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1.
Emerg Microbes Infect ; : 1-31, 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34877923

RESUMO

AbstractJapanese encephalitis virus (JEV), an important neurotropic pathogen, belongs to the genus Flavivirus of the family Flaviviridae and has caused huge threat to public health. It is still obscure regarding the functions of stem loop (SL) and dumbbell (DB) domains of JEV 3' UTR in viral replication and virulence. In the current study, using the infectious clone of JEV SA14 strain as a backbone, we constructed a series of deletion mutants of 3' UTR to investigate their effects on virus replication. The results showed that partial deletions within SL or DB domain had no apparent effects on virus replication in both mammalian (BHK-21) and mosquito (C6/36) cells, suggesting that they were not involved in viral host-specific replication. However, the entire SL domain deletion (ΔVR) significantly reduced virus replication in both cell lines, indicating the important role of the complete SL domain in virus replication. The revertant of ΔVR mutant virus was obtained by serial passage in BHK-21 cells that acquired a duplication of DB domain (DB-dup) in the 3' UTR, which greatly restored virus replication as well as the capability to produce the subgenomic flavivirus RNAs (sfRNAs). Interestingly, the DB-dup mutant virus was highly attenuated in C57BL/6 mice despite replicating similar to WT JEV. These findings demonstrate the significant roles of the duplicated structures in 3' UTR in JEV replication and provide a novel strategy for the design of live attenuated vaccine.

2.
Front Immunol ; 12: 753044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34887859

RESUMO

Background: Approximately 10-40% of people with human immunodeficiency virus (HIV) infection are unable to obtain successful improvements in immune function after antiretroviral therapy (ART). These patients are at greater risk of developing non-acquired immunodeficiency syndrome (AIDS)-related conditions, with the accompanying increased morbidity and mortality. Discovering predictive biomarkers can help to identify patients with a poor immune response earlier and provide new insights into the mechanisms of this condition. Methods: A total of 307 people with HIV were enrolled, including 110 immune non-responders (INRs) and 197 immune responders (IRs). Plasma samples were taken before ART, and quantities of plasma microRNAs (miRNAs) were determined using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Candidate biomarkers were established through four phases: discovery, training, validation, and blinded test. Binary logistic regression was used to analyze the combined predictive capacity of the identified miRNAs. The effect of one miRNA, miR-16-5p, on T cell function was assessed in vitro. Results: Expression of five miRNAs (miR-580, miR-627, miR-138-5p, miR-16-5p, and miR-323-3p) was upregulated in the plasma of INRs compared with that in IRs. Expression of these miRNAs was negatively correlated with both CD4+ T cell counts and the increase in the proportion of CD4+ T cells after one year of ART. These five miRNAs were combined in a predictive model, which could effectively identify INRs or IRs. Furthermore, we found that miR-16-5p inhibits CD4+ T cell proliferation by regulating calcium flux. Conclusion: We established a five-miRNA panel in plasma that accurately predicts poor immune response after ART, which could inform strategies to reduce the incidence of this phenomenon and improve the clinical management of these patients.

3.
J Agric Food Chem ; 2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34878279

RESUMO

Succinate dehydrogenase (SDH) is an effective target of SDH inhibitor (SDHI) fungicides which received more and more attention in recent years. However, there is no good solution to their rapidly growing drug resistance caused by frequent use. In this study, three triphenylphosphonium (TPP)-conjugated boscalid analogues were synthesized and tested for antifungal activities. They all, especially 2c, exhibited enhanced fungicidal activity and broader spectra compared to boscalid. The action mechanism study revealed that 2c was also an SDH inhibitor acting on the Qp site. However, the rapid accumulation of 2c in mitochondria because of TPP-targeting triggered reactive oxygen species burst in mitochondria, resulting in irreversible damage to the mitochondrial structure and function. Thus, 2c made the fungicidal activity output mode changing from mainly relying on ATP production inhibition (as traditional SDHIs) to significant damage of the cell structure and functions. This mechanism change made it difficult for plant pathogenic fungi to develop resistance to 2c and its analogues, which was of great significance for the increasingly challenging management of field resistance to SDHI fungicides.

