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1.
Adv Exp Med Biol ; 1131: 321-336, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646516

RESUMO

Ryanodine receptor calcium release channels (RyRs) play central roles in controlling intracellular calcium concentrations in excitable and non-excitable cells. RyRs are located in the sarcoplasmic or endoplasmic reticulum, intracellular Ca2+ storage compartment, and release Ca2+ during cellular action potentials or in response to other cellular stimuli. Mammalian cells express three structurally related isoforms of RyR. RyR1 and RyR2 are the major RyR isoforms in skeletal and cardiac muscle, respectively, and RyR3 is expressed in various tissues along with the other two isoforms. A prominent feature of RyRs is that the Ca2+ release channel activities of RyRs are regulated by calcium ions; therefore, intracellular Ca2+ release controls positive- and negative-feedback phenomena through the RyRs. RyR channel activities are also regulated by Ca2+ indirectly, i.e. through Ca2+ binding proteins at both cytosolic and sarco/endoplasmic reticulum luminal sides. Here, I summarize Ca2+-dependent feedback regulation of RyRs including recent progress in the structure/function aspects.


Assuntos
Cálcio , Regulação da Expressão Gênica , Canal de Liberação de Cálcio do Receptor de Rianodina , Animais , Cálcio/metabolismo , Citosol/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/química , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Relação Estrutura-Atividade
3.
Phys Chem Chem Phys ; 21(41): 22700-22703, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31579899

RESUMO

We use cold ion spectroscopy and quantum-chemical computations to solve the structures of opioid peptides enkephalins in the gas phase. The derived structural parameters clearly correlate with the known pharmacological efficiency of the studied drugs, suggesting that gas-phase methods, perhaps, can be used for predicting the relative potency of ligand drugs that target the hydrophobic pockets of receptors.


Assuntos
Encefalinas/química , Gases/química , Modelos Moleculares , Análise Espectral , Encefalinas/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neurotransmissores/química , Neurotransmissores/farmacologia , Relação Estrutura-Atividade
4.
Phys Chem Chem Phys ; 21(41): 23187-23197, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31612872

RESUMO

Carotenoids in photosynthetic proteins carry out the dual function of harvesting light and defending against photo-damage by quenching excess energy. The latter involves the low-lying, dark, excited state labelled S1. Here "dark" means optically-forbidden, a property that is often attributed to molecular symmetry, which leads to speculation that its optical properties may be strongly-perturbed by structural distortions. This has been both explicitly and implicitly proposed as an important feature of photo-protective energy quenching. Here we present a theoretical analysis of the relationship between structural distortions and S1 optical properties. We outline how S1 is dark not because of overall geometric symmetry but because of a topological symmetry related to bond length alternation in the conjugated backbone. Taking the carotenoid echinenone as an example and using a combination of molecular dynamics, quantum chemistry, and the theory of spectral lineshapes, we show that distortions that break this symmetry are extremely stiff. They are therefore absent in solution and only marginally present in even a very highly-distorted protein binding pocket such as in the Orange Carotenoid Protein (OCP). S1 remains resolutely optically-forbidden despite any breaking of bulk molecular symmetry by the protein environment. However, rotations of partially conjugated end-rings can result in fine tuning of the S1 transition density which may exert some influence on interactions with neighbouring chromophores.


Assuntos
Carotenoides/química , Fenômenos Ópticos , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade
5.
Adv Exp Med Biol ; 1172: 79-96, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628652

RESUMO

The Interleukin (IL)-10 cytokine family includes IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26, which are considered as Class 2α-helical cytokines. IL-10 is the most important cytokine in suppressing pro-inflammatory responses in all kinds of autoimmune diseases and limiting excessive immune responses. Due to protein structure homology and shared usage of receptor complexes as well as downstream signaling pathway, other IL-10 family cytokines also show indispensable functions in immune regulation, tissue homeostasis, and host defense. In this review, we focus on immune functions and structures of different cytokines in this family and try to better understand how their molecular mechanisms connect to their biological functions. The molecular details regarding their actions also provide useful information in developing candidate immune therapy reagents for a variety of diseases.


