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1.
FEBS Lett ; 595(15): 2007-2014, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34105773

RESUMO

AlkB homolog 5 (ALKBH5) has been reported as a key m6A demethylase that is involved in development and diseases; however, the function of ALKBH5 in osteogenesis remains unknown. In this study, we report that ALKBH5 mRNA and protein expression were upregulated during osteoblast differentiation and that ALKBH5 knockdown suppressed osteoblast differentiation, mineralization, and the expression of osteogenic biomarkers. Conversely, ALKBH5 overexpression promoted osteogenesis. Moreover, the expression of wild-type ALKBH5, but not the m6A-modified active site mutant ALKBH5, could rescue ALKBH5 knockdown-induced osteogenesis inhibition. Furthermore, knockdown of ALKBH5 significantly impaired the mRNA stability of the transcription factor Runx2, which plays a key role in osteoblast differentiation. Taken together, our results suggest that ALKBH5 promotes osteogenesis through modulating Runx2 mRNA stability.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase/fisiologia , Diferenciação Celular/fisiologia , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Osteoblastos/citologia , RNA Mensageiro/genética , Homólogo AlkB 5 da RNA Desmetilase/genética , Animais , Células Cultivadas , Técnicas de Silenciamento de Genes , Masculino , Ratos
2.
J Agric Food Chem ; 69(21): 5804-5817, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34008970

RESUMO

A series of novel 2,6-dimethyl-4-aminopyrimidine hydrazones 5 were rationally designed and synthesized as pyruvate dehydrogenase complex E1 (PDHc-E1) inhibitors. Compounds 5 strongly inhibited Escherichia coli (E. coli) PDHc-E1 (IC50 values 0.94-15.80 µM). As revealed by molecular docking, site-directed mutagenesis, enzymatic, and inhibition kinetic analyses, compounds 5 competitively inhibited PDHc-E1 and bound in a "straight" pattern at the E. coli PDHc-E1 active site, which is a new binding mode. In in vitro antifungal assays, most compounds 5 at 50 µg/mL showed more than 80% inhibition against the mycelial growth of six tested phytopathogenic fungi, including Botrytis cinerea, Monilia fructigena, Colletotrichum gloeosporioides, andBotryosphaeria dothidea. Notably, 5f and 5i were 1.8-380 fold more potent against M. fructigena than the commercial fungicides captan and chlorothalonil. In vivo, 5f and 5i controlled the growth of M. fructigena comparably to the commercial fungicide tebuconazole. Thus, 5f and 5i have potential commercial value for the control of peach brown rot caused by M. fructigena.


Assuntos
Piruvato Desidrogenase (Lipoamida) , Complexo Piruvato Desidrogenase , Antifúngicos/farmacologia , Botrytis , Candida , Colletotrichum , Inibidores Enzimáticos , Escherichia coli , Hidrazonas/farmacologia , Simulação de Acoplamento Molecular , Pirimidinas
3.
Radiat Oncol ; 16(1): 24, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531014

RESUMO

OBJECTIVE: This meta-analysis evaluated the efficacy and safety of accelerated partial breast irradiation versus whole-breast irradiation for early-stage breast cancer after breast-conserving surgery. MATERIALS AND METHODS: A systematic search of PubMed, Embase, and the Cochrane libraries was performed according to the PRISMA statement the last 10 years to April 7, 2020 to identify the randomized controlled trials of APBI versus WBI for treating patients with early-stage breast cancer. Two independent observers evaluated the identified studies. The obtained data were analyzed using the RevMan 5.3 software. RESULTS: A total of 10 randomized controlled trials involving 15,500 patients with early-stage breast cancer were selected according to the inclusion and exclusion criteria and included in this meta-analysis. In this meta-analysis, we included ten studies that reported local recurrence and found significant differences in local recurrence rates (HR = 1.46; 95% CI 1.20-1.79, P = 0.0002). Further analysis showed that this difference may be related to the choice of treatment methods. No differences in distant metastasis, breast cancer deaths, contralateral breast cancer, disease-free survival, and overall survival rates were observed between WBI and APBI groups. There was no significant difference in late toxicity, cosmetic outcomes and quality of life between the two groups, the compliance and tolerance of the patients were well. Compared to whole breast irradiation, accelerated partial breast irradiation significantly reduced serious (≥ grade 2) early toxicities, especially regarding acute skin toxicity. CONCLUSIONS: The analysis showed that patients receiving APBI had a higher local recurrence rate, but no differences in distant metastasis, breast cancer deaths, contralateral breast cancer, disease-free survival, and overall survival rates.


