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1.
Drug Des Devel Ther ; 15: 4701-4711, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34815665

RESUMO

Purpose: The resistance of C. albicans to traditional antifungal drugs brings a great challenge to clinical treatment. To overcome the resistance, developing antifungal agent sensitizers has attracted considerable attention. This study aimed to determine the anti-Candida activity of BEH alone or BEH-FLC combination and to explore the underlying mechanisms. Materials and Methods: In vitro antifungal effects were performed by broth microdilution assay and XTT reduction assay. Infected Galleria mellonella larvae model was used to determine the antifungal effects in vivo. Probes Fluo-3/AM, FITC-VAD-FMK and rhodamine 6G were used to study the influence of BEH and FLC on intracellular calcium concentration, metacaspase activity and drug efflux of C. albicans. Results: BEH alone exhibited obvious antifungal activities against C. albicans. BEH plus FLC not only showed synergistic effects against planktonic cells and preformed biofilms within 8 h but also enhanced the antifungal activity in infected G. mellonella larvae. Mechanistic studies indicated that antifungal effects of drugs might be associated with the increasement of calcium concentration, activation of metacaspase activity to reduce virulence and anti-biofilms, but were not related to drug efflux. Conclusion: BEH alone or combined with FLC displayed potent antifungal activity both in vitro and in vivo, and the underlying mechanisms were related to reduced virulence factors.

2.
Biomed Mater ; 17(1)2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34731839

RESUMO

In this study, we established a procedure to prepare a Semaphorin4D (SEMA4D)-immobilized titanium surface and explored its effects on macrophage behaviors in an endothelial cell/macrophage indirect coculture model. The SEMA4D-bovine serum albumin complex was immobilized onto a preprocessed poly L-lysine titanium surface through NaOH hydrothermal treatment and self-assembly technology. All titanium specimens were examined for surface microstructure, surface element composition, and surface wettability by field emission scanning electron microscopy, x-ray photoelectron spectroscopy (XPS), and water contact angle measurement, respectively. Subsequently, we constructed an endothelial cell/macrophage indirect coculture model and evaluated the activation of NF-κB signaling pathway and the expression of proinflammatory cytokines (TNFα, IL-6, and IL-1ß) in macrophages. In XPS analysis, the SEMA4D-immobilized titanium surface appeared as a loose porous structure covered with uniform film, which exhibited better hydrophilicity than the control smooth titanium surface. In the indirect coculture model, SEMA4D attenuated the activation of NF-κB signaling pathway of lipopolysaccharide-stimulated THP-1 macrophages, thereby downregulating the expression of proinflammatory cytokines in macrophages. In conclusion, SEMA4D could be immobilized on titanium surfaces through NaOH hydrothermal treatment and self-assembly technology. Meanwhile, SEMA4D immobilization altered the characteristics of the titanium surfaces, which negatively regulated macrophage behaviors in the endothelial cell/macrophage indirect coculture model.

3.
Ann Transl Med ; 9(18): 1475, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34734027

RESUMO

Background: Immune checkpoint inhibitors (ICIs) have brought clinical benefits to patients with various histological types of lung cancer. Previous studies have shown an association between mesenchymal-epithelial transition (MET) and the immunotherapy response in non-small cell lung cancer (NSCLC) but there is a lack of clinical data on the correlation of MET amplification with the ICI response in NSCLC. Methods: Copy number alteration (CNA), somatic mutation, and clinical data from two immunotherapy cohorts (Rizvi et al. cohort and our local cohort) were collected and pooled to further investigate the key role of MET amplification in patients with NSCLC receiving ICIs. The correlations between MET amplification and tumor immunogenicity and antitumor immunity were further investigated in The Cancer Genome Atlas (TCGA)-NSCLC [lung adenocarcinoma (LUAD)/lung squamous cell carcinoma (LUSC)] data-set. Results: In the immunotherapy cohorts, MET amplification was associated with longer progression-free survival (PFS) times in patients receiving ICI treatment (P=0.039; HR =0.37; 95% CI: 0.18-0.73). In the TCGA-NSCLC data-set, MET amplification was associated with high MET mRNA and protein levels, tumor mutation burden (TMB), neoantigen load (NAL), immune-activated cell patterns, immune-related gene expression levels, and the number of gene alterations in the DNA damage response and repair (DDR) pathway. Gene set enrichment analysis (GSEA) results indicated significant up-regulation of the immune response-related pathways in the MET-amplification group. Conclusions: Our results suggest that MET amplification may be a novel predictive marker for immunotherapy efficacy in NSCLC.

4.
Virus Res ; 306: 198593, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34637814

RESUMO

Zika virus (ZIKV) is a typical mosquito-borne flavivirus known to cause severe fetal microcephaly and adult Guillain-Barré syndrome. Currently, there are no specific drugs or licensed vaccines available for ZIKV infection, and further research is required to identify host cell proteins involved in the virus's life cycle. Viruses are known to use host cell membrane skeletal proteins, such as actin and spectrin, to complete cell entry, transportation, and release. Here, based on immunoprecipitation, the Axl and ZIKV envelope (E) protein were shown to interact with the cell membrane skeleton protein 4.1R. Furthermore, deletion of 4.1R significantly reduced virus titer and viral protein synthesis. Our study showed that 4.1R is an important host cell protein during ZIKV infection and may be involved in the process of viral entry into host cells.

5.
Sci Prog ; 104(3): 368504211039375, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34490803

RESUMO

Porous media combustion has significant advantages of high thermal efficiency and low pollution emissions. However, the flow state in the porous media will affect the reaction rate. In order to increase the rate of chemical reactions, the fluid flow resistance in the porous media must be reduced. The pressure drop test of SiC foam ceramics was carried out. By changing the pore density of the experimental materials, the pressure drop characteristics of SiC foam ceramic are tested and analyzed. Based on the classical Ergun equation, a semi-empirical formula for calculating the pressure drop gradient of SiC foam ceramics with the airflow velocity is proposed. The two constants in the formula are calculated by measurement, and the applicability of the formula is verified. This formula can quickly analyze the pressure drop characteristics of SiC foam ceramic materials. The accurate measurement of pressure drop is helpful to determine the rated pressure of the head of foam ceramic burner and reduce the investment of front-end fans in industrial burners.

6.
J Gastrointest Oncol ; 12(4): 1285-1300, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34532088

RESUMO

Background: Accurate staging plays a pivotal role in cancer care. The lymph node (LN) ratio (LNR) and the log odds of positive LNs (LODDS) have been suggested as alternatives to the N staging since the TNM system has the risk of stage migration. The prognostic significance of LNR and LODDS in young patients with gastric cancer (GC) has not been reported. This study aims to investigate the correlations between LNR and LODDS and survival of young patients with GC, and compare the predictive performance of these LN staging methods. Methods: GC patients before the age of 40 from 2004 to 2016 in the Surveillance, Epidemiology and End Results database were enrolled. The prognostic evaluation of the N factor, LNR and LODDS was compared using the time-dependent receiver operating characteristic (ROC) analysis, area under the curve (AUC), C-index and Akaike information criterion (AIC). Results: Multivariate survival analysis identified that the LNR and LODDS were significantly independent prognostic indicators for overall survival (OS) in young patients with GC and in the subgroups comprised of patients with ≤15 LNs examined. The time-dependent ROC curves of the LNR and LODDS were continuously superior to that of the N factor in predicting OS during the observation period. And the AUCs revealed that the predictive accuracy of the LNR and LODDS was remarkably superior to the N factor at 1 and 3 years (P<0.05). The model incorporating LNR or LODDS had higher C-index and lower AIC when comparing to the model incorporating the N factor. Conclusions: The LNR and LODDS improve accuracy of survival risk prediction in young patients with GC when comparing to the N factor. These two novel LN classification methods should be considered as alternatives to the N staging for the prognostic prediction of young patients with GC.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34335824

RESUMO

This study investigated the effect and mechanism of electroacupuncture (EA) on the contralesional hemisphere in rats with ischemic stroke. EA of 2 Hz was applied on the contralesionally Luoque (BL8) and Tongtian (BL7) acupoints of the scalp to investigate the neurological status and mechanism in ischemia-reperfusion injury rats. The differences in the neurological deficit score and Rotarod test time between days 3 and 15 after reperfusion were significantly lower in the sham group (0.00 (-1.00, 0.00) and 3.53 (-0.39, 7.48) second, respectively) than in the EA group (-4.00 (-4.00, -3.00) and 44.80 (41.69, 54.13) second, respectively, both p < 0.001). The ratio of infarction volume was 0.19 ± 0.04 in the sham group greater than 0.07 ± 0.04 in the EA group (p < 0.001). On day 15, in the cerebral cortex of the lesioned hemisphere, the gamma-aminobutyric acid (GABA)-A/actin ratio in the normal group (1.11 ± 0.36) was higher than that in the sham group (0.38 ± 0.07, p < 0.05) and similar to that in the EA group (0.69 ± 0.18, p > 0.05); the difference between the EA and sham groups was significant (p < 0.05). EA of 2 Hz on the BL8 and BL7 acupoints on the contralesional scalp can improve motor function and also can reduce infarction volume, and this effect of EA, and that GABA-A, plays at least a partial role in ischemia-reperfusion injury rats.

8.
Acta Pharm Sin B ; 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34367893

RESUMO

The development of broad-spectrum antivirals against human coronaviruses (HCoVs) is critical to combat the current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, as well as future outbreaks of emerging CoVs. We have previously identified a polyethylene glycol-conjugated (PEGylated) lipopeptide, EK1C4, with potent pan-CoV fusion inhibitory activity. However, PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo. Therefore, we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment (HR2-CF) of HCoV-OC43. Among these lipopeptides, EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike (S) mutants, as well as other HCoVs and some bat SARS-related coronaviruses (SARSr-CoVs) tested. The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes, better metabolic stability in mouse serum, higher thermostability than the PEGylated lipopeptide EK1C4, suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.

10.
Expert Rev Anti Infect Ther ; : 1-18, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34128761

RESUMO

Introduction: Candida species have been regarded as global health threats due to their ability to cause invasive infections. It is challenging to treat Candida bloodstream infections, which are associated with high mortality levels. Monotherapy with antifungals is sometimes not effective against severe Candida infections, and combination therapy is needed in clinical practice.Areas covered: This review was undertaken based on data from a PubMed search for English language reports published before March 2021 by using the terms 'caspofungin,' 'Candida species,' 'combination therapy,' 'antifungal effect,' and 'novel antifungal agent.'Expert opinion: Combination therapy is an empirical strategy for treating refractory Candida infections. Caspofungin has been recommended to treat candidaemia. Caspofungin in combination therapy has some applications, while the efficacy of combination therapy in the treatment of refractory Candida infections needs more study, such as randomized controlled trials. In addition, novel compounds or drugs with potential antifungal activities have been examined, and some of them exhibit synergistic interactions with caspofungin. Thus, the antifungal activity of caspofungin in combination with antifungals or non-antifungals against Candida species in vitro and in clinical therapy is summarized.

11.
Chem Commun (Camb) ; 57(48): 5901-5904, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34008620

RESUMO

By using in-site generated formate, 2D HOFs of TCPP, with excellent stability and permanent porosity (BET surface area larger than 560 m2 g-1), have been obtained. The constructed 2D square-like TCPP-HCO2 grid sheets have shown considerable in-plane stability that comparable to the TCPP-based 2D MOFs, that can be exfoliated into atomically thin 2D nanosheets with efficient photocatalytic activity in aqueous system. These results are expected to shed light on the application-orientated one-pot synthesis for new kinds of multi-dimensional HOFs.

12.
Colloids Surf B Biointerfaces ; 204: 111779, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33901810

RESUMO

Native carbonic anhydrase (CA) has been widely used in several different applications due to its catalytic function in the interconversion of carbon dioxide (CO2) and carbonic acid. However, subject to its stability and recyclability, native CA often deactivates when in harsh environments, which restricts its applications in the commercial market. Maintaining the stability and high catalytic activity of CA is challenging. Immobilization provides an effective route that can improve enzymatic stability. Through the interaction of covalent bonds and van der Waals forces, water-soluble CA can be combined with various insoluble supports to form water-insoluble immobilized CA so that CA stability and utilization can be greatly improved. However, if the immobilization method or immobilization condition is not suitable, it often leads to a decrease in CA activity, reducing the application effects on CO2 conversion. In this review, we discuss existing immobilization methods and applications of immobilized CA in the environmental field, such as the mineralization of carbon dioxide and multienzyme cascade catalysis based on CA. Additionally, prospects in current development are outlined. Because of the many outstanding and superior properties after immobilization, CA is likely to be used in a wide variety of scientific and technical areas in the future.


Assuntos
Anidrases Carbônicas , Dióxido de Carbono , Anidrases Carbônicas/metabolismo , Estabilidade Enzimática , Enzimas Imobilizadas/metabolismo , Água
13.
Neoplasma ; 68(3): 465-471, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33904316

RESUMO

HOX transcript antisense intergenic RNA (HOTAIR) is a lncRNA with a length of 2,158 nucleotides and its two terminal domains could combine with different complexes to function at the level of transcription and translation. It overexpresses in many cancers including gastric cancer. HOTAIR could play an oncogenic role in the initiation and progression of gastric cancer through interaction with microRNAs, such as miR-330/618/126 in the PI3K/Akt signaling pathways. HOTAIR single nucleotide polymorphisms (SNPs) may have genotype-function and allele-specific effect on gastric cancer by a mechanism that specific SNP could give rise to a variation of HOTAIR and alter the binding site of microRNAs. Both rs920778 T allele and rs4759314 G allele will enhance the susceptibility to gastric cancer in the Chinese populations. In a word, the suppression of HOTAIR and overexpression of downstream microRNAs may be potential therapeutic strategies of gastric cancer related to HOTAIR.


Assuntos
MicroRNAs , RNA Longo não Codificante , Neoplasias Gástricas , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , MicroRNAs/genética , Fosfatidilinositol 3-Quinases , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética
14.
15.
Cell ; 184(6): 1604-1620, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33740455

RESUMO

Historically, emerging viruses appear constantly and have cost millions of human lives. Currently, climate change and intense globalization have created favorable conditions for viral transmission. Therefore, effective antivirals, especially those targeting the conserved protein in multiple unrelated viruses, such as the compounds targeting RNA-dependent RNA polymerase, are urgently needed to combat more emerging and re-emerging viruses in the future. Here we reviewed the development of antivirals with common targets, including those against the same protein across viruses, or the same viral function, to provide clues for development of antivirals for future epidemics.


Assuntos
Antivirais/uso terapêutico , Doenças Transmissíveis Emergentes/tratamento farmacológico , Doenças Transmissíveis Emergentes/epidemiologia , Terapia de Alvo Molecular/métodos , Pandemias , Viroses/tratamento farmacológico , Viroses/epidemiologia , Vírus/enzimologia , Animais , Antivirais/farmacologia , Doenças Transmissíveis Emergentes/virologia , Humanos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas do Envelope Viral/antagonistas & inibidores , Viroses/virologia , Internalização do Vírus/efeitos dos fármacos
18.
Sci Rep ; 11(1): 2001, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33479417

RESUMO

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a complicated maternally inherited disorder lacking of sensitive and specific biomarkers. The objective of this study was to investigate the serum neurofilament light chain (NfL) as a novel biomarker of neurological dysfunction in MELAS. Patients with different status of MELAS were enrolled in this study. The Mini-Mental State Examination (MMSE) was given to the participants to evaluate cognition status. Multiple functional MRI was performed on the participants. Blood samples were collected and the serum NfL concentrations were determined by the single-molecule array technology (Simoa). This study enrolled 23 patients with MELAS, 15 people in the acute attack phase of MELAS and 10 people in the remission phase, including 2 patients in both acute attack and remission phase. Sixteen healthy controls (HCs) were also enrolled. Serum NfL level increased significantly in patients with MELAS. Serum NfL level in the acute attack group (146.73 [120.91-411.31] pg/ml, median [IQR]) was higher than in the remission group (40.31 [19.54-151.05] pg/ml, median [IQR]) and HCs group (7.70 [6.13-9.78] pg/ml, median [IQR]) (p < 0.05). The level of NfL in the remission phase group was higher than in HCs group (p < 0.05). A negative correlation was found between the serum NfL level and MMSE (p = 0.006, r = -0.650). The NfL concentration correlated positively with stroke-like lesion volume in the brain (r = 0.740, p < 0.001). Serum NfL may serve as a novel biomarker for the neurological dysfunction in MELAS patients.


Assuntos
Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Síndrome MELAS/sangue , Proteínas de Neurofilamentos/sangue , Adolescente , Adulto , Encéfalo/patologia , Feminino , Humanos , Filamentos Intermediários/genética , Síndrome MELAS/diagnóstico por imagem , Síndrome MELAS/genética , Síndrome MELAS/patologia , Imageamento por Ressonância Magnética , Masculino , Herança Materna/genética , Pessoa de Meia-Idade , Adulto Jovem
19.
Protoplasma ; 258(4): 905-922, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33496857

RESUMO

Petals are important floral organs that exhibit considerable morphological diversity in terms of colour, shape, and size. The varied morphologies of mature petals can be linked to developmental differences. The petals of Berberidaceae (a core group of Ranunculales) range from flat sheets to complex structures with nectaries, but studies on petal development and structural diversity in this group are lacking. Here, the petal development, structure, and micromorphology of seven Berberidaceae genera are characterized by microscopy to clarify the diversity of petals within this group. The results indicate that no common petal-stamen primordium exists, that petal development proceeds through five stages, and that the differentiation responsible for the diversity of the mature petals occurs during stage 4. Processes contributing to the morphological diversity of mature petals include edge thickening, gland formation, and spur formation. Nandina and Diphylleia lack nectaries. Gymnospermium has saccate nectaries, Caulophyllum has nectaries on the petal margin, Epimedium has spur nectaries, and Berberis and Mahonia have glands at the base of petals. Petal nectaries usually consist of a secretory epidermis, two to twenty layers of secretory parenchyma cells, and vascular tissues. Eleven distinct cell types were observed in the petal epidermis, three of which are secretory; papillose cells appear to be absent in Diphylleia, which shows relatively little micromorphological variation. The ancestors of Berberidaceae may have nectaries in thickened areas of their petals. The micromorphology and nectary structures of the petals in Ranunculales are also compared.

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