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1.
J Phys Chem A ; 128(5): 829-839, 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38266177

RESUMO

Global-minimum optimizations combined with relativistic quantum chemistry calculations have been performed to characterize the ground-state stable structures of four titled compounds and to analyze the bonding properties. Th2C8 was identified as being a ThC4-Th(C2)2 structure, U2C8 has been found to favor the U-U(C8) structure, and both Th3C8 and U3C8 adopt the (AnC3)2-(AnC2) structure. Then, the wave function analyses reveal that the interactions between the Th 7s-based orbital and the σg molecular orbital of the C2 unit compensate for the excitation energy of 7s16d1 → 6d2 and lead to the stabilization of two Th(IV)s in the ThC4-Th(C2)2 structure. It also reveals that the U species exhibit magnetic exchange coupling behavior in UxC8, for instance, as seen in the direct interaction of U2C8 and the superexchange pathway of U3C8, which effectively stabilizes their low-spin states. This interpretation indicates that the geometric and electronic structures of AnxC8 species are largely influenced by the local magnetic moment and spin correlation.

2.
FASEB J ; 36(3): e22213, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35192728

RESUMO

High-risk solid tumors continue to pose a tremendous therapeutic challenge due to multidrug resistance. Biological mechanisms driving chemoresistance in high-risk primary and recurrent disease are distinct: in newly diagnosed patients, non-response to therapy is often associated with a higher level of tumor "stemness" paralleled by overexpression of the ABCG2 drug efflux pump, whereas in tumors relapsing after non-curative therapy, poor drug sensitivity is most commonly linked to the dysfunction of the tumor suppressor protein, p53. In this study, we used preclinical models of aggressive neuroblastoma featuring these characteristic mechanisms of primary and acquired drug resistance to experimentally evaluate a macromolecular prodrug of a structurally enhanced camptothecin analog, SN22, resisting ABCG2-mediated export, and glucuronidation. Together with extended tumor exposure to therapeutically effective drug levels via reversible conjugation to Pluronic F-108 (PF108), these features translated into rapid tumor regression and long-term survival in models of both ABCG2-overexpressing and p53-mutant high-risk neuroblastomas, in contrast to a marginal effect of the clinically used camptothecin derivative, irinotecan. Our results demonstrate that pharmacophore enhancement, increased tumor uptake, and optimally stable carrier-drug association integrated into the design of the hydrolytically activatable PF108-[SN22]2  have the potential to effectively combat multiple mechanisms governing chemoresistance in newly diagnosed (chemo-naïve) and recurrent forms of aggressive malignancies. As a macromolecular carrier-based delivery system exhibiting remarkable efficacy against two particularly challenging forms of high-risk neuroblastoma, PF108-[SN22]2 can pave the way to a robust and clinically viable therapeutic strategy urgently needed for patients with multidrug-resistant disease presently lacking effective treatment options.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neuroblastoma/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Inibidores da Topoisomerase I/uso terapêutico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Camptotecina/análogos & derivados , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Poloxâmero/química , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Inibidores da Topoisomerase I/química
3.
J Chem Phys ; 158(2): 024203, 2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36641419

RESUMO

A rapid and accurate diagnostic modality is essential to prevent the spread of SARS-CoV-2. In this study, we proposed a SARS-CoV-2 detection sensor based on surface-enhanced Raman scattering (SERS) to achieve rapid and ultrasensitive detection. The sensor utilized spike protein deoxyribonucleic acid aptamers with strong affinity as the recognition entity to achieve high specificity. The spherical cocktail aptamers-gold nanoparticles (SCAP) SERS substrate was used as the base and Au nanoparticles modified with the Raman reporter molecule that resonates with the excitation light and spike protein aptamers were used as the SERS nanoprobe. The SCAP substrate and SERS nanoprobes were used to target and capture the SARS-CoV-2 S protein to form a sandwich structure on the Au film substrate, which can generate ultra-strong "hot spots" to achieve ultrasensitive detection. Analysis of SARS-CoV-2 S protein was performed by monitoring changes in SERS peak intensity on a SCAP SERS substrate-based detection platform. This assay detects S protein with a LOD of less than 0.7 fg mL-1 and pseudovirus as low as 0.8 TU mL-1 in about 12 min. The results of the simulated oropharyngeal swab system in this study indicated the possibility of it being used for clinical detection, providing a potential option for rapid and accurate diagnosis and more effective control of SARS-CoV-2 transmission.


Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , COVID-19 , Nanopartículas Metálicas , Humanos , Glicoproteína da Espícula de Coronavírus , Nanopartículas Metálicas/química , Ouro/química , Análise Espectral Raman/métodos , COVID-19/diagnóstico , SARS-CoV-2 , Aptâmeros de Nucleotídeos/química , Técnicas Biossensoriais/métodos
4.
Anal Chem ; 94(51): 17795-17802, 2022 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-36511436

RESUMO

Addressing the spread of coronavirus disease 2019 (COVID-19) has highlighted the need for rapid, accurate, and low-cost diagnostic methods that detect specific antigens for SARS-CoV-2 infection. Tests for COVID-19 are based on reverse transcription PCR (RT-PCR), which requires laboratory services and is time-consuming. Here, by targeting the SARS-CoV-2 spike protein, we present a point-of-care SERS detection platform that specifically detects SARS-CoV-2 antigen in one step by captureing substrates and detection probes based on aptamer-specific recognition. Using the pseudovirus, without any pretreatment, the SARS-CoV-2 virus and its variants were detected by a handheld Raman spectrometer within 5 min. The limit of detection (LoD) for the pseudovirus was 124 TU µL-1 (18 fM spike protein), with a linear range of 250-10,000 TU µL-1. Moreover, this assay can specifically recognize the SARS-CoV-2 antigen without cross reacting with specific antigens of other coronaviruses or influenza A. Therefore, the platform has great potential for application in rapid point-of-care diagnostic assays for SARS-CoV-2.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , Teste para COVID-19 , Técnicas de Laboratório Clínico/métodos
5.
J Transl Med ; 20(1): 621, 2022 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-36572895

RESUMO

Ophthalmic epidemiology is concerned with the prevalence, distribution and other factors relating to human eye disease. While observational studies cannot avoid confounding factors from interventions, human eye composition and structure are unique, thus, eye disease pathogenesis, which greatly impairs quality of life and visual health, remains to be fully explored. Notwithstanding, inheritance has had a vital role in ophthalmic disease. Mendelian randomization (MR) is an emerging method that uses genetic variations as instrumental variables (IVs) to avoid confounders and reverse causality issues; it reveals causal relationships between exposure and a range of eyes disorders. Thus far, many MR studies have identified potentially causal associations between lifestyles or biological exposures and eye diseases, thus providing opportunities for further mechanistic research, and interventional development. However, MR results/data must be interpreted based on comprehensive evidence, whereas MR applications in ophthalmic epidemiology have some limitations worth exploring. Here, we review key principles, assumptions and MR methods, summarise contemporary evidence from MR studies on eye disease and provide new ideas uncovering aetiology in ophthalmology.


Assuntos
Oftalmopatias , Análise da Randomização Mendeliana , Humanos , Análise da Randomização Mendeliana/métodos , Qualidade de Vida , Causalidade , Oftalmopatias/epidemiologia , Oftalmopatias/genética , Genética Humana , Variação Genética
6.
Hereditas ; 159(1): 20, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35546682

