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1.
Kidney Int ; 97(3): 528-537, 2020 Mar.
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.

2.
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
3.
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.

4.
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.

5.
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
6.
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 Drogas , 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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
PLoS One ; 12(1): e0168582, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28045910

RESUMO

BACKGROUND: Antihypertensive treatment mitigates the progression of chronic kidney disease. Here, we comparatively assessed the effects of antihypertensive agents in normotensive and hypertensive diabetic patients with microalbuminuric kidney disease. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were systematically searched for randomized controlled trials (RCTs) comparing oral antihypertensive agents in adult diabetic patients with microalbuminuria. The primary efficacy outcome was reduction in albuminuria, and the primary safety outcomes were dry cough, presyncope, and edema. Random-effects pairwise and Bayesian network meta-analyses were performed to produce outcome estimates for all RCTs, only hypertensive RCTs, or only normotensive RCTs. Surface under the cumulative ranking (SUCRA) probability rankings were calculated for all outcomes. Sensitivity analyses on type 2 diabetes status, age, or follow-up duration were also performed. RESULTS: A total of 38 RCTs were included in the meta-analyses. The angiotensin-converting enzyme inhibitor-calcium channel blocker (ACEI-CCB) combination therapy of captopril+diltiazem was most efficacious in reducing albuminuria irrespective of blood pressure status. However, the ACEI-angiotensin receptor blocker (ACEI-ARB) combination therapy of trandolapril+candesartan was the most efficacious in reducing albuminuria for normotensive patients, while the ACEI-CCB combination therapy of fosinopril+amlodipine was the most efficacious in reducing albuminuria for hypertensive patients. The foregoing combination therapies displayed inferior safety profiles relative to ACEI monotherapy with respect to dry cough, presyncope, and edema. With respect to type 2 diabetic patients with microalbuminuria, the Chinese herbal medicine Tangshen formula followed by the ACEI ramipril were the most efficacious in reducing albuminuria. CONCLUSIONS: Trandolapril+candesartan appears to be the most efficacious intervention for reducing albuminuria for normotensive patients, while fosinopril+amlodipine appears to be the most efficacious intervention for reducing albuminuria for hypertensive patients. For practitioners opting for monotherapy, our SUCRA analysis supports the use of trandolapril and fosinopril in normotensive and hypertensive adult diabetic patients with microalbuminuria, respectively.


Assuntos
Albuminúria/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Tipo 2/terapia , Nefropatias/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Teorema de Bayes , Benzimidazóis/administração & dosagem , Seguimentos , Fosinopril/administração & dosagem , Humanos , Hipertensão/tratamento farmacológico , Indóis/administração & dosagem , Nefropatias/complicações , Pessoa de Meia-Idade , Segurança do Paciente , Probabilidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Tetrazóis/administração & dosagem , Resultado do Tratamento , Adulto Jovem
15.
Cardiology ; 136(4): 230-240, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27825159

RESUMO

OBJECTIVES: Cultured endothelial progenitor cells (EPCs) display troubling issues that adversely affect their applicability to endothelial regeneration. We hypothesized that transduction of the human telomerase catalytic subunit (hTERT) gene would enhance EPC function in treating dietary-induced early atherosclerosis (AS). METHODS: A dietary-induced early AS model was successfully constructed in 90 healthy male rats, while 30 healthy control (HC) rats were normally fed. Four experimental groups were constructed: an untreated HC group; an untreated AS group injected with PBS; a null EPC AS group injected with null vector-transduced EPCs, and an hTERT EPC AS group injected with hTERT-transduced EPCs. Two months postinjection, abdominal aortas were extracted to validate EPC integration and comparatively assess mRNA and protein expression of the early atherosclerotic markers VCAM-1, ICAM-1, LFA-1, Mac-1, CD44, MCP-1, endothelial nitric oxide synthase (eNOS), and apolipoprotein E. RESULTS: In vitro, hTERT transduction of EPCs resulted in a significantly superior proliferative capacity as well as significantly higher NO, iNOS, and LDH secretory capacity. In vivo injection of hTERT-transduced EPCs produced significant reductions in CD44 and MCP-1 expression as well as a significant increase in eNOS expression relative to injection with null vector-transduced EPCs (all p < 0.05). CONCLUSION: hTERT-transduced human EPCs may be useful in treating dietary-induced early AS.


Assuntos
Aorta/metabolismo , Aterosclerose/terapia , Células Progenitoras Endoteliais/transplante , Telomerase/genética , Animais , Biomarcadores/metabolismo , Proliferação de Células/genética , Células Cultivadas , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Transdução Genética
16.
J Am Soc Nephrol ; 28(2): 494-503, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27432743

RESUMO

Primary hyperoxaluria type 1 (PH1), an inherited rare disease of glyoxylate metabolism, arises from mutations in the enzyme alanine-glyoxylate aminotransferase. The resulting deficiency in this enzyme leads to abnormally high oxalate production resulting in calcium oxalate crystal formation and deposition in the kidney and many other tissues, with systemic oxalosis and ESRD being a common outcome. Although a small subset of patients manages the disease with vitamin B6 treatments, the only effective treatment for most is a combined liver-kidney transplant, which requires life-long immune suppression and carries significant mortality risk. In this report, we discuss the development of ALN-GO1, an investigational RNA interference (RNAi) therapeutic targeting glycolate oxidase, to deplete the substrate for oxalate synthesis. Subcutaneous administration of ALN-GO1 resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and increased serum glycolate concentrations in wild-type mice, rats, and nonhuman primates. ALN-GO1 also increased urinary glycolate concentrations in normal nonhuman primates and in a genetic mouse model of PH1. Notably, ALN-GO1 reduced urinary oxalate concentration up to 50% after a single dose in the genetic mouse model of PH1, and up to 98% after multiple doses in a rat model of hyperoxaluria. These data demonstrate the ability of ALN-GO1 to reduce oxalate production in preclinical models of PH1 across multiple species and provide a clear rationale for clinical trials with this compound.


Assuntos
Oxirredutases do Álcool , Hiperoxalúria Primária/enzimologia , Hiperoxalúria Primária/terapia , Oxalatos/metabolismo , Terapêutica com RNAi , Oxirredutases do Álcool/genética , Animais , Modelos Animais de Doenças , Inativação Gênica , Fígado/enzimologia , Masculino , Camundongos , Primatas , RNA Mensageiro , Ratos
17.
Front Plant Sci ; 8: 2156, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29410672

RESUMO

Aluminum (Al) is present in approximately 50% of the arable land worldwide and is regarded as the main limiting factor of crop yield on acidic soil. Al-induced root malate efflux plays an important role in the Al tolerance of plants. Here, the aluminum induced malate transporter BoALMT1 (KF322104) was cloned from cabbage (Brassica oleracea). BoALMT1 showed higher expression in roots than in shoots. The expression of BoALMT1 was specifically induced by Al treatment, but not the trivalent cations lanthanum (La), cadmium (Cd), zinc (Zn), or copper (Cu). Subcellular localization studies were performed in onion epidermal cells and revealed that BoALMT1 was localized at the plasma membrane. Scanning Ion-selective Electrode Technique was used to analyze H+ flux. Xenopus oocytes and Arabidopsis thaliana expressing BoALMT1 excreted more H+ under Al treatment. Overexpressing BoALMT1 in transgenic Arabidopsis resulted in enhanced Al tolerance and increased malate secretion. The results suggested that BoALMT1 functions as an Al-resistant gene and encodes a malate transporter. Expressing BoALMT1 in Xenopus oocytes or A. thaliana indicated that BoALMT1 could increase malate secretion and H+ efflux to resist Al tolerance.

18.
Appl Environ Microbiol ; 82(23): 6952-6960, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27663026

RESUMO

Colonization with Oxalobacter formigenes may reduce the risk of calcium oxalate kidney stone disease. To improve our limited understanding of host/O.formigenes and microbe/O.formigenes interactions, germ-free or altered Schaedler flora (ASF) mice were colonized with O.formigenes Germ-free mice were stably colonized with O.formigenes suggesting O.formigenes does not require other organisms to sustain its survival. Examination of intestinal material indicated no viable O.formigenes in the small intestine, ∼4 × 106 O.formigenes per 100mg contents in the cecum and proximal colon, and ∼0.02% of total cecal O. formigenes cells were tightly associated to the mucosa. O.formigenes did not alter the overall microbial composition of ASF, and ASF did not impact O.formigenes capacity to degrade dietary oxalate in the cecum. 24-hour urine and fecal collections within metabolic cages in semi-rigid isolators demonstrated that introduction of ASF into germ-free mice significantly reduced urinary oxalate excretion. These experiments also showed that mono-colonized O.formigenes mice excrete significantly more urinary calcium compared to germ-free mice, which may be due to degradation of calcium oxalate crystals by O.formigenes and the subsequent intestinal absorption of free calcium. In conclusion, the successful establishment of defined-flora O.formigenes mouse models should improve our understanding of O.formigenes host and microbe interactions. These data support the use of O.formigenes as a probiotic that has limited impact on the composition of the resident microbiota but providing efficient oxalate degrading function. IMPORTANCE: Despite evidence suggesting a lack of O. formigenes colonization is a risk factor for calcium oxalate stone formation, little is known about O. formigenes biology. This study is the first to utilize germ-free mice to examine the response to mono-colonization with O. formigenes and the impact of a defined bacterial cocktail, altered Schaedler flora, on O. formigenes colonization. This study demonstrates that germ-free mice on their regular diet remain mono-colonized with O. formigenes, and suggests that further studies with O. formigenes gnotobiotic mouse models could improve our understanding of O. formigenes biology and host/O. formigenes and microbe/O. formigenes interactions.

19.
Arch Microbiol ; 198(10): 1019-1026, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27449000

RESUMO

Oxalobacter formigenes (O. formigenes) is a nonpathogenic, Gram-negative, obligate anaerobic bacterium that commonly inhabits the human gut and degrades oxalate as its major energy and carbon source. Results from a case-controlled study suggested that lack of O. formigenes colonization is a risk factor for recurrent calcium oxalate stone formation. Hence, O. formigenes colonization may prove to be an efficacious method for limiting calcium oxalate stone risk. However, challenges exist in the preparation of O. formigenes as a successful probiotic due to it being an anaerobe with fastidious growth requirements. Here we examine in vitro properties expected of a successful probiotic strain. The data show that the Group 1 O. formigenes strain OxCC13 is sensitive to pH < 5.0, persists in the absence of oxalate, is aerotolerant, and survives for long periods when freeze-dried or mixed with yogurt. These findings highlight the resilience of this O. formigenes strain to some processes and conditions associated with the manufacture, storage and distribution of probiotic strains.


Assuntos
Microbioma Gastrointestinal , Oxalatos/metabolismo , Oxalobacter formigenes/crescimento & desenvolvimento , Oxalobacter formigenes/metabolismo , Probióticos/metabolismo , Carbono/metabolismo , Metabolismo Energético/fisiologia , Humanos , Fatores de Risco
20.
Oncotarget ; 7(25): 38292-38305, 2016 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-27203677

RESUMO

Tumor-associated macrophages, crucial components of the microenvironment in hepatocellular carcinoma, hamper anti-cancer immune responses. The aim of the present study was to investigate the effect of sorafenib on the formation of the tumor microenvironment, especially the relationship between polarized macrophages and hepatocytes. Macrophage infiltration was reduced in patients with hepatocellular carcinoma who were treated with sorafenib. In vitro, sorafenib abolished polarized macrophage-induced epithelial mesenchymal transition (EMT) and migration of hepatocellular carcinoma cells but not normal hepatocytes. Moreover, sorafenib attenuated HGF secretion in polarized macrophages, and decreased plasma HGF in patients with hepatocellular carcinoma. Additionally, sorafenib abolished the polarized macrophage-induced activation of the HGF receptor Met in hepatocellular carcinoma cells. Our findings suggest that sorafenib inhibits polarized macrophage-induced EMT in hepatocellular carcinoma cells via the HGF-Met signaling pathway. These results contribute to our understanding of the immunological mechanisms that underlie the protective effects of sorafenib in hepatocellular carcinoma therapy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Niacinamida/análogos & derivados , Compostos de Fenilureia/uso terapêutico , Idoso , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/patologia , Macrófagos/patologia , Masculino , Niacinamida/uso terapêutico , Transdução de Sinais , Sorafenibe
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