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1.
JAMA Oncol ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944221

RESUMO

Importance: A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Objective: To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. Interventions: Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. Main Outcomes and Measures: The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. Results: Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Conclusions and Relevance: Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.

2.
Nat Commun ; 11(1): 411, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964863

RESUMO

Alzheimer's disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-ß (Aß) via its N-terminal Aß binding domain, and facilitates Aß aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD.

4.
Biochim Biophys Acta Mol Basis Dis ; 1866(1): 165580, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678156

RESUMO

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized clinically by progressive decline in cognitive function and neuropathologically by the presence of senile plaques and neuronal loss in the brain. While current drugs for AD are always employed as symptomatic therapies with variable benefits, there is no treatment to delay its progression or halt neurodegeneration. TAR DNA-binding protein 43 (TDP-43) proteinopathy has increasingly been implicated as a prominent histopathological feature of AD and related dementias. Our recent studies have implicated mitochondria as critical targets of TDP-43 neurotoxicity. Here, we demonstrate that the suppression of mitochondrial-associated TDP-43 protects against neuronal loss and behavioral deficits in 5XFAD transgenic mice recapitulating AD-related phenotypes. In AD patients and 5XFAD mice, the level of TDP-43 is increased in mitochondria, and TDP-43 highly co-localizes with mitochondria in brain neurons exhibiting TDP-43 proteinopathy. Chronic administration of a TDP-43 mitochondrial localization inhibitory peptide, PM1, significantly alleviates TDP-43 proteinopathy, mitochondrial abnormalities, microgliosis and even neuronal loss without effect on amyloid plaque load in 12-month-old 5XFAD mice well after the onset of symptoms. Additionally, PM1 also improves the cognitive and motor function in 12-month-old 5XFAD mice and completely prevents the onset of mild cognitive impairment in 6-month-old 5XFAD mice. These data indicate that mitochondria-associated TDP-43 is likely involved in AD pathogenesis and that the inhibitor of mitochondria-associated TDP-43 may be a valuable drug to treat underlying AD.

5.
Biomed Rep ; 11(6): 241-252, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31798869

RESUMO

Aggrephagy, the aggresome-related protein degradation system, represents a protective cellular response to shuttle misfolded proteins into the microtubule-organizing center for degradation through the autophagic pathway during stress conditions, including heat shock, oxidative stress and proteasome inhibition. In response to proteasome failure, many genes are transcriptionally activated to facilitate ubiquitinated proteins to be cleared via the aggrephagy pathway. Although many regulators involved in aggresome formation have been identified, the mechanism how transcriptional activation promotes aggresome formation remains unknown. Here, we have demonstrated that nuclear factor erythroid 2-related factor 2 (Nrf2) accumulated in the nucleus and activated the transcription of sequestosome-1 (p62) during proteasome inhibition in 293 cells. Loss of Nrf2 resulted in failure of aggresome formation and cell death; whereas overexpression of p62 alleviated Nrf2 knockdown-induced aggresome formation defects and promoted cell survival. Notably, blocking Nrf2 activation using a p38/MAPK inhibitor prevented proteasome inhibitor-induced aggresome formation. These findings suggested that Nrf2 may be a critical regulator of aggresome formation, which protects cells from proteasome dysfunction-induced stress.

6.
BMC Med Inform Decis Mak ; 19(Suppl 8): 259, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31842854

RESUMO

BACKGROUND: Electronic health records (EHRs) provide possibilities to improve patient care and facilitate clinical research. However, there are many challenges faced by the applications of EHRs, such as temporality, high dimensionality, sparseness, noise, random error and systematic bias. In particular, temporal information is difficult to effectively use by traditional machine learning methods while the sequential information of EHRs is very useful. METHOD: In this paper, we propose a general-purpose patient representation learning approach to summarize sequential EHRs. Specifically, a recurrent neural network based denoising autoencoder (RNN-DAE) is employed to encode inhospital records of each patient into a low dimensional dense vector. RESULTS: Based on EHR data collected from Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, we experimentally evaluate our proposed RNN-DAE method on both mortality prediction task and comorbidity prediction task. Extensive experimental results show that our proposed RNN-DAE method outperforms existing methods. In addition, we apply the "Deep Feature" represented by our proposed RNN-DAE method to track similar patients with t-SNE, which also achieves some interesting observations. CONCLUSION: We propose an effective unsupervised RNN-DAE method to summarize patient sequential information in EHR data. Our proposed RNN-DAE method is useful on both mortality prediction task and comorbidity prediction task.

7.
Materials (Basel) ; 12(23)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31766646

RESUMO

Polarization has always been an important issue in modern communication systems, especially in sensitive measurements. Conventional polarization converters show limited applications due to their large size and narrow bandwidth. In this paper, we demonstrate an ultra-wide band, multifunctional, and highly efficient metamaterial-based polarization converter that is capable of converting a linearly polarized wave into its cross-polarized wave and circularly polarized wave over different frequency bands. The design principle is based on the field transformation theory and the anisotropic plate is made with high/low permittivity strip metamaterials. The simulation results show that the metamaterial-based polarization converter is able to achieve linear-to-linear conversion over 11.5-12.6 GHz, and linear-to-circular conversion over two frequency bands, 3.0-11.5 GHz and 12.6-17.0 GHz, with an average polarization conversion efficiency over 90%. The polarization converter proposed in this paper provides an important stepping stone for future communication systems' polarization control and can also be extended to higher frequency bands.

8.
Crit Care ; 23(1): 372, 2019 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-31757222

RESUMO

BACKGROUND: Accurate volume assessment is crucial in children under fluid therapy. Over the last decade, respiratory variation of aortic peak velocity (△VPeak) has been applied in intensive care unit and surgeries to help clinicians guide fluid management. The aim of this systematic review and meta-analysis was to test diagnostic performance of △VPeak in predicting fluid responsiveness of ventilated children and to explore the potential factors that influence the accuracy of △VPeak. METHODS: We searched PubMed, Embase, and Cochrane from inception to April 2019 that evaluated association between △VPeak and fluid responsiveness after fluid challenge in children receiving mechanical ventilation. Data synthesis was performed within the bivariate mixed-effects regression model modified for synthesis of diagnostic test data. RESULTS: Eleven studies with a total of 302 pediatric patients were included in our meta-analysis. The pooled sensitivity and specificity of △VPeak was 0.89 (95%CI = 0.77 to 0.95) and 0.85 (95%CI = 0.77 to 0.91), respectively. The diagnostic odds ratio (DOR) of △VPeak was 48 (95%CI = 15 to 155). SROC yielded an area under the curve of 0.91 (95%CI = 0.88-0.93). The △VPeak cutoff value was nearly conically symmetrical distribution and varied from 7 to 20%. After excluding several extreme studies, most data were centered between 12 and 13%. The medium and mean cutoff values of △VPeak were 12.2% and 12.7%, respectively. In subgroup analysis, compared to total data analysis, △VPeak performed weaker in the younger children group (mean ages < 25 months), with lower area under the summary receiver operating characteristic curve (AUSROC) of 0.80 (0.76 to 0.83), but stronger in the older children group (mean ages > 25 months), with AUSROC of 0.96 (0.94 to 0.97). CONCLUSIONS: Overall, △VPeak has a good ability in predicting fluid responsiveness of children receiving mechanical ventilation, but this ability decreases in younger children (mean age < 25 months). The optimal threshold of △VPeak to predict fluid responsiveness in ventilated children is reliable between 12 and 13%. TRIAL REGISTRATION: The study protocol was registered prospectively on PROSPERO no. CRD42019129361.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31751195

RESUMO

Two yellow-pigmented, Gram-stain-negative and rod-shaped bacterial strains, designated as RY24T and ZYY160, were isolated from rice. Results of phylogenetic analysis based on 16S rRNA gene sequences showed that strains RY24T and ZYY160 belonged to the genus Pseudomonas, and the 16S rRNA gene sequence similarity was 100 % The DNA homology between the two strains was 99.7 %. The 16S rRNA and rpoD gene sequences of the two strains showed highest similarity values to Pseudomonas oryzihabitans CGMCC 1.3392T and Pseudomonas psychrotolerans DSM 15758T (sharing 99.31 and 94.34 %, respectively). The major fatty acids of two strains were identified as summed feature 8 (C18:1ω7c and/or C18:1ω6c), C16;0 and summed feature 3 (C16:1ω7c and/or C16:1ω6c), and the major respiratory quinone was identified as ubiquinone Q-9, which are typical chemotaxonomic features of members of the genus Pseudomonas. The genomic DNA G+C contents of strains RY24T and ZYY160 were determined to be 64.25 and 64.21 mol%, respectively. The DNA-DNA relatedness and average nucleotide identity values between the two strains and their closely related type strains were below 36 and 90 %, which supported that RY24T and ZYY160 represent a novel species in the genus Pseudomonas. Phylogenetic and chemotaxonomic evidence, together with phenotypic characteristics, showed that the two isolates constitute a novel species of the genus Pseudomonas. The type strain is RY24T (JCM 33201T=ACCC 61555T), for which the name Pseudomonas rhizoryzae sp. nov. is proposed.

10.
BMC Musculoskelet Disord ; 20(1): 423, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31510985

RESUMO

BACKGROUND: Percutaneous kyphoplasty (PKP) can effectively treat osteoporotic vertebral compression fractures (OVCFs). Although satisfactory clinical outcomes can be achieved, bone cement leakage remains a primary complication of PKP. Previous studies have found many high risk factors for bone cement leakage into the spinal canal; however, less attention to the posterior wall morphologies of different vertebral bodies may be one reason for the leakage. Here, we investigated the effect of posterior vertebral wall morphology in OVCF patients on bone cement leakage into the spinal canal during PKP. METHODS: Ninety-eight OVCF patients with plain computed tomography (CT) scans and three-dimensional (3D) reconstruction images from T6 to L5 were enrolled. 3D-CT and multiplanar reconstructions (MPR) were used to measure the concave posterior vertebral wall depth (PVWCD) and the corresponding midsagittal diameter of the nonfractured vertebral body (VBSD), and the PVWCD/VBSD ratio was calculated. All subjects were divided into the thoracic or lumbar groups based on the location of the measured vertebrae to observe the value and differences in the PVWCD between both groups. The differences in PVWCD and PVWCD/VBSD between the thoracic and lumbar groups were compared. Three hundred fifty-seven patients (548 vertebrae) who underwent PKP within the same period were also divided into the thoracic and lumbar groups. The maximal sagittal diameter (BCSD), the area of the bone cement intrusion into the spinal canal (BCA), and the spinal canal encroachment rate (BCA/SCA × 100%) were measured to investigate the effect of the thoracic and lumbar posterior vertebral wall morphologies on bone cement leakage into the spinal canal through the Batson vein during PKP. RESULTS: The PVWCDs gradually deepened from T6 to T12 (mean, 4.6 mm); however, the values gradually became shallower from L1 to L5 (mean, 0.6 mm). The PVWCD/VBSD ratio was approximately 16% from T6 to T12 and significantly less at 3% from L1 to L5 (P < 0.05). The rate of bone cement leakage into the spinal canal through the Batson vein was 10.1% in the thoracic group and 3.7% in the lumbar group during PKP. In the thoracic group, the BCSD was 3.1 ± 0.5 mm, the BCA was 30.2 ± 3.8 mm2, and the BCA/SCA ratio was 17.2 ± 2.0%. In the lumbar group, the BCSD was 1.4 ± 0.3 mm, the BCA was 14.8 ± 2.2 mm2, and the BCA/SCA ratio was 7.4 ± 1.0%. The BCSD, BCA and BCA/SCA ratio were significantly higher in the thoracic group than in the lumbar group (P < 0.05). CONCLUSIONS: The PVWCD in the middle and lower thoracic vertebrae can help reduce bone cement leakage into the spinal canal by enabling avoiding bone cement distribution over the posterior 1/6 of the vertebral body during PKP. The effect of the difference between the thoracic and lumbar posterior vertebral wall morphology on bone cement leakage into the spinal canal through the Batson vein in OVCF patients during PKP is one reason that the rate of bone cement leakage into the thoracic spinal canal is significantly higher than that into the lumbar spinal canal.


