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1.
J Med Food ; 24(8): 883-893, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34406877

RESUMO

During constipation, indigestible foods, such as probiotics, prebiotics, and dietary fiber, may improve the bowel environment and activity. In this randomized, double-blind, and placebo-controlled study, the effects of ID-HWS1000, composed of Lactobacillus and Bifidobacterium species, xylooligosaccharide, and dietary fiber, were evaluated to determine whether it improves the perception of bowel activity or cause changes in the gut microbiome. Thirty Korean adults with "functional constipation" according to the Rome III criteria were randomly assigned to the following groups: 20 in the ID-HWS1000 group and 10 in the placebo group. ID-HWS1000 or the placebo was consumed by the participants for 4 weeks. To assess the changes in the perception of bowel activity, clinical data and gut microbiome analyses were conducted before and after the experiment. There were significant differences between the groups in the response to 9 of the 12 survey questions (the number and duration of bowel movements, amount of feces, number of irritant bowel movements, number of times bowel movements felt incomplete, shape of the feces, amount of gas in the gut, discomfort after defecation, and discomfort owing to constipation) (P < .05). There was a decrease in the proportion of Firmicutes (Ruminococcaceae and Lachnospiraceae) and an increase in Bacteroidetes (Bacteroidaceae) (P < .05). Moreover, ID-HWS1000 directly improved the discomfort associated with bowel movements, decreased the proportion of Lachnospiraceae, and increased the proportion of Bacteroidaceae. These results confirmed that ID-HWS1000 improves the perception of bowel activity and exerts positive changes in individuals with functional constipation.


Assuntos
Microbioma Gastrointestinal , Probióticos , Adulto , Constipação Intestinal , Defecação , Método Duplo-Cego , Humanos , Percepção , Resultado do Tratamento
2.
J Med Chem ; 64(2): 958-979, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33428419

RESUMO

Janus kinase 1 (JAK1) plays a key role in most cytokine-mediated inflammatory and autoimmune responses through JAK/STAT signaling; thus, JAK1 inhibition is a promising therapeutic strategy for several diseases. Analysis of the binding modes of current JAK inhibitors to JAK isoforms allowed the design of N-alkyl-substituted 1-H-pyrrolo[2,3-b] pyridine carboxamide as a JAK1-selective scaffold, and the synthesis of various methyl amide derivatives provided 4-((cis-1-(4-chlorobenzyl)-2-methylpiperidin-4-yl)amino)-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (31g) as a potent JAK1-selective inhibitor. In particular, the (S,S)-enantiomer of 31g (38a) exhibited excellent potency for JAK1 and selectivity over JAK2, JAK3, and TYK2. On investigating the effect of 31g on hepatic fibrosis, it was found that it reduces the proliferation and fibrogenic gene expression of TGF-ß-induced hepatic stellate cells (HSCs). Specifically, 31g significantly inhibited TGF-ß-induced migration of HSCs at 0.25 µM in wound-healing assays.


Assuntos
Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular , Desenho de Fármacos , Descoberta de Drogas , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Cirrose Hepática/patologia , Camundongos , Modelos Moleculares , Relação Estrutura-Atividade , Especificidade por Substrato , Fator de Crescimento Transformador beta/antagonistas & inibidores , Cicatrização/efeitos dos fármacos
3.
Front Pharmacol ; 9: 128, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593527

RESUMO

The primary goal of rational drug discovery is the identification of selective ligands which act on single or multiple drug targets to achieve the desired clinical outcome through the exploration of total chemical space. To identify such desired compounds, computational approaches are necessary in predicting their drug-like properties. G Protein-Coupled Receptors (GPCRs) represent one of the largest and most important integral membrane protein families. These receptors serve as increasingly attractive drug targets due to their relevance in the treatment of various diseases, such as inflammatory disorders, metabolic imbalances, cardiac disorders, cancer, monogenic disorders, etc. In the last decade, multitudes of three-dimensional (3D) structures were solved for diverse GPCRs, thus referring to this period as the "golden age for GPCR structural biology." Moreover, accumulation of data about the chemical properties of GPCR ligands has garnered much interest toward the exploration of GPCR chemical space. Due to the steady increase in the structural, ligand, and functional data of GPCRs, several cheminformatics approaches have been implemented in its drug discovery pipeline. In this review, we mainly focus on the cheminformatics-based paradigms in GPCR drug discovery. We provide a comprehensive view on the ligand- and structure-based cheminformatics approaches which are best illustrated via GPCR case studies. Furthermore, an appropriate combination of ligand-based knowledge with structure-based ones, i.e., integrated approach, which is emerging as a promising strategy for cheminformatics-based GPCR drug design is also discussed.

4.
Int J Biol Macromol ; 107(Pt B): 1650-1658, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29030185

RESUMO

The DJ-1 protein engages in diverse cellular and pathological processes, including tumorigenesis, apoptosis, sperm fertilization, and the progression of Parkinson's disease (PD). The functional dimeric form of DJ-1 transforms into non-functional filamentous aggregates in an inorganic phosphate (Pi)-dependent manner in vitro. Here, we demonstrated that Pi and reactive oxygen species (ROS) induce DJ-1 aggregation in Neuro2A and SH-SY5Y cells. Remarkably, tartrate treatment significantly reduced Pi- and ROS-induced DJ-1 aggregation and restored Pi- and ROS-provoked cell death using quantitative data as mean±standard deviation, and statistics. Mechanistically, tartrate prevented DJ-1 aggregation via occupying the Pi-binding site. These findings revealed an unexpected physiological role of tartrate in the maintenance of DJ-1 function, and thus, a potential use as an inhibitor of DJ-1 aggregation.


Assuntos
Fosfatos/toxicidade , Agregados Proteicos/efeitos dos fármacos , Proteína Desglicase DJ-1/química , Tartaratos/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Peróxido de Hidrogênio/farmacologia , Corpos de Inclusão/metabolismo , Camundongos , Modelos Moleculares , Neurônios/citologia , Estresse Oxidativo/efeitos dos fármacos , Tartaratos/química
5.
Bioorg Med Chem Lett ; 27(18): 4383-4388, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28838698

RESUMO

A series of 1-substituted 3-(t-butyl/trifluoromethyl)pyrazole C-region analogues of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The structure activity relationship indicated that the 3-chlorophenyl group at the 1-position of pyrazole was the optimized hydrophobic group for antagonistic potency and the activity was stereospecific to the S-configuration, providing exceptionally potent antagonists 13S and 16S with Ki(CAP)=0.1nM. Particularly significant, 13S exhibited antagonism selective for capsaicin and NADA and not for low pH or elevated temperature. Both compounds also proved to be very potent antagonists for rTRPV1, blocking in vivo the hypothermic action of capsaicin, consistent with their in vitro mechanism. The docking study of compounds 13S and 16S in our hTRPV1 homology model indicated that the binding modes differed somewhat, with that of 13S more closely resembling that of GRT12360.


Assuntos
Mesilatos/farmacologia , Fenilpropionatos/farmacologia , Pirazóis/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Mesilatos/síntese química , Mesilatos/química , Modelos Moleculares , Estrutura Molecular , Fenilpropionatos/síntese química , Fenilpropionatos/química , Pirazóis/química , Relação Estrutura-Atividade
6.
J Med Chem ; 60(8): 3422-3437, 2017 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-28380296

RESUMO

Potent and selective A3 adenosine receptor (AR) agonists were identified by the replacement of 4'-oxo- or 4'-thionucleosides with bioisosteric selenium. Unlike previous agonists, 4'-seleno analogues preferred a glycosidic syn conformation and South sugar puckering, as shown in the X-ray crystal structure of 5'-N-methylcarbamoyl derivative 3p. Among the compounds tested, N6-3-iodobenzyl analogue 3d was found to be the most potent A3AR full agonist (Ki = 0.57 nM), which was ≥800- and 1900-fold selective for A1AR and A2AAR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA3AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N9 isomers, but compound 3t lacked A3AR activation, appearing to be a weak antagonist. 2-Cl-N6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 µM. This suggests the potential for the development of 4'-selenonucleoside A3AR agonists as novel antistroke agents.


Assuntos
Agonistas do Receptor A3 de Adenosina/farmacologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Compostos Organosselênicos/química , Adenosina/química , Agonistas do Receptor A3 de Adenosina/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Espectrometria de Massas , Modelos Moleculares , Espectroscopia de Prótons por Ressonância Magnética
7.
J Med Chem ; 60(6): 2573-2590, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28234463

RESUMO

Glutaminyl cyclase (QC) has been implicated in the formation of toxic amyloid plaques by generating the N-terminal pyroglutamate of ß-amyloid peptides (pGlu-Aß) and thus may participate in the pathogenesis of Alzheimer's disease (AD). We designed a library of glutamyl cyclase (QC) inhibitors based on the proposed binding mode of the preferred substrate, Aß3E-42. An in vitro structure-activity relationship study identified several excellent QC inhibitors demonstrating 5- to 40-fold increases in potency compared to a known QC inhibitor. When tested in mouse models of AD, compound 212 significantly reduced the brain concentrations of pyroform Aß and total Aß and restored cognitive functions. This potent Aß-lowering effect was achieved by incorporating an additional binding region into our previously established pharmacophoric model, resulting in strong interactions with the carboxylate group of Glu327 in the QC binding site. Our study offers useful insights in designing novel QC inhibitors as a potential treatment option for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminoaciltransferases/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Doença de Alzheimer/metabolismo , Aminoaciltransferases/química , Aminoaciltransferases/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Derivados de Benzeno/uso terapêutico , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular
8.
J Microbiol ; 51(3): 380-8, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23812819

RESUMO

Rhizoctonia solani has a wide host range, including almost all cultivated crops and its subgroup anastomosis group (AG)-1 IA causes sheath blight in rice. An accurate measurement of pathogen's biomass is a convincing tool for enumeration of this disease. Mycological characteristics and molecular diagnosis simultaneously supported that all six strains in this study were R. solani AG-1 IA. Heterokaryons between strains Rs40104, Rs40105, and Rs45811 were stable and viable, whereas Rs40103 and Rs40106 did not form viable fused cells, except for the combination of Rs40106 and Rs40104. A primer pair was highly specific to RsAROM gene of R. solani strains and the amplified fragment exists as double copies within fungal genome. The relationship between crossing point (CP) values and the amount of fungal DNA was reliable (R (2) >0.99). Based on these results, we determined R. solani's proliferation within infected stems through real time PCR using a primer pair and a Taqman probe specific to the RsAROM gene. The amount of fungal DNA within the 250 ng of tissue DNA from rice cv. Dongjin infected with Rs40104, Rs40105, and Rs45811 were 7.436, 5.830, and 5.085 ng, respectively. In contrast, the fungal DNAs within the stems inoculated with Rs40103 and Rs40106 were 0.091 and 0.842 ng. The sheath blight symptom progression approximately coincided with the amount of fungal DNA within the symptoms. In summary, our quantitative evaluation method provided reliable and objective results reflecting the amount of fungal biomass within the infected tissues and would be useful for evaluation of resistance germplasm or fungicides and estimation of inoculum potential.


Assuntos
Oryza/microbiologia , Rhizoctonia/genética , DNA Fúngico/genética , Genoma Fúngico/genética , Doenças das Plantas/microbiologia , Reação em Cadeia da Polimerase em Tempo Real , Rhizoctonia/patogenicidade
9.
Microbiology (Reading) ; 159(Pt 9): 1946-1955, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23842466

RESUMO

Black spot caused by Alternaria brassicicola is an important fungal disease affecting cruciferous crops, including Korean cabbage (Brassica rapa subsp. pekinensis). The interaction between Arabidopsis thaliana and Alt. brassicicola is a representative model system, and objective estimation of disease progression is indispensable for accurate functional analyses. Five strains caused black spot symptom progression on Korean cabbage and Ara. thaliana ecotype Col-0. In particular, challenge with the strains Ab44877 and Ab44414 induced severe black spot progression on Korean cabbage. Ab44877 was also highly infective on Col-0; however, the virulence of Ab44414 and the remaining strains on Col-0 was lower. To unveil the relationship between mycelial growth in the infected tissues and symptom progression, we have established a reliable quantification method using real-time PCR that employs a primer pair and dual-labelled probe specific to a unigene encoding A. brassicicola SCYTALONE DEHYDRATASE1 (AbSCD1), which is involved in fungal melanin biosynthesis. Plotting the crossing point values from the infected tissue DNA on a standard curve revealed active fungal ramification of Ab44877 in both host species. In contrast, the proliferation rate of Ab44414 in Korean cabbage was 3.8 times lower than that of Ab44877. Massive infective mycelial growth of Ab44877 was evident in Col-0; however, inoculation with Ab44414 triggered epiphytic growth rather than actual in planta ramification. Mycelial growth did not always coincide with symptom development. Our quantitative evaluation system is applicable and reliable for the objective estimation of black spot disease severity.


Assuntos
Alternaria/crescimento & desenvolvimento , Arabidopsis/microbiologia , Brassica rapa/microbiologia , Doenças das Plantas/microbiologia , Alternaria/classificação , Alternaria/genética , Alternaria/patogenicidade , Proteínas Fúngicas/genética , Micélio/classificação , Micélio/crescimento & desenvolvimento , Micélio/patogenicidade , Virulência
10.
Mol Biotechnol ; 55(1): 43-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23653313

RESUMO

Rice blast caused by Magnaporthe oryzae is a major disease in the paddy field and also a representative model system in the investigation of plant-microbe interactions. This study was undertaken to provide the quantitative evaluation method that specifically determines the amount of M. oryzae proliferation in planta. Real-time PCR was used as the detection strategy in combination with the primer pair and Taqman probe specific to MHP1, a unigene encoding HYDROPHOBIN that is indispensable for normal virulence expression. Based on the crossing point values from the PCR reactions containing a series of increasing concentration of cloned amplicon or fungal genomic DNA, correlation among the template's copy number or its amount and amplification pattern was calculated. Reliability of this equation was further confirmed using the DNA samples from the rice leaves infected with compatible or incompatible strains of M. oryzae. The primer pair used in the Taqman real-time PCR reaction can recognize the existence of fungal DNA as low as 1 pg. In sum, our quantitative evaluation system is applicable and reliable in the blast diagnosis and also in the estimation of objective blast disease progression.


Assuntos
DNA Fúngico/análise , Proteínas Fúngicas/análise , Magnaporthe/crescimento & desenvolvimento , Oryza/microbiologia , Doenças das Plantas/microbiologia , Folhas de Planta/microbiologia , Fatores de Virulência/análise , Primers do DNA , DNA Fúngico/genética , Eletroforese em Gel de Ágar , Proteínas Fúngicas/biossíntese , Proteínas Fúngicas/genética , Dosagem de Genes , Magnaporthe/patogenicidade , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Fatores de Virulência/biossíntese , Fatores de Virulência/genética
11.
J Microbiol ; 50(6): 947-54, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23274981

RESUMO

Rice brown leaf spot is a major disease in the rice paddy field. The causal agent Cochliobolus miyabeanus is an ascomycete fungus and a representative necrotrophic pathogen in the investigation of rice-microbe interactions. The aims of this research were to identify a quantitative evaluation method to determine the amount of C. miyabeanus proliferation in planta and determine the method's sensitivity. Real-time polymerase chain reaction (PCR) was employed in combination with the primer pair and Taqman probe specific to CmSCD1, a C. miyabeanus unigene encoding SCYTALONE DEHYDRATASE, which is involved in fungal melanin biosynthesis. Comparative analysis of the nucleotide sequences of CmSCD1 from Korean strains with those from the Japanese and Taiwanese strains revealed some sequence differences. Based on the crossing point (CP) values from Taqman real-time PCR containing a series of increasing concentrations of cloned amplicon or fungal genomic DNA, linear regressions with a high level of reliability (R(2)>0.997) were constructed. This system was able to estimate fungal genomic DNA at the picogram level. The reliability of this equation was further confirmed using DNA samples from both resistant and susceptible cultivars infected with C. miyabeanus. In summary, our quantitative system is a powerful alternative in brown leaf spot forecasting and in the consistent evaluation of disease progression.


Assuntos
Ascomicetos/genética , Ascomicetos/metabolismo , Hidroliases/genética , Melaninas/biossíntese , Oryza/microbiologia , Doenças das Plantas/microbiologia , Sequência de Aminoácidos , Sequência de Bases , Evolução Biológica , DNA Fúngico/genética , Hidroliases/química , Hidroliases/metabolismo , Dados de Sequência Molecular , Reação em Cadeia da Polimerase em Tempo Real , Alinhamento de Sequência
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