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1.
Dev Cell ; 56(18): 2592-2606.e7, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34508658

RESUMO

Membrane contact between intracellular organelles is important in mediating organelle communication. However, the assembly of molecular machinery at membrane contact site and its internal organization correlating with its functional activity remain unclear. Here, we demonstrate that a gel-like condensation of Cidec, a crucial protein for obesity development by facilitating lipid droplet (LD) fusion, occurs at the LD-LD contact site (LDCS) through phase separation. The homomeric interaction between the multivalent N terminus of Cidec is sufficient to promote its phase separation both in vivo and in vitro. Interestingly, Cidec condensation at LDCSs generates highly plastic and lipid-permeable fusion plates that are geometrically constrained by donor LDs. In addition, Cidec condensates are distributed unevenly in the fusion plate generating stochastic sub-compartments that may represent unique lipid passageways during LD fusion. We have thus uncovered the organization and functional significance of geometry-constrained Cidec phase separation in mediating LD fusion and lipid homeostasis.

2.
J Int Med Res ; 49(6): 3000605211022967, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34159826

RESUMO

OBJECTIVE: To determine the associations between matrix metalloproteinase-2 (MMP-2, encoded by the MMP2 gene) 1306C/T and 735C/T polymorphisms and first and recurrent ischemic stroke in a Chinese population. METHODS: Patients with first and recurrent ischemic stroke were included. Serum MMP-2 was measured, and MMP2 1306C/T and 735C/T polymorphisms were detected. The associations between MMP2 1306C/T and 735C/T polymorphisms and first and recurrent ischemic stroke were analyzed. RESULTS: Serum MMP-2 in patients with first and recurrent ischemic stroke was significantly higher compared with controls, and patients with recurrent ischemic stroke had higher MMP-2 than those with first ischemic stroke. The frequency of the CC genotype and C allele of MMP2 735C/T was highest in patients with recurrent ischemic stroke, followed by patients with first ischemic stroke, and controls. Conversely, the genotype and allele of MMP2 1306C/T did not significantly differ between groups. The CC genotype of MMP2 735C/T was independently associated with first and recurrent ischemic stroke (odds ratios = 1.45 and 1.64, respectively), as was the C allele of MMP2 735C/T (odds ratios = 1.68 and 1.77, respectively). CONCLUSIONS: The CC genotype and C allele of MMP2 735C/T were associated with first and recurrent ischemic stroke in a Chinese population.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Metaloproteinase 2 da Matriz , Acidente Vascular Cerebral , Isquemia Encefálica/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Metaloproteinase 2 da Matriz/genética , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/genética
4.
Chem Commun (Camb) ; 2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34023866

RESUMO

A covalent post-assembly strategy is developed to prepare a composite of dispersive MOF particles in an aerogel matrix. Briefly, the anhydride group-decorated MOF (UiO-66-NH2) particles covalently coupled with polyimide (PI) monomers through a one-pot amidation polymerization reaction, succeeding a process of gel-sol, freeze-drying and thermal-imidization to obtain the UiO-66-PI aerogel. The designed composite shows outstanding catalytic activity in CO2 cycloaddition and excellent adsorption capacity for dyes.

5.
J Alzheimers Dis ; 81(1): 389-401, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814427

RESUMO

BACKGROUND: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer's disease (AD) pathology remains unclear. OBJECTIVE: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. METHODS: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-ß [Aß], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. RESULTS: Levels of SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aß1 - 42 (p = 0.019) and Aß1 - 42/Aß1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aß1 - 42 (p = 0.009) and t-Tau/Aß1 - 42 (p = 0.043) were increased with the highest (> 75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. CONCLUSION: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA.


Assuntos
Doença de Alzheimer/etiologia , Amiloidose/etiologia , Cognição/fisiologia , Ácido Úrico/sangue , Idoso , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Amiloidose/sangue , Biomarcadores/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Proteínas tau/líquido cefalorraquidiano
6.
Biomolecules ; 11(2)2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33567640

RESUMO

Chimeric antigen receptor (CAR) T therapy represents a form of immune cellular therapy with clinical efficacy and a specific target. A typical chimeric antigen receptor (CAR) construct consists of an antigen binding domain, a transmembrane domain, and a cytoplasmic domain. Nanobodies have been widely applied as the antigen binding domain of CAR-T due to their small size, optimal stability, high affinity, and manufacturing feasibility. The nanobody-based CAR structure has shown a proven function in more than ten different tumor-specific targets. After being transduced in Jurkat cells, natural killer cells, or primary T cells, the resulting nanobody-based CAR-T or CAR-NK cells demonstrate anti-tumor effects both in vitro and in vivo. Interestingly, anti-BCMA CAR-T modulated by a single nanobody or bi-valent nanobody displays comparable clinical effects with that of single-chain variable fragment (scFv)-modulated CAR-T. The application of nanobodies in CAR-T therapy has been well demonstrated from bench to bedside and displays great potential in forming advanced CAR-T for more challenging tasks.


