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1.
Adv Sci (Weinh) ; 8(19): e2004162, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34378353

RESUMO

Toll-like receptor 2 and 4 (TLR2, TLR4) signaling is implicated in atherosclerotic plaque formation. The two-stage master regulator Virtual Inference of Protein-activity by Enriched Regulon (VIPER) analysis of macrophage TLR2 and TLR4 signature genes integrated with coexpression network genes derived from 371 patient-derived carotid specimens identifies activated RNA polymerase II transcriptional coactivator p15 (SUB1/Sub1, PC4) as a master regulon in the atherogenic TLR response. It is found that TLR2 and TLR4 signaling is proinflammatory and proatherosclerotic in chow-fed apolipoprotein E-deficient (ApoE-/- ) mice. Through transgenic myeloid-specific Sub1 knockout in ApoE-/- mice, it is discovered that these proatherosclerotic effects of TLR2 and TLR4 signaling are mediated by Sub1. Sub1 knockout in macrophages enhances anti-inflammatory M2 macrophage polarization and cholesterol efflux. Irradiated low density lipoprotein receptor-deficient (Ldlr-/- ) mice transplanted with Sub1-/- murine bone marrow display reduced atherosclerosis. Promoter analysis reveals Sub1-dependent activation of interferon regulatory factor 1 (Irf1) transcription in a casein kinase 2 (Ck2)-dependent manner, and Sub1-knockout macrophages display decreased Irf1 expression. Artificial Irf1 overexpression in Sub1-knockout macrophages enhances proinflammatory M1 skewing and lowers cholesterol clearance. In conclusion, the TLR master regulon Sub1, and its downstream effect on the transcription factor Irf1, promotes a proinflammatory M1 macrophage phenotype and enhances atherosclerotic burden in vivo.

2.
Int J Immunopathol Pharmacol ; 35: 20587384211032098, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34275383

RESUMO

Hepatic ischemia-reperfusion injury (IRI) is a major unavoidable clinical problem often accompanying various liver surgery and transplantation. d-Pinitol, a cyclic polyol, exhibits hepatoprotective efficacy. The objective of this study is to determine the possible mechanism of action of pinitol against endoplasmic reticulum (ER) stress regulation-mediated hepatic IRI and compare its effects with thymoquinone (TQ) in experimental rats. Male Sprague Dawley rats were pre-treated orally with either vehicle (DMSO) or d-Pinitol (5, 10, and 20 mg/kg) or TQ (30 mg/kg) for 21 days and subjected to 60 min of partial hepatic ischemia followed by 24 h of reperfusion. Pre-treatment with pinitol (10 and 20 mg/kg) effectively (P < 0.05) protected against IRI-induced hepatic damage reflected by attenuation of elevated oxidative stress and pro-inflammatory cytokines. Additionally, western blot and ELISA analyses suggested that pinitol significantly (P < 0.05) down-regulated expression of endoplasmic reticulum stress apoptotic markers, namely glucose-regulated protein (GRP)-78, CCAAT/enhancer-binding protein homologous protein (CHOP), activating transcription factor (AFT)-4 and -6α, X-box binding protein-1, and caspase-3, 9, and 12. Additionally, pinitol pre-treatment effectively (P < 0.05) improved mitochondrial function and phosphorylation of Extracellular signal-regulated kinase (ERK)-1/2 and p38. Pinitol markedly (P < 0.05) protected hepatic apoptosis determined by flow cytometry. Further, pinitol provided effective (P < 0.05) protection against hepatic histological and ultrastructural aberrations induced by IRI. TQ showed more pronounced protective effect against attenuation of IRI-induced hepatic injury as compared to d-Pinitol. Pinitol offered protection against endoplasmic reticulum stress-mediated phosphorylation of ERK1/2 and p38, thereby inhibiting AFT4-CHOP/GRP78 signaling response and caspase-3 induced hepatocellular apoptosis during hepatic ischemia-reperfusion insults. Thus, Pinitol can be considered as a viable option for the management of hepatic IRI.

