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1.
Cell ; 175(4): 1045-1058.e16, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30388443

RESUMEN

Protein N-glycosylation is a widespread post-translational modification. The first committed step in this process is catalysed by dolichyl-phosphate N-acetylglucosamine-phosphotransferase DPAGT1 (GPT/E.C. 2.7.8.15). Missense DPAGT1 variants cause congenital myasthenic syndrome and disorders of glycosylation. In addition, naturally-occurring bactericidal nucleoside analogues such as tunicamycin are toxic to eukaryotes due to DPAGT1 inhibition, preventing their clinical use. Our structures of DPAGT1 with the substrate UDP-GlcNAc and tunicamycin reveal substrate binding modes, suggest a mechanism of catalysis, provide an understanding of how mutations modulate activity (thus causing disease) and allow design of non-toxic "lipid-altered" tunicamycins. The structure-tuned activity of these analogues against several bacterial targets allowed the design of potent antibiotics for Mycobacterium tuberculosis, enabling treatment in vitro, in cellulo and in vivo, providing a promising new class of antimicrobial drug.


Asunto(s)
Antibióticos Antituberculosos/farmacología , Trastornos Congénitos de Glicosilación/metabolismo , Inhibidores Enzimáticos/farmacología , N-Acetilglucosaminiltransferasas/química , Animales , Antibióticos Antituberculosos/química , Sitios de Unión , Trastornos Congénitos de Glicosilación/genética , Inhibidores Enzimáticos/química , Femenino , Células HEK293 , Células Hep G2 , Humanos , Metabolismo de los Lípidos , Ratones , Simulación del Acoplamiento Molecular , Mutación , N-Acetilglucosaminiltransferasas/antagonistas & inhibidores , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Unión Proteica , Células Sf9 , Spodoptera , Tunicamicina/química , Tunicamicina/farmacología , Uridina Difosfato Ácido Glucurónico/química , Uridina Difosfato Ácido Glucurónico/metabolismo
2.
J Transl Med ; 22(1): 528, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38824544

RESUMEN

Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 µmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.


Asunto(s)
Aminoácidos , Proliferación Celular , Fluoruros , Músculo Liso Vascular , Ratas Sprague-Dawley , Animales , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/efectos de los fármacos , Fluoruros/farmacología , Línea Celular , Aminoácidos/metabolismo , Proliferación Celular/efectos de los fármacos , Ratas , Movimiento Celular/efectos de los fármacos , Masculino , Aorta/patología , Aorta/efectos de los fármacos , Aorta/metabolismo , Metabolómica , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/patología , Redes Reguladoras de Genes/efectos de los fármacos
3.
J Exp Bot ; 75(5): 1314-1330, 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38069660

RESUMEN

Sphingolipids are membrane lipids and play critical roles in signal transduction. Ceramides are central components of sphingolipid metabolism that are involved in cell death. However, the mechanism of ceramides regulating cell death in plants remains unclear. Here, we found that ceramides accumulated in mitochondria of accelerated cell death 5 mutant (acd5), and expression of mitochondrion-localized ceramide kinase (ACD5) suppressed mitochondrial ceramide accumulation and the acd5 cell death phenotype. Using immuno-electron microscopy, we observed hyperaccumulation of ceramides in acer acd5 double mutants, which are characterized by mutations in both ACER (alkaline ceramidase) and ACD5 genes. The results confirmed that plants with specific ceramide accumulation exhibited localization of ceramides to mitochondria, resulting in an increase in mitochondrial reactive oxygen species production. Interestingly, when compared with the wild type, autophagy-deficient mutants showed stronger resistance to ceramide-induced cell death. Lipid profiling analysis demonstrated that plants with ceramide accumulation exhibited a significant increase in phosphatidylethanolamine levels. Furthermore, exogenous ceramide treatment or endogenous ceramide accumulation induces autophagy. When exposed to exogenous ceramides, an increase in the level of the autophagy-specific ubiquitin-like protein, ATG8e, associated with mitochondria, where it directly bound to ceramides. Taken together, we propose that the accumulation of ceramides in mitochondria can induce cell death by regulating autophagy.


Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Ceramidas/metabolismo , Ceramidas/farmacología , Arabidopsis/metabolismo , Mitocondrias/metabolismo , Autofagia , Muerte Celular , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo
4.
Anal Chem ; 95(8): 4077-4085, 2023 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-36787389

RESUMEN

Herein, by directly limiting the reaction space, an ingenious three-dimensional (3D) DNA walker (IDW) with high walking efficiency is developed for rapid and sensitive detection of miRNA. Compared with the traditional DNA walker, the IDW immobilized by the DNA tetrahedral nanostructure (DTN) brings stronger kinetic and thermodynamic favorability resulting from its improved local concentration and space confinement effect, accompanied by a quite faster reaction speed and much better walking efficiency. Once traces of target miRNA-21 react with the prelocked IDW, the IDW could be largely activated and walk on the interface of the electrode to trigger the cleavage of H2 with the assistance of Mg2+, resulting in the release of amounts of methylene blue (MB) labeled on H2 from the electrode surface and the obvious decrease of the electrode signal. Impressively, the IDW reveals a conversion efficiency as high as 9.33 × 108 in 30 min with a much fast reaction speed, which is at least five times beyond that of typical DNA walkers. Therefore, the IDW could address the inherent challenges of the traditional DNA walker easily: slow walking speed and low efficiency. Notably, the IDW as a DNA nanomachine was utilized to construct a sensitive sensing platform for rapid miRNA-21 detection with a limit of detection (LOD) of 19.8 aM and realize the highly sensitive assay of biomarker miRNA-21 in the total RNA lysates of cancer cell. The strategy thus helps in the design of a versatile nucleic acid conversion and signal amplification approach for practical applications in the areas of biosensing assay, DNA nanotechnology, and clinical diagnosis.


Asunto(s)
Técnicas Biosensibles , MicroARNs , Nanoestructuras , MicroARNs/genética , Técnicas Biosensibles/métodos , Técnicas Electroquímicas/métodos , ADN/química , Nanoestructuras/química , Límite de Detección
5.
Mol Cancer ; 21(1): 163, 2022 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-35974338

RESUMEN

Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine (m6A), the most abundant post-transcriptional modification in eukaryotes, exerts important roles in regulating mRNA metabolism including stability, decay, splicing, transport, and translation. As the key component of the m6A methyltransferase complex, methyltransferase-like 14 (METTL14) catalyzes m6A methylation on mRNA or non-coding RNA to regulate gene expression and cell phenotypes. Dysregulation of METTL14 was deemed to be involved in various aspects of gastrointestinal cancer, such as tumorigenesis, progression, chemoresistance, and metastasis. Plenty of findings have opened up new avenues for exploring the therapeutic potential of gastrointestinal cancer targeting METTL14. In this review, we systematically summarize the recent advances regarding the biological functions of METTL14 in gastrointestinal cancer, discuss its potential clinical applications and propose the research forecast.


Asunto(s)
Neoplasias Gastrointestinales , Metiltransferasas , Neoplasias Gastrointestinales/genética , Humanos , Metilación , Metiltransferasas/genética , Metiltransferasas/metabolismo , ARN/metabolismo , ARN Mensajero/metabolismo
6.
Reprod Biomed Online ; 45(5): 858-866, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36210273

RESUMEN

RESEARCH QUESTION: What are the potential clinical benefits of embryo culture and assessment in a time-lapse incubator compared with a standard incubator using static assessment? DESIGN: This large multicentre, single-blinded, randomized controlled study included 1224 participants randomly assigned (1:1) to the time-lapse or standard incubator group. In all patients one or two embryos were transferred on day 3. The primary outcome was the implantation rate in the first embryo transfer cycle. Secondary outcomes included the cumulative implantation rate, live birth rate in the first embryo transfer cycle and cumulative live birth rate. RESULTS: Among 1224 participants recruited, 1182 underwent embryo transfer. The number of successfully implanted embryos in the first transfer cycle was significantly higher in the time-lapse incubator group (time-lapse group: 52.35%, standard incubator group: 47.11%, P = 0.014). The implantation rate in the first embryo transfer cycle was still significantly higher in the time-lapse group than the standard incubator group after adjusting for age, body mass index, medical centre and embryo status (relative risk 1.11, 95% confidence interval 1.02-1.20, P = 0.020). However, the cumulative implantation rate, live birth rate in the first embryo transfer cycle and cumulative live birth rate were not statistically different between the groups. CONCLUSIONS: The implantation rate in the first embryo transfer cycle was significantly improved in the time-lapse group, but the effect of the time-lapse system on the cumulative implantation rate or cumulative live birth rate was not significant. The embryo assessment method offered by time-lapse systems rather than an undisturbed environment may play an important role in improving the implantation rate in the first embryo transfer cycle. These results are only applicable to young patients.


Asunto(s)
Técnicas de Cultivo de Embriones , Incubadoras , Humanos , Embarazo , Femenino , Imagen de Lapso de Tiempo , Implantación del Embrión , Transferencia de Embrión/métodos , Índice de Embarazo , Nacimiento Vivo , Fertilización In Vitro
7.
Acta Pharmacol Sin ; 43(8): 2156-2167, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34912007

RESUMEN

Excessive exposure to UVB induces skin diseases. Silibinin, a flavonolignan used for treating liver diseases, is found to be effective against UVB-caused skin epidermal and dermal cell damage. In this study we investigated the molecular mechanisms underlying. Human nonmalignant immortalized keratinocyte HaCaT cells and neonatal human foreskin fibroblasts HFFs were exposed to UVB irradiation. We showed that pre-treatment with silibinin dose-dependently decreased UVB-induced apoptosis of HaCaT cells. Furthermore, we showed that silibinin treatment inhibited nuclear translocation of YAP after UVB irradiation. Molecular docking analysis and DARTS assay confirmed the direct interaction of silibinin with YAP. Silencing YAP by siRNA had no influence on the survival of HaCaT cells, whereas inhibiting classical YAP-TEAD signaling pathway by siRNA targeting TEAD1 or its pharmaceutical inhibitor verteporfin further augmented UVB-induced apoptosis, suggesting that YAP-TEAD pathway was prosurvival, which did not participate in the protective effect of silibinin. We then explored the pro-apoptotic YAP-p73 pathway. p73 was upregulated in UVB-irradiated cells, but reduced by silibinin cotreatment. The mRNA and protein levels of p73 target genes (PML, p21 and Bax) were all increased by UVB but decreased by silibinin co-treatment. Inhibiting p73 by using siRNA reduced UVB-induced apoptosis, suggesting that downregulation of p73 was responsible for the cytoprotective effect of silibinin. In HFFs, the upregulated YAP-p73 pathway by UVB irradiation was also suppressed by silibinin. Collectively, YAP-p73 pathway is a major cause of the death of UVB-exposed epidermal HaCaT cells and dermal HFFs. Silibinin directly inhibits YAP-p73 pathway, exerting the protective action on UVB-irradiated skin cells.


Asunto(s)
Silimarina , Apoptosis , Humanos , Recién Nacido , Simulación del Acoplamiento Molecular , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Silibina/farmacología , Silimarina/farmacología
8.
Mikrochim Acta ; 189(5): 212, 2022 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-35507110

RESUMEN

Loop-mediated isothermal amplification (LAMP) is a promising diagnostic tool for genetic amplification, which is known for its rapid process, simple operation, high amplification efficiency, and excellent sensitivity. However, most of the existing heating methods are external for completion of molecular amplification with possibility of contamination of specimens. The present research provided an internal heating method for LAMP using magnetic nanoparticles (MNPs), which is called nano-LAMP. Near-infrared light with an excitation wavelength of 808 nm was employed as the heating source; hydroxy naphthol blue (HNB) was used as an indicator to conduct methodological research. We demonstrate that the best temperature was controlled at a working power of 2 W and 4.8 µg/µL concentration of nanoparticles. The lowest limit for the detection of HPV by the nano-LAMP method is 102 copies/mL, which was confirmed by a gel electrophoresis assay. In the feasibility investigation of validated clinical samples, all 10 positive HPV-6 specimens amplified by nano-LAMP were consistent with conventional LAMP methods. Therefore, the nano-LAMP detection method using internal heating of MNPs may bring a new vision to the exploration of thermostatic detection in the future.


Asunto(s)
Calefacción , Técnicas de Amplificación de Ácido Nucleico , ADN , Papillomavirus Humano 6 , Técnicas de Diagnóstico Molecular , Técnicas de Amplificación de Ácido Nucleico/métodos , Sensibilidad y Especificidad
9.
J Nurs Manag ; 30(8): 3736-3742, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36216773

RESUMEN

AIM: The article aims to outline a contrast between three priorities for nursing management proposed a decade ago and key features of the following 10 years of developments on artificial intelligence for health care and nursing management. This analysis intends to contribute to update the international debate on bridging the essence of health care and nursing management priorities and the focus of artificial intelligence developers. BACKGROUND: Artificial intelligence research promises innovative approaches to supporting nurses' clinical decision-making and to conduct tasks not related to patient interaction, including administrative activities and patient records. Yet, even though there has been an increase in international research and development of artificial intelligence applications for nursing care during the past 10 years, it is unclear to what extent the priorities of nursing management have been embedded in the devised artificial intelligence solutions. EVALUATION: Starting from three priorities for nursing management identified in 2011 in a special issue of the Journal Nursing Management, we went on to identify recent evidence concerning 10 years of artificial intelligence applications developed to support health care management and nursing activities since then. KEY ISSUE: The article discusses to what extent priorities in health care and nursing management may have to be revised while adopting artificial intelligence applications or, alternatively, to what extent the direction of artificial intelligence developments may need to be revised to contribute to long acknowledged priorities of nursing management. CONCLUSION: We have identified a conceptual gap between both sets of ideas and provide a discussion on the need to bridge that gap, while admitting that there may have been recent field developments still unreported in scientific literature. IMPLICATIONS FOR NURSING MANAGEMENT: Artificial intelligence developers and health care nursing managers need to be more engaged in coordinating the future development of artificial intelligence applications with a renewed set of nursing management priorities.


Asunto(s)
Inteligencia Artificial , Atención de Enfermería , Humanos , Atención a la Salud
10.
Small ; 17(43): e2101359, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34121319

RESUMEN

Colloidal all-inorganic perovskites nanocrystals (NCs) have emerged as a promising material for display and lighting due to their excellent optical properties. However, blue emissive NCs usually suffer from low photoluminescence quantum yields (PLQYs) and poor stability, rendering them the bottleneck for full-color all-perovskite optoelectronic applications. Herein, a facile approach is reported to enhance the emission efficiency and stability of blue emissive perovskite nano-structures via surface passivation with potassium bromide. By adding potassium oleate and excess PbBr2 to the perovskite precursor solutions, potassium bromide-passivated (KBr-passivated) blue-emitting (≈450 nm) CsPbBr3 nanoplatelets (NPLs) is successfully synthesized with a respectably high PLQY of 87%. In sharp contrast to most reported perovskite NPLs, no shifting in emission wavelength is observed in these passivated NPLs even after prolonged exposures to intense irradiations and elevated temperature, clearly revealing their excellent photo- and thermal-stabilities. The enhancements are attributed to the formation of K-Br bonding on the surface which suppresses ion migration and formation of Br-vacancies, thus improving both the PL emission and stability of CsPbBr3 NPLs. Furthermore, all-perovskite white light-emitting diodes (WLEDs) are successfully constructed, suggesting that the proposed KBr-passivated strategy can promote the development of the perovskite family for a wider range of optoelectronic applications.

11.
Genomics ; 112(6): 5021-5028, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32927007

RESUMEN

Feeding and bone traits are vital for breeding and reproduction in the commercial duck industry. In this study, we performed a genome-wide association study for feeding and bone traits in a population of 540 lean-type Pekin ducks, followed by genotyping-by-sequencing procedures. The genetic parameters of feeding and bone traits were also estimated using genomic information. In total, seventy-eight significant SNPs were determined, and eleven of them reached the genome-wide significant level for 7 traits except for body weight at 42-day old. A peak of genome-wide significant SNPs was detected on chromosome 2 for feed conversion ratio (P-value = 7.46E-11), and the top SNP (P-value = 2.23E-08) for bone-breaking strength was also obtained in the upstream of gene RAPGEF5. This study provided a list of novel markers and candidate genes associated with feeding and bone traits in Pekin ducks, which could contribute to the genetic selection in duck breeding.


Asunto(s)
Huesos , Patos/genética , Animales , Peso Corporal , Densidad Ósea , Ingestión de Alimentos/genética , Estudio de Asociación del Genoma Completo , Genotipo , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo
12.
J Craniofac Surg ; 32(2): e167-e171, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33705062

RESUMEN

ABSTRACT: The calcifying epithelial odontogenic tumor (CEOT) is a rare benign odontogenic tumor, which usually presents with distension of affected tissues. Radiologically, the lesions are often associated with an unerupted tooth and may have spot calcification shadows. The authors report a case of a CEOT in a 48-year-old male involving the right mandibular jaw bone and mentum soft tissues. The authors performed hemimandibulectomy and enucleation followed by reconstruction of the mandible using a vascularized free fibular flap through a digital surgical technique in order to restore the patient's facial symmetry and prepare the area for functional restorations. The case illustrates who the free fibular flap graft can be used for satisfactory mandibular reconstruction and restoration of the morphology and functions.


Asunto(s)
Colgajos Tisulares Libres , Neoplasias Mandibulares , Reconstrucción Mandibular , Tumores Odontogénicos , Neoplasias Cutáneas , Peroné/cirugía , Humanos , Masculino , Neoplasias Mandibulares/diagnóstico por imagen , Neoplasias Mandibulares/cirugía , Persona de Mediana Edad , Tumores Odontogénicos/diagnóstico por imagen , Tumores Odontogénicos/cirugía
13.
Environ Microbiol ; 22(1): 329-342, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31691434

RESUMEN

Thermoprofundales (Marine Benthic Group D archaea, MBG-D) is a newly proposed archaeal order and widely distributed in global marine sediment, and the members in the order may play a vital role in carbon cycling. However, the lack of pure cultures of these oeganisms has hampered the recognition of their catabolic roles. Here, by constructing high-quality metagenome-assembled genomes (MAGs) of two new subgroups of Thermoprofundales from hydrothermal sediment and predicting their catabolic pathways, we here provide genomic evidences that Thermoprofundales are capable of degrading aromatics via the phenylacetic acid (PAA) pathway. Then, the gene sequences of phenylacetyl-CoA ligase (PCL), a key enzyme for the PAA pathway, were searched in reference genomes. The widespread distribution of PCL genes among 14.9% of archaea and 75.9% of Thermoprofundales further supports the importance of the PAA pathway in archaea, particularly in Thermoprofundales where no ring-cleavage dioxygenases were found. Two PCLs from Thermoprofundales MAGs, PCLM8-3 and PCLM10-15 , were able to convert PAA to phenylacetyl-CoA (PA-CoA) in vitro, demonstrating the involvement of Thermoprofundales in aromatics degradation through PAA via CoA activation. Their acid tolerance (pH 5-7), high-optimum temperatures (60°C and 80°C), thermostability (stable at 60°C and 50°C for 48 h) and broad substrate spectra imply that Thermoprofundales are capable of transforming aromatics under extreme conditions. Together with the evidence of in situ transcriptional activities for most genes related to the aromatics pathway in Thermoprofundales, these genomic, and biochemical evidences highlight the essential role of this ubiquitous and abundant archaeal order in the carbon cycle of marine sediments.


Asunto(s)
Archaea/metabolismo , Sedimentos Geológicos/microbiología , Fenilacetatos/metabolismo , Hidrocarburos Policíclicos Aromáticos/metabolismo , Acetilcoenzima A/genética , Archaea/clasificación , Archaea/genética , Ciclo del Carbono , Coenzima A Ligasas/genética , Genómica , Respiraderos Hidrotermales/microbiología , Metagenoma
14.
J Neurol Neurosurg Psychiatry ; 91(5): 526-532, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32165373

RESUMEN

OBJECTIVE: Direct inhibition of acetylcholine receptor (AChR) function by autoantibodies (Abs) is considered a rare pathogenic mechanism in myasthenia gravis (MG), but is usually studied on AChRs expressed in cell lines, rather than tightly clustered by the intracellular scaffolding protein, rapsyn, as at the intact neuromuscular junction. We hypothesised that clustered AChRs would provide a better target for investigating the functional effects of AChR-Abs. METHODS: Acetylcholine-induced currents were measured using whole-cell patch clamping and a fast perfusion system to assess fast (<2 min) functional effects of the serum samples. The sensitivity, specificity and rapidity of the system were first demonstrated by applying maternal AChR-Ab positive plasmas known to inhibit fetal AChR function in TE671 cells. Eleven previously untested AChR-Ab positive MG sera, 10 AChR-Ab negative MG sera and 5 healthy control sera were then applied to unclustered and rapsyn-clustered human adult AChRs in CN21 cells. RESULTS: The maternal AChR-Ab positive plasmas reduced fetal AChR currents, but not adult AChR currents, by >80% within 100 s. Only 2/11 AChR-Ab positive sera inhibited AChR currents in unclustered AChRs, but 6/11 AChR-Ab positive sera compared with none of the 10 AChR-Ab negative sera (p=0.0020) inhibited rapsyn-clustered AChR currents, and current inhibition by the AChR-Ab positive sera was greater when the AChRs were clustered (p=0.0385). None of the sera had detectable effects on desensitisation or recovery from desensitisation. CONCLUSION: These results show that antibodies can inhibit AChR function rapidly and demonstrate the importance of clustering in exploring pathogenic disease mechanisms of MG Abs.


Asunto(s)
Autoanticuerpos/inmunología , Proteínas Musculares/inmunología , Miastenia Gravis/inmunología , Receptores Colinérgicos/inmunología , Adolescente , Adulto , Anciano , Bungarotoxinas/farmacología , Línea Celular , Fenómenos Electrofisiológicos , Femenino , Fluoxetina/farmacología , Humanos , Masculino , Microscopía Fluorescente , Persona de Mediana Edad , Miastenia Gravis/etiología , Técnicas de Placa-Clamp , Receptores Colinérgicos/efectos de los fármacos , Adulto Joven
15.
Brain ; 142(12): 3713-3727, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31633155

RESUMEN

Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a ß2-adrenergic receptor agonist to their medication. The working mechanism of ß2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of ß2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the ß2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature end-plate potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment.


Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/farmacología , Albuterol/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Síndromes Miasténicos Congénitos/tratamiento farmacológico , Unión Neuromuscular/efectos de los fármacos , Bromuro de Piridostigmina/uso terapéutico , Potenciales de Acción/fisiología , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Albuterol/uso terapéutico , Animales , Inhibidores de la Colinesterasa/farmacología , Modelos Animales de Enfermedad , Humanos , Ratones , Bromuro de Piridostigmina/farmacología , Transmisión Sináptica/efectos de los fármacos
16.
J Am Chem Soc ; 141(23): 9134-9139, 2019 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-31131600

RESUMEN

The flexible organic amine cations on the interfaces of two-dimensional (2D) hybrid organic-inorganic perovskite nanosheets could form relaxed structures, which would lead to exotic optoelectronic properties but are hard to understand. Here, the unusual interfacial relaxation of nanosheets exfoliated from an orthorhombic 2D lead halide perovskite, [(C6H5CH2NH3)2]PbCl4, is interrogated via ultrafast second-harmonic generation (SHG) spectroscopy. The in-plane SHG intensity anisotropy of these nanosheets is found to decrease with reducing layer thickness. Combined first-principles calculations and Monte Carlo simulations reveal that the induced second-order polarization arises primarily from the (C6H5CH2NH3)+ cations; and these organic amine cations form significantly reorganized conformations with decreasing nanosheet thickness due to weakened van der Waals interactions. Because the orientations of organic components at the interface determine their electric properties and specifically the dipolar susceptibility, the resulting structure leads to striking changes in the SHG properties.

17.
Connect Tissue Res ; 60(4): 323-334, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30277081

RESUMEN

Purpose: Our previous studies indicate that phorbol 12-myristate 13-acetate (PMA)-treated U937 cells cultured on collagen I-coated dishes express lowered production of pro-inflammatory mediators in parallel through reduced reactive oxygen species (ROS) levels. By contrast, PMA-treated U937 cells on gelatin, the denatured collagen, show enhanced production of pro-inflammatory mediators, mediated by up-regulating autophagy levels. The present study is aimed to investigate the effect of ROS levels in PMA-treated U937 cells cultured on gelatin-coated surface. Material and methods: MTT assay, flow cytometric analysis of ROS and autophagy, biochemical detection of antioxidant levels, enzyme-linked immunosorbent assay, and western blot were used. Results: Gelatin-coating increased ROS levels in PMA-treated U937 cells. Increased ROS levels are involved in the regulation of cell aggregation and the release of pro-inflammatory mediators in gelatin-coated culture. These results lead to the query about the crosstalk between the two positive regulators, the autophagy and ROS. Autophagy induction is attenuated by N-acetyl-L-cysteine treatment, but the treatment with autophagy inhibitor, 3-methyladenine, does not affect ROS levels, suggesting ROS are upstream of autophagy in the regulation axis of differentiated U937 cells on gelatin-coated surface. Further study confirmed that upregulation of autophagy was responsible for ROS-induced cell aggregation and production of pro-inflammatory mediators. Conclusion: The results suggest that gelatin-coating promotes the aggregation of PMA-treated U937 cells and the production of pro-inflammatory mediators by ROS-autophagy signaling pathway.


Asunto(s)
Autofagia/efectos de los fármacos , Gelatina/química , Mediadores de Inflamación/metabolismo , Ésteres del Forbol/farmacología , Especies Reactivas de Oxígeno/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Animales , Agregación Celular/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Dinoprostona/metabolismo , Humanos , Interleucina-1beta/metabolismo , Modelos Biológicos , Transducción de Señal/efectos de los fármacos , Porcinos , Factor de Necrosis Tumoral alfa/metabolismo , Células U937
18.
Zhongguo Zhong Yao Za Zhi ; 44(19): 4129-4133, 2019 Oct.
Artículo en Zh | MEDLINE | ID: mdl-31872689

RESUMEN

Traditional Chinese medicine is planted in mountainous areas with suitable natural conditions. The planting area is complex in terrain,and the planting plots are mostly irregularly shaped. It is difficult to accurately calculate the planting area by traditional survey methods. The method of extracting Chinese herbal medicine planting area combined with remote sensing and GIS technology is of great significance for the rational development and utilization of traditional Chinese medicine resources. Taking Bletilla striata planting in Ningshan county of Shaanxi province as an example,the extraction method of planting area of traditional Chinese medicine in county was studied. High-resolution ZY-3 and GF-1 multi-spectral multi-temporal remote sensing images were used as data sources. Through field sampling,samples such as B. striata,cultivated land,forest land,water body,artificial surface,alpine meadow,etc. are collected. The spectral features,texture features and shape features of remotely identifiable objects in different planting areas and cultivated land,vegetable sheds were analyzed,confusing ground objects were eliminated and interpretation marks were establish. The method of visual interpretation is used to realize the extraction of B. striata planting areas,and the B. striata planting area are calculated by combining GIS technology. The results showed that the method of visual interpretation,using high-resolution ZY-3 and GF-1 multi-spectral multi-temporal remote sensing image data extracted the planting area of 403.05 mu. It can effectively extract the B. striata planting area in research region.


Asunto(s)
Medicina Tradicional China , Orchidaceae , Tecnología de Sensores Remotos , Bosques
19.
Phys Chem Chem Phys ; 20(38): 25016-25022, 2018 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-30246198

RESUMEN

Extensive first principles calculations were performed to study the structural and electrochemical features of Co3O4 during its lithiation process as an anode material for lithium-ion batteries (LIBs). We found that with up to 8 mol Li in Co3O4, the formed LinCo3O4 structures are stable for low Li concentrations of n ≤ 1, but obvious structure distortions and volume expansions occur for LinCo3O4 with n > 1. This may be the reason why Co3O4 has a high Li capability but low cycling life as a LIB anode. The ab initio molecular dynamics simulations for LinCo3O4 (n = 2, 4, 8) further suggest a two-step electrochemistry process of Co3O4 → CoO → Co upon the lithiation process. We detected a distorted surface structure as Li atoms react with the Co3O4(110) surface, which also reduces the rate capability of the Co3O4 anode.

20.
Connect Tissue Res ; 58(5): 456-463, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27764545

RESUMEN

PURPOSE: Type I collagen is one of the most abundant components of extracellular matrix. We previously illustrated that murine fibrosarcoma L929 cells grew well on type I collagen gel and escaped from TNFα-induced cell death. In this study, we investigated the mechanism underlying the protective effect of collagen gel. MATERIAL AND METHODS: We used western blot, confocal microscopy, MTT assay and flow cytometry by introducing fluorescence staining to determine the expression levels of nuclear factor kappa B (NF-κB), inhibitory ratio and autophagy. RESULTS: L929 cells on collagen gel showed higher expression of NF-κB in the nucleus. Inhibition of NF-κB with pyrrolidine dithiocarbamate hydrochloride (PDTC) or knockdown by NF-κB-siRNA canceled the protective effect of collagen gel on L929 cells from TNFα-induced death, suggesting for the role of NF-κB in the protection from cell death. We found a new aspect of the effect of PDTC on L929 cells cultured on collagen gel. PDTC alone without TNFα induced apoptosis in the L929 cells cultured on collagen gel but not the cells on plastic dish. The apoptosis induction of the L929 cells cultured on collagen gel with PDTC was repressed by inhibiting autophagy with chloroquine, an autophagy inhibitor, suggesting that autophagy contributes to the death induced by the treatment with PDTC. Possible underlying mechanism of this finding is discussed. CONCLUSION: NF-κB played an important role in protecting the L929 cells cultured on collagen gel from TNFα-induced death.


Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Colágeno Tipo I , Hidrogeles , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Animales , Línea Celular , Colágeno Tipo I/química , Colágeno Tipo I/farmacología , Hidrogeles/química , Hidrogeles/farmacología , Ratones , Prolina/análogos & derivados , Prolina/farmacología , Tiocarbamatos/farmacología
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