Assuntos
Braquiterapia/métodos , Neoplasias da Mama/radioterapia , Neoplasias da Mama/patologia , Feminino , Humanos , Prognóstico , Dosagem Radioterapêutica
4.
ACS Chem Neurosci ; 12(1): 244-255, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33356131

RESUMO

The protein-protein interaction between neuronal nitric oxide syntheses (nNOS) and the carboxy-terminal PDZ ligand of nNOS (CAPON) is a potential target for the treatment of ischemic stroke. Our previous study had identified ZLc-002 as a promising lead compound for inhibiting nNOS-CAPON coupling. To find better neuroprotective agents disrupting the ischemia-induced nNOS-CAPON interaction, a series of N-cyclohexylethyl-[A/G]-[D/E]-X-V peptides based on the carboxy-terminal tetrapeptide of CAPON was designed, synthesized, and evaluated in this study. Herein, we reported an affinity-based fluorescence polarization (FP) method using 5-carboxyfluorescein (5-FAM) labeled CAPON (496-506) peptide as the probe for high-throughput screening of the small-molecule inhibitors of the PDZ domain of nNOS. N-Cyclohexylethyl-ADAV displayed the most potent affinity for the nNOS PDZ domain in the FP and isothermal titration calorimetry (ITC) (ΔH = -1670 ± 151.0 cal/mol) assays. To improve bioavailability, lipophilicity, and membrane permeability, the Asp methylation was employed to get N-cyclohexylethyl-AD(OMe)AV, which possesses good blood-brain barrier (BBB) permeability in vitro parallel artificial membrane permeability assay (PAMPA)-BBB (Pe = 6.07 cm/s) and in vivo assays. In addition, N-cyclohexylethyl-AD(OMe)AV (10 mg/kg body weight, i.v., immediately after reperfusion) substantially reduced infarct size in rats, which was measured 24 h after reperfusion and subjected to 120 min of middle cerebral artery occlusion (MCAO).


Assuntos
Isquemia Encefálica , AVC Isquêmico , Fármacos Neuroprotetores , Acidente Vascular Cerebral , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Ratos , Acidente Vascular Cerebral/tratamento farmacológico
5.
J Asian Nat Prod Res ; : 1-7, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32819169

RESUMO

Strepyrazinone (1), a tricyclic diketopiperazine derivative with a carbon skeleton unprecedented in natural products, was isolated from the marine-derived Streptomyces sp. B223. Its structure was elucidated by spectroscopic analyses and electronic circular dichroism calculation. Compound 1 showed cytotoxic activity against HCT-116 cancer cell lines with an IC50 value of 0.34 µM.[Figure: see text].

6.
Chem Biol Drug Des ; 96(5): 1305-1314, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32526055

RESUMO

Hybrid analogues of the µ opioid agonists endomorphin and [Dmt1 ]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2 , Dmt = 2',6'-dimethyltyrosine) containing cis-4-amino-Pro, trans-4-amino-Pro, cis-4-aminoethyl-Pro or cis-4-guanidinylethyl-Pro in the 2 position of the peptide sequence were synthesized. None of the compounds retained high µ opioid agonist activity and, unexpectedly, substitution of cis-4-amino-Pro resulted in a novel class of potent µ opioid antagonists. In particular, the compound H-Dmt-cis-4-amino-Pro-Trp-Lys-NH2 (CZ-1) turned out to be a highly selective µ opioid antagonist with ~1 nM µ receptor binding affinity.


Assuntos
Antagonistas de Entorpecentes/farmacologia , Oligopeptídeos/química , Receptores Opioides mu/antagonistas & inibidores , Animais
7.
Environ Sci Technol ; 54(14): 8811-8820, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32463659

RESUMO

Harmful Microcystis blooms (HMBs) seriously threaten the ecology of environments and human health. Microcystins (MCs) produced by Microcystis are powerful mediators of HMB induction and maintenance. In this study, microcystinase A (MlrA), an enzyme with MC-degrading ability, was successfully obtained at over 90% purity for the first time through overexpression in Escherichia coli K12 TB1. The obtained MlrA exhibited high stability at high temperature and under alkaline conditions, while also exhibiting a long half-life. MlrA selectively inhibited MC-producing Microcystis cultures, but had no effect on MC-nonproducing Synechocystis cultures. The inhibition mechanism of MlrA against Microcystis was investigated by evaluating the morphological and physiological characteristics of cultures. MlrA effectively degraded extracellular MCs and decreased the synthesis of intracellular MCs by causing downregulation of genes involved in the microcystin biosynthesis pathway. Concomitantly, MlrA inhibited Microcystis photosynthesis by causing the downregulated expression of important photosynthesis pathway genes and interrupting electron transport chain activities and pigment synthesis. Thus, MlrA achieved the inhibition of Microcystis growth by reducing its photosynthetic capacity and intracellular MC contents, while also degrading extracellular MCs. On the basis of these results, we propose a new paradigm to achieve the simultaneous removal of MCs and HMBs using the single enzyme characterized here.


Assuntos
Microcystis , Humanos , Microcistinas/metabolismo , Microcystis/genética , Microcystis/metabolismo , Oxirredução , Fotossíntese
8.
J Med Chem ; 63(11): 6238-6247, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32375478

RESUMO

Fructose 1,6-bisphosphatase (FBPase) has attracted substantial interest as a target associated with cancer and type 2 diabetes. Herein, we found that disulfiram and its derivatives can potently inhibit FBPase by covalently binding to a new C128 allosteric site distinct from the original C128 site in APO FBPase. Further identification of the allosteric inhibition mechanism reveals that the covalent binding of a fragment of 214 will result in the movement of C128 and the dissociation of helix H4 (123-128), which in turn allows S123 to more easily form new hydrogen bonds with K71 and D74 in helix H3 (69-72), thereby inhibiting FBPase activity. Notably, both disulfiram and 212 might moderately reduce blood glucose output in vivo. Therefore, our current findings not only identify a new covalent allosteric site of FBPase but also establish a structural foundation and provide a promising way for the design of covalent allosteric drugs for glucose reduction.


Assuntos
Dissulfiram/análogos & derivados , Frutose-Bifosfatase/metabolismo , Sítio Alostérico , Animais , Sítios de Ligação , Glicemia/análise , Cristalografia por Raios X , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Dissulfiram/metabolismo , Dissulfiram/uso terapêutico , Desenho de Fármacos , Frutose-Bifosfatase/antagonistas & inibidores , Frutose-Bifosfatase/genética , Humanos , Ligação de Hidrogênio , Cinética , Camundongos , Camundongos Endogâmicos ICR , Camundongos Obesos , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Conformação Proteica em alfa-Hélice
9.
AMB Express ; 10(1): 4, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31912323

RESUMO

In this study, we evaluated the combined therapeutic efficacy of erythropoietin (a hematopoietic hormone produced by the fetal liver and kidney in response to inflammation and apoptosis) and sesame oil (from Sesamum indicum L.) on ischemic kidney injury following kidney transplantation in a rat model. Rats were assigned to the following groups: sham, control, 1000 U/kg erythropoietin, 1 mL/kg sesame oil, 1000 U/kg erythropoietin + 1 mL/kg sesame oil, and positive control. We measured the levels of blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), lipid peroxidation, reactive oxygen species (ROS), reduced glutathione (GSH), antioxidant enzymes, and proinflammatory markers and performed renal histopathological evaluation. The combined erythropoietin and sesame oil treatment significantly reduced BUN, ALT, creatinine, lipid peroxidation, ROS, and proinflammatory markers and GSH and antioxidant enzyme levels. Histopathological examination showed that the combined erythropoietin and sesame oil treatment significantly reduced necrosis. Therefore, combined treatment of sesame oil and erythropoietin may represent an effective therapeutic approach against ischemic kidney injury after kidney transplantation.

10.
Org Lett ; 22(1): 140-144, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31858804

RESUMO

We report an I2/FeCl3-co-promoted formal [2 + 2+1] annulation of aryl methyl ketones, 2-aminobenzyl alcohols, and p-toluenesulfonylmethyl isocyanide (TosMIC) by neighboring group (-CH2OH) assistance. This is a novel example of using the Van Leusen reagent as a unique C1N1 "two-atom synthon" in the synthesis of imidazoles. Preliminary mechanism studies showed that TsCH2NH2 might be the key intermediate in this reaction. Furthermore, this reaction not only unlocks a novel strategy for imidazole synthesis, but also exploits a new reactivity of TosMIC.

11.
Bioorg Med Chem ; 27(24): 115159, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31699453

RESUMO

Harmful cyanobacteria bloom (HCB) has occurred frequently in recent years and it is urgent to develop novel algicides to deal with this problem. In this paper, a series of novel thiamin diphosphate (ThDP) analogs 5a-5g were designed and synthesized targeting cyanobacterial pyruvate dehydrogenase complex E1 (Cy-PDHc E1). Our results showed that compounds 5a-5g have higher inhibitory activities against Cy-PDHc E1 (IC50 9.56-3.48 µM) and higher inhibitory activities against two model cyanobacteria strains Synechocystis sp PCC6803 (EC50 2.03-1.58 µM) and Microcystis aeruginosa FACHB905 (EC50 1.86-0.95 µM). Especially, compound 5b displayed highest inhibitory activities (IC50 = 3.48 µM) against Cy-PDHc E1 and powerful inhibitory activities against cyanobacteria Synechocystis sp PCC6803 (EC50 = 1.58 µM) and Microcystis aeruginosa FACHB905 (EC50 = 1.04 µM). Moreover, the inhibitory activities of compound 5b were even higher than those of copper sulfate (EC50 = 2.02 and 1.71 µM separately) which has been widely used as algicide against cyanobacteria PCC6803 and FACHB905. The more important was that compound 5b display much higher inhibitory selectivity between Cy-PDHc E1 (Inhibitory rate 97.4%) and porcine PDHc E1 (Inhibitory rate 11.8%) under the same concentration (100 µM). The inhibition kinetic experiment and molecular docking research showed that compound 5b can inhibit Cy-PDHc E1 by occupying the ThDP-binding pocket and then blocking Cy-PDHc E1 bound to ThDP as competitive inhibitor. The imagines of SEM and TEM showed that cellular microstructures were heavily destroyed under compound 5b stress. Our results demonstrated compound 5b could be taken as a potential lead compound targeting Cy-PDHc E1 to obtain environment-friendly algicide for harmful cyanobacterial blooms control.


Assuntos
Inibidores Enzimáticos/farmacologia , Microcystis/efeitos dos fármacos , Piruvato Desidrogenase (Lipoamida)/antagonistas & inibidores , Synechocystis/efeitos dos fármacos , Tiamina/análogos & derivados , Tiamina/farmacologia , Animais , Sítios de Ligação , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Relação Estrutura-Atividade , Suínos , Tiamina/química
12.
J Agric Food Chem ; 67(45): 12538-12546, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31638796

RESUMO

Cyanobacteria harmful algal blooms are of global concern, but all currently available algicides in the market are nonselective and have potential side effects on nontarget species. In the present work, two series of compounds (4 and 6) comprising 16 novel 1,2,3-triazole aminopyrimidines were rationally designed and synthesized as control agent for cyanobacteria. Our design focus was the inhibiting cyanobacteria by inhibition against pyruvate dehydrogenase complex E1 (PDHc-E1). Compounds 4 and 6 showed potent inhibition against Escherichia coli PDHc-E1 (IC50 = 4.13-23.76 µM) and also strong algicidal activities against Synechocystis sp. PCC 6803 (EC50 = 1.7-8.1 µM) and Microcystis sp. FACHB905 (EC50 = 2.1-11.8 µM). In particular, the algicidal activities of 6d against four algal species were not only higher than that of prometryn; they were also comparable to or higher than that of copper sulfate. The analogues 4c, 4d, 6d, and 6e displayed potent algicidal activities and inhibition of E. coli PDHc-E1 but exhibited negligible inhibition of porcine PDHc-E1. As revealed by molecular docking, site-directed mutagenesis, enzymatic assays, and an inhibition kinetic analysis, 4c and 6d inhibited PDHc-E1 in a competitive manner. Our results suggest that highly selective, effective algicides can be developed by rationally designing competitive PDHc-E1 inhibitors.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Microcystis/efeitos dos fármacos , Pirimidinas/farmacologia , Piruvato Desidrogenase (Lipoamida)/antagonistas & inibidores , Synechocystis/efeitos dos fármacos , Triazóis/farmacologia , Proteínas de Bactérias/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Herbicidas/síntese química , Herbicidas/química , Cinética , Microcystis/química , Microcystis/enzimologia , Simulação de Acoplamento Molecular , Pirimidinas/química , Piruvato Desidrogenase (Lipoamida)/química , Relação Estrutura-Atividade , Synechocystis/química , Synechocystis/enzimologia , Triazóis/química
13.
Nature ; 574(7780): 722-725, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645759

RESUMO

The enzyme protochlorophyllide oxidoreductase (POR) catalyses a light-dependent step in chlorophyll biosynthesis that is essential to photosynthesis and, ultimately, all life on Earth1-3. POR, which is one of three known light-dependent enzymes4,5, catalyses reduction of the photosensitizer and substrate protochlorophyllide to form the pigment chlorophyllide. Despite its biological importance, the structural basis for POR photocatalysis has remained unknown. Here we report crystal structures of cyanobacterial PORs from Thermosynechococcus elongatus and Synechocystis sp. in their free forms, and in complex with the nicotinamide coenzyme. Our structural models and simulations of the ternary protochlorophyllide-NADPH-POR complex identify multiple interactions in the POR active site that are important for protochlorophyllide binding, photosensitization and photochemical conversion to chlorophyllide. We demonstrate the importance of active-site architecture and protochlorophyllide structure in driving POR photochemistry in experiments using POR variants and protochlorophyllide analogues. These studies reveal how the POR active site facilitates light-driven reduction of protochlorophyllide by localized hydride transfer from NADPH and long-range proton transfer along structurally defined proton-transfer pathways.


Assuntos
Clorofila/biossíntese , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/química , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Synechococcus/enzimologia , Synechocystis/enzimologia , Catálise , Clorofila/química , Estrutura Molecular , Fotoquímica , Protoclorifilida/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato
14.
Eur J Med Chem ; 184: 111749, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31589992

RESUMO

Fructose-1,6-bisphosphatase (FBPase) is an essential enzyme of GNG pathway. Significant advances demonstrate the FBPase plays a critical role in treatment of diabetes. Numerous FBPase inhibitors were developed by targeting AMP site, nevertheless, none of these inhibitors has exhibited suitable potency and druggability. Herein, a new allosteric site (C128) on FBPase was discovered, and several nitrostyrene compounds exhibiting potent FBPase inhibitions were found covalently bind to C128 site on FBPase. Mutagenesis suggest that C128 is the only cysteine that can influence FBPase inhibition, the N125-S124-S123 pathway was most likely involved in allosteric signaling transmission between C128 and active site. However, these nitrostyrenes may bind with multiple cysteine besides C128 in FBPase. To improve pocket selectivity, a series of novel compounds (14a-14n) were re-designed rationally by integrating fragment-based covalent virtual screening and machine-learning-based synthetic complexity evaluation. As expected, the mass spectrometry validated that the proportion of title compounds binding to the C128 in FBPase was significantly higher than that of nitrostyrenes. Notably, under physiological and pathological conditions, the treatment of compounds 14b, 14c, 14i or 14n led to potent inhibition of glucose production, as well as decreased triglyceride and total cholesterol levels in mouse primary hepatocytes. We highlight a novel paradigm that molecular targeting C128 site on FBPase can have potent hypoglycemic effect.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Frutose-Bifosfatase/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Sítio Alostérico/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Frutose-Bifosfatase/metabolismo , Glucose/antagonistas & inibidores , Glucose/biossíntese , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
15.
Med Sci Monit ; 25: 5336-5342, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31318849

RESUMO

BACKGROUND This study aimed to evaluate superb microvascular imaging (SMI) as an adjunctive imaging method to evaluate mesenteric lymph nodes in children with mesenteric lymphadenitis compared with healthy children. MATERIAL AND METHODS A retrospective study compared children with mesenteric lymphadenitis (n=27) and healthy children (n=30). Lymph node size was determined using grayscale ultrasonography and parameters of lymph node vascularity were compared using color Doppler flow imaging (CDFI) and SMI. The diagnostic performance of ultrasound (US), US combined with SMI, and US combined with CDFI were compared. RESULTS Lymph nodes from children with mesenteric lymphadenitis (n=77) and normal lymph nodes (n=84) were evaluated by SMI, which showed that the least diameter of lymph nodes in cases of mesenteric lymphadenitis was 0.58±0.15 mm and of normal mesenteric lymph nodes was 0.47±0.08 mm (p<0.001). SMI identified 92.6% of abnormal mesenteric lymph nodes while CDFI detected 85.2%. US combined with SMI had the highest sensitivity (81.5%), and specificity (78.9%) compared with US alone (sensitivity, 63.0%; specificity, 64.9%), and compared with US combined with CDFI (sensitivity, 74.1%; specificity, 75.4%). US combined with SMI and US combined with CDFI achieved the same specificity (76.7%), which was higher than that of US alone (66.7%). CONCLUSIONS SMI was superior to color Doppler flow imaging in evaluating the microvasculature in lymphadenopathy in mesenteric lymphadenitis. SMI may be used as an adjunct to grayscale ultrasonography to assist in identifying mesenteric lymphadenopathy in pediatric patients.


Assuntos
Linfadenite Mesentérica/diagnóstico por imagem , Linfadenite Mesentérica/fisiopatologia , Microvasos/diagnóstico por imagem , Criança , Pré-Escolar , China , Diagnóstico Diferencial , Feminino , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/fisiopatologia , Masculino , Linfadenite Mesentérica/metabolismo , Mesentério/metabolismo , Estudos Retrospectivos , Sensibilidade e Especificidade , Ultrassonografia/métodos , Ultrassonografia Doppler em Cores/métodos
16.
Cell Mol Life Sci ; 76(19): 3899-3914, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30993352

RESUMO

The P3H1/CRTAP/PPIB complex is essential for prolyl 3-hydroxylation and folding of procollagens in the endoplasmic reticulum (ER). Deficiency in any component of this ternary complex is associated with the misfolding of collagen and the onset of osteogenesis imperfecta. However, little structure information is available about how this ternary complex is assembled and retained in the ER. Here, we assessed the role of the KDEL sequence of P3H1 and probed the spatial interactions of PPIB in the complex. We show that the KDEL sequence is essential for retaining the P3H1 complex in the ER. Its removal resulted in co-secretion of P3H1 and CRTAP out of the cell, which was mediated by the binding of P3H1 N-terminal domain with CRTAP. The secreted P3H1/CRTAP can readily bind PPIB with their C-termini close to PPIB in the ternary complex. Cysteine modification, crosslinking, and mass spectrometry experiments identified PPIB surface residues involved in the complex formation, and showed that the surface of PPIB is extensively covered by the binding of P3H1 and CRTAP. Most importantly, we demonstrated that one disease-associated pathological PPIB mutation on the binding interface did not affect the PPIB prolyl-isomerase activity, but disrupted the formation of P3H1/CRTAP/PPIB ternary complex. This suggests that defects in the integrity of the P3H1 ternary complex are associated with pathological collagen misfolding. Taken together, these results provide novel structural information on how PPIB interacts with other components of the P3H1 complex and indicate that the integrity of P3H1 complex is required for proper collagen formation.


Assuntos
Ciclofilinas/química , Proteínas da Matriz Extracelular/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteoglicanas/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Ciclofilinas/genética , Ciclofilinas/metabolismo , Proteínas da Matriz Extracelular/genética , Humanos , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Modelos Moleculares , Chaperonas Moleculares , Mutação , Prolil Hidroxilases , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteoglicanas/química , Proteoglicanas/genética , Deleção de Sequência
17.
Radiol Oncol ; 53(1): 6-14, 2019 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-30840594

RESUMO

Background The mainstay therapy for locally advanced non-small cell lung cancer is concurrent chemoradiotherapy. Loco-regional recurrence constitutes the predominant failure patterns. Previous studies confirmed the relationship between increased biological equivalent doses and improved overall survival. However, the large randomized phase III study, RTOG 0617, failed to demonstrate the benefit of dose-escalation to 74 Gy compared with 60 Gy by simply increasing fraction numbers. Conclusions Though effective dose-escalation methods have been explored, including altered fractionation, adapting individualized increments for different patients, and adopting new technologies and new equipment such as new radiation therapy, no consensus has been achieved yet.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/métodos , Neoplasias Pulmonares/terapia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Quimioterapia de Consolidação , Progressão da Doença , Fracionamento da Dose de Radiação , Radioterapia com Íons Pesados/métodos , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Medicina de Precisão/métodos , Terapia com Prótons/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
18.
Bioorg Med Chem ; 27(5): 805-812, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30711311

RESUMO

By using a new Fragment-Based Virtual Screen strategy, two series of novel FBA-II inhibitors (thiourea derivatives) were de novo discovered based on the active site of fructose-1, 6-bisphosphate aldolase from Cyanobacterial (CyFBA). In comparison, most of the N-(2-benzoylhydrazine-1-carbonothioyl) benzamide derivatives (L14∼L22) exhibit higher CyFBA-II inhibitory activities compared to N-(phenylcarbamothioyl) benzamide derivatives (L1∼L13). Especially, compound L14 not only shows higher CyFBA-II activity (Ki = 0.65 µM), but also exhibits most potent in vivo activity against Synechocystis sp. PCC 6803 (EC50 = 0.09 ppm), higher (7-fold) than that of our previous inhibitor (EC50 = 0.6 ppm). The binding modes of compound L14 and CyFBA-II were further elucidated by jointly using DOX computational protocol, MM-PBSA and site-directed mutagenesis assays. The positive results suggest that strategy adopted in this study was promising to rapidly discovery the potent inhibitors with novel scaffolds. The satisfactory algicide activities suggest that the thiourea derivatives is very likely to be a promising lead for the development of novel specific algicides to solve Cyanobacterial harmful algal blooms (CHABs).


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Frutose-Bifosfato Aldolase/antagonistas & inibidores , Herbicidas/farmacologia , Tioureia/análogos & derivados , Tioureia/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Frutose-Bifosfato Aldolase/química , Frutose-Bifosfato Aldolase/genética , Herbicidas/síntese química , Herbicidas/química , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Mutação , Synechocystis/efeitos dos fármacos , Synechocystis/enzimologia , Tioureia/síntese química
19.
Clin Hemorheol Microcirc ; 72(2): 129-138, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30636730

RESUMO

BACKGROUND: Plasma cell mastitis (PCM), a common type of mastitis often mimics malignancy clinically and radiologically. OBJECTIVE: The study was designed to explore the diagnostic value of superb microvascular imaging (SMI) in differentiating PCM from malignant breast lesions. METHODS: A total of 95 breast lesions underwent conventional ultrasound (US) and SMI examination between May 2016 and April 2018. Vessels were detected in SMI in a quantitative manner. Blood flow parameters including systolic peak velocity (SPV), resistance index (RI), and pulsatility index (PI) were evaluated. We further assessed the diagnostic performances of US and US+SMI. RESULTS: The majority of PCM were in regular shape and displayed no calcification compared with malignant breast lesions. Regarding blood flow parameters, PCM obtained significantly lower mean value of RI and PI compared with malignant lesions (P < 0.05). The sensitivity, specificity and accuracy rate of US+SMI (84.62%, 76.47%, 83.16%) was significantly higher than those of US (78.21%, 64.71%, 75.59%). CONCLUSIONS: The present study supports that SMI is a novel ultrasound technology in revealing micro-vessels in breast lesions. The combined modality of US+SMI presented a better diagnostic performance in making a distinction between PCM and malignant breast carcinomas.


Assuntos
Neoplasias da Mama/patologia , Microvasos/diagnóstico por imagem , Plasmócitos/metabolismo , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
20.
Bioorg Med Chem ; 27(12): 2413-2420, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30692021

RESUMO

Cyanobacterial pyruvate dehydrogenase multienzyme complex E1 (PDHc E1) is a potential target enzyme for finding inhibitors to control harmful cyanobacterial blooms. In this study, a series of novel triazole thiamin diphosphate (ThDP) analogs were designed and synthesized by modifying the substituent group of triazole ring and optimizing triazole-benzene linker as potential cyanobacterial PDHc E1 (Cy-PDHc E1) inhibitors. Their inhibitory activities against Cy-PDHc E1 in vitro and algicide activities in vivo were further examined. Most of these compounds exhibited prominent inhibitory activities against Cy-PDHc E1 (IC50 1.48-4.48 µM) and good algicide activities against Synechocystis PCC6803 (EC50 0.84-2.44 µM) and Microcystis aeruginosa FACHB905 (EC50 0.74-1.77 µM). Especially, compound 8d showed not only the highest inhibitory activity against Cy-PDHc E1 (IC50 1.48 µM), but also the most powerful inhibitory selectivity between Cy-PDHc E1 (inhibitory rate 98.90%) and porcine PDHc E1 (inhibitory rate only 9.54%). Furthermore, the potential interaction between compound 8d and Cy-PDHc E1 was analyzed by a molecular docking method and site-directed mutagenesis and enzymatic analysis and fluorescence spectral analysis. These results indicated that compound 8d could be used as a hit compound for further optimization and might have potential to be developed as a new algicide.


Assuntos
Cianobactérias/enzimologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Complexo Piruvato Desidrogenase/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Complexo Piruvato Desidrogenase/genética , Complexo Piruvato Desidrogenase/metabolismo , Relação Estrutura-Atividade , Synechocystis/efeitos dos fármacos , Triazóis/química , Triazóis/metabolismo , Triazóis/farmacologia
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