3.
BMC Plant Biol ; 21(1): 340, 2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34273968

RESUMO

BACKGROUND: TLPs (Tubby-like proteins) are widespread in eukaryotes and highly conserved in plants and animals. TLP is involved in many biological processes, such as growth, development, biotic and abiotic stress responses, while the underlying molecular mechanism remains largely unknown. In this paper we characterized the biological function of cucumber (Cucumis sativus L.) Tubby-like protein 8 (CsTLP8) in Arabidopsis. RESULTS: In cucumber, the expression of the tubby-like protein CsTLP8 was induced by NaCl treatment, but reduced by PEG (Polyethylene Glycol) and ABA (Abscisic Acid) treatment. Subcellular localization and transcriptional activation activity analysis revealed that CsTLP8 possessed two characteristics of classical transcription factors: nuclear localization and trans-activation activity. Yeast two-hybrid assay revealed interactions of CsTLP8 with CsSKP1a and CsSKP1c, suggesting that CsTLP8 might function as a subunit of E3 ubiquitin ligase. The growth activity of yeast with ectopically expressed CsTLP8 was lower than the control under NaCl and mannitol treatments. Under osmotic and salt stresses, overexpression of CsTLP8 inhibited seed germination and the growth of Arabidopsis seedlings, increased the content of MDA (Malondialdehyde), and decreased the activities of SOD (Superoxide Dismutase), POD (Peroxidase) and CAT (Catalase) in Arabidopsis seedlings. Overexpression of CsTLP8 also increased the sensitivity to ABA during seed germination and ABA-mediated stomatal closure. CONCLUSION: Under osmotic stress, CsTLP8 might inhibit seed germination and seedling growth by affecting antioxidant enzymes activities. CsTLP8 acts as a negative regulator in osmotic stress and its effects may be related to ABA.


Assuntos
Ácido Abscísico/metabolismo , Cucumis sativus/metabolismo , Germinação , Pressão Osmótica , Proteínas de Plantas/metabolismo , Sementes , Transdução de Sinais , Antioxidantes/metabolismo , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Cucumis sativus/efeitos dos fármacos , Cucumis sativus/crescimento & desenvolvimento , Plântula/metabolismo , Sementes/embriologia , Cloreto de Sódio , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
4.
Can J Cardiol ; 37(1): 162-171, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32485140

RESUMO

BACKGROUND: Cardiac rehabilitation is a medically supervised program after coronary events that involves exercise and dietary modification. We evaluated the comparative benefits and harms of cardiac rehabilitation strategies via a network meta-analysis. METHODS: We followed a pre-specified protocol (PROSPERO: CRD42018094998). We searched Embase, MEDLINE, and Cochrane Central Register of Randomized Trials databases for randomized controlled trials that evaluated cardiac rehabilitation vs a second form of rehabilitation or standard/usual care in adults after myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, or angiography. Risk of bias and evidence quality was evaluated using the Cochrane tool and Grading of Recommendations Assessment, Development and Evaluation (GRADE), respectively. Pairwise and Bayesian network meta-analyses were performed for 11 clinical outcomes. RESULTS: We included 134 randomized controlled trials involving 62,322 participants. Compared with standard care, exercise-only cardiac rehabilitation reduced the odds of cardiovascular mortality (odds ratio [OR], 0.70; 95% credibility interval [CrI], 0.51-0.96; moderate-quality evidence), major adverse cardiovascular events (OR, 0.57; 95% CrI, 0.40-0.78; low-quality evidence), nonfatal myocardial infarction (OR, 0.71; 95% CrI, 0.54-0.93; moderate-quality evidence), all-cause hospitalization (OR, 0.74; 95% CrI, 0.54-0.98; moderate-quality evidence), and cardiovascular hospitalization (OR, 0.69; 95% CrI, 0.51-0.88; moderate-quality evidence). Exercise-only cardiac rehabilitation was associated with lower cardiovascular hospitalization risk relative to cardiac rehabilitation without exercise (OR, 0.68; 95% CrI, 0.48-0.97; moderate-quality evidence). CONCLUSIONS: Cardiac rehabilitation programs containing exercise might provide broader cardiovascular benefits compared with those without exercise.


Assuntos
Reabilitação Cardíaca , Doença Crônica/reabilitação , Cardiopatias/reabilitação , Terapia por Exercício , Hospitalização , Humanos , Infarto do Miocárdio/prevenção & controle
5.
Am J Physiol Renal Physiol ; 320(1): F87-F96, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33283645

RESUMO

Injured tubule epithelium stimulates a profibrotic milieu that accelerates loss of function in chronic kidney disease (CKD). This study tested the role of signal transducer and activator of transcription 1 (STAT1) in the progressive loss of kidney function in aristolochic acid (AA) nephropathy, a model of CKD. Mean serum creatinine concentration increased in wild-type (WT) littermates treated with AA, whereas Stat1-/- mice were protected. Focal increases in the apical expression of kidney injury molecule (KIM)-1 were observed in the proximal tubules of WT mice with AA treatment but were absent in Stat1-/- mice in the treatment group as well as in both control groups. A composite injury score, an indicator of proximal tubule injury, was reduced in Stat1-/- mice treated with AA. Increased expression of integrin-ß6 and phosphorylated Smad2/3 in proximal tubules as well as interstitial collagen and fibronectin were observed in WT mice following AA treatment but were all decreased in AA-treated Stat1-/- mice. The data indicated that STAT1 activation facilitated the development of progressive kidney injury and interstitial fibrosis in AA nephropathy.


Assuntos
Ácidos Aristolóquicos , Matriz Extracelular/metabolismo , Deleção de Genes , Túbulos Renais Proximais/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Fator de Transcrição STAT1/deficiência , Animais , Modelos Animais de Doenças , Matriz Extracelular/patologia , Fibrose , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Cadeias beta de Integrinas/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Fator de Transcrição STAT1/genética , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo
6.
BMC Cardiovasc Disord ; 20(1): 422, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32962654

RESUMO

BACKGROUND: To determine whether intermittent hypoxia (IH) can reduce the infarct size (IS) after acute myocardial infarction (AMI) in rats. METHODS: Articles were identified in PubMed, EMBASE and the Web of Science and were included if they evaluated the effect of IH on the changes in the infarcted area after AMI in rats. RESULTS: A preliminary search identified 3633 articles and 29 data sets from 23 articles (12 in vivo, 16 in vitro). The IS decreased after AMI in IH rats both in vitro (SMD -1.46, 95% CI [- 2.37, - 0.55]; I2 = 85.6%, P = 0.000) and in vivo (SMD -1.43, 95% CI [- 2.05, - 0.82], I2 = 73.6%, P = 0.000). Sensitivity analysis indicated that IH had a strong protective effect against myocardial infarction, and the hypoxia concentration was significantly correlated with the change in IS after AMI. CONCLUSION: IH can reduce IS after AMI in rats. This effect of IH may be related to the dose of hypoxia, and the oxygen concentration may be one of the most important influencing factors.


Assuntos
Hipóxia/metabolismo , Infarto do Miocárdio/prevenção & controle , Miocárdio/patologia , Oxigênio/metabolismo , Animais , Modelos Animais de Doenças , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Ratos
7.
Can J Cardiol ; 36(11): 1782-1794, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32473103

RESUMO

BACKGROUND: The most dangerous atherosclerotic plaques, referred to as "vulnerable," are most likely to trigger acute atherothrombotic events such as myocardial infarction (heart attack) and stroke. Our goal was to uncover the molecular drivers of vulnerable plaque formation. METHODS: To elucidate the functional gene modules that drive vulnerable plaque formation, we performed a weighted gene coexpression network analysis integrated with a protein-protein interaction network analysis in human atherosclerotic carotid samples, which identified the candidate gene granulocyte-macrophage colony-stimulating factor 2 (GM-CSF) receptor alpha subunit (CSF2RA). Follow-up in vitro experiments were performed to elucidate the regulatory relationship between CSF2RA and the microRNA miR-532-3p as well as modifiers of macrophagic miR-532-3p-CSF2RA axis expression. Microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) studies elucidated the effect of statins on carotid miR-532-3p-CSF2RA axis expression in patients with carotid atherosclerotic disease. Apoe-/-, Ldlr-/-, and Csf2ra mutant Apoe-/- mouse models of atherosclerosis were employed to assess the effects of agomiR-532-3p therapy in vivo. RESULTS: The integrated weighted gene coexpression network analysis/protein-protein interaction network analysis revealed that the macrophagic GM-CSF receptor CSF2RA is significantly upregulated in macrophage-rich vulnerable plaques. Follow-up analysis identified the miR-532-3p-CSF2RA axis, as miR-532-3p downregulates CSF2RA via binding to CSF2RA's 3'UTR. Macrophagic miR-532-3p-CSF2RA dysregulation was enhanced via modified low-density lipoprotein or tumor necrosis factor α exposure in vitro. Moreover, this miR-532-3p-CSF2RA dysregulation was observed in human vulnerable plaques and Apoe-/- mouse plaques, effects rescued by statin therapy. In vivo, agomiR-532-3p therapy suppressed murine plaque formation and promoted plaque stabilization in a Csf2ra-dependent manner. CONCLUSION: Macrophagic miR-532-3p-CSF2RA axis dysregulation is a key driver in vulnerable plaque formation.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/genética , RNA/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Mutantes , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Placa Aterosclerótica/patologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/biossíntese , Regulação para Cima
8.
Kidney Int ; 97(3): 528-537, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932071

