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BACKGROUND: Severe asthma, characterized by inflammation and airway remodeling, involves fibroblast differentiation into myofibroblasts expressing α-SMA. This process leads to the production of fibronectin and connective tissue growth factor (CTGF), driven by factors such as transforming growth factor (TGF)-ß. Furthermore, the persistent presence of myofibroblasts is associated with resistance to apoptosis and mitochondrial dysfunction. The chemokine (C-X3-C motif) ligand 1 (CX3CL1) plays a role in tissue fibrosis. However, it is currently unknown whether neutralization of CX3CL1 decreases TGF-ß-induced fibroblast differentiation and mitochondrial dysfunction in normal human lung fibroblasts (NHLFs). METHODS: CX3CL1/C-X3-C motif chemokine receptor 1 (CX3CR1), CX3CL1 was analyzed by immunofluorescence (IF) or immunohistochemical (IHC) staining of ovalbumin-challenged mice. CX3CL1 release was detected by ELISA. TGF-ß-induced CTGF, fibronectin, and α-SMA expression were evaluated in NHLFs following neutralization of CX3CL1 (TP213) treatment for the indicated times by Western blotting or IF staining. Mitochondrion function was detected by a JC-1 assay and seahorse assay. Cell apoptosis was observed by a terminal uridine nick-end labeling (TUNEL) assay. RESULTS: An increase in CX3CL1 expression was observed in lung tissues from mice with ovalbumin-induced asthma by IF staining. CX3CR1 was increased in the subepithelial layer of the airway by IHC staining. Moreover, CX3CR1 small interfering (si)RNA downregulated TGF-ß-induced CTGF and fibronectin expression in NHLFs. CX3CL1 induced CTGF and fibronectin expression in NHLFs. TGF-ß-induced CX3CL1 secretion from NHLFs. Furthermore, TP213 decreased TGF-ß-induced CTGF, fibronectin, and α-SMA expression in NHLFs. Mitochondrion-related differentially expressed genes (DEGs) were examined after CX3CL1 neutralization in TGF-ß-treated NHLFs. TP213 alleviated TGF-ß-induced mitochondrial dysfunction and apoptosis resistance in NHLFs. CX3CL1 induced p65, IκBα, and IKKα phosphorylation in a time-dependent manner. Furthermore, CX3CL1-induced fibronectin expression and JC-1 monomer were decreased by p65 siRNA. TP213 reduced TGF-ß-induced p65 and α-SMA expression in NHLFs. CONCLUSIONS: These findings suggest that neutralizing CX3CL1 attenuates lung fibroblast activation and mitochondrial dysfunction. Understanding the impacts of CX3CL1 neutralization on fibroblast mitochondrial function could contribute to the development of therapeutic strategies for managing airway remodeling in severe asthma.
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Apoptosis , Receptor 1 de Quimiocinas CX3C , Diferenciación Celular , Quimiocina CX3CL1 , Factor de Crecimiento del Tejido Conjuntivo , Fibroblastos , Fibronectinas , Mitocondrias , Fibrosis Pulmonar , Factor de Crecimiento Transformador beta , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/genética , Animales , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Humanos , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Factor de Crecimiento del Tejido Conjuntivo/genética , Diferenciación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Factor de Crecimiento Transformador beta/metabolismo , Receptor 1 de Quimiocinas CX3C/metabolismo , Receptor 1 de Quimiocinas CX3C/genética , Fibronectinas/metabolismo , Ratones , Actinas/metabolismo , Pulmón/patología , Pulmón/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Asma/metabolismo , Asma/patología , Modelos Animales de Enfermedad , Células Cultivadas , Miofibroblastos/metabolismo , Miofibroblastos/patología , Miofibroblastos/efectos de los fármacos , OvalbúminaRESUMEN
Structural analysis of tazemetostat, an FDA-approved EZH2 inhibitor, led us to pinpoint a suitable site for appendage with a pharmacophoric fragment of second-generation HSP90 inhibitors. Resultantly, a magnificent dual EZH2/HSP90 inhibitor was pinpointed that exerted striking cell growth inhibitory efficacy against TMZ-resistant Glioblastoma (GBM) cell lines. Exhaustive explorations of chemical probe 7 led to several revelations such as (i) compound 7 increased apoptosis/necrosis-related gene expression, whereas decreased M phase/kinetochore/spindle-related gene expression as well as CENPs protein expression in Pt3R cells; (ii) dual inhibitor 7 induced cell cycle arrest at the M phase; (iii) compound 7 suppressed reactive oxygen species (ROS) catabolism pathway, causing the death of TMZ-resistant GBM cells; and (iv) compound 7 elicited substantial in vivo anti-GBM efficacy in experimental mice xenografted with TMZ-resistant Pt3R cells. Collectively, the study results confirm the potential of dual EZH2-HSP90 inhibitor 7 as a tractable anti-GBM agent.
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Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Animales , Ratones , Temozolomida/farmacología , Apoptosis , Resistencia a Antineoplásicos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Glioblastoma/metabolismo , Inhibidores Enzimáticos/farmacología , Neoplasias Encefálicas/tratamiento farmacológicoRESUMEN
Cancer represents a profound challenge to healthcare systems and individuals worldwide. The development of multiple drug resistance is a major problem in cancer therapy and can result in progression of the disease. In our previous studies, we developed small-molecule inhibitors targeting ubiquitin-specific peptidase 24 (USP24) to combat drug-resistant lung cancer. Recently, we found that the USP24 inhibitor NCI677397 induced ferroptosis, a type of programmed cell death, in drug-resistant cancer cells by increasing lipid reactive oxygen species (ROS) levels. In the present study, we investigated the molecular mechanisms and found that the targeting of USP24 by NCI677397 increased gene expression of most lipogenesis-related genes, such as acyl-CoA synthetase long-chain family member 4 (ACSL4), and activated autophagy. In addition, the activity of several antioxidant enzymes, such as glutathione peroxidase 4 (GPX4) and dihydrofolate reductase (DHFR), was inhibited by NCI677397 treatment via an increase in protein degradation, thereby inducing lipid ROS production and lipid peroxidation. In summary, we demonstrated that NCI677397 induced a marked increase in lipid ROS levels, subsequently causing lipid peroxidation and leading to the ferroptotic death of drug-resistant cancer cells. Our study provides new insights into the clinical use of USP24 inhibitors as ferroptosis inducers (FINs) to block drug resistance during chemotherapy.
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BACKGROUND: Longan is a fruit tree known to contain many phenolic components, which are capable of protecting people from oxidative damage through an anti-inflammatory mechanism. It may be also worthwhile to study the effect on lowering uric acid activity. MATERIALS AND METHODS: This study investigates the lowering of uric acid using longan extracts, including flowers, pericarps, seeds, leaves, and twigs, on potassium-oxonate-induced hyperuricemia mice and its inhibitory actions against xanthine oxidase (XO) activities. RESULTS: The findings revealed that ethyl acetate fraction of longan extracts exhibited strong XO-inhibitory activity, and the flower extracts (IC50 = 115.8 µg/mL) revealed more potent XO-inhibitory activity to those of pericarps (118.9 µg/mL), twigs (125.3 µg/mL), seeds (262.5 µg/mL), and leaves (331.1 µg/mL) in vitro. In addition, different dosages of longan extract (50-100 mg/kg) were administered to hyperuricemic mice. The lowering effect of longan extracts on uric acid at 75 mg/kg markedly reduced plasma uric acid levels in decreasing order: Flowers (80%) > seeds (72%) > pericarps (64%) > twigs (59%) > leaves (41%), compared with allopurinol (89%). Finally, 10 isolated phytochemicals from longan flowers were then examined in vitro. The results indicated that proanthocyanidin A2 and acetonylgeraniin A significantly inhibited XO activity in vitro. This is the first report providing new insights into the urate-reducing effect of phenolic dimer and hydrolyzable tannin, which can be developed to potential hypouricemic agents. SUMMARY: Longan flower extracts possess more potent XO-inhibitory activity than pericarps, twigs, seeds, and leaves in vitroThe lowering effect of longan flowers and seeds extracts markedly reduced plasma uric acid levels as compared to allopurinol in vivoThe extract proanthocyanidin A2 and acetonylgeraniin A were demonstrated potent XO inhibitory activity in vitro Abbreviations used: PO: Potassium-oxonate, XO: xanthine oxidase, HE: n-hexane, EA: ethyl acetate, i.p.: intraperitoneal, PBS: phosphate-buffered saline, AP: allopurinol, PUA: plasma uric acid.
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Nontoxic natural products useful in skin care cosmetics are of considerable interest. Tyrosinase is a rate-limiting enzyme for which its inhibitor is useful in developing whitening cosmetics. Pyracantha koidzumii (Hayata) Rehder is an endemic species in Taiwan that exhibits tyrosinase-inhibitory activity. To find new active natural compounds from P. koidzumii, we performed bioguided isolation and studied the related activity in human epidermal melanocytes. In total, 13 compounds were identified from P. koidzumii in the present study, including two new compounds, 3,6-dihydroxy-2,4-dimethoxy-dibenzofuran (9) and 3,4-dihydroxy-5-methoxybiphenyl-2'-O-ß-d-glucopyranoside (13), as well as 11 known compounds. The new compound 13 exhibited maximum potency in inhibiting cellular tyrosinase activity, the protein expression of cellular tyrosinase and tyrosinase-related protein-2, as well as the mRNA expression of Paired box 3 and microphthalmia-associated transcription factor in a concentration-dependent manner. In the enzyme kinetic assay, the new compound 13 acted as an uncompetitive mixed-type inhibitor against the substrate l-3,4-dihydroxyphenylalanine and had a Km value against this substrate of 0.262 mM, as calculated using the Lineweaver-Burk plots. Taken together, our findings show compound 13 exhibits tyrosinase inhibition in human melanocytes and compound 13 may be a potential candidate for use in cosmetics.
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Blanqueadores/química , Blanqueadores/farmacología , Extractos Vegetales/química , Extractos Vegetales/farmacología , Pyracantha/química , Blanqueadores/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Células Epidérmicas , Epidermis/efectos de los fármacos , Humanos , Melanocitos/efectos de los fármacos , Melanocitos/metabolismo , Estructura Molecular , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/química , Resonancia Magnética Nuclear Biomolecular , Extractos Vegetales/aislamiento & purificación , TaiwánRESUMEN
Pterosins are abundant in ferns, and pterosin A was considered a novel activator of adenosine monophosphate-activated protein kinase, which is crucial for regulating blood glucose homeostasis. However, the distribution of pterosins in different species of ferns from various places in Taiwan is currently unclear. To address this question, the distribution of pterosins, glucose-uptake efficiency, and protective effects of pterosin A on ß-cells were examined. Our results showed that three novel compounds, 13-chloro-spelosin 3-O-ß-d-glucopyranoside (1), (3R)-Pterosin D 3-O-ß-d-(3'-p-coumaroyl)-glucopyranoside (2), and (2R,3R)-Pterosin L 3-O-ß-d-(3'-p-coumaroyl)-glucopyranoside (3), were isolated for the first time from four fern species (Ceratopteris thalictroides, Hypolepis punctata, Nephrolepis multiflora, and Pteridium revolutum) along with 27 known compounds. We also examined the distribution of these pterosin compounds in the mentioned fern species (except N. multiflora). Although all pterosin analogs exhibited the same effects in glucose uptake assays, pterosin A prevented cell death and reduced reactive oxygen species (ROS) production. This paper is the first report to provide new insights into the distribution of pterosins in ferns from Taiwan. The potential anti-diabetic activity of these novel phytocompounds warrants further functional studies.
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Helechos/química , Hipoglucemiantes/química , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Helechos/metabolismo , Hipoglucemiantes/aislamiento & purificación , Hipoglucemiantes/farmacología , Indanos/química , Indanos/aislamiento & purificación , Indanos/farmacología , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Palmitatos/toxicidad , Ratas , Especies Reactivas de Oxígeno/metabolismo , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Sesquiterpenos/farmacología , TaiwánRESUMEN
Five new 5ß,19-epoxycucurbitane triterpenoids, taikugausins A-E (1-5), together with 5ß,19-epoxy-25-methoxycucurbita-6,23-diene-3ß,19-diol (6), have been isolated and characterized from the 70â% EtOH extract of the fresh fruits of Momordica charantia. The chemical structures of compounds 1-6 were elucidated on the basis of extensive spectroscopic analyses, especially 2D NMR (HMQC, HMBC, and NOESY) experiments and HRESIMS data. The relationship between NMR chemical shifts and the configuration of C-19 with an OMe group in 5ß,19-epoxycucurbitane are described. Among them, compounds 3 and 4 exhibited remarkable anti-inflammatory activities by the inhibition of nitric oxide production at the concentration of 10 µg/mL. In addition, 3 and 4 also showed moderate cytotoxicity against WiDr, Hep G2, MCF-7, and HEp-2 human tumor cell lines.
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Antiinflamatorios no Esteroideos/farmacología , Momordica charantia/química , Animales , Antiinflamatorios no Esteroideos/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Células Hep G2/efectos de los fármacos , Humanos , Macrófagos/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Óxido Nítrico/metabolismo , Saponinas/química , Saponinas/farmacología , Triterpenos/química , Triterpenos/farmacologíaRESUMEN
Clinical studies show that hyperuricemia is a risk factor in the progression and development of cardiovascular and metabolic disease. Elevated serum levels of uric acid induce renal injury via an inflammation response, but the detailed mechanism is still under study. To better understand the effect of hyperuricemia on the kidney, we used gas chromatography-mass spectrometry-based metabolomics to investigate the role of uric acid in the mouse kidney. Partial least-squares discriminant analysis revealed significant differences between control and hyperuricemia groups in urine metabolic profiles. We identified 33 metabolites from 76 highly reproducible peaks and found abnormal uric acid levels related to comprehensive kidney injury, including excretive function and energy metabolism. Additionally, inflammation induced by the interleukin 6/signal transducer and activator of transcription 3 signaling pathway participated in hyperuricemia-induced kidney injury. This study helps understand the relationship between hyperuricemia and kidney injury. Metabolomics may be a useful strategy for early diagnosis of kidney damage.
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Lesión Renal Aguda/etiología , Hiperuricemia/complicaciones , Metabolómica , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/orina , Animales , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Hiperuricemia/metabolismo , Hiperuricemia/orina , Interleucina-6/fisiología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Metabolómica/métodos , Ratones Endogámicos ICR , Nefronas/efectos de los fármacos , Proteinuria/etiología , Proteinuria/metabolismo , Factor de Transcripción STAT3/fisiología , Transducción de Señal/fisiología , Ácido Úrico/sangreRESUMEN
Abnormal serum urate levels are recognized as a critical factor in the progression of several chronic diseases. To evaluate the antihyperuricemic effect of Davallia formosana, the inhibitory activities of 15 isolated phytochemicals, including five novel compounds of 6,8-dihydroxychromone-7-C- ß -d-glucopyranoside (1), 6,8,3',4'-tetrahydroxyflavanone-7-C- ß -d-glucopyranoside (2), 6,8,4'-trihydroxyflavanone-7-C- ß -d-glucopyranoside (3), 8-(2-pyrrolidinone-5-yl)-catechin-3-O- ß -d-allopyranoside (4), and epiphyllocoumarin-3-O- ß -d-allopyranoside (5), were examined against xanthine oxidase (XOD) and in a potassium oxonate-(PTO-) induced acute hyperuricemic mice model. The results indicated that compounds 3 and 5 significantly inhibited XOD activity in vitro and reduced serum uric acid levels in vivo. This is the first report providing new insights into the antihyperuricemic activities of flavonoid glycosides which can possibly be developed into potential hypouricemic agents.
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Background. Traditional Chinese medicine (TCM), when given as a therapy for symptom relief, has gained widespread popularity among diabetic patients. The aim of this study is to analyze the utilization of TCM among type 2 diabetic patients in Taiwan. Methods. The use of TCM for type 2 diabetic patients were evaluated using a randomly sampled cohort of 1,000,000 beneficiaries recruited from the National Health Insurance Research Database. Results. Overall, 77.9% (n = 31,289) of type 2 diabetic patients utilized TCM and 13.9% (n = 4,351) of them used TCM for the treatment of type 2 diabetes. Among the top ten most frequently prescribed herbal formulae, four remedies, Zhi-Bo-Di-Huang-Wan, Qi-Ju-Di-Huang-Wan, Ji-Sheng-Shen-Qi-Wan and Ba-Wei-Di-Huang-Wan are derivative formulae of Liu-Wei-Di-Huang-Wan. In other words, Liu-Wei-Di-Huang-Wan and its derivatives were found to be the most common herbal formulae prescribed by TCM doctors for the treatment of diabetes in Taiwan. Conclusion. Although some evidence does support the use TCM to treat diabetes, the results from the current study may have been confounded by placebo effect, which emphasize the need for well conducted, double-blind, randomized, placebo-controlled studies in order to further evaluate the efficacy of Liu-Wei-Di-Huang-Wan on patients with type 2 diabetes.
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OBJECTIVES: This study describes a novel carrier, the ethosome-based system, which is composed of non-ionic surfactants, ethanol, and water. METHODS: Brij(®) 52 (non-ionic surfactants), soya phosphatidylcholine (PC), cholesterol, and the major compounds (caffeine and gallic acid) of black tea extracts were dissolved in the ethanolic phase. The aqueous phase containing Paragon III was heated to 60 °C and mixed with the previous solution. Finally, 3.4 ml NaOH (6.5 N) was added to adjust the pH level to 4.05. The mixture was centrifuged at 2000 g for two minutes, and the precipitate was taken as the end product. Black tea extracts were applied in ethosome-based formulations, and the efficacy of these formulations in penetrating nude mouse skin and in dyeing white hairs was investigated. RESULTS: Compared with an ethanolic solution and black tea extracts, the non-ionic ethosomal delivery system dramatically enhanced the adsorption of black tea extracts onto hair surfaces in vitro. The non-ionic ethosomal system was much more efficient in delivering and facilitating the adsorption of black tea extracts to the hair surface than hydroalcoholic black tea extracts. CONCLUSIONS: This formulation may have potential for development as a hair dye and protective agent.
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Cafeína/farmacocinética , Portadores de Fármacos/farmacocinética , Ácido Gálico/farmacocinética , Tinturas para el Cabello/farmacocinética , Cabello/metabolismo , Extractos Vegetales/farmacocinética , Piel/metabolismo , Adsorción , Animales , Cafeína/química , Cetomacrogol/química , Química Farmacéutica , Colesterol/química , Portadores de Fármacos/química , Etanol/química , Ácido Gálico/química , Tinturas para el Cabello/química , Ratones , Ratones Desnudos , Permeabilidad , Fosfatidilcolinas/química , Extractos Vegetales/química , Absorción Cutánea , Tensoactivos/química , Té , Lana/metabolismoRESUMEN
This paper reports that bioassay-guided fractionations of EtOH extract of Momordica charantia fruits led to the isolation of 15 cucurbitane-type triterpene glycosides including 4 new compounds, kuguaosides A-D (1-4), along with 11 known ones, charantoside A (5), momordicosides I (6), F1 (7), F2 (8), K (9), L (10), and U (11), goyaglycosides-b (12) and -d (13), 7ß,25-dihydroxycucurbita-5,23(E)-dien-19-al 3-O-ß-d-allopyranoside (14), and 25-hydroxy-5ß,19-epoxycucurbita-6,23-dien-19-on-3ß-ol 3-O-ß-d-glucopyranoside (15). Their structures were elucidated on the basis of spectroscopic analyses and chemical methods. This study also established the HPLC-ELSD fingerprinting profile of an antiproliferative fraction of which 11 main peaks were identified. Biological evaluation showed that several isolated cucurbitane-type triterpene glycosides had antiproliferative activities against MCF-7, WiDr, HEp-2, and Doay human tumor cell lines. In addition, compound 14 showed potent hypoglycemic activities by glucose uptake assay.
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Antineoplásicos Fitogénicos/farmacología , Frutas/química , Glicósidos/farmacología , Hipoglucemiantes/farmacología , Momordica charantia/química , Triterpenos/farmacología , Animales , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Glicósidos/química , Glicósidos/aislamiento & purificación , Humanos , Ratones , Estructura Molecular , Extractos Vegetales/química , Triterpenos/química , Triterpenos/aislamiento & purificaciónRESUMEN
OBJECTIVES: The primary objective of this study was to investigate the feasibility of using niosomes as a delivery vehicle for the dermal administration in vitro of black tea extract (BTE) as a sunscreen. METHODS: Multi-lamellar niosomes were obtained by means of a previously reported method of lipid hydration films. In vitro penetration experiments through nude mouse skin were carried out to evaluate the potential of niosomes as a dermal formulation. The nude mouse skin membrane allowed the effects of penetration with a niosome formulation to be evaluated. Penetration rates of caffeine- and gallic acid-loaded niosomes in a steady state were higher than dispersion in aqueous solutions. RESULTS: For skin permeation, higher transdermal absorption rates were seen with solutions of caffeine and gallic acid. CONCLUSIONS: In the near future, BTE as a sunscreen agent will be dermally delivered by niosomes.
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Dermis/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Liposomas/farmacocinética , Extractos Vegetales/farmacocinética , Protectores Solares/farmacocinética , Té/química , Animales , Cafeína/análisis , Cafeína/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacocinética , Cromatografía Líquida de Alta Presión , Ácido Gálico/análisis , Ácido Gálico/farmacocinética , Masculino , Ratones , Ratones Desnudos , Extractos Vegetales/química , Agua/metabolismoRESUMEN
The therapeutic effect of pterosin A, a small-molecular-weight natural product, on diabetes was investigated. Pterosin A, administered orally for 4 weeks, effectively improved hyperglycemia and glucose intolerance in streptozotocin, high-fat diet-fed, and db/db diabetic mice. There were no adverse effects in normal or diabetic mice treated with pterosin A for 4 weeks. Pterosin A significantly reversed the increased serum insulin and insulin resistance (IR) in dexamethasone-IR mice and in db/db mice. Pterosin A significantly reversed the reduced muscle GLUT-4 translocation and the increased liver phosphoenolpyruvate carboxyl kinase (PEPCK) expression in diabetic mice. Pterosin A also significantly reversed the decreased phosphorylations of AMP-activated protein kinase (AMPK) and Akt in muscles of diabetic mice. The decreased AMPK phosphorylation and increased p38 phosphorylation in livers of db/db mice were effectively reversed by pterosin A. Pterosin A enhanced glucose uptake and AMPK phosphorylation in cultured human muscle cells. In cultured liver cells, pterosin A inhibited inducer-enhanced PEPCK expression, triggered the phosphorylations of AMPK, acetyl CoA carboxylase, and glycogen synthase kinase-3, decreased glycogen synthase phosphorylation, and increased the intracellular glycogen level. These findings indicate that pterosin A may be a potential therapeutic option for diabetes.
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Productos Biológicos/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Indanos/uso terapéutico , Sesquiterpenos/uso terapéutico , Animales , Transporte Biológico/efectos de los fármacos , Células Cultivadas , Dexametasona/efectos adversos , Modelos Animales de Enfermedad , Glucosa/metabolismo , Intolerancia a la Glucosa/tratamiento farmacológico , Transportador de Glucosa de Tipo 4/metabolismo , Humanos , Hiperglucemia/tratamiento farmacológico , Insulina/sangre , Resistencia a la Insulina/fisiología , Hígado/enzimología , Masculino , Ratones , Músculo Esquelético/efectos de los fármacosRESUMEN
Thirteen polyphenolics were isolated from fresh pods of Caesalpinia pulcherrima using various methods of column chromatography. The structures of these polyphenolics were elucidated as gallic acid (1), methyl gallate (2), 6-O-galloyl-d-glucoside (3), methyl 6-O-galloyl-ß-d-glucoside (4), methyl 3,6-di-O-galloyl-α-d-glucopyranoside (5), gentisic acid 5-O-α-d-(6'-O-galloyl)glucopyranoside (6), guaiacylglycerol 4-O-ß-d-(6'-O-galloyl)glucopyranoside (7), 3-methoxy-4-hydroxyphenol 1-O-ß-d-(6'-O-galloyl) glucopyranoside (8), (+)-gallocatechin (9), (+)-catechin (10), (+)-gallocatechin 3-O-gallate (11), myricetin 3-rhamnoside (12), and ampelopsin (13). All isolated compounds were tested for their antioxidant activities in the 1,1-diphenyl-2-picrylhydrazyl (DPPH), hydroxyl, and peroxynitrite radicals scavenging assays. Among those compounds, 11, 12, and 2 exhibited the best DPPH-, hydroxyl-, and peroxynitrite radical-scavenging activities, respectively. Compound 7 is a new compound, and possesses better scavenging activities towards DPPH but has equivalent hydroxyl radical scavenging activity when compared to BHT. The paper is the first report on free radical scavenging properties of components of the fresh pods of Caesalpinia pulcherrima. The results obtained from the current study indicate that the free radical scavenging property of fresh pods of Caesalpinia pulcherrima may be one of the mechanisms by which this herbal medicine is effective in several free radical mediated diseases.
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Antioxidantes/química , Caesalpinia/química , Depuradores de Radicales Libres/química , Polifenoles/química , Compuestos de Bifenilo/química , Catequina/química , Cromatografía/métodos , Ácido Gálico/química , Glucósidos/química , Picratos/química , Extractos Vegetales/químicaRESUMEN
The metabolic profile of the potent hypoglycemic agent, (2S)-pterosin A (1), in rat urine via intragastrical oral administration was investigated. In total, 19 metabolites (M1-M19) were identified. Among these, 16 metabolites were characterized by high-performance liquid chromatography solid-phase extraction-tube transfer-NMR, and seven metabolites were further isolated from the treated urine to enable further structural determination. Twelve of these are new compounds. The phase I metabolites of 1 were formed via various oxidations at positions C-3, C-10, C-12, C-13, or C-1 followed by decarboxylation of C-10 or C-14, and lactonization at C-12/C-14 or C-14/C-12. The phase II metabolites were glucuronide conjugates from the parent compound or phase I metabolites. The major metabolites were found to be (2S)-14-O-glucuronylpterosin A (M9), (2S)-2-hydroxymethylpterosin E (M14), and (±)-pterosin B (M19). Quantitative HPLC analysis of metabolites, based on similar UV absorption and use of the regression equation of 1, indicated that â¼71% 1 was excreted as metabolites in rat urine.
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Indanos/metabolismo , Sesquiterpenos/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Indanos/orina , Espectroscopía de Resonancia Magnética , Ratas , Sesquiterpenos/orinaRESUMEN
Microbiota in the gut are considered an important environmental factor associated with host metabolism and physiology. Although gut microbiota are known to contribute to hepatic lipogenesis and fat storage, little is known about how the condition influences the deposition of glycogen in the liver. To better understand and characterize the host energy metabolism in guts lacking microbiota, we compared the liver metabolome of specific pathogen-free and germ-free mice by gas chromatography-mass spectrometry combined with partial least-squares discriminant analysis. We identified 30 of 52 highly reproducible peaks in chromatograms of liver tissue extracts from the two groups of mice. The two groups showed significant differences in metabolic profile. Changes in liver metabolism involved metabolites such as amino acids, fatty acids, organic acids and carbohydrates. The metabolic profile of germ-free mice suggests that they synthesize glycogen and accumulate it in the liver through gluconeogenesis and glycogenesis. Our findings shed light on a new perspective of the role of gut microbiota in energy metabolism and will be useful to help study probiotics, obesity and metabolic diseases.
Asunto(s)
Metabolismo Energético , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/microbiología , Glucógeno/metabolismo , Metabolómica/métodos , Metagenoma , Aminoácidos/metabolismo , Animales , Carbohidratos/análisis , Análisis Discriminante , Ácidos Grasos/metabolismo , Cromatografía de Gases y Espectrometría de Masas , Vida Libre de Gérmenes , Gluconeogénesis , Hígado/metabolismo , Masculino , Metaboloma , Ratones , Ratones Endogámicos C57BLRESUMEN
1. Tanshinone IIA, one of the active components of the Radix of Salvia miltiorrhiza, is used in traditional Chinese medicine to treat cardiovascular diseases. However, the intracellular mechanism of action of tanshinone IIA remain to be determined. The aims of the present study were to test the hypothesis that tanshinone IIA alters strain-induced endothelin (ET)-1 expression and nitric oxide (NO) production, as well as to identify the putative signalling pathways involved, in human umbilical vein endothelial cells (HUVEC). 2. Cultured HUVEC were exposed to cyclic strain in the presence of 1-10 µmol/L tanshinone IIA. Expression of ET-1 was examined by reverse transcription-polymerase chain reaction and ELISA. Phosphorylation of endothelial NO synthase (eNOS) and activating transcription factor (ATF) 3 was assessed by western blot analysis. 3. Tanshinone IIA (3 and 10 µmol/L) inhibited strain-induced ET-1 expression. In contrast, NO production, eNOS phosphorylation and ATF3 expression were enhanced by tanshinone IIA. The eNOS inhibitor N(G) -nitro-L-arginine methyl ester (l-NAME; 100 µmol/L), the phosphatidylinositol 3-kinase inhibitor LY294002 (5 µmol/L) and the soluble guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ; 10 µmol/L) inhibited tanshinone IIA-induced increases in ATF3 expression. Moreover, treatment of HUVEC with either an NO donor (3,3-bis [aminoethyl]-1-hydroxy-2-oxo-1-triazene; 500 µmol/L) or an ATF3 activator (carbobenzoxy-L-leucyl-L-leucyl-L-leucinal; 5 µmol/L) resulted in the repression of strain-induced ET-1 expression. The inhibitory effect of tanshinone IIA on strain-induced ET-1 expression was significantly attenuated by l-NAME, ODQ and the transfection of small interfering RNA for ATF3. 4. In conclusion, tanshinone IIA inhibits strain-induced ET-1 expression by increasing NO and upregulating ATF3 in HUVEC. The present study provides important new insights into the molecular pathways that may contribute to the beneficial effects of tanshinone IIA in the cardiovascular system.
Asunto(s)
Abietanos/farmacología , Enfermedades Cardiovasculares/prevención & control , Microambiente Celular , Regulación hacia Abajo/efectos de los fármacos , Endotelina-1/metabolismo , Endotelio Vascular/efectos de los fármacos , Factor de Transcripción Activador 3/agonistas , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Células Cultivadas , Endotelina-1/genética , Endotelio Vascular/metabolismo , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Interferencia de ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Guanilil Ciclasa SolubleRESUMEN
Coumarin derivative 1, 5,7-dihydroxy-6-(3-methyl-1-butyryl)-4-phenyl-chromen- 2-one, has been reported to possess radical scavenging activity and DNA protection. We have synthesized a series of coumarins with structural modifications at positions C4, C5, C6 and C7 and evaluated them for their anti-UVC properties. Coumarin 7, 6-benzoyl-5,6-dihydroxy-4-phenyl-chromen-2-one, was found to have the most potent activity in protecting porcine γ-crystallin against UVC insults. Results of fluorescence assays indicated that compound 7 was capable of decreasing the loss of intensity while lens crystallins and DNA PUC19 were irradiated with UVC. Presence of compound 7 decreased hydroxyl radical levels determined by probe 1b and the free iron concentrations determined by Ferrozine reagent. The chelation assay showed that compound 7 was chelated to metal via 6-CO and 5-OH on the benzopyrone ring. The observed protective effects of compound 7 towards crystallins from insults of UVC and free radicals may be due to its iron-chelating activity and its peak absorption at 254 nm.
Asunto(s)
Catarata/prevención & control , Quelantes/química , Cumarinas/química , Metales/química , Sustancias Protectoras/química , Animales , Cumarinas/farmacología , Cumarinas/uso terapéutico , ADN/química , ADN/metabolismo , Radical Hidroxilo/química , Radical Hidroxilo/toxicidad , Cristalino/efectos de los fármacos , Cristalino/efectos de la radiación , Nefelometría y Turbidimetría , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Fotólisis/efectos de los fármacos , Fotólisis/efectos de la radiación , Plásmidos/metabolismo , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Porcinos , Rayos UltravioletaRESUMEN
From the screening of 21 microbial strains, Absidia pseudocylindrospora ATCC 24169 and Aspergillus niger BCRC 32720 were found to reproducibly transform isosteviol lactam (4α-carboxy-13α-amino-13,16-seco-ent-19-norbeyeran-16-oic acid 13,16-lactam) (3) into various compounds. Preparative-scale transformation of 3 with Abs. pseudocylindrospora yielded two new hydroxylated compounds (4 and 5), with conservation of the lactam ring. Preparative-scale transformation of 3 with Asp. niger afforded seven new compounds, 6 and 9-14, together with the known compounds 7 and 8. A single-crystal X-ray diffraction experiment confirmed the structure of 14. The suppressive effects of compounds 1-14 on the lipopolysaccharide-induced expression of the inducible nitric oxide synthase gene in RAW 264.7 macrophages were examined by a reverse-transcription real-time PCR analysis. With the exception of 7, all other compounds significantly reduced levels of iNOS mRNA relative to control cells, which were induced by LPS alone. Compounds 2, 3, and 5 were similar in activity to dexamethasone, while 9 was more potent.