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1.
Plant Dis ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34664979

RESUMO

Species belonging to the genus Erwinia cause diseases in many economically important plants. In May 2021, celery (Apium graveolens var. dulce) plants (cv. Queen of France) showing soft rot symptoms were observed in greenhouses in Boye County, Baoding, Hebei Province (North China). Disease symptoms began with pinkish water-soaked lesions on the midrib of celery stalks, but at the same time the leaves and root were asymptomatic; and the infected celery plants rapidly developed brownish rotten stalks. The disease incidence in two greenhouses (0.15 ha in size) was more than 50%. Affected celery stalk pieces ca. 0.5 cm in length were surface-sterilized by dipping them in 75% ethanol for one min and then three successive rinses with sterile distilled water. Then, the tissues were immersed in 200 µl 0.9% saline for 15 min. Aliquots (20 µl) of two tenfold dilutions of the tissue specimen soaking solution were plated onto Luria-Bertani (LB) medium and incubated at 28°C for 24 h. Single colonies were picked and restreaked onto LB agar three times for purity. The bacterial gDNA was extracted using the EasyPure Bacteria Genomic DNA Kit (TransGen Biotech, Beijing, China). The 16S rDNA region was amplified by PCR using the universal primers 27F/1492R and sequenced. Result of blastn analysis of the 16S rDNA amplicons (MZ614654, MZ614655) indicated that the bacterial isolates (BY21211 and BY21212) belonged to the genus Erwinia. Housekeeping genes including mdh, gapA, icdA, rpoS, acnA and proA were also amplified using a set of PCR primers (Ma et al. 2007) followed by sequencing (MZ643221-MZ643232). No sequence variation was observed at any MLSA locus between isolates BY21211 and BY21212. To determine the species of the Erwinia isolate BY21211 and BY21212, multi-locus sequence analysis (MLSA) was performed with six housekeeping genes, and phylogenetic tree was reconstructed using RAxML v8.2.12 (github.com/stamatak/standard-RAxML). The result of phylogenetic analysis showed that the celery stalk rot isolate BY21211 and BY21212 was clustered with E. persicina type strain NBRC102418T (Hao et al. 1990). When celery plants (cv. Queen of France) have eight to nine true leaves, plants were inoculated with the isolate BY21211 by injecting 20 µl of bacterial suspensions (107 CFU·mL-1) into the celery stalks, and negative controls were injected with 20 µl of 0.9% saline. The seedlings were grown at 25°C and 50% relative humidity. Three days after inoculation, only the bacterial-inoculated seedlings showed disease symptoms resembled to those observed in greenhouses. Bacterial colonies were obtained from the infected stalks and were identified using the same PCR primers of housekeeping genes as described above. Therefore, E. persicina isolate BY21211 fulfill Koch's postulates for stalk rot of celery. Isolates BY21211 and BY21212 produce water-soluble pink pigment on sucrose-peptone agar. These isolates were gram negative and rod shaped, negative for oxidase, urease, indole production, gelatin liquefaction and acid production from xylose and glycerol. They were positive for catalase, citrate utilization, acid production from sorbitol, raffinose, glucose, arabinose, cellobiose, rhamnose, maltose, saccharose, inositol, lactose and esculin (hydrolysis). E. persicina has been reported to cause pink seed, crown and stem rot, soft rot or leaf spot on many plant hosts including pea (Pisum sativum), soybean (Glycine max), common bean (Phaseolus vulgaris), lucerne (Medicago sativa), barley (Hordeum vulgare), onion (Allium cepa), garlic bulbs (Allium sativum), tomato (Lycopersicon esculentum) and cucumber (Cucumis sativus) (Hao et al. 1990; González et al. 2005, 2007; Zhang and Nan 2014; Gálvez et al. 2015; Cho et al. 2019; Kawaguchi et al. 2021). To our knowledge, this is the first report of E. persicina causing stalk rot in celery. Stalk rot of celery has increased in prevalence over recent years in the Baoding region, it can cause significant yield loss and no cultivar has been found to be resistant to this disease so far. The stalk rot poses significant threat to local celery production, and further research on epidemiology and disease management options is needed.

