Efeito quimiopreventivo da Beta-ionona na hepatocarcinogênese associada à fibrose hepática / Chemopreventive effect of Beta-ionone in hepatocarcinogenesis associated with hepatic fibrosis

O carcinoma hepatocelular (HCC) é a neoplasia primária mais frequente que acomete o fígado, a quarta principal causa de morte relacionada ao câncer e apresenta mau prognóstico. A fibrose hepática está presente em grande parte dos casos de HCC e é um dos principais fatores de risco para esta afecção. Segundo estudos prévios do grupo, a ß-ionona (BI), presente em uvas e aromatizantes de vinho, apresenta potencial quimiopreventivo na hepatocarcinogênese principalmente por reduzir o número e tamanho de lesão pré neoplásica (LPN) e inibir a proliferação celular. No entanto, até o presente não foram identificados na literatura estudos que investigaram o efeito deste isoprenóide no processo fibrótico e na hepatocarcinogênese a ele associada. Desta forma, este estudo pretendeu investigar o potencial efeito quimiopreventivo da BI na hepatocarcinogênese associada à fibrose hepática. Para tanto, ratos machos Wistar foram tratados com óleo de milho (OM) [0,25 ml / 100 g de peso corporal (p.c.); Grupo de OM] ou BI (16mg / 100g p.c.; Grupo BI) durante 18 semanas. A partir da 2ª semana, todos os animais receberam uma dose intraperitoneal de dietilnitrosamina (DEN - 50 mg / Kg p.c.) uma vez por semana até a 16ª semana. Os animais foram eutanasiados em diferentes períodos do protocolo experimental: na 10a semana (grupos OMP1 e BIP1), na 14a semana (grupos OMP2 e BIP2) e na 18ª semana (grupos OMP3 e BIP3). O isoprenóide demonstrou, de maneira inédita na literatura, inibir o desenvolvimento da fibrose hepática em diferentes estágios da hepatocarcinogênese (pontos 1, 2 e 3) por reduzir (p < 0,05) a porcentagem de área marcada para picrosirius. Além disso, BI reduziu a porcentagem de área positiva para α- SMA (p < 0,05) e as concentrações de hidroxiprolina (p < 0,05) no ponto 2. Foi observada ação quimiopreventiva da BI nas fases iniciais da hepatocarcinogênese (pontos 1 e 2) mesmo em modelo associada a fibrose por reduzir (p < 0,05) o número e porcentagem de área do corte ocupada por LPN GSTP positivas. Este efeito não foi observado em fase mais avançada da hepatocarcinogênese (ponto 3). Corroborando este dado não foram observadas diferenças em relação ao número de tumores (p>=0,05) avaliados por imageamento e por análise histopatológica. No entanto, quando comparados ao seu controle (OMP3), os animais do grupo BIP3 apresentaram menor mortalidade e menor incidência (p < 0,05) de HCC high, considerado um tipo mais agressivo de HCC, sugerindo que este composto possa atuar na agressividade das células tumorais. O grupo BIP2 demonstrou ainda menor proliferação celular (p < 0,05) quando comparado ao grupo OMP2. Assim foram avaliadas as vias de proliferação celular PI3K/AKT e MAPK/ERK, bem como as proteínas p21 e p53, relacionadas a progressão do ciclo celular. Não foram observadas(p≥0,05) alterações nestas vias por parte do isoprenóide. O presente estudo demonstrou ação protetora da BI no desenvolvimento de fibrose, bem como na hepatocarcinogênese a ela associada. Contudo, são necessárias análises complementares para elucidar mecanismos pelos quais a BI atua na carcinigênese hepática associada à fibrose

