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1.
Circulation ; 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32354235

RESUMO

Background: Abdominal aortic aneurysm (AAA) is a severe aortic disease with a high mortality rate in the event of rupture. Pharmacological therapy is needed to inhibit AAA expansion and prevent aneurysm rupture. Transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, is critical to maintain cell homeostasis. In this study, we aim to investigate the role of vascular smooth muscle cell (VSMC) TFEB in the development of AAA and establish TFEB as a novel target to treat AAA. Methods: The expression of TFEB was measured in human and mouse aortic aneurysm samples. We used loss/gain-of-function approaches to understand the role of TFEB in VSMC survival and explored the underlying mechanisms through transcriptome and functional studies. Utilizing vascular smooth muscle cell (VSMC)-selective Tfeb knockout mice and employing different mouse AAA models, we determined the role of VSMC TFEB and a TFEB activator on AAA in vivo. Results: We found that TFEB is downregulated in both human and mouse aortic aneurysm lesions. TFEB potently inhibits apoptosis in VSMCs and transcriptome analysis revealed that TFEB regulates apoptotic signaling pathways, especially apoptosis inhibitor B-cell lymphoma 2 (BCL2). BCL2 is significantly upregulated by TFEB and is required for TFEB to inhibit VSMC apoptosis. Consistently, we observed that TFEB deficiency increases VSMC apoptosis and promotes AAA formation in different mouse AAA models. Furthermore, we demonstrated that 2-hydroxypropyl-ß-cyclodextrin (HPßCD), a clinical agent used to enhance the solubility of drugs, activates TFEB and inhibits AAA formation and progression in mice. Finally, we found that HPßCD inhibits AAA in a VSMC TFEB-dependent manner in mouse models. Conclusions: Our study demonstrated that TFEB protects against VSMC apoptosis and AAA. TFEB activation by HPßCD may be a promising therapeutic strategy for the prevention and treatment of AAA.

2.
Plant Physiol Biochem ; 151: 391-399, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32278293

RESUMO

Lily, a famous cut flower with highly fragrance, has high ornamental and economic values. Monoterpenes are the main components contributing to its fragrance, and terpene synthase (TPS) genes play critical roles in the biosynthesis of monoterpenoids. To understand the function of TPS and to explore the molecular mechanism of floral scent in cultivar Lilium 'Siberia', transcriptomes of petal at different flowering stages and leaf were obtained by RNA sequencing and three unigenes related to TPS genes were selected for further validation. Quantitative real-time PCR showed that the expression level of LiTPS2 was greater than that of the other two TPS genes. Phylogenetic analysis indicated that LiTPS2 belonged to the TPSb subfamily, which was responsible for monoterpenes synthesis. Subcellular localization demonstrated that LiTPS2 was located in the chloroplasts. Furthermore, functional characterization showed that LiTPS2 utilized both geranyl pyrophosphate (GPP) and farnesyl pyrophosphate (FPP) to produce monoterpenoids such as linalool and sesquiterpenes like trans-nerolidol, respectively. Ectopic expression in transgenic tobacco plants suggested that the amount of linalool from the flowers of transgenic plants was 2-3 fold higher than that of wild-type plants. And the emissions of myrcene and (E)-ß-ocimene were also accumulated from the flowers of LiTPS2 transgenic lines. Surprisingly, these three compounds were the main fragrance components of oriental lily hybrids. Our results indicated that LiTPS2 contributed to the production of monoterpenes and could effectively regulate the aroma of Lilium cultivars, laying the foundation for biotechnological modification of floral scent profiles.

3.
Crit Care ; 24(1): 73, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131872

RESUMO

INTRODUCTION: Patient safety and critical care quality remain a challenging issue in the ICU. However, the effects of the national quality improvement (QI) program remain unknown in China. METHODS: A national ICU QI program was implemented in a controlled cohort of 586 hospitals from 2016 to 2018. The effects of the QI program on critical care quality were comprehensively investigated. MAIN RESULTS: A total of 81,461,554 patients were enrolled in 586 hospitals, and 1,587,724 patients were admitted to the ICU over 3 years. In 2018, there was a significantly higher number of ICU beds (2016 vs. 2018: 10668 vs. 13,661, P = 0.0132) but a lower doctor-to-bed ratio (2016 vs. 2018: 0.64 (0.50, 0.83) vs. 0.60 (0.45, 0.75), P = 0.0016) and nurse-to-bed ratio (2016 vs. 2018: 2.00 (1.64, 2.50) vs. 2.00 (1.50, 2.40), P = 0.031) than in 2016. Continuous and significant improvements in the ventilator-associated pneumonia (VAP) incidence rate, microbiology detection rate before antibiotic use and deep vein thrombosis (DVT) prophylaxis rate were associated with the implementation of the QI program (VAP incidence rate (per 1000 ventilator-days), 2016 vs. 2017 vs. 2018: 11.06 (4.23, 22.70) vs. 10.20 (4.25, 23.94) vs. 8.05 (3.13, 17.37), P = 0.0002; microbiology detection rate before antibiotic use (%), 2016 vs. 2017 vs. 2018: 83.91 (49.75, 97.87) vs. 84.14 (60.46, 97.24) vs. 90.00 (69.62, 100), P < 0.0001; DVT prophylaxis rate, 2016 vs. 2017 vs. 2018: 74.19 (33.47, 96.16) vs. 71.70 (38.05, 96.28) vs. 83.27 (47.36, 97.77), P = 0.0093). Moreover, the 6-h SSC bundle compliance rates in 2018 were significantly higher than those in 2016 (6-h SSC bundle compliance rate, 2016 vs. 2018: 64.93 (33.55, 93.06) vs. 76.19 (46.88, 96.67)). A significant change trend was not found in the ICU mortality rate from 2016 to 2018 (ICU mortality rate (%), 2016 vs. 2017 vs. 2018: 8.49 (4.42, 14.82) vs. 8.95 (4.89, 15.70) vs. 9.05 (5.12, 15.80), P = 0.1075). CONCLUSIONS: The relationship between medical human resources and ICU overexpansion was mismatched during the past 3 years. The implementation of a national QI program improved ICU performance but did not reduce ICU mortality.

4.
Sci Rep ; 10(1): 2627, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060321

RESUMO

Opisthopappus taihangensis (Ling) Shih, as a relative of chrysanthemum, mainly survives on the cracks of steep slopes and cliffs. Due to the harsh environment in which O. taihangensis lives, it has evolved strong adaptive traits to drought stress. The root system first perceives soil water deficiency, triggering a multi-pronged response mechanism to maintain water potential; however, the drought tolerance mechanism of O. taihangensis roots remains unclear. Therefore, roots were selected as materials to explore the physiological and molecular responsive mechanisms. We found that the roots had a stronger water retention capacity than the leaves. This result was attributed to ABA accumulation, which promoted an increased accumulation of proline and trehalose to maintain cell osmotic pressure, activated SOD and POD to scavenge ROS to protect root cell membrane structure and induced suberin depositions to minimize water backflow to dry soil. Transcriptome sequencing analyses further confirmed that O. taihangensis strongly activated genes involved in the ABA signalling pathway, osmolyte metabolism, antioxidant enzyme activity and biosynthesis of suberin monomer. Overall, these results not only will provide new insights into the drought response mechanisms of O. taihangensis but also will be helpful for future drought breeding programmes of chrysanthemum.

5.
BMC Endocr Disord ; 20(1): 5, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31914999

RESUMO

BACKGROUND: Patients with primary hyperparathyroidism (PHPT) may be asymptomatic, and some may present with normocalcemic PHPT (NPHPT). Patients with vitamin D deficiency may also be asymptomatic, with normal calcium and elevated PTH concentrations. These latter patients are usually diagnosed with vitamin D deficiency-induced secondary hyperparathyroidism (VD-SHPT). Therefore, it is very difficult to distinguish PHPT and NPHPT from VD-SHPT based on calcium or PTH concentrations in clinical settings. In this case-control study, we aimed to verify the diagnostic power of a new parathyroid function index (PFindex = Ca*PTH/P). METHODS: This study enrolled 128 patients with surgically and pathologically confirmed PHPT, including 36 with NPHPT, at a hospital in West China between January 2009 and September 2017. Thirty-seven patients with VD-SHPT and 45 healthy controls were selected from the population of a cross-sectional epidemiological study as the SHPT and healthy groups, respectively. We used the PFindex to describe the characteristics of PHPT, NPHPT, and VD-SHPT.. Differences between the four groups were compared, and a receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic power of PFindex. RESULTS: The PHPT group had the highest PFindex (454 ± 430), compared to the other three groups (NPHPT: 101 ± 111; SHPT: 21.7 ± 6.38; healthy: 12.2 ± 2.98, all p < 0.001). A PFindex cut-off value of 34 yielded sensitivity and specificity rates of 96.9 and 97.6% and of 94.4 and 94.6% for the diagnoses of PHPT and NPHPT, respectively. The use of a PFindex > 34 to differentiate NPHPT from VD-SHPT yielded the highest positive likelihood ratio and lowest negative likelihood ratio. CONCLUSION: The PFindex provided excellent diagnostic power for the differentiation of NPHPT from VD-SHPT. This simple tool may be useful for guiding timely decision-making processes regarding the initiation of vitamin D treatment or surgery for PHPT.

