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1.
Arch Toxicol ; 93(10): 2863-2878, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444509

RESUMO

Acetaminophen (APAP)-induced liver injury is the main cause of acute liver failure. This study investigated the role of microsomal prostaglandin E synthase 2 (mPGES-2), discovered as one of the prostaglandin E2 (PGE2) synthases, in mediating APAP-induced liver injury. Using mPGES-2 wild-type (WT) and knockout (KO) mice, marked resistance to APAP-induced liver damage was found in mPGES-2 KO, as indicated by robust improvement of liver histology, changes in liver enzyme release, and marked decrease in APAP-cysteine adducts (APAP-CYS) and inflammatory markers. Moreover, the results confirmed that increase in liver PGE2 content in KO mice under basal conditions was not critical for the protection from APAP-induced liver injury. Importantly, mPGES-2 deletion inhibited the production of malondialdehyde (MDA), increasing glutathione (GSH) level. Enhanced GSH level may contribute to the inhibition of APAP toxicity in mPGES-2 KO mice. To further elucidate the role of mPGES-2 in the liver injury induced by APAP, adeno-associated viruses (AAV) were used to overexpress mPGES-2 in the liver. The results showed that mPGES-2 overexpression aggravates liver injury associated with an increase in inflammatory markers and chemokines after APAP treatment. Moreover, a lower level of GSH was detected in the mPGES-2 overexpression group compared to the control group. Collectively, our findings indicate that mPGES-2 plays a critical role in regulating APAP-induced liver injury, possibly by regulating GSH and APAP-CYS level, which may provide a potential therapeutic strategy for the prevention and treatment of APAP-induced liver injury.

2.
J Colloid Interface Sci ; 554: 157-165, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31295687

RESUMO

The development of porous organic polymer (POP)-based materials with controllable structures is highly desirable for catalysis, drug delivery, and chemical adsorption. In this work, we prepared unique porous magnetic core-shell POP nanospheres (Fe3O4@PDA@POP) through a facile strategy. These nanospheres contained a core of magnetic Fe3O4 nanoparticles (NPs), a hydrophilic intermediate layer of dopamine and a POP outer layer. The Fe3O4@PDA@POP showed high porosity, making it an ideal supporting material for fabricating ultrafine and highly dispersed noble-metal NPs (NMNPs). Thus, highly dispersed ultrafine Pd NPs (1.5-2.1 nm) were confined and stabilized within the pores of Fe3O4@PDA@POP via a reverse double-solvent approach (RDSA) to obtain Fe3O4@PDA@POP@Pd catalyst. The Fe3O4@PDA@POP@Pd-2.5% catalyst showed excellent catalytic performance and recyclability towards the hydrogenation of nitrobenzene, alkenes, and alkynes. Hence, this work can pave the way for the development and application of functionalized POP materials to construct efficient catalytic systems.

3.
J Colloid Interface Sci ; 553: 588-597, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31238229

RESUMO

The fabrication of ultrafine noble metal nanoparticle (NMNP)-based catalysts is significant for heterogeneous catalysis due to their excellent performance for organic transformations. In this study, N-doped micro-mesoporous hollow carbon nanospheres (HCN) with a nitrogen content of ∼3.5 wt% are easily prepared by simple carbonization. Then, ultrafine Pd NPs are immobilized on HCN, affording Pd/HCN as a dual-function catalyst which exhibits superior catalytic activity for the selective oxidation of 5-hydroxymethylfurfural (HMF) and hydrogenation of nitroarenes, under mild reaction conditions. The doping of HCN with nitrogen is beneficial for the high dispersion, anchoring, and particle size control of ultrafine Pd NPs, leading to the maximum utilization of Pd atoms and further enhancing the catalytic activity of Pd/HCN. In addition, the obtained Pd/HCN catalyst exhibits excellent reusability and stability. Hence, this study demonstrates the prospect of developing ultrafine NMNP-supported catalysts with high performance for organic transformations.

4.
J Exp Med ; 216(7): 1664-1681, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31123085

RESUMO

Follicular helper T (Tfh) cells are essential for germinal center formation and effective humoral immunity, which undergo different stages of development to become fully polarized. However, the detailed mechanisms of their regulation remain unsolved. Here we found that the E3 ubiquitin ligase VHL was required for Tfh cell development and function upon acute virus infection or antigen immunization. VHL acted through the hypoxia-inducible factor 1α (HIF-1α)-dependent glycolysis pathway to positively regulate early Tfh cell initiation. The enhanced glycolytic activity due to VHL deficiency was involved in the epigenetic regulation of ICOS expression, a critical molecule for Tfh development. By using an RNA interference screen, we identified the glycolytic enzyme GAPDH as the key target for the reduced ICOS expression via m6A modification. Our results thus demonstrated that the VHL-HIF-1α axis played an important role during the initiation of Tfh cell development through glycolytic-epigenetic reprogramming.

5.
J Colloid Interface Sci ; 533: 259-267, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30170277

RESUMO

Use of renewable raw materials for fabrication catalysts with excellent catalytic performance is of considerable importance for sustainable chemistry. Here, biowaste soybean curd residue (SCR) was used to prepare porous N-doped carbon materials (PNCM) via the carbonization method, and subsequently modified with small Pd nanoparticles (NPs) to generate the Pd/PNCM catalyst. Pd/PNCM was used for catalytic hydrogenation of phenol to cyclohexanone, as the latter is an important chemical intermediate that is usually produced under harsh reaction conditions. The Pd/PNCM catalyst can hydrogenate phenol to cyclohexanone in aqueous solution under mild reaction conditions with excellent catalytic performance. In addition, compared to commercial Pd/C, Pd/PNCM exhibits excellent catalytic performance and stability, which is attributed to the synergetic effects of N-doping of porous carbon supports and stabilization of ultra-small Pd NPs. Thus, this study highlights a new pathway for preparing N-doped porous carbon materials using biomass waste as the precursor material, and subsequently fabricating precious metal-modified catalysts with excellent catalytic performance for sustainable and green catalysis.


Assuntos
Carbono/química , Nitrogênio/química , Paládio/química , Fenóis/química , Alimentos de Soja , Resíduos , Biomassa , Catálise , Cicloexanonas/síntese química , Cicloexanonas/química , Hidrogenação , Tamanho da Partícula , Porosidade , Propriedades de Superfície
6.
Artigo em Inglês | MEDLINE | ID: mdl-30398340

RESUMO

Inflammasomes, a critical component of the innate immune system, mediate much of the inflammatory response manifested by engineered nanomaterials. Iron oxide nanoparticles (IONPs), a type of nanoparticles that have gained widespread acceptance in preclinical and clinical settings, are known to induce inflammasome activation, but how morphology affects the inflammasome-activating property of IONPs has not been addressed. In this report, we have synthesized four morphologically distinct IONPs having the same aspect ratio and similar surface charge, thus offering an ideal system to assess the impact of morphology on nanoparticle-elicited biological effect. We show that morphology was a critical determinant for IONP-induced IL-1ß release and pyroptosis, with the octapod and plate IONPs exhibiting significantly higher activity than the cube and sphere IONPs. The inflammasome-activating capacity of different IONPs correlated with their respective ability to elicit intracellular reactive oxygen species generation, lysosomal damage, and potassium efflux, three well-known mechanisms for nanoparticle-facilitated inflammasome activation. Furthermore, we demonstrate that the release of IL-1ß induced by IONPs was only partly mediated by NLRP3, suggesting that inflammasomes other than NLRP3 are also involved in IONP-induced inflammasome activation. Our results may have implications for designing safer nanoparticles for in vivo applications.

7.
ChemSusChem ; 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30240135

RESUMO

Fabrication of non-noble metal-based heterogeneous catalysts by a facile and cost-effective strategy for ecofriendly catalytic transfer hydrogenation (CTH) is of great significance for organic transformations. A cobalt@nitrogen-doped carbon (Co@NC) catalyst was prepared from renewable biomass-derived sucrose, harmless melamine, and earth-abundant Co(AcO)2 as the precursor materials by hydrothermal treatment and carbonization. Co nanoparticles (NPs) were coated with NC shells and uniformly embedded in the NC framework. The as-obtained Co@NC-600 (carbonized at 600 °C) catalyst exhibited excellent catalytic efficiency for CTH of various functionalized nitroarenes with formic acid (FA) as hydrogen donor in aqueous solution. The uniformly incorporated N atoms in the C matrix and the encapsulated Co NPs showed synergistic effects in the CTH reactions. A mechanistic analysis indicated that the protons from FA were activated by Co sites after being captured by N atoms, and then reacted with nitroarenes adsorbed on the surface of the catalysts to generate the corresponding aromatic amines. Moreover, the catalyst showed excellent durability and reusability without obvious decrease in activity even after five reaction cycles. Thus, the study reported herein provides a cost-effective, sustainable strategy for fabrication of biomass-derived non-noble metal-based catalysts for green and efficient catalytic transformations.

8.
Oncotarget ; 9(1): 394-403, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29416622

RESUMO

Ureteral obstruction is associated with reduced expressions of renal sodium transporters, which contributes to impaired urinary concentrating capacity. In this study, we employed a synthetic mitochondrial superoxide dismutase 2 (SOD2) mimic MnTBAP to investigate the role of mitochondrial oxidative stress in modulating the sodium transporters in obstructive kidney disease. Following unilateral ureteral obstruction (UUO) for 7 days, a global reduction of sodium transporters including NHE3, NCC, NKCC2, and ENaCα was observed as determined by qRT-PCR, Western Blotting or immunohistochemistry. Among these sodium transporters, the downregulation of NHE3, NCC, and NKCC2 was partially reversed by MnTBAP treatment. In contrast, the reduction of ENaCα was not affected by MnTBAP. The ß and γ subunits of ENaC were not significantly altered by ureteral obstruction or MnTBAP therapy. To further confirm the anti-oxidant effect of MnTBAP, we examined the levels of TBARs in the urine collected from the obstructed ureters of UUO mice and bladder of sham mice. As expected, the increment of urinary TBARs in UUO mice was entirely abolished by MnTBAP therapy, indicating an amelioration of oxidative stress. Meantime, we found that three types of SOD were all reduced in obstructed kidneys determined by qRT-PCR, which was unaffected by MnTBAP. Collectively, these results demonstrated an important role of mitochondrial oxidative stress in mediating the downregulation of sodium transporters in obstructive kidney disease.

9.
Food Funct ; 9(1): 389-396, 2018 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-29215110

RESUMO

Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by massive enlargement of fluid-filled cysts in the kidney. There is an urgent need to develop effective ADPKD therapies. We used an in vitro Madin-Darby canine kidney (MDCK) cyst model and a murine embryonic kidney cyst model to evaluate whether quercetin inhibits cyst development. We then used a polycystic kidney disease (PKD) mouse model to further determine the in vivo effects of quercetin (100 mg per kg body weight twice per day) on PKD mice via subcutaneous injections. The results show that quercetin significantly and dose-dependently inhibited cyst formation and enlargement in the MDCK cyst and embryonic kidney cyst models. Quercetin also noticeably reduced the cystic index in PKD mice. Furthermore, the effective dose of quercetin did not cause cytotoxicity in MDCK cells. Quercetin treatment decreased the levels of intracellular signalling proteins in PKD mouse kidneys, including phosphorylated protein kinase B (also known as AKT) and phosphorylated extracellular signal-regulated kinase (ERK), which are upregulated and promote cyst development in ADPKD. Quercetin also reversed E-cadherin expression, which is localized in normal proximal tubules in PKD mouse kidneys. Taken together, these results demonstrate that quercetin hinders renal cyst development in vivo and in vitro and represents a novel candidate strategy for the treatment of ADPKD.


Assuntos
Rim Policístico Autossômico Dominante/tratamento farmacológico , Quercetina/administração & dosagem , Animais , Cistos/tratamento farmacológico , Cistos/embriologia , Cistos/genética , Modelos Animais de Doenças , Cães , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Infusões Parenterais , Rim/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Rim Policístico Autossômico Dominante/embriologia , Rim Policístico Autossômico Dominante/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo
10.
Biomed Pharmacother ; 96: 328-335, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29024899

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. The progression of NAFLD is complex and associated with inflammation, oxidative stress, autophagy, endoplasmic reticulum stress, and insulin resistance. Mangiferin, a natural C-glucosyl xanthone, has been reported to show multiple biological activities. The aim of this study was to investigate the therapeutic effect of mangiferin on NAFLD and the underlying molecular mechanism. We established a mouse model of NAFLD using a high-fat diet (HFD), and injected the mice with different doses of mangiferin (15, 30, and 60mg/kg, intraperitoneal) for 12 weeks. Liver tissue was assessed to evaluate changes in inflammatory responses, autophagy, and glycolipid metabolism. We found that mangiferin decreased body weight, as well as the levels of triglycerides and total cholesterol in plasma and the liver. It also increased glucose tolerance in HFD-fed mice. In addition, mangiferin decreased inflammatory responses by inhibiting the activities of nuclear factor kappa B and c-Jun N-terminal kinase, regulated autophagy via the AMP-activated protein kinase/mechanistic target of rapamycin signaling pathway, and improved glycolipid metabolism via modulation of the insulin receptor substrate/phosphoinositide 3-kinase/protein kinase B signaling pathway. This study demonstrated that mangiferin significantly ameliorates NAFLD development in HFD-fed mice by inhibiting inflammatory responses, activating autophagy, and improving glycolipid metabolism.


Assuntos
Autofagia/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Xantonas/uso terapêutico , Animais , Autofagia/fisiologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Distribuição Aleatória , Xantonas/farmacologia
11.
J Colloid Interface Sci ; 501: 231-240, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28456107

RESUMO

Inexpensive and reusable transition metal heterogeneous catalysts exhibiting excellent catalytic performance represent an attractive alternative to noble metal and homogeneous catalysts. In this work, we fabricated a novel nanocatalyst comprised of Co nanoparticles (NPs) supported on a N-doped mesoporous carbon (Co/mCN-900) by simple one-pot pyrolysis of a homogeneous mixture of melamine, polyacrylonitrile, and Co(NO3)2·6H2O under a N2 atmosphere at 900°C. The as-obtained Co/mCN-900 catalyst displayed a fluffy mesoporous structure with highly dispersed and accessible Co NPs acting as catalytic active sites. The Co/mCN-900 catalyst was effective in hydrogenating nitroarenes at milder conditions (i.e., 1MPa H2 and 120°C) as compared to previously reported Co- and Ni-based catalysts. The Co/mCN-900 catalyst also catalyzed the reductive N-alkylation of nitroarenes with carbonyl compounds to form the corresponding aromatic secondary amines under very mild reaction conditions. In addition, the Co/mCN-900 catalyst showed good reusability since its morphology and activity were maintained after several reaction cycles. Therefore, this work provides a facile and promising method for fabricating non-precious transition metal-based catalysts with excellent performance and great potential for sustainable chemistry applications.

12.
Am J Physiol Renal Physiol ; 311(4): F777-F786, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27413198

RESUMO

Obstructive kidney disease is a common complication in the clinic. Downregulation of aquaporins (AQPs) in obstructed kidneys has been thought as a key factor leading to the polyuria and impairment of urine-concentrating capability after the release of kidney obstruction. The present study was to investigate the role of mitochondrial complex-1 in modulating AQPs in obstructive nephropathy. Following 7-day unilateral ureteral obstruction (UUO), AQP1, AQP2, AQP3, and vasopressin 2 (V2) receptor were remarkably reduced as determined by qRT-PCR and/or Western blotting. Notably, inhibition of mitochondrial complex-1 by rotenone markedly reversed the downregulation of AQP1, AQP2, AQP3, and V2 In contrast, AQP4 was not affected by kidney obstruction or rotenone treatment. In a separate study, rotenone also attenuated AQPs' downregulation after 48-h UUO. To study the potential mechanisms in mediating the rotenone effects on AQPs, we examined the regulation of the COX-2/microsomal prostaglandin E synthase (mPGES)-1/PGE2/EP pathway and found that COX-2, mPGES-1, and renal PGE2 content were all significantly elevated in obstructive kidneys, which was not affected by rotenone treatment. For EP receptors, EP2 and EP4 but not EP1 and EP3 were upregulated in obstructive kidneys. Importantly, rotenone strikingly suppressed EP1 and EP4 but not EP2 and EP3 receptors. However, treatment of EP1 antagonist SC-51322 could not affect AQPs' reduction in obstructed kidneys. Collectively, these findings suggested an important role of mitochondrial dysfunction in modulating AQPs and V2 receptor in obstructive nephropathy possibly via prostaglandin-independent mechanisms.


Assuntos
Aquaporinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Nefropatias/metabolismo , Receptores de Vasopressinas/metabolismo , Obstrução Ureteral/metabolismo , Animais , Aquaporinas/genética , Ciclo-Oxigenase 2/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Prostaglandina-E Sintases/metabolismo , Receptores de Vasopressinas/genética , Rotenona/farmacologia , Desacopladores/farmacologia
13.
Carbohydr Polym ; 143: 327-35, 2016 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-27083376

RESUMO

Polymorphic and morphological transformations of cellulosic materials are strongly associated to their properties and applications, especially in the case of emerging nanocelluloses. Related changes that take place upon treatment of cellulose nanocrystals (CNC) in alkaline conditions are studied here by XRD, TEM, AFM, and other techniques. The results indicate polymorphic transformation of CNC proceeds gradually in a certain range of alkali concentrations, i.e. from about 8% to 12.5% NaOH. In such transition alkali concentration, cellulose I and II allomorphs coexists. Such value and range of the transition concentration is strongly interdependent with the crystallite size of CNCs. In addition, it is distinctively lower than that for macroscopic fibers (12-15% NaOH). Transmission electron microscopy and particle sizing reveals that after mercerization CNCs tend to associate. Furthermore, TEMPO-oxidized mercerized CNC reveals the morphology of individual nanocrystal of the cellulose II type, which is composed of some interconnected granular structures. Overall, this work reveals how the polymorphism and morphology of individual CNC change in alkali conditions and sheds light onto the polymorphic transition from cellulose I to II.


Assuntos
Celulose/química , Nanopartículas , Oxirredução , Tamanho da Partícula , Piperidinas/química , Hidróxido de Sódio/química , Difração de Raios X
14.
Int J Comput Biol Drug Des ; 9(1-2): 102-119, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27034719

RESUMO

Three-dimensional (3D) high resolution microscopic images have high potential for improving the understanding of both normal and disease processes where structural changes or spatial relationship of disease features are significant. In this paper, we develop a complete framework applicable to 3D pathology analytical imaging, with an application to whole slide images of sequential liver slices for 3D vessel structure analysis. The analysis workflow consists of image registration, segmentation, vessel cross-section association, interpolation, and volumetric rendering. To identify biologically-meaningful correspondence across adjacent slides, we formulate a similarity function for four association cases. The optimal solution is then obtained by constrained Integer Programming. We quantitatively and qualitatively compare our vessel reconstruction results with human annotations. Validation results indicate a satisfactory concordance as measured both by region-based and distance-based metrics. These results demonstrate a promising 3D vessel analysis framework for whole slide images of liver tissue sections.

15.
Arthritis Rheumatol ; 68(5): 1251-61, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26749424

RESUMO

OBJECTIVE: Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells. METHODS: We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro-ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1(+/-) mice. RESULTS: Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro-ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro-ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14(low) cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIα1+ cells in all settings. Netrin-1(+/-) mice were protected against bleomycin-induced lung fibrosis and fibrocyte accumulation. CONCLUSION: Factors present in the lung matrices of patients with scleroderma regulate fibrocyte accumulation via a netrin-1-dependent pathway. Netrin-1 regulates bleomycin-induced pulmonary fibrosis in mice. Netrin-1 might be a novel therapeutic target in SSc-related ILD.


Assuntos
Doenças Pulmonares Intersticiais/metabolismo , Pulmão/metabolismo , Fatores de Crescimento Neural/metabolismo , Fibrose Pulmonar/metabolismo , Escleroderma Sistêmico/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Antibióticos Antineoplásicos/toxicidade , Anticorpos Neutralizantes/farmacologia , Fenômenos Biomecânicos , Bleomicina/toxicidade , Estudos de Casos e Controles , Diferenciação Celular , Colágeno/metabolismo , Colágeno Tipo I/metabolismo , Fibrose , Citometria de Fluxo , Imunofluorescência , Heterozigoto , Humanos , Antígenos Comuns de Leucócito/metabolismo , Leucócitos Mononucleares , Pulmão/efeitos dos fármacos , Pulmão/patologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/patologia , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Varredura , Fatores de Crescimento Neural/antagonistas & inibidores , Fatores de Crescimento Neural/genética , Netrina-1 , Proteômica , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Escleroderma Sistêmico/complicações , Tecidos Suporte , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética
16.
Int Immunol ; 28(4): 173-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26714592

RESUMO

CD4(+)T follicular helper (Tfh) cells are recognized as a distinct T-cell subset, which provides help for germinal center (GC) formation, B-cell development and affinity maturation, and immunoglobulin class switching, as an indispensable part of adaptive immunity. Tfh cell differentiation depends on various factors including cell-surface molecule interactions, extracellular cytokines and multiple transcription factors, with B-cell lymphoma 6 (Bcl-6) being the master regulator. T follicular regulatory (Tfr) cells are also located in the GC and share phenotypic characteristics with Tfh cells and regulatory T cells, but function as negative regulators of GC responses. Dysregulation of either Tfh or Tfr cells is linked to the pathogenesis of autoimmune diseases such as systemic lupus erythematosus. This review covers the basic Tfh and Tfr biology including their differentiation and function, and their close relationship with autoimmune diseases.


Assuntos
Autoimunidade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular , Diferenciação Celular , Humanos , Subpopulações de Linfócitos T/citologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Reguladores/citologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-26478919

RESUMO

Three dimensional microscopy images present significant potential to enhance biomedical studies. This paper presents an automated method for quantitative analysis of 3D primary vessel structures with histology whole slide images. With registered microscopy images of liver tissue, we identify primary vessels with an improved variational level set framework at each 2D slide. We propose a Vessel Directed Fitting Energy (VDFE) to provide prior information on vessel wall probability in an energy minimization paradigm. We find the optimal vessel cross-section associations along the image sequence with a two-stage procedure. Vessel mappings are first found between each pair of adjacent slides with a similarity function for four association cases. These bi-slide vessel components are further linked by Bayesian Maximum A Posteriori (MAP) estimation where the posterior probability is modeled as a Markov chain. The efficacy of the proposed method is demonstrated with 54 whole slide microscopy images of sequential sections from a human liver.


Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Imagem Tridimensional/métodos , Fígado/irrigação sanguínea , Microscopia/métodos , Algoritmos , Teorema de Bayes , Humanos , Fígado/diagnóstico por imagem , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
18.
Proc IEEE Int Symp Biomed Imaging ; 2015: 182-185, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26405504

RESUMO

The emergence of digital pathology has enabled numerous quantitative analyses of histopathology structures. However, most pathology image analyses are limited to two-dimensional datasets, resulting in substantial information loss and incomplete interpretation. To address this, we have developed a complete framework for three-dimensional whole slide image analysis and demonstrated its efficacy on 3D vessel structure analysis with liver tissue sections. The proposed workflow includes components on image registration, vessel segmentation, vessel cross-section association, object interpolation, and volumetric rendering. For 3D vessel reconstruction, a cost function is formulated based on shape descriptors, spatial similarity and trajectory smoothness by taking into account four vessel association scenarios. An efficient entropy-based Relaxed Integer Programming (eRIP) method is proposed to identify the optimal inter-frame vessel associations. The reconstructed 3D vessels are both quantitatively and qualitatively validated. Evaluation results demonstrate high efficiency and accuracy of the proposed method, suggesting its promise to support further 3D vessel analysis with whole slide images.

19.
Proc IEEE Int Symp Biomed Imaging ; 2015: 1212-1215, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26405506

RESUMO

A large number of cell-oriented cancer investigations require an effective and reliable cell segmentation method on three dimensional (3D) fluorescence microscopic images for quantitative analysis of cell biological properties. In this paper, we present a fully automated cell segmentation method that can detect cells from 3D fluorescence microscopic images. Enlightened by fluorescence imaging techniques, we regulated the image gradient field by gradient vector flow (GVF) with interpolated and smoothed data volume, and grouped voxels based on gradient modes identified by tracking GVF field. Adaptive thresholding was then applied to voxels associated with the same gradient mode where voxel intensities were enhanced by a multiscale cell filter. We applied the method to a large volume of 3D fluorescence imaging data of human brain tumor cells with (1) small cell false detection and missing rates for individual cells; and (2) trivial over and under segmentation incidences for clustered cells. Additionally, the concordance of cell morphometry structure between automated and manual segmentation was encouraging. These results suggest a promising 3D cell segmentation method applicable to cancer studies.

20.
Cell Stem Cell ; 16(5): 504-16, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25891907

RESUMO

Long noncoding RNAs (lncRNAs) have been implicated in controlling various aspects of embryonic stem cell (ESC) biology, although the functions of specific lncRNAs, and the molecular mechanisms through which they act, remain unclear. Here, we demonstrate discrete and opposing roles for the lncRNA transcript Haunt and its genomic locus in regulating the HOXA gene cluster during ESC differentiation. Reducing or enhancing Haunt expression, with minimal disruption of the Haunt locus, led to upregulation or downregulation of HOXA genes, respectively. In contrast, increasingly large genomic deletions within the Haunt locus attenuated HOXA activation. The Haunt DNA locus contains potential enhancers of HOXA activation, whereas Haunt RNA acts to prevent aberrant HOXA expression. This work reveals a multifaceted model of lncRNA-mediated transcriptional regulation of the HOXA cluster, with distinct roles for a lncRNA transcript and its genomic locus, while illustrating the power of rapid CRISPR/Cas9-based genome editing for assigning lncRNA functions.


Assuntos
Células-Tronco Embrionárias/fisiologia , Proteínas de Homeodomínio/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Sistemas CRISPR-Cas , Diferenciação Celular/genética , Linhagem Celular , Montagem e Desmontagem da Cromatina , DNA/genética , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica , Loci Gênicos/genética , Genoma , Proteínas de Homeodomínio/genética , Camundongos , RNA Longo não Codificante/genética , Ativação Transcricional
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