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1.
Neuroradiology ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32239241

RESUMO

PURPOSE: Telomerase reverse transcriptase (TERT) promoter mutation status is an important biomarker for the precision diagnosis and prognosis prediction of lower grade glioma (LGG). This study aimed to construct a radiomic signature to noninvasively predict the TERT promoter status in LGGs. METHODS: Eighty-three local patients with pathology-confirmed LGG were retrospectively included as a training cohort, and 33 patients from The Cancer Imaging Archive (TCIA) were used as for independent validation. Three types of regions of interest (ROIs), which covered the tumor, peri-tumoral area, and tumor plus peri-tumoral area, were delineated on three-dimensional contrast-enhanced T1 (3D-CE-T1)-weighted and T2-weighted images. One hundred seven shape, first-order, and texture radiomic features from each modality under each ROI were extracted and selected through least absolute shrinkage and selection operator. Radiomic signatures were constructed with multiple classifiers and evaluated using receiver operating characteristic (ROC) analysis. The tumors were also stratified according to IDH status. RESULTS: Three radiomic signatures, namely, tumoral radiomic signature, tumoral plus peri-tumoral radiomic signature, and fusion radiomic signature, were built, all of which exhibited good accuracy and balanced sensitivity and specificity. The tumoral signature displayed the best performance, with area under the ROC curves (AUC) of 0.948 (0.903-0.993) in the training cohort and 0.827 (0.667-0.988) in the validation cohort. In the IDH subgroups, the AUCs of the tumoral signature ranged from 0.750 to 0.940. CONCLUSION: The MRI-based radiomic signature is reliable for noninvasive evaluation of TERT promoter mutations in LGG regardless of the IDH status. The inclusion of peri-tumoral area did not significantly improve the performance.

2.
Genet Test Mol Biomarkers ; 24(5): 230-238, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32267777

RESUMO

Background and Objective: Recently, AMP-activated protein kinase (AMPK) signaling was confirmed to be intimately associated with atherosclerosis. Evidence indicates that genetic susceptibility plays an important role in the etiology of symptomatic intracranial atherosclerotic stenosis (sICAS), however few genes have been pinpointed being etiologically associated. This study investigated possible links between single nucleotide polymorphisms (SNPs) of AMPK-related genes and sICAS in Han Chinese subjects. Methods: Target gene sequencing was carried out in 400 sICAS Han Chinese patients and 1007 healthy controls for 11 AMPK pathway-related genes. Chi-squared testing and multiple logistic regression in dominant, recessive, and additive models were used to evaluate the association between SNPs and risk of sICAS. Bonferroni corrections were performed with a p < (0.05/44 = 0.0011) as statistically significant. Further subgroup data analyses was conducted using chi-squared or t-tests. Results: There were 44 common variants of 11 candidate genes distributed differently between sICAS patients and healthy controls, among which the INSR rs78312382 SNP remained significant even after a Bonferroni correction. Logistic regression analysis showed that rs78312382 was significantly associated with the risk of sICAS in both dominant and additive models (pBonferroni = 7.874e-5 and 0.000506, respectively), with the A allele being much more prevalent in the sICAS group (p = 0.000404). Conclusions: Variants of the INSR rs7831282 locus may play an important role in the development of sICAS among the Han Chinese with the A allele being a risk factor and a potential biomarker for this illness.

3.
J Mater Chem B ; 8(3): 438-446, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31833531

RESUMO

Two novel Ru(ii) polypyridyl complexes bearing imidazo-phenanthroline conjugated hydroxybenzoic acid groups were designed to enhance the tumor targeting ability as photosensitizers for photodynamic therapy. [Ru(bpy)2(phcpip)] (ClO4)2 (Ru-1) and [Ru(bpy)2(ohcpip)] (ClO4)2 (Ru-2) (bpy = 2,2'-bipyridine; phcpip = 2-(3-carboxyl-4-hydroxyphenyl) imidazo [4,5-f]phenanthroline; ohcpip = 2-(2-hydroxyl-3-carboxyphenyl) imidazo [4,5-f] [1,10] phenanthroline) were synthesized and their photodynamic antitumor activities were investigated. Both complexes displayed high photocytotoxicity toward cancerous cell lines HepG2, A549, MCF-7, and MDA-MB-231, but low photocytotoxicity toward normal cell lines GES-1 and Huvec. They were mainly localized at the nucleus of HepG2 cells after 24 h incubation, arrested the cell cycle at the G2/M phase and induced cancer cell apoptosis through reactive oxygen species (ROS) mediated pathways. Tumor targeting of the complexes is attributed to stronger molecular binding to DNA.

