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1.
Small ; : e1903108, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31482681

RESUMO

Single-atom catalysts (SACs) have attracted extensive attention in the catalysis field because of their remarkable catalytic activity, gratifying stability, excellent selectivity, and 100% atom utilization. With atomically dispersed metal active sites, Fe-N-C SACs can mimic oxidase by activating O2 into reactive oxygen species, O2 - • radicals. Taking advantages of this property, single-atom nanozymes (SAzymes) can become a great impetus to develop novel biosensors. Herein, the performance of Fe-N-C SACs as oxidase-like nanozymes is explored. Besides, the Fe-N-C SAzymes are applied in biosensor areas to evaluate the activity of acetylcholinesterase based on the inhibition toward nanozyme activity by thiols. Moreover, this SAzymes-based biosensor is further used for monitoring the amounts of organophosphorus compounds.

2.
J Agric Food Chem ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464438

RESUMO

Adulteration of meat and meat products causes a concerning threat for consumers. It is necessary to develop novel robust and sensitive methods which can authenticate the origin of meat by qualitative and quantitative means to compensate the drawbacks of the existing methods. This study has shown that the protein N-glycosylation profiles of different meats are species specific and thus can be used for meat authentication. Based on N-glycan pattern, the investigated five meat species (beef, chicken, pork, duck and mutton) can be distinguished by principal component analysis (PCA), and partial least square (PLS) regression was performed to build a calibration and validation model for prediction of the adulteration ratio. Using this method, beef samples adulterated with the lower value duck meat could be detected down to the addition ratio as low as 2.2%. The most distinguishing N-glycans from beef and duck were elucidated for the detailed structures.

3.
Proc Natl Acad Sci U S A ; 116(33): 16314-16319, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31363054

RESUMO

Critical for diverse biological processes, proteases represent one of the largest families of pharmaceutical targets. To inhibit pathogenic proteases with desired selectivity, monoclonal antibodies (mAbs) hold great promise as research tools and therapeutic agents. However, identification of mAbs with inhibitory functions is challenging because current antibody discovery methods rely on binding rather than inhibition. This study developed a highly efficient selection method for protease inhibitory mAbs by coexpressing 3 recombinant proteins in the periplasmic space of Escherichia coli-an antibody clone, a protease of interest, and a ß-lactamase modified by insertion of a protease cleavable peptide sequence. During functional selection, inhibitory antibodies prevent the protease from cleaving the modified ß-lactamase, thereby allowing the cell to survive in the presence of ampicillin. Using this method to select from synthetic human antibody libraries, we isolated panels of mAbs inhibiting 5 targets of 4 main protease classes: matrix metalloproteinases (MMP-14, a predominant target in metastasis; MMP-9, in neuropathic pain), ß-secretase 1 (BACE-1, an aspartic protease in Alzheimer's disease), cathepsin B (a cysteine protease in cancer), and Alp2 (a serine protease in aspergillosis). Notably, 37 of 41 identified binders were inhibitory. Isolated mAb inhibitors exhibited nanomolar potency, exclusive selectivity, excellent proteolytic stability, and desired biological functions. Particularly, anti-Alp2 Fab A4A1 had a binding affinity of 11 nM and inhibition potency of 14 nM, anti-BACE1 IgG B2B2 reduced amyloid beta (Aß40) production by 80% in cellular assays, and IgG L13 inhibited MMP-9 but not MMP-2/-12/-14 and significantly relieved neuropathic pain development in mice.

4.
J Mater Chem B ; 7(31): 4854-4866, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31389952

RESUMO

The efficient delivery of vaccines to draining lymph nodes and the induction of robust local immune responses are crucial for immunotherapy. Transdermal administration has been evidenced to facilitate the delivery of ingredients to lymph nodes. In this study, transfersomes with opposite surface charges were applied for antigen encapsulation and these were integrated with dissolving microneedles to investigate their effects on immune responses via transdermal immunization. The microneedles were easily inserted into mouse skin and achieved the local release of nanovaccines into the dermis through dissolution. Although anionic nanovaccines promoted cellular uptake via DC2.4, cationic nanovaccines exhibited stronger escape capacities from endocytic compartments, facilitating antigen processing via an MHC-I presentation pathway, and formed larger accumulations in lymph nodes. Compared with their anionic counterparts, the cationic nanovaccines more efficiently activated DC maturation and induced Th1 immunity; this was suggested by the significantly increased IgG2a/IgG1 ratio and elevated cytokine secretion from Th1 cells, without an enhancement in the Th2 response. Such an enhanced Th1 antigen-specific immune response in lymph nodes via a transdermal vaccine delivery platform is beneficial for potential immunotherapy approaches.

5.
Microbiome ; 7(1): 105, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311609

RESUMO

BACKGROUND: Dysbiosis of gut microbiota exists in the pathogenesis of many autoimmune diseases, including systemic lupus erythematosus (lupus). Lupus patients who experienced pregnancy usually had more severe disease flares post-delivery. However, the possible role of gut microbiota in the link between pregnancy and exacerbation of lupus remains to be explored. RESULTS: In the classical lupus mouse model MRL/lpr, we compared the structures of gut microbiota in pregnant and lactating individuals vs. age-matched naïve mice. Consistent with studies on non-lupus mice, both pregnancy and lactation significantly changed the composition and diversity of gut microbiota. Strikingly, modulation of gut microbiota using the same strategy resulted in different disease outcomes in postpartum (abbreviated as "PP," meaning that the mice had undergone pregnancy and lactation) vs. control (naïve; i.e., without pregnancy or lactation) MRL/lpr females; while vancomycin treatment attenuated lupus in naïve mice, it did not do so, or even exacerbated lupus, in PP mice. Lactobacillus animalis flourished in the gut upon vancomycin treatment, and direct administration of L. animalis via oral gavage recapitulated the differential effects of vancomycin in PP vs. control mice. An enzyme called indoleamine 2,3-dioxygenase was significantly inhibited by L. animalis; however, this inhibition was only apparent in PP mice, which explained, at least partially, the lack of beneficial response to vancomycin in these mice. The differential production of immunosuppressive IL-10 and proinflammatory IFNγ in PP vs. control mice further explained why the disease phenotypes varied between the two types of mice bearing the same gut microbiota remodeling strategy. CONCLUSIONS: These results suggest that pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota. Further studies are necessary to better understand the complex relationship between pregnancy and lupus.

6.
J Neurosci ; 39(35): 6848-6864, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31270160

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) remains a pressing clinical problem; however, our understanding of sexual dimorphism in CIPN remains unclear. Emerging studies indicate a sex-dimorphic role of Toll-like receptor 4 (TLR4) in driving neuropathic pain. In this study, we examined the role of TLR9 in CIPN induced by paclitaxel in WT and Tlr9 mutant mice of both sexes. Baseline pain sensitivity was not affected in either Tlr9 mutant male or female mice. Intraplantar and intrathecal injection of the TLR9 agonist ODN 1826 induced mechanical allodynia in both sexes of WT and Tlr4 KO mice but failed to do so in Tlr9 mutant mice. Moreover, Trpv1 KO or C-fiber blockade by resiniferatoxin failed to affect intraplantar ODN 1826-induced mechanical allodynia. Interestingly, the development of paclitaxel-evoked mechanical allodynia was attenuated by TLR9 antagonism or Tlr9 mutation only in male mice. Paclitaxel-induced CIPN caused macrophage infiltration to DRGs in both sexes, and this infiltration was not affected by Tlr9 mutation. Paclitaxel treatment also upregulated TNF and CXCL1 in macrophage cultures and DRG tissues in both sexes, but these changes were compromised by Tlr9 mutation in male animals. Intraplantar adoptive transfer of paclitaxel-activated macrophages evoked mechanical allodynia in both sexes, which was compromised by Tlr9 mutation or by treatment with TLR9 inhibitor only in male animals. Finally, TLR9 antagonism reduced paclitaxel-induced mechanical allodynia in female nude mice (T-cell and B-cell deficient). Together, these findings reveal sex-dimorphic macrophage TLR9 signaling in chemotherapy-induced neuropathic pain.SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect in cancer patients undergoing clinical chemotherapy treatment regimens. The role of sex dimorphism with regards to the mechanisms of CIPN and analgesia against CIPN remains unclear. Previous studies have found that the infiltration of immune cells, such as macrophages into DRGs and their subsequent activation promote CIPN. Interestingly, the contribution of microglia to CIPN appears to be limited. Here, we show that macrophage TLR9 signaling promotes CIPN in male mice only. This study suggests that pathways in macrophages may be sex-dimorphic in CIPN. Our findings provide new insights into the role of macrophage signaling mechanisms underlying sex dimorphism in CIPN, which may inspire the development of more precise and effective therapies.

7.
Sensors (Basel) ; 19(14)2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31319596

RESUMO

The Gravity Recovery and Climate Experiment (GRACE) level-2 spherical harmonic (SH) solutions are noisy and thus require filtering. Filtering reduces noise but affects signal quality via signal leakage. Generally, a leakage correction is required for GRACE applications to remove leakage signal and recover the true signal. Forward modelling based on some a priori information is a widely used approach for leakage correction of GRACE data. The a priori information generally relies on global hydrological model simulations. There are many global hydrological models and therefore it is of interest to explore how different global hydrology model simulations influence leakage correction results. This study investigated the sensitivity of three leakage correction methods (additive method, scaling factor method and multiplicative method) to five global hydrology model simulations (four models from the Global Land Data Assimilation System (GLDAS) and the WaterGAP Global Hydrology Model (WGHM)). The sensitivity analysis was performed with observational data in Southwest China and one sub-region, Guangxi. Results show that although large differences were identified among the five global model simulations, the additive and scaling factor methods are less affected by the choice of a priori model in comparison to the multiplicative approach. For the additive and scaling factor methods, WGHM outperforms the other four GLDAS models in leakage correction of GRACE data. GRACE data corrected with the multiplicative method shows the highest amount of error, indicating this method is not applicable for leakage correction in the study area. This study also assessed the level-3 mascon (mass concentration) solutions of GRACE data. The mascon-based results are nearly as good as the leakage corrected results based on SH solutions.

8.
J Nutr ; 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152671

RESUMO

BACKGROUND: Lactobacillus rhamnosus GG culture supernatant (LGGs) promotes intestinal integrity and ameliorates acute liver injury induced by alcohol in mice. OBJECTIVES: The aim of this study was to investigate the protective effects and molecular mechanisms of Lactobacillus reuteri ZJ617 culture supernatant (ZJ617s) on acute liver injury induced by lipopolysaccharide (LPS) in mice. METHODS: Male C57BL/6 mice (20 ± 2 g, 8 wk old) were randomly divided into 4 groups (6 mice/group): oral inoculation with phosphate-buffered saline (control), intraperitoneal injection of LPS (10 mg/kg body weight) (LPS), oral inoculation with ZJ617s 2 wk before intraperitoneal injection of LPS (ZJ617s + LPS), or oral inoculation with LGGs 2 wk before intraperitoneal injection of LPS (LGGs + LPS). Systemic inflammation, intestinal integrity, biomarkers of hepatic function, autophagy, and apoptosis signals in the liver were determined. RESULTS: Twenty-four hours after LPS injection, the activities of serum alanine transaminase and aspartate transaminase were 32.2% and 30.3% lower in the ZJ617s + LPS group compared with the LPS group, respectively (P < 0.05). The ZJ617s + LPS group exhibited higher intestinal expression of claudin 3 (62.5%), occludin (60.1%), and zonula occludens 1 (60.5%) compared with the LPS group (P < 0.05). The concentrations of hepatic interleukin-6 and tumor necrosis factor-α were 21.4% and 27.3% lower in the ZJ617s + LPS group compared with the LPS group, respectively (P < 0.05). However, the concentration of interleukin-10 was 22.2% higher in the ZJ617s + LPS group. LPS increased the expression of Toll-like receptor 4 (TLR4; by 50.5%), phosphorylation p38 mitogen-activated protein kinase (p38MAPK; by 57.1%), extracellular signal-regulated kinase (by 77.8%), c-Jun N-terminal kinase (by 42.9%), and nuclear factor-κB (NF-κB; by 36.0%) compared with the control group. Supplementation with ZJ617s or LGGs ameliorated these effects (P < 0.05). Moreover, the hepatic expression of active caspase-3 and microtubule-associated protein 1 light chain 3 II was 23.8% and 28.6% lower in the ZJ617s + LPS group compared with the LPS group, respectively (P < 0.05). CONCLUSIONS: ZJ617s exerts beneficial effects on the mouse liver through suppression of hepatic TLR4/MAPK/NF-κB activation, apoptosis, and autophagy. This trial was registered at Zhejiang University (http://www.lac.zju.edu.cn) as NO.ZJU20170529.

9.
Sci Rep ; 9(1): 8482, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186444

RESUMO

To investigate the artificial vaginal microecological features in patients who underwent laparoscopic peritoneal vaginoplasty. 54 cases of patients with artificial vagina after laparoscopic peritoneal vaginoplasty were included in this study. Microecosystem evaluation was performed. Artificial vaginal functional tests and biopsy from vaginal walls were performed. After laparoscopic peritoneal vaginoplasty, the artificial vaginal flora intensity was level II∼III (88.9%); the vaginal flora diversity was level II∼III (72.2%); the predominant vaginal bacteria were gram-positive macrobacillus (27.8%); approximately 57.4% of the patients had vaginal pH ≤ 4.5; there was no pathogenic bateria or other pathogens; dysbiosis accounted for 53.7% of the patients (64.5% of the patients who had the vaginoplasty operation less than 2 years ago exhibited dysbiosis; 39.1% of the patients who had the operation at least 2 years ago exhibited dysbiosis). Vaginal dysbiosis is common after laparoscopic peritoneal vaginoplasty. However, as time goes by, the artificial vaginal microecological condition gradually becomes normal. Evaluation of vaginal microenvironment after laparoscopic peritoneal vaginoplasty might play an important role in reproductive tract infection prevention and neovagina health care.

10.
Ear Hear ; 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31246660

RESUMO

OBJECTIVES: The most commonly employed speech processing strategies in cochlear implants (CIs) only extract and encode amplitude modulation (AM) in a limited number of frequency channels. Zeng et al. (2005) proposed a novel speech processing strategy that encodes both frequency modulation (FM) and AM to improve CI performance. Using behavioral tests, they reported better speech, speaker, and tone recognition with this novel strategy than with the AM-alone strategy. Here, we used the scalp-recorded human frequency following responses (FFRs) to examine the differences in the neural representation of vocoded speech sounds with AM alone and AM + FM as the spectral and temporal cues were varied. Specifically, we were interested in determining whether the addition of FM to AM improved the neural representation of envelope periodicity (FFRENV) and temporal fine structure (FFRTFS), as reflected in the temporal pattern of the phase-locked neural activity generating the FFR. DESIGN: FFRs were recorded from 13 normal-hearing, adult listeners in response to the original unprocessed stimulus (a synthetic diphthong /au/ with a 110-Hz fundamental frequency or F0 and a 250-msec duration) and the 2-, 4-, 8- and 16-channel sine vocoded versions of /au/ with AM alone and AM + FM. Temporal waveforms, autocorrelation analyses, fast Fourier Transform, and stimulus-response spectral correlations were used to analyze both the strength and fidelity of the neural representation of envelope periodicity (F0) and TFS (formant structure). RESULTS: The periodicity strength in the FFRENV decreased more for the AM stimuli than for the relatively resilient AM + FM stimuli as the number of channels was increased. Regardless of the number of channels, a clear spectral peak of FFRENV was consistently observed at the stimulus F0 for all the AM + FM stimuli but not for the AM stimuli. Neural representation as revealed by the spectral correlation of FFRTFS was better for the AM + FM stimuli when compared to the AM stimuli. Neural representation of the time-varying formant-related harmonics as revealed by the spectral correlation was also better for the AM + FM stimuli as compared to the AM stimuli. CONCLUSIONS: These results are consistent with previously reported behavioral results and suggest that the AM + FM processing strategy elicited brainstem neural activity that better preserved periodicity, temporal fine structure, and time-varying spectral information than the AM processing strategy. The relatively more robust neural representation of AM + FM stimuli observed here likely contributes to the superior performance on speech, speaker, and tone recognition with the AM + FM processing strategy. Taken together, these results suggest that neural information preserved in the FFR may be used to evaluate signal processing strategies considered for CIs.

11.
J Agric Food Chem ; 67(26): 7274-7280, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31244200

RESUMO

Bioactivity-guided separation led to the isolation of six novel phenanthrenes, spiranthesphenanthrenes A-F (1-6), together with 19 known compounds, including seven phenanthrenes (7-13), one bibenzyl compound (14), five flavonoids (15-16 and 20-22), and six simple phenolic compounds (17-19 and 23-25), from the petroleum ether (PE) and ethyl acetate (EtOAc) extracts of Spiranthes sinensis (Pers.) Ames, an edible medicinal plant named "panlongshen" in Chinese that is popularly used in medicinal foods and herbal teas. The structures of the obtained compounds were identified on the basis of extensive NMR spectroscopy and HR-ESI-MS analyses. The cytotoxicities of the phenanthrenes (1-13), the bibenzyl compound (14) , and the flavonoids (15-16 and 20-22) toward SGC-7901, HepG2, and B16-F10 cell lines were examined in vitro. Compounds 1 and 7 exhibited moderate cytotoxic activities toward all of the selected cancer cell lines, and their IC50 values ranged from 19.0 ± 7.3 to 30.2 ± 5.6 µM. Spiranthesphenanthrene A (1) exhibited higher cytotoxic activity than the positive control cisplatin toward the B16-F10 cell line (IC50 = 19.0 ± 7.3 µM). A wound healing assay revealed the inhibition of the migration of B16-F10 cancer cells in a time- and dose-dependent pattern by treatment with 2.5, 5, and 10 µM solutions of compound 1 for 24 and 48 h, respectively. Western blots revealed that compound 1 obviously increased the level of the E-cadherin protein (an epithelial marker) and decreased the levels of the vimentin and N-cadherin proteins (mesenchymal markers). Furthermore, the level of the transcription factor Snail was also obviously decreased by compound 1 in a dose-dependent manner. Taken together, compound 1 inhibits the migration of B16-F10 cancer cells, which may be closely related to the inhibition of the epithelial-mesenchymal transition. Compound 1 represents a promising drug candidate for the prevention of tumor metastasis.


Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Orchidaceae/química , Fenantrenos/química , Fenantrenos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Antineoplásicos Fitogênicos/isolamento & purificação , Caderinas/genética , Caderinas/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Fenantrenos/isolamento & purificação , Extratos Vegetais/isolamento & purificação
12.
Nano Lett ; 19(8): 5595-5603, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31241969

RESUMO

Photodetectors usually operate in the wavelength range with photon energy above the bandgap of channel semiconductors so that incident photons can excite electrons from valence band to conduction band to generate photocurrent. Here, however, we show that monolayer WS2 photodetectors can detect photons with energy even lying 219 meV below the bandgap of WS2 at room temperature. With the increase of excitation wavelength from 620 to 680 nm, photoresponsivity varies from 551 to 59 mA/W. This anomalous phenomenon is ascribed to energy upconversion, which is a combination effect of one-photon excitation and multiphonon absorption through an intermediate state created most likely by sulfur divacancy with oxygen adsorption. These findings will arouse research interests on other upconversion optoelectronic devices, photovoltaic devices, for example, of monolayer transition metal dichalcogenides (TMDCs).

13.
Clin Genet ; 2019 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-31231788

RESUMO

In recent years, gene editing, especially that using clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9, has made great progress in the field of gene function. Rapid development of gene editing techniques has contributed to their significance in the field of medicine. Because the CRISPR/Cas9 gene editing tool is not only powerful but also has features such as strong specificity and high efficiency, it can accurately and rapidly screen the whole genome, facilitating the administration of gene therapy for specific diseases. In the field of tumor research, CRISPR/Cas9 can be used to edit genomes to explore the mechanisms of tumor occurrence, development, and metastasis. In these years, this system has been increasingly applied in tumor treatment research. CRISPR/Cas9 can be used to treat tumors by repairing mutations or knocking out specific genes. To date, numerous preliminary studies have been conducted on tumor treatment in related fields. CRISPR/Cas9 holds great promise for gene-level tumor treatment. Personalized and targeted therapy based on CRISPR/Cas9 will possibly shape the development of tumor therapy in the future. In this study, we review the findings of CRISPR/Cas9 for tumor treatment research to provide references for related future studies on the pathogenesis and clinical treatment of tumors.

14.
Sci Total Environ ; 679: 346-358, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31085414

RESUMO

Groundwater discharge to river and the related heavy metal transportation were estimated for Dabaoshan, a mountain mining area where extensive mining activities had been conducted over 40 years. In the lower reach of the mining area, shallow aquifers were contaminated by varies heavy metals due to the discharge of acid mine drainage. Polluted aquifers act as long-term pollution sources to the surrounding gaining rivers, even after the mining activities were stopped. The natural tracer 222Rn was measured for river water of the Hengshi River and groundwater adjacent to the river channel in both wet and dry seasons. The total groundwater discharge rate was estimated to be 17.4-26.7 × 103 m3 day-1 in wet season and 1.9-2.1 × 103 m3 day-1 in dry season; and the river recharge was 5.6 ±â€¯1.0 × 103 m3 day-1 in wet season and 2.1 ±â€¯1.0 × 103 m3 day-1 in dry season. Compared with other mining and natural/artificial factor influenced areas, groundwater discharge rate in Dabaoshan was much lower, but the magnitudes of groundwater-borne Cu, Zn, Mn and Co fluxes were comparable or even much higher. This suggested that groundwater-derived heavy metal fluxes were significant pollution sources to river in the mountain mining area. Meanwhile, the results also suggested that concentrations of Cd, Pb, Cu, Ni, Mn, Fe, Zn and Tl in groundwater increased where the recharge of river water to groundwater occurred, suggesting the recharge of river water can affect heavy metal concentrations of the beneath aquifers, even in a gaining river.

15.
Clin Exp Allergy ; 49(7): 990-999, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31046155

RESUMO

BACKGROUND: Neutrophil accumulation has been observed in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the functions of neutrophils are poorly understood. Neutrophils produce neutrophil extracellular traps (NETs), which are involved in a variety of chronic inflammatory pathologies. LL-37 is the only member of the cathelicidin family in human. OBJECTIVE: Our aims were to examine the presence of NETs in CRSwNP and to investigate the regulatory effect of LL-37 on NET formation. METHODS: Nasal polyp tissues were investigated for the presence of NETs by using immunofluorescent (IF) staining. The expression and distribution of LL-37 were examined by using quantitative RT-PCR, ELISA, IF, and immunohistochemistry. Purified peripheral neutrophils were stimulated with LL-37 and stained with IF to identify NETs. NETs% was defined as percentage of NET-generating neutrophils to the total number of neutrophils. RESULTS: Neutrophil extracellular traps were located in the subepithelial layer of nasal polyps and control tissues. Nasal polyps had higher NETs% compared with that of controls (23.01% ± 3.43% vs 4.52% ± 1.33%, P < 0.0001). NET count was also increased in nasal polyps. NET count correlated with neutrophil count (r = 0.908, P < 0.001). LL-37 protein and mRNA levels were upregulated in nasal polyps. LL-37 was distributed in the epithelial and subepithelial layer and mainly expressed by neutrophils. Moreover, LL-37 promoted peripheral neutrophils to form NETs in a dose-dependent manner ex vivo. Interestingly, dexamethasone did not inhibit the effect of LL-37 on inducing NET formation. Furthermore, peripheral neutrophils from CRSwNP patients were more susceptible to LL-37-mediated NET formation, compared with neutrophils derived from control subjects. In addition, NETs released LL-37 in vivo and ex vivo. CONCLUSION: Neutrophil extracellular traps are significantly increased in nasal polyps and LL-37 induces NET formation in CRSwNP patients. These findings indicate that NETs may contribute to the pathogenesis of neutrophilic inflammation in CRSwNP.

16.
Medicine (Baltimore) ; 98(19): e15561, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083221

RESUMO

Insulin-like growth factor binding proteins (IGFBPs) are a family of proteins binding to insulin-like growth factors, generally consisting 6 high-affinity IGFBPs, namely IGFBP1 through IGFBP6. IGFBP family members have been indicated to be involved in the development and progression of tumors and may be useful prognostic biomarkers in various malignancies. However, the prognostic role of individual IGFBPs, especially at the mRNA level in breast cancer patients remains elusive.We accessed the prognostic roles of IGFBPs family (IGFBP1-6) in breast cancer through the "Kaplan-Meier plotter" online database and OncoLnc database.Our results showed that the high expression of IGFBP1 mRNA was associated with favorable relapsed free survival (RFS) in all breast cancer patients. The high expression of IGFBP2 mRNA was associated with favorable overall survival (OS) and RFS in all breast cancer patients. The high expression of IGFBP3 mRNA was significantly correlated to worsen RFS in all breast cancer patients. The high expression of IGFBP4 mRNA was associated with favorable OS, RFS, distant metastasis-free survival, and post-progression survival in all breast cancer patients.Our results indicated that expression of IGFBPs mRNA may have prognostic values in breast cancer patients, and have a benefit for developing tools to predict the prognosis more accurately.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática/diagnóstico , Gradação de Tumores , Prognóstico , RNA Mensageiro/metabolismo
17.
Sci Rep ; 9(1): 6886, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053738

RESUMO

Prediction of disease prognosis is essential for improving cancer patient care. Previously, we have demonstrated the feasibility of using quantitative morphological features of tumor pathology images to predict the prognosis of lung cancer patients in a single cohort. In this study, we developed and validated a pathology image-based predictive model for the prognosis of lung adenocarcinoma (ADC) patients across multiple independent cohorts. Using quantitative pathology image analysis, we extracted morphological features from H&E stained sections of formalin fixed paraffin embedded (FFPE) tumor tissues. A prediction model for patient prognosis was developed using tumor tissue pathology images from a cohort of 91 stage I lung ADC patients from the Chinese Academy of Medical Sciences (CAMS), and validated in ADC patients from the National Lung Screening Trial (NLST), and the UT Special Program of Research Excellence (SPORE) cohort. The morphological features that are associated with patient survival in the training dataset from the CAMS cohort were used to develop a prognostic model, which was independently validated in both the NLST (n = 185) and the SPORE (n = 111) cohorts. The association between predicted risk and overall survival was significant for both the NLST (Hazard Ratio (HR) = 2.20, pv = 0.01) and the SPORE cohorts (HR = 2.15 and pv = 0.044), respectively, after adjusting for key clinical variables. Furthermore, the model also predicted the prognosis of patients with stage I ADC in both the NLST (n = 123, pv = 0.0089) and SPORE (n = 68, pv = 0.032) cohorts. The results indicate that the pathology image-based model predicts the prognosis of ADC patients across independent cohorts.

18.
J Transl Med ; 17(1): 143, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060551

RESUMO

BACKGROUND: The distant metastasis of cancer cells is a risk factor for tumor lethality and poor prognosis in non-small-cell lung carcinoma (NSCLC). Increased SOX9 expression has been associated with clinical stage and poor prognosis in NSCLC, but the molecular mechanisms by which SOX9 promotes metastasis in NSCLC are still unknown. METHODS: The relationship between SOX9 expression and T, N, M classification was assessed using the χ2 test and Spearman's analysis in 142 immunohistochemically diagnosed specimens of NSCLC. We also generated SOX9-overexpression and SOX9-knockdown cells lines and their corresponding control cell lines by transfection with lentiviral constructs. In vivo assay, SOX9-overexpressing and SOX9-knockdown NSCLC cells were injected in zebrafish to examine distance metastasis. Gene set enrichment analysis (GSEA) was applied to analysis the correlation between SOX9 overexpression and Wnt/ß-catenin pathway. Luciferase assay was used to check transcriptional activity of TCF/LEF and western blot and immunofluorescence was employed to detect ß-catenin translocation in SOX9-overexpression, SOX9-knockdown and their corresponding control cell lines. RESULTS: We found that SOX9 overexpression correlates with the T, N and M stage significantly (p = 0.03, 0.000, and 0.032 respectively) in 142 immunohistochemically diagnosed specimens of NSCLC. SOX9 overexpression was found to decrease the expression of the epithelial cell markers E-cadherin and γ-catenin and increase the expression of the mesenchymal cell markers N-cadherin and vimentin. An in vivo assay showed distant metastasis of the SOX9-overexpressing cells, which was not observed in the SOX9-knockdown cells. These findings indicate that SOX9 promotes distant metastasis by promoting EMT in NSCLC cells. GSEA showed that SOX9 overexpression was significantly correlated with the Wnt/ß-catenin pathway which was corroborated by the expression of EMT-associated proteins in this pathway and its downstream target genes. SOX9 overexpression was also found to enhance the transcriptional activity of TCF/LEF, promote the nuclear translocation of ß-catenin and increase the phosphorylation of GSK3ß at Ser9. Further, inhibition of ß-catenin suppressed the metastasis-promoting effects of SOX9 overexpression. CONCLUSIONS: This study is the first to report that SOX9 is associated with clinical TNM stage and indicates that SOX9 promotes migration, invasion and the EMT process through the Wnt/ß-catenin pathway.

19.
Artigo em Inglês | MEDLINE | ID: mdl-31056514

RESUMO

Human immunodeficiency virus 1 (HIV-1) protease (PR) plays a crucial role in the maturation of the virus. The study of substrate specificity of HIV-1 PR as a new endeavor strives to increase our ability to understand how HIV-1 PR recognizes its various cleavage sites. To predict HIV-1 PR cleavage sites, most of existing approaches have been developed solely based on the homogeneity of substrate sequence information with supervised classification techniques. Although efficient, these approaches are found to be restricted to the ability of explaining their results and probably provide few insights into the mechanisms by which HIV-1 PR cleaves the substrates in a site-specific manner. In this work, a coevolutionary pattern-based prediction model for HIV-1 PR cleavage sites, namely EvoCleave, is proposed by integrating the coevolving information obtained from substrate sequences with a linear SVM classifier. The experiment results showed that EvoCleave yielded a very promising performance in terms of ROC analysis and f-measure. We also prospectively assessed the biological significance of coevolutionary patterns by applying them to study three fundamental issues of HIV-1 PR cleavage site. The analysis results demonstrated that the coevolutionary patterns offered valuable insights into the understanding of substrate specificity of HIV-1 PR.

20.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(4): 401-408, 2019 Apr 30.
Artigo em Chinês | MEDLINE | ID: mdl-31068282

RESUMO

OBJECTIVE: To explore whether bortezomib and a Bcl-2 inhibitor exhibit synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells. METHODS: MTT assay was used to determine the cytotoxicity of bortezomib in the absence or presence of Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) in Jurkat cells. The effects of drug treatment on the expression of Bcl-2 family proteins, LC3B, p62, ubiquitin, BiP/Grp78, p-JNK, p-p38 and CHOP proteins were examined by Western blotting. Flow cytometry was used to determine the effects of bortezomib and Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) on cell apoptosis. Quantitative real-time PCR was used to measure the mRNA expression levels of the key regulatory factors of unfolded protein reaction (UPR). A zebrafish xenograft model was used to study the anti-tumor effect of bortezomib, obatoclax and their combination in vivo. RESULTS: Bortezomib or Bcl-2 inhibitors alone inhibited the cell viability of Jurkat cells, but only obatoclax and bortezomib showed synergistic cytotoxicity and pro-apoptotic effect. Obatoclax, rather than AT-101 and ABT- 199, blocked autophagic flux in the cells evidenced by concomitant accumulation of LC3B-Ⅱ and p62. Both bortezomib and obatoclax alone caused accumulation of polyubiquinated proteins, and their combination showed a synergistic effect, which was consistent with their synergistic cytotoxicity. The dual blockade of proteasome and autophagy by the combination of bortezomib and obatoclax triggered unfolded protein response followed by cell apoptosis. Preventing UPS dysfunction by tauroursodeoxycholic acid (TUDCA) significantly attenuated the cytotoxicity and pro-apoptotic effect of bortezomib in combination with obatoclax. In zebrafish xenograft models, bortezomib combined with obatoclax significantly decreased tumor foci formation. CONCLUSIONS: Bortezomib and obatoclax for dual blockade of protein degradation pathways show synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Antineoplásicos , Apoptose , Bortezomib , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Proteólise , Proteínas Proto-Oncogênicas c-bcl-2 , Pirróis
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