Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 916
Filtrar
1.
Mater Sci Eng C Mater Biol Appl ; 107: 110324, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31761161

RESUMO

Bismuth (Bi)-based nanoagents for synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) are attracting attention and are highly desired for malignant tumor diagnosis and treatment, but producing these materials is still a challenge. Here, we designed theranostic nanoparticles (NPs) based on AgBiS2 for computed tomography (CT) imaging and phototherapy of malignant tumors. These AgBiS2 NPs could effectively convert light into heat (with a high photothermal conversion efficiency of 36.51%) and significantly increase the generation of intracellular reactive oxygen species (ROS) under near infrared (NIR) laser irradiation. Remarkably, the combined PTT/PDT successfully inhibited the growth of a highly malignant osteosarcoma in vivo. In addition, AgBiS2 NPs exhibited an enhanced CT contrast ability for tumor imaging and killed clinically derived Staphylococcus aureus (S. aureus) to prevent infection. In conclusion the ability of AgBiS2 NPs to be used in phototherapy and CT imaging and their antibacterial abilities indicate that they are promising candidates for malignant tumor theranostics.

2.
Mol Ther Nucleic Acids ; 19: 15-30, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31790972

RESUMO

Osteoarthritis (OA) is a major cause of joint pain and disability, and chondrocyte senescence is a key pathological process in OA and may be a target of new therapeutics. MicroRNA-140 (miR-140) plays a protective role in OA, but little is known about its epigenetic effect on chondrocyte senescence. In this study, we first validated the features of chondrocyte senescence characterized by increased cell cycle arrest in the G0/G1 phase and the expression of senescence-associated ß-galactosidase (SA-ßGal), p16INK4a, p21, p53, and γH2AX in human knee OA. Then, we revealed in interleukin 1ß (IL-1ß)-induced OA chondrocytes in vitro that pretransfection with miR-140 effectively inhibited the expression of SA-ßGal, p16INK4a, p21, p53, and γH2AX. Furthermore, in vivo results from trauma-induced early-stage OA rats showed that intra-articularly injected miR-140 could rapidly reach the chondrocyte cytoplasm and induce molecular changes similar to the in vitro results, resulting in a noticeable alleviation of OA progression. Finally, bioinformatics analysis predicted the potential targets of miR-140 and a mechanistic network by which miR-140 regulates chondrocyte senescence. Collectively, miR-140 can effectively attenuate the progression of early-stage OA by retarding chondrocyte senescence, contributing new evidence of the involvement of miR-mediated epigenetic regulation of chondrocyte senescence in OA pathogenesis.

3.
J Physiol Biochem ; 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31786730

RESUMO

Previous studies have shown that stromal interaction molecule1 (STIM1)-mediated store-operated Ca2+ entry (SOCE) contributes to intracellular Ca2+ accumulation in H9C2 cells subjected to hypoxia/reoxygenation(H/R) injury. The aim of the present study was to investigate the effect of resveratrol on STIM1-mediated intracellular Ca2+ accumulation and subsequent cell death in the context of myocardial ischemia/reperfusion (I/R) injury. C57 BL/6 mice were fed with either saline or resveratrol (50 mg/kg daily for 2 weeks) and then subjected to myocardial I/R injury. TTC/Evans Blue staining and TUNEL assay were performed to quantify the infarct size and apoptosis index. The cardiac function was evaluated by echocardiography. Neonatal rat ventricular cardiomyocytes (NRVCs) underwent hypoxia/reoxygenation (H/R) to establish the in vitro model. To achieve over-expression, NRVCs were transfected with STIM1-adenovirus vector. Apoptosis was analyzed by TUNEL assay. Cell viability was measured using MTS assay and cell necrosis was determined by LDH release assay. Intracellular Ca2+ concentration was detected by laser scanning confocal microscopy using a Fluo-3AM probe. Resveratrol significantly reduced apoptosis, decreased infarct size, and improved cardiac function in mice subjected to myocardial I/R injury. In NRVCs, resveratrol also downregulated STIM1 expression accompanied by decreased intracellular Ca2+ accumulation elicited by H/R injury. In addition, resveratrol reduced cell apoptosis, upregulated the Bcl-2, decreased Bax, and cleaved caspase-3 expression. Furthermore, the effects of resveratrol on STIM1-mediated intracellular Ca2+ accumulation, apoptotic proteins, and H/R-induced cell injury were exacerbated by STIM1 over-expression and were partly abolished by SOCE inhibitor SKF96365 in NRVCs in vitro. Our findings demonstrate that resveratrol exerts anti-apoptotic activity and improves cardiac functional recovery following myocardial I/R by inhibiting STIM1-induced intracellular Ca2+ accumulation.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31787230