RESUMO

BACKGROUND: Spindle and kinetochore­associated complex subunit 3 (SKA3) has recently been considered a key regulator of carcinogenesis. However, the connection between SKA3 and immune cell infiltration remains unknown. METHODS: The current study investigated the expression mode, prognostic effect, and functional role of SKA3 in different tumors, particularly bladder cancer using numerous databases, comprising TIMER, GEPIA, HPA, UALCAN, PrognoScan, and Kaplan-Meier Plotter. Differentially expressed gene and enrichment analyses were implemented on SKA3 using R packages "edgR" and "clusterProfiler". Immunohistochemistry was further used to validate the expression of SKA3 gene in bladder cancer. Following that, the relevance of SKA3 expression to immune infiltration level in bladder cancer was evaluated using TIMER. RESULTS: Overall, the level of SKA3 expression in tumor tissue significantly increased than in normal tissue. In bladder cancer and other tumors, patients with high SKA3 expression levels had worse overall survival (OS) (p = 0.016), disease-specific survival (DSS) (p = 0.00004), and disease-free survival (DFS) (p = 0.032). Additionally, the major molecular functions for SKA3 included nuclear division, mitotic nuclear division, mitotic sister chromatid segregation, humoral immune response, and cell chemotaxis. Additionally, SKA3 expression was found to be positively associated with enhanced M2 macrophage and T helper (Th) 2 cell infiltration in bladder cancer. CONCLUSIONS: Our study implies that SKA3 contributes to M2 macrophage and Th2 cell polarization by acting as an oncogene in bladder cancer. SKA3 might be a novel biomarker for evaluating prognosis and immune infiltration in bladder cancer.


Assuntos
Neoplasias da Bexiga Urinária , Biomarcadores Tumorais/genética , Proteínas de Ciclo Celular/genética , Humanos , Imuno-Histoquímica , Proteínas Associadas aos Microtúbulos/genética , Prognóstico , Neoplasias da Bexiga Urinária/genética
7.
Int J Mol Sci ; 23(3)2022 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-35163672

RESUMO

Despite the use of intensive multimodality therapy, the majority of high-risk neuroblastoma (NB) patients do not survive. Without significant improvements in delivery strategies, anticancer agents used as a first-line treatment for high-risk tumors often fail to provide clinically meaningful results in the settings of disseminated, recurrent, or refractory disease. By enhancing pharmacological selectivity, favorably shifting biodistribution, strengthening tumor cell killing potency, and overcoming drug resistance, nanocarrier-mediated delivery of topoisomerase I inhibitors of the camptothecin family has the potential to dramatically improve treatment efficacy and minimize side effects. In this study, a structurally enhanced camptothecin analog, SN22, reversibly coupled with a redox-silent tocol derivative (tocopheryl oxamate) to allow its optimally stable encapsulation and controlled release from PEGylated sub-100 nm nanoparticles (NP), exhibited strong NB cell growth inhibitory activity, translating into rapid regression and durably suppressed regrowth of orthotopic, MYCN-amplified NB tumors. The robust antitumor effects and markedly extended survival achieved in preclinical models recapitulating different phases of high-risk disease (at diagnosis vs. at relapse with an acquired loss of p53 function after intensive multiagent chemotherapy) demonstrate remarkable potential of SN22 delivered in the form of a hydrolytically cleavable superhydrophobic prodrug encapsulated in biodegradable nanocarriers as an experimental strategy for treating refractory solid tumors in high-risk cancer patients.


Assuntos
Camptotecina/análogos & derivados , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neuroblastoma/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Tocoferóis/uso terapêutico , Camptotecina/química , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neuroblastoma/patologia , Fatores de Risco , Análise de Sobrevida , Tocoferóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Mol Cell Biochem ; 476(7): 2603-2611, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33656642

RESUMO

Astragaloside IV (AsIV), an active ingredient isolated from traditional Chinese medicine astragalus membranaceus, is beneficial to cardiovascular health. This study aimed to characterize the functional role of AsIV against adriamycin (ADR)-induced cardiomyopathy. Here, healthy rats were treated with ADR and/or AsIV for 35 days. We found that AsIV protected the rats against ADR-induced cardiomyopathy characterized by myocardial fibrosis and cardiac dysfunction. Meanwhile, ADR increased type I and III collagens, TGF-ß, NOX2, and NOX4 expression and SMAD2/3 activity in the left ventricles of rats, while those effects were countered by AsIV through suppressing oxidative stress. Moreover, ADR was found to promote cardiac ferroptosis, whereas administration of AsIV attenuated the process via activating Nrf2 signaling pathway and the subsequent GPx4 expression increasing. These results suggest that AsIV might play a protective role against ADR-induced myocardial fibrosis, which may partly attribute to its anti-ferroptotic action by enhancing Nrf2 signaling.


Assuntos
Doxorrubicina/farmacologia , Ferroptose/efeitos dos fármacos , Miocárdio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Saponinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Proteínas Musculares/biossíntese , Miocárdio/patologia , Ratos , Ratos Sprague-Dawley
9.
Proc Natl Acad Sci U S A ; 115(25): 6375-6380, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29866833

RESUMO

The origin of dramatic slowing down of dynamics in metallic glass-forming liquids toward their glass transition temperatures is a fundamental but unresolved issue. Through extensive molecular dynamics simulations, here we show that, contrary to the previous beliefs, it is not local geometrical orderings extracted from instantaneous configurations but the intrinsic correlation between configurations that captures the structural origin governing slow dynamics. More significantly, it is demonstrated by scaling analyses that it is the correlation length extracted from configuration correlation rather than dynamic correlation lengths that is the key to determine the drastic slowdown of supercooled metallic liquids. The key role of the configuration correlation established here sheds important light on the structural origin of the mysterious glass transition and provides an essential piece of the puzzle for the development of a universal theoretical understanding of glass transition in glasses.

10.
Sensors (Basel) ; 21(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067166

RESUMO

Migration imaging is a key step in tunnel seismic data processing. Due to the limitation of tunnel space, tunnel seismic data are small-quantity, multi-component, and have a small offset. Kirchhoff migration based on the ray theory is limited to the migration aperture and has low migration imaging accuracy. Kirchhoff migration can no longer meet the requirements of high-precision migration imaging. The reverse time migration (RTM) method is used to realize cross-correlation imaging by reverse-time recursion principle of the wave equation. The 3-D RTM method cannot only overcome the effect of small offset, but also realize multi-component data imaging, which is the most accurate migration method for tunnel seismic data. In this paper, we will study the 3-D RTM method for multi-component tunnel seismic data. Combined with the modeled data and the measured data, the imaging accuracy of the 3-D Kirchhoff migration and 3-D RTM is analyzed in detail. By comparing single-component and multi-component Kirchhoff migration and RTM profile, the advantages of the multi-component RTM method are summarized. Compared with the Kirchhoff migration method, the 3-D RTM method has the following advantages: (1) it can overcome the effect of small offset and expand the range of migration imaging; (2) multi-component data can be realized to improve the energy of anomalous interface; (3) it can make full use of multiple waves to realize migration imaging and improve the resolution of the anomalous interface. The modeled data and the measured data prove the advantages of the 3-D multi-component RTM method.

11.
J Environ Manage ; 297: 113306, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34280864

RESUMO

Forest soil acidification caused by acid deposition is a serious threat to the forest ecosystem. To investigate the liming effects of biomass ash (BA) and alkaline slag (AS) on the acidic topsoil and subsoil, a three-year field experiment under artificial Masson pine was conducted at Langxi, Anhui province in Southern China. The surface application of BA and AS significantly increased the soil pH, and thus decreased exchangeable acidity and active Al in the topsoil. Soil exchangeable Ca2+ and Mg2+ in topsoil were significantly increased by the surface application of BA and AS, while an increase in soil exchangeable K+ was only observed in BA treatments. The soil acidity and active Al in subsoil were decreased by the surface application of AS. Compared with the control, soluble monomeric and exchangeable Al in the subsoil was decreased by 38.0% and 29.4% after 3 years of AS surface application. There was a minimal effect on soluble monomeric and exchangeable Al after the application of BA. The soil exchangeable Ca2+ and Mg2+ in the subsoil increased respectively by 54% and 141% after surface application of 10 t ha-1 AS. The decrease of soil active Al and increase of base cations in subsoil were mainly attributed to the high migration capacity of base cations in AS. In conclusion, the effect of surface application of AS was superior to BA in ameliorating soil acidity and alleviating soil Al toxicity in the subsoil of this Ultisol.


