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1.
Amino Acids ; 48(2): 523-33, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26433892

RESUMEN

Dietary supplementation with N-acetylcysteine (NAC) has been reported to improve intestinal health and treat gastrointestinal diseases. However, the underlying mechanisms are not fully understood. According to previous reports, NAC was thought to exert its effect through glutathione synthesis. This study tested the hypothesis that NAC enhances enterocyte growth and protein synthesis independently of cellular glutathione synthesis. Intestinal porcine epithelial cells were cultured for 3 days in Dulbecco's modified Eagle medium containing 0 or 100 µM NAC. To determine a possible role for GSH (the reduced form of glutathione) in mediating the effect of NAC on cell growth and protein synthesis, additional experiments were conducted using culture medium containing 100 µM GSH, 100 µM GSH ethyl ester (GSHee), diethylmaleate (a GSH-depletion agent; 10 µM), or a GSH-synthesis inhibitor (buthionine sulfoximine, BSO; 20 µM). NAC increased cell proliferation, GSH concentration, and protein synthesis, while inhibiting proteolysis. GSHee enhanced cell proliferation and GSH concentration without affecting protein synthesis but inhibited proteolysis. Conversely, BSO or diethylmaleate reduced cell proliferation and GSH concentration without affecting protein synthesis, while promoting protein degradation. At the signaling level, NAC augmented the protein abundance of total mTOR, phosphorylated mTOR, and phosphorylated 70S6 kinase as well as mRNA levels for mTOR and p70S6 kinase in IPEC-1 cells. Collectively, these results indicate that NAC upregulates expression of mTOR signaling proteins to stimulate protein synthesis in enterocytes independently of GSH generation. Our findings provide a hitherto unrecognized biochemical mechanism for beneficial effects of NAC in intestinal cells.


Asunto(s)
Acetilcisteína/farmacología , Proliferación Celular/efectos de los fármacos , Enterocitos/metabolismo , Glutatión/metabolismo , Biosíntesis de Proteínas/efectos de los fármacos , Animales , Butionina Sulfoximina/farmacología , Línea Celular , Cisteína/metabolismo , Factores Eucarióticos de Iniciación/metabolismo , Glutatión/análogos & derivados , Glutatión/farmacología , Maleatos/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Sus scrofa , Serina-Treonina Quinasas TOR/metabolismo
2.
Amino Acids ; 47(1): 65-78, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25280462

RESUMEN

Neonates (including human infants) require L-glutamine (Gln) for optimal intestinal health. This study tested the hypothesis that Gln enhances enterocyte growth via both mammalian target of rapamycin (mTOR) and AMP-activated kinase (AMPK) signaling pathways. Intestinal porcine epithelial cells (IPEC-1) were cultured for 3 days in Gln-free Dulbecco's modified Eagle medium containing 0 or 2 mM Gln. To determine the role of mTOR and AMPK on cell growth, additional experiments were conducted where medium contained 2 mM Gln and 10 nM rapamycin (Rap, an inhibitor of mTOR) or 1 µM compound C (an inhibitor of AMPK). IPEC-1 cell growth increased with increasing concentrations of Gln from 0 to 2 mM. Compared with 0 mM Gln, 2 mM Gln increased (P < 0.05) the amounts of phosphorylated 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase (p70S6 kinase) proteins but did not affect abundances of total or phosphorylated AMPK protein. Gln also increased mRNA levels for Bcl-2, mTOR, p70S6 kinase, 4E-BP1, COX7C, ASCT2, ODC, SGLT-1, CFTR, Na(+)/K(+)-ATPase, HSP70, and ZO-1. Similarly, cells cultured with Rap and Gln exhibited higher (P < 0.05) abundances of phosphorylated 4E-BP1 and p70S6 kinase proteins than the Rap-only group, whereas abundances of phosphorylated mTOR and 4E-BP1 proteins were increased when AMPK was inhibited by compound C. Conversely, the amount of phosphorylated AMPK increased when mTOR was inhibited by Rap, suggesting a negative cross-talk between mTOR and AMPK. Collectively, these results indicate that Gln stimulates enterocyte growth by activating the mTOR signaling pathway independently of AMPK.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proliferación Celular , Enterocitos/citología , Enterocitos/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Animales , Glutamina , Fosforilación , Proteínas Quinasas S6 Ribosómicas/genética , Proteínas Quinasas S6 Ribosómicas/metabolismo , Transducción de Señal , Porcinos , Serina-Treonina Quinasas TOR/genética
3.
Br J Nutr ; 111(1): 46-54, 2014 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-23829996

RESUMEN

The present study was carried out to determine whether N-acetylcysteine (NAC) could modulate liver injury in a lipopolysaccharide (LPS)-challenged piglet model. For this purpose, eighteen piglets were randomly assigned to the control, LPS or NAC group. Piglets in the control and LPS groups were fed a basal diet, whereas those in the NAC group were fed the basal diet supplemented with 500 mg/kg NAC. On days 10, 13 and 20 of the trial, the LPS- and NAC-treated piglets were intraperitoneally administered LPS (100 µg/kg body weight), while the control group was administered the same volume of saline. On day 20 of the trial, blood samples were obtained 3 h after LPS or saline injection. On day 21, the piglets were killed to collect liver samples. Dietary NAC supplementation attenuated LPS-induced liver histomorphological abnormalities. Compared with the control group, in the LPS-challenged piglets, the activities of alanine aminotransferase and aspartate aminotransferase and the concentrations of H2O2, TNF-α, IL-6 and PGE2 were dramatically increased in the plasma and the activity of superoxide dismutase in the plasma and that of glutathione peroxidase in the liver were significantly decreased. The LPS challenge also increased the concentration of AMP and the ratio of AMP:ATP, but decreased adenylate energy charges and the levels of ATP and ADP. These adverse effects of the LPS challenge were ameliorated by NAC supplementation. Moreover, NAC inhibited the LPS-induced increases in the abundance of liver heat shock protein 70 and NF-κB proteins. In conclusion, these results suggest that dietary NAC supplementation alleviates LPS-induced liver injury by reducing the secretion of pro-inflammatory cytokines, increasing the antioxidative capacity and improving energy metabolism.


Asunto(s)
Acetilcisteína/uso terapéutico , Antioxidantes/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Citocinas/metabolismo , Suplementos Dietéticos , Mediadores de Inflamación/metabolismo , Hígado/efectos de los fármacos , Acetilcisteína/farmacología , Adenosina Monofosfato/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocinas/sangre , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Femenino , Proteínas HSP70 de Choque Térmico/metabolismo , Lipopolisacáridos , Hígado/enzimología , Hígado/metabolismo , Hígado/patología , FN-kappa B/metabolismo , Distribución Aleatoria , Porcinos
4.
BMC Gastroenterol ; 13: 133, 2013 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-24001404

RESUMEN

BACKGROUND: Ulcerative colitis is a chronic inflammatory disease and involves multiple etiological factors. Acetic acid (AA)-induced colitis is a reproducible and simple model, sharing many characteristics with human colitis. N-acetylcysteine (NAC) has been widely used as an antioxidant in vivo and in vitro. NAC can affect several signaling pathways involving in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and inflammatory response. Therefore, NAC may not only protect against the direct injurious effects of oxidants, but also beneficially alter inflammatory events in colitis. This study was conducted to investigate whether NAC could alleviate the AA-induced colitis in a porcine model. METHODS: Weaned piglets were used to investigate the effects of NAC on AA-induced colitis. Severity of colitis was evaluated by colon histomorphology measurements, histopathology scores, tissue myeloperoxidase activity, as well as concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon. The protective role of NAC was assessed by measurements of antioxidant status, growth modulator, cell apoptosis, and tight junction proteins. Abundances of caspase-3 and claudin-1 proteins in colonic mucosae were determined by the Western blot method. Epidermal growth factor receptor, amphiregulin, tumor necrosis factor-alpha (TNF-α), and toll-like receptor 4 (TLR4) mRNA levels in colonic mucosae were quantified using the real-time fluorescent quantitative PCR. RESULTS: Compared with the control group, AA treatment increased (P < 0.05) the histopathology scores, intraepithelial lymphocyte (IEL) numbers and density in the colon, myeloperoxidase activity, the concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon, while reducing (P < 0.05) goblet cell numbers and the protein/DNA ratio in the colonic mucosa. These adverse effects of AA were partially ameliorated (P < 0.05) by dietary supplementation with NAC. In addition, NAC prevented the AA-induced increase in caspase-3 protein, while stimulating claudin-1 protein expression in the colonic mucosa. Moreover, NAC enhanced mRNA levels for epidermal growth factor and amphiregulin in the colonic mucosa. CONCLUSION: Dietary supplementation with NAC can alleviate AA-induced colitis in a porcine model through regulating anti-oxidative responses, cell apoptosis, and EGF gene expression.


