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1.
Immun Ageing ; 20(1): 56, 2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-37872562

RESUMO

Sarcopenia is closely associated with gut dysbiosis. Probiotics alleviate gut dysbiosis. Therefore, we selected probiotics Lactobacillus paracasei P62 (Lp) and Bifidobacterium bifidum P61 (Bb), which suppressed muscle RING-finger protein-1 (MuRF1) expression and NF-κB activation in C2C12 cells, and examined their effects on muscle mass loss and dysfunction in aged mice. Oral administration of Lp, Bb, or their mix (LB) increased grip strength and treadmill running distance and time. They significantly increased muscle weight in aged mice. They also increased AKT activation, PGC1α, SIRT1, and myosin heavy chain (MyHC) expression, MyHC-positive cell population, and cell size in the gastrocnemius (GA) muscle, while FOXO3a and NF-κB activation, MuRF1, muscle atrophy F-box, and p16 expression, and NF-κB+CD11c+ cell population decreased. Furthermore, they reduced cognitive impairment-like behavior, IL-6 expression, FOXO3a activation, and NF-κB-positive cell population in the hippocampus, GA, and colon, while hippocampal brain-derived neurotropic factor expression increased. They shifted gut microbiota composition in aged mice: they increased Akkermansiaceae and Bacteroidaceae populations, which were positively correlated with total muscle weight and MyHC expression, and decreased Odoribacteraceae and Deferribacteriaceae populations, which were positively correlated with MuRF1 and IL-6 expression. LB alleviated sarcopenia- and cognitive impairment-like symptoms more potently than Lp or Bb alone. Based on these findings, probiotics, particularly Lp, Bb, and LB, can alleviate aging-dependent sarcopenia and cognitive impairment by regulating gut microbiota-mediated AKT, NF-κB, and/or FOXO3a signaling pathways.

2.
Eur J Med Chem ; 265: 116052, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38134745

RESUMO

The bromodomain and extraterminal domain (BET) family proteins recognize acetyl-lysine (Kac) at the histone tail through two tandem bromodomains, i.e., BD1 and BD2, to regulate gene expression. BET proteins are attractive therapeutic targets in cancer due to their involvement in oncogenic transcriptional activation, and bromodomains have defined Kac-binding pockets. Here, we present DW-71177, a potent BET inhibitor that selectively interacts with BD1 and exhibits strong antileukemic activity. X-ray crystallography, isothermal titration calorimetry, and molecular dynamic studies have revealed the robust and specific binding of DW-71177 to the Kac-binding pocket of BD1. DW-71177 effectively inhibits oncogenes comparable to the pan-BET inhibitor OTX-015, but with a milder impact on housekeeping genes. It efficiently blocks cancer-associated transcriptional changes by targeting genes that are highly enriched with BRD4 and histone acetylation marks, suggesting that BD1-selective targeting could be an effective and safe therapeutic strategy against leukemia.


Assuntos
Leucemia Mieloide Aguda , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Histonas , Proteínas Nucleares , Quinoxalinas/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Proteínas que Contêm Bromodomínio
3.
Nutrients ; 15(13)2023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-37447399

RESUMO

Obesity is a global health problem that affects the quality of life. It is a multidimensional chronic risk factor for major medical conditions, such as cardiovascular diseases, diabetes, and cancer. This clinical trial evaluated the efficacy of Lactobacillus sakei OK67 (DW2010), a lactic acid bacterium, in reducing body and visceral fat in overweight individuals (body mass index ≥25 kg/m2 and <30 kg/m2), aged 20-60 years. A total of 100 subjects placed in a lifestyle modification program were randomly assigned to receive either DW2010 (2.0 g/day, 1.0 × 1010 CFU) or a placebo for 12 weeks. The efficacy of DW2010 was evaluated by measuring body fat mass using dual-energy X-ray absorptiometry and visceral fat area using computed tomography. After 12 weeks, the change in body fat in the DW2010 group was not markedly different from that in the placebo group. However, visceral fat area decreased more in the DW2010 group than in the placebo group (p = 0.035). During the clinical trial, no major adverse events were reported. Moreover, no statistical differences were observed in the biochemical parameters of the DW2010 and placebo groups. Overall, we concluded that the intake of DW2010 for 12 weeks is safe and potentially reduces visceral fat in lifestyle-modified overweight subjects.


Assuntos
Latilactobacillus sakei , Sobrepeso , Humanos , Sobrepeso/tratamento farmacológico , Gordura Intra-Abdominal/diagnóstico por imagem , Qualidade de Vida , Índice de Massa Corporal , Estilo de Vida , Método Duplo-Cego
4.
Front Cell Infect Microbiol ; 11: 677648, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34568084

RESUMO

Vaginal dysbiosis, such as bacterial vaginosis (BV) and aerobic vaginitis (AV), is an important cause of premature birth in pregnant women. However, there is very little research on vaginal microbial distribution in AV compared to that in BV. This study aimed to analyze the composition of the vaginal microbiota of pregnant women with AV using microbial community analysis and identify the causative organism using each criterion of the AV scoring system. Also, we compared the quantification of aerobic bacteria using quantitative polymerase chain reaction (qPCR) and their relative abundances (RA) using metagenomics. This prospective case-control study included 228 pregnant Korean women from our previous study. A wet mount test was conducted on 159 women to diagnose AV using the AV scoring system. Vaginal samples were analyzed using metagenomics, Gram staining for Nugent score determination, conventional culture, and qPCR for Staphylococcus spp., Streptococcus spp., and Enterobacteriaceae. The relative abundances (RAs) of eleven species showed significant differences among the three groups (Normal flora (NF), mild AV, and moderate AV). Three species including Lactobacillus crispatus were significantly lower in the AV groups than in the NF group, while eight species were higher in the AV groups, particularly moderate AV. The decrease in the RA of L. crispatus was common in three criteria of the AV scoring system (Lactobacillary, WBC, and background flora grades), while it did not show a significant difference among the three grade groups of the toxic leukocyte criterion. Also, the RAs of anaerobes, such as Gardnerella and Megasphaera, were higher in the AV groups, particularly moderate AV, while the RAs of aerobes were very low (RA < 0.01). Therefore, qPCR was performed for aerobes (Staphylococcus spp., Streptococcus spp., and Enterobacteriaceae); however, their quantification did not show a higher level in the AV groups when compared to that in the NF group. Therefore, AV might be affected by the RA of Lactobacillus spp. and the main anaerobes, such as Gardnerella spp. Activation of leukocytes under specific conditions might convert them to toxic leukocytes, despite high levels of L. crispatus. Thus, the pathogenesis of AV can be evaluated under such conditions.


Assuntos
Microbiota , Vaginite , Estudos de Casos e Controles , Disbiose , Feminino , Humanos , Gravidez , Gestantes , Vagina
5.
Nutrients ; 11(2)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717153

RESUMO

Early intervention using dietary supplements may be effective in alleviating cognitive impairment among individuals with mild cognitive impairment (MCI). This study investigated the efficacy and safety of Lactobacillus plantarum C29-fermented soybean (DW2009) as a nutritional supplement for cognitive enhancement. One hundred individuals with MCI were randomly assigned to take DW2009 (800 mg/day, n = 50) or placebo (800 mg/day, n = 50) for 12 weeks. The primary outcome measure was change in the composite score of cognitive functions related to memory and attention, measured by computerized neurocognitive function tests. Associations between changes in serum brain-derived neurotrophic factor (BDNF) levels and cognitive performance for each treatment group were evaluated. Compared to the placebo group, the DW2009 group showed greater improvements in the combined cognitive functions (z = 2.36, p for interaction = 0.02), especially in the attention domain (z = 2.34, p for interaction = 0.02). Cognitive improvement was associated with increased serum BDNF levels after consumption of DW2009 (t = 2.83, p = 0.007). The results of this clinical trial suggest that DW2009 can be safely administered to enhance cognitive function in individuals with MCI. Increased serum BDNF levels after administering DW2009 may provide preliminary insight into the underlying effects of cognitive improvement, which suggests the importance of the gut-brain axis in ameliorating cognitive deficits in MCI.


Assuntos
Disfunção Cognitiva/dietoterapia , Lactobacillus plantarum , Probióticos/uso terapêutico , Alimentos de Soja , Idoso , Fator Neurotrófico Derivado do Encéfalo/sangue , Disfunção Cognitiva/fisiopatologia , Método Duplo-Cego , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal , Humanos , Masculino , Pessoa de Meia-Idade , Probióticos/efeitos adversos , Resultado do Tratamento
6.
Arch Pharm Res ; 31(7): 850-5, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18704326

RESUMO

Eleven xanthones (1-11), three flavonoids (12-14) and three secoiridoids (15-17) were isolated from the aerial parts of Halenia corniculata. Among those compounds, 1-hydroxy-2,3,4,5-tetramethoxyxanthone (1), 1-hydroxy-2,3,4,7-tetramethoxyxanthone (2), 1-hydroxy-2,3,4,5,7-pentamethoxyxanthone (3), 1-hydroxy-2,3,5-trimethoxyxanthone (4), 1,8-dihydroxy-3,5-dimethoxyxanthone (7), and luteolin (12), at the concentration of 1 microg/mL, effectively inhibited the osteoclast differentiation in a co-culture system with mouse osteoblastic calvarial cells and bone marrow cells. Notably, compounds 1, 3, and 4 exhibited, in a dose-dependent manner, significant inhibition of osteoclast differentiation even at a low concentration (0.01 microg/mL). All the inhibitory compounds, except for compound 7, significantly reduced the pit formation on the dentine slice compared with the control group. For the survival of the mature osteoclasts, compounds 1-4 and 12 (1 microg/mL), significantly decreased the survival number through induction of cell apoptosis, and compound 4 exhibited a significant inhibitory effect on osteoclast survival even at the low concentration of 0.1 microg/mL.


Assuntos
Reabsorção Óssea/tratamento farmacológico , Gentianaceae/química , Animais , Reabsorção Óssea/patologia , Sobrevivência Celular , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Iridoides/isolamento & purificação , Iridoides/farmacologia , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos ICR , Osteoclastos/efeitos dos fármacos , Extratos Vegetais/química , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Xantonas/isolamento & purificação , Xantonas/farmacologia
7.
Mol Nutr Food Res ; 62(20): e1800359, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30152045

RESUMO

SCOPE: The study aims to determine whether Lactobacillus plantarum C29-fermented defatted soybean (FDS, DW2009) can attenuate memory impairment in 5XFAD transgenic (Tg) mice. METHODS AND RESULTS: Oral administration of FDS or C29 increases cognitive function in Tg mice in passive avoidance, Y-maze, novel object recognition, and Morris water maze tasks. FDS or C29 treatment significantly suppresses amyloid-ß, ß/γ-secretases, caspase-3 expression, and NF-κB activation, and activates microglia and apoptotic neuron cell populations, and increases BDNF expression in the brain. FDS or C29 treatment suppresses blood and fecal lipopolysaccharide levels and Enterobacteriaceae population and increases lactobacilli/bifidobacteria populations. CONCLUSION: FDS and C29 alleviates the decrease in cognitive function and inhibited amyloid-ß expression in Tg mice by regulating microglia activation and gut microbiota composition.


Assuntos
Microbioma Gastrointestinal/fisiologia , Lactobacillus plantarum , Transtornos da Memória/dietoterapia , Microglia/fisiologia , Alimentos de Soja/microbiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Caspase 3/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Masculino , Camundongos Transgênicos , NF-kappa B/metabolismo , Fosforilação
8.
J Agric Food Chem ; 65(32): 6877-6885, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28771341

RESUMO

Lactobacillus plantarum C29-fermented defatted soybean (FDS), which contains soyasaponins such as soyasaponin I (SI) and soyasapogenol B (SB) and isoflavones such as genistin (GE) and genistein (GT), attenuated memory impairment in mice. Moreover, in the preliminary study, FDS and its soyasaponins and isoflavones significantly inhibited NF-κB activation in LPS-stimulated microglial BV2 cells. Therefore, we examined the effects of FDS and its constituents SI, SB, GT, and GE on LPS-induced memory impairment in mice. Oral administration of FDS (80 mg/kg), which has higher concentrations of SB and GE than DS, recovered LPS-impaired cognitive function in Y-maze (55.1 ± 3.5%) and passive avoidance tasks (50.9 ± 19.2 s) to 129.2% (74.1 ± 3.5%) and 114.2% (290.0 ± 22.4 s) of normal mice, respectively (P < 0.05). SB and GE (10 µM) also more potently attenuated LPS-impaired cognitive behavior than SI and GT, respectively. SB (10 mg/kg) was the most effective: treatment recovered LPS-impaired spontaneous alternation and latency time to 105.7% and 126.8% of normal control mice, respectively (P < 0.05). SB and GE significantly increased BDNF expression and CREB phosphorylation in LPS-treated mice and corticosterone-stimulated SH-SY5Y cells. Furthermore, SB and GE (10 µM) also significantly inhibited NF-κB activation in LPS-treated mice. These findings suggested that FDS and its constituent soyasaponins and isoflavones may attenuate memory impairment by the regulation of NF-κB-mediated BDNF expression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Genisteína/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/genética , NF-kappa B/genética , Ácido Oleanólico/análogos & derivados , Extratos Vegetais/administração & dosagem , Saponinas/administração & dosagem , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fermentação , Genisteína/metabolismo , Humanos , Lipopolissacarídeos/efeitos adversos , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/metabolismo , Extratos Vegetais/metabolismo , Saponinas/metabolismo , Glycine max/metabolismo , Glycine max/microbiologia
11.
J Nat Prod ; 70(12): 2029-32, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17994703

RESUMO

Three new flavonoid glycosides ( 1- 3), 11-hydroxyhainanolidol ( 4), and a new dibenzylbutyrolactone lignan glycoside ( 5) were isolated from the aerial parts of Cephalotaxus koreana Nakai, along with 19 known flavonoids. The structures of the new compounds were elucidated using spectroscopic evidence, primarily NMR and MS. Twenty-four compounds were isolated, and among these isoscutellarein 5-O-beta-D-glucopyranoside ( 3), apigenin ( 6), kaempferol 3-O-alpha-L-rhamnopyranosyl(1'''-->6'')-beta-D-glucopyranoside ( 7), tamarixetin 3-O-alpha-L-rhamnopyranosyl(1'''-->6'')-beta-D-glucopyranoside ( 8), quercetin 3-O-[6''-O-acetyl]-beta-D-glucopyranoside ( 9), and quercetin 3-O-alpha-L-rhamnopyranoside ( 10) showed significant inhibitory activities against osteoclast differentiation at concentrations of 0.1 and 1.0 microg/mL.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Cephalotaxus/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Glucosídeos/isolamento & purificação , Glucosídeos/farmacologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Plantas Medicinais/química , Relação Dose-Resposta a Droga , Flavonoides/química , Glucosídeos/química , Glicosídeos , Coreia (Geográfico) , Estrutura Molecular , Osteoclastos/citologia
12.
Biochem Biophys Res Commun ; 337(3): 815-23, 2005 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-16213465

RESUMO

Osteoclasts originating from hematopoietic precursor cells differentiate into multinucleated cells through multiple steps. The essential roles of NF-kappaB and AP-1 in osteoclast differentiation have been clearly demonstrated in numerous studies. c-Fos, a component of AP-1 transcription factor, plays a key role in osteoclast differentiation. Recently, we found a strong inhibitor of AP-1 transcriptional activity, named momordin I, based on the structure of oleanolic acid glycosides and originally isolated from Ampelopsis radix. So, we hypothesized that momordin I might be able to regulate osteoclast formation, activity, and survival. Here, we report the ability of momordin I to suppress osteoclastogenesis in a co-cultured system and a RANKL-induced osteoclast precursor system. Momordin I remarkably inhibited the activation of NF-kappaB as well as AP-1 in RANKL-induced RAW264.7 cells, in which momordin I appeared to target IkappaB degradation and c-Fos expression, respectively, but not MAPK signaling pathways. The ability of momordin I to change the ratio of RANKL and OPG in primary osteoblasts was partially responsible for the reduction of osteoclast formation. Furthermore, pit formation on dentin slices was suppressed by momordin I with stimulating actin ring disruption. Our results also showed that momordin I highly shortened osteoclast lifespan and induced osteoclast apoptosis. In conclusion, the present results demonstrate for the first time that momordin I is a potent inhibitor of osteoclast differentiation via the reduction of NF-kappaB and AP-1, and also suppresses osteoclast function and survival.


Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , NF-kappa B/metabolismo , Ácido Oleanólico/análogos & derivados , Osteoclastos/citologia , Osteoclastos/fisiologia , Fator de Transcrição AP-1/metabolismo , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células-Tronco Hematopoéticas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Ácido Oleanólico/administração & dosagem , Osteoclastos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fator de Transcrição AP-1/antagonistas & inibidores
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