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1.
Stem Cell Res Ther ; 10(1): 229, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358069

RESUMO

The skin has important barrier, sensory, and immune functions, contributing to the health and integrity of the organism. Extensive skin injuries that threaten the entire organism require immediate and effective treatment. Wound healing is a natural response, but in severe conditions, such as burns and diabetes, this process is insufficient to achieve effective treatment. Epidermal stem cells (EPSCs) are a multipotent cell type and are committed to the formation and differentiation of the functional epidermis. As the contributions of EPSCs in wound healing and tissue regeneration have been increasingly attracting the attention of researchers, a rising number of therapies based on EPSCs are currently under development. In this paper, we review the characteristics of EPSCs and the mechanisms underlying their functions during wound healing. Applications of EPSCs are also discussed to determine the potential and feasibility of using EPSCs clinically in wound healing.

2.
Hepatology ; 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31155734

RESUMO

The oncogene c-Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c-Myc is significantly up-regulated by tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/- mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63-linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c-Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c-Myc. Second, the K63-linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c-Myc and promotes c-Myc protein acetylation, which thereby enhances c-Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70-kDa-interacting protein-mediated c-Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c-Myc signaling is also primed in hepatitis B virus-transgenic mice, unveiling a critical role for a mechanism in inflammation-cancer transition. In clinical specimens, TRAF6 positively correlates with c-Myc at both the mRNA and protein levels, and high TRAF6 and c-Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c-Myc to promote human hepatocarcinogenesis. Consistently, curbing c-Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c-Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c-Myc signaling, with potential implications for HCC therapy.

3.
Alcohol ; 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31175945

RESUMO

Problems of stability were found for biomarkers of alcohol consumption, ethyl glucuronide (EtG), ethyl sulfate (EtS), phosphatidylethanols (PEths) and fatty acid ethyl esters (FAEEs) in whole blood. The purpose of this study was to establish a method for the determination of these 4 kinds of ethanol's non-oxidative metabolites in dried blood spots (DBS) by liquid chromatography tandem mass spectrometry (LC-MS/MS), and to evaluate their stability. In this method, 50 µL of human blood was spotted on a filter paper for DBS analysis. Samples were extracted by methanol, reconstituted by 2-propanol and injected in the LC-MS/MS system. Limits of detection were among 0.5 - 50 ng/mL, deviations in accuracy and precision were all lower than 15% at three quality control levels. The stability of the 4 kinds of ethanol non-oxidative metabolites in DBS was investigated during a 90-day range under 3 temperatures, -20 °C, 4 °C and 25 °C. EtG and EtS showed a high level of stability in DBS in the 90-day range, regardless of the temperature. FAEEs was unstable in 3 days. PEths showed a stability within 15 days in postmortem DBS and 60 days in antemortem DBS respectively at all temperatures.

4.
J Immunol ; 203(1): 31-38, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31092638

RESUMO

Alternaria is a major outdoor allergen. Immunotherapy with Alternaria extracts has been documented to be effective in the sensitized patients. However, Alternaria extracts are notoriously difficult to standardize. Our aim is to screen the B cell mimotopes of Alternaria and to evaluate the therapeutic effects of B cell mimotope peptides on a BALB/c mouse model of Alternaria allergy. After a human sera pool from Alternaria monosensitized patients was established, B cell mimotopes were screened by a phage-displayed random heptamer peptide library that was identified via mixed Alternaria-specific IgE in the sera pool. B cell mimotopes with phage as a carrier were used to perform immunotherapy in an Alternaria allergy mouse model. Serological Ab levels, lung histology, and cytokine profiles were compared in the mimotope immunotherapy group, natural extract immunotherapy group, irrelevant phage control group, Alternaria-sensitized model group, and saline-blank group. Two mimotopes (MISTSRK and QKRNTIT) presented high binding ability with the sera of the Alternaria-allergic patients and mice and, therefore, were selected for immunotherapy in the mouse model. Compared with irrelevant phage control, model, and natural extract immunotherapy group, mimotope immunotherapy group significantly reduced serum IgE levels, inflammatory cells infiltration in the lung tissue, and IL-4 levels in bronchoalveolar lavage fluid, whereas serum IgG1 and IFN-γ levels in bronchoalveolar lavage fluid were increased. Our results indicate that B cell mimotopes of Alternaria alleviates allergic response in a mouse model and have potential as novel therapeutic agents for IgE-mediated Alternaria-allergic diseases.