2.
Plant Dis ; 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34664982

RESUMO

Species belonging to the genus Erwinia cause diseases in many economically important plants (Mansfield et al. 2012). In May 2021, celery plants (Apium graveolens var. dulce) showing soft rot symptoms were observed in greenhouses (cv. Queen of France) in Boye County, Baoding, Hebei Province (North China). Disease symptoms began with pinkish water-soaked lesions on the midrib of celery stalks, but at the same time the leaves and root did not show symptoms. The infected celery plants rapidly developed brownish rotten stalks and leaves turned dry and yellow, but root remained asymptomatic. The disease incidence in two greenhouses (0.15 ha in size) was more than 50%. Affected celery stalk tissues were cut into 0.5 cm pieces, followed by surface sterilization using 75% ethanol for 60 sec and then three successive rinses with sterile distilled water. Then, the tissues were immersed in 200 µl 0.9% saline for 15 min. Aliquots of two tenfold dilutions of the tissue specimen soaking solution were plated onto Luria-Bertani (LB) agar plates and incubated at 28°C for 24 h. Single colonies were picked and restreaked onto LB agar three times for purity. The bacterial gDNA was extracted using the EasyPure Bacteria Genomic DNA Kit (TransGen Biotech). The 16S rDNA region was amplified by PCR using the universal primers 27F/1492R and sequenced. Result of blastn analysis of the 16S rDNA amplicons (MZ489246-MZ489247) indicated that the bacterial isolates (BY21311 and BY21312) belonged to the genus Erwinia. Biolog analysis (GEN III Microplate) identified the two isolates BY21311 (SIM=0.668) and BY21312 (SIM=0.638) as E. rhapontici. Housekeeping genes including acnA, gapA, icdA, mdh and rpoS were also amplified using a set of PCR primers (Ma et al. 2007; Waleron et al. 2008) followed by sequencing (MZ463029-MZ463038). To determine the species of the Erwinia isolates BY21311 and BY21312, multi-locus sequence analysis (MLSA) was performed with five housekeeping genes, and phylogenetic tree was reconstructed using RAxML v8.2.12 (Stamatakis et al. 2005). No sequence variation was observed at any MLSA locus between BY21311 and BY21312. The result of phylogenetic analysis showed that the celery stalk rot isolates BY21311 and BY21312 were clustered with E. rhapontici isolates. These celery isolates are closely related to the cabbage (Brassica rapa) isolate MAFF311153 (AP024329.1) in Japan. When celery plants have eight to nine true leaves, plants (cv. Queen of France) were inoculated with the isolate BY21311 by injecting 20 µl of bacterial suspensions (106 CFU·mL-1) into the celery stalks, or injected with 20 µl of 0.9% saline as control. The seedlings were grown at 25 °C and 50% relative humidity. Three days after inoculation, only infected seedling showed disease symptoms resembled to those observed in greenhouses. Bacterial colonies were obtained from the infected stalks and were identified using the same PCR primers of housekeeping genes as described above, fulfill Koch's postulates. E. rhapontici has been reported to cause pink seed, crown and stem rot, soft rot or leaf spot on many plant hosts including pea (Pisum sativum), chickpea (Cicer arietinum), lentil (Lens culinaris), common bean (Phaseolus vulgaris), lucerne (Medicago sativa), wheat (Triticum aestivum), hyacinth (Hyacinthus orientalis), onion (Allium cepa), kiwifruit (Actinidia chinensis) and peach (Prunus persica) (Huang et al. 2003; Wang et al. 2017; Zhang et al. 2018; Kovács et al. 2020). To our knowledge, this is the first report of E. rhapontici causing stalk rot in celery. Stalk rot of celery has increased in prevalence over recent years in the Baoding region, it can cause significant yield loss and no cultivar has been found to be resistant to this disease so far. The stalk rot poses significant threat to local celery production, and further research on epidemiology and disease management options is needed.

3.
Plant Dis ; 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34410861

RESUMO

In July 2020, potato plants (cv. Xisen 6) showing characteristic symptoms of aerial stem rot were observed in a field in Fengning Manchu Autonomous County, Chengde, Hebei Province (northern China). The disease incidence in that field (5 ha in size) was more than 50%. Aerial stem rot of potato has increased in prevalence over recent years in Chengde, it can cause significant yield loss on susceptible cultivars such as Xisen 6 and Huangxin 226. Affected stem (light brown and water-soaked stem sections) pieces ca. 0.5 cm in length were surface-sterilized by dipping them in 75% ethanol for one min and then three successive rinses with sterile distilled water. Then, the tissues were soaked in 200 µl 0.9% saline for 20 min. Aliquots (20 µl) of three tenfold dilutions of the tissue specimen soaking solution were plated onto the crystal violet pectate (CVP) medium. The CVP plates were incubated at 28°C for 48 h. Colonies producing pits were restreaked and purified on Luria-Bertani (LB) agar plates. The bacterial gDNA was extracted using the EasyPure Bacteria Genomic DNA Kit (TransGen Biotech, Beijing, China). The 16S rDNA region was amplified by PCR using the universal primers 27F/1492R (Weisburg et al. 1991) and sequenced. Results of the Blastn analysis of the 16S rDNA amplicons (MZ348607, MZ348608) suggested that the isolates FN20211 and FN20222 belonged to the genus Pectobacterium. Housekeeping genes including acnA, gapA, icdA, mdh, proA and rpoS were also amplified using a set of primers (Ma et al. 2007; Waleron et al. 2008) followed by sequencing (MZ356250-MZ356261). To determine the species of the stem rot Pectobacterium isolates, multi-locus sequence analysis (MLSA) was performed with six housekeeping genes, and phylogenetic tree was reconstructed using RAxML (github.com/stamatak/standard-RAxML). No sequence variation was observed at any MLSA locus between FN20211 and FN20222. The result of phylogenetic analysis showed that the isolates clustered with P. polaris type strain NIBIO1006T, which was isolated from potato (Dees et al. 2017). And the concatenated sequence of the six loci of isolate FN20211/FN20222 is 100% identical to those of the strains PZ1 (CP046377.1) and WBC1 (GCF_011378945.1), which were isolated from potato in South Korea and from Chinese cabbage in China, respectively. Potato seedlings (cv. Xisen 6 and Favorita) were inoculated with the isolates FN20211 and FN20222 by injecting 100 µl of bacterial suspensions (108 CFU·mL-1) into the upper parts of the stems of potato plants, or injected with 100 µl of 0.9% saline as control. The seedlings were grown at 25°C and 50% relative humidity. Three days after inoculation, only the bacteria-inoculated seedlings showed disease symptoms resembling to those observed in the field. Bacterial colonies were obtained from the infected stems and were identified using the same PCR primers as described above. Therefore, P. polaris isolates FN20211 and FN20222 fulfill Koch's postulates for aerial stem rot of potato. P. polaris causing blackleg and soft rot on potato plants has been reported in European countries including Netherlands, Norway (Dees et al. 2017) and Poland (Waleron et al. 2019), and also in Pakistan (Sarfraz et al. 2019) and Russia (Voronina et al. 2021). To our knowledge, this is the first report of P. polaris causing aerial stem rot of potato in China. The stem rot poses a significant threat to the local potato industry, and further research on epidemiology and disease management options is needed.

4.
Biochim Biophys Acta Gen Subj ; 1865(11): 129990, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34390793

RESUMO

BACKGROUND: Histone lysine-specific demethylase 1 (LSD1) has become a potential anticancer target for the novel drug discovery. Recent reports have shown that SP2509 and its derivatives strongly inhibit LSD1 as allosteric inhibitors. However, the binding mechanism of these allosteric inhibitors in the allosteric site of LSD1 is not known yet. METHODS: The stability and binding mechanism of allosteric inhibitors in the binding site of LSD1 were evaluated by molecular docking, ligand-based pharmacophore, molecular dynamics (MD) simulations, molecular mechanics generalized born surface area (MM/GBSA) analysis, quantum mechanics/molecular mechanics (QM/MM) calculation and Hirshfeld surface analysis. RESULTS: The conformational geometry and the intermolecular interactions of allosteric inhibitors showed high binding affinity towards allosteric site of LSD1 with the neighboring amino acids (Gly358, Cys360, Leu362, Asp375 and Glu379). Meanwhile, MD simulations and MM/GBSA analysis were performed on selected allosteric inhibitors in complex with LSD1 protein, which confirmed the high stability and binding affinity of these inhibitors in the allosteric site of LSD1. CONCLUSION: The simulation results revealed the crucial factors accounting for allosteric inhibitors of LSD1, including different protein-ligand interactions, the positions and conformations of key residues, and the ligands flexibilities. Meanwhile, a halogen bond interaction between chlorine atom of ligand and key residues Trp531 and His532 was recurrent in our analysis confirming its importance. GENERAL SIGNIFICANCE: Overall, our research analyzed in depth the binding modes of allosteric inhibitors with LSD1 and could provide useful information for the design of novel allosteric inhibitors.

5.
Eur J Med Chem ; 225: 113740, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34388384

RESUMO

A series of 5-phenylthiophene derivatives with novel structures were designed and synthesized to combat the increasing incidence of susceptible and drug-resistant fungal infections. The antifungal activity of the synthesized compounds was assessed against seven susceptible strains and six fluconazole-resistant strains. It is especially encouraging that compounds 17b and 17f displayed significant antifungal activities against all tested strains. Furthermore, the potent compounds 17b and 17f could prevent the formation of fungi biofilms and 17f displayed satisfactory fungicidal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 17f stemmed from inhibition of C. albicans CYP51. In addition, Compounds 17b and 17f were almost nontoxic to mammalian A549, MCF-7, and THLE-2 cells. These results strongly suggested that compounds 17b and 17f are promising as novel antifungal drugs.

6.
Eur J Med Chem ; 224: 113715, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34364163

RESUMO

l-amino alcohol derivatives exhibited high antifungal activity, but the metabolic stability of human liver microsomes in vitro was poor, and the half-life of optimal compound 5 was less than 5 min. To improve the metabolic properties of the compounds, the scaffold hopping strategy was adopted and a series of antifungal compounds with a dihydrooxazole scaffold was designed and synthesized. Compounds A33-A38 substituted with 4-phenyl group on dihydrooxazole ring exhibited excellent antifungal activities against C. albicans, C. tropicalis and C. krusei, with MIC values in the range of 0.03-0.25 µg/mL. In addition, the metabolic stability of compounds A33 and A34 in human liver microsomes in vitro was improved significantly, with the half-life greater than 145 min and the half-life of 59.1 min, respectively. Moreover, pharmacokinetic studies in SD rats showed that A33 exhibited favourable pharmacokinetic properties, with a bioavailability of 77.69%, and half-life (intravenous administration) of 9.35 h, indicating that A33 is worthy of further study.

7.
Plant Dis ; 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384251

RESUMO

Pectobacterium species cause blackleg, soft rot and stem rot in potato and many other vegetable crops (Charkowski 2015). In July 2020, potato plants showing characteristic symptoms of aerial stem rot were observed in a field (cv. Xisen 6) in Fengning Manchu Autonomous County, Chengde, Hebei Province (North China). The disease incidence in that field (5 ha in size) was more than 50%. Putative pectolytic bacteria were obtained from symptomatic stem tissues (light brown and water-soaked stem sections) by culturing on the crystal violet pectate (CVP) medium. Bacterial colonies producing pits, were restreaked and purified on Luria-Bertani (LB) agar. The isolates causing stem rot were gram negative and rod shaped, negative for oxidase, urease, indole production, gelatin liquefaction and acid production from maltose and D-sorbitol. All isolates were catalase positive, produced acid from lactose, rhamnose, saccharose, raffinose and D-arabinose, and were tolerant to 5% NaCl, and able to utilize citrate. The bacterial gDNA was extracted using the EasyPure Bacteria Genomic DNA Kit (TransGen Biotech). The 16S rDNA region was amplified by PCR using the universal primer pair 27F/1492R and sequenced. Result of the Blastn analysis of the 16S rDNA amplicons (MZ379788, MZ379789) suggested that the isolates FN20111 and FN20121 belonged to the genus Pectobacterium. To determine the species of the stem rot Pectobacterium isolates, multi-locus sequence analysis (MLSA) was performed with six housekeeping genes acnA, gapA, icdA, mdh, proA and rpoS (MZ403781-MZ403792), and phylogenetic tree was reconstructed using RAxML v8.2.12 (https://github.com/stamatak/standard-RAxML). The result of phylogenetic analysis showed that the stem rot Pectobacterium isolates FN20111 and FN20121 clustered with P. versatile (syn. 'Candidatus Pectobacterium maceratum') strains CFBP6051T (Portier et al. 2019), SCC1 (Niemi et al. 2017) and F131 (Shirshikov et al. 2018). And the isolates FN20111 and FN20121 were more closely related to the type strain CFBP6051T than to strains SCC1 and F131. Potato seedlings (cv. Xisen 6 and Favorita) were inoculated with the isolates FN20111 and FN20121 by injecting 100 µl of bacterial suspensions (108 CFU·mL-1) into the upper parts of the stems of potato plants, or injected with 100 µl of 0.9% saline solution as control. The seedlings were grown at 28°C and 50% relative humidity. Three days post-inoculation, only the bacteria-inoculated seedlings showed diseased symptoms resembling to those observed in the field. Bacterial colonies were obtained from the infected stems and were identified using the same PCR primers of housekeeping genes as described above, fulfill Koch's postulates. P. versatile causing soft rot and blackleg on potato plants has been reported in Finland (Niemi et al. 2017), Russia (Shirshikov et al. 2018), Netherlands (Portier et al. 2019), Poland (Waleron et al. 2019) and in New York State (Ma et al. 2021). To our knowledge, this is the first report of P. versatile causing aerial stem rot of potato in China.

8.
Rev Sci Instrum ; 92(4): 043103, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-34243435

RESUMO

We present a velocity-map imaging (VMI) apparatus coupled with a magneto-optical trap (MOT) of 87Rb atoms designed for low-energy photo-ion spectroscopy. The VMI-electrode geometry uses a three-electrode configuration, and the focusing electric field is optimized based on systematic simulations of relatively low-energy ions. To calibrate the apparatus, we use resonant two-color two-photon ionization of rubidium atoms as Doppler-selected ions. This VMI system provides an accuracy of 0.15 m/s and a resolution of 7.5 m/s for photoions with speeds below 100 m/s. Finally, details of the design, construction, and testing of the VMI-MOT system are presented.

9.
Mycologia ; 113(5): 949-955, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34125655

RESUMO

Multiple alleles were constantly detected in Alternaria solani isolates by simple sequence repeat (SSR) analysis, and sectors were also observed in their subcultures. These preliminary results and observations point to a possible parasexual cycle in A. solani. In this study, codominant SSR markers were used as molecular markers on the chromosomes of A. solani and single-conidium subculture was used to simulate the mitosis process of A. solani in nature. The number of alleles at locus As-95236 changed from 2 to 1 as a molecular marker for haploidy of parasexuality of A. solani. Fifty monosporic F1 strains were tested. The results showed that two parent strains lost allele with a haploid probability of 38%. For F2 strains, the results showed that all four F1 strains lost allele with a haploid probability of 75%. Since sexual recombination of A. solani has not been found so far, the allele lost in the subcultures of A. solani isolates provides molecular evidence for the existence of parasexual reproduction in A. solani.

10.
Eur J Med Chem ; 223: 113627, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34171657

RESUMO

The tropomyosin receptor kinases TRKs are responsible for different tumor types which caused by NTRK gene fusion, and have been identified as a successful target for anticancer therapeutics. Herein, we report a potent and selectivity TRKs inhibitor 19m through rational drug design strategy from a micromolar potency hit 17a. Compound 19m significantly inhibits the proliferation of TRK-dependent cell lines (Km-12), while it has no inhibitory effect on TRK-independent cell lines (A549 and THLE-2). Furthermore, kinases selectivity profiling showed that in addition to TRKs, compound 19m only displayed relatively strong inhibitory activity on ALK. These data may indicate that compound 19m has a good drug safety. Partial ADME properties were evaluated in vitro and in vivo. Compound 19m exhibited a good AUC values and volume of distribution and low clearance in the pharmacokinetics experiment of rats. Finally, a pharmacophore model guided by experimental results is proposed. We hope this theoretical model can help researchers find type I TRK inhibitors more efficiently.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirróis/farmacologia , Receptor trkA/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Estabilidade de Medicamentos , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirazóis/síntese química , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirróis/síntese química , Pirróis/metabolismo , Pirróis/farmacocinética , Ratos Sprague-Dawley , Receptor trkA/metabolismo
11.
Eur J Med Chem ; 220: 113501, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33945992

RESUMO

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC50 = 0.065 µM, as well as anti-proliferation against MCF-7, MGC-803, H460, A549 and THP-1 tumor cells with IC50 values of 2.90 ± 0.32, 5.85 ± 0.35, 2.06 ± 0.27, 5.74 ± 1.03 and 6.15 ± 0.49 µM, respectively. The binding modes of these compounds were rationalized by molecular docking. Meanwhile, a preliminary druggability evaluation showed that compound 17i displayed favorable liver microsomal stability and weak inhibitory activity against CYPs at 10 µM. Remarkably, H460 xenograft tumors studies revealed that 17i demonstrated robust in vivo antitumor efficacy without significant side effects. All the results demonstrated that compound 17i could represent a promising lead for further development.


Assuntos
Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzofuranos/síntese química , Benzofuranos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Histona Desmetilases/metabolismo , Humanos , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade
12.
Arch Pharm (Weinheim) ; 354(8): e2100102, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33987875

RESUMO

The abnormal expression of lysine-specific histone demethylase 1 (LSD1) is associated with different cancer types, and LSD1 inhibitory activity seems to have high therapeutic potential in cancer treatment. Here, we report the design, synthesis, and biochemical evaluation of novel 5-aminotetrahydroquinoline-based LSD1 inhibitors. Among them, compounds A6, A8, B1-B5, and C4 showed preferable inhibitory effects on LSD1, with IC50 = 0.19-0.82 µM. Several potent compounds were selected to evaluate their antiproliferative activity on A549 cells and MCF-7 cells with a high expression of LSD1. The potential binding modes of the compounds were revealed through molecular docking to rationalize the potency of compounds toward LSD1. Our data recognized that the 5-aminotetrahydroquinoline scaffold may serve as a starting point for developing potent LSD1 inhibitors for cancer therapy.

14.
J Inorg Biochem ; 218: 111381, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33647540

RESUMO

This study investigated whether captopril can reverse drug resistance in metallo-ß-lactamase (MBL)-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) and increase their sensitivity to antimicrobial agents. And also aimed to further characterize the affinity of captopril for imipenemase 4 (IMP-4) to explore the drug resistance treatment of MBL-producing bacteria. Five clinically isolated MBL-producing strains of CRKP were screened and the combined effects of captopril and meropenem were examined in vitro and in vivo to analyze whether captopril can reverse antimicrobial resistance in drug-resistant bacteria. Additionally, enzyme inhibition kinetics was analyzed to characterize the affinity of captopril for IMP-4. In MBL-producing Klebsiella pneumoniae, combined treatment with captopril significantly reduced the minimum inhibitory concentration (MIC) of carbapenems to 1 µg/mL at least, and captopril inhibited New-Delhi metallo-ß-lactamase 1 (NDM-1) and IMP-4 in a concentration-dependent manner in vitro. Following the infection of Galleria mellonella by IMP-expressing bacteria, the survival rates were significantly higher in the combination treatment group than in the monotherapy groups. And the bacterial load in the combination treatment group was significantly lower than those in the monotherapy groups and IMP-4-producing bacteria were more sensitive to the combination treatment than NDM-1-producing bacteria. Additionally, enzyme inhibition kinetics firstly illustrated that the half-maximal inhibitory concentration of captopril for IMP-4 was 26.34 µM, and the dissociation constant was 37.14 µM. In brief, captopril potentiated meropenem activity and restored its efficacy against MBL-producing CRKP. Additionally, analysis of enzyme inhibition kinetics confirmed that captopril has good inhibitory effects on IMP-4 activity. Therefore, captopril or its derivatives may have clinical utility for overcoming antibiotic resistance.

16.
Gynecol Endocrinol ; 37(4): 337-341, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32851887

RESUMO

AIMS: The effective treatment of polycystic ovary syndrome (PCOS)-related hormonal disorders necessitates the development of novel treatment strategies. Resveratrol is found in certain food products, and is known to exhibit phytoestrogen properties. The present study was to assess whether resveratrol exhibits beneficial phytoestrogenic effects and associated hormonal modulation in a rat model of PCOS. MATERIALS AND METHODS: This model was established by administering oral letrozole to female Sprague-Dawley (SD) rats prior to randomizing them into control, model and resveratrol treatment groups (40, 80, or 160 mg/kg). Animals were treated for 30 days, after which time ovarian tissues were collected and evaluated via hematoxylin and eosin staining. In addition, serum levels of estradiol and adiponectin were assessed via ELISA, and ovarian expression of nesfatin-1 and aromatase was assessed through RT-PCR and western blotting. RESULTS: We found that resveratrol administration was associated with increased levels of plasma adiponectin and estradiol levels and restoration of normal ovarian morphology in PCOS model animals. In addition, this treatment was linked to the increased ovarian expression of nesfatin-1 and aromatase at the RNA and protein levels. CONCLUSIONS: Together things findings suggest that resveratrol may represent an effective tool for treating PCOS owing to its phytoestrogenic properties.

17.
J Mol Neurosci ; 71(3): 583-595, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32901373

RESUMO

Spinal cord microcirculation plays an important role in maintaining the function of spinal cord neurons and other cells. Previous studies have largely focused on the ability of microtubule stabilization to inhibit the fibroblast migration and promote axon regeneration after spinal cord injury (SCI). However, the effect of microtubule stabilization treatment on microcirculation reconstruction after SCI remains unclear. By using immunofluorescence, we found that microtubule stabilization treatment improved microcirculation reconstruction via increasing the number of microvessels, pericytes, and the perfused microvessels after SCI. To clarify the underlying mechanisms, rat brain microvascular endothelial cells and pericytes were subjected to glucose oxygen deprivation. By using flow cytometry and western blotting, we found that microtubule stabilization treatment inhibited apoptosis and migration of endothelial cells and pericytes but promoted proliferation and survival of endothelial cells and pericytes through upregulated expression of vascular endothelial growth factor A (VEGFA), VEGF receptor 2, platelet-derived growth factor-B (PDGFB), PDGF receptor ß, and angiopoietin-1 after SCI. Taken together, this study provides evidence for the mechanisms underlying the promotion of microcirculation reconstruction after SCI by microtubule stabilization treatment. Importantly, this study suggests the potential of microtubule stabilization as a therapeutic target to reduce microcirculation dysfunction after SCI in the clinic.

18.
J Biomol Struct Dyn ; 39(4): 1189-1202, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32036765

RESUMO

Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which has been proposed as a promising target for anticancer drug development. Extensive research on LSD1 inhibitors has been performed since its discovery. In order to get more information for lead identification and optimization, we carried out a molecular modeling study on a set of 43 thieno[3,2-b]pyrrole competitive inhibitors of LSD1 using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations. Based on the co-crystallized conformer-based alignment (CCBA) method, 3D-QSAR model of thieno[3,2-b]pyrrole derivatives as LSD1 inhibitors was established. The significant statistics (q2 = 0.595, r2 = 0.959, r2pred = 0.846) of the 3D-QSAR indicated the good predictive power and statistical reliability of this model. Based on the corresponding contour maps six LSD1 inhibitors were designed and their activities were predicted by 3D-QSAR model. Meanwhile, molecular docking was performed to simulate the probable binding modes between ligands and LSD1 protein. The molecular interactions mainly contributions to the binding affinity for LSD1 inhibitions were further supplemented by 100 ns MD simulations and binding free energy calculation.


Assuntos
Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Sítios de Ligação , Histona Desmetilases/metabolismo , Simulação de Acoplamento Molecular , Pirróis , Reprodutibilidade dos Testes
19.
Microb Drug Resist ; 27(2): 204-211, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32614722

RESUMO

This study was conducted to acknowledge microbiological and clinical characteristics of hospital-acquired pneumonia (HAP) caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). A retrospective, 1:1 matched (age, gender, specimen source, and ward) case-control study was conducted during 2015-2017 in a tertiary teaching hospital in Anhui, China. Multivariate logistic regression analysis demonstrated that prior central venous catheter use, sputum suction, continuous renal replacement therapy, and exposure to fluroquinolones were independent risk factors for the morbidity of CRKP infection for HAP. Treatment failure for infection was an independent risk factor for crude in-hospital mortality, while the use of fluroquinolones may improve the effective treatment for infection (p = 0.040). Among 74 CRKP strains, 85.1% of them were positive for the production of KPC-2, and one of them was detected for co-harboring blaKPC-2 and blaIMP-38-like. Separately, sequence type (ST) 11 (81.1%) was the predominant ST in this study, and ST11 CRKP isolates were related with higher detection rate of blaKPC-2 and lower resistance rate to trimethoprim/sulfamethoxazole when compared with non-ST11 ones. Moreover, resistance to carbapenem was associated with higher mortality (35.1%) and hospitalization costs for HAP patients with K. pneumoniae infection. Invasive procedures may increase the morbidity of CRKP infection for HAP. Prior exposure to fluroquinolones is associated with the development of resistance, but as a targeted treatment it may be effective.

20.
Bioorg Med Chem Lett ; 33: 127749, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340663

RESUMO

In an in-house screening, 1H-pyrrolo[2,3-b]pyridine scaffold was found to have high inhibition on TNIK. Several series of compounds were designed and synthesized, among which some compounds had potent TNIK inhibition with IC50 values lower than 1 nM. Some compounds showed concentration-dependent characteristics of IL-2 inhibition. These results provided new applications of TNIK inhibitors and new prospects of TNIK as a drug target.


Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Pirróis/farmacologia , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Piridinas/síntese química , Piridinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
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