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1.
Chem Rev ; 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39288258

RESUMEN

In this Review, all known chemical methods for the conversion of renewable resources into benzenoid aromatics are summarized. The raw materials that were taken into consideration are CO2; lignocellulose and its constituents cellulose, hemicellulose, and lignin; carbohydrates, mostly glucose, fructose, and xylose; chitin; fats and oils; terpenes; and materials that are easily obtained via fermentation, such as biogas, bioethanol, acetone, and many more. There are roughly two directions. One much used method is catalytic fast pyrolysis carried out at high temperatures (between 300 and 700 °C depending on the raw material), which leads to the formation of biochar; gases, such as CO, CO2, H2, and CH4; and an oil which is a mixture of hydrocarbons, mostly aromatics. The carbon selectivities of this method can be reasonably high when defined small molecules such as methanol or hexane are used but are rather low when highly oxygenated compounds such as lignocellulose are used. The other direction is largely based on the multistep conversion of platform chemicals obtained from lignocellulose, cellulose, or sugars and a limited number of fats and terpenes. Much research has focused on furan compounds such as furfural, 5-hydroxymethylfurfural, and 5-chloromethylfurfural. The conversion of lignocellulose to xylene via 5-chloromethylfurfural and dimethylfuran has led to the construction of two large-scale plants, one of which has been operational since 2023.

2.
Small ; 20(33): e2400963, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38686696

RESUMEN

Biomolecule-functionalized nanoparticles represent a type of promising biomaterials in biomedical applications owing to their excellent biocompatibility and versatility. DNA-based reactions on nanoparticles have enabled emerging applications including intelligent biosensors, drug delivery, and biomimetic devices. Among the reactions, strand hybridization is the critical step to control the sensitivity and specificity of biosensing, and the efficiency of drug delivery. However, a comprehensive understanding of DNA hybridization on nanoparticles is still lacking, which may differ from the process in homogeneous solutions. To address this limitation, coarse-grained model-based molecular dynamic simulation is harnessed to disclose the critical factors involved in intermolecular hybridization. Based on simulation guidance, DNA walker-based smart theranostic platform (DWTP) based on "on-particle" hybridization is developed, showing excellent consistency with simulation. DWTP is successfully applied for highly sensitive miRNA 21 detection and tumor-specific miRNA 21 imaging, driven by tumor-endogenous APE 1 enzyme. It enables the precise release of antisense oligonucleotide triggered by tumor-endogenous dual-switch miRNA 21 and APE 1, facilitating effective gene silencing therapy with high biosafety. The simulation of "on-particle" DNA hybridization has improved the corresponding biosensing performance and the release efficiency of therapeutic agents, representing a conceptually new approach for DNA-based device design.


Asunto(s)
ADN , MicroARNs , Nanomedicina Teranóstica , ADN/química , Nanomedicina Teranóstica/métodos , Humanos , Hibridación de Ácido Nucleico , Nanopartículas/química , Simulación de Dinámica Molecular , Técnicas Biosensibles/métodos
3.
J Nanobiotechnology ; 22(1): 458, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39085923

RESUMEN

Cochlear implants can directly activate the auditory system's primary sensory neurons, the spiral ganglion neurons (SGNs), via circumvention of defective cochlear hair cells. This bypass restores auditory input to the brainstem. SGN loss etiologies are complex, with limited mammalian regeneration. Protecting and revitalizing SGN is critical. Tissue engineering offers a novel therapeutic strategy, utilizing seed cells, biomolecules, and scaffold materials to create a cellular environment and regulate molecular cues. This review encapsulates the spectrum of both human and animal research, collating the factors contributing to SGN loss, the latest advancements in the utilization of exogenous stem cells for auditory nerve repair and preservation, the taxonomy and mechanism of action of standard biomolecules, and the architectural components of scaffold materials tailored for the inner ear. Furthermore, we delineate the potential and benefits of the biohybrid neural interface, an incipient technology in the realm of implantable devices. Nonetheless, tissue engineering requires refined cell selection and differentiation protocols for consistent SGN quality. In addition, strategies to improve stem cell survival, scaffold biocompatibility, and molecular cue timing are essential for biohybrid neural interface integration.


Asunto(s)
Regeneración Nerviosa , Ganglio Espiral de la Cóclea , Ingeniería de Tejidos , Andamios del Tejido , Ganglio Espiral de la Cóclea/citología , Humanos , Ingeniería de Tejidos/métodos , Animales , Andamios del Tejido/química , Neuronas , Implantes Cocleares , Células Madre/citología , Diferenciación Celular
4.
J Med Genet ; 59(2): 147-154, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-33323469

RESUMEN

BACKGROUND: Nephronophthisis-related ciliopathies (NPHP-RC) account for the majority of cases of monogenetically caused end-stage renal disease (ESRD) in children. Exploring the correlation between the phenotype and genotype of NPHP-RC is helpful for early diagnosis and management. We investigated the phenotype and genotype spectra of NPHP-RC in a Chinese multicentre cohort. METHODS: Crosss-ectional and longitudinal data of 60 patients from 57 families with pathogenic NPHP-RC gene mutations distributed in 22 regions of China were collected into a unified, anonymous database. The mean observation time of this cohort was 3.5±3.1 years. RESULTS: Mutations in NPHP1 and NPHP3 were the most common genetic defects. Overall, 45% of patients presented with isolated nephronophthisis (NPH), and 55% exhibited the extrarenal phenotype, which frequently involved the liver (41.7%, n=25), central nervous system (26.7%, n=16), eyes (26.7%, n=16) and skeletal system (11.7%, n=7). Accidental detection of elevated serum creatinine and non-specific symptoms caused by chronic kidney disease occurred in 65% of patients. Patients carrying NPHP1 mutations mainly presented with isolated NPH (90%, 18/20) and progressed to ESRD at a mean age of 12.9±0.5 years. The mean age of ESRD onset in the non-NPHP1 group was lower than that in the NPHP1 group (6.2±1.4 years, p<0.001), especially for patients carrying NPHP3 mutations (3.1±1.2 years), showing a heterogeneous phenotype characterised by Bardet-Biedl syndrome (12.5%, n=5), Joubert syndrome (7.5%, n=3), COACH syndrome (2.5%, n=1), Mainzer-Saldino syndrome (2.5%, n=1), short-rib thoracic dysplasia (2.5%, n=1) and unclassified symptoms (32.5%, n=13). CONCLUSIONS: The Chinese Children Genetic Kidney Disease Database registry characterised the spectrum of the phenotype and genotype of NPHP-RC in the Chinese population. NPHP1 and NPHP3 were the most common pathogenic genes. Rapid progression to ESRD and liver involvement were noted in patients with NPHP3 mutations.


Asunto(s)
Ciliopatías/genética , Enfermedades Renales Quísticas/congénito , Pueblo Asiatico , Niño , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Enfermedades Renales Quísticas/genética , Fallo Renal Crónico/genética , Masculino , Mutación , Fenotipo , Estudios Prospectivos
5.
Phys Rev Lett ; 127(8): 087203, 2021 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-34477416

RESUMEN

The magnon cat state represents a macroscopic quantum superposition of collective magnetic excitations of large number spins that not only provides fundamental tests of macroscopic quantum effects but also finds applications in quantum metrology and quantum computation. In particular, remote generation and manipulation of Schrödinger cat states are particularly interesting for the development of long-distance and large-scale quantum information processing. Here, we propose an approach to remotely prepare magnon even or odd cat states by performing local non-Gaussian operations on the optical mode that is entangled with the magnon mode through pulsed optomagnonic interaction. By evaluating key properties of the resulting cat states, we show that for experimentally feasible parameters, they are generated with both high fidelity and nonclassicality, as well as with a size large enough to be useful for quantum technologies. Furthermore, the effects of experimental imperfections such as the error of projective measurements and dark count when performing single-photon operations have been discussed, where the lifetime of the created magnon cat states is expected to be t∼1 µs.

6.
Pharmacol Res ; 169: 105639, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33932607

RESUMEN

Atherosclerosis is now the major cause of mortality and morbidity worldwide. Formation of macrophage-derived foam cells is a hallmark of atherosclerosis, which is regulated by cholesterol uptake, intracellular metabolism, and efflux. PPARγ-LXRα-ABCA1/ABCG1 pathway plays an important part in regulating cholesterol efflux and this pathway could be a promising target for treating atherosclerosis. However, due to undesirable systemic effects, PPARγ agonist therapy for atherosclerosis remains challenging. Many traditional Chinese medicine has been well accepted and applied in atherosclerosis treatment. Yin-xing-tong-mai decoction (YXTMD) has been applied for treating atherosclerosis for decades. However, the mechanism remains to be explored. Here, we showed that YXTMD effectively attenuated atherosclerosis in ApoE-/- mice. YXTMD increased cholesterol efflux of foam cell by upregulation of ABCA1 and ABCG1 in vivo and in vitro. Through bioinformatic analysis and experimental validation, we found that PPARγ was an important downstream effector of YXTMD in macrophages. Reduction of PPARγ significantly decreased LXRα, ABCA1, and ABCG1 expression in macrophages, with reduced cholesterol efflux. In conclusion, these findings confirmed that YXTMD attenuated atherosclerosis by activating the PPARγ-LXRα- ABCA1/ABCG1 pathway to enhance cholesterol efflux.


Asunto(s)
Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Aterosclerosis/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Receptores X del Hígado/metabolismo , PPAR gamma/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Colesterol/metabolismo , Modelos Animales de Enfermedad , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL
7.
Angew Chem Int Ed Engl ; 60(48): 25318-25322, 2021 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-34585486

RESUMEN

MXenes have attracted great interests as supercapacitors due to their metallic conductivity, high density, and hydrophilic nature. Herein we report Ti3 C2 -Cu/Co hybrids via molten salt etching in which the existence of metal atoms and their interactions with MXene via surficial O atoms were elucidated by XAFS for the first time. The electrochemical investigation of Ti3 C2 -Cu electrode demonstrated the pseudocapacitive contribution of Cu and a splendid specific capacitance of 885.0 F g-1 at 0.5 A g-1 in 1.0 M H2 SO4 . Symmetric supercapacitor Ti3 C2 -Cu//Ti3 C2 -Cu was demonstrated with operating voltage of 1.6 V, areal capacitance of 290.5 mF cm-2 at 1 mA cm-2 , and stability over 10 000 cycles. It delivered an areal energy density of 103.3 µWh cm-2 at power density of 0.8 mW cm-2 , based on which a supercapacitor pouch was fabricated. It provides deeper insights into the molten salt mechanism and strategies for designing MXene-based materials for electrochemical energy storage.

8.
Phys Rev Lett ; 124(5): 053602, 2020 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-32083914

RESUMEN

We show that parity-time (PT) symmetry can be spontaneously broken in the recently reported energy level attraction of magnons and cavity photons. In the PT-broken phase, the magnon and photon form a high-fidelity Bell state with maximum entanglement. This entanglement is steady and robust against the perturbation of the environment, which is in contrast to the general wisdom that expects instability of the hybridized state when the symmetry is broken. This anomaly is further understood by the compete of non-Hermitian evolution and particle number conservation of the hybrid system. As a comparison, neither PT-symmetry breaking nor steady magnon-photon entanglement is observed inside the normal level repulsion case. Our results may open an exciting window to utilize magnon-photon entanglement as a resource for quantum information science.

9.
Mikrochim Acta ; 187(3): 168, 2020 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-32055955

RESUMEN

The ultrathin 2D metal-organic framework structure effectively increases the metal sites of the active molecules and endows Ni-MOF with good current sensing performance. The ultrathin 2D nanosheet Ni-MOF assemblies have been successfully synthesized by using (Ni3(OH)2(C8H4O4)2(H2O)4)·2H2O as the molecular formula. The sensor performance of Ni-MOF assemble was investigated by amperometric method. The resulting products are characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and X-ray photoelectron spectroscopy. The electric signal generated by the electrochemical reaction on the electrode surface indicates that the assemble of Ni-MOF with ultrathin folded-like structure and special aggregation state has high electrocatalytic performance. In the detection of hydrazine hydrate, Ni-MOF assemble shows good stability, low detection limit (0.23 nm), and high selectivity in the range of 0.5 µM to 8.0 mM at a voltage of 0.25 V. This study provides a new idea for the application of MOF assemble in hydrazine hydrate sensor. Graphical abstract Schematic of illustration of the synthesis of the Ni-MOF and the Ni-MOF applied for catalyzing N2H4.

10.
Mikrochim Acta ; 187(8): 426, 2020 07 04.
Artículo en Inglés | MEDLINE | ID: mdl-32623528

RESUMEN

The published article is revised due to diagram errors. The authors express their sincere apology, and corrected Figure 2a (XPS), Figure S4 (IR), and Figure S7 (XPS) are given.

11.
Small ; 15(11): e1804600, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30690873

RESUMEN

Ordered mesoporous materials, porous materials with a pore size of 2-50 nm which are prepared via the sol-gel process using surfactant molecular aggregates as a template to assemble channels through the interfacial action of organic and inorganic substances, have recently triggered a heated debate. In addition to applications in the catalytic cracking of heavy oils and residues, the manufacturing of graft materials, the purification of water, the conversion of automobile exhaust, biochips, and the treatment of environmental pollutants via photocatalysts, ordered mesoporous materials have drawn substantial attention in the field of electrochemical energy storage due to advantages such as large specific surface area, uniform and continuously adjustable pore size, and orderly arrangement. Here, a general summary and appraisal of the study of ordered mesoporous materials for batteries in recent years is given, including the synthesis methods, meso/nanostructural features, and electrochemical capabilities of such materials.

12.
Clin Genet ; 96(5): 402-410, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31328266

RESUMEN

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.


Asunto(s)
Exoma/genética , Predisposición Genética a la Enfermedad , Enfermedades Renales Quísticas/genética , Insuficiencia Renal Crónica/genética , Niño , Preescolar , China/epidemiología , Estudios de Cohortes , Femenino , Pruebas Genéticas , Humanos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/patología , Masculino , Fenotipo , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/patología , Sistema Urinario/metabolismo , Sistema Urinario/patología , Secuenciación del Exoma
13.
Org Biomol Chem ; 17(17): 4291-4300, 2019 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-30969301

RESUMEN

We describe an expedient access to a 5',6',7'-trifluoro dihydroxanthene-hemicyanine fused scaffold in 2 steps and 54% overall yield from the corresponding salicylic aldehyde. A 6'-regioselective nucleophilic aromatic substitution (SNAr) reaction with a wide range of nitrogen, sulfur or selenium nucleophiles then gives access to 16 near-infrared (NIR) fluorophores emitting in the 710-750 nm range. We also report the experimental and theoretical photophysical investigations of these unique optical agents that include the first series of 6'-heavy atom substituted dihydroxanthenes, extending the pool of polyfluorinated markers for biomedical and material applications.

14.
Small ; 14(28): e1800426, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29761631

RESUMEN

A breakthrough in technologies having "green" and sustainable energy storage conversion is urgent, and supercapacitors play a crucial role in this area of research. Owing to their unique porous structure, amorphous materials are considered one of the best active materials for high-performance supercapacitors due to their high specific capacity, excellent cycling stability, and fast charging rate. This Review summarizes the synthesis of amorphous materials (transition metal oxides, carbon-based materials, transition metal sulfides, phosphates, hydroxides, and their complexes) to highlight their electrochemical performance in supercapacitors.

15.
Int J Mol Sci ; 19(12)2018 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-30558203

RESUMEN

DNA methylation is a vital modification process in the control of genetic information, which contributes to the epigenetics by regulating gene expression without changing the DNA sequence. Abnormal DNA methylation-both hypomethylation and hypermethylation-has been associated with improper gene expression, leading to several disorders. Two types of risk factors can alter the epigenetic regulation of methylation pathways: genetic factors and modifiable factors. Nutrition is one of the strongest modifiable factors, which plays a direct role in DNA methylation pathways. Large numbers of studies have investigated the effects of nutrition on DNA methylation pathways, but relatively few have focused on the biochemical mechanisms. Understanding the biological mechanisms is essential for clarifying how nutrients function in epigenetics. It is believed that nutrition affects the epigenetic regulations of DNA methylation in several possible epigenetic pathways: mainly, by altering the substrates and cofactors that are necessary for proper DNA methylation; additionally, by changing the activity of enzymes regulating the one-carbon cycle; and, lastly, through there being an epigenetic role in several possible mechanisms related to DNA demethylation activity. The aim of this article is to review the potential underlying biochemical mechanisms that are related to diet modifications in DNA methylation and demethylation.


Asunto(s)
Metilación de ADN/efectos de los fármacos , Dieta/efectos adversos , Animales , Ciclo del Carbono/efectos de los fármacos , ADN-Citosina Metilasas/metabolismo , Epigénesis Genética/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos
16.
J Cell Biochem ; 118(9): 2664-2671, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28067413

RESUMEN

Echinacea purpurea is an indigenous North American purple cone flower used by North Americans for treatment of various infectious diseases and wounds. This study investigated the effect of polysaccharide enriched extract of Echinacea purpurea (EE) on the polarization of macrophages. The results showed that 100 µg/mL of EE could markedly activate the macrophage by increasing the expression of CD80, CD86, and MHCII molecules. Meanwhile, EE upregulated the markers of classically activated macrophages (M1) such as CCR7 and the production of IL-1ß, IL-6, IL-12p70, TNF-αand NO. The functional tests showed that EE enhanced the phagocytic and intracellular bactericidal activity of macrophage against ST. Furthermore, we demonstrated that JNK are required for EE-induced NO and M1-related cytokines production. Together, these results demonstrated that EE can polarize macrophages towards M1 phenotype, which is dependent on the JNK signaling pathways. J. Cell. Biochem. 118: 2664-2671, 2017. © 2017 Wiley Periodicals, Inc.


Asunto(s)
Células de la Médula Ósea/metabolismo , Echinacea/química , MAP Quinasa Quinasa 4/metabolismo , Macrófagos/metabolismo , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Citocinas/metabolismo , Activación Enzimática/efectos de los fármacos , Ratones , Extractos Vegetales/química
17.
Small ; 13(33)2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28660696

RESUMEN

Currently, metal molybdates compounds can be prepared by several methods and are considered as prospective electrode materials in many fields because the metal ions possess the ability to exist in several oxidation states. These multiple oxidation states contribute to prolonging the discharge time, improving the energy density, and increasing the cycling stability. The high electrochemical performance of metal molybdates as electrochemical energy storage devices are discussed in this review. According to recent publications and research progress on relevant materials, the investigation of metal molybdate compounds are discussed via three main aspects: synthetic methods, material properties and measured electrochemical performance of these compounds as electrode materials. The recent progress in general metal molybdate nanomaterials for LIBs and supercapacitors are carefully presented here.

18.
J Immunol ; 195(1): 217-26, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-26019273

RESUMEN

Proper regulation of microbial-induced cytokines is critical to intestinal immune homeostasis. Acute stimulation of nucleotide-binding oligomerization domain 2 (NOD2), the Crohn's disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, chronic NOD2 stimulation in macrophages decreases cytokines upon pattern recognition receptor (PRR) restimulation; cytokine attenuation to PRR stimulation is similarly observed in intestinal macrophages. The role for the transcriptional repressors Twist1 and Twist2 in regulating PRR-induced cytokine outcomes is poorly understood and has not been reported for NOD2. We found that Twist1 and Twist2 were required for optimal cytokine downregulation during acute and, particularly, chronic NOD2 stimulation of human macrophages. Consistently, Twist1 and Twist2 expression was increased after chronic NOD2 stimulation; this increased expression was IL-10 and TGF-ß dependent. Although Twist1 and Twist2 did not coregulate each other's expression, they cooperated to enhance binding to cytokine promoters after chronic NOD2 stimulation. Moreover, Twist1 and Twist2 contributed to enhance expression and promoter binding of the proinflammatory inhibitor c-Maf and the transcriptional repressor Bmi1. Restoring c-Maf and Bmi1 expression in Twist-deficient macrophages restored NOD2-induced cytokine downregulation. Furthermore, with chronic NOD2 stimulation, Twist1 and Twist2 contributed to the decreased expression and cytokine promoter binding of the transcriptional activators activating transcription factor 4, C/EBPα, Runx1, and Runx2. Knockdown of these transcriptional activators in Twist-deficient macrophages restored cytokine downregulation after chronic NOD2 stimulation. Finally, NOD2 synergized with additional PRRs to increase Twist1 and Twist2 expression and Twist-dependent pathways. Therefore, after chronic NOD2 stimulation Twist1 and Twist2 coordinate the regulation of both transcriptional activators and repressors, thereby mediating optimal cytokine downregulation.


Asunto(s)
Activación de Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Proteína Adaptadora de Señalización NOD2/inmunología , Proteínas Nucleares/inmunología , Proteínas Represoras/inmunología , Proteína 1 Relacionada con Twist/inmunología , Acetilmuramil-Alanil-Isoglutamina/farmacología , Factor de Transcripción Activador 4/antagonistas & inhibidores , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/inmunología , Anticuerpos Neutralizantes/farmacología , Proteínas Potenciadoras de Unión a CCAAT/antagonistas & inhibidores , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/inmunología , Subunidad alfa 1 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/inmunología , Subunidad alfa 2 del Factor de Unión al Sitio Principal/antagonistas & inhibidores , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/inmunología , Regulación de la Expresión Génica , Humanos , Interleucina-10/antagonistas & inhibidores , Interleucina-10/genética , Interleucina-10/inmunología , Macrófagos/citología , Macrófagos/efectos de los fármacos , Proteína Adaptadora de Señalización NOD2/agonistas , Proteína Adaptadora de Señalización NOD2/genética , Proteínas Nucleares/genética , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/inmunología , Cultivo Primario de Células , Regiones Promotoras Genéticas , Unión Proteica , Proteínas Proto-Oncogénicas c-maf/genética , Proteínas Proto-Oncogénicas c-maf/inmunología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunología , Proteínas Represoras/genética , Transducción de Señal , Transcripción Genética , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología , Proteína 1 Relacionada con Twist/genética
19.
J Immunol ; 194(4): 1928-37, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25567680

RESUMEN

Microbial-induced cytokine regulation is critical to intestinal immune homeostasis. Acute stimulation of nucleotide-binding oligomerization domain 2 (NOD2), the Crohn's disease-associated sensor of bacterial peptidoglycan, induces cytokines. However, cytokines are attenuated after chronic NOD2 and pattern recognition receptor stimulation of macrophages; similar attenuation is observed in intestinal macrophages. The role of Tyro3, Axl, and Mer (TAM) receptors in regulating chronic pattern recognition receptor stimulation and NOD2-induced outcomes has not been examined. Moreover, TAM receptors have been relatively less investigated in human macrophages. Whereas TAM receptors did not downregulate acute NOD2-induced cytokines in primary human macrophages, they were essential for downregulating signaling and proinflammatory cytokine secretion after chronic NOD2 and TLR4 stimulation. Axl and Mer were similarly required in mice for cytokine downregulation after chronic NOD2 stimulation in vivo and in intestinal tissues. Consistently, TAM expression was increased in human intestinal myeloid-derived cells. Chronic NOD2 stimulation led to IL-10- and TGF-ß-dependent TAM upregulation in human macrophages, which, in turn, upregulated suppressor of cytokine signaling 3 expression. Restoring suppressor of cytokine signaling 3 expression under TAM knockdown conditions restored chronic NOD2-mediated proinflammatory cytokine downregulation. In contrast to the upregulated proinflammatory cytokines, attenuated IL-10 secretion was maintained in TAM-deficient macrophages upon chronic NOD2 stimulation. The level of MAPK activation in TAM-deficient macrophages after chronic NOD2 stimulation was insufficient to upregulate IL-10 secretion; however, full restoration of MAPK activation under these conditions restored c-Fos, c-Jun, musculoaponeurotic fibrosarcoma oncogene homolog K, and PU.1 binding to the IL-10 promoter and IL-10 secretion. Therefore, TAM receptors are critical for downregulating proinflammatory cytokines under the chronic NOD2 stimulation conditions observed in the intestinal environment.


Asunto(s)
Macrófagos/inmunología , Proteínas Quinasas Activadas por Mitógenos/inmunología , Proteína Adaptadora de Señalización NOD2/inmunología , Proteínas Tirosina Quinasas Receptoras/inmunología , Proteínas Supresoras de la Señalización de Citocinas/inmunología , Animales , Western Blotting , Inmunoprecipitación de Cromatina , Colitis/inmunología , Citocinas/biosíntesis , Regulación hacia Abajo , Regulación de la Expresión Génica/inmunología , Humanos , Inflamación/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína 3 Supresora de la Señalización de Citocinas , Transfección
20.
J Immunol ; 192(12): 5924-32, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24842757

RESUMEN

Fine-tuning of cytokine-inducing pathways is essential for immune homeostasis. Consistently, a dysregulated increase or decrease in pattern-recognition receptor (PRR)-induced signaling and cytokine secretion can lead to inflammatory bowel disease. Multiple gene loci are associated with inflammatory bowel disease, but their functional effects are largely unknown. One such region in chromosome 2q12 (rs917997), also associated with other immune-mediated diseases, encompasses IL18RAP. We found that human monocyte-derived macrophages (MDMs) from rs917997 AA risk carriers secrete significantly less cytokines than G carriers upon stimulation of multiple PRRs, including nucleotide-binding oligomerization domain 2 (NOD2). We identified that IL-18 signaling through IL-18RAP was critical in amplifying PRR-induced cytokine secretion in MDMs. IL-18RAP responded to NOD2-initiated early, caspase-1-dependent autocrine IL-18, which dramatically enhanced MAPK, NF-κB, PI3K, and calcium signaling. Reconstituting MAPK activation was sufficient to rescue decreased cytokines in NOD2-stimulated IL-18RAP-deficient MDMs. Relative to GG carriers, MDM from rs917997 AA carriers had decreased expression of cell-surface IL-18RAP protein, as well as of IL-18R1 and IL-1R1, genes also located in the IL18RAP region. Accordingly, these risk-carrier MDMs show diminished PRR-, IL-18-, and IL-1-induced MAPK and NF-κB signaling. Taken together, our results demonstrate clear functional consequences of the rs917997 risk polymorphism; this polymorphism leads to a loss-of-function through decreased IL-18RAP, IL-18R1, and IL-1R1 protein expression, which impairs autocrine IL-18 and IL-1 signaling, thereby leading to decreased cytokine secretion in MDMs upon stimulation of a broad range of PRRs.


Asunto(s)
Comunicación Autocrina/inmunología , Señalización del Calcio/inmunología , Regulación de la Expresión Génica/inmunología , Subunidad alfa del Receptor de Interleucina-18/inmunología , Subunidad beta del Receptor de Interleucina-18/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Macrófagos/inmunología , Polimorfismo de Nucleótido Simple/inmunología , Receptores Tipo I de Interleucina-1/inmunología , Comunicación Autocrina/genética , Señalización del Calcio/genética , Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 2/inmunología , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Femenino , Regulación de la Expresión Génica/genética , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-18/genética , Interleucina-18/inmunología , Subunidad alfa del Receptor de Interleucina-18/genética , Subunidad beta del Receptor de Interleucina-18/genética , Sistema de Señalización de MAP Quinasas/genética , Masculino , FN-kappa B/genética , FN-kappa B/inmunología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/inmunología , Receptores Tipo I de Interleucina-1/genética
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