Assuntos
Imunoterapia Adotiva/métodos , Anticorpos de Domínio Único , Humanos , Células Jurkat , Células Matadoras Naturais/imunologia , Anticorpos de Cadeia Única/imunologia
7.
Fundam Clin Pharmacol ; 35(5): 870-881, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33481320

RESUMO

Glutamate excitotoxicity in cerebral ischemia/reperfusion is an important cause of neurological damage. The aim of this study was to investigate the mechanism of Na+, K+-ATPase (NKA) involved in l ow concentration of ouabain (Oua, activating NKA)-induced protection of rat cerebral ischemia-reperfusion injury. The 2,3,5-triphenyltetrazolium chloride (TTC) staining and neurological deficit scores (NDS) were performed to evaluate rat cerebral injury degree respectively at 2 h, 6 h, 1 d and 3 d after reperfusion of middle cerebral artery occlusion (MCAO) 2 h in rats. NKA α1/α2 subunits and glutamate transporter-1 (GLT-1) protein expression were investigated by Western blotting. The cerebral infarct volume ratio were evidently decreased in Oua group vs MCAO/R group at 1 d and 3 d after reperfusion of 2 h MCAO in rats (*p < 0.05 ). Moreover, NDS were not significantly different (p > 0.05 ). NKA α1 was decreased at 6 h and 1 d after reperfusion of 2 h MCAO in rats, and was improved in Oua group. However, NKA α1 and α2 were increased at 3 d after reperfusion of 2 h MCAO in rats, and was decreased in Oua group. GLT-1 was decreased at 6 h, 1 d and 3 d after reperfusion of 2 h MCAO in rats, and was improved in Oua group. These data indicated that l ow concentration of Oua could improve MCAO/R injury through probably changing NKA α1/α2 and GLT-1 protein expression, then increasing GLT-1 function and promoting Glu transport and absorption, which could be useful to determine potential therapeutic strategies for patients with stroke. Low concentration of Oua improved rat MCAO/R injury via NKA α1/α2 and GLT-1.

8.
Am J Med Sci ; 361(3): 336-343, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33309135

RESUMO

BACKGROUND: This study aimed to explore the associations between the complement factor H (CFH) rs6677604 and clinico-pathological characteristics of lupus nephritis. MATERIALS AND METHODS: A total of 188 patients with lupus nephritis with complete clinico-pathological data were enrolled and genotyping of CFH rs6677604 was conducted by TaqMan SNP genotyping assays. Patients were divided into two groups by rs6677604-AA/AG or -GG, and the clinico-pathological features between the two groups were further compared. RESULTS: We found that patients with rs6677604-AA/AG presented with lower prevalence of anti-dsDNA antibody (12/24 [50.0%] vs 121/164 [73.8%], P = 0.028), higher level of plasma C3a (2642.96 ± 1575.05 vs 1640.01 ± 1209.40, ng/ml, P = 0.024), and a tendency for higher level of plasma CFH (505.76 ± 169.28 vs 397.67 ± 179.11, µg/ml, P = 0.087). Patients with rs6677604-AA/AG had milder renal histopathological features, including total activity indices score (4.5[0, 13] vs 8[0, 19], P = 0.013), endocapillary hypercellularity (1.5[0, 3] vs 3[0, 3], P = 0.013), sub-endothelial hyaline deposits (0.5[0, 3] vs 1[0,3], P = 0.021), glomerular leukocyte infiltration (0.5[0, 1] vs 1[0, 12], P = 0.023) and tubular atrophy (1[0, 1] vs 1[0, 3], P = 0.027) than those with rs6677604-GG, which was further confirmed by the stratified analysis. The rs6677604-A was not a risk factor for patients' renal outcomes (hazard ratio=0.898; 95% CI: 0.264-3.059, P = 0.863). CONCLUSIONS: The rs6677604-A genotype in CFH was associated with milder renal pathological features in lupus nephritis, and its protective effect on the pathogenesis of the disease remained to be elucidated.


Assuntos
Nefrite Lúpica/genética , Adolescente , Adulto , Idoso , Fator H do Complemento/genética , Fator H do Complemento/metabolismo , Feminino , Variação Genética , Genótipo , Humanos , Nefrite Lúpica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Math Biosci Eng ; 17(5): 5709-5726, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-33120574

RESUMO

The aim of this study was to develop a prototype three-dimensional optical motion capture system based on binocular stereo vision, Back-propagation (BP) Neural Network and 3D compen-sation method for accurate and real-time recording of mandibular movement. A specialized 3D method of compensation to eliminate the involuntary vibration motions by human heart beating and respiration. A kind of binocular visual 3D measurement method based on projection line and a calibration method based on BP neural network is proposed to solve the problem of the high complexity of camera calibration process and the low accuracy of 3D measurement. The accuracy of the proposed system is systematically evaluated by means of electric platform and clinical trials, and the root-mean-square is 0.0773 mm. Finally, comparisons with state-of-the-art methods demonstrate that our system has higher reliability and accuracy. Meanwhile, the motion trajectory-tracking system is expected to be used in the diagnosis of clinical oral diseases and digital design of restoration.


Assuntos
Mandíbula , Movimento , Calibragem , Humanos , Imageamento Tridimensional , Redes Neurais de Computação , Reprodutibilidade dos Testes
10.
Nano Lett ; 20(9): 6387-6395, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32787151

RESUMO

Bridging integrator-1 (BIN1) is a family of banana-shaped molecules implicated in cell membrane tubulation. To understand the curvature sensitivity and functional roles of BIN1 splicing isoforms, we engineered vertical nanobars on a cell culture substrate to create high and low curvatures. When expressed individually, BIN1 isoforms with phosphoinositide-binding motifs (pBIN1) appeared preferentially at high-curvature nanobar ends, agreeing well with their membrane tubulation in cardiomyocytes. In contrast, the ubiquitous BIN1 isoform without phosphoinositide-binding motif (uBIN1) exhibited no affinity to membranes around nanobars but accumulated along Z-lines in cardiomyocytes. Importantly, in pBIN1-uBIN1 coexpression, pBIN1 recruited uBIN1 to high-curvature membranes at nanobar ends, and uBIN1 attached the otherwise messy pBIN1 tubules to Z-lines. The complementary cooperation of BIN1 isoforms (comboBIN1) represents a novel mechanism of T-tubule formation along Z-lines in cardiomyocytes. Dysregulation of BIN1 splicing, e.g., during myocardial infarction, underlied T-tubule disorganization, and correction of uBIN1/pBIN1 stoichiometry rescued T-tubule morphology in heart disease.


Assuntos
Proteínas Nucleares , Proteínas Supressoras de Tumor , Proteínas Adaptadoras de Transdução de Sinal , Morfogênese , Proteínas Nucleares/genética , Isoformas de Proteínas/genética , Proteínas Supressoras de Tumor/metabolismo
11.
Mol Cancer ; 19(1): 102, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503543

RESUMO

Extracellular vesicles (EVs), a class of heterogeneous membrane vesicles, are generally divided into exosomes and microvesicles on basis of their origination from the endosomal membrane or the plasma membrane, respectively. EV-mediated bidirectional communication among various cell types supports cancer cell growth and metastasis. EVs derived from different cell types and status have been shown to have distinct RNA profiles, comprising messenger RNAs and non-coding RNAs (ncRNAs). Recently, ncRNAs have attracted great interests in the field of EV-RNA research, and growing numbers of ncRNAs ranging from microRNAs to long ncRNAs have been investigated to reveal their specific functions and underlying mechanisms in the tumor microenvironment and premetastatic niches. Emerging evidence has indicated that EV-RNAs are essential functional cargoes in modulating hallmarks of cancers and in reciprocal crosstalk within tumor cells and between tumor and stromal cells over short and long distance, thereby regulating the initiation, development and progression of cancers. In this review, we discuss current findings regarding EV biogenesis, release and interaction with target cells as well as EV-RNA sorting, and highlight biological roles and molecular mechanisms of EV-ncRNAs in cancer biology.


