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1.
Cytotherapy ; 26(7): 719-728, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38530690

RESUMEN

BACKGROUND AIMS: Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity. METHODS: We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs. RESULTS: We showed that Tregs could be enriched to 87- 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136-732×106 gene-marked cells, sufficient for a cell dose of at least 2 × 106 cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro, but a small percentage could secrete proinflammatory cytokines, including interferon-γ and interleukin-17A. CONCLUSIONS: This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response.


Asunto(s)
Citometría de Flujo , Factores de Transcripción Forkhead , Linfocitos T Reguladores , Linfocitos T Reguladores/inmunología , Humanos , Citometría de Flujo/métodos , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Separación Celular/métodos , Vectores Genéticos/genética
2.
Gen Comp Endocrinol ; 338: 114274, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-36940834

RESUMEN

Photoperiod has been well-documented to be involved in regulating many activities of animals. However, whether photoperiod takes part in mood control, such as fear response in fish and the underlying mode(s) of action remain unclear. In this study, adult zebrafish males and females (Danio rerio) were exposed to different photoperiods, Blank (12 h light: 12 h dark), Control (12 h light: 12 h dark), Short daylight (SD, 6 h light: 18 h dark) and Long daylight (LD, 18 h light: 6 h dark) for 28 days. After exposure, fear response of the fish was investigated using a novel tank diving test. After alarm substance administration, the onset to higher half, total duration in lower half and duration of freezing in SD-fish were significantly decreased, suggesting that short daylight photoperiod is capable of alleviating fear response in zebrafish. In contrast, comparing with the Control, LD didn't show significant effect on fear response of the fish. Further investigation revealed that SD increased the levels of melatonin (MT), serotonin (5-HT) and dopamine (DA) in the brain while decreased the plasma level of cortisol comparing to the Control. Moreover, the expressions of genes in MT, 5-HT and DA pathways and HPI axis were also altered consistently. Our data indicated that short daylight photoperiod might alleviate fear response of zebrafish probably through interfering with MT/5-HT/DA pathways and HPI axis.


Asunto(s)
Melatonina , Fotoperiodo , Animales , Femenino , Masculino , Pez Cebra/metabolismo , Serotonina , Miedo , Melatonina/metabolismo , Dopamina/metabolismo
3.
Angew Chem Int Ed Engl ; 62(40): e202310393, 2023 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-37574867

RESUMEN

Anion-π catalysis operates by stabilizing anionic transition states on π-acidic aromatic surfaces. In anion-(π)n -π catalysis, π stacks add polarizability to strengthen interactions. In search of synthetic methods to extend π stacks beyond the limits of foldamers, the self-assembly of micelles from amphiphilic naphthalenediimides (NDIs) is introduced. To interface substrates and catalysts, charge-transfer complexes with dialkoxynaphthalenes (DANs), a classic in supramolecular chemistry, are installed. In π-stacked micelles, the rates of bioinspired ether cyclizations exceed rates on monomers in organic solvents by far. This is particularly impressive considering that anion-π catalysis in water has been elusive so far. Increasing rates with increasing π acidity of the micelles evince operational anion-(π)n -π catalysis. At maximal π acidity, autocatalytic behavior emerges. Dependence on position and order in confined micellar space promises access to emergent properties. Anion-(π)n -π catalytic micelles in water thus expand supramolecular systems catalysis accessible with anion-π interactions with an inspiring topic of general interest and great perspectives.

4.
Beilstein J Org Chem ; 19: 1881-1894, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38116243

RESUMEN

Anion-π catalysis, introduced in 2013, stands for the stabilization of anionic transition states on π-acidic aromatic surfaces. Anion-π catalysis on carbon allotropes is particularly attractive because high polarizability promises access to really strong anion-π interactions. With these expectations, anion-π catalysis on fullerenes has been introduced in 2017, followed by carbon nanotubes in 2019. Consistent with expectations from theory, anion-π catalysis on carbon allotropes generally increases with polarizability. Realized examples reach from enolate addition chemistry to asymmetric Diels-Alder reactions and autocatalytic ether cyclizations. Currently, anion-π catalysis on carbon allotropes gains momentum because the combination with electric-field-assisted catalysis promises transformative impact on organic synthesis.

5.
Sheng Li Xue Bao ; 72(5): 605-616, 2020 Oct 25.
Artículo en Zh | MEDLINE | ID: mdl-33106831

RESUMEN

Epithelial-mesenchymal transition (EMT) plays an important role in the development and pathogenesis of respiratory system. Epithelial cells are characterized by well-developed, intercellular contacts, whereas EMT triggers the sequential destabilization of cell-cell adhesive junctions. The dynamic remodeling of the epithelial cell adhesion molecules is important for maintaining the integrity and normal function of epithelium. This paper reviews the research progress of EMT in lung development, lung injury repair and chronic lung diseases, and summarizes the effect of cell junctions and cell adhesion molecules on EMT molecular events.


Asunto(s)
Transición Epitelial-Mesenquimal , Sistema Respiratorio , Adhesión Celular , Moléculas de Adhesión Celular , Células Epiteliales
6.
Angew Chem Int Ed Engl ; 59(52): 23649-23658, 2020 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-33047450

RESUMEN

Despite the aesthetically appealing structures and tantalizing physical and chemical properties, zigzag hydrocarbon belts and their heteroatom-embedded analogues remain challenging synthetic targets. We report herein the synthesis of diverse O/N-doped zigzag hydrocarbon belts based on selective bridging of the fjords of resorcin[4]arene derivatives through intramolecular SN Ar and palladium-catalyzed intermolecular C-N bond formation reactions. Preorganized conformations of mono-macrocyclic, half-belt and quasi-belt compounds were revealed to facilitate cyclization reactions to construct heteroatom-linked octahydrobelt[8]arenes. The acquired products had strained square-prism-shaped belt structures in which all six-membered heterocyclic rings adopted an unusual boat conformation with equatorially configured alkyl groups. The unprecedented heteroatom-bearing belts also exhibited different photophysical and redox properties to those of octahydrobelt[8]arene analogues.

7.
Sheng Li Xue Bao ; 67(6): 596-602, 2015 Dec 25.
Artículo en Zh | MEDLINE | ID: mdl-26701635

RESUMEN

To explore the relationship between the epithelial adhesion molecules and immune responses of airway epithelium, we observed the expression of integrin ß4 and intercellular adhesion molecule-1 (ICAM-1) in the mice airway epithelium after sensitization with allergens. BALB/c mice were sensitized with intraperitoneal injection of ovalbumin (OVA) or house dust mite (HDM) and then developed airway hyper-responsiveness as determined by barometric whole-body plethysmography. Both OVA and HDM sensitization led to increases of the number of peripheral leukocytes as well as inflammatory cells infiltration in lungs. OVA sensitized mice showed more severe inflammatory cells infiltration than HDM sensitized mice. Immunohistochemistry analysis of mice lung tissues revealed that sensitization with both allergens also led to a decrease of integrin ß4 expression and an increase of ICAM-1 expression in airway epithelia. OVA sensitized mice showed a more significant increase of ICAM-1 expression compared with HDM sensitized mice. siRNA mediated silencing of integrin ß4 gene in 16HBE cells resulted in an up-regulation of ICAM-1 expression. Our results indicate a possible role of airway epithelial adhesion molecules in allergen-induced airway immune responses.


Asunto(s)
Alérgenos/farmacología , Integrina beta4/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Pulmón/metabolismo , Hipersensibilidad Respiratoria/metabolismo , Animales , Pulmón/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Pyroglyphidae
8.
Aquat Toxicol ; 273: 107008, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38941808

RESUMEN

Environmental estrogens (EEs) are found extensively in natural waters and negatively affect fish reproduction. Research on the reproductive toxicity of EEs mixtures in fish at environmentally relevant concentrations is scarce. In this study, adult male zebrafish were exposed for 60 days to EES (a mixture of EEs), EE2-low (5.55 ng/L, with an estrogenic potency equal to EES), and EE2-high (11.1 ng/L). After exposure, the expression levels of vtg1, vtg3, and esr1 in the livers in EES-treated fish remained unaltered, whereas they were significantly increased in EE2-treated fish. Both EE2-high and EES exposures notably reduced the gonad somatic index and sperm count. A disrupted spermatogenesis was also observed in the testes of EE2-high- and EES-exposed fish, along with an alteration in the expression of genes associated with spermatogonial proliferation (pcna, nanog), cell cycle transition (cyclinb1, cyclind1), and meiosis (aldh1a2, cyp26a1, sycp3). Both EE2 and EES significantly lowered plasma 11-ketotestosterone levels in males, likely by inhibiting the expression level of genes for its synthesis (scc, cyp17a1 and cyp11b2), and increased 17ß-estradiol (E2) levels, possibly through upregulating the expression of cyp19a1a. A significant increase in tnfrsf1a expression and the tnfrsf1a/tnfrsf1b ratio in EE2-high and EES-treated males also suggests increased apoptosis via the extrinsic pathway. Further investigation showed that both EE2-high and EES diminished the sexual behavior of male fish, accompanied with reduced E2 levels in the brain and the expression of genes in the kisspeptin/gonadotropin-releasing hormone system. Interestingly, the sexual behavior of unexposed females paired with treated males was also reduced, indicating a synergistic effect. This study suggests that EES have a more severe impact on reproduction than EE2-low, and EEs could interfere not only with spermatogenesis in fish, but also with the sexual behaviors of both exposed males and their female partners, thereby leading to a more significant disruption in fish reproduction.

9.
Adv Mater ; : e2406192, 2024 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-39003609

RESUMEN

Bioelectricity provides electrostimulation to regulate cell/tissue behaviors and functions. In the human body, bioelectricity can be generated in electromechanically responsive tissues and organs, as well as biomolecular building blocks that exhibit piezoelectricity, with a phenomenon known as the piezoelectric effect. Inspired by natural bio-piezoelectric phenomenon, efforts have been devoted to exploiting high-performance synthetic piezoelectric biomaterials, including molecular materials, polymeric materials, ceramic materials, and composite materials. Notably, piezoelectric biomaterials polarize under mechanical strain and generate electrical potentials, which can be used to fabricate electronic devices. Herein, a review article is proposed to summarize the design and research progress of piezoelectric biomaterials and devices toward bionanotechnology. First, the functions of bioelectricity in regulating human electrophysiological activity from cellular to tissue level are introduced. Next, recent advances as well as structure-property relationship of various natural and synthetic piezoelectric biomaterials are provided in detail. In the following part, the applications of piezoelectric biomaterials in tissue engineering, drug delivery, biosensing, energy harvesting, and catalysis are systematically classified and discussed. Finally, the challenges and future prospects of piezoelectric biomaterials are presented. It is believed that this review will provide inspiration for the design and development of innovative piezoelectric biomaterials in the fields of biomedicine and nanotechnology.

10.
JACS Au ; 3(4): 1039-1051, 2023 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-37124310

RESUMEN

The autocatalysis of epoxide-opening ether cyclizations on the aromatic surface of anion-π catalysts stands out as a leading example of emergent properties expected from the integration of unorthodox interactions into catalysis. A working hypothesis was proposed early on, but the mechanism of anion-π autocatalysis has never been elucidated. Here, we show that anion-π autocatalysis is almost independent of peripheral crowding in substrate and product. Inaccessible asymmetric anion-π autocatalysis and sometimes erratic reproducibility further support that the origin of anion-π autocatalysis is more complex than originally assumed. The apparent long-distance communication without physical contact calls for the inclusion of water between substrate and product on the catalytic aromatic surface. Efficient anion-π autocatalysis around equimolar amounts but poor activity in dry solvents and with excess water indicate that this inclusion of water requires high precision. Computational models suggest that two water molecules transmit dual substrate activation by the product and serve as proton shuttles along antiparallel but decoupled hydrogen-bonded chains to delocalize and stabilize evolving charge density in the transition state by "anion-π double bonds". This new transition-state model of anion-π autocatalysis provides a plausible mechanism that explains experimental results and brings anion-π catalysis to an unprecedented level of sophistication.

11.
Singapore Med J ; 2023 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-37721304

RESUMEN

Introduction: Workplace safety and health are interrelated - a worker who is not healthy may cause safety lapses at the workplace; conversely, safety lapses could affect the health of the workers. This study was part of a larger Total Workplace Safety and Health (WSH) programme run by the Workplace Safety and Health Council, Singapore. The objectives were to obtain a baseline health profile of workers across four major industries and identify important health risks for targeted workplace interventions. Methods: Five service providers (SPs) were appointed to run the Total WSH programme. As part of the programme, SPs conducted an anonymous basic health survey among workers of participating companies. Results: The responses of 6,373 respondents from the cleaning, construction, manufacturing, and transport and storage industries were studied. The overall response rate was 62%. Key health issues identified were high rates of obesity (22%) and smoking (24%) and low prevalence of regular exercise and healthy dietary habits. Chronic disease rates were similar to population self-reported rates (hypertension 15%, high lipid 12% and diabetes mellitus 6%). The workers reported high work stress (13%). Conclusion: Health issues are prevalent in the workforce and may affect work and employee safety. It is increasingly important for employees' health to be considered in risk assessments and prioritised in workplace safety and health management systems and strategies. Health promotion interventions should be targeted, and multilevel and multicomponent initiatives should be integrated with pre-existing occupational safety programmes.

12.
Sci Adv ; 9(41): eadj5502, 2023 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-37824606

RESUMEN

The vision to control the charges migrating during reactions with external electric fields is attractive because of the promise of general catalysis, emergent properties, and programmable devices. Here, we explore this idea with anion-π catalysis, that is the stabilization of anionic transition states on aromatic surfaces. Catalyst activation by polarization of the aromatic system is most effective. This polarization is induced by electric fields. The use of electrochemical microfluidic reactors to polarize multiwalled carbon nanotubes as anion-π catalysts emerges as essential. These reactors provide access to high fields at low enough voltage to prevent electron transfer, afford meaningful effective catalyst/substrate ratios, and avoid interference from additional electrolytes. Under these conditions, the rate of pyrene-interfaced epoxide-opening ether cyclizations is linearly voltage-dependent at positive voltages and negligible at negative voltages. While electromicrofluidics have been conceived for redox chemistry, our results indicate that their use for supramolecular organocatalysis has the potential to noncovalently electrify organic synthesis in the broadest sense.

13.
Ind Health ; 61(4): 269-274, 2023 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-35584948

RESUMEN

Return to Work (RTW) programmes have become imperative in manpower scarce countries. This paper describes a RTW programme in a Singapore tertiary hospital, reports patient outcomes and discusses the practicality and effectiveness of the programme. Seventy-three workers participated in the programme over a two-year period. A statistically significant increase in work ability and self-perceived overall health status from first contact with worker (baseline) to discharge was observed. Continued programme participation till first RTW was associated with higher work ability and self-perceived overall health status at baseline. The RTW Coordinator-anchored multidisciplinary model which provided holistic support to the worker and addressed stakeholder interests were central to the programme's success. Greater awareness of RTW programme benefits will improve sustained participation. Our RTW programme features, implementation experiences and participant reported effectiveness may inform the development of improved return to work models.


Asunto(s)
Hospitales , Reinserción al Trabajo , Humanos , Singapur
14.
Artículo en Inglés | MEDLINE | ID: mdl-36781090

RESUMEN

Carbamazepine (CBZ) is one of the widely distributed pharmaceutical residues in aquatic environments, yet few researches have addressed its chronic effect on the anxiety of fish, and the mechanisms possibly involved remained elusive. In this study, adult female zebrafish (Danio rerio) were exposed to environmental relevant concentrations of CBZ (CBZ-low, 10 µg/L; CBZ-high, 100 µg/L) for 28 days. After exposure, CBZ-high didn't affect the anxiety of fish. However, the onset time to the higher half of the tank was delayed and the total duration in the lower half of the tank was increased in CBZ-low fish, suggesting an increased anxiety. Further investigation indicated that CBZ-low significantly decreased the gamma-aminobutyric acid (GABA) level in the brain, while increased the serotonin (5-HT) level in the brain and cortisol level in plasma. Accordingly, the mRNA levels of genes in GABA (gad2, abat, gabrb2, gabrg2, gria1a and slc12a2) pathway and HPI (crha, actha, pc1 and pc2) axis were also altered. Despite the upregulation of tph2 was consistent with increased 5-HT level in the brain, significantly downregulated htr1aa and htr1b may indicate attenuated 5-HT potency. Although CBZ-high significantly reduced GABA level in the brain and increased cortisol level in plasma, the effects were dramatically alleviated than that of CBZ-low. Consistently, the expression of genes in HPI (crha, actha, pc1 and pc2) axis and GABA (gad2 and abat) pathway were also altered by CBZ-high, probably due to inconspicuous anxiety response of CBZ-high. Briefly, our data suggested that low concentration of CBZ disrupted zebrafish anxiety by interfering with neurotransmission and endocrine system, thereby bringing about adverse ecological consequences.


Asunto(s)
Contaminantes Químicos del Agua , Pez Cebra , Animales , Femenino , Pez Cebra/metabolismo , Serotonina/metabolismo , Hidrocortisona/metabolismo , Carbamazepina/toxicidad , Ansiedad/inducido químicamente , Ácido gamma-Aminobutírico , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/metabolismo
15.
Int J Biol Sci ; 18(3): 1254-1270, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35173551

RESUMEN

Background: In airway disease such as asthma a hyperactive cellular event of epithelial-mesenchymal transition (EMT) is considered as the mechanism of pathological airway tissue remodeling after injury to the airway epithelium. And the initiation of EMT in the airways depends on the epithelial disruption involving dissolution and/or destabilization of the adhesive structures between the cells and ECM. Previously, we have shown that integrin-ß4, an epithelial adhesion molecule in bronchial epithelium is an important regulator of cell proliferation and wound repair in human airway epithelial cells. Therefore, in this study we aimed to investigate whether integrin-ß4 also regulates EMT phenotypes during injury and repair in airway epithelial cells of both wild type/integrin-ß4-/- mice in vivo and cultured cells treated with integrin-ß4/nonsense siRNA in vitro. Methods: We induced injury to the airway epithelial cells by either repeated exposure to ozone and mechanical scratch wound, and subsequently examined the EMT-related phenotypic features in the airway epithelial cells including biomarkers expression, adhesion and cytoskeleton reorganization and cell stiffness. Results: The results show that in response to injury (ozone exposure/scratch wound) and subsequent spontaneous repair (ozone withdrawal/wound healing) both in vivo and in vitro, the airway epithelial cells underwent dynamic changes in the epithelial and mesenchymal biomarkers expression, adhesion and cytoskeleton structures as well as cell stiffness, all together exhibiting enhanced EMT phenotypic features after injury and reversal of the injury-induced effects during repair. Importantly, these injury/repair-associated EMT phenotypic changes in airway epithelial cells appeared to be dependent on integrin-ß4 expression. More specifically, when integrin-ß4 was deficient in mice (integrin-ß4-/-) the repair of ozone-injured airway epithelium was impaired and the recovery of ozone-enhanced EMT biomarkers expression in the airway epithelium was delayed. Similarly, in the scratch wounded airway epithelial cells with integrin-ß4 knockdown, the cells were impaired in all aspects related to EMT during wound and repair including cell proliferation, wound closure rate, adhesion and cytoskeleton protein expression (vinculin and vimentin), mesenchymal-like F-actin reorganization, cell stiffness and RhoA activation. Conclusion: Taken together, these results suggested that integrin-ß4 may be essential in regulating the effects of injury and repair on EMT in airway epithelial cells via influencing both the cell adhesion to ECM and cells' physical phenotypes through RhoA signaling pathway.


Asunto(s)
Transición Epitelial-Mesenquimal , Ozono , Animales , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Integrina beta4/genética , Integrina beta4/metabolismo , Ratones , Fenotipo
16.
Org Lett ; 22(14): 5417-5422, 2020 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-32588635

RESUMEN

We reported herein CuI/DMEDA catalyzed N,N-diarylation reaction of amides with various di(o-bromoaryl)methanes to produce diverse 9,10-dihydroacridine derivatives. The resulting 9,10-dihydroacridine derivatives were oxidized selectively under mild conditions to afford acridine, acridinone, and acridinium derivatives. The copper-catalyzed N,N-diarylation reaction coupled with oxidative aromatization reaction enabled the facile construction of nitrogen atom-embedded tetracenes and pentacenes of different ortho-fused patterns. The luminescence properties, especially the effect of fusion pattern on fluorescence emission of acquired N-polycenes, were also demonstrated.

17.
Cureus ; 11(9): e5764, 2019 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-31723523

RESUMEN

A wide spectrum of neurological manifestations may be induced in patients with impaired renal function when receiving beta-lactam antibiotics due to the altered pharmacokinetics. Beta-lactam antibiotics is commonly chosen for treatment in patients with end-stage renal disease due to its good penetration into the cerebrospinal fluid and long half-life. Here, we present a case of a 73-year-old Malay lady with end-stage renal disease who was admitted for treatment of gastroenteritis. She presented with acute onset of diarrhoea and vomiting for two days. She was febrile during admission and was prescribed intravenous ceftriaxone 2 grams daily for coverage of bacterial gastroenteritis. Among the investigations done, white cell count were raised together with the C-reactive protein. Stool and blood cultures were also sent for further investigations. Over a three-day period, her general condition improved and she was discharged home. The onset of clinical manifestation of choreoathetosis was noticed by her caregiver on the same day of discharge. She was brought back to the emergency department and was readmitted for further workup of the new presenting complain of abnormal movement and disorientation. Haemodialysis was arranged and immediately commenced during her admission. The renal nurses reported that her neurological symptoms were noticeably improved after completion of the initial dialysis without any treatment. Ceftriaxone including other beta lactam antibiotics penetrates the blood-brain barrier and induces glutamate in excess in the striatum and cerebral cortex, resulting in neurological hyper excitability disorders despite appropriate renal adjusted dosage for end-stage renal disease patients on haemodialysis.

18.
PLoS One ; 9(4): e95533, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24740264

RESUMEN

Accumulated research has suggested the importance of the adhesion molecules modulation as therapeutic approach for bronchial asthma. Adhesion molecules expression alteration contributes to the pathogenesis of asthma. In order to probe the roles of expression imbalance of adhesion molecules in asthma pathogenesis, expression profiling of adhesion molecules was performed using cDNA microarray assay. The results showed that the expression pattern of adhesion molecules was altered in peripheral blood leucocytes of asthma patients. In this study, we focused on one of the abnormally expressed molecule, integrin ß4, which was down-regulated in all asthma patients, to analyze the relevance of asthma susceptibility with the alteration of integrin ß4 expressions. Real time PCR was used to verify the down-regulation of integrin ß4 in additional 38 asthma patients. Next, the 5'flanking region of integrin ß4 DNA were amplified, sequenced and site-directed mutagenesis technology in correspondent variation sites were carried out. Among 4 variation sites found in 5' flanking region of integrin ß4, 3 were related to asthma susceptibility: -nt1029 G/A, -nt 1051 G/A, and -nt 1164 G/C. A reduction of human integrin ß4 promoter activity was observed at mutants of these sites. This study demonstrates that various adhesion molecules in asthma patients are abnormally expressed. Mutations in 5' flanking region result in reduced integrin ß4 expression, which is related to increased risk of asthma.


Asunto(s)
Región de Flanqueo 5' , Asma/genética , Integrina beta4/genética , Leucocitos Mononucleares/metabolismo , Adolescente , Adulto , Anciano , Asma/inmunología , Asma/patología , Estudios de Casos y Controles , Niño , Susceptibilidad a Enfermedades , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Integrina beta4/inmunología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo Genético , Regiones Promotoras Genéticas
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