Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32.799
Filtrar
1.
Sheng Wu Gong Cheng Xue Bao ; 36(2): 226-240, 2020 Feb 25.
Artigo em Chinês | MEDLINE | ID: mdl-32147995

RESUMO

As a member of the histone lysine-specific demethylase family, KDM1A plays a pivotal role in biological processes including signal transduction, chromatin reprogramming, embryo development, hematopoiesis, glucose and lipid metabolism. Recently, increasing studies and clinical evidences suggest that the expression of KDM1A is related to initiation and development of tumors and plays a key role in regulating of initiation and development of tumors, such as prostate cancer, breast cancer, lung cancer and liver cancer. KDM1A binds to distinct complexes and mediates different downstream signaling pathways. However, KDM1A often plays an oncogenic role in the initiation and development of tumors. Based on the current literatures, we describe the latest research of KDM1A in the initiation and progression of various tumors, and summarize its mechanism of actions, to provide clues for cancer therapy.


Assuntos
Carcinogênese , Transformação Celular Neoplásica , Histona Desmetilases , Histonas , Humanos , Lisina , Oncogenes
2.
Emerg Microbes Infect ; 9(1): 639-650, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32192413

RESUMO

Acinetobacter baumannii, a Gram-negative opportunistic pathogen, is a leading cause of hospital- and community-acquired infections. Acinetobacter baumannii can rapidly acquire diverse resistance mechanisms and undergo genetic modifications that confer resistance and persistence to all currently used clinical antibiotics. In this study, we found exogenous L-lysine sensitizes Acinetobacter baumannii, other Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae) and a Gram-positive bacterium (Mycobacterium smegmatis) to aminoglycosides. Importantly, the combination of L-lysine with aminoglycosides killed clinically isolated multidrug-resistant Acinetobacter baumannii and persister cells. The exogenous L-lysine can increase proton motive force via transmembrane chemical gradient, resulting in aminoglycoside acumination that further accounts for reactive oxygen species production. The combination of L-lysine and antibiotics highlights a promising strategy against bacterial infection.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Lisina/farmacologia , Acinetobacter baumannii/metabolismo , Ciclo do Ácido Cítrico , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Escherichia coli/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Força Próton-Motriz/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
3.
J Agric Food Chem ; 68(10): 3050-3060, 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32069040

RESUMO

Industrial wastewater has brought great disaster to water bodies and soils and seriously affected the growth of crops. It is necessary to prepare a stable, effective, and sustainable treatment agent to control water pollution to obtain clean water. The adsorption effect of a lignosulfonate-lysine hydrogel (CLS-Lys adsorbent) on heavy metal ions (Cu2+ and Co2+) in water is studied. In the synthesis experiment, a response surface method is used to optimize the content of sodium lignosulfonate, lysine, initiator, and cross-linker. The CLS-Lys adsorbent is characterized by Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, thermal analysis, and zeta potential analysis. The performance of the CLS-Lys adsorbent under different influencing factors is studied. The kinetic and isothermal models of the CLS-Lys adsorbent are established. The results show that the main adsorption model of the CLS-Lys adsorbent is chemical adsorption, accompanied by electrostatic adsorption. These two ions have a competitive adsorption relationship, and when the two ions are present at the same time, they inhibit each other. In addition, the CLS-Lys adsorbent has good adsorption and analytical regeneration performance. It is an economic and effective adsorbent and has a broad application prospect.


Assuntos
Hidrogéis/química , Lignina/análogos & derivados , Lisina/química , Metais Pesados/química , Poluentes Químicos da Água/química , Purificação da Água/métodos , Adsorção , Hidrogéis/síntese química , Cinética , Lignina/química , Águas Residuárias/química , Purificação da Água/instrumentação
4.
Chem Commun (Camb) ; 56(20): 3039-3042, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32048637

RESUMO

We report synthesis and enzymatic assays on human histone lysine methyltransferase catalysed methylation of histones that possess lysine and its geometrically constrained analogues containing rigid (E)-alkene (KE), (Z)-alkene (KZ) and alkyne (Kyne) moieties. Methyltransferases G9a and GLP do have a capacity to catalyse methylation in the order K ≫ KE > KZ ∼ Kyne, whereas monomethyltransferase SETD8 catalyses only methylation of K and KE.


Assuntos
Histona-Lisina N-Metiltransferase/metabolismo , Lisina/metabolismo , Alcenos/química , Alcenos/metabolismo , Alquinos/química , Alquinos/metabolismo , Biocatálise , Humanos , Lisina/análogos & derivados , Lisina/química , Metilação , Conformação Molecular
5.
Bioresour Technol ; 302: 122844, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32006927

RESUMO

Cadaverine is the monomer of bio-based nylons polyamide 5.4, 5.6 and 5.10. In this study, a litre-scale integrated strategy was developed for high-efficiency and low-cost production of cadaverine using an engineered Escherichia coli. Firstly, the engineered strain BL21-Pcad-CadA induced by cheap l-lysine-HCl instead of IPTG was constructed. Then the permeabilized cells were served as the biocatalyst for the production of cadaverine, because the enhanced permeability facilitated the mass transfer of the substrate and the release of products. After the replacement of industrial materials and the solution of the scale-up permeabilization process, cadaverine concentration reached 205 g/L with the yield of 92.1% after 20 h in a 2 L bioconversion system, achieving the level of industrial production. Furthermore, the costs of industrial materials for 2 L integrated strategy ($2.78) was only 1/11 of the lab reagents ($30.88). Therefore, the proposed strategy is a promising candidate for the industrial process of cadaverine.


Assuntos
Carboxiliases , Escherichia coli , Cadaverina , Lisina
6.
Food Chem ; 312: 126122, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31901825

RESUMO

This study investigated how l-lysine/l-arginine/l-cysteine improved cured sausage color. Visible detection showed that Mb(Fe2+)NO did not form when MetMb(Fe3+) was treated with a combination of l-lysine and NaNO2, l-arginine and NaNO2, or l-cysteine and NaNO2. Visible spectra and electron paramagnetic resonance (EPR) detection together indicated formation of Mb(Fe2+)O2 when MetMb(Fe3+) was treated with l-lysine, l-arginine, or l-cysteine; Mb(Fe2+)NO was formed when MetMb(Fe3+) was treated with a combination of l-lysine and NO, l-arginine and NO, or l-cysteine and NO. Visible, EPR, and fourier transform infrared results suggested formation of a complex of Mb(Fe2+) and l-cysteine by the coordination of sulfydryl and ferrous porphyrin. Therefore, l-lysine, l-arginine, or l-cysteine can promote the formation of Mb(Fe2+)NO by reducing MetMb(Fe3+) to Mb(Fe2+)O2, and l-cysteine promotes formation of a complex of Mb(Fe2+) and l-cysteine via coordination of sulfydryl and ferrous porphyrin, which may improve cured sausage color.


Assuntos
Produtos da Carne/análise , Arginina/química , Cor , Cisteína/química , Espectroscopia de Ressonância de Spin Eletrônica , Lisina/química
7.
Chem Pharm Bull (Tokyo) ; 68(1): 34-45, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902900

RESUMO

Enzymatic and post-translational modifications (PTMs) such as ubiquitination, acetylation, and methylation occur at lysine residues. The PTMs play critical roles in the regulation of the protein functions, and thus, various cellular processes. In addition, aberrations of the PTMs are associated with various diseases, such as cancer and neurodegenerative disorders. Therefore, we hypothesized that modulation of the PTMs and normalization of the PTM abnormalities could be useful as methods to control various cellular mechanisms and as a therapeutic strategy, respectively. To modulate the PTMs, we have focused on lysine-modifying enzymes and have pursued drug discovery researches on ubiquitination inducers, lysine deacetylase (KDAC) inhibitors, and lysine demethylase (KDM) inhibitors. For the identification of the modulators, we have used not only conventional drug design, such as structure-based drug design (SBDD) and ligand-based drug design (LBDD), but also "strategic chemistry approaches," such as drug design based on enzyme catalytic mechanism. As a result, we have identified several modulators which have pharmacological effects in animal models or in cellular studies. In this review, focusing on the drug design based on enzyme catalytic mechanism, our drug discovery researches have been discussed.


Assuntos
Carboxiliases/metabolismo , Inibidores Enzimáticos/química , Histona Desmetilases/metabolismo , Lisina/química , Carboxiliases/antagonistas & inibidores , Desenho de Drogas , Inibidores Enzimáticos/síntese química , Histona Desmetilases/antagonistas & inibidores , Humanos , Lisina/metabolismo , Processamento de Proteína Pós-Traducional , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Enzimas de Conjugação de Ubiquitina/metabolismo
8.
Life Sci ; 241: 117114, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31790687

RESUMO

AIMS: Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide. Over-expression of tetraspanin 8 (TSPAN8) is related to the development and progression of CRC. Whether TSPAN8 plays a role in the growth of colorectal cancer and its epigenetic mechanisms regulated by Lysine Specific Demethylase 1 (LSD1) are still unknown. MAIN METHODS: In this study, RT-PCR and western blotting were used to analyze the mRNA and protein expression, respectively; cell viability was assayed with MTS analysis; cell migration was measured with Trans-well analysis. KEY FINDINGS: In the present study, the results indicated that the mRNA levels of LSD1 and TSPAN8 in CRC were significantly higher than that in corresponding adjacent non-tumor tissue. Down-regulation of LSD1 or TSPAN8 as well as LSD1 inhibitor Tranylcypromine hemisulfate inhibited the proliferation and migration of CRC cells, while over-expression of LSD1 exhibited opposite effects. LSD1 up-regulated TSPAN8 expression and reduced H3K9me2 occupancy on the TSPAN8 promoter in CRC cells. TSPAN8 promoted epithelial-mesenchymal transition (EMT) in CRC cells in LSD1-dependent manner. SIGNIFICANCE: TSPAN8 may be considered as a promising biomarker for the diagnosis and prognosis in patients with CRC. Furthermore, TSPAN8 could be a novel therapeutic target and potent LSD1 inhibitors could be designed and developed in the treatment of CRC.


Assuntos
Neoplasias Colorretais/patologia , Histona Desmetilases/metabolismo , Tetraspaninas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metilação , Regiões Promotoras Genéticas , Tetraspaninas/genética
9.
Nat Rev Cardiol ; 17(2): 96-115, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31350538

RESUMO

Lysine acetylation is a conserved, reversible, post-translational protein modification regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs; also known as histone deacetylases (HDACs)) that is involved in many cellular signalling pathways and diseases. Studies in animal models have revealed a regulatory role of reversible lysine acetylation in hypertension, vascular diseases, arrhythmia, heart failure and angiogenesis. Evidence from these studies indicates a therapeutic role of KDAC inhibitors (also known as HDAC inhibitors) in cardiovascular diseases. In this Review, we describe the diverse roles of KATs and KDACs in both the normal and the diseased heart. Among KDACs, class II and class III HDACs seem to have a protective role against both cardiac damage and vessel injury, whereas class I HDACs protect against vessel injury but have deleterious effects on the heart. These observations have important implications for the clinical utility of HDAC inhibitors as therapeutic agents for cardiovascular diseases. In addition, we summarize the latest data on nonacetylation acylations in the context of cardiovascular disease.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Sistema Cardiovascular/efeitos dos fármacos , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Lisina Acetiltransferases/antagonistas & inibidores , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Acetilação , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/enzimologia , Sistema Cardiovascular/fisiopatologia , Humanos , Lisina , Lisina Acetiltransferases/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais
10.
Int J Cancer ; 146(5): 1281-1292, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31456217

RESUMO

Tumor-initiating cells are a subpopulation of cells that have self-renewal capacity to regenerate a tumor. Here, we identify stem cell-like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DNA damage response genes. Upon knockdown of histone demethylases, KDM4C and KDM7A both differentiation and DNA damage were induced. Thus, the H3K9me3-H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.


Assuntos
Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Células-Tronco Neoplásicas/metabolismo , Acetilação , Animais , Apoptose/genética , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Cromatina/metabolismo , Metilação de DNA , Reparo do DNA/genética , Técnicas de Silenciamento de Genes , Glioblastoma/patologia , Células HEK293 , Histonas , Humanos , Histona Desmetilases com o Domínio Jumonji/genética , Lisina/metabolismo , Camundongos , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Int J Radiat Oncol Biol Phys ; 106(3): 546-555, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730876

RESUMO

PURPOSE: Radio-recurrent prostate cancer is typically detected by a rising prostate-specific antigen and may reflect local or distant disease. Positron emission tomography (PET) radiotracers targeting prostate-specific membrane antigen, such as 18F-DCFPyL have shown promise in restaging men with recurrent disease postprostatectomy but are less well characterized in the setting of radio-recurrent disease. METHODS AND MATERIALS: A prospective, multi-institutional study was conducted to evaluate the effect of 18F-DCFPyL PET/computed tomography (CT) when added to diagnostic imaging (DI; CT abdomen and pelvis, bone scan, multiparametric magnetic resonance imaging pelvis) for men with radio-recurrent prostate cancer. All men were imaged with DI and subsequently underwent 18F-DCFPyL PET/CT with local and central reads. Tie break reads were performed as required. Management questionnaires were completed after DI and again after 18F-DCFPyL PET/CT. Discordance in patterns of disease detected with 18F-DCFPyL PET/CT versus DI and changes in management were characterized. RESULTS: Seventy-nine men completed the study. Most men had T1 disease (62%) and Gleason score <7 (95%). Median prostate-specific antigen at diagnosis was 7.4 ng/mL and at relapse was 4.8 ng/mL. DI detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 9 out of 79 (11%), distant disease in 12 out of 79 (15%), and no disease in 26 out of 79 (33%). 18F-DCFPyL PET/CT detected isolated intraprostatic recurrence in 38 out of 79 men (48%), regional nodal recurrence in 21 out of 79 (27%), distant disease in 24 out of 79 (30%), and no disease in 10 out of 79 (13%). DI identified 8 out of 79 (10%) patients to have oligometastatic disease, compared with 21 out of 79 (27%) with 18F-DCFPyL PET/CT. 18F-DCFPyL PET/CT changed proposed management in 34 out of 79 (43%) patients. CONCLUSIONS: 18F-DCFPyL PET/CT identified extraprostatic disease in twice as many men with radio-recurrent prostate cancer compared with DI and detected a site of recurrence in 87% of men compared with 67% with DI. Furthermore, 18F-DCFPyL PET/CT identified potentially actionable disease (prostate only recurrence or oligometastatic disease) in 75% of men and changed proposed management in 43% of men.


Assuntos
Lisina/análogos & derivados , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Ureia/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície/sangue , Radioisótopos de Flúor , Glutamato Carboxipeptidase II/sangue , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/radioterapia , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia
12.
Ecotoxicol Environ Saf ; 190: 110077, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31864122

RESUMO

Nε-(carboxymethyl)lysine (CML) is a potentially noxious compound that is causing widespread concern due to its use in various food products. In this study, we investigated CML neurotoxicity via an in vivo experiment with mice, and an in vitro experiment using a 3D microvascular network model (with human brain vascular endothelial cell and human astrocyte) that simulated the blood-brain barrier. We found that CML could induce cell survival status variations, and histopathological changes to the brain. In addition, CML increased levels of oxidative stress, prompted the protein expression of the receptor for advanced glycation end-products (RAGE). CML up-regulated both the gene expression of RAGE, the activating protein-1 (AP-1), the inflammatory cytokines Interleukin-6 (IL-6), vascular cell adhesion molecule1 (VCAM-1), monocyte chemotactic protein1 (MCP-1). We, therefore, postulated that CML has the potential to deleteriously affect the nervous system through oxidative stress and that activation of the p38 MAPK-AP-1 signaling pathway might be implicated in this pathological process.


Assuntos
Lisina/análogos & derivados , Síndromes Neurotóxicas , Animais , Astrócitos/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Técnicas de Cultura de Células , Células Cultivadas , Citocinas/genética , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Manipulação de Alimentos , Humanos , Lisina/toxicidade , Camundongos , Microvasos/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Fator de Transcrição AP-1/metabolismo
13.
Toxicol Lett ; 318: 30-43, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31647946

RESUMO

Lead (Pb), a widespread heavy metal, may induce serious diseases, particularly male reproductive injury. However, the mechanisms by which Pb induces testicular injury remain unclear. In this paper, we established a mouse model of Pb-induced testicular injury via an intraperitoneal injection of lead chloride at a concentration of 1.5 mg/kg body weight. We confirmed that Pb could induce a series of injuries, including a low litter size, smaller testes, more weak offspring, direct injury, and aberrant spermiogenesis. Our study demonstrated that Pb could inhibit lysine acetylation (Kac) and succinylation (Ksuc) via western blot (WB) and immunofluorescence (IF) analyses. We subsequently separated different germ cells that contained Pre-meiotic spermatogonia (SPG), meiotic spermatocyte (SPC), and round spermatid (RS) into the Pb-treated and control groups and verified that Pb inhibited Kac in SPC, RS, and particularly, during meiosis. Furthermore, our results regarding the inhibition of pyruvate kinase and mitochondrial electron transport chain complex I and II in the Pb-treated groups suggested that Pb may restrain key enzymes to block the TCA cycle and that the low TCA cycle activity could reduce the contents of two important metabolites, acetyl-CoA and succinyl-CoA, to inhibit Kac and Ksuc. Moreover, we examined the influences of the inhibition of Kac and Ksuc on spermiogenesis, which indicated that decreased Kac and Ksuc could impede the replacement of transition proteins in elongating sperm and disorder the distribution of germ cells in the seminiferous tubule. Our research provides novel insights into the mechanisms of Pb reproductive toxicity with respect to lysine acetylation and succinylation.


Assuntos
Chumbo/toxicidade , Lisina/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Acetilação , Animais , Metabolismo Energético/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia , Testículo/metabolismo , Testículo/patologia
14.
Food Chem ; 307: 125554, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31648176

RESUMO

The reaction of Nε-(carboxymethyl) lysine (CML) with eight kinds of non-flavonoid o-benzoquinones and five kinds of flavonoid o-benzoquinones were investigated by cyclic voltammetry at pH 5.0, 7.0 and 8.0 and scan rate of 10, 50 and 100 mV/s. The reactivity of o-benzoquinones towards CML is weakened by the electron-donating substituent and strengthened by the electron-withdrawing substituent on the o-benzoquinone rings. The steric hindrance of the substituents on o-benzoquinone rings also weakens the quinone reactivity. Reaction of 4-methylbenzoquinone with CML (38.0 ±â€¯1.3%) was found to be faster than that with l-lysine (31.3 ±â€¯1.5%) and Nα-acetyl-l-lysine (14.5 ±â€¯0.1%) but slower than that with l-cysteine (≥100.0%) and Nα-acetyl-l-cysteine (≥100.0%) at pH 7.0 and scan rate of 10 mV/s. Products obtained by the reaction of CML with o-benzoquinones were found to include a CML-quinone adduct according to the cyclic voltammetry and UPLC-QTOF-MS/MS analysis.


Assuntos
Benzoquinonas/química , Lisina/análogos & derivados , Catecóis , Cisteína/química , Flavonoides , Lisina/química
15.
Eur J Med Chem ; 187: 111960, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31869654

RESUMO

A series of l-lysine-conjugated pyridophenoxazinones 2-5 and 2'-5' were designed and synthesized for developing compounds with multimodal anticancer potentialities. All compounds inhibited the proliferation of a panel of human liquid and solid neoplastic cell lines. 2 and 5 were the most active compounds with IC50 values in the submicromolar range. UV-vis, 1H NMR, unwinding, and docking experiments demonstrated that they intercalate between the middle 5'-GC-3' base pairs with the carboxamide side chain lying into major groove. Charge-transfer contribution to the complex stability, evaluated by ab initio calculations, was found to correlate with cytotoxicity. Relaxation and cleavage assays showed that 2 and 5 selectively target Topo IIα over Topo IIß and stimulate the formation of covalent Topo II-DNA complexes, functioning as poisons. Moreover, compound 5 induced DNA damage and arrested MCF-7 cells at the G2/M phase. Altogether, the work provides interesting structure-activity relationships in the pyridophenoxazinone-l-lysine conjugate series and identifies 5 as a promising candidate for further in vivo evaluation.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , DNA de Neoplasias/efeitos dos fármacos , Lisina/farmacologia , Oxazinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Modelos Lineares , Lisina/química , Modelos Moleculares , Estrutura Molecular , Oxazinas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
16.
Meat Sci ; 159: 107911, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31474317

RESUMO

The partial reduction of Sodium Chloride (NaCl) and the use of lysine, yeast extract and substitute salts Potassium Chloride (KCl) and Calcium Chloride (CaCl2) in the characteristics of salted meat was investigated. Proximate composition, physicochemical properties (pH, water activity, lipid oxidation), instrumental analysis (color, shear force), microbiological analysis (total counts, lactic acid bacteria counts, thermally tolerant coliforms, and total coliforms) and sensory evaluation (120 consumers) were performed. The partial replacement of NaCl by KCl and CaCl2 significantly reduced the sodium content of salted meat treatments, while lysine and yeast extract minimized the negative sensory effects due to the addition of KCl and CaCl2. The addition of lysine and yeast extract increased the sensory acceptance and decreased rancid aroma, salty taste, and aftertaste of salted meat made with a blend of NaCl + KCl + CaCl2, with no differences in the physiochemical quality parameters. Moreover, the treatments made with the blend NaCl + KCl exhibited characteristics similar to traditional salted meat formulations.


Assuntos
Lisina/farmacologia , Carne Vermelha/análise , Carne Vermelha/normas , Leveduras , Adolescente , Adulto , Animais , Bovinos , Comportamento do Consumidor , Feminino , Manipulação de Alimentos , Qualidade dos Alimentos , Humanos , Masculino , Produtos da Carne/análise , Pessoa de Meia-Idade , Sensação , Paladar , Adulto Jovem
17.
Food Chem ; 309: 125708, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31683151

RESUMO

Herein, corn silk extract and its flavonoids were used to inhibit the formation of Nε-carboxymethyllysine (CML) in a casein glucose-fatty acid model system. Under these optimum extraction conditions, nine major flavonoids were identified and quantified by HPLC-MS/MS. The percent inhibition of CML formation by corn silk extract was 76.57%. The inhibitory mechanism of corn silk extract toward CML formation was further investigated by examining the trapping of glyoxal/methyl glyoxal by the major flavonoids (5 mM) using HPLC-ESI-MS, and mono-, di-, and tri-adducts were found for some flavonoid compounds. The antioxidant activity of the corn silk extract was evaluated by the DPPH and ABTS assays. The scavenging activity of the corn silk extract for DPPH and ABTS was 84.38% and 89.11%, respectively. The results suggested that corn silk extract inhibited CML formation through glyoxal/methyl glyoxal scavenging or by its antioxidant activity attributed to its flavonoid content.


Assuntos
Flavonoides/química , Glioxal/química , Lisina/análogos & derivados , Modelos Biológicos , Zea mays/química , Antioxidantes/química , Caseínas/química , Cromatografia Líquida de Alta Pressão , Ácidos Graxos/química , Flavonoides/análise , Glucose/química , Lisina/química , Lisina/metabolismo , Extratos Vegetais/química , Seda/química , Espectrometria de Massas em Tandem , Zea mays/metabolismo
18.
Food Microbiol ; 86: 103349, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31703858

RESUMO

Pistachio powder was added to flour or semolina to evaluate its contribution to increase the amount of lysine in bread. Bread production was carried out by sourdough technology using a selected 3-species (Lactobacillus sanfranciscensis/Leuconostoc citreum/Weissella cibaria) lactic acid bacterial (LAB) starter culture. All sourdoughs were subjected to a long-time fermentation (21 h) and showed levels of LAB around 109 CFU/g, indicating the suitability of pistachio powder for lactic fermentation. Yeasts were also detected, in particular in semolina trials. MiSeq Illumina technology was applied to investigate the bacterial composition of sourdoughs evidencing a different distribution of LAB species among the trials with Lactobacillus as major LAB group in almost all sourdoughs. Physicochemical parameters were comparable among the trials. After baking, pistachio powder was found not to influence the height of the breads, but pistachio breads were more firm than control breads. Color of the breads, void fraction and cell density, were influenced by pistachio powder. The amount of lysine increased consistently thanks to pistachio supplementation which also determined a higher presence of o-xylene, p-cymene and limonene and the appearance of α-pinene and 1-octen-3-ol in breads. Sensory tests showed the best appreciation scores for the breads produced with flour and pistachio powder.


Assuntos
Pão/análise , Aditivos Alimentares/análise , Lactobacillus/metabolismo , Leuconostoc/metabolismo , Lisina/análise , Pistacia/química , Weissella/metabolismo , Pão/microbiologia , Fermentação , Farinha/análise , Aditivos Alimentares/metabolismo , Alimentos Fortificados/análise , Alimentos Fortificados/microbiologia , Humanos , Lisina/metabolismo , Paladar
19.
Mater Sci Eng C Mater Biol Appl ; 106: 110288, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31753411

RESUMO

A new kind of core-crosslinked zwitterionic polymer nano aggregates was prepared by two steps: (1) terpolymers of lipoic acid, polyethylene glycol diglycidyl ether and l-lysine were prepared, forming nano aggregates with hydrodynamic radius of 80 nm-183 nm by self-assembly; (2) the crosslinking of the nano aggregates took place through a reaction of side chain group in lipoic acid structural unit with 1,4-dimercaptothreotol, producing zwitterionic polymer core-crosslinked nano aggregates. The aggregates were stable against dilution and protein adsorption, and they demonstrated good pH/redox dual-responsiveness due to the introduction of disulfide bonds and zwitterionic groups to the nano aggregates. Doxorubicin (DOX) was loaded into the nano aggregates for controlled release. The drug-loaded nano aggregates exhibited obvious pH and reduction sensitivities in response to the environmental conditions in tumor cells. The nano aggregates were biocompatible and could be potentially applied as anticancer drug vehicles for enhancement of cellular uptake of anticancer drugs.


Assuntos
Portadores de Fármacos/química , Nanoestruturas/química , Polímeros/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Íons/química , Lisina/química , Nanoestruturas/toxicidade , Oxirredução , Tamanho da Partícula , Polietilenoglicóis/química , Ácido Tióctico/química
20.
Toxicol Lett ; 321: 1-11, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31846690

RESUMO

Upon entering the body, nerve agents can bind active amino acid residues to form phosphonylated adducts. Tabun derivatives (O-alkyl-N,N-dialkyl phosphoroamidocyanidates) have strikingly different structural features from other G-series nerve agents, such as sarin and soman. Here, we investigate the binding mechanism for the phosphonylated adducts of nerve agents of tabun derivatives. Binding sites for three tabun derivatives, O-ethyl-N,N- dimethyl phosphoramidocyanidate (GA), O-ethyl-N,N-ethyl(methyl) phosphoramidocyanidate, and O-ethyl-N,N-diethylphosphoramidocyanidate were studied. Quadrupole-orbitrap mass spectrometry (Q-Orbitrap-MS) coupled to proteomics was used to screen adducts between tabun derivatives and albumin, immunoglobulin, and hemoglobin. The results reveal that all three tabun derivatives exhibit robust selectivity to lysine residues, rather than other amino acid residue types. A set of 10 lysine residues on human serum albumin are labeled by tabun derivatives in vitro, with K525 (K*QTALVELVK) and K199 (LK*CASLQK) peptides displaying the most reactivity. Tabun derivatives formed stable adducts on K525 and K414 (K*VPQVSTPTLVEVSR) for at least 7 days and on K351 (LAK*TYETTLEK) for at least 5 days in a rabbit model. Three of these peptides-K525, K414, and K351-have the highest homology with human serum albumin of all 5 lysine residues that bound to examined rabbit blood proteins in vivo. Molecular simulation of the tabun-albumin interaction using structural analysis and molecular docking provided theoretical evidence supporting lysine residue reactivity to phosphonylation by tabun derivatives. K525 has the lowest free binding energy and the strongest hydrogen bonding to human albumin. In summary, these findings identify unique binding properties for tabun derivatives to blood proteins.


Assuntos
Substâncias para a Guerra Química/metabolismo , Organofosfatos/metabolismo , Albumina Sérica Humana/metabolismo , Animais , Sítios de Ligação , Substâncias para a Guerra Química/química , Feminino , Hemoglobinas/metabolismo , Humanos , Ligações de Hidrogênio , Imunoglobulina G/metabolismo , Lisina , Masculino , Espectrometria de Massas , Simulação de Dinâmica Molecular , Organofosfatos/química , Ligação Proteica , Conformação Proteica , Coelhos , Albumina Sérica Humana/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA