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1.
Environ Res ; 252(Pt 1): 118839, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38570131

RESUMO

Weeds pose multifaceted challenges in rice cultivation, leading to substantial economic losses through reduced yield and poor grain quality. Harnessing the natural genetic diversity in germplasm collections becomes crucial for identifying novel herbicide resistance loci in crops. A comprehensive analysis was conducted on 475 rice accessions from the KRICE depository, assessing their response to TFT (tefuryltrione) and probing the underlying HIS1 (HPPD INHIBITOR SENSITIVE 1) genotypic variations. The HIS1 gene, responsible for detoxifying benzobicyclon (BBC) and imparting broad-spectrum herbicide resistance, holds significant promise in rice breeding. This study explores the genetic landscape of HIS1 within Korean rice collection (KRICE), aiming to unveil genetic variations, haplotype diversity, and evolutionary relationships across diverse rice ecotypes. The indica ecotype showed the highest nucleotide diversity, while the wild and temperate japonica groups exhibited low diversity, hinting at selective sweeps and possible population expansion. Negative Tajima's D values in temperate japonica and wild groups indicate an excess of low-frequency mutations, potentially resulting from selective sweeps. In contrast, with positive Tajima's D values, admixture, indica, and aus groups suggest balancing selection. Furthermore, haplotype analysis uncovered 42 distinct haplotypes within KRICE, with four shared haplotypes between cultivated and wild accessions, four specific to cultivated accessions, and 34 specific to wild types. Phenotypic assessments of these haplotypes revealed that three haplotypes, viz., Hap_1 (predominant in japonica), Hap_2 (predominant in indica), and Hap_3 (specific to indica), displayed significant differences from aus-specific Hap_4 and indica-specific Hap_5. This study offers insights into genetic diversity, selective pressures, and ecotype-specific responses, ultimately paving the way for developing HPPD-inhibiting herbicide-resistant rice cultivars.


Assuntos
Variação Genética , Haplótipos , Herbicidas , Oryza , Oryza/genética , Resistência a Herbicidas/genética , Evolução Molecular
2.
Antioxidants (Basel) ; 13(2)2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38397832

RESUMO

Gamma-tocopherol methyltransferase (γ-TMT), a key gene in the vitamin E biosynthesis pathway, significantly influences the accumulation of tocochromanols, thereby determining rice nutritional quality. In our study, we analyzed the γ-TMT gene in 475 Korean rice accessions, uncovering 177 genetic variants, including 138 SNPs and 39 InDels. Notably, two functional SNPs, tmt-E2-28,895,665-G/A and tmt-E4-28,896,689-A/G, were identified, causing substitutions from valine to isoleucine and arginine to glycine, respectively, across 93 accessions. A positive Tajima's D value in the indica group suggests a signature of balancing selection. Haplotype analysis revealed 27 haplotypes, with two shared between cultivated and wild accessions, seven specific to cultivated accessions, and 18 unique to wild types. Further, profiling of vitamin E isomers in 240 accessions and their association with haplotypes revealed that Hap_2, distinguished by an SNP in the 3' UTR (tmt-3UTR-28,897,360-T/A) exhibited significantly lower α-tocopherol (AT), α-tocotrienol (AT3), total tocopherol, and total tocotrienol, but higher γ-tocopherol (GT) in the japonica group. Additionally, in the indica group, Hap_2 showed significantly higher AT, AT3, and total tocopherol, along with lower GT and γ-tocotrienol, compared to Hap_19, Hap_20, and Hap_21. Overall, this study highlights the genetic landscape of γ-TMT and provides a valuable genetic resource for haplotype-based breeding programs aimed at enhancing nutritional profiles.

3.
Mar Drugs ; 21(10)2023 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-37888466

RESUMO

Prolonged thymic involution results in decreased thymopoiesis and thymic output, leading to peripheral T-cell deficiency. Since the thymic-dependent pathway is the only means of generating fully mature T cells, the identification of strategies to enhance thymic regeneration is crucial in developing therapeutic interventions to revert immune suppression in immunocompromised patients. The present study clearly shows that fish collagen peptides (FCPs) stimulate activities of thymic epithelial cells (TECs), including cell proliferation, thymocyte adhesion, and the gene expression of thymopoietic factors such as FGF-7, IGF-1, BMP-4, VEGF-A, IL-7, IL-21, RANKL, LTß, IL-22R, RANK, LTßR, SDF-1, CCL21, CCL25, CXCL5, Dll1, Dll4, Wnt4, CD40, CD80, CD86, ICAM-1, VCAM-1, FoxN1, leptin, cathepsin L, CK5, and CK8 through the NF-κB signal transduction pathway. Furthermore, our study also revealed the cytoprotective effects of FCPs on TECs against cyclophosphamide-induced cellular injury through the NF-κB signaling pathway. Importantly, FCPs exhibited a significant capability to facilitate thymic regeneration in mice after cyclophosphamide-induced damage via the NF-κB pathway. Taken together, this study sheds light on the role of FCPs in TEC function, thymopoiesis, and thymic regeneration, providing greater insight into the development of novel therapeutic strategies for effective thymus repopulation for numerous clinical conditions in which immune reconstitution is required.


Assuntos
NF-kappa B , Timócitos , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Citoproteção , Timo , Células Epiteliais , Colágeno/metabolismo , Expressão Gênica , Proliferação de Células , Ciclofosfamida/efeitos adversos
4.
Front Plant Sci ; 14: 1225445, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37560030

RESUMO

Early season flooding is a major constraint in direct-seeded rice, as rice genotypes vary in their coleoptile length during anoxia. Trehalose-6-phosphate phosphatase 7 (OsTPP7, Os09g0369400) has been identified as the genetic determinant for anaerobic germination (AG) and coleoptile elongation during flooding. We evaluated the coleoptile length of a diverse rice panel under normal and flooded conditions and investigated the Korean rice collection of 475 accessions to understand its genetic variation, population genetics, evolutionary relationships, and haplotypes in the OsTPP7 gene. Most accessions displayed enhanced flooded coleoptile lengths, with the temperate japonica ecotype exhibiting the highest average values for normal and flooded conditions. Positive Tajima's D values in indica, admixture, and tropical japonica ecotypes suggested balancing selection or population expansion. Haplotype analysis revealed 18 haplotypes, with three in cultivated accessions, 13 in the wild type, and two in both. Hap_1 was found mostly in japonica, while Hap-2 and Hap_3 were more prevalent in indica accessions. Further phenotypic performance of major haplotypes showed significant differences in flooded coleoptile length, flooding tolerance index, and shoot length between Hap_1 and Hap_2/3. These findings could be valuable for future selective rice breeding and the development of efficient haplotype-based breeding strategies for improving flood tolerance.

5.
Antioxidants (Basel) ; 12(8)2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37627582

RESUMO

Liver fibrosis, defined by the aberrant accumulation of extracellular matrix proteins in liver tissue due to chronic inflammation, represents a pressing global health issue. In this study, we investigated the transcriptomic signatures of three independent liver fibrosis models induced by bile duct ligation, carbon tetrachloride, and dimethylnitrosamine (DMN) to unravel the pathological mechanisms underlying hepatic fibrosis. We observed significant changes in gene expression linked to key characteristics of liver fibrosis, with a distinctive correlation to the burn-wound-healing pathway. Building on these transcriptomic insights, we further probed the p53 signaling pathways within the DMN-induced rat liver fibrosis model, utilizing western blot analysis. We observed a pronounced elevation in p53 protein levels and heightened ratios of BAX/BCL2, cleaved/pro-CASPASE-3, and cleaved/full length-PARP in the livers of DMN-exposed rats. Furthermore, we discovered that orally administering oligonol-a polyphenol, derived from lychee, with anti-oxidative properties-effectively countered the overexpressions of pivotal apoptotic genes within these fibrotic models. In conclusion, our findings offer an in-depth understanding of the molecular alterations contributing to liver fibrosis, spotlighting the essential role of the apoptosis pathway tied to the burn-wound-healing process. Most importantly, our research proposes that regulating this pathway, specifically the balance of apoptosis, could serve as a potential therapeutic approach for treating liver fibrosis.

6.
Sci Total Environ ; 902: 165779, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37495147

RESUMO

Understanding the temporal behaviors of naturally occurring radioactive materials is important for safeguarding groundwater as a secure water resource for drinking, agriculture, and industry usage. This study reports the vertical profiles of 238U concentration and 222Rn activity and the management of in situ monitoring systems during intensive field sampling of a national groundwater-monitoring borehole for seven years (2015-2021). The aim was to capture the seasonal characteristics of the 238U concentrations and 222Rn activity. Both factors were low in the rainy season and high in the winter season, reflecting the dilution effect of rainfall recharge. The 238U and 222Rn behaviors were associated with water-rock interactions of calcite dissolution in fracture zones filled with carbonate minerals. Furthermore, multilayer perceptron models estimated the 238U concentration and 222Rn activity with reasonable regression and classification accuracy. Hydrometeorological indicators (temperature and groundwater-level fluctuations) were more important estimators of 238U concentration and 222Rn activity than geochemical process indicators. The regression accuracy performance was higher at deeper sampling depths, where seasonality in the 238U and 222Rn behaviors dominated. From the predicted distributions of 238U concentrations and 222Rn activities, we could estimate the ranges of 238U concentrations and 222Rn activities emerging from groundwater boreholes. High exposure threats from 238U and 222Rn during groundwater usage were found in the winter season. When the multilayer perceptron models use the entire in situ monitoring data at refined temporal resolution, we can quickly determine the naturally occurring radioactive materials and further develop the national groundwater-monitoring borehole equipped with the in-situ monitoring system, supplementing the occasionally obtained field-measurement data.

7.
Int J Mol Sci ; 24(8)2023 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-37108064

RESUMO

Oxidative stress plays a critical role in the development of liver disease, making antioxidants a promising therapeutic approach for the prevention and management of liver injuries. The aim of this study was to investigate the hepatoprotective effects of kaempferol, an antioxidant flavonoid found in various edible vegetables, and its underlying mechanism in male Sprague-Dawley rats with carbon tetrachloride (CCl4)-induced acute liver damage. Oral administration of kaempferol at doses of 5 and 10 mg/kg body weight resulted in the amelioration of CCl4-induced abnormalities in hepatic histology and serum parameters. Additionally, kaempferol decreased the levels of pro-inflammatory mediators, TNF-α and IL-1ß, as well as COX-2 and iNOS. Furthermore, kaempferol suppressed nuclear factor-kappa B (NF-κB) p65 activation, as well as the phosphorylation of Akt and mitogen-activated protein kinase members (MAPKs), including extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 in CCl4-intoxicated rats. In addition, kaempferol improved the imbalanced oxidative status, as evidenced by the reduction in reactive oxygen species levels and lipid peroxidation, along with increased glutathione content in the CCl4-treated rat liver. Administering kaempferol also enhanced the activation of nuclear factor-E2-related factor (Nrf2) and heme oxygenase-1 protein, as well as the phosphorylation of AMP-activated protein kinase (AMPK). Overall, these findings suggest that kaempferol exhibits antioxidative, anti-inflammatory, and hepatoprotective effects through inhibiting the MAPK/NF-κB signaling pathway and activating the AMPK/Nrf2 signaling pathway in CCl4-intoxicated rats.


Assuntos
Hepatopatias , NF-kappa B , Ratos , Masculino , Animais , NF-kappa B/metabolismo , Tetracloreto de Carbono/toxicidade , Proteínas Quinases Ativadas por AMP/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Quempferóis/farmacologia , Quempferóis/uso terapêutico , Quempferóis/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Hepatopatias/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fígado/metabolismo , Estresse Oxidativo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo
8.
Mar Drugs ; 20(4)2022 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-35447905

RESUMO

Thymic epithelial cells (TECs) account for the most abundant and dominant stromal component of the thymus, where T cells mature. Oxidative- or cytotoxic-stress associated injury in TECs, a significant and common problem in many clinical settings, may cause a compromised thymopoietic capacity of TECs, resulting in clinically significant immune deficiency disorders or impairment in the adaptive immune response in the body. The present study demonstrated that fish collagen peptides (FCP) increase cell viability, reduce intracellular levels of reactive oxygen species (ROS), and impede apoptosis by repressing the expression of Bax and Bad and the release of cytochrome c, and by upregulating the expression of Bcl-2 and Bcl-xL in cisplatin-treated TECs. These inhibitory effects of FCP on TEC damage occur via the suppression of ROS generation and MAPK (p38 MAPK, JNK, and ERK) activity. Taken together, our data suggest that FCP can be used as a promising protective agent against cytotoxic insults- or ROS-mediated TEC injury. Furthermore, our findings provide new insights into a therapeutic approach for the future application of FCP in the prevention and treatment of various types of oxidative- or cytotoxic stress-related cell injury in TECs as well as age-related or acute thymus involution.


Assuntos
Cisplatino , Estresse Oxidativo , Animais , Apoptose , Cisplatino/farmacologia , Colágeno/metabolismo , Células Epiteliais , Sistema de Sinalização das MAP Quinases , Camundongos , Peptídeos/metabolismo , Peptídeos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Chem Biol Drug Des ; 98(5): 733-750, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34310065

RESUMO

Type 2 diabetes is characterized by chronic hyperglycemia. Insulin, a hormone secreted from pancreatic ß-cells, decreases blood glucose levels, and glucagon, a hormone secreted from pancreatic α-cells, increases blood glucose levels by counterregulation of insulin through stimulation of hepatic glucose production. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, inhibition of the glucagon receptor is one strategy for the treatment of hyperglycemia in type 2 diabetes. In this paper, we report a series of biphenylsulfonamide derivatives that were designed, synthesized, and then evaluated by cAMP and hepatic glucose production assays as glucagon receptor antagonists. Of these, compound 7aB-3 decreased glucagon-induced cAMP production and glucagon-induced glucose production in the in vitro assays. Glucagon challenge tests and glucose tolerance tests showed that compound 7aB-3 significantly inhibited glucagon-induced glucose increases and improved glucose tolerance. These results suggest that compound 7aB-3 has therapeutic potential for the treatment of type 2 diabetes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/síntese química , Receptores de Glucagon/antagonistas & inibidores , Sulfonamidas/síntese química , Animais , Diabetes Mellitus Experimental , Glucagon/metabolismo , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/farmacologia
10.
Antioxidants (Basel) ; 10(3)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33671028

RESUMO

Oligonol is a low molecular weight polyphenol product derived from lychee fruit by a manufacturing process. We investigated oligonol's anti-fibrotic effect and the underlying mechanism in dimethylnitrosamine (DMN)-induced chronic liver damage in male Sprague-Dawley rats. Oral administration of oligonol (10 and 20 mg/kg body weight) ameliorated the DMN-induced abnormalities in liver histology and serum parameters in rats. Oligonol prevented the DMN-induced elevations of TNF-α, IL-1ß, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase expressions at the mRNA level. NF-κB activation and JNK phosphorylation in DMN-treated rats were ablated by oligonol. Oligonol reduced the enhanced production of hepatic malondialdehyde and reactive oxygen species and recovered protein SH, non-protein SH levels, and catalase activity in the DMN treated liver. Nrf2 translocation into the nucleus was enhanced, and PI3K and phosphorylated Akt levels were increased by administering oligonol. The level of hepatic fibrosis-related factors such as α-smooth muscle actin, transforming growth factor-ß1, and type I collagen was reduced in rats treated with oligonol. Histology and immunohistochemistry analysis showed that the accumulation of collagen and activation of hepatic stellate cells (HSCs) in liver tissue were restored by oligonol treatment. Taken together, oligonol showed antioxidative, hepatoprotective, and anti-fibrotic effects via JNK/NF-κB and PI3K/Akt/Nrf2 signaling pathways in DMN-intoxicated rats. These results suggest that antioxidant oligonol is a potentially useful agent for the protection against chronic liver injury.

11.
PLoS One ; 15(7): e0236139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32667944

RESUMO

In this study, we suggested a hypothesis test method that was robust to different genotype encodings in a genome-wide association analysis of continuous traits. When the population stratification is corrected for using a method based on principal component analysis, ordinally (or categorically) encoded genotypes are adjusted and turn into continuous values. Due to the adjustment of the encoded genotype, the association test result using conventional methods, such as the test of Pearson's correlation coefficient, was shown to be dependent on how genotypes were encoded. To overcome this shortcoming, we proposed a non-parametric test based on Kendall's tau. Because Kendall's tau deals with rank, rather than value, associations between adjusted genotype and phenotype values, Kendall's test can be more robust than Pearson's test under different genotype encodings. We assessed the robustness of Kendall's test and compared with that of Pearson's test in terms of the difference in p-values obtained by using different genotype encodings. With simulated as well as real data set, we demonstrated that Kendall's test was more robust than Pearson's test under different genotype encodings. The proposed method can be applicable to the broad topics of interest in population genetics and comparative genomics, in which novel genetic variants are associated with traits. This study may also bring about a cautious approach to the genotype encoding in the numerical analysis.


Assuntos
Algoritmos , Genoma de Planta , Genótipo , Oryza/genética , Fenótipo , Proteínas de Plantas/genética , Estudos de Associação Genética , Estudo de Associação Genômica Ampla
12.
Comput Biol Chem ; 87: 107278, 2020 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-32563074

RESUMO

Motivated by the characteristics of highly clustered single nucleotide polymorphism (SNP) across the human genome, we propose a set of chromosome-wise fractal dimensions as a measure for identifying an individual for human polymorphism. The fractal dimension quantifies the degree of clustered distribution of SNPs and represents parsimoniously the genetic variation in a chromosome. In this sense, the proposed scheme projects the SNP genotype data into a new space which is simpler and lower in dimension. As an illustrative example, we estimate the chromosome-wise fractal dimensions of SNPs that are extracted from the HapMap of Phase III data set. To determine the validity of the proposed measure, we apply principal component analysis (PCA) to the set of estimated fractal dimensions and demonstrate that the set more or less described the population structure of 11 global populations. We also use multidimensional scaling to relate the genetic distances based on PCA to the geographical distances between global populations. This shows that, similar to the SNP genotype data, the fractal dimensions also has a role in genetic distance in the population structure. In addition, we apply the proposed measure to a signature for the classification of global populations by developing a support vector machine model. The selected feature model predicts the global population with a balanced accuracy of about 77%. These results support that the fractal dimension is an efficient way to describe the genetic variation of global populations.

13.
Lab Anim Res ; 35: 30, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32257917

RESUMO

Signal transducer and activator of transcription 3 (STAT3) modulates a variety of genes involved in the regulation of critical functions, including cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, and immunity. For many cancers, elevated levels of STAT3 signaling have been associated with a poor prognosis and the development of chemotherapy resistance. In this study, we investigated the inhibitory effects of a novel small-molecule inhibitor of STAT3, STX-0119, on the cell viability and survival of human lung cancer cells. STX-0119 inhibited activated STAT3 and the expression of STAT3-regulated oncoproteins such as c-Myc, cyclin D1, and survivin in lung cancer cells. STX-0119 also decreased the amount of STAT3 in the nuclear fraction as well as induced apoptosis of these lung cancer cell lines as evidenced by increases in apoptotic cells (Annexin V positive) and poly (ADP-ribose) polymerase (PARP) cleavage. The efficacy of STX-0119 in a mouse xenograft model was confirmed. However, a hematological side effect, which had not been previously reported, was observed. The level of white blood cells was significantly lowered when treated at the dose at which STX-0119 alone showed a significant tumor-suppressive effect. In conclusion, we suggest that STX-0119 may be a potent therapeutic agent against lung cancer. Consideration of the side effect suggests, it is necessary to study whether low-dose STX-0119 is effective for lung treatment with a combination of classic lung cancer therapeutics.

14.
Bioorg Med Chem ; 26(21): 5701-5710, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30366787

RESUMO

The hormone glucagon increases blood glucose levels through increasing hepatic glucose output. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, the inhibition of glucagon receptor is one target for the treatment of hyperglycemia in type 2 diabetes. Here we designed and synthesized a series of small molecules based on phenylpyrimidine. Of these, the compound (R)-7a most significantly decreased the glucagon-induced cAMP production and glucagon-induced glucose production during in vitro and in vivo assays. In addition, (R)-7a showed good efficacy in glucagon challenge tests and lowered blood glucose levels in diabetic db/db mice. Our results suggest that the compound (R)-7a could be a potential glucose-lowering agent for treating type 2 diabetes.


Assuntos
Hipoglicemiantes/uso terapêutico , Pirimidinas/uso terapêutico , Receptores de Glucagon/antagonistas & inibidores , Animais , Glicemia/análise , Glicemia/metabolismo , Células CHO , Cricetulus , AMP Cíclico/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/toxicidade , Masculino , Camundongos Endogâmicos C57BL , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , Estereoisomerismo
15.
Sci Rep ; 8(1): 13832, 2018 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-30218055

RESUMO

Osteoarthritis (OA) is a major degenerative joint condition that causes articular cartilage destruction. It was recently found that enhancement of chondroclasts and suppression in Treg cell differentiation are involved in the pathogenesis of OA. Kartogenin (KGN) is a small drug-like molecule that induces chondrogenesis in mesenchymal stem cells (MSCs). This study aimed to identify whether KGN can enhance severe pain behavior and improve cartilage repair in OA rat model. Induction of OA model was loaded by IA-injection of MIA. In the OA rat model, treatment an intra-articular injection of KGN. Pain levels were evaluated by analyzing PWL and PWT response in animals. Histological analysis and micro-CT images of femurs were used to analyze cartilage destruction. Gene expression was measured by real-time PCR. Immunohistochemistry was analyzed to detect protein expression. KGN injection significantly decreased pain severity and joint destruction in the MIA-induced OA model. KGN also increased mRNA levels of the anti-inflammatory cytokine IL-10 in OA patients' chondrocytes stimulated by IL-1ß. Decreased chondroclast expression, and increased Treg cell expression. KGN revealed therapeutic activity with the potential to reduce pain and improve cartilage destruction. Thus, KGN could be a therapeutic molecule for OA that inhibits cartilage damage.


Assuntos
Anilidas/farmacologia , Condrócitos/efeitos dos fármacos , Osteoartrite/tratamento farmacológico , Ácidos Ftálicos/farmacologia , Anilidas/metabolismo , Animais , Cartilagem/efeitos dos fármacos , Cartilagem Articular/patologia , Celecoxib/farmacologia , Condrócitos/metabolismo , Condrogênese , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/patologia , Injeções Intra-Articulares , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Masculino , Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos DBA , Camundongos Knockout , Osteoartrite/patologia , Dor/tratamento farmacológico , Manejo da Dor/métodos , Ácidos Ftálicos/metabolismo , Ratos , Ratos Wistar
16.
Free Radic Biol Med ; 124: 232-240, 2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-29898414

RESUMO

Bilirubin (BR) is generated by the reduction of biliverdin (BV), a metabolite that results from the catalytic degradation of heme by the isoforms of heme oxygenase (HO). BV is nontoxic and water-soluble but BR is potentially toxic and lipophilic. Therefore, a further metabolic step is required for BR before excretion is possible. The reductive conversion of BV to BR costs energy and is evolutionarily conserved in human physiology. There must be a compelling reason for this apparently nonsensical evolutionary conservation. In addition to the differences between BR and BV-such as water solubility, antioxidant activity, and participation as a receptor ligand-in the present study, we focused on the chemistry of the two metabolites with regard to an electrophilic functional group called a Michael reaction acceptor (MRA). Our data reveal that the BR reacts with thiol compounds forming adducts, whereas no reaction occurs with BV. Furthermore, the binding of biotin-tagged BR to Kelch-like ECH-associated protein 1 (KEAP1)-a biological electrophile sensor-was prevented by pretreatment with BR or a thiol compound, but was not by pretreatment with BV. In cells, BR could bind to KEAP1 to release and activate nuclear factor-erythroid 2 (NF-E2) p45-related factor 2, a cytoprotective transcription factor, leading to the induction of HO-1. These findings may provide a physiological rationale for the energy-consuming conversion of BV to BR.


Assuntos
Bilirrubina/metabolismo , Biliverdina/metabolismo , Metabolismo Energético/fisiologia , Bilirrubina/química , Biliverdina/química , Células Cultivadas , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo
17.
J Control Release ; 280: 1-10, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29723615

RESUMO

Despite the extremely high substrate specificity and catalytically amplified activity of enzymes, the lack of efficient cellular internalization limits their application as therapeutics. To overcome this limitation and to harness enzymes as practical biologics for targeting intracellular functions, we developed the streptavidin-mirror DNA tetrahedron hybrid as a platform for intracellular delivery of various enzymes. The hybrid consists of streptavidin, which provides a stoichiometrically controlled loading site for the enzyme cargo and an L-DNA (mirror DNA) tetrahedron, which provides the intracellular delivery potential. Due to the cell-penetrating ability of the mirror DNA tetrahedron of this hybrid, enzymes loaded on streptavidin can be efficiently delivered into the cells, intracellularly expressing their activity. In addition, we demonstrate tumor delivery of enzymes in an animal model by utilizing the potential of the hybrid to accumulate in tumors. Strikingly, the hybrid is able to transfer the apoptotic enzyme specifically into tumor cells, leading to strong suppression of tumor growth without causing significant damage to other tissues. These results suggest that the hybrid may allow anti-proliferative enzymes and proteins to be utilized as anticancer drugs.


Assuntos
Caspase 3/química , DNA/química , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Estreptavidina/química , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Transporte Biológico , Caspase 3/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoplasma/efeitos dos fármacos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/uso terapêutico , Liberação Controlada de Fármacos , Humanos , Camundongos Endogâmicos BALB C , Distribuição Tecidual/efeitos dos fármacos
18.
Bioorg Med Chem Lett ; 26(20): 4907-4910, 2016 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-27666633

RESUMO

The present study reports the cancer chemopreventive activities of phenyl polyyne diols derived from polyacetylene triol. Thirty-seven analogues based on a 1-phenylhexa-2,4-diyne-1,6-diol scaffold were prepared and their effects on QR activity were elucidated, as well as their cytotoxicities. We found that most of the derivatives based on phenylhexa-2,4-diyne-1,6-diol exhibited good QR induction activity and relatively low cytotoxicity and systemic structure-activity relationship was revealed. In particular, 4-fluorophenyl, 3-chlorophenyl, and 3,4-dioxolophenyl derivatives showed the best profiles in terms of QR induction, cytotoxicity, and CI.


Assuntos
Anticarcinógenos/química , Anticarcinógenos/farmacologia , Poli-Inos/química , Poli-Inos/farmacologia , Relação Estrutura-Atividade
19.
Comput Biol Chem ; 64: 94-98, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27318295

RESUMO

Motivated by a non-random but clustered distribution of SNPs, we introduce a phenomenological model to account for the clustering properties of SNPs in the human genome. The phenomenological model is based on a preferential mutation to the closer proximity of existing SNPs. With the Hapmap SNP data, we empirically demonstrate that the preferential model is better for illustrating the clustered distribution of SNPs than the random model. Moreover, the model is applicable not only to autosomes but also to the X chromosome, although the X chromosome has different characteristics from autosomes. The analysis of the estimated parameters in the model can explain the pronounced population structure and the low genetic diversity of the X chromosome. In addition, correlation between the parameters reveals the population-wise difference of the mutation probability. These results support the mutational non-independence hypothesis against random mutation.


Assuntos
Genoma Humano , Polimorfismo de Nucleotídeo Único , Cromossomos Humanos X , Feminino , Haplótipos , Humanos , Masculino , Modelos Teóricos
20.
BMC Genomics ; 17: 408, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27229151

RESUMO

BACKGROUND: Rice germplasm collections continue to grow in number and size around the world. Since maintaining and screening such massive resources remains challenging, it is important to establish practical methods to manage them. A core collection, by definition, refers to a subset of the entire population that preserves the majority of genetic diversity, enhancing the efficiency of germplasm utilization. RESULTS: Here, we report whole-genome resequencing of the 137 rice mini core collection or Korean rice core set (KRICE_CORE) that represents 25,604 rice germplasms deposited in the Korean genebank of the Rural Development Administration (RDA). We implemented the Illumina HiSeq 2000 and 2500 platform to produce short reads and then assembled those with 9.8 depths using Nipponbare as a reference. Comparisons of the sequences with the reference genome yielded more than 15 million (M) single nucleotide polymorphisms (SNPs) and 1.3 M INDELs. Phylogenetic and population analyses using 2,046,529 high-quality SNPs successfully assigned rice accessions to the relevant rice subgroups, suggesting that these SNPs capture evolutionary signatures that have accumulated in rice subpopulations. Furthermore, genome-wide association studies (GWAS) for four exemplary agronomic traits in the KRIC_CORE manifest the utility of KRICE_CORE; that is, identifying previously defined genes or novel genetic factors that potentially regulate important phenotypes. CONCLUSION: This study provides strong evidence that the size of KRICE_CORE is small but contains high genetic and functional diversity across the genome. Thus, our resequencing results will be useful for future breeding, as well as functional and evolutionary studies, in the post-genomic era.


Assuntos
Cruzamento , Evolução Molecular , Genoma de Planta , Estudo de Associação Genômica Ampla , Genômica/métodos , Oryza/genética , Análise de Sequência de DNA , Variação Genética , Genética Populacional , Mutação INDEL , Polimorfismo de Nucleotídeo Único
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