Asunto(s)
Ácido Acético , Acetilcisteína/farmacología , Colitis Ulcerosa , Colitis/prevención & control , Depuradores de Radicales Libres/farmacología , Acetilcisteína/uso terapéutico , Anfirregulina , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/efectos de los fármacos , Caspasa 3/metabolismo , Claudina-1/efectos de los fármacos , Claudina-1/metabolismo , Colitis/inducido químicamente , Colitis/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Suplementos Dietéticos , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Familia de Proteínas EGF , Factor de Crecimiento Epidérmico/sangre , Factor de Crecimiento Epidérmico/efectos de los fármacos , Receptores ErbB/efectos de los fármacos , Receptores ErbB/genética , Depuradores de Radicales Libres/uso terapéutico , Glicoproteínas/efectos de los fármacos , Glicoproteínas/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Interleucina-6/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Porcinos , Receptor Toll-Like 4/efectos de los fármacos , Receptor Toll-Like 4/genética , Factor de Crecimiento Transformador alfa/efectos de los fármacos , Factor de Crecimiento Transformador alfa/metabolismo , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
5.
Environ Pollut ; 256: 113342, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31676093

RESUMEN

PM2.5 exposure aggravates type 2 diabetes, in which inflammatory factors play an important role. In this study, we aimed to explore the mechanisms responsible for aggravating diabetes after PM2.5 exposure, and study the roles of inflammatory factors in insulin-resistant type 2 diabetes. Our study indicated that short-time PM2.5 exposure enhances insulin resistance in type 2 diabetic rats and significantly raises inflammatory factors, including IL-6, TNF-α, and MCP-1, in lungs. However, we found that of these inflammatory factors only IL-6 levels are elevated in blood, liver, adipose tissue, and macrophages, but not in skeletal muscle. IL-6 induced activation of the STAT3/SOCS3 pathway in liver, but not other downstream pathways including STAT1, ERK1/2, and PI3K. Both STAT3 inhibition and IL-6 neutralization effectively alleviated the disorders of glucose metabolism after PM2.5 exposure. Taken together, this suggests that the systemic increase in IL-6 may play an important role in the deterioration of the type 2 diabetes via IL-6/STAT3/SOCS3 pathway in liver after short-time exposure to PM2.5. Besides, we unexpectedly found a stronger resistance to the PM2.5 exposure-induced increase in IL-6 in skeleton muscle than those of many other tissues.


Asunto(s)
Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Tipo 2/inmunología , Interleucina-6/sangre , Material Particulado/toxicidad , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Animales , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Hígado/efectos de los fármacos , Hígado/inmunología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inmunología , Material Particulado/metabolismo , Ratas , Ratas Wistar , Transducción de Señal
6.
Int J Biol Sci ; 16(1): 49-60, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31892845

RESUMEN

PM2.5 exposure exacerbates cardiovascular diseases via oxidative stress and inflammation, the detailed mechanism of which is unclear. In this study, the effects of oxidative stress and inflammation, as well as vascular structure and function were studied by multiple PM2.5 exposure model of ApoE-/- mice. The results indicated that NO produced by iNOS not cNOS might play important roles in inducing vascular dysfunction after PM2.5 exposure. The occurrence order and causality among NO, other oxidative stress indicators and inflammation is explored by single PM2.5 exposure. The results showed that NO generated by iNOS occurred earlier than that of other oxidative stress indicators, which was followed by the increased inflammation. Inhibition of NOS could effectively block the raise of NO, oxidative stress and inflammation after PM2.5 exposure. All in all, we firstly confirmed that NO was the initiation factor of PM2.5 exposure-induced oxidative stress, which led to inflammation and the following vascular dysfunction.


Asunto(s)
Apolipoproteínas E/metabolismo , Inflamación/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Material Particulado/toxicidad , Animales , Apolipoproteínas E/genética , Western Blotting , Inmunohistoquímica , Inflamación/genética , Interleucina-6/sangre , Masculino , Ratones , Ratones Mutantes , Óxido Nítrico Sintasa de Tipo II/genética , Estrés Oxidativo/efectos de los fármacos , Factor de Necrosis Tumoral alfa/sangre
7.
Int J Biol Sci ; 15(1): 24-33, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30662344

RESUMEN

Exposure to airborne particulate matter with an aerodynamic diameter less than or equivalent to 2.5 microns (PM2.5) easily induces acute myocardial infarction in populations with high-risk cardiovascular diseases such as hyperlipidemia, but its mechanism remains unclear. In this study, hyperlipidemic rats were used to examine the effects of PM2.5 exposure on the cardiovascular system and the mechanism for its induction of cardiovascular events. We found that PM2.5 exposure resulted in bigger changes in the myocardial enzyme profile (cTnI, LDH, CK, CK-MB) in hyperlipidemic rats than that of control rats, as well as a significant increase in the C-reactive protein (CRP) level and a decrease in the superoxide dismutase (SOD) activity. It promoted a hypercoagulable state, significantly increased blood pressure and heart rate, while decreased the variability of heart rate in hyperlipidemic rats. In addition, pathological test showed that PM2.5 exposure more easily deteriorated myocardial injury in hyperlipidemic rats. It upregulated the phosphorylation levels of myocardial c-Jun NH2-terminal kinase (JNK) and P53, resulting in the elevated expression of downstream effector protein Bax and the decreased expression of Bcl-2, and then increased caspase3 level leading to cardiomyocyte apoptosis, while little change of caspase2 was observed. Taken together, PM2.5 exposure induced more serious inflammation and oxidative stress in the circulation system of hyperlipidemic rats, promoted a hypercoagulable state and triggered cardiomyocyte apoptosis, in which JNK/P53 pathway played a key role.


Asunto(s)
Apoptosis/efectos de los fármacos , Caspasa 3/metabolismo , Hiperlipidemias/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Material Particulado/toxicidad , Proteína p53 Supresora de Tumor/metabolismo , Animales , Proteína C-Reactiva/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Tiempo de Protrombina , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo
8.
Oncol Rep ; 39(6): 2915-2923, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29693188

RESUMEN

Receptor­interacting protein 2 (RIP2) has recently been reported to be involved in tumor infiltration and cancer metastasis. However, the function of RIP2 in human astrocytoma remains unclear. In the present study, we showed that the expressions of RIP2 and Bcl­xL were positively correlated with the malignant grade in 28 cases of astrocytoma of various grades and 6 cases of normal human tissues. In addition, increased activity of the NF­κB and p38 signaling pathways in astrocytoma tissue was observed. Cytological experiments indicated that RIP2 promoted human glioblastoma cell proliferation by inducing expression of Bcl­xL, and knockdown of endogenous RIP2 promoted cell apoptosis. Mechanistically, knockdown of RIP2 suppressed downstream events including the canonical and alternative NF­κB pathway as well as the mitogen­activated protein kinase (p38) pathway. In addition, the present study also demonstrated that tumor necrosis factor receptor­associated factor 3 (TRAF3), as a novel RIP2 binding partner, was downregulated in glioma tissues and functionally was a negative regulator involved in RIP2­induced glioma cell growth. Taken together, the present study established a negative link between RIP2 and TRAF3 proteins and identifies a new pathway for regulating astrocytoma progression.


Asunto(s)
Neoplasias Encefálicas/patología , Glioma/patología , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/genética , Factor 3 Asociado a Receptor de TNF/genética , Proteína bcl-X/genética , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Clasificación del Tumor , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor/metabolismo , Factor 3 Asociado a Receptor de TNF/metabolismo , Proteína bcl-X/metabolismo
9.
Int J Biol Sci ; 14(5): 557-564, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29805307

RESUMEN

The biggest victim of ambient air pollution is the respiratory system. Mainly because of the harmful components, especially the particulate matters with an aerodynamic diameter of ≤ 2.5µm (PM2.5), can be directly inhaled and deeply penetrate into the lung alveoli, thus causing severe lung dysfunction, including chronic cough, bronchitis and asthma, even lung cancer. Unfortunately, the toxicological mechanisms of PM2.5 associations with these adverse respiratory outcomes have still not been clearly unveiled. Here, we found that PM2.5 rapidly induced inflammatory responses, oxidative injure and cell death in human bronchial epithelium cells through upregulation of IL-6 expression, ROS production and apoptosis. Furthermore, PM2.5 specifically induced nitric oxide synthase 2 (NOS2) expression and NO generation to elevate excessive autophagy. Finally, disruption of NOS2 signaling effectively blocked autophayosome formation and the subsequent cell death. Our novel findings systemically reveled the role of autophagy-mediated cell death in PM2.5-treated human bronchial epithelium cells and provided potential strategy for future clinic intervention.


Asunto(s)
Autofagia , Células Epiteliales/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Material Particulado/efectos adversos , Contaminantes Atmosféricos/efectos adversos , Apoptosis , Bronquios/citología , Muerte Celular , Células Epiteliales/citología , Epitelio/metabolismo , Humanos , Inflamación , Interleucina-6/metabolismo , Pulmón/citología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Regulación hacia Arriba
10.
Theranostics ; 7(6): 1749-1769, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28529649

RESUMEN

The accumulations of excess lipids within liver and serum are defined as non-alcoholic fatty liver disease (NAFLD) and hyperlipemia respectively. Both of them are components of metabolic syndrome that greatly threaten human health. Here, a recombinant fusion protein (SAK-HV) effectively treated NAFLD and hyperlipemia in high-fat-fed ApoE-/- mice, quails and rats within just 14 days. Its triglyceride and cholesterol-lowering effects were significantly better than that of atorvastatin during the observation period. We explored the lipid-lowering mechanism of SAK-HV by the hepatic transcriptome analysis and serials of experiments both in vivo and in vitro. Unexpectedly, SAK-HV triggered a moderate energy and material-consuming liver proliferation to dramatically decrease the lipids from both serum and liver. We provided the first evidence that PGC-1α mediated the hepatic synthesis of female hormones during liver proliferation, and proposed the complement system-induced PGC-1α-estrogen axis via the novel STAT3-C/EBPß-PGC-1α pathway in liver as a new energy model for liver proliferation. In this model, PGC-1α ignited and fueled hepatocyte activation as an "igniter"; PGC-1α-induced estrogen augmented the energy supply of PGC-1α as an "ignition amplifier", then triggered the hepatocyte state transition from activation to proliferation as a "starter", causing triglyceride and cholesterol-lowering effects via PPARα-mediated fatty acid oxidation and LDLr-mediated cholesterol uptake, respectively. Collectively, the SAK-HV-triggered distinctive lipid-lowering strategy based on the new energy model of liver proliferation has potential as a novel short-period biotherapy against NAFLD and hyperlipemia.


Asunto(s)
Anticolesterolemiantes/administración & dosificación , Terapia Biológica/métodos , Hiperlipidemias/terapia , Enfermedad del Hígado Graso no Alcohólico/terapia , Proteínas Recombinantes de Fusión/administración & dosificación , Animales , Modelos Animales de Enfermedad , Estrógenos/metabolismo , Hirudinas/administración & dosificación , Hirudinas/genética , Hígado/patología , Metaloendopeptidasas/administración & dosificación , Metaloendopeptidasas/genética , Ratones , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Codorniz , Ratas , Proteínas Recombinantes de Fusión/genética , Resultado del Tratamiento
11.
FEBS Open Bio ; 6(7): 720-8, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27398311

RESUMEN

Exposure to concentrated ambient fine particulate matter (PM2.5) has been associated with cardiovascular diseases (CVDs). The barrier function of vascular endothelial cells is critical for the development of CVDs. Here, we employed human umbilical vein endothelial cells to clarify the function of ambient PM2.5 pollution in the regulation of membrane permeability of vascular endothelial cells. The results show that a high concentration of PM2.5, which mainly includes heavy metals and polycyclic aromatic hydrocarbons, induces barrier dysfunction of vascular endothelial cells. This was mediated in part by promoting IL-6 expression, which then increases the transcriptional activity of HIF-1α by promoting its translocation to the nucleus. Our findings indicate that concentrated PM2.5 can destroy membrane integrity and promote permeability in vascular endothelial cells, thereby contributing to the development of CVDs.

12.
J Pharm Biomed Anal ; 107: 119-24, 2015 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-25590941

RESUMEN

Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, is a promising natural anticancer candidate. Although the anticancer activity of PPI has been well demonstrated, information regarding the pharmacokinetics and bioavailability is limited. In this study, a series of reliable and rapid liquid chromatography-tandem mass spectrometry methods were developed and successfully applied to determinate PPI in rat plasma, cell incubation media and cell homogenate. Then the pharmacokinetics of PPI in rats was studied and the result revealed that PPI was slowly eliminated with low oral bioavailability (about 0.62%) at a dose of 50 mg/kg, and when co-administrated with verapamil (VPL) and cyclosporine A (CYA), the oral bioavailability of PPI could increase from 0.62% to 3.52% and 3.79% respectively. In addition, in vitro studies showed that with the presence of VPL and CYA in Caco-2 cells, the efflux ratio of PPI decreased from 12.5 to 2.96 and 2.22, and the intracellular concentrations increased 5.8- and 5.0-fold respectively. These results demonstrated that PPI, with poor oral bioavailability, is greatly impeded by P-gp efflux, and inhibition of P-gp can enhance its bioavailability.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Diosgenina/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Línea Celular Tumoral , Cromatografía Liquida/métodos , Ciclosporina/administración & dosificación , Diosgenina/sangre , Diosgenina/farmacocinética , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Saponinas/sangre , Saponinas/farmacocinética , Espectrometría de Masas en Tándem/métodos , Verapamilo/administración & dosificación
13.
Sci Rep ; 5: 17536, 2015 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-26625948

RESUMEN

Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes' activities and GSH's level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co-administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Ciclofosfamida/efectos adversos , Glutatión/metabolismo , Homeostasis/efectos de los fármacos , Panax/química , Extractos Vegetales/farmacología , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Ciclofosfamida/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Extractos Vegetales/química , Ratas , Ratas Sprague-Dawley
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 17(3): 670-3, 2009 Jun.
Artículo en Zh | MEDLINE | ID: mdl-19549385

RESUMEN

This study was aimed to explore the influence of staphylokinase derivative (SAKD) on the hemoagglutinative and fibrinolytic systems, and to determine the safety of the staphylokinase derivative in application. The normal and model rats each 30 were divided into normal saline, SAKD and rSAK groups. The hemorrhage, bleeding time (BT), blood platelet count (BPC), activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fg), D-dimer (D-D), plasminogen (PLG) and plasmin inhibitor activity (PI) were detected before and after the administration with staphylokinase derivative 0.5 mg/kg body weight, once three days for consecutive 15 days. The results indicated that one case of normal rats with SAKD and two cases of high fat diet model group had mild hemorrhage, all of which showed automatic hemostasis; and 3 cases in rSAK group had mild hemorrhage. And the platelet counting, D-D, PLG and PI in all groups did not significantly change. The rats of high fat diet group treated with SAKD showed the significant extension of APTT, PT and TT times, and the decrease of Fg time (p < 0.05). All the experimental results demonstrated that the influence of SAKD on the hemagglutination of the normal animals was lower, however, which can improve the high-hemagglutination status of the rats with high fat diet. It is concluded that the SAKD at the dosage of this study has the higher safety, which can alleviate the high hemagglutination symptoms of the rats with high fat diet.


Asunto(s)
Fibrinólisis/efectos de los fármacos , Fibrinolíticos/efectos adversos , Hemaglutinación/efectos de los fármacos , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacología , Terapia Trombolítica , Animales , Grasas de la Dieta , Productos de Degradación de Fibrina-Fibrinógeno , Fibrinolíticos/farmacología , Hemostasis , Masculino , Metaloendopeptidasas/farmacología , Tiempo de Tromboplastina Parcial , Recuento de Plaquetas , Tiempo de Protrombina , Ratas , Ratas Wistar , Tiempo de Trombina
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