RESUMO

Prior studies reported that haploinsufficiency of the transcription factor ETS-1 is renoprotective in Dahl salt-sensitive rats, but the mechanism is unclear. Here, we tested whether ETS-1 is involved in hypertension-induced renal microvascular pathology and autoregulatory impairment. Hypertension was induced in salt-sensitive rats and salt-sensitive rats that are heterozygous with 1 wild-type or reference allele of Ets1 (SSEts1+/-) by feeding a diet containing 4% sodium chloride for 1 week. Increases in blood pressure did not differ. However, phosphorylated ETS-1 increased in afferent arterioles of hypertensive salt-sensitive rats, but not in hypertensive SSEts1+/- rats. Afferent arterioles of hypertensive salt-sensitive rats showed increased monocyte chemotactic protein-1 expression and infiltration of CD68 positive monocytes/macrophages. Isolated kidney microvessels showed increased mRNA expression of vascular cell adhesion molecule, intercellular adhesion molecule, P-selectin, fibronectin, transforming growth factor-ß, and collagen I in hypertensive salt-sensitive rats compared with hypertensive SSEts1+/- rats. Using the in vitro blood-perfused juxtamedullary nephron preparation, pressure-mediated afferent arteriolar responses were significantly blunted in hypertensive salt-sensitive rats compared to hypertensive SSEts1+/- rats. Over a 65-170 mm Hg pressure range tested baseline arteriolar diameters averaged 15.1 µm and remained between 107% and 89% of baseline diameter in hypertensive salt-sensitive rats vs. 114% and 73% in hypertensive SSEts1+/- rats (significantly different). Thus, ETS-1 participates in renal arteriolar pathology and autoregulation and thereby is involved in hypertension-mediated kidney injury in salt-sensitive rats.


Assuntos
Alpharetrovirus , Hipertensão , Animais , Pressão Sanguínea , Hipertensão/genética , Rim , Oncogenes , Ratos , Ratos Endogâmicos Dahl
9.
World Neurosurg ; 133: e84-e88, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31470152

RESUMO

BACKGROUND: Spinopelvic sagittal parameters have a significant influence on adjacent segment degeneration (ASD) after fusion surgery. The association between ASD and sagittal balance is not well understood. The purpose of this study was to investigate the biomechanical influence of various sacral slope (SS) degrees on adjacent segments after transforaminal lumbar interbody fusion (TLIF) at the L4-L5 level. METHODS: We conducted a finite element model of the L1-S1 based on computed tomography scan images. The L1-S1 model with L4-L5 TLIF was modified with various SS degrees (33°, 38°, 43°, and 48°) to investigate the biomechanical influence of SS on adjacent segments. The range of motion (ROM) and intradiscal pressure (IDP) of the adjacent segments (L3-L4 and L5-S1) were compared among models using various SS angles. RESULTS: When the SS angle increased, the ROM and IDP in L5-S1 decreased gradually after TLIF at the L4-L5 level in all motion patterns. Nevertheless, the ROM and IDP in L3-L4 were not significantly different among various SS angles. CONCLUSIONS: Decreased SS after lumbar fusion surgery may pose a higher risk of ASD. Therefore, restoring appropriate SS should be considered during decision-making prior to fusion surgery to reduce the risk of degenerative changes.


Assuntos
Vértebras Lombares/cirurgia , Sacro/diagnóstico por imagem , Fusão Vertebral/métodos , Antropometria , Fenômenos Biomecânicos , Análise de Elementos Finitos , Humanos , Disco Intervertebral/fisiopatologia , Vértebras Lombares/diagnóstico por imagem , Pressão , Amplitude de Movimento Articular , Sacro/patologia , Tomografia Computadorizada por Raios X
10.
Sci Rep ; 9(1): 10838, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346201

RESUMO

In order to improve the capacity and rate performance of nickel-metal hydride (Ni-MH) batteries, we proposed a simple phase transformation method to synthesis 3D ß-nickel hydroxide nanowires/reduced graphene oxide (ß-Ni(OH)2 NWs/RGO) composite. ß-Ni(OH)2 nanowires with diameters of 20-30 nm and lengths up to several micrometers were decorated on RGO layers, forming 3D network structure. The 3D ß-Ni(OH)2 NWs/RGO composite displayed a discharge capacity of 343.2 mAh/g at 0.2C, and the capacity values has almost no loss after 100th cycles. When the discharge rate was at 5C, the capacity reached a value of 272.7 mAh/g, and its capacity retention was 79.5%. It showed good capacity and rate performance as a positive material for Ni-MH batteries.

11.
J Clin Invest ; 129(7): 2792-2806, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31205024

RESUMO

Because of the less-than-robust response to therapy and impact on choice of optimal chemotherapy and prognosis, chronic kidney disease has drawn attention in the treatment of multiple myeloma, a malignant hematologic disorder that can produce significant amounts of monoclonal immunoglobulin free light chains (FLCs). These low-molecular-weight proteins are relatively freely filtered through the glomerulus and are reabsorbed by the proximal tubule. The present study demonstrated that during the process of metabolism of immunoglobulin FLCs, ROS activated the STAT1 pathway in proximal tubule epithelium. STAT1 activation served as the seminal signaling molecule that produced the proinflammatory molecule IL-1ß, as well as the profibrotic agent TGF-ß by this portion of the nephron. These effects occurred in vivo and were produced specifically by the generation of hydrogen peroxide by the VL domain of the light chain. To the extent that the experiments reflect the human condition, these studies offer insights into the pathogenesis of progressive kidney failure in the setting of lymphoproliferative disorders, such as multiple myeloma, that feature increased circulating levels of monoclonal immunoglobulin fragments that require metabolism by the kidney.


Assuntos
Cadeias Leves de Imunoglobulina/metabolismo , Nefropatias/metabolismo , Glomérulos Renais/metabolismo , Túbulos Renais Proximais/metabolismo , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , Linhagem Celular , Fibrose , Humanos , Inflamação/metabolismo , Inflamação/patologia , Nefropatias/etiologia , Nefropatias/patologia , Glomérulos Renais/patologia , Túbulos Renais Proximais/patologia , Camundongos , Camundongos Knockout , Mieloma Múltiplo/patologia
12.
World Neurosurg ; 126: e819-e824, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30862579

RESUMO

OBJECTIVE: To analyze the biomechanical changes of lumbar adjacent segment by comparing the biomechanics after the surgery of transforaminal lumbar interbody fusion (TLIF) and oblique lumbar interbody fusion (OLIF). METHODS: The finite element model of the L1-S1 was reconstructed via computed tomography scan images. The models of TLIF and OLIF were constructed and analyzed. A 400-N vertical axial pre-load was imposed on the superior surface of L1 and a 10-N·m moment was applied on the L1 superior surface along the radial direction to simulate 4 different physiological motions: flexion, extension, bending, and torsion. The range of motion (ROM) and the intradiscal pressure (IDP) were evaluated and compared with investigate the biomechanical influences of TLIF and OLIF on the adjacent segments (L3-L4 and L5-S1). RESULTS: Compared with the normal model, TLIF and OLIF in all motion patterns increased the ROM and the IDP of adjacent segments. However, the ROM and the IDP between TLIF and OLIF had no significant difference. CONCLUSIONS: The biomechanical analysis showed that both TLIF and OLIF can increase ROM and IDP. It indicates that TLIF and OLIF probably increase the potential risk of adjacent segment degeneration similarly.


