RESUMO
Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is a serious clinical concern and myofibroblasts have been suggested to have a major role, with it recently being revealed that some of these myofibroblasts are derived from lung epithelial cells through epithelial-mesenchymal transition (EMT). In this study, we examined the EMT-inducing abilities of drugs known to induce ILD clinically. EMT-like phenotypes were induced by A771726, an active metabolite of leflunomide having an inhibitory effect on dihydroorotate dehydrogenase (DHODH). Smad-interacting protein 1 (a transcription factor regulating EMT) and the Notch-signaling pathway but not transforming growth factor-ß was shown to be involved in A771726-induced EMT-like phenotypes. When the cultures were supplemented with exogenous uridine, the A771726-induced EMT-like phenotypes and activation of the Notch-signaling pathway disappeared. Similarly, an A771726 analog without inhibitory activity on DHODH produced no induction, suggesting that this process is mediated through the inhibition of DHODH. In vivo, administration of leflunomide stimulated bleomycin-induced EMT-like phenomenon in pulmonary tissue, and exacerbated bleomycin-induced pulmonary fibrosis, both of which were suppressed by coadministration of uridine. Taken together, these findings suggest that leflunomide-dependent exacerbation of bleomycin-induced pulmonary fibrosis is mediated by stimulation of EMT of lung epithelial cells, providing the first evidence that drug-induced pulmonary fibrosis involves EMT of these cells.
Assuntos
Compostos de Anilina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hidroxibutiratos/farmacologia , Fibrose Pulmonar/metabolismo , Compostos de Anilina/química , Compostos de Anilina/uso terapêutico , Animais , Bleomicina/farmacologia , Células Cultivadas , Crotonatos , Di-Hidro-Orotato Desidrogenase , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Hidroxibutiratos/química , Hidroxibutiratos/uso terapêutico , Hidroxiprolina/metabolismo , Camundongos , Nitrilas , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Fenótipo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Interferência de RNA , RNA Interferente Pequeno , Ratos , Receptores Notch/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Toluidinas , Fator de Crescimento Transformador beta/metabolismo , Uridina/farmacologia , Homeobox 2 de Ligação a E-box com Dedos de ZincoRESUMO
Previously, 185 ribosomal RNA gene and matK gene sequences of Chinese herbal medicines, Ginseng Radix, Panacis Japonici Rhizoma and Panacis Quinquefolli Radix were shown to correspond with those of the original plants, Panax ginseng, P. japonicus and P. quinquefolius, respectively, with the species-specific sequences especially for 18S rRNA gene sequences. In P. notoginseng and its derivative, Notoginseng Radix, however, we found two genetic groups with respect to both gene sequences. Five base substitutions were detected on both gene sequences and the homology between two groups was 99.7% for the 18S rRNA gene and 99.6% for the matK gene, respectively. One genetic group was found to have the identical sequences as those of P. ginseng.
Assuntos
Heterogeneidade Genética , Panax/química , Plantas Medicinais , Proteínas Tirosina Quinases/genética , RNA Ribossômico 18S/genética , FilogeniaRESUMO
An aqueous extract of Apocynum venetum leaves and its constituents inhibited thiobarbituric acid reactive substances (TBARS) and conjugated-diene formation in the Cu(2+)-induced oxidation of low density lipoprotein (LDL) in vitro. The TBARS formation was most strongly inhibited by chlorogenic acid with an IC(50) value of 1.9 microM, but other constituents were in a range of 2.3-23.3 microM. On the other hand, the lag time in the conjugated-diene formation was dose-dependently prolonged by addition of the aqueous extract. Catechin prolonged the lag time more than 300 min and other constituents such as chlorogenic acid, epicatechin, epigallocatechin, hyperoside and isoquercitrin led to no conjugated-diene formation within 700 min under the experimental conditions.
