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1.
Int J Surg ; 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38652147

RESUMO

BACKGROUND: We aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS: We performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival actualization after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients (3-year DFS: 91.1% vs. 90.0%, P=0.328; 3-year OS: 94.4% vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment CEA levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P=0.029 and OS: (HR=0.476, 95% CI: 0.223-1.017, P=0.049). CONCLUSIONS: Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.

2.
MedComm (2020) ; 5(5): e539, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38680520

RESUMO

Urgent research into innovative severe acute respiratory coronavirus-2 (SARS-CoV-2) vaccines that may successfully prevent various emerging emerged variants, particularly the Omicron variant and its subvariants, is necessary. Here, we designed a chimeric adenovirus-vectored vaccine named Ad5-Beta/Delta. This vaccine was created by incorporating the receptor-binding domain from the Delta variant, which has the L452R and T478K mutations, into the complete spike protein of the Beta variant. Both intramuscular (IM) and intranasal (IN) vaccination with Ad5-Beta/Deta vaccine induced robust broad-spectrum neutralization against Omicron BA.5-included variants. IN immunization with Ad5-Beta/Delta vaccine exhibited superior mucosal immunity, manifested by higher secretory IgA antibodies and more tissue-resident memory T cells (TRM) in respiratory tract. The combination of IM and IN delivery of the Ad5-Beta/Delta vaccine was capable of synergically eliciting stronger systemic and mucosal immune responses. Furthermore, the Ad5-Beta/Delta vaccination demonstrated more effective boosting implications after two dosages of mRNA or subunit recombinant protein vaccine, indicating its capacity for utilization as a booster shot in the heterologous vaccination. These outcomes quantified Ad5-Beta/Delta vaccine as a favorable vaccine can provide protective immunity versus SARS-CoV-2 pre-Omicron variants of concern and BA.5-included Omicron subvariants.

3.
J Inorg Biochem ; 256: 112571, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38669912

RESUMO

In this paper, a series of cyclometalated bismuth(III) complexes bearing C,O-bidentate ligands were synthesized and characterized by techniques such as UV-vis, NMR, HRMS, and single crystal X-ray diffraction. Meanwhile, their cytotoxicities against various human cell lines, including colon cancer cells (HCT-116), breast cancer cells (MDA-MB-231), lung cancer cells (A549), gastric cancer cells (SGC-7901), and normal embryonic kidney cells (HEK-293) were assessed in vitro. Compared with the clinical cisplatin, most of the synthesized complexes possessed significantly higher degrees of anticancer activity and selectivity, giving a selectivity index of up to 71.3. The structure-activity relationship study revealed that the anticancer performance of these bismuth(III) species depends on the factors of coordination environment surrounding the metal center, such as coordination number, coordination bonding strength, lone 6s2 electron pair stereoactivity. The Annexin V-FITC/PI double staining assay results suggested that the coordination environment-dependent cytotoxicity is ascribable to apoptosis. Western blot analysis confirmed the proposal, as evidenced by the down-regulating level of Bcl-2 and the activation of caspase-3. Furthermore, the representative complexes Bi1, Bi4, Bi6, and Bi8 exhibited relatively lower inhibitory efficiency on human ovarian cancer cells (A2780) than on its cisplatin-resistant daughter cells (A2780/cis), thus demonstrating that such compounds are capable of circumventing the cisplatin-induced resistance. This investigation elucidated the excellent anticancer performance of C,O-coordinated bismuth(III) complexes and established the correlation between cytotoxic activity and coordination chemistry, which provides a practical basis for in-depth designing and developing bismuth-based chemotherapeutics.


Assuntos
Antineoplásicos , Bismuto , Complexos de Coordenação , Humanos , Bismuto/química , Bismuto/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Ligantes , Apoptose/efeitos dos fármacos , Quelantes/química , Quelantes/farmacologia , Quelantes/síntese química , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Células HEK293
4.
Eur J Radiol ; 173: 111363, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38367415

RESUMO

PURPOSE: To assess diagnostic performance and reproducibility of reduced bowel wall enhancement evaluated by quantitative methods using CT to identify bowel necrosis among closed-loop small bowel obstruction (CL-SBO) patients. METHODS: This retrospective single-center study included patients who diagnosed with CL-SBO caused by adhesion or internal hernia during January 2016 and May 2022. Patients were divided into necrotic group (n = 41) and non-necrotic group (n = 67) according to surgical exploration and postoperative pathology. Two doctors independently measured the attenuation of bowel wall and consensus was reached through panel discussion with a third gastrointestinal radiologist. Reduced bowel wall enhancement was assessed by four quantitative methods. Univariate analyses were used to evaluate the association between each method and bowel necrosis, and kappa/intraclass correlation coefficient values were used to assess interobserver agreement. Diagnostic performance parameters were calculated for each method. RESULTS: Reduced bowel wall enhancement in arterial phase (OR 8.98, P < 0.0001), reduced bowel wall enhancement in portal phase (OR 16.84, P < 0.001), adjusted reduced bowel wall enhancement in arterial phase (OR 29.48, P < 0.001), adjusted reduced bowel wall enhancement in portal phase (OR 145.69, P < 0.001) were significantly associated with bowel necrosis. Adjusted reduced bowel wall enhancement in portal phase had the best diagnostic performance (AUC: 0.92; Youden index: 0.84; specificity: 94.03 %) and interobserver agreement (kappa value of 0.59-0.73) to predict bowel necrosis. CONCLUSION: When assessing reduced bowel enhancement to predict bowel necrosis among CL-SBO patients, using unenhanced CT images and proximal dilated loop as standard references in portal phase is the most accurate quantitative method among those tested.


Assuntos
Traumatismos Abdominais , Obstrução Intestinal , Doenças Vasculares , Humanos , Tomografia Computadorizada por Raios X/métodos , Estudos Retrospectivos , Reprodutibilidade dos Testes , Intestino Delgado/diagnóstico por imagem , Sensibilidade e Especificidade , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/cirurgia , Doenças Vasculares/patologia , Necrose/diagnóstico por imagem , Necrose/patologia , Traumatismos Abdominais/complicações
5.
Environ Pollut ; 344: 123330, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38199484

RESUMO

Alveolar nitric oxide is a non-invasive indicator of small-airway inflammation, a key pathophysiologic mechanism underlying lower respiratory diseases. However, no epidemiological studies have investigated the impact of fine particulate matter (PM2.5) exposure on the concentration of alveolar nitric oxide (CANO). To explore the associations between PM2.5 exposure in multiple periods and CANO, we conducted a nationwide cross-sectional study in 122 Chinese cities between 2019 and 2021. Utilizing a satellite-based model with a spatial resolution of 1 × 1 km, we matched long-term, mid-term, and short-term PM2.5 exposure for 28,399 individuals based on their home addresses. Multivariable linear regression models were applied to estimate the associations between PM2.5 at multiple exposure windows and CANO. Stratified analyses were also performed to identify potentially vulnerable subgroups. We found that per interquartile range (IQR) unit higher in 1-year average, 1-month average, and 7-day average PM2.5 concentration was significantly associated with increments of 17.78% [95% confidence interval (95%CI): 12.54%, 23.26%], 8.76% (95%CI: 7.35%, 10.19%), and 4.00% (95%CI: 2.81%, 5.20%) increment in CANO, respectively. The exposure-response relationship curves consistently increased with the slope becoming statistically significant beyond 20 µg/m3. Males, children, smokers, individuals with respiratory symptoms or using inhaled corticosteroids, and those living in Southern China were more vulnerable to PM2.5 exposure. In conclusion, our study provided novel evidence that PM2.5 exposure in long-term, mid-term, and short-term periods could significantly elevate small-airway inflammation represented by CANO. Our results highlight the significance of CANO measurement as a non-invasive tool for early screening in the management of PM2.5-related inflammatory respiratory diseases.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Doenças Respiratórias , Masculino , Criança , Humanos , Poluentes Atmosféricos/análise , Cidades , Estudos Transversais , Óxido Nítrico/análise , Poluição do Ar/análise , Material Particulado/análise , Poeira/análise , Doenças Respiratórias/induzido quimicamente , Doenças Respiratórias/epidemiologia , Inflamação/induzido quimicamente , Inflamação/epidemiologia , China/epidemiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise
6.
Org Biomol Chem ; 22(5): 990-997, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38180390

RESUMO

A thiosuccinimide enabled S-N cross-coupling strategy has been established for the intermolecular N-sulfenylation of clinically approved sulfa drugs under additive-free conditions. This approach features simple operation, high chemoselectivity for sulfenylating the phenylamino group of sulfonamides, wide substrate scope, and easy scale production, affording N-sulfenylated products in moderate to excellent yields (up to 90%). In addition, we also found that this transformation can be realized in a one-pot manner by employing readily available thiols as starting materials, and the obtained sulfonamide derivatives are capable of various late-stage functionalizations, including oxidation, arylation, benzylation, and methylation.