Assuntos
Vértebras Lombares/cirurgia , Fusão Vertebral/métodos , Adulto , Fenômenos Biomecânicos/fisiologia , Parafusos Ósseos , Análise de Elementos Finitos , Humanos , Vértebras Lombares/diagnóstico por imagem , Masculino , Modelos Anatômicos , Amplitude de Movimento Articular/fisiologia , Tomografia Computadorizada por Raios X
13.
ACS Appl Mater Interfaces ; 11(9): 9355-9366, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30734551

RESUMO

Sonodynamic therapy (SDT), a promising alternative for cancer therapy, utilizes a sonosensitizer combined with ultrasound (US) irradiation to damage tumor cells/tissues for therapeutic purposes. The ability of sonosensitizers to specifically accumulate in tumor cells/tissues could greatly influence their therapeutic efficiency. In this work, we report the use of US-activated sonosensitizer (IR780)-based nanodroplets (IR780-NDs) for SDT, which provide numerous benefits for killing cancer cells compared with traditional methods. For instance, IR780-NDs showed effective surface-to-core diffusion both in vitro and in vivo. In the presence of US, the acoustic droplet vaporization (ADV) effect significantly assisted the conveyance of IR780-NDs from the circulatory system to tumor regions, and the acoustic wave force also increased the penetration depth within tumor tissues. Furthermore, IR780-NDs possesses mitochondrial targeting capabilities, which improves the precision and accuracy of SDT delivery. During the in vitro assessment, the overproduction of reactive oxygen species (ROS) was observed following mitochondrial targeting, which rendered cancer cells more susceptible to ROS-induced apoptosis. Additionally, IR780-ND is a suitable candidate for photoacoustic and fluorescence imaging and can also enhance US imaging because of the ADV-generated bubbles, which provides the potential for SDT guidance and monitoring. Therefore, with combined modalities, IR780-NDs can be a promising theranostics nanoplatform for cancer therapy.


Assuntos
Mitocôndrias/metabolismo , Nanoestruturas/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Camundongos , Camundongos Nus , Microscopia Confocal , Mitocôndrias/efeitos dos fármacos , Nanoestruturas/uso terapêutico , Neoplasias/patologia , Neoplasias/terapia , Nanomedicina Teranóstica , Distribuição Tecidual , Transplante Heterólogo , Terapia por Ultrassom
14.
Plant Cell Physiol ; 60(3): 562-574, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30496548

RESUMO

Melatonin plays an important role in stress tolerance in plants. In this study, exogenous melatonin significantly alleviated the dwarf phenotype and inhibited the decrease of plant fresh weight induced by excess copper (Cu2+). Our results indicated that melatonin alleviated Cu2+ toxicity by improving Cu2+ sequestration, carbon metabolism and ROS (reactive oxygen species) scavenging, rather than by influencing the Cu2+ uptake under excess Cu2+ conditions. Transcriptome analysis showed that melatonin broadly altered gene expression under Cu2+ stress. Melatonin increased the levels of glutathione and phytochelatin to chelate excess Cu2+ and promoted cell wall trapping, thus keeping more Cu2+ in the cell wall and vacuole. Melatonin inhibited ROS production and enhanced antioxidant systems at the transcriptional level and enzyme activities, thus building a line of defense in response to excess Cu2+. The distribution of nutrient elements was recovered by melatonin which was disturbed by Cu2+. In addition, melatonin activated carbon metabolism, especially glycolysis and the pentose phosphate pathway, to generate more ATP, an intermediate for biosynthesis. Taken together, melatonin alleviated Cu2+ toxicity in cucumber via multiple mechanisms. These results will help to resolve the toxic effects of Cu2+ stress on plant growth and development. These results can be used for new strategies to solve problems associated with Cu2+ stress.


Assuntos
Cucumis sativus/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Peroxidação de Lipídeos/genética , Peroxidação de Lipídeos/fisiologia , Melatonina/metabolismo , Melatonina/farmacologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Transcriptoma/genética
15.
Sci Rep ; 8(1): 13349, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30190519

RESUMO

NACs are one of the largest transcription factor families in plants and are involved in the response to abiotic stress. BoNAC019, a homologue of AtNAC019, was isolated from cabbage (Brassica oleracea). BoNAC019 was localized in the nucleus and functioned as a transcriptional activator. The expression of BoNAC019 was induced by dehydration, salt, abscisic acid (ABA), and H2O2 treatments. BoNAC019 overexpressing plants were generated to explore the function of BoNAC019 in response to drought stress. Overexpression (OE) of BoNAC019 reduced drought tolerance with lower survival rate, higher water loss rate, lower proline content and ABA content. The seed germination and root length assays of BoNAC019-OE plants showed decreased sensitivity to ABA. Under drought condition, antioxidant enzymes and anthocyanin content decreased in BoNAC019 -OE plants, resulting in the accumulation of more reactive oxygen species (ROS), which cause damage to plants. Several stress-responsive genes, antioxidant enzymatic genes, anthocyanin biosynthetic genes and ABA signaling genes were down-regulated under drought condition while the ABA catabolism genes were induced in BoNAC019-OE plants under both normal and drought conditions. Our results demonstrated that BoNAC019 might participated in regulating drought tolerance by inducing ABA catabolism genes and decreasing ABA content.


