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1.
Cell ; 2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39378879

RESUMEN

The gut microbiota is crucial for human health, functioning as a complex adaptive system akin to a vital organ. To identify core health-relevant gut microbes, we followed the systems biology tenet that stable relationships signify core components. By analyzing metagenomic datasets from a high-fiber dietary intervention in type 2 diabetes and 26 case-control studies across 15 diseases, we identified a set of stably correlated genome pairs within co-abundance networks perturbed by dietary interventions and diseases. These genomes formed a "two competing guilds" (TCGs) model, with one guild specialized in fiber fermentation and butyrate production and the other characterized by virulence and antibiotic resistance. Our random forest models successfully distinguished cases from controls across multiple diseases and predicted immunotherapy outcomes through the use of these genomes. Our guild-based approach, which is genome specific, database independent, and interaction focused, identifies a core microbiome signature that serves as a holistic health indicator and a potential common target for health enhancement.

2.
Cell ; 187(13): 3373-3389.e16, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38906102

RESUMEN

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Microbioma Gastrointestinal , Inmunoterapia , Neoplasias Pulmonares , Neoplasias , Femenino , Humanos , Masculino , Akkermansia , Carcinoma de Pulmón de Células no Pequeñas/microbiología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Disbiosis/microbiología , Heces/microbiología , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Neoplasias Pulmonares/microbiología , Neoplasias Pulmonares/tratamiento farmacológico , Metagenómica/métodos , Neoplasias/microbiología , Resultado del Tratamiento
3.
Nature ; 600(7887): 110-115, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34819672

RESUMEN

The human microbiome encodes a large repertoire of biochemical enzymes and pathways, most of which remain uncharacterized. Here, using a metagenomics-based search strategy, we discovered that bacterial members of the human gut and oral microbiome encode enzymes that selectively phosphorylate a clinically used antidiabetic drug, acarbose1,2, resulting in its inactivation. Acarbose is an inhibitor of both human and bacterial α-glucosidases3, limiting the ability of the target organism to metabolize complex carbohydrates. Using biochemical assays, X-ray crystallography and metagenomic analyses, we show that microbiome-derived acarbose kinases are specific for acarbose, provide their harbouring organism with a protective advantage against the activity of acarbose, and are widespread in the microbiomes of western and non-western human populations. These results provide an example of widespread microbiome resistance to a non-antibiotic drug, and suggest that acarbose resistance has disseminated in the human microbiome as a defensive strategy against a potential endogenous producer of a closely related molecule.


Asunto(s)
Acarbosa/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Hipoglucemiantes/farmacología , Inactivación Metabólica , Metagenoma/genética , Boca/microbiología , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Acarbosa/metabolismo , Amilasas/metabolismo , Animales , Humanos , Hipoglucemiantes/metabolismo , Metagenoma/efectos de los fármacos , Modelos Moleculares , Boca/efectos de los fármacos , Fosfotransferasas (Aceptor de Grupo Alcohol)/química , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo
4.
Rev Med Virol ; 34(4): e2565, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-39031738

RESUMEN

Global attention is riveted on neurodegenerative diseases due to their unresolved aetiologies and lack of efficacious therapies. Two key factors implicated include mitochondrial impairment and microglial ageing. Several viral infections, including Herpes simplex virus-1 (HSV-1), human immunodeficiency virus (HIV) and Epstein-Barr virus, are linked to heightened risk of these disorders. Surprisingly, numerous studies indicate viruses induce these aforementioned precipitating events. Epstein-Barr virus, Hepatitis C Virus, HIV, respiratory syncytial virus, HSV-1, Japanese Encephalitis Virus, Zika virus and Enterovirus 71 specifically impact mitochondrial function, leading to mitochondrial malfunction. These vital organelles govern various cell activities and, under specific circumstances, trigger microglial ageing. This article explores the role of viral infections in elucidating the pathogenesis of neurodegenerative ailments. Various viruses instigate microglial ageing via mitochondrial destruction, causing senescent microglia to exhibit activated behaviour, thereby inducing neuroinflammation and contributing to neurodegeneration.


Asunto(s)
Microglía , Mitocondrias , Enfermedades Neurodegenerativas , Virosis , Humanos , Enfermedades Neurodegenerativas/virología , Enfermedades Neurodegenerativas/patología , Mitocondrias/metabolismo , Virosis/virología , Virosis/patología , Microglía/virología , Microglía/patología , Animales
5.
BMC Microbiol ; 24(1): 25, 2024 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-38238663

RESUMEN

BACKGROUND: Oligoribonuclease (orn) of P. aeruginosa is a highly conserved exonuclease, which can regulate the global gene expression levels of bacteria through regulation of both the nanoRNA and c-di-GMP. NanoRNA can regulate the expression of the bacterial global genome as a transcription initiator, and c-di-GMP is the most widely second messenger in bacterial cells. OBJECTIVE: This study seeks to elucidate on the regulation by orn on pathogenicity of P. aeruginosa. METHODS: P. aeruginosa with orn deletion was constructed by suicide plasmid homologous recombination method. The possible regulatory process of orn was analyzed by TMT quantitative labeling proteomics. Then experiments were conducted to verify the changes of Δorn on bacterial motility, virulence and biofilm formation. Bacterial pathogenicity was further detected in cell and animal skin trauma models. ELISA detection c-di-GMP concentration and colony aggregation and biofilm formation were observed by scanning electron microscope. RESULTS: orn deletion changed the global metabolism of P. aeruginosa and reduced intracellular energy metabolism. It leads to the disorder of the quorum sensing system, the reduction of bacterial motility and virulence factors pyocyanin and rhamnolipids. But, orn deletion enhanced pathogenicity in vitro and in vivo, a high level of c-di-GMP and biofilm development of P. aeruginosa. CONCLUSION: orn regulates the ability of P. aeruginosa to adapt to the external environment.


Asunto(s)
Proteínas Bacterianas , Exorribonucleasas , Pseudomonas aeruginosa , Humanos , Animales , Pseudomonas aeruginosa/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , GMP Cíclico/metabolismo , Sistemas de Mensajero Secundario , Biopelículas , Regulación Bacteriana de la Expresión Génica
6.
J Med Virol ; 96(5): e29643, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38695269

RESUMEN

Severe pneumonia caused by respiratory viruses has become a major threat to humans, especially with the SARS-CoV-2 outbreak and epidemic. The aim of this study was to investigate the universal molecular mechanism of severe pneumonia induced by multiple respiratory viruses and to search for therapeutic strategies targeting this universal molecular mechanism. The common differential genes of four respiratory viruses, including respiratory syncytial virus (RSV), rhinovirus, influenza, and SARS-CoV-2, were screened by GEO database, and the hub gene was obtained by Sytohubba in Cytoscape. Then, the effect of hub genes on inflammasome and pyrodeath was investigated in the model of RSV infection in vitro and in vivo. Finally, through virtual screening, drugs targeting the hub gene were obtained, which could alleviate severe viral pneumonia in vitro and in vivo. The results showed that CMPK2 is one of the hub genes after infection by four respiratory viruses. CMPK2 activates the inflammasome by activating NLRP3, and promotes the releases of inflammatory factors interleukin (IL)-1ß and IL-18 to induce severe viral pneumonia. Z25 and Z08 can reduce the expression level of CMPK2 mRNA and protein, thereby inhibiting NLRP3 and alleviating the development of severe viral pneumonia. In conclusion, the inflammatory response mediated by CMPK2 is the common molecular mechanism of severe pneumonia induced by viral infection, and Z25 and Z08 can effectively alleviate viral infection and severe pneumonia through this mechanism.


Asunto(s)
Inflamasomas , Piroptosis , Piroptosis/efectos de los fármacos , Humanos , Animales , Inflamasomas/metabolismo , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Interleucina-18/metabolismo , Interleucina-18/genética , SARS-CoV-2 , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/virología
7.
J Med Virol ; 95(1): e28352, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36437481

RESUMEN

Lots of epidemiological and clinical studies have shown that human cytomegalovirus (HCMV) is related to the pathogenesis of atherosclerosis. Released by inflammatory cells and vascular smooth muscle cell (VSMCs), metalloproteinases are observed in many pathological vessel conditions, including atherosclerosis and restenosis. This study was designed to investigate the effect of HCMV infection on the expression of metalloproteinases and their involvements in the HCMV-induced functional changes of VSMCs. Differential metalloproteinase after HCMV infection was assayed using reverse transcription-polymerase chain reaction (RT-PCR) microarray. The most significant increased a disintegrin and metalloprotease 9 (ADAM9) was chosen to investigate the mechanism of its specific increase after infection using the treatment of UV-irradiated replication-deficient HCMV, HCMV-infected cell lysate filters or Foscarnet. The function of proliferation, migration, production of inflammatoty factors and phenotypic transformation were determined by using cell counting kit-8, transwell, Enzyme-linked immunosorbent assay, RT-quantitative PCR (qPCR) and Western blot, respectively. Moreover, the effect of ADAM9 deficiency on HCMV replication was also determined using RT-qPCR and immunofluorescence. The expression levels of 6 genes were upregulated and 14 genes were downregulated at different time points after HCMV infection. Among these, the expression level of ADAM9 increased most significantly at each time point and the abnormal expression of ADAM9 might be induced by the early gene products of HCMV. Further studies found that ADAM9 promoted the proliferation, the migration, the production of inflammatory factors and the transit from the contractile phenotype (decreased ACTA2 expression) to the synthetic phenotype (increased osteopontin [OPN] expression). Knockdown theADAM9 expression could rescue the decreased ACTA2 expression, but has no effect on OPN expression. ADAM-9 deficiency didn't affect the replication of HCMV. The findings of our study suggest that HCMV infection changed VSMC function through ADAM9 expression, which may contribute to the understanding of the underlying pathological mechanisms of HCMV-induced atherosclerosis.


Asunto(s)
Aterosclerosis , Miocitos del Músculo Liso , Humanos , Miocitos del Músculo Liso/metabolismo , Citomegalovirus/genética , Ensayo de Inmunoadsorción Enzimática , Western Blotting , Proliferación Celular , Movimiento Celular/genética , Células Cultivadas , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas ADAM/genética , Proteínas ADAM/metabolismo
8.
Microb Pathog ; 181: 106197, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37321423

RESUMEN

The unique microbiome found in the lungs has been studied and shown to be associated with both pulmonary homeostasis and lung diseases. The lung microbiome has the potential to produce metabolites that modulate host-microbe interactions. Specifically, short-chain fatty acids (SCFAs) produced by certain strains of the lung microbiota have been shown to regulate immune function and maintain gut mucosal health. In response, this review described the distribution and composition of the microbiota in lung diseases and discussed the impact of the lung microbiota on health and lung disease. In addition, the review further elaborated on the mechanism of microbial metabolites in microbial-host interaction and their application in the treatment of lung diseases. A better understanding of the interaction between the microbiota, metabolites, and host will provide potential strategies for the development of novel methods for the treatment of pulmonary microbial induced lung diseases.


Asunto(s)
Enfermedades Pulmonares , Microbiota , Humanos , Pulmón/metabolismo , Enfermedades Pulmonares/terapia , Ácidos Grasos Volátiles/metabolismo
9.
Cerebrovasc Dis ; 52(2): 145-152, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36044836

RESUMEN

INTRODUCTION: The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) showed that a low-dose alteplase was safe but not clearly non-inferior to standard-dose alteplase in acute ischemic stroke (AIS). Given the significant cost of this medicine, we undertook a cost-effectiveness analysis to determine the probability that low-dose is cost-effective relative to standard-dose alteplase in China. METHODS: For ENCHANTED participants in China with available health cost data, cost-effectiveness and cost-utility analyses were undertaken in which death or disability (modified Rankin scale scores 2-6) at 90 days and quality-adjusted life-years (QALYs) were used as outcome measures, respectively. There was adherence to standard guidelines for health economic evaluations alongside non-inferiority trials and according to a health-care payer's perspective. The equivalence margin for cost and effectiveness was set at USD 691 and -0.025 QALYs, respectively, for the base-case analysis. Probabilistic sensitivity analyses were used to evaluate the probability of low-dose alteplase being non-inferior. RESULTS: While the mean cost of alteplase was lower in the low-dose group (USD 1,569 vs. USD 2,154 in the standard-dose group), the total cost was USD 56 (95% confidence interval [CI]: -1,000-1,113) higher compared to the standard-dose group due to higher hospitalization costs in the low-dose group. There were 462 (95% CI: 415-509) and 410 (95% CI: 363-457) patients with death or disability per 1,000 patients in the low-dose and standard-dose groups, respectively. The low-dose group had marginally lower (0.008, 95% CI: -0.016-0.001) QALYs compared to their standard-dose counterparts. The low-dose group was found to have an 88% probability of being non-inferior based on cost-effectiveness versus the standard-dose group. CONCLUSIONS: This health economic evaluation alongside the ENCHANTED indicates that the use of low-dose alteplase does not save overall healthcare costs nor lead to a gain in QALYs in the management of Chinese patients with AIS compared to the use of standard dose. There is little justification on economic grounds to shift from standard-of-care thrombolysis in AIS.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Activador de Tejido Plasminógeno/efectos adversos , Análisis Costo-Beneficio , Fibrinolíticos/efectos adversos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , China , Resultado del Tratamiento
10.
Artículo en Inglés | MEDLINE | ID: mdl-38064602

RESUMEN

Objectives: This study aimed to explore the clinical characteristics of patients with prostate cancer with prostate-specific antigen (PSA) concentrations of less than 4 ng/mL (normal PSA) to provide clinical insights regarding diagnosis and treatment. Methods: We recruited 35 patients with prostate cancer with normal PSA who were admitted to Xi'an People's Hospital from January 2013 to January 2018, and further determined their clinical characteristics, serum PSA concentration, prostate volume, tumor pathology, surgical margins, seminal vesicle invasion, lymph node metastasis, Gleason score, TNM staging, risk classification, and survival, and described the patients' interventions and treatments. All patients and their families signed informed consent forms before enrollment. Results: In our study, we observed a 3-year survival rate of 77.14% for patients with prostate cancer and normal PSA concentrations. This outcome can be attributed to several clinical characteristics, including the absence of obvious clinical presentation, a high detection rate of seminal vesicle invasion, as well as high Gleason scores and risk levels. The primary outcome, 3-year survival rate, reflects the long-term prognosis of this specific patient subgroup. We also conducted correlation analyses to better understand the relationships between these clinical characteristics and patient survival.

11.
Semin Cancer Biol ; 68: 105-122, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-31883910

RESUMEN

The ubiquitin-proteasome system (UPS) plays a central role in the degradation of cellular proteins. Targeting protein degradation has been validated as an effective strategy for cancer therapy since 2003. Several components of the UPS have been validated as potential anticancer targets, including 20S proteasomes, 19S proteasome-associated deubiquitinases (DUBs) and ubiquitin ligases (E3s). 20S proteasome inhibitors (such as bortezomib/BTZ and carfilzomib/CFZ) have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM) and some other liquid tumors. Although survival of MM patients has been improved by the introduction of BTZ-based therapies, these clinical 20S proteasome inhibitors have several limitations, including emergence of resistance in MM patients, neuro-toxicities, and little efficacy in solid tumors. One of strategies to improve the current status of cancer treatment is to repurpose old drugs with UPS-inhibitory properties as new anticancer agents. Old drug reposition represents an attractive drug discovery approach compared to the traditional de novo drug discovery process which is time-consuming and costly. In this review, we summarize status of repurposed inhibitors of various UPS components, including 20S proteasomes, 19S-associated DUBs, and ubiquitin ligase E3s. The original and new mechanisms of action, molecular targets, and potential anticancer activities of these repurposed UPS inhibitors are reviewed, and their new uses including combinational therapies for cancer treatment are discussed.


Asunto(s)
Antineoplásicos/uso terapéutico , Descubrimiento de Drogas , Reposicionamiento de Medicamentos/métodos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal/química , Inhibidores de Proteasoma/uso terapéutico , Animales , Humanos , Ubiquitina/metabolismo
12.
J Antimicrob Chemother ; 78(1): 169-179, 2022 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-36322459

RESUMEN

OBJECTIVES: Respiratory syncytial virus (RSV) infection is one of the three most common causes of death in the infants, pre-schoolers, immunocompromised patients and elderly individuals due to many complications and lack of specific treatment. During RSV infection, the fusion protein (F protein) mediates the fusion of the virus envelope with the host cell membrane. Therefore, the F protein is an effective target for viral inhibition. METHODS: We identified potential small-molecule inhibitors against RSV-F protein for the treatment of RSV infection using virtual screening and molecular dynamics (MD) simulations. The CCK8 assay was used to determine the cytotoxicity and quantitative RT-PCR and indirect fluorescence assay (IFA) were used to determine the viral replication and RSV-induced inflammation in vitro. An RSV-infected mouse model was established, and viral replication was assayed using real-time quantitative PCR and IFA. Virus-induced complications were also examined using histopathological analysis, airway resistance and the levels of IL-1ß, IL-6 and TNF-α. RESULTS: The top three potential inhibitors against the RSV-F protein were screened from the FDA-approved drug database. Z65, Z85 and Z74 significantly inhibited viral replication and RSV-induced inflammation. They also significantly alleviated RSV infection and RSV-induced complications in vivo. Z65 and Z85 had no cytotoxicity and better anti-RSV effects than Z74. CONCLUSIONS: Z65 and Z85 may be suitable candidates for the treatment of RSV and serve as the basis for the development of new drugs.


Asunto(s)
Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Animales , Ratones , Antivirales/farmacología , Antivirales/uso terapéutico , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Pulmón/patología , Inflamación
13.
Molecules ; 28(1)2022 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-36615445

RESUMEN

To solve the problem that turbidity in water has a significant effect on the spectra of nitrate and reduces the accuracy of nitrate detection, a turbidity-compensation method for nitrate measurement based on ultraviolet difference spectra is proposed. The effect of turbidity on the absorption spectra of nitrate was studied by using the difference spectra of the mixed solution and a nitrate solution. The results showed that the same turbidity had different effects on the absorbance of different concentrations of nitrate. The change in absorbance due to turbidity decreased with an increase in the nitrate concentration at wavelengths from 200 nm to 230 nm, although this change was constant when the wavelength was greater than 230 nm. On the basis of this characteristic, we combined the residual sum of squares (RSS) and interval partial least squares (iPLS) to select wavelengths of 230-240 nm as the optimal modeling interval. Furthermore, the turbidity-compensation model was established by the linear fitting of the difference spectra of various levels of turbidity. The absorption spectra of the nitrate were extracted by subtracting the turbidity-compensation curve from the original spectra of the water samples, and the nitrate concentration was calculated by using a partial least squares (PLS)-based nitrate-prediction model. The experimental results showed that the average relative error of the nitrate predictions was reduced by 50.33% to 1.33% by the proposed turbidity-compensation method. This indicated that this method can better correct the deviation in nitrate's absorbance caused by turbidity and improve the accuracy of nitrate predictions.


Asunto(s)
Nitratos , Espectroscopía Infrarroja Corta , Espectroscopía Infrarroja Corta/métodos , Análisis de los Mínimos Cuadrados
14.
J Proteome Res ; 19(8): 3109-3122, 2020 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-32567865

RESUMEN

The decline of clinically effective antibiotics has made it necessary to develop more effective antimicrobial agents, especially for refractory biofilm-related infections. Silver nanoparticles (AgNPs) are a new type of antimicrobial agent that can eradicate biofilms and reduce bacterial resistance, but its anti-biofilm mechanism has not been elucidated. In this study, we investigated the molecular mechanism of AgNPs against multidrug-resistant Pseudomonas aeruginosa by means of anti-biofilm tests, scanning electron microscopy (SEM), and tandem mass tag (TMT)-labeled quantitative proteomics. The results of anti-biofilm tests demonstrated that AgNPs inhibited the formation of P. aeruginosa biofilm and disrupted its preformed biofilm. SEM showed that when exposed to AgNPs, the structure of the P. aeruginosa biofilm was destroyed, along with significant reduction of its biomass. TMT-labeled quantitative proteomic analysis revealed that AgNPs could defeat the P. aeruginosa biofilm in multiple ways by inhibiting its adhesion and motility, stimulating strong oxidative stress response, destroying iron homeostasis, blocking aerobic and anaerobic respiration, and affecting quorum sensing systems. Our findings offer a new insight into clarifying the mechanism of AgNPs against biofilms, thus providing a theoretical basis for its clinical application.


Asunto(s)
Nanopartículas del Metal , Pseudomonas aeruginosa , Antibacterianos/farmacología , Biopelículas , Pruebas de Sensibilidad Microbiana , Proteómica , Plata/farmacología
15.
BMC Urol ; 20(1): 140, 2020 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-32878607

RESUMEN

BACKGROUND: To investigate the functions of the hyperpolarization-activated cation currents in medium-size dorsal root ganglion cells in a rat model of overactive bladder syndrome. METHODS: Rats with OAB were screened using a urodynamic testing device. The whole-cell patch clamp technique was used to investigate changes in excitability and hyperpolarization-activated cation current (Ih) of medium-size cells in the L6 dorsal root ganglia (DRG) of the OAB rats. Intrathecal injection of the specific Ih inhibitor ZD7288 was used to investigate changes of voiding function and Ih of medium-size cells in the L6 DRG. RESULTS: The urinary bladder weight of the OAB rats was significantly increased (p < 0.01); However, 7 days after intrathecally administration of ZD7288 (2 µM), the weight of rat bladder was significantly reduced (p < 0.01). The excitability of the medium-size cells in the L6 DRG of the OAB rats was significantly increased, and the number of action potentials elicited by a 500 pA stimulus was also markedly increased. Furthermore, ZD7288 significantly reduced the excitability of the medium-size DRG cells. The medium-size cells in the DRG of the OAB rats had a significantly increased Ih current density, which was blocked by ZD7288. CONCLUSIONS: The Ih current density significantly increased in medium-size cells of the L6 DRG in the OAB model. A decrease of the Ih current was able to significantly improve the voiding function of the OAB rats, in addition to lowering their urinary bladder weight. Our finding suggested that the observed increase of Ih current in the medium-size DRG neurons might play an important role in the pathological processes of OAB.


Asunto(s)
Potenciales de Acción , Ganglios Espinales/citología , Vejiga Urinaria Hiperactiva/fisiopatología , Animales , Cationes , Femenino , Ratas , Síndrome
16.
Nucleic Acids Res ; 46(4): e23, 2018 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-29194524

RESUMEN

The vast majority of microorganisms on Earth reside in often-inseparable environment-specific communities-microbiomes. Meta-genomic/-transcriptomic sequencing could reveal the otherwise inaccessible functionality of microbiomes. However, existing analytical approaches focus on attributing sequencing reads to known genes/genomes, often failing to make maximal use of available data. We created faser (functional annotation of sequencing reads), an algorithm that is optimized to map reads to molecular functions encoded by the read-correspondent genes. The mi-faser microbiome analysis pipeline, combining faser with our manually curated reference database of protein functions, accurately annotates microbiome molecular functionality. mi-faser's minutes-per-microbiome processing speed is significantly faster than that of other methods, allowing for large scale comparisons. Microbiome function vectors can be compared between different conditions to highlight environment-specific and/or time-dependent changes in functionality. Here, we identified previously unseen oil degradation-specific functions in BP oil-spill data, as well as functional signatures of individual-specific gut microbiome responses to a dietary intervention in children with Prader-Willi syndrome. Our method also revealed variability in Crohn's Disease patient microbiomes and clearly distinguished them from those of related healthy individuals. Our analysis highlighted the microbiome role in CD pathogenicity, demonstrating enrichment of patient microbiomes in functions that promote inflammation and that help bacteria survive it.


Asunto(s)
Metagenómica/métodos , Microbiota , Anotación de Secuencia Molecular/métodos , Algoritmos , Proteínas Bacterianas/fisiología , Niño , Enfermedad de Crohn/microbiología , Humanos , Síndrome de Prader-Willi/microbiología , Alineación de Secuencia
17.
Int Arch Allergy Immunol ; 179(1): 43-52, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30943513

RESUMEN

BACKGROUND: The aim of this study was to investigate the role of Notch-1 signaling through Notch-1 ligands on bronchial epithelial cells (BECs) in regulating the development of T helper 2 (Th2) lymphocytes after RSV infection. METHODS: Firstly, we analyzed the expression of cytokines and Notch-1 ligands in BECs by using real-time PCR. Then, RSV-infected BECs were co-cultured with CD4+ T cells in a transwell chamber for 48 h, and differentiation of T cells in the lower chamber was determined using flow cytometry and real-time PCR. JAG1 siRNA was then used to determine the effects of Jagged/Notch-1 signaling on the differentiation of Th2. An RSV-infected mouse model was also used to analyze the secretion of Th differentiation-associated cytokines in serum and lung tissues using ELISA, the histopathological changes using HE staining, and the expression of JAG1 and JAG2 in BECs. RESULTS: The results showed that RSV promoted the expression of Th2-type cytokines and Jagged-1 and inhibited the expression of Jagged-2 in normal BECs. RSV-infected BECs induced Th2 differentiation. In addition, JAG1 downregulation inhibited the differentiation of Th2 and promoted differentiation of Th1. In the RSV-infected mouse model, the RSV titer, inflammation decreased with time. IL-4 and IL-17 increased on day 28 and 60, while IFNγ increased on day 7 and 28. Moreover, the expression of Jagged-1 increased and that of Jagged-2 decreased in BECs, which was consistent with IL-4 production in lung tissues. CONCLUSION: Our data showed that BECs had the potential to promote the differentiation of Th2 lymphocytes through Jagged-1/Notch-1 signaling.


Asunto(s)
Bronquios/fisiología , Proteína Jagged-1/fisiología , Proteína Jagged-2/fisiología , Receptor Notch1/fisiología , Infecciones por Virus Sincitial Respiratorio/inmunología , Transducción de Señal/fisiología , Células Th2/citología , Animales , Bronquios/inmunología , Bronquios/patología , Diferenciación Celular , Citocinas/biosíntesis , Células Epiteliales/fisiología , Células HeLa , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL
18.
Cell Physiol Biochem ; 47(5): 2077-2087, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29975932

RESUMEN

BACKGROUND/AIMS: Breast cancer (BC) is the most common cancer in women worldwide. Despite great advancements in cancer therapy in recent years, surgery and chemotherapy are still the mainstays of BC treatment. However, cancer cells usually develop mechanisms to evade cell death induced by chemotherapy. Thus, strategies are needed to reverse the chemoresistance of cancer cells. METHODS: We established cisplatin-resistant BC models in MDA-MB-231 and MCF-7 BC cell lines through long-term exposure to cisplatin. Quantitative reverse transcription PCR was used to examine the expression of microRNA (miR)-100. MTT cell viability assays were performed to determine cell viability. Regulation of hematopoietic cell-specific protein 1-associated protein X-l (HAX-1) targeted by miR-100 was confirmed by western blotting and luciferase reporter assays. The mitochondrial membrane potential and apoptosis were measured by flow cytometry. Release of cytochrome c from the mitochondria into the cytoplasm, HAX-1 expression, and activation of caspase-9 and caspase-3 were detected by western blotting. RESULTS: A clear decrease in miR-100 expression was observed in cisplatin-resistant MDA-MB-231 and MCF-7 cells (MDA-MB-231/R and MCF-7/R). Overexpression of miR-100 increased the sensitivity of MDA-MB-231/R and MCF-7/R cells to cisplatin treatment and promoted cisplatin-induced mitochondrial apoptosis by targeting HAX-1 gene. CONCLUSIONS: MiR-100 targeted HAX-1 to increase the chemosensitivity of BC by mediating the mitochondrial apoptosis pathway.


Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Cisplatino/farmacología , Resistencia a Antineoplásicos , MicroARNs/biosíntesis , ARN Neoplásico/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , MicroARNs/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , ARN Neoplásico/genética
19.
Biochem Biophys Res Commun ; 501(3): 628-635, 2018 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-29753747

RESUMEN

Homeobox gene C10 (HOXC10), known to regulate cell differentiation and proliferation, is upregulated in gastric cancer (GC). The mechanism underlying HOXC10 involvement in GC metastasis is unclear. Herein, we found that HOXC10 is overexpressed in GC relative to normal controls. In the 73 GC patients tissue microarrays (TMA) tested, HOXC10 expression was closely related with tumor-node-metastasis (TNM) stage, lymph node metastasis, and distant metastasis. HOXC10 overexpression tended to associate with low 5-year cumulative survival. Cox regression analysis identified HOXC10 as an independent prognostic factor for poor patient survival. HOXC10 promoted GC cell invasion and migration, regulated the expression of activated ATM and markers of NF-κB signaling. HOXC10 may promote invasion and migration of GC by regulating ATM/NF-κB signaling pathway. HOXC10 should be explored as a clinical marker of GC prognosis.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , FN-kappa B/metabolismo , Invasividad Neoplásica/genética , Transducción de Señal , Neoplasias Gástricas/genética , Línea Celular Tumoral , Movimiento Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología
20.
Cell Physiol Biochem ; 39(5): 1804-1812, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27744449

RESUMEN

BACKGROUND: The present study was designed to observe the infection of human cytomegalovirus (HCMV) to human vascular smooth muscle cells (VSMCs), and the effect of viral infection on lipid metabolism in VSMCs. METHODS: The cytopathic effects were observed by inverted microscopy and viral infection were examined by electron microscopy and RT-PCR. The lipid metabolism related gene profiling of VSMCs after HCMV infection was assayed by cDNA assay and the abnormal expression of genes were validated by quantitative RT-PCR. The content of cholesterol in VSMCs after HCMV infection was assayed by cholesterol detection kit. RESULTS: VSMCs showed obvious cytopathic effects after HCMV infection. Intact viral particles could be detected in VSMCs using electron microscope. By use of RT-PCR technology, IE gene of HCMV could be amplified from VSMCs. The expression of cell lipid metabolism related gene profiling showed obvious disorders. The expression levels of HMG-CoA synthase and HMG-CoA reductase after infection increased significantly. The cellular cholesterol content (µmol/106 cells) was significantly higher than that of mock infected group at 72h post infection. CONCLUSION: HCMV can infect VSMCs and the infection can affect cellular lipid metabolism related gene expression, which get involved in the occurrence and development of atherosclerosis (AS).


Asunto(s)
Colesterol/metabolismo , Hidroximetilglutaril-CoA Sintasa/genética , Metabolismo de los Lípidos/genética , Miocitos del Músculo Liso/metabolismo , Oxidorreductasas/genética , Células Cultivadas , Citomegalovirus/patogenicidad , Citomegalovirus/fisiología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Hidroximetilglutaril-CoA Sintasa/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/virología , Miocitos del Músculo Liso/virología , Oxidorreductasas/metabolismo , Transducción de Señal
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