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1.
Brain Topogr ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31691912

RESUMO

Both functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) have been used to non-invasively localize the human motor functional area. These locations can be clinically used as stimulation target of TMS treatment. However, it has been reported that the finger tapping fMRI activation and TMS hotspot were not well-overlapped. The aim of the current study was to measure the distance between the finger tapping fMRI activation and the TMS hotspot, and more importantly, to compare the network difference by using resting-state fMRI. Thirty healthy participants underwent resting-state fMRI, task fMRI, and then TMS hotspot localization. We found significant difference of locations between finger tapping fMRI activation and TMS hotspot. Specifically, the finger tapping fMRI activation was more lateral than the TMS hotspot in the premotor area. The fMRI activation peak and TMS hotspot were taken as seeds for resting-state functional connectivity analyses. Compared with TMS hotspot, finger tapping fMRI activation peak showed more intensive functional connectivity with, e.g., the bilateral premotor, insula, putamen, and right globus pallidus. The findings more intensive networks of finger tapping activation than TMS hotspot suggest that TMS treatment targeting on the fMRI activation area might result in more remote effects and would be more helpful for TMS treatment on movement disorders.

2.
Mol Med Rep ; 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31702019

RESUMO

Thyroid hormone resistance syndrome is a rare disease in which the level of thyroid hormone is elevated and the level of thyroid stimulating hormone is not suppressed. Mutations in the thyroid hormone receptor ß (THRß) gene are thought to be the primary cause of pathogenesis. In the present study, a Chinese boy of 4 years and 8 months, who had been pre­diagnosed with resistance to thyroid hormone, was assessed for mutations. The clinical features and thyroid function of the proband and his parents were collected and gene mutations were analyzed using DNA sequencing. Gene sequencing showed that the THRß genes in the parents of the proband were consistent with the standard sequence, however, in the proband there was a mutation in the tenth exon of the THRß gene (c. 824 T>C). This is a newly identified mutation site and, to the best of our knowledge, there have been no previous reports of this mutation site. Therefore, it is hypothesized that this mutation is the cause of the pathology in the proband.

3.
Phytother Res ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31667930

RESUMO

Mas-related G protein-coupled receptor-X2 (MRGPRX2) expressed on mast cells (MCs) has been shown to be a pivotal target for pseudo-allergic diseases. Therefore, MRGPRX2 might be a therapeutic target for allergic contact dermatitis, atopic dermatitis, and red man syndrome. Paeoniflorin (PF) was reported to have an antiinflammatory effect in neuroinflammation, enteritis, and so forth. In this study, we investigated the anti-pseudo-allergic effect of PF and the underlying molecular mechanisms. Our results showed that PF can suppress compound 48/80 (C48/80)-induced PCA and MCs degranulation in vivo, in a dose-dependent manner. Moreover, PF can reduce C48/80-induced calcium influx and suppress MC degranulation and chemokines release in vitro. PF can downregulate the phosphorylation levels of key kinases in PLCγ-regulated calcium influx and subsequent cytokine synthesis pathways. Our study revealed that PF could inhibit C48/80-induced allergic responses both in vivo and in vitro. As such, it may be regarded as a novel inhibitor for preventing MRGPRX2-mediated allergic diseases.

4.
Int Orthod ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31668665

RESUMO

This case reports the unsuccessful first treatment and the subsequent retreatment of a 35-year old Asian female with a skeletal class II with bimaxillary protrusion, complicated by a deep bite and vertical maxillary excess. This case report highlights the multiple facets of a challenging treatment plan and discusses the ramifications of treatment when treatment does not go as planned. The initial treatment plan consisted of a surgical approach with a maxillary Le Fort I surgery to correct the malocclusion as per the patient's requests without mandibular surgery due to the inherent risk of paraesthesia. The second treatment plan consisted of a bimaxillary surgery with genioplasty. The surgical treatment utilized virtual surgical planning (VSP). The orthodontic treatment was concluded with a corrected overjet and overbite achieving optimum function and balancing the facial profile aesthetically. This case report highlights the need for clear communication of the treatment plan and also the unpredictability of certain treatment outcomes especially when the literature does not provide for definitive conclusions. In addition, it sheds light on the challenge of unpredictable response of soft tissue after surgical treatment and the importance of patient expectations of outcomes. It is hoped that the paper provides a platform for future discussions of difficult malocclusions.

5.
Am J Orthod Dentofacial Orthop ; 156(5): 685-693, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31677677

RESUMO

The treatment of skeletal Class III malocclusion with anterior open bite is a complex and challenging aspect of orthodontics. Facial esthetic factors, practicality and the anticipated stability of a provisional surgical plan must all be factored into the final decision of the actual orthodontic-orthognathic treatment. This case report presents the multidisciplinary treatment of a 39-year-old female patient with skeletal Class III, severe open bite with first dental contact being on the second molars, lateral crossbite, and crowding in both arches. The nonextraction treatment started with aligning and leveling of the teeth in both arches followed by an initial surgical plan based on the clinical evaluation of the smile esthetics. Precise surgical planning information was imported into the Virtual Surgica (VSP Orthognathics) workflow to visualize the direction and amount of movement necessary. The final plan was adjusted because of anticipated practical limitations of the surgery as well as to insure the stability. LeFort I, bilateral sagittal split osteotomies, and setback genioplasty were thus performed. After the surgery, the treatment concluded with the fine adjustment of the occlusion. In the end, good esthetic and functional outcomes with long-term stability were achieved as a result of this delicate multidisciplinary approach.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31670939

RESUMO

The porous structure composed of nonmetal elements of the covalent organic frameworks (COFs) contributes to the large surface area and multifunction, rendering it a brilliant material for energy storage. Unfortunately, the low conductivity of most COFs limits their application in batteries. Herein, we fabricate COF-derived nitrogen-doped porous carbon (NPC) using nitrogen rich COF-JLU2 as precursors by a simple carbonization for potassium-ion batteries (PIBs) and aluminum (Al) batteries for the first time. The computational results suggest that NPC has an enhanced conductivity and optimized electron density distribution. NPC could overcome the low conductivity of COF, and thus further optimize its electrochemical performance in PIBs and Al batteries. It displays an excellent stability even after 2500 cycles (as the anode for PIBs) and 30000 cycles (as the cathode for Al batteries) with a high Coulombic efficiency. This fascinating study may be extended in other COFs for energy storage applications.

7.
Food Chem Toxicol ; : 110924, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31672514

RESUMO

BACKGROUND: Allergic conjunctivitis (AC) resulting from conjunctival reactive inflammation is a common ocular surface disease. Quercetin is known for its anti-allergic properties but its effects on conjunctivitis are less well understood. PURPOSE: In this study, we evaluated the anti-allergic effects of quercetin in animal models of conjunctivitis, and explored its molecular mechanism(s) of action in cultured human mast cells (MCs). KEY RESULTS: Quercetin inhibited the ovalbumin (OVA) induced expression of IgE, HA, IL-4, TNF-α and substance-P in the peripheral blood of AC mouse models. Quercetin also attenuated OVA induced MC degranulation, eosinophil number, substance P concentrations, and mRNA IL-4/TNF-α expression in the conjunctival tissue of AC models. In vitro analysis showed that quercetin reduced DNP-HSA/IgE induced calcium (Ca2+) influx, and suppressed degranulation and chemokine release in LAD2 cells (human primary mast cell). Quercetin also inhibited DNP-HSA/IgE induced Lyn/PLCγ/IP3R-Ca2+ activation, Lyn/ERK1/2 signaling, and Lyn/NF-κB activation in LAD2 cells, all of which promote inflammation. When added alone, quercetin had no effect on PLCγ1 phosphorylation or expression, but potently inhibited Lyn and phosphorylation-Lyn. Quercetin (200 µM) and Lyn inhibitors (Bafetinib, 10 µM) inhibit the activity of Lyn kinase, and quercetin can reduce the activation of Lyn kinase by Lyn agonist (Tolimidone, 10 µM). These data can be preliminarily determined that quercetin can inhibit allergic conjunctivitis as a Lyn kinase inhibitor. CONCLUSIONS AND IMPLICATIONS: This study illustrated the use of quercetin for the treatment of allergic conjunctivitis, which might act through its ability to inhibit Lyn/PLCγ/IP3R-Ca2+, Lyn/ERK1/2, and Lyn/NF-κB signaling. The inhibition of Lyn likely represents a major mechanism by which quercetin dampens the inflammatory response in AC disease models.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31580221

RESUMO

In situ thrombus formation is one of the major pathological features of pulmonary hypertension (PH). The mechanism of in situ thrombosis has not been clearly identified. Fgl2 prothrombinase is an immune coagulant that can cleave prothrombin to thrombin which then converts fibrinogen into fibrin. This mechanism triggers in situ thrombus formation directly, bypassing both the intrinsic and extrinsic coagulation pathways. Fgl2 prothrombinase is mainly expressed in endothelia cells and mediates multiple pathological processes. This implies it may also play a role in PH. In this study, we examined the expression of Fgl2 in IPAH patients, and in MCT-induced rat and hypoxia-induced mouse PH models. Fgl2-/-mice were used to evaluate the development of PH and explore associated pathological changes. These included in situ thrombosis, vascular remodeling and endothelial apoptosis. Following these analyses, we examined possible signaling pathways downstream of Fgl2 in PH. We show Fgl2 is upregulated in pulmonary vascular endothelium in human IPAH, and two animal PH models. Genetic knockout of Fgl2 limited the development of PH, indicated by decreased in situ thrombus formation, less vascular remodeling and reduced endothelial dysfunction. In addition, loss of Fgl2 downregulated Par1 expression and decreased the over-activation and consumption of platelets in hypoxia-induced PH. These results indicate Fgl2 participate in the development of PH and loss of Fgl2 could attenuate PH by reducing in situ thrombosis and suppressing Par1 signaling. Thus, we provide evidence that suggests Fgl2 prothrombinase presents a potential therapeutic target for clinical treatment of PH.

9.
J Xray Sci Technol ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31594280

RESUMO

 The aim of this study is to present a fully automated registration algorithm that allows for alignment and errors analysis of the 3D surface model obtained from industrial computed tomography (CT) images with the computer-aided design (CAD) model. First, two pre-processing steps are executed by the algorithm namely, CAD model subdivision and representing models. Next, two improved registration procedures are applied including covariance descriptors-based coarse registration with a novel and automatic calibration, followed by a fine registration technique that utilizes an improved iterative closest points (ICP) algorithm, which is what we proposed with a novel estimation method for registration error. Finally, using a novel strategy that we proposed for error display, the quantitative data analysis results can simultaneously estimate both positive and negative deviation of the surface registration errors more precisely and fully expressed. Comparing to the original ICP algorithm, the quantitative data of experimental results demonstrate that the average registration errors of carburetors and valves are reduced by 0.80 millimeter at least. Therefore, this study demonstrates that the proposed new algorithm is not only capable of fully automating the registration of 3D surface model to a CAD model but also beneficial for quantitatively determining the surface manufacturing error more precisely.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31617993

RESUMO

Cd doping and metallic Ag additives in Ca3Co4O9+δ polycrystalline materials are shown to result in improved thermoelectric (TE) transport properties. Carrier concentration and mobility were optimized through the combination of doping and compositional modulation approaches. The formation of filiform Ag nanoinclusions between the interlayers and grain boundaries enhances the anisotropic carrier transport, leading to higher carrier mobility. A spin entropy enhancement due to the change of the net valence of Co induced by Cd substitution on the Ca site was confirmed by X-ray photoelectron spectroscopy. High carrier mobility and enhanced spin entropy results in higher electrical conductivity and Seebeck coefficient, leading to the increase of the power factor. In conjunction, mass fluctuation between Cd and Ca on the same crystal site along with the increase of metallic Ag nanoinclusions effectively lowers thermal conductivity. Consequently, the figure-of-merit, zT, has been improved to 0.31 at 950 K for 10 wt % Ag-modified Ca2.9Cd0.1Co4O9+δ specimen, which is a significant improvement compared to the pristine material. This dual-mode control of electron and phonon transport by including Ag additives and Cd doping offers an approach for tuning the correlated TE parameters.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31613764

RESUMO

General image completion and extrapolation methods often fail on portrait images where parts of the human body need to be recovered -a task that requires accurate human body structure and appearance synthesis. We present a twostage deep learning framework for tackling this problem. In the first stage, given a portrait image with an incomplete human body, we extract a complete, coherent human body structure through a human parsing network, which focuses on structure recovery inside the unknown region with the help of full-body pose estimation. In the second stage, we use an image completion network to fill the unknown region, guided by the structure map recovered in the first stage. For realistic synthesis the completion network is trained with both perceptual loss and conditional adversarial loss.We further propose a face refinement network to improve the fidelity of the synthesized face region. We evaluate our method on publicly-available portrait image datasets, and show that it outperforms other state-of-the-art general image completion methods. Our method enables new portrait image editing applications such as occlusion removal and portrait extrapolation. We further show that the proposed general learning framework can be applied to other types of images, e.g. animal images.

12.
Molecules ; 24(20)2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31614942

RESUMO

Mahonia bealei (Fort.) Carr. (M. bealei) plays an important role in the treatment of many diseases. In the present study, a comprehensive method combining supercritical fluid chromatography (SFC) fingerprints and chemical pattern recognition (CPR) for quality evaluation of M. bealei was developed. Similarity analysis, hierarchical cluster analysis (HCA), principal component analysis (PCA) were applied to classify and evaluate the samples of wild M. bealei, cultivated M. bealei and its substitutes according to the peak area of 11 components but an accurate classification could not be achieved. PLS-DA was then adopted to select the characteristic variables based on variable importance in projection (VIP) values that responsible for accurate classification. Six characteristics peaks with higher VIP values (≥1) were selected for building the CPR model. Based on the six variables, three types of samples were accurately classified into three related clusters. The model was further validated by a testing set samples and predication set samples. The results indicated the model was successfully established and predictive ability was also verified satisfactory. The established model demonstrated that the developed SFC coupled with PLS-DA method showed a great potential application for quality assessment of M. bealei.

13.
Medicine (Baltimore) ; 98(39): e17350, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574877

RESUMO

BACKGROUND: Shenqi Fuzheng injection (SFI) is a commonly used anti-cancer Chinese patent medicine and has long been prescribed as adjunctive treatment to platinum-based chemotherapy (PBC) in patients with stage III/IV non-small cell lung cancer (NSCLC). However, the efficacy and safety of this combination therapy remain unclear. METHODS: A systematic review and meta-analysis will be conducted following the Preferred Reported Items for Systematic Review and Meta-analysis (PRISMA) guidelines. Seven databases will be searched for relevant studies from their inception to the present date: PubMed, Web of Science, Cochrane Library, EMBASE, ClinicalTrials.gov, China National Knowledge Infrastructure (CNKI), and Wanfang Databases. All randomized clinical trials comparing SFI in combination with PBC versus PBC alone will be retrieved and assessed for inclusion. Two researchers will independently perform the selection of the studies, data extraction, and synthesis. The Cochrane Risk of Bias Tool will be used to evaluate the risk of bias of the RCTs. The primary endpoint is the disease control rate (DCR), the secondary outcomes are the objective response rate (ORR), survival rate, quality of life (QOL), cellular immune function, and toxicities. Review Manager 5.3 (Nordic Cochrane Centre, Cochrane Collaboration, 2014 Copenhagen, Denmark) will be used to analyze the outcomes. RESULTS: This study will systematically evaluate the efficacy and safety of SFI combined with platinum-based chemotherapy in the treatment of stage III/IV NSCLC. The results will be published in a peer-reviewed journal. CONCLUSION: This systematic review will evaluate the effects of SFI as adjunctive treatment to platinum-based chemotherapy in the patients with stage III/IV non-small cell lung cancer, thus providing evidence to the clinical application of this combination therapy. PROSPERO REGISTRATION NUMBER: CRD42019137196.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Compostos de Platina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Injeções , Neoplasias Pulmonares/patologia , Metanálise como Assunto , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisão Sistemática como Assunto , Resultado do Tratamento
14.
Medicine (Baltimore) ; 98(39): e17382, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574890

RESUMO

BACKGROUND: Long-term use of aspirin for primary prevention of cancer remains inconclusive, and variation in the effects of aspirin use on cancer outcomes by cancer site, aspirin dose, follow-up duration, or different populations has never been systematically evaluated. METHODS: Seven electronic databases (PubMed, EMBASE, ClinicalTrials.gov, etc) will be searched from inception to September 30, 2019. Randomized clinical trials (RCTs) comparing aspirin versus no aspirin in participants without pre-existing cancer and reporting cancer incidence, and/or cancer mortality outcomes will be selected and assessed for inclusion. The Cochrane's Risk of Bias Tool and the Jadad scale will be used to evaluate the risk of bias and the methodologic quality of the RCTs. Data will be screened and extracted by independent investigators. Total cancer incidence will be defined as the primary clinical endpoint, and total cancer mortality, all-cause mortality, and the risk of major bleeding will be the secondary outcomes. Subgroup analyses based on cancer site, aspirin dose, follow-up duration, or different populations will be conducted. Analyses will be performed using Review Manager 5.3, Comprehensive Meta-Analysis 2.0, and Trial Sequential Analysis (TSA) software. RESULTS: This study will systematically evaluate the effects of long-term aspirin use on total cancer incidence, cancer mortality, all-cause mortality, and the risk of major bleeding. Subgroup analyses will indicate whether the effects of aspirin on cancer outcomes are associated with cancer site, daily dose of aspirin, follow-up duration, or different subgroup of participants. The results will be submitted and published in a peer-reviewed scientific journal. CONCLUSIONS: This systematic review will systematically evaluate the efficacy and safety of long-term use of aspirin for primary prevention of cancer and determine whether there are some potential influencing factors affecting the effects of aspirin on cancer outcomes, thus strengthening the evidence base for the clinical practice and future research of this intervention.


Assuntos
Aspirina/uso terapêutico , Neoplasias/prevenção & controle , Prevenção Primária/métodos , Humanos , Incidência , Metanálise como Assunto , Neoplasias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Revisão Sistemática como Assunto , Fatores de Tempo
15.
J Immunother Cancer ; 7(1): 271, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640816

RESUMO

BACKGROUND: Chimeric antigen receptor-modified (CAR) T-cell immunotherapy is a novel promising therapy for treatment of B-cell malignancy. Cytokine release syndrome (CRS) and infection are the most common adverse events during CAR T-cell therapy. Similar clinical presentation of concurrent CRS and infection makes it difficult to differentially diagnose and timely treat the condition. METHODS: We analyzed the features of infection events during the first 30 days after CAR T-cell infusion (CTI) in 109 patients from three clinical trials (ChiCTR-OPN-16008526, ChiCTR-OPC-16009113, ChiCTR-OPN-16009847). Based on the dynamic changes of interleukin (IL)-6 and ferritin, we proposed the "double peaks of IL-6" pattern as a feature of life-threatening infection during the first 30 days after CTI. Meanwhile, we screened candidate biomarkers from 70-biomarker panel to establish a prediction model for life-threatening infection. RESULTS: In this study, 19 patients (17.4%) experienced a total of 19 infection events during the first 30 days after CAR T-cell infusion. Eleven patients (10.1%) had grade 4-5 infection, which were all bacterial infection and predominantly sepsis (N = 9). "Double peaks of IL-6" appeared in 9 out of 11 patients with life-threatening infection. The prediction model of three-cytokines (IL-8, IL-1ß and interferon-γ) could predict life-threatening infection with high sensitivity (training: 100.0%; validation: 100.0%) and specificity (training: 97.6%; validation: 82.8%). On base of the aforementioned methods, we proposed a workflow for quick identification of life-threatening infection during CAR T-cell therapy. CONCLUSIONS: In this study, we worked out two diagnostic methods for life-threatening infection during CAR T-cell therapy by analyzing inflammatory signatures, which contributed to reducing risks of infection-induced death.

16.
Leuk Lymphoma ; : 1-10, 2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31549889

RESUMO

Exposure-response relationships from a phase 1b (M13-365) and phase 3 (MURANO) study were investigated to assess benefit/risk of venetoclax 400 mg daily plus rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Dose intensities were summarized by tertiles of predicted venetoclax steady-state average concentrations based on nominal venetoclax dose (CmeanSS,nominal) for tolerability; exposure-safety analyses used logistic regression. Exposure-progression-free survival (PFS) relationships were assessed using MURANO data, with CmeanSS,nominal as a grouping factor. Covariates were demographics, geographic region, study, baseline disease characteristics, ECOG performance status, responsiveness to prior therapy, and chromosomal abnormalities. There was no significant effect of covariates on grade ≥3 neutropenia/infection or PFS, and no relationship between venetoclax exposure and these endpoints, or venetoclax or rituximab dose intensity. These results support the recommended venetoclax 400 mg daily dose in combination with rituximab in patients with R/R CLL or small lymphocytic leukemia.

17.
Scand J Gastroenterol ; 54(9): 1124-1131, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31491354

RESUMO

Background: The Enhanced Recovery After Surgery (ERAS) pathway is widely applied in the perioperative period of stomach and colorectal surgery, and can decrease the length of hospital stay of the patients without compromising the safety of the patients. However, some patients are removed from this pathway for various reasons. Here we found some factors that taking the patients out from the procedures. Methods: A retrospective analysis of collected data of 550 patients over a 3-year period was conducted, with 292 in the ERAS group and 258 in the conventional care group. Then various basic elements were analyzed to explore the reasons for the failure to complete the ERAS program. Results: Total length of hospital stay after surgery was significantly shorter in the ERAS group, and a similar incidence of complication rates were observed in the two groups. In this study, the significant factors that associated with complications were advanced age (OR 2.18; p = .031), history of abdominal surgery (OR 2.03; p = .04), incomplete gastrointestinal obstruction (OR 3.42; p < .001), laparoscopic surgery (OR 0.39; p = .004) and intraoperative neostomy (OR 2.37; p = .006). Conclusions: We found that advanced age (>80 years old), history of abdominal surgery, gastrointestinal obstruction and stoma formation were the risk factors. We anticipated to design a risk assessment system upon the high-risk patients from the present ERAS pathway, and make a modified ERAS pathway for those patients.

18.
J Immunol ; 203(7): 1701-1714, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484729

RESUMO

Intrathecal morphine infusion is often applied to treat chronic pain related to cancer and other conditions. However, persistent pain can be caused by nerve compression because of granuloma formation. In this study, a mouse model of morphine-induced granuloma formation by intrathecal catheterization morphine infusion into the atlanto-occipital membrane of the foramen magnum was established in wild-type mice, MrgprB2 mutant (MrgprB2-/-) mice, and in mast cell-deficient W-sash c-kit mutant (KitW-sh/W-sh) mice. Heat-related pain after surgery was performed to investigate the antipain effect of morphine. H&E staining and immunofluorescence staining of the spinal cord were applied to analyze the mechanism of granuloma formation. Morphine-induced mast cell degranulation was assessed by measuring the Ca2+ influx and mediator release. Anaphylactoid reactions were measured after s.c. morphine infusion to the paws. Chemokine release by mast cells was determined by Human XL Cytokine Array. Experiments with wild-type, MrgprB2 mutant, and mast cell-deficient W-sash c-kit mutant mice demonstrated that morphine activated mast cells and inflammatory cell aggregation through MrgprB2 in intrathecal infusion sites. The chemokine production of human mast cells demonstrated that granuloma formation is correlated with chemokines release. In addition, morphine activated mouse primary mast cells and de novo chemokine synthesis via the MRGPRX2 in human LAD2 cells. We concluded that granuloma formation during intrathecal morphine infusion was associated with MrgprB2/X2. Reducing MRGPRX2 potentially blocks morphine-induced side effects, including granuloma formation.

19.
J Dermatol Sci ; 95(3): 99-106, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31558225

RESUMO

BACKGROUND: Thimerosal has been used as a preservative in many products which may cause contact dermatitis. It is the second most common allergen in positive patch test reactions, though being a clinical irrelevant allergen. Thimerosal-induced contact dermatitis is generally considered to be a delayed-type hypersensitivity reaction, but it is difficult to explain the fact that most patients develop an allergic reaction upon first encounter with thimerosal. Recent studies have demonstrated the association between Mas-related G protein coupled receptor X2 (MRGPRX2) and pseudo-allergic reactions which occur at the first contact with stimulation. This suggests the possibility that thimerosal may cause contact dermatitis via MRGPRX2 mediated mechanism. OBJECTIVES: To investigate the role of Mas-related G-protein coupled receptor B2 (MrgprB2)/MRGPRX2 in contact dermatitis induced by thimerosal. METHODS: Thimerosal induced pseudo-allergic reactions via MrgprB2/ MRGPRX2 were investigated using a novel skin pseudo-allergic reaction mouse model, footpad swelling and extravasation assays in vivo and mast cell degranulation assay in vitro. RESULTS: Thimerosal induced contact dermatitis in dorsal skin and footpad swelling in wild-type mice, but had no significant effect in MrgprB2-knockout mice. Thimerosal-induced dermatitis is characterized by infiltration of inflammatory cells and elevation of serum histamine and inflammatory cytokines, rather than elevation of serum IgE level. Thimerosal increased the intracellular Ca2+ concentration in HEK293 cells overexpressing MrgprB2/MRGPRX2. Downregulation of MRGPRX2 resulted in the reduced degranulation of LAD2 human mast cells. CONCLUSIONS: MrgprB2 mediates thimerosal-induced mast cell degranulation and pseudo-allergic reaction in mice. MRGPRX2 may be a key contributor to human contact dermatitis.

20.
Life Sci ; : 116866, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31518606

RESUMO

Neural stem cells (NSCs) are pluripotent cells that are capable of differentiating into neurons and considered as the most promising cell source for cell replacement therapy. However, the difficulty in inducing neuronal differentiation and maturation from NSCs is a major challenge for their clinical application. Clarifying the molecular mechanisms underlying the neuronal differentiation of NSCs can provide a basis for expanding their uses. Brain 4 (Brn4) is a member of the POU domain family of transcription factors and can induce the neuronal differentiation of NSCs, but its precise function in NSCs is unclear. To address this question, in this study we isolated and expanded radial glial cells (RGCs), a type of NSC, from the cerebral cortex of 14-day embryonic rats and used lentivirus carrying the human Brn4 gene to overexpress Brn4 in these cells. This induced the differentiation of RGCs into neurons and inhibited the expression of C-terminal binding protein 2 (CtBP2), a transcriptional co-repressor. CtBP2 overexpression in RGCs suppressed their differentiation into neurons, whereas CtBP2 knockdown had the opposite effect. These results indicated that Brn4 promoted the neuronal differentiation of NSCs via inhibition of CtBP2 and is a potential tool for generating neurons in cell replacement therapy of neurodegenerative diseases and brain injury.

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