Assuntos
Interleucina-10 , Doenças Autoimunes/imunologia , Humanos , Imunoterapia , Interleucina-10/química , Interleucina-10/imunologia , Transdução de Sinais/imunologia , Relação Estrutura-Atividade
6.
Adv Exp Med Biol ; 1172: 189-205, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628657

RESUMO

Gasdermin is a recently identified family of pore-forming proteins consisting of Gasdermin A (GSDMA), Gasdermin B (GSDMB), Gasdermin C (GSDMC), Gasdermin D (GSDMD), Gasdermin E (GSDME), and DFNB59. Gasdermin D (GSDMD) is a downstream effector of inflammasomes, which are supramolecular complexes that activate inflammatory caspases (-1, -4, and -5 in human and -1 and -11 in mouse). GSDMD contains a functionally important N-terminal domain (GSDMD-N), a C-terminal domain, and a linker in between that is recognized and cleaved by the activated inflammatory caspases. Upon cleavage, the GSDMD-N fragments translocate on the membrane and oligomerize to form membrane-embedded pores after specifically binding to acidic lipids such as phosphatidylinositol phosphates (PIPs), phosphatidic acid (PA), phosphatidylserine (PS), and cardiolipin. The pore exhibits strong membrane-disrupting cytotoxicity in mammalian cells by disrupting the osmotic potential and also serves as a gate for extracellular release of mature IL-1ß and IL-18 during pyroptosis. In this chapter, we review our current understanding of GSDM proteins in physiological and pathological cell death, with more focused discussions on its structural basis for GSDM activation and pore formation.


Assuntos
Proteínas de Neoplasias , Piroptose , Animais , Caspases/metabolismo , Ativação Enzimática , Humanos , Inflamassomos , Camundongos , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Relação Estrutura-Atividade
7.
Hum Genet ; 138(10): 1183-1200, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31471722

RESUMO

The glutamate pyruvate transaminase 2 (GPT2) gene produces a nuclear-encoded mitochondrial enzyme that catalyzes the reversible transfer of an amino group from glutamate to pyruvate, generating alanine and alpha-ketoglutarate. Recessive mutations in GPT2 have been recently identified in a new syndrome involving intellectual and developmental disability (IDD), postnatal microcephaly, and spastic paraplegia. We have identified additional families with recessive GPT2 mutations and expanded the phenotype to include small stature. GPT2 loss-of-function mutations were identified in four families, nine patients total, including: a homozygous mutation in one child [c.775T>C (p.C259R)]; compound heterozygous mutations in two siblings [c.812A>C (p.N271T)/c.1432_1433delGT (p.V478Rfs*73)]; a novel homozygous, putative splicing mutation [c.1035C>T (p.G345=)]; and finally, a recurrent mutation, previously identified in a distinct family [c.1210C>T (p.R404*)]. All patients were diagnosed with IDD. A majority of patients had remarkably small stature throughout development, many < 1st percentile for height and weight. Given the potential biological function of GPT2 in cellular growth, this phenotype is strongly suggestive of a newly identified clinical susceptibility. Further, homozygous GPT2 mutations manifested in at least 2 of 176 families with IDD (approximately 1.1%) in a Pakistani cohort, thereby representing a relatively common cause of recessive IDD in this population, with recurrence of the p.R404* mutation in this population. Based on variants in the ExAC database, we estimated that approximately 1 in 248 individuals are carriers of moderately or severely deleterious variants in GPT2.


Assuntos
Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Genes Recessivos , Predisposição Genética para Doença , Mutação , Fenótipo , Transaminases/genética , Adolescente , Alelos , Substituição de Aminoácidos , Deficiências do Desenvolvimento/metabolismo , Ativação Enzimática , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Genética Populacional , Genótipo , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Imagem por Ressonância Magnética , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Modelos Moleculares , Linhagem , Conformação Proteica , Sítios de Splice de RNA , Análise de Sequência de DNA , Relação Estrutura-Atividade , Transaminases/química , Transaminases/metabolismo
8.
J Cancer Res Clin Oncol ; 145(10): 2413-2422, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31492983

RESUMO

PURPOSE: Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase that regulates centriole duplication. PLK4 deregulation causes centrosome number abnormalities, mitotic defects, chromosomal instability and, consequently, tumorigenesis. Therefore, PLK4 has emerged as a therapeutic target for the treatment of multiple cancers. In this review, we summarize the critical role of centrosome amplification and PLK4 in cancer. We also highlight recent advances in the development of PLK4 inhibitors and discuss potential combination therapies for cancer. METHODS: The relevant literature from PubMed is reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS: PLK4 is aberrantly expressed in multiple cancers and has prognostic value. Targeting PLK4 with inhibitors suppresses tumor growth in vitro and in vivo. CONCLUSIONS: PLK4 plays an important role in centrosome amplification and tumor progression. PLK4 inhibitors used alone or in combination with other drugs have shown significant anticancer efficacy, suggesting a potential therapeutic strategy for cancer. The results of relevant clinical trials await evaluation.