Assuntos
Biomarcadores Tumorais/genética , Vesículas Extracelulares/genética , MicroRNAs/genética , Neoplasias/patologia , RNA Mensageiro/genética , RNA não Traduzido/genética , Microambiente Tumoral/imunologia , Animais , Progressão da Doença , Humanos , Metástase Neoplásica , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo
12.
Clin Chim Acta ; 508: 1-8, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32387092

RESUMO

BACKGROUND: This study aimed to investigate the role of anti-CFH autoantibodies in lupus nephritis based on a well-defined cohort. METHODS: One hundred twenty patients with biopsy-proven active lupus nephritis were collected as the discovery cohort, sixty patients served as the validation cohort, thirty-four patients with SLE without renal involvement (NR-SLE) were as disease controls, and thirty healthy donors were also included. The anti-CFH autoantibodies and IgG subclasses were detected by ELISA, and epitopes were evaluated by western blot. Anti-CFH autoantibodies were purified by affinity chromatography column, and the interference on the biofunctions of CFH was further studied by the C3b binding assay and cofactor activity assay in vitro. RESULTS: The prevalence of anti-CFH autoantibodies in lupus nephritis was significantly higher than that in healthy controls (8.3% (10/120) vs. 0% (0/30), P = 0.017), and no significant difference was found between the discovery and the validation group (8.3% (10/120) vs. 11.7% (7/60), P = 0.268) or the discovery and the NR-SLE group (8.3% (10/120) vs. 11.8% (4/34), P = 0.231). The subclass was mainly IgG2 (7/10), and major epitopes were in the middle (8/10 in SCRs 11-14) and N-terminal (7/10 in SCRs 1-4) regions of CFH. Patients with anti-CFH autoantibodies had a significantly lower prevalence of acute kidney injury (0% (0/10) vs. 40.0%(4/10), P = 0.025), lower serum creatinine levels (0.76 (0.40, 1.06) vs. 1.43 (0.46, 11.15), mg/dL, P = 0.023), and higher hemoglobin levels (113.8 ± 24.63 vs. 90.0 ± 22.53, g/L, P = 0.037) than those who were negative after further stratified analysis. A functional study showed that anti-CFH autoantibodies purified from patients with lupus nephritis could improve the binding between CFH and C3b, and also enhance the cofactor activity of CFH in vitro. CONCLUSIONS: Anti-CFH autoantibodies were detected in patients with lupus nephritis in approximately 10% of patients with polyepitopes and IgG2 subclass predominance. Patients with anti-CFH autoantibodies presented with milder renal damage, and the purified autoantibodies could enhance the C3b binding and CFI cofactor activity of CFH in vitro, which suggested a protective role in the lupus nephritis.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Autoanticorpos , Humanos , Imunoglobulina G , Fatores Imunológicos , Rim
13.
PeerJ ; 8: e8731, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32195055

RESUMO

Although lung cancer is one of the greatest threats to human health, its signaling pathway and related genes are still unknown. This study integrates data from three groups of people to study potential key candidate genes and pathways related to lung cancer. Expression profiles (GSE18842, GSE19188 and GSE27262), including 162 tumor tissue and 135 adjacent normal lung tissue samples, were integrated and analyzed. Differentially expressed genes (DEGs) and candidate genes were identified, their expression pathways were analyzed, and the diethylene glycol-related protein-protein interaction (PPI) network was analyzed. We identified 232 shared DEGs (40 upregulated and 192 down-regulated) from the three GSE datasets. The DEGs were clustered according to function and signaling pathway for significant enrichment analysis. In total, 129 nodes/DEGs were identified from the DEG PPI network complex. An improved prognosis was associated with increased Helicase, Lymphoid-Specific (HELLS) and decreased Intercellular adhesion molecule 1 (ICAM1) mRNA expression in lung cancer patients. In conclusion, we used integrated bioinformatics analysis to identify candidate genes and pathways in lung cancer to show that HELLS and ICAM1 might be the key genes related to tumorigenesis or tumor progression in lung cancer. Additional studies are needed to further explore the involved functional mechanisms.

