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1.
Genome Res ; 33(4): 612-621, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37041035

RESUMO

Rare species are vital members of a microbial community, but retrieving their genomes is difficult because of their low abundance. The ReadUntil (RU) approach allows nanopore devices to sequence specific DNA molecules selectively in real time, which provides an opportunity for enriching rare species. Despite the robustness of enriching rare species by reducing the sequencing depth of known host sequences, such as the human genome, there is still a gap in RU-based enriching of rare species in environmental samples whose community composition is unclear, and many rare species have poor or incomplete reference genomes in public databases. Therefore, here we present metaRUpore to overcome this challenge. When we applied metaRUpore to a thermophilic anaerobic digester (TAD) community and human gut microbial community, it reduced coverage of the high-abundance populations and modestly increased (∼2×) the genome coverage of the rare taxa, facilitating successful recovery of near-finished metagenome-assembled genomes (nf-MAGs) of rare species. The simplicity and robustness of the approach make it accessible for laboratories with moderate computational resources, and hold the potential to become the standard practice in future metagenomic sequencing of complicated microbiomes.


Assuntos
Microbiota , Nanoporos , Humanos , Microbiota/genética , Metagenoma , Metagenômica
2.
Brief Bioinform ; 23(6)2022 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-36259361

RESUMO

Metagenomic sequencing analysis (mNGS) has been implemented as an alternative approach for pathogen diagnosis in recent years, which is independent of cultivation and is able to identify all potential antibiotic resistance genes (ARGs). However, current mNGS methods have to deal with low amounts of prokaryotic deoxyribonucleic acid (DNA) and high amounts of host DNA in clinical samples, which significantly decrease the overall microbial detection resolution. The recently released nanopore adaptive sampling (NAS) technology facilitates immediate mapping of individual nucleotides to a given reference as each molecule is sequenced. User-defined thresholds allow for the retention or rejection of specific molecules, informed by the real-time reference mapping results, as they are physically passing through a given sequencing nanopore. We developed a metagenomics workflow for ultra-sensitive diagnosis of bacterial pathogens and ARGs from clinical samples, which is based on the efficient selective 'human host depletion' NAS sequencing, real-time species identification and species-specific resistance gene prediction. Our method increased the microbial sequence yield at least 8-fold in all 21 sequenced clinical Bronchoalveolar Lavage Fluid (BALF) samples (4.5 h from sample to result) and accurately detected the ARGs at species level. The species-level positive percent agreement between metagenomic sequencing and laboratory culturing was 100% (16/16) and negative percent agreement was 100% (5/5) in our approach. Further work is required for a more robust validation of our approach with large sample size to allow its application to other infection types.


Assuntos
Antibacterianos , Nanoporos , Humanos , Fluxo de Trabalho , Farmacorresistência Bacteriana/genética , Metagenômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Bactérias/genética , DNA
3.
Mol Divers ; 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38687399

RESUMO

Asymmetric synthesis of spiro[4H-chromene-3,3'-oxindole] derivatives was realized through an organocatalytic cascade Knoevenagel/Michael/cyclization reaction using a quinidine-derived squaramide. Under the optimized conditions, the reactions of isatins, malononitrile, and sesamol yield the desired spirooxindoles in good yields (75-87%) and moderate to high ee values (up to 90% ee).

4.
Artigo em Inglês | MEDLINE | ID: mdl-38940793

RESUMO

Background: Feeding intolerance poses a significant risk of malnutrition in premature infants and may result in postnatal growth restriction, leading to irreversible damage to brain function and structure. Objective: This study aims to investigate the impact of various early hospital feeding methods on feeding tolerance and the early growth and development of premature infants. Design: A retrospective study design was adopted in this study. Setting: This study was conducted at Tongling Maternal and Child Health Hospital between January 2018 and June 2023. Participants: A total of premature, low birth-weight infants admitted to our hospital between January 2018 and June 2023 were selected for the study. The preterm infants were randomly assigned to either the experimental group (EG) or the control group (CG) using the random number table method. Interventions: The EG group received deep hydrolyzed protein formula (DHPF) milk for 1-3 weeks after opening, whereas the CG group received preterm infant formula milk continuously after the milk was opened. Primary Outcome Measures: (1) Growth and development, (2) Feeding tolerance, and (3) Incidence of complications. Results: Following 14 days of feeding, both study groups exhibited notable increases in body length, body weight, and head circumference (P < .05). These measurements were significantly higher in the EG compared to the CG (P < .05). Furthermore, the EG demonstrated a marked improvement in feeding tolerance relative to the CG (P < .01). Notably, there was no significant difference in the incidence of complications between the two groups (P > .05). Conclusions: The administration of deep hydrolyzed protein formula (DHPF) milk presents a promising strategy for enhancing the growth and development of premature infants while concurrently improving feeding tolerance. These findings underscore the potential clinical benefits of incorporating DHPF milk into neonatal care protocols.

5.
Molecules ; 29(5)2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38474601

RESUMO

Three new phenols (1-3), one new cyclohexanol (4), two known phenols (5-6), and six known flavonoids (7-12) were isolated from the n-butanol of the 75% ethanol extract of all plants of Chimaphila japonica Miq. Among them, compound 5 was named and described in its entirety for the first time, and compounds 9 and 10 were reported in C. japonica for the first time. The structures of all compounds were confirmed using a comprehensive analysis of 1D and 2D NMR and HRESIMS data. Biological results show that compounds 4, 7, and 11 exhibited potent diuretic activity. The modes of interaction between the selected compounds and the target diuretic-related WNK1 kinase were investigated in a preliminary molecular docking study. These results provided insight into the chemodiversity and potential diuretic activities of metabolites in C. japonica.


Assuntos
Antioxidantes , Flavonoides , Simulação de Acoplamento Molecular , Flavonoides/química , Antioxidantes/química , Fenóis/química , Extratos Vegetais/química
6.
Eur J Nucl Med Mol Imaging ; 50(2): 453-464, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36121463

RESUMO

PURPOSE: Retrospective analysis revealed increased [18F]AlF-NOTA-FAPI-04 uptake in the myocardium of patients with esophageal squamous cell cancer (ESCC) treated with concurrent chemoradiotherapy (CCRT). This study investigated and verified the feasibility of [18F]AlF-NOTA-FAPI-04 PET/CT for detecting radiation-induced myocardial damage (RIMD). METHODS: Myocardial FAPI uptake was analyzed before and during radiotherapy in thirteen ESCC patients treated with CCRT. In the animal study, a single dose of 50 Gy was delivered to the cardiac apex of Wistar rats (24 rats, including 16 RIMD model rats and 8 control model rats). RIMD model rats were scanned with [18F]AlF-NOTA-FAPI-04 PET/CT weekly for 12 weeks, and left ventricular ejection fraction (LVEF) was measured by magnetic resonance imaging. Dynamic, blocking, and [18F]FDG PET/CT studies (4 rats/group) were performed on RIMD rats at 5 weeks post-radiation, and histopathological analyses were conducted. RESULTS: Increased FAPI uptake in the myocardium was found after CCRT (1.53 ± 0.53 vs 1.88 ± 0.70, P = 0.015). In RIMD rats, significantly increased FAPI uptake in the damaged myocardium was observed from the 2nd week post-radiation exposure and peaked in the 5th week. Significantly more intense tracer accumulation was observed in the damaged myocardium than in the remote myocardium, as identified by decreased [18F]FDG uptake and confirmed by autoradiography, hematoxylin-eosin, Masson's trichrome, and immunohistochemical staining. The LVEF remained unchanged at the 3rd week post-radiation exposure but was remarkably decreased compared with that in the control group at the 8th week. CONCLUSION: Through clinical phenomena and animal experimental studies, this study indicated that [18F]AlF-NOTA-FAPI-04 PET/CT imaging can detect RIMD noninvasively and before a decrease in LVEF, indicating the clinical potential of [18F]AlF-NOTA-FAPI-04 as a PET/CT tracer for early monitoring of RIMD.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Quinolinas , Animais , Ratos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Estudos Retrospectivos , Volume Sistólico , Ratos Wistar , Função Ventricular Esquerda , Detecção Precoce de Câncer , Miocárdio , Tomografia por Emissão de Pósitrons , Radioisótopos de Gálio
7.
World Wide Web ; : 1-16, 2023 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-37361139

