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Introduction: Pseudomonas aeruginosa is present throughout nature and is a common opportunistic pathogen in the human body. Carbapenem antibiotics are typically utilized as a last resort in the clinical treatment of multidrug-resistant infections caused by P. aeruginosa. The increase in carbapenem-resistant P. aeruginosa poses an immense challenge for the treatment of these infections. Bacteriophages have the potential to be used as antimicrobial agents for treating antibiotic-resistant bacteria. Methods and Results: In this study, a new virulent P. aeruginosa phage, Phage_Pae01, was isolated from hospital sewage and shown to have broad-spectrum antibacterial activity against clinical P. aeruginosa isolates (83.6%). These clinical strains included multidrug-resistant P. aeruginosa and carbapenem-resistant P. aeruginosa. Transmission electron microscopy revealed that the phage possessed an icosahedral head of approximately 80 nm and a long tail about 110 m, indicating that it belongs to the Myoviridae family of the order Caudovirales. Biological characteristic analysis revealed that Phage_Pae01 could maintain stable activity in the temperature range of 4~ 60°C and pH range of 4 ~ 10. According to the in vitro lysis kinetics of the phage, Phage_Pae01 demonstrated strong antibacterial activity. The optimal multiplicity of infection was 0.01. The genome of Phage_Pae01 has a total length of 93,182 bp and contains 176 open reading frames (ORFs). The phage genome does not contain genes related to virulence or antibiotic resistance. In addition, Phage_Pae01 effectively prevented the formation of biofilms and eliminated established biofilms. When Phage_Pae01 was combined with gentamicin, it significantly disrupted established P. aeruginosa biofilms. Conclusion: We identified a novel P. aeruginosa phage and demonstrated its effective antimicrobial properties against P. aeruginosa in both the floating and biofilm states. These findings offer a promising approach for the treatment of drug-resistant bacterial infections in clinical settings.
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Purpose: Elizabethkingia spp. infections have recently increased, and they are difficult to treat because of intrinsic antimicrobial resistance. This study aimed to investigate the clinical characteristics of patients with pulmonary infection with Elizabethkingia spp. and reveal the risk factors for infection and death. Patients and Methods: In this retrospective case-control study, patients were divided into infection and control groups based on the bacterial identification results. Patients in the infection group were further divided into survival and death groups according to their hospital outcomes. Clinical characteristics between different groups were compared. We further analyzed antimicrobial susceptibility testing results of the isolated strains. Results: A total of the 316 patients were divided into infection (n = 79), 23 of whom died, and control (n = 237) groups. Multivariate logistic regression analysis showed that glucocorticoid consumption (OR: 2.35; 95% CI: 1.14-4.81; P = 0.02), endotracheal intubation (OR: 3.74; 95% CI: 1.62-8.64; P = 0.002), and colistin exposure (OR: 2.50; 95% CI: 1.01-6.29; P = 0.046) were significantly associated with pulmonary infection with Elizabethkingia spp. Advanced age (OR: 1.07, 95% CI: 1.00-1.15; P = 0.046), high acute physiology and chronic health evaluation (APACHE) II score (OR: 1.21; 95% CI: 1.01-1.45; P = 0.037), and low albumin level (OR: 0.73, 95% CI: 0.56-0.96; P = 0.025) were significantly associated with in-hospital mortality of infected patients. Elizabethkingia spp. was highly resistant to cephalosporins, carbapenems, macrolides, and aminoglycoside, and was sensitive to fluoroquinolones, minocycline, and co-trimoxazole in vitro. Conclusion: Glucocorticoid consumption, tracheal intubation, and colistin exposure were associated with pulmonary infection with Elizabethkingia spp. for critically ill patients. Patients with advanced age, high APACHE II score, and low albumin level had higher risk of death from infection.
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Xanthine oxidase (XO) is a typical target for hyperuricemia and gout, for which there are only three commercial xanthine oxidase inhibitors (XOIs): febuxostat, topiroxostat and allopurinol. However, these inhibitors have problems such as low bioactivity and several side effects. Therefore, the development of novel XOIs with high bioactivity for the treatment of hyperuricemia and gout is urgently needed. In this work we constructed a XO immobilized cellulose membrane colorimetric biosensor (XNCM) by the TEMPO oxidation, amide bond coupling and nitro blue tetrazolium chloride (NBT) loading method. As expected, the XNCM was able to detect xanthine, with high selectivity and sensitivity by colorimetric method with a distinctive color change from yellow to purple, which can be easily observed by the naked-eye in just 8 min without any complex instrumentation. In addition, the XNCM sensor performed screening of 21 different compounds and have been successfully pre-screened out XOIs with biological activity. Most importantly, the XNCM was able to quantitatively detect the IC50 values of two commercial inhibitors (febuxostat and allopurinol). All the results confirmed that the XNCM is a simple and effective tool which can be used for the accelerated screening of XOIs and has the potential to uncover additional XOIs.
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Técnicas Biosensibles , Celulosa , Inhibidores Enzimáticos , Enzimas Inmovilizadas , Xantina Oxidasa , Humanos , Alopurinol/farmacología , Técnicas Biosensibles/métodos , Celulosa/química , Colorimetría/métodos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/análisis , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/antagonistas & inhibidores , Membranas Artificiales , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismoRESUMEN
BACKGROUND: Cysteine (Cys), glutathione (GSH), and homocysteine (Hcy), as three major biothiols are involved in a variety of physiological processes and play a crucial role in plant growth. Abnormal levels of Cys can cause plants to fail to grow properly. To date, although a very large number of fluorescent probes have been reported for the detection of biothiols, very few of them can be used for the selective discrimination of Cys from GSH and Hcy due to their structural similarity, and only a few of them can be used for plant imaging. RESULTS: Here, three fluorescent probes (o-/m-/p-TMA) based on TMN fluorophore and the ortho-/meta-/para-substituted maleimide recognition groups were constructed to investigate the selective response effect of Cys. Compared to the o-/m-TMA, p-TMA can selectively detect Cys over GSH and Hcy with a rapid response time (10 min) and a low detection limit (0.26 µM). The theoretical calculation confirmed that the intermediate p-TMA-Cys-int has shorter interatomic reaction distances (3.827 Å) compared to o-/m-TMA-Cys (5.533/5.287 Å), making it more suitable for further transcyclization reactions. Additionally, p-TMA has been employed for selective tracking of exogenous and endogenous Cys in Arabidopsis thaliana using both single-/two-photon fluorescence imaging. Furthermore, single cell walls produced obvious two-photon fluorescence signals, indicating that p-TMA can be used for high-concentration Cys analysis in single cells. Surprisingly, p-TMA can be used as a fluorescent dye for protein staining in SDS-PAGE with higher sensitivity (7.49 µg/mL) than classical Coomassie brilliant blue (14.11 µg/mL). SIGNIFICANCE: The outstanding properties of p-TMA make it a promising multifunctional molecular tool for the highly selective detection of Cys over GSH and Hcy in various complex environments, including water solutions, zebrafish, and plants. Additionally, it has the potential to be developed as a fluorescent dye for a simple and fast SDS-PAGE fluorescence staining method.
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Cisteína , Electroforesis en Gel de Poliacrilamida , Colorantes Fluorescentes , Glutatión , Homocisteína , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Cisteína/análisis , Cisteína/química , Glutatión/análisis , Glutatión/química , Homocisteína/análisis , Homocisteína/química , Animales , Fotones , Imagen Óptica , Arabidopsis/química , Humanos , Ciclización , Pez CebraRESUMEN
Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and gout, as they can effectively inhibit the production of uric acid. Previous studies indicated that both indole and isoxazole derivatives have good inhibitory effects against XO. Here, we designed and synthesized a novel series of N-5-(1H-indol-5-yl)isoxazole-3-carboxylic acids according to bioisosteric replacement and hybridization strategies. Among the obtained target compounds, compound 6c showed the best inhibitory activity against XO with an IC50 value of 0.13 µM, which was 22-fold higher than that of the classical antigout drug allopurinol (IC50 = 2.93 µM). Structure-activity relationship analysis indicated that the hydrophobic group on the nitrogen atom of the indole ring is essential for the inhibitory potencies of target compounds against XO. Enzyme kinetic studies proved that compound 6c acted as a mixed-type XOI. Molecular docking studies showed that the target compound 6c could not only retain the key interactions similar to febuxostat at the XO binding site but also generate some new interactions, such as two hydrogen bonds between the oxygen atom of the isoxazole ring and the amino acid residues Ser876 and Thr1010. These results indicated that 5-(1H-indol-5-yl)isoxazole-3-carboxylic acid might be an efficacious scaffold for designing novel XOIs and compound 6c has the potential to be used as a lead for further the development of novel anti-gout candidates.
