Current evidences have expended the concept that chronic inflammation might play a crucial role in the development and progression of colorectal cancer. For instance, chronic ulcerative colitis (UC) is associated with a 10- to 40-fold increased risk of developing colorectal cancer (CRC) compared to the general population. However, the specific mechanistic link between chronic inflammation and carcinogenesis in colon has not been integrated into molecular understanding. In this current review, we will provide an update on the molecular pathogenesis of colitis-associated colorectal cancer, focused on 1) the differences of molecular mechanism between the colitis-associated colorectal cancer (CAC) and the sporadic colorectal cancer (SCC), 2) the plausible and contributive role of chronic inflammation in colon carcinogenesis, and 3) lessons learned from colitis-associated animal model. Understanding of molecular pathogenic mechanism underlying the colitis-associated colorectal cancer will facilitate the development of novel treatment strategies for prevention of colitis-associated colorectal cancer.
Carcinogenesis* ; Colitis, Ulcerative ; Colon* ; Colorectal Neoplasms ; Inflammation* ; Inflammatory Bowel Diseases ; Models, Animal

Tetrahydropapaveroline (THP), a neurotoxic tetrahydroisoquinoline alkaloid formed by condensation between dopamine and dopaldehyde, has been speculated to cause Parkinson's disease and also to contribute to alcohol dependence. Having two catechol moieties, THP may readily undergo oxidation to form an o-quinone intermediate with concomitant production of reactive oxygen species, which can cause neuronal cell death and DNA damage. This review will deal with the current knowledge of neurotoxic effects of this endogenous alkaloid and underlying biochemical mechanisms.
Alcoholism ; Catechols ; Cell Death ; DNA Damage ; Dopamine ; Neurons ; Parkinson Disease ; Reactive Oxygen Species ; Tetrahydroisoquinolines ; Tetrahydropapaveroline

Accumulating evidence from epidemiologic and laboratory studies support an inverse relationship between a regular consumption of fruits and vegetables and the risk of specific cancers. Numerous phytochemicals derived from edible plants have been reported to possess ability to interfere with a specific stage of carcinogenic process. Multiple mechanisms have been proposed to account for the anti-carcinogenic actions of dietary constituents, but more attention has recently focussed on intracellular signaling cascades as common molecular targets of a wide variety of chemopreventive phytochemicals.
Chemoprevention ; Fruit ; Mitogen-Activated Protein Kinases ; Phytochemicals* ; Plants, Edible ; Signal Transduction ; Transcription Factor AP-1 ; Transcription Factors* ; Vegetables

In the present study, we investigated the effects of exhaustive exercise and recovery on inflammatory, pro-apoptotic, and anti-oxidative responses in human peripheral blood mononuclear cells (PBMCs). Sixteen volunteers participated in a guided physical activity program in which they were subjected to progressive exercise on the treadmill until they were exhausted followed by an 1-hour recovery period. Isolated human PBMCs were collected before exercise, immediately after exercise, and after 1-hour recovery. Exhaustive exercise induced expression of heme oxygenase-1 and glutamate cysteine ligase catalytic subunit and activation of NF-κB and NF-E2 related factor 2 (Nrf2). Apoptosis, as measured by activity and cleavage of caspase-3 and its substrate PARP also significantly increased. However, induction of redox signaling and the pro-apoptotic response fully returned to the baseline level during the 1-hour recovery period. On the other hand, COX-2 expression was continuously elevated after exercise cessation throughout the 1-hour recovery period. Taking all these findings into account, we conclude that exhaustive exercise transiently induces Nrf2-mediated antioxidant gene expression and eliminates damaged cells through apoptosis as part of an adaptive cytoprotective response against oxidative and inflammatory stress.

Recently, there have been considerable efforts to search for naturally occurring substances that can inhibit, reverse, or retard the multi-stage carcinogenesis. A wide array of phenolic substances derived from edible and medicinal plants have been reported to possess anticarcinogenic and antimutagenic activities and in many cases, the chemopreventive activities of phytochemicals are associated with their anti-inflammatory and/or antioxidative properties. Panax ginseng C.A. Meyer cultivated in Korea has been widely used in traditional herbal medicine for the treatment of various diseases. Certain fractions or purified ingredients of ginseng have been shown to exert anticarcinogenic and antimutagenic activities. Our previous studies have revealed that the methanol extract of heat-processed Panax ginseng C.A. Meyer attenuates the lipid peroxidation in rat brain homogenates and is also capable of scavenging superoxide generated by xanthine- xanthine oxidase or by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocytic leukemia (HL-60) cells. Topical application of the same extract onto shaven backs of female ICR mice also suppressed TPA-induced skin tumor promotion. Likewise, topical application of ginsenoside Rg3, one of the constituents of heat-treated ginseng, significantly inhibited TPA-induced mouse epidermal ornithine decarboxylase activity and skin tumor promotion. Expression of cyclooxygenase-2 (COX-2) in TPA-stimulated mouse skin was markedly suppressed by Rg3 pretreatment. In addition, Rg3 inhibited TPA-stimulated activation of NF-kB and extracellular-regulated protein kinase (ERK), one of the mitogen-activated protein (MAP) kinase in mouse skin and also in cultured human breast epithelial cells (MCF-10A).
Animal ; Antineoplastic Agents, Phytogenic/*therapeutic use ; Antioxidants ; Heating ; Human ; Mitogen-Activated Protein Kinases/metabolism ; Molecular Structure ; NF-kappa B/metabolism ; *Panax ; Plant Extracts/*therapeutic use

BACKGROUND: NAD(P)H:quinone oxidoreductase-1 (NQO1) is a widely-distributed flavin adenine dinucleotide-dependent flavoprotein that promotes obligatory 2-electron reductions of quinones, quinoneimines, nitroaromatics, and azo dyes. This reduces quinone levels and thereby minimizes generation of excess reactive oxygen species (ROS) formed by redox cycling, and concurrent depletion of intracellular thiol pools. Ajoene is derived from crushed garlic. It is formed by a reaction involving two allicin molecules, and is composed of allyl sulfide and vinyl disulfide. Ajoene is present in two isomers, E- and Z-form. METHODS: Expression of antioxidant enzymes and nuclear factor E2-related factor-2 (Nrf2) was measured by Western blot analysis. NQO1 promoter activity was assessed by the luciferase reporter gene assay. ROS accumulation was monitored by using the fluorescence-generating probe 2′,7′-dichlorofluorescein diacetate. The intracellular glutathione levels were measured by using a commercially available kit. RESULTS: Z-ajoene significantly up-regulated the expression of representative antioxidant enzyme NQO1 in non-tumorigenic breast epithelial MCF-10A cells at non-toxic concentrations. Z-ajoene enhanced up-regulation and nuclear translocation of Nrf2, which plays a pivotal role in the induction of many genes encoding antioxidant enzymes and other cytoprotective proteins. Z-ajoene treatment also increased the activity of nqo1-promoter harboring antioxidant response element consensus sequences in MCF-10A cells. Silencing of Nrf2 by small interfering RNA abrogated ajoene-induced expression of NQO1. Z-ajoene activated extracellular signal-regulated kinase (ERK). Inhibition of ERK activation by U0126 abrogated ability of Z-ajoene to activate Nrf2 and to induce NQO1 expression. Intracellular ROS accumulation was observed after treatment with Z-ajoene, whereas the E-isoform was not effective. The inhibition of ROS by treatment with N-acetylcysteine, a radical scavenger, abrogated Z-ajoene-induced expression of NQO1 as well as activation of ERK and Nrf2, suggesting that Z-ajoene augments the Nrf2-dependent antioxidant defense via ROS generation and ERK activation. CONCLUSIONS: Z-ajoene induces NQO1 expression in MCF-10A cells through ROS-mediated activation of Nrf2.
Acetylcysteine ; Adenine ; Antioxidant Response Elements ; Azo Compounds ; Blotting, Western ; Breast ; Consensus Sequence ; Epithelial Cells ; Flavoproteins ; Garlic ; Genes, Reporter ; Glutathione ; Humans ; Luciferases ; NF-E2-Related Factor 2 ; Oxidation-Reduction ; Phosphotransferases ; Quinones ; Reactive Oxygen Species ; RNA, Small Interfering ; Up-Regulation

Silent mating type information regulator 2 homolog 1 (SIRT1), an NAD + -dependent histone/protein deacetylase, has multifarious physiological roles in development, metabolic regulation, and stress response. Thus, its abnormal expression or malfunction is implicated in pathogenesis of various diseases. SIRT1 undergoes post-translational modifications, including phosphorylation, oxidation/reduