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1.
Biochim Biophys Acta Mol Basis Dis ; 1866(3): 165625, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785406

RESUMO

One of the hallmarks of cancer progression is strong drug resistance during clinical treatments. The tumor microenvironment is closely associated with multidrug resistance, the optimization of tumor microenvironments may have a strong therapeutic effect. In this study, we configured polyacrylamide hydrogels of varying stiffness [low (10 kPa), intermediate (38 kPa) and high (57 kPa)] to simulate tissue physical matrix stiffness across different stages of breast cancer. After treatment with doxorubicin, cell survival rates on intermediate stiffness substrate are significantly higher. We find that high expression of ILK and YAP reduces the survival rates of breast cancer patients. Drug resistance is closely associated with the inactivation of the hippo pathway protein Merlin/MST/LATS and the activation of YAP. These results not only highlight the understanding of drug resistance mechanisms but also serve as a new basis for developing breast cancer treatment delivery systems.

2.
Plant Cell Environ ; 43(2): 293-302, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31675441

RESUMO

Both seed germination and early seedling establishment are important biological processes in a plant's lifecycle. Seed longevity is a key trait in agriculture, which directly influences seed germination and ultimately determines crop productivity and hence food security. Numerous studies have demonstrated that seed deterioration is regulated by complex interactions between diverse endogenous genetically controlled factors and exogenous environmental cues, including temperature, relative humidity, and oxygen partial pressure during seed storage. The endogenous factors, including the chlorophyll concentration, the structure of the seed coat, the balance of phytohormones, the concentration of reactive oxygen species, the integrity of nucleic acids and proteins and their associated repair systems, are also involved in the control of seed longevity. A precise understanding of the regulatory mechanisms underlying seed longevity is becoming a hot topic in plant molecular biology. In this review, we describe recent research into the regulation of seed longevity and the interactions between the various environmental and genetic factors. Based on this, the current state-of-play regarding seed longevity regulatory networks will be presented, particularly with respect to agricultural seed storage, and the research challenges to be faced in the future will be discussed.

3.
Brain Res ; 1726: 146503, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31605698

RESUMO

Baicalin (BA) is a major active component from the traditional Chinese medicine, which has been widely used to treat brain diseases. Previously, the baicalin liposome (BA-LP) was prepared to improve its low bioavailability. However, the existence of the obstacles such as the blood-brian-barrier (BBB) still make it difficult to enter brain effectively. Meanwhile, many reports have shown that drugs can be transported into brain through intranasal administration without the BBB. Therefore, we aim to explore the effect of BA-LP on middle cerebral artery occlusion (MCAO) rats via i.n. administration. The results showed that BA and BA-LP had no obvious impact on mucosa after i.n. administration. And in pharmacokinetics study after i.n. administration, the value of t 1/2 and AUC 0-t in BA-LP group were significantly higher than that of the BA group (p < 0.05), indicating BA-LP could prolong the extension time of BA in vivo and further improve the bioavailability. In the brain biodistribution, the BA-LP group showed a higher BA concentration in brain tissues. Pharmacodynamics studies showed that BA-LP through i.n. administration could significantly improve the neurological deficits, cerebral infarction and brain pathological status in rats with MCAO surgery. Obviously, the BA-LP was more effective after nasal administration than intravenous administration, suggesting the nasal administration is more advantageous route in brain concentration enrichment. In conclusion, BA-LP could be safely used in i.n. administration, which can effectively improve brain targeting effect and thus protect the MCAO rats. Furthermore, successful use of the BA-LP via nasal delivery can provide a model for other drugs with neuroprotective effect and further promote the cure rate of brain diseases.

4.
Int J Nanomedicine ; 14: 9497-9512, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819446

RESUMO

Background: Critical-sized bone defects raise great challenges. Zein is of interest for bone regeneration, but it has limited ability to stimulate cell proliferation. In this regard, a poly (aspartic acid) (PAsp)-zein hybrid is promising, as PAsp can promote rat bone marrow stromal cell (rBMSCs) proliferation and osteogenic differentiation. This research aimed to develop electrospun PAsp-modified zein nanofibers to realize critical-sized bone defects repair. Methods: Three groups of PAsp-modified zein nanofibers were prepared, they were PAsp grafting percentages of 0% (zein), 5.32% (ZPAA-1), and 7.63% (ZPAA-2). Using rBMSCs as in vitro cell model and SD rats as in vivo animal model, fluorescence staining, SEM, CCK-8, ALP, ARS staining, µCT and histological analysis were performed to verify the biological and osteogenic activities for PAsp-modified zein nanofibers. Results: As the Asp content increased from 0% to 7.63%, the water contact angle decreased from 129.8 ± 2.3° to 105.5 ± 2.5°. SEM, fluorescence staining and CCK-8 assay showed that ZPAA-2 nanofibers had a superior effect on rBMSCs spreading and proliferation than did zein and ZPAA-1 nanofibers, ALP activity and ARS staining showed that ZPAA-2 can improve rBMSCs osteogenic differentiation. In vivo osteogenic activities was evaluated by µCT analysis, HE, Masson and immunohistochemical staining, indicating accelerated bone formation in ZPAA-2 SD rats after 4 and 8 weeks treatment, with a rank order of ZPAA-2 > ZPAA-1 > zein group. Moreover, the semiquantitative results of the Masson staining revealed that the maturity of the new bone was higher in the ZPAA-2 group than in the other groups. Conclusion: Electrospun PAsp-modified zein can provide a suitable microenvironment for osteogenic differentiation of rBMSCs, as well as for bone regeneration; the optimal membrane appears to have a PAsp grafting percentage of 7.63%.

5.
Retina ; 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31860522

RESUMO

PURPOSE: To report the surgical outcomes of primary rhegmatogenous retinal detachment (RRD) repaired by 27-gauge pars plana vitrectomy combined with Healaflow patch and air tamponade. METHODS: In an initial vitro experiment, we observed and compared the dissolution and displacement of the dispersion spots of 0.05-mL Healaflow and sodium hyaluronate. We then performed a prospective, interventional cohort study on 38 eyes in 37 consecutive patients with primary rhegmatogenous retinal detachment. All eyes underwent pars plana vitrectomy combined with Healaflow patch and air tamponade; the postoperative period did not involve prone positioning. The primary and final anatomical attachment rate, best-corrected visual acuity, and intraoperative and postoperative complications were evaluated. RESULTS: In the in vitro experiment, the viscoelastic Healaflow remained adherent with no change in the size of the area; however, the control dissolved completely in the balance solution. The patient study included 16 women (43.2%) and 21 men (56.8%) (mean age, 59.5 ± 9.5 years; mean follow-up period, 8.9 ± 3.8 months). A single break was present in 21 (55.3%) and 2 to 5 breaks in 17 cases (44.8%). The macula was involved in 25 (65.8%) and attached in 13 cases (34.2%) intraoperatively. Initial reattachment was achieved in 37 (97.4%) and final reattachment in 38 cases (100%). In one case (2.6%), the macula redetached because of failure of the chorioretinal scar to develop around the treated break. Mean preoperative and postoperative best-corrected visual acuities were 1.02 ± 0.82 logarithm of the minimum angle of resolution (median Snellen acuity: 20/125, range: 20/20,000-20/20) and 0.23 ± 0.17 logarithm of the minimum angle of resolution (median Snellen acuity: 20/32, range: 20/100-20/20), respectively (P < 0.001). Intraocular pressure was elevated transiently in 28 eyes (73.7%). There were no other intraoperative complications or postoperative scleral incision leakage. CONCLUSION: A 27-gauge pars plana vitrectomy combined with Healaflow patch, and air tamponade results in a high reattachment rate in the treatment of rhegmatogenous retinal detachment. Thus, patients can benefit from early visual recovery and less complications.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31749434

RESUMO

Autophagy, an intricate response to nutrient deprivation, pathogen infection, Endoplasmic Reticulum (ER)-stress and drugs, is crucial for homeostatic maintenance in living cells. This highly regulated, multi-step process has been involved in several diseases including cardiovascular and neurodegenerative diseases, especially in cancer. It can function as either a promoter or a suppressor in cancer, which underlining the potential utility as a therapeutic target. In recent years, increasing evidence has suggested that many natural products could modulate autophagy through diverse signaling pathways, either inducing or inhibiting. In this review, we briefly introduce autophagy and systematically describe several classes of natural products that implicated in autophagy modulation. These compounds are of great interest for their potential activity against many types of cancer, such as ovarian, breast, cervical, pancreatic, and so on, hoping to provide valuable information for the development of cancer treatments based on autophagy.

7.
ACS Appl Mater Interfaces ; 11(47): 43865-43878, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31684723

RESUMO

To realize precise tumor therapy, a versatile oncotherapy nanoplatform integrating both diagnostic and therapeutic functions is necessary. Herein, we fabricated a hybrid micelle (HM) utilizing two amphiphilic diblock copolymers, polyethylenimine-polycaprolactone (PEI-PCL) and diethylenetriaminepentaacetic acid gadolinium(III)  (Gd-DTPA)-conjugated polyethyleneglycol-polycaprolactone (Gd-PEG-PCL), to codeliver the small-molecule chemotherapy drugs doxorubicin (Dox) and microRNA-34a (miR-34a), denoted as Gd-HM-Dox/34a. Conjugating Gd-DTPA on the surface of hybrid micelles, leading the relaxation rate of Gd-DTPA increased more than 1.4 times (13.6 mM-1 S-1). Furthermore, hybrid micelles enhanced the ability of miR-34a to escape from lysosomes/endosomes and Dox release to the nucleus. In addition, the released miR-34a subsequently downregulates Bcl-2, cyclin D1, CDK6, and Bax expression and inhibits proliferation and migration of MDA-MB-231 breast cancer cells. Moreover, the suitable micelle size improved the penetration of Dox into three-dimensional (3D) multicellular spheroids compared with Gd-HM-Dox and Free Dox, generating efficient cell killing in the 3D multicellular spheroids. Furthermore, the Gd-HM-Dox/34a exhibited augmented accumulation in the tumor tissue, which improved the magnetic resonance (MR) imaging contrast of solid tumors and enhanced the combined efficiency of chemotherapeutic drugs Dox and therapeutic gene miR-34a in suppressing tumor growth on MDA-MB-231 tumor-bearing mice. Therefore, we established a hybrid micelle to offer a promising theranostic approach that inhibits tumor growth and enhances MR imaging.

8.
Sci Rep ; 9(1): 13258, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519965

RESUMO

This study presents the generalization of geometric phases in density matrices. We show that the extended sub-geometric phase has an unified expression during the adiabatic or nonadiabatic process and establish the relations between them and the usual Berry or Aharonov-Anandan phases. We also demonstrate the influence of sub-geometric phases on the physical observables. Finally, the above treatment is used to investigate the geometric phase in a mixed state.

9.
Theranostics ; 9(20): 5784-5796, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534519

RESUMO

Background & Aims: The use of antisense oligonucleotide-based nanosystems for the detection and regulation of tumor-related gene expression is thought to be a promising approach for cancer diagnostics and therapies. Herein, we report that a cubic-shaped iron oxide nanoparticle (IONC) core nanobeacon is capable of delivering an HSP90α mRNA-specific molecular beacon (HSP90-MB) into living cells and enhancing T 2-weighted MR imaging in a tumor model. Methods: The nanobeacons were built with IONC, generation 4 poly(amidoamine) dendrimer (G4 PAMAM), Pluronic P123 (P123) and HSP90-MB labeled with a quencher (BHQ1) and a fluorophore (Alexa Fluor 488). Results: After internalization by malignant cells overexpressing HSP90α, the fluorescence of the nanobeacon was recovered, thus distinguishing cancer cells from normal cells. Meanwhile, MB-mRNA hybridization led to enzyme activity that degraded DNA/RNA hybrids and resulted in downregulation of HSP90α at both the mRNA and protein levels. Furthermore, the T 2-weighted MR imaging ability of the nanobeacons was increased after PAMAM and P123 modification, which exhibited good biocompatibility and hemocompatibility. Conclusions: The nanobeacons show promise for applicability to tumor-related mRNA detection, regulation and multiscale imaging in the fields of cancer diagnostics and therapeutics.

11.
Oncol Lett ; 18(3): 2977-2984, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31452776

RESUMO

Treatment strategies involving tyrosine kinase inhibitors (TKIs) for patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations have advanced significantly; however, challenges still remain regarding the development of resistance. It has been reported that receptor tyrosine kinase-like orphan receptor 1 (ROR1) acts as a hepatocyte growth factor receptor (MET) and c-Src substrate, and that the extracellular domain of ROR1 is associated with EGFR to sustain EGFR-ERBB3-PI3K signaling. Our previous study reported that blocking ROR1 significantly decreased the activity of key signal molecules in the AKT/mammalian target of rapamycin (mTOR) signaling pathway, which was associated with a significant increase of apoptosis and significant decrease of proliferation of lung adenocarcinoma cells. The present study hypothesized that inhibiting ROR1 could potentially prevent erlotinib resistance in NSCLC cell lines. Investigations were performed with two erlotinib-resistant cell lines XLA-07 and NCI-H1975, and an erlotinib-acquired-resistant cell line PC-9erlo, which was developed from its parental cell line PC-9. It was identified that the inhibition of ROR1 via small interfering RNA treatment significantly improved the anti-proliferation and apoptosis-inducing roles of erlotinib in TKI-resistant tumor cells. This was in accordance with the activity of key molecules of the AKT/mTOR signaling pathway, including glycogen synthase kinase-3α/ß (GSK-3α/ß), phosphatase and tensin homolog (PTEN), AKT, mTOR and ribosomal protein S6 kinase ß-1 (p70S6K). The current data suggest that targeting ROR1 is a potential novel treatment strategy for patients with ROR1-positive NSCLC, particularly those with acquired resistance to EGFR-TKI.

12.
Environ Pollut ; 252(Pt A): 216-226, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31151060

RESUMO

Microcystins (MCs) have been shown to be carcinogenic by animal and cellular experiments and found to be associated with the development of human hepatocellular carcinoma (HCC) through epidemiological studies. However, the molecular mechanism of microcystin-LR (MC-LR) induced HCC is still unclear. This study is determined to clarify the role and mechanism of LHX6 in MC-LR-induced hepatocarcinogenesis. Using the previously established MC-LR-induced malignant transformation model in L02 cells, we screened out LHX6, homeobox gene that was significantly changed. We found that LHX6 was significantly down-regulated in MC-LR treated L02 cells and the liver tissue of rats treated for 35 weeks with 10 µg/kg body weight of MC-LR. Expression of LHX6 in human tumor tissue was significantly down-regulated in high MC-LR-exposure group. LHX6 was hypermethylated in MC-LR treated L02 cells and up-regulated after treatment with 10 µM of 5-aza-2'-deoxycytidine. Furthermore, overexpression of LHX6 inhibited proliferation, invasion and migration of malignantly transformed L02 cells in vitro and in vivo, while knockdown of LHX6 resulted in an opposite phenotype. In addition, we found that up-regulation of P53 and Bax resulted in apoptosis, and that down-regulation of CTNNB1 and MMP7 led to migration of MC-LR treated L02 cells. Blockade of P53 and CTNNB1 by its inhibitor significantly diminished the effect of LHX6. These genes were working together during the process of MC-LR-induced hepatocarcinogenesis. Our study demonstrated for the first time that LHX6 gene expression is regulated by DNA methylation and can inhibit the proliferation, invasion and migration through Wnt/ß-catenin and P53 signaling pathways during the MC-LR-induced hepatocarcinogenesis. This result may suggest that LHX6 gene can be used as a potential target gene and a biomarker for liver cancer treatment.


Assuntos
Carcinoma Hepatocelular/induzido quimicamente , Transformação Celular Neoplásica/induzido quimicamente , Proteínas com Homeodomínio LIM/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Microcistinas/toxicidade , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Epigênese Genética , Humanos , Proteínas com Homeodomínio LIM/genética , Metaloproteinase 7 da Matriz/metabolismo , Proteínas do Tecido Nervoso/genética , Ratos , Transdução de Sinais , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismo
13.
BMC Plant Biol ; 19(1): 269, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226949

RESUMO

BACKGROUND: The Growth-regulating factor (GRF) family encodes plant-specific transcription factors which contain two conserved domains, QLQ and WRC. Members of this family play vital roles in plant development and stress response processes. Although GRFs have been identified in various plant species, we still know little about the GRF family in soybean (Glycine max). RESULTS: In the present study, 22 GmGRFs distributed on 14 chromosomes and one scaffold were identified by searching soybean genome database and were clustered into five subgroups according to their phylogenetic relationships. GmGRFs belonging to the same subgroup shared a similar motif composition and gene structure. Synteny analysis revealed that large-scale duplications played key roles in the expansion of the GmGRF family. Tissue-specific expression data showed that GmGRFs were strongly expressed in growing tissues, including the shoot apical meristems, developing seeds and flowers, indicating that GmGRFs play critical roles in plant growth and development. On the basis of expression analysis of GmGRFs under shade conditions, we found that all GmGRFs responded to shade stress. Most GmGRFs were down-regulated in soybean leaves after shade treatment. CONCLUSIONS: Taken together, this research systematically analyzed the characterization of the GmGRF family and its primary roles in soybean development and shade stress response. Further studies of the function of the GmGRFs in the growth, development and stress tolerance of soybean, especially under shade stress, will be valuable.


Assuntos
Proteínas de Plantas/genética , Soja/genética , Fatores de Transcrição/genética , Cromossomos de Plantas , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Luz , Proteínas de Plantas/metabolismo , Soja/metabolismo , Estresse Fisiológico , Sintenia , Fatores de Transcrição/metabolismo , Transcriptoma
14.
Sci Total Environ ; 683: 317-330, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31132711

RESUMO

Recent studies have shown that microcystin-LR (MC-LR) is one of the principal factors that cause liver cancer. Previously we have found that Aristaless-like Homeobox 4 (ALX4) was differentially expressed in MC-LR-induced malignant transformed L02 cells. However, the expression regulation, role and molecular mechanism of ALX4 during the process of liver cancer induced by MC-LR are still unclear. The expression of ALX4 was detected by quantitative reverse-transcription PCR and Western blot in MC-LR induced malignantly transformed cell and rat models. Methylation status of ALX4 promoter region was evaluated by methylation-specific PCR and bisulfite genomic sequencing. The anti-tumor effects of ALX4 on MC-LR induced liver cancer were identified in vitro and in vivo. ALX4 expression was progressively down-regulated in MC-LR-induced malignantly transformed L02 cells and the MC-LR exposed rat models. ALX4 promoter regions were highly methylated in malignantly transformed cells, while treatment with demethylation agent 5-aza-dC significantly increased ALX4 expression. Functional studies showed that overexpression of ALX4 inhibits cell proliferation, migration, invasion and metastasis in vitro and in vivo, blocks the G1/S phase and promotes the apoptosis. Conversely, knockdown of ALX4 promotes cell proliferation, migration and invasion. Mechanism study found that ALX4 exerts its antitumor function through the P53 pathway, C-MYC and MMP9. More importantly, ALX4 expression level showed a negative relation with serum MC-LR levels in patients with hepatocellular carcinoma. Our results suggested that ALX4 was inactivated by DNA methylation and played a tumor suppressor function through the P53 pathway in MC-LR induced liver cancer.


Assuntos
Testes de Carcinogenicidade , Carcinoma Hepatocelular/induzido quimicamente , Proteínas de Ligação a DNA/genética , Epigênese Genética , Neoplasias Hepáticas/induzido quimicamente , Microcistinas/toxicidade , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese , Carcinoma Hepatocelular/genética , Proteínas de Ligação a DNA/metabolismo , Neoplasias Hepáticas/genética , Ratos , Proteína Supressora de Tumor p53/metabolismo
15.
Med Sci Monit ; 25: 2583-2590, 2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30962415

RESUMO

Glioblastoma multiforme (GBM) is the most common primary CNS cancer and has a poor prognosis. This study searched for significant genes and the mechanisms involved in GBM. We used the Gene Expression Omnibus (GEO) to test the WHO normal and IV glioma database, used R tool to identify the significant gene, and finally, combined these with The Cancer Genome Atlas (TCGA) to verify the significant genes. Subsequently, we explored the biological mechanisms involved. Phytanoyl-CoA 2-hydroxylase-interacting protein-like gene (PHYHIPL) is downregulated in grade IV glioma (GBM). The downregulation of PHYHIPL in GBM is accompanied by poor overall survival in the TCGA database, which indicates that PHYHIPL is a protection gene in GBM development. Bioinformatics analysis shows that the poor prognosis with downregulated PHYHIPL may be the result of the TNF signaling pathway and the IL-17 signaling pathway, but good prognosis accompanied by upregulated PHYHIPL may be the result of retrograde endocannabinoid signaling and the cAMP signaling pathway. Protein-protein interactions (PPI) net indicated that PHYHIPL may play a vital role in cell metabolism, and we hypothesize that the downregulation mechanism may be the result of mutations of the ß-catenin gene and the endogenous siRNA, as shown in previous studies. PHYHIPL may be a target gene for the treatment and prognosis of GBM.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioblastoma/genética , Glioblastoma/terapia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas do Tecido Nervoso/metabolismo , Coenzima A/genética , Coenzima A/metabolismo , Biologia Computacional/métodos , Bases de Dados Genéticas , Redes Reguladoras de Genes/genética , Glioma/genética , Humanos , Mutação/genética , Ácido Fitânico/análogos & derivados , Ácido Fitânico/metabolismo , Prognóstico , Transdução de Sinais
16.
Artigo em Inglês | MEDLINE | ID: mdl-30915142

RESUMO

Cryptotanshinone (CTS) was reported to repress a variety of systemic inflammation and alleviate cardiac fibrosis, but it is still unclear whether CTS could prevent radiation-induced lung injury (RILI). Here, we investigated the effects and underlying mechanisms of CTS on a RILI rat model. Our data revealed that CTS could efficiently preserve pulmonary function in RILI rats and reduce early pulmonary inflammation infiltration elicited, along with marked decreased levels of IL-6 and IL-10. Moreover, we found that CTS is superior to prednisone in attenuating collagen deposition and pulmonary fibrosis, in parallel with a marked drop of HYP (a collagen indicator) and α-SMA (a myofibroblast marker). Mechanistically, CTS inhibited profibrotic signals TGF-ß1 and NOX-4 expressions, while enhancing the levels of antifibrotic enzyme MMP-1 in lung tissues. It is noteworthy that CTS treatment, in consistent with trichrome staining analysis, exhibited a clear advantage over PND in enhancing MMP-1 levels. However, CTS exhibited little effect on CTGF activation and on COX-2 suppression. Finally, CTS treatment significantly mitigated the radiation-induced activation of CCL3 and its receptor CCR1. In summary, CTS treatment could attenuate RILI, especially pulmonary fibrosis, in rats. The regulation on production and release of inflammatory or fibrotic factors IL-6, IL-10, TGF-ß1, NOX-4, and MMP-1, especially MMP-1 and inhibition on CCL3/CCR1 activation, may partly attribute to its attenuating RILI effect.

17.
Sci Rep ; 9(1): 4968, 2019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30899067

RESUMO

Different kinds of factors contribute to gastric ulcer development which characterized by damaging gastric mucosal layer. However, gastric vascular homeostasis is not well defined and whether andrographolide has a protective function is largely unknown. The goal of this study is to investigate the potential function roles and underlying mechanism by which andrographolide regulates gastric vascular homeostasis in vivo and in vitro. Gastric ulcer animal model induced on andrographolide pretreated C57/BL6 mouse by ethanol intragastric administration. Hematoxylin and Eosin Stain, Masson's trichrome stain and Immunohistochemistry stain performed to observe gastric vascular homeostasis, which associated hemorrhage, extracellular matrix deposition and macrophage infiltration. The activity of vascular endothelial cells were associated with the proliferation and migration, which were detected using cell counting, MTS, and wound scratch healing assay. The underlying endothelial glycolytic mechanism investigated in vivo and in vitro. Andrographolide pretreatment dramatically attenuates ethanol intragastric administration induced imbalance of gastric vascular homeostasis which characterized by severe hemorrhage, increase extracellular matrix deposition and augment macrophage infiltration. Andrographolide treatment conspicuous inhibits HUVEC-C activity characterized by suppressing proliferation and migration of endothelial cells. Mechanically, andrographolide treatment significant suppresses the expression of glycolytic genes, especially decrease PFKFB3 expression. The treatment with PFKFB3 inhibitor, 3-PO, exacerbates the inhibitory function of andrographolide on vascular endothelial cell proliferation and migration. Those data Suggests that andrographolide contributes to maintain gastric vascular homeostasis, at least partially, by inhibiting PFKFB3 mediated glycolysis pathway. Andrographolide plays a crucial role in maintaining gastric vascular homeostasis during gastric ulcer development through regulating vascular endothelial cell glycolytic pathway.

18.
Acta Biomater ; 88: 86-101, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771534

RESUMO

Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The importance of ECM stiffness in cancer is well known. However, the biomechanical behavior of tumor cells and the underlying mechanotransduction pathways remain unclear. Here, we used polyacrylamide (PAA) substrates to simulate tissue stiffness at different progress stages of breast cancer in vitro, and we observed that moderate substrate stiffness promoted breast cancer cell motility. The substrate stiffness directly activated integrin ß1 and focal adhesion kinase (FAK), which accelerate focal adhesion (FA) maturation and induce the downstream cascades of intracellular signals of the RhoA/ROCK pathway. Interestingly, the differential regulatory mechanism between two ROCK isoforms (ROCK1 and ROCK2) in cell motility and mechanotransduction was clearly identified. ROCK1 phosphorylated the myosin regulatory light chain (MRLC) and facilitated the generation of traction force, while ROCK2 phosphorylated cofilin and regulated the cytoskeletal remodeling by suppressing F-actin depolymerization. The ROCK isoforms differentially regulated the pathways of RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin in a coordinate fashion to modulate breast cancer cell motility in a substrate stiffness-dependent manner through integrin ß1-activated FAK signaling. Our findings provide new insights into the mechanisms of matrix mechanical property-induced cancer cell migration and malignant behaviors. STATEMENT OF SIGNIFICANCE: Here, we examined the relationship between substrate stiffness and tumor cellular motility by using polyacrylamide (PAA) substrates to simulate the stages in vivo of breast cancer. The results elucidated the different regulatory roles between the two ROCK isoforms in cell motility and demonstrated that stiff substrate (38 kPa) mediated RhoA/ROCK1/p-MLC and RhoA/ROCK2/p-cofilin pathways through integrin ß1-FAK activation and eventually promoted directional migration. Our discoveries would have significant implications in the understanding of the interaction between cancer cells and tumor microenvironments, and hence, it might provide new insights into the metastasis inhibition, which could be an adjuvant way of cancer therapy.

19.
Mol Pharm ; 16(3): 1367-1384, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30776896

RESUMO

A promising approach toward cancer therapy is expected to integrate imaging and therapeutic agents into a versatile nanocarrier for achieving improved antitumor efficacy and reducing the side effects of conventional chemotherapy. Herein, we designed a poly(d,l-lactic- co-glycolic acid) (PLGA)-based theranostic nanoplatform using the double emulsion solvent evaporation method (W/O/W), which is associated with bovine serum albumin (BSA) modifications, to codeliver indocyanine green (ICG), a widely used near-infrared (NIR) dye, and doxorubicin (Dox), a chemotherapeutic drug, for dual-modality imaging-guided chemo-photothermal combination cancer therapy. The resultant ICG/Dox co-loaded hybrid PLGA nanoparticles (denoted as IDPNs) had a diameter of around 200 nm and exhibited excellent monodispersity, fluorescence/size stability, and biocompatibility. It was confirmed that IDPNs displayed a photothermal effect and that the heat induced faster release of Dox, which led to enhanced drug accumulation in cells and was followed by their efficient escape from the lysosomes into the cytoplasm and drug diffusion into the nucleus, resulting in a chemo-photothermal combinatorial therapeutic effect in vitro. Moreover, the IDPNs exhibited a high ability to accumulate in tumor tissue, owing to the enhanced permeability and retention (EPR) effect, and could realize real-time fluorescence/photoacoustic imaging of solid tumors with a high spatial resolution. In addition, the exposure of tumor regions to NIR irradiation could enhance the tumor penetration ability of IDPNs, almost eradicating subcutaneous tumors. In addition, the inhibition rate of IDPNs used in combination with laser irradiation against EMT-6 tumors in tumor-bearing nude mice (chemo-photothermal therapy) was approximately 95.6%, which was much higher than that for chemo- or photothermal treatment alone. Our study validated the fact that the use of well-defined IDPNs with NIR laser treatment could be a promising strategy for the early diagnosis and passive tumor-targeted chemo-photothermal therapy for cancer.


Assuntos
Terapia Combinada/métodos , Doxorrubicina/química , Verde de Indocianina/química , Raios Infravermelhos/uso terapêutico , Nanopartículas/química , Neoplasias/terapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Soroalbumina Bovina/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Doxorrubicina/efeitos adversos , Doxorrubicina/metabolismo , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Feminino , Temperatura Alta , Verde de Indocianina/efeitos adversos , Verde de Indocianina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3 , Nanopartículas/efeitos adversos , Nanopartículas/metabolismo , Imagem Óptica , Fototerapia/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/efeitos adversos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Soroalbumina Bovina/efeitos adversos , Soroalbumina Bovina/metabolismo , Distribuição Tecidual , Resultado do Tratamento
20.
Chemosphere ; 215: 554-562, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30342400

RESUMO

The hygroscopicity of aerosols is dependent upon their chemical composition. When their chemical compositions are altered, the water content in aerosols often changes, which may further modify phase behaviour. However, the study of phase behaviour dependence on chemical reactions is still limited. In this work, internally mixed sodium pyruvate (SP)/ammonium sulfate (AS) droplets were studied using an in-situ ATR-FTIR spectrometer. FTIR spectral analysis showed that solid sodium sulfate (SS) formed during the dehydration process, indicating a chemical reaction between SP and AS. In addition, the water content decreased after a dehydration-hydration process despite organic salt (SS) to inorganic salt (AS) mole ratios (OIRs) During the second relative humidity (RH) cycle, the water content remained constant, however, the efflorescence relative humidity (ERH) was lower than that in the first dehydration. The crystal relative humidities (CRHs) of SS are 66.7-53.1%, 66.0-58.2%, 62.2-57.1% and 49.6-43.6% for OIRs of 3:1, 2:1, 1:1 and 1:3, respectively, suggesting the crystallization of SS was favoured by higher SP content. For 2:1 OIRs, the solid SS was the greatest and an excess of either SP or AS blocked the solid SS formation. At a constant 80% RH, depletion of reagents was ∼0.97, and water loss was ∼0.6 in ∼40 min. After 90 min, solid SS formed. The chemical reaction was faster than water loss; furthermore, water loss from the chemical reaction led to solid SS above the ERH of pure SS particles (∼75% RH). When the RH changed rapidly, the reaction was slow and solid SS decreased.


Assuntos
Aerossóis/química , Sulfato de Amônio/química , Piruvatos/química , Sulfatos/química , Cristalização , Umidade , Água/química , Molhabilidade
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