Assuntos
Biomarcadores Tumorais , Neoplasias/etiologia , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Centrossomo/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Especificidade de Órgãos/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
9.
Adv Exp Med Biol ; 1148: 81-103, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482495

RESUMO

Enzymes are key biological macromolecules that support life by accelerating the conversion of target molecules to desired products in many biochemical reactions. Enzymes are characterized by high affinity, specificity and great catalytic efficiency. Owing to their unique characteristics, enzymes have attracted significant attention for use in therapeutic settings as a distinct class of drugs different from other types of medicines. Enzyme-based therapies are currently in use for the treatment of a wide range of diseases, including leukemia, metabolic disorders, inflammation and cardiovascular disease. However, several challenges, such as immunogenicity and stability, remain. X-ray crystallography has provided key structural insights into the understanding of the molecular basis of diseases and development of enzyme-based therapies. Here, the role of X-ray crystallography in the development of therapeutic enzymes is examined and several examples are provided.


Assuntos
Cristalografia por Raios X , Enzimas/química , Enzimas/farmacologia , Relação Estrutura-Atividade
10.
Adv Exp Med Biol ; 1148: 115-129, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31482497

RESUMO

Therapeutic proteins are a rapidly growing class of drugs in clinical settings. The pharmacokinetics (PK) of therapeutic proteins relies on their absorption, distribution, metabolism, and excretion (ADME) properties. Moreover, the ADME properties of therapeutic proteins are impacted by their physicochemical characteristics. Comprehensive evaluation of these characteristics and their impact on ADME properties are critical to successful drug development. This chapter summarizes all relevant physicochemical characteristics and their effect on ADME properties of therapeutic proteins.


Assuntos
Proteínas/farmacologia , Proteínas/farmacocinética , Fenômenos Químicos , Proteínas/química , Relação Estrutura-Atividade
11.
J Agric Food Chem ; 67(40): 10997-11004, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31487170

RESUMO

The enantioselective bioactivity, toxicity, and environmental behaviors of isocarbophos (ICP) were investigated. The order of the bioactivity and toxicity was S-(+) ≥ rac > R-(-), and the difference of R-(-) and S-(+) was up to 232 times. The usage of S-(+)-ICP may efficiently reduce the usage amount of rac-ICP by 35% under the same effect, and the toxicity was not increased. Based on the toxic unit analysis, the additive effect and synergistic effect of ICP enantiomers were found in the four nontarget organisms, and R-(-)-ICP might cooperate the side-effects of S-(+)-ICP. The accumulation of rac-ICP in earthworms was enantioselective with an enantioenrichment of R-(-)-ICP, so the usage of racemic ICP might increase the exposure risk of R-(-)-ICP to earthworms. From the comprehensive results, the production of enantiomer enriched S-(+)-ICP might increase bioactivity and reduce environmental pollution, while the toxicity of S-(+)-ICP to other nontarget organisms needs to be further assessed.


Assuntos
Inseticidas/química , Inseticidas/toxicidade , Malation/análogos & derivados , Animais , Malation/química , Malation/toxicidade , Oligoquetos/efeitos dos fármacos , Oligoquetos/crescimento & desenvolvimento , Estereoisomerismo , Relação Estrutura-Atividade
12.
J Agric Food Chem ; 67(40): 11005-11017, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31532657

