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1.
J Microbiol Biotechnol ; 34(1): 157-166, 2024 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-38282410

RESUMEN

Sarcopenia is an age-related loss of muscle mass and function for which there is no approved pharmacological treatment. We tested direct efficacy by evaluating grip strength improvement in a sarcopenia mouse model rather than drug screening, which inhibits specific molecular mechanisms. Various physiological functions of ginseng berries are beneficial to the human body. The present study aimed to evaluate the efficacy and safety of steamed ginseng berry powder (SGBP). SGBP administration increased myotube diameter and suppressed the mRNA expression of sarcopenia-inducing molecules. SGBP also reduced the levels of inflammatory transcription factors and cytokines that are known to induce sarcopenia. Oral administration of SGBP improved muscle mass and physical performance in a mouse model of sarcopenia. In summary, our data suggest that SGBP is a novel therapeutic candidate for the amelioration of muscle weakness, including sarcopenia.


Asunto(s)
Panax , Sarcopenia , Animales , Ratones , Humanos , Sarcopenia/tratamiento farmacológico , Sarcopenia/metabolismo , Frutas , Polvos/metabolismo , Polvos/farmacología , Atrofia Muscular/tratamiento farmacológico , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo
2.
Int Immunopharmacol ; 121: 110461, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37331298

RESUMEN

Ginsenosides are steroid glycosides derived from ginseng plants such as Panax ginseng, Panax quinquefolium, and Panax notoginseng. Advances in recent studies have identified numerous physiological functions of each type of ginsenoside, i.e., immunomodulatory, antioxidative, and anti-inflammatory functions, in the context of inflammatory diseases. Accumulating evidence has revealed the molecular mechanisms by which the single or combined ginsenoside(s) exhibit anti-inflammatory effects, although it remains largely unclear. It is well known that excessive production of reactive oxygen species (ROS) is associated with pathological inflammation and cell death in a variety of cells, and that inhibition of ROS generation ameliorates the local and systemic inflammatory responses. The mechanisms by which ginsenosides attenuate inflammation are largely unknown; however, targeting ROS is suggested as one of the crucial mechanisms for the ginsenosides to control the pathological inflammation in the immune and non-immune cells. This review will summarize the latest progress in ginsenoside studies, particularly in the context of antioxidant mechanisms for its anti-inflammatory effects. A better understanding of the distinct types and the combined action of ginsenosides will pave the way for developing potential preventive and therapeutic modalities in treating various inflammation-related diseases.


Asunto(s)
Ginsenósidos , Panax notoginseng , Ginsenósidos/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo , Antioxidantes/metabolismo , Inflamación/tratamiento farmacológico
3.
Int J Mol Sci ; 23(18)2022 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-36142743

RESUMEN

Sepsis is an uncontrolled response to inflammatory infection and is associated with high levels of mortality and morbidity. Rg4 is a rare ginsenoside mainly found in the leaves of Panax ginseng C. A. Meyer and the major protopanaxatriol-type ginsenoside of black ginseng. In this study, we determined whether Rg4 affects cecal ligation and puncture (CLP)-induced sepsis. Animals were separated into the following six groups: control group, CLP-operated group, CLP plus maslinic acid (MA), and CLP plus Rg4 (5, 10, or 15 mg/kg). Survival rate, body weight changes, inflammatory cytokines, and histological analyses were assessed. Human endothelial cells were activated with the high-mobility group box 1 (HMGB1) protein and Rg4. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were used to assess inflammation and gene expression, respectively. After CLP surgery, the Rg4-administered group exhibited a higher survival rate and body weight compared with the untreated control group. Rg4 treatment reduced cytokine levels, including tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, as well as nitric oxide (NO) levels and renal inflammation. After Rg4 treatment of HMGB1-activated cells, the expressions of toll-like receptor (TLR) 4 and TNF-α were decreased, and the activation of phosphoinositide 3-kinase (PI3K)/AKT signaling increased cell viability. In summary, Rg4 inhibited inflammation and exhibited a protective effect against CLP-induced sepsis, thereby reinforcing cell survival against septic responses.


