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1.
Invest New Drugs ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33566253

RESUMO

Our previous studies revealed that MYCN downregulates the expression of DKK3, activates the Wnt/ß-catenin signalling pathway at the transcriptional level, and thereby promotes the development of B cell acute lymphocytic leukaemia (B-ALL) but does not affect the methylation of the DKK3 promoter. Some studies have shown that MYCN is associated with histone acetylation. We speculate that histone deacetylase inhibitors (HDACis) can inhibit the Wnt/ß-catenin signalling pathway by inhibiting MYCN and increasing the expression of DKK3. Based on previous experiments, we tested this hypothesis by analysing the changes in MYCN, DKK3 and the Wnt/ß-catenin signalling pathways in B-ALL cells after treatment with the selective HDACi chidamide. The in vitro and in vivo experiments confirmed that chidamide inhibited the expression of MYCN and increased the expression of DKK3 by inhibiting the activity of histone deacetylase, and these effects resulted in inhibition of the Wnt/ß-catenin signalling pathway and the proliferation of B-ALL cells. These findings indicate that chidamide might be used alone or in combination with other chemotherapy regimens for patients with B-ALL and thus provide a new approach to the treatment of B-ALL.

2.
Invest New Drugs ; 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33534026

RESUMO

As a potential cancer therapy, we developed a recombinant adenovirus named Ad-VT, which was designed to express the apoptosis-inducing gene (apoptin) and selectively replicate in cancer cells via E1a manipulation. However, how it performs in bladder cancer remains unclear. We examined the antitumor efficacy of Ad-VT in bladder cancers using CCK-8 assays and xenograft models. Autophagy levels were evaluated by western blotting, MDC staining, and RFP-GFP-LC3 aggregates' analyses. Here, we report the selective replication and antitumor efficacy (viability inhibition and apoptosis induction) of Ad-VT in bladder cancer cells. Using xenograft tumor models, we demonstrate that its effects are tumor specific resulting in the inhibition of tumor growth and improvement of the survival of mice models. Most Importantly, Ad-VT induced a complete autophagy flux leading to autophagic cancer cell death through a signaling pathway involving AMPK, raptor and mTOR. Finally, we suggest that treatment combination of Ad-VT and rapamycin results in a synergistic improvement of tumor control and survival compared to monotherapy. This study suggests that Ad-VT can induce selective autophagic antitumor activities in bladder cancer through the AMPK-Raptor-mTOR pathway, which can be further improved by rapamycin.

3.
J Org Chem ; 86(4): 3367-3376, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33497233

RESUMO

The chemical investigation of the South China Sea soft coral Sinularia humilis has resulted in the isolation of a library of diverse diterpenoids, including four new cembranoids, namely, humilisins A-D (1-4), two new uncommon diterpenoids possessing a tetradecahydrocyclopenta[3',4']cyclobuta[1',2':4,5]cyclonona[1,2-b]oxirene ring system, namely, humilisins E and F (5 and 6), and eight known related compounds (7-14). Humilisin A (1) is the first cembranoid with an ether linkage between C-3 and C-7. The structures and absolute configurations of 1-8 were determined by extensive spectroscopic data analyses, chemical reactions, and a series of quantum chemical calculations including quantum mechanical-nuclear magnetic resonance (QM-NMR), time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD), and optical rotatory dispersion (ORD) methods. In bioassay, compound 6 displayed anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells.

4.
Spectrochim Acta A Mol Biomol Spectrosc ; 251: 119468, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33508683

RESUMO

N-doped carbon dots (N-CDs) were successfully synthesized via simple one-step hydrothermal carbonization using chitosan as carbon and nitrogen sources. The obtained N-CDs contained a variety of functional groups on the NCDs surface, and exhibited excitation-independent behavior and strong blue fluorescence with a relatively higher fluorescence quantum yield (QY = 35%). It also presented excellent water solubility, resistance to pH change, high ion strength and UV irradiation. Since the fluorescence of the N-CDs could be selectively quenched by NO2-, they could act as a fluorescent sensor for the determination of NO2- in real tap water and lake water samples with a wide linear range (1-500 µM) and low detection limit (0.1 µM). They could also be used for bacterial imaging as multicolor fluorescent probes. The results indicated that N-CDs could be a promising candidate material for biomedical applications.

5.
J Orthop Surg (Hong Kong) ; 28(3): 2309499020975212, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33295239

RESUMO

INTRODUCTION: Lumbar spinal stenosis (LSS) is caused by structural changes of the spine, which lead to several severe symptoms, including back pain, leg pain, numbness and tingling in the legs, as well as reduced physical function. However, there is little evidence suggesting whether a patient with LSS should be treated with surgery. If surgery is recommended, which type of surgery benefits the patient most? To answer these questions, we will conduct a network meta-analysis and a systematic review to compare surgical and nonsurgical interventions in terms of efficacy as well as safety in adult patients with LSS. METHODS AND ANALYSIS: We will search the PubMed, Cochrane library, and EMBASE databases for articles published prior to October 10, 2019. We will search for randomized controlled trials assessing surgical and nonsurgical interventions for adult patients with degenerative LSS without any language restrictions. The primary outcome measures will be pain and disability. The secondary outcomes will include adverse events (number of events or number of people with each type of adverse event), reoperations, complications, blood loss and operation time. We will obtain the full texts of the potentially relevant studies and independently assess them. The quality of evidence will be evaluated according to the Grading of Recommendations Assessment, Development and Evaluation framework. A random-effects network meta-analysis will be performed to analyze all the evidence under the frequentist framework, and the ranking results will be presented. We will generate plots depicting the network geometry using Stata. The network meta-analysis will be performed according to the Bayesian framework. Ethics and dissemination Ethics approval is not required. The research will be published in a peer-reviewed journal.

6.
Hematol Oncol ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33300153

RESUMO

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy. Understanding of the molecular pathogenesis may lead to novel therapeutic targets. Rapamycin, the mTOR inhibitor, showed inhibitory effects on T-ALL cells. In this study, we showed that rapamycin significantly reduced MYCN mRNA and protein in a concentration-dependent manner in T-ALL cells. Selective knockdown of MYCN by small interfering RNA had similar effects to rapamycin to inhibit T-ALL proliferation and colony formation and to induce G1-phase cell-cycle arrest and apoptosis. The inhibitory effects of rapamycin and MYCN depletion were also found in a Molt-4 xenograft model. Rapamycin and MYCN inhibition suppressed both Wnt/ß-catenin and mTOR signaling pathways. The results suggest the effects of rapamycin on adult T-ALL is likely mediated by downregulation of MYCN. The findings suggest MYCN a potential target for the treatment of adult T-ALL. Additionally, dual-targeting of mTOR and Wnt/ß-catenin pathways may represent a novel strategy in the treatment of adult T-ALL. This article is protected by copyright. All rights reserved.

7.
J Cell Mol Med ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33305893

RESUMO

Apoptin can specifically kill cancer cells but has no toxicity to normal cells. Human telomerase reverse transcriptase (hTERT) can act as a tumour-specific promoter by triggering the expression of certain genes in tumour cells. This study aims to investigate the inhibitory effects and to explore the inhibitory pathway of a dual cancer-specific recombinant adenovirus (Ad-apoptin-hTERTp-E1a, Ad-VT) on breast cancer stem cells. Breast cancer cell spheres were obtained from MCF-7 cells through serum-free suspension culture. The cell spheres were detected by flow cytometry for CD44+ CD24- cell subsets. The stemness of MCF-7-CSC cells was confirmed by in vivo tumorigenesis experiments. The inhibitory effect of the recombinant adenoviruses on MCF-7-CSC cells was evaluated by CCK-8 assay. In addition, the stemness of adenovirus-infected MCF-7-CSC cells was analysed by testing the presence of CD44+ CD24- cell subsets. The ability of the recombinant adenovirus to induce MCF-7-CSC cell apoptosis was detected by staining JC-1, TMRM and Annexin V. Our results showed that a significantly higher proportion of the CD44+ CD24- cell subsets was present in MCF-7-CSC cells with a significantly increased expression of stem cell marker proteins. The MCF-7-CSC cells, whlist exhibited a strong tumorigenic ability with a certain degree of stemness in mice, were shown to be strongly inhibited by recombinant adenovirus Ad-VT through cell apoptosis. In addition, Ad-VT was shown to exert a killing effect on BCSCs. These results provide a new theoretical basis for the future treatment of breast cancer.

8.
Math Biosci Eng ; 17(6): 6573-6600, 2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-33378867

RESUMO

This paper proposed a novel image interpolation algorithm with an arbitrary upscaling factor based on the spatial general autoregressive model. First, to accommodate arbitrary scale factors, a non-integer mapping method was modulated into the spatial general autoregressive model, which was employed to model the piecewise stationary pattern with a higher description capacity than autoregressive models. A gradient angle guided extension method was utilized to extend the spatial general autoregressive model, and more pixels in the neighborhood were included to estimate the parameters of the spatial general autoregressive model. To realize the high-accuracy estimation of the model parameters, a regularization method via an elastic network was adopted to maintain the complexity of the object function in a reasonable state and address the overfitting problem. We also introduced an iterative curvature method to refine the interpolation result of those image blocks with large variances of gray intensities. Experiments on 25 images were conducted with integer and non-integer magnification factors to systematically verify the objective and subjective measures of the proposed method. The visual artifacts were effectively suppressed by the proposed method, and a flexible interpolation method for arbitrary scale factors was implemented.

9.
Zhonghua Nan Ke Xue ; 26(5): 436-440, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-33354953

RESUMO

Objective: To explore the application of psychological nursing in patients with genital herpes receiving acyclovir combined with thymosin and its effect on the incidence of adverse reactions. METHODS: A total of 160 patients with genital herpes treated with acyclovir plus thymosin in our hospital from January 2016 to December 2018 were randomly allocated to receive conventional nursing (the control group, n = 80) and psychological nursing (the trial group, n = 80). Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) were used to evaluate the anxiety and depression of the patients, and comparisons were made between the two groups of patients in their SAS and SDS scores, the incidence of adverse reactions and their satisfaction with nursing intervention. RESULTS: After nursing intervention, the patients of the trial group, compared with the controls, showed significantly lower SAS scores (39.05 ± 2.97 vs 45.71 ± 3.36, P < 0.01), SDS scores (41.74 ± 2.86 vs 47.28 ± 3.95, P < 0.01), and incidence of adverse reactions (22.50% vs 47.50%, P < 0.05), but a markedly higher rate of satisfaction with nursing intervention (95.00% vs 77.5%, P < 0.01). CONCLUSIONS: Psychological nursing can reduce the incidence of adverse reactions in genital herpes patients receiving acyclovir combined with thymosin and meanwhile improve the mental status of the patients by alleviating their anxiety and depression.


Assuntos
Aciclovir/uso terapêutico , Herpes Genital/tratamento farmacológico , Herpes Genital/enfermagem , Timosina/uso terapêutico , Aciclovir/efeitos adversos , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Herpes Genital/psicologia , Humanos , Incidência , Satisfação do Paciente , Timosina/efeitos adversos
10.
Int J Surg ; 85: 19-28, 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33253898

RESUMO

BACKGROUND: Conventional paired meta-analyses have shown inconsistent results regarding the safety and efficacy of different interventions. OBJECTIVE: To perform a network meta-analysis (NMA) and systematic review based on randomized controlled trials (RCTs) evaluating the efficacies of different interventions for lumbar spinal stenosis (LSS). METHODS: We searched PubMed, Embase, Cochrane Library, Web of Science, and major scientific websites from inception to October 10, 2019, for randomized controlled trials comparing the nine most commonly used interventions for LSS. The main outcomes were disability and pain intensity. The PROSPERO number was CRD42020154247. RESULTS: First, laminotomy was better in improving patients' short- and long-term dysfunction (probability 49% and 25%, respectively). Second, decompression, decompression plus fusion, endoscopic decompression, interspinous process spacer device implantation, laminectomy, laminotomy and minimally invasive decompression were significantly more efficacious in relieving pain than non-surgical interventions (mean difference in the short-term -21.82, -22.00, -16.68, -17.47, -17.75, -17.61 and -18.86; in the long-term -37.14, -34.04, -34.07, -39.79, -36.14, -32.75 and -39.14, respectively). Third, endoscopic decompression had a lower complication rate (probability 51%). In addition, laminotomy had a lower reoperation rate (probability 45%). Fourth, decompression plus fusion resulted in more blood loss than any other surgical intervention (probability 96%). Finally, endoscopic decompression had the shortest hospitalization time (probability 96%). CONCLUSIONS: There were no significant differences among the different interventions in improving patient function. Surgical interventions were associated with better pain relief but a higher incidence of complications. Decompression plus fusion is not necessary for patients. In addition, endoscopic decompression as a novel and less invasive surgical approach may be a good choice for LSS patients.

11.
FEBS Lett ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33053208

RESUMO

The four-and-a-half LIM domain protein 1 (FHL1) plays a key role in multiple cancers. Here, we characterized its role in glioblastoma (GBM), the most common and incurable form of brain cancer. Overexpression of FHL1 promotes growth, migration, and invasion of GBM cells in vivo and in vitro. In contrast, FHL1 silencing by RNAi exhibits the opposite effects. FHL1 interacts with the transcription factor SP1 to upregulate epidermal growth factor receptor (EGFR) expression and activate the downstream signaling cascades, including Src, Akt, Erk1/2, and Stat3, leading to GBM malignancy. FHL1 is highly expressed and positively correlated with EGFR levels in human GBM, particularly those of the classical subtype. Our results suggest that the FHL1-SP1-EGFR axis plays a tumor-promoting role, and highlight the translational potential of inhibiting FHL1 for GBM treatment.

12.
Front Pharmacol ; 11: 578091, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117170

RESUMO

Lung cancer is one of the most common cancers and the leading cause of cancer-related deaths worldwide. Most of these patients with non-small cell lung cancer (NSCLC) present with the advanced stage of the disease at the time of diagnosis, and thus decrease the 5-year survival rate to about 5%. Immune checkpoint inhibitors (ICIs) can act on the inhibitory pathway of cancer immune response, thereby restoring and maintaining anti-tumor immunity. There are already ICIs targeting different pathways, including the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) pathway. Since March 2015, the US Food and Drug Administration (FDA) approved nivolumab (anti-PD-1 antibody) as the second-line option for treatment of patients with advanced squamous NSCLC. Additionally, a series of inhibitors related to PD-1/PD-L1 immune-checkpoints have helped in the immunotherapy of NSCLC patients, and modified the original treatment model. However, controversies remain regarding the use of ICIs in a subgroup with targeted oncogene mutations is a problem that we need to solve. On the other hand, there are continuous efforts to find biomarkers that effectively predict the response of ICIs to screen suitable populations. In this review, we have reviewed the history of the continuous developments in cancer immunotherapy, summarized the mechanism of action of the immune-checkpoint pathways. Finally, based on the results of the first-line recent trials, we propose a potential first-line immunotherapeutic strategy for the treatment of the patients with NSCLC.

13.
Analyst ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33078789

RESUMO

In this work, amino acids (AAs) including serine (S), histidine (H) and glutamic acid (E)-conjugated poly(3-thiophene acetate acid) (P3TAA) were synthesized to promote the catalytic hydrolysis and in situ electrochemical detection of organophosphorus pesticides (OPs). The hydrolysis of OPs followed the mechanism of proton transfer relay composed of AAs of S, H, E, called the "catalytic triad", found in biomimetic hydrolases. P3TAA was used as a carrier to attach S, H, E, and these AA sites have the hydrolysis activity of Ops; the polymer P3TAA-AAs behaved like biomimetic enzymes. After the hydrolysis of OPs (e.g., methyl paraoxon, ethyl paraoxon and methyl parathion), p-nitrophenol (PNP) was generated, which can be detected electrochemically. Herein, an electrochemical method using P3TAA-conjugated S, H, E-modified electrodes for the determination of OPs was developed. OPs can be quantified by the electrochemical responses of PNP. This technique was selective toward OPs with the p-nitrophenol group. The detection limit of OPs (methyl paraoxon, methyl parathion and ethyl paraoxon) reached 0.5 µM. This detection technique was successfully applied to the detection of OPs in real samples with high detection accuracy.

14.
Plant Cell Physiol ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33079183

RESUMO

Plants possess a regeneration capacity that enables them to survive after wounding. For example, detached Arabidopsis thaliana leaves are able to form adventitious roots from their cutting sites even in the absence of exogenous hormone supplements; as process termed de novo root regeneration (DNRR). Wounding rapidly induces auxin biosynthesis at the cutting sites and then elicits a signaling cascade to promote cell fate transitions and finally generate the adventitious roots. However, rooting rates in older plants are much lower than in younger leaf explants. In this review, we highlight the recent breakthroughs in the understanding of DNRR decay in older plants from at least two independent signaling routes: (1) via the accumulation of EIN3 protein in older plants, which directly suppresses expression of WUSCHEL RELATED HOMEOBOX (WOX) genes to inhibit rooting; (2) the miR156-SPLs-AP2/ERFs pathway, which modulates root regeneration by reducing auxin biosynthesis.

15.
Research (Wash D C) ; 2020: 3405826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33083787

RESUMO

The intrinsically rigid and limited strain of most conjugated polymers has encouraged us to optimize the extensible properties of conjugated polymers. Herein, learning from the hydrogen bonds in glucose, which were facilitated to the toughness enhancement of cellulose, we introduced interchain hydrogen bonds to polydiarylfluorene by amide-containing side chains. Through tuning the copolymerization ratio, we systematically investigated their influence on the hierarchical condensed structures, rheology behavior, tensile performances, and optoelectronic properties of conjugated polymers. Compared to the reference copolymers with a low ratio of amide units, copolymers with 30% and 40% amide units present a feature of the shear-thinning process that resembled the non-Newtonian fluid, which was enabled by the interchain dynamic hydrogen bonds. Besides, we developed a practical and universal method for measuring the intrinsic mechanical properties of conjugated polymers. We demonstrated the significant impact of hydrogen bonds in solution gelation, material crystallization, and thin film stretchability. Impressively, the breaking elongation for P4 was even up to ~30%, which confirmed the partially enhanced film ductility and toughness due to the increased amide groups. Furthermore, polymer light-emitting devices (PLEDs) based on these copolymers presented comparable performances and stable electroluminescence (EL). Thin films of these copolymers also exhibited random laser emission with the threshold as low as 0.52 µJ/cm2, suggesting the wide prospective application in the field of flexible optoelectronic devices.

16.
Cell Transplant ; 29: 963689720963936, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33028108

RESUMO

We have previously reported that miR-9 promotes the homing, proliferation, and angiogenesis of endothelial progenitor cells (EPCs) by targeting transient receptor potential melastatin 7 via the AKT autophagy pathway. In this way, miR-9 promotes thrombolysis and recanalization following deep vein thrombosis (DVT). However, the influence of miR-9 on messenger RNA (mRNA) expression profiles of EPCs remains unclear. The current study comprises a comprehensive exploration of the mechanisms underlying the miR-9-regulated angiogenesis of EPCs and highlights potential treatment strategies for DVT. We performed RNA sequence analysis, which revealed that 4068 mRNAs were differentially expressed between EPCs overexpressing miR-9 and the negative control group, of which 1894 were upregulated and 2174 were downregulated. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that these mRNAs were mainly involved in regulating cell proliferation/migration processes/pathways and the autophagy pathway, both of which represent potential EPC-based treatment strategies for DVT. Reverse transcriptase quantitative polymerase chain reaction confirmed the changes in mRNA expression related to EPC angiogenesis, migration, and autophagy. We also demonstrate that miR-9 promotes EPC migration and angiogenesis by regulating FGF5 directly or indirectly. In summary, miR-9 enhances the expression of VEGFA, FGF5, FGF12, MMP2, MMP7, MMP10, MMP11, MMP24, and ATG7, which influences EPC migration, angiogenesis, and autophagy. We provide a comprehensive evaluation of the miR-9-regulated mRNA expression in EPCs and highlight potential targets for the development of new therapeutic interventions for DVT.

17.
J Diabetes Res ; 2020: 2583257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123595

RESUMO

Aims: Obesity is highly associated with type 2 diabetes mellitus (T2DM). The TIM3/galectin-9 pathway plays an important role in immune tolerance. Herein, we aimed to investigate the expression of TIM3 and galectin-9 in peripheral blood and to evaluate their clinical significance in patients with obesity and obesity-related T2DM. Methods: We performed flow cytometry on peripheral blood samples from healthy donors (HC), patients with simple obesity (OB), and patients with obesity comorbid T2DM (OD). The expression of TIM3 on CD3+, CD4+, and CD8+ T cells was determined. The level of galectin-9 in plasma was detected by ELISA. Results: We demonstrated the enhancement of TIM3 on CD3+, CD4+, and CD8+ T cells in the OB group when compared with healthy controls, while it was decreased significantly in the OD group. The TIM3+CD8+ T cells of the OB group were positively correlated with risk factors including BMI, body fat rate, and hipline. The concentration of galectin-9 of the OD group in plasma was significantly higher than that of healthy donors and the OB group. Moreover, the level of galectin-9 of the OD group was positively correlated with fasting insulin and C-peptide, which were two clinical features that represented pancreatic islet function in T2DM. Conclusions: Our results suggested that TIM3 and galectin-9 may be potential biomarkers related to the pathogenesis of obesity-related T2DM.

18.
J Int Med Res ; 48(8): 300060520930856, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32865094

RESUMO

OBJECTIVE: Complications frequently occur in patients with breast cancer after surgery. Anesthesia nursing plays an important role in decreasing complications for such patients. Thus, this study investigated the effects of anesthesia with intensive care nursing (AICN) on complication rates in patients with breast cancer after surgery. METHODS: Eighty-two patients with breast cancer were recruited in this study. Complications were compared between the anesthesia with usual nursing care (AUCN) and AICN groups. RESULTS: The results demonstrated that AICN decreased the rates of incision infection, drug extravasation, and catheter exposure, as well as pain and inflammation scores, compared with the findings in the AUCN group. AICN improved the time to orientation and decreased the incidence of nausea, anxiety, depression, and vomiting versus AUCN. In addition, AICN shortened the time to awakening after anesthesia compared with the effects of AUCN. Furthermore, AICN shortened hospital stay and increased survival rates. Notably, AICN improved health-related quality of life as measured using the EORTC QLQ-C30 questionnaire. CONCLUSION: AICN provided more benefits and better postoperative outcomes than AUCN, suggesting its utility for minimizing complications in patients with breast cancer after surgery.

19.
Mol Pharmacol ; 98(5): 586-597, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32938721

RESUMO

This study investigated the roles of transient receptor potential (TRP) ankyrin-1 (TRPA1) and TRP vanilloid-3 (TRPV3) in regulating endoplasmic reticulum stress (ERS) and cytotoxicity in human bronchial epithelial cells (HBECs) treated with pneumotoxic wood smoke particulate matter (WSPM) and chemical agonists of each channel. Functions of TRPA1 and TRPV3 in pulmonary epithelial cells remain largely undefined. This study shows that TRPA1 activity localizes to the plasma membrane and endoplasmic reticulum (ER) of cells, whereas TRPV3 resides primarily in the ER. Additionally, treatment of cells using moderately cytotoxic concentrations of pine WSPM, carvacrol, and other TRPA1 agonists caused ERS as a function of both TRPA1 and TRPV3 activities. Specifically, ERS and cytotoxicity were attenuated by TRPA1 inhibition, whereas inhibiting TRPV3 exacerbated ERS and cytotoxicity. Interestingly, after treatment with pine WSPM, TRPA1 transcription was suppressed, whereas TRPV3 was increased. TRPV3 overexpression in HBECs conferred resistance to ERS and an attenuation of ERS-associated cell cycle arrest caused by WSPM and multiple prototypical ERS-inducing agents. Alternatively, short hairpin RNA-mediated knockdown of TRPV3, like the TRPV3 antagonist, exacerbated ERS. This study reveals previously undocumented roles for TRPA1 in promoting pathologic ERS and cytotoxicity elicited by pneumotoxic WSPM and TRPA1 agonists, and a unique role for TRPV3 in fettering pathologic facets of the integrated ERS response. SIGNIFICANCE STATEMENT: These findings provide new insights into how wood smoke particulate matter and other transient receptor potential ankyrin-1 (TRPA1) and transient receptor potential vanilloid-3 (TRPV3) agonists can affect human bronchial epithelial cells and highlight novel physiological and pathophysiological roles for TRPA1 and TRPV3 in these cells.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Material Particulado/administração & dosagem , Fumaça/efeitos adversos , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Linhagem Celular , Cimenos/efeitos adversos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Células Epiteliais/metabolismo , Células HEK293 , Humanos , Pulmão/metabolismo , Pinus/efeitos adversos , Canais de Receptores Transientes de Potencial/metabolismo , Madeira/efeitos adversos
20.
Cell Death Dis ; 11(8): 695, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32826874

RESUMO

Endothelial to mesenchymal transition (EndMT) is an important pathological change in many diseases. Semaphorin7A (Sema7A) has been reported to regulate nerve and vessel homeostasis, but its role in EndMT remains unclear. Here we investigate the effect of Sema7A on EndMT and the underlying mechanism. Sema7A-overexpressed human umbilical vein endothelial cells (Sema7A-HUVECs) were generated and showed lower levels of endothelial cell markers and higher levels of mesenchymal cell markers indicating the occurrence of EndMT. RNA-sequencing analysis showed a total of 1168 upregulated genes and 886 downregulated genes. Among them, most of the molecules associated with EndMT were upregulated in Sema7A-HUVECs. Mechanistically, Sema7A-HUVECs showed a higher TGF-ß2 expression and activated TGF-ß/Smad Signaling. Importantly, Sema7A overexpression upregulated activating transcription factor 3 (ATF3) that was found to selectively bind the promotor region of TGF-ß2, but not TGF-ß1, promoting TGF-ß2 transcription, which was further confirmed by ATF3-siRNA knockdown approach. Blocking ß1 integrin, a known Sema7A receptor, alleviated the expression of ATF3, TGF-ß2, and EndMT in Sema7A-overexpressed HUVECs, implying a role of ß1 integrin/ATF3/TGF-ß2 axis in mediating Sema7A-induced EndMT. Using Sema7A-deficient mice and the partial carotid artery ligation (PCL) model, we showed that Sema7A deletion attenuated EndMT induced by blood flow disturbance in vivo. In conclusion, Sema7A promotes TGF-ß2 secretion by upregulating transcription factor ATF3 in a ß1 integrin-dependent manner, and thus facilitates EndMT through TGF/Smad signaling, implying Sema7A as a potential therapeutic target for EndMT-related vascular diseases.

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