Fruit Extract, Rich in Polyphenols and Flavonoids, Modifies the Expression of DNMT and HDAC Genes Involved in Epigenetic Processes.

Recently, the field of epigenetics has been intensively studied in relation to nutrition. In our study, the gene expression patterns of histone deacetylases (HDACs), which regulate the stability of histone proteins, and DNA methyltransferases (DNMTs), which regulate DNA methylation, were determined in mice. The animals were fed a human-equivalent dose of the aqueous extract of fruit seeds and peels, which is rich in flavonoids and polyphenols, for 28 days and then exposed to the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). The concentrations of trans-resveratrol and trans-piceid were determined in the consumed extract by HPLC and were 1.74 mg/L (SD 0.13 mg/L) and 2.37 mg/L (SD 0.32 mg/L), respectively, which corresponds to the consumption of 0.2-1 L of red wine, the main dietary source of resveratrol, in humans daily. Subsequently, 24 h after DMBA exposure, the expression patterns of the HDAC and DNMT genes in the liver and kidneys were determined by qRT-PCR. The DMBA-induced expression of the tested genes HDAC1, HDAC2, DNMT1, DNMT3A and DNMT3B was reduced in most cases by the extract. It has already been shown that inhibition of the DNMT and HDAC genes may delay cancer development and tumour progression. We hypothesise that the extract studied may exert chemopreventive effects.

The effects of flavonoids, green tea polyphenols and coffee on DMBA induced LINE-1 DNA hypomethylation.

The intake of carcinogenic and chemopreventive compounds are important nutritional factors related to the development of malignant tumorous diseases. Repetitive long interspersed element-1 (LINE-1) DNA methylation pattern plays a key role in both carcinogenesis and chemoprevention. In our present in vivo animal model, we examined LINE-1 DNA methylation pattern as potential biomarker in the liver, spleen and kidney of mice consuming green tea (Camellia sinensis) extract (catechins 80%), a chinese bayberry (Morella rubra) extract (myricetin 80%), a flavonoid extract (with added resveratrol) and coffee (Coffee arabica) extract. In the organs examined, carcinogen 7,12-dimethylbenz(a)anthracene (DMBA)-induced hypomethylation was prevented by all test materials except chinese bayberry extract in the kidneys. Moreover, the flavonoid extract caused significant hypermethylation in the liver compared to untreated controls and to other test materials. The tested chemopreventive substances have antioxidant, anti-inflammatory properties and regulate molecular biological signaling pathways. They increase glutathione levels, induce antioxidant enzymes, which decrease free radical damage caused by DMBA, and ultimately, they are able to increase the activity of DNA methyltransferase enzymes. Furthermore, flavonoids in the liver may inhibit the procarcinogen to carcinogen activation of DMBA through the inhibition of CYP1A1 enzyme. At the same time, paradoxically, myricetin can act as a prooxidant as a result of free radical damage, which can explain that it did not prevent hypomethylation in the kidneys. Our results demonstrated that LINE-1 DNA methylation pattern is a useful potential biomarker for detecting and monitoring carcinogenic and chemopreventive effects of dietary compounds.

Metachronous Bilateral Extremity Soft Tissue Sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) account for approximately 1% of adult malignancies, with 50 to 60% occurring in the extremities. Liposarcoma is the most common type of STS and represent about 20% of total adult sarcomas. There are rare syndromes associated with increased risk of developing STS. Further, chemical compounds such as chlorinated phenols and a few chemotherapeutic drugs have been linked to STS, along with ionizing radiation. Nevertheless, the etiology is uncertain for most of these lesions. CASE REPORT: This report details 2 cases of metachronous bilateral STS of the lower extremities. The first of these presented as a local recurrence of a previously resected right thigh liposarcoma and a new liposarcoma in the left thigh. As mentioned above, among the different subtypes of STS, liposarcoma has the highest tendency for multifocality. The second patient had multifocal metachronous leiomyosarcoma with lung metastases occurring simultaneously with the second presentation. Leiomyosarcoma is another subtype reported to present with multifocal disease. CONCLUSIONS: Despite the rarity of bilateral lesions, their occurrence should not be overlooked in the initial diagnosis and follow-up of the initially detected tumor. Early detection can affect patient survival because their presence predicts unfavorable outcomes.

Uncommon metastasis of laryngeal cancer to small bowel causing intestinal obstruction treated by laparoscopic approach.

Metastatic laryngeal cancer to the small bowel is extremely rare. Management of small bowel obstruction used to constitute a relative contraindication for the use of laparoscopic modality. We are reporting a case of an elderly man known to have laryngeal cancer who presented with small bowel obstruction due to metastatic deposit to the small bowel. The condition was successfully treated by laparoscopic assisted approach. A review of the natural history of advanced laryngeal cancer, common and uncommon sites of metastasis, and the rare presentation as small bowel obstruction is illustrated in this review.

Mixtures of Uncaria and Tabebuia extracts are potentially chemopreventive in CBA/Ca mice: a long-term experiment.

A long-term experimental animal model was developed by our research group for the evaluation of potential chemopreventive effects. The inhibitory effects of agents on carcinogen (7,12-dimethylbenz[a]anthracene (DMBA) induced molecular epidemiological biomarkers, in this case the expression of key onco/suppressor genes were investigated. The expression pattern of c-myc, Ha-ras, Bcl-2, K-ras protooncogene and p53 tumour suppressor gene were studied to elucidate early carcinogenic and potential chemopreventive effects. The consumption of so-called Claw of Dragon tea (CoD™ tea) containing the bark of Uncaria guianensis, Cat's Claw (Uncaria sp. U. tomentosa) and Palmer trumpet-tree (Tabebuia sp. T. avellanedae) was able to decrease the DMBA-induced onco/suppressor gene overexpression in a short-term animal experiment. In a following study CBA/Ca mice were treated with 20 mg/kg bw DMBA intraperitoneally (i.p.) and the expression patterns of onco/suppressor genes were examined at several time intervals. According to the examined gene expression patterns in this long-term experiment the chemopreventive effect of CoD™ tea consumption could be confirmed.

The effect of fenugreek on the gene expression of arachidonic acid metabolizing enzymes.

The main bioactive compounds of Trigonella foenum graecum L. (fenugreek) seeds are protodioscin, trigoneoside, diosgenin and yamogenin, which have anticarcinogenic potency through inhibition of cell proliferation and inhibition of prostaglandin synthesis. The effect of fenugreek on ALOX and COX genes was examined in AKR/J H-2(k) mice exposed to dimethylbenz[α]anthracene (DMBA), a potent carcinogen. The expression pattern of these genes was determined by detecting the mRNA expression in various tissues (the lungs, liver, spleen and the kidneys) in four groups of mice. Two groups were fed with normal and two of them with fenugreek containing nutriment. Each group divided into DMBA treated and control groups. Mice were autopsied on day 7 after DMBA treatment for mRNA isolation. Fenugreek consumption itself did not change gene expression compared with the control group. DMBA could increase the expression of ALOX12, ALOX15, ALOX5 genes mainly in all organs. Fenugreek consumption was generally protective in each organ in a different manner. DMBA treatment increased COX2 gene expression, but fenugreek was protective in all tissues examined. In COX1 gene, the fenugreek diet could suppress the expression, except for spleen, independently from carcinogen exposure. Therefore by inhibiting the arachidonic acid metabolism fenugreek may prevent tumorigenesis.

Early modification of c-myc, Ha-ras and p53 expressions by chemical carcinogens (DMBA, MNU).

7,12-Dimethylbenz[a]anthracene (DMBA) and N-methyl-N-nitrosourea (MNU) are important environmental carcinogens. Their different biological effects were examined in CBA/Ca H-2(K) haplotype inbred mice on the gene expression of c-myc, Ha-ras and p53 through a 24 hour period. Elevated expression of c-myc and Ha-ras genes was found in the spleen, lung, thymus and lymph nodes 6 and 12 hours after DMBA treatment and in the lung and thymus 3 hours after MNU treatment. In the liver, DMBA induced strong onco/suppressor gene expression as early as 6 hours after the treatment, but MNU increased the p53 gene expression 12 hours after the treatment. The gene expression patterns reflected the different mechanism of the direct acting MNU and metabolically activated DMBA. This phenomenon provides evidence as to the usefulness of detection of onco/supressor key gene expression as early molecular epidemiological biomarkers of carcinogenesis and carcinogenic exposure in animal model, useful in human cancer prevention practice as well.

Early modification of c-myc, Ha-ras and p53 expressions by N-methyl-N-nitrosourea.

Methylnitrosourea (MNU) is a well-known pluripotent direct-acting carcinogen. Formation of MNU following incubation of various meats with additional nitrite under in vitro acidic conditions is possible. It is possible that many species, including humans, are exposed to carcinogenic MNU, generated in their alimentary tract. Previously, an animal model was developed by our research group to investigate the expression of three genes c-myc, Ha-ras and p53 as early molecular epidemiological biomarkers of carcinogenic exposure or carcinogenesis caused by DMBA (dimethylbenz[alpha]anthracene). The aim of this study was to investigate the early effect of MNU on the gene expression levels. MNU is a direct-acting carcinogen which spontaneously and rapidly degrades, so any effect on the gene expression is observed in 24 hours. Our results show the maximum effect in vivo on the gene expression at 12 hours after the MNU treatment; on the other hand, 24 hours after the treatment, the elevated gene expressions decreased in target organs (bone marrow, lung, lymph nodes). Our results correspond to "long-term" experiments of the carcinogenic effect of MNU in different target organs. Our findings suggest that MNU has an impact on the expression of c-myc, Ha-ras and p53 genes in 12 hours, especially in bone marrow. Overexpression of these genes occurs as an early biological effect of exposure to chemical carcinogens. According to our results, the high expression of these genes could indicate MNU exposure and these genes could take part in MNU-induced tumorigenesis.

The effect of aspartame administration on oncogene and suppressor gene expressions.

BACKGROUND: Aspartame (L-phenylalanine N-L-alpha-aspartyl-1-methyl ester) is an artificial sweetener with widespread applications. Previously published results have shown that among rats receiving aspartame a significant increase of lymphoreticular neoplasms, brain tumours and transitional cell tumours occurred. The aim of our short-term experiment was to investigate the biological effect of aspartame consumption by determining the expressions of key oncogenes and a tumour suppressor gene. MATERIALS AND METHODS: After one week per os administration of various doses of aspartame to CBA/CA female mice, p53, c-myc, Ha-ras gene expression alterations were determined in individual organs. RESULTS: The results showed an increase in gene expressions concerning all the investigated genes especially in organs with a high proliferation rate: lymphoreticular organs, bone-marrow and kidney. CONCLUSION: Aspartame has a biological effect even at the recommended daily maximum dose.