Assuntos
Antocianinas , Arabidopsis , Brassica/genética , Proteínas de Plantas , Plantas Geneticamente Modificadas , Fatores de Transcrição , Antocianinas/biossíntese , Antocianinas/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Desidratação/genética , Desidratação/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
Int J Cardiol ; 273: 207-212, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29960763

RESUMO

AIMS: The present network meta-analysis was performed to comprehensively compare the ability of different types of antihypertensive agents to ameliorate arterial stiffness in hypertensive patients. METHODS AND RESULTS: To conduct this network meta-analysis, we searched PubMed, the Embase database, and the https://clinicaltrials.gov/ website for all relevant articles concerning clinical trials on hypertension therapy. The last search date was 10 August 2017. As a result, 28 eligible articles were enrolled in our meta-analysis. According to the included studies, there was no significant difference in pulse wave velocity (PWV) between these treatments. The eight types of antihypertension agents outperformed placebo in controlling systolic blood pressure (SBP). Angiotensin-converting enzyme inhibitor (ACEI) outperformed angiotensin II receptor blocker (ARB) in SBP; and angiotensin receptor-neprilysin inhibitor (ARNI) outperformed diuretic (D)in SBP. CONCLUSIONS: This study found that the eight antihypertensive agents show obvious effect on reducing SBP other than arterial stiffness.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Rigidez Vascular/efeitos dos fármacos , Anti-Hipertensivos/farmacologia , Humanos , Hipertensão/diagnóstico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Rigidez Vascular/fisiologia
17.
J Am Soc Nephrol ; 28(11): 3239-3250, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28696249

RESUMO

Studies using Dahl salt-sensitive (SS) rats identified specific quantitative trait loci that predispose animals to hypertension-associated albuminuria and kidney injury. We explored the hypothesis that kidney-specific expression of the transcription factor Ets-1, located within one of these loci on chromosome 8, mediates glomerular injury in SS hypertension. During the first week on a high-salt diet, SS rats and SS rats with only one functioning Ets-1 gene (ES rats) demonstrated similar increases in BP. However, serum creatinine concentration, albuminuria, and glomerular expression of ETS-1 and two ETS-1 targets, MCP-1 and MMP2, did not increase as substantially in ES rats as in SS rats. Mean BP subsequently increased further in SS rats and remained higher than that of ES rats for the rest of the study. After 4 weeks of high-salt intake, ES rats still showed a lower mean serum creatinine concentration and less albuminuria, as well as less histologic evidence of glomerular injury and kidney fibrosis, than SS rats did. To investigate the specific contribution of renal Ets-1, we transplanted kidneys from ES or SS rats into salt-resistant SS-Chr 13BN/McwiCrl (SS-13BN) rats. Within 10 days on a high-salt diet, BP increased similarly in ES and SS allograft recipients, becoming significantly higher than the BP of control isograft recipients. However, mean serum creatinine concentration and albuminuria remained lower in ES allograft recipients than in SS allograft recipients at 2 weeks, and ES allografts showed less glomerular injury and interstitial fibrosis. In conclusion, reduced renal expression of ETS-1 prevented hypertension-associated kidney injury in SS rats.


Assuntos
Haploinsuficiência , Hipertensão/genética , Nefropatias/genética , Proteína Proto-Oncogênica c-ets-1/genética , Animais , Masculino , Mutação , Ratos , Ratos Endogâmicos Dahl
18.
Sci Rep ; 7(1): 2150, 2017 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-28526834