4.
Int J Nanomedicine ; 14: 8611-8626, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31802873

RESUMO

Background: Bacterial resistance to antibiotics is a persistent and intractable problem. The sapogenin isolated from the seeds of Camellia oleifera can inhibit antibiotic-resistant bacteria after structural modification. Purpose: This study aims to improve sapogenin's antibacterial activity and avoid bacterial resistance based on nano-preparation with photo responsiveness. Methods: The liposome shell material of carboxymethyl chitosan-phosphatidyl ethanolamine (CMC-PE) was prepared using amidation reaction, and photo-responsive cationic (PCC) liposomes containing Camellia sapogenin derivative (CSD) and photosensitizer pheophorbide-a were prepared by film dispersion method. Encapsulation efficiency, drug loading, zeta potential, particle size distribution, morphology and stability of the PCC liposomes were determined by HPLC, particle size analyzer, transmission electron microscopy (TEM) and fluorescence microscopy. Photo-responsive release of CSD in the PCC liposomes was determined by laser (0.5 mW/cm2) at 665 nm. Antibacterial activity of the PCC liposomes with or without irradiation was analyzed by MIC50, MBC, MBIC50, and bacterial morphology to evaluate the antibacterial effects on amoxicillin resistant Escherichia coli and Staphylococcus aureus. Results: Size distribution, zeta potential, encapsulation efficiency and drug loading of the PCC liposomes were 189.23 ± 2.12 nm, 18.80 ± 1.57 mV, 83.52 ± 1.53% and 2.83 ± 0.05%, respectively. The PCC liposomes had higher storage stability and gastrointestinal stability, and no obvious hemolytic toxicity to rabbit red blood cells and no cytotoxicity after incubation with Hela cells. The photosensitizer pheophorbide-a was uniformly dispersed in the phospholipid layer of the PCC liposomes and increased the CSD release after irradiation. The PCC liposomes could bind to bacteria and impaired their morphology and structure, and had significant bactericidal effect on amoxicillin resistant E. coli and S. aureus. Conclusion: The photo-responsive PCC liposomes are efficient antibacterial agents for avoidance of bacterial resistance against antibiotics.


Assuntos
Antibacterianos/farmacologia , Camellia/química , Quitosana/análogos & derivados , Fármacos Fotossensibilizantes/farmacologia , Sapogeninas/farmacologia , Animais , Cátions/farmacologia , Morte Celular/efeitos dos fármacos , Quitosana/síntese química , Quitosana/química , Quitosana/farmacologia , Liberação Controlada de Fármacos , Escherichia coli/efeitos dos fármacos , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Lipossomos , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Fosfatidiletanolaminas/síntese química , Fosfatidiletanolaminas/química , Espectroscopia de Prótons por Ressonância Magnética , Coelhos , Staphylococcus aureus/efeitos dos fármacos , Eletricidade Estática
5.
Front Neurol ; 10: 1228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803136