Assuntos
Cimentos para Ossos/efeitos adversos , Corpos Estranhos/epidemiologia , Cifoplastia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Canal Vertebral/lesões , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Corpos Estranhos/diagnóstico por imagem , Corpos Estranhos/etiologia , Fraturas por Compressão/diagnóstico por imagem , Fraturas por Compressão/cirurgia , Humanos , Imagem Tridimensional , Cifoplastia/métodos , Vértebras Lombares/anatomia & histologia , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Masculino , Pessoa de Meia-Idade , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Canal Vertebral/irrigação sanguínea , Canal Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/cirurgia , Vértebras Torácicas/anatomia & histologia , Vértebras Torácicas/diagnóstico por imagem , Vértebras Torácicas/cirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Veias
11.
Int J Mol Sci ; 20(18)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487931

RESUMO

The anthocyanin biosynthesis of rice is a major concern due to the potential nutritional value. Purple appears in various organs and tissues of rice such as pericarp, flower organs, leaves, leaf sheaths, internodes, ligules, apex, and stigma. At present, there are many studies on the color of rice pericarp, but the gene and mechanism of other organs such as leaves are still unclear, and the gene regulatory network of specific organ coloring has not been systematically understood. In this study, genetic analysis demonstrated that the purple leaf traits of rice were regulated by a recessive gene. The green leaf cultivar Y58S and purple leaf cultivar XianHongB were used to construct the mapping population. A set of near isogenicline (NIL) (BC3F1) was bred via crossing and back-crossing. The generations of BC3F2 appeared to separate four phenotypes, pl1, pl2, pl3, and pl4, due to the occurrence of a purple color in different organs. We constructed three bulked segregant analysis (BSA) pools (pl1-pl2, pl1-pl3, and pl1-pl4) by using the separated generations of BC3F5 and mapped the purple leaf gene plr4 to the vicinity of 27.9-31.1 Mb on chromosome 4. Subsequently, transcriptome sequencing (RNA-Seq) for pl3 and pl2 was used to analyze the differentially expressed genes in the localization interval, where 12 unigenes exhibited differential expression in which two genes (Os04g0577800, Os04g0616400) were downregulated. The two downregulated genes (Os04g0577800 and Os04g0616400) are possible candidate genes because of the recessive genetic characteristics of the purple leaf genes. These results will facilitate the cloning of plr4 and illustrate the molecular mechanisms of the anthocyanin synthesis pathway.


Assuntos
Antocianinas/genética , Oryza/genética , Proteínas de Plantas/genética , Transcriptoma , Antocianinas/biossíntese , Cromossomos de Plantas/genética , Regulação da Expressão Gênica de Plantas , Folhas de Planta/genética , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo
12.
Commun Biol ; 2: 278, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31372517

RESUMO

The course, tempo and mode of chloroplast genome evolution remain largely unknown, resulting in limited knowledge about how plant plastome gene and genome evolve during the process of recent plant speciation. Here, we report the complete plastomes of 22 closely related Oryza species in chronologically ordered stages and generate the first precise map of genomic structural variation, to our knowledge. The occurrence rapidity was estimated on average to be ~7 insertions and ~15 deletions per Myr. Relatively fewer deletions than insertions result in an increased repeat density that causes the observed growth of Oryza chloroplast genome sizes. Genome-wide scanning identified 14 positively selected genes that are relevant to photosynthesis system, eight of which were found independently in shade-tolerant or sun-loving rice species. psaA seemed positively selected in both shade-tolerant and sun-loving rice species. The results show that adaptive evolution of chloroplast genes makes rice species adapt to diverse ecological habitats related to sunlight preferences.

13.
Mol Cell Neurosci ; 100: 103396, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31445085

RESUMO

Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Importantly, TDP-43 proteinopathy, characterized by aberrant phosphorylation, ubiquitination, cleavage or nuclear depletion of TDP-43 in neurons and glial cells, is a common prominent pathological feature of various major neurodegenerative diseases including ALS, FTD, and Alzheimer's disease (AD). Although the pathomechanisms underlying TDP-43 proteinopathy remain elusive, pathologically relevant TDP-43 has been repeatedly shown to be present in either the inside or outside of mitochondria, and functionally involved in the regulation of mitochondrial morphology, trafficking, and function, suggesting mitochondria as likely targets of TDP-43 proteinopathy. In this review, we first describe the current knowledge of the association of TDP-43 with mitochondria. We then review in detail multiple mitochondrial pathways perturbed by pathological TDP-43, including mitochondrial fission and fusion dynamics, mitochondrial trafficking, bioenergetics, and mitochondrial quality control. Lastly, we briefly discuss how the study of TDP-43 proteinopathy and mitochondrial abnormalities may provide new avenues for neurodegeneration therapeutics.

14.
BMC Psychiatry ; 19(1): 254, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420036

RESUMO

BACKGROUND: To measure the serum levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in deficit schizophrenia (DS), in order to examine the association between these two neurotrophic factors (NFs) and cognitive performance. METHODS: A total of 109 male patients [51 DS and 58 non-deficit schizophrenia (NDS)] with schizophrenia and 40 sex and age matched healthy controls (HC) participated in this study. Processing speed, attention, executive function, and working memory of all subjects were assessed by means of a battery of classical neuropsychological tests. Serum BDNF and GDNF levels were measured simultaneously using a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: There were significant differences in the overall cognitive test scores between three groups (all p < 0.001). Serum BDNF levels were significantly lower in patients (DS and NDS) than in HC (p < 0.001). Furthermore, BDNF levels were lower in the DS compared to the NDS group, although not significantly. However, there was no difference in the GDNF levels between patients (DS and NDS) and HC. GDNF levels were positively correlated with scores of Stroop words only (r = 0.311, p = 0.033), Stroop colors only (r = 0.356, p = 0.014) and Stroop interference (r = 0.348, p = 0.016) in DS group. CONCLUSION: Serum BDNF may be an unsuitable biomarker for DS, despite a significant decrease in schizophrenia patients. The different neurocognitive performance between the DS and NDS patients indicates that DS may be a separate clinical entity of schizophrenia. Finally, higher serum GDNF levels are associated with better cognitive performance in DS patients, indicating a possible neuroprotective function in DS.