Asunto(s)
Ginsenósidos , Proteína HMGB1 , Panax , Sepsis , Animales , Peso Corporal , Citocinas/metabolismo , Células Endoteliales/metabolismo , Ginsenósidos/farmacología , Ginsenósidos/uso terapéutico , Proteína HMGB1/genética , Humanos , Inflamación , Ligadura , Óxido Nítrico , Panax/metabolismo , Fosfatidilinositol 3-Quinasa , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Punciones , Sepsis/tratamiento farmacológico , Sepsis/etiología , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa
4.
Braz. J. Pharm. Sci. (Online) ; 58: e19473, 2022. tab, graf
Artículo en Inglés | LILACS | ID: biblio-1384023

RESUMEN

Abstract RGX-365 is the main fraction of black ginseng conmprising protopanaxatriol (PPT)-type rare ginsenosides (ginsenosides Rg4, Rg6, Rh4, Rh1, and Rg2). No studies on the antiseptic activity of RGX-365 have been reported. High mobility group box 1 (HMGB1) is recognized as a late mediator of sepsis, and the inhibition of HMGB1 release and recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. In this study, we examined the effects of RGX-365 on HMGB1-mediated septic responses and survival rate in a mouse sepsis model. RGX-365 was administered to the mice after HMGB1 challenge. The antiseptic activity of RGX-365 was assessed based on the production of HMGB1, measurement of permeability, and septic mouse mortality using a cecal ligation and puncture (CLP)-induced sepsis mouse model and HMGB1-activated human umbilical vein endothelial cells (HUVECs). We found that RGX-365 significantly reduced HMGB1 release from LPS- activated HUVECs and CLP-induced release of HMGB1 in mice. RGX-365 also restored HMGB1-mediated vascular disruption and inhibited hyperpermeability in the mice. In addition, treatment with RGX-365 reduced sepsis-related mortality in vivo. Our results suggest that RGX- 365 reduces HMGB1 release and septic mortality in vivo, indicating that it is useful in the treatment of sepsis.


Asunto(s)
Proteína HMGB1/análisis , Panax/efectos adversos , Permeabilidad , Sepsis/patología , Ginsenósidos , Células Endoteliales de la Vena Umbilical Humana/clasificación , Antiinfecciosos Locales/efectos adversos
5.
J Med Food ; 24(8): 852-859, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34382871

RESUMEN

CYJ-27, a synthetic analog of decursin, prevents the generation of proinflammatory cytokines and oxidative stress. In this study, the effects of CYJ-27 on the regulation of inducible nitric oxide synthase (iNOS), heme oxygenase (HO)-1, and cyclooxygenase (COX-)2 were characterized in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs). In addition, the effects of CYJ-27 on the production of iNOS and representative proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, were tested in the lung tissues of LPS-treated mice. CYJ-27 promoted the expression of HO-1, suppressed NF-κB-luciferase activity, and reduced COX-2/PGE2 and iNOS/NO, resulting in a diminution in phosphorylated-STAT-1. Furthermore, CYJ-27 promoted the nuclear translocation of Nrf2, enhanced the combination of Nrf2 to antioxidant response elements, and diminished IL-1ß production in LPS-activated HUVECs. CYJ-27-downregulated iNOS/NO expression was rescued after the RNAi suppression of HO-1. In LPS-treated mice, CYJ-27 significantly diminished iNOS production in the lung tissues and TNF-α expression in the bronchoalveolar lavage fluid. These findings indicate that CYJ-27 exerts anti-inflammatory activities by regulating iNOS through downregulation of both NF-κB activation and phosphorylated-STAT-1. Hence, it can act as a template for the development of novel substances to treat inflammatory diseases.


