF has antiviral activity against influenza A virus (IAV), which was probably associated with increased expression of radical S-adenosyl methionine domain containing 2 (RSAD2) and suppression of endosomal acidification. Moreover, IV-infected A549 cells with 5-MF treatment markedly reduced proinflammatory mediator expression (IL-6, CXCL8, TNF-α, CXCL10, CCL2, CCL3, CCL4, GM-CSF, COX-2, and PGE2) and prevented P-IKBα, P-P65, and P-P38 activation. Interestingly, we demonstrated that 5-MF treatment could trigger activation of AMP-activated protein kinase (AMPK)α in IV-infected A549 cells, as evidenced by activation of the AMPKα downstream molecule P53. Importantly, the addition of AMPKα blocker compound C dramatically abolished 5-MF-mediated increased levels of RSAD2, the inhibitory effects on H1N1 virus-elicited endosomal acidification, and the suppression expression of proinflammatory mediators (IL-6, TNF-α, CXCL10, COX-2 and PGE2), as well as the inactivation of P-IKBα, P-P65, and P-P38 MAPK signaling pathways. Furthermore, inhibition of AMPKα abrogated the protective effects of 5-MF on H1N1 virus-mediated lung injury and excessive inflammation in vivo. Taken together, these results indicate that 5-MF alleviated IV-mediated ALI and suppressed excessive inflammatory responses through activation of AMPKα signaling.
Subject(s)
Acute Lung Injury , Influenza A Virus, H1N1 Subtype , Influenza A virus , AMP-Activated Protein Kinases/metabolism , Acute Lung Injury/metabolism , Animals , Antiviral Agents/pharmacology , Cyclooxygenase 2 , Flavones , Flavonoids/pharmacology , Flavonoids/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Inflammation/drug therapy , Influenza A Virus, H1N1 Subtype/metabolism , Influenza A virus/metabolism , Interleukin-6/metabolism , Methionine/pharmacology , Methionine/therapeutic use , Mice , NF-kappa B/metabolism , Prostaglandins E/pharmacology , Prostaglandins E/therapeutic use , Tumor Necrosis Factor-alpha/metabolism , Tumor Suppressor Protein p53 , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
The main challenges in clinical applications of mesenchymal stem cells (MSCs) are attributed to their heterogeneity. It is believed that preconditioning of MSCs with active compounds may enhance the expression of potentially therapeutic molecules and thus achieve stable and effective therapeutic outcomes. In the present study, we investigated the mechanism by which pyrogallol increased the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) against LPS-induced acute lung injury (ALI). hUCMSCs with pyrogallol treatment increased expression of HO-1 at both mRNA and protein levels, accompanied by Kelch-Like ECH-Associated Protein 1 (Keap1) degradation, and upregulation of the Nrf2 protein levels as well as nuclear translocation of Nrf2. Moreover, the modulation of Keap1 and Nrf2 as well as HO-1 upregulation by pyrogallol was reversed by pretreatment with N-acetylcysteine (NAC) and a P38 kinase inhibitor (SB203580). Whereas, NAC pretreatment abrogated pyrogallol-mediated activation of P38 kinase, indicating that pyrogallol-derived ROS led to P38 kinase activation, thus promoting Nrf2/HO-1 signaling. Additionally, we found that the induction of p62 by the pyrogallol-mediated ROS/P38/Nrf2 axis interacted with Keap1 and resulted in autophagic degradation of Keap1, which created a positive feedback loop to further release of Nrf2. Furthermore, the increased expression of HO-1 in pyrogallol-pretreated hUCMSCs led to enhanced inhibitory effects on LPS-mediated TLR4/P-P65 signaling in BEAS-2B cells, resulting in increasing suppression of LPS-indued expression of a series of pro-inflammatory mediators. Compared to untreated hUCMSCs, Sprague-Dawley (SD) rats with pyrogallol-primed hUCMSCs transplantation showed enhanced improvements in LPS-mediated lung pathological alterations, the increased lung index (lung/body ratio), apoptosis of epithelial cells, the activation of TLR4/NF-κB signaling as well as the release of pro-inflammatory mediators. Together, these results suggested that hUCMSCs with pyrogallol pretreatment enhanced the therapeutic efficacy of hUCMSCs, which may provide a promising therapeutic strategy to maximize the therapeutic efficacy of hUCMSC-based therapy for treating LPS-associated ALI.
Subject(s)
Acute Lung Injury , Mesenchymal Stem Cell Transplantation , Pyrogallol , Acetylcysteine/metabolism , Acute Lung Injury/drug therapy , Acute Lung Injury/therapy , Animals , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Humans , Inflammation/drug therapy , Inflammation/therapy , Inflammation Mediators/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , Kelch-Like ECH-Associated Protein 1/metabolism , Lipopolysaccharides , Mesenchymal Stem Cells/cytology , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Pyrogallol/pharmacology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Umbilical Cord/cytologySubject(s)
Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/diagnostic imaging , Dyspnea/etiology , Cardiomyopathy, Dilated/diagnosis , Diagnosis, Differential , Dyspnea/diagnostic imaging , Echocardiography , Heart Valve Diseases/diagnosis , Humans , Male , Middle Aged , Mitral Valve/diagnostic imagingABSTRACT
In a time when cardiac troponin assays are widely used to detect myocardial injury, data remain scarce concerning the incidence and predictors of substantial obstructive coronary artery disease that causes unstable angina. This retrospective single-center study included consecutive patients hospitalized for unstable angina from January 2015 through January 2016. Patients with troponin I levels above the upper reference limit and those who did not undergo angiography were excluded. Multivariate logistic regression analysis was used to identify predictors of obstructive coronary artery disease that warranted revascularization and of major adverse cardiac events up to 6 months after discharge from the hospital. Of the 114 patients who met the inclusion criteria, 46 (40%) had obstructive coronary artery disease. In the univariate analysis, male sex, white race, history of coronary artery disease, prior revascularization, hyperlipidemia, chronic kidney disease, aspirin use, long-acting nitrate use, and Thrombolysis in Myocardial Infarction score ≥3 were associated with obstructive coronary artery disease. History of coronary artery disease, prior revascularization, hyperlipidemia, and long-acting nitrate use were associated with major adverse cardiac events. Male sex was an independent predictor of obstructive coronary artery disease (adjusted odds ratio=4.82; 95% CI, 1.79-13; P=0.002) in the multivariate analysis. Our results showed that coronary artery disease warranting revascularization is present in a considerable proportion of patients who have unstable angina. The association that we found between male sex and obstructive coronary artery disease suggests that the risk stratification of patients presenting with unstable angina may need to be refined to improve outcomes.
Subject(s)
Angina, Unstable/blood , Coronary Occlusion/epidemiology , Risk Assessment/methods , Troponin/blood , Angina, Unstable/diagnosis , Angina, Unstable/etiology , Biomarkers/blood , Coronary Angiography , Coronary Occlusion/blood , Coronary Occlusion/complications , Electrocardiography , Female , Follow-Up Studies , Humans , Incidence , Male , Middle Aged , Predictive Value of Tests , Prognosis , Retrospective Studies , Risk Factors , United States/epidemiologyABSTRACT
OBJECTIVE: Natriuretic peptides (NPs) are hormones with cardioprotective effects. NP levels vary by race; however, the pathophysiological consequences of lower NP levels are not well understood. We aimed to quantify the association between NPs and endothelial function as measured by flow-mediated dilation (FMD) and the contribution of NP levels to racial differences in endothelial function. METHODS: In this cross-sectional study of 2938 Multi-Ethnic Study of Atherosclerosis participants (34% Caucasian, 20% African-American, 20% Asian-American and 26% Hispanic) without cardiovascular disease at baseline, multivariable linear regression models were used to examine the association between serum N-terminal pro-B-type NP (NT-proBNP) and natural log-transformed FMD. We also tested whether NT-proBNP mediated the relationship between race and FMD using the product of coefficients method. RESULTS: Among African-American and Chinese-American individuals, lower NT-proBNP levels were associated with lower FMD, ß=0.06 (95% CI: 0.03 to 0.09; p<0.001) and ß=0.06 (95% CI: 0.02 to 0.09; p=0.002), respectively. Non-significant associations between NT-proBNP and FMD were found in Hispanic and Caucasian individuals. In multivariable models, endothelial function differed by race, with African-American individuals having the lowest FMD compared with Caucasians, p<0.001. Racial differences in FMD among African-Americans and Chinese-Americans were mediated in part by NT-proBNP levels (African-Americans, mediation effect: -0.03(95% CI: -0.05 to -0.01); Chinese-Americans, mediation effect: -0.03(95% CI: -0.05 to -0.01)). CONCLUSIONS: Lower NP levels are associated with worse endothelial function among African-Americans and Chinese-Americans. A relative NP deficiency in some racial/ethnic groups may contribute to differences in vascular function.
Subject(s)
Atherosclerosis , Endothelium, Vascular/physiopathology , Natriuretic Peptide, Brain/analysis , Peptide Fragments/analysis , Black or African American/statistics & numerical data , Asian/statistics & numerical data , Atherosclerosis/blood , Atherosclerosis/ethnology , Atherosclerosis/physiopathology , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Risk Factors , United States/epidemiology , VasodilationSubject(s)
Ebstein Anomaly/diagnostic imaging , Hypertrophy, Right Ventricular/diagnostic imaging , Tricuspid Valve Insufficiency/diagnostic imaging , Tricuspid Valve/diagnostic imaging , Adult , Cardiomegaly/diagnostic imaging , Cardiomegaly/etiology , Dyspnea/etiology , Ebstein Anomaly/complications , Ebstein Anomaly/surgery , Echocardiography , Edema/etiology , Heart Valve Prosthesis Implantation , Humans , Hypertrophy, Right Ventricular/etiology , Magnetic Resonance Imaging , Male , Tricuspid Valve/abnormalities , Tricuspid Valve/surgery , Tricuspid Valve Insufficiency/complications , Tricuspid Valve Insufficiency/surgeryABSTRACT
The outcomes of patients with end-stage renal disease on dialysis (chronic kidney disease stage 5 on dialysis [CKD 5D]) who undergo transcatheter aortic valve implantation (TAVI) are not well described due to the exclusion of this group in randomized trials. We analyzed the National Inpatient Sample database and compared clinical characteristics and in-hospital outcomes for patients with CKD 5D versus those without CKD 5D (nondialysis group) who underwent TAVI in 2011 to 2014 in the United States. The study population included 1,708 patients (4%) with CKD 5D and 40,481 patients (96%) without CKD 5D who underwent TAVI. Patients with CKD 5D were younger (75.3 ± 9.9 vs 81.4 ± 8.4 years, p <0.001), more likely to be men (62.8% vs 52%, p <0.001), and less likely to be Caucasian (73.6% vs 87.8%, p <0.001). Patients with CKD 5D were more likely to have congestive heart failure (16% vs 11.7%, p <0.001), diabetes with chronic complications (19% vs 5.4%, p <0.001), hypertension (86.5% vs 79.3%, p <0.001), and peripheral vascular disease (34.5% vs 29.4%, p <0.001), but were less likely to have atrial fibrillation (38.6% vs 44.8%, p <0.001) and chronic pulmonary disease (27.5% vs 33.6%, p <0.001). In-hospital mortality was significantly higher in the dialysis group (8.2% vs 4%; adjusted odds ratio 2.21, 95% confidence interval1.81 to 2.69, p <0.001) after adjusting for age, gender, co-morbidities, and hospital characteristics in a robust multivariate regression model. In conclusion, patients with CKD 5D who undergo TAVI have a higher in-hospital mortality than those without CKD 5D.
Subject(s)
Aortic Valve Stenosis/surgery , Aortic Valve/surgery , Inpatients , Kidney Failure, Chronic/complications , Registries , Renal Dialysis , Transcatheter Aortic Valve Replacement/methods , Aged , Aged, 80 and over , Aortic Valve Stenosis/mortality , Female , Follow-Up Studies , Glomerular Filtration Rate , Hospital Mortality/trends , Humans , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/therapy , Male , Prognosis , Retrospective Studies , Risk Factors , Survival Rate/trends , Treatment Outcome , United States/epidemiologyABSTRACT
OBJECT: In this study, the authors' goal was to investigate the long-term progression of disc degeneration and the participating mechanisms induced by needle puncture in a rat caudal disc model. METHODS: The C5-6 and C7-8 intervertebral discs of the caudal spine in rats were stabbed laterally using 21-gauge hypodermic needles to a depth of 5 mm from the subcutaneous surface with the aid of fluoroscopy. Signs of degeneration in the disc of the tail were analyzed from Day 1 to Week 30 by in vivo MR imaging, histology, and biochemical and/or molecular analyses. RESULTS: Magnetic resonance imaging showed a progressive decrease in T2 density and MR imaging index throughout the entire investigation, starting at Day 1 after the needle puncture. However, histological scores revealed a bimodal pattern, showing that severity increased in the first 17 days, declined thereafter, and increased again by 30 weeks. Gene expression analysis showed a transient up-regulation in gene expression of aggrecan, type II collagen, and BMP-2, and inhibition of type I collagen. The MMP-3 mRNA levels were up-regulated at all tested time points within 6 weeks postinjury. Furthermore, the degenerated disc did not recover spontaneously, as shown by decreases in T2 density, MR imaging index, and sulfated glycosaminoglycan content in conjunction with increases in histological scores at 15 and 30 weeks postsurgery. CONCLUSIONS: This study demonstrates that needle puncture into a tail disc in the rat induces a rapid and progressive disc degeneration process without spontaneous recovery. Changes in gene expression profiles of the disc matrix molecules as well as anabolic and catabolic factors at early time points further delineate the mechanism of disc degeneration in this newly developed animal model.