4.
Chem Biol Drug Des ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34862744

RESUMO

Bacterial resistance caused by metallo-ß-lactamases (MßLs) has become an emerging public health threat, and the development of MßLs inhibitor is an effective way to overcome the resistance. In this study, thirteen novel O-aryloxycarbonyl hydroxamates were constructed and assayed against MßLs. The obtained molecules specifically inhibited imipenemase-1 (IMP-1) and New Delhi metallo-ß-lactamase-1, exhibiting an IC50 value in the range of 0.10-18.42 and 0.23-22.33 µM, respectively. The hydroxamate 5 was found to be the most potent inhibitor, with an IC50 of 0.1 and 0.23 µM using meropenem and cefazolin as substrates. ICP-MS analysis showed that 5 did not coordinate to the Zn(II) ions at the active site of IMP-1, while the rapid dilution, thermal shift and MALDI-TOF assays revealed that the hydroxamate formed a covalent bond with the enzyme. Cytotoxicity assays indicated that the hydroxamates have low toxicity in MCF-7 cells. This work provided a potent scaffold for the development of MßLs inhibitors.

5.
Zhongguo Zhong Yao Za Zhi ; 46(23): 6224-6230, 2021 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-34951249

RESUMO

Alzheimer's disease(AD) patients in China have been surging, and the resultant medical burden and care demand have a huge impact on the development of individuals, families, and the society. The active component compound of Epimedii Folium, Astragali Radix, and Puerariae Lobatae Radix(YHG) can regulate the expression of iron metabolism-related proteins to inhibit brain iron overload and relieve hypofunction of central nervous system in AD patients. Hepcidin is an important target regulating iron metabolism. This study investigated the effect of YHG on the expression of a disintegrin and metalloprotease-17(ADAM17), a key enzyme in the hydrolysis of ß amyloid precursor protein(APP) in HT22 cells, by mediating hepcidin. To be specific, HT22 cells were cultured in vitro, followed by liposome-mediated siRNA transfection to silence the expression of hepcidin. Real-time PCR and Western blot were performed to examine the silencing result and the effect of YHG on hepcidin in AD cell model. HT22 cells were randomized into 7 groups: control group, Aß25-35 induction(Aß) group, hepcidin-siRNA(siRNA) group, Aß25-35 + hepcidin-siRNA(Aß + siRNA) group, Aß25-35+YHG(Aß+YHG) group, hepcidin-siRNA+YHG(siRNA+YHG) group, Aß25-35+hepcidin-siRNA+YHG(Aß+siRNA+YHG) group. The expression of ADAM17 mRNA in cells was detected by real-time PCR, and the expression of ADAM17 protein by immunofluorescence and Western blot. Immunofluorescence showed that the ADAM17 protein expression was lower in the Aß group, siRNA group, and Aß+siRNA group than in the control group(P<0.05) and the expression was lower in the Aß+siRNA group(P<0.05) and higher in the Aß+YHG group(P<0.05) than in the Aß group. Moreover, the ADAM17 protein expression was lower in the Aß+siRNA group(P<0.05) and higher in the siRNA+YHG group(P< 0.05) than in the siRNA group. The expression was higher in the Aß+siRNA+YHG group than in the Aß+siRNA group(P<0.05). The results of Western blot and real-time PCR were consistent with those of immunofluorescence. The experiment showed that YHG induced hepcidin to up-regulate the expression of ADAM17 in AD cell model and promote the activation of non-starch metabolic pathways, which might be the internal mechanism of YHG in preventing and treating AD.


Assuntos
Doença de Alzheimer , Medicamentos de Ervas Chinesas , Pueraria , Proteína ADAM17 , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Peptídeos beta-Amiloides , Medicamentos de Ervas Chinesas/farmacologia , Hepcidinas/genética , Humanos
6.
Orthop Surg ; 2021 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-34904370

RESUMO

OBJECTIVE: To assess and compare the therapeutic effects of Anterior Cervical Discectomy and Fusion (ACDF) and Cervical Laminectomy and Fusion (CLF) in the treatment of 4-level cervical. METHODS: We performed a retrospective review on 39 patients with 4-level CSM who underwent ACDF or CLF in the Third Hospital of Hebei Medical University from January 2010 to December 2018. The patients were divided into ACDF group and CLF group according to the treatment. The operative index was evaluated based on intraoperative blood loss and operation time. The functional outcomes including Japanese Orthopedic Association (JOA) score and visual analogue scale (VAS) of axial pain were compared. The Cobb angle, Cobb angle improvement rate, range of motion (ROM) and ROM loss ratio were measured for radiographic evaluation. RESULTS: No major complications or deaths occurred. The average age at baseline was 55 years. There was no significant difference between the ACDF and CLF group in follow-up time (26.29 months, 25.39 months, P > 0.05). The intraoperative blood loss was higher in the CLF group than in the ACDF group (692.67 ± 38.68 vs 392.14 ± 128.06, P < 0.05). The operation time was longer in the CLF group than in the ACDF group (206.60 ± 49.37 vs 172.64 ± 31.96, P < 0.05). Significant improvements in the VAS and JOA scores were observed in both groups (P < 0.05). No significant difference in VAS was found between the ACDF and CLF groups (P < 0.05). There was a significantly larger improvement rate of JOA score in the ACDF group than in the CLF group (60.9% ± 9.57% vs 31.5% ± 15.70%, P < 0.05). There were two (9.6%) cases with complications In the ACDF group, including one (4.8%) case of dysphagia and one (4.8%) case of pharyngodynia. In the CLF group, two patients (11.1%) developed C5 palsy. No significant difference in the incidence of complications, ROM loss ratio and Cobb angle improvement rate was found between group ACDF and group CLF (all P < 0.05). CONCLUSION: Both ACDF and CLF were effective in the treatment of multi-level cervical spondylosis and ACDF is more suitable for patients with 4-level CSM.

7.
J Agric Food Chem ; 69(47): 14103-14114, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34784717

RESUMO

The mechanism of nanoselenium (nano-Se) improving the resistance induced by plant components to aphids is unclear. In this study, foliar sprayed nano-Se (5.0 mg/L) could significantly reduce the Sitobion avenae number (36%) compared with that in the control. Foliar application of nano-Se enhanced the antioxidant capacity by reducing malondialdehyde (MDA) and increasing GSH-Px, CAT, GSH, Pro, and VE concentrations in wheat seedlings. The phenylpropane pathway was activated by nano-Se biofortification, which increased apigenin and caffeic acid concentrations. The high-level expression of the related genes (TaBx1A, TaBx3A, TaBx4A, TaASMT2, and TaCOMT) induced the promotion of melatonin (88.6%) and 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA) (64.3%). Different ratios of the secondary metabolites to nano-Se were taken to examine the effects on resistance of wheat to S. avenae. The results revealed that the combination of nano-Se and melatonin could achieve the best overall performance by reducing the S. avenae number by 52.2%. The study suggests that the coordinated applications of nano-Se and melatonin could more effectively improve the wheat resistance to aphids via the promotion of volatile organic compound synthesis and modulation in phenylpropane and indole metabolism pathways.

8.
Dis Markers ; 2021: 5669635, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777633

RESUMO

Tumor microenvironment (TME) has been demonstrated to exhibit a regulatory effect on the progressions of gastric cancer (GC). However, the related functions of stromal and immune components (TME-associated genes) in TME remain largely unclear. From the TCGA dataset, we downloaded the clinical data of 375 GC cases and then estimated the percentage of tumor-infiltrating immunocytes (TICs) and the levels of immune and stromal constituents by the use of CIBERSORT and ESTIMATE tolls. Univariate assays were applied to study the differentially expressed genes. The associations between the clinical information of GC patients and the expressions of the specific genes were analyzed based on the TCGA datasets. The effect of Plexin domain containing 2 (PLXDC2) expression on TICs was conducted. We observed that PLXDC2 expression was distinctly upregulated in GC specimens compared with nontumor gastric specimens. Its upregulation was associated with advanced clinical stages and predicted a shorter overall survival of GC patients. The genes in the group of higher expressing PLXDC2 were primarily enriched in immunity-associated events. By the use of CIBERSORT, we observed that PLXDC2 expressions were related to the proportion of dendritic cells resting, T cell CD4 memory resting, eosinophils, mastocyte resting, mononuclear cells, plasma cells, T cell follicle helper, macrophage M2, and dendritic cells activated. Overall, our discoveries revealed that the expression of PLXDC2 was remarkable in GC, might be a possible biomarker for GC, and provided novel contents regarding immune infiltrates, offering novel insight for treatments of GC.

9.
J Nanobiotechnology ; 19(1): 316, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641908

RESUMO

Selenium (Se) can promote the growth and resistance of agricultural crops as fertilizers, while the role of nano-selenium (nano-Se) against Cd remains unclear in pepper plants (Capsicum annuum L.). Biofortification with nano-Se observably restored Cd stress by decreasing the level of Cd in plant tissues and boosting the accumulation in biomass. The Se compounds transformed by nano-Se were primarily in the form of SeMet and MeSeCys in pepper tissues. Differential metabolites and the genes of plant signal transduction and lignin biosynthesis were measured by employing transcriptomics and determining target metabolites. The number of lignin-related genes (PAL, CAD, 4CL, and COMT) and contents of metabolites (sinapyl alcohol, phenylalanine, p-coumaryl alcohol, caffeyl alcohol, and coniferaldehyde) were remarkably enhanced by treatment with Cd1Se0.2, thus, maintaining the integrity of cell walls in the roots. It also enhanced signal transduction by plant hormones and responsive resistance by inducing the biosynthesis of genes (BZR1, LOX3, and NCDE1) and metabolites (brassinolide, abscisic acid, and jasmonic acid) in the roots and leaves. In general, this study can enable a better understanding of the protective mechanism of nano-Se in improving the capacity of plants to resist environmental stress.

10.
Signal Transduct Target Ther ; 6(1): 369, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34697295

RESUMO

The lung is the prophylaxis target against SARS-CoV-2 infection, and neutralizing antibodies are a leading class of biological products against various infectious viral pathogen. In this study, we develop a safe and cost-effective platform to express neutralizing antibody in the lung with replicating mRNA basing on alphavirus replicon particle (VRP) delivery system, to prevent SARS-CoV-2 infections. First, a modified VEEV replicon with two subgenomic (sg) promoters was engineered to translate the light and heavy chains of antibody simultaneously, for expression and assembly of neutralizing anti-SARS-CoV-2 antibody CB6. Second, the feasibility and protective efficacy of replicating mRNA against SARS-CoV-2 infection were demonstrated through both in vitro and in vivo assays. The lung target delivery with the help of VRP system resulted in efficiently block SARS-CoV-2 infection with reducing viral titer and less tissue damage in the lung of mice. Overall, our data suggests that expressing neutralizing antibodies in the lungs with the help of self-replicating mRNA could potentially be a promising prophylaxis approach against SARS-CoV-2 infection.


Assuntos
Alphavirus , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/terapia , Replicon , SARS-CoV-2/metabolismo , Animais , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/genética , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/genética , COVID-19/genética , COVID-19/metabolismo , Chlorocebus aethiops , Cricetinae , Feminino , Camundongos , Camundongos Endogâmicos BALB C , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , SARS-CoV-2/genética , Células Vero
11.
Mol Divers ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34585322

RESUMO

A series of compounds containing trifluoroacetyl groups were synthesized, and their insecticidal activity against Nilaparvata lugens and Aphis craccivora was evaluated. The compound structure was identified by NMR, HRMS, and single-crystal diffraction. The bioassay results indicated that compound 4-1 (R1 is chloropyridine, R2 is H), 4-2 (R1 is chlorothiazole, R2 is H) and 4-19 (R1 is benzyl, R2 is isopropyl) had the best activity against Nilaparvata lugens (93.5%, 94.1% and 95.5%) at 100 mg/L concentration. The effect of different substituents of R1 or R2 on the activity was studied through the structure-activity relationship. Molecular docking of compounds 4-1 and 4-2 was discussed.

12.
Zhongguo Zhong Yao Za Zhi ; 46(14): 3551-3559, 2021 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-34402277

RESUMO

Viscum plants,the evergreen perennial parasitic shrubs or subshrubs,are mainly distributed in tropical and subtropical regions. There are about 70 Viscum species around the world,including 11 species and one variety in China. Mistletoe lectins are typeⅡ ribosome-inactivating proteins( RIPs) extracted from Viscum plants with anticancer and immunoregulatory activities. Many studies have focused on the mistletoe lectins isolated from V. album in Europe and V. album var. coloratum distributed in South Korea,respectively,and several preparations,such as Iscucin Ⓡ,were developed and clinically applied for cancer treatment. Although Viscum plants are widely distributed in China,only a few studies of mistletoe lectins have been reported. The recent progress of mistletoe lectins was reviewed from extraction,purification,quantitative/qualitative detection,molecular structure,pharmacological activities,toxicities,and clinical application,aiming at providing a reference for in-depth research and utilization of mistletoe lectins produced in China.


Assuntos
Toxinas Biológicas , Viscum , Humanos , Lectinas , Extratos Vegetais , Lectinas de Plantas , Proteínas de Plantas/genética
14.
Toxins (Basel) ; 13(8)2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34437419

RESUMO

Given that the venom system in sea snakes has a role in enhancing their secondary adaption to the marine environment, it follows that elucidating the diversity and function of venom toxins will help to understand the adaptive radiation of sea snakes. We performed proteomic and de novo NGS analyses to explore the diversity of venom toxins in the annulated sea snake (Hydrophis cyanocinctus) and estimated the adaptive molecular evolution of the toxin-coding unigenes and the toxicity of the major components. We found three-finger toxins (3-FTxs), phospholipase A2 (PLA2) and cysteine-rich secretory protein (CRISP) in the venom proteome and 59 toxin-coding unigenes belonging to 24 protein families in the venom-gland transcriptome; 3-FTx and PLA2 were the most abundant families. Nearly half of the toxin-coding unigenes had undergone positive selection. The short- (i.p. 0.09 µg/g) and long-chain neurotoxin (i.p. 0.14 µg/g) presented fairly high toxicity, whereas both basic and acidic PLA2s expressed low toxicity. The toxicity of H. cyanocinctus venom was largely determined by the 3-FTxs. Our data show the venom is used by H. cyanocinctus as a biochemically simple but genetically complex weapon and venom evolution in H. cyanocinctus is presumably driven by natural selection to deal with fast-moving prey and enemies in the marine environment.

15.
J Antibiot (Tokyo) ; 74(9): 574-579, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34234284

RESUMO

The superbug infection caused by metallo-ß-lactamases (MßLs) carrying drug-resistant bacteria, specifically, New Delhi metallo-ß-lactamase (NDM-1) has become an emerging threat. In an effort to develop novel inhibitors of NDM-1, thirteen thiosemicarbazones (1a-1m) were synthesized and assayed. The obtained molecules specifically inhibited NDM-1, with an IC50 in the range of 0.88-20.2 µM, and 1a and 1f were found to be the potent inhibitors (IC50 = 1.79 and 0.88 µM) using cefazolin as substrate. ITC and kinetic assays indicated that 1a irreversibly and non-competitively inhibited NDM-1 in vitro. Importantly, MIC assays revealed that these molecules by themselves can sterilize NDM-producing clinical isolates EC01 and EC08, exhibited 78-312-fold stronger activities than the cefazolin. MIC assays suggest that 1a (16 µg ml-1) has synergistic antimicrobial effect with ampicillin, cefazolin and meropenem on E. coli producing NDM-1, resulting in MICs of 4-32-, 4-32-, and 4-8-fold decrease, respectively. These studies indicate that the thiosemicarbazide is a valuable scaffold for the development of inhibitors of NDM-1 and NDM-1 carrying drug-resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Tiossemicarbazonas/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Cefazolina/farmacologia , Farmacorresistência Bacteriana , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química
16.
Bioorg Chem ; 114: 105138, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34229201

RESUMO

The expression of ß-lactamases, especially metallo-ß-lactamases (MßLs) in bacteria is one of the main causes of drug resistance. In this work, an effective N-acylhydrazone scaffold as MßL inhibitor was constructed and characterized. The biological activity assays indicated that the synthesized N-acylhydrazones 1-11 preferentially inhibited MßL NDM-1, and 1 was found to be the most effective inhibitor with an IC50 of 1.2 µM. Analysis of IC50 data revealed a structure-activity relationship, which is that the pyridine and hydroxylbenzene substituents at 2-position improved inhibition of the compounds on NDM-1. ITC and enzyme kinetics assays suggested that it reversibly and competitively inhibited NDM-1 (Ki = 0.29 ± 0.05 µM). The synthesized N-acylhydrazones showed synergistic antibacterial activities with meropenem, reduced 4-16-fold MIC of meropenem on NDM-1- producing E. coli BL21 (DE3), while 1 restored 4-fold activity of meropenem on K. pneumonia expressing NDM-1 (NDM-K. pneumoniae). The mice experiments suggested that 1 combined meropenem to fight against NDM-K. pneumoniae infection in the spleen and liver. Cytotoxicity assays showed that 1 and 2 have low cytotoxicity. This study offered a new framework for the development of NDM-1 inhibitors.

17.
J Gen Virol ; 102(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33956592

RESUMO

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus, which is highly pathogenic and classified as a biosafety level 3 (BSL-3) agent, has greatly threatened global health and efficacious antivirals are urgently needed. The high requirement of facilities to manipulate the live virus has limited the development of antiviral study. Here, we constructed a reporter replicon of SARS-CoV-2, which can be handled in a BSL-2 laboratory. The Renilla luciferase activity effectively reflected the transcription and replication levels of the replicon genome. We identified the suitability of the replicon in antiviral screening using the known inhibitors, and thus established the replicon-based high-throughput screening (HTS) assay for SARS-CoV-2. The application of the HTS assay was further validated using a few hit natural compounds, which were screened out in a SARS-CoV-2 induced cytopathic-effect-based HTS assay in our previous study. This replicon-based HTS assay will be a safe platform for SARS-CoV-2 antiviral screening in a BSL-2 laboratory without the live virus.


Assuntos
Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Replicon/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Descoberta de Drogas , Ensaios de Triagem em Larga Escala/métodos , Humanos , Replicon/genética , SARS-CoV-2/genética , Células Vero , Replicação Viral/efeitos dos fármacos
18.
Zhongguo Zhong Yao Za Zhi ; 46(8): 2037-2044, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33982517

RESUMO

As a traditional Chinese medicine, Chinese dragon's blood has multiple effects, such as activating blood to remove blood stasis, softening and dispelling stagnation, astringent and hemostasis, clearing swelling and relieving pain, regulating menstruation and rectifying the blood, so it is called "an effective medicine of promoting blood circulation". It has been widely used clinically to treat a variety of diseases. With the further research on Chinese dragon's blood, its anti-tumor medicinal value is gradually emerging. Modern pharmacological studies have shown that Chinese dragon's blood exerts anti-tumor effects mainly by inhibiting cell proliferation, inducing apoptosis, inducing DNA damage and cell cycle arrest, inducing senescence and autophagy of tumor cells, inhibiting metastasis and angiogenesis, as well as reversing multidrug resistance. This article focuses on the research progress on anti-tumor effects of Chinese dragon's blood extract and its chemical components, with a view to provide new references for the in-depth research and reasonable utilization of Chinese dragon's blood.


Assuntos
Dracaena , China , Feminino , Extratos Vegetais , Resinas Vegetais
19.
Bioorg Chem ; 112: 104889, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33915460

RESUMO

The emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised a global catastrophe. To date, there is no specific antiviral drug available to combat this virus, except the vaccine. In this study, the main protease (Mpro) required for SARS-CoV-2 viral replication was expressed and purified. Thirty-six compounds were tested as inhibitors of SARS-CoV-2 Mpro by fluorescence resonance energy transfer (FRET) technique. The half-maximal inhibitory concentration (IC50) values of Ebselen and Ebsulfur analogs were obtained to be in the range of 0.074-0.91 µM. Notably, the molecules containing furane substituent displayed higher inhibition against Mpro, followed by Ebselen 1i (IC50 = 0.074 µM) and Ebsulfur 2k (IC50 = 0.11 µM). The action mechanism of 1i and 2k were characterized by enzyme kinetics, pre-incubation and jump dilution assays, as well as fluorescent labeling experiments, which suggested that both compounds covalently and irreversibly bind to Mpro, while molecular docking suggested that 2k formed an SS bond with the Cys145 at the enzymatic active site. This study provides two very potent scaffolds Ebsulfur and Ebselen for the development of covalent inhibitors of Mpro to combat COVID-19.


Assuntos
Antivirais/metabolismo , Azóis/metabolismo , Compostos Organosselênicos/metabolismo , SARS-CoV-2/metabolismo , Compostos de Enxofre/metabolismo , Proteínas da Matriz Viral/metabolismo , Antivirais/química , Antivirais/uso terapêutico , Azóis/química , Azóis/uso terapêutico , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração Inibidora 50 , Isoindóis , Cinética , Simulação de Acoplamento Molecular , Compostos Organosselênicos/química , Compostos Organosselênicos/uso terapêutico , SARS-CoV-2/isolamento & purificação , Relação Estrutura-Atividade , Compostos de Enxofre/química , Compostos de Enxofre/uso terapêutico , Proteínas da Matriz Viral/antagonistas & inibidores , Proteínas da Matriz Viral/genética
20.
Bioorg Med Chem ; 38: 116128, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862468

RESUMO

To combat the superbug infection caused by metallo-ß-lactamases (MßLs), a dipyridyl-substituted thiosemicarbazone (DpC), was identified to be the broad-spectrum inhibitor of MßLs (NDM-1, VIM-2, IMP-1, ImiS, L1), with an IC50 value in the range of 0.021-1.08 µM. It reversibly and competitively inhibited NDM-1 with a Ki value of 10.2 nM. DpC showed broad-spectrum antibacterial effect on clinical isolate K. pneumonia, CRE, VRE, CRPA and MRSA, with MIC value ranged from 16 to 32 µg/mL, and exhibited synergistic antibacterial effect with meropenem on MßLs-producing bacteria, resulting in a 2-16-, 2-8-, and 8-fold reduction in MIC of meropenem against EC-MßLs, EC01-EC24, K. pneumonia, respectively. Moreover, mice experiments showed that DpC also had synergistic antibacterial action with meropenem. In this work, DpC was identified to be a potent scaffold for the development of broad-spectrum inhibitors of MßLs.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Tiossemicarbazonas/farmacologia , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Bactérias/enzimologia , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Inibidores de beta-Lactamases/síntese química , Inibidores de beta-Lactamases/química
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