RESUMO

Sleep deprivation (SD) has detrimental effects on the physiological function of the brain. However, the underlying mechanism remains elusive. In the present study, we investigated the expression of candidate plasticity-related gene 15 (cpg15), a neurotrophic gene, and its potential role in SD using a REM-SD mouse model. Immunofluorescent and Western blot analysis revealed that the expression of cpg15 protein decreased in the hippocampus, ventral group of the dorsal thalamus (VENT), and somatosensory area of cerebral cortex (SSP) after 24-72 h of REM-SD, and the oxidative stress in these brain regions was increased in parallel, as indicated by the ratio of glutathione (GSH) to its oxidative product (GSSG). Over-expression of cpg15 in thalamus, hippocampus, and cerebral cortex mediated by AAV reduced the oxidative stress in these regions, indicating that the decrease of cpg15 might be a cause that augments oxidative stress in the sleep deprived mouse brain. Collectively, the results imply that cpg15 may play a protective function in the SD-subjected mouse brain via an anti-oxidative function. To our knowledge, this is the first time to provide evidences in the role of cpg15 against SD-induced oxidative stress in the brain.

5.
Oncol Rep ; 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31789401

RESUMO

Acyl­CoA synthetase long­chain family member 4 (ACSL4) is a member of the long chain family of acyl­CoA synthetase proteins, which have recently been shown to serve an important role in ferroptosis. Previous studies have suggested that ferroptosis is involved in the occurrence of glioma; however, the role of ACSL4 in glioma remains unknown. In the present study, a reduction of ferroptosis in human glioma tissues and glioma cells was observed. Subsequently, it was demonstrated that the expression of ACSL4 was also downregulated in human glioma tissues and cells. A ferroptosis inhibitor and inducer were used to investigate the effects of ferroptosis on viability. The results showed that promoting ferroptosis inhibited the proliferation of glioma cells, and that the use of inducers had the reverse effect. Therefore, it was hypothesized that the reduction in ACSL4 expression may have been involved in ferroptosis and proliferation in glioma. Overexpression of ACSL4 decreased expression of glutathione peroxidase 4 and increased the levels of ferroptotic markers, including 5­hydroxyeicosatetraenoic (HETE), 12­HETE and 15­HETE. Additionally, ACSL4 overexpression resulted in an increase in lactate dehydrogenase release and a reduction in cell viability. The opposite results were observed when ACSL4 was silenced. These findings suggest that ACSL4 regulates ferroptosis and proliferation of glioma cells. To further investigate the mechanism underlying ACSL4­mediated regulation of proliferation in glioma cells, cells were treated with small interfering (si)­ACSL4 and sorafenib, a ferroptosis inducer. sorafenib attenuated the ability of siRNA­mediated silencing of ACSL4, thus improving cell viability. These results demonstrate that ACSL4 protects glioma cells and exerts anti­proliferative effects by activating a ferroptosis pathway and highlight the pivotal role of ferroptosis regulation by ACSL4 in its protective effects on glioma. Therefore, ACSL4 may serve as a novel therapeutic target for the treatment of glioma.

6.
Mol Cell Biol ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712391

RESUMO

Multiple myeloma (MM) accounts for over twenty percent of hematological cancer-related death worldwide. Long non-coding RNA (lncRNA) H19 is associated with multiple tumorigenesis and is increased in MM, but the underlying mechanism of H19 in MM is unclear. In this study, the expression of H19, miR-152-3p and BRD4 in MM patients was evaluated by qRT-PCR and Western blotting. Colony formation and flow cytometry analysis were used to determine the effects of H19 and miR-152-3p on MM cell proliferation, apoptosis and cell cycle. Luciferase reporter assay was conducted to confirm the interaction among H19, miR-152-3p and BRD4. Nude mice xenograft model was established, and the cell proliferation and apoptosis were evaluated by immunohistochemistry (IHC) staining and TUNEL assay. We found that levels of H19 and BRD4 were up-regulated, and the expression of miR-152-3p was down-regulated in MM patients. Dual luciferase reporter assay showed H19 targeted miR-152-3p to promote BRD4 expression. Knockdown of H19 repressed proliferation, and enhanced apoptosis and cell cycle G1 arrest by up-regulating miR-152-3p in MM cells. Furthermore, H19 knockdown suppressed the growth of xenograft tumor, and reduced Ki-67 and BRD4 level, as well as increased cell apoptosis in xenograft tumor tissues. Taken together, H19 knockdown suppresses MM tumorigenesis via inhibiting BRD4-mediated cell proliferation through targeting miR-152-3p, implying that H19 may be a promising biomarker and drug target for MM.

7.
Proc Natl Acad Sci U S A ; 116(49): 24463-24469, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31740599

RESUMO

From 2013 to 2017, with the implementation of the toughest-ever clean air policy in China, significant declines in fine particle (PM2.5) concentrations occurred nationwide. Here we estimate the drivers of the improved PM2.5 air quality and the associated health benefits in China from 2013 to 2017 based on a measure-specific integrated evaluation approach, which combines a bottom-up emission inventory, a chemical transport model, and epidemiological exposure-response functions. The estimated national population-weighted annual mean PM2.5 concentrations decreased from 61.8 (95%CI: 53.3-70.0) to 42.0 µg/m3 (95% CI: 35.7-48.6) in 5 y, with dominant contributions from anthropogenic emission abatements. Although interannual meteorological variations could significantly alter PM2.5 concentrations, the corresponding effects on the 5-y trends were relatively small. The measure-by-measure evaluation indicated that strengthening industrial emission standards (power plants and emission-intensive industrial sectors), upgrades on industrial boilers, phasing out outdated industrial capacities, and promoting clean fuels in the residential sector were major effective measures in reducing PM2.5 pollution and health burdens. These measures were estimated to contribute to 6.6- (95% CI: 5.9-7.1), 4.4- (95% CI: 3.8-4.9), 2.8- (95% CI: 2.5-3.0), and 2.2- (95% CI: 2.0-2.5) µg/m3 declines in the national PM2.5 concentration in 2017, respectively, and further reduced PM2.5-attributable excess deaths by 0.37 million (95% CI: 0.35-0.39), or 92% of the total avoided deaths. Our study confirms the effectiveness of China's recent clean air actions, and the measure-by-measure evaluation provides insights into future clean air policy making in China and in other developing and polluting countries.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31769644

RESUMO

Solid polymer electrolytes can be used to construct solid-state lithium batteries (SSLBs) using lithium metals as the anode. However, the lifespan and safety problems of SSLBs caused by lithium dendrite growth have hindered their practical application. Here, we have designed and prepared a rigid-flexible asymmetric solid electrolyte (ASE) that is used in building SSLBs. The ASE can inhibit efficiently the growth of lithium dendrites and lead to a long cycle life of SSLBs due to the hierarchical structure of a combination of "polymer-in-ceramic" (i.e., rigid ceramic layer of Li6.4La3Zr1.4Ta0.6O12) and "LiBOB-in-polymer" (i.e., soft polymer-layer of polyethylene oxide and LiBOB components). The results demonstrated that a symmetrical battery with ASE (Li|ASE|Li) can be steadily cycled for more than 2000 h and yielded a flat plating/stripping voltage profile under a current density of 0.1 mA cm-2. As a consequence, the SSLB of LiFePO4|ASE|Li delivered a specific capacity of 155.1 mA h g-1 with a capacity retention rate up to 90.2% after 200 cycles with the Coulombic efficiency over 99.6% per cycle. This asymmetric structure combines the advantages of ceramics and polymers, providing an ingenious solution for building rigid and flexible solid electrolytes.

9.
J Neuroinflammation ; 16(1): 214, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722723

RESUMO

BACKGROUND: Neonatal hypoxic-ischemic brain damage (HIBD), a leading cause of neonatal mortality, has intractable sequela such as epilepsy that seriously affected the life quality of HIBD survivors. We have previously shown that ion channel dysfunction in the central nervous system played an important role in the process of HIBD-induced epilepsy. Therefore, we continued to validate the underlying mechanisms of TRPV1 as a potential target for epilepsy. METHODS: Neonatal hypoxic ischemia and oxygen-glucose deprivation (OGD) were used to simulate HIBD in vivo and in vitro. Primarily cultured astrocytes were used to assess the expression of TRPV1, glial fibrillary acidic protein (GFAP), cytoskeletal rearrangement, and inflammatory cytokines by using Western blot, q-PCR, and immunofluorescence. Furthermore, brain electrical activity in freely moving mice was recorded by electroencephalography (EEG). TRPV1 current and neuronal excitability were detected by whole-cell patch clamp. RESULTS: Astrocytic TRPV1 translocated to the membrane after OGD. Mechanistically, astrocytic TRPV1 activation increased the inflow of Ca2+, which promoted G-actin polymerized to F-actin, thus promoted astrocyte migration after OGD. Moreover, astrocytic TRPV1 deficiency decreased the production and release of pro-inflammatory cytokines (TNF, IL-6, IL-1ß, and iNOS) after OGD. It could also dramatically attenuate neuronal excitability after OGD and brain electrical activity in HIBD mice. Behavioral testing for seizures after HIBD revealed that TRPV1 knockout mice demonstrated prolonged onset latency, shortened duration, and decreased seizure severity when compared with wild-type mice. CONCLUSIONS: Collectively, TRPV1 promoted astrocyte migration thus helped the infiltration of pro-inflammatory cytokines (TNF, IL-1ß, IL-6, and iNOS) from astrocytes into the vicinity of neurons to promote epilepsy. Our study provides a strong rationale for astrocytic TRPV1 to be a therapeutic target for anti-epileptogenesis after HIBD.

10.
Chin Med J (Engl) ; 132(22): 2705-2715, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31725455

RESUMO

BACKGROUND: Malignant pleural effusion (MPE) is a complicated condition of patients with advanced tumors. Further dissecting the microenvironment of infiltrated immune cells and malignant cells are warranted to understand the immune-evasion mechanisms of tumor development and progression. METHODS: The possible involvement of microRNAs (miRNAs) in malignant pleural fluid was investigated using small RNA sequencing. Regulatory T cell (Treg) markers (CD4, CD25, forkhead box P3), and Helios (also known as IKAROS Family Zinc Finger 2 [IKZF2]) were detected using flow cytometry. The expression levels of IKZF2 and miR-4772-3p were measured using quantitative real-time reverse transcription polymerase chain reaction. The interaction between miR-4772-3p and Helios was determined using dual-luciferase reporter assays. The effects of miR-4772-3p on Helios expression were evaluated using an in vitro system. Correlation assays between miR-4772-3p and functional molecules of Tregs were performed. RESULTS: Compared with non-malignant controls, patients with non-small cell lung cancer had an increased Tregs frequency with Helios expression in the MPE and peripheral blood mononuclear cells. The verified downregulation of miR-4772-3p was inversely related to the Helios Tregs frequency and Helios expression in the MPE. Overexpression of miR-4772-3p could inhibit Helios expression in in vitro experiments. However, ectopic expression of Helios in induced Tregs reversed the effects induced by miR-4772-3p overexpression. Additionally, miR-4772-3p could regulate Helios expression by directly targeting IKZF2 mRNA. CONCLUSION: Downregulation of miR-4772-3p, by targeting Helios, contributes to enhanced Tregs activities in the MPE microenvironment.

11.
Pediatrics ; 144(6)2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31694978

RESUMO

BACKGROUND: Lower weight has historically been equated with more severe illness in anorexia nervosa (AN). Reliance on admission weight to guide clinical concern is challenged by the rise in patients with atypical anorexia nervosa (AAN) requiring hospitalization at normal weight. METHODS: We examined weight history and illness severity in 12- to 24-year-olds with AN (n = 66) and AAN (n = 50) in a randomized clinical trial, the Study of Refeeding to Optimize Inpatient Gains (www.clinicaltrials.gov; NCT02488109). Amount of weight loss was the difference between the highest historical percentage median BMI and admission; rate was the amount divided by duration (months). Unpaired t tests compared AAN and AN; multiple variable regressions examined associations between weight history variables and markers of illness severity at admission. Stepwise regression examined the explanatory value of weight and menstrual history on selected markers. RESULTS: Participants were 16.5 ± 2.6 years old, and 91% were of female sex. Groups did not differ by weight history or admission heart rate (HR). Eating Disorder Examination Questionnaire global scores were higher in AAN (mean 3.80 [SD 1.66] vs mean 3.00 [SD 1.66]; P = .02). Independent of admission weight, lower HR (ß = -0.492 [confidence interval (CI) -0.883 to -0.100]; P = .01) was associated with faster loss; lower serum phosphorus was associated with a greater amount (ß = -0.005 [CI -0.010 to 0.000]; P = .04) and longer duration (ß = -0.011 [CI -0.017 to 0.005]; P = .001). Weight and menstrual history explained 28% of the variance in HR and 36% of the variance in serum phosphorus. CONCLUSIONS: Weight history was independently associated with markers of malnutrition in inpatients with restrictive eating disorders across a range of body weights and should be considered when assessing illness severity on hospital admission.

12.
Commun Biol ; 2: 389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31667363

RESUMO

Billions of people have obesity-related metabolic syndromes such as diabetes and hyperlipidemia. Promoting the browning of white adipose tissue has been suggested as a potential strategy, but a drug still needs to be identified. Here, genetic deletion of activating transcription factor 3 (ATF3 -/- ) in mice under a high-fat diet (HFD) resulted in obesity and insulin resistance, which was abrogated by virus-mediated ATF3 restoration. ST32da, a synthetic ATF3 inducer isolated from Salvia miltiorrhiza, promoted ATF3 expression to downregulate adipokine genes and induce adipocyte browning by suppressing the carbohydrate-responsive element-binding protein-stearoyl-CoA desaturase-1 axis. Furthermore, ST32da increased white adipose tissue browning and reduced lipogenesis in HFD-induced obese mice. The anti-obesity efficacy of oral ST32da administration was similar to that of the clinical drug orlistat. Our study identified the ATF3 inducer ST32da as a promising therapeutic drug for treating diet-induced obesity and related metabolic disorders.

13.
Intern Med J ; 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31707755

RESUMO

BACKGROUND: H7N9 avian influenza is an infection of public health concern, in part because of its high mortality rate and pandemic potential. OBJECTIVES: We aimed to describe the clinical features of H7N9 avian influenza and the response to treatment. METHODS: Clinical, radiological, and histopathological data, and treatment-related of H7N9-infected patients hospitalized during 2014-2017 were extracted and analyzed. RESULTS: A total of 17 H7N9 patients (three females; mean age, 58.4 ± 13.7 years) were identified; of these six died. All patients presented with fever and productive cough; four patients had hemoptysis and 13 had chest distress and/or shortness of breath. Early subnormal white blood cell count and elevation of serum liver enzymes were common. Multilobar patchy shadows, rapid progression to ground-glass opacities, air bronchograms, and consolidation were the most common imaging findings. Histopathological examination of lung tissue of three patients who died showed severe alveolar epithelial cell damage, with inflammatory exudation into the alveolar space and hyaline membrane formation; widened alveolar septae, prominent inflammatory cell infiltration; and hyperplasia of pneumocytes. Viral inclusions were found in the lung tissue of two patients. All patients received antiviral drugs (oseltamivir ± peramivir). Four patients carried the rs12252-C/C IFN-induced transmembrane protein-3 (IFITM3) genotype, while the others had the C/T genotype. CONCLUSIONS: H7N9 virus infection causes human influenza-like symptoms, but may rapidly progress to severe pneumonia and even death. Clinicians should be alert to the possibility of H7N9 infection in high-risk patients. The presence of the IFITM3 rs12252-C genotype may predict severe illness. This article is protected by copyright. All rights reserved.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31657493

RESUMO

Grandparents caring for grandchildren has become a common experience in China. However, the health implications of grandparenting, especially for health self-management, remain unclear. A cross-sectional study was conducted to investigate the effects of grandparenting on health self-management in older adults in China. Information on socioeconomic characteristics, grandparenting, and health self-management was collected through interviewer-administered questionnaires. Age less than 50, male gender, higher education level, being a local resident, having a chronic illness, and supporting themselves financially were all factors that were significantly positively associated with health self-management (P < .05) in grandparents. Grandparenting characteristics, including caring for grandchildren at night, a caregiving burden of more than 50%, poorly behaved grandchildren, caring for grandchildren more than 6 hours per day, and caring for grandchildren less than 1 year in age were significantly negatively associated with health self-management in grandparents (P < .05). Multiple regression analyses indicated that grandparent age, receiving financial support from children, being a local resident, education level, grandchild behavior and age, and being an urban resident were all statistically significant factors associated with health self-management in grandparents involved in grandparenting. Taken together, these results suggested that financial condition and caregiving burden might be the major factors affecting health self-management in grandparents involved in grandparenting.

15.
Platelets ; : 1-6, 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621450

RESUMO

The pathogenesis of thrombocytopenia can be divided into increased destruction (ID) of platelets in the peripheral blood and decreased production (DP) of platelets in the bone marrow. This study aimed to analyze the efficacy of immature platelet fraction (IPF) related parameters, including the IPF count (IPF#), IPF percentage (IPF%) and highly fluorescence IPF percentage (H-IPF%), measured by XN-9000, in the differential diagnosis of thrombocytopenia. One hundred and twenty healthy volunteers were enrolled in the healthy control (HC) group, and 180 thrombocytopenia patients were grouped into either the increased destruction (ID) group or the decreased production (DP) group according to their final diagnosis. IPF# was significantly lower in the DP group than in the ID and HC groups (P < .01). Among the three groups, the ID group had the highest IPF% and H-IPF%, and the HC group had the lowest IPF% and H-IPF%. The differences between the three groups were all statistically significant (P < .01). In differentiating the ID patients from the DP patients, the areas under the operating characteristics curve of IPF#, IPF% and H-IPF% were 0.859, 0.944 and 0.930, respectively. False positive rates were below 0.04 when IPF#, IPF% and H-IPF% were above 2.65, 7.55 and 2.35, respectively. IPF related parameters showed high efficacy in the differential diagnosis of thrombocytopenia. However, due to the small numerical values of the IPF related parameters in some thrombocytopenia patients, the fluctuations of IPF% and H-IPF% should also be taken into consideration. Though H-IPF% is a new parameter, its effectiveness in the differential diagnosis of thrombocytopenia is not better than IPF%'s.

16.
Br J Pharmacol ; 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31658493

RESUMO

BACKGROUND AND PURPOSE: To test the hypothesis that angiotensin-(1-7) [Ang-(1-7)] treatment may attenuate abdominal aortic aneurysm (AAA) via inhibiting vascular inflammation, extracellular matrix degradation and smooth muscle cells (SMCs) apoptosis, an animal model of AAA was established by angiotensin II (Ang II) infusion to apolipoprotein E-knockout (ApoE-/- ) mice. EXPERIMENTAL APPROACH: All mice and cultured SMCs or macrophages were divided into control, Ang II-treated, Ang II + Ang-(1-7)-treated, Ang II + Ang-(1-7) + A779-treated and Ang II + Ang-(1-7) + PD123319-treated groups, respectively. KEY RESULTS: In the in vivo experiment, Ang-(1-7) treatment reduced the incidence and severity of AAA induced by Ang II infusion, and the mechanisms involved inhibited macrophage infiltration, attenuated expression of interleukin 6(IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein 1(MCP-1) and matrix metalloprotease 2(MMP2), as well as abated SMCs apoptosis in the abdominal aortic tissues. However, the addition of A779 or PD123319 treatment in these mice reversed Ang-(1-7)-mediated beneficial effects on AAA. In the in vitro experiment, Ang-(1-7) treatment mitigated the mRNA expression of IL-6, TNF-α and MCP-1 induced by Ang II stimulation in macrophages. In addition, Ang-(1-7) treatment significantly suppressed apoptosis and MMP2 expression and activity in Ang II-treated SMCs. The molecular mechanism may involve inhibition of extracellular signal-regulated kinase1/2 (ERK1/2) signaling pathways via Ang-(1-7) stimulation of Mas and angiotensin II type 2 receptors. CONCLUSION AND IMPLICATIONS: Ang-(1-7) treatment attenuated Ang II-induced AAA via inhibiting vascular inflammation, extracellular matrix degradation and SMCs apoptosis. Ang-(1-7) may provide a novel and promising approach to the prevention and treatment of AAA.

18.
Oncol Rep ; 42(6): 2213-2227, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638169

RESUMO

B-cell receptor (BCR) signaling is important for the development and maturation of normal B-cells and plays a key role in B-cell malignancies. Bruton's tyrosine kinase (BTK), a crucial terminal kinase enzyme in BCR signaling, has emerged as an attractive target and has been successfully applied in the treatment of hematological malignancies. Ibrutinib, a BTK inhibitor, has demonstrated marked efficacy and tolerability in treatment-naïve, relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). Ibrutinib has been approved by the Food and Drug Administration (FDA) for the treatment of CLL/SLL, MCL, marginal zone lymphoma and Waldenström macroglobulinemia and by the China FDA for the treatment of CLL/SLL and MCL. Clinical trials of ibrutinib, as a single agent or combined with chemoimmunotherapy and other promising novel agents in the treatment of B-cell malignancy therapy, such as diffuse large B-cell lymphoma, follicular lymphoma, multiple myeloma, primary and secondary CNS lymphoma and acute lymphoblastic leukemia, T-cell lymphoma and myelodysplastic syndrome, are ongoing (https://clinicaltrials.gov/). The aim of the present review was mainly to cover the clinical developments regarding the use of ibrutinib in the treatment of CLL/SLL, as well as its safety and toxicity profile.

19.
Am J Hum Genet ; 105(4): 803-812, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31564438

RESUMO

Concurrent hearing and genetic screening of newborns is expected to play important roles not only in early detection and diagnosis of congenital deafness, which triggers intervention, but also in predicting late-onset and progressive hearing loss and identifying individuals who are at risk of drug-induced HL. Concurrent hearing and genetic screening in the whole newborn population in Beijing was launched in January 2012. This study included 180,469 infants born in Beijing between April 2013 and March 2014, with last follow-up on February 24, 2018. Hearing screening was performed using transiently evoked otoacoustic emission (TEOAE) and automated auditory brainstem response (AABR). For genetic testing, dried blood spots were collected and nine variants in four genes, GJB2, SLC26A4, mtDNA 12S rRNA, and GJB3, were screened using a DNA microarray platform. Of the 180,469 infants, 1,915 (1.061%) were referred bilaterally or unilaterally for hearing screening; 8,136 (4.508%) were positive for genetic screening (heterozygote, homozygote, or compound heterozygote and mtDNA homoplasmy or heteroplasmy), among whom 7,896 (4.375%) passed hearing screening. Forty (0.022%) infants carried two variants in GJB2 or SLC26A4 (homozygote or compound heterozygote) and 10 of those infants passed newborn hearing screening. In total, 409 (0.227%) infants carried the mtDNA 12S rRNA variant (m.1555A>G or m.1494C>T), and 405 of them passed newborn hearing screening. In this cohort study, 25% of infants with pathogenic combinations of GJB2 or SLC26A4 variants and 99% of infants with an m.1555A>G or m.1494C>T variant passed routine newborn hearing screening, indicating that concurrent screening provides a more comprehensive approach for management of congenital deafness and prevention of ototoxicity.

20.
J Cell Mol Med ; 23(11): 7449-7461, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31512366

RESUMO

The role of Non-POU-domain-containing octamer-binding protein (NONO) in the formation and development of angiotensin II (Ang II)-induced abdominal aortic aneurysm (AAA) in apolipoprotein E-knockout (ApoE-/- ) mice is still unknown. In Part I, the protein level of NONO was suggestively greater in the AAA tissues compare to that in the normal abdominal aortas. In Part II, 20 ApoE-/- male mice were used to examine the transfection efficiency of lentivirus by detecting GFP fluorescence. In Part III, mice were arbitrarily separated into two groups: one was the control group without Ang II infusion, and another was the Ang II group. Mice treated with Ang II were further randomly divided into three groups to receive the same volume of physiological saline (NT group), sh-negative control lentivirus (sh-NC group) and si-NONO lentivirus (sh-NONO group). NONO silencing suggestively reduced the occurrence of AAA and abdominal aortic diameter. Compare to the NT group, NONO silencing markedly augmented the content of collagen and vascular smooth muscle cells but reduced macrophage infiltration in AAA. In addition, knockdown of NONO also increased the expression of prolyl-4-hydroxylase α1, whereas also decreased the levels of collagen degradation and pro-inflammatory cytokines in AAA. We detected the interface of NONO and NF-κB p65, and found that NONO silencing inhibited both the nuclear translocation and the phosphorylation levels of NF-κB p65. Silencing of NONO prevented Ang II-influenced AAA in ApoE-/- mice through increasing collagen deposition and inhibiting inflammation. The mechanism may be that silencing of NONO decreases the nuclear translocation and phosphorylation of NF-κB.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA