Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.257
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-32023032

RESUMO

It is important to detect pathogens rapidly, sensitively and selectively for clinical medicine, homeland security, food safety and environmental control. We report here a specific and sensitive colorimetric assay that incorporated bovine serum albumin templated Co3O4 magnetic nanozyme (Co3O4 MNE) with a novel specific fusion phage protein and magnetophoretic chromatography to detect Staphylococcus aureus (S. aureus). The Co3O4 MNE was conjugated to S. aureus-specific fusion-pVIII (Co3O4 MNE@fusion-pVIII), screened from the S. aureus-specific phage AQTFLGEQD (the phage monoclone is denoted by the peptide sequence). The as-prepared triple functional Co3O4 MNE@fusion-pVIII particles were capable of capturing S. aureus in sterile milk, which were then isolated from milk magnetically. Assisted by polyethylene glycol, the Co3O4 MNE@fusion-pVIII@S. aureus complex was separated from the free Co3O4 MNE@fusion-pVIII by magnetophoretic chromatography in external magnetic field. After tansferring the isolated Co3O4 MNE@fusion-pVIII@S. aureus complexes into a 96-well plate, 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) and H2O2 were added to develop color due to the peroxidase mimetics activity of Co3O4 MNE. The S. aureus concentration within 10-10000 CFU/mL in milk can be detected (detection limit: 8 CFU/mL). The as-developed method is simple, cost-efficient and sensitive, which is useful for rapidly diagnosing pathogenic bacteria and helpful to prevent diseases outbreaks induced by pathogens in developing countries.

2.
Int J Cancer ; 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32086952

RESUMO

Patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein overexpression have very poor prognosis. The CDK7/super-enhancer inhibitor THZ1 suppresses MYCN gene transcription, reduces neuroblastoma cell proliferation, but does not cause significant cell death. The protein kinase PNUTS has recently been shown to interact with c-Myc protein and suppresses c-Myc protein degradation. Here we screened the US Food and Drug Administration-Approved Oncology Drugs Set V from the National Cancer Institute, and identified tyrosine kinase inhibitors (TKIs), including ponatinib and lapatinib, as the Approved Oncology Drugs exerting the best synergistic anticancer effects with THZ1 in MYCN-amplified neuroblastoma cells. Combination therapy with THZ1 and ponatinib or lapatinib synergistically induced neuroblastoma cell apoptosis, whilst having little effects in normal non-malignant cells. Differential gene expression analysis identified PNUTS as one of the genes most synergistically reduced by the combination therapy. RT-PCR and immunoblot analyses confirmed that THZ1 and the TKIs synergistically downregulated PNUTS mRNA and protein expression and reduced N-Myc protein but not N-Myc mRNA expression. In addition, PNUTS knockdown resulted in decreased N-Myc protein but not mRNA expression and decreased MYCN-amplified neuroblastoma cell proliferation and survival. As CDK7 inhibitors are currently under clinical evaluation in patients, our data suggestion the addition of the TKI ponatinib or lapatinib in CDK7 inhibitor clinical trials in patients. This article is protected by copyright. All rights reserved.

3.
J Mater Chem B ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32049084

RESUMO

Porous polymer microneedles (MNs) have great potential in transdermal medical applications due to their three-dimensional (3D) porous structures and high porosity. However, existing approaches for the fabrication of such porous polymer MNs are complicated and only applicable to limited types of polymers. Here, we describe a facile yet effective phase inversion route to prepare polymer MNs with highly porous and interconnected pore structures. The fabrication process is simple and mild without involving high temperatures or irradiation, and can be applied to a broad spectrum of commonly used polymers (e.g., cellulose acetate (CA), polysulfone (PSF), polyethersulfone (PES), polylactic acid (PLA), etc.). Thanks to the capillary effect and large cavity given by highly porous and interconnected structures, the resulting porous polymer MNs show the capability of rapidly extracting dermal interstitial fluid (ISF) and efficiently loading/releasing drug compounds. As a proof of concept, we demonstrate the use of these porous CA MNs in the highly efficient extraction of ISF for glucose level detection and administration of insulin for hyperglycemia. Given the recent trend of painless techniques in diagnosis and treatment, the current study provides a new opportunity for the fabrication of MN-based devices for transdermal ISF extraction and drug delivery.

4.
Cancer Res ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060145

RESUMO

The role of Ataxia Telangiectasia Mutated (ATM) gene in human malignancies, especially in solid tumors, remains poorly understood. In the present study, we explored the involvement of ATM in transforming primary human cells into cancer stem cells. We show that ATM plays an unexpected role in facilitating oncogene-induced malignant transformation through transcriptional reprogramming. Exogenous expression of an oncogene cocktail induced a significant amount of DNA double strand breaks in human fibroblasts that caused persistent activation of ATM, which in turn enabled global transcriptional reprogramming through chromatin relaxation, allowing oncogenic transcription factors to access chromatin. Consistently, deficiencies in ATM significantly attenuated oncogene-induced transformation of human cells. In addition, ATM inhibition significantly reduced tumorigenesis in a mouse model of mammary cancer. ATM and cellular DNA damage response (DDR) therefore play a previously unknown role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells.

5.
ChemSusChem ; 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32061039

RESUMO

Herein we report an efficient and selective procedure for the direct C2-H arylation of indoles using a Metal-Organic-Framework (MOF) containing palladium as heterogeneous catalyst and the non-toxic biomass derived solvent GVL (γ-valerolactone) as reaction medium. The developed method allows to reach excellent yields and C-2 selectivity and tolerates various substitutions on the indole scaffold. The established conditions ensure stability of the catalyst as well as recoverability, reusability and low metal leaching into solution.

6.
Adv Ther ; 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32062814

RESUMO

INTRODUCTION: The complication rates of proximal hypospadias, especially fistula, are much higher than those of distal hypospadias. Urethral coverage is an effective method for reducing fistulas. Acellular dermal matrix (ADM) has been shown to exhibit structural compatibility and biocompatibility, both of which promote tissue healing. METHODS: The present non-randomized study evaluated the efficiency, feasibility, and safety of using ADM for urethroplasty coverage in patients with proximal hypospadias. This prospective study enrolled 35 patients (age range 15-60 months) with proximal hypospadias who underwent operation between September 2018 and March 2019 at Beijing Children's Hospital (Beijing, China). Urethroplasties were performed by the transverse preputial island flap (TPIF) technique. ADM was applied and sutured over the urethroplasty as an additional covering layer. Patient outcomes were compared with those of 80 non-matched control patients with proximal hypospadias who underwent the same procedure, with dartos as a covering layer. RESULTS: During a median follow-up of 11.56 months (range 9-15 months), urethral fistula occurred in six patients (17.1%) in the ADM group and 28 patients (35%) in the dartos group. Superficial wound infection was observed in six patients (17.1%) in the ADM group and 10 patients (12.5%) in the dartos group. One patient in the ADM group had diverticulum, compared with five patients (6.25%) in the dartos group. Meatal stenosis and urethral stricture were observed in four patients (11.4%) in the ADM group and six patients (7.5%) in the dartos group; all of these complications were treated conservatively. No glans dehiscence was observed in either group. CONCLUSION: Use of ADM may be a safe and efficient covering technique to provide an additional coverage layer for proximal hypospadias repair, thereby reducing the incidence of fistula formation, especially among patients who have poor-quality covering materials.

7.
J Orthop Surg Res ; 15(1): 52, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059737

RESUMO

BACKGROUND: Compression bandage often is used after total knee arthroplasty (TKA) to alleviate pain, ameliorate swelling, and reduce bleeding. However, there is controversy about its application due to conflicting clinical outcomes and potential compression-related complications. This meta-analysis aimed to answer the question of if compression bandage should be implemented routinely after TKA. METHODS: Relevant randomized controlled trials (RCTs) on compression bandage were comprehensively retrieved utilizing search engines such as PubMed, EMBASE, Web of Science, and the Cochrane Library, up to September 2019. Studies included in the meta-analysis were those that compared post-operative pain score, swelling, total blood loss, pre- and post-operative hematocrit levels differences, range of motion (ROM), and complications, using Review Manager 5.3.0. RESULTS: Included were seven RCTs, which reported on 511 knees. The pooled results showed the compression bandage group was associated with a greater post-operative pain score during ambulation at 48 h (WMD = 0.70, 95% CI 0.07 to 1.34, P = 0.03), compared with the non-compression bandage group. No statistically significant differences were found between the groups in post-operative pain scores at the other times, swelling, blood loss, ROM, or other complications (P > 0.05). CONCLUSIONS: The current evidence is unable to conclude that compression bandage is necessary after primary TKA. Surgeons routinely undertaking compression bandage should deliberate whether there is enough clinical evidence.

8.
J Agric Food Chem ; 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32031791

RESUMO

Enzymatic browning is a major issue affecting the quality of processed potato (Solanum tuberosum L.). To understand the molecular mechanism of browning, transcriptional analyses were performed by employing potatoes that differed in browning. Coexpression analysis indicated that 9 out of 15 upregulated genes in browning-less groups encoded for potato protease inhibitors (StPIs). In addition, gene otology analysis showed that the enriched terms were mainly involved in protease inhibitors. Overexpression of cysteine StPI 143 and StPI 146 individually reduced browning and lowered protease activities and tyrosine and total free amino acid (FAA) contents, but they could not decrease polyphenol oxidase activity. Moreover, supplementing exogenous tyrosine or total FAAs into transgenic potato mash to wild-type amounts promoted mash browning, browning with total FAAs, more than with tyrosine, resembling wild-type levels. These results implied that cysteine StPIs reduced browning via lowering the accumulation of FAAs in addition to tyrosine. Our findings have enriched the knowledge about the roles and mechanisms of protease inhibitors in regulating enzymatic browning of potato, which provide new ways for controlling potato browning.

9.
FASEB J ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32072664

RESUMO

Alcohol consumption is regarded as one of the leading risk factors for secondary osteopenia. Coupled angiogenesis and osteogenesis via distinct type-H vessels orchestrates subtle biological processes of bone homeostasis. The dysfunction of angiogenesis and osteogenesis contributes to decreased bone mass during the development of osteopenia. Herein, we identified microRNA-136-3p was remarkedly downregulated in the mouse model of alcohol-induced osteopenia. Following the alcohol administration, downregulated microRNA-136-3p significantly suppressed vascularization and osteogenic differentiation in human umbilical vein endothelial cells (HUVECs) and bone mesenchymal stem cells (BMSCs), respectively. Furthermore, microRNA-136-3p could target phosphatase and tensin homolog deleted on chromosome ten (PTEN) in both HUVECs and BMSCs, thus substantially modulating the capacity of vessel formation and osteogenic differentiation. In the mouse model, microRNA-136-3p Agomir ameliorated alcohol-induced osteopenia, with the concomitant restoration of bone mass and type-H vessel formation. For the first time, this study demonstrated the pivotal role of microRNA-136-3p/PTEN axis in regulations of vascularization and bone formation, which might become the potential therapeutic target of alcohol-induced bone loss.

10.
Sci Rep ; 10(1): 1829, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31996768

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

11.
Acta Pharmacol Sin ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31969689

RESUMO

Vonoprazan is characterized as having a long-lasting antisecretory effect on gastric acid. In this study we developed a physiologically based pharmacokinetic (PBPK)-pharmacodynamic (PD) model linking to stomach to simultaneously predict vonoprazan pharmacokinetics and its antisecretory effects following administration to rats, dogs, and humans based on in vitro parameters. The vonoprazan disposition in the stomach was illustrated using a limited-membrane model. In vitro metabolic and transport parameters were derived from hepatic microsomes and Caco-2 cells, respectively. We found the most predicted plasma concentrations and pharmacokinetic parameters of vonoprazan in rats, dogs and humans were within twofold errors of the observed data. Free vonoprazan concentrations (fu × C2) in the stomach were simulated and linked to the antisecretory effects of the drug (I) (increases in pH or acid output) using the fomula dI/dt = k × fu × C2 × (Imax - I) - kd × I. The vonoprazan dissociation rate constant kd (0.00246 min-1) and inhibition index KI (35 nM) for H+/K+-ATPase were obtained from literatures. The vonoprazan-H+/K+-ATPase binding rate constant k was 0.07028 min-1· µM-1 using ratio of kd to KI. The predicted antisecretory effects were consistent with the observations following intravenous administration to rats (0.7 and 1.0 mg/kg), oral administration to dogs (0.3 and 1.0 mg/kg) and oral single dose or multidose to humans (20, 30, and 40 mg). Simulations showed that vonoprazan concentrations in stomach were 1000-fold higher than those in the plasma at 24 h following administration to human. Vonoprazan pharmacokinetics and its antisecretory effects may be predicted from in vitro data using the PBPK-PD model of the stomach. These findings may highlight 24-h antisecretory effects of vonoprazan in humans following single-dose or the sustained inhibition throughout each 24-h dosing interval during multidose administration.