14.
Sci Rep ; 10(1): 439, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949205

RESUMO

Flavanomarein (FM) is a major natural compound of Coreopsis tinctoria Nutt with protective effects against diabetic nephropathy (DN). In this study, we investigated the effects of FM on epithelial-mesenchymal transition (EMT) in high glucose (HG)-stimulated human proximal tubular epithelial cells (HK-2) and the underlying mechanisms, including both direct targets and downstream signal-related proteins. The influence of FM on EMT marker proteins was evaluated via western blot. Potential target proteins of FM were searched using Discovery Studio 2017 R2. Gene Ontology (GO) analysis was conducted to enrich the proteins within the protein-protein interaction (PPI) network for biological processes. Specific binding of FM to target proteins was examined via molecular dynamics and surface plasmon resonance analyses (SPR). FM promoted the proliferation of HK-2 cells stimulated with HG and inhibited EMT through the Syk/TGF-ß1/Smad signaling pathway. Spleen tyrosine kinase (Syk) was predicted to be the most likely directly interacting protein with FM. Combined therapy with a Syk inhibitor and FM presents significant potential as an effective novel therapeutic strategy for DN.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glucose/farmacologia , Quinase Syk/metabolismo , Actinas/metabolismo , Caderinas/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fibronectinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Rim/citologia , Simulação de Acoplamento Molecular , Conformação Proteica , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Quinase Syk/química , Fator de Crescimento Transformador beta1/metabolismo , Vimentina/metabolismo
15.
Acta Pharmacol Sin ; 41(5): 678-685, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31937933

RESUMO

Fecal microbiota transplantation (FMT) has become an effective strategy to treat metabolic diseases, including type 2 diabetes mellitus (T2DM). We previously reported that the intestinal microbiome had significant difference between individuals with normal glucose tolerance and T2DM in Chinese Kazak ethnic group. In this study, we investigated the effects of transplanted fecal bacteria from Kazaks with normal glucose tolerance (KNGT) in db/db mice. The mice were treated with 0.2 mL of fecal bacteria solution from KNGT daily for 10 weeks. We showed that the fecal bacteria from KNGT successfully colonized in the intestinal tract of db/db mice detected on day 14. In the FMT-treated db/db mice, the levels of fasting blood glucose, postprandial glucose, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol were significantly downregulated, whereas high-density lipoprotein-cholesterol levels were upregulated. In the FMT-treated db/db mice, Desulfovibrio and Clostridium coccoides levels in gut were significantly decreased, but the fecal levels of Akkermansia muciniphila and colon histone deacetylase-3 (HDAC3) protein expression were increased. At 8 weeks, both intestinal target bacteria and HDAC3 were correlated with glycolipid levels; Akkermansia muciniphila level was positively correlated with HDAC3 protein expression (r = +0.620, P = 0.037). Our results suggest that fecal bacteria from KNGT could potentially be used to treat diabetic patients.


Assuntos
Clostridiales/metabolismo , Desulfovibrio/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/metabolismo , Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Akkermansia/metabolismo , Animais , Diabetes Mellitus Tipo 2/terapia , Modelos Animais de Doenças , Dislipidemias/terapia , Humanos , Masculino , Camundongos
16.
Thorac Cancer ; 11(2): 346-352, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31794146

RESUMO

BACKGROUND: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and unique subtype of lung cancer. However, the prevalence of driver alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, and the response of tyrosine kinase inhibitor (TKIs) in PLELC has not been thoroughly investigated. METHOD: We retrospectively reviewed the genetic profiles and treatment course of 330 PLELC patients at the Guangdong Lung Cancer Institute (GLCI) from 1st January, 2008 to 30th December, 2018. We searched and analyzed related literature published in PubMed and Web of Science from 1st January, 2000 and 31th August, 2019 based on their mention of "driver mutations" and "the response of TKIs to mutant PLELC". RESULTS: Genetic alterations of EGFR/ALK were tested in 203 patients (203/330, 61.5%). Five patients (5/175, 2.9%) had EGFR mutation and three patients (3/140, 2.1%) had ALK alteration. From the total of 15 articles identified from electronic searches, 1071 PLELC cases mentioned the driver mutations. EGFR mutation and ALK rearrangement were detected in 15 patients and one patient, respectively. In total, there were four EGFR/ALK mutant PLELC patients who received targeted therapy as palliative treatment at the GLCI and in the literature. However, there was disease progression in all cases one month after use of TKIs. CONCLUSION: The mutation rates of EGFR and ALK were low in PLELC. EGFR and ALK TKIs showed limited response in EGFR/ALK mutant PLELC. Further studies are needed to explore other molecular targets to optimize the therapeutic strategy for PLELC.