Assuntos
LDL-Colesterol/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Hipolipemiantes/farmacologia , LDL-Colesterol/metabolismo , Sulfato de Cobre/toxicidade , Relação Dose-Resposta a Droga , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
Effects of aqueous extracts of Apocynum venetum leaves (Luobuma extracts) on the blood pressure were evaluated in hypertensive animal models, such as spontaneously hypertensive rats (SHR), renal hypertensive rats and NaCl-induced hypertensive rats. In SHR, administration of Luobuma (heat-processed and unprocessed leaves) extracts at a dose of 70 mg/rat per day significantly decreased the systolic blood pressure value, but their decreasing effects were weaker than that of captopril. The urine volume, and the urinary Na(+), K(+) and protein excretions were not significantly different between Luobuma-treated and untreated groups. In 3/4 nephrectomized rats, the Luobuma extracts significantly decreased the systolic blood pressure value, accompanied by significant increases of the urine volume and the urinary Na(+) and K(+) excretions. Furthermore, they decreased the blood urea nitrogen (BUN) level. In NaCl-induced hypertensive rats, the Luobuma extract decreased the systolic blood pressure value. However, it did not change the urinary excretions of Na(+), K(+) and protein. The BUN level was lower than that of control rats, but the serum total cholesterol (TC) level did not changed. From these findings, the Luobuma extracts have an anti-hypertensive effect, possibly due to amelioration of the kidney functions in the three experimental animal models.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Renal/tratamento farmacológico , Hipertensão/tratamento farmacológico , Plantas Medicinais/química , Animais , Nitrogênio da Ureia Sanguínea , China , Colesterol/sangue , Hipertensão/fisiopatologia , Hipertensão Renal/fisiopatologia , Masculino , Nefrectomia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Sódio na Dieta/efeitos adversos , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
The absorption, distribution and excretion of butylidenephthalide after dermal application to hairless mouse have been examined with [8-14C]butylidenephthalide. By the investigation of the whole body autoradiogram and liquid scintillation analysis, it was indicated that the transdermally applied butylidenephthalide quickly permeate into peripheral circulation system without accumulation in the skin and then distribute into lung, liver, bile and kidney. The total radioactivity, however, was decreased due to excretion into urine, and in the case of i.v.-administration, 80% of the administered butylidenephthalide was excreted into urine within 24 h, while only 5% was excreted into feces within 24 h. Then, the metabolite in urine was determined to be a cysteine conjugate by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method. Thus, it has been concluded that after dermal application butylidenephthalide quickly permeates through skin into peripheral circulation system; distributes to lung, liver, bile and kidney; and then excreted into urine as a cysteine adduct.
Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Anidridos Ftálicos/farmacocinética , Administração Cutânea , Animais , Cromatografia Líquida , Fezes/química , Feminino , Espectrometria de Massas , Camundongos , Camundongos Pelados , Absorção Cutânea , Distribuição TecidualRESUMO
Nitric oxide (NO) is one of the pro-inflammatory molecules. Some phenylethanoids have been previously shown to possess anti-inflammatory effects. Seven phenylethanoids from the stems of Cistanche deserticola, viz. isoacteoside, tubuloside B, acteoside, 2'-O-acetylacteoside, echinacoside, cistanoside A and tubuloside A, were tested for their effect on NO radical generation by activated murine macrophages. At the concentration of 100-200 microM, all the phenylethanoids reduced (6.3-62.3%) nitrite accumulation in lipopolysaccharide (0.1 microgram/ml)-stimulated J774.1 cells. At 200 microM, they inhibited by 32.2-72.4% nitrite accumulation induced by lipopolysaccharide (0.1 microgram/ml)/interferon-gamma (100 U/ml) in mouse peritoneal exudate macrophages. However, these compounds did not affect the expression of inducible nitric oxide (iNOS) mRNA, the iNOS protein level, or the iNOS activity in lipopolysaccharide-stimulated J774.1 cells. Instead, they showed a clear scavenging effect (6.9-43.9%) at the low concentrations of 2-10 microM of about 12 microM nitrite generated from an NO donor, 1-propanamine-3-hydroxy-2-nitroso-1-propylhydrazino (PAPA NONOate). These results indicate that the phenylethanoids have NO radical-scavenging activity, which possibly contributes to their anti-inflammatory effects.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Flavonoides , Sequestradores de Radicais Livres/farmacologia , Macrófagos/metabolismo , Óxido Nítrico/antagonistas & inibidores , Fenóis/farmacologia , Plantas Medicinais , Polímeros/farmacologia , Animais , Linhagem Celular , Concentração de Íons de Hidrogênio , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , Polifenóis , RNA Mensageiro/análiseRESUMO
The leaves of Apocynum venetum L. are used as a tea material in north China and Japan. A water extract (500 mg/kg/day, one week administration) of the leaves of A. venetum showed protective effects against carbon tetrachloride (CCl4, 30 microliters/mouse) or D-galactosamine (D-GalN, 700 mg/kg)/lipopolysaccharide (LPS, 20 micrograms/kg)-induced liver injury in mice. Tumor necrosis factor-alpha (TNF-alpha) secreted from LPS-stimulated macrophages is the most crucial mediator in the D-GalN/LPS-induced liver injury model. The extract had no significant inhibition on the increase of serum TNF-alpha (1169 +/- 132 pg/ml vs. 1595 +/- 314 pg/ml of control), but exhibited a complete inhibition at the concentration of 100 micrograms/ml on TNF-alpha (100 ng/ml)-induced cell death in D-GalN (0.5 mM)-sensitized mouse hepatocytes. Further activity-guided fractionation resulted in the isolation of fifteen flavonoids viz. (-)-epicatechin (1), (-)-epigallocatechin (2), isoquercetin (3), hyperin (4), (+)-catechin (5), (+)-gallocatechin (6), kaempferol-6'-O-acetate (7), isoquercetin-6'-O-acetate (8), catechin-[8,7-e]-4 alpha-(3,4-dihydroxpyhenyl)-dihydro-2(3H)-pyranone (9), apocynin B (10), apocynin A (11), cinchonain Ia (12), apocynin C (13), apocynin D (14) and quercetin (15). All the compounds showed inhibitory effects on TNF-alpha-induced cell death with different intensities. The flavonol glycosides 3, 4, 7 and 8 and the phenylpropanoid-substituted flavan-3-ols 11 and 12 showed potent inhibitory effects on TNF-alpha-induced cell death with IC50 values of 37.5, 14.5, 31.2, 55.1, 71.9 and 41.2 microM, respectively. In contrast, the clinically used 5 and its analogues 1, 2 and 6 showed apparent activity only at 80 microM. These flavonoids appeared to be the hepatoprotective principles of the leaves of A. venetum. The hepatoprotective effects exhibited by the extract and its constituents suggest a validation of the leaves as a tea material.
Assuntos
Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Animais , Tetracloreto de Carbono/toxicidade , Morte Celular/efeitos dos fármacos , Fígado/citologia , Masculino , Camundongos , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
We assessed the effect of acteoside, a naturally occurring antioxidative phenylethanoid, on hepatic apoptosis and the subsequent liver failure induced by D-Galactosamine (D-GalN) and lipopolysaccharide (LPS). A co-administration of D-GalN (700 mg/kg) and LPS (35 microg/kg) to mice evoked typical hepatic apoptosis characterized by DNA fragmentation and apoptotic body formation, resulting in fulminant hepatitis and lethality of mice. Pre-administration of acteoside at 10 or 50 mg/kg subcutaneously at 12 and 1 h prior to D-GalN/LPS intoxication significantly inhibited hepatic apoptosis, hepatitis and lethality. Tumor necrosis factor-alpha (TNF-alpha) secreted from LPS-stimulated macrophages is an important mediator of apoptosis in this model. Acteoside showed no apparent effect on the marked elevation of serum TNF-alpha, but it partially prevented in vitro TNF-alpha (100 ng/ml)-induced cell death in D-GalN (0.5 mM)-sensitized hepatocytes at the concentrations of 50, 100 and 200 microM. These results indicated that D-GalN/LPS-induced hepatic apoptosis can be blocked by an exogenous antioxidant, suggesting the involvement of reactive oxygen intermediates (ROIs) in TNF-alpha-dependent hepatic apoptosis.
Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Glucosídeos/farmacologia , Falência Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Fenóis , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Sobrevivência Celular , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/patologia , DNA/efeitos dos fármacos , Sinergismo Farmacológico , Galactosamina/toxicidade , Lipopolissacarídeos/toxicidade , Fígado/patologia , Falência Hepática/sangue , Falência Hepática/induzido quimicamente , Falência Hepática/patologia , Masculino , Camundongos , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
We previously isolated berberine from aqueous extracts of tsu-kan-gan, a Kampo formula used for the treatment of osteoporosis. Berberine caused an inhibitory effect on parathyroid hormone (PTH)-stimulated bone resorption in neonatal mouse bone. In this report we describe the inhibitory effect of berberine on the formation of osteoclast-like multinucleated cells (OCLs) in the co-culture of mouse osteoblastic cells and bone marrow cells in the presence of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3], PTH and interleukin-1alpha (IL-1alpha). Berberine dose-dependently inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive OCLs induced by 1alpha25(OH)2D3, PTH and IL-1alpha. We prepared OCLs in the co-culture of osteoblastic cells and bone marrow cells. The effect of berberine on pit formation by OCLs was examined using dentin slices. As OCLs are terminally differentiated multinucleated cells, the survival of OCLs affects the bone-resorbing activity of OCLs. This prompted us to count the number of TRAP-positive OCLs on the slices. Berberine dose-dependently inhibited pit formation and caused a decrease in the number of TRAP-positive OCLs. Calcitonin (CT) inhibited pit formation without affecting the number of OCLs. Berberine accelerated the cell death in OCLs cultivated on a culture plate, but CT did not affect the cell death of OCLs. This suggests that the decrease in the number of OCLs on dentin slices may be due to apoptotic cell death in OCLs. In fact, Hoechst 33258 staining revealed that the treatment of OCLs with berberine resulted in condensed nuclei and a decrease in cell size. Oral administration of the berberine (30 and 50 mg/kg/d) to ovariectomized rats prevented a decrease in bone mineral density (BMD) of the lumbar vertebra without affecting the weight of the uterus and plasma concentration of estradiol. These results suggested that berberine prevented a decrease in BMD in vivo by inhibiting osteoclastic bone resorption.
Assuntos
Berberina/farmacologia , Reabsorção Óssea , Medicamentos de Ervas Chinesas/farmacologia , Macrolídeos , Animais , Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Calcitonina/farmacologia , Calcitriol/farmacologia , Feminino , Interleucina-1/farmacologia , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Ovariectomia , Hormônio Paratireóideo/farmacologia , Ratos , Ratos Wistar , Útero/efeitos dos fármacosRESUMO
Rhus javanica, a medicinal herb, has been shown to exhibit oral therapeutic anti-herpes simplex virus (HSV) activity in mice. We purified two major anti-HSV compounds, moronic acid and betulonic acid, from the herbal extract by extraction with ethyl acetate at pH 10 followed by chromatographic separations and examined their anti-HSV activity in vitro and in vivo. Moronic acid was quantitatively a major anti-HSV compound in the ethyl acetate-soluble fraction. The effective concentrations for 50% plaque reduction of moronic acid and betulonic acid for wild-type HSV type 1 (HSV-1) were 3.9 and 2.6 microgram/ml, respectively. The therapeutic index of moronic acid (10.3-16.3) was larger than that of betulonic acid (6.2). Susceptibility of acyclovir-phosphonoacetic acid-resistant HSV-1, thymidine kinase-deficient HSV-1, and wild-type HSV type 2 to moronic acid was similar to that of the wild-type HSV-1. When this compound was administered orally to mice infected cutaneously with HSV-1 three times daily, it significantly retarded the development of skin lesions and/or prolonged the mean survival times of infected mice without toxicity compared with the control. Moronic acid suppressed virus yields in the brain more efficiently than those in the skin. This was consistent with the prolongation of mean survival times. Thus, moronic acid was purified as a major anti-HSV compound from the herbal extract of Rhus javanica. Mode of the anti-HSV activity was different from that of ACV. Moronic acid showed oral therapeutic efficacy in HSV-infected mice and possessed novel anti-HSV activity that was consistent with that of the extract.
Assuntos
Antivirais/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Plantas Tóxicas , Toxicodendron/química , Animais , Antivirais/isolamento & purificação , Encéfalo/efeitos dos fármacos , Encéfalo/virologia , Etanol , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/virologia , Camundongos , Camundongos Endogâmicos BALB C , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Extratos Vegetais/química , Pele/efeitos dos fármacos , Pele/virologia , Solventes , Ensaio de Placa ViralRESUMO
Prolyl endopeptidase (PEP, EC 3.4.21.26) is an enzyme which plays a role in the metabolism of proline-containing neuropeptides, e.g., vasopressin, substance P and thyrotropin-releasing hormone (TRH), which have been suggested to be involved in learning and memory processes. In our systematic screening for PEP inhibitors from traditional Chinese medicines, we found that MeOH extract from the underground part of Rhodiola sacra S. H. Fu shows significant inhibitory activity against PEP from Flavobacterium meningosepticum. Examination of the constituents of the extract resulted in the isolation of nineteen known compounds, identified as hydroquinone (1), 4-hydroxybenzoic acid (2), caffeic acid (3), 4-hydroxycinnamic acid (4), suberic acid (5), protocatechuic acid (6), gallic acid (7), (-)-epigallocatechin 3-O-gallate (8), 2-phenylethyl beta-D-glucopyranoside (9), 3-O-galloylepigallocatechin-(4beta-->8)-epigallocatechin+ ++ 3-O-gallate (10), 2-phenylethyl alpha-L-arabinopyranosyl-(1-->6)-beta-D-glucopyranoside (11), sacranoside A (12), beta-D-glucopyranosyl 4-hydroxybenzoate (13), rhodiocyanoside A (14), rhodiooctanoside (15), sarmentosin (16), heterodendrin (17), arbutin (18) and 4-O-(beta-D-glucopyranosyl)-gallic acid (19). Among these, 1, 2, 5, 8-10, 13, 16, 18 and 19 have been isolated for the first time from R. sacra, among which 5, 9, 10, 13, 16, 18 and 19 have been isolated from Rhodiola plants for the first time. On the PEP inhibition, seven compounds (6-8, 10, 12, 18, 19) showed inhibition with an 1C50 of 27.8, 487, 1.47, 0.437, 348, 391 and 215 microM, respectively. The kinetic study of these inhibitors indicated that they are noncompetitive inhibitors, except for 6 which is a competitive inhibitor.
Assuntos
Raízes de Plantas/química , Plantas Medicinais/química , Inibidores de Proteases/farmacologia , Serina Endopeptidases/efeitos dos fármacos , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Flavobacterium/enzimologia , Medicina Tradicional Chinesa , Prolil Oligopeptidases , Inibidores de Proteases/isolamento & purificaçãoRESUMO
From the rhizome of Smilax glabra Roxb., a new flavanone was isolated and named as smitilbin (1), together with 6 known compounds, engeletin (2), astilbin (3), dihydroquercetin (4), eurryphin (5), resveratrol (6), and 5-O-caffeoylshikimic acid (7). These compounds were applied to the assay of liver nonparenchymal cells (NPC) against hepatocytes (HC) isolated from mice with an immunological liver injury. Against the NPC-caused elevation of ALT (alanine transminase) in culture supernatant from HC, the pretreatment of NPC with flavanoids (1-3) dose-dependently blocked the ALT release while 4, the aglycone of 3, did not. The chromone 5 showed a much stronger inhibition. Compound 6 also showed the activity. However, 1-7 did not show any suppression of NPC or CCl4-induced ALT release when they were used to pretreat HC. These results suggest that compounds 1-3, 5, and 6 could protect the hepatocyte damage from NPC through selectively producing the dysfunction of NPC with an essential requirement of rhamnose, and the chromone part in their structures may be critical for exhibiting the activity rather than through protecting the hepatocyte membranes.
Assuntos
Medicamentos de Ervas Chinesas/isolamento & purificação , Flavanonas , Flavonoides/isolamento & purificação , Hepatopatias/prevenção & controle , Plantas Medicinais/química , Animais , Células Cultivadas , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Hepatopatias/imunologia , Espectroscopia de Ressonância Magnética , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos BALB C , Estrutura MolecularRESUMO
The active-oxygen scavenging activity of 70 traditional herbal medicines used in China and Japan as nourishing tonics were evaluated by electron spin resonance (ESR) technique, in order to evaluate their effectiveness for anti-aging and to search for new active-oxygen scavengers from natural resources. Most of the 70 herbal medicines showed scavenging activity with various intensities. Areca catechu (methanol extract), Dendrobium plicatile (methanol extract), Juglans regia (water extract), Paeonia lactiflora (methanol extract), Psychotria serpens (water and methanol extracts), Rhodiola sacra (water and methanol extracts) and Uncaria rhynchophylla (water extract) especially showed strong scavenging activity against superoxide anion radical (*O2-), while J. regia (water and methanol extracts), Morus alba (water extract) and Schisandra chinensis (water extract) revealed strong scavenging activity against hydroxyl radical (HO*). In addition, the active-oxygen scavenging activities of 19 compounds isolated from R. sacra were also examined, and hydroquinone (1), caffeic acid (3), protocatechuic acid (6), gallic acid (7), (-)-epigallocatechin 3-O-gallate (8), 3-O-galloylepigallocatechin-(4beta-->8)-epigallocatechin+ ++ 3-O-gallate (10), heterodendrin (17) and gallic acid 4-O-beta-D-glucopyranoside (19) were found to show mild or strong inhibitory activity against superoxide anion radical (*O2-), while 4-hydroxybenzoic acid (2), 3, 4-hydroxycinnamic acid (4), 6-8 and 19 inhibited hydroxyl radical (OH*). These active-oxygen scavengers may contribute, to different extents, to their anti-aging action.
Assuntos
Antioxidantes/química , Sequestradores de Radicais Livres/química , Medicina Tradicional do Leste Asiático , Extratos Vegetais/química , Plantas Medicinais/química , China , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , JapãoRESUMO
We have investigated the anti-metastatic effect of Celosia argentea seed extracts (CAE), which have traditionally been used as a therapeutic drug for eye and hepatic diseases in China and Japan. Intraperitoneal (i.p.) administration of CAE for 7 d before tumor inoculation significantly inhibited liver metastasis caused by intraportal injection of colon 26-L5 carcinoma cells in a dose-dependent manner. CAE also showed concentration dependent mitogenic activity on BALB/c whole splenocytes, whereas incubation of the non-adherent fraction of splenocytes with CAE did not induce this activity. CAE has the ability to induce interleukin (IL)-12 production from macrophages in vitro. Following i.p. administration of CAE the maximal levels of IL-12 and interferon (IFN)-gamma production in serum were achieved at 2-3 and 6 h, respectively. Experiments using macrophage- or NK cell-deficient mice revealed that CAE-induced IL-12 in serum was not mediated by macrophages and that IFN-gamma production was mainly dependent on natural killer (NK) cells. Since CAE was inactive when the contributions of macrophages were removed in our system, its inhibitory mechanism is likely to be mainly associated with the activation of macrophages to an anti-metastatic state rather than NK cells. CAE administration resulted in increased production of IL-2, IFN-gamma and decreased production of a Th2 cytokine (IL-4) from splenocytes stimulated by PMA and A23187. Thus, the anti-metastatic effect by CAE is based on its immunomodulating properties including induction of cytokines such as IL-12, IL-2 and IFN-gamma leading to a Th1 dominant immune state and activating macrophages to the tumoricidal state. This may provide a basis for the inhibition of cancer metastasis.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Fitoterapia , Plantas Medicinais , 2-Cloroadenosina/farmacologia , Adjuvantes Imunológicos/farmacologia , Animais , Anticorpos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Divisão Celular/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/imunologia , Feminino , Gangliosídeo G(M1)/imunologia , Interleucina-2/biossíntese , Interleucina-2/imunologia , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/secundário , Macrófagos/imunologia , Macrófagos/metabolismo , Magnoliopsida/química , Camundongos , Camundongos Endogâmicos BALB C , Extratos Vegetais , Plantas Medicinais/química , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Células Th1/metabolismo , Células Th2/metabolismo , Células Tumorais Cultivadas , ÁguaRESUMO
Tribulusamides A (1) and B (2), new lignanamides embracing two cinnamic amide parts joined in a cis configuration, were isolated from the fruits of Tribulus terrestris, together with four known compounds, N-trans-feruloyltyramine (3), terrestriamide (4), N-trans-coumaroyltyramine (5), and beta-sitosterol. The structures were elucidated by 2D-NMR spectroscopy. Addition of compounds 1-5, especially 1 and 2, to primary cultured mouse hepatocytes significantly prevented cell death induced by D-galactosamine (D-GalN)/tumor necrosis factor alpha (TNF-alpha).
Assuntos
Ácidos Cumáricos/farmacologia , Fígado/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ácidos Cumáricos/química , Ácidos Cumáricos/isolamento & purificação , Medicamentos de Ervas Chinesas , Fígado/citologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , Análise EspectralRESUMO
Traditional medicines contain various metabolites derived from nucleic acid, protein, and lipid metabolism. Some of these specific metabolites may recognize the differences between viral and host metabolism resulting in anti-viral activity; hence traditional medicines may be useful sources for new antiviral agents. Traditional medicines can be cheaply obtained and have been orally administered as hot-water extracts. Therefore, they may be used for the prophylactic and therapeutic treatment of viral infection by drinking them, such as coffee or tea. Here we describe how the antiviral activity of traditional medicines was screened in vitro and how their therapeutic antiviral activities were verified in vivo, to obtain traditional antiviral medicines that can be clinically used. Therefore, we have selected 12 herbal extracts, from more than 250 herbal medicines, that exhibit therapeutic activities against cutaneous herpes simplex virus (HSV) type 1 (HSV-1) infection in mice. Four of the 12 augmented the therapeutic efficacy of acyclovir (ACV) in mice and showed potent anti-HSV activity against infection with ACV-resistant HSV-1 mutants in mice. These herbal extracts selectively inhibited viral DNA synthesis and showed a different mode of anti-HSV-1 action from that of ACV. They were also effective against both recurrent HSV and cytomegalovirus infections, without toxicity. Such prophylactic and therapeutic antiviral activities of the traditional medicines were verified by the purification of major active compounds. We could show new indications of traditional medicines as antiviral agents. Thus, the drinking of the extracts, in a daily tea or coffee, may be used for prophylaxis and therapy of diseases caused by herpes virus infection and improve the quality of life.
Assuntos
Antivirais/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Herpesvirus Humano 1/efeitos dos fármacos , Animais , Antivirais/química , Infecções por Citomegalovirus/tratamento farmacológico , DNA Viral/biossíntese , Avaliação Pré-Clínica de Medicamentos , Resistência Microbiana a Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Ácido Gálico/análogos & derivados , Ácido Gálico/isolamento & purificação , Glucosídeos/isolamento & purificação , Cobaias , Herpes Simples/tratamento farmacológico , Herpes Simples/prevenção & controle , Herpesvirus Humano 1/metabolismo , Hospedeiro Imunocomprometido , Camundongos , RecidivaRESUMO
Rhus javanica has been shown to exhibit anti-herpes simplex virus (HSV) activity and potentiate the anti-HSV activity of acyclovir in vitro and in vivo. This extract was examined for its suppressive efficacy on recurrent genital infection in guinea pigs. Guinea pigs were primarily infected intravaginally with HSV type 2 (HSV-2). Prophylactic oral administration, at the dose corresponding to human use, of R. javanica significantly reduced the incidence, severity and/or frequency of spontaneous and severe skin lesions as compared with latently infected guinea pigs administered with water. This prophylactic efficacy was confirmed by the crossover administration, for more than 2 months, of R. javanica and water to the infected guinea pigs. Toxicity, such as weight loss, from R. javanica administration was not observed in the guinea pigs. When recurrent HSV-2 disease was induced by ultraviolet irradiation 3 months after primary infection, the prophylaxis with R. javanica was also significantly effective in reducing the severity of ultraviolet-induced skin lesions. Thus, prophylaxis of recurrent genital HSV-2 infection with R. javanica may preserve the efficacy of acyclovir by reducing both the use of acyclovir and the appearance of acyclovir-resistant viruses.
Assuntos
Antivirais/uso terapêutico , Herpes Genital/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Administração Intravaginal , Administração Oral , Animais , Chlorocebus aethiops , Feminino , Cobaias , Herpes Genital/prevenção & controle , Herpesvirus Humano 2 , Humanos , Fitoterapia , Plantas Tóxicas , Recidiva , Fatores de Tempo , Toxicodendron/uso terapêutico , Células VeroRESUMO
We previously found that a methanolic extract of the stems of Sambucus sieboldiana inhibited bone resorption in organ culture. In this study, we further fractionated the methanol extract guided by the activity towards bone resorption stimulated by parathyroid hormone (PTH) in vitro. The ethyl acetate fraction (EtOAc Fr.) of the methanolic extract inhibited PTH-stimulated bone resorption of neonatal mouse bones, and the inhibitory activity was more potent than those of other fractions. Oral administration of the EtOAc Fr. (50 and 100 mg/kg/d) to ovariectomized (OVX) rat prevented the decrease in bone mineral density (BMD) of the lumbar (L2-4) vertebra, indicating that the EtOAc Fr. is effective in vivo. Furthermore, the EtOAc Fr. (50, 100 and 150 mg/kg/d) decreased the serum calcium level elevated in low calcium dietary rats. The phenolic constituents of the EtOAc fraction were examined for their inhibitory effect on bone resorption stimulated by PTH in neonatal mouse bone. Among them, vanillic acid, vanillin and coniferyl alcohol showed significant inhibitory effects on bone resorption. Of the compounds examined, vanillic acid was found to have a significant inhibitory effect on the decrease of BMD in OVX mice. Therefore, the EtOAc Fr. of S. sieboldiana showed a suppressive effect on bone resorption in vitro and in vivo. In addition, the inhibitory effects of the EtOAc Fr. on bone resorption may be at least partly due to the inhibitory action of vanillic acid.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Plantas Medicinais/química , Acetatos , Animais , Benzaldeídos/farmacologia , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/induzido quimicamente , Cálcio/sangue , Cálcio/deficiência , Cálcio da Dieta/administração & dosagem , Camundongos , Ovariectomia , Hormônio Paratireóideo/toxicidade , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Solventes , Fatores de Tempo , Ácido Vanílico/farmacologiaRESUMO
Three new phenylethanoid glycoside, named scrosides A-C and a new iridoid glycosides, named picroside IV, have been isolated from the underground parts of Picrorhiza scrophulariiflora, together with 11 known compounds. Their structures were elucidated by the means of 2D NMR spectroscopy and chemical methods.