Screening of drugs for hepatocellular carcinoma prevention based on drug repositioning and network pharmacology / 第二军医大学学报

ObjectiveTo screen novel drugs for hepatocellular carcinoma (HCC) prevention based on drug repositioning strategy. Methods We collected the gene expression profiles of tissue samples representing the stepwise carcinogenic process covering 4 stages: Cirrhosis, low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN) and early HCC, and identified the gene signatures between two consecutive stages. We also collected the gene expression data of human hepatocellular carcinoma cell lines HepG2 treated by 3 927 drugs and small molecules. The similarity between disease expressions and the drug gene expressions was calculated using gene set enrichment analysis (GSEA) algorithm, and drugs negatively correlated with the disease signatures were selected. Finally, we constructed the activated sub-network and performed pathway enrichment analysis to explore the underlying mechanisms of these drugs. Results We screened out the drugs that could prevent HCC during different stages, and found that importazole, picotamide and paclitaxel exhibited preventive potentials at all stages from cirrhosis to early HCC. The genes affected by these 3 drugs showed inverse expression pattern during HCC development, and pathways such as cancer-related pathway, p53 signaling pathway, focal adhesion and retinol metabolism pathway were enriched. Conclusion Preventive drugs for HCC have been screened through drug repositioning strategy, and our results indicated that antiplatelet therapy may play a role in the prevention of HCC, which provides information for further study.

Extracto acuoso de uchuva (Physalis peruviana): actividades antiproliferativa, apoptótica y antioxidante / Aqueous extract of golden berry (Physalis peruviana): antiproliferative, apoptotic and antioxidant activities

Antecedentes: extractos etanólicos de P. peruviana han mostrado actividad citotóxica contra diferentes células cancerosas. Objetivo: estudiar la actividad anticancerígena de un extracto acuoso del fruto uchuva en células de cáncer de colon SW480 y SW620. Materiales y métodos: se analizaron citotoxicidad e índice de selectividad (SI) (MTT), antiproliferación (sulforodamina-B), apoptosis (ciclo celular, anexina-V, receptores TRAIL-DR4/-DR5 y caspasa-3), actividad antioxidante (contenido de flavonoides y carotenoides totales). Resultados: el extracto acuoso de uchuva mostró efecto citotóxico y antiproliferativo en células SW480 (IC50=44,2 mg/mL, SI=11,6) y SW620 (IC50=85,1mg/mL, SI=6,0). Las células hipodiploides SW480 y SW620 aumentaron 13% y 12%, respectivamente. Las células apoptóticas incrementaron 19% y 21% en SW480 y SW620, respectivamente, con incremento en la expresión de receptores TRAIL-DR4/-DR5 en SW480 (+59%/+53%) y SW620 (+67%/+65%), y activación de caspasa-3 en ambas líneas celulares. El extracto neutralizó radicales OH-, presentó baja capacidad reductora y atrapadora de especies reactivas del oxígeno y nitrógeno. El contenido de flavonoides y carotenoides fue 487,1 mg catequina y 0,9 mg β-caroteno por 100 g de liofilizado, respectivamente. Conclusiones: estos hallazgos sugieren que la uchuva puede ser una fuente prometedora de compuestos bioactivos con actividad quimiopreventiva en cáncer de colon humano.

Background: Ethanolic extracts from P. peruviana showed cytotoxic activity against different cancer cell lines. Objective: To evaluate the antiproliferative activity of aqueous extract of the fruit golden berryin colon cancer cells. Materials and Methods: We analyzed cytotoxicity and selectivity index (SI) (MTT), antiproliferation (sulforhodamine-B), apoptosis (cell cycle, Annexin-V, receptors TRAIL-DR4/-DR5 and caspase-3), and antioxidant activity (content of total carotenoids and flavonoids). Results: The aqueous extract showed cytotoxic and antiproliferative effect on SW480 (IC50 = 44.2 mg/ml, SI = 11.6) and SW620 (IC50 = 85.1 mg/ml, SI = 6.0). The hypodiploid SW480 and SW620 cells increased 13% and 12% respectively as well as apoptotic SW480 and SW620 cells (19% and 21 %, respectively), expression of receptors TRAIL-DR4 /-DR5 (SW480: +59% / +53%; SW620: +67% / +65%) and activation of caspase-3. The aqueous extract scavenged OH- radicals, showed low oxygen radical capacity and low scavenging capacity for reactive oxygen and nitrogen species. The total flavonoids and carotenoids contente was 487.1 mg catechin y 0.9 mg β-carotene by 100 g powder, respectively. Conclusions: These findings suggest that golden berry may be a promising source of bioactive compounds with chemopreventive activity against human colon cancer.

El benzo(a)pireno en los alimentos y su relación con el cáncer / Benzo[a]pyrene from food and cancer

Antecedentes: el benzo(a)pireno es un hidrocarburo aromático policíclico con efectos adversos para la salud, una de las fuentes es la ingestión de alimentos, formados durante procesamiento industrial o en el hogar. Objetivo: indagar sobre la formación de benzo(a)pireno en los alimentos, su activación biológica, relación con el cáncer, contenido en los alimentos y la normativa que regula la cantidad en alimentos para humanos. Materiales y métodos: se realizó una búsqueda bibliográfica de artículos publicados en las bases de datos nacionales e internacionales. Resultados: el benzo(a)pireno ingerido con los alimentos se absorbe por el intestino, se metaboliza predominantemente en el hígado, allí se activa y puede inducir cáncer de diversa localización, como esófago, estómago, intestino, piel, vejiga, pulmón e hígado, evidenciado en estudios experimentales en animales. El benzo(a)pireno atraviesa la placenta y es potencialmente tóxico para el feto. Las cantidades en algunos alimentos exceden las máximas permitidas por la Comisión Europea entidad que periódicamente actualiza las normas sobre el tema. En Colombia no se encontró reglamentación. Conclusión: el benzo(a)pireno procedente de alimentos genera compuestos capaces de desarrollar cáncer principalmente del tracto gastrointestinal. La Comisión Europea actualiza periódicamente la normativa que regula el contenido de benzo(a)pireno en alimentos, Colombia carece de normas sobre el tema.

Background: Benzo[a]pyrene is a polycyclic aromatic hydrocarbon which has been related with adverse health outcomes. Food is a source of benzo[a]pyrene; which is produced during industrial processing or cooking. Objective: To review information about benzo(a)pyrene formation in food, biological activation, association with cancer, food content and regulation of benzo(a)pyrene content in human food. Methods: A literature search from national and international scientific databases was developed. Results: benzo[a]pyrene ingested is absorbed by the intestine metabolized and activated, predominantly, by the liver. Animal studies have associated benzo[a]pyrene with esophagus, stomach, intestine, skin, bladder, lung, and liver cancer. Benzo[a]pyrene is potentially toxic to the fetus, due to it passes trough placenta. Benzo[a]pyrene amounts in some foods exceed the maximum level allowed by the European Commission; which periodically updates legislation on this topic. In Colombia there is not regulation about benzo[a]pyrene. Conclusion: benzo[a]pyrene in food generates compounds that may be associated with cancer, mainly gastrointestinal cancer. The European Commission regularly updates regulation about benzo[a] pyrene content in foods. Colombia does not have regulation on this topic.

Biomedical Issues of Dietary fiber beta-Glucan

beta-Glucan is a polysaccharide in the form of fiber and the main element of fiber in grains such as barley, oats, yeast and mushrooms. Many studies have examined the efficacy of beta-Glucan in terms of the lipid lowering effects, blood sugar reduction, weight reduction, immune modulator, and anticarcinogenic effect. However, there is no comprehensive review article on the biomedical issues regarding beta-Glucan. The authors searched for systematic reviews and clinical experiments for each relevant topic and reviewed the biomedical effects of beta-Glucan, for the purpose of developing research strategies for the future.

Epidemiological Study on Cancer Prevention by Ginseng: Are All Kinds of Cancers Preventable by Ginseng?

In the light of experimental results, two case-control studies and one cohort study in a population of ginseng cultivation area were conducted to confirm whether ginseng has any anticarcinogenic effect on human cancers. All participants were interviewed using a standardised questionnaire to obtain the information on demographics, cigarette smoking, alcohol consumption and ginseng intake. In 905 pairs case-control study, 62% had a history of ginseng intake compared to 75% of the controls, a statistically significant difference (p<0.01). The odds ratio (OR) for cancer in relation to ginseng intake was 0.56. In extended case-control study with 1987 pairs, the ORs for cancer were 0.37 in fresh ginseng extract users, 0.57 in white ginseng extract users, 0.30 in white ginseng extract users, 0.30 in white ginseng powder users, and 0.20 in red ginseng users. Those who took fresh ginseng slices, fresh ginseng juice, and white ginseng tea, however, did not show decrease in the risk. Overall, the risk decreased as the frequency and duration of ginseng intake increased. With respect to the site of cancer, the ORs for cancers of the lip, oral cavity, pharynx, esophagus, stomach, colorectum, liver, pancreas, larynx, lung and ovary were significantly reduced by ginseng intake. Smokers with ginseng intake showed lower ORs for cancers of lung, lip, oral cavity and pharynx and liver than those without ginseng intake. In 5 yr follow- up cohort study conducted in the ginseng cultivation area, Kangwha-eup, ginseng intakers had significantly lower risk than non-intakers. As for the type of ginseng, cancer risk significantly decreased among intakers of fresh ginseng extract, alone or together with other ginseng preparations. Among 24 red ginseng intakers, no cancer death occurred during the follow-up period. The risk for stomach and lung cancers was significantly reduced by ginseng intake, showing a statistically significant dose-response relationship in each follow-up year. In conclusion, Panax ginseng C.A. Meyer has been established as non-organ specific cancer preventive, having dose response relationship. These results warrant that ginseng extracts and its synthetic derivatives should be examined for their preventive effect on various types of human cancers.

Chemoprevention of Mammary, Cervix and Nervous system Carcinogenesis in Animals using Cultured Panax ginseng Drugs and Preliminary Clinical Trials in Patients with Precancerous Lesions of the Esophagus and Endometrium

The anticarcinogenic effects and mechanisms of the biotechnological drugs of Panax ginseng C.A. Meyer cultivated in Russia, bioginseng, panaxel and panaxel- 5, were studied. Bioginseng was produced from a tissue culture of ginseng root cultured on standard medium, whereas panaxel and panaxel-5 were produced from ginseng tissue root cultures using standard mediums enriched with 2-carboxyethylgermanium sesquioxide and 1-hydroxygermatran-monohydrate respectively. All three ginseng drugs inhibited the development of mammary tumors induced by intramammary injections of N-methyl-N-nitrosourea (MNU) in rats, the development of the brain and spinal cord tumors induced by transplacental administration of N-ethyl-N-nitrosourea (ENU) in rats, and the development of uterine, cervical and vaginal tumors induced by intravaginal applications of 7,12-dimethylbenz(a)anthracene (DMBA) in mice. The ginseng drugs induced the cytotoxic activity of macrophages in mice, enhanced T-lymphocyte rosette formation in guinea pigs exposed to cyclophosphamide, and stimulated the production of thyroid hormones in rats. These mechanisms may contribute to the anticarcinogenic action of the ginseng drugs. The organic germanium compounds present in panaxel and panaxel-5 did not potentiate the anticarcinogenic or immuno- stimulatory effects as much as biogeinseng. Preliminary clinical trials with panaxel and bioginseng were carried out in patients with precancerous lesions of the esophagus and endometrium. Panaxel was found to have a strong therapeutic effect in patients suffering from chronic erosive esophagitis. Bioginseng induced the regression of adenomatous-cystic hyperplasia of the endometrium in some patients. Thus, we conclude that the drugs of ginseng appear to hold considerable promise for future cancer chemoprevention.

Anticarcinogenic Effect of Red Ginseng on the Development of Liver Cancer Induced by Diethylnitrosamine in Rats

Anticarcinogenic effect of red ginseng (Panax ginseng C.A. Meyer cultivated in JiLin, China) on the development of liver cancer induced by diethylnitrosamine (DEN) in rats was studied, especially in preventive and curative groups. In the preventive group, the rats were given with DEN concomitantly with red ginseng fluid, and in the curative group, the rats were administered with red ginseng fluid after they developed liver cancer nodules induced by DEN. The result of the preventive group revealed that the developmental rate of liver cancer in the experimental group was 14.3%, while 100% in the control group, with the difference being statistically significant. DNA, RNA, glycogen, gamma-GT, SDH, and 5'-NT were maintained at relatively normal level in experimental group, and decreased or increased in the control group. The result of curative group showed that hepatoma nodules of the DEN-red ginseng group I were smaller than those of control group I, the structure of hepatic tissue was well preserved, the area with gamma-GT positive was smaller, and the ultrastructure of hepatocytes was normal. The average life span the DEN-red ginseng group II and the DEN control group II were 72.8 and 42.3 days, respectively. To sum up, all findings on preventive and curative groups had clearly proved that the red ginseng had the anticarcinogenic effect on the development of liver cancer induced by DEN in rats.