5.
BMC Bioinformatics ; 20(Suppl 7): 200, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31074373

RESUMO

BACKGROUND: Transcription factors (TFs) play important roles in the regulation of gene expression. They can activate or block transcription of downstream genes in a manner of binding to specific genomic sequences. Therefore, motif discovery of these binding preference patterns is of central significance in the understanding of molecular regulation mechanism. Many algorithms have been proposed for the identification of transcription factor binding sites. However, it remains a challengeable problem. RESULTS: Here, we proposed a novel motif discovery algorithm based on support vector machine (MD-SVM) to learn a discriminative model for TF binding sites. MD-SVM firstly obtains position weight matrix (PWM) from a set of training datasets. Then it translates the MD problem into a computational framework of multiple instance learning (MIL). It was applied to several real biological datasets. Results show that our algorithm outperforms MI-SVM in terms of both accuracy and specificity. CONCLUSIONS: In this paper, we modeled the TF motif discovery problem as a MIL optimization problem. The SVM algorithm was adapted to discriminate positive and negative bags of instances. Compared to other svm-based algorithms, MD-SVM show its superiority over its competitors in term of ROC AUC. Hopefully, it could be of benefit to the research community in the understanding of molecular functions of DNA functional elements and transcription factors.


Assuntos
Algoritmos , Motivos de Nucleotídeos , Máquina de Vetores de Suporte , Fatores de Transcrição/metabolismo , Sítios de Ligação , Humanos , Ligação Proteica
6.
Nanoscale ; 11(17): 8319-8326, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-30982840

RESUMO

The temporal response of conventional ZnO nanowire-based photodetectors suffers from the influence of carrier mobility and high electrical resistance. As a result, these devices can be prohibitively slow for some applications, generally with a response time on the order of 1 second. This study presents a novel ZnO nanowire-based microfiber coupler structure for all-optical photodetection without the demand for photocurrent generation. In this design, two waveguides are directly adsorbed by van der Waals forces or electrostatic forces. Compared with the conventional electrical bridge structure, the optical coupling architecture makes the device both compact and stable. In this configuration, resonance dips form in the transmission spectrum when the phase-matching conditions of the two waveguides are satisfied. The measurements of the resulting wavelength shift, low noise levels, and repetition time confirmed that the proposed optical device could operate as a photodetector. The device exhibits superior performance with a sensitivity of 1.657 nm (W cm-2)-1 and a response time of 0.43 ms. In addition, the detector features a simple fabrication as there is no need for extra modification of ZnO nanowires. The resulting photodetection capabilities could provide a new functionality for novel all-optical applications.

7.
Autophagy ; 15(9): 1506-1522, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30806153

RESUMO

Aberrant CTNNB1 signaling is one of the fundamental processes in cancers, especially colorectal cancer (CRC). Here, we reported that TRAF6, an E3 ubiquitin ligase important for inflammatory signaling, inhibited epithelial-mesenchymal transition (EMT) and CRC metastasis through driving a selective autophagic CTNNB1 degradation machinery. Mechanistically, TRAF6 interacted with MAP1LC3B/LC3B through its LC3-interacting region 'YxxL' and catalyzed K63-linked polyubiquitination of LC3B. The K63-linked ubiquitination of LC3B promoted the formation of the LC3B-ATG7 complex and was critical to the subsequent recognition of CTNNB1 by LC3B for the selective autophagic degradation. However, TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. Clinically, decreased expression of TRAF6 was associated with elevated GSK3B protein levels and activity and reduced overall survival in CRC patients. Pharmacological inhibition of GSK3B activity stabilized the TRAF6 protein, promoted CTNNB1 degradation, and effectively suppressed EMT and CRC metastasis. Thus, targeting TRAF6 and its pathway may be meaningful for treating advanced CRC. Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; AOM: azoxymethane; ATG5: autophagy related 5; ATG7: autophagy related 7; Baf A1: bafilomycin A1; BECN1: beclin 1; CoIP: co-immunoprecipitation; CQ: chloroquine; CRC: colorectal cancer; CTNNB1/ß-catenin: catenin beta 1; DSS: dextran sodium sulfate; EMT: epithelial-mesenchymal transition; FBS: fetal bovine serum; GFP: green fluorescent protein; GSK3B/GSK3ß: glycogen synthase kinase 3 beta; IgG: Immunoglobulin G; IHC: immunohistochemistry; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; RFP: red fluorescent protein; RT: room temperature; shRNA: short hairpin RNA; siRNA: small interfering RNA; TRAF6: TNF receptor-associated factor 6; WT: wild-type; ZEB1: zinc finger E-box binding homeobox 1.

8.
Int J Nanomedicine ; 14: 195-204, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30636872

RESUMO

Background: 3-(2-Nitrophenyl) propionic acid-paclitaxel (NPPA-PTX) is a paclitaxel (PTX) bioreductive prodrug synthesized by our lab. We hypothesize that NPPA-PTX can self-assemble to form nanoparticles (NPs). Materials and methods: In the present research, the theoretical partition coefficient (XlogP) and Hansen solubility parameters of NPPA-PTX were calculated. NPPA-PTX nanoparticles prepared by NPPA-PTX and DSPE-PEG (NPPA-PTX:DSPE-PEG =1:0.1, w/w) (NPPA-PTX@PEG NPs) were prepared and characterized. The cellular uptake, in vitro antitumor activity, in vivo targeting effect, tumor distribution, in vivo antitumor activity, and safety of NPPA-PTX@PEG NPs were investigated. Results: Our results indicate that NPPA-PTX can self-assemble to form NPPA-PTX@PEG NPs. Both the cellular uptake and safety of NPPA-PTX@PEG NPs were higher than those of Taxol. NPPA-PTX@PEG NPs could target tumor tissues by a passive targeting effect. In tumor tissues, NPPA-PTX@PEG NPs could completely transform into active PTX. The in vivo antitumor activity of NPPA-PTX@PEG NPs was confirmed in MDA-MB-231 tumor-bearing nude mice. Conclusion: The bioreductive prodrug NPPA-PTX could self-assemble to form NPs. The safety and antitumor activity of NPPA-PTX@PEG were confirmed in our in vitro and in vivo experiments. The NPPA-PTX@PEG NPs developed in this study could offer a new way of preparing bioreductive prodrug, self-assembled NPs suitable for antitumor therapy.


Assuntos
Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Nanopartículas/administração & dosagem , Paclitaxel/análogos & derivados , Fenilpropionatos/farmacologia , Pró-Fármacos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Fenilpropionatos/administração & dosagem , Pró-Fármacos/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Control Release ; 295: 102-117, 2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30582952

RESUMO

Nucleus-targeting drug delivery systems (NTDDs) deliver chemotherapeutic agents to nuclei in order to improve the efficacy of anti-tumour therapy. Histone H1 (H1) plays a key role in establishing and maintaining higher order chromatin structures and could bind to cell membranes. In the present study, we selected H1 as a target to prepare a novel H1-mediated NTDD. Low molecular weight heparin (LMHP) and doxorubicin (DOX) were combined to form LMHP-DOX. Then, a novel NTDD consisting of LMHP-DOX nanoparticles (LMHP-DOX NPs) was prepared by self-assembly. The characteristics of LMHP-DOX and LMHP-DOX NPs were investigated. Histone H1 high-expressive prostate cancer PC-3M cell line was selected as the cell model. Cellular uptake, and the in vitro and in vivo anti-tumour activity of LMHP-DOX NPs were evaluated on H1 high-expressive human prostate cancer PC-3M cells. Our results indicated that intact LMHP-DOX NPs mediated by H1 could be absorbed by H1 high-expressive PC-3M cells, escape from the lysosomes to the cytoplasm, and localize in the perinuclear region via H1-mediated, whereby DOX could directly enter the cell nucleus and quickly increase the concentration of DOX in the nuclei of H1 high-expressive PC-3M cells to enhance the apoptotic activity of cancer cells. The anti-coagulant activity of LMHP-DOX NPs was almost completely diminished in rat blood compared with that of LMHP, indicating the safety of LMHP-DOX NPs. Compared to traditional NTDD strategies, LMHP-DOX NPs avoid the complicated modification of nucleus-targeting ligands and provide a compelling solution for the substantially enhanced nuclear uptake of chemotherapeutic agents for the development of more intelligent NTDDs.

10.
Dev Biol ; 2018 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-30476483

RESUMO

Local transplantation of stem cells has therapeutic effects on skin damage but cannot provide satisfactory wound healing. Studies on the mechanisms underlying the therapeutic effects of stem cells on skin wound healing will be needed. Hence, in the present study, we explored the role of Caveolin-1 in epidermal stem cells (EpiSCs) in the modulation of wound healing. We first isolated EpiSCs from mouse skin tissues and established stable EpiSCs with overexpression of Caveolin-1 using a lentiviral construct. We then evaluated the epidermal growth factor (EGF)-induced cell proliferation ability using cell counting Kit-8 (CCK-8) assay and assessed EpiSC pluripotency by examining Nanog mRNA levels in EpiSCs. Furthermore, we treated mice with skin burn injury using EpiSCs with overexpression of Caveolin-1. Histological examinations were conducted to evaluate re-epithelialization, wound scores, cell proliferation and capillary density in wounds. We found that overexpression of Caveolin-1 in EpiSCs promoted EGF-induced cell proliferation ability and increased wound closure in a mouse model of skin burn injury. Histological evaluation demonstrated that overexpression of Caveolin-1 in EpiSCs promoted re-epithelialization in wounds, enhanced cellularity, and increased vasculature, as well as increased wound scores. Taken together, our results suggested that Caveolin-1 expression in the EpiSCs play a critical role in the regulation of EpiSC proliferation ability and alteration of EpiSC proliferation ability may be an effective approach in promoting EpiSC-based therapy in skin wound healing.

11.
Heliyon ; 4(11): e00909, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30450437

RESUMO

Cannabinoid receptor 2 (CB2R) is a therapeutic target in inflammatory diseases; its activation by agonists provides important clinical information, but there are currently no methods to quantify CB2R activation in humans. Chinese hamster ovary (CHO)-K1 cells and mouse and human whole blood cells were used for experiments. CB2R was activated in cells by treatment with the agonist CP55,940. Cells were also pretreated with proprietary Compound A and B (experimental agonists). We developed our method based on the finding that CB2R ligand binding and activation stimulates acute-phase extracellular signal-regulated kinase (ERK) phosphorylation in human and rodent immune cells, after which CB2R becomes unresponsive to stimulation by a second CB2R agonist CP55940 for a certain time period. We detected ERK phosphorylation as a measure of target engagement in mouse and human whole blood cells by flow cytometry. In cells overexpressing human or mouse CB2R, pretreatment with Compound A dose-dependently inhibited ERK phosphorylation for 2 h, prolonging the time window for measuring ERK phosphorylation. Our method enables measurement of CB2R activation by its agonists in human blood cells based on detection of ERK phosphorylation, which is useful for therapeutic drug monitoring and other clinical applications.

12.
Phytother Res ; 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-30461085

RESUMO

We aimed to explore the effect of curcumin on epidermal stem cells (ESCs) in regulating wound healing and the underlying molecular mechanism. We treated mouse ESCs isolated from skin tissues with curcumin, and then assessed the proliferation ability of cells induced by epidermal growth factor using cell counting kit-8 assay. The pluripotency of ESCs was evaluated as well through examination of Nanog expression in ESCs. Further, mice with skin burns were treated with ESCs with or without curcumin pretreatments. Histological evaluations were then preformed to determine wound scores, cell proliferation, reepithelialization, and capillary density in wounds. Curcumin treatment promoted the proliferative ability of ESCs and conditioned medium from curcumin-treated ESCs enhanced human umbilical vein endothelial cell (HUVEC) tube formation. We also found curcumin treatment elevated caveolin-1 expression in ESCs, which was required for the beneficial effect of curcumin on ESC proliferation and HUVEC tube formation. Next, using a mouse model of burn wound healing, curcumin-treated ESCs exhibited enhanced wound closure, which also required caveolin-1 expression. Our current study demonstrates the beneficial effect of curcumin on burn wound healing in mice, which is mediated by upregulating caveolin-1 in ESCs, and supports the potential therapeutic role of curcumin in ESC-based treatment against skin wound healing.

13.
AoB Plants ; 10(5): ply053, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30310559

RESUMO

Homoploid hybrid speciation (HHS), characterized by hybrid speciation without a change in chromosome number and facilitated by ecological divergence, is well known in angiosperms but rare in gymnosperms. Picea purpurea as one of two demonstrably conifer diploid hybrid species in gymnosperms has been found to occupy colder alpine habitats than its parents. However, studies on whether leaf frost tolerance and hydraulic safety exhibit transgressive segregation and thus play a role in conifer HHS are still lacking. In this study, we compared the frost tolerance of photosystem stability (the maximum efficiency of PSII, F v/F m), pressure-volume parameters, and xylem resistance to dysfunction of leaves (current-year twigs) and stems (annual shoots) between P. purpurea and its progenitors. The results indicated that P. purpurea had significantly lower osmotic potential at full turgor, water potential at turgor loss point, water potential at 12 % loss of conductance of stem, the maximum hydraulic conductance of stem and the temperature causing a 50 % reduction in initial F v/F m than its parental species. In contrast, the leaf and stem xylem pressure inducing 50 % loss of hydraulic conductivity (leaf Ψ50 and stem Ψ50, respectively) and hydraulic safety margin in leaf Ψ50, stem Ψ50 in P. purpurea showed no significant difference with those of P. wilsonii, but significantly larger than those of P. likiangensis. This suggests that the frost tolerance of photosystem stability and the cell dehydration tolerance in P. purpurea are superior to its parental species, facilitating its successful colonization and establishment in colder habitats.

14.
Int Forum Allergy Rhinol ; 8(11): 1267-1273, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30048045

RESUMO

BACKGROUND: Allergen immunotherapy (AIT) is still the only causal treatment for allergic diseases. However, conventional subcutaneous immunotherapy (SCIT) administration schedules are time-consuming and patient nonadherence is a major barrier to achieving a satisfactory therapeutic effect. Our study aimed to analyze the causes leading to discontinuation of SCIT and to determine risk factors associated with nonadherence in respiratory allergies. METHODS: This was a prospective study. Patients with respiratory allergies who had received standardized dust mite SCIT were enrolled from January 2012 to January 2014. And a follow-up study on these subjects was conducted via telephone interviews on an interval of 3 months and online communication through social network applications. Reasons for discontinuation were documented when patients claimed to stop treatment. RESULTS: A total of 311 patients were enrolled in the study. The adherence rate at year 3 was 64.6%. Fifty-nine patients (19.0%) dropped out in year 1, 31 (10.0%) in year 2, and 20 (6.4%) in year 3. Reasons for nonadherence included inconvenience (32.7%), ineffectiveness (25.5%), improvement of symptoms (22.7%), and adverse reactions (14.5%). Children had higher adherence than adults (70.7% vs 55.0%) (p < 0.05). The dropout reasons were different among the children and adults groups (p < 0.005). The follow-up work was carefully and thoroughly done. All the 311 (100%) patients accepted the telephone interview, and 296 (95.2%) patients submitted questions and got rapid replies from doctors online. CONCLUSION: Adherence to SCIT was less than satisfactory in the real-life study. A close communication between doctors and patients is helpful in enhancing adherence with AIT in clinical practice.

15.
J Hematol Oncol ; 11(1): 95, 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-30016968

RESUMO

BACKGROUND: Ubiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC. METHODS: Immunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression. RESULTS: Ube2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC. CONCLUSIONS: Our study functionally links Ube2v1, an E2 member in the ubiquitin-proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.

16.
Int J Biol Sci ; 14(8): 901-906, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29989071

RESUMO

Alpha-helical transmembrane protein (αTMP) is one of the two major categories of transmembrane protein (TMP). They are abundant existing in eukaryotic cells and involved in many biological processes. The special physicochemical properties, the structures of αTMP are hard to be experimentally solved, but αTMP's sequential segments are important to determine their conformations, so that TM-specific alignment is necessary to benefit their structure prediction. We used segment information extracted from topology structure and evolutionary information as features to implement a αTMP Segment Alignment method (TMSA). The method was trained using one non-redundant dataset and tested using another non-redundant dataset. Comparing the results to a general alignment method HHalign, TMSA achieved higher alignment accuracy, and easier to recognize the fold of αTMPs.

17.
Artigo em Inglês | MEDLINE | ID: mdl-29886146

RESUMO

BACKGROUND: Allergic Rhinitis Control Test (ARCT) has been validated in the allergic rhinitis (AR) step-up pharmacotherapy management approach. OBJECTIVE: The aim of our study was to evaluate the potential of ARCT in AR step-down pharmacotherapy. METHODS: In an open-labeled randomized controlled study, patients with AR controlled with intranasal corticosteroid (INS) plus antihistamine (step 4) were included and randomized into an ARCT or a control group. In the ARCT group, the patients were followed up every 15 days; if the ARCT score was ≥20 (controlled AR), the patient would step down to step 3 (INS), step 2 (daily antihistamine), step 1 (antihistamine as needed), and step 0 (no medication) consecutively; if the ARCT score was strictly <20, the treatment would not be adjusted. In the control group, patients would be treated with step 4 medications during the whole study. Rhinitis Quality-of-Life Questionnaire (RQLQ), Morisky Questionnaire, and Brief Illness Perception Questionnaire (B-IPQ) were completed at baseline and the end of the study. Medication use and side effects were recorded. RESULTS: A total of 255 patients with AR were enrolled into the study; 27 patients dropped out. The control rates at day 45 were 77.8% in the ARCT group and 85.8% in the control group (P > .05). The ARCT group had less mean medication use than the control group (INS 1.27 vs 2.22 bottle, antihistamines 35.9 vs 61.4 tablets) (P < .05). RQLQ, Morisky, and B-IPQ score were significantly improved in both groups after treatment (P < .05). CONCLUSIONS: Stepping down AR medications in controlled patients led to similar clinical outcomes at reduced cost compared with those who maintained their current treatment level. ARCT is an optimal tool for evaluating the step-down eligibility.

18.
Mol Plant Microbe Interact ; 31(12): 1232-1243, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29717915

RESUMO

The type III secretion system (T3SS) is the main machinery for Pseudomonas savastanoi and other gram-negative bacteria to invade plant cells. HrpR and HrpS form a hetero-hexamer, which activates the expression of HrpL, which induces all T3SS genes by binding to a 'hrp box' in promoters. However, the individual molecular mechanism of HrpR or HrpS has not been fully understood. Through chromatin immunoprecipitation coupled to high-throughput DNA sequencing, we found that HrpR, HrpS, and HrpL had four, 47, and 31 targets on the genome, respectively. HrpS directly bound to the promoter regions of a group of T3SS genes and non-T3SS genes. HrpS independently regulated these genes in a hrpL deletion strain. Additionally, a HrpS-binding motif (GTGCCAAA) was identified, which was verified by electrophoretic mobility shift assay and lux-reporter assay. HrpS also regulated motility and biofilm formation in P. savastanoi. The present study strongly suggests that HrpS alone can work as a global regulator on both T3SS and non-T3SS genes in P. savastanoi. [Formula: see text] Copyright © 2018 The Author(s). This is an open-access article distributed under the CC BY-NC-ND 4.0 International license .

19.
Genet Test Mol Biomarkers ; 22(5): 320-326, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29694791

RESUMO

BACKGROUND: The cannabinoid receptor 2 (CB2R) is primarily expressed in immune tissues and implicated in immune regulation. In models of inflammatory diseases, modulation of CB2R alters function of immune cells and affects the progression of disease. We therefore believe that CB2R modulation could be a promising therapy for inflammatory diseases. In humans, the nonsynonymous mutation Q63R, the most common variant of the CB2 receptor, has been found to be associated with multiple diseases, including idiopathic arthritis, obesity, and celiac diseases. However, it is not clear whether the Q63R variant indeed alters signaling of CB2R and whether the change in a specific signaling pathway contributes to the pathogenesis of inflammatory diseases. Better understanding of the signaling downstream of CB2R in immune cells may provide a molecular base for better usage of CB2R modulators. METHODS: We studied the signaling caused by CB2R activation in cell lines and primary immune cells possessing Q63R variant. RESULTS: We found that activation of CB2R in immune cells by either an endogenous (2-AG) or a synthetic (CP5,940) ligand causes transient phosphorylation of extracellular signal-regulated kinases (ERK). Phosphorylation of ERK in immune cells due to activation of CB2R is coupled to Gi protein. In human peripheral blood mononuclear cells, phosphorylation of ERK caused by CB2R activation is especially intense in B cells and T cells. CONCLUSIONS: Activation of both CB2R variants 63Q and 63R causes phosphorylation of ERK. However, the signal intensity caused by 63R activation is relatively weaker than that caused by 63Q activation.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Receptor CB2 de Canabinoide/genética , Animais , Células CHO , Cricetulus , Ativação Enzimática , Humanos , Leucócitos Mononucleares/enzimologia , Leucócitos Mononucleares/metabolismo , Fosforilação , Transdução de Sinais
20.
Oncotarget ; 9(15): 12035-12049, 2018 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-29552291

RESUMO

The pathogenesis and key functional molecules involved in inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) remain unclear. Here, we reported that Erbin, a protein required for the polarity of epithelial cells, is conserved across species and highly expressed in the intestinal mucosa in mice and zebrafish. Pathologically, Erbin expression in the intestinal mucosa was significantly decreased in DSS induced acute colitis mice, IL-10 deficient mice and clinical biopsy specimens from patients with ulcerative colitis. Moreover, Erbin deficient mice are more susceptible to experimental colitis, exhibiting more severe intestinal barrier disruption, with increased histological scores and excessive production of proinflammatory cytokines. Mechanistically, Erbin deficiency or knockdown significantly exacerbated activation of autophagic program and autophagic cell death in vivo and in vitro. And, inhibition of autophagy by Chloroquine attenuates excessive inflammatory response in the DSS-induced colitis mouse model of Erbin deletion. Generally, our study uncovers a crucial role of Erbin in autophagic cell death and IBD, giving rise to a new strategy for IBD therapy by inhibiting excessive activation of autophagy and autophagic cell death.

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