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Ácidos Carboxílicos , Diseño de Fármacos , Inhibidores Enzimáticos , Isoxazoles , Xantina Oxidasa , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismo , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Isoxazoles/química , Isoxazoles/farmacología , Isoxazoles/síntesis química , Ácidos Carboxílicos/farmacología , Ácidos Carboxílicos/química , Ácidos Carboxílicos/síntesis química , Estructura Molecular , Humanos , Simulación del Acoplamiento Molecular , Indoles/farmacología , Indoles/química , Indoles/síntesis química , Relación Dosis-Respuesta a DrogaRESUMEN
Catalytic reduction of p-nitrophenol is usually carried out using transition metal nanoparticles such as gold, palladium, silver, and copper, especially palladium nanoparticles (Pd NPs), which are characterized by fast reaction rate, high turnover frequency, good selectivity, and high yield. However, the aggregation and precipitation of the metals lead to the decomposition of the catalyst, which results in a significant reduction of the catalytic activity. Therefore, the preparation of homogeneous stabilized palladium nanoparticles catalysts has been widely studied. Stabilized palladium nanoparticles mainly use synthetic polymers. Cellulose microspheres, as a natural polymer material with low-cost and porous fiber network structure, are excellent carriers for stabilizing metal nanoparticles. Cellulose microspheres impregnated with palladium metal nanoparticles were carbonized to have a larger specific surface area and highly dispersed palladium nanoparticles, which exhibited excellent catalytic activity in the catalytic reduction of p-nitrophenol. In this work, the cellulose carbon-based microspheres palladium (Pd@CCM) catalysts were designed and characterized by SEM, TEM, EDS, XRD, FTIR, XPS, TGA, BET, and so on. Furthermore, the catalytic performance of Pd@CCM catalysts was investigated via p-nitrophenol reduction, which showed high catalytic activity. This catalyst also exhibited excellent catalytic performance in the Suzuki-Miyaura coupling reaction. Linking aromatic monomer and benzene through Suzuki-Miyaura coupling was presented as an effective route to obtaining biaryls, and the synthesis method is low-cost and simple. In addition, Pd@CCM showed desirable recyclability while maintaining its catalytic activity even after five recycles. This work is highly suggestive of the design and application of the heterogeneous catalyst.
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Carbono , Celulosa , Nanopartículas del Metal , Microesferas , Nitrofenoles , Paladio , Paladio/química , Catálisis , Nitrofenoles/química , Nanopartículas del Metal/química , Celulosa/química , Carbono/química , Oxidación-ReducciónRESUMEN
Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv oryzae (Xoo) is extremely harmful to rice production. The traditional control approach is to use bactericides that target key bacterial growth factors, but the selection pressure on the pathogen makes resistant strains the dominant bacterial strains, leading to a decline in bactericidal efficacy. Type III secretion system (T3SS) is a conserved and critical virulence factor in most Gram-negative bacteria, and its expression or absence does not affect bacterial growth, rendering it an ideal target for creating drugs against Gram-negative pathogens. In this work, we synthesized a range of derivatives from cryptolepine and neocryptolepine. We found that compound Z-8 could inhibit the expression of Xoo T3SS-related genes without affecting the growth of bacteria. an in vivo bioassay showed that compound Z-8 could effectively reduce the hypersensitive response (HR) induced by Xoo in tobacco and reduce the pathogenicity of Xoo in rice. Furthermore, it exhibited synergy in control of bacterial leaf blight when combined with the quorum quenching bacterial F20.
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Alcaloides , Alcaloides Indólicos , Oryza , Quinolinas , Xanthomonas , Oryza/genética , Sistemas de Secreción Tipo III/genética , Bacterias/metabolismo , Xanthomonas/genética , Enfermedades de las Plantas/prevención & control , Enfermedades de las Plantas/microbiologíaRESUMEN
The aggregation of amyloid-ß (Aß) is one of the important pathological markers of Alzheimer's disease. Ruthenium(II) complexes have good stability, low cytotoxicity, a high fluorescence quantum yield, and a good Stokes shift as fluorescent probes. Based on this, we constructed a fluorescent probe for in vivo real-time imaging and inhibition of Aß-fibril formation using a complex of Ru polypyridine with organic fluorophores (N,N-dimethylaniline) and hydrophobic peptides (KLVFF). DLS and TEM studies have shown that Ru-YH has an inhibitory effect on the fibrotic aggregation of Aß. Both in vivo and in vitro studies have shown that Ru-WJ and Ru-YH can quickly cross the blood-brain barrier and successfully detect Aß in early (2.5-month old) transgenic mouse models. In summary, we have explored the potential of Ru complex based biological probes for early diagnosis and inhibition of AD.