7.
Food Chem ; 443: 138526, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38290298

RESUMO

The construction of protein-based nano-gels as curcumin delivery system effectively enhances the stability and bioavailability of curcumin. In this study, acylation modification and self-assembly techniques were jointly employed to construct acylated kidney bean protein isolate (AKBPI)-nanogels. Optimal conditions for AKBPI-nanogels were determined to be pH 7, concentration of 2 mg/mL, and temperature at 90℃ for 30 min. The optimized AKBPI-nanogels exhibited excellent uniformity as evidenced by decreasing average particle size (137.35 nm) and polydispersity index (0.38). Acylation enhanced the intermolecular interactions within the nanogel by reducing the polarity of tyrosine microenvironment and free sulfhydryl groups. AKBPI-nanogels demonstrated remarkable characteristics in terms of pH sensitivity, salt concentration, and storage tolerance. The curcumin-loaded AKBPI-nanogels exhibited an encapsulation efficiency of 92.30 % and maintained high antioxidant activity. In simulated gastrointestinal digestion, AKBPI-nanogels facilitated the controlled release and higher bioavailability of curcumin. Therefore, AKBPI-nanogels can be a stable tool for delivering curcumin.


Assuntos
Curcumina , Phaseolus , Nanogéis , Curcumina/química , Géis , Temperatura , Portadores de Fármacos/química
8.
Chem Asian J ; 19(2): e202300940, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38100510

RESUMO

Circularly polarized luminescence (CPL) materials are promising candidates for future display technology. However, such highly efficient emitters suffer from the issues of difficult chiral separation and low photoluminescence quantum yield (PLQY). In this work, the chiral 4,4'-biphenanthrene-3,3'-diol (BIPOL) unit was introduced into a thermally activated delayed fluorescence (TADF) framework for the first time. We presented two series of enantiomers, R/S-o-DCzBPNCN and R/S-p-DCzBPNCN, and the synthesis of enantiopure BIPOL can be prepared via normal column chromatography. Notably, o-DCzBPNCN showed narrow singlet-triplet gap of 0.05 eV, efficient TADF, and high PLQYs of 82 % in doped films. In addition, R/S-o-DCzBPNCN exhibited high luminescence dissymmetry factor (gPL ) values of -1.94×10-2 /+1.91×10-2 in doped films. The strategy of BIPOL introduction offers a new approach to organic emitters with stereospecific synthesis, TADF, and chiroptical properties.

9.
Bioorg Chem ; 143: 107001, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38101266

RESUMO

Although the SARS-CoV-2 pandemic has ended, multiple sporadic cases still exist, posing a request for more antivirals. The main protease (Mpro) of SARS-CoV-2, a key enzyme for viral replication, is an attractive target for drug development. Here, we report the discovery of a new potent α-ketoamide-containing Mpro inhibitor, N-((R)-1-cyclohexyl-2-(((R)-3-methoxy-1-oxo-1-((1-(2-oxo-2-((thiazol-2-ylmethyl)amino)acetyl)cyclobutyl)amino)propan-2-yl)amino)-2-oxoethyl)-4,4-difluorocyclohexane-1-carboxamide (20j). This compound presented promising enzymatic inhibitory activity against SARS-CoV-2 Mpro with an IC50 value of 19.0 nM, and an excellent antiviral activity in cell-based assay with an EC50 value of 138.1 nM. This novel covalent inhibitor may be used as a lead compound for subsequent drug discovery against SARS-CoV-2.


Assuntos
COVID-19 , Proteases 3C de Coronavírus , SARS-CoV-2 , Humanos , Antivirais/farmacologia , Inibidores de Proteases/farmacologia , Simulação de Acoplamento Molecular
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 31(6): 1733-1738, 2023 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-38071053

RESUMO

OBJECTIVE: To observe the levels of soluble programmed cell death protein 1 (sPD-1) and soluble programmed cell death ligand 1 (sPD-L1) in peripheral blood of lymphoma patients, and reveal their clinical significances. METHODS: The peripheral blood specimens and clinical data of 64 newly diagnosed lymphoma patients and 30 healthy volunteers were collected. The levels of sPD-1 and sPD-L1 were detected by enzyme-linked immunosorbent assay (ELISA), and their correlations with clinical characteristics of the patients including pathological type, stage, lactate dehydrogenase (LDH) level, T cell subsets were analyzed. RESULTS: The levels of both sPD-1 and sPD-L1 in peripheral blood of lymphoma patients were higher than those of normal controls (P <0.05). There were no significant differences in sPD-1 and sPD-L1 levels in peripheral blood between Hodgkin lymphoma and non-Hodgkin lymphoma patients. Different pathological subtypes of lymphoma had different levels of sPD-1. The level of sPD-1 in patients with T-cell lymphoma was higher than that in patients with B-cell lymphoma (P =0.001). The levels of both sPD-1 and sPD-L1 in patients with Ann Arbor stage III and IV were higher than those in patients with stage I and II (P <0.05). The level of sPD-L1 in patients with abnormally increased LDH was higher than that in patients with normal LDH (P =0.001), but there was no significant difference in sPD-1 level. T cell subset analysis showed that the level of sPD-L1 was negatively correlated to CD4+ T cell content (r =-0.265). CONCLUSION: The levels of sPD-1 and sPD-L1 in peripheral blood of lymphoma patients are related to the pathological type, Ann Arbor stage, LDH content and T cell subsets, and will be potential biomarkers in predicting the prognosis of lymphoma.


Assuntos
Relevância Clínica , Linfoma de Células T Periférico , Humanos , Prognóstico , Subpopulações de Linfócitos T/metabolismo , Ensaio de Imunoadsorção Enzimática , Antígeno B7-H1/metabolismo
12.
Genes (Basel) ; 14(12)2023 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-38136933

RESUMO

Leafy sweet potato is a new type of sweet potato, whose leaves and stems are used as green vegetables. However, sweet potato tips can be affected by pre-harvest factors, especially the intensity of light. At present, intercropping, greenhouse planting, and photovoltaic agriculture have become common planting modes for sweet potato. Likewise, they can also cause insufficient light conditions or even low light stress. This research aimed to evaluate the influence of four different shading levels (no shading, 30%, 50%, and 70% shading degree) on the growth profile of sweet potato leaves. The net photosynthetic rate, chlorophyll pigments, carbohydrates, and polyphenol components were determined. Our findings displayed that shading reduced the content of the soluble sugar, starch, and sucrose of leaves, as well as the yield and Pn. The concentrations of Chl a, Chl b, and total Chl were increased and the Chl a/b ratio was decreased for the more efficient interception and absorption of light under shading conditions. In addition, 30% and 50% shading increased the total phenolic, total flavonoids, and chlorogenic acid. Transcriptome analysis indicated that genes related to the antioxidant, secondary metabolism of phenols and flavonoids, photosynthesis, and MAPK signaling pathway were altered in response to shading stresses. We concluded that 30% shading induced a high expression of antioxidant genes, while genes related to the secondary metabolism of phenols and flavonoids were upregulated by 50% shading. And the MAPK signaling pathway was modulated under 70% shading, and most stress-related genes were downregulated. Moreover, the genes involved in photosynthesis, such as chloroplast development, introns splicing, and Chlorophyll synthesis, were upregulated as shading levels increased. This research provides a new theoretical basis for understanding the tolerance and adaptation mechanism of leafy sweet potato in low light environments.


Assuntos
Ipomoea batatas , Antioxidantes/metabolismo , Fotossíntese/genética , Clorofila/metabolismo , Perfilação da Expressão Gênica , Flavonoides , Fenóis
13.
Artif Intell Med ; 144: 102664, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37783552

RESUMO

Accurate measurement of blood flow velocity is important for the prevention and early diagnosis of atherosclerosis. However, due to the uncertainty of parameter settings, the autocorrelation velocimetry methods based on clutter filtering are prone to incorrectly filter out the near-wall blood flow signal, resulting in poor velocimetric accuracy. In addition, the Doppler coherent compounding acts as a low-pass filter, which also leads to low values of blood flow velocity estimated by the above methods. Motivated by this status quo, here we propose a deep learning estimator that combines clutter filtering and blood flow velocimetry based on the adaptive property of one-dimensional convolutional neural network (1DCNN). The estimator is operated by first extracting the blood flow signal from the original Doppler echo signal through an affine transformation of the 1D convolution, and then converting the extracted signal into the desired blood flow velocity using a linear transformation function. The effectiveness of the proposed method is verified by simulation as well as in vivo carotid artery data. Compared with typical velocimetry methods such as high-pass filtering (HPF) and singular value decomposition (SVD), the results show that the normalized root means square error (NRMSE) obtained by 1DCNN is reduced by 54.99 % and 53.50 % for forward blood flow velocimetry, and 70.99 % and 69.50 % for reverse blood flow velocimetry, respectively. Consistently, the in vivo measurements demonstrate that the goodness-of-fit of the proposed estimator is improved by 8.72 % and 4.74 % for five subjects. Moreover, the estimation time consumed by 1DCNN is greatly reduced, which costs only 2.91 % of the time of HPF and 12.83 % of the time of SVD. In conclusion, the proposed estimator is a better alternative to the current blood flow velocimetry, and is capable of providing more accurate diagnosis information for vascular diseases in clinical applications.


Assuntos
Aprendizado Profundo , Humanos , Ultrassonografia , Artérias Carótidas/diagnóstico por imagem , Ultrassonografia Doppler/métodos , Reologia
15.
Medicine (Baltimore) ; 102(34): e34685, 2023 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-37653746

RESUMO

INTRODUCTION: Shugan Jieyu Capsule (SGJYC) has been prescribed to treat primary and secondary depression; however, whether it can benefit depression of patients with coronary heart disease (CHD) remains controversial. This meta-analysis aimed to evaluate the efficacy and safety of SGJYC in treating depression in patients with CHD. PATIENT CONCERNS: A total of 644 CHD patients with depression were selected from China National Knowledge Infrastructure, Wanfang, China Biomedical Database, MEDLINE, the Cochrane library from their inceptions until June, 2021. DIAGNOSIS: All patients with CHD or coronary artery disease were confirmed to suffer from depression based on recognized criteria. INTERVENTION: Patients were assigned randomly to receive SGJYC-based regimens or conventional antidepressants alone. OUTCOMES: Meta-analysis of 6 studies showed that antidepressants (MD, 2.12; 95% confidence interval [CI], 0.73~3.50) or sertraline (MD, 2.15; 95%CI, 0.61~3.68) significantly alleviated depression level compared to SGJYC; however, SGJYC plus antihypertensive drugs (AHD) (MD, -8.33; 95%CI, -13.90 ~ -2.75) significantly improved depression symptoms compared to AHD. A significant difference in risk of adverse cardiac events (risk ratios [RR], 2.72; 95%CI, 1.07~6.94) between SGJYC and sertraline was detected in patients with simple CHD. CONCLUSIONS: SGJYC has a poor effect on depressive symptoms, and the effect of combination with AHD is better than AHD but its efficacy and cardiac safety are inferior to antidepressants.


Assuntos
Doença da Artéria Coronariana , Sertralina , Humanos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Anti-Hipertensivos , China/epidemiologia , Bases de Dados Factuais , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Bioorg Med Chem Lett ; 92: 129407, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37437852

RESUMO

The COVID-19 pandemic has caused people immense suffering all over the world. Although the World Health Organization (WHO) has announced the end of the pandemic, the sporadic virus epidemic is still ongoing and may exist permanently. Effective antivirals against SARS-CoV-2 are important to deal with the long-term threat. The main protease (Mpro) is a crucial target for drug development due to its role in the process of virus's replication and transcription. Herein, we report benzodiazepine derivatives as a new class of Mpro inhibitors. Structure-activity relationship (SAR) studies led to the discovery of the most active compound, methyl 10-(2-chloroacetyl)-1-oxo-11-(4-(trifluoromethyl)phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]-diazepine-7-carboxylate (11a), which shows an IC50 value of 0.180 ± 0.004 µM. The X-ray crystal structure shows that 11a covalently binds to Mpro. Collectively, we have obtained a new small molecule inhibitor targeting Mpro, which can serve as a lead compound for subsequent drug discovery against SARS-CoV-2.


Assuntos
Benzodiazepinas , COVID-19 , Proteases 3C de Coronavírus , Inibidores de Proteases , Humanos , Anticonvulsivantes , Antivirais/farmacologia , Benzodiazepinas/farmacologia , Hipnóticos e Sedativos , Simulação de Acoplamento Molecular , Pandemias , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , SARS-CoV-2/metabolismo , Proteases 3C de Coronavírus/antagonistas & inibidores
17.
Eur J Med Chem ; 259: 115657, 2023 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-37517202

RESUMO

The SARS-CoV-2 main protease (Mpro, also named 3CLpro) is a promising antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of α-ketoamide derivatives as a new class of SARS-CoV-2 Mpro inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent Mpro inhibitor (27h) with an IC50 value of 10.9 nM. The crystal structure of Mpro in complex with 27h revealed that α-ketoamide warhead covalently bound to Cys145s of the protease. In an in vitro antiviral assay, 27h showed excellent activity with an EC50 value of 43.6 nM, comparable to the positive control, Nirmatrelvir. This compound displayed high target specificity for Mpro against human proteases and low toxicity. It also possesses favorable pharmacokinetic properties. Overall, compound 27h could be a promising lead compound for drug discovery targeting SARS-CoV-2 Mpro and deserves further in-depth studies.


Assuntos
COVID-19 , Humanos , SARS-CoV-2/metabolismo , Inibidores de Proteases/química , Proteínas não Estruturais Virais , Antivirais/química , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular
18.
Cell Rep ; 42(8): 112831, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37467108

RESUMO

Proton-dependent oligopeptide transporters (POTs) are promiscuous transporters of the major facilitator superfamily that constitute the main route of entry for a wide range of dietary peptides and orally administrated peptidomimetic drugs. Given their clinical and pathophysiological relevance, several POT homologs have been studied extensively at the structural and molecular level. However, the molecular basis of recognition and transport of diverse peptide substrates has remained elusive. We present 14 X-ray structures of the bacterial POT DtpB in complex with chemically diverse di- and tripeptides, providing novel insights into the plasticity of the conserved central binding cavity. We analyzed binding affinities for more than 80 peptides and monitored uptake by a fluorescence-based transport assay. To probe whether all 8400 natural di- and tripeptides can bind to DtpB, we employed state-of-the-art molecular docking and machine learning and conclude that peptides with compact hydrophobic residues are the best DtpB binders.


Assuntos
Proteínas de Membrana Transportadoras , Peptídeos , Simulação de Acoplamento Molecular , Modelos Moleculares , Proteínas de Membrana Transportadoras/metabolismo , Peptídeos/metabolismo
19.
ACS Appl Mater Interfaces ; 15(28): 33819-33828, 2023 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-37418573

RESUMO

The strategy of acceptor modification is a powerful technique for tuning the emission color of thermally activated delayed fluorescence (TADF) emitters. In this study, we have successfully designed and synthesized three TADF emitters with donor-acceptor (D-A) structures using a 4-(diphenylamino)-2,6-dimethylphenyl (TPAm) donor and various pyridine-3,5-dicarbonitrile (PC) acceptor units. As a result, three compounds named TPAmbPPC, TPAm2NPC, and TPAmCPPC exhibited greenish-yellow to orange-red emissions with high photoluminescent quantum yields (76-100%) in thin films. Remarkably, a greenish-yellow device based on TPAmbPPC and TPAm2NPC showed a high maximum external quantum efficiency (EQEmax) of 39.1 and 39.0%, respectively. Furthermore, benefiting from the suitable steric hindrance between the acceptor and donor, the nondoped organic light-emitting diodes (OLEDs) based on TPAmbPPC demonstrated an exceptional EQEmax of 21.6%, indicating its promising potential as an efficient emitter for the application of OLED applications. Furthermore, orange-red OLED devices based on TPAmCPPC exhibited a high EQEmax of 26.2%, a CE of 50.1 cd A-1, and a PE of 52.4 lm W-1.

20.
Discov Oncol ; 14(1): 100, 2023 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-37314589

RESUMO

BACKGROUND: To illuminate the precise roles of MOB Kinase Activator 1 A (MOB1A) in the development of ovarian cancer (OC). METHODS: MOB1A expression and clinical data of OC were obtained from the public database on gene expression and proteomics. Meanwhile, verification of expression was carried out in Gene Expression Omnibus, the Human Protein Atlas, and OC cell lines. The prognosis of MOB1A was explored in the Kaplan-Meier plotter. RNA interference and lentivirus vectors were applied to construct knockdown and overexpressed cell models. Changes in the malignant behaviors of OC cells were detected by cholecystokinin octopeptide cell counting kit, wound healing, colony formation assay, transwell, flow cytometry assays, and in vivo experiments. Changes in proteins in the PI3K and autophagy-related makers were detected by western blot analysis. RESULTS: The expression of MOB1A was significantly upregulated and accompanied by an inferior survival rate in OC. Knockdown of MOB1A inhibited the proliferation, invasion, migration, and cell cycle of OC cells, whereas induced cell autophagy. MOB1A upregulation had the opposite effects. In addition, bioinformatics analysis and western blot experiments showed that MOB1A plays an important role in the PI3K/AKT/mTOR pathway. CONCLUSIONS: Our findings indicated that MOB1A is highly expressed and related to poor prognosis in OC. MOB1A plays a role in promoting the malignant biological behavior of tumor cells through PI3K/AKT/mTOR signaling pathway.

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