12.
J Exp Bot ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31960925

RESUMO

Arabidopsis thaliana hybrids have similar properties to hybrid crops with greater biomass relative to the parents. We asked whether the greater biomass was due to increased photosynthetic efficiency per unit leaf area or to overall increased leaf area and increased total photosynthate per plant. We found that photosynthetic parameters (electron transport rate, CO2 assimilation rate, chlorophyll content, chloroplast number) were unchanged on a leaf unit area and unit fresh weight basis between parents and hybrids indicating that heterosis is not a result of increased photosynthetic efficiency. To investigate the possibility of increased leaf area producing more photosynthate per plant we studied C24/ Landsberg erecta (Ler) hybrids in detail. These hybrids have earlier germination and leaf growth than the parents leading to a larger leaf area at any point in development of the plant. The developing leaves of the hybrids are significantly larger than those of the parents with consequent greater production of photosynthate and an increased contribution to heterosis. The set of leaves contributing to heterosis changes as the plant develops; the four most recently emerged leaves make the greatest contribution. As a leaf matures, its contribution to heterosis attenuates. While photosynthesis per unit leaf area is unchanged at any stage of development in the hybrid, leaf area is greater and the amount of photosynthate per plant is increased.

13.
ACS Appl Mater Interfaces ; 12(4): 4276-4284, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31896256

RESUMO

Various squaraine dyes have been developed for biological imaging. Nevertheless, squaraine dyes with emission in the second window (NIR-II, 1000-1700 nm) have few reports largely due to the short of a simple and universal design strategy. In this contribution, molecular engineering strategy is explored to develop squaraine dyes with NIR-II emission. First, NIR-I squaraine dye SQ2 is constructed by the ethyl-grafted 1,8-naphtholactam as donor units and square acid as acceptor unit in a donor-acceptor-donor (D-A-D) structure. To red-shift the fluorescence emission into NIR-II window, malonitrile, as a forceful electron-withdrawing group, is introduced to strengthen square acid acceptor. As a result, the fluorescence spectrum of acceptor-engineered squaraine dye SQ1 exhibits a significant red-shift into NIR-II window. To translate NIR-II fluorophores SQ1 into effective theranostic agents, fibronectin-targeting SQ1 nanoprobe was constructed and showed excellent NIR-II imaging performance in angiography and tumor imaging, including lung metastatic foci in deep tissue. Furthermore, SQ1 nanoprobe can be used for photoacoustic imaging and photothermal ablation of tumors. This research demonstrates that the donor-acceptor engineering strategy is feasible and effective to develop NIR-II squaraine dyes.

14.
Neurogastroenterol Motil ; : e13803, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31989744

RESUMO

BACKGROUND: Cisplatin is a widely used antineoplastic drug. However, cisplatin-induced dyspepsia syndromes, including delayed gastric emptying, gastric distension, early satiety, nausea, and vomiting, often force patients to take doses lower than those prescribed or even refuse treatment. D-methionine has an appetite-enhancing effect and alleviates weight loss during cisplatin treatment. METHODS: This work established a model of anorexia and dyspepsia symptoms with intraperitoneal injection of cisplatin (5 mg/kg) once a week for three cycles. Presupplementation with or without D-methionine (300 mg/kg) was performed. Orexigenic and anorexigenic hormones (ghrelin, leptin, and glucagon-like peptide-1), tryptophan hydroxylase 1 (TPH1), 5-hydroxytryptamine receptors (5-HT2C and 5-HT3 ), and hypothalamic feeding-related peptides were measured by immunohistochemistry staining, enzyme-linked immunosorbent assay, and real-time PCR assay. KEY RESULTS: Cisplatin administration caused marked decrease in appetite and body weight, promoted adipose and fat tissue atrophy, and delayed gastric emptying and gastric distension, and D-methionine preadministration prior to cisplatin administration significantly ameliorated these side effects. Besides, cisplatin induced an evident increase in serum ghrelin level, TPH1 activity, and 5-HT3 receptor expression in the intestine and decreased plasma leptin levels and gastric ghrelin mRNA gene expression levels. D-methionine supplementation recovered these changes. The expression of orexigenic neuropeptide Y/agouti-related peptide and anorexigenic cocaine- and amphetamine-regulated transcript proopiomelanocortin neurons were altered by D-methionine supplementation in cisplatin-induced anorexia rats. CONCLUSIONS AND INFERENCES: D-methionine supplementation prevents cisplatin-induced anorexia and dyspepsia syndrome possibly by attenuating intestinal tryptophan hydroxylase 1 activity and increasing plasma leptin concentration. Therefore, D-methionine can be used as an adjuvant therapy for treating cisplatin-induced adverse effects.

15.
FASEB J ; 34(1): 1481-1496, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914615

RESUMO

As the key factor of the polarity protein complex, Par6 not only regulates polarization processes, but also plays important roles in tumor metastasis and progression in many epithelium malignancy tumors. Here, we showed that Par6 is an essential component in glioma tumorigenesis. Our results indicated the aberrant expression of Par6 in malignant glioma tissues and cell lines. We found that the regulation of Par6 expression induces cell proliferation and tumor growth in vivo and in vitro. Additionally, RNA-seq revealed the effects of Par6 were associated with cyclin D1-regulated cell cycle progression in glioma cells. Moreover, our results demonstrated that the regulation of Par6 can enhance the activation of Akt/PI3K signaling pathway, and subsequently upregulate the expression level of GSK-3ß protein, which then regulate cyclin D1-mediated cell cycle regulation. Furthermore, we found that TGF-ß-induced the upregulation of Par6 expression may be involved in this process. The pathological analysis confirmed the correlation between Par6 expression and the prognosis in human glioma tissues, suggesting the regulation of Par6 expression regulates glioma tumorigenesis and progression. Thus, our findings showed that Par6 might be a potential biomarker for the diagnosis and providing a therapeutic strategy for the treatment of malignant glioma.

16.
J Ethnopharmacol ; 251: 112535, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31926315

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima is a traditional Chinese medicine that has been used since the Ming dynasty. It is famous for its apoptotic effects on lung cancer. However, limited information is available about the underlying mechanisms. AIM OF THE STUDY: We aimed to determine the mechanisms by which different organic M. tenacissima extracts induce apoptosis in lung cancer cells. MATERIALS AND METHODS: PubMed and CNKI databases were screened for M. tenacissima components that may targets lung cancer; 223 components were selected for drug-like and pharmacokinetic analysis. Moreover, the inhibitory effect of different extracts of M. tenacissima on tumor cells was illustrated using CCK-8 and apoptosis assays, and intracellular [Ca2+] was measured. The in vivo effects were examined by body weight, tumor pathology, and TUNEL staining analysis in a Lewis lung carcinoma mouse model. In vivo levels of the Ca2+ signaling-related proteins Calmodulin, CaMKⅡ, p-CaMKⅡ, MEK1/2, p-MEK1/2, ERK, and p-ERK were measured by Western blot. RESULTS: Petroleum ether and ethyl acetate extracts of M. tenacissima have stronger inhibitory effects than other extracts on lung cancer cells, with IC50 values of 0.35 ± 0.04 mg/ml and 0.29 ± 0.02 mg/ml for LLC cells and 0.56 ± 0.05 mg/ml and 0.85 ± 0.04 mg/ml for A549 cells, respectively. Compared with the normal control group, A549 and LLC cells of treatment groups exhibited morphological changes typical of apoptosis, and the apoptosis rate was significantly higher, as determined by flow cytometry. Furthermore, the i[Ca2+] changed accordingly, causing a decrease in vivo in Calmodulin, CaMKⅡ, p-CaMKⅡ, p-MEK1/2 and p-ERK levels. CONCLUSIONS: M. tenacissima induces apoptosis, both in vitro and in vivo. Hydrophobic extracts are most effective; they increase i[Ca2+], decrease intracellular Calmodulin, CaMKⅡ, p-CaMKⅡ, p-MEK1/2 and p-ERK levels, and activate the apoptotic cascade.

17.
ACS Appl Mater Interfaces ; 12(6): 7575-7585, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31958010

RESUMO

A simple and green layer-by-layer assembly strategy is developed for the preparation of a highly bioavailable nanocomposite photosensitizer by assembling near-infrared (NIR) light-sensitive porphyrin/G-quadruplex complexes on the surface of a highly biocompatible nanoparticle that is prepared via Zn2+-assisted coordination self-assembly of an amphiphilic amino acid. After being efficiently delivered to the target site and internalized into tumor cells via enhanced permeability and retention effect and interactions between aptamers and tumor markers, the as-prepared nanoassembly can be directly used as an NIR light-responsive photosensitizer for tumor photodynamic therapy (PDT) since the porphyrin/G-quadruplex complexes are exposed on the nanoassembly surface and kept in an active state. It can also disassemble under the synergistic stimuli of an acidic pH environment and overexpressed glutathione, leasing more efficient porphyrin/G-quadruplex composite photosensitizers while reducing the interference caused by glutathione-dependent 1O2 consumption. Since the nanoassembly can work no matter if it is disassembled or not, the compulsory requirement for in vivo photosensitizer release is eliminated, thus resulting in the great improvement of the bioavailability of the photosensitizer. The PDT applications of the nanoassembly were well demonstrated in both in vitro cell and in vivo animal experiments.

18.
J Mater Chem B ; 8(5): 928-934, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-31912081

RESUMO

Angiogenesis plays an important role in the occurrence and development of skin tumors and vascular anomalies (VAs). Many drugs have been adopted for the inhibition of angiogenesis, among which rapamycin (RAPA) possesses good application prospects. However, the clinical potential of RAPA for VAs is limited by its poor solubility, low bioavailability, and high cytotoxicity. To extend its application prospect for VAs treatment, in this study, we develop RAPA-loaded dissolving polymeric microneedles (RAPA DMNs) made of polyvinylpyrrolidone (PVP) due to its excellent solubilizing ability. RAPA DMNs are shown to have sufficient mechanical strength to overcome the skin barrier of the stratum corneum and could deliver RAPA to a depth of 200 µm. The microneedle shafts completely dissolve and 80% of the drug could be released within 10 min after insertion ex vivo. The DMNs-penetrated mice skin could repair itself within 4 h after the application of RAPA DMNs. RAPA DMNs also show good anti-angiogenic effect by inhibiting the growth of human umbilical vein endothelial cells (HUVECs) and decreasing the secretion of vascular endothelial growth factor (VEGF). Therefore, RAPA DMNs promisingly provide a safe and efficient approach for VAs treatment.

19.
Yi Chuan ; 42(1): 18-31, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31956094

RESUMO

CRISPR/Cas9 system has significant advantages in gene editing strategy, offering cost-effective and efficient means to modify and edit the genomes of animals, plants, and microorganisms. Three-dimensional (3D) genome is an emerging and interdisciplinary field catapulted by combined technological breakthroughs of chromosome conformation capture with next-generation sequencing and live imaging with super-resolution microscopy. An important aspect of 3D genomics is to model structural variations and label specific genomic fragments to investigate the effects of manipulation of genomic elements on gene expression regulation, cell development and differentiation, and spatial location of chromosomal regions. Therefore, CRISPR/Cas9 system and its derivative technologies of DNA-fragment editing are excellent toolboxes for investigating dynamics and functions of the higher-order chromatin organization and three-dimensional genome structure. In this review, we describe the opportunities and challenges of CRISPR as well as its derivative technologies in 3D genome research, thereby providing some critical references and future research directions in the field.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes , Genômica , Genoma
20.
J Cell Mol Med ; 24(1): 1046-1058, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31756785

RESUMO

CD8+ T cells play a central role in antitumour immunity, which often exhibit 'exhaustion' in the setting of malignancy and chronic viral infection due to T cell immunoglobulin and mucin domain 3 (TIM3) and myeloid-derived suppressor cells (MDSCs). Our team previously found that overactive MDSCs and exhausted TIM3+ CD8+ T cells were observed in myelodysplastic syndromes (MDS) patients. However, it is not obvious whether MDSCs suppress CD8+ T cells through TIM3/Gal-9 pathway. Here, Gal-9, as the ligand of TIM3, was overexpressed in MDSCs. The levels of Gal-9 in bone marrow supernatants, serum and culture supernatants of MDSCs from MDS patients were elevated. CD8+ T cells from MDS or normal controls produced less perforin and granzyme B and exhibited increased early apoptosis after co-culture with MDSCs from MDS. Meanwhile, the cytokines produced by CD8+ T cells could be partially restored by TIM3/Gal-9 pathway inhibitors. Furthermore, CD8+ T cells produced less perforin and granzyme B after co-culture with excess exogenous Gal-9, and the function of CD8+ T cells was similarly restored by TIM3/Gal-9 pathway inhibitors. Expression of Notch1, EOMES (associated with perforin and granzyme B secretion), p-mTOR and p-AKT (associated with cell proliferation) was decreased in CD8+ T cells from MDS after co-culture with excess exogenous Gal-9. These suggested that MDSCs might be the donor of Gal-9, and TIM3/Gal-9 pathway might be involved in CD8+ T cells exhaustion in MDS, and that TIM3/Gal-9 pathway inhibitor might be the promising candidate for target therapy of MDS in the future.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA