Xanthorrhizol is an active component isolated from Curcuma xanthorrhiza Roxb. (Zingiberaceae) that is traditionally used in Indonesia for medicinal purposes. In the present study, we found that the topical application of xanthorrhizol before 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment significantly inhibits TPA-induced mouse ear edema and TPA-induced tumor promotion in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated ICR mouse skin. The topical application of xanthorrhizol following the induction of papillomas with TPA-induced hyperplasia and dysplasia also reduced tumor multiplicity and incidence in DMBA-initiated mouse skin. To further elucidate the molecular mechanisms underlying the antitumor-promoting activity of xanthorrhizol, its effect on the TPA-induced expression of ornithine decarboxylase (ODC), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and the upstream signaling molecules controlling these proteins were explored in mouse skin. The pre-treatment with xanthorrhizol inhibited the expression of ODC, iNOS and COX-2 proteins and nuclear factor-kappaB (NF-kappaB) activation in both mouse skin with TPA-induced acute inflammation and DMBA-initiated mouse skin promoted by TPA for 19 weeks. When mouse skin was treated after TPA-induced production of papillomas, xanthorrhizol remarkably suppressed the expression of ODC, iNOS and COX-2 and inhibited the activation of NF-kappaB. Furthermore, western blot analysis showed that xanthorrhizol suppressed the activation of extracellular signal-regulated protein kinase, p38, c-Jun-N-terminal kinase and Akt in mice after topical application for 6 weeks following the induction of papillomas. Taken together, the present study demonstrates that xanthorrhizol not only delays or inhibits tumor formation, but also reverses the carcinogenic process at pre-malignant stages by reducing the protein levels of ODC, iNOS and COX-2 regulated by the NF-kappaB, mitogen-activated protein kinases and/or Akt.

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Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are frequently overexpressed in tumor tissues or transformed cells. In the present work, we assessed the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on expression of iNOS and COX-2 in mouse skin. Topical application to the dorsal skin of female ICR mice of 10 nmol TPA led to maximal induction of iNOS and COX-2 protein expression at approximately 2 and 4 h, respectively. When applied topically onto shaven backs of mice 30 min prior to TPA, the NOS inhibitor aminoguanidine (AG) inhibited the expression of COX-2 protein at the pharmacologically effective dose. Pretreatment with a more specific iNOS inhibitor, N(G)-nitro-l-arginine-methyl ester, also suppressed TPA-induced COX-2 expression. Immunohistochemical analysis of TPA-treated mouse skin using an anti-nitrotyrosine antibody reveals enhanced levels of nitrotyrosine protein localized in epidermal and dermal layers. Topical application of NO donors, such as sodium nitroprusside (SNP) and S-nitroso-N-acetyl-d,l-penicillamine, induced expression of COX-2 in mouse skin, which was attenuated by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide. SNP treatment stimulated NF-kappaB activation in mouse skin, which was associated with the degradation of IkappaBalpha. Topical application of inhibitors of NF-kappaB, such as pyrrolidine dithiocarbamate or N-alpha-p-tosyl-l-lysine chloromethylketone, inhibited the SNP-induced COX-2 expression. SNP induced a weak but concentration-related increase in COX-2 expression in cultured mouse keratinocytes, which was abolished by treatment with SN50, a specific inhibitor of nuclear translocation of NF-kappaB. Mouse keratinocytes treated with SNP exhibited an elevated NF-kappaB-driven COX-2 promoter activity. Topical application of AG (10 micro mol) prior to each TPA treatment after initiation reduced the multiplicity of papillomas by 44% at 22 weeks. In conclusion, up-regulation of COX-2 by NO may be mediated by activation of NF-kappaB in mouse skin, which provides a molecular mechanism by which COX-2 is induced during tumor promotion.

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It is well-known that microbiota dysbiosis is closely associated with numerous diseases in the human body. The oral cavity and gut are the two largest microbial habitats, playing a major role in microbiome-associated diseases. Even though the oral cavity and gut are continuous regions connected through the gastrointestinal tract, the oral and gut microbiome profiles are well-segregated due to the oral–gut barrier. However, the oral microbiota can translocate to the intestinal mucosa in conditions of the oral–gut barrier dysfunction. Inversely, the gut-to-oral microbial transmission occurs as well in inter- and intrapersonal manners. Recently, it has been reported that oral and gut microbiomes interdependently regulate physiological functions and pathological processes. Oral-to-gut and gut-to-oral microbial transmissions can shape and/or reshape the microbial ecosystem in both habitats, eventually modulating pathogenesis of disease. However, the oral–gut microbial interaction in pathogenesis has been underappreciated to date. Here, we will highlight the oral–gut microbiome crosstalk and its implications in the pathogenesis of the gastrointestinal disease and cancer. Better understanding the role of the oral–gut microbiome axis in pathogenesis will be advantageous for precise diagnosis/prognosis and effective treatment.

The association of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers was assessed through a metaanalysis of published case-control studies and a pooled analysis of both published and unpublished case-control studies from the Genetic Susceptibility to Environmental Carcinogens database (http://www.upci.upmc.edu/research/ccps/ccontrol/ index.html). Thirty publications used in the meta-analysis included a total of 7783 subjects (3177 cases and 4606 controls); 21 datasets, 9397 subjects (3130 cases and 6267 controls) were included in the pooled analysis. The GSTM1 deletion was 2-fold more likely to occur in African American and African cases than controls (odds ratio: 1.7, 95% confidence interval: 0.9-3.3), although this was not observed among whites (odds ratio: 1.0, 95% confidence interval: 0.9-1.1). The metaanalysis and pooled analysis showed a significant association between oral and pharyngeal cancer and the CYP1A1 MspI homozygous variant (meta-OR m2/m2 : 1.9, 95% confidence interval: 1.4-2.7; Pooled OR m2m2 : 2.0, 95% confidence interval:1.3-3.1; OR m1m2 or [infi]m2m2 : 1.3, 95% confidence interval: 1.1-1.6). The association was present for the CYP1A1 (exon 7) polymorphism (OR Val/Val : 2.2, 95% confidence interval: 1.1-4.5) in ever smokers. A joint effect was observed for GSTM1 homozygous deletion and the CYP1A1 m1m2 variant on cancer risk. Our findings suggest that tobacco use and genetic factors play a significant role in oral and pharyngeal cancer. Genet Med 2008:10(6):369-384. Key Words: GSTM1, CYP1A1, oral and pharyngeal cancers, epidemiology, meta-analysis and pooled analysis Glutathione S-transferasesThe Glutathione S-transferases (GSTs) comprise a family of phase II detoxifying enzymes that catalyze a large number of reactions taking place between the cytosolic glutathione and compounds containing an electrophilic center. 1 These enzymes are involved in the elimination of xenobiotics and endogenous products of oxidative stress formed as a result of aerobic metabolism, exposure to ionizing radiation or any other process that causes cellular damage. Substrates for GSTs include acetaldehyde and several polyaromatic hydrocarbons (PAHs) found in tobacco smoke. The main steps for GST catalysis includes the formation of a complex with the cytosolic glutathione and the ionization of the sulfydryl group of this enzyme bound to glutathione to yield a highly reactive thiolate anion through hydrogen bonding with the adjacent hydroxyl

Cisplatin (cis-diamminedichloroplatinum II) is a platinum coordinated complex that is widely used as an antineoplastic agent for the treatment of many solid tumors, including cancers of the ovary, testis, lung, bladder, head and neck, cervix and endometrium.1) Despite its excellent anticancer activity, the clinical use of cisplatin is often limited by its undesirable side effects, such as severe nephrotoxicity and hepatotoxicity. 2,3) Although the precise mechanism for this cisplatin-induced toxicity is not well understood, cisplatin is taken up preferentially and accumulates in the human liver and kidney cells, 4) resulting in the enhanced production of reactive oxygen species (ROS) and the decrease in the antioxidant enzymes.5,6) Therefore, antioxidants have been administered before a cisplatin treatment to protect against nephrotoxicity. 7)Licorice is an esteemed crude drug in both the Orient and Occident that is originated from the dried roots of several Glycyrrhiza species, including Glycyrrhiza uralensis FISCHER, G. glabra LINNE and G. inflata BATALIN. 8,9) In Chinese traditional medicine, licorice remains one of the most commonly prescribed herbs and has been used in the treatment of various ailments ranging from tuberculosis to peptic ulcers.10) Licorice has also been employed as a flavoring and sweetening agent, as well as a demulcent and expectorant in Western countries.11) The chemical constituents of licorice include glycyrrhizin and its aglycone, glycyrrhetinic acid, which are originally isolated from aqueous extracts and are used in the treatment of hyperlipemia, atherosclerosis, viral diseases, allergic inflammation and hepatotoxicity.12,13) The acetone or ethanol extract of licorice has species-specific flavonoids, such as liquiritin, isoliquiritin and their corresponding aglycones, glabridin, glabrol, glabrene, hispaglabridin A and hispaglabridin B.14,15) These flavonoids exhibit antioxidative, 16) superoxide scavenging 16) and anticarcinogenic activities.17) However, in vivo antitumor activity of a licorice extract and its protective activity on cisplatin-induced toxicity have not yet been studied.In the present study to assess the antitumor activity of a licorice extract and whether it has the potential to serve as a beneficial supplement during cisplatin chemotherapy, we examined the inhibitory effect of the licorice extract alone and in combination with cisplatin on the tumor growth, and its protective effect against cisplatin-induced nephrotoxicity and hepatotoxicity in mice xenografted with mouse colon carcinoma cells. MATERIALS AND METHODSChemical Cisplatin, phenylmethylsulfonyl fluoride (PMSF), sodium nitrite, 1,1,3,3-tetramethoxypropane, reduced glutathione (GSH), 5,5Ј-dithiobis(2-nitrobenzoic acid) (DTNB), glutathione reductase, reduced nicotinamide adenine dinucleotide phosphate (NADPH), superoxide dismutase (SOD), xanthine oxidase, a-naphthylamine, sulfanilic acid, xanthine, catalase and 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (purpald ® ) were purchased from SigmaAldrich Chem...