6.
Light Sci Appl ; 8: 107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798846

RESUMO

Photonic sensors that are able to detect and track biochemical molecules offer powerful tools for information acquisition in applications ranging from environmental analysis to medical diagnosis. The ultimate aim of biochemical sensing is to achieve both quantitative sensitivity and selectivity. As atomically thick films with remarkable optoelectronic tunability, graphene and its derived materials have shown unique potential as a chemically tunable platform for sensing, thus enabling significant performance enhancement, versatile functionalization and flexible device integration. Here, we demonstrate a partially reduced graphene oxide (prGO) inner-coated and fiber-calibrated Fabry-Perot dye resonator for biochemical detection. Versatile functionalization in the prGO film enables the intracavity fluorescent resonance energy transfer (FRET) to be chemically selective in the visible band. Moreover, by measuring the intermode interference via noise canceled beat notes and locked-in heterodyne detection with Hz-level precision, we achieved individual molecule sensitivity for dopamine, nicotine and single-strand DNA detection. This work combines atomic-layer nanoscience and high-resolution optoelectronics, providing a way toward high-performance biochemical sensors and systems.

7.
Med Sci Monit ; 25: 8975-8983, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31767824

RESUMO

BACKGROUND Oxidative stress and neuroinflammation are 2 pivotal mechanisms in the progression of cerebral ischemia/reperfusion injury. Biochanin A, a natural phytoestrogen, has been reported to protect against ischemic brain injury in animal experiments, but the possible pharmacological mechanisms of its neuroprotection remain elusive. In this research, we sought to investigate the neuroprotective effects of biochanin A in experimental stroke rats and the probable mechanisms underlying oxidative stress and inflammation signaling pathways. MATERIAL AND METHODS An ischemic stroke model was induced by inserting thread into the middle cerebral artery. Rats were pre-administered intraperitoneally with a vehicle solution or biochanin A (10, 20, or 40 mg·kg·d--⁻¹) for 14 days prior to ischemic stroke. Neurological score, infarct volume, and cerebral edema were assessed after 2 h of ischemia and 24 h of reperfusion. The activities of SOD and GSH-Px and MDA content were measured. The expressions of Nrf2, HO-1, and NF-kappaB and the activity of phosphor-IkappaBalpha were detected by Western blotting. RESULTS Biochanin A pretreatment significantly improved neurological deficit and decreased infarct size and brain edema. Biochanin A also enhanced SOD and GSH-Px activities and suppressed the production of MDA. Additionally, biochanin A promoted Nrf2 nuclear translocation, promoted the expression of HO-1, and inhibited NF-kappaB activation in ischemic brain injury. CONCLUSIONS The results indicated that biochanin A protected the brain against ischemic injury in rats by anti-oxidative and anti-inflammatory actions. The activation of the Nrf2 pathway and the inhibition of the NF-kappaB pathway may contribute to the neuroprotective effects of biochanin A.


