Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.950
Filtrar
1.
Invest Ophthalmol Vis Sci ; 62(14): 5, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34730792

RESUMO

Purpose: The arrangement of lens cells is regulated by ocular growth factors. Although the effects of these inductive molecules on lens cell behavior (proliferation, survival, and fiber differentiation) are well-characterized, the precise mechanisms underlying the regulation of growth factor-mediated signaling in lens remains elusive. Increasing evidence highlights the importance of heparan sulfate proteoglycans (HSPGs) for the signaling regulation of growth factors; however, the identity of the different lens HSPGs and the specific roles they play in lens biology are still unknown. Methods: Semiquantitative real-time (RT)-PCR and immunolabeling were used to characterize the spatial distribution of all known HSPG core proteins and their associated glycosaminoglycans (heparan and chondroitin sulfate) in the postnatal rat lens. Fibroblast growth factor (FGF)-2-treated lens epithelial explants, cultured in the presence of Surfen (an inhibitor of heparan sulfate [HS]-growth factor binding interactions) were used to investigate the requirement for HS in FGF-2-induced proliferation, fiber differentiation, and ERK1/2-signaling. Results: The lens expresses all HSPGs. These HSPGs are differentially localized to distinct functional regions of the lens. In vitro, inhibition of HS-sulfation with Surfen blocked FGF-2-mediated ERK1/2-signaling associated with lens epithelial cell proliferation and fiber differentiation, highlighting that these cellular processes are dependent on HS. Conclusions: These findings support a requirement for HSPGs in FGF-2 driven lens cell proliferation and fiber differentiation. The identification of specific HSPG core proteins in key functional lens regions, and the divergent expression patterns of closely related HSPGs, suggests that different HSPGs may differentially regulate growth factor signaling networks leading to specific biological events involved in lens growth and maintenance.


Assuntos
Regulação da Expressão Gênica/fisiologia , Proteoglicanas de Heparan Sulfato/genética , Cristalino/metabolismo , Animais , Animais Recém-Nascidos , Western Blotting , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Sulfatos de Condroitina/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Proteoglicanas de Heparan Sulfato/metabolismo , Heparitina Sulfato/antagonistas & inibidores , Heparitina Sulfato/metabolismo , Cristalino/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Técnicas de Cultura de Órgãos , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Ureia/análogos & derivados , Ureia/farmacologia
2.
ACS Chem Neurosci ; 12(22): 4302-4318, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34726394

RESUMO

Multiple factors are causally responsible and/or contribute to the progression of Alzheimer's and Parkinson's diseases. The protein kinase Dyrk1A was identified as a promising target as it phosphorylates tau protein, α-synuclein, and parkin. The first goal of our study was to optimize our previously identified Dyrk1A inhibitors of the 6-hydroxy benzothiazole urea chemotype in terms of potency and selectivity. Our efforts led to the development of the 3-fluorobenzyl amide derivative 16b, which displayed the highest potency against Dyrk1A (IC50 = 9.4 nM). In general, the diversification of the benzylamide moiety led to an enhanced selectivity over the most homologous isoform, Dyrk1B, which was a meaningful indicator, as the high selectivity could be confirmed in an extended selectivity profiling of 3b and 16b. Eventually, we identified the novel phenethyl amide derivative 24b as a triple inhibitor of Dyrk1A kinase activity (IC50 = 119 nM) and the aggregation of tau and α-syn oligomers. We provide evidence that the novel combination of selective Dyrk1A inhibition and suppression of tau and α-syn aggregations of our new lead compound confers efficacy in several established cellular models of neurotoxic mechanisms relevant to neurodegenerative diseases, including α-syn- and 6-hydroxydopamine-induced cytotoxicities.


Assuntos
Doenças Neurodegenerativas , Proteínas Tirosina Quinases , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Proteínas Serina-Treonina Quinases , Ureia/farmacologia , alfa-Sinucleína , Proteínas tau
3.
BMC Vet Res ; 17(1): 304, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503491

RESUMO

BACKGROUND: Total fresh cassava root (FCR) production was 275 million tonnes in 2018 which equals 61.1 % of the total production, and Thailand produced 10.7 % FCR of the total production. FCR is one of the main energy source for ruminant. The limitation of FCR utilization is due to the presence of hydrogen cyanide (HCN). The study aimed to evaluate the effect of sulfur, urea and FCR at various levels on in vitro gas production, ruminal fermentation and in vitro degradability. The study hypothesized that: (1) sulfur, urea and FCR have no interaction effect and (2) effect of FCR and urea is related to sulfur addition. RESULTS: The study aimed to elucidate the optimum level of elemental sulfur, fresh cassava root (FCR) and urea and their effect on in vitro gas production, ruminal fermentation, thiocyanate concentration, and in vitro degradability. A 3 × 2 × 4 in a completely randomized design were conducted. Factor A was level of sulfur at 0 %, 1 and 2 % of concentrate dry matter (DM), factor B was level of urea at 2 and 4 % of concentrate DM, and factor C was level of the FCR at 0, 200, 300 and 400 mg DM of the total substrate. The study found that elemental sulfur, urea and FCR had no interaction effect on the kinetics of in vitro gas, ruminal fermentation, HCN and in vitro degradability. Elemental sulfur supplementation (P < 0.05) significantly increased the in vitro gas produced from an insoluble fraction (b), in vitro DM degradability and either neutral detergent fiber (NDF) or acid detergent fiber (ADF) degradability and propionate (C3) concentration while decreased the ruminal HCN concentration. Urea levels showed a (P < 0.05) significant increase of the potential extent of in vitro gas production, ruminal ammonia nitrogen (NH3-N) and total volatile fatty acid (TVFA). Fresh cassava root supplementation (P < 0.05) significantly increased the in vitro gas produced from an immediate soluble fraction (a), in vitro gas produced from insoluble fraction, in vitro gas production rate constant, total VFA, C3 concentration and HCN while decreased ruminal pH, acetate and butyrate concentration. It could be concluded that 2 % elemental sulfur, 4 % urea and 300 mg FCR showed a greater effect on in vitro gas production, ruminal fermentation and HCN reduction. CONCLUSIONS: The study found that elemental sulfur, urea, and FCR had no interaction effect on the kinetics of in vitro gas, total in vitro gas, ruminal fermentation, and HCN concentration. It could be concluded that 2 % elemental sulfur, 4 % urea, and 300 mg FCR showed a greater effect on in vitro gas production, ruminal fermentation, and HCN reduction.


Assuntos
Ração Animal/análise , Metano/metabolismo , Raízes de Plantas/metabolismo , Rúmen/efeitos dos fármacos , Enxofre/farmacologia , Ureia/farmacologia , Animais , Suplementos Nutricionais/análise , Digestão/efeitos dos fármacos , Digestão/fisiologia , Fermentação/efeitos dos fármacos , Fermentação/fisiologia , Manihot/metabolismo , Metano/análise
4.
Molecules ; 26(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34443446

RESUMO

A novel series of proflavine ureas, derivatives 11a-11i, were synthesized on the basis of molecular modeling design studies. The structure of the novel ureas was obtained from the pharmacological model, the parameters of which were determined from studies of the structure-activity relationship of previously prepared proflavine ureas bearing n-alkyl chains. The lipophilicity (LogP) and the changes in the standard entropy (ΔS°) of the urea models, the input parameters of the pharmacological model, were determined using quantum mechanics and cheminformatics. The anticancer activity of the synthesized derivatives was evaluated against NCI-60 human cancer cell lines. The urea derivatives azepyl 11b, phenyl 11c and phenylethyl 11f displayed the highest levels of anticancer activity, although the results were only a slight improvement over the hexyl urea, derivative 11j, which was reported in a previous publication. Several of the novel urea derivatives displayed GI50 values against the HCT-116 cancer cell line, which suggest the cytostatic effect of the compounds azepyl 11b-0.44 µM, phenyl 11c-0.23 µM, phenylethyl 11f-0.35 µM and hexyl 11j-0.36 µM. In contrast, the novel urea derivatives 11b, 11c and 11f exhibited levels of cytotoxicity three orders of magnitude lower than that of hexyl urea 11j or amsacrine.


Assuntos
Entropia , Proflavina/síntese química , Ureia/síntese química , Fenômenos Químicos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Cinética , Masculino , Modelos Moleculares , Proflavina/química , Proflavina/farmacologia , Ureia/química , Ureia/farmacologia
5.
Int J Mol Sci ; 22(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34360791

RESUMO

Rhabdomyosarcoma (RMS) is a malignant soft tissue cancer that develops mostly in children and young adults. With regard to histopathology, four rhabdomyosarcoma types are distinguishable: embryonal, alveolar, pleomorphic and spindle/sclerosing. Currently, increased amounts of evidence indicate that not only gene mutations, but also epigenetic modifications may be involved in the development of RMS. Epigenomic changes regulate the chromatin architecture and affect the interaction between DNA strands, histones and chromatin binding proteins, thus, are able to control gene expression. The main aim of the study was to assess the role of protein arginine methyltransferases (PRMT) in the cellular biology of rhabdomyosarcoma. In the study we used two pan-inhibitors of PRMT, called AMI-1 and SAH, and evaluated their effects on proliferation and apoptosis of RMS cells. We observed that AMI-1 and SAH reduce the invasive phenotype of rhabdomyosarcoma cells by decreasing their proliferation rate, cell viability and ability to form cell colonies. In addition, microarray analysis revealed that these inhibitors attenuate the activity of the PI3K-Akt signaling pathway and affect expression of genes related to it.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Naftalenossulfonatos/farmacologia , Proteína-Arginina N-Metiltransferases , Rabdomiossarcoma , Transdução de Sinais/efeitos dos fármacos , Ureia/análogos & derivados , Linhagem Celular Tumoral , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/enzimologia , Rabdomiossarcoma/patologia , Ureia/farmacologia
6.
Molecules ; 26(16)2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34443515

RESUMO

Current therapy against herpes simplex viruses (HSV) relies on the use of a few nucleoside antivirals such as acyclovir, famciclovir and valacyclovir. However, the current drugs are ineffective against latent and drug-resistant HSV infections. A series of amidinourea compounds, designed as analogues of the antiviral drug moroxydine, has been synthesized and evaluated as potential non-nucleoside anti-HSV agents. Three compounds showed micromolar activity against HSV-1 and low cytotoxicity, turning to be promising candidates for future optimization. Preliminary mode of action studies revealed that the new compounds act in an early stage of the HSV replication cycle, just after the viral attachment and the entry phase of the infection.


Assuntos
Guanidina/análogos & derivados , Herpes Simples/tratamento farmacológico , Herpesvirus Humano 1/efeitos dos fármacos , Simplexvirus/efeitos dos fármacos , Ureia/análogos & derivados , Aciclovir/efeitos adversos , Aciclovir/farmacologia , Antivirais/farmacologia , Farmacorresistência Viral/genética , Guanidina/síntese química , Guanidina/farmacologia , Herpes Simples/virologia , Herpesvirus Humano 1/patogenicidade , Humanos , Simplexvirus/genética , Simplexvirus/patogenicidade , Ureia/síntese química , Ureia/farmacologia
7.
J Steroid Biochem Mol Biol ; 213: 105975, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34418527

RESUMO

It is established that steroid based agents are an example of compounds obtained from natural patterns and are of great importance due to their application in the prevention and treatment of diseases. Selenosteroids are hybrids formed by attaching Se-moiety to a steroid molecule. In these types of hybrids, selenium can be present as selenide or as a part of selenosemicarbazones, isoselenocyanates, selenourea, etc. Attaching a Se-moiety to a biologically active steroid might enhance the biological properties of both fragments. Available literature indicates that these kinds of hybrids demonstrate significant anticancer activity, which renders them interesting in terms of medical use. In this review, we present various methods of synthesis and demonstrate that seleno-steroid compounds are promising molecules for further pharmaceutical application.


Assuntos
Antineoplásicos Hormonais/síntese química , Técnicas de Química Sintética/métodos , Cianatos/síntese química , Compostos Organosselênicos/síntese química , Compostos de Selênio/síntese química , Esteroides/síntese química , Ureia/análogos & derivados , Antineoplásicos Hormonais/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cianatos/farmacologia , Humanos , Concentração Inibidora 50 , Compostos Organosselênicos/farmacologia , Compostos de Selênio/farmacologia , Semicarbazonas/química , Esteroides/farmacologia , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacologia
8.
Sci Rep ; 11(1): 15579, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341408

RESUMO

Human acidic fibroblast growth factor (hFGF1) is an all beta-sheet protein that is involved in the regulation of key cellular processes including cell proliferation and wound healing. hFGF1 is known to aggregate when subjected to thermal unfolding. In this study, we investigate the equilibrium unfolding of hFGF1 using a wide array of biophysical and biochemical techniques. Systematic analyses of the thermal and chemical denaturation data on hFGF1 variants (Q54P, K126N, R136E, K126N/R136E, Q54P/K126N, Q54P/R136E, and Q54P/K126N/R136E) indicate that nullification of charges in the heparin-binding pocket can significantly increase the stability of wtFGF1. Triple variant (Q54P/K126N/R136E) was found to be the most stable of all the hFGF1 variants studied. With the exception of triple variant, thermal unfolding of wtFGF1 and the other variants is irreversible. Thermally unfolded triple variant refolds completely to its biologically native conformation. Microsecond-level molecular dynamic simulations reveal that a network of hydrogen bonds and salt bridges linked to Q54P, K126N, and R136E mutations, are responsible for the high stability and reversibility of thermal unfolding of the triple variant. In our opinion, the findings of the study provide valuable clues for the rational design of a stable hFGF1 variant that exhibits potent wound healing properties.


Assuntos
Fator 1 de Crescimento de Fibroblastos/química , Fator 1 de Crescimento de Fibroblastos/metabolismo , Desdobramento de Proteína , Temperatura , Sequência de Aminoácidos , Animais , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Guanidina/farmacologia , Heparina/metabolismo , Humanos , Camundongos , Proteínas Mutantes/química , Mutação/genética , Células NIH 3T3 , Conformação Proteica , Desnaturação Proteica/efeitos dos fármacos , Estabilidade Proteica , Eletricidade Estática , Ureia/farmacologia
9.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200178

RESUMO

As a therapeutic approach, epigenetic modifiers have the potential to enhance the efficacy of chemotherapeutic agents. Protein arginine methyltransferase 5 (PRMT5), highly expressed in lung adenocarcinoma, was identified to be involved in tumorigenesis. In the current study, we examined the potential antineoplastic activity of PRMT5 inhibitor, arginine methyltransferase inhibitor 1 (AMI-1), and cisplatin on lung adenocarcinoma. Bioinformatic analyses identified apoptosis, DNA damage, and cell cycle progression as the main PRMT5-associated functional pathways, and survival analysis linked the increased PRMT5 gene expression to worse overall survival in lung adenocarcinoma. Combined AMI-1 and cisplatin treatment significantly reduced cell viability and induced apoptosis. Cell cycle arrest in A549 and DMS 53 cells was evident after AMI-1, and was reinforced after combination treatment. Western blot analysis showed a reduction in demethylation histone 4, a PRMT5- downstream target, after treatment with AMI-1 alone or in combination with cisplatin. While the combination approach tackled lung cancer cell survival, it exhibited cytoprotective abilities on HBEpC (normal epithelial cells). The survival of normal bronchial epithelial cells was not affected by using AMI-1. This study highlights evidence of novel selective antitumor activity of AMI-1 in combination with cisplatin in lung adenocarcinoma cells.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Naftalenossulfonatos/farmacologia , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Ureia/análogos & derivados , Apoptose , Ciclo Celular , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Células Tumorais Cultivadas , Ureia/farmacologia
10.
Molecules ; 26(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201326

RESUMO

The development of cancer treatments requires continuous exploration and improvement, in which the discovery of new drugs for the treatment of cancer is still an important pathway. In this study, based on the molecular hybridization strategy, a new structural framework with an N-aryl-N'-arylmethylurea scaffold was designed, and 16 new target compounds were synthesized and evaluated for their antiproliferative activities against four different cancer cell lines A549, MCF7, HCT116, PC3, and human liver normal cell line HL7702. The results have shown seven compounds with 1-methylpiperidin-4-yl groups having excellent activities against all four cancer cell lines, and they exhibited scarcely any activities against HL7702. Among them, compound 9b and 9d showed greatly excellent activity against the four kinds of cells, and the IC50 for MCF7 and PC3 cell lines were even less than 3 µM.


Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Ureia/química , Ureia/síntese química , Células A549 , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células HCT116 , Humanos , Células PC-3 , Relação Estrutura-Atividade , Ureia/farmacologia
11.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205587

RESUMO

Heart failure (HF) is a syndrome encompassing several important etiologies that lead to the imbalance between oxygen demand and supply. Despite the usage of guideline-directed medical therapy for HF has shown better outcomes, novel therapeutic strategies are desirable, especially for patients with preserved or mildly reduced left ventricular ejection fraction. In this regard, understanding the molecular basis for cardiomyopathies is expected to fill in the knowledge gap and generate new therapies to improve prognosis for HF. This review discusses an evolutionary mechanism designed to regulate cardiac contraction and relaxation through the most often genetically determined cardiomyopathies associated with HF. In addition, both the myosin inhibitor and myosin activator are promising new treatments for cardiomyopathies. A comprehensive review from genetic mutations to the molecular basis of direct sarcomere modulators will help shed light on future studies for a better characterization of HF etiologies and potential therapeutic targets.


Assuntos
Benzilaminas/uso terapêutico , Miosinas Cardíacas/genética , Insuficiência Cardíaca/tratamento farmacológico , Terapia de Alvo Molecular , Uracila/análogos & derivados , Ureia/análogos & derivados , Benzilaminas/farmacologia , Miosinas Cardíacas/antagonistas & inibidores , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Humanos , Miócitos Cardíacos/patologia , Uracila/farmacologia , Uracila/uso terapêutico , Ureia/farmacologia , Ureia/uso terapêutico
12.
Eur J Med Chem ; 222: 113579, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34098465

RESUMO

Genetic models validated Inhibitor of nuclear factor (NF) kappa B kinase beta (IKKß) as a therapeutic target for KRAS mutation associated pancreatic cancer. Phosphorylation of the activation loop serine residues (S177, S181) in IKKß is a key event that drives tumor necrosis factor (TNF) α induced NF-κB mediated gene expression. Here we conducted structure activity relationship (SAR) study to improve potency and oral bioavailability of a quinoxaline analog 13-197 that was previously reported as a NFκB inhibitor for pancreatic cancer therapy. The SAR led to the identification of a novel quinoxaline urea analog 84 that reduced the levels of p-IKKß in dose- and time-dependent studies. When compared to 13-197, analog 84 was ∼2.5-fold more potent in TNFα-induced NFκB inhibition and ∼4-fold more potent in inhibiting pancreatic cancer cell growth. Analog 84 exhibited ∼4.3-fold greater exposure (AUC0-∞) resulting in ∼5.7-fold increase in oral bioavailability (%F) when compared to 13-197. Importantly, oral administration of 84 by itself and in combination of gemcitabine reduced p-IKKß levels and inhibited pancreatic tumor growth in a xenograft model.


Assuntos
Antineoplásicos/farmacologia , Quinase I-kappa B/antagonistas & inibidores , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/farmacologia , Ureia/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Quinase I-kappa B/metabolismo , Camundongos , Estrutura Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
13.
Int J Mol Sci ; 22(11)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063817

RESUMO

Soluble epoxide hydrolase (sEH) is abundant in the brain, is upregulated in type 2 diabetes mellitus (DM2), and is possible mediator of ischemic injury via the breakdown of neuroprotective epoxyeicosatrienoic acids (EETs). Prophylactic, pre-ischemic sEH blockade with 4-[[trans-4-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]-benzoic acid (tAUCB) reduces stroke-induced infarct in normal and diabetic mice, with larger neuroprotection in DM2. The present study tested whether benefit occurs in normal and DM2 mice if tAUCB is administered after stroke onset. We performed 60 min middle cerebral artery occlusion in young adult male C57BL mice divided into four groups: normal or DM2, with t-AUCB 2 mg/kg or vehicle 30 min before reperfusion. Endpoints were (1) cerebral blood flow (CBF) by laser Doppler, and (2) brain infarct at 24 h. In nondiabetic mice, t-AUCB reduced infarct size by 30% compared to vehicle-treated mice in the cortex (31.4 ± 4 vs. 43.8 ± 3 (SEM)%, respectively) and 26% in the whole hemisphere (26.3 ± 3 vs. 35.2 ± 2%, both p < 0.05). In contrast, in DM2 mice, tAUCB failed to ameliorate either cortical or hemispheric injury. No differences were seen in CBF. We conclude that tAUCB administered after ischemic stroke onset exerts brain protection in nondiabetic but not DM2 mice, that the neuroprotection appears independent of changes in gross CBF, and that DM2-induced hyperglycemia abolishes t-AUCB-mediated neuroprotection after stroke onset.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Epóxido Hidrolases/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Acidente Vascular Cerebral/metabolismo , Animais , Benzoatos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/tratamento farmacológico , Ureia/análogos & derivados , Ureia/farmacologia
15.
Sci Rep ; 11(1): 12545, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131184

RESUMO

Unbalanced utilization of nitrogen (N) rice not economically viable neither is this practice environmental friendly. Co-application of biochar and urea could reduce the unbalanced use of this N fertilizer in rice cultivation. Thus, a field study was carried out to: (i) determine the effects of chicken litter biochar and urea fertilization on N concentration in soil solution of a cultivated rice (MR219) using dielectric measurement at a low frequency and (ii) correlate soil dielectric conductivity with rice grain yield at maturity. Dielectric response of the soil samples at 20, 40, 55, and 75 days after transplanting were determined using an inductance-capacitance-resistance meter HIOKI 3522-50 LCR HiTESTER. Selected soil chemical properties and yield were determined using standard procedures. The dielectric conductivity and permittivity of the soil samples measured before transplanting the rice seedlings were higher than those for the soil samples after transplanting. This was due to the inherent nitrogen of the chicken litter biochar and the low nitrogen uptake at the transplanting stage. The soil N response increased with increasing measurement frequency and N concentration. The permittivity of the soil samples was inversely proportional to frequency but directly proportional to N concentration in the soil solution. The estimated contents of N in the soil using the dielectric conductivity approach at 1000 Hz decreased with increasing days of fertilization and the results were similar to those of soil NH4+ determined using chemical analysis. The conductivity measured within 1000 Hz and 100,000 Hz correlated positively with the rice grain yield suggesting that nitrogen concentration of the soil can be used to estimate grain yield of the cultivated rice plants.


Assuntos
Fertilizantes , Nitrogênio/química , Oryza/metabolismo , Solo/química , Agricultura , Animais , Carvão Vegetal/química , Carvão Vegetal/farmacologia , Galinhas , Grão Comestível/química , Grão Comestível/metabolismo , Nitrogênio/metabolismo , Ureia/química , Ureia/farmacologia
16.
World Neurosurg ; 152: e321-e331, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34062300

RESUMO

OBJECTIVE: Previous studies have shown that deep brain stimulation (DBS) can improve the level of consciousness of comatose patients with traumatic brain injuries (TBIs). However, the most suitable targets for DBS are unknown, and the mechanisms underlying recovery remain to be determined. The aim of the present study was to assess the effects of lateral hypothalamic area-DBS (LHA-DBS) in comatose rats with TBIs. METHODS: A total of 55 Sprague-Dawley rats were randomly assigned to 5 groups: the control group, TBI group, stimulated (TBI+LHA-DBS) group, antagonist (TBI+SB334867+LHA-DBS) group, and antagonist control (TBI+saline+LHA-DBS) group. The rats in the control group had undergone a sham operation and anesthesia, without coma induction. Coma was induced using a free-fall drop method. The rats in the stimulated group received bilateral LHA stimulation (frequency, 200 Hz; voltage, 2-4 V; pulse width, 0.1 ms) for 1 hour, with 5-minute intervals between subsequent stimulations, which were applied alternately to the left and right sides of the lateral hypothalamus. The comatose rats in the antagonist group received an intracerebroventricular injection with an orexins receptor type 1 (OX1R) antagonist (SB334867) and then received LHA-DBS. A I-VI consciousness scale and electroencephalography were used to assess the level of consciousness in each group of rats after LHA-DBS. Western blotting and immunofluorescence were used to detect OX1R expression in the LHA and α1-adrenoceptor (α1-AR) subtype and gamma-aminobutyric acid ß receptor (GABABR) expression in the prefrontal cortex. RESULTS: In the TBI, stimulated, antagonist, and antagonist control groups, 5, 10, 6, and 9 rats were awakened. The electroencephalographic readings indicated that the proportion of δ waves was lower in the stimulated group than in the TBI and antagonist groups (P < 0.05). Western blotting and immunofluorescence analysis showed that OX1R expression was greater in the stimulated group than in the TBI group (P < 0.05). The expression of α1-AR was also greater in the stimulated group than in the TBI and antagonist groups (P < 0.05). In contrast, the GABABR levels in the stimulated group were lower than those in the TBI and antagonist groups (P < 0.05). A statistically significant difference was found between the antagonist and antagonist control groups. CONCLUSIONS: Taken together, these results suggest that LHA-DBS promotes the recovery of consciousness in comatose rats with TBIs. Upregulation of α1-AR expression and downregulation of GABABR expression in the prefrontal cortex via the orexins and OX1R pathways might be involved in the wakefulness-promoting effects of LHA-DBS.


Assuntos
Lesões Encefálicas Traumáticas/psicologia , Lesões Encefálicas Traumáticas/cirurgia , Coma/psicologia , Coma/cirurgia , Estimulação Encefálica Profunda/métodos , Região Hipotalâmica Lateral/cirurgia , Orexinas/genética , Receptores Adrenérgicos alfa 1/biossíntese , Receptores de GABA/biossíntese , Transdução de Sinais/genética , Vigília , Anestesia , Animais , Benzoxazóis/farmacologia , Estado de Consciência/efeitos dos fármacos , Ritmo Delta/efeitos dos fármacos , Eletroencefalografia , Feminino , Lateralidade Funcional , Injeções Intraventriculares , Masculino , Naftiridinas/farmacologia , Receptores de Orexina/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Ureia/análogos & derivados , Ureia/farmacologia
17.
Bioorg Chem ; 112: 104940, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33965780

RESUMO

A series of novel substituted bisurea 1,4-Diisocyanatobenzene compounds were designed, synthesized and introduced as potent anticancer compounds and screened for their in vitro anti-proliferative activities in human cancer cell lines. The structures of all titled compounds were characterized using Fourier-transform infrared mass spectra, nuclear magnetic resonance spectroscopy, elemental analysis and evaluated their sustainability using biological experiments. A selected group of ten derivatives were apprised for their anti-proliferative activity. The compounds 3d and 3e displayed potent anticancer activity with low IC50 value of 5.40, and 5.89 µM against HeLa cancer cell lines. The observed apoptosis data has demonstrated that compounds 3d and 3e induce the activaties of caspase-9 and caspase-3, the compounds 3d and 3e regulated fungal zone inhibition. Due to promising growth inhibitions, the all synthesized compounds were allowed to campaign includes quantum-polarized-ligand, quantum mechanical and molecular mechanical, docking experiments. The compounds 3d and 3e have exhibited a higher affinity for ERK/MAP kinase and CDK2 proteins. The molecular docking interactions have demonstrated two stage inhibition of cancer cells by binding with ERK/MAP kinase and CDK2 leads to inactivation of cell proliferation,cell cycle progression,cell divisionanddifferentiation, and hypo-phosphorylation of ribosome leading cells to restricts at point boundary of the G1/S phase. The long-range molecular dynamics, 150 ns, simulations were also revealed more consistency by 3d. Our study conclude good binding propensity for active-tunnel of ERK/MAP kinase and CDK2 proteins, by 3d (1,1'-(1,4-phenylene) bis(3-(2-chlorobenzyl)urea)), to suggest that the designed and synthesized 3d is to use as selective novel nuclei in anti-cancer chemotherapeutics.


Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Derivados de Benzeno/farmacologia , Isocianatos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Ureia/farmacologia , Animais , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Proliferação de Células/efeitos dos fármacos , Ciclina E/antagonistas & inibidores , Ciclina E/metabolismo , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/deficiência , Quinase 2 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isocianatos/síntese química , Isocianatos/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Estrutura Molecular , Proteínas Oncogênicas/antagonistas & inibidores , Proteínas Oncogênicas/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Saccharomyces cerevisiae/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química
18.
Bioorg Chem ; 112: 104953, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33964581

RESUMO

The reaction of an alkyl or aryl isocyanates with some primary amines in acetonitrile at room temperature afforded the corresponding alkyl- and aryl-urea derivatives. All the prepared urea compounds have been elucidated by FTIR, NMR, and elemental analysis. The compounds 1 and 3 were confirmed by single-crystal X-ray diffraction. The 4-tolylsulfonyl isocyanate reacted with the aryl amines 1, 2, 3, and 2,4-dichloroaniline to afford the corresponding sulfonylurea derivatives 5-8. Likewise, the reaction of the isocyanates with 2,4-dichloroaniline, 5-methyl isoxazole-3-amine, and 2-aminothiazole derivatives gave the corresponding urea derivatives 9-17. All the prepared compounds 5-17 were tested in vitro as anti-microbial and anti-HepG2 agents. Moreover, analyzing gene expression of TP53-exon4 and TP53-exon7, DNA damage values, and DNA fragmentation percentages have been discussed. The compounds 5 and 8 recorded the highest activity against the tested microbial strains with maximum activity against C. albicans (50 mm) and B. mycoides (40 mm), respectively. The compounds 5 inhibited the growth of E. coli, S. aureus, and C. Albicans at the MIC level of 0.0489 µM, while the compound 8 was able to inhibit the visible growth of E. coli and C. albicans at MIC value of 3.13 µM and S. aureus at 0.3912 µM. In the same line, compound 5 showed the best cytotoxic activity against the HepG2 cell line (IC50 = 4.25 µM) compared to 5 fluorouracil with IC50 = 316.25 µM. Expression analysis of liver cancer related to a gene including TP53-exon4 and TP53-exon7 was used in HepG2 Liver cancer cell lines using RT-qPCR. The expression values of TP53-exon4 and TP53-exon7 genes were decreased. The DNA damage values and DNA fragmentation percentages were increased significantly (P < 0.01) in the treated HepG2 (5) sample compared with the negative control. Docking studies were performed for the synthetic compounds against 2 bacterial proteins (DNA gyrase subunit B, and penicillin binding protein 1a) that are known targets for some antibiotics, and one cell division protein kinase 2 (CDK2) as target for anticancer drugs.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Ureia/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Bacillus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Ureia/análogos & derivados , Ureia/química
19.
Sci Rep ; 11(1): 10927, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035359

RESUMO

Nitrogen source is required for the growth of Cordyceps cicadae and involved in the regulation of metabolite synthesis. In order to further investigate the regulatory effects of nitrogen sources on the ergosterol synthesis by C. cicadae. We first confirmed that urea could significantly increase the ergosterol synthesis. The transcriptome analysis showed that compared with biomass cultured in the control fermentation medium (CFM), 1340 differentially expressed genes (DEGs) were obtained by Gene Ontology (GO) annotation, and 312 DEGs were obtained by Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation from the biomass cultured in CFM + CO(NH2)2. Urea up-regulated D-3-phosphoglycerate dehydrogenase gene transcription level and down-regulated enolase and L-serine/L-threonine ammonialyase gene transcription level, increased serine synthesis, allosterically activate pyruvate kinase, to promote the synthesis of pyruvate and CH3CO ~ SCOA, the primer of ergosterol; Urea increase the genes transcription related with ergosterol synthesis by up-regulating the steroid regulatory element binding protein gene transcription levels. The transcriptome results were provided by those of qRT-PCR. Collectively, our finding provided valuable insights into the regulatory effect of nitrogen source on the ergosterol synthesis by C. cicadae.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Cordyceps/crescimento & desenvolvimento , Ergosterol/biossíntese , Ureia/farmacologia , Cordyceps/efeitos dos fármacos , Cordyceps/genética , Fermentação , Proteínas Fúngicas/genética , Perfilação da Expressão Gênica , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Fosfoglicerato Desidrogenase/genética , Fosfopiruvato Hidratase/genética
20.
J Med Chem ; 64(9): 5447-5469, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33904752

RESUMO

The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-XL, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic "p5" pocket identified in BCL-XL. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-XL. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-XL and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC50)) and displaying mechanism-based killing in cells engineered to depend on BCL-XL for survival.


Assuntos
Antineoplásicos/química , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Ureia/análogos & derivados , Proteína bcl-X/antagonistas & inibidores , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sítios de Ligação , Compostos de Bifenilo/química , Compostos de Bifenilo/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Camundongos , Simulação de Dinâmica Molecular , Nitrofenóis/química , Nitrofenóis/metabolismo , Piperazinas/química , Piperazinas/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismo , Ressonância de Plasmônio de Superfície , Ureia/metabolismo , Ureia/farmacologia , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...