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1.
Nano Lett ; 2024 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-39475013

RESUMEN

Ferroptosis has shown great potential in activating antitumor immunity. However, the cunning tumor cells can evade ferroptosis by increasing the efflux of iron and promoting the production of the reductant glutathione to mitigate oxidative stress. Herein, a multifunctional exosome loaded with manganese-doped iron oxide nanoparticles (MnIO), GW4869, and l-buthionine sulfoximine (BSO) is developed to disrupt the iron metabolism homeostasis and redox homeostasis to enhance tumor immunotherapy. The efficient transport of MnIO by exosomes and the inhibition of iron exocytosis by GW4869 led to a high retention of up to 29.57% ID/g for iron in the tumors. Such a high retention of iron, in combination with the BSO-induced disruption of the redox homeostasis, effectively promotes the ferroptosis of tumor cells. Consequently, the multifunctional exosomes that noticeably enhance ferroptosis by dual homeostasis disruption provoke the cGAS-STING-based antitumor immune response and effectively suppress tumor growth and lung metastasis in orthotopic breast cancer.

2.
Anal Chem ; 95(2): 955-965, 2023 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-36573885

RESUMEN

Sepsis is one of the leading causes of death worldwide. The disease progression of sepsis is very fast, and there is a 7-9% increase in mortality every hour. Therefore, rapid and sensitive detection of pathogenic bacteria is crucial for the timely treatment of sepsis as well as the reduction of mortality. Herein, we present a sensitive near-infrared (NIR) fluorescence identification and a rapid magnetic capture based on bioorthogonal nanoprobes for the detection of multiple bacteria in whole blood. The nanoprobes with NIR fluorescence/magnetic properties were modified with dibenzocyclooctyne groups and used to capture and recognize the bacteria via bioorthogonal reaction. The magnetic nanoprobes showed superparamagnetic properties with a saturation magnetization as high as 63 emu/g. Through clicking with the azide groups inserted on the bacteria walls by metabolic engineering, the bioorthogonal magnetic nanoprobes allow fast and broad-spectrum capture of both Gram-positive and Gram-negative bacteria. The bioorthogonal NIR fluorescent nanoprobes with a maximum emission at 900 nm can effectively avoid background interference, further enabling sensitive identification of the bacteria in whole blood. The detection limit was as low as 4 CFU/mL in less than 2.5 h and the nanoprobes were successfully applied to the detection of bacteria in blood samples from the patients with sepsis, showing the potential application in early sepsis diagnosis and clinical studies.


Asunto(s)
Nanopartículas , Sepsis , Humanos , Fluorescencia , Antibacterianos , Bacterias Gramnegativas , Bacterias Grampositivas , Bacterias , Sepsis/diagnóstico
3.
J Exp Bot ; 73(1): 197-212, 2022 01 05.
Artículo en Inglés | MEDLINE | ID: mdl-34453430

RESUMEN

Embryo abortion often occurs during distant hybridization events. Apetala 2/ethylene-responsive factor (AP2/ERF) proteins are key transcription factor (TF) regulators of plant development and stress resistance, but their roles in hybrid embryo development are poorly understood. In this study, we isolated a novel AP2/ERF TF, CmERF12, from chrysanthemum and show that it adversely affects embryo development during distant hybridization. Transcriptome and real-time quantitative PCR demonstrate that CmERF12 is expressed at significantly higher levels in aborted ovaries compared with normal ones. CmERF12 localizes to the cell nucleus and contains a conserved EAR motif that mediates its transcription repressor function in yeast and plant cells. We generated artificial microRNA (amiR) CmERF12 transgenic lines of Chrysanthemum morifolium var. 'Yuhualuoying' and conducted distant hybridization with the wild-type tetraploid, Chrysanthemum nankingense, and found that CmERF12-knock down significantly promoted embryo development and increased the seed-setting rates during hybridization. The expression of various genes related to embryo development was up-regulated in developing ovaries from the cross between female amiR-CmERF12 C. morifolium var. 'Yuhualuoying'× male C. nankingense. Furthermore, CmERF12 directly interacted with CmSUF4, which is known to affect flower development and embryogenesis, and significantly reduced its ability to activate its target gene CmEC1 (EGG CELL1). Our study provides a novel method to overcome barriers to distant hybridization in plants and reveals the mechanism by which CmERF12 negatively affects chrysanthemum embryo development.