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Enfermedad de Alzheimer , Ratones , Animales , Barrera Hematoencefálica/patologíaRESUMEN
BACKGROUND: γ-Aminobutyric acid (GABA) receptors (GABARs) are validated targets of insecticides. Bicyclophosphorothionates are a group of insecticidal compounds that act as noncompetitive antagonists of GABARs. We previously reported that the analogs exhibit various degrees of selectivity for housefly versus rat GABARs, depending on substitutions at the 3- and 4-positions. We here sought to elucidate the unsolved mechanisms of the receptor selectivity using quantitative structure-activity relationship (QSAR), molecular docking, and molecular dynamics approaches. RESULTS: Three-dimensional (3D)-QSAR studies using Topomer comparative molecular field analysis quantitatively demonstrated how the introduction of a small alkyl group at the 3-position of bicyclophosphorothionates contributes to the housefly versus rat GABAR selectivity. To investigate the molecular mechanisms of the selective action, bicyclophosphorothionates were docked into housefly Resistance to dieldrin (RDL) GABAR and rat α1ß2γ2 GABAR homology models built using the published 3D-structures of human GABARs as templates. The results of molecular docking and molecular dynamics simulations revealed that the 2'Ala and 6'Thr residues of the RDL subunit within the channel are the key amino acids for binding to the housefly GABARs, whereas the 2'Ser residue of γ2 subunit plays a crucial role in binding to rat GABARs. CONCLUSION: We revealed the molecular mechanisms underlying the selective antagonistic action of bicyclophosphorothionates on housefly versus rat GABARs. The information presented should help design and develop novel, safe GABAR-targeting insecticides. © 2023 Society of Chemical Industry.
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Moscas Domésticas , Insecticidas , Ratas , Animales , Humanos , Receptores de GABA/metabolismo , Insecticidas/química , Moscas Domésticas/metabolismo , Simulación del Acoplamiento Molecular , Antagonistas del GABA/químicaRESUMEN
Opportunistic fungal infections, particularly caused by Candida albicans, remain a common cause of high morbidity and mortality in immunocompromised patients. The escalating prevalence of antifungal drug resistance necessitates the immediate exploration of alternative treatment strategies to combat these life-threatening fungal diseases. In this study, we investigated the antifungal efficacy of firsocostat, a human acetyl-CoA carboxylase (ACC) inhibitor, against C. albicans. Firsocostat alone displayed moderate antifungal activity, while combining it with voriconazole, itraconazole, or amphotericin B exhibited synergistic effects across almost all drug-sensitive and drug-resistant C. albicans strains tested. These observed synergies were further validated in two mouse models of oropharyngeal and systemic candidiasis, where the combination therapies demonstrated superior fungicidal effects compared to monotherapy. Moreover, firsocostat was shown to directly bind to C. albicans ACC and inhibit its enzymatic activity. Sequencing spontaneous firsocostat-resistant mutants revealed mutations mapping to C. albicans ACC, confirming that firsocostat has retained its target in C. albicans. Overall, our findings suggest that repurposing firsocostat, either alone or in combination with other antifungal agents, holds promising potential in the development of antifungal drugs and the treatment of candidiasis.
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Antifúngicos , Candidiasis , Animales , Ratones , Humanos , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Acetil-CoA Carboxilasa , Reposicionamiento de Medicamentos , Pruebas de Sensibilidad Microbiana , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Candida albicans , Farmacorresistencia Fúngica , Fluconazol/farmacologíaRESUMEN
Dicofol has been widely used to control phytophagous mites. Although dicofol is chemically related to DDT, its mode of action has remained elusive. Here, we mapped dicofol resistance in the spider mite Tetranychus urticae to two genomic regions. Each region harbored a glutamate-gated chloride channel (GluCl) gene that contained a mutation-G314D or G326E-known to confer resistance against the unrelated acaricide abamectin. Using electrophysiology assays we showed that dicofol and other diphenylcarbinol acaricides-bromopropylate and chlorobenzilate-induce persistent currents in Xenopus oocytes expressing wild-type T. urticae GluCl3 receptors and potentiate glutamate responses. In contrast, the G326E substitution abolished the agonistic activity of all three compounds. Assays with the wild-type Drosophila GluClα revealed that this receptor was unresponsive to dicofol. Homology modeling combined with ligand-docking confirmed the specificity of electrophysiology assays. Altogether, this work elucidates the mode of action of diphenylcarbinols as mite-specific agonists of GluCl.
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Acaricidas , Acaricidas/farmacología , Dicofol , Canales de Cloruro/genética , MutaciónRESUMEN
A cobalt(II) complex and manganese(II) coordination polymer, formulated as [Co2(H2btca)(mbpy)4][H2btca]·4H2O (1) and {Mn2(btca)(mbpy)2(H2O)2}n (2) (H4btca = 1,2,4,5-benzenetetracarboxylic acid; mbpy = 4,4'-dimethyl-2,2'-bipyridyl), constructed by mixed bipyridine-tetracarboxylic ligands were synthesized and characterized. Single-crystal structural analyses reveal that compound 1 is a discrete neutral binuclear molecule, while compound 2 is a two-dimensional (2D) coordination polymer. The metal ions in these compounds are well isolated, with an intramolecular Co2+â¯Co2+ distance of 9.170 Å for 1 and Mn2+â¯Mn2+ separation of 10.984 and 11.164 Å for 2 due to the bulk tetracarboxylic linker. This isolation gives rise to a single-ion magnetism origin of the compounds. Magnetic studies reveal a large zero-field splitting parameter D of 82.6 cm-1 for 1, while a very small D of 0.42 cm-1 was observed for 2. Interestingly, dynamic ac magnetic measurements exhibited slow magnetic relaxation under the external dc field of the two compounds, revealing the field-supported single-ion magnet (SIM) of 1 and 2. The detailed theoretical calculations were further applied to understand the electronic structures, magnetic anisotropy, and relaxation dynamics in 1 and 2. Combined with our recently reported compound (Eur. J. Inorg. Chem., 2022, e202200354), the foregoing results provide not only a rare binuclear cobalt(II) SIM and the first 2D manganese(II) SIM coordination polymer but also a bipyridine-tetracarboxylic ligand approach toward novel SIMs.
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Polymyxin resistance is conferred by MCR-1 (mobile colistin resistance 1)-induced lipopolysaccharide (LPS) modification of G- bacteria. However, the peptide MSI-1 exerts potent antimicrobial activity against mcr-1-carrying bacteria. To further investigate the potential role of MCR-1 in improving bacterial virulence and facilitating immune evasion, and the immunomodulatory effect of peptide MSI-1, we first explored outer membrane vesicle (OMV) alterations of mcr-1-carrying bacteria in the presence and absence of sub-MIC MSI-1, and host immune activation during bacterial infection and OMV stimulation. Our results demonstrated that LPS remodelling induced by MCR-1 negatively affected OMV formation and protein cargo by E. coli. In addition, MCR-1 diminished LPS-stimulated pyroptosis but facilitated mitochondrial dysfunction, further aggravating apoptosis in macrophages induced by OMVs of E. coli. Similarly, TLR4-mediated NF-κB activation was markedly alleviated once LPS was modified by MCR-1. However, peptide MSI-1 at the sub-MIC level inhibited the expression of MCR-1, further partly rescuing OMV alteration and attenuation of immune responses in the presence of MCR-1 during both infection and OMV stimulation, which can be exploited for anti-infective therapy.
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Proteínas de Escherichia coli , Escherichia coli , Escherichia coli/metabolismo , Lipopolisacáridos , Evasión Inmune , Colistina/farmacología , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Péptidos/farmacología , Farmacorresistencia Bacteriana , Antibacterianos/farmacología , Pruebas de Sensibilidad MicrobianaRESUMEN
Meta-diamides (e.g. broflanilide) and isoxazolines (e.g. fluralaner) are novel insecticides that target the resistant to dieldrin (RDL) subunit of insect γ-aminobutyric acid receptors (GABARs). In this study, we used in silico analysis to identify residues that are critical for the interaction between RDL and these insecticides. Substitution of glycine at the third position (G3') in the third transmembrane domain (TMD3) with methionine (G3'M TMD3), which is present in vertebrate GABARs, had the strongest effect on fluralaner binding. This was confirmed by expression of RDL from the rice stem borer, Chilo suppressalis (CsRDL) in oocytes of the African clawed frog, Xenopus laevis, where the G3'MTMD3 mutation almost abolished the antagonistic action of fluralaner. Subsequently, G3'MTMD3 was introduced into the Rdl gene of the fruit fly, Drosophila melanogaster, using the CRISPR/Cas9 system. Larvae of heterozygous lines bearing G3'MTMD3 did not show significant resistance to avermectin, fipronil, broflanilide, and fluralaner. However, larvae homozygous for G3'MTMD3 were highly resistant to broflanilide and fluralaner whilst still being sensitive to fipronil and avermectin. Also, homozygous lines showed severely impaired locomotivity and did not survive to the pupal stage, indicating a significant fitness cost associated with G3'MTMD3. Moreover, the M3'GTMD3 mutation in the mouse Mus musculus α1ß2 GABAR increased sensitivity to fluralaner. Taken together, these results provide convincing in vitro and in vivo evidence for both broflanilide and fluralaner acting on the same amino acid site, as well as insights into potential mechanisms leading to target-site resistance to these insecticides. In addition, our findings could guide further modification of isoxazolines to achieve higher selectivity for the control of insect pests with minimal effects on mammals.
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Insecticidas , Receptores de GABA , Animales , Ratones , Receptores de GABA/genética , Receptores de GABA/metabolismo , Dieldrín , Insecticidas/farmacología , Insecticidas/química , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Larva/metabolismo , Mamíferos/metabolismoRESUMEN
Objective: To investigate the transmission pathway of a MRSA prevalence in a pancreatic surgery ward in a Chinese teaching hospital. Methods: Molecular epidemiology investigations were carried out combined PFGE, MLST, SCCmec typing and whole-genome sequencing for 20 successive MRSA isolates (2 isolates from the ward environment). Resistance and virulence genes were detected using specific PCR. Bacterial identification and AST were performed using the Vitek 2 Compact System. Clinical data of enrolled cases were retrieved from electronic case records. Results: From January 2020 to May 2020, successive isolated 20 MRSA strains were clarified to 2 PFGE patterns (A = 19, B = 1) in the ward. Both isolates from environment and patients belonged to sequence type ST5-SCCmec II-spa type t311. MRSA-related resistance genes mecA, blaZ, ermA, ant(4')-Ia and norA were found in each clone. All 20 isolates carried tst, hlg, hla, eta, eap, fnbA and seo virulence genes, other virulence genes such as sea, sec, seb, seg, sei, sem, sen, ebpS and fnbB were also found in partial stains. All patients had fever symptom, 27.8% were accompanied by diarrhea, 88.9% had undergone surgery or invasive procedures within 30 days. Finally, 94.4% of these patients recovered. Conclusion: This study confirmed a prevalence of ST5-MRSA-II-t311 clone in a surgery ward, indicated MRSA is a risk factor for post-surgery nosocomial infection and hand hygiene and environmental surveillance should not be ignored.
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Neutrophil elastase (NE) is an important regulator of immune response and is widely regarded as a biomarker for inflammatory diseases. To date, all the NE probe is designed by linking pentafluoropropionyl and amino-containing fluorophores through amide bond. This method is limited by the fluorophores, which must contain amino functional groups. To overcome this problem, we use the self-immolative group to convert hydroxyl groups to fluorophores HFC (4-trifluoromethyl-7-hydroxyl coumarin) into amino groups, and to connect recognition groups (pentafluoropropionyl) to construct a novel NE fluorescent probe HFC-NE. Predictably, HFC-NE can detect NE activity selectively and sensitively with many advantages, such as good water solubility and biocompatibility, high fluorescence enhancement and high affinity. Besides, HFC-NE is successfully applied to real-time and specific detection of NE activity in living cells and zebrafish models. These excellent outcomes confirmed that this strategy based on self-immolative group is a useful method to design more NE fluorescent probes.
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Colorantes Fluorescentes , Elastasa de Leucocito , Animales , Pez Cebra , Fluorescencia , IonóforosRESUMEN
Tyrosinase is widely regarded as an important biomarker for melanocytic and liver cancer. However, most currently reported tyrosinase probes have been focused on malignant melanoma study, and few tyrosinase probe have been applied for liver cancer investigation. Herein, we developed a novel probe HFC-TYR for sensitive and selective tracking of tyrosinase activity at enzyme and cellular level, and investigated its application for liver cancer diagnosis. As expected, HFC-TYR has excellent response ability for tyrosinase sensing at enzyme level, such as large Stokes shift (170 nm), high fluorescence enhancement (178-fold), low detection limit (0.12 U/mL), which indicates its potential for efficient identification of endogenous tyrosinase activity at cellular levels. Unsurprisingly, HFC-TYR is proved to be able detect endogenous tyrosinase levels in various living cells. More importantly, HFC-TYR is successfully used to distinguish HepG2 cells from other cells (SKOV3, HeLa and 293T), indicating that tyrosinase is overexpressed in HepG2 cells and HFC-TYR can specifically identify HepG2 cells at cellular level. Meanwhile, HFC-TYR is able to further monitor the endogenous tyrosinase activity in zebrafish models. Therefore, all the findings confirm that HFC-TYR has the application potential of liver cancer diagnosis.
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Colorantes Fluorescentes , Neoplasias Hepáticas , Humanos , Animales , Monofenol Monooxigenasa , Fluorescencia , Pez Cebra , Células HeLa , Neoplasias Hepáticas/diagnóstico por imagenRESUMEN
A highly fluorinated porphyrin-based covalent organic frameworks magnetic adsorbent (FPy-COF@PDA@Fe3O4) was fabricated by using polydopamine (PDA) grafting Fe3O4 nanospheres as magnetic core and FPy-COF as shell for magnetic solid phase extraction (MSPE) of fluoroquinolones (FQs). FPy-COF was constructed by using 5,15-bis(4-aminophenyl)-10,20-bis(perfluorophenyl)porphyrin and 4,4'-biphenyldicarboxaldehyde as two building blocks. PDA as a bridge grafting on the surface of Fe3O4 nanospheres facilitated the growth of FPy-COF. The morphology and structure of FPy-COF@PDA@Fe3O4 adsorbent were characterized in detail. The prepared magnetic adsorbent exhibited good extraction capability to amphiphilic FQs due to their superior chemical affinities such as fluorophilic interaction and hydrogen-bond interaction from nitrogen-rich skeleton. Under the optimized conditions, the MSPE method combined with high performance liquid chromatography with ultraviolet detection (HPLC-UV) was developed to sensitively quantify trace level of six FQs in milk samples. The developed MSPE-HPLC method showed good linearity with wide concentration range, precision, and low limits of detection (S/N = 3) for six FQs as low as 2.3 ngêmL-1 in milk. The extraction recoveries of different spiked concentrations were in the range 77.8-110.4% for milk samples with RSD less than 9.7%.
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Estructuras Metalorgánicas , Nanosferas , Porfirinas , Estructuras Metalorgánicas/química , Fluoroquinolonas/análisis , Extracción en Fase Sólida/métodos , Fenómenos MagnéticosRESUMEN
A series of N-arylsulfonyl-indole-2-carboxamide derivatives have been identified as potent fructose-1,6-bisphosphatase (FBPase) inhibitors (FBPIs) with excellent selectivity for the potential therapy of type II diabetes mellitus. To explore the structure-activity relationships (SARs) and the mechanisms of action of these FBPIs, a systematic computational study was performed in the present study, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, pharmacophore modeling, molecular dynamics (MD), and virtual screening. The constructed 3D-QSAR models exhibited good predictive ability with reasonable parameters using comparative molecular field analysis (q2 = 0.709, R2 = 0.979, rpre2 = 0.932) and comparative molecular similarity indices analysis (q2 = 0.716, R2 = 0.978, rpre2 = 0.890). Twelve hit compounds were obtained by virtual screening using the best pharmacophore model in combination with molecular dockings. Three compounds with relatively higher docking scores and better ADME properties were then selected for further studies by docking and MD analyses. The docking results revealed that the amino acid residues Met18, Gly21, Gly26, Leu30, and Thr31 at the binding site were of great importance for the effective bindings of these FBPIs. The MD results indicated that the screened compounds VS01 and VS02 could bind with FBPase stably as its cognate ligand in dynamic conditions. This work identified several potential FBPIs by modeling studies and might provide important insights into developing novel FBPIs.