Hepatocellular carcinoma (HCC) is the primary liver cancer, the fourth leading cause of death related to cancer and presents a poor prognosis. Hepatic fibrosis is present in most cases of HCC and represents one of the main risk factors for this condition. According to previous studies of the group, ß-ionone (BI), present in grapes and wine flavorings, has a potential chemopreventive in hepatocarcinogenesis mainly by reducing the number and size of preneoplastic lesions (LPN) and inhibiting cell proliferation. However, to date, no studies have been identified in the literature that investigated the effect of this isoprenoid on the fibrotic process and in its association with hepatocarcinogenesis. Thus, this study aimed to investigate the potential chemopreventive effect of BI in hepatocarcinogenesis associated with hepatic fibrosis. Male Wistar rats were treated with corn oil (OM) [0.25 ml / 100 g body weight (b.w.); OM] or BI group (16mg / 100g b.w; BI group) for 18 weeks. From week 2, all animals received an intraperitoneal dose of diethylnitrosamine (DEN - 50 mg / kg b.w.) once in a week until week 16. The animals were euthanized at different periods of the experimental protocol: at week 10 (groups OMP1 and BIP1), at week 14 (groups OMP2 and BIP2) and week 18 (groups OMP3 and BIP3). The isoprenoid, for the first time in the literature, shown to inhibit the development of liver fibrosis at different stages of hepatocarcinogenesis (points 1, 2 and 3) by reducing (p <0.05) the percentage of the area labeled for picrosirius. Also, BI reduced the percentage of α-SMA positive area (p <0.05) and hydroxyproline concentrations (p <0.05) at point 2. BI chemopreventive action was observed in the early stages of hepatocarcinogenesis (point 1 and 2) even in a model associated with fibrosis for reducing (p <0.05) the number and percentage of the liver section area occupied by GSTP positive LPN. This effect was not observed at a later stage of hepatocarcinogenesis (point 3). Corroborating this data, no differences were observed regarding the number of tumors (p>=0.05) evaluated by imaging and histopathological analysis. However, when compared to its control (OMP3), animals from the BIP3 group had lower mortality and lower incidence (p<0.05) of HCC high, considered a more aggressive type of HCC, suggesting that this compound may act in aggressiveness of tumor cells. The BIP2 group also showed lower cell proliferation (p <0.05) when compared to the OMP2 group. Thus, PI3K / AKT and MAPK / ERK cell proliferation pathways were evaluated, as well as p21 and p53 proteins, related to cell cycle progression. No changes were observed in these pathways by the isoprenoid (p≥0.05). The present study demonstrated the protective action of BI in the development of fibrosis, as well as its association with hepatocarcinogenesis. However, further analysis is needed to elucidate mechanisms by which BI acts on fibrosis-associated liver carcinogenesis

Megastigmane glucosides isolated from Dichrocephala benthamii / 中国天然药物

The present study was designed to investigate the chemical constituents of the whole herb of Dichrocephala benthamii. A new megastigmane glucoside (compound 1), together with its four known analogues (compounds 2-5), was obtained. Their structures were elucidated on the basis of spectroscopic analyses (UV, IR, MS, and 1D and 2D NMR). The absolute configuration of compound 1 was assigned on the basis of CD method and chemical evidence. In addition, their cytotoxicity against human hepatoma cells (HepG-2) was evaluated by the MTT method. Compound 5 showed weak activity against HepG-2, while the other compounds did not show remarkable inhibitory effects.

Structural elucidation of two new megastigmane glycosides from the leaves of Aquilaria sinensis / 中国天然药物

The present study was designed to determine the chemical constituents and identify new components of the leaves of Aquilaria sinensis (Lour.) Gilg. The compounds were isolated and purified by repeated silica gel, Sephadex LH-20, and ODS column chromatography and their structures were elucidated by NMR and HR-ESI-MS spectrometry. Eight megastigmane glycosides and two cucurbitacins were isolated and identified as (9S) megastigma-4,7-diene-2,3,9-triol 9-O-β-D-glucopyranoside (1), (9S) megastigma-4(13),7-diene-3,6,9-triol 9-O-β-D-glucopyranoside (2), macarangloside D (3), corchoionoside C (4), staphylionoside H (5), (+) 3-oxo-α-ionol-β-D-glucopyranoside (6), (-) 3-oxo-α-ionol-β-D-glucopyranoside (7), citroside B (8), 2-O-β-D-glucopyranosyl cucurbitacin I (9), bryoamaride (10). Compounds 1 and 2 were newly identified megstigmane glucosides and reported from this genus for the first time.

Study on chemical constituents from cultivated Gynura nepalensis / 中国中药杂志

Taking application of some isolation and purification technologies, such as solvent extraction, preliminary solvent isolation, column chromatographies over silica gel and Sephadex LH-20 gel and preparative HPLC, 10 compounds were obtained from Gynura nepalensis cultivated in the suburban area of Beijing. Their structures were identified by spectroscopic methods and comparison with literature as (3R) -3-hydroxy-β-ionone (1), (3S,5R, 6S, 7E) -5, 6-epoxy-3-hydroxy-7-megastigmen-9-one (2), (+) -boscialin (3), 3, 6-trans-3-hydroxy-α-ionone (4), 3, 6-cis-3-hydroxy-α-ionone (5), 3, 4-cis-3, 4-dihydroxy-β-ionone (6), ethyl caffeate (7), loliolide (8), 1H-indole-3-carbaldehyde (9), and 3-(hydroxyacetyl)indole (10), respectively. All compounds were isolated from the title plant for the first time, and with compounds 1, 2, 4-7, 9 and 10 being isolated from Gynura species for the first time. Structurally, the above compounds 1-6 belong to C13 nor-sesquiterpenoids, sharing the same carbon skeleton of megastigmane. According to this study, they are one of major kinds of chemical constituents of Gynura nepalensis and have important reference value for the investigation on phytotaxonomy of this species.

Two new sulfated sesquiterpenoids from Petasites tricholobus / 药学学报

Two new sulfated sesquiterpenoids, megastigman-7-ene-3, 5, 6, 9-tetrol-3-O-β-D-6'-sulfonated-glucopyranoside (1) and 3-O-β-D-6'-sulfonated-glucopyranosyl-6-(3-oxo-2-butenylidenyl)-1, 1, 5-trimethylcyclohexan-5-ol (2), along with one known sesquitepenoid compound icariside B1 (3) were isolated from the whole herb of Petasites tricholobus Franch. Their structures were identified by their chemical and spectroscopic characters. All obtained compounds were tested for their cytotoxicity against four cancer cell lines.

A new megastigmane glycoside from the aerial parts of Cirsium setosum / 中国天然药物

AIM@#To study the chemical constituents of the aerial parts of Cirsium setosum (Willd.) MB..@*METHODS@#The chemical constituents were isolated and purified by various chromatographic techniques. Their structures were determined on the basis of physical properties and spectroscopic data.@*RESULTS@#A new megastigmane glycoside and six known compounds were obtained and identified as (7E, 9R)-9-hydroxy-5, 7-megastigmadien-4-one-9-O-α-L-arabinopyranosyl-(1→6)-β-D-glucopyanoside (1), (6R, 7E, 9R)-9-hydroxy-4, 7-megastigmadien-3-one-9-O-α-L-arabinopyranosyl-(1→6)-β-D-glucopyranoside (2), urolignoside (3), 4, 9, 9'-trihydroxy-3, 3'-dimethoxy-8-O-4$\prime $-neolignan-7-O-β-D-glucopyranoside (4), citroside A (5), salidrosidin (6), and adenosine (7).@*CONCLUSION@#Compound 1 is a new megastigmane glycoside, named as Xiaojiglycoside A.

Chemical constituents from Hypericum perforatum / 中国中药杂志

<p><b>OBJECTIVE</b>To study the chemical constituents from Hypericum perforatum.</p><p><b>METHOD</b>Compouds were isolated by chromatographic techniques. Their structures were identified by spectral methods. The inhibitory activity of recombinant human PTP1B was evaluated.</p><p><b>RESULT</b>Nine compounds were elucidated as D-Mannitol (1), 1,2-benzenedicarboxylic acid bis(1-methylpropyl) ester (2), (7E, 6R,9S)-9-hydroxy-4,7-megastigmadien-3-one (3), (6S,9R)-roseoside (4) , 2,6-dimethoxy-4-hydroquinone-l-O-beta-D-glucopyranoside (5), 2,6-di-methoxy-4-hydroxybenzyl alcohol 1 -O-beta-D-glucopyranoside (6), syringate 4-O-beta-glucopyranoside (7), hypericin (8), skyrin-6-0-beta-D-glucopyranoside (9) , (R)-2,3-dihydroxypropyl 3,4-dihydroxy-benzoate (10). At a concentration of 2 micromol x L(-1), compound 8 inhibited recombinant human PTP1B with inhibitory rate of 96.4% and IC50 of 2.5 micromol x L(-1).</p><p><b>CONCLUSION</b>compound 10 was new, compounds 2-4, 7 were obtained from Hypericum for the first time and compounds 5-6 was isolated from this plant for the first time. Compound 8 showed remarkable PTP1B inhibitory activity.</p>

Efficacy of geraniol but not of β-ionone or their combination for the chemoprevention of rat colon carcinogenesis

β-ionone (βI), a cyclic isoprenoid, and geraniol (GO), an acyclic monoterpene, represent a promising class of dietary chemopreventive agents against cancer, whose combination could result in synergistic anticarcinogenic effects. The chemopreventive activities of βI and GO were evaluated individually or in combination during colon carcinogenesis induced by dimethylhydrazine in 48 3-week-old male Wistar rats (12 per group) weighing 40-50 g. Animals were treated for 9 consecutive weeks with βI (16 mg/100 g body weight), GO (25 mg/100 g body weight), βI combined with GO or corn oil (control). Number of total aberrant crypt foci (ACF) and of ACF ≥4 crypts in the distal colon was significantly lower in the GO group (66 ± 13 and 9 ± 2, respectively) compared to control (102 ± 9 and 17 ± 3) and without differences in the βI (91 ± 11 and 14 ± 3) and βI+GO groups (96 ± 5 and 19 ± 2). Apoptosis level, identified by classical apoptosis morphological criteria, in the distal colon was significantly higher in the GO group (1.64 ± 0.06 apoptotic cells/mm²) compared to control (0.91 ± 0.07 apoptotic cells/mm²). The GO group presented a 0.7-fold reduction in Bcl-2 protein expression (Western blot) compared to control. Colonic mucosa concentrations of βI and GO (gas chromatography/mass spectrometry) were higher in the βI and GO groups, respectively, compared to the control and βI+GO groups. Therefore, GO, but not βI, represents a potential chemopreventive agent in colon carcrvpdate=20110329inogenesis. Surprisingly, the combination of isoprenoids does not represent an efficient chemopreventive strategy.

Norisoprenoids from red alga Gymnogongrus flabelliformis / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the chemical constituents of the red alga Gymnogongrus flabelliformis Harv.</p><p><b>METHOD</b>Compounds were isolated by normal phase silica gel and Sephadex LH - 20 gel column chromatography and reverse phase HPLC. Their structures were elucidated by spectroscopic methods including MS, 1H-NMR, 13C-NMR. Cytotoxicity of the compounds was screened by using standard MIT method.</p><p><b>RESULT</b>Five compounds were isolated from G. flabelliforrmis, their structures were identified as(3S, 6R, 7E)-( + )-3-hydroxyl-4, 7-mega-stigmadien-9-one (1), (3S, 5R, 6S, 7E)-(-)-3-hydroxy-5, 6-epoxy-7-megastigmene-9-one (2), (3S, 5S, 6R, 7E)-(+)3-hydroxy-5, 6-epoxy-7-megastigmene-9-one (3), dehydrovomifoliol (4), (3R)-(-)4-[(2R, 4S)-4-acetoxy-2-hydroxy-2, 6, 6-trimethylcyclohexylidene] -3-buten-2-one (5).</p><p><b>CONCLUSION</b>All of the compounds were obtained from this species for the first time and compound 1 was a new natural product. These compounds were inactive (IC50 > 10 microg x mL(-1)) in the MTT assay against several human cancer cell lines.</p>

Study on the chemical constituents in herb of Hypericum attenuatum / 中国中药杂志

<p><b>OBJECTIVE</b>To study the constituents of Hypericum attenatum.</p><p><b>METHOD</b>The compounds were isolated by chromatography on silica gel, the structures were identified by their physical, chemical properties and IR, NMR and MS spectral data respectively.</p><p><b>RESULT</b>Nine compounds were isolated and identified as p-hydroxybenzoic acid (1), 6, 9-dihydroxy-4, 7-megastigmadien-3-one (2), butyl alcohol-O-alpha-D-fructoside (3), 24-ethyl-cholest-7-ene-3 beta, 5 alpha, 6 beta-thtroil (4), hexanol (5), 1 beta, 6 alpha-dihydroxyeudesmane-4(14)-ene (6), beta-sitosterol (7), 5, 5-dimethyl-4-hydroxy-tetrahydrofuran-2-one (8), beta-daucosterol (9).</p><p><b>CONCLUSION</b>All of the compounds were isolated from H. attenuatum for the first time.</p>

The megastigman glycosides from herb of Potentilla multifida / 中国中药杂志

<p><b>OBJECTIVE</b>To investigate the chemical constituents of Potentilla multifida.</p><p><b>METHOD</b>Various chromatographic techniques were employed for isolation and purification of the constituents. The structures were elucidated by spectral analysis.</p><p><b>RESULT</b>Four megastigmane glycosides were isolated from P. multifida and their structures were identified as citroside A (1), icariside B1 (2), (6S,7E,9R)-roseoside (3), (6S,7E,9R)-vomifoliol-9-O-beta-D-xylopyranosyl-(1-->6)-O-beta-D-glucopyranoside (4), respectively.</p><p><b>CONCLUSION</b>All compounds were obtained from the genus Potentilla for the first time.</p>