Assuntos
Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Rearranjo Gênico , Neoplasias Pulmonares/patologia , Mutação , Adolescente , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
17.
Ecotoxicol Environ Saf ; 189: 110043, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31812821

RESUMO

Ethylene signaling was addressed, for the first time, in plant responses to nitrogen dioxide (NO2) by comparatively analyzing the performance of Arabidopsis ethylene insensitive 2 (ein2-1) with wild-type (WT) plants. Following NO2 fumigation, severe leaf wilting and chlorosis occurred in WT plants, but much less symptoms were observed in ein2-1. The activities of superoxide dismutase (SOD), peroxidase (PRX) and catalase (CAT) were 39%, 92%, and 11% higher, respectively, in ein2-1 than in WT following NO2 exposure. Although glutathione contents and the ratio of its reduced form (GSH) to oxidized form (GSSG) were decreased by NO2, an obviously alleviated degree was detected in ein2-1 relative to WT. Correspondingly, the contents of hydrogen peroxide (H2O2) and malondialdehyde (MDA), and electrolyte leakage were 25%, 24%, and 29% lower, respectively, in ein2-1 than in WT. The difference of oxidative stress between two tested genotypes was also revealed by the leaf staining regarding the production and distribution of H2O2, superoxide anion (O2˙-), and cell death. The genes involved in antioxidation or oxidation-reduction processes mostly presented a stronger expression in ein2-1 than in WT under NO2 stress. The photosynthesis-related parameters including chlorophyll and soluble sugar contents, net photosynthetic rate (Pn), and ribulose bisphosphate carboxylase/oxygenase (Rubisco) activity and gene expression, and chlorophyll fluorescence parameters were affected, generally, to a lesser degree in ein2-1 than in WT following NO2 fumigation. The enzymatic activities and gene expressions of invertases mostly displayed a higher level in ein2-1 relative to WT following NO2 fumigation. For example, the activities of cytoplasmic, cell wall and vacuolar invertases were 76%, 26%, and 26% higher, respectively, in ein2-1 than in WT. Together, these data suggest that ethylene signal insensitivity efficiently improves plant tolerance to NO2 exposure, and the possible mechanisms might be correlated with leaf antioxidative defense, photosynthesis-related processes, and sucrose metabolisms.


Assuntos
Adaptação Fisiológica/genética , Poluentes Atmosféricos/toxicidade , Antioxidantes/metabolismo , Proteínas de Arabidopsis/genética , Arabidopsis/genética , Dióxido de Nitrogênio/toxicidade , Receptores de Superfície Celular/genética , Adaptação Fisiológica/efeitos dos fármacos , Arabidopsis/metabolismo , Mutação , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fotossíntese/efeitos dos fármacos , Fotossíntese/genética
18.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(6): 1862-1868, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31839051

RESUMO

OBJECTIVE: To analyze the effect of serum free light chain (sFLC) on renal function and prognosis in patients with newly diagnosed multiple myeloma (MM). METHODS: The clinical data of 70 newly diagnosed MM patients who received sFLC examination in Fujian Medical University Union Hospital were retrospectively analyzed from April 2012 to November 2016. Univariate analysis was used to analyze the risk factors that associated with renal impairment (RI) and prognosis. Logistic regression and Kaplan-Meier analyze were used to analyze the roles of sFLC in RI and the prognosis. RESULTS: Out of the 70 patients, 20 patients had RI at the initial diagnosis. Compared to normal renal function group, RI group had lower level of hemoglobin, elevated levels of serum uric acid, corrected calcium, serum creatinine, serum ß2 microglobulin, and involved sFLC, higher proportion of patients with ISS stage III, involved sFLC≥500 mg/L, hemodialysis (all P<0.05). Multivariate logistic regression analysis showed that serum uric acid≥430 µmol/L, ISS stage III and a involved sFLC≥500 mg/L were all the independent risk factors for RI in patients with newly diagnosed MM patients (all P<0.05). Receiver operating characteristic (ROC) curves analysis showed that the involved sFLC was 705.0 mg/L, which was a best cut-off value area under curve (AUC) for prediting RI in patients with MM was 0.727 (P=0.003), sensitivity was 65.0% and specificity was 82.0%). After a median follow-up period of 31 (1-84) months, the median overall survival (OS) of patients with involved sFLC≥500mg/L and involved sFLC<500 mg/L were 52.0 and 27.0 months, respectively, there was no statistically significant difference (P=0.137). There was also no statistically significant difference in median OS between the high sFLC ratio group (κ/λ>32 or <0.03) and the low sFLC ratio group (0.03≤κ/λ≤32) (27 months vs 40 months, P=0.436). CONCLUSION: The involved sFLC in the RI group is significantly higher than that in the normal renal function group in newly diagnosed MM patients. Serum uric acid≥430 µmol/L, ISS stage III and involved sFLC≥500 mg/L are the independent risk factors for RI. Monitoring sFLC in newly diagnosed MM patients is helpful to the prediction of RI, and the involved sFLC level or sFLC ratio may not affect the prognosis of newly diagnosed MM patients.


