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1.
Nucleic Acids Res ; 51(D1): D1046-D1052, 2023 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-36043442

RESUMEN

Functional interpretation of disease-associated non-coding variants remains a significant challenge in the post-GWAS era. Our recent study has identified 3'UTR alternative polyadenylation (APA) quantitative trait loci (3'aQTLs) and connects APA events with QTLs as a major driver of human traits and diseases. Besides 3'UTR, APA events can also occur in intron regions, and increasing evidence has connected intronic polyadenylation with disease risk. However, systematic investigation of the roles of intronic polyadenylation in human diseases remained challenging due to the lack of a comprehensive database across a variety of human tissues. Here, we developed ipaQTL-atlas (http://bioinfo.szbl.ac.cn/ipaQTL) as the first comprehensive portal for intronic polyadenylation. The ipaQTL-atlas is based on the analysis of 15 170 RNA-seq data from 838 individuals across 49 Genotype-Tissue Expression (GTEx v8) tissues and contains ∼0.98 million SNPs associated with intronic APA events. It provides an interface for ipaQTLs search, genome browser, boxplots, and data download, as well as the visualization of GWAS and ipaQTL colocalization results. ipaQTL-atlas provides a one-stop portal to access intronic polyadenylation information and could significantly advance the discovery of APA-associated disease susceptibility genes.


Asunto(s)
Intrones , Poliadenilación , Sitios de Carácter Cuantitativo , Humanos , Regiones no Traducidas 3'/genética , Intrones/genética , Perfilación de la Expresión Génica , Atlas como Asunto
2.
Sci Rep ; 14(1): 1131, 2024 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-38212429

RESUMEN

The main objective of this study was to investigate the potential probiotic properties of Lacticaseibacillus rhamnosus VHProbi®M15 (M15). This study examined the effects of M15 on sucralfate-induced constipation in a mouse model. The BALB/c mice were randomly divided into four groups: the normal group (NOR) was without any treatment, while the constipation (CON), phenolphthalein (PHE), and probiotic (PRO) treatment groups were fed with sucralfate until the appearance of constipation symptoms. Afterward, the NOR and CON groups were given 1 ml saline orally every day until the end of the experiment; the PHE and PRO groups were given phenolphthalein or M15 suspension in 1 ml orally, respectively. Compared with the CON group, the fecal water content and intestinal peristalsis improved in the PRO group. Here, intake of M15 effectively attenuated sucralfate-induced constipation, recuperated colonic epithelial integrity, and increased serum levels of gastrointestinal excitatory neurotransmitters (motilin, gastrin, substance P). Analysis of the intestinal microbiota of mice by 16S rRNA metagenomic revealed an increase in the relative abundance of Bacteroides and a decrease in Sclerotinia, Verrucosa and Proteus in the PRO group. Compared with the CON group, the constipation-induced intestinal microecological changes were partially recovered in the PHE and PRO groups. These results demonstrate that M15 enhanced gastrointestinal transit and alleviated in mice with sucralfate-induced constipation.


Asunto(s)
Galanina/análogos & derivados , Lacticaseibacillus rhamnosus , Probióticos , Sustancia P/análogos & derivados , Ratones , Animales , Sucralfato/efectos adversos , ARN Ribosómico 16S , Estreñimiento/inducido químicamente , Estreñimiento/tratamiento farmacológico , Probióticos/farmacología , Probióticos/uso terapéutico , Fenolftaleínas/efectos adversos
3.
Int Immunopharmacol ; 140: 112763, 2024 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-39083925

RESUMEN

Nogo-B, a ubiquitously expressed member of the reticulon family, plays an important role in maintaining endoplasmic reticulum (ER) structure, regulating protein folding, and calcium homeostasis. In this study, we demonstrate that Nogo-B expression and secretion are upregulated in lung cancer and correlate to overall survival. Nogo-B is secreted by various cells, particularly lung cancer cells. ER stress and phosphorylation at serine 107 can induce Nogo-B secretion. Secretory Nogo-B suppresses the differentiation of Th2 cells and the release of type 2 cytokines, thus influencing the anti-tumor effects of Th2-related immune cells, including IgE+B cell class switching and eosinophil activation.


Asunto(s)
Diferenciación Celular , Neoplasias Pulmonares , Proteínas Nogo , Células Th2 , Microambiente Tumoral , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Microambiente Tumoral/inmunología , Células Th2/inmunología , Proteínas Nogo/metabolismo , Proteínas Nogo/genética , Estrés del Retículo Endoplásmico/inmunología , Línea Celular Tumoral , Citocinas/metabolismo , Masculino , Femenino , Fosforilación
4.
Neuropsychopharmacology ; 49(2): 433-442, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37715107

RESUMEN

Genome-wide association studies (GWASs) have reported multiple single nucleotide polymorphisms (SNPs) associated with schizophrenia, yet the underlying molecular mechanisms are largely unknown. In this study, we aimed to identify schizophrenia relevant genes showing alterations in mRNA and protein expression associated with risk SNPs at the 10q24.32-33 GWAS locus. We carried out the quantitative trait loci (QTL) and summary data-based Mendelian randomization (SMR) analyses, using the PsychENCODE dorsolateral prefrontal cortex (DLPFC) expression QTL (eQTL) database, as well as the ROSMAP and Banner DLPFC protein QTL (pQTL) datasets. The gene CNNM2 (encoding a magnesium transporter) at 10q24.32-33 was identified to be a robust schizophrenia risk gene, and was highly expressed in human neurons according to single cell RNA-seq (scRNA-seq) data. We further revealed that reduced Cnnm2 in the mPFC of mice led to impaired cognition and compromised sensorimotor gating function, and decreased Cnnm2 in primary cortical neurons altered dendritic spine morphogenesis, confirming the link between CNNM2 and endophenotypes of schizophrenia. Proteomics analyses showed that reduced Cnnm2 level changed expression of proteins associated with neuronal structure and function. Together, these results identify a robust gene in the pathogenesis of schizophrenia.


Asunto(s)
Proteínas de Transporte de Catión , Esquizofrenia , Humanos , Ratones , Animales , Estudio de Asociación del Genoma Completo/métodos , Predisposición Genética a la Enfermedad/genética , Espinas Dendríticas/metabolismo , Corteza Prefrontal/metabolismo , Cognición , Filtrado Sensorial , Morfogénesis , Polimorfismo de Nucleótido Simple/genética , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo
5.
Microbiol Resour Announc ; 12(1): e0094122, 2023 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-36453928

RESUMEN

The probiotic strain Lactobacillus helveticus VHProbi Y21 confers beneficial effects in the prevention and treatment of acne. Here, we report the whole-genome sequence of this bacterium, which contains a chromosome and two plasmids, with a GC content of 37.52%.

6.
PLoS One ; 18(5): e0285480, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37186610

RESUMEN

A strain of lactic acid bacteria from cheese was isolated, that showed strong growth inhibitory effects on Streptococcus mutans. The API 50CH system and 16S rDNA sequencing verified that this was a novel strain, and was named Lacticaseibacillus rhamnosus VHProbi M14. The strain inhibited the growth of S. mutans and Fusobacterium nucleatum under mixed culture conditions, coaggregated with S. mutans and F. nucleatum, and reduced the adhesion of S. mutans and F. nucleatum on cultured human primary gingival epithelial (HPGE) cells. The pH, peroxidase and protease sensitivity testing found antibacterial substances of protein- and peptide-like structures in addition to organic acids. The antimicrobial substances were sensitive to hydrolysis with trypsin, papain and pineapple protease and were inactived at temperatures above 100°C. Ammonium sulphate-precipitated proteins from the M14 strain retained the ability to inhibit the growth of S. mutans and F. nucleatum. The M14 strain contained 23 bacteriocin-related genes encoding for metabolites, belonging to class II bacteriocins. The M14 strain also showed inhibitory effects on 8 other pathogenic strains (A. actinomycetemcomitans, C. albicans, E. coli, G. vaginalis, P. acnes, P. gingivalis, S. aureus, S. enteritids), and thus has a broad spectrum of bacterial inhibition. This new isolate has been identified as having potential to be used as a probiotic bacterium in clinical applications.


Asunto(s)
Bacteriocinas , Lacticaseibacillus rhamnosus , Humanos , Lacticaseibacillus , Staphylococcus aureus , Escherichia coli/metabolismo , Streptococcus mutans , Bacteriocinas/metabolismo , Genómica
7.
Sci Rep ; 13(1): 16879, 2023 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-37803101

RESUMEN

There is an emergent need to develop functional cosmetic ingredients for the topical management of skin barrier function. This study aimed to investigate the efficacy of a lotion containing fermented lysates VHProbi® Mix R for enhancing the skin barrier. In vitro studies demonstrated that fermented cultures of both Lacticaseibacillus rhamnosus VHProbi® E06 (E06) and L. paracasei VHProbi® E12 (E12) had antioxidant capacity, showing promising scavenging capability for 2,2-diphenyl-1-picryl-hydrazyl. The antioxidant capacity of these strains was also demonstrated in the model of Caenorhabditis elegans. In addition, the fermented lysates of both E06 and E12 enhanced the proliferation of HaCaT cells and ameliorated the toxicity induced by Staphylococcus aureus ATCC 25923, hydrogen peroxide, and ultraviolet B radiation in the HaCaT cell models, which simulated the irritants that facial sensitive skin is exposed to. Subsequently, the ingredient VHProbi® Mix R was formulated using four kinds of fermented lysates: E06, E12, Lactiplantibacillus plantarum VHProbi® E15, and Lactobacillus helveticus VHProbi® Y21. A clinical study was conducted to investigate whether a lotion containing VHProbi® Mix R would be beneficial for people to enhance skin barrier. The participants were asked to use the investigational product for 30 days. Several indicators, including transepidermal water loss (TEWL), skin moisturization, and redness were measured at day 0 and day 30 using VISIA®-CR and CK®-MPA systems. Meanwhile, the burden of sensitive skin (BoSS) and self-assessment questionnaires were performed at baseline and endpoint of this study. The study data showed that at day 30, there was a significant decrease in TEWL (P < 0.01), redness measured by CK®-MPA (P < 0.01), and redness profile measured by VISIA®-CR compared with the baseline measurements. Skin moisturization had significantly increased after treatment with the lotion for 30 days. BoSS and self-assessment questionnaires also substantiated that the participants felt a markedly positive change in their sensitive skin. Hence, we hypothesize that applying the topical functional VHProbi® Mix R could confer effective benefits for people with sensitive skin and this represents a promising intervention for enhancing skin barrier.


Asunto(s)
Fármacos Dermatológicos , Probióticos , Humanos , Antioxidantes/farmacología , Fármacos Dermatológicos/farmacología , Emolientes/farmacología , Emolientes/uso terapéutico , Piel , Probióticos/farmacología , Fibrinolíticos/uso terapéutico , Agua/farmacología
8.
Biomed Pharmacother ; 169: 115856, 2023 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-37949698

RESUMEN

Given the important role of polymyxin B (PB) in the treatment of drug-resistant Gram-negative bacterial infections, the emergence of PB resistance poses a serious threat to public health. Adjuvant development is a supplementary strategy that can compensate for the lack of novel antibiotics by protecting PB. In this study, we found a small molecule named Lyb24 that showed weak antibacterial activity (minimum inhibitory concentration ≥ 10 µg/ml) but potentiated and revitalized the efficacy of PB against Gram-negative pathogens, including mcr-1- and mgrB-deletion-mediated PB-resistant strains. Our results showed that Lyb24 inhibits the translational levels of genes associated with the modification of lipid A. In addition, Lyb24 increases the permeability, disrupts the integrity and induces the depolarization of the membrane. We further found that both Lyb24 and PB could directly bind to AzoR and inhibit its activity. Structural analysis showed that Lyb24 binds to the isoalloxazine ring of flavin mononucleotide (FMN) through pi-pi stacking and loop η4 of AzoR. A pneumonia model was used to confirm that the activity against clinical PB-resistant Klebsiella pneumoniae was enhanced due to Lyb24 on PB. In conclusion, we provide a potential therapeutic regimen by combining Lyb24 and PB to treat Gram-negative-resistant bacterial infections. Our findings not only explain the synergistic effect of Lyb24, but also expand our knowledge on the mechanism of action of PB.


Asunto(s)
Combinación Besilato de Amlodipino y Olmesartán Medoxomilo , Polimixina B , Polimixina B/farmacología , Antibacterianos/farmacología , Klebsiella pneumoniae , Pruebas de Sensibilidad Microbiana
9.
Immun Inflamm Dis ; 11(12): e1114, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38156397

RESUMEN

BACKGROUND: Cells and tissues, such as macrophages, express inducible nitric oxide synthase (INOS) after stimulation by certain factors. INOS helps mediate the macrophage inflammatory reaction, but few studies have explored how INOS affects macrophage function in nonalcoholic fatty liver disease (NAFLD). OBJECTIVE: This study investigated the role of INOS-mediated macrophage activity in NAFLD. METHODS: A high-fat diet was used to establish an NAFLD mouse model. After 12 weeks, blood was collected for immune cell and lipid analyses, and liver tissues were collected for pathological analyses with hematoxylin and eosin and Oil Red O staining. Peritoneal macrophages were extracted in situ, cultured in Dulbecco's modified Eagle's medium, and stimulated with palmitic acid to mimic in vivo conditions for further assays. Real-time polymerase chain reaction, western blot analysis, and immunofluorescence were used to verify the expression of target genes or proteins. RESULTS: In the NAFLD model, INOS expression in macrophages increased, and INOS knockdown significantly decreased the number of macrophages. Pathological examinations confirmed that INOS knockdown slowed NAFLD progression and macrophage infiltration during inflammation. INOS knockdown also enhanced phagocytosis and lipid transport by macrophages, and increased the expression of autophagy-related molecules in macrophages, which improved the autophagy level, promoted apoptotic cell degradation, and maintained intracellular environment homeostasis. CONCLUSIONS: These results indicate a correlation between INOS expression and macrophage function in NAFLD.


Asunto(s)
Óxido Nítrico Sintasa de Tipo II , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Autofagia , Inflamación/metabolismo , Lípidos , Macrófagos/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo
10.
STAR Protoc ; 3(3): 101566, 2022 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-35874472

RESUMEN

3' UTR alternative polyadenylation (APA) quantitative trait loci (3'aQTL) can explain approximately 16.1% of trait-associated non-coding variants and is largely distinct from other molecular QTLs. Here, we describe a bioinformatic protocol for identifying 3'aQTLs through standard RNA-seq and matched genomic data. This protocol allows users to analyze dynamic APA events, identify common genetic variants associated with differential 3' UTR usage, and predict the potential causal variants that affect APA. For complete details on the use and execution of this protocol, please refer to Li et al. (2021).


Asunto(s)
Poliadenilación , Transcriptoma , Regiones no Traducidas 3'/genética , Genómica , Poliadenilación/genética , Sitios de Carácter Cuantitativo/genética , Transcriptoma/genética
11.
Front Pharmacol ; 13: 949869, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36147339

RESUMEN

The emergence of polymyxin B (PB) resistant Gram-negative bacteria poses an important clinical and public health threat. Antibiotic adjuvants development is a complementary strategy that fills the gap in new antibiotics. Here, we described the discovery of the enhancement capacity of compound 666-15, previously identified as an inhibitor of cyclic adenosine monophosphate response element-binding protein (CREB), on the activity of PB against Klebsiella pneumoniae in vitro and in vivo. Mechanistic studies showed that this compound reduced the transcription and translation levels of genes related to lipid A modification in the presence of PB. We also identified that 666-15 reduces the ATP hydrolyzation activity of CrrB, and P151L mutation mediates the resistance of bacteria to the enhancement of 666-15. Our results demonstrated the potential of 666-15 in clinical application and support the further development of a PB synergist based on this compound.

12.
Infect Drug Resist ; 15: 295-306, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35115797

RESUMEN

BACKGROUND: The use of antibiotic adjuvants is a complementary strategy to the development of new antibiotics. The essential role of the ArnA dehydrogenase domain (ArnA_DH) in the addition of 4-amino-L-arabinose (L-Ara4N) to lipid A makes it a potential target in polymyxin adjuvant design. PURPOSE: This study aimed to identify a dehydrogenase inhibitor that enhances the antibacterial effect of polymyxin B (PB) and to further understand the mechanism of this drug combination. METHODS: A susceptible K. pneumoniae strain, ATCC13883, was used to screen a dehydrogenase inhibitor library based on 3-(4,5)-dimethylthiazol(-z-y1)-2,5-diphenyltetrazolium bromide (MTT) and chequerboard assays. The protein- and cell-based effects of disulfiram (DSF) on ArnA activity were assessed, and the transcription levels of genes in the arn operon were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Lipid A was isolated, and a structural analysis was performed. The cell wall function was evaluated through membrane integrity and bacterial viability assays. The in vivo antibacterial activity was evaluated using a mouse pulmonary infection model. RESULTS: We screened a dehydrogenase inhibitor library and found that the anti-alcoholism drug DSF significantly enhanced the antibacterial activity of PB in vitro and in vivo. The protein-based enzyme activity assay showed that DSF exerted no direct effect on the dehydrogenase activity of ArnA. Treatment with the combination of DSF and PB but not with PB alone decreased both the transcription level of genes in the arn operon and the modification level of lipid A. DSF also strengthened the disruption of the cell membrane integrity of PB. Moreover, the enhanced PB antibacterial activity was effective against clinical PB-resistant strains. CONCLUSION: We identified a new drug combination that can be used to reduce the necessary dosage of PB and overcome PB resistance, and this drug combination has good prospects for clinical application.

13.
Int J Biol Sci ; 18(1): 276-291, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34975332

RESUMEN

Esophageal carcinoma (EC) ranks sixth among cancers in mortality worldwide and effective drugs to reduce EC incidence and mortality are lacking. To explore potential anti-esophageal cancer drugs, we conducted drug screening and discovered that verdinexor, a selective inhibitor of nuclear exportin 1 (XPO1/CRM1), has anti-esophageal cancer effects both in vivo and in vitro. However, the mechanism and role of verdinexor in esophageal cancer remain unknown. In the present study, we observed that verdinexor inhibited the proliferation and migration of EC cells in vitro and suppressed tumor growth in vivo. Additionally, we found that verdinexor induced cleavage of PARP and downregulated XPO1, c-Myc, and FOSL1 expression. RNA-sequence analysis and protein-protein interaction (PPI) analysis revealed that verdinexor regulated the XPO1/c-Myc/FOSL1 axis. The results of immunoprecipitation and proximity ligation assays confirmed that verdinexor disrupted the interaction between XPO1 and c-Myc. Overexpression of c-Myc rescued the inhibition of cell proliferation and cell migration caused by verdinexor. Overexpressed FOSL1 restored the inhibited migration by verdinexor. Taken together, verdinexor inhibited cell proliferation and migration of esophageal cancer via XPO1/c-Myc/FOSL1 axis. Our findings provide a new option for the development of anti-esophageal cancer drugs.


Asunto(s)
Acrilamidas/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Neoplasias Esofágicas/tratamiento farmacológico , Hidrazinas/farmacología , Carioferinas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Línea Celular Tumoral , Humanos , Masculino , Ratones , Ratones Desnudos , alfa-Amilasas Salivales/metabolismo , Proteína Exportina 1
14.
Immun Inflamm Dis ; 10(7): e643, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35759238

RESUMEN

INTRODUCTION: Acute liver inflammatory reactions contribute to many health problems; thus, it is critical to understand the underlying pathogenic mechanisms of acute hepatitis. In this study, an experimental in vivo model of concanavalin A (ConA)-induced hepatitis was used. MATERIALS AND METHODS: C57BL/6 (wild-type, WT) or inducible nitric oxide synthase-deficient (iNOS-/- ) mice were injected with PBS or 15 mg/kg ConA via tail vein. Detection of liver injury by histological examination and apoptosis, and flow cytometry to detect the effect of immune cells on liver injury. RESULTS: iNOS-/-  mice had lower levels of the liver enzymes aspartate aminotransferase and alanine aminotransferase, suggesting that they were protected against ConA-induced pathological liver injury and that iNOS participated in the regulation of hepatitis. Furthermore, iNOS deficiency was found to lower CD86 expression and suppressed the messenger RNA levels of inflammatory factors in the liver. In vitro experiments also demonstrated that iNOS deficiency suppressed the sequential phosphorylation of the mitogen-activated protein kinase pathway cascade, thereby inhibiting the M1 polarization of macrophages and consequently suppressing the transcription of inflammation factors. CONCLUSION: iNOS may contribute to ConA-induced inflammation by promoting the activation of proinflammatory macrophages.


Asunto(s)
Hepatitis , Animales , Concanavalina A/metabolismo , Concanavalina A/toxicidad , Hepatitis/etiología , Hepatitis/metabolismo , Hepatitis/patología , Inflamación , Macrófagos , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo
15.
Sci Total Environ ; 782: 146893, 2021 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-33848860