RESUMO

Background: Adipokines have been proven to be associated with atherosclerotic diseases such as ischemic stroke and coronary heart disease. The role of novel adipokines in the development of symptomatic intracranial atherosclerotic stenosis (sICAS) and extracranial atherosclerotic stenosis (sECAS) has not yet been investigated. This study aimed to evaluate the plasma levels of novel adipokines in patients with sICAS and sECAS and their associations with the prognosis of sICAS groups. Methods: A total of 134 patients with acute ischemic stroke attribute to large-artery atherosclerosis (LAA) and 66 age- and sex-matched controls without atherosclerotic stenosis (NCAS) were included in this study. The LAA group was further sub-classified as sICAS (n = 102) and sECAS (n = 32) according to the location of atherosclerosis. Demographics, clinical parameters, angiographical features and plasma levels of novel adipokines (apelin, visfatin, omentin, RBP-4) were assayed and compared among groups. Results: LAA patients had significantly lower levels of omentin [39.92 (30.74-52.61) ng/ml vs. 54.42 (34.73-79.91) ng/ml, P < 0.001] and visfatin [11.32 (7.62-16.44) ng/ml vs. 13.01 (9.46-27.54) ng/ml, P < 0.001] than those in the NCAS group. Multiple logistic regression analysis identified that the lowest tertile of omentin was independently associated with LAA (OR, 3.423; 95% CI, 1.267-9.244, when referenced to the third tertile). Levels of omentin, visfatin and RBP-4 showed no significant difference between sICAS and sECAS groups. However, median concentrations of apelin were lower in sECAS [84.94 (46.88-130.41) ng/mL) than in sICAS [118.64 (93.22-145.08) ng/mL, P = 0.002] and NCAS [114.38 (80.56-162.93) ng/mL, P = 0.004]. Logistic regression analysis showed that the lowermost tertile of apelin was independently associated with sECAS (OR, 5.121; 95% CI, 1.597-16.426) when adjusted for risk factors. As for sICAS patients, spearman coefficient analysis showed no significant correlation between these four adipokines and the severity of sICAS or the number of vessels with intracranial stenoses. Patients with severe stroke had lower levels of apelin (P = 0.005), while the other three adipokines showed no such difference. During follow up, no difference was found between these four novel adipokines and short- and long-term outcome of sICAS. Conclusions: Lower levels of omentin are independent biomarkers of LAA while low apelin plasma levels seem to be risk factors of sECAS.

6.
BMC Complement Altern Med ; 19(1): 158, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272505

RESUMO

BACKGROUND: Wumei Pill (WMP), a famous herbal formula, has been widely used to treat digestive system diseases in clinical practice in China for centuries. We have found a correlation between the indications of WMP and the typical symptoms of pancreatic neoplasms. However, the pharmacological mechanisms of WMP still remain unknown. METHODS: In the present work, we used a network pharmacological method to predict its underlying complex mechanism of treating pancreatic neoplasms. Firstly, we obtained relative compounds of WMP based on TCMSP database, TCM database@Taiwan and TCMID database and collected potential targets of these compounds by target fishing. Then we built the pancreatic neoplasms target database by CTD, TTD, PharmGKB. Based on the matching results between WMP potential targets and pancreatic neoplasms targets, we built a PPI network to analyze the interactions among these targets and screen the hub targets by topology. Furthermore, DAVID bioinformatics resources were utilized for the enrichment analysis on GO_BP and KEGG. RESULTS: A total of 80 active ingredients and 77 targets of WMP were picked out. The results of DAVID enrichment analysis indicated that 58 cellular biological processes (FDR < 0.01) and 17 pathways (FDR < 0.01) of WMP mostly participated in the complex treating effects associated with proliferation, apoptosis, inflammatory response and angiogenesis. Moreover, 17 hub nodes of WMP (PTGS2, BCL2, TP53, IL6, MAPK1, EGFR, EGF, CASP3, JUN, MAPK8, MMP9, VEGFA, TNF, MYC, AKT1, FOS and TGFB1) were recognized as potential targets of treatments, implying the underlying mechanisms of WMP acting on pancreatic neoplasms. CONCLUSION: WMP could alleviate the symptoms of pancreatic neoplasms through the molecular mechanisms predicted by network pharmacology. This study proposes a strategy to elucidate the mechanisms of Traditional Chinese Medicine (TCM) at the level of network pharmacology.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Células CACO-2 , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Mapas de Interação de Proteínas
7.
Front Oncol ; 9: 576, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312613

RESUMO

Targeted drug delivery could increase the efficacy of chemotherapy, however, a plethora of obstacles exist in the current targeted delivery designs. In this study, we introduce a novel avenue of targeted drug delivery using electro-acupuncture and evaluate its effect on the distribution of paclitaxel in a breast cancer mouse model. Our results show that electro-acupuncture intervention significantly increased the intratumoral concentration of paclitaxel. The mice in acupuncture group showed shorter t max, longer t 1/2 and higher AUC of paclitaxel as compared with that in paclitaxel-only group. Moreover, we found that the acupuncture intervention significantly induced cell apoptosis in tumors. The levels of COL IV and α-SMA increased in tumors of acupuncture group. The negative tumor metastasis biomarker, NM23, was significantly upregulated in tumors of mice in acupuncture group. Our results suggest that acupuncture intervention around the tumor area increases the local concentration of chemotherapeutic agents. The targeted effect of acupuncture is achieved by altering tumor microvasculature and microenvironment. Therefore, combined therapy of acupuncture with chemotherapeutic agents is promising in improving cancer treatment efficacy.

8.
Colloids Surf B Biointerfaces ; 182: 110352, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306831

RESUMO

Psoriasis is a severe disfiguring skin disease affecting approximately 3% of people worldwide and negatively affecting their daily lives. The pathogenesis of psoriasis is complicated, and typical therapeutic strategies for psoriasis mainly focus on anti-inflammation. Considering the side effects, withdrawal rebound, high cost, and many other disadvantages of existing treatments, we developed a new topical therapeutic formulation consisting of niosomes loaded with celastrol, a triterpenoid extracted from Tripterygium. Celastrol niosomes were prepared by the thin film hydration method and probe sonication. The niosomes were composed of Span 20, Span 60, and cholesterol at a weight ratio of 3:1:1. The particle size of the niosomes was approximately 147 nm, with yield of up to 90%. Celastrol niosomes showed improved in vitro permeation ability compared to the raw drug. In our in vivo study, celastrol niosomes effectively alleviated erythema and scaling on the dorsal skin of psoriasis mouse models. Spleen weight and the levels of cytokines, including IL-22, IL-23, and IL-17, decreased after the treatment, indicating the high therapeutic potential of this formulation for psoriasis. In conclusion, encapsulation of celastrol by niosomes increased the water-solubility and permeation of celastrol into the skin, significantly improving its anti-psoriasis activity in mice.


Assuntos
Anti-Inflamatórios/farmacologia , Lipossomos/química , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Tripterygium/química , Triterpenos/farmacologia , Administração Cutânea , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/metabolismo , Biomarcadores/metabolismo , Colesterol/química , Modelos Animais de Doenças , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Feminino , Hexoses/química , Imiquimode/farmacologia , Indutores de Interferon/farmacologia , Interleucinas/antagonistas & inibidores , Interleucinas/imunologia , Interleucinas/metabolismo , Lipossomos/administração & dosagem , Lipossomos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/química , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Pele/imunologia , Pele/patologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Triterpenos/isolamento & purificação , Triterpenos/metabolismo
9.
Bioorg Chem ; 90: 103085, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279233

RESUMO

A series of iron(III), manganese(III) and copper(III) mono-hydroxyl corrole complexes had been prepared and well characterized by UV-vis, 1H NMR, 19F NMR and HR-MS. These metallocorroles may bind to CT-DNA through external binding mode. Metallocorrole Fe-2c exhibited significant phototoxicity and low toxicity toward A549 tumor cells. While manganese (III) and copper (III) corroles showed hypotoxicity to A549, MCF-7 and HepG-2 tumor cells, whether under dark or illumination conditions. All tested metallocorroles exhibited non-toxicity to human normal cells (GES-1) with or without irradiation at 625 nm. Cell cycle analysis indicated that metallocorrole Fe-2c arrested the cell cycle at G2/M phase and increased the Sub-G1 phase in A549 cell lines. It was mainly localized at mitochondria and could significantly reduce mitochondrial membrane potential after photodynamic treatment, which would further induce tumor cell apoptosis.

10.
J Chem Inf Model ; 59(7): 3110-3119, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31268306

RESUMO

Machine learning techniques are being applied in quantifying structure-property relationships for a wide variety of materials, where the properly represented materials play key roles. Although algorithms for representation learning are extensively studied, their applications to domain-specific areas, such as polymers, are limited largely due to the lack of benchmark databases. In this work, we investigate different types of polymer representations, including Morgan fingerprint (MF), molecular embedding (ME), and molecular graph (MG), based on the benchmark database from a subset of the well-known web-based polymer databases, PolyInfo. We evaluate the quality of different polymer representations via quantifying the relationships between the representations and polymer properties, including density, melting temperature, and glass transition temperature. Different representation learning schemes for MEs, such as supervised learning, semisupervised learning, and transfer learning, are investigated. In supervised learning, only labeled molecules in our benchmark database are used for representation learning, in semisupervised learning, both labeled and unlabeled molecules in our benchmark database are used, and in transfer learning, molecules from an external database that is different from the benchmark database are used for representation learning. It is found that ME (with the R2 of 0.724 in the density case, 0.684 in the melting temperature case, and 0.865 in the glass transition temperature case) outperforms the other representations for structure-property relationship quantification in all cases studied, and MG (with the R2 of 0.260 in the density case, -0.149 in the melting temperature case, and 0.711 in the glass transition case) is shown to be much inferior to ME and MF (with the R2 of 0.562 in the density case, 0.645 in the melting temperature case, and 0.849 in the glass transition case), likely due to the relatively small volumes of training data available. For MEs, it is found that the similarities of substructure MEs under different learning schemes (e.g., SL, SSL, and TL) are differently estimated, thus leading to different performance scores in structure-property relation quantification. Combinations of MEs show little effect on predictive performance when comparing to the single MEs in the corresponding regression tasks, proving no information gain in mixing MEs.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31362144

