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1.
Brief Bioinform ; 24(2)2023 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-36907650

RESUMEN

Proteomic studies characterize the protein composition of complex biological samples. Despite recent advancements in mass spectrometry instrumentation and computational tools, low proteome coverage and interpretability remains a challenge. To address this, we developed Proteome Support Vector Enrichment (PROSE), a fast, scalable and lightweight pipeline for scoring proteins based on orthogonal gene co-expression network matrices. PROSE utilizes simple protein lists as input, generating a standard enrichment score for all proteins, including undetected ones. In our benchmark with 7 other candidate prioritization techniques, PROSE shows high accuracy in missing protein prediction, with scores correlating strongly to corresponding gene expression data. As a further proof-of-concept, we applied PROSE to a reanalysis of the Cancer Cell Line Encyclopedia proteomics dataset, where it captures key phenotypic features, including gene dependency. We lastly demonstrated its applicability on a breast cancer clinical dataset, showing clustering by annotated molecular subtype and identification of putative drivers of triple-negative breast cancer. PROSE is available as a user-friendly Python module from https://github.com/bwbio/PROSE.


Asunto(s)
Proteoma , Proteómica , Proteómica/métodos , Proteoma/análisis
2.
Brief Bioinform ; 24(4)2023 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-37419612

RESUMEN

Missing values (MVs) can adversely impact data analysis and machine-learning model development. We propose a novel mixed-model method for missing value imputation (MVI). This method, ProJect (short for Protein inJection), is a powerful and meaningful improvement over existing MVI methods such as Bayesian principal component analysis (PCA), probabilistic PCA, local least squares and quantile regression imputation of left-censored data. We rigorously tested ProJect on various high-throughput data types, including genomics and mass spectrometry (MS)-based proteomics. Specifically, we utilized renal cancer (RC) data acquired using DIA-SWATH, ovarian cancer (OC) data acquired using DIA-MS, bladder (BladderBatch) and glioblastoma (GBM) microarray gene expression dataset. Our results demonstrate that ProJect consistently performs better than other referenced MVI methods. It achieves the lowest normalized root mean square error (on average, scoring 45.92% less error in RC_C, 27.37% in RC_full, 29.22% in OC, 23.65% in BladderBatch and 20.20% in GBM relative to the closest competing method) and the Procrustes sum of squared error (Procrustes SS) (exhibits 79.71% less error in RC_C, 38.36% in RC full, 18.13% in OC, 74.74% in BladderBatch and 30.79% in GBM compared to the next best method). ProJect also leads with the highest correlation coefficient among all types of MV combinations (0.64% higher in RC_C, 0.24% in RC full, 0.55% in OC, 0.39% in BladderBatch and 0.27% in GBM versus the second-best performing method). ProJect's key strength is its ability to handle different types of MVs commonly found in real-world data. Unlike most MVI methods that are designed to handle only one type of MV, ProJect employs a decision-making algorithm that first determines if an MV is missing at random or missing not at random. It then employs targeted imputation strategies for each MV type, resulting in more accurate and reliable imputation outcomes. An R implementation of ProJect is available at https://github.com/miaomiao6606/ProJect.


Asunto(s)
Algoritmos , Genómica , Teorema de Bayes , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Espectrometría de Masas/métodos
3.
Rev Med Virol ; 34(1): e2495, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38017632

RESUMEN

With the popularity of Coronavirus disease 2019 (COVID-19) vaccine and the development of vaccination strategies, the impact of COVID-19 vaccine on cancer patients receiving immune checkpoint inhibitors (ICIs) is still unclear. In the systematic review and meta-analysis of patients with ICIs, we assessed the serological response of cancer patients receiving COVID-19 vaccine, and explored the risk of immune related adverse events (irAEs). We searched PubMed, EMBASE and Cochrane Library as of 10 June 2023, and included cancer patients who received ICIs and COVID-19 vaccine. The systematic review and meta-analysis include cohort study, cross-sectional study and case report. The outcome included the serological response, Spike-specific T-cell response, irAEs and rare adverse events. When possible, the data were analysed by random effect analysis, and the statistical heterogeneity was assessed by Q-test and I2 statistics. We explored the sources of heterogeneity through L'Abbe plots, Galbraith radial plots, and sensitivity analysis. The publication bias was evaluated by Egger's, Begg's linear regression test and funnel plot, and the impact of publication bias was further analysed by trim and fill method. 27 studies were eligible (19 cohort studies, 1 cross-sectional study and 7 case reports), involving 8331 patients (with 4724 receiving ICIs). Most studies used mRNA vaccine (BNT162b2 or mRNA-1273). Compared with cancer patients receiving chemotherapy, cancer patients receiving ICIs were significantly more likely to have seroconversion (RR = 1.05, 95%CI 1.01-1.10, P = 0.02). There were no statistically significant differences in seroconversion rates when comparing cancer patients receiving ICIs with controls without cancer (RR = 0.95, 95% CI 0.89-1.01, P = 0.09) or with cancer patients receiving targeted therapy (RR = 1.05, 95% CI 0.79-1.39, P = 0.75). The incidence of irAEs in patients receiving ICIs before and after COVID-19 vaccination was (21.96%, 95%CI 16.66%-28.94%) and (14.88%, 95%CI 8.65%-25.57%), respectively. The most common irAEs were endocrine abnormalities, skin disorders, etc. The certainty of evidence was low in cancer patients with ICIs, compared with those receiving chemotherapy, and very low versus controls without cancer. Cancer patients treated with ICIs seem to be able to receive COVID-19 vaccine safely without increasing the incidence of irAEs.


Asunto(s)
COVID-19 , Neoplasias , Humanos , Vacuna BNT162 , Estudios de Cohortes , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Estudios Transversales , Inhibidores de Puntos de Control Inmunológico , Neoplasias/tratamiento farmacológico
4.
Proteomics ; 24(1-2): e2200332, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37876146

RESUMEN

This article summarizes the PROTREC method and investigates the impact that the different hyper-parameters have on the task of missing protein prediction using PROTREC. We evaluate missing protein recovery rates using different PROTREC score selection approaches (MAX, MIN, MEDIAN, and MEAN), different PROTREC score thresholds, as well as different complex size thresholds. In addition, we included two additional cancer datasets in our analysis and introduced a new validation method to check both the robustness of the PROTREC method as well as the correctness of our analysis. Our analysis showed that the missing protein recovery rate can be improved by adopting PROTREC score selection operations of MIN, MEDIAN, and MEAN instead of the default MAX. However, this may come at a cost of reduced numbers of proteins predicted and validated. The users should therefore choose their hyper-parameters carefully to find a balance in the accuracy-quantity trade-off. We also explored the possibility of combining PROTREC with a p-value-based method (FCS) and demonstrated that PROTREC is able to perform well independently without any help from a p-value-based method. Furthermore, we conducted a downstream enrichment analysis to understand the biological pathways and protein networks within the cancerous tissues using the recovered proteins. Missing protein recovery rate using PROTREC can be improved by selecting a different PROTREC score selection method. Different PROTREC score selection methods and other hyper-parameters such as PROTREC score threshold and complex size threshold introduce accuracy-quantity trade-off. PROTREC is able to perform well independently of any filtering using a p-value-based method. Verification of the PROTREC method on additional cancer datasets. Downstream Enrichment Analysis to understand the biological pathways and protein networks in cancerous tissues.


Asunto(s)
Algoritmos , Neoplasias , Humanos
5.
Nature ; 553(7687): 217-221, 2018 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-29258297

RESUMEN

Although genetic factors contribute to almost half of all cases of deafness, treatment options for genetic deafness are limited. We developed a genome-editing approach to target a dominantly inherited form of genetic deafness. Here we show that cationic lipid-mediated in vivo delivery of Cas9-guide RNA complexes can ameliorate hearing loss in a mouse model of human genetic deafness. We designed and validated, both in vitro and in primary fibroblasts, genome editing agents that preferentially disrupt the dominant deafness-associated allele in the Tmc1 (transmembrane channel-like gene family 1) Beethoven (Bth) mouse model, even though the mutant Tmc1Bth allele differs from the wild-type allele at only a single base pair. Injection of Cas9-guide RNA-lipid complexes targeting the Tmc1Bth allele into the cochlea of neonatal Tmc1Bth/+ mice substantially reduced progressive hearing loss. We observed higher hair cell survival rates and lower auditory brainstem response thresholds in injected ears than in uninjected ears or ears injected with control complexes that targeted an unrelated gene. Enhanced acoustic startle responses were observed among injected compared to uninjected Tmc1Bth/+ mice. These findings suggest that protein-RNA complex delivery of target gene-disrupting agents in vivo is a potential strategy for the treatment of some types of autosomal-dominant hearing loss.


Asunto(s)
Proteínas Asociadas a CRISPR/administración & dosificación , Edición Génica/métodos , Genes Dominantes/genética , Terapia Genética/métodos , Pérdida Auditiva/genética , Estimulación Acústica , Alelos , Animales , Animales Recién Nacidos , Umbral Auditivo , Secuencia de Bases , Proteínas Asociadas a CRISPR/metabolismo , Proteínas Asociadas a CRISPR/uso terapéutico , Sistemas CRISPR-Cas , Supervivencia Celular , Cóclea/citología , Cóclea/metabolismo , Modelos Animales de Enfermedad , Potenciales Evocados Auditivos del Tronco Encefálico , Femenino , Fibroblastos , Células Ciliadas Auditivas/citología , Pérdida Auditiva/fisiopatología , Pérdida Auditiva/prevención & control , Humanos , Liposomas , Masculino , Proteínas de la Membrana/genética , Ratones , Reflejo de Sobresalto
6.
Proc Natl Acad Sci U S A ; 118(19)2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33941687

RESUMEN

Here, we present a physiologically relevant model of the human pulmonary alveoli. This alveolar lung-on-a-chip platform is composed of a three-dimensional porous hydrogel made of gelatin methacryloyl with an inverse opal structure, bonded to a compartmentalized polydimethylsiloxane chip. The inverse opal hydrogel structure features well-defined, interconnected pores with high similarity to human alveolar sacs. By populating the sacs with primary human alveolar epithelial cells, functional epithelial monolayers are readily formed. Cyclic strain is integrated into the device to allow biomimetic breathing events of the alveolar lung, which, in addition, makes it possible to investigate pathological effects such as those incurred by cigarette smoking and severe acute respiratory syndrome coronavirus 2 pseudoviral infection. Our study demonstrates a unique method for reconstitution of the functional human pulmonary alveoli in vitro, which is anticipated to pave the way for investigating relevant physiological and pathological events in the human distal lung.


Asunto(s)
Dispositivos Laboratorio en un Chip , Modelos Biológicos , Alveolos Pulmonares/fisiología , Células Epiteliales Alveolares , Antivirales/farmacología , Fumar Cigarrillos/efectos adversos , Dimetilpolisiloxanos/química , Gelatina/química , Humanos , Hidrogeles/química , Metacrilatos/química , Porosidad , Alveolos Pulmonares/citología , Alveolos Pulmonares/patología , Respiración , Mucosa Respiratoria/citología , Mucosa Respiratoria/fisiología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/patogenicidad
7.
Int J Mol Sci ; 25(8)2024 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-38674126

RESUMEN

Toona ciliata, also known as Chinese mahogany, is a high-quality and fast-growing wood species with a high economic value. The wood properties of T. ciliata of different provenances vary significantly. In this study, we conducted comprehensive transcriptome and metabolome analyses of red and non-red T. ciliata wood cores of different provenances to compare their wood properties and explore the differential metabolites and genes that govern the variation in their wood properties. Through combined analyses, three differential genes and two metabolites were identified that are possibly related to lignin synthesis. The lignin content in wood cores from T. ciliata of different provenances shows significant variation following systematic measurement and comparisons. The gene Tci09G002190, one of the three differential genes, was identified as a member of the CAD (Cinnamyl alcohol dehydrogenase) gene family of T. ciliata, which is associated with lignin synthesis. Our data provide insights into the determinants of the wood properties in T. ciliata, providing a solid foundation for research into the subsequent mechanisms of the formation of T. ciliata wood.


Asunto(s)
Regulación de la Expresión Génica de las Plantas , Lignina , Metaboloma , Transcriptoma , Madera , Madera/metabolismo , Madera/genética , Lignina/biosíntesis , Lignina/metabolismo , Perfilación de la Expresión Génica/métodos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Oxidorreductasas de Alcohol/genética , Oxidorreductasas de Alcohol/metabolismo
8.
Ear Hear ; 44(5): 1212-1220, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37046369

RESUMEN

OBJECTIVES: The oldest-old (aged ≥80 years) are the most rapidly growing population and age is related to hearing impairment (HI) and cognitive decline. We aimed to estimate the association between HI and fall, and the effect of different cognitive states on this association among the oldest-old Chinese population. DESIGN: A total of 6931 Chinese oldest-old were included in the 2018 cross-cohort from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). The presence of HI was identified by using a dichotomized metric of self-reported hearing status. Cognitive function was evaluated by using the modified Mini-Mental State Examination (MMSE). Cognitive impairment was defined as the MMSE score below 24 points. Data on fall history were collected by questionnaires survey from the participants or their relatives. We studied the association of hearing status and cognitive function with fall by using multivariable logistic regressions, upon adjustment of sociodemographic characteristics, lifestyles, and health conditions. RESULTS: Our participants were aged 92 (range 80 to 117) on average, with 60.1% being women. In total, 39.1% of the participants had reported HI, 50.1% had cognitive impairment, and 26.2% had a history of falling. Participants with HI had a higher incidence of cognitive impairment (79.4%), as compared with their counterparts without HI (31.3%). Compared with those without HI, HI patients had a higher risk of falling after full adjustment for potential confounders (OR = 1.16 [95% confidence interval, CI, 1.01, 1.32], p = 0.031). In comparison with HI participants without cognitive impairment, HI patients with cognitive impairment had a higher fall risk (OR = 1.45 [95% CI = 1.23, 1.72], p < 0.001). CONCLUSIONS: Association of hearing status and cognition with fall was, for the first time, examined on the basis of a nationally-representative oldest-old Chinese population. Poor cognitive performance was common in individuals with HI, and those with HI and cognitive impairment further increased the risk of falling.


Asunto(s)
Accidentes por Caídas , Disfunción Cognitiva , Pérdida Auditiva , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Accidentes por Caídas/prevención & control , Accidentes por Caídas/estadística & datos numéricos , China/epidemiología , Cognición , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/diagnóstico , Estudios de Cohortes , Pueblos del Este de Asia , Audición , Pérdida Auditiva/diagnóstico , Pérdida Auditiva/epidemiología
9.
BMC Public Health ; 23(1): 2462, 2023 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-38066478

RESUMEN

BACKGROUND: With rapid urban sprawl, growing people are living in the vicinity of major roadways. However, little is known about the relationship between residential proximity to major roadways and hearing impairment (HI). METHODS: We derived data from the 2018 wave of the Chinese Longitudinal Healthy Longevity Survey, and included 13,775 participants aged 65 years or older. Multivariate logistic regressions were employed to examine the association between residential proximity to major roadways and HI. The effects of corresponding potentially modifiable factors were studied by three-way interaction analyses. Sensitivity analyses were performed to verify the robustness of the results. RESULTS: The prevalence of HI was 38.3%. Participants living near major roadways were more likely to have a higher socioeconomic status. An exposure-response relation between residential proximity to major roadways and HI was observed (Ptrend < 0.05). Compared with individuals living > 300 m away from major roadways, the adjusted odds ratios (OR) were 1.07 (95% CI: 0.96-1.24), 1.15 (95% CI: 1.07-1.34), and 1.12 (95% CI: 1.01-1.31) for those living 101-200 m, 50-100 m, and < 50 m away from the roadways, respectively. Particularly, the association was more pronounced among individuals exposed to carbon monoxide (CO) pollution or opening windows frequently (Pinteraction < 0.05). Three-way interaction analyses confirmed that participants exposed to CO pollution and frequently leaving windows open had the highest OR of 1.73 (95% CI: 1.58-1.89). CONCLUSIONS: This nation-wide cohort study suggested that residential proximity to major roadways was significantly associated with an increased exposure-response risk of HI in Chinese older adults. Exposure to CO pollution and opening windows frequently might strengthen the relations.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Pérdida Auditiva , Humanos , Anciano , Estudios de Cohortes , Emisiones de Vehículos/análisis , Características de la Residencia , Pérdida Auditiva/epidemiología , China/epidemiología , Exposición a Riesgos Ambientales/efectos adversos , Contaminantes Atmosféricos/análisis
10.
Proteomics ; 22(23-24): e2200092, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36349819

RESUMEN

Proteomics data are often plagued with missingness issues. These missing values (MVs) threaten the integrity of subsequent statistical analyses by reduction of statistical power, introduction of bias, and failure to represent the true sample. Over the years, several categories of missing value imputation (MVI) methods have been developed and adapted for proteomics data. These MVI methods perform their tasks based on different prior assumptions (e.g., data is normally or independently distributed) and operating principles (e.g., the algorithm is built to address random missingness only), resulting in varying levels of performance even when dealing with the same dataset. Thus, to achieve a satisfactory outcome, a suitable MVI method must be selected. To guide decision making on suitable MVI method, we provide a decision chart which facilitates strategic considerations on datasets presenting different characteristics. We also bring attention to other issues that can impact proper MVI such as the presence of confounders (e.g., batch effects) which can influence MVI performance. Thus, these too, should be considered during or before MVI.


Asunto(s)
Algoritmos , Proteómica
11.
Methods ; 190: 72-79, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-32278014

RESUMEN

Lymphatic vessels, as a means to metastasize, are frequently recruited by tumor tissues during their progression. However, reliable in vitro models to dissect the intricate crosstalk between lymphatic vessels and tumors are still in urgent demand. Here, we describe a tissue-engineering method based on sacrificial bioprinting, to develop an enabling model of the human breast tumor with embedded multiscale lymphatic vessels, which is compatible with existing microscopy to examine the processes of lymphatic vessel sprouting and breast tumor cell migration in a physiologically relevant volumetric microenvironment. This platform will potentially help shed light on the complex biology of the tumor microenvironment, tumor lymphangiogenesis, lymphatic metastasis, as well as tumor anti-lymphangiogenic therapy in the future. We further anticipate wide adoption of the method to the production of various tissues and their models with incorporation of lymphatics vessels towards relevant applications.


Asunto(s)
Neoplasias de la Mama , Linfangiogénesis , Vasos Linfáticos , Mama , Células Endoteliales , Femenino , Humanos , Vasos Linfáticos/diagnóstico por imagen , Microambiente Tumoral
12.
Int J Mol Sci ; 23(21)2022 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-36362134

RESUMEN

Different serum thyroxine levels may influence the morphology of the inner ear during development. A well-developed organ of Corti (OC) is considered to be critical to the function of hearing. In our study, we treated mice with triiodothyronine (T3) and found that the opening of the OC occurred sooner than in control mice. We also observed an increased formation of acetylated microtubules and a decrease in the adhesion junction molecule P-cadherin the during opening of the OC. Our investigation indicates that thyroxin affects P-cadherin expression and microtubule acetylation to influence the opening of the OC.


Asunto(s)
Oído Interno , Tiroxina , Ratones , Animales , Tiroxina/farmacología , Tiroxina/metabolismo , Microtúbulos/metabolismo , Órgano Espiral/metabolismo , Cadherinas/genética , Cadherinas/metabolismo
13.
Carcinogenesis ; 42(11): 1337-1346, 2021 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-34643214

RESUMEN

Genetic alterations in the cell cycle pathway are common in head and neck squamous cell carcinoma (HNSCC). We identified four novel HNSCC susceptibility loci (CDKN1C rs452338, CDK4 rs2072052, E2F2 rs3820028 and E2F2 rs2075993) through a two-stage matched case-control study. There was a combined effect among the four single nucleotide polymorphisms (SNPs), as the number of risk genotypes increased, the risk of HNSCC displayed an increasing trend (Ptrend < 0.001). And there were multiplicative interactions between rs452338 and rs2072052, rs2072052 and rs3820028, rs2072052 and rs2075993. Functional bioinformatics analysis and dual-luciferase reporter assay revealed that E2F2 rs2075993 T>C reduced the stability of E2F2 3'-UTR secondary structure and affected the binding of E2F2 to miR-940, which was up-regulated in HNSCC tumor tissues (P = 2.9e-8) and was correlated with poor overall survival of HNSCC (HR = 1.39, 95% CI = 1.02-1.90). In vitro assays, we discovered that the expression of miR-940 was regulated by METTL3, and miR-940 promoted the proliferation, migration and invasion, and inhibited the senescence and autophagy of tumor cells. In terms of mechanism, compared with rs2075993 allele T, we found that the protective variant rs2075993 allele C interfered with the translational inhibition of E2F2 by miR-940, resulting in increased expression of E2F2 protein, which further reduced the proliferation, migration, invasion, and increased the senescence of tumor cells.


Asunto(s)
Genes cdc , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Regiones no Traducidas 3' , Estudios de Casos y Controles , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , China , Factor de Transcripción E2F2/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Metiltransferasas/genética , MicroARNs/metabolismo , Invasividad Neoplásica/genética , Polimorfismo de Nucleótido Simple , Unión Proteica , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
14.
Exp Cell Res ; 394(1): 112093, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32450067

RESUMEN

Regulating proteasome activity is a potent therapeutic aspect of age-related hearing loss, which has been proven to protect neurons from age-related damaging. PSMD11, subunit of the 19S proteasome regulatory particle, is known to mainly up-regulate proteasome activity and prolong aging. However, the mechanism of PSMD11 in age-related hearing loss has not been deeply explored. In the present study, we explore the function and mechanism of PSMD11 protecting neurons in d-Galactose (D-Gal) mimetic aging models. Age-related pathologies were detected by Taq-PCR, ABR, Transmission electron microscopy, toluidine blue and ß-galactosidase staining. The relative expressions of the proteins were explored by Western blotting, oxyblot, immunoprecipitation and immunofluorescence. Flow cytometry was used to manifest the oxidative state. We discovered that proteasome activity was impaired with aging, and that ROS and toxic protein accumulated in D-Gal induced aging models. PSMD11 changed with aging, and was associated with the metabolism of proteasome activity in the D-Gal treated models. Moreover, the knockdown or overexpression of PSMD11 was sufficient to change the oxidative state caused by D-Gal. Our results also demonstrated that PSMD11 could bond to AMPKα1/2 in the auditory cortex and PC12 cells, and AMPKα2 but not AMPKα1 was efficient to regulate the function of PSMD11. Deeper insights into the mechanisms of regulating PSMD11 for the anti-aging process are needed, and may offer novel therapeutic methods for central presbycusis.


Asunto(s)
Envejecimiento/metabolismo , Galactosa/metabolismo , Galactosa/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Corteza Auditiva/metabolismo , Corteza Auditiva/patología , Citoplasma/metabolismo , ADN Mitocondrial/metabolismo , Masculino , Estrés Oxidativo/fisiología , Presbiacusia/metabolismo , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Ratas Wistar
15.
Bioorg Chem ; 115: 105196, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34333425

RESUMEN

So far, there is still no specific drug against COVID-19. Taking compound 1 with anti-EBOV activity as the lead, fifty-four 12N-substituted aloperine derivatives were synthesized and evaluated for the anti-SARS-CoV-2 activities using pseudotyped virus model. Among them, 8a exhibited the most potential effects against both pseudotyped and authentic SARS-CoV-2, as well as SARS-CoV and MERS-CoV, indicating a broad-spectrum anti-coronavirus profile. The mechanism study disclosed that 8a might block a late stage of viral entry, mainly via inhibiting host cathepsin B activity rather than directly targeting cathepsin B protein. Also, 8a could significantly reduce the release of multiple inflammatory cytokines in a time- and dose-dependent manner, such as IL-6, IL-1ß, IL-8 and MCP-1, the major contributors to cytokine storm. Therefore, 8a is a promising agent with the advantages of broad-spectrum anti-coronavirus and anti-cytokine effects, thus worthy of further investigation.


Asunto(s)
Antivirales/farmacología , Piperidinas/farmacología , Quinolizidinas/farmacología , SARS-CoV-2/efectos de los fármacos , Internalización del Virus/efectos de los fármacos , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Antivirales/toxicidad , Catepsina B/antagonistas & inhibidores , Chlorocebus aethiops , Citocinas/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/farmacocinética , Piperidinas/toxicidad , Quinolizidinas/síntesis química , Quinolizidinas/farmacocinética , Quinolizidinas/toxicidad , Ratas Sprague-Dawley , Relación Estructura-Actividad , Células Vero
16.
Neural Plast ; 2021: 9957712, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34093702

RESUMEN

Congenital deafness is one of the most common causes of disability in humans, and more than half of cases are caused by genetic factors. Mutations of the MYO15A gene are the third most common cause of hereditary hearing loss. Using next-generation sequencing combined with auditory tests, two novel compound heterozygous variants c.2802_2812del/c.5681T>C and c.5681T>C/c.6340G>A in the MYO15A gene were identified in probands from two irrelevant Chinese families. Auditory phenotypes of the probands are consistent with the previously reported for recessive variants in the MYO15A gene. The two novel variants, c.2802_2812del and c.5681T>C, were identified as deleterious mutations by bioinformatics analysis. Our findings extend the MYO15A gene mutation spectrum and provide more information for rapid and precise molecular diagnosis of congenital deafness.


Asunto(s)
Sordera/genética , Miosinas/genética , Adolescente , Pueblo Asiatico , Niño , Preescolar , Biología Computacional , Sordera/congénito , Sordera/diagnóstico por imagen , Femenino , Genes Recesivos , Pruebas Genéticas , Pruebas Auditivas , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Mutación/genética , Linaje , Fenotipo , Tomografía Computarizada por Rayos X
17.
Neural Plast ; 2020: 9260807, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32908492

RESUMEN

Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss. It is responsible for 2-5% of congenital deafness. WS is classified into four types depending on the clinical phenotypes. Currently, pathogenic mutation of PAX3, MITF, EDNRB, EDN3, SNAI2, or SOX10 can cause corresponding types of WS. Among them, SOX10 mutation is responsible for approximately 15% of type II WS or 50% of type IV WS. We report the case of a proband in a Chinese family who was diagnosed with WS type II. Whole exome sequencing (WES) of the proband detected a novel heterozygous spontaneous mutation: SOX10 c.246delC. According to analysis based on nucleic acid and amino acid sequences, this mutation may produce a truncated protein, with loss of the HMG structure domain. Therefore, this truncated protein may fail to activate the expression of the MITF gene, which regulates melanocytic development and plays a key role in WS. Our finding expands the database of SOX10 mutations associated with WS and provides more information regarding the molecular mechanism of WS.


Asunto(s)
Mutación , Factores de Transcripción SOXE/genética , Síndrome de Waardenburg/genética , Pueblo Asiatico/genética , Niño , China , Humanos , Masculino , Linaje , Secuenciación del Exoma
18.
Neural Plast ; 2020: 3569359, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32508908

RESUMEN

Jervell and Lange-Nielsen syndrome (JLNS) is a rare but severe autosomal recessive disease characterized by profound congenital deafness and a prolonged QTc interval (greater than 500 milliseconds) in the ECG waveforms. The prevalence of JLNS is about 1/1000000 to 1/200000 around the world. However, exceed 25% of JLNS patients suffered sudden cardiac death with kinds of triggers containing anesthesia. Approximately 90% of JLNS cases are caused by KCNQ1 gene mutations. Here, using next-generation sequencing (NGS), we identified a compound heterozygosity for two mutations c.1741A>T (novel) and c.477+5G>A (known) in KCNQ1 gene as the possible pathogenic cause of JLNS, which suggested a high risk of cardiac events in a deaf child. The hearing of this patient improved significantly with the help of cochlear implantation (CI). But life-threatening arrhythmias occurred with a trigger of anesthesia after the end of the CI surgery. Our findings extend the KCNQ1 gene mutation spectrum and contribute to the management of deaf children diagnosed with JLNS for otolaryngologists (especially cochlear implant teams).


Asunto(s)
Síndrome de Jervell-Lange Nielsen/genética , Canal de Potasio KCNQ1/genética , Mutación , Pueblo Asiatico , Preescolar , China , Análisis Mutacional de ADN , Sordera/genética , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndrome de Jervell-Lange Nielsen/fisiopatología , Masculino , Linaje
19.
Int J Med Sci ; 16(12): 1631-1641, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31839751

RESUMEN

Epithelial-mesenchymal transition (EMT) has been reported to occur in eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP). Among the cytokines that cause EMT, high mobility group box 1 (HMGB1) has been shown to give rise to EMT in airway epithelial cells. However, the mechanism of HMGB1-induced EMT in ECRSwNP is unknown. We explored the mechanism and possible inhibitor. Immunohistochemistry (IHC), immunofluorescence (IF), and western blot assay were used to detect the expression and location of HMGB1, peroxisome proliferator-activated receptor-γ (PPAR-γ), and EMT markers in eighteen ECRSwNP and twelve normal nasal mucosa tissues. Epithelial cells isolated from ECRSwNP were cultured with various doses of recombinant human HMGB1 (rhHMGB1) to study the expression of PPAR-γ, and EMT markers. Additionally, the ligand of PPAR-γ was incubated with epithelial cells to interfere with the effects of lipopolysaccharide (LPS) or rhHMGB1 to explore the effect on expression of HMGB1 and EMT markers. These results suggest that HMGB1 was highly expressed in ECRSwNP compared with its expression in control tissues, and EMT was also found highly in ECRSwNP compared with control tissues. Moreover, the cytoplasmic accumulation of HMGB1 in ECRSwNP was obvious compared with normal tissues. We also found dose-dependent induction by rhHMGB1 of up-regulation of N-cadherin and vimentin and down-regulation of ZO-1 and E-cadherin in epithelial cells isolated from ECRSwNP. The agonist of PPAR-γ not only reduced release of HMGB1 induced by LPS, but also reversed the EMT. The protective role of PPAR-γ also appeared in cells that had been incubated with rhHMGB1. In the current study, we discovered that the agonist of PPAR-γ has a potential role in inhibited HMGB1-induced EMT in ECRSwNP. The agonist of PPAR-γ may contribute to inhabit epithelial cells to become mesenchymal-like cells which play an important role in the pathogenesis of ECRSwNP.


Asunto(s)
Proteína HMGB1/genética , Pólipos Nasales/genética , PPAR gamma/genética , Rinitis/genética , Sinusitis/genética , Cadherinas/genética , Células Epiteliales/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Regulación de la Expresión Génica/efectos de los fármacos , Proteína HMGB1/farmacología , Humanos , Ligandos , FN-kappa B/genética , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/patología , Pólipos Nasales/complicaciones , PPAR gamma/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Rinitis/complicaciones , Rinitis/patología , Transducción de Señal/efectos de los fármacos , Sinusitis/complicaciones , Sinusitis/patología , Vimentina/genética , Proteína de la Zonula Occludens-1/genética
20.
Adv Exp Med Biol ; 1130: 59-71, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30915701

RESUMEN

Presbycusis is a sensorineural hearing loss caused by hearing system aging and degeneration. The clinical manifestations are progressive bilateral symmetrical hearing loss, and the hearing curve is mostly slope-shaped with high-frequency reduction, sometimes flat. The results of the second national sample survey of disabled persons (2006) showed that the total number of hearing and speech disability in China was 27.8 million, accounting for 34% of the total number of disabled people in China. Among them are people over 60 years old. There are 20.4541 million people with hearing disabilities. There are 9.49 million senile deaf patients, accounting for 34.1% of the total number of hearing disabilities. As society gradually becomes aging, the incidence of presbycusis is getting higher and higher. The study of its pathogenesis is of great significance for the diagnosis, treatment, and prevention of presbycusis. The rapid progress of molecular biology experimental technology has provided us with a new opportunity to fully understand and reveal the presbycusis. In the near future, early diagnosis of presbycusis-related genes and early prevention or delay of the occurrence and development of presbycusis will become a reality.


Asunto(s)
Pérdida Auditiva Sensorineural/prevención & control , Presbiacusia/prevención & control , China , Humanos
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