RESUMO

The limited number of agrochemicals targeting plant bacterial diseases has driven us to develop highly efficient, low-cost, and versatile antibacterial alternatives. Herein, a novel type of simple furan-functionalized quinazolin-4-amines was systematically fabricated and screened for their antibacterial activity. Bioassay results revealed that compounds C1 and E4 could substantially block the growth of two frequently mentioned pathogens Xanthomonas oryzae pv oryzae and X. axonopodis pv citri in vitro, displaying appreciable EC50 values of 7.13 and 10.3 mg/L, respectively. This effect was prominently improved by comparing those of mainly used agrochemicals. An in vivo experiment against bacterial blight further illustrated their viable applications as antimicrobial ingredients. Quantitative proteomics demonstrated that C1 possessed a remarkable ability to manipulate the upregulation and downregulation of expressed proteins, which probably involved d-glucose and biotin metabolic pathways. This finding was substantially verified by parallel reaction monitoring analysis. Scanning electron microscopy images and fluorescence spectra also indicated that the designed compounds had versatile capacities for destroying the integrity of bacteria. Given these remarkable characteristics, furan-functionalized quinazoline hybrids can serve as a viable platform for developing innovative antibiotic alternatives against bacterial infections.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Furanos/farmacologia , Quinazolinas/farmacologia , Xanthomonas/efeitos dos fármacos , Antibacterianos/síntese química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Furanos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Doenças das Plantas/microbiologia , Proteômica , Quinazolinas/química , Relação Estrutura-Atividade , Xanthomonas/genética , Xanthomonas/crescimento & desenvolvimento , Xanthomonas/metabolismo
13.
J Agric Food Chem ; 67(41): 11340-11353, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31532201

RESUMO

Inspired by quinine and its analogues, we designed, synthesized, and evaluated two series of quinoline small molecular compounds (a and 2a) and six series of quinoline derivatives (3a-f) for their antifungal activities. The results showed that compounds 3e and 3f series exhibited significant fungicidal activities. Significantly, compounds 3f-4 (EC50 = 0.41 µg/mL) and 3f-28 (EC50 = 0.55 µg/mL) displayed the superior in vitro fungicidal activity and the potent in vivo curative effect against Sclerotinia sclerotiorum. Preliminary mechanism studies showed that compounds 3f-4 and 3f-28 could cause changes in the cell membrane permeability, accumulation of reactive oxygen species, loss of mitochondrial membrane potential, and effective inhibition of germination and formation of S. sclerotiorum sclerotia. These results indicate that compounds 3f-4 and 3f-28 are novel potential fungicidal candidates against S. sclerotiorum derived from natural products.


Assuntos
Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Quinina/farmacologia , Quinolinas/farmacologia , Ascomicetos/efeitos dos fármacos , Produtos Biológicos/química , Desenho de Drogas , Fungicidas Industriais/química , Estrutura Molecular , Quinina/química , Quinolinas/química , Relação Estrutura-Atividade
14.
J Agric Food Chem ; 67(41): 11354-11363, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31532666

RESUMO

A series of dehydrozingerone derivatives were synthesized, and their fungicidal activities and action mechanism against Colletotrichum musae were evaluated. The bioassay result showed that most compounds exhibited excellent fungicidal activity in vitro at 50 µg mL-1. Compounds 13, 16, 18, 19, and 27 exhibited broad-spectrum fungicidal activity; especially, compounds 19 and 27 were found to have more potent fungicidal activity than azoxystrobin. The EC50 values of compounds 19 and 27 against Rhizoctonia solani were 0.943 and 0.161 µg mL-1 respectively. Moreover, compound 27 exhibited significant in vitro bactericidal activity against Xanthomonas oryzae pv. oryzae, with an EC50 value of 11.386 µg mL-1, and its curative effect (49.64%) and protection effect (51.74%) on rice bacterial blight disease was equivalent to that of zhongshengmycin (42.90%, 40.80% respectively). Compound 27 could also effectively control gray mold (87.10%, 200 µg mL-1) and rice sheath blight (100%, 200 µg mL-1; 82.89%, 100 µg mL-1) in vivo. Preliminary action mechanism study showed that compound 27 mainly acted on the cell membrane and significantly inhibited ergosterol biosynthesis in Colletotrichum musae.


Assuntos
Ergosterol/antagonistas & inibidores , Fungicidas Industriais/síntese química , Fungicidas Industriais/farmacologia , Estirenos/síntese química , Estirenos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Colletotrichum/efeitos dos fármacos , Colletotrichum/metabolismo , Ergosterol/biossíntese , Fungicidas Industriais/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oryza/microbiologia , Doenças das Plantas/microbiologia , Rhizoctonia/efeitos dos fármacos , Rhizoctonia/metabolismo , Relação Estrutura-Atividade , Estirenos/química , Xanthomonas/efeitos dos fármacos , Xanthomonas/metabolismo
15.
Chem Soc Rev ; 48(20): 5242-5265, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31549709

RESUMO

The formal replacement of one dialkylamino group in rhodamines with a hydroxyl group transforms them into rhodols. This apparently minor difference is not as small as one may think; rhodamines belong to the cyanine family whereas rhodols belong to merocyanines. Discovered in the late 19th century, rhodols have only very recently begun to gain momentum in the field of advanced fluorescence imaging. This is in part due to the increased understanding of their photophysical properties, and new methods of synthesis. Rationalization of how the nature and arrangement of polar substituents around the core affect the photophysical properties of rhodols is now possible. The emergence of so-called π-expanded and heteroatom-modified rhodols has also allowed their fluorescence to be bathochromically shifted into regions applicable for biological imaging. This review serves to outline applicable synthetic strategies for the synthesis of rhodols, and to highlight important structure-property relationships. In the first part of this Review, various synthetic methods leading to rhodols are presented, followed by structural considerations and an overview of photophysical properties. The second part of this review is entirely devoted to the applications of rhodols as fluorescent reporters in biological imaging.


Assuntos
Corantes Fluorescentes/química , Xantonas/química , Corantes Fluorescentes/síntese química , Estrutura Molecular , Processos Fotoquímicos , Relação Estrutura-Atividade , Xantonas/síntese química
16.
J Agric Food Chem ; 67(42): 11598-11606, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31560195

RESUMO

A total of 22 quinazoline thioether derivatives incorporating a 1,2,4-triazolo[4,3-a]pyridine moiety were designed, synthesized, and evaluated as antimicrobial agents in agriculture. Among these compounds, the chemical structure of compound 6l was further confirmed via single-crystal X-ray diffraction analysis. The bioassay results revealed that some of the compounds possessed noticeable in vitro antibacterial activities against the tested phytopathogenic bacteria. For example, compounds 6b and 6g had EC50 values as low as 10.0 and 24.7 µg/mL against Xanthomonas axonopodis pv. citri (Xac), respectively, which were significantly better than that of the commercial agrobactericide bismerthiazol (56.9 µg/mL). Particularly, compound 6b was also found to be capable of suppressing the pathogenic bacterium Xanthomonas oryzae pv. oryzae (Xoo) approximately 12-fold more potent than control bismerthiazol, in terms of their EC50 values (7.2 versus 89.8 µg/mL). Importantly, the most active compound 6b turned out to be one with the highest hydrophilicity and the lowest molecular weight within the series. In vivo bioassays further showed the application prospect of 6b as a promising plant bactericide for controlling Xoo. Additionally, in vitro antifungal activities of these compounds were also evaluated at the concentration of 50 µg/mL. Overall, the present study demonstrated the potential of 1,2,4-triazolo[4,3-a]pyridine-bearing quinazoline thioether derivatives as efficient agricultural antibacterial agents for crop protection.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Sulfetos/química , Sulfetos/farmacologia , Agroquímicos/química , Agroquímicos/farmacologia , Antibacterianos/síntese química , Desenho de Drogas , Piridinas/química , Relação Estrutura-Atividade , Xanthomonas/efeitos dos fármacos
17.
Chem Biodivers ; 16(10): e1900391, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31479201

RESUMO

A series of novel 2-oxoimidazolidine derivatives were synthesized and their antiviral activities against BK human polyomavirus type 1 (BKPyV) were evaluated in vitro. Bioassays showed that the synthesized compounds 1-{[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfamoyl}piperidine-4-carboxylic acid (5) and N-Cyclobutyl-N'-[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfuric diamide (4) exhibited moderate activities against BKPyV (EC50 =5.4 and 5.5 µm, respectively) that are comparable to the standard drug Cidofovir. Compound 5 exhibited the same cytotoxicity in HFF cells and selectivity index (SI50 ) as Cidofovir. The selectivity index of compound 4 is three times less than that of Cidofovir due to the higher toxicity of this compound. Hence, these compounds may be taken as lead compound for further development of novel ant-BKPyV agents.


Assuntos
Antivirais/farmacologia , Vírus BK/efeitos dos fármacos , Cidofovir/farmacologia , Desenho de Drogas , Imidazolidinas/farmacologia , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cidofovir/química , Relação Dose-Resposta a Droga , Humanos , Imidazolidinas/síntese química , Imidazolidinas/química , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
18.
Chem Biodivers ; 16(10): e1900347, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31532890

RESUMO

Catechins in green tea are well-known to be effective in reducing the risk of obesity. The purpose of this study was to elucidate the effects of catechins present in green tea on adipocyte differentiation and mature adipocyte metabolism. Treatment of 3T3-L1 mouse adipocyte during differentiation adipocytes with (-)-epigallocatechin (EGC) and gallic acid (GA) resulted in dose-dependent inhibition of adipogenesis. Specifically, EGC increased adiponectin and uncoupling protein 1 (UCP1) transcription in mature adipocytes. Transcription levels of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) were not significantly impacted by either of the compounds. These results suggest that the EGC is the most effective catechin having anti-obesity activity. Finally, EGC is an attractive candidate component for remodeling obesity.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Catequina/análogos & derivados , Células 3T3-L1 , Tecido Adiposo Marrom/metabolismo , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Catequina/química , Catequina/isolamento & purificação , Catequina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Chá/química
19.
J Agric Food Chem ; 67(39): 10844-10852, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31525997

RESUMO

The discovery of 4-hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) inhibitors has been an active area of research due to their great potential as herbicides for weed control. Starting from the binding mode of known inhibitors of HPPD, a series of HPPD inhibitors with new molecular scaffolds were designed and synthesized by hybridizing 2-benzoylethen-1-ol and isoindoline-1,3-dione fragments. The results of the in vitro tests indicated that the newly synthesized compounds showed good HPPD inhibitory activity with IC50 values against the recombinant Arabidopsis thaliana HPPD (AtHPPD) ranging from 0.0039 µM to over 1 µM. Most promisingly, compound 4ae, 2-benzyl-5-(5-hydroxy-1,3-dimethyl-1H-pyrazole-4- carbonyl)isoindoline-1,3-dione, showed the highest AtHPPD inhibitory activity with a Ki value of 3.92 nM, making it approximately 10 times more potent than pyrasulfotole (Ki = 44 nM) and slightly more potent than mesotrione (Ki = 4.56 nM). In addition, the cocrystal structure of the AtHPPD-4ae complex was successfully resolved at a resolution of 1.8 Å. The X-ray diffraction analysis indicated that the two carbonyl groups of 2-benzoylethen-1-ol formed a bidentate chelating interaction with the metal ion, while the isoindoline-1,3-dione moiety formed pronounced π-π stacking interactions with Phe381 and Phe424. Moreover, water-mediated hydrogen bonding interactions were observed between Asn282 and the nitrogen atoms of the pyrazole ring of 4ae. The above results showed that the pyrazole-isoindoline-1,3-dione hybrid is a promising scaffold for developing HPPD inhibitors.


Assuntos
4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Herbicidas/farmacologia , Isoindóis/farmacologia , Proteínas de Plantas/antagonistas & inibidores , Pirazóis/farmacologia , 4-Hidroxifenilpiruvato Dioxigenase/química , 4-Hidroxifenilpiruvato Dioxigenase/metabolismo , Arabidopsis/efeitos dos fármacos , Arabidopsis/crescimento & desenvolvimento , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Herbicidas/síntese química , Herbicidas/química , Isoindóis/química , Cinética , Estrutura Molecular , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/crescimento & desenvolvimento , Pirazóis/química , Relação Estrutura-Atividade
20.
Physiol Rev ; 99(4): 2015-2113, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31507243

RESUMO

Na+/H+ exchangers play pivotal roles in the control of cell and tissue pH by mediating the electroneutral exchange of Na+ and H+ across cellular membranes. They belong to an ancient family of highly evolutionarily conserved proteins, and they play essential physiological roles in all phyla. In this review, we focus on the mammalian Na+/H+ exchangers (NHEs), the solute carrier (SLC) 9 family. This family of electroneutral transporters constitutes three branches: SLC9A, -B, and -C. Within these, each isoform exhibits distinct tissue expression profiles, regulation, and physiological roles. Some of these transporters are highly studied, with hundreds of original articles, and some are still only rudimentarily understood. In this review, we present and discuss the pioneering original work as well as the current state-of-the-art research on mammalian NHEs. We aim to provide the reader with a comprehensive view of core knowledge and recent insights into each family member, from gene organization over protein structure and regulation to physiological and pathophysiological roles. Particular attention is given to the integrated physiology of NHEs in the main organ systems. We provide several novel analyses and useful overviews, and we pinpoint main remaining enigmas, which we hope will inspire novel research on these highly versatile proteins.


Assuntos
Equilíbrio Ácido-Base , Trocadores de Sódio-Hidrogênio/metabolismo , Animais , Evolução Molecular , Regulação da Expressão Gênica , Humanos , Conformação Proteica , Trocadores de Sódio-Hidrogênio/química , Trocadores de Sódio-Hidrogênio/genética , Relação Estrutura-Atividade , Distribuição Tecidual
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