Assuntos
Mieloma Múltiplo , Humanos , Cadeias Leves de Imunoglobulina , Prognóstico , Estudos Retrospectivos , Ácido Úrico
19.
BMC Nephrol ; 20(1): 459, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823738

RESUMO

BACKGROUND: C3 glomerulonephritis (C3GN) is a rare disease caused by inherited or acquired complement alternative pathway (CAP) dysregulation, which could also be secondary to monoclonal gammopathy of undetermined significance (MGUS). Herein, we described a patient presenting with C3GN and monoclonal gammopathy, and the pathogenic association between the two diseases was further explored in vitro. CASE PRESENTATION: A 76-year-old Chinese man presented with low serum C3 level, haematuria and nephrotic syndrome, and experienced rapid worsening of renal function over a period of 10 months. His serum and urine immunofixation electrophoresis both revealed a monoclonal IgGλ. A bone marrow puncture showed plasma cell dyscrasias with the highest plasma cell count of 5.25%. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence, a membranoproliferative pattern on light microscopy and electron dense deposits in sub-epithelial, intramembranous, sub-endothelial and mesangial regions by electron microscopy. The patient was positive for C3 nephritic factor (C3NeF) activity and anti-CFH autoantibodies, and all became negative during disease remission. The anti-CFH autoantibodies purified from the patient's plasma exchange fluids were proven to be a monoclonal IgGλ, and could inhibit CFH binding to C3b and accelerate the formation of C3 convertase indirectly by interfering with the formation-impeding activity of CFH. No deficiency of candidate genes, especially variants in CFH, was detected in our patient. Based on the pathological and laboratory findings, the diagnosis of monoclonal gammopathy of renal significance (MGRS)-associated C3GN was finally made. CONCLUSIONS: This is the first demonstration that intact monoclonal immunoglobulin (IgGλ) could act as an anti-CFH antibody and lead to MGRS-associated C3GN by activating the CAP.


Assuntos
Complemento C3/metabolismo , Glomerulonefrite/sangue , Glomerulonefrite/diagnóstico , Imunoglobulina G/sangue , Paraproteinemias/sangue , Paraproteinemias/diagnóstico , Idoso , Autoanticorpos/sangue , Humanos , Masculino
20.
Nat Commun ; 10(1): 5277, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754099

RESUMO

Mitochondrial calcium ([Ca2+]mito) dynamics plays vital roles in regulating fundamental cellular and organellar functions including bioenergetics. However, neuronal [Ca2+]mito dynamics in vivo and its regulation by brain activity are largely unknown. By performing two-photon Ca2+ imaging in the primary motor (M1) and visual cortexes (V1) of awake behaving mice, we find that discrete [Ca2+]mito transients occur synchronously over somatic and dendritic mitochondrial network, and couple with cytosolic calcium ([Ca2+]cyto) transients in a probabilistic, rather than deterministic manner. The amplitude, duration, and frequency of [Ca2+]cyto transients constitute important determinants of the coupling, and the coupling fidelity is greatly increased during treadmill running (in M1 neurons) and visual stimulation (in V1 neurons). Moreover, Ca2+/calmodulin kinase II is mechanistically involved in modulating the dynamic coupling process. Thus, activity-dependent dynamic [Ca2+]mito-to-[Ca2+]cyto coupling affords an important mechanism whereby [Ca2+]mito decodes brain activity for the regulation of mitochondrial bioenergetics to meet fluctuating neuronal energy demands as well as for neuronal information processing.


Assuntos
Encéfalo/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Citosol/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Córtex Visual/metabolismo , Animais , Encéfalo/citologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência por Excitação Multifotônica , Mitocôndrias/ultraestrutura , Córtex Motor/citologia , Córtex Motor/metabolismo , Córtex Visual/citologia
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