Asunto(s)
Chrysanthemum , Chrysanthemum/genética , Chrysanthemum/metabolismo , Desarrollo Embrionario , Regulación de la Expresión Génica de las Plantas , Hibridación Genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Factores de Transcripción/metabolismo
4.
Phytopathology ; 112(6): 1299-1309, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35000433

RESUMEN

Fusarium pseudograminearum is a soilborne, hemibiotrophic phytopathogenic fungus that causes Fusarium crown rot and Fusarium head blight in wheat. The basic leucine zipper proteins (bZIPs) are evolutionarily conserved transcription factors that play crucial roles in a range of growth and developmental processes and the responses to biotic and abiotic stresses. However, the roles of bZIP transcription factors remains unknown in F. pseudograminearum. In this study, a bZIP transcription factor Fpkapc was identified to localize to the nucleus in F. pseudograminearum. A mutant strain (Δfpkapc) was constructed to determine the role of Fpkapc in growth and pathogenicity of F. pseudograminearum. Transcriptomic analyses revealed that many genes involved in basic metabolism and oxidation-reduction processes were downregulated, whereas many genes involved in metal iron binding were upregulated in the Δfpkapc strain, compared with the wild type (WT). Correspondingly, the mutant had severe growth defects and displayed abnormal hyphal tips. Conidiation in the Fpkapc mutant was reduced, with more conidia in smaller size and fewer septa than in the WT. Also, relative to WT, the Δfpkapc strain showed greater tolerance to ion stress, but decreased tolerance to H2O2. The mutant caused smaller disease lesions on wheat and barley plants, but significantly increased TRI gene expression, compared with the WT. In summary, Fpkapc plays multiple roles in governing growth, development, stress responses, and virulence in F. pseudograminearum.


Asunto(s)
Fusarium , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Perfilación de la Expresión Génica , Peróxido de Hidrógeno , Enfermedades de las Plantas/microbiología , Triticum/genética , Triticum/microbiología , Virulencia
5.
Biochem Genet ; 60(5): 1601-1614, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35064361

RESUMEN

Homeobox transcription factors have been implicated in filamentous growth, conidia formation and virulence in fungal pathogens. However, the presence of the homeobox gene family and their potential influence on pathogenesis in Fusarium pseudograminearum have not been investigated. F. pseudograminearum is an important plant pathogen that causes wheat and barley crown rot. In this study, we performed a genome-wide survey for F. pseudograminearum homeobox genes, and 11 FpHtfs were identified and characterized. Domain analyses revealed that all of these proteins contain a complete homeobox domain that contains three helices. Expression profiles of FpHtf genes at different pathogen stages showed that six FpHtf genes were induced during infection. Further, we generated and characterized FpHtf3 deletion mutants in F. pseudograminearum, showing it was essential for virulence. These results indicated that members of the homeobox gene family are likely involved in F. pseudograminearum pathogenicity. Our work also provides a useful foundation for further studies on the complexity and function of the homeobox gene family in F. pseudograminearum.


Asunto(s)
Fusarium , Genes Homeobox , Fusarium/genética , Fusarium/metabolismo , Enfermedades de las Plantas/microbiología , Virulencia/genética
6.
Nano Lett ; 21(19): 8418-8425, 2021 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-34546061

RESUMEN

A cancer vaccine has been widely applied in clinical tumor therapy as one of the main strategies of immunotherapy. However, the traditional cancer vaccine for a single antigen has a low benefit rate due to the individual differences in patients. Here, we report a R837-loaded poly(lactic-co-glycolic acid) nanovaccine coated with a calcinetin (CRT)-expressed cancer cell membrane antigen for immunotherapy. The cell membrane antigen that possessed a complete antigen array was obtained by inducing immunogenic cell death in vitro, avoiding the severe systemic toxicity of chemotherapy in vivo. The nanovaccine codelivers the adjuvant R837 and the Luc-4T1 membrane antigen, triggering a personalized immune response to the corresponding tumor. Moreover, the calcinetin exposed on the surface of the nanovaccine induces the active uptake of dendritic cells, consequently enhancing the antitumor effect. Meanwhile, the nanovaccine activates immune memory cells to provide long-term protection. Our work provides a new strategy for a clinical personalized antitumor vaccine.


