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1.
J Ethnopharmacol ; 246: 112243, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31541722

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba leaves and Panax ginseng are Chinese medicine commonly used in combination for cerebral disease. AIM OF THE STUDY: To investigate the effect of standard extract of Ginkgo biloba leaves (EGb) on facilitating brain uptake of ginsenoside and its underlying mechanisms. MATERIALS AND METHODS: The increasing uptake of ginsenosides in the brain of rats by EGb were detected by LC-MS/MS analysis. Evans blue and FITC-dextran leakage were determined to evaluate blood-brain barrier (BBB) permeability in vivo. Transendothelial electrical resistance (TEER) and Na-F penetration rate were measured with a co-culture of the human cerebral microvascular endothelial cell line (hCMEC/D3) and human normal glial cell line (HEB) in vitro BBB model. WB were used to analyzed the expression of BBB tight junctions (TJs) related protein (ZO-1, Occludin, Claudin-3, p-ERM, and p-MLC), ultrastructure of TJs was determined by transmission electron microscope. RESULTS: LC-MS/MS analysis demonstrated that EGb could improve brain uptake of ginsenoside Rg1, Re, Rd and Rb1. In vivo study showed that, BBB permeability was significantly increased after EGb administration, evidenced by the markedly increased penetration of FITC-dextran and Evans Blue into the mice brain parenchyma. In the in vitro BBB model, reduced TEER and increased Na-F penetration rate was observed in EGb group, which was associated with alteration of TJs ultrastructure. Furthermore, the expression of p-ERM and p-MLC in hCMEC/D3 as well as mice brain microvessels were significantly upregulated, but no significant change on the expression of TJs proteins (ZO-1, Occludin and Claudin-3). Moreover, the effect of EGb on in vitro BBB permeability and ERM, MLC phosphorylation was counteracted by DPCPX, an A1 adenosine receptor (A1R) antagonist. CONCLUSIONS: EGb might induce ERM/MLC phosphorylation and increase the cell-cell junction gaps to cause a reversible increase of the BBB permeability via A1R signaling pathway. Our results may contribute to better use of EGb in the treatment of brain diseases.

2.
Talanta ; 206: 120183, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31514879

RESUMO

Mobility capillary electrophoresis (MCE) was developed previously in our group, which has the capabilities of ion separation and biomolecule hydrodynamic radius analysis. The coupling of MCE with mass spectrometry (MS) would greatly improve complex sample identification capability as well as system detection sensitivity. In the present study, a simple and robust ionization source, named as straight nano-electrospray ionization (nanoESI) source was developed, which was applied to couple MCE with MS. A stainless-steel needle attached directly at the end of an MCE capillary was used as the nanoESI emitter, and the connection between this emitter to the liquid flow in the MCE separation channel was established through a liquid bridge. After optimization, this straight nanoESI source enhanced the ion signal intensity by ~10 times when compared with a commercial nanoESI source. The MCE-straight nanoESI-MS system was also characterized in terms of mixture separation and peptide hydrodynamic radius measurements. Compared to our previous work when a UV detector was used in a commercial Lumex CE system (model Capel 105 M, St. Petersburg, Russia), peptides with much lower concentrations could be analyzed (from ~1 mg/mL to ~20 µg/mL) in terms of radius measurement.

3.
Dev Comp Immunol ; 102: 103477, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31470020

RESUMO

Two continuous macrophage cell lines (LCM07 and LCM10) were established for the first time from the head kidney of the marine fish large yellow croaker (Larimichthys crocea). To date, both cell lines have been subcultured for more than 100 passages in 12 months. Notably, the LCM07 and LCM10 cells have distinct morphology and immune function. LCM07 cells showed strong contact inhibition in crowded conditions, while this was not observed in the LCM10 cells because they could grow in an overlapping manner. Correspondingly, LCM10 cells were slenderer than LCM07 cells. LCM07 cells had stronger phagocytic ability than LCM10 cells, while LCM10 cells had stronger respiratory burst activity after incubation with lipopolysaccharide (LPS) and phorbol ester (PMA). LCM07 cells had stronger Escherichia coli killing ability than LCM10 cells. The mRNA of macrophage markers, namely that of CD11b, CD114, CD68, CD86, CD209, and CD163, were all expressed in primary macrophages as well as the two cell lines. The mRNA expression levels of selected inflammatory cytokines, namely interleukin (IL)-1ß, IL-8, and tumor necrosis factor (TNF)α, were all upregulated after incubation with LPS. LPS also regulated key components of the mitogen-activated protein kinase (MAPK) signaling pathway, i.e., p38, ERK (extracellular signal-regulated kinase), and JNK (Jun N-terminal kinase) and their phosphorylated forms. Arachidonic acid (ARA) downregulated the LPS-induced upregulation of IL-1ß, IL-8, and TNFα, revealing that LCM07 and LCM10 cells are useful for studying nutritional immunity. In conclusion, two distinct macrophage cell lines have been established for the first time from the head kidney of marine fish, which could be useful for studying immunity and nutritional immunity.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31671669

RESUMO

Water resources utilization, social economy development, and ecological environment protection are key factors in regional sustainable development. Scientific evaluation of regional coordinated development status and diagnosis of regional uncoordinated development constraints will improve the management level of decision-makers. At present, most developing countries have the problem of unbalanced regional development caused by the one-sided pursuit of a certain system. Taking 14 prefecture-level cities in Hunan Province as cases, this paper analyzed the spatial and temporal distribution characteristics of the carrying capacity level of the water resources system, the development level of the social economy system and the protection level of the ecological environment system in each evaluation unit based on entropy weight method and order parameter analysis. Based on the theory of coordinated development, a calculation model of a coordinated development degree was constructed, and the corresponding evaluation criteria were formulated. The spatial and temporal distribution characteristics of a coordinated development degree in each research unit were analyzed and evaluated. The results showed that the average coordinated development degree of Hunan Province from 2004 to 2016 evolved from "Light disorder recession" to "Nearly disorder recession", then to "Reluctance coordinated development". Restricted by different systems, the coordinated development degree in each research unit presented spatial and temporal differences. According to different development stages and the characteristics of different regions, corresponding development strategies can be formulated to provide the guidance for coordinated the development of regions.

5.
Cancer Res Treat ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671936

RESUMO

Purpose: To investigate the prognostic impact of EBV-miR-BHRF1-1 with chronic lymphocytic leukemia (CLL) as well as role of EBV-miR-BHRF1-1 in p53 gene. Materials and Methods: Quantitative reverse transcription-PCR (qRT-PCR) and western blotting (WB) were used to quantify EBV-miR-BHRF1-1 and p53 expression in cultured CLL. Results: p53 aberration was associated with higher expression level of Epstein-Barr virus (EBV)-microRNA (miRNA, miR)-BHRF1-1 (p<0.001) which was also an independent prognostic marker for overall survival (OS) (p=0.028; HR 5.335 [1.193, 23.846]) in 97 newly-diagnosed CLL patients after adjusted with CLL-international prognostic index (CLL-IPI). We identified EBV-miR-BHRF1-1 as a viral miRNA regulator of p53. EBV-miR-BHRF1-1 repressed luciferase reporter activity by specific interaction with the seed region within the p53 3' untranslated region. Discordance of p53 messenger RNA and protein expression was associated with high EBV-miR-BHRF1-1 levels in CLL patients and cell lines. EBV-miR-BHRF1-1 inhibition upregulated p53 protein expression, induced cell cycle arrest and apoptosis and decreased cell proliferation in cell lines. EBV-miR-BHRF1-1 mimics downregulated p53 protein expression, decreased cell cycle arrest and apoptosis, and induced cell proliferation in cell lines. Conclusion: This study supported a role of EBV-miR-BHRF1-1 in p53 regulation in vitro. Our results support the potential of EBV-miR-BHRF1-1 as a therapeutic target in EBV-associated CLL with p53 gene aberration.

6.
Opt Lett ; 44(21): 5354-5357, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675006

RESUMO

Flower-like silver vanadium oxide (SVO) micropatterns were realized by femtosecond laser in situ writing from its precursor. Self-assembled petals irradiated by a femtosecond laser were observed standing on the substrate along the scanned routine assisted by the formation of silver seeds and plasmonic-mediated effects. By controlling the concentration of ammonium monovanadate and the laser exposure time, a different thickness of petals was manipulated from ∼100 nm to micrometers. The SVO products were confirmed Ag4V2O7, AgVO3, and part of Ag3VO4 by x-ray diffraction (XRD) measurement. Photon-driven self-assembly for in situ fabrication of microstructures looks to be an effective and facile technique for SVO and other functional compounds.

7.
J Colloid Interface Sci ; 560: 186-197, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31670016

RESUMO

Non-precious efficient bifunctional catalysts towards oxygen reduction/evolution reactions (ORR/OER) are highly desired to enable the widespread application of rechargeable Zn-air batteries (r-ZABs). Herein, Prussian blue analogues (PBA) anchored on CdS nanorods (CdS NRs) pre-coated with polydopamine (PDA) are utilized as precursors to prepare ultrafine Co4S3 nanoparticles supported on N, S-codoped CNTs (Co4S3@N,S-CNT), where CdS NRs are served as sulfur sources and hard templates. After pyrolysis, the resulting Co4S3@N,S-CNT-800 shows a high specific surface area of 142.4 m2 g-1, together with merely 0.780 V difference between the OER potential at 10 mA cm-2 and the ORR potential at 3 mA cm-2. The Co4S3@N,S-CNT-800 based air cathode displays a higher discharge capacity of 787 mAh gZn-1 at 10 mA cm-2, a higher output power density of 154 mW cm-2, better working stability, as well as a lower charge-discharge voltage gap than the Pt/C + RuO2 based air electrode at various working current density. The remarkable oxygen reversible catalytic activities are mainly attributed to the presence of a thin layer of mesoporous carbon on partial sections of the open-end N,S-CNTs, which not only shortens the mass diffusion length but also prevents N,S-CNTs from excessively bundling to maximize the exposure of Co4S3 nanocrystallites and graphitized carbon skeletons with N or S heteroatoms.

8.
J Control Release ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682910

RESUMO

Stimuli-responsive drug delivery systems based on tumor microenvironment conditions show tremendous promise to enhance tumor-targeted delivery and drug release. Herein, a multifunctional peptide (P51) was developed for programmed delivery of the hydrophobic chemotherapeutic agent pirarubicin. P51 was prepared with a ligand-specific targeting for the cancer biomarker Arg-Gly-Asp (RGD), and three tumor microenvironment-sensitive release triggers, acid environment, reducing agent, and a specific enzyme. The peptides Cys-s-s-Cys (disulfide linkage) and Pro-Val-Gly-Leu-Ile-Gly correspond to the cleavage sites of a reducing agent (DTT) and an enzyme (MMP-2). The peptides act as a junction between Ser-Glu-Glu-Asp-Pro (a negatively charged sequence) and a 41-residue peptide containing an α-helix that has the capacity to encapsulate pirarubicin via electrostatic and hydrophobic interactions. These interactions can be disrupted by the acidic tumor microenvironment. Self-assembly of P51 and pirarubicin (P51-THP NPs) results into stable spherical nanoparticles in a single step. We demonstrate that the acid environment, DTT, and MMP-2 stimulated the release of pirarubicin from P51-THP NPs and, more importantly, the efficiency of drug release is markedly increased when all three release triggers are present. In addition, more effective tumor targeting, antitumor effect, and reduced systemic toxicity of P51-THP NPs were confirmed by in vitro and in vivo results.

9.
Cancer Res ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31690668

RESUMO

The tumorigenic role and underlying mechanisms of lipid accumulation, commonly observed in many cancers, remains insufficiently understood. In this study we identified an AMP-activated protein kinase (AMPK)-GATA-binding protein 3 (GATA3)-enoyl-CoA hydratase short-chain 1 (ECHS1) pathway that induces lipid accumulation and promotes cell proliferation in clear cell renal cell carcinoma (ccRCC). Decreased expression of ECHS1, which is responsible for inactivation of fatty acid oxidation (FAO) and activation of de novo fatty acid (FA) synthesis, positively associated with ccRCC progression and predicted poor patient survival. Mechanistically, ECHS1 downregulation induced FA and branched-chain amino acid (BCAA) accumulation which inhibited AMPK-promoted expression of GATA3, a transcriptional activator of ECHS1. BCAA accumulation induced activation of mTORC1, de novo FA synthesis, and promoted cell proliferation. Furthermore, GATA3 expression phenocopied ECHS1 in predicting ccRCC progression and patient survival. The AMPK-GATA3-ECHS1 pathway may offer new therapeutic approaches and prognostic assessment for ccRCC in the clinic.

10.
Neurotox Res ; 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31691187

RESUMO

Correlation between the level of high-sensitivity C-reactive protein (hs-CRP) and the incidence of intracranial arterial stenosis (ICAS) is unclear. We aim to investigate the relationship between hs-CRP levels and ICAS. A total of 1458 patients aged ≥ 40 years were enrolled in this study. All the participants had a magnetic resonance angiography (MRA) examination for the evaluation of ICAS. Participants were classified into four groups according to stroke and ICAS. Multivariable logistic regression models were used to assess the relationship of hs-CRP levels and ICAS status. A total of 432 (29.63%) subjects had ICAS. The levels of hs-CRP in stroke group were significantly higher than those in non-stroke group (p < 0.001). Patients with ICAS tend to have higher hs-CRP levels (p < 0.001). In multivariate analysis, the fourth hs-CRP quartile had the strongest association with ICAS in both stroke group and non-stroke group (OR 2.512, 95% CI 1.651-3.853, p < 0.001 for stroke group, and OR 2.534, 95% CI 1.435-4.595, p = 0.002 for non-stroke group) among the four quartiles of hs-CRP levels. Our study suggests that elevated serum hs-CRP levels are associated with higher risk of ICAS, in both stroke patients and non-stroke participants.

11.
Chaos ; 29(10): 103150, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31675845

RESUMO

Recently, a large number of studies have concentrated on aging transition, but they have so far been restricted to coupled integer-order oscillators. Here, we report the first study of aging transition in mixed active and inactive fractional-order oscillators. It has been demonstrated that while the heterogeneity is caused by the distance parameter, both the coupling strength and the fractional-order derivative can modulate the critical ratio at which aging transition occurs. In addition, a small fractional-order derivative may ruin the ability of oscillation and, thus, reduce the critical ratio in globally coupled fractional-order Stuart-Landau oscillators. Remarkably, the larger the natural frequency is the more easily the aging transition occurs in coupled fractional-order oscillators. Further studies have shown that, being diverse from an integer-order Stuart-Landau oscillator, the natural frequency may induce a Hopf bifurcation in a fractional-order Stuart-Landau oscillator, accordingly, introducing a new heterogeneity in the coupled fractional-order Stuart-Landau oscillators. Therein, a counterintuitive phenomenon has been found that the critical ratio depends unmonotonously on the coupling strength, which implies that the coupled fractional-order Stuart-Landau oscillators possess the weakest robustness of oscillation at a certain level of coupling strength.

12.
J Nat Prod ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31702148

RESUMO

The Arctic fungus Eutypella sp. D-1, previously found to produce a variety of cytotoxic cyclopropyl-fused and cyclobutyl-fused pimarane diterpenoids when grown in the defined medium, was induced to produce unusual metabolites by growing on solid rice medium. A chemical investigation on the rice medium extract led to the isolation of four new meroterpenoids, eutypellacytosporins A-D (1-4), along with the known biogenetically related compound cytosporin D (5). The structures of the new compounds were elucidated by their detailed spectroscopic analysis and modified Mosher's method. Compounds 1-4 may be formed by the 12,32-ester linkage of two moieties, cytosporin D (5) and decipienolide A or B. All isolated compounds, except 5, showed weak cytotoxicity against DU145, SW1990, Huh7, and PANC-1 cell lines with IC50 values ranging from 4.9 to 17.1 µM.

13.
Braz J Microbiol ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31667800

RESUMO

NADPH oxidases are enzymes that have been reported to generate reactive oxygen species (ROS) in animals, plants and many multicellular fungi in response to environmental stresses. Six genes of the NADPH oxidase complex components, including vvnoxa, vvnoxb, vvnoxr, vvbema, vvrac1 and vvcdc24, were identified based on the complete genomic sequence of the edible fungus Volvariella volvacea. The number of vvnoxa, vvrac1, vvbema and vvcdc24 transcripts fluctuated with ageing, and the gene expression patterns of vvnoxa, vvrac1 and vvbema were significantly positively correlated. However, the expression of vvnoxb and vvnoxr showed no significant difference during ageing. In hyphae subjected to mechanical injury stress, both O2- and H2O2 concentrations were increased. The expression of vvnoxa, vvrac1, vvbema and vvcdc24 was substantially upregulated, but vvnoxb and vvnoxr showed no response to mechanical injury stress at the transcriptional level. Additionally, the transcription of vvnoxa, vvrac1, vvbema and vvcdc24 could be repressed when the intracellular ROS were eliminated by diphenyleneiodonium (DPI) chloride and reduced glutathione (GSH) treatments. These results indicated a positive feedback loop involving NADPH oxidase and intracellular ROS, which might be the reason for the oxidative burst during injury stress.

14.
Front Immunol ; 10: 2421, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681309

RESUMO

Wound healing-promoting peptides exhibit excellent therapeutic potential in regenerative medicine. However, amphibian-derived wound healing-promoting peptides and their mechanism of action remain to be further elucidated. We hereby characterized a wound healing-promoting peptide, Ot-WHP, derived from Chinese concave-eared frog Odorrana tormota. It efficiently promoted wound healing in a mouse model of full-thickness wounds. Ot-WHP significantly increased the number of neutrophils in wounds, and modestly promoted neutrophil phagocytosis and phorbol myristate acetate (PMA)-induced neutrophil extracellular trap formation. Ot-WHP also significantly increased the number of macrophages in wound sites, and directly induced chemokine, cytokine and growth factor production in macrophages by activating mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways. Of note, Ot-WHP did not act as a chemoattractant for neutrophils and macrophages, suggesting its chemotactic activity depends on inducing chemoattractant production in macrophages. Besides, Ot-WHP directly promoted keratinocyte migration by enhancing integrin expression and cell adhesion. In addition, Ot-WHP significantly enhanced the cross-talk between macrophages and keratinocytes/fibroblasts by promoting keratinocyte/fibroblast proliferation, and fibroblast-to-myofibroblast transition despite having no direct effects on keratinocyte/fibroblast proliferation, and fibroblast differentiation. Collectively, Ot-WHP directly elicited the production of regulatory factors in macrophages, consequently initiated and accelerated the inflammatory phase by recruiting neutrophils and macrophages to wounds, and in turn enhanced the cross-talk between macrophages and keratinocytes/fibroblasts, additionally promoted keratinocyte migration, and finally promoted cutaneous wound healing. Our findings provide a promising immunomodulator for acute wound management and new clues for understanding the mechanism of action of amphibian-derived wound healing-promoting peptides.

15.
J Mass Spectrom ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31697856

RESUMO

Current miniature mass spectrometers mainly focus on the analyses of organic and small biological molecules. In this study, we explored the possibility of developing high resolution miniature ion trap mass spectrometers for whole protein analysis. Theoretical derivation, GPU assisted ion trajectory simulation and initial experiments on home-developed "brick" mass spectrometer were carried out. Results show that ion-neutral collisions have smaller damping effect on large protein ions, and a higher buffer gas pressure should be applied during ion trap operations for protein ions. As a result, higher pressure ion trap operation not only benefit instrument miniaturization, but also improve mass resolution of protein ions. Dynamic mass scan rate and generation of low charge state protein ions are also found to be helpful in terms of improving mass resolutions. Theory and conclusions found in this work are also applicable in the development of benchtop mass spectrometers.

16.
Math Biosci Eng ; 16(6): 7217-7229, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31698611

RESUMO

This study intended to gain new insight into the genetic basis underlying ganglioneuroma (GN), ganglioneuroblastoma (GNB), and neuroblastoma (NB). Three fresh-frozen surgically resected tumor tissues (GN1, GNB1, and NB1) and matched blood samples (GN2, GNB2, and NB2) were respectively obtained from three pediatric patients with GN, GNB, and NB. After exome sequencing, we predicted the somatic single nucleotide variants (SNV) and insertion and deletion (InDel), and screened the predisposing genes. Finally, we detected and filtered the fusion gene using Fusionmap. Exome sequencing identified 815, 985, and 884 somatic SNV, and 56, 43, and 34 InDel for GN, NB, and GNB respectively. Total 29, 19 and 37 predisposing genes were identified from GN, GNB and NB samples, such as PIK3CA (GN), MUC4 (GN), PML (NB), TFR2 (GNB), and MAX (GNB). Additionally, four common fusion genes, such as HOXD11-AGAP3 and SAMD1-CDC42EP5, were identified from three tumor samples. Moreover, SAMD1-CDC42EP5 was also a common fusion position in three blood samples. These previously unrecognized predisposing genes, such as PIK3CA, MUC4, PML, TFR2 and MAX, and fusion genes, like HOXD11-AGAP3, and SAMD1-CDC42EP5 may have the potential to impact the progression and development of neuroblastic tumors.

17.
Lung ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31705271

RESUMO

INTRODUCTION: The value of postoperative radiotherapy (PORT) for resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) is controversial with few studies focusing on whether PORT always plays a part in clinical practice and generates benefits to patients across different time periods. We investigated this issue using the Surveillance, Epidemiology, and End Results Database (SEER) and assessed the temporal trends spanning 27 years. METHODS: Within SEER, we selected stage IIIA-N2 NSCLC patients who underwent a lobectomy or pneumonectomy and coded as receiving PORT or never receiving radiotherapy over three time periods: 1988 to 1996, 1997 to 2005, 2006 to 2014. For each period, survival analyses were performed and propensity score matching (PSM) was used in the potentially beneficial subgroup. RESULTS: 45.4% of 5568 eligible patients received PORT. The yearly PORT use rates varied largely from 27.8% to 74.4%. Overall survival (OS) was distinctly improved over the period. The application of PORT had a significant impact on survival only in period 1 and 3. In subgroup analysis, the OS benefit of PORT was significant in each period in patients with 50% or more lymph node ratio (LNR) both before (hazard ratios, and P values of 0.647, P = .002; 0.804, P = .008; 0.721, P < .001 for period 1, 2, 3, respectively) and after PSM (0.642, P = .006; 0.785, P = .004; 0.748, P = .003 for period 1, 2, 3, respectively). CONCLUSIONS: The benefits of PORT are lasting and stable throughout the years in patients with LNR of 50% or more. This might provide a clue on proper patient selection for PORT application.

18.
Neuroscience ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31705888

RESUMO

Synaptosomal-associated protein 25 (SNAP-25) plays an important role in neuropathic pain. However, the underlying mechanism is largely unknown. Vesicular glutamate transporter 2 (VGluT2) is an isoform of vesicular glutamate transporters that controls the storage and release of glutamate. In the present study, we found the expression levels of VGluT2 correlated with the upregulation of SNAP-25 in the spinal cord of rats following chronic constriction injury (CCI)-induced neuropathic pain. Cleavage of SNAP-25 by Botulinum toxin A (BoNT/A) attenuated mechanical allodynia, downregulated the expression of VGluT2 and reduced glutamate release. Overexpression of VGluT2 abolished the antinociceptive effect of BoNT/A. Upregulation of SNAP-25 in naive rats increased VGluT2 expression and induced pain-responsive behaviors. In pheochromocytoma (PC12) cells, the expression of VGluT2 was also depended on SNAP-25 dysregulation. Moreover, we found VGluT2 was involved in SNAP-25-mediated regulation of astrocyte expression and activation of the PKA/p-CREB pathway mediated the upregulation of SNAP-25 in neuropathic pain. The findings of our study indicate that VGluT2 contributes to the effect of SNAP-25 in maintaining the development of neuropathic pain and suggests a novel mechanism underlying SNAP-25 regulation of neuropathic pain.

20.
Elife ; 82019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31657716

RESUMO

CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 (6a in this work) is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 (6a) can rapidly penetrate cell membranes and then be processed into active inhibitors, which are retained intracellularly with 10-fold enrichment for several days. These compounds were characterized for their potency, selectivity, modes of action, and on-target engagement. SKI-73 (6a) recapitulates the effect of CARM1 knockout against breast cancer cell invasion. Single-cell RNA-seq analysis revealed that the SKI-73(6a)-associated reduction of invasiveness acts via altering epigenetic plasticity and suppressing the invasion-prone subpopulation. Interestingly, SKI-73 (6a) and CARM1 knockout alter the epigenetic plasticity with remarkable difference, arguing distinct modes of action between the small-molecule and genetic perturbation. We therefore discovered a CARM1-addiction mechanism of cancer metastasis and developed a chemical probe to target this process.

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