Asunto(s)
Inflamación , FN-kappa B , Animales , Benzopiranos , Butiratos , Ciclooxigenasa 2/metabolismo , Regulación hacia Abajo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Lipopolisacáridos , Ratones , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo
6.
Commun Biol ; 4(1): 5, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33398110

RESUMEN

Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient's cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011). This chemical can extend the life span of LmnaG609G/G609G mouse for about 10 weeks and increase its body weight. Progerinin can also extend the life span of LmnaG609G/+ mouse for about 14 weeks via oral administration, whereas treatment with lonafarnib (farnesyl-transferase inhibitor) can only extend the life span of LmnaG609G/+ mouse for about two weeks. In addition, progerinin can induce histological and physiological improvement in LmnaG609G/+ mouse. These results indicate that progerinin is a strong drug candidate for HGPS.


Asunto(s)
Progeria/tratamiento farmacológico , Adolescente , Animales , Niño , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Células HEK293 , Humanos , Lamina Tipo A/antagonistas & inhibidores , Masculino , Ratones , Cultivo Primario de Células
7.
J Microbiol Biotechnol ; 30(10): 1536-1542, 2020 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-32807763

RESUMEN

Dekkera anomala YAE-1 strain separated from "airag" (Mongolian fermented mare's milk) produces ß-glucosidase, which can convert ginsenoside Rb1 from Panax ginseng. Ginseng-derived bioactive components such as ginsenoside Rb1 have various immunological and anticancer activities. Airag was collected from five different mare milk farms located near Ulaanbaatar, Mongolia. YAE-1 strains were isolated from airag to examine the hydrolytic activities of ß-glucosidase on Korean Panax ginseng using an API ZYM kit. Supernatants of selected cultures having ß-glucosidase activity were examined for hydrolysis of the major ginsenoside Rb1 at 40°C, pH 5.0. The YAE-1 strain was found to be nearly identical at 99.9% homology with Dekkera anomala DB-7B, and was thus named Dekkera anomala YAE-1. This strain exerted higher ß-glucosidase activity than other enzymes. Reaction mixtures from Dekkera anomala YAE-1 showed great capacity for converting ginsenoside Rb1 to ginsenoside Rd. The ß-glucosidase produced by Dekkera anomala YAE-1 was able to hydrolyze ginsenoside Rb1 and convert it to Rd during fermentation of the ginseng. The amount of ginsenoside Rd was highly increased from 0 to 1.404 mg/ml in fermented 20% ginseng root at 7 days.


Asunto(s)
Brettanomyces/metabolismo , Ginsenósidos/metabolismo , Leche/microbiología , Animales , Biotransformación , Productos Lácteos Cultivados/microbiología , Fermentación , Caballos , Hidrólisis , Panax/metabolismo , Panax/microbiología , Raíces de Plantas/metabolismo , Raíces de Plantas/microbiología , beta-Glucosidasa/metabolismo
8.
Am J Chin Med ; 48(5): 1091-1102, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32668967

RESUMEN

Black ginseng (BG), which is ginseng that has been steamed and dried nine times, and its main protopanaxatriol-type ginsenosides Rg4, Rg6, Rh4, and Rg2 have been reported to exhibit various forms of biological activity, including antiseptic, antidiabetic, wound-healing, immune-stimulatory, and anti-oxidant activity. The aim of the this study was to examine the effects of [Formula: see text] (a rare protopanaxatriol-type ginsenoside fraction; Rg2, Rg4, Rg6, Rh1, and Rh4) on heme oxygenase-1 (HO-1) induction and on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-)2 in lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs). [Formula: see text] was tested to determine its effect on iNOS protein expression and inflammatory markers (interleukin [IL]-1[Formula: see text] and tumor necrosis factor [TNF]-[Formula: see text] in the lung tissue of LPS-treated mice. The results showed that [Formula: see text] induced the expression of HO-1, reduced LPS-activated NF-[Formula: see text]B-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, which contributed to the inhibition of STAT-1 phosphorylation. In particular, [Formula: see text] induced the translocation of Nrf2 from the cytosol to the nucleus by increasing Nrf2-ARE activity and decreased IL-1[Formula: see text] production in LPS-activated HPAECs. This reduction in iNOS/NO expression due to [Formula: see text] was reversed by siHO-1 RNA transfection. In LPS-treated mice, [Formula: see text] significantly reduced lung tissue iNOS protein levels and TNF-[Formula: see text] levels in the bronchoalveolar lavage fluid. In conclusion, these findings indicate that [Formula: see text] has a critical anti-inflammatory effect due to its ability to regulate iNOS via the inhibition of p-STAT-1 and NF-[Formula: see text]B, and thus it may be suitable for the treatment of inflammatory disease.


Asunto(s)
Expresión Génica/efectos de los fármacos , Ginsenósidos/farmacología , Inflamación/genética , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Panax/química , Factor de Transcripción STAT1/metabolismo , Animales , Antiinflamatorios , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Ginsenósidos/aislamiento & purificación , Hemo-Oxigenasa 1/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación/tratamiento farmacológico , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Luciferasas/metabolismo , Masculino , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Fitoterapia
9.
Am J Chin Med ; 47(6): 1237-1251, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31495180

RESUMEN

Inhalation of fine particulate matter (PM2.5) is associated with elevated pulmonary injury caused by the loss of vascular barrier integrity. Black ginseng (BG), steamed and dried ginseng nine times, exhibits various pharmacological activities such as antibacterial, antihyperglycemic, anti-atopic, antibacterial, and anti-inflammatory activities. In this study, we investigated the beneficial effects of black ginseng extract (BGE) against PM-induced lung endothelial cell (EC) barrier disruption and pulmonary inflammation. Permeability, leukocyte migration, activation of proinflammatory proteins, generation of reactive oxygen species (ROS), and histology were examined in PM2.5-treated ECs and mice. BGE significantly scavenged PM2.5-induced ROS and inhibited the ROS-induced activation of p38 mitogen-activated protein kinase (MAPK). Concurrently, BGE activated Akt, which helped maintain endothelial integrity. Furthermore, BGE reduced vascular protein leakage, leukocyte infiltration, and proinflammatory cytokine release in the bronchoalveolar lavage fluid in PM-induced lung tissues. These results indicated that BGE may exhibit protective effects against PM-induced inflammatory lung injury and vascular hyperpermeability.


Asunto(s)
Lesión Pulmonar/etiología , Lesión Pulmonar/prevención & control , Panax/química , Material Particulado/efectos adversos , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Animales , Permeabilidad Capilar/efectos de los fármacos , Células Cultivadas , Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Lesión Pulmonar/metabolismo , Lesión Pulmonar/patología , Masculino , Ratones Endogámicos BALB C , Extractos Vegetales/aislamiento & purificación , Neumonía/etiología , Neumonía/prevención & control , Proteínas Proto-Oncogénicas c-akt/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
10.
Am J Chin Med ; 47(1): 119-133, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30630344

RESUMEN

High mobility group box 1 (HMGB1) is considered as a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses, and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Ginsenoside Rh1, a protopanaxatriol type ginsenoside, is one of the major bioactive components of Korean red ginseng, which has been increasingly used for enhancing cognition and physical health worldwide. Ginsenoside Rh1 exhibits potent biological activities such as antistress, anti-oxidant, anti-inflammatory and immunomodulatory effects. We examined the effects of ginsenoside Rh1 on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. Ginsenoside-Rh1 was administered after the HMGB1 challenge. The antiseptic activity of ginsenoside Rh1 was determined by measuring the permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and mice, and the survival rate in a sepsis mouse model. Ginsenoside Rh1 significantly reduced HMGB1 release in lipopolysaccharide (LPS)-activated HUVECs. Furthermore, ginsenoside Rh1 suppressed the production of tumor necrosis factor (TNF)- α , interleukin (IL)-6, activation of nuclear factor (NF)- κ B and extracellular signal-regulated kinase (ERK) 1/2 by HMGB1. Ginsenoside Rh1 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ginsenoside Rh1 reduced the cecal ligation and puncture (CLP)-induced release of HMGB1, sepsis-related mortality and tissue injury in vivo. Our results indicated that ginsenoside Rh1 might be useful in the treatment of sepsis by targeting HMGB1.


Asunto(s)
Ginsenósidos/administración & dosificación , Ginsenósidos/farmacología , Proteína HMGB1/metabolismo , Mediadores de Inflamación/metabolismo , Fitoterapia , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Choque Séptico/tratamiento farmacológico , Choque Séptico/metabolismo , Animales , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Depresión Química , Modelos Animales de Enfermedad , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leucocitos , Lipopolisacáridos/efectos adversos , Masculino , Ratones Endogámicos C57BL , Panax/química
11.
J Cell Biochem ; 120(4): 6277-6289, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30378167

RESUMEN

Inhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as attractive therapeutic strategies for the management of severe vascular inflammatory diseases. Recently, we found that JH-4, a synthesized decursin derivative, exhibited a strong anti-Hutchinson-Gilford progeria syndrome by efficiently blocking progerin-lamin A/C binding. In this study, we examined the effects of JH-4 on HMGB1-mediated septic responses and the survival rate in a mouse sepsis model. The anti-inflammatory activities of JH-4 were monitored based on its effects on lipopolysaccharide- or cecal ligation and puncture (CLP)-mediated release of HMGB1. The antiseptic activities of JH-4 were determined by measuring permeability, leukocyte adhesion, migration, and the activation of proinflammatory proteins in HMGB1-activated human umbilical vein endothelial cells and mice. JH-4 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. JH-4 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with JH-4 reduced CLP-induced release of HMGB1, sepsis-related mortality, and pulmonary injury in vivo. Our results indicate that JH-4 is a possible therapeutic agent to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.


Asunto(s)
Antiinfecciosos Locales/uso terapéutico , Antiinflamatorios/uso terapéutico , Benzopiranos/uso terapéutico , Butiratos/uso terapéutico , Proteína HMGB1/metabolismo , Extractos Vegetales/uso terapéutico , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Angelica/química , Animales , Antiinfecciosos Locales/farmacología , Antiinflamatorios/farmacología , Benzopiranos/farmacología , Butiratos/farmacología , Permeabilidad Capilar/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Proteína HMGB1/antagonistas & inhibidores , Proteína HMGB1/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Leucocitos/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/farmacología , Sepsis/metabolismo , Tasa de Supervivencia
12.
Food Chem Toxicol ; 124: 45-53, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30496780

RESUMEN

High mobility group box 1 (HMGB1) is considered to be a late mediator of sepsis. The inhibition of HMGB1-mediated severe inflammatory response and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Rare ginsenosides, Rk1 (SB1) and Rg5 (SB2), are among the main components of black ginseng and are prepared from ginsenoside Rd by steaming at 120 °C for 3 h. We examined the effects of SB1 and SB2 on HMGB1-mediated septic response and survival rate in a mouse model of sepsis. SB1 and SB2 were administered after challenge with HMGB1. SB1 and SB2 significantly reduced the release of HMGB1 in lipopolysaccharide (LPS)-activated primary human umbilical vein endothelial cells (HUVECS) via the SIRT1-mediated deacetylation of HMGB1. Moreover, SB1 and SB2 suppressed the production of TNF-α and IL-6 and the activation of NF-κB and ERK 1/2 by HMGB1. SB1 and SB2 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with SB1 and SB2 reduced the cecal ligation and puncture-induced release of HMGB1, sepsis-related mortality, and tissue injury in vivo. Our results indicate that SB1 and SB2 might be useful in the treatment of sepsis by targeting HMGB1.


Asunto(s)
Antiinflamatorios/uso terapéutico , Ginsenósidos/uso terapéutico , Sepsis/tratamiento farmacológico , Animales , Movimiento Celular/efectos de los fármacos , Proteína HMGB1/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Lesión Pulmonar/tratamiento farmacológico , Masculino , Ratones Endogámicos C57BL , Neutrófilos/efectos de los fármacos , Sirtuina 1/metabolismo
13.
Bioorg Med Chem Lett ; 27(14): 3060-3064, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28551100

RESUMEN

Sialidases are key virulence factors that remove sialic acid from host cell surface glycans, thus unmasking receptors to facilitate bacterial adherence and colonization. In this study, we report the isolation and characterization of novel inhibitors of the Streptococcus pneumoniae sialidases NanA, NanB, and NanC from Myristica fragrans seeds. Of the isolated compounds (1-12), malabaricone C showed the most pneumococcal sialidases inhibition (IC50 of 0.3µM for NanA, 3.6µM for NanB, and 2.9µM for NanC). These results suggested that malabaricone C and neolignans could be potential agents for combating S. pneumoniae infection agents.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Lignanos/farmacología , Myristica/química , Neuraminidasa/antagonistas & inhibidores , Extractos Vegetales/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Concentración 50 Inhibidora , Cinética , Lignanos/química , Lignanos/aislamiento & purificación , Myristica/metabolismo , Neuraminidasa/metabolismo , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Resorcinoles/síntesis química , Resorcinoles/aislamiento & purificación , Resorcinoles/farmacología , Semillas/química , Semillas/metabolismo , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/enzimología
14.
J Clin Invest ; 126(10): 3879-3893, 2016 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-27617860

RESUMEN

Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated ß-gal (SA-ß-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin-lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging.


Asunto(s)
Acrilatos/farmacología , Cumarinas/farmacología , Lamina Tipo A/metabolismo , Progeria/tratamiento farmacológico , Acrilatos/química , Animales , Senescencia Celular , Cumarinas/química , Evaluación Preclínica de Medicamentos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Progeria/metabolismo , Unión Proteica , Isoformas de Proteínas/metabolismo , Transporte de Proteínas/efectos de los fármacos
15.
Drug Dev Ind Pharm ; 39(10): 1523-30, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23003006

RESUMEN

Angelica gigas Nakai and its components are known to have neuroprotective, antiplatelet, and anticancer activities. The present study evaluated the in vitro and in vivo biopharmaceutical characterization of Angelica gigas component substances, including decursin (the main substance), decursinol angelate (decursin isomer), JH714 (ether form of decursin) and epoxide decursin (epoxide form of decursin). Decursin, decursinol angelate and JH714 exhibited acceptable metabolic stability (>50%) in liver microsomes from human and higher bound fraction (>90%) in human plasma operating ultrafiltration. Decursin and decursinol angelate in CYP1A2 and CYP2C19 indicated less than 50% CYP activity, suggesting inhibition of the CYP isoforms using Vivid® CYP screening kit. JH714 only showed an apparent permeability coefficient of <10 × 10⁻6 cm/s in MDCK cells, suggesting that it is poorly absorbed. Blood brain barrier permeability was examined after oral administration to male Sprague-Dawley (SD) rats, and pharmacokinetic studies were performed after oral and intravenous administration of 10 mg/kg compounds. Decursin, decursinol angelate and JH714 showed ratios of compound concentration in brain with respect to plasma (Cbrain/Cplasma) of >1.5, suggesting good brain/plasma ratio at 0.5, 1, 3, and 5 h. In contrast, Cbrain/Cplasma was <0.5 for epoxide decursin. For all test compounds, >1.5% of the dose remained in GI tract after 8 h, and the excretion rate in urine was <0.5% which suggests that gastro intestinal tract may be major site of disposition following oral administration. Finally, these results may be useful for the design of dosage regimens of decursin and its derivatives.


Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Benzopiranos/farmacocinética , Butiratos/farmacocinética , Fármacos Neuroprotectores/farmacocinética , Angelica/química , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/metabolismo , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Hidrocarburo de Aril Hidroxilasas/metabolismo , Benzopiranos/administración & dosificación , Benzopiranos/química , Benzopiranos/metabolismo , Biotransformación , Barrera Hematoencefálica/metabolismo , Butiratos/administración & dosificación , Butiratos/química , Butiratos/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Inhibidores del Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2C19 , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Compuestos Epoxi/administración & dosificación , Compuestos Epoxi/química , Compuestos Epoxi/metabolismo , Compuestos Epoxi/farmacocinética , Éteres/química , Éteres/metabolismo , Éteres/farmacología , Etnofarmacología , Humanos , Absorción Intestinal , Células de Riñón Canino Madin Darby , Masculino , Medicina Tradicional de Asia Oriental , Microsomas Hepáticos/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/metabolismo , Ratas , Ratas Sprague-Dawley
16.
Biol Pharm Bull ; 35(7): 1084-90, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22791156

RESUMEN

Angelica gigas NAKAI is used to treat dysmenorrhea, amenorrhea, menopause, abdominal pain, injuries, migraine, and arthritis. The present study provided a physicochemical and toxicological characterization of compounds in A. gigas NAKAI (decursin, decursinol angelate, diketone decursin, ether decursin, epoxide decursin and oxim decursin). Diketone decursin (173.16 µg/mL) and epoxide decursin (122.12 µg/mL) exhibited >100 µg/mL kinetic solubility after applying nephelometry, suggesting a highly soluble compound. The Student's t-test revealed significant differences in the pKa ranges of the compounds by automatic titration from capillary electrophoresis (p<0.05). Diketone decursin, epoxide decursin and oxim decursin might be formulated into an oral dosage form (log P: 0-3) by an automatic titration analysis. A parallel artificial membrane permeability assay demonstrated permeability coefficients of <10 x 10⁻6 cm/s for all of the compounds, suggesting poor permeability. Ether decursin exhibited a toxic effect after being applied to mouse (NIH 3T3, EC50: 57.9 µM) and human (HT-29, EC50: 36.1 µM; Hep-G2, EC50: 4.92 µM) cells. Additionally, epoxide and oxim decursin were toxic through acute oral toxicity (four and three deaths of Institute of Cancer Research (ICR) mice) and mutation toxicity testing by applying Salmonella typhimurium cells with and without S9. Although diketone decursin exhibited less permeability, it is potentially valuable pharmacological compound that should be investigated.


Asunto(s)
Angelica/química , Benzopiranos/toxicidad , Butiratos/toxicidad , Extractos Vegetales/toxicidad , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Pruebas de Mutagenicidad , Células 3T3 NIH , Permeabilidad , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética
17.
Arch Pharm Res ; 35(4): 647-51, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22553057

RESUMEN

A new lupane-triterpene, 3ß-cis-feruloyloxy-16ß-hydroxylup-20(29)-ene (1) were isolated from the ethyl acetate extract of Panax ginseng seeds along with the known compound, 3ß-transferuloyloxy-16ß-hydroxylup-20(29)-ene (2). Compound 2 was isolated from this plant for the first time. Their chemical structures were determined by mass spectroscopy and one-dimensional and two-dimensional magnetic resonance spectra. The bioactive effects of these compounds on TNF-α-induced NF-κB transcription were evaluated in transfected HepG2 cells. Effects on the expression of NF-κB target genes were also examined using a reverse transcription-polymerase chain reaction. Both compounds 1 and 2 were inhibited NF-κB activity in HepG2 cells by decreasing the cellular concentrations of inflammatory factors iNOS and COX2.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , FN-kappa B/antagonistas & inhibidores , Panax/química , Triterpenos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , FN-kappa B/genética , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Semillas/química , Espectrometría de Masa por Ionización de Electrospray , Transfección , Triterpenos/química , Triterpenos/aislamiento & purificación
18.
Food Chem ; 132(1): 333-7, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-26434298

RESUMEN

The antioxidant activity of saponins isolated from Platycodon grandiflorum (PG; Balloon flower) was determined using the total oxidant-scavenging capacity (TOSC) assay. Platycodigenin, polygalacic acid, platycodin D, platycoside E and deapioplatycoside E were isolated and their structures were characterised based on their physical and spectral properties and by comparison of these results with similar data in the literature. Platycodin D showed the greatest TOSC value against peroxyl radicals, followed (in decreasing order) by polygalacic acid, platycodigenin, deapioplatycosides E and platycoside E. Although the TOSC value of the saponins against peroxyl radicals was less than that of glutathione (GSH) and Trolox used as positive controls. However, TOSC value of platycodigenin, deapioplatycoside E, platycodin D or platycoside E against peroxynitrite was 2.35-, 1.27-, 1.02- or 0.75-fold of GSH, respectively, while polygalacic acid exhibited no scavenging capacity of peroxynitrites. These results suggest importance of the presence of hydroxyl group at carbon 24 in platycodigenin in peroxynitrite scavenging. As the number of attached sugar residues in the saponin glycosides is increased, the scavenging capacity of peroxyl radical, but not peroxynitrite was significantly decreased. These results showed that PG saponins have potent antioxidant activities, which is different according to the structure of aglycones and the number of attached sugar residues.


Asunto(s)
Extractos Vegetales/química , Raíces de Plantas/química , Platycodon/química , Saponinas/química , Oxidación-Reducción , Estrés Oxidativo , Extractos Vegetales/análisis , Relación Estructura-Actividad
19.
Arch Pharm Res ; 34(4): 681-5, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21544734

RESUMEN

Interleukin-12, a heterodimeric cytokine comprising p40 and p35 subunits, plays an essential role in the regulating the differentiation of Th cells, which establish and maximize the capabilities of the immune system. The aim of present study is to screen the effect of 21 ginsenosides from steamed ginseng-leaves and flowers on IL-12 production in bone marrow-derived dendritic cells induced by lipopolysaccharide. Noticeably, ginsenoside Rg(6) (12) and ginsenoside F(4) (13) exhibited particularly inhibitory effect on LPS-induced IL-12 production with the inhibition values of 80 and 82%; and ginsenoside ST(1) (4), ginsenoside SL(2) (8), ginsenoside SL(3) (9), ginsenoside Rh(3) (14), ginsenoside Rk(2) (15), and ginsenoside Rs(4) (18) showed moderate effects with inhibition rates of 63, 65, 67, 68, 71, 73, and 67%, respectively. These results warrant further studies concerning potential of saponin extracts of steamed ginseng-leaves and flowers for medicinal uses.


Asunto(s)
Células de la Médula Ósea/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Ginsenósidos/farmacología , Interleucina-12/biosíntesis , Panax/química , Preparaciones de Plantas/farmacología , Animales , Células de la Médula Ósea/inmunología , Células Cultivadas , Células Dendríticas/inmunología , Relación Dosis-Respuesta a Droga , Flores/química , Ginsenósidos/química , Ginsenósidos/aislamiento & purificación , Interleucina-12/inmunología , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Hojas de la Planta/química , Preparaciones de Plantas/química , Preparaciones de Plantas/aislamiento & purificación , Vapor , Relación Estructura-Actividad
20.
Chem Pharm Bull (Tokyo) ; 58(8): 1111-5, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20686271

RESUMEN

Three new dammarane-type glycosides, named ginsenosides SL(1)-SL(3) (1-3), and eleven known compounds (4-14) were isolated from the heat-processed leaves of Panax ginseng. Their structures were elucidated on the basis of extensive chemical and spectroscopic methods. Cytotoxic-activity testing of compounds 1-14 against human leukemia HL-60 cells showed that ginsenosides Rh(3) (11) and Rk(2) (12) exhibited potent effects with IC(50) values of 0.8 and 0.9 microM. In addition, ginsenosides SL(3) (3), 20S-Rg(2) (7), F(4) (10), 20S-Rh(2) (13) displayed strong activity with IC(50) values of 9.0, 9.0, 7.5, and 8.2 microM, respectively. This is the first report on chemical components of the steamed ginseng leaves.


Asunto(s)
Antineoplásicos/toxicidad , Ginsenósidos/toxicidad , Panax/química , Extractos Vegetales/toxicidad , Hojas de la Planta/química , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Ginsenósidos/química , Ginsenósidos/aislamiento & purificación , Células HL-60 , Humanos , Concentración 50 Inhibidora , Conformación Molecular , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Estereoisomerismo
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