RESUMEN

Marine aerosols are believed to have an organic surface coating on which fatty acids act as an important component due to their high surface activity. In addition, various kinds of enzyme species are abundantly found in seawater, some of which have been identified to exist in marine aerosols. Herein, from the perspective of marine aerosol interface simulation, we investigate the effect of Burkholderia cepacia lipase on the surface properties of stearic acid (SA) monolayer at the air-water interface by using surface-sensitive techniques of Langmuir trough and Infrared reflection-absorption spectroscopy (IRRAS). Our findings indicate that the stearic acid film undergoes a significant expansion, especially when the lipase concentration is 500 nM, because of the incorporation of lipase as observed from the surface pressure-area (π-A) isotherms. IRRAS spectra also show reduced intensities and ordering in the methylene stretching vibration region of stearic acid as a result of low surface density and disordered packing as the enzyme concentration increases. In particular, when the concentration of lipase is 500 nM, the lowest Ias/Is values are shown on both pure water subphase and artificial seawater subphase, indicating more gauche conformations for SA. Furthermore, SA films with lipase incorporation were also studied at three different pH of subphase environment, considering the decrease of pH caused by the reaction with acidic gases during the aerosol aging process. The results reflect a more pronounced expansion of SA monolayer in acidic environment at pH 2.5, suggesting that hydrophobic interaction plays an important role in the disorder of the SA monolayer. In view of the coexistence of fatty acids and enzymes in the marine environment, this study provides a further understanding of the surface organization and behavior of organic-coated marine aerosols and deepen the knowledge of lipid-enzyme interfacial interactions occurring in the atmosphere.


Asunto(s)
Lipasa , Agua de Mar , Aerosoles , Propiedades de Superficie , Agua
16.
Biomed Pharmacother ; 137: 111342, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33581652

RESUMEN

Liver fibrosis is one of the major threats to human health. At present, anti-liver fibrosis drugs exist some problems,such as, lack of targeting, limited treatment effect and more or less toxic side effects. In order to improve the efficacy of targeted therapy for liver fibrosis, the development of a large number of nanocarriers and strategies of targeted therapy for liver fibrosis have been widely studied. In this paper, the research progress of nano-delivery vectors targeting cells related to the process of liver fibrosis in recent years was reviewed in terms of targeting vectors and the types of modified ligands, providing a new strategy for targeted cell therapy and theoretical reference for the realization of high efficient targeted therapy of liver fibrosis.


Asunto(s)
Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Cirrosis Hepática/tratamiento farmacológico , Nanopartículas/uso terapéutico , Animales , Portadores de Fármacos/química , Células Endoteliales/metabolismo , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/metabolismo , Humanos , Macrófagos del Hígado/metabolismo , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Nanopartículas/química
17.
J Antibiot (Tokyo) ; 74(5): 324-329, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33456052

RESUMEN

The threat of antimicrobial resistance calls for more efforts in basic science, drug discovery, and clinical development, particularly gram-negative carbapenem-resistant pathogens. We sought to identify novel antibacterial agents against Acinetobacter baumannii ATCC19606 using whole cell-based screening. A small molecule named 6D1 with the chemical structure of 6-fluorobenzo[d]isothiazol-3(2H)-one was identified and exhibited activity against A. baumannii ATCC19606 strain (minimal inhibitory concentration, MIC = 1 mg l-1). The mutation in the plasmid-derived ohrB gene that encodes a peroxidase was identified in spontaneously resistant mutants. Treatment of the bacteria with 6D1 resulted in increased sensitivity to peroxide, such as tert-butyl hydroperoxide. The binding of 6D1 and OhrB was confirmed by surface plasmon resonance. Interestingly, the MIC of kanamycin and gentamicin against spontaneously resistant mutants decreased. Finally, we identified the effect of 6D1 on enhancing the antibacterial activity of kanamycin and gentamicin, including against New Delhi metallo-ß-lactamase (NDM-1)-producing carbapenem-resistant Klebsiella pneumoniae, but not in strains carrying aminoglycosides resistance genes. In this study, we identified a small molecule that suppresses the growth of A. baumannii, interacts with hydroperoxide reductase from A. baumannii ATCC19606 plasmid pMAC, and enhances the antibacterial activity of kanamycin and gentamicin. We propose that peroxidase may be potentially used as a target for aminoglycosides adjuvant development.


Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Aminoglicósidos/farmacología , Antibacterianos/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Peroxirredoxinas/metabolismo , Pseudomonas aeruginosa/efectos de los fármacos , Aminoglicósidos/administración & dosificación , Farmacorresistencia Bacteriana Múltiple , Sinergismo Farmacológico , Regulación Bacteriana de la Expresión Génica , Genoma Bacteriano , Pruebas de Sensibilidad Microbiana , Secuenciación Completa del Genoma
18.
Front Bioeng Biotechnol ; 9: 762489, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34950642

RESUMEN

Multidrug resistance (MDR) is a serious problem during cancer therapy. The purpose of the present study was to formulate D-α-Tocopheryl polyethylene glycol 1000 succinate-resveratrol-solid lipid nanoparticles (TPGS-Res-SLNs) to improve its therapeutic efficacy against breast cancer. In this study, the solvent injection method was used to prepare the TPGS-Res-SLNs. It was found that the TPGS-Res-SLNs exhibited zeta potential and drug-loading of -25.6 ± 1.3 mV and 32.4 ± 2.6%, respectively. Therefore, it was evident that the TPGS-Res-SLNs can increase cellular uptake of chemotherapeutic drugs, induce mitochondrial dysfunction, and augment tumor treatment efficiency by inducing apoptosis. Moreover, it was found that SKBR3/PR cells treated with TPGS-Res-SLNs exhibited significant inhibition of cell migration and invasion, as compared with free resveratrol. In addition, results from in vivo SKBR3/PR xenograft tumor models revealed that TPGS-Res-SLNs has better efficacy in promoting apoptosis of tumor cells owing to high therapeutic outcomes on tumors when compared with the efficacy of free resveratrol. In conclusion, the findings of the present study indicate significant potential for use of TPGS-Res-SLNs as an efficient drug delivery vehicle to overcome drug resistance in breast cancer therapy.

19.
Sci Total Environ ; 699: 134362, 2020 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-31522042

RESUMEN

Heterogeneous reactions between gaseous pollutants and mineral particles have gradually become a research hotspot in the field of atmospheric chemistry. In this paper, competitive reactions between SO2 and acetic acid on the surface of α-Al2O3 and CaCO3 particles were studied by the diffuse reflectance infrared Fourier transform spectroscopic (DRIFTS) technique in dark and dry conditions. At the same time, the temporary evolution of the integrated absorbance of acetate and sulfite was investigated to further understand the interaction of SO2 and acetic acid on the mineral particles. On the surface of α-Al2O3 particles, acetate and sulfite can compete for surface-active sites, resulting in a decrease in the total amount of acetates. In dark and dry conditions, the effect of acetic acid on SO2 cannot be obtained by the DRIFTS method. On the surface of CaCO3 particles, SO2 can have a competitive impact on acetic acid by grabbing active sites, leading to a slight decrease of the amount of acetates. The heterogeneous reaction of SO2 can be impeded by coexisting acetic acid, resulting in a drastic reduction of the number of sulfites. It can be seen that the formation mechanisms of acetate and sulfite on the surface of different mineral particles in the atmosphere are different, which provides a variety of ideas and possibilities for the formation of related inorganic and organic salts in the atmosphere.

20.
Environ Sci Process Impacts ; 22(2): 408-417, 2020 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-31994557

RESUMEN

The effects of NO2 and SO2 on the atmospheric heterogeneous reaction of acetic acid on α-Al2O3 in the presence and absence of simulated irradiation were investigated at ambient conditions by using the diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) technique. The experiment was divided into two parts: the heterogeneous reaction experiment and the pre-adsorption reaction experiment under light and dark conditions. In the heterogeneous reaction experiment, solar radiation stimulates the formation of more acetate and nitrate. At the same time, it can promote the partial conversion of sulfites to sulfates in the heterogeneous reaction of SO2 on α-Al2O3 particles. It can be seen that solar radiation plays a significant role in the heterogeneous reactions of inorganic and organic gases on mineral particles. In the pre-adsorption reaction experiment, the pre-adsorbed nitrate, sulfite or sulfate have conspicuous inhibition influence on the formation of acetate in the presence and absence of simulated irradiation. This indicates that the role of pre-adsorbed species should be given more attention for the heterogeneous reaction of acetic acid on the surface of α-Al2O3 particles. When α-Al2O3 particles were pre-adsorbed by different species, simulated irradiation could facilitate the growth of different amounts of acetate. It was found that the extent to which solar radiation contributes to heterogeneous reactions of different kinds of gases on different mineral particles is different. This further emphasizes the complexities of the heterogeneous conversion processes of atmospheric trace gases on the surface of mineral aerosols, promoting a better understanding of the effects of solar radiation and pre-adsorption on the heterogeneous reaction in the atmosphere.


Asunto(s)
Ácido Acético , Atmósfera , Adsorción , Aerosoles , Sulfatos
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