Asunto(s)
Vacunas contra el Cáncer , Nanopartículas , Neoplasias , Animales , Membrana Celular , Células Dendríticas , Humanos , Inmunoterapia , Ratones , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico
7.
Antimicrob Agents Chemother ; 65(12): e0029121, 2021 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-34516252

RESUMEN

Aspergillus fumigatus causes a series of invasive diseases, including the high-mortality invasive aspergillosis, and has been a serious global health threat because of its increased resistance to the first-line clinical triazoles. We analyzed the whole-genome sequence of 15 A. fumigatus strains from China and found that long terminal repeat retrotransposons (LTR-RTs), including Afut1, Afut2, Afut3, and Afut4, are most common and have the largest total nucleotide length among all transposable elements in A. fumigatus. Deleting one of the most enriched Afut4977-sac1 in azole-resistant strains decreased azole resistance and downregulated its nearby gene, sac1, but it did not significantly affect the expression of genes of the ergosterol synthesis pathway. We then discovered that 5'LTR of Afut4977-sac1 had promoter activity and enhanced the adjacent sac1 gene expression. We found that sac1 is important to A. fumigatus, and the upregulated sac1 caused elevated resistance of A. fumigatus to azoles. Finally, we showed that Afut4977-sac1 has an evolution pattern similar to that of the whole genome of azole-resistant strains due to azoles; phylogenetic analysis of both the whole genome and Afut4977-sac1 suggests that the insertion of Afut4977-sac1 might have preceded the emergence of azole-resistant strains. Taking these data together, we found that the Afut4977-sac1 LTR-RT might be involved in the regulation of azole resistance of A. fumigatus by upregulating its nearby sac1 gene.


Asunto(s)
Aspergillus fumigatus , Azoles , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Aspergillus fumigatus/genética , Azoles/farmacología , Farmacorresistencia Fúngica/genética , Proteínas Fúngicas/genética , Pruebas de Sensibilidad Microbiana , Filogenia , Retroelementos/genética , Secuencias Repetidas Terminales/genética
8.
New Phytol ; 231(5): 1858-1874, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33973259

RESUMEN

Artemisinin, isolated from Artemisia annua, is recommended as the preferred drug to fight malaria. Previous research showed that jasmonate (JA)-mediated promotion of artemisinin accumulation depended on light. However, the mechanism underlying the interaction of light and JA in regulating artemisinin accumulation is still unknown. We identified a WRKY transcription factor, AaWRKY9, using transcriptome analysis. The glandular trichome-specific AaWRKY9 positively regulates artemisinin biosynthesis by directly binding to the promoters of AaDBR2 and AaGSW1. The key regulator in the light pathway AaHY5 activates the expression of AaWRKY9 by binding to its promoter. In addition, AaWRKY9 interacts with AaJAZ9, a repressor in the JA signalling pathway. AaJAZ9 represses the transcriptional activation activity of AaWRKY9 in the absence of methyl jasmonate. Notably, in the presence of methyl jasmonate, the transcriptional activation activity of AaWRKY9 is increased. Taken together, our results reveal a novel molecular mechanism underlying AaWRKY9 contributes to light-mediated and jasmonate-mediated to regulate the biosynthesis of artemisinin in A. annua. Our study provides new insights into integrating the two signalling pathways to regulate terpene biosynthesis in plants.


Asunto(s)
Artemisia annua , Artemisininas , Artemisia annua/genética , Ciclopentanos , Oxilipinas , Proteínas de Plantas/genética , Tricomas
9.
Biotechnol Appl Biochem ; 68(2): 338-344, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32339306

RESUMEN

Artemisinin, an effective antimalarial compound, is isolated from the medicinal plant Artemisia annua L. However, because of the low content of artemisinin in A. annua, the demand of artemisinin exceeds supply. Previous studies show that the artemisinin biosynthesis is promoted by light in A. annua. Cryptochrome1 (CRY1) is involved in many processes in the light response. In this study, AaCRY1 was cloned from A. annua. Overexpressing AaCRY1 in Arabidopsis thaliana cry1 mutant resulted in blue-light-dependent short hypocotyl phenotype and short coleoptile under blue light. Yeast two-hybrid and subcellular colocalization showed that AaCRY1 interacted with AtCOP1 (ubiquitin E3 ligase CONSTITUTIVE PHOTOMORPHOGENIC1). Overexpression of AaCRY1 in transgenic A. annua increased the artemisinin content. When AaCRY1 was overexpressed in A. annua driven by the CYP71AV1 (cytochrome P450 dependent amorpha-4,11-diene 12-hydroxylase) promoter, the artemisinin content was 1.6 times higher than that of the control. Furthermore, we expressed the C terminal of AaCRY1(CCT) involved a GUS-CCT fusion protein in A. annua. The results showed that the artemisinin content was increased to 1.7- to 2.4-fold in GUS-CCT transgenic A. annua plants. These results demonstrate that overexpression of GUS-CCT is an effective strategy to increase artemisinin production in A. annua.


Asunto(s)
Artemisia annua , Artemisininas/metabolismo , Criptocromos , Lactonas/metabolismo , Plantas Modificadas Genéticamente , Artemisia annua/genética , Artemisia annua/metabolismo , Criptocromos/biosíntesis , Criptocromos/genética , Plantas Modificadas Genéticamente/genética , Plantas Modificadas Genéticamente/metabolismo
10.
Emerg Infect Dis ; 26(1): 81-89, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31855142

RESUMEN

In 2018, we conducted a cross-sectional study to investigate azole resistance in environmental Aspergillus fumigatus isolates obtained from different agricultural fields in China. Using 63 soil cores, we cultured for azole-resistant A. fumigatus and characterized isolates by their cyp51A gene type, short tandem repeat genotype, and mating type. Of 206 A. fumigatus isolates, 21 (10.2%) were azole resistant. Nineteen of 21 had mutations in their cyp51A gene (5 TR34/L98H, 8 TR34/L98H/S297T/F495I, 6 TR46/Y121F/T289A). Eighteen were cultured from soil samples acquired from strawberry fields, suggesting this soil type is a potential hotspot for azole resistance selection. Twenty resistant isolates were mating type MAT1-1, suggesting asexual sporulation contributed to their evolution. Prochloraz, difenoconazole, and tebuconazole were the most frequently detected fungicides in soil samples with azole-resistant fungus. Our study results suggest that managing the fungicides used in agriculture will help contain the problem of antifungal drug resistance in clinics.


Asunto(s)
Aspergillus fumigatus/efectos de los fármacos , Producción de Cultivos , Fragaria , Fungicidas Industriales/farmacología , Aspergillus fumigatus/genética , Aspergillus fumigatus/aislamiento & purificación , China/epidemiología , Estudios Transversales , Farmacorresistencia Fúngica/genética , Técnicas de Genotipaje , Pruebas de Sensibilidad Microbiana , Repeticiones de Microsatélite/genética , Filogenia , Análisis de Secuencia de ADN , Microbiología del Suelo
11.
Int J Cancer ; 146(1): 103-114, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31199508

RESUMEN

Next-generation sequencing of cell-free circulating DNA (cfDNA) has emerged as promising technique for identifying minimally invasive genomic profiling of tumor cells recently. However, it remains relatively unknown in LAM disease. In our study, paired cfDNA and genomic DNA (gDNA) in blood samples were obtained from 23 LAM patients and seven healthy controls to explore mutations profiles of targeted 70 cancer-related genes. As results, log2-based allele frequencies of mutations in cfDNA were significantly different from those of gDNA. By comparing the mutual mutations identified both in cfDNA and gDNA, a significant correlation was also observed. After removing mutations in gDNA, distinct somatic mutation profiles of cfDNA were observed in LAM patients. Forty of 70 targeted genes had recurrent mutations, of which ATM, BRCA2 and APC showed the highest frequency. Based on the mutation, correlation network constructed of 40 mutated genes, 11 hub genes bearing intensive interactions were highlighted, including BRCA1, BRCA2, RAD50, RB1, NF1, APC, MLH3, ATM, PDGFRA, PALB2 and BLM. Expression of the hub genes showed significant clusters between LAM patients and controls and that RAD50 and BRCA2 had the strongest associations with subject phenotypes. Myogenesis and estrogen response were confirmed to be positively regulated in LAM patients. Collectively, our study provided a landscape of genomic alterations in LAM and discovered several potential driver genes, that is, BRCA2 and RAD50, which shed a substantial light on the clinical application of key molecular markers and potential therapy targets for precision diagnosis and treatment in the future.


Asunto(s)
Ácidos Nucleicos Libres de Células/genética , Neoplasias Pulmonares/genética , Linfangioleiomiomatosis/genética , Mutación/genética , Adulto , Proteína BRCA2/genética , ADN Tumoral Circulante/genética , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Femenino , Frecuencia de los Genes/genética , Genoma/genética , Genómica/métodos , Humanos , Masculino , Persona de Mediana Edad
12.
Artículo en Inglés | MEDLINE | ID: mdl-31740554

RESUMEN

To understand the characterizations of azole resistance in Aspergillus fumigatus from potting soil samples in the hospital, a total of 58 samples were collected. Among 106 A. fumigatus samples obtained, 5 isolates from 4 soil samples located in the gerontology department were identified as azole-resistant A. fumigatus (ARAF). Four ARAF isolates harbored the TR34/L98H allele, and the other one had no mutation in the cyp51A gene. Among 174 A. fumigatus samples selected for genotyping, TRESPERG typing obtained a close discriminatory power (Simpson's index of diversity [DI], 0.9941; 95% confidence interval [CI], 0.9913 to 0.9968) compared with the short tandem repeat (STR) typing (DI, 0.9997; 95% CI, 0.9976 to 1.0000). Genotyping showed that the TR34/L98H isolates in the hospital had a close genetic relationship with ARAF isolates from China and many other countries. In conclusion, this study indicated the presence of ARAF in potting soil samples from the hospital, which might pose a risk of causing ARAF infection in patients.


Asunto(s)
Antifúngicos/farmacología , Aspergillus fumigatus/efectos de los fármacos , Azoles/farmacología , Farmacorresistencia Fúngica/efectos de los fármacos , Pruebas de Sensibilidad Microbiana/métodos , Microbiología del Suelo , Alelos , Aspergillus fumigatus/genética , China , Infección Hospitalaria/microbiología , Farmacorresistencia Fúngica/genética , Genotipo , Repeticiones de Microsatélite , Técnicas de Tipificación Micológica , Reproducibilidad de los Resultados
13.
Curr Genet ; 66(3): 507-515, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31696258

RESUMEN

Fusarium pseudograminearum is an important pathogen of Fusarium crown rot and Fusarium head blight, which is able to infect wheat and barley worldwide, causing great economic losses. Transcription factors (TFs) of the basic leucine zipper (bZIP) protein family control important processes in all eukaryotes. In this study, we identified a gene, designated FpAda1, encoding a bZIP TF in F. pseudograminearum. The homolog of FpAda1 is also known to affect hyphal growth in Neurospora crassa. Deletion of FpAda1 in F. pseudograminearum resulted in defects in hyphal growth, mycelial branching and conidia formation. Pathogenicity assays showed that virulence of the Δfpada1 mutant was dramatically decreased on wheat coleoptiles and barley leaves. However, wheat coleoptile inoculation assay showed that Δfpada1 could penetrate and proliferate in wheat cells. Moreover, the FpAda1 was required for abnormal nuclear morphology in conidia and transcription of FpCdc2 and FpCdc42. Taken together, these results indicate that FpAda1 is an important transcription factor involved in growth and development in F. pseudograminearum.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas Fúngicas/metabolismo , Fusarium/crecimiento & desarrollo , Hordeum/microbiología , Enfermedades de las Plantas/microbiología , Esporas Fúngicas/crecimiento & desarrollo , Triticum/microbiología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Proteínas Fúngicas/genética , Fusarium/genética , Fusarium/patogenicidad , Hojas de la Planta/microbiología , Esporas Fúngicas/genética
14.
Small ; 16(38): e2003543, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32812355

RESUMEN

The progress of antitumor immunotherapy is usually limited by tumor-associated macrophages (TAMs) that account for the highest proportion of immunosuppressive cells in the tumor microenvironment, and the TAMs can also be reversed by modulating the M2-like phenotype. Herein, a biomimetic polymer magnetic nanocarrier is developed with selectively targeting and polarizing TAMs for potentiating immunotherapy of breast cancer. This nanocarrier PLGA-ION-R837 @ M (PIR @ M) is achieved, first, by the fabrication of magnetic polymer nanoparticles (NPs) encapsulating Fe3 O4 NPs and Toll-like receptor 7 (TLR7) agonist imiquimod (R837) and, second, by the coating of the lipopolysaccharide (LPS)- treated macrophage membranes on the surface of the NPs for targeting TAMs. The intracellular uptake of the PIR @ M can greatly polarize TAMs from M2 to antitumor M1 phenotype with the synergy of Fe3 O4 NPs and R837. The relevant mechanism of the polarization is deeply studied through analyzing the mRNA expression of the signaling pathways. Different from previous reports, the polarization is ascribed to the fact that Fe3 O4 NPs mainly activate the IRF5 signaling pathway via iron ions instead of the reactive oxygen species-induced NF-κB signaling pathway. The anticancer effect can be effectively enhanced through potentiating immunotherapy by the polarization of the TAMs in the combination of Fe3 O4 NPs and R837.


Asunto(s)
Polímeros , Macrófagos Asociados a Tumores , Biomimética , Humanos , Inmunoterapia , Factores Reguladores del Interferón , Fenómenos Magnéticos
15.
Plant Cell Physiol ; 60(8): 1747-1760, 2019 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-31076768

RESUMEN

Artemisinin, the frontline drug against malaria, is a sesquiterpenoid extracted from Artemisia annua. Light has been proposed to play an important role in the activation of artemisinin biosynthesis. Here, we report the basic leucine zipper transcription factor (TF) AaHY5 as a key regulator of light-induced biosynthesis of artemisinin. We show that AaHY5 transcription overlaps with that of artemisinin biosynthesis genes in response to light and in A. annua tissues. Analysis of AaHY5 overexpression and RNAi-suppression lines suggests that AaHY5 is a positive regulator of the expression of artemisinin biosynthesis genes and accumulation of artemisinin. We show that AaHY5 complements the hy5 mutant in Arabidopsis thaliana. Our data further suggest that AaHY5 interacts with AaCOP1, the ubiquitin E3 ligase CONSTITUTIVE PHOTOMORPHOGENIC1 in A. annua. In yeast one-hybrid and transient expression assays, we demonstrate that AaHY5 acts via the TF GLANDULAR TRICHOME-SPECIFIC WRKY 1 (AaGSW1) in artemisinin regulation. In summary, we present a novel regulator of artemisinin gene expression and propose a model in which AaHY5 indirectly controls artemisinin production in response to changing light conditions.


Asunto(s)
Artemisia annua/metabolismo , Artemisininas/metabolismo , Luz , Artemisia annua/efectos de la radiación , Regulación de la Expresión Génica de las Plantas/efectos de la radiación , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/metabolismo , Plantas Modificadas Genéticamente/efectos de la radiación , Factores de Transcripción
16.
Artículo en Inglés | MEDLINE | ID: mdl-29483117

RESUMEN

Through some specific amino acid residues, cofilin, a ubiquitous actin depolymerization factor, can significantly affect mitochondrial function related to drug resistance and apoptosis in Saccharomyces cerevisiae; however, this modulation in a major fungal pathogen, Aspergillus fumigatus, was still unclear. Hereby, it was found, first, that mutations on several charged residues in cofilin to alanine, D19A-R21A, E48A, and K36A, increased the formation of reactive oxygen species and induced apoptosis along with typical hallmarks, including mitochondrial membrane potential depolarization, cytochrome c release, upregulation of metacaspases, and DNA cleavage, in A. fumigatus Two of these mutations (D19A-R21A and K36A) increased acetyl coenzyme A and ATP concentrations by triggering fatty acid ß-oxidation. The upregulated acetyl coenzyme A affected the ergosterol biosynthetic pathway, leading to overexpression of cyp51A and -B, while excess ATP fueled ATP-binding cassette transporters. Besides, both of these mutations reduced the susceptibility of A. fumigatus to azole drugs and enhanced the virulence of A. fumigatus in a Galleria mellonella infection model. Taken together, novel and key charged residues in cofilin were identified to be essential modules regulating the mitochondrial function involved in azole susceptibility, apoptosis, and virulence of A. fumigatus.


Asunto(s)
Factores Despolimerizantes de la Actina/genética , Antifúngicos/farmacología , Apoptosis/genética , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/genética , Azoles/farmacología , Farmacorresistencia Fúngica/genética , Mitocondrias/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Acetilcoenzima A/biosíntesis , Aspergillus fumigatus/patogenicidad , Sistema Enzimático del Citocromo P-450/biosíntesis , Ergosterol/biosíntesis , Proteínas Fúngicas/biosíntesis , Humanos , Virulencia/genética
17.
Artículo en Inglés | MEDLINE | ID: mdl-29507067

RESUMEN

The use of azole fungicides in agriculture is believed to be one of the main reasons for the emergence of azole resistance in Aspergillus fumigatus Though widely used in agriculture, imidazole fungicides have not been linked to resistance in A. fumigatus This study showed that elevated MIC values of imidazole drugs were observed against A. fumigatus isolates with TR34/L98H/S297T/F495I mutation, but not among isolates with TR34/L98H mutation. Short-tandem-repeat (STR) typing analysis of 580 A. fumigatus isolates from 20 countries suggested that the majority of TR34/L98H/S297T/F495I strains from China were genetically different from the predominant major clade comprising most of the azole-resistant strains and the strains with the same mutation from the Netherlands and Denmark. Alignments of sterol 14α-demethylase sequences suggested that F495I in A. fumigatus was orthologous to F506I in Penicillium digitatum and F489L in Pyrenophora teres, which have been reported to be associated with imidazole resistance. In vitro antifungal susceptibility testing of different recombinants with cyp51A mutations further confirmed the association of the F495I mutation with imidazole resistance. In conclusion, this study suggested that environmental use of imidazole fungicides might confer selection pressure for the emergence of azole resistance in A. fumigatus.


Asunto(s)
Antifúngicos/farmacología , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/genética , Sistema Enzimático del Citocromo P-450/genética , Farmacorresistencia Fúngica/genética , Proteínas Fúngicas/genética , Imidazoles/farmacología , Esterol 14-Desmetilasa/genética , Agricultura/métodos , Secuencia de Aminoácidos , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/aislamiento & purificación , Humanos , Pruebas de Sensibilidad Microbiana , Selección Genética/genética , Alineación de Secuencia
19.
Small ; 14(12): e1702994, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29205795

RESUMEN

Mitochondrial-targeting therapy is an emerging strategy for enhanced cancer treatment. In the present study, a multistage targeting strategy using doxorubicin-loaded magnetic composite nanoparticles is developed for enhanced efficacy of photothermal and chemical therapy. The nanoparticles with a core-shell-SS-shell architecture are composed of a core of Fe3 O4 colloidal nanocrystal clusters, an inner shell of polydopamine (PDA) functionalized with triphenylphosphonium (TPP), and an outer shell of methoxy poly(ethylene glycol) linked to the PDA by disulfide bonds. The magnetic core can increase the accumulation of nanoparticles at the tumor site for the first stage of tumor tissue targeting. After the nanoparticles enter the tumor cells, the second stage of mitochondrial targeting is realized as the mPEG shell is detached from the nanoparticles by redox responsiveness to expose the TPP. Using near-infrared light irradiation at the tumor site, a photothermal effect is generated from the PDA photosensitizer, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the loaded doxorubicin can rapidly enter the mitochondria and subsequently damage the mitochondrial DNA, resulting in cell apoptosis. Thus, the synergism of photothermal therapy and chemotherapy targeting the mitochondria significantly enhances the cancer treatment.


Asunto(s)
Nanopartículas/química , Fármacos Fotosensibilizantes/química , Fototerapia/métodos , Indoles/química , Mitocondrias/metabolismo , Compuestos Organofosforados/química , Polímeros/química
20.
BMC Infect Dis ; 18(1): 491, 2018 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-30268099

RESUMEN

BACKGROUND: Carbapenem resistance in Acinetobacter baumannii in China was mainly mediated by OXA-23-like carbapenemases, while OXA-24/40-like carbapenemases were rarely identified. OXA-72 is one variant of OXA-24/40-like carbapenemases. This study aimed to demonstrate the epidemiology and characterizations of OXA-72-producing A. baumannii in a Chinese hospital. METHODS: A total of 107 clinical A. calcoaceticus-A. baumannii (Acb) complex isolates were collected in a Chinese hospital during between 2014 and 2016. These isolates were identified using Vitek 2 system and gyrB multiplex PCR. Vitek 2 system was used for antibiotic susceptibility testing. Genes encoding for major classes of carbapenemases were investigated by PCR. Rep-PCR was used for genotyping of all the A. baumannii isolates. The risk factors for carriage of OXA-72-producing or OXA-23-producing A. baumannii were analyzed through univariate and multivariate logistic regression. RESULTS: Of the 107 Acb isolates collected, 101 isolates (94.4%) and 6 isolates (5.6%) were identified as A. baumannii and A. pittii, respectively. 78 A. baumannii isolates (77.2%) were carbapenem resistant and mainly cultured from intensive care unit (ICU). blaOXA-72 and blaOXA-23 genes were identified in 45(57.7%) and 33(42.3%) carbapenem-resistant A. baumannii (CRAB), respectively. Multivariate risk factor analyses showed that prior carbapenem usage and nasogastric intubation were significantly associated with carriage of OXA-72-producing A. baumannii or OXA-23-producing A. baumannii. Rep-PCR analysis showed that 9 and 22 Rep-PCR types were assigned to 78 CRAB isolates and 23 carbapenem-susceptible A. baumannii (CSAB) isolates, respectively. A higher diverstiy of Rep-PCR patterns was observed among OXA-72-producing A. baumannii isolates than OXA-23-producing A. baumannii isolates, but all of them belonged to the same clone complex. MLST analysis suggested that the OXA-72 isolates from this study correspond to CC92/CC2 clone complex. CONCLUSIONS: This study demonstrates high prevalence and potential clonal spread of closely related genotypes of OXA-72-producing A. baumannii within a Chinese hospital. Continuous surveillance is necessary to monitor the dissemination of these strains in other healthcare settings to guide infection control policies in order to curb the spread of this bacterium.


Asunto(s)
Infecciones por Acinetobacter/diagnóstico , Acinetobacter baumannii/metabolismo , Proteínas Bacterianas/genética , beta-Lactamasas/genética , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/epidemiología , Infecciones por Acinetobacter/microbiología , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/aislamiento & purificación , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Proteínas Bacterianas/metabolismo , Carbapenémicos/farmacología , Carbapenémicos/uso terapéutico , China/epidemiología , Estudios Transversales , Farmacorresistencia Bacteriana/genética , Femenino , Humanos , Unidades de Cuidados Intensivos , Modelos Logísticos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Prevalencia , Adulto Joven , beta-Lactamasas/metabolismo
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