15.
Exp Mol Pathol ; 110: 104295, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31419406

RESUMO

BACKGROUND: We used a two-hit lung injury rat model that involves mechanical ventilation (MV) following lipopolysaccharide exposure to investigate the effects of propofol on the expression of GABAA receptors (GABAAR) and cytokine responses, and we then determined the specific effects of GABA on cytokine responses in vitro in alveolar epithelial cells (AECs). METHODS: Forty-eight adult male Wister rats were equally and randomly divided into the following 4 groups (n = 12) using a random number table: sham group, sham+propofol group, lipopolysaccharide (LPS) + VILI group, and LPS + VILI + propofol group. All animals were anesthetized, and the animals received a 3.75 mg/kg intratracheal instillation of endotoxins or phosphate-buffered saline (PBS) as the control, as described previously. After 30 min, rats were ventilated for 5 h in a volume-controlled ventilation mode. In the LPS + VILI group, animals were ventilated with a tidal volume (Vt) of 22 ml/kg and zero positive end-expiratory pressure (PEEP) at a respiratory rate of 16-18 breaths/min, whereas control (sham) rats were ventilated with a Vt of 6 ml/kg and PEEP of 5 cmH2O at a rate of 45-55 breaths/min. The FiO2 remained constant as 0.4, propofol was administered intravenously in the LPS + VILI + propofol and sham + propofol groups at a rate of 10 mg·kg-1·h-1 while normal saline at the same rate was intravenously administered in the LPS + VILI and sham groups during the entire mechanical ventilation period. Five hours after mechanical ventilation, the rats were killed. Survival rates, histopathology, concentrations of inflammatory mediators in bronchoalveolar lavage fluid (BALF), wet weight/dry weight (W/D) ratio of the lung, myeloperoxidase (MPO) activity in lung tissues, and expression of GAD and GABAAR by immunohistochemical detection and Western blotting were assessed. Then, human type II-like alveolar epithelial cells (A549 cells) were cultured to full confluence and incubated with GABA (100 nM) alone, picrotoxin alone, a GABAAR antagonist (PTX, 50 nM), or GABA + PTX for 10 min, followed by stimulation with LPS (control) at 100 ng/ml for 4 h. The concentrations of IL-1ß, IL-2, IL-8, and IL-10 were then measured. RESULTS: Administration of propofol in a two-hit lung injury rat model can increase survival rates and the expression of GAD and GABAAR (P < .05). The administration of propofol can attenuate the release of pro-inflammatory cytokines both in vivo and in vitro, and the administration of propofol can attenuate histopathological changes, the W/D ratio, and MPO activity (P < .05). CONCLUSIONS: In this study, we found that the administration of propofol improved lung function, alleviated lung injury, and up-regulated the GAD and GABAAR expressions in a two-hit model of acute lung injury (ALI) characterized by intratracheal instillation of an endotoxin and prolonged MV. Therefore, the protective effects of propofol may be associated with the up-regulation of GABAA receptors in AECs.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Propofol/farmacologia , Receptores de GABA-A/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Citocinas/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Ratos , Ratos Wistar , Receptores de GABA-A/genética , Regulação para Cima
16.
Int Immunopharmacol ; 75: 105741, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31323531

RESUMO

Sepsis is a potentially fatal systemic inflammatory response syndrome caused by infection. In this study, we evaluated the effects of MCP-induced protein 1 (MCPIP1), a recently discovered inflammation-related ribonuclease, on sepsis-induced acute lung injury (ALI) and investigated the underlying mechanisms. Cecal ligation puncture and lipopolysaccharide induction were performed on Sprague-Dawley rats and RAW264.7 cells, respectively, to establish sepsis-induced ALI models. The proteasome inhibitor MG132 used as an activator of MCPIP1 overexpression, and we showed that MG132 can indeed increase the expression of MCPIP1. MCPIP1 overexpression induced by MG132 alleviated sepsis-induced pathologic changes, water content and protein leakage in the lungs, and induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats. We also showed that MCPIP1 p showed romoted macrophage polarization from the M1 to the M2 type in sepsis-induced ALI. Furthermore, MCPIP1-enhanced M2 polarization was inhibited by an MCPIP1-targeting small interfering RNA (siMCPIP1) in RAW264.7 cells. Further mechanistic studies showed that the promotive effect of MCPIP1 on M2 polarization was related to the inhibition of c-Jun N-terminal kinase (JNK) and its downstream transcription factor c-Myc in the in vitro model. Conversely, siMCPIP1 transfection resulted in the recovery of JNK and c-Myc expression in LPS-treated cells. Taken together, these findings indicate that MCPIP1 plays a protective role in sepsis-induced ALI by modulating macrophage polarization through inhibition of the JNK/c-Myc signaling pathway. Our study presents a potentially novel therapeutic strategy for the treatment of lung injury involving the inflammatory cascade.

17.
Cancer Cell Int ; 19: 113, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168295

RESUMO

Background: Although contemporary chemotherapy has improved the cure rate of childhood acute lymphoblastic leukemia (ALL) to nearly 90%, relapsed/refractory ALL is still a leading cause of tumor-related death in children. To clarify the underlying mechanisms of relapsed/refractory childhood ALL, researchers urgently need to establish novel cell models from patients with relapsed ALL after treatment with contemporary chemotherapy. Methods: Cell culture technique was used to establish the HXEX-ALL1 cell line from primary B cell precursor ALL (BCP-ALL) cells. Molecular and cellular biological techniques including flow cytometry, polymerase chain reaction (PCR), short tandem repeat (STR) analysis, conventional cytogenetics, and chromosomal microarray analysis (CMA) were used to characterize the HXEX-ALL1 cell line. Nude mice were used for xenograft studies. Results: A stable ALL cell line, HXEX-ALL1, derived from a 6-year-old boy of Han nationality with BCP-ALL at the second relapse, was established and maintained in culture for more than 18 months. The HXEX-ALL1 cell line was authenticated as being derived from primary leukemia cells based on morphologic, immunophenotypic, cytogenetic and STR analyses and demonstrated tumorigenicity in nude mice. WGS data showed that there were 27,006 novel single nucleotide polymorphisms (SNPs) and 193,951 novel insertion/deletions (InDels) in HXEX-ALL1 cells. Compared with the other BCP-ALL cell lines in use, the HXEX-ALL1 cells have a special karyotype represented by trisomy 8 and 9p and 17p deletions with a multidrug resistance phenotype, especially highly resistant to asparaginase. Conclusions: The HXEX-ALL1 cell line may prove to be a useful model for the study of relapsed/refractory childhood ALL, particularly for the researches on asparaginase resistance.

18.
J Alzheimers Dis ; 69(4): 1077-1087, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31156179

RESUMO

Alzheimer's disease (AD) and other tauopathies are characterized by intracellular accumulation of microtubule-associated tau protein leading to neurodegeneration. Calpastatin is the endogenous inhibitor of calpain, a calcium-dependent cysteine protease that has been increasingly implicated in tauopathies. In this study, we generated a neuron specific calpastatin overexpressing knock-in transgenic mouse model and crossed it with the PS19 tauopathy mouse model expressing human P301S mutant tau protein. The forced expression of calpastatin in neurons significantly alleviated tau hyperphosphorylation measured by immunocytochemistry and immunoblot. The genetic inhibition of calpain by calpastatin also greatly suppressed characteristic hippocampal neuron loss and widespread astrogliosis and microgliosis in PS19 mice. Consistently, PS19 mice with neuronal calpastatin overexpression exhibited remarkably alleviated cognitive deficits, muscle weakness, skeletal muscle atrophy, and neuromuscular denervation, together implying the neuroprotective effects of neuronal calpastatin in PS19 mice of tauopathy. In sum, this study provides additional evidence supporting the pathological role of calpain in neurodegenerative diseases associated with tau pathology, and suggests that targeting calpain is likely a promising therapeutic approach for these devastating diseases.

20.
Breed Sci ; 69(1): 40-46, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31086482

RESUMO

The brown planthopper (BPH) is a serious insect pest of rice and a substantial threat to rice production. Identification of new BPH resistance genes and their transfer into modern rice cultivars are effective breeding approaches to reduce the damage caused by BPH. In this study, we mapped a BPH resistance gene to a 50-kb genomic interval between two InDel markers 4M03980 and 4M04041 on the short arm of chromosome 4 in indica rice cultivar BP60, where the BPH resistance gene was mapped in Rathu Heenati by Liu et al. (2015) and named "Bph3". This region contains two annotated genes Os04g0201900 and Os04g0202300, which encode lectin receptor kinases responsible for BPH resistance. We also developed a molecular marker "MM28T" for Bph3, and introgression Bph3 into susceptible rice restorer lines Guihui582 and Gui7571 by the marker-assisted selection (MAS) approach. The BPH resistance level is significantly enhanced in the Bph3-introgression lines, the resistance scores decrease from 8.2 to 3.6 for Guihui582 and decrease from 8.7 to around 3.8 for Gui7571. Therefore, developing molecular markers for the BPH resistance gene Bph3 and using them for molecular breeding will facilitate the creation of BPH-resistance rice cultivars to reduce damage caused by BPH.

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