RESUMO

The COVID-19 is still spreading today, and it has caused great harm to human beings. The system at the entrance of public places such as shopping malls and stations should check whether pedestrians are wearing masks. However, pedestrians often pass the system inspection by wearing cotton masks, scarves, etc. Therefore, the detection system not only needs to check whether pedestrians are wearing masks, but also needs to detect the type of masks. Based on the lightweight network architecture MobilenetV3, this paper proposes a cascaded deep learning network based on transfer learning, and then designs a mask recognition system based on the cascaded deep learning network. By modifying the activation function of the MobilenetV3 output layer and the structure of the model, two MobilenetV3 networks suitable for cascading are obtained. By introducing transfer learning into the training process of two modified MobilenetV3 networks and a multi-task convolutional neural network, the ImagNet underlying parameters of the network models are obtained in advance, which reduces the computational load of the models. The cascaded deep learning network consists of a multi-task convolutional neural network cascaded with these two modified MobilenetV3 networks. A multi-task convolutional neural network is used to detect faces in images, and two modified MobilenetV3 networks are used as the backbone network to extract the features of masks. After comparing with the classification results of the modified MobilenetV3 neural network before cascading, the classification accuracy of the cascading learning network is improved by 7%, and the excellent performance of the cascading network can be seen.

8.
Biochem Biophys Res Commun ; 622: 37-44, 2022 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-35843092

RESUMO

Breast cancer is a leading cause of tumor-related death among women around the world, but its pathogenesis is still unclear. Transmembrane protein 189 (TMEM189) is widely expressed in many types of tissues and plays a critical role in tumorigenesis partly through mediating cell death. However, its regulatory function on breast cancer progression and particularly the underlying mechanisms have not been fully understood. In the present study, we found that TMEM189 knockdown significantly reduced the proliferation of breast cancer cells, while its over-expression facilitated the proliferative capacity of tumor cells. The effects of TMEM189 to promote breast cancer were validated in the constructed xenograft mouse models. RNA-sequencing studies subsequently showed that TMEM189 deletion was closely associated with ferroptosis signaling pathway, accompanied with elevated lipid reactive oxygen species (ROS) accumulation, cellular ROS production, malondialdehyde (MDA) and the intracellular iron releases. However, GSH levels in breast cancer cells were highly impeded upon TMEM189 inhibition. Intriguingly, we found that TMEM189 knockdown-induced ferroptotic cell death was considerably abolished after autophagy inhibitor 3-MA co-treatment, as evidenced by the markedly decreased ROS generation and intracellular iron accumulation. Moreover, TMEM189 ablation strongly up-regulated LC3BII and transferrin receptor 1 (TfR1) expression levels in breast cancer cells, whereas down-regulated p62 and GPX4. Importantly, the expression changes of these molecules related to autophagy and ferroptosis were almost diminished in response to 3-MA exposure, along with restored cell proliferation. These findings suggested that TMEM189 could inhibit autophagy to mediate ferroptosis in breast cancer cells. Collectively, all our findings revealed the therapeutic potential of TMEM189 in the treatment of breast cancer.


Assuntos
Neoplasias da Mama , Ferroptose , Animais , Autofagia , Neoplasias da Mama/metabolismo , Feminino , Humanos , Ferro/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Enzimas de Conjugação de Ubiquitina
9.
BMC Ophthalmol ; 22(1): 318, 2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35883052

RESUMO

BACKGROUND: Intraoperative intraocular pressure (IOP) elevation is a risk factor for postoperative blindness. Surgical position is associated with intraoperative IOP elevation. In China, there are few studies on the effect of various surgical positions on intraoperative IOP. This study was conducted to explore IOP change and its related factors in four common surgical positions in China. METHODS: This was a cross-sectional observational study. A total of 325 surgical patients who had non-ocular surgery from January 2019 to December 2019 in the hospital, were enrolled in this study. During their surgeries for general anesthesia, these participants were placed in lithotomy position/lateral position/prone position/supine position according to their surgery requirement. IOP was measured by icareTA03 handheld portable tonometer at 9 different time points from admission to exiting the operation room. And general information, postural position, and surgery information were collected through a uniform questionnaire. Multivariate analysis was performed to explore the related factors of IOP change. RESULTS: IOP of both eyes on lithotomy position, lateral position, and supine position showed statistical differences by ANOVA test at each time point (p < 0.05). IOP of both eyes in the prone position before exit from the operating room was significantly higher than IOP 10-min after anesthesia (p < 0.01). IOP under different postural angles showed statistical differences (F value = 4.85, P < 0.05), and the larger the head-down angle, the higher the IOP. IOP on the compressed side in the lateral position was higher than that on the non-compressed side (p < 0.01). In the multivariate linear regression analysis adjusted by other factors, postural position and baseline IOP were associated with IOP difference between before and after surgery (p < 0.01). CONCLUSION: IOP in the four surgical positions showed different change patterns with the surgical process and position change. Nurses should assist the surgeon to reduce the head-down angle without interfering with the surgical operation and strengthen the inspection of IOP on patients with long-time surgery, to avoid intraoperative rapid IOP changes.


Assuntos
Oftalmopatias , Pressão Intraocular , Estudos Transversais , Humanos , Postura , Estudos Prospectivos , Tonometria Ocular
10.
Planta ; 253(2): 34, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33459878

RESUMO

MAIN CONCLUSION: BnPGIPs interacted with Sclerotinia sclerotiorum PGs to improve rapeseed SSR resistance at different levels; the BnPGIP-overexpression lines did not affect plant morphology or seed quality traits. Plant polygalacturonase-inhibiting proteins (PGIPs) play a crucial role in plant defence against phytopathogenic fungi by inhibiting fungal polygalacturonase (PG) activity. We overexpressed BnPGIP2, BnPGIP5, and BnPGIP10 genes in an inbred line 7492 of rapeseed (Brassica napus). Compared with 7492WT, the overexpression of BnPGIP2 lines significantly increased Sclerotinia sclerotiorum resistance in both seedlings and adult plants. BnPGIP5 overexpression lines exhibited decreased S. sclerotiorum disease symptoms in seedlings only, whereas BnPGIP10 overexpression lines did not improve Sclerotinia resistance for seedlings or adult plants. Quantitative real-time PCR analysis of S. sclerotiorum PG1, SsPG3, SsPG5, and SsPG6 genes in overexpressing BnPGIP lines showed that these pathogenic genes in the Sclerotinia resistance transgenic lines exhibited low expression in stem tissues. Split-luciferase complementation experiments confirmed the following: BnPGIP2 interacts with SsPG1 and SsPG6 but not with SsPG3 or SsPG5; BnPGIP5 interacts with SsPG3 and SsPG6 but not with SsPG1 or SsPG5; and BnPGIP10 interacts with SsPG1 but not SsPG3, SsPG5, or SsPG6. Leaf crude protein extracts from BnPGIP2 and BnPGIP5 transgenic lines displayed high inhibitory activity against the SsPG crude protein. BnPGIP-overexpression lines with Sclerotinia resistance displayed a lower accumulation of H2O2 and higher expression of the H2O2-removing gene BnAPX (ascorbate peroxidase) than 7492WT, as well as elevated expression of defence response genes including jasmonic acid/ethylene and salicylic acid pathways after S. sclerotiorum infection. The plants overexpressing BnPGIP exhibited no difference in either agronomic traits or grain yield from 7492WT. This study provides potential target genes for developing S. sclerotiorum resistance in rapeseed.


Assuntos
Ascomicetos , Brassica napus , Resistência à Doença , Proteínas de Plantas , Poligalacturonase , Ascomicetos/enzimologia , Brassica napus/enzimologia , Brassica napus/genética , Brassica napus/microbiologia , Resistência à Doença/genética , Expressão Gênica , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Peróxido de Hidrogênio/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Proteínas de Plantas/metabolismo , Poligalacturonase/metabolismo
11.
Hum Genomics ; 14(1): 5, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32000849

RESUMO

BACKGROUND: Preeclampsia (PE) is a heterogeneous, hypertensive disorder of pregnancy, with no robust biomarkers or effective treatments. PE increases the risk of poor outcomes for both the mother and the baby. Methylation-mediated transcriptional dysregulation motifs (methTDMs) could contribute the PE development. However, precise functional roles of methTDMs in PE have not been globally described. METHODS: Here, we develop a comprehensive and computational pipeline to identify PE-specific methTDMs following TF, gene, methylation expression profile, and experimentally verified TF-gene interactions. RESULTS: The regulation patterns of methTDMs are multiple and complex in PE and contain relax inhibition, intensify inhibition, relax activation, intensify activation, reverse activation, and reverse inhibition. A core module is extracted from global methTDM network to further depict the mechanism of methTDMs in PE. The common and specific features of any two kinds of regulation pattern are also analyzed in PE. Some key methylation sites, TFs, and genes such as IL2RG are identified in PE. Functional analysis shows that methTDMs are associated with immune-, insulin-, and NK cell-related functions. Drug-related network identifies some key drug repurposing candidates such as NADH. CONCLUSION: Collectively, the study highlighted the effect of methylation on the transcription process in PE. MethTDMs could contribute to identify specific biomarkers and drug repurposing candidates for PE.


Assuntos
Biomarcadores/análise , Biologia Computacional/métodos , Metilação de DNA , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/patologia , Regiões Promotoras Genéticas , Transcrição Gênica , Estudos de Casos e Controles , Ilhas de CpG , Feminino , Perfilação da Expressão Gênica , Humanos , Gravidez
12.
Med Sci Monit ; 27: e934275, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34776507

RESUMO

BACKGROUND We aimed to explore the risk factors that affect the serum concentration of sodium valproate (VPA-Na) in patients with epilepsy and to provide references for the rationale of the use of VPA-Na. MATERIAL AND METHODS The enzyme-multiplied immunoassay technique was used to determine the serum VPA-NA concentrations of 109 patients, and the results were retrospectively analyzed and summarized. A multivariate logistic regression model was used to analyze substandard serum VPA-Na concentrations. RESULTS Fifty-six patients (51.38%) treated with VPA-Na tablets were within the effective treatment range of 50-100 µg/mL, while 53 patients (48.62%) were out of the treatment range. The results indicated that the standard-reaching rate of serum drug concentration in the juvenile group was higher than that in the adult and elderly groups; the standard-reaching rates of serum drug concentrations in the low-dose group and the intermediate-dose group were lower than that in the high-dose group; and the standard-reaching rate of serum drug concentration in the group receiving carbapenems in combination was lower than that in the non-combination group; all differences were statistically significant. The combination with carbapenems and enzyme inducers was an independent risk factor for VPA-Na serum concentration below the target level in hospitalized patients. CONCLUSIONS To improve clinical efficacy and reduce the occurrence of adverse reactions, there is a need for therapeutic drug monitoring of VPA-Na. Moreover, individual administration should be implemented when VPA-Na tablets are used in the treatment of epilepsy because of the significant fluctuation in VPA-Na blood concentration.


Assuntos
Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Ácido Valproico/sangue , Ácido Valproico/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
13.
Yi Chuan ; 43(7): 654-664, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284981

RESUMO

Long non-coding RNA (lncRNA) is a class of non-coding RNAs with a length greater than 200 nucleotides. Although lncRNAs do not have any protein coding capability, they can affect the phenotypes of traits by influencing gene expression through transcriptional regulation, post-transcriptional regulation, and epigenetic modification. In modern animal husbandry production, besides increasing growth and yield traits, investigations on the regulation mechanisms of immune factors, cytokines and other disease resistance-related indicators and traits are particularly important for improving the health and welfare of domesticated animals as well as public health. In recent years, researchers have made significant progress in understanding the regulatory mechanisms of lncRNA on the disease resistance traits of chickens (Gallus gallus), pigs (Sus scrofa), cattle (Bos taurus) and other important domesticated animals, thereby laying the basic foundation for the translational application of epigenetic markers in breeding of animals with disease resistance. In this review, we briefly introduce the biological functions and the origins of lncRNAs, then focus on the research progress on the regulatory effects of lncRNAs on disease resistance traits of domesticated animals, and thus providing the scientific basis for the research of lncRNA and its application in the breeding of disease-resistant animals.


Assuntos
RNA Longo não Codificante , Animais , Animais Domésticos/genética , Bovinos , Galinhas/genética , Resistência à Doença/genética , Fenótipo , RNA Longo não Codificante/genética , Suínos/genética
14.
Ann Diagn Pathol ; 46: 151493, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32179442

RESUMO

Cervical squamous cell carcinoma develops through a series of stages, including low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), microinvasive squamous cell carcinoma (MISCC), and invasive squamous cell carcinoma (ISCC). The difference between HSIL and MISCC is the appearance of microinvasion, which determines the treatment for patients. However, sometimes it is difficult to differentiate HSIL from MISCC in morphology, and no effective markers are available to help determine microinvasion. Here, we evaluated the expression patterns of podoplanin in cervical tissues by immunohistochemistry staining. Results showed that podoplanin was specifically expressed in a continuous or discontinuous linear pattern within the basal layer of cells from normal cervical squamous epithelium (NS) (100%, 96/96) and HSIL (81%, 57/70). However, its expression was completely absent in microinvasive lesions (0%, 72/72), and the location of podoplanin expression loss was consistent with that of microinvasive lesions. Thus, for HSIL with positive podoplanin expression, the sudden loss of podoplanin represents the occurrence of early invasion. Furthermore, podoplanin was expressed in 3.4% (4/118) of ISCC, and its expression was not correlated with the age of the patient, tumor size, differentiation, FIGO stage, depth of invasion, lymph node, or distant metastasis. The prognosis of patients with positive podoplanin was slightly better than those without it (p > 0.05). Therefore, we found that podoplanin, as a new specific marker for the basal layer cells of cervical squamous epithelium, could assist the diagnosis of microinvasion in cervical squamous cell carcinoma. The specific staining pattern of podoplanin provides the possibility of clinical application in the future.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Glicoproteínas de Membrana/metabolismo , Displasia do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Adulto , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/patologia , Displasia do Colo do Útero/patologia
15.
Bioorg Chem ; 86: 696-704, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30831531

RESUMO

A series of novel N-hydroxypropenamides containing adamantane moiety were identified and most of them exhibited HDAC inhibitory activity and could reverse the resistance of cisplatin in NSCLC cell lines. In this process, molecular docking was employed to verify the rationality of designing, subsequently, target compounds were synthesized and conducted to enzyme- and cell-based biological evaluation. Most of synthesized compounds could inhibit HDAC activity with the IC50 values lower than 50 nM and result in the increase of Ac-H4 and p21 in A549 cells. Importantly, we assessed the reversal effect of those compounds and found several compounds display an anti-resistant effect in lung cancer cells, especially compound 8f. As compared to belinostat and cisplatin, compound 8f showed improved inhibitory activity against A549/CDDP cell lines with IC50 value of 5.76 µM, and far lower resistance index of 1.24. Moreover, the structure-activity relationships of these compounds were summarized and compound 8f could serve as a research tool for identifying the mechanism of reversing resistance and a template for designing novel compounds to reverse cisplatin resistance.


Assuntos
Adamantano/farmacologia , Amidas/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Células A549 , Adamantano/síntese química , Adamantano/química , Amidas/síntese química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
16.
Br J Cancer ; 117(7): 974-983, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28850563

RESUMO

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have demonstrated clinical benefits in the treatment of several tumour types. However, the emergence of TKI resistance restricts the therapeutic effect. This study uses non-small cell lung cancer (NSCLC) to explore the mechanisms contributing to TKI resistance in tumours. METHODS: Biological phenotypes and RNA microarray expression data were analysed in NSCLC cells with and without TKI pretreatment. Specific inhibitors and siRNAs were used to validate the direct involvement of an AKT/FOXM1/STMN1 pathway in TKI resistance. Patients' tissues were analysed to explore the clinical importance of FOXM1 and STMN1. RESULTS: In vitro and in vivo studies showed that TKIs induced the enrichment of cancer stem cells (CSC), promoted epithelial to mesenchymal transition (EMT), and conferred multidrug resistance on NSCLC cells in a cell type- and TKI class-dependent manner. Mechanistically, TKIs activated an AKT/FOXM1/STMN1 pathway. The crucial role of this pathway in TKI-induced enrichment of CSC and drug resistance was verified by silencing FOXM1 and STMN1 or blocking the AKT pathway. Additionally, overexpression of STMN1 was associated with upregulation of FOXM1 in advanced NSCLC patients, and STMN1/FOXM1 upregulation predicted a poor outcome. CONCLUSIONS: Our findings elucidate an additional common mechanism for TKI resistance and provide a promising therapeutic target for reversing TKI resistance in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteína Forkhead Box M1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estatmina/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/química , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteína Forkhead Box M1/análise , Proteína Forkhead Box M1/genética , Gefitinibe , Inativação Gênica , Humanos , Neoplasias Pulmonares/química , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Fenótipo , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Quinazolinas/farmacologia , RNA Neoplásico/análise , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Estatmina/análise , Estatmina/genética , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Phytother Res ; 31(3): 507-515, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28164397

RESUMO

Guanxin Shutong capsule is a traditional Chinese medicine for the treatment of myocardial ischemia (MI). Previous studies have shown that the formula has four main active ingredients (FMAI), protocatechuic acid, cryptotanshinone, borneol, and eugenol. However, the mechanisms of action of these FMAI against MI injury are still not well known. The aim of the present study was to evaluate the protective effects of the FMAI on MI in vitro and in vivo. In vitro, rat neonatal cardiomyocytes were isolated, the cell viability and apoptosis rate were, respectively, measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and fluorescence activating cell sorter, and the intracellular calcium concentration ([Ca2+ ]i ) and CaM and CaMKII δ mRNA as well as protein levels were determined. Meanwhile, their downstream targets of RyR2 and PLB were also measured by western blot. In vivo, a rat model of coronary artery ligation was used to evaluate the cardioprotective effects. Infarct sizes of heart tissues and levels of serum biochemical indicators, including creatine kinase, lactate dehydrogenase, superoxide dismutase, and glutamate oxaloacetic transaminase, were measured. The in vitro results showed that the FMAI inhibited cell apoptosis, reduced [Ca2+ ]i , decreased the expression of CaM and CaMKII δ, and increased the expression of RyR2 and PLB. In vivo, the FMAI diminished infract size, reduced creatine kinase, lactate dehydrogenase, and aspartate aminotransferase levels, and enhanced superoxide dismutase activity. In conclusion, our data suggest that the FMAI suppressed calcium overload and exerted its protective effect via its antioxidant, antiinflammatory, and anti-apoptosis activities. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Canfanos/farmacologia , Cardiotônicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Eugenol/farmacologia , Hidroxibenzoatos/farmacologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fenantrenos/farmacologia , Animais , Animais Recém-Nascidos , Antioxidantes/farmacologia , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Canfanos/química , Cápsulas , Cardiotônicos/química , Células Cultivadas , Medicamentos de Ervas Chinesas/química , Eugenol/química , Hidroxibenzoatos/química , Masculino , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fenantrenos/química , Ratos , Ratos Sprague-Dawley
18.
Physiol Mol Biol Plants ; 23(3): 619-628, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28878500

RESUMO

The early auxin responsive SAUR family is an important gene family in auxin signal transduction. We here present the first report of a genome-wide identification of SAUR genes in watermelon genome. We successfully identified 65 ClaSAURs and provide a genomic framework for future study on these genes. Phylogenetic result revealed a Cucurbitaceae-specific SAUR subfamily and contribute to understanding of the evolutionary pattern of SAUR genes in plants. Quantitative RT-PCR analysis demonstrates the existed expression of 11 randomly selected SAUR genes in watermelon tissues. ClaSAUR36 was highly expressed in fruit, for which further study might bring a new prospective for watermelon fruit development. Moreover, correlation analysis revealed the similar expression profiles of SAUR genes between watermelon and Arabidopsis during shoot organogenesis. This work gives us a new support for the conserved auxin machinery in plants.

19.
Med Sci Monit ; 22: 2471-83, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27418244

RESUMO

BACKGROUND Asthma accounts for 0.4% of all deaths worldwide, a figure that increases annually. Ketamine induces bronchial smooth muscle relaxation, and increasing evidence suggests that its anti-inflammatory properties might protect against lung injury and ameliorate asthma. However, there is a lack of evidence of the usefulness and mechanism of ketamine in acute asthma exacerbation. This study aimed to analyze the therapeutic effects and mechanism of action of ketamine on acute ovalbumin (OVA)-induced murine asthma. MATERIAL AND METHODS In vivo, BALB/c mice with OVA-induced asthma were treated with or without ketamine (25 or 50 mg/mL). Serum, lung sections, and mononuclear cell suspensions from the lung were collected for histological, morphometric, immunofluorescence, microRNA, quantitative polymerase chain reaction, regulatory T cell identification, cytokine, and Western blotting analyses. In vitro, bronchial epithelial cells were cultured to analyze the effect and mechanism of ketamine on epithelial-mesenchymal transition (EMT) and transforming growth factor-ß (TGF-ß) signaling. RESULTS The inhalation of ketamine 25 or 50 mg/mL markedly suppressed OVA-induced airway hyper-responsiveness and airway inflammation, significantly increased the percentage of CD4+CD25+ T cells, and significantly decreased OVA-induced up-regulation of TGF-ß1 and the EMT. MiR-106a was present at higher amounts in OVA-induced lung samples and was suppressed by ketamine treatment. The in vitro results showed that TGF-ß1-induced EMT was suppressed by ketamine via miR-106a level regulation. CONCLUSIONS Ketamine ameliorates lung fibrosis in OVA-induced asthmatic mice by suppressing EMT and regulating miR-106a level, while ketamine inhalation might be a new therapeutic approach to the treatment of allergic asthma.


Assuntos
Asma/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Ketamina/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Asma/genética , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , MicroRNAs/metabolismo , Ovalbumina , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/patologia , Distribuição Aleatória , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
Arch Esp Urol ; 77(2): 210-216, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38583014

RESUMO

OBJECTIVE: To analyse the incidence and influencing factors of delirium during recovery in urological postoperative patients undergoing sevoflurane anaesthesia. METHODS: The clinical data of patients undergoing sevoflurane anaesthesia in the urology surgery department in our hospital from January 2022 to December 2022 were retrospectively analysed. The incidence of delirium during the recovery period was recorded by using the Chinese version of the Confusion Assessment Method (CAM) for Severity of Delirium after surgery, and the patients were divided into occurrence and non-occurrence groups. Whether delirium occurred during recovery was determined through univariate analysis. In binary logistic regression analysis, the occurrence of emergence delirium was the dependent variable, and the variables with statistical differences in the univariate analysis were the independent variables. The influencing factors of emergence delirium in post-urological surgery patients who underwent sevoflurane anaesthesia were determined. RESULTS: Delirium during recovery occurred in 10 of 100 patients (10.00%). Odds ratio (OR) of age (OR = 1.445, p = 0.022), history of diabetes (OR = 1.798, p = 0.010), operation time (OR = 1.670, p = 0.008), American Society of Anesthesiologists (ASA) classification (OR = 1.740, p = 0.006) and sevoflurane inhalation concentration (OR = 1.890, p = 0.001) are the influencing factors of postoperative delirium in urologic patients undergoing sevoflurane anaesthesia. CONCLUSIONS: Age, history of diabetes, operation time, ASA classification and sevoflurane inhalation concentration are the influencing factors.


Assuntos
Anestesia , Anestésicos Inalatórios , Diabetes Mellitus , Delírio do Despertar , Humanos , Sevoflurano/efeitos adversos , Anestésicos Inalatórios/efeitos adversos , Delírio do Despertar/epidemiologia , Estudos Retrospectivos
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