Assuntos
Pinus , Poluentes do Solo , Biomassa , Ecossistema , Solo , Poluentes do Solo/análise , Poluentes do Solo/toxicidade
12.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3599-3604, 2021 Jul.
Artigo em Zh | MEDLINE | ID: mdl-34402283

RESUMO

Isomers are widely distributed in Chinese herbal medicines,and can be discriminated by energy-resolved mass spectrometry( ER-MS). However,ER-MS was performed through direct injection of reference compounds with syringe pump,which encountered a significant technical barrier for high-throughput and automated measurements. Herein,online ER-MS was conducted using LC-MS platform,and a pair of isomers,kaempferol vs luteolin,were employed as a case study to illustrate and assess the utility of online ER-MS for isomeric discrimination. High-resolution tandem mass spectrometry data of both flavonoids were acquired on LC-QE-Orbitrap-MS,and the fragmentation pathways responsible for the primary fragment ions were proposed. The primary signal in MS1 occurred at m/z 285( [M-H]-),and the primary signals of either compound generated by retro-Diels-Alder fragmentation were observed at m/z 151 and 133. The spectral information was subsequently transferred onto LC-Qtrap-MS platform to carry out online ER-MS. Two precursor-to-product ion transition candidates were constructed as m/z 285>151 and 285>133,and either afterward derived a set of pseudo-ion transitions( PITs) and so forth,exactly corresponding to a series of progressive collision energies( eg-5,-8,-11 e V,and so on). All PITs were typed into the monitoring list of multiple reaction monitoring program to generate the peak area datasets. Either dataset was normalized using the highest values in the set and imported into Graph Pad Prism software to plot the Gaus-sian-shaped curve that was termed as the break-down graph. The apex of the regressive curve was termed as optimal collision energy( OCE). The OCE values corresponding to m/z 285>151 were calculated as-29. 06 e V and-35. 71 e V for kaempferol and luteolin,respectively. In the case of m/z 285>133,the OCEs were yielded as-44. 15 e V for kaempferol and-49. 01 e V for luteolin. With re-ference to their chemical structures,the location of hydroxyl group was regarded to be responsible for the differences of either m/z 285>151 or 285>133 between the isomers,attributing to their different bond properties. Above all,online ER-MS offers an eligible tool for isomeric discrimination,and provides meaningful information for the accurate chemical composition characterization based on LC-MS,which is not limited to Chinese herbal medicines.


Assuntos
Quempferóis , Luteolina , Cromatografia Líquida , Flavonoides , Espectrometria de Massas em Tandem
13.
Angew Chem Int Ed Engl ; 60(42): 22693-22699, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34355483

RESUMO

Lead-free halide perovskites have triggered interest in the field of optoelectronics and photocatalysis because of their low toxicity, and tunable optical and charge-carrier properties. From an application point of view, it is desirable to develop stable multifunctional lead-free halide perovskites. We have developed a series of Cs2 Ptx Sn1-x Cl6 perovskites (0≤x≤1) with high stability, which show switchable photoluminescence and photocatalytic functions by varying the amount of Pt4+ substitution. A Cs2 Ptx Sn1-x Cl6 solid solution with a dominant proportion of Pt4+ shows broadband photoluminescence with a lifetime on the microsecond timescale. A Cs2 Ptx Sn1-x Cl6 solid solution with a small amount of Pt4+ substitution exhibits photocatalytic hydrogen evolution activity. An optical spectroscopy study reveals that the switch between photoluminescence and photocatalysis functions is controlled by sub-band gap states. Our finding provides a new way to develop lead-free multifunctional halide perovskites with high stability.

14.
Ann Rheum Dis ; 79(11): 1460-1467, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32737104

RESUMO

OBJECTIVES AND METHODS: With 432 513 samples from UK Biobank dataset, multivariable linear/logistic regression were used to estimate the relationship between psoriasis/psoriatic arthritis (PsA) and estimated bone mineral density (eBMD)/osteoporosis, controlling for potential confounders. Here, confounders were set in three ways: model0 (including age, height, weight, smoking and drinking), model1 (model0 +regular physical activity) and model2 (model1 +medication treatments). The eBMD was derived from heel ultrasound measurement. And 4904 patients with psoriasis and 847 patients with PsA were included in final analysis. Mendelian randomisation (MR) approach was used to evaluate the causal effect between them. RESULTS: Lower eBMD were observed in patients with PsA than in controls in both model0 (ß-coefficient=-0.014, p=0.0006) and model1 (ß-coefficient=-0.013, p=0.002); however, the association disappeared when conditioning on treatment with methotrexate or ciclosporin (model2) (ß-coefficient=-0.005, p=0.28), mediation analysis showed that 63% of the intermediary effect on eBMD was mediated by medication treatment (p<2E-16). Patients with psoriasis without arthritis showed no difference of eBMD compared with controls. Similarly, the significance of higher risk of osteopenia in patients with PsA (OR=1.27, p=0.002 in model0) could be eliminated by conditioning on medication treatment (p=0.244 in model2). Psoriasis without arthritis was not related to osteopenia and osteoporosis. The weighted Genetic Risk Score analysis found that genetically determined psoriasis/PsA were not associated with eBMD (p=0.24 and p=0.88). Finally, MR analysis showed that psoriasis/PsA had no causal effect on eBMD, osteoporosis and fracture. CONCLUSIONS: The effect of PsA on osteoporosis was secondary (eg, medication) but not causal. Under this hypothesis, psoriasis without arthritis was not a risk factor for osteoporosis.


Assuntos
Antirreumáticos/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose/epidemiologia , Psoríase/complicações , Psoríase/tratamento farmacológico , Humanos , Análise da Randomização Mendeliana
15.
Int J Mol Sci ; 21(14)2020 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-32708464

RESUMO

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes characterized by the expression of an invariant T cell receptor (iTCR) that recognizes glycolipid antigens presented by the MHC I-like CD1d molecule. Following antigenic stimulation, iNKT cells rapidly produce large amounts of cytokines that can trans-activate dendritic cells (DC) and promote the anti-tumor functions of cytotoxic lymphocytes, such as natural killer (NK) and CD8 T cells. Additionally, iNKT cells can mediate robust and direct cytotoxicity against CD1d+ tumor targets. However, many tumors down-regulate CD1d and evade iNKT cell attack. To circumvent this critical barrier to iNKT cell anti-tumor activity, a novel monoclonal antibody (mAb), NKT14 has been recently developed. This agonistic antibody binds directly and specifically to the iTCR of murine iNKT cells. In the current study, we demonstrate that NKT14m mediates robust activation, cytokine production and degranulation of murine iNKT cells, in vitro. Consistently, NKT14m also promoted iNKT cell activation and immunomodulatory functions, in vivo. Finally, administration of NKT14m with low dose interleukin (IL)-12 further augmented iNKT cell IFN-γ production in vivo, and this combination conferred superior suppression of tumor cell growth compared to NKT14m or IL-12 alone. Together, these data demonstrate that a combination treatment consisting of low dose IL-12 and iTCR-specific mAb may be an attractive alternative to activate iNKT cell anti-tumor functions.


Assuntos
Anticorpos Monoclonais/farmacologia , Quimioterapia Combinada/métodos , Interferon gama/metabolismo , Interleucina-12/farmacologia , Linfoma/tratamento farmacológico , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/imunologia , Antígenos CD1d/imunologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Sinergismo Farmacológico , Imunomodulação/efeitos dos fármacos , Linfoma/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/metabolismo
16.
Int J Mol Sci ; 21(12)2020 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-32560408

RESUMO

Invariant natural killer T cells (iNKTs) directly kill tumor cells and trans-activate the anti-tumor functions of dendritic cells (DC), natural killer (NK) cells, and T and B cells. As such, iNKTs serve as a powerful tool for use in cell-based cancer immunotherapy. iNKT cell activation commonly requires engagement of the invariant T cell receptor (iTCR) by CD1d presenting glycolipid antigens. However, transformed cells often down-regulate CD1d expression, which results in a reduction of iNKT cell anti-tumor functions. One approach to circumvent this critical barrier to iNKT cell activation is to develop an agonistic antibody that binds directly to the iTCR without the requirement for CD1d-mediated antigen presentation. To this end, we have characterized the iNKT cell stimulatory properties of NKTT320, a novel, recombinant, humanized, monoclonal antibody that binds selectively and with high affinity to human iTCRs. Strikingly, immobilized NKTT320 mediated robust iNKT cell activation (upregulation of CD25 and CD69) and proliferation (carboxyfluorescein succinimidyl ester (CFSE) dilution), as well as Th1 and Th2 cytokine production. Additionally, iNKTs stimulated by plate-bound NKTT320 exhibited increased intracellular levels of granzyme B and degranulation (exposure of CD107 on the cell surface). Furthermore, both soluble and immobilized NKTT320 induced iNKT cell-mediated activation of bystander immune cells, suggesting that this novel anti-iTCR antibody facilitates both direct and indirect iNKT cell cytotoxicity. These studies are significant, as they provide a framework by which iNKT cell anti-cancer functions could be enhanced for therapeutic purposes.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/efeitos dos fármacos , Células T Matadoras Naturais/imunologia , Biomarcadores , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/imunologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Imunofenotipagem , Células T Matadoras Naturais/metabolismo
17.
Environ Health Prev Med ; 25(1): 1, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898483

RESUMO

BACKGROUND: This study aimed to describe the changing distribution of human brucellosis between 2004 and 2017 in mainland China and seek scientific evidence of the relationship between socio-economic, environmental, and ecological factors and human brucellosis incidence. METHODS: The annual numbers of brucellosis cases and incidence rates from 31 provinces in mainland China between 2004 and 2017 were obtained from the Data-Center for China Public Health Science. The number of monthly brucellosis cases in 2018 was obtained from the Chinese Center for Disease Control and Prevention. The electronic map of the People's Republic of China was downloaded from the National Earth System Science Data Sharing Platform. Human population density, gross domestic product (GDP), and an inventory of cattle and sheep at the end of each year from 2004 to 2017 were obtained from the National Bureau of Statistics of China. Annual rainfall data from 31 provinces in the People's Republic of China from 2004 to 2017 were collected from the China Meteorological Data Service Center. The risk distribution and changing trends of human brucellosis were mapped with ArcGIS. A cluster analysis was employed to identify geographical areas and periods with statistically significant incidence rates. Multivariate linear regression was used to determine possible factors that were significantly correlated with the presence of human brucellosis cases. RESULTS: Human brucellosis cases have spread throughout the whole country. Human brucellosis cases occurred mostly from March to August and were concentrated from April to July. The inventory of sheep, GDP, and climate were significantly correlated with the presence of brucellosis cases in mainland China. CONCLUSIONS: The geographical expansion of human brucellosis in mainland China was observed, so did the high-incidence clusters between 2004 and 2017. Most of the cases were reported during the early spring to early summer (February-August). Results from the multivariate linear regression suggested that the inventory of sheep, GDP, and climate were significantly associated with the incidence of human brucellosis in mainland China.


Assuntos
Brucelose/epidemiologia , Brucelose/microbiologia , China/epidemiologia , Análise por Conglomerados , Meio Ambiente , Humanos , Saúde Pública , Fatores de Risco , Estações do Ano , Análise Espaço-Temporal
18.
J Cell Biochem ; 120(3): 3998-4008, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30259991

RESUMO

Molecular hydrogen is reported to be used medically to ameliorate various systemic pathological conditions. This study aimed to investigate the effect of hydrogen (H2 ) gas on hypertension induced by intermittent hypoxia in rats. The adult rats were exposed to chronic intermittent hypoxia (CIH) 8 hours/day for 5 weeks and/or H 2 gas 2 hours/day. We found that the systolic and diastolic blood pressure (BP) increased significantly in rats exposed to intermittent hypoxia, both of which were markedly attenuated after H treatment. Furthermore, intermittent hypoxia exposure elevated renal sympathetic nerve activity, consistent with plasma norepinephrine. Additionally, H 2 gas significantly improved CIH-induced abnormal vascular relaxation. Nevertheless, inhalation of H 2 gas alone did not cause such changes. Moreover, H 2 gas-treated rats exposed to CIH showed a significant reduction in 8-hydroxy-2 deoxyguanosine content and increases in superoxide dismutase activity, indicating improved oxidative stress. Taken together, these results indicate that H 2 gas has significant effects on the reduction of BP without any side effects. Mechanistically, inhibition of sympathetic activity and reduction of systemic vascular resistance may participate in this process via the antioxidant activity of H 2 .


Assuntos
Antioxidantes/farmacologia , Hipertensão/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Desoxiadenosinas/metabolismo , Gases/farmacologia , Humanos , Hidrogênio/farmacologia , Hipertensão/etiologia , Hipertensão/metabolismo , Hipóxia/complicações , Hipóxia/metabolismo , Hipóxia/patologia , Ratos , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Sistema Nervoso Simpático/patologia , Vasodilatação/efeitos dos fármacos
19.
Analyst ; 144(4): 1361-1368, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30566141

RESUMO

In this work, we report a new fluorescent material for pentaerythritol tetranitrate (PETN) vapor detection. A series of fluorene substituted vinyl-SiO microspheres with different ratios has been designed and easily synthesized. Sensing films on quartz plates were obtained by a solid phase transfer method. With a specific diameter of SiO and a specific density of surrounding fluorene, the microspheres performed a rapid fluorescence color change via oxidation with highly selective PETN catalysis. The emission peak at 355 nm was rapidly quenched while an enhancement at 525 nm appeared under exposure to PETN saturated vapor. Herein, we present this fluorescent silica nanoparticle as an excellent sensing material towards vapor phase PETN, making contributions to many fields such as public security and military use.

20.
BMC Infect Dis ; 19(1): 414, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088391

RESUMO

BACKGROUND: Establishing epidemiological models and conducting predictions seems to be useful for the prevention and control of human brucellosis. Autoregressive integrated moving average (ARIMA) models can capture the long-term trends and the periodic variations in time series. However, these models cannot handle the nonlinear trends correctly. Recurrent neural networks can address problems that involve nonlinear time series data. In this study, we intended to build prediction models for human brucellosis in mainland China with Elman and Jordan neural networks. The fitting and forecasting accuracy of the neural networks were compared with a traditional seasonal ARIMA model. METHODS: The reported human brucellosis cases were obtained from the website of the National Health and Family Planning Commission of China. The human brucellosis cases from January 2004 to December 2017 were assembled as monthly counts. The training set observed from January 2004 to December 2016 was used to build the seasonal ARIMA model, Elman and Jordan neural networks. The test set from January 2017 to December 2017 was used to test the forecast results. The root mean squared error (RMSE), mean absolute error (MAE) and mean absolute percentage error (MAPE) were used to assess the fitting and forecasting accuracy of the three models. RESULTS: There were 52,868 cases of human brucellosis in Mainland China from January 2004 to December 2017. We observed a long-term upward trend and seasonal variance in the original time series. In the training set, the RMSE and MAE of Elman and Jordan neural networks were lower than those in the ARIMA model, whereas the MAPE of Elman and Jordan neural networks was slightly higher than that in the ARIMA model. In the test set, the RMSE, MAE and MAPE of Elman and Jordan neural networks were far lower than those in the ARIMA model. CONCLUSIONS: The Elman and Jordan recurrent neural networks achieved much higher forecasting accuracy. These models are more suitable for forecasting nonlinear time series data, such as human brucellosis than the traditional ARIMA model.


Assuntos
Brucelose/diagnóstico , Redes Neurais de Computação , Brucelose/epidemiologia , China/epidemiologia , Humanos , Incidência , Jordânia , Modelos Estatísticos , Recidiva , Estações do Ano
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