RESUMO

Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in the cerebrovascular endothelium is a key suppressor of post-stroke brain damage. However, the role of PPARγ's co-regulators during cerebral ischemia remains largely unknown. Here, we show that the transcription factor IRF6 is a novel PPARγ co-regulator that directly binds to and suppresses PPARγ activity in murine cerebrovascular endothelial cells. Moreover, IRF6 was also revealed to be a transcriptional target of PPARγ suppression, with PPARγ silencing significantly promoting IRF6 expression in cerebrovascular endothelial cells. In addition, IRF6 silencing significantly promoted pioglitazone's cytoprotective effects in ischemic murine cerebrovascular endothelial cells. Mechanistically, IRF6 significantly suppressed PPARγ's transcriptional inhibition of the ischemia-induced, pro-apoptotic microRNA miR-106a. In conclusion, we identified IRF6 as a novel PPARγ co-suppressor that serves a key role in suppressing PPARγ-mediated cerebrovascular endothelial cytoprotection following ischemia. Further investigation into IRF6 and other PPARγ co-regulators should provide additional insights into PPARγ's cytoprotective role in the cerebrovascular endothelium following stroke.


Assuntos
Isquemia Encefálica/metabolismo , Células Endoteliais/metabolismo , Fatores Reguladores de Interferon/metabolismo , PPAR gama/metabolismo , Animais , Sítios de Ligação , Isquemia Encefálica/genética , Morte Celular , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Mutação com Ganho de Função , Regulação da Expressão Gênica , Fatores Reguladores de Interferon/genética , Ataque Isquêmico Transitório/genética , Ataque Isquêmico Transitório/metabolismo , Mutação com Perda de Função , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/genética , Regiões Promotoras Genéticas , Ligação Proteica , Transdução de Sinais
19.
Sci Rep ; 7(1): 503, 2017 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-28356562

RESUMO

Seed germination is a critical and complex process in the plant life cycle. Although previous studies have found that melatonin can promote seed germination under salt stress, the involvement of melatonin in the regulation of proteomic changes remains poorly understood. In this study, a total of 157 proteins were significantly influenced (ratio ≥ 2 or ≤ -2) by melatonin during seed germination under salt stress using a label-free quantitative technique. Our GO analysis revealed that several pathways were obviously regulated by melatonin, including ribosome biosynthesis, lipid metabolism, carbohydrate metabolism, and storage protein degradation. Not only stress-tolerant proteins but also proteins that produce ATP as part of glycolysis, the citric acid cycle, and the glyoxylate cycle were upregulated by melatonin. Overall, this study provides new evidence that melatonin alleviates the inhibitory effects of NaCl stress on seed germination by promoting energy production. This study is the first to provide insights at the proteomic level into the molecular mechanism of melatonin in response to salt stress in cucumber seeds. This may be helpful to further understand the role of melatonin in cucumber seed germination under stress conditions.


Assuntos
Cucumis sativus/fisiologia , Metabolismo Energético , Germinação , Melatonina/metabolismo , Proteômica , Salinidade , Sementes/fisiologia , Estresse Fisiológico , Redes e Vias Metabólicas , Proteínas de Plantas/metabolismo , Proteoma/metabolismo , Proteômica/métodos
20.
PLoS One ; 12(2): e0172631, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28231268

RESUMO

BACKGROUND: Serum gamma-glutamyltransferase (GGT) elevation likely contributes to cardiovascular (CV) mortality, however it has remained unknown whether a dose-response relationship exists between serum GGT and CV mortality. METHODS: We searched the PubMed, EMBASE, and Cochrane library databases for prospective cohort studies published up to October 2, 2016. Summary hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were calculated using a fixed effects model. FINDINGS: Nine prospective studies, including 527,589 participants and more than 7,011 cases, were included in this meta-analysis. For the moderate, high, and highest levels of GGT, the pooled HRs of CV mortality were 1.11 (95% CI = 1.04-1.19), 1.29 (95% CI = 1.21-1.38) and 1.59 (95% CI = 1.47-1.72), respectively (all p < 0.05 as compared to the lowest levels of GGT). Additionally, the HR per incremental increase of GGT by 10 U/L was 1.10 (95% CI = 1.08-1.11). Evidence of a positive relationship with nonlinear trend for GGT elevation with CV mortality in females was found (P = 0.04 for nonlinearity). However, a linear model was better fit to illustrate the GGT-CV mortality among males (P = 0.304 for nonlinearity). CONCLUSIONS: These findings indicate that serum GGT activity within the reference interval is positively associated with increased risk of CV mortality in a dose-response manner.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , gama-Glutamiltransferase/sangue , Feminino , Humanos , Masculino , Prognóstico , Risco , Fatores Sexuais
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