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2.
Prog Orthod ; 20(1): 25, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31257550

RESUMO

BACKGROUND: To evaluate the three-dimensional (3D) changes after mandibular setback surgery (MSS) in skeletal Class III malocclusion using cone-beam computed tomography (CBCT) and a structured light-based scanner. METHODS: Twenty-eight adult Korean patients with skeletal Class III malocclusion treated by MSS were evaluated. CBCT and facial scan images were recorded one week before and six months after surgery. To use an identical 3D coordinate system, superimposition was performed, and nine skeletal and 18 soft tissue landmarks were identified. Changes in the landmarks and correlation coefficients and ratios between hard and soft tissue changes were evaluated. Paired t test and Pearson's correlation test were performed. RESULTS: After MSS, the amount of transverse correction was 2.45 mm; mandibular setback, 5.80 mm; and vertical reduction, 1.64 mm at the menton, on average. In the transverse axis, there were significant changes and correlations in the lips and chin and an increasing gradient of ratios from the lower lip to the chin. In the anteroposterior axis, the lower lip and chin moved backward significantly and showed notable correlation with hard tissue movement. In the vertical axis, significant upward movement was observed in the landmarks related to the chin, but only lower facial height was significantly decreased. CONCLUSIONS: Soft tissue changes according to hard tissue movement after MSS exhibited a distinct pattern of an increasing gradient from the lips to the chin in a transverse aspect.

3.
Toxicol In Vitro ; 60: 412-419, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31247334

RESUMO

WST-1 [Water Soluble Tetrazolium-1; 2-(4-Iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt)] is widely used in the cell viability assays replacing MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). A water-soluble formazan dye (4-[1-(4-Iodophenyl)-5-(4-nitrophenyl)formaz-3-yl]-1,3-benzene disulfonate, disodium salt) is produced from the reduction of WST-1 tetrazolium, of which optical density at 450 nm is measured to evaluate cell viability. Colorful substances may interfere with spectrometric measurement, and a method to specifically detect WST-1 formazan is required. Here, a simple, rapid, sensitive, and specific ultra-performance liquid chromatography coupled to UV detector (UPLC-UV) was developed and validated for the WST-1 formazan. For the application to cell viability assay, the supernatant from WST-1 assay was injected without sample preparation procedure and a single run was completed within 5 min. Chromatographic separation was achieved on BEH C18 column (1.7 µm, 2.1 × 50 mm) using gradient elution with the mobile phase of water and acetonitrile. The standard curves were linear over the concentration range of 2.5-120 µg/mL WST-1 formazan, which encompasses WST-1 formazan concentrations from 2% cell viability to 2 fold of 100% cell viability. The intra- and inter-day precisions were measured to be below 5% and accuracies were within the range of 91.8-104.9%. The validated method was successfully applied to the test of colorful substances in vitro eye irritation test with a human cornea-like epithelium, and in vitro cytotoxicity in HaCaT, human keratinocyte cell line.

4.
Sci Rep ; 9(1): 6212, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30996297

RESUMO

The regulatory properties of pyruvate kinase M2 isoform (PKM2), the key glycolytic enzyme, influence altered energy metabolism including glycolysis in cancer. In this study, we found that PKM2 was highly expressed in patients with ulcerative colitis or colorectal cancer (CRC). We then investigated the effectiveness of conditionally ablating PKM2 in Lgr5+ intestinal stem cells (ISC) using a mouse model of colitis-associated CRC (AOM plus DSS). Tamoxifen-inducible Lgr5-driven deletion of PKM2 in ISC (PKM2ΔLgr5-Tx) significantly promoted tumor incidence and size in the colon and lower body weight compared with findings in vehicle-treated mice (PKM2ΔLgr5-Veh). Histopathologic analysis revealed considerable high-grade dysplasia and adenocarcinoma in the colon of PKM2ΔLgr5-Tx mice while PKM2ΔLgr5-Veh mice had low- and high-grade dysplasia. Loss of PKM2 was associated with dominant expression of PKM1 in Lgr5+ ISC and their progeny cells. Further, the organoid-forming efficiency of whole cancer cells or Lgr5+ cells obtained from colon polyps of PKM2ΔLgr5-Tx mice was significantly increased when compared with PKM2ΔLgr5-Veh mice. Cancer organoids from PKM2ΔLgr5-Tx mice exhibited increased mitochondrial oxygen consumption and a shift of metabolites involved in energy metabolism. These findings suggest that loss of PKM2 function in ISC promotes colitis-associated CRC.

5.
Phytomedicine ; 55: 1-8, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668419

RESUMO

BACKGROUND: Many bone-related diseases such as osteoporosis and rheumatoid arthritis are commonly associated with excessive activity of the osteoclast. Ganomycin I (GMI), a meroterpenoid isolated from Vietnamese mushroom Ganoderma lucidum, possesses a variety of beneficial effects on human health. However, its impact and underlying mechanism on osteoclastogenesis remain unclear. In the present study, we investigated the effect of GMI on RANKL-induced osteoclast formation in mouse BMMs and RAW264.7 cells. METHODS: BMMs or RAW264.7 cells were treated with GMI followed by an evaluation of cell viability, RANKL-induced osteoclast differentiation, actin-ring formation, and resorption pits activity. Effects of GMI on RANKL-induced phosphorylation of MAPKs as well as the expression levels of NFATc1 and c-Fos were evaluated by Western blot analysis. Expression levels of osteoclast marker genes were evaluated by Western blot analysis and reverse transcription-qPCR. RESULTS: GMI significantly inhibited RANKL-induced osteoclast differentiation by decreasing the number of osteoclasts, osteoclast actin-ring formation, and bone resorption in a dose-dependent manner without affecting cell viability. At molecular level, GMI inhibited the RANKL-induced phosphorylation of ERK, JNK, and p38 MAPKs, as well as the expression levels of c-Fos and NFATc1, which are known to be crucial transcription factors for osteoclast formation. In addition, GMI decreased expression levels of osteoclastogenesis specific marker genes including c-Src, CtsK, TRAP, MMP-9, OSCAR, and DC-STAMP in RANKL-stimulated BMMs. CONCLUSION: Our findings suggest that GMI can attenuate osteoclast formation by suppressing RANKL-mediated MAPKs and NFATc1 signaling pathways and the anti-osteoclastogenic activity of GMI may extend our understanding of molecular mechanisms underlying biological activities and pharmacological use of G. lucidum as a traditional anti-osteoporotic medicine.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Hidroquinonas/farmacologia , Fatores de Transcrição NFATC/antagonistas & inibidores , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Animais , Reabsorção Óssea/tratamento farmacológico , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroquinonas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/fisiologia , Osteogênese/fisiologia , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Reishi/química
6.
Arch Pharm Res ; 42(4): 332-343, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30610615

RESUMO

As part of our ongoing program to develop anti-inflammatory agents, an extract derived from Saururus chinensis collected in Korea was found to inhibit nitric oxide (NO) production in RAW264.7 cells. Bioassay-guided fractionation led to the isolation two new (1 and 2) and six known dineolignans (3-8). To the best of our knowledge, manassatin B1 (3) was isolated from S. chinensis for the first time. All structures were elucidated using extensive spectroscopic analysis. Of these compounds, 2 and 8 inhibited lipopolysaccharide (LPS)-induced production of NO and showed IC50 values of 5.80 and 1.52 µM, respectively. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) was also significantly suppressed by the administration of 2 and 8. In addition, these lignans induced the expression of heme oxygenase-1 (HO-1) in a concentration-dependent manner. Nuclear translocation of nuclear-E2-related factor 2 (Nrf2), a key regulator of HO-1 protein expression, was also induced in RAW264.7 cells treated with 2 and 8. These findings suggested that these lignans exerted anti-inflammatory effects in RAW264.7 cells through modulation of the Nrf2/HO-1 pathway and that they were potential HO-1 inducers for preventing or treating inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Proteínas de Membrana/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Saururaceae/química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Heme Oxigenase-1/metabolismo , Ligantes , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Proteínas de Membrana/metabolismo , Camundongos , Conformação Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Componentes Aéreos da Planta/química , Extratos Vegetais/química , Células RAW 264.7 , Relação Estrutura-Atividade
7.
Toxicol In Vitro ; 55: 173-184, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30572010

RESUMO

The need for in vitro eye irritation test replacing in vivo is steadily increasing. The MCTT HCE™ eye irritation test (EIT) using 3D reconstructed human cornea-like epithelium, was developed to identify ocular irritants from non-irritants those that are not requiring classification and labelling for eye irritation. Here, we report the results of me-too validation study, which was conducted to evaluate the reliability and relevance of the MCTT HCETM EIT, according to performance standards (PS) of OECD TG 492. The optimal cutoff to determine irritation in the prediction model was preliminarily established at 45% with the receiver operation characteristics (ROC) curve for 141 reference substances. To demonstrate the reproducibility of within- and between-laboratory (WLR and BLR), a set of 30 PS reference chemicals were tested in three laboratories three times. The WLR and BLR concordance with the binary decision of whether non-irritant or irritant was estimated to be 90-100% and 90%, respectively, and both met the PS requirements. The predictive capacity of the respective laboratories for the 30 reference chemicals were evaluated based on three different estimation methods, and the results were comparable, with sensitivity ranging from 89.6 to 93.3%, the specificity ranging from 62.2 to 66.7%, and the accuracy ranging from 75.9 to 80.0%. Additional test with the new set of 30 PS substances in the revised OECD GD 216 yielded a performance of sensitivity ranging from 92.6-93.3%, the specificity 62.2-66.7% and the accuracy 77.4-80.0%. 95.0% sensitivity, 67.2% specificity, and 83.0% accuracy were obtained for 141 reference substances in total. Furthermore, separate cutoffs for liquids and solids, 35% and 60%, respectively, produced better predictivity, which was established as a final prediction model. Collectively, our study demonstrated that MCTT HCETM EIT meets the reproducibility and predictivity criteria stated in OECD TG 492 PS.


Assuntos
Alternativas aos Testes com Animais , Epitélio Anterior/efeitos dos fármacos , Irritantes/toxicidade , Testes de Toxicidade/métodos , Humanos , Reprodutibilidade dos Testes
8.
Cell Host Microbe ; 24(6): 833-846.e6, 2018 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-30543778

RESUMO

Symbionts play an indispensable role in gut homeostasis, but underlying mechanisms remain elusive. To clarify the role of lactic-acid-producing bacteria (LAB) on intestinal stem-cell (ISC)-mediated epithelial development, we fed mice with LAB-type symbionts such as Bifidobacterium and Lactobacillus spp. Here we show that administration of LAB-type symbionts significantly increased expansion of ISCs, Paneth cells, and goblet cells. Lactate stimulated ISC proliferation through Wnt/ß-catenin signals of Paneth cells and intestinal stromal cells. Moreover, Lactobacillus plantarum strains lacking lactate dehydrogenase activity, which are deficient in lactate production, elicited less ISC proliferation. Pre-treatment with LAB-type symbionts or lactate protected mice in response to gut injury provoked by combined treatments with radiation and a chemotherapy drug. Impaired ISC-mediated epithelial development was found in mice deficient of the lactate G-protein-coupled receptor, Gpr81. Our results demonstrate that LAB-type symbiont-derived lactate plays a pivotal role in promoting ISC-mediated epithelial development in a Gpr81-dependent manner.


Assuntos
Células Caliciformes/citologia , Ácido Láctico/metabolismo , Lactobacillus plantarum/metabolismo , Celulas de Paneth/citologia , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/efeitos da radiação , Células HEK293 , Humanos , L-Lactato Desidrogenase/genética , L-Lactato Desidrogenase/metabolismo , Lactobacillus plantarum/genética , Metotrexato/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Celulas de Paneth/efeitos dos fármacos , Celulas de Paneth/efeitos da radiação , Receptores Acoplados a Proteínas-G/genética
9.
Korean J Fam Med ; 2018 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-30360032

RESUMO

Background: This double-blind, randomized controlled design study aimed to assess the dose-dependent effects of synbiotics on gastrointestinal symptoms of and fatigue in irritable bowel syndrome (IBS). Methods: Thirty subjects with IBS were randomly assigned into the following three groups and received 2 capsules a day for 8 weeks: (1) high-dose (2 capsules of synbiotics); (2) low-dose (1 capsule of synbiotics and 1 capsule of placebo); and (3) placebo (2 capsules of placebo). At baseline and 8 weeks, they completed the study questionnaires. Results: Two subjects in the high-dose group were lost to follow-up, leaving a total of 28 patients for the analysis. After 8 weeks, abdominal discomfort, abdominal bloating, frequency of formed stool, fatigue Visual Analog Scale (VAS), and Multidimensional Fatigue Inventory were significantly different among the groups (P=0.002, 0.006, 0.007, 0.028, and 0.041, respectively, by Kruskal-Wallis test). However, only abdominal discomfort, abdominal bloating, frequency of formed stool, and fatigue VAS were significantly improved in the high-dose group compared with those in the placebo group (P=0.002, 0.003, 0.002, and 0.013, respectively) by Mann-Whitney test with Bonferroni correction. No adverse drug reactions were reported. Conclusion: High-dose synbiotics were superior to placebo in improving bowel symptoms and fatigue of IBS patients, suggesting that synbiotic dosage plays an important role in the treatment of IBS.

10.
BMC Geriatr ; 18(1): 230, 2018 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-30268096

RESUMO

BACKGROUND: Stair ascent is one of the most important and challenging activities of daily living to maintain mobility and independence in elderly adults. Recently, various types of wearable walking assist robots have been developed to improve gait function and metabolic efficiency for elderly adults. Several studies have shown that walking assist robots can improve cardiopulmonary metabolic efficiency during level walking in elderly. However, there is limited evidence demonstrating the effect of walking assist robots on cardiopulmonary metabolic efficiency during stair walking in elderly adults. Therefore, the aim of this study was to investigate the assistance effect of a newly developed wearable hip assist robot on cardiopulmonary metabolic efficiency during stair ascent in elderly adults. METHODS: Fifteen healthy elderly adults participated. The Gait Enhancing Mechatronic System (GEMS), developed by Samsung Electronics Co., Ltd., Korea, was used in the present study. The metabolic energy expenditure was measured using a K4b2 while participants performed randomly assigned two conditions consecutively: free ascending stairs without the GEMS or robot-assisted ascending stair with the GEMS. RESULTS: There were significant differences in the oxygen consumption per unit mass (ml/min/kg), metabolic power per unit mass (W/kg) and metabolic equivalents (METs) values between the GEMS and NoGEMS conditions. A statistically significant difference was found between the two conditions in net oxygen consumption and net metabolic power, with a reduction of 8.59% and 10.16% respectively in GEMS condition (p < 0.05). The gross oxygen consumption while climbing stairs under the GEMS and NoGEMS conditions was equivalent to 6.38 METs and 6.85 METs, respectively. CONCLUSION: This study demonstrated that the GEMS was helpful for reducing cardiopulmonary metabolic energy expenditure during stair climbing in elderly adults. The use of the GEMS allows elderly adults to climb stairs with less metabolic energy, therefore, they may experience more endurance in stair climbing while using the GEMS. TRIAL REGISTRATION: NCT03389165 , Registered 26 December 2017 - retrospectively registered.

11.
Food Funct ; 9(7): 3895-3905, 2018 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-29968885

RESUMO

Ziziphus jujuba var. inermis Rehder is an edible fruit-producing species of the Rhamnaceae family. In the present study, we isolated eight triterpenoids (1-8) from the fruits of Z. jujuba var. inermis and evaluated their apoptotic cell-death-inducing activities in human cancer cell lines (A549, PC-3, and MDA-MB-231). The structures of compounds 1-8 were determined by spectroscopic methods. Among these, four isomers of coumaroyl alphitolic acid showed potent cytotoxic activities on these cancer cells: 3-O-cis-p-coumaroyl alphitolic acid (3), 3-O-trans-p-coumaroyl alphitolic acid (4), 2-O-trans-p-coumaroyl alphitolic acid (5), and 2-O-cis-p-coumaroyl alphitolic acid (6). Moreover, compounds 3-6 induced apoptotic cell death in a concentration-dependent manner. We further investigated the apoptosis-inducing effects of compound 4 in PC-3 cells which triggered the cleavage of procaspase-3, procaspase-7, procaspase-8, bid, and PARP. Compound 4 increased both the mitochondrial reactive oxygen species (ROS) production and the phosphorylation of p38 MAPK (mitogen-activated protein kinase), but decreased the mitochondrial membrane potential. Pretreatment with Mito-TEMPO (a specific mitochondrial-targeted antioxidant) or a specific p38 inhibitor (SB203580) attenuated apoptotic cell death triggered by compound 4 which suggests that compound 4 may induce apoptotic cell death in these cancer cells by increasing the mitochondrial ROS production as well as the subsequent p38 MAPK activation. The study findings provide a rational base to use Ziziphus extracts for cancer treatments in traditional oriental medicine.


Assuntos
Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Triterpenos/farmacologia , Ziziphus/química , Caspase 3/genética , Caspase 3/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Linhagem Celular Tumoral , Citocromos c/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Extratos Vegetais/química , Triterpenos/química
12.
Acta Neuropathol Commun ; 6(1): 32, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29703245

RESUMO

Heterozygous mutations in glucocerebrosidase 1 (GBA1) are a major genetic risk factor for Parkinson's disease and Dementia with Lewy bodies. Mutations in GBA1 leads to GBA1 enzyme deficiency, and GBA1-associated parkinsonism has an earlier age of onset and more progressive parkinsonism. To investigate a potential influence of GBA1 deficiency caused by mutations in GBA1 on the disease progression of PD, GBA1 mice carrying D409H knock-in mutation were crossbred with the human A53T (hA53T) α-synuclein transgenic mice. Here, we show that GBA1 enzyme activity plays a significant role in the hA53T α-synuclein induced α-synucleinopathy. The expression of D409H GBA1 markedly shortens the lifespan of hA53T α-synuclein transgenic mice. Moreover, D409H GBA1 expression exacerbates the formation of insoluble aggregates of α-synuclein, glial activation, neuronal degeneration, and motor abnormalities in the hA53T α-synuclein transgenic mice. Interestingly, the expression of D409H GBA1 results in the loss of dopaminergic neurons in the substantia nigra pars compacta of hA53T transgenic mice. Taken together, these results indicate that GBA1 deficiency due to D409H mutation affects the disease onset and course in hA53T α-synuclein transgenic mice. Therefore, strategies aimed to maintain GBA1 enzyme activity could be employed to develop an effective novel therapy for GBA1 linked-PD and related α-synucleinopathies.

13.
Cancer Med ; 7(5): 1766-1773, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29577681

RESUMO

Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). Here, using the data from a Phase 3 study conducted in patients with newly diagnosed CP-CML, the dose-efficacy as well as dose-safety relationship analyses were performed to determine a safe and effective initial dosage regimen of radotinib. A significant positive association was detected between the starting dose of radotinib adjusted for body weight (Dose/BW) and the probability of dose-limiting toxicity (≥grade 3 hematologic and nonhematologic toxicity) (P = 0.003). In contrast, a significant inverse association was discovered between Dose/BW and the probability of major molecular response (BCR-ABL1/ABL1 ≤ 0.1%) when controlled for sex (P = 0.033). Moreover, frequent dose interruptions and reductions secondary to radotinib toxicities occurred in the Phase 3 study, resulting in nearly half (44%) of patients receiving a reduced dose at a 12-month follow-up. In conclusion, the results of this study demonstrate the need for initial radotinib dose attenuation to improve the long-term efficacy and safety of radotinib. Hence, the authors suggest a new upfront radotinib dose of 400 mg once daily be tested in patients with newly diagnosed CP-CML.

14.
Biomol Ther (Seoul) ; 26(6): 599-607, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-29429148

RESUMO

Fasiglifam (TAK-875) a G-protein coupled receptor 40 (GPR40) agonist, significantly improves hyperglycemia without hypoglycemia and weight gain, the major side effects of conventional anti-diabetics. Unfortunately, during multi-center Phase 3 clinical trials, unexpected liver toxicity resulted in premature termination of its development. Here, we investigated whether TAK-875 directly inflicts toxicity on hepatocytes and explored its underlying mechanism of toxicity. TAK-875 decreased viability of 2D and 3D cultures of HepG2, a human hepatocarcinoma cell line, in concentration- (>50 µM) and time-dependent manners, both of which corresponded with ROS generation. An antioxidant, N-acetylcysteine, attenuated TAK-875-mediated hepatotoxicity, which confirmed the role of ROS generation. Of note, knockdown of GPR40 using siRNA abolished the hepatotoxicity of TAK-875 and attenuated ROS generation. In contrast, TAK-875 induced no cytotoxicity in fibroblasts up to 500 µM. Supporting the hepatotoxic potential of TAK-875, exposure to TAK-875 resulted in increased mortality of zebrafish larvae at 25 µM. Histopathological examination of zebrafish exposed to TAK-875 revealed severe hepatotoxicity as manifested by degenerated hypertrophic hepatocytes with cytoplasmic vacuolation and acentric nuclei, confirming that TAK-875 may induce direct hepatotoxicity and that ROS generation may be involved in a GPR40-dependent manner.

15.
Mol Neurodegener ; 13(1): 1, 2018 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-29310663

RESUMO

BACKGROUND: Mutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA +/L444P ) mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic mitochondrial neurotoxin. METHOD: We used GBA +/L444P mice, α-synuclein knockout (SNCA -/- ) mice at 8 months of age, and adeno-associated virus (AAV)-human GBA overexpression to investigate the rescue effect of DA neuronal loss and susceptibility by MPTP. Mitochondrial morphology and functional assay were used to identify mitochondrial defects in GBA +/L444P mice. Motor behavioral test, immunohistochemistry, and HPLC were performed to measure dopaminergic degeneration by MPTP and investigate the relationship between GBA mutation and α-synuclein. Mitochondrial immunostaining, qPCR, and Western blot were also used to study the effects of α-synuclein knockout or GBA overexpression on MPTP-induced mitochondrial defects and susceptibility. RESULTS: L444P GBA heterozygous mutation reduced GBA protein levels, enzymatic activity and a concomitant accumulation of α-synuclein in the midbrain of GBA +/L444P mice. Furthermore, the deficiency resulted in defects in mitochondria of cortical neurons cultured from GBA +/L444P mice. Notably, treatment with MPTP resulted in a significant loss of dopaminergic neurons and striatal dopaminergic fibers in GBA +/L444P mice compared to wild type (WT) mice. Levels of striatal DA and its metabolites were more depleted in the striatum of GBA +/L444P mice. Behavioral deficits, neuroinflammation, and mitochondrial defects were more exacerbated in GBA +/L444P mice after MPTP treatment. Importantly, MPTP induced PD-like symptoms were significantly improved by knockout of α-synuclein or augmentation of GBA via AAV5-hGBA injection in both WT and GBA +/L444P mice. Intriguingly, the degree of reduction in MPTP induced PD-like symptoms in GBA +/L444P α-synuclein (SNCA) -/- mice was nearly equal to that in SNCA -/- mice after MPTP treatment. CONCLUSION: Our results suggest that GBA deficiency due to L444P GBA heterozygous mutation and the accompanying accumulation of α-synuclein render DA neurons more susceptible to MPTP intoxication. Thus, GBA and α-synuclein play dual physiological roles in the survival of DA neurons in response to the mitochondrial dopaminergic neurotoxin, MPTP.


Assuntos
Neurônios Dopaminérgicos/patologia , Glucosilceramidase/deficiência , Transtornos Parkinsonianos/patologia , alfa-Sinucleína/metabolismo , Animais , Técnicas de Introdução de Genes , Glucosilceramidase/genética , Humanos , Mesencéfalo/patologia , Camundongos , Camundongos Knockout , Mutação , Degeneração Neural/patologia
16.
Int Immunopharmacol ; 55: 165-173, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29258000

RESUMO

Prenylated flavonoids are a unique class of naturally occurring flavonoids that have various pharmacological activities. In the present study, we investigated the anti-inflammatory effect in murine macrophages of a prenylated flavonoid, 10-oxomornigrol F (OMF), which was isolated from the twigs of Morus alba (Moraceae). OMF inhibited the lipopolysaccharide (LPS)-induced production of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6 in RAW264.7 cells, as well as in mouse bone marrow-derived macrophages (BMMs). OMF also rescued LPS-induced septic mortality in ICR mice. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 was also significantly suppressed by OMF treatment in RAW264.7 cells. Treatment of RAW264.7 cells with OMF induced heme oxygenase (HO)-1 mRNA and protein expression and increased the nuclear translocation of the nuclear factor-E2-related factor 2 (Nrf2) as well as the expression of Nrf2 target genes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1). Treatment of RAW264.7 cells with OMF increased the intracellular level of reactive oxygen species (ROS) and the phosphorylation levels of p38 mitogen-activated protein kinase (MAPK); co-treatment with the antioxidant N-acetyl-cysteine (NAC) blocked this OMF-induced p38 MAPK phosphorylation. Moreover, NAC, or SB203580 (a p38 MAPK inhibitor), blocked the OMF-induced nuclear translocation of Nrf2 and HO-1 expression, suggesting that OMF induces HO-1 expression by activating Nrf2 through the p38 MAPK pathway. Consistent with the notion that the Nrf2/HO-1 pathway has anti-inflammatory properties, inhibiting HO-1 significantly abrogated the anti-inflammatory effects of OMF in LPS-stimulated RAW264.7 cells. Taken together, these findings suggest that OMF exerts its anti-inflammatory effect by activating the Nrf2/HO-1 pathway, and may be a potential Nrf2 activator to prevent or treat inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Flavonoides/uso terapêutico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Heme Oxigenase-1/metabolismo , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Morus/imunologia , Fator 2 Relacionado a NF-E2/metabolismo , Prenilação , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo
17.
Oncotarget ; 8(54): 92346-92358, 2017 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-29190920

RESUMO

Angiogenesis is one of the hallmarks of cancer, playing an essential role in tumor growth, invasion, and metastasis. 3ß-Acetyl-nor-erythrophlamide (3-ANE), a cassaine diterpene alkaloid compound from Erythrophleum fordii, exerts various pharmacological effects, including antitumor activity. However, the effects of 3-ANE on tumor angiogenesis and its potential molecular mechanism are still unknown. Here, we demonstrated that 3-ANE inhibited the vascular endothelial growth factor (VEGF)-mediated proliferation, migration, invasion, and capillary-like tube formation of human umbilical vascular endothelial cells (HUVECs), without inducing apoptosis. We also found that 3-ANE blocked angiogenesis in vivo, and suppressed tumor angiogenesis and human lung adenocarcinoma growth in the xenograft tumor model. Furthermore, we showed that 3-ANE blocked VEGF-mediated endothelial nitric oxide synthase (eNOS) phosphorylation, vascular permeability and NO production in HUVECs, via disrupting the VEGF-induced association of eNOS and heat-shock protein 90 (HSP90). Our studies therefore provide the first evidence that 3-ANE inhibits tumor angiogenesis by inhibiting the VEGF-mediated eNOS activation and NO production, and 3-ANE could be a potential candidate in angiogenesis-related disease therapy.

18.
J Neuroeng Rehabil ; 14(1): 123, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29183379

RESUMO

BACKGROUND: A robotic exoskeleton device is an intelligent system designed to improve gait performance and quality of life for the wearer. Robotic technology has developed rapidly in recent years, and several robot-assisted gait devices were developed to enhance gait function and activities of daily living in elderly adults and patients with gait disorders. In this study, we investigated the effects of the Gait-enhancing Mechatronic System (GEMS), a new wearable robotic hip-assist device developed by Samsung Electronics Co, Ltd., Korea, on gait performance and foot pressure distribution in elderly adults. METHODS: Thirty elderly adults who had no neurological or musculoskeletal abnormalities affecting gait participated in this study. A three-dimensional (3D) motion capture system, surface electromyography and the F-Scan system were used to collect data on spatiotemporal gait parameters, muscle activity and foot pressure distribution under three conditions: free gait without robot assistance (FG), robot-assisted gait with zero torque (RAG-Z) and robot-assisted gait (RAG). RESULTS: We found increased gait speed, cadence, stride length and single support time in the RAG condition. Reduced rectus femoris and medial gastrocnemius muscle activity throughout the terminal stance phase and reduced effort of the medial gastrocnemius muscle throughout the pre-swing phase were also observed in the RAG condition. In addition, walking with the assistance of GEMS resulted in a significant increase in foot pressure distribution, specifically in maximum force and peak pressure of the total foot, medial masks, anterior masks and posterior masks. CONCLUSION: The results of the present study reveal that GEMS may present an alternative way of restoring age-related changes in gait such as gait instability with muscle weakness, reduced step force and lower foot pressure in elderly adults. In addition, GEMS improved gait performance by improving push-off power and walking speed and reducing muscle activity in the lower extremities. TRIAL REGISTRATION: NCT02843828 .


Assuntos
Exoesqueleto Energizado , Transtornos Neurológicos da Marcha/reabilitação , Marcha/fisiologia , Robótica/instrumentação , Idoso , Eletromiografia , Feminino , Humanos , Masculino
19.
Sci Rep ; 7(1): 6348, 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28740238

RESUMO

IκBζ, which is encoded by the Nfkbiz gene, is a member of the nuclear IκB family of proteins that act as transcriptional regulators via association with NF-κB. Nfkbiz-deficient (Nfkbiz -/-) mice develop spontaneous dermatitis; however, the underlying mechanism has yet to be elucidated. In our study, we found higher skin pathology scores and more serum IgE antibodies and trans-epidermal water loss in Nfkbiz -/- than in Nfkbiz-sufficient (Nfkbiz +/-) mice. There was also greater expansion of IFN-γ-, IL-17A-, and IL-22-secreting CD4+ T cells and of IL-17A-secreting γδ+ T cells in the skin of Nfkbiz -/- mice than in with Nfkbiz +/- mice. Pyrosequencing analysis showed decreased diversity of resident bacteria and markedly expanded Staphylococcus (S.) xylosus in the skin of Nfkbiz -/- mice. Oral administration of antibiotics including cephalexin and enrofloxacin ameliorated skin inflammation. Topical application of S. xylosus also resulted in the expansion of IL-17A-secreting CD4+ T cells along with high levels of pro-inflammatory cytokines and chemokines in the skin of Nfkbiz -/- mice. The expansion of commensal S. xylosus may be one cause of skin dysbiosis in Nfkbiz -/- mice and suggests that the Nfkbiz gene may play a regulatory role in the microbiota-skin immunity axis.

20.
Bioorg Med Chem Lett ; 27(13): 2946-2952, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28506750

RESUMO

A phytochemical investigation into the bark of Erythrophleum fordii yielded four new compounds, two new cassaine diterpenoids (erythrofordin T and U, 1 and 2) and two new cassaine diterpenoid amines (erythroformine A and B, 6 and 7), as well as nine known compounds. We report for the first time the isolation of erythrofordin V (3) from a natural source and that of the remaining eight known diterpenoids (4-5, 8-13) from E. fordii. All structures were elucidated using spectroscopic analysis. Cytotoxic activity of the isolated compounds (1-13) was examined in vitro against three non-small cell lung cancer cell lines (A549, NCI-H1975, and NCI-H1229) using the MTT assay. Cassaine diterpene amines (6-10, 12, 13) exhibited potent cytotoxic activity against all three cell lines with IC50 values between 0.4µM and 5.9µM. Erythroformine B (7) significantly induced apoptosis in all three cancer cells in a concentration-dependent manner.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Diterpenos/farmacologia , Fabaceae/química , Neoplasias Pulmonares/tratamento farmacológico , Casca de Planta/química , Alcaloides/química , Alcaloides/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/patologia , Estrutura Molecular , Relação Estrutura-Atividade
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