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1.
Nanomaterials (Basel) ; 11(11)2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34835696

RESUMO

The synthesis of ultra-small gold nanoclusters (Au NCs) with sizes down to 2 nm has received increasing interest due to their unique optical and electronic properties. Like many peptide-coated gold nanospheres synthesized before, modified gold nanoclusters with peptide conjugation are potentially significant in biomedical and catalytic fields. Here, we explore whether such small-sized gold nanoclusters can be conjugated with peptides also and characterize them using atomic force microscopy. Using a long and flexible elastin-like polypeptide (ELP)20 as the conjugated peptide, (ELP)20-Au NCs was successfully synthesized via a one-pot synthesis method. The unique optical and electronic properties of gold nanoclusters are still preserved, while a much larger size was obtained as expected due to the peptide conjugation. In addition, a short and rigid peptide (EAAAK)3 was conjugated to the gold nanoclusters. Their Yong's modulus was characterized using atomic force microscopy (AFM). Moreover, the coated peptide on the nanoclusters was pulled using AFM-based single molecule-force spectroscopy (SMFS), showing expected properties as one of the first force spectroscopy experiments on peptide-coated nanoclusters. Our results pave the way for further modification of nanoclusters based on the conjugated peptides and show a new method to characterize these materials using AFM-SMFS.

2.
Anal Chem ; 93(38): 13054-13062, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34519478

RESUMO

Probe-modified nanopores/nanochannels are one of the most advanced sensors because the probes interact strongly with ions and targets in nanoconfinement and create a sensitive and selective ionic signal. Recently, ionic signals have been demonstrated to be sensitive to the probe-target interaction on the outer surface of nanopores/nanochannels, which can offer more open space for target recognition and signal conversion than nanoconfined cavities. To enhance the ionic signal, we investigated the effect of grafting density, a critical parameter of the sensing interface, of the probe on the outer surface of nanochannels on the change rate of the ionic signal before and after target recognition (ß). Electroneutral peptide nucleic acids and negatively charged DNA are selected as probes and targets, respectively. The experimental results showed that when adding the same number of targets, the ß value increased with the probe grafting density on the outer surface. A theoretical model with clearly defined physical properties of each probe and target has been established. Numerical simulations suggest that the decrease of the background current and the aggregation of targets at the mouth of nanochannels with increasing probe grafting density contribute to this enhancement. This work reveals the signal mechanism of probe-target recognition on the outer surface of nanochannels and suggests a general approach to the nanochannel/nanopore design leading to sensitivity improvement on the basis of relatively good selectivity.


Assuntos
Nanoporos , Ácidos Nucleicos Peptídicos , DNA , Íons , Modelos Teóricos
3.
Anal Chem ; 93(40): 13711-13718, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34581576

RESUMO

Nanochannels have advantage in sensitive analyses due to the confinement effects on ionic signal in nano- or sub-nanometric confines but could realize further gains by optimizing signal mechanism. Making target recognitions on the outer surface of nanochannels has been verified to improve target recognitions and signal conversions by maximizing surfaces accessible to targets and ions, but until recently, the signal mechanism has been still unclear. Using electroneutral peptide nucleic acid (PNA) and negative-charged DNA, we verified a dominant space charge effect on an ionic signal on the outer surface of nanochannels. A typical exponential increase of the ionic signal with the charge density on the outer surface has been demonstrated through the PNA-PNA, PNA-DNA, DNA-DNA hybrid, DNA cleavage, and hybridization chain reaction. These results challenge the essential role of steric hindrance on the ionic signal and describe a new ion passageway surrounded and accelerated by the stern layer of charged species on the nanochannel outer surface.


Assuntos
Ácidos Nucleicos Peptídicos , DNA , Íons , Hibridização de Ácido Nucleico
4.
Research (Wash D C) ; 2021: 9756945, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368766

RESUMO

Human metallothionein (MT) is a small-size yet efficient metal-binding protein, playing an essential role in metal homeostasis and heavy metal detoxification. MT contains two domains, each forming a polynuclear metal cluster with an exquisite hexatomic ring structure. The apoprotein is intrinsically disordered, which may strongly influence the clusters and the metal-thiolate (M-S) bonds, leading to a highly dynamic structure. However, these features are challenging to identify due to the transient nature of these species. The individual signal from dynamic conformations with different states of the cluster and M-S bond will be averaged and blurred in classic ensemble measurement. To circumvent these problems, we combined a single-molecule approach and multiscale molecular simulations to investigate the rupture mechanism and chemical stability of the metal cluster by a single MT molecule, focusing on the Zn4S11 cluster in the α domain upon unfolding. Unusual multiple unfolding pathways and intermediates are observed for both domains, corresponding to different combinations of M-S bond rupture. None of the pathways is clearly preferred suggesting that unfolding proceeds from the distribution of protein conformational substates with similar M-S bond strengths. Simulations indicate that the metal cluster may rearrange, forming and breaking metal-thiolate bonds even when MT is folded independently of large protein backbone reconfiguration. Thus, a highly dynamic polynuclear metal cluster with multiple conformational states is revealed in MT, responsible for the binding promiscuity and diverse cellular functions of this metal-carrier protein.

5.
Analyst ; 146(16): 5089-5094, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34297030

RESUMO

Nanopores attached to charged species realize the artificial regulation of ion transport by the electrostatic effect in nanoconfines, produce a sensitive ion current signal and play a critical role in nanopore-based analyses. However, until now, the contribution of the charged species at the outer surface, an inherent component of nanopores, to the ion current signal has not yet been fully investigated. Here, we theoretically investigate the contribution of the charged species at the outer surface to the ion current signal of a conical nanopore. The results indicate that when the electrostatic effect at the tip of the conical nanopore is strengthened, the contribution from the charged species at the outer surface to the ionic current signal becomes stronger or even predominant compared with that of the inner walls. This effect can be further enhanced using nanopore arrays with small openings and low pore density in a low concentration electrolyte. This work focuses on the working mechanism of nanopores with a high-efficient signal conversion and promotes the performance of nanopores with a regional distribution of charged probes and targets.


Assuntos
Nanoporos , Eletrólitos , Transporte de Íons , Modelos Teóricos , Eletricidade Estática
6.
Artigo em Inglês | MEDLINE | ID: mdl-34234835

RESUMO

Hyperuricemia (HUA) as a metabolic disease is closely associated with metabolic disorders. The etiology and pathogenesis of HUA are not fully understood, so there is no radical cure so far. Metabolomics, a specialized study of endogenous small molecule substances, has become a powerful tool for metabolic pathway analysis of selected differential metabolites, which is helpful for initially revealing possible development mechanisms of various human diseases. Twenty HUA patients and 20 healthy individuals participated in the experiment, and ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was employed to investigate serum samples to find differential metabolites. The statistical techniques used were principal component analysis and orthogonal partial least-squares discriminant analysis. The differences in metabolomics results of samples after pretreatment with different solvents were compared, 38, 20, 26, 28, 33, 50, and 40 potential differential metabolites were found, respectively, in HUA patient samples, and each group involved different metabolic pathways. Repetitive metabolites were removed, 138 differential metabolites in HUA serum were integrated for analysis, and the human body was affected by 7 metabolic pathways of glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and α-linolenic acid metabolism. In this work, the metabolomics approach based on UPLC-Q-TOF/MS was employed to investigate serum metabolic changes in HUA patients, 138 potential differential metabolites related to HUA were identified, which provided associations of lipids, amino acids, fatty acids, organic acids, and nucleosides profiles of HUA individuals. Metabolic pathways involved in glycerophospholipid metabolism, sphingolipid metabolism, arachidonic acid metabolism, linoleic acid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and a-linolenic acid metabolism shed light on the understanding of the etiology and pathogenesis process of HUA.

7.
Nat Protoc ; 16(9): 4201-4226, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34321637

RESUMO

Solid-state nanochannels (SSNs) provide a promising approach for biosensing due to the confinement of molecules inside, their great mechanical strength and diversified surface chemical properties; however, until now, their sensitivity and specificity have not satisfied the practical requirements of sensing applications, especially in complex matrices, i.e., media of diverse constitutions. Here, we report a protocol to achieve explicit regional and functional division of functional elements at the outer surface (FEOS) and inner wall (FEIW) of SSNs, which offers a nanochannel-based sensing platform with enhanced specificity and sensitivity. The protocol starts with the fabrication and characterization of the distribution of FEOS and FEIW. Then, the evaluation of the contributions of FEOS and FEIW to ionic gating is described; the FEIW mainly regulate ionic gating, and the FEOS can produce a synergistic effect. Finally, hydrophobic or highly charged FEOS are applied to ward off interference molecules, non-target molecules that may affect the ionic signal of nanochannels, which decreases false signals and helps to achieve the highly specific ionic output in complex matrices. Compared with other methods currently available, this method will contribute to the fundamental understanding of substance transport in SSNs and provide high specificity and sensitivity in SSN-based analyses. The procedure takes 3-6 d to complete.


Assuntos
Técnicas Biossensoriais , Nanoporos , Sensibilidade e Especificidade
8.
Plants (Basel) ; 10(6)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070469

RESUMO

Shift of phytoplankton niches from low to high latitudes has altered their experienced light exposure durations and temperatures. To explore this interactive effect, the growth, physiology, and cell compositions of smaller Alexandrium minutum and larger A. catenella, globally distributed toxic red tide dinoflagellates, were studied under a matrix of photoperiods (light:dark cycles of 8:16, 16:8, and 24:0) and temperatures (18 °C, 22 °C, 25 °C, and 28 °C). Under continuous growth light condition (L:D 24:0), the growth rate (µ) of small A. minutum increased from low to medium temperature, then decreased to high temperature, while the µ of large A. catenella continuously decreased with increasing temperatures. Shortened photoperiods reduced the µ of A. minutum, but enhanced that of A. catenella. As temperature increased, cellular Chl a content increased in both A. minutum and A. catenella, while the temperature-induced effect on RubisCO content was limited. Shortened photoperiods enhanced the Chl a but reduced RubisCO contents across temperatures. Moreover, shortened photoperiods enhanced photosynthetic capacities of both A. minutum and A. catenella, i.e., promoting the PSII photochemical quantum yield (FV/FM, ΦPSII), saturation irradiance (EK), and maximum relative electron transfer rate (rETRmax). Shortened photoperiods also enhanced dark respiration of A. minutum across temperatures, but reduced that of A. catenella, as well as the antioxidant activities of both species. Overall, A. minutum and A. catenella showed differential growth responses to photoperiods across temperatures, probably with cell size.

9.
Pharmacol Res Perspect ; 9(4): e00797, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34128350

RESUMO

Daratumumab was approved in patients with relapsed or refractory multiple myeloma (MM) who previously received proteasome inhibitors or immunomodulatory drugs. However, the efficacy and safety of the addition of daratumumab in subpopulations of patients with relapsed or refractory MM is still unknown. We systematically searched MEDLINE, EMBASE, and Cochrane for randomized controlled trials (inception to September 2020). All phase 3 randomized controlled trials (RCTs) which were conducted in patients with relapsed or refractory MM and compared the efficacy or safety with the addition of daratumumab versus control were adopted. Three studies including 1497 patients met our criteria. The addition of daratumumab increased the rates of overall response (RR 1.21, 95% CI 1.15-1.28, p < .001), complete response or better (RR 2.43, 95% CI 2.00-2.96, p < .001), very good partial response or better (RR 1.63, 95% CI 1.48-1.80, p < .001) compared with those with control. No clear evidence of heterogeneity was found in comparisons of progression-free survival obtained from subsets of studies grouped by the age of participant, ISS disease stage, type of measurable MM, the level of baseline renal function, cytogenetic profile. The results showed progression-free survival benefit was consistent between the treatment groups regarding previous clinical therapy information. Patients receiving daratumumab had higher risks of lymphopenia and infusion-related reactions of any grade and grade 3 or 4. In conclusions, this study provides a clear proof of beneficial effects of daratumumab-based therapy in patients with relapsed or refractory MM with an acceptable safety profile. The progression-free survival benefit was consistent regardless of patient's baseline characteristics or previous therapy agents.

10.
BMC Complement Med Ther ; 21(1): 175, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172058

RESUMO

BACKGROUND: Plantaginis Semen has been widely used as folk medicine and health care food against hyperuricemia (HUA) and gout, but its pharmacological mechanism remains unclear. This study investigated the therapeutic mechanism of Plantaginis Semen extract on potassium oxonate -induced HUA rats based on a lipidomics approach. METHODS: A model of HUA was established by potassium oxonate intragastric administration. 42 Sprague-Dawley (SD) male rats were randomly divided into the control group, model group, benzbromarone group (10 mg/kg) and three Plantaginis Semen groups (n = 7). The Plantaginis Semen groups were treated orally with Plantaginis Semen, 0.9375, 1.875  or 3.75 g/kg for 28 days. The levels of serum uric acid (UA), creatinine (Cr), triacylglycerol (TG) and tumor necrosis factor-α (TNF-α) were  measured using enzyme-linked immunosorbent assay kits. Ultra performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) was used for the serum lipidomics analysis, multivariate statistical analysis and independent samples t-test were carried out for the pattern recognition and characteristic metabolites identification. The relative levels of critical regulatory factors were determined by quantitative real-time polymerase chain reaction (RT-qPCR). RESULTS: Compared with the model group, the levels of serum UA, Cr, TG and TNF-α were significantly (p < 0.05) decreased in benzbromarone and three Plantaginis Semen groups. With lipidomics analysis, significant lipid metabolic perturbations were observed in HUA rats, 13 metabolites were identified as potential biomarkers and glycerophospholipid metabolism pathway was  most affected. These perturbations  were partially restored via treatment of benzbromarone and Plantaginis Semen. Additionally, the mRNA expression levels of urate anion transporter 1 (URAT1) and phosphatidylinositol 3-kinase/protein kinases B (PI3K/Akt) were significantly decreased (p < 0.01) after treatment with benzbromarone and high dose of Plantaginis Semen. CONCLUSIONS: Plantaginis Semen had significant effects on anti-HUA, anti-inflammatory and renal protection. It attenuated potassium oxonate-induced HUA through regulation of lipid metabolism disorder.

11.
Front Immunol ; 12: 680068, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025679

RESUMO

Toll-like receptors (TLRs) play critical roles in regulating the abnormal activation of the immune cells resulting in the pathogenesis of inflammation and autoimmune diseases. Pyruvate kinase M2 (PKM2), which governs the last step of glycolysis, is involved in multiple cellular processes and pathological conditions. However, little is known about the involvement of PKM2 in regulating TLR-mediated inflammation and autoimmunity. Herein, we investigated the role of PKM2 in the activation of the TLR pathways and the pathogenesis of inflammation and autoimmune diseases. The activation of TLR4, TLR7 and TLR9 pathways was found to induce the up-regulation of PKM2 expression in macrophages, dendritic cells (DCs) and B cells. The over-expression of PKM2 promotes the activation of TLR4, TLR7 and TLR9 pathways while interference with the PKM2 expression or the addition of the PKM2 inhibitor (PKM-IN) markedly inhibited the activation of TLR4, TLR7 and TLR9 pathways. Mechanistically, PKM2 augmented the activation of TLR4, TLR7 and TLR9 pathways by promoting the activation of the proline-rich tyrosine kinase 2 (Pyk2). Intriguingly, the PKM2 inhibitor PKM2-IN significantly protected the mice from the endotoxic shock mediated by the TLR4-agonist LPS. Additionally, it alleviated the progression in the TLR7-agonist imiquimod-mediated lupus mice and spontaneous lupus MRL/lpr mice. Moreover, PKM2 expression was highly elevated in the monocytes, DCs and B cells from systemic lupus erythematous (SLE) patients compared with those from the healthy donors. Besides, the PKM2 expression level was positively correlated with the degree of activation of these immune cells. In summary, PKM2 contributed to TLR-mediated inflammation and autoimmunity and can be a valuable target to control inflammation and autoimmunity.


Assuntos
Autoimunidade , Proteínas de Transporte/metabolismo , Quinase 2 de Adesão Focal/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Receptores Toll-Like/metabolismo , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Proteínas de Transporte/antagonistas & inibidores , Sobrevivência Celular , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Inflamação/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos MRL lpr , Modelos Biológicos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo
12.
Sci Rep ; 11(1): 7187, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785794

RESUMO

Dispersal ability is important for the introduction, establishment, and spread of alien plant species. Therefore, determination of the geographical distribution of the dispersal ability of such species, and the relationship between dispersal ability and socio-climatic factors are essential to elucidate the invasion strategies of the alien plant species. Analytic hierarchy process and inventory, risk rank, and dispersal mode data available on Chinese alien plant species were used to determine their dispersal ability, the geographical distribution thereof, and the relationship between socio-climatic factors and dispersal ability. High-risk alien plant species had a higher natural dispersal ability (or several natural dispersal modes) but a lower anthropogenic dispersal ability (or few anthropogenic dispersal modes) than low-risk alien plant species. The geographical distribution of the dispersal ability of the alien plant species showed an inverse relationship with species density. Alien plant species with low dispersal ability (i.e., with fewer dispersal modes and distribution in the southeast) showed a tendency to adapt to environments with mild climates, while those with high dispersal ability (i.e., with more disposal nodes and distribution in the northwest) showed a tendency to adapt to harsh environments. It is essential for land managers and policy makers to understand the geographical distribution of the dispersal ability of alien plant species and their socio-climatic control factors to formulate strategies to control the natural and anthropogenic dispersal of such plants.

13.
J Ethnopharmacol ; 277: 114057, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-33771643

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cimicifuga dahurica (Turcz.) Maxim (C. dahurica) has a long history of treating breast cancer. From the Qing Dynasty to the Tang Dynasty and even earlier, C. dahurica has been documented in the treatment of breast carbuncle (Breast cancer is classified as breast carbuncle in Chinese medicine). In traditional prescriptions such as "Sheng Ge Decoction", "Sheng Ma Powder" and "Breast Carbuncle Pill", as the main medicine, C. dahurica plays an important role. At present, the systematic studies on the in vitro and in vivo effects of Cimicifuga against breast cancer are rare, especially the C. dahurica. AIM OF THE STUDY: In this article, we evaluated the in vitro activity and in vivo effects of CREE (extract of the root of C. dahurica) against breast cancer, and discussed the possible mechanism of CREE in promoting breast cancer cell apoptosis. MATERIALS AND METHODS: The main component in the CREE was analyzed by HPLC. The effects of CREE on the proliferation, migration and invasion of human breast cancer cells were evaluated through SRB, colony assay, LDH release, wound healing and transwell assay. The pro-apoptotic effect of CREE was investigated in Hochest33342 and Annexin V-FITC/PI assay. To verify the results of CREE in vivo effects, we applied nude mice subcutaneous xenograft experiments. The possible mechanism of CREE treating breast cancer was investigated through mitochondrial membrane potential and western blot experiments. RESULTS: CREE contains cycloartane triterpene saponins. CREE can significantly inhibit the proliferation, migration and invasion of human breast cancer MCF-7 and MDA-MB-231 cells in vitro and it can effectively inhibit the growth of MDA-MB-231 cell subcutaneous tumors in vivo. Besides, we also found that CREE up-regulated the expression levels of Bax, caspase-9/3 and cytochrome C, and down-regulated the expression of Bcl-2. Therefore, regulation of the mitochondrial pathway may be one of the mechanisms by which CREE promotes breast cancer cell apoptosis. CONCLUSIONS: CREE exhibits sufficient anti-breast cancer activity in vivo and in vitro, this study provides persuasive evidence for the further research and development of C. dahurica.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cimicifuga/química , Extratos Vegetais/farmacologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Células MCF-7 , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/prevenção & controle , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nat Commun ; 12(1): 1573, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692350

RESUMO

Function elements (FE) are vital components of nanochannel-systems for artificially regulating ion transport. Conventionally, the FE at inner wall (FEIW) of nanochannel-systems are of concern owing to their recognized effect on the compression of ionic passageways. However, their properties are inexplicit or generally presumed from the properties of the FE at outer surface (FEOS), which will bring potential errors. Here, we show that the FEOS independently regulate ion transport in a nanochannel-system without FEIW. The numerical simulations, assigned the measured parameters of FEOS to the Poisson and Nernst-Planck (PNP) equations, are well fitted with the experiments, indicating the generally explicit regulating-ion-transport accomplished by FEOS without FEIW. Meanwhile, the FEOS fulfill the key features of the pervious nanochannel systems on regulating-ion-transport in osmotic energy conversion devices and biosensors, and show advantages to (1) promote power density through concentrating FE at outer surface, bringing increase of ionic selectivity but no obvious change in internal resistance; (2) accommodate probes or targets with size beyond the diameter of nanochannels. Nanochannel-systems with only FEOS of explicit properties provide a quantitative platform for studying substrate transport phenomena through nanoconfined space, including nanopores, nanochannels, nanopipettes, porous membranes and two-dimensional channels.

15.
Anal Chem ; 93(4): 1984-1990, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33393771

RESUMO

The grafting density of probes at sensor interface plays a critical role in the performance of biochemical sensors. However, compared with macroscopic interface, the effects of probe grafting density at nanometric confinement are rarely studied due to the limitation of precise grafting density regulation and characterization at the nanoscale. Here, we investigate the effect from the grafting density of DNA probes on ionic signal for nucleic acid detection in a cylindrical nanochannel array (with diameter of 25 nm) by combing experiments and theories. We set up a theoretical model of charge distribution from close to inner wall of nanochannels at low probe grafting density to spreading in whole space at high probe grafting density. The theoretical results fit well with the experimental results. A reverse of ionic output from signal-off to signal-on occurs with increasing probe grafting density. Low probe grafting density offers a high current change ratio that is further enhanced using long-chain DNA probes or the electrolyte with a low salt concentration. This work develops an approach to enhance performance of nanochannel-based sensors and explore physicochemical properties in nanometric confines.


Assuntos
Sondas de DNA/química , DNA/química , Nanoestruturas/química , Análise de Sequência com Séries de Oligonucleotídeos , Eletrodos , Modelos Teóricos , Tamanho da Partícula , Propriedades de Superfície
16.
Inflammation ; 44(2): 671-681, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33083887

RESUMO

Fulminant hepatitis (FH) is an acute clinical disease with a poor prognosis and high mortality rate. The purpose of this study was to determine the protective effect of the Toll-like receptor 4 (TLR4) inhibitor TAK-242 on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced explosive hepatitis and explore in vivo and in vitro mechanisms. Mice were pretreated with TAK-242 for 3 h prior to LPS (10 µg/kg)/D-GalN (250 mg/kg) administration. Compared to the LPS/D-GalN group, the TAK-242 pretreatment group showed significantly prolonged survival, reduced serum alanine aminotransferase and aspartate aminotransferase levels, relieved oxidative stress, and reduced inflammatory interleukin (IL)-6, IL-12, and tumor necrosis factor-α levels. In addition, TAK-242 increased the accumulation of myeloid-derived suppressor cells (MDSCs). Next, mice were treated with an anti-Gr-1 antibody to deplete MDSCs, and adoptive transfer experiments were performed. We found that TAK-242 protected against FH by regulating MDSCs. In the in vitro studies, TAK-242 regulated the accumulation of MDSCs and promoted the release of immunosuppressive inflammatory cytokines. In addition, TAK-242 inhibited protein expression of nuclear factor-κB and mitogen-activated protein kinases. In summary, TAK-242 had a hepatoprotective effect against LPS/D-GalN-induced explosive hepatitis in mice. Its protective effect may be involved in suppressing inflammation, reducing oxidative stress, and increasing the proportion of MDSCs.

17.
Biomed Res Int ; 2020: 5217405, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299870

RESUMO

Background: Gegen Qinlian (GGQL) decoction is a common Chinese herbal compound for the treatment of ulcerative colitis (UC). In this study, we aimed to identify its molecular target and the mechanism involved in UC treatment by network pharmacology and molecular docking. Material and Methods. The active ingredients of Puerariae, Scutellariae, Coptis, and Glycyrrhiza were screened using the TCMSP platform with drug-like properties (DL) ≥ 0.18 and oral availability (OB) ≥ 30%. To find the intersection genes and construct the TCM compound-disease regulatory network, the molecular targets were determined in the UniProt database and then compared with the UC disease differential genes with P value < 0.005 and ∣log2 (fold change) | >1 obtained in the GEO database. The intersection genes were subjected to protein-protein interaction (PPI) construction and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. After screening the key active ingredients and target genes, the AutoDock software was used for molecular docking, and the best binding target was selected for molecular docking to verify the binding activity. Results: A total of 146 active compounds were screened, and quercetin, kaempferol, wogonin, and stigmasterol were identified as the active ingredients with the highest associated targets, and NOS2, PPARG, and MMP1 were the targets associated with the maximum number of active ingredients. Through topological analysis, 32 strongly associated proteins were found, of which EGFR, PPARG, ESR1, HSP90AA1, MYC, HSPA5, AR, AKT1, and RELA were predicted targets of the traditional Chinese medicine, and PPARG was also an intersection gene. It was speculated that these targets were the key to the use of GGQL in UC treatment. GO enrichment results showed significant enrichment of biological processes, such as oxygen levels, leukocyte migration, collagen metabolic processes, and nutritional coping. KEGG enrichment showed that genes were particularly enriched in the IL-17 signaling pathway, AGE-RAGE signaling pathway, toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, transcriptional deregulation in cancer, and other pathways. Molecular docking results showed that key components in GGQL had good potential to bind to the target genes MMP3, IL1B, NOS2, HMOX1, PPARG, and PLAU. Conclusion: GGQL may play a role in the treatment of ulcerative colitis by anti-inflammation, antioxidation, and inhibition of cancer gene transcription.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Terapia de Alvo Molecular , Colite Ulcerativa/genética , Regulação para Baixo/genética , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Ontologia Genética , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular , Mapeamento de Interação de Proteínas , Termodinâmica , Regulação para Cima/genética
19.
AAPS PharmSciTech ; 21(7): 253, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32888086

RESUMO

We developed a pH-triggered in situ gel (ISG) for ocular delivery of vinpocetine to achieve systemic absorption and a brain-targeting effect in rats. Carbopol acted as a gelling agent combined with hydroxypropyl methylcellulose (HPMC) as a viscosity-enhancing agent. The concentration of Carbopol (0.2%, w/v) and HPMC (1.5%, w/v) was optimized for the ISG system. The optimized formulation was evaluated for studies on release in vitro, rheology, differential scanning calorimetry, ocular irritation, residence time, and in vivo pharmacokinetics. The vinpocetine ISG stayed longer in rabbit eyes than vinpocetine ointment. In vivo pharmacokinetics showed that compared with vinpocetine ointment, vinpocetine ISG attained a peak plasma concentration and area under the curve that was 1-2 folds greater in rat plasma. The Drug Targeting Index (DTI) was 1.06 and 1.26 for vinpocetine ointment and vinpocetine ISG, respectively, after ocular administration, showing that vinpocetine ISG had better distribution in rat brain. These results revealed that a pH-triggered ISG system via ocular administration could be an alternative approach compared with traditional ophthalmic formulations.


Assuntos
Sistemas de Liberação de Medicamentos , Géis/química , Concentração de Íons de Hidrogênio , Vasodilatadores/administração & dosagem , Alcaloides de Vinca/administração & dosagem , Resinas Acrílicas/química , Administração Oftálmica , Animais , Derivados da Hipromelose/química , Masculino , Coelhos , Ratos , Viscosidade
20.
Int J Mol Sci ; 21(17)2020 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-32887217

RESUMO

Invasive breast cancer is highly regulated by tumor-derived cytokines in tumor microenvironment. The development of drugs that specifically target cytokines are promising in breast cancer treatment. In this study, we reported that arctigenin, a bioactive compound from Arctium lappa L., could decrease tumor-promoting cytokines GM-CSF, MMP-3, MMP-9 and TSLP in breast cancer cells. Arctigenin not only inhibited the proliferation, but also the invasion and stemness of breast cancer cells via decreasing GM-CSF and TSLP. Mechanistically, arctigenin decreased the promoter activities of GM-CSF and TSLP via reducing the nuclear translocation of NF-κB p65 which is crucial for the transcription of GM-CSF and TSLP. Furthermore, arctigenin-induced depletion of GM-CSF and TSLP inhibited STAT3 phosphorylation and ß-catenin signaling resulting in decreased proliferation, invasion and stemness of breast cancer cells in vitro and in vivo. Our findings provide new insights into the mechanism by which tumor-promoting cytokines regulate breast cancer progression and suggest that arctigenin is a promising candidate for cytokine-targeted breast cancer therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Citocinas/metabolismo , Furanos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Lignanas/farmacologia , Fator de Transcrição STAT3/metabolismo , beta Catenina/metabolismo , Animais , Apoptose , Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Movimento Celular , Proliferação de Células , Citocinas/genética , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator de Transcrição STAT3/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética
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