Assuntos
Genisteína/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Edema Encefálico/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Genisteína/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/fisiologia , NF-kappa B/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo
8.
World J Biol Psychiatry ; 20(10): 778-789, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31595816

RESUMO

Objectives: This is the first study to investigate the oxidative stress (OxS) levels in drug-free bipolar disorder (BD) patients and their association with lithium response.Methods: A total of 61 drug-free BD patients and 49 controls were included. Patients treated with lithium were followed-up for 6 weeks. The levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and malondialdehyde (MDA) were measured at baseline and at the end of the sixth week.Results: Compared to controls, the SOD levels were lower, whereas the MDA were higher in the BD-depression (BD-D) group (both P < 0.001). GSH-Px levels were higher in both the BD-D and the BD-mania (BD-M) group (both P < 0.001). Both GSH-Px and MDA levels in the BD (P = 0.009, P < 0.001) and the BD-D subgroup (P = 0.006, P = 0.001) decreased significantly after the 6-week treatment with lithium. Interestingly, both GSH-Px and MDA levels decreased in responders (P = 0.03, P = 0.002) but not in the non-responders of BD-D (both p > 0.05). Moreover, the reduction in the MDA levels were associated with lithium response (B = 1.47, Wald statistic = 5.94, P = 0.015, odds ratio = 4.35, 95% confidence interval 1.33-14.20).Conclusions: Our study demonstrates an imbalance of OxS in drug-free BD, especially BD-D. Lithium reduces the GSH-Px and MDA levels in BD patients. The reduction in MDA levels may predict individual responsiveness to lithium.

9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(2): 618-622, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-30998180

RESUMO

OBJECTIVE: The explore the molecular basis of iron-overload in Tibet nationality population of Tibet. METHODS: The inpatients with iron-overload in our department from Dec. 1st 2014 to Jul.31st 2016 were enrolled in this study. Abdominal MRI and the mutation sites C282Y and H63D in HFE exon were examined. For HFE mutation-negative patients, the non-HFE mutation was detected, including 5 HJV mutations of G320V, p.Q312X, p.D249H, p.I281T, p.C321X and 2 TFR2 mutations: (Y250X, I238M), and 2 SLC40A1 mutations: (V162del, N144H). RESULTS: Among 113 iron overload patients, only one showed homozygous p.H63D mutation, and one showed heterozygosis p.H63D mutation. In 73 patients accepted non-HFE gene detection, only one was heterozygosis p.D249N mutation in HJV, and one was heterozygosis p.I238M mutation in TFR2. CONCLUSION: Currently, the pathogenic gene for Tibetan iron-overload has not yet been found.


Assuntos
Sobrecarga de Ferro , Genótipo , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I , Humanos , Mutação , Tibet
10.
Hepatobiliary Surg Nutr ; 8(1): 87, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30881979

RESUMO

[This corrects the article DOI: 10.21037/hbsn.2018.01.06.].

11.
EBioMedicine ; 41: 62-72, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30772307

RESUMO

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) and resulting nonalcoholic steatohepatitis (NASH) are reaching global epidemic proportions. Lack of non-invasive diagnostic tools and effective therapies constitute two of the major hurdles for a bona fide treatment and a reversal of NASH progression and/or regression of the disease. Nitro-oleic acid (OA-NO2) has been proven effective in multiple experimental models of inflammation and fibrosis. Thus, the potential benefit of in vivo administration of OA-NO2 to treat advanced NAFLD was tested herein in a model of long-term NASH diet-induced liver damage. METHODS: Non-invasive imaging (e.g. photoacustic-ultrasound (PA-US)) was pursued to establish advanced experimental model of NASH in mice in which both steatosis and fibrosis were diagnosed prior experimental therapy with OA-NO2. Experimental controls included equimolar amounts of the non-nitrated oleic acid (OA). CLAMS and NMR-based analysis was used for energy metabolism. FINDINGS: CLAMS and NMR-based analysis demonstrates that OA-NO2 improves body composition and energy metabolism and inhibits hepatic triglyceride (TG) accumulation. Photoacoustic-ultrasound imaging revealed a robust inhibition of liver steatosis and fibrosis by OA-NO2. RNA-sequencing analysis uncovered inflammation and fibrosis as major pathways suppressed by OA-NO2 administration, as well as regulation of lipogenesis and lipolysis pathways, with a robust inhibition of SREBP1 proteolytic activation and subsequent lipogenesis gene expression by OA-NO2. These results were further supported by histological analysis and quantification of lipid accumulation, lobular inflammation (F4/80 staining) and fibrosis (collagen deposition, αSMA staining) as well as established parameters of liver damage (ALT). In vitro studies indicate that OA-NO2 inhibits TG biosynthesis and accumulation in hepatocytes and inhibits fibrogenesis in human stellate cells. INTERPRETATION: OA-NO2 improve steatohepatitis and fibrosis and may constitute an effective therapeutic approach against advanced NAFLD that warrants further clinical evaluation.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ácidos Oleicos/uso terapêutico , Animais , Metabolismo Energético , Lipogênese , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Oleicos/administração & dosagem , Ácidos Oleicos/farmacologia , Proteólise , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
12.
BMC Nephrol ; 20(1): 50, 2019 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-30760236

RESUMO

Following publication of the original article [1], it was reported that, due to a typesetting mistake, the three tables and two figures for this article were included as an Additional file instead of in the body of the article. The original publication of this article has been updated to correct this.

13.
Biomed Pharmacother ; 109: 2084-2089, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551465

RESUMO

Many breast cancer patients suffer from obvious side effects induced by chemotherapy. Formononetin (FM), one kind ingredient of Chinese herbal medicine, has been suggested to inhibit MCF-7 breast cancer cells. And recently metformin (MET) has gained more attention as a potential anti-cancer drug. The aim of this study was to investigate the synergistic effects of FM and MET on the proliferation of MCF-7 cells and to clarify the possible molecular mechanism involved. MCF-7 cells were treated with various concentrations of FM (40 and 80 µM) or FM (40 and 80 µM) combined with MET (150 µM) for 48 h. Cell proliferation was tested by an methyl tetrazolium (MTT) (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide) assay. The percentage of apoptotic cells was measured by flow cytometry. The expression level of b-cell lymphoma/leukemia-2 (bcl-2) mRNA was examined by RT-PCR, while the expression levels of phosphorylated extracellular signal-regulated kinases (p-ERK1/2) and bcl-2 protein were detected by Western blotting. Compared with untreated cells, 40 µM and 80 µM FM efficiently inhibited proliferation and increased apoptosis in MCF-7 cells. Additionally, 40 µM and 80 µM FM greatly downregulated bcl-2 mRNA expression when compared with untreated cells. Furthermore, the protein expression of bcl-2 and p-ERK1/2 was significantly reduced by 40 µM and 80 µM FM. The cytotoxic effect of FM was more remarkable when 150 µM MET was added. Taken together, the combinational use of FM and MET enhanced cell growth inhibition, and the induction of apoptosis in MCF-7 cells mediated by the ERK1/2 signaling pathway.


Assuntos
Neoplasias da Mama/patologia , Inibidores do Crescimento/administração & dosagem , Isoflavonas/administração & dosagem , Metformina/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Hipoglicemiantes/administração & dosagem , Células MCF-7 , Fitoestrógenos/administração & dosagem
14.
BMC Nephrol ; 19(1): 357, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541470

RESUMO

BACKGROUND: Immunosuppressive treatment will predispose an idiopathic membranous nephropathy (iMN) patient to opportunistic infections. Disease severity is one of the main concerns for making the treatment decision. Urinary angiotensinogen (UAGT) level has been shown highly correlated with intrarenal renin-angiotensin system (RAS) activity and severity of chronic kidney diseases (CKD). We aimed to test the relationship between the UAGT level and the severity of iMN. METHODS: This cross-sectional study included a total of 48 biopsy-proven iMN patients, 46 minimal change disease (MCD) patients, and 44 healthy volunteers. The clinical and laboratory data and urine samples were collected from all subjects before the use of RAS inhibitors. We determined the UAGT levels with a method of enzyme-linked immunosorbent assay. RESULTS: The UAGT levels were not different between the iMN (277.05 ± 61.25, µg/g.Cr) and MCD patients (244.19 ± 40.24, µg/g.Cr), but both of them were significantly higher than those of healthy controls (6.85 ± 1.10, µg/g.Cr). UAGT levels were correlated negatively with serum albumin (r = - 0.393, p = 0.006) and estimated glomerular filtration rate (eGFR) (r = - 0.352, p = 0.014) and positively with 24-h proteinuria (r = 0.614, p < 0.001) in iMN patients but not in MCD patients. Multivariate linear regression analysis revealed that only proteinuria independently determinate the levels of UAGT (ß = 0.649, p < 0.001) in iMN patients. CONCLUSIONS: UAGT levels were correlated negatively with serum albumin and glomerular filtration rate and positively with proteinuria in iMN patients at the onset. This suggests that elevated levels of UAGT are associated with the severity of iMN. The UAGT level may be used as a cofactor for deciding immunosuppressive therapy in iMN patient.


Assuntos
Angiotensinogênio/urina , Glomerulonefrite Membranosa/urina , Nefrose Lipoide/urina , Proteinúria/urina , Adolescente , Adulto , Idoso , Biomarcadores/urina , Estudos de Casos e Controles , Estudos Transversais , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/complicações , Humanos , Pessoa de Meia-Idade , Nefrose Lipoide/sangue , Nefrose Lipoide/complicações , Proteinúria/etiologia , Albumina Sérica/metabolismo , Índice de Gravidade de Doença , Adulto Jovem
15.
Atherosclerosis ; 278: 39-48, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30248551

RESUMO

BACKGROUND AND AIMS: Human genetic studies indicated that variations near the transcription factor Krüppel-like factor 14 (KLF14) gene locus are highly associated with coronary artery disease. Activation of endothelial cells (ECs) by pro-inflammatory molecules and pathways is a primary step in atherosclerosis development. We aimed to investigate the effects and mechanism of KLF14 on inflammatory responses in ECs. METHODS: Adenovirus-mediated overexpression of human KLF14 and EC specific Klf14 knockout mice were applied to study the role of KLF14 in EC inflammation. Intravital microscopy was used to examine leukocyte-endothelial cell interactions in vivo. RESULTS: The expression of Klf14 was markedly decreased in mouse aortic ECs in both acute and chronic inflammatory conditions. Overexpression of KLF14 inhibited inflammatory activation of human ECs stimulated by interleukin 1ß and tumor necrosis factor α. Primary pulmonary ECs from Klf14 knockout mice showed increased expression of adhesion molecules under IL-1ß stimuli. Mechanistically, KLF14 inhibited NF-κB signaling pathway by transcriptionally suppressing the expression of p65, resulting in significantly decreased leukocyte adhesion to activated ECs. Using intravital microscopy, an increased leukocyte-endothelial cell interaction was observed in endothelial specific Klf14 knockout mice compared to wild type control mice. Additionally, perhexiline, a KLF14 activator, induces KLF14 expression in ECs and reduced leukocyte-endothelial cell interactions in vitro and in vivo. CONCLUSIONS: The data revealed that KLF14 inhibited the inflammatory response in ECs and the protective effects were mediated by transcriptional inhibition of NF-κB signaling pathway. Endothelial KLF14 could be a potential therapeutic target for cardiovascular diseases.


Assuntos
Doença da Artéria Coronariana/metabolismo , Endotélio Vascular/patologia , Inflamação/patologia , Fatores de Transcrição Sp/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Regulação para Baixo , Células Endoteliais da Veia Umbilical Humana , Humanos , Fatores de Transcrição Kruppel-Like/metabolismo , Leucócitos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
16.
Diabetes Care ; 41(11): 2431-2437, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30201848

RESUMO

OBJECTIVE: Phagocyte-derived myeloperoxidase (MPO) and proinflammatory HDL are associated with metabolic syndrome (MetS) and increased cardiovascular disease risk. Therapeutic lifestyle changes (TLCs), such as a Mediterranean diet and exercise, decrease this risk. However, the link among TLCs, HDL, and MPO-mediated oxidative stress remains unclear. RESEARCH DESIGN AND METHODS: In this study, we characterized changes in cholesterol efflux capacity (CEC), a metric of HDL function; MPO-mediated oxidation; and the HDL proteomic profile in 25 patients with MetS who underwent 12 weeks of TLCs. RESULTS: After 12 weeks, before significant changes to HDL levels, most MetS components improved as a result of the TLCs. CEC was significantly increased, and HDL MPO oxidation products, 3-chlorotyrosine and 3-nitrotyrosine, were decreased with TLCs. The changes in CEC were inversely related to the unit changes in 3-chlorotyrosine after we controlled for changes in the other MetS components. TLCs did not remodel the HDL proteome. CONCLUSIONS: In summary, TLCs improved HDL function by inhibiting MPO-mediated oxidative stress even before appreciable changes in HDL levels.


Assuntos
HDL-Colesterol/metabolismo , Estilo de Vida , Lipoproteínas HDL/metabolismo , Síndrome Metabólica/terapia , Adolescente , Adulto , Idoso , Animais , Transporte Biológico , Restrição Calórica , Células Cultivadas , Dietoterapia , Dieta Mediterrânea , Terapia por Exercício , Feminino , Humanos , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Pessoa de Meia-Idade , Oxirredução , Estresse Oxidativo/fisiologia , Educação de Pacientes como Assunto , Peroxidase/antagonistas & inibidores , Peroxidase/metabolismo , Projetos Piloto , Proteômica , Comportamento de Redução do Risco , Adulto Jovem
17.
Clin Chem Lab Med ; 57(2): 195-203, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30016272

RESUMO

Background As effective quality management tools, quality indicators (QIs) are widely used in laboratory medicine. This study aimed to analyze the results of QIs, identify errors and provide quality specifications (QSs) based on the state-of-the-art. Methods Clinical laboratories all over China participated in the QIs survey organized by the National Health Commission of People' Republic of China from 2015 to 2017. Most of these QIs were selected from a common model of QIs (MQI) established by the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). All participants were asked to submit general information and original QIs data through a medical quality control data collection system. The results of QIs were reported in percentages and sigma, except turnaround time (TAT) which was measured in minutes. The 25th, 50th and 75th percentiles were, respectively, calculated as three levels of QSs, which were defined starting from the model proposed during the 1st Strategic Conference of the EFLM on "Defining analytical performance 15 years after the Stockholm Conference on Quality Specification in Laboratory Medicine". Results A total of 76 clinical laboratories from 25 provinces in China continuously participated in this survey and submitted complete data for all QIs from 2015 to 2017. In general, the performance of all reported QIs have improved or at least kept stable over time. Defect percentages of blood culture contamination were the largest in the pre-analytical phase. Intra-laboratory TAT was always larger than pre-examination TAT. Percentage of tests covered by inter-laboratory comparison was relatively low than others in the intra-analytical phase. The performances of critical values notification and timely critical values notification were the best with 6.0σ. The median sigma level of incorrect laboratory reports varied from 5.5σ to 5.7σ. Conclusions QSs of QIs provide useful guidance for laboratories to improve testing quality. Laboratories should take continuous quality improvement measures in all phases of total testing process to ensure safe and effective tests.


Assuntos
Técnicas de Laboratório Clínico/normas , Laboratórios/normas , Indicadores de Qualidade em Assistência à Saúde , Inquéritos e Questionários , China , Humanos
18.
Front Plant Sci ; 9: 909, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30038631

RESUMO

Lilium, the famous and significant cut flower, emits a variety of volatile organic compounds, which mainly contain monoterpenes, such as myrcene, (E)-ß-ocimene, and linalool. To understand the molecular mechanism of monoterpene synthesis in Lilium, we cloned two potential genes in the methylerythritol 4-phosphate pathway, namely LiDXS and LiDXR, from the strong-flavored oriental Lilium 'Siberia' using a homology-based PCR strategy. The expression levels of LiDXS and LiDXR were consistent with the emission and accumulation of monoterpenes in different floral organs and during the floral development, indicating that these two genes may play key roles in monoterpene synthesis. Subcellular localization demonstrated that LiDXS and LiDXR are expressed in the chloroplasts. Ectopic expression in transgenic tobacco suggested that the flowers of LiDXS and LiDXR transgenic lines accumulated substantially more diterpene, sclareol, compared to the plants transformed with empty vector. Surprisingly, increased content of the monoterpene, linalool and sesquiterpene, caryophyllene, were detected in the LiDXR transgenic lines, whereas the emission of caryophyllene, increased in one of the LiDXS transgenic tobacco lines, indicating that these two genes play significant roles in the synthesis of floral volatiles in the transgenic plants. These results demonstrate that LiDXR can contribute to monoterpene biosynthesis in Lilium 'Siberia'; however, the role of LiDXS in the biosynthesis of monoterpenes needs further study.

19.
Am J Cardiol ; 122(4): 565-570, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30005891

RESUMO

Fine particulate matter (PM2.5) air pollution and environmental temperatures influence cardiovascular morbidity and mortality. Recent evidence suggests that several air pollutants can promote dyslipidemia; however, the impact of ambient PM2.5 and temperature on high-density lipoprotein (HDL) function remains unclear. We hypothesized that daily exposures to higher levels of ambient PM2.5 and colder outdoor temperatures would impair HDL functionality. Lipoproteins, serum cholesterol efflux capacity (CEC), and HDL oxidation markers were measured twice in 50 healthy adults (age 32.1 ± 9.6 years) living in southeast Michigan and associated with ambient and personal-level exposures using mixed models. Although previous 7-day mean outdoor temperature (4.4 ± 9.8°C) and PM2.5 levels (9.1 ± 1.8 µg/m3) were low, higher ambient PM2.5 exposures (per 10 µg/m3) were associated with significant increases in the total cholesterol-to-HDL-C ratio (rolling average lag days 1 and 2) as well as reductions in CEC by -1.93% (lag day 5, p = 0.022) and -1.62% (lag day 6, p = 0.032). Colder outdoor temperatures (per 10°C) were also associated with decreases in CEC from -0.62 to -0.63% (rolling average lag days 5 and 7, p = 0.027 and 0.028). Previous 24-hour personal-level PM2.5 and temperature exposures did not impact outcomes, nor were any exposures associated with changes in HDL-oxidation metrics. In conclusion, we provide the first evidence that ambient PM2.5 (even at low levels) and outdoor temperatures may influence serum CEC, a critical antiatherosclerotic HDL function.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Temperatura Baixa/efeitos adversos , Exposição Ambiental/efeitos adversos , Lipoproteínas HDL/sangue , Material Particulado/efeitos adversos , Adolescente , Adulto , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Feminino , Seguimentos , Humanos , Masculino , Michigan/epidemiologia , Pessoa de Meia-Idade , Morbidade/tendências , Taxa de Sobrevida/tendências , Fatores de Tempo , Adulto Jovem
20.
Arterioscler Thromb Vasc Biol ; 38(8): 1738-1747, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29954752

RESUMO

Objective- Perivascular adipose tissue (PVAT) contributes to vascular homeostasis by producing paracrine factors. Previously, we reported that selective deletion of PPARγ (peroxisome proliferator-activated receptor γ) in vascular smooth muscle cells resulted in concurrent loss of PVAT and enhanced atherosclerosis in mice. To address the causal relationship between loss of PVAT and atherosclerosis, we used BA-PPARγ-KO (brown adipocyte-specific PPARγ knockout) mice. Approach and Results- Deletion of PPARγ in brown adipocytes did not affect PPARγ in white adipocytes or vascular smooth muscle cells or PPARα and PPARδ expression in brown adipocytes. However, development of PVAT and interscapular brown adipose tissue was remarkably impaired, associated with reduced expression of genes encoding lipogenic enzymes in the BA-PPARγ-KO mice. Thermogenesis in brown adipose tissue was significantly impaired with reduced expression of thermogenesis genes in brown adipose tissue and compensatory increase in subcutaneous and gonadal white adipose tissues. Remarkably, basal expression of inflammatory genes and macrophage infiltration in PVAT and brown adipose tissue were significantly increased in the BA-PPARγ-KO mice. BA-PPARγ-KO mice were crossbred with ApoE KO (apolipoprotein E knockout) mice to investigate the development of atherosclerosis. Flow cytometry analysis confirmed increased systemic and PVAT inflammation. Consequently, atherosclerotic lesions were significantly increased in mice with impaired PVAT development, thus indicating that the lack of normal PVAT is sufficient to drive increased atherosclerosis. Conclusions- PPARγ is required for functional PVAT development. PPARγ deficiency in PVAT, while still expressed in vascular smooth muscle cell, enhances atherosclerosis and results in vascular and systemic inflammation, providing new insights on the specific roles of PVAT in atherosclerosis and cardiovascular disease at large.


Assuntos
Adipócitos Marrons/metabolismo , Adipogenia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , PPAR gama/deficiência , Adipócitos Marrons/patologia , Tecido Adiposo Marrom/patologia , Tecido Adiposo Marrom/fisiopatologia , Tecido Adiposo Branco/patologia , Tecido Adiposo Branco/fisiopatologia , Adiposidade , Animais , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/fisiopatologia , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Lipogênese/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , PPAR gama/genética , Placa Aterosclerótica , Transdução de Sinais , Termogênese
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