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1.
Proc Natl Acad Sci U S A ; 120(12): e2220032120, 2023 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-36917662

RESUMEN

Finely controlled flow forces in extrusion-based additive manufacturing can be exploited to program the self-assembly of malleable nanostructures in soft materials by integrating bottom-up design into a top-down processing approach. Here, we leverage the processing parameters offered by direct ink-writing (DIW) to reconfigure the photonic chiral nematic liquid crystalline phase in hydroxypropyl cellulose (HPC) solutions prior to deposition on the writing substrate to direct structural evolution from a particular initial condition. Moreover, we incorporate polyethylene glycol (PEG) into iridescent HPC inks to form a physically cross-linked network capable of inducing kinetic arrest of the cholesteric/chiral pitch at length scales that selectively reflect light throughout the visible spectrum. Based on thorough rheological measurements, we have found that printing the chiral inks at a shear rate where HPC molecules adopt pseudonematic state results in uniform chiral recovery following flow cessation and enhanced optical properties in the solid state. Printing chiral inks at high shear rates, on the other hand, shifts the monochromatic appearance of the extruded filaments to a highly angle-dependent state, suggesting a preferred orientation of the chiral domains. The optical response of these filaments when exposed to mechanical deformation can be used in the development of optical sensors.

2.
Small ; 19(19): e2206847, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36732856

RESUMEN

Architected materials with nano/microscale orders can provide superior mechanical properties; however, reproducing such levels of ordering in complex structures has remained challenging. Inspired by Bouligand structures in nature, here, 3D printing of complex geometries with guided long-order radially twisted chiral hierarchy, using cellulose nanocrystals (CNC)-based inks is presented. Detailed rheological measurements, in situ flow analysis, polarized optical microscopy (POM), and director field analysis are employed to evaluate the chiral assembly over the printing process. It is demonstrated that shear flow forces inside the 3D printer's nozzle orient individual CNC particles forming a pseudo-nematic phase that relaxes to uniformly aligned concentric chiral nematic structures after the flow cessation. Acrylamide, a photo-curable monomer, is incorporated to arrest the concentric chiral arrangements within the printed filaments. The time series POM snapshots show that adding the photo-curable monomer at the optimized concentrations does not interfere with chiral self-assemblies and instead increases the chiral relaxation rate. Due to the liquid-like nature of the as-printed inks, optimized Carbopol microgels are used to support printed filaments before photo-polymerization. By paving the path towards developing bio-inspired materials with nanoscale hierarchies in larger-scale printed constructs, this biomimetic approach expands 3D printing materials beyond what has been realized so far.

3.
Mol Syst Biol ; 18(2): e10629, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35156780

RESUMEN

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a chloride and bicarbonate channel in secretory epithelia with a critical role in maintaining fluid homeostasis. Mutations in CFTR are associated with Cystic Fibrosis (CF), the most common lethal autosomal recessive disorder in Caucasians. While remarkable treatment advances have been made recently in the form of modulator drugs directly rescuing CFTR dysfunction, there is still considerable scope for improvement of therapeutic effectiveness. Here, we report the application of a high-throughput screening variant of the Mammalian Membrane Two-Hybrid (MaMTH-HTS) to map the protein-protein interactions of wild-type (wt) and mutant CFTR (F508del), in an effort to better understand CF cellular effects and identify new drug targets for patient-specific treatments. Combined with functional validation in multiple disease models, we have uncovered candidate proteins with potential roles in CFTR function/CF pathophysiology, including Fibrinogen Like 2 (FGL2), which we demonstrate in patient-derived intestinal organoids has a significant effect on CFTR functional expression.


Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Animales , Membrana Celular/metabolismo , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Fibrinógeno/genética , Fibrinógeno/metabolismo , Fibrinógeno/farmacología , Ensayos Analíticos de Alto Rendimiento , Humanos , Mamíferos , Mutación
4.
Langmuir ; 38(7): 2192-2204, 2022 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-35133841

RESUMEN

Studying the flow-induced alignment of anisotropic liquid crystalline materials is of major importance in the 3D printing of advanced architectures. However, in situ characterization and quantitative measurements of local orientations during the 3D printing process are challenging. Here, we report a microfluidic strategy integrated with polarized optical microscopy (POM) to perform the in situ characterization of the alignment of cellulose nanocrystals (CNCs) under the shear-flow condition of the 3D printer's nozzle in the direct ink writing process. To quantify the alignment, we exploited birefringence measurements under white and monochromatic light. We show that the flow-induced birefringence patterns are significantly influenced by the initial structure of the aqueous CNC suspensions. Depending on the CNC concentration and sonication treatment, various structures can form in the CNC suspensions, such as isotropic, chiral nematic (cholesteric), and nematic (gel-like) structures. In the chiral nematic phase, in particular, the shear flow in the microfluidic capillary has a distinct effect on the alignment of the CNC particles. Our experimental results, complemented by hydrodynamic simulations, reveal that at high flow rates (Er ≈ 1000), individual CNC particles align with the flow exhibiting a weak chiral structure. In contrast, at lower flow rates (Er ≈ 241), they display the double-twisted cylinder structure. Understanding the flow effect on the alignment of the chiral liquid crystal can pave the way to designing 3D printed architectures with internal chirality for advanced mechanical and smart photonic applications.

5.
PLoS Genet ; 15(2): e1008007, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30807572

RESUMEN

Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10(-7)). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10(-8)), SLC6A14 (p = 1.12x10(-10)) and SLC26A9 (p = 4.48x10(-5)) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10(-4)). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies.


Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/genética , Antiportadores/genética , Fibrosis Quística/genética , Perfilación de la Expresión Génica/métodos , Estudio de Asociación del Genoma Completo/métodos , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , Transportadores de Sulfato/genética , Tripsina/genética , Sistemas de Transporte de Aminoácidos , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Antiportadores/metabolismo , Fibrosis Quística/metabolismo , Femenino , Regulación de la Expresión Génica , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Humanos , Pulmón/metabolismo , Masculino , Especificidad de Órganos , Páncreas Exocrino/metabolismo , Transportadores de Sulfato/metabolismo , Tripsina/metabolismo
6.
Arch Biochem Biophys ; 596: 126-37, 2016 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-26970045

RESUMEN

Peroxynitrite has been implicated in type 2 diabetes and diabetic complications. As a follow-up study to our previous work on SR-135 (Arch Biochem Biophys 577-578: 49-59, 2015), we provide evidence that this series of compounds are effective when administered orally, and their mechanisms of actions extend to the peripheral tissues. A more soluble analogue of SR-135, SR-110 (from a new class of Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes) was orally administered for 2 weeks to B6D2F1 mice fed a high fat-diet (HFD). Mice fed a HFD for 4 months gained significantly higher body weights compared to lean diet-fed mice (52 ± 1.5 g vs 34 ± 1.3 g). SR-110 (10 mg/kg daily) treatment significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control or vehicle (peanut butter) group. SR-110 treatment enhanced insulin signaling in the peripheral organs, liver, heart, and skeletal muscle, and reduced lipid accumulation in the liver. Furthermore, SR-110 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration. These results suggest that a peroxynitrite decomposing catalyst is effective in improving glucose homeostasis and restoring islet morphology and ß-cell insulin content under nutrient overload.


Asunto(s)
Grasas de la Dieta/efectos adversos , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Ácido Peroxinitroso/metabolismo , Porfobilinógeno/análogos & derivados , Transducción de Señal/efectos de los fármacos , Administración Oral , Animales , Glucemia/metabolismo , Grasas de la Dieta/farmacología , Homeostasis/efectos de los fármacos , Ratones , Porfobilinógeno/química , Porfobilinógeno/farmacología , Ratas , Ratas Sprague-Dawley
7.
Mol Cancer ; 13: 214, 2014 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-25216853

RESUMEN

BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer mortality of men in Western countries. The androgen receptor (AR) and AR-agonists (androgens) are required for the development and progression of the normal prostate as well as PCa. However, it is discussed that in addition to their tumor promoting activity, androgens may also exhibit tumor suppressive effects. A biphasic growth response to androgens a growth-promoting and -inhibition has been observed that suggests that administration of supraphysiological androgen levels mediates growth reduction in AR expressing PCa cells. METHODS: Detection of senescence markers, three dimensional interphase fluorescence in situ hybridization (3D-iFISH), qRT-PCR, Western blotting, detection of GFP fusions, prostatectomy, ex vivo culturing. RESULTS: Here, we describe that supraphysiological levels of androgens induce cell cycle arrest and markers of cellular senescence in human PCa cells, which may in part explain the growth inhibitory role of androgens. The expression of the senescence associated beta galactosidase is observed by treatment with the natural androgen DHT or the less metabolized synthetic androgen R1881. The induction of senescence marker was detected in human PCa cell lines as well as in human primary PCa tissue derived from prostatectomy treated ex vivo. Using interphase FISH (iFISH) suggests that the androgen-induced cellular senescence is associated with localizing the genomic E2F1 locus to senescence associated heterochromatic foci. Analysis of different signaling pathways in LNCaP cells suggest that the p16-Rb-E2F1 pathway is essential for the induction of cellular senescence since treatment with siRNA directed against p16 reduces the level of androgen-induced cellular senescence. Based on the rapid induction of androgen-mediated cellular senescence we identified the Src-PI3K-Akt-signaling pathway and autophagy being in part involved in androgen regulation. CONCLUSIONS: Taken together, our data suggest that AR-agonists at supraphysiological levels mediate induction of cellular senescence in human PCa cells, which may have a protective anti-cancer role. These results provide also new insights for understanding androgen-mediated regulation of PCa growth.


Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Dihidrotestosterona/farmacología , Metribolona/farmacología , Neoplasias de la Próstata/patología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Senescencia Celular , Factor de Transcripción E2F1/genética , Humanos , Imagenología Tridimensional , Hibridación Fluorescente in Situ , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía
8.
J Colloid Interface Sci ; 656: 577-586, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38035482

RESUMEN

HYPOTHESIS: Hetero-aggregation of oppositely charged colloidal particles with controlled architectural and interactional asymmetry allows modifying gel nanostructure and properties. We hypothesize the relative size ratio between cationic nanospheres and varied-size anionic two-dimensional nanoclays will influence the gel formation mechanisms and resulting rheological performance. EXPERIMENTS: Hybrid colloidal gels formed via hetero-aggregation of cationic gelatin nanospheres (∼400 nm diameter) and five types of nanoclays with similar 1 nm thickness but different lateral sizes ranging from âˆ¼ 30 nm to âˆ¼ 3000 nm. Structure-property relationships were elucidated using a suite of techniques. Microscopy and scattering probed gel nanostructure and particle configuration. Rheology quantified linear and non-linear viscoelastic properties and yielding behavior. Birefringence and polarized imaging assessed size-dependent nanoclay alignment during shear flow. FINDINGS: Nanoclay size ratio relative to nanospheres affected the gelation process, network structure, elasticity, yielding, and shear response. Gels with comparably sized components showed maximum elasticity, while yield stress depended on nanoclay rotational mobility. Shear-induced nanoclay alignment was quantified by birefringence, which is more pronounced for larger nanoclay. Varying nanoclay size and interactions with nanospheres controlled dispersion, aggregation, and nematic ordering. These findings indicate that architectural and interactional asymmetry enables more control over gel properties through controlled assembly of anisotropic building blocks.

9.
Chem Commun (Camb) ; 59(82): 12231-12247, 2023 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-37750291

RESUMEN

Blue phase (BP) liquid crystals represent a fascinating state of soft matter that showcases unique optical and electro-optical properties. Existing between chiral nematic and isotropic phases, BPs are characterized by a three-dimensional cubic lattice structure resulting in selective Bragg reflections of light and consequent vivid structural colors. However, the practical realization of these material systems is hampered by their narrow thermal stability and multi-domain crystalline nature. This feature article provides an overview of the efforts devoted to stabilizing these phases and creating monodomain structures. In particular, it delves into the complex relationship between geometrical confinement, induced curvature, and the structural stability and photonic features of BPs. Understanding the interaction of curved confinement and structural stability of BPs proves crucially important for the integration of these materials into flexible and miniaturized devices. By shedding light on these critical aspects, this feature review aims to highlight the significance of understanding the coupling effects of physical and mechanical forces on the structural stability of these systems, which can pave the way for the development of efficient and practical devices based on BP liquid crystals.

10.
Nanomicro Lett ; 16(1): 54, 2023 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-38108930

RESUMEN

Helical hierarchy found in biomolecules like cellulose, chitin, and collagen underpins the remarkable mechanical strength and vibrant colors observed in living organisms. This study advances the integration of helical/chiral assembly and 3D printing technology, providing precise spatial control over chiral nano/microstructures of rod-shaped colloidal nanoparticles in intricate geometries. We designed reactive chiral inks based on cellulose nanocrystal (CNC) suspensions and acrylamide monomers, enabling the chiral assembly at nano/microscale, beyond the resolution seen in printed materials. We employed a range of complementary techniques including Orthogonal Superposition rheometry and in situ rheo-optic measurements under steady shear rate conditions. These techniques help us to understand the nature of the nonlinear flow behavior of the chiral inks, and directly probe the flow-induced microstructural dynamics and phase transitions at constant shear rates, as well as their post-flow relaxation. Furthermore, we analyzed the photo-curing process to identify key parameters affecting gelation kinetics and structural integrity of the printed object within the supporting bath. These insights into the interplay between the chiral inks self-assembly dynamics, 3D printing flow kinematics and photo-polymerization kinetics provide a roadmap to direct the out-of-equilibrium arrangement of CNC particles in the 3D printed filaments, ranging from uniform nematic to 3D concentric chiral structures with controlled pitch length, as well as random orientation of chiral domains. Our biomimetic approach can pave the way for the creation of materials with superior mechanical properties or programable photonic responses that arise from 3D nano/microstructure and can be translated into larger scale 3D printed designs.

11.
Life Sci Alliance ; 6(6)2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37024122

RESUMEN

Highly effective drugs modulating the defective protein encoded by the CFTR gene have revolutionized cystic fibrosis (CF) therapy. Preclinical drug-testing on human nasal epithelial (HNE) cell cultures and 3-dimensional human intestinal organoids (3D HIO) are used to address patient-specific variation in drug response and to optimize individual treatment for people with CF. This study is the first to report comparable CFTR functional responses to CFTR modulator treatment among patients with different classes of CFTR gene variants using the three methods of 2D HIO, 3D HIO, and HNE. Furthermore, 2D HIO showed good correlation to clinical outcome markers. A larger measurable CFTR functional range and access to the apical membrane were identified as advantages of 2D HIO over HNE and 3D HIO, respectively. Our study thus expands the utility of 2D intestinal monolayers as a preclinical drug testing tool for CF.


Asunto(s)
Fibrosis Quística , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Mutación , Intestinos , Organoides/metabolismo
12.
J Colloid Interface Sci ; 627: 40-52, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35841707

RESUMEN

Colloidal gels based on electrostatic interparticle attractions hold unexploited potential for tailoring their microstructure and properties. Here, we demonstrate that hetero-aggregation between oppositely charged particles with different geometries is a viable strategy for controlling their properties. Specifically, we studied hybrid colloidal gels prepared by the charge-driven assembly of oppositely charged spherical gelatin nanoparticles and two-dimensional (2D) nanosilicates. We show that the asymmetry between the building blocks and the resulting anisotropic interparticle interactions produces a variety of nanostructures and hybrid colloidal gels that exhibit high elasticity at low colloidal volume fractions. Tuning the competition between different attractive interactions in the system by varying the spatial charge heterogeneity on the 2D nanosheets, composition, and ionic strength was found to alter the mechanism of gel formation and their rheological properties. Remarkably, increasing the mass ratio of 2D nanosheets to spherical nanoparticles at a constant total mass fraction affords hybrid gels that exhibit an inverse relationship between elasticity and volume fraction. However, these hybrid gels are easily fluidized and exhibit rapid structural recovery once the stress is removed. These features allow for the engineering of versatile 3D-printable hybrid colloidal gels, whose structure and viscoelastic response are governed by parameters that have not been explored before.


Asunto(s)
Gelatina , Nanopartículas , Coloides/química , Elasticidad , Gelatina/química , Geles/química , Nanopartículas/química
13.
Sci Rep ; 12(1): 15209, 2022 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-36076021

RESUMEN

Opium is one of the most abused substances in the Middle East. The effects of opium use on coronary artery disease (CAD) are a matter of debate. This study aimed to assess the association between opium use and angiographic findings as well as the complexity of CAD in patients with acute coronary syndrome (ACS) diagnosis. In this case-control study, all patients admitted for coronary angiography from 2019 to 2020 were evaluated. After applying the eligibility criteria, they were categorized into two groups opium and non-opium based on their history of opium use. Both groups were matched regarding the demographic features. The prevalence, location, and severity of obstruction of the vessels were compared between the non-opium and opium groups. The SYNTAX score was also calculated and compared between the two groups. The scores ≤ 22 are considered low risk and the higher scores are a non-low risk. P value < 0.05 is considered significant. A total of 170 patients with a mean age of 61.59 ± 9.07 years were finally enrolled in our study. Regarding the severity of vascular involvement, there was a significant difference between the non-opium and opium groups in LAD (P = 0.025), and PLV (P = 0.018) vessels. From the location points of view of obstructive coronary artery involved segments, only in the PDA (P = 0.006), and LCX (P = 0.004) vessels, a significant difference was observed. Moreover, 47.1% of opium and 30.6% of non-opium use group were in the non-low risk SYNTAX score classification which is a statistically significant difference between these two groups (P value = 0.048). Opium, as an independent risk factor for cardiovascular diseases, can have specific effects on angiographic findings in patients with acute coronary syndrome. Likewise, the complexity of CAD in opium users who undergo percutaneous coronary intervention is significantly higher.


Asunto(s)
Síndrome Coronario Agudo , Enfermedad de la Arteria Coronaria , Adicción al Opio , Síndrome Coronario Agudo/diagnóstico por imagen , Síndrome Coronario Agudo/epidemiología , Síndrome Coronario Agudo/etiología , Anciano , Estudios de Casos y Controles , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Humanos , Persona de Mediana Edad , Opio/efectos adversos , Adicción al Opio/diagnóstico por imagen , Adicción al Opio/epidemiología , Índice de Severidad de la Enfermedad
14.
NPJ Genom Med ; 7(1): 28, 2022 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-35396391

RESUMEN

Over 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF. We investigate the relationship between rs7512462, a marker of SLC26A9 activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD). Rs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p = 0.008); and for gating (p = 0.033) and p.Phe508del/ p.Phe508del (p = 0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p = 0.0022). Beyond CF, rs7512462 is associated with peak expiratory flow in a meta-analysis of the UK Biobank and Spirometa Consortium (p = 2.74 × 10-44) and provides p = 0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry. These findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

15.
Cancers (Basel) ; 13(16)2021 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-34439179

RESUMEN

The human telomerase is a key factor during tumorigenesis in prostate cancer (PCa). The androgen receptor (AR) is a key drug target controlling PCa growth and regulates hTERT expression, but is described to either inhibit or to activate. Here, we reveal that androgens repress and activate hTERT expression in a concentration-dependent manner. Physiological low androgen levels activate, while, notably, supraphysiological androgen levels (SAL), used in bipolar androgen therapy (BAT), repress hTERT expression. We confirmed the SAL-mediated gene repression of hTERT in PCa cell lines, native human PCa samples derived from patients treated ex vivo, as well as in cancer spheroids derived from androgen-dependent or castration resistant PCa (CRPC) cells. Interestingly, chromatin immuno-precipitation (ChIP) combined with functional assays revealed a positive (pARE) and a negative androgen response element (nARE). The nARE was narrowed down to 63 bp in the hTERT core promoter region. AR and tumor suppressors, inhibitor of growth 1 and 2 (ING1 and ING2, respectively), are androgen-dependently recruited. Mechanistically, knockdown indicates that ING1 and ING2 mediate AR-regulated transrepression. Thus, our data suggest an oppositional, biphasic function of AR to control the hTERT expression, while the inhibition of hTERT by androgens is mediated by the AR co-repressors ING1 and ING2.

16.
Cells ; 9(10)2020 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-33023010

RESUMEN

While females are less affected by non-diabetic kidney diseases compared to males, available data on sex differences in diabetic nephropathy (DN) are controversial. Although there is evidence for an imbalance of sex hormones in diabetes and hormone-dependent mechanisms in transforming growth factor ß1 (TGF-ß1) signaling, causes and consequences are still incompletely understood. Here we investigated the influence of sex hormones and sex-specific gene signatures in diabetes- and TGF-ß1-induced renal damage using various complementary approaches (a db/db diabetes mouse model, ex vivo experiments on murine renal tissue, and experiments with a proximal tubular cell line TKPTS). Our results show that: (i) diabetes affects sex hormone concentrations and renal expression of their receptors in a sex-specific manner; (ii) sex, sex hormones and diabetic conditions influence differences in expression of TGF-ß1, its receptor and bone morphogenetic protein 7 (BMP7); (iii) the sex and sex hormones, in combination with variable TGF-ß1 doses, determine the net outcome in TGF-ß1-induced expression of connective tissue growth factor (CTGF), a profibrotic cytokine. Altogether, these results suggest complex crosstalk between sex hormones, sex-dependent expression pattern and profibrotic signals for the precise course of DN development. Our data may help to better understand previous contradictory findings regarding sex differences in DN.


Asunto(s)
Nefropatías Diabéticas/genética , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Nefropatías Diabéticas/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Caracteres Sexuales
17.
Heliyon ; 6(1): e03251, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32042976

RESUMEN

Obesity is one of the primary causes of type 2 diabetes mellitus (T2DM). To better understand how obesity impairs glucose-insulin homeostasis, we tracked fasting blood glucose and insulin levels and the key components of glucose-insulin homeostasis for 7 months in high fat diet (HFD; 45% fat) fed mice (n = 8). Every 2 weeks we measured body weight, fasting blood glucose and insulin levels, and estimated 5 key rate constants of glucose-insulin homeostasis using the methods established previously (Heliyon 3: e00310, 2017). Mice gained weight steadily, more than doubling their weights after 7 months (23.6 ± 0.5 to 52.3 ± 1.4 g). Fasting (basal) insulin levels were elevated (221.3 ± 16.7 to 1043.1 ± 90.5 pmol l-1) but fasting blood glucose levels unexpectedly returned to the baseline levels (152.8 ± 7.0 to 152.0 ± 7.2 mg/dl) despite significantly elevated levels (216.8 ± 44.9 mg/dl, average of 3 highest values for 8 mice) during the experimental period. After 7 months of HFD feeding, the rate constants for insulin secretion (k1), insulin-independent glucose uptake (k3), and insulin concentration where liver switches from glucose uptake to release (Ipi) were significantly elevated. Insulin-dependent glucose uptake (k2) and rate constant of liver glucose transfer (k4) were lowered but no statistical significance was reached. The novel and key finding of this study is the wide range of fluctuations of the rate constants during the course of obesity, reflecting the body's compensatory responses against metabolic alterations caused by obesity.

18.
Rheumatol Int ; 30(2): 285-9, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19774383

RESUMEN

Genetic factors that predispose individuals to Behcet's disease (BD) are considered to play an important role in the development of the disease. The serum level of tumor necrosis factor (TNF) is elevated in patients with BD, and a dramatic response to anti-TNF-alpha antibody treatment further supports the role of TNF in BD. We investigated the distribution of TNF-alpha promoter -1031T/C and -308G/A polymorphisms in 53 BD patients of Iranian Azeri Turks and 79 matched healthy controls, via the PCR-RFLP technique. The frequency of the TNF-alpha -1031C allele was significantly higher in Behcet's patients than in healthy controls (p < 0.0001, OR = 3.08; 95% CI = 1.73-5.47), whereas the frequency of the TNF-alpha -308A allele was similar in the two compared groups. The frequency of CG haplotype was significantly higher (p < 0.0001, OR = 3.42; 95% CI = 1.89-6.18), and that of the TA haplotype was significantly lower in BD patients than in healthy controls. These results suggest that TNF-alpha is a susceptibility gene for BD in patients from Iranian Azeri Turk ethnic group.


Asunto(s)
Síndrome de Behçet/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Adulto , Síndrome de Behçet/epidemiología , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Irán/epidemiología , Masculino , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas
19.
Semin Arthritis Rheum ; 37(5): 334-8, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18006045

RESUMEN

OBJECTIVES: To identify the frequency and distribution of familial Mediterranean fever (FMF) gene (MEFV) mutations among Azeri Turkish patients from northwestern Iran. METHODS: One hundred ninety unrelated patients were referred by specialists to the Molecular-Medical Genetic Center of Tabriz. A clinical diagnosis of FMF was made according to published criteria. Mutation screening of the MEFV gene was performed for the 5 most commonly known mutations, namely M694V, V726A, M680I, M694I, and E148Q, by using amplification refractory mutation system for the first 4 and by polymerase chain reaction restriction-digestion testing for E148Q. These methods may also be used as a screening tool within affected families. RESULTS: Of the unrelated patients investigated, 120 (63%) had 1 or 2 mutations. Of those with mutations, 41 were homozygous, 37 were compound heterozygous, and 42 had only 1 identifiable mutation. Of the studied alleles, the most frequent mutation was M694V (28%), followed by V726A (9%), E148Q (7%), M680I (7%), and M694I (1%) mutations. CONCLUSIONS: Our results indicate that the common Mediterranean mutations are frequent in the Azeri Turkish FMF patients but with some differences in the frequency of individual mutations. The high frequency of E148Q in Azeri Turks compared with Mediterranean ethnic groups is rather interesting. The results open the way for further investigations on patients diagnosed as having FMF and in whom no mutations or only 1 mutated allele were found.


Asunto(s)
Proteínas del Citoesqueleto/genética , ADN/genética , Fiebre Mediterránea Familiar/genética , Mutación , Adolescente , Adulto , Anciano , Niño , Preescolar , Análisis Mutacional de ADN , Fiebre Mediterránea Familiar/etnología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Irán/epidemiología , Masculino , Persona de Mediana Edad , Pirina , Turquía/etnología
20.
Gynecol Obstet Invest ; 66(1): 68-72, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18500169

RESUMEN

BACKGROUND/AIMS: The role of human papillomavirus (HPV) in the etiology of cervical cancer is now well established. This investigation was designed to study the prevalence of the four most common high-risk HPVs in the archival tissues with precancerous and cancerous lesions from patients from northwestern Iran. METHODS: 133 formalin-fixed paraffin-embedded tissue specimens were tested for HPV DNA by using GP5+/6+-based general PCR and two type-specific PCRs. RESULTS: In total, 84 (64%) out of 131 amplifiable samples were positive for HPV DNA. The most prevalent oncogenic HPV was type 16 (67.6%) followed by types 31 (22.8%), 18 (7.6%) and 33 (1%). Multiple HPV infections were present in 20 (15.3%) of the 131 samples. Notably, of these 20 cases with multiple infections, 15 were from patients with invasive cervical cancer. CONCLUSIONS: The multiplicity of HPV genotypes was noted in invasive cervical carcinoma samples, along with rather different circulating HPV types in the study population. Hence, relevant HPV typing information in cervical carcinoma is very important for planning more efficient screening programs and for further HPV vaccine design.


Asunto(s)
Adenocarcinoma/virología , Carcinoma de Células Escamosas/virología , Infecciones por Papillomavirus/diagnóstico , Lesiones Precancerosas/virología , Neoplasias del Cuello Uterino/virología , Adulto , Anciano , Carcinoma in Situ/virología , ADN Viral/análisis , Femenino , Genotipo , Humanos , Irán , Persona de Mediana Edad , Infecciones por Papillomavirus/complicaciones , Reacción en Cadena de la Polimerasa , Factores de Riesgo
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