RESUMO

Piwi-interacting RNA (piRNA) pathway is essential for germline specification, gametogenesis, and genome integrity as defense against transposable elements (TEs). This pathway has been suggested to have undergone rapid adaptive evolution in spite of its conserved role in TE silencing. However, with diverse sexual development patterns, piRNA pathway evolution and its adaptation to transposon activity in teleost lineages remain less known. This study illustrated the evolutionary significance of piRNA pathway via a systematic comparative analysis on diverse teleosts, including flatfish lineages. Molecular evolution of piRNA pathway and microRNA/small interfering RNA pathway genes indicated a faster evolution of piRNA pathway in teleosts than in mammals. Positive selection was detected at the PAZ (Piwi-Argonaute-Zwille) domain involved in Piwi-piRNA interaction, thereby suggesting that the amino acid substitutions were adaptive to their functions in teleost piRNA pathway. Notably, Piwil1 evolved faster in Japanese flounder than in other teleosts, and the piRNA pathway genes expressed higher in testes than in ovaries. In addition, gonadal transcriptomic analysis revealed male under-represented TE families mainly from DNA transposons, which were the potential targets of the complex formed by male-biased Piwi genes and male over-represented piRNAs in Japanese flounder testes. The potential piRNA-TE regulatory relationships suggested that the rapidly evolved piRNA pathway in Japanese flounder was likely involved in the regulation of transposon activity in germlines and could play important roles in Japanese flounder gonadal development and spermatogenesis.


Assuntos
Elementos de DNA Transponíveis , Linguado/genética , RNA Interferente Pequeno/genética , Animais , Proteínas Argonauta/genética , Evolução Molecular , Feminino , Masculino , Filogenia
12.
Angew Chem Int Ed Engl ; 58(35): 12096-12101, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31246340

RESUMO

The photophysical process of localized surface plasmon resonance (LSPR) is, for the first time, exploited for broadband photon harvesting in photo-regulated controlled/living radical polymerization. Efficient macromolecular synthesis was achieved under illumination with light wavelengths extending from the visible to the near-infrared regions. Plasmonic Ag nanostructures were in situ generated on Ag3 PO4 photocatalysts in a reversible addition-fragmentation chain transfer (RAFT) system, thereby promoting polymerization of various monomers following a LSPR-mediated electron transfer mechanism. Owing to the LSPR-enhanced broadband photon harvesting, high monomer conversion (>99 %) was achieved under natural sunlight within 0.8 h. The deep penetration of NIR light enabled successful polymerization with reaction vessels screened by opaque barriers. Moreover, by trapping active oxygen species generated in the photocatalytic process, polymerization could be implemented without pre-deoxygenation.

13.
BMC Vet Res ; 15(1): 110, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971257

RESUMO

BACKGROUND: Bovine respiratory syncytial virus (BRSV) is a common pathogen causing respiratory disease in cattle and a significant contributor to the bovine respiratory disease (BRD) complex. BRSV is widely distributed around the world, causing severe economic losses. This study we established a new molecular detection method of BRSV pathogen NanoPCR attributed to the combination of nano-particles in traditional PCR (Polymerase chain reaction) technology. RESULTS: In this study, the BRSV NanoPCR assay was developed, and its specificity and sensitivity were investigated. The results showed that no cross-reactivity was observed for the NanoPCR assay for related viruses, including the infectious bovine rhinotracheitis virus (IBRV), bovine viral diarrhea virus (BVDV), and bovine parainfluenza virus type 3 (BPIV3), and the assay was more sensitive than the conventional PCR assay, with a detection limit of 1.43 × 102 copies recombinant plasmids per reaction, compared with 1.43 × 103 copies for conventional PCR analysis. Moreover, thirty-nine clinical bovine samples collected from two provinces in North-Eastern China, 46.15% were determined BRSV positive by our NanoPCR assay, compared with 23.07% for conventional PCR. CONCLUSIONS: This is the first report to demonstrate the application of a NanoPCR assay for the detection of BRSV. The sensitive and specific NanoPCR assay developed in this study can be applied widely in clinical diagnosis and field surveillance of BRSV infection.


Assuntos
Doenças dos Bovinos/virologia , Nanopartículas/virologia , Reação em Cadeia da Polimerase/métodos , Infecções por Vírus Respiratório Sincicial/veterinária , Vírus Sincicial Respiratório Bovino , Animais , Bovinos , Doenças dos Bovinos/diagnóstico , DNA Viral/genética , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Bovino/genética , Sensibilidade e Especificidade
14.
World J Gastroenterol ; 25(14): 1741-1752, 2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31011258

RESUMO

BACKGROUND: Patients with hypothalamic-pituitary disease have the feature of central obesity, insulin resistance, and dyslipidemia, and there is increased prevalence of liver dysfunction consistent with non-alcoholic fatty liver disease (NAFLD) in this population. The causes of hypopituitarism in the reported studies varied and combined pituitary hormone deficiency including central diabetes insipidus is much common in this population. This retrospective cross-sectional study was performed to analyze the clinical characteristics and related factors with NAFLD and cirrhosis in Chinese adult hypopituitary/panhypopituitary patients. AIM: To analyze the clinical characteristics of and related risk factors for NAFLD in Chinese adult hypopituitary patients. METHODS: Adult Chinese patients with hypopituitarism and/or panhypopituitarism were enrolled at the Pituitary Center of Peking Union Medical College Hospital between August 2012 and April 2018. According to abdominal ultrasonography, these patients were divided into an NAFLD (-) group and an NAFLD (+) group, and the latter was further divided into an NAFLD group and a cirrhotic group. The data, such as patient characteristics, diagnosis, and treatment, were extracted from medical records, and statistical analysis was performed. RESULTS: A total of 36 male and 14 female adult Chinese patients with hypopituitarism were included in this retrospective study; 43 (87.0%) of these patients exhibited growth hormone (GH) deficiency, and 39 (78.3%) had diabetes insipidus. A total of 27 (54.0%) patients were diagnosed with NAFLD, while seven patients were cirrhotic. No significant differences were noted in serum GH or insulin-like growth factor 1 among patients with cirrhosis, subjects with NAFLD, and those without NAFLD. However, plasma osmolality and serum sodium concentration of the cirrhotic patients were 314.9 mOsm/kgH2O and 151.0 mmol/L, respectively, which were significantly higher than those of the NAFLD patients (P = 0.036 and 0.042, respectively). Overweight/obesity and insulin resistance were common metabolic disorders in this population. The body mass index (BMI) and homeostasis model assessment of insulin resistance parameters of the cirrhotic patients were 27.7 kg/m2 and 9.57, respectively, which were significantly higher than those of the patients without NAFLD (P = 0.011 and 0.044, respectively). A correlation analysis was performed, and fasting insulin concentration was positively associated with plasma osmolality in patients with NAFLD, after adjusting for gender, age, and BMI (r = 0.540, P = 0.046), but no correlation was noted in patients without NAFLD. CONCLUSION: NAFLD is common in patients with hypopituitarism. Plasma osmolality and serum sodium levels of hypopituitary patients with cirrhosis are higher than those of subjects with NAFLD, and fasting insulin concentration is positively associated with plasma osmolality in patients with NAFLD, which suggests that hyperosmolality might be a contributor to the worsening of NAFLD in hypopituitary patients.


Assuntos
Hipopituitarismo/metabolismo , Cirrose Hepática/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Adulto , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Hipopituitarismo/sangue , Insulina/sangue , Cirrose Hepática/sangue , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Concentração Osmolar , Plasma/química , Prevalência , Estudos Retrospectivos , Fatores de Risco , Sódio/sangue , Adulto Jovem
15.
J Biol Chem ; 294(18): 7472-7487, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30885942

RESUMO

A critical function of the PTEN-induced kinase 1 (PINK1)-Parkin pathway is to mediate the clearing of unhealthy or damaged mitochondria via mitophagy. Loss of either PINK1 or Parkin protein expression is associated with Parkinson's disease. Here, using a high-throughput screening approach along with recombinant protein expression and kinase, immunoblotting, and immunofluorescence live-cell imaging assays, we report that celastrol, a pentacyclic triterpenoid isolated from extracts of the medicinal plant Tripterygium wilfordii, blocks recruitment pof Parkin to mitochondria, preventing mitophagy in response to mitochondrial depolarization induced by carbonyl cyanide m-chlorophenylhydrazone or to gamitrinib-induced inhibition of mitochondrial heat shock protein 90 (HSP90). Celastrol's effect on mitophagy was independent of its known role in microtubule disruption. Instead, we show that celastrol suppresses Parkin recruitment by inactivating PINK1 and preventing it from phosphorylating Parkin and also ubiquitin. We also observed that PINK1 directly and strongly associates with TOM20, a component of the translocase of outer mitochondrial membrane (TOM) machinery and relatively weak binding to another TOM subunit, TOM70. Moreover, celastrol disrupted binding between PINK1 and TOM20 both in vitro and in vivo but did not affect binding between TOM20 and TOM70. Using native gel analysis, we also show that celastrol disrupts PINK1 complex formation upon mitochondrial depolarization and sequesters PINK1 to high-molecular-weight protein aggregates. These results reveal that celastrol regulates the mitochondrial quality control pathway by interfering with PINK1-TOM20 binding.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Proteínas Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Tripterygium/química , Triterpenos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Células HeLa , Humanos , Hidrazonas/antagonistas & inibidores , Hidrazonas/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microtúbulos/metabolismo , Polimerização , Ligação Proteica , Ubiquitina-Proteína Ligases/metabolismo
17.
Int J Neurosci ; 129(7): 635-641, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30251575

RESUMO

BACKGROUND: It is uncertain that the effect of free triiodothyronine (FT3) within normal ranges on initial severity and early functional outcomes in acute ischemic stroke (AIS) patients with Intracranial Atherosclerotic Stenosis (ICAS). The predictive values of white blood cell (WBC) and FT3 are also unclear in symptomatic ICAS (sICAS) patients. METHODS: We consecutively reviewed 848 ischemic stroke patients admitted into Xiangya Hospital within 72 h after symptom onset. sICAS was defined as AIS patient with degree of ICAS ≥50% proved by magnetic resonance angiography, computed tomography angiography or digital subtraction angiography. WBC and FT3 were assessed within 24 h after admission. Neurological severity was evaluated on admission using the National Institutes of Health Stroke Scale (NIHSS). Stroke outcomes were defined by the modified Rankin Scale (mRS) on the 14th day after admission. RESULTS: Logistic regression analysis showed that hypertension, lower FT3 and higher WBC concentrations independently associated with severe stroke [FT3 (odds ratio(OR) = 0.543, 95% confidence interval(95% CI): 0.383-0.769); hypertension (OR = 0.436, 95% CI: 0.238-0.800); WBC (OR = 1.17; 95% CI:1.041-1.316]. Besides, lower FT3, higher FT4, higher WBC and higher plasma glucose concentrations independently associated with unfavorable outcomes [FT3 (OR = 0.460; 95% CI: 0.306-0.690); FT4 (OR = 1.151; 95% CI: 1.055-1.255); WBC (OR = 1.178; 95% CI: 1.039-1.334); Plasma glucose (OR = 1.160; 95% CI: 1.002-1.342)]. CONCLUSIONS: Lower FT3 levels within normal ranges and higher WBC count are independently associated with the severity and early poor prognosis of sICAS simultaneously, FT3 and WBC count might be important biomarkers for sICAS patients.


Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , Arteriosclerose Intracraniana/complicações , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Tri-Iodotironina/sangue , Isquemia Encefálica/complicações , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/complicações
18.
Int J Med Sci ; 15(14): 1702-1712, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30588194

RESUMO

Cancer-testis antigen MAGEA3, being restrictedly expressed in testis and various kinds of tumors, has long been considered as an ideal target for immunotherapy. In this study, we report that MAGEA3 interacts with STAT1 and regulates the expression of tyrosine phosphorylated STAT1 (pY-STAT1) in tumor cells. We show that pY-STAT1 is significantly up-regulated when MAGEA3 is silenced by MAGEA3-specific siRNA. RNA sequencing analysis identified 274 STAT1-related genes to be significantly altered in expression level in MAGEA3 knockdown cells. Further analysis of these differentially expressed genes with GO enrichment and KEGG pathway revealed that they are mainly enriched in plasma membrane, extracellular region and MHC class I protein complex, and involved in the interferon signaling pathways, immune response, antigen presentation and cell chemotaxis. The differentially expressed genes associated with chemokines, antigen presentation and vasculogenic mimicry formation were validated by biological experiments. Matrigel matrix-based tube formation assay showed that silencing MAGEA3 in tumor cells impairs tumor vasculogenic mimicry formation. These data indicate that MAGEA3 expression in tumor cells is associated with immune cells infiltration into tumor microenvironment and anti-tumor immune responses, implying that it may play an important role in tumor immune escape. Our findings reveal the potential impact of MAGEA3 on the immunosuppressive tumor microenvironment and will provide promising strategies for improving the efficacy of MAGEA3-targeted immunotherapy.


Assuntos
Antígenos de Neoplasias/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/imunologia , Fator de Transcrição STAT1/metabolismo , Evasão Tumoral , Microambiente Tumoral/imunologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Neoplasias/patologia , Fosforilação , RNA Interferente Pequeno/metabolismo , Fator de Transcrição STAT1/imunologia , Transdução de Sinais/imunologia , Tirosina/metabolismo , Regulação para Cima
19.
Nano Lett ; 18(12): 7469-7477, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30412411

RESUMO

We present experimental measurements of the thermal boundary conductance (TBC) from 78-500 K across isolated heteroepitaxially grown ZnO films on GaN substrates. This data provides an assessment of the underlying assumptions driving phonon gas-based models, such as the diffuse mismatch model (DMM), and atomistic Green's function (AGF) formalisms used to predict TBC. Our measurements, when compared to previous experimental data, suggest that TBC can be influenced by long wavelength, zone center modes in a material on one side of the interface as opposed to the '"vibrational mismatch"' concept assumed in the DMM; this disagreement is pronounced at high temperatures. At room temperature, we measure the ZnO/GaN TBC as 490[+150,-110] MW m-2 K-1. The disagreement among the DMM and AGF, and the experimental data at elevated temperatures, suggests a non-negligible contribution from other types of modes that are not accounted for in the fundamental assumptions of these harmonic based formalisms, which may rely on anharmonicity. Given the high quality of these ZnO/GaN interfaces, these results provide an invaluable, critical, and quantitative assessment of the accuracy of assumptions in the current state of the art computational approaches used to predict phonon TBC across interfaces.

20.
Int J Nanomedicine ; 13: 5625-5635, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271151

RESUMO

Background: As an immune-mediated skin disease, psoriasis encounters therapeutic challenges on topical drug development due to the unclear mechanism, and complicated morphological and physiological changes in the skin. Methods: In this study, imiquimod-induced psoriatic mouse skin (IMQ-psoriatic skin) was chosen as the in vitro pathological model to explore the penetration behaviors of drugs and nanoparticles (NPs). Results: Compared with normal skin, significantly higher penetration and skin accumulation were observed in IMQ-psoriatic skin for all the three model drugs. When poorly water-soluble curcumin was formulated as NPs that were subsequently loaded in gel, the drug's penetration and accumulation in both normal and IMQ-psoriatic skins were significantly improved, in comparison with that of the curcumin suspension. Interestingly, the NPs' size effect, in terms of their penetration and accumulation behaviors, was more pronounced for IMQ-psoriatic skin. Furthermore, by taking three sized FluoSpheres® as model NPs, confocal laser scanning microscopy demonstrated that the penetration pathways of NPs no longer followed the hair follicles channels, instead they were more widely distributed in the IMQ-psoriatic skin. Conclusion: In conclusion, the alternation of the IMQ-psoriatic skin structure will lead to the enhanced penetration of drug and NPs, and should be considered in topical drug formulation and further clinical practice for psoriasis therapy.


Assuntos
Aminoquinolinas/toxicidade , Anti-Inflamatórios não Esteroides/administração & dosagem , Curcumina/administração & dosagem , Nanopartículas/administração & dosagem , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Adjuvantes Imunológicos/toxicidade , Animais , Anti-Inflamatórios não Esteroides/química , Curcumina/química , Modelos Animais de Doenças , Feminino , Imiquimode , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Psoríase/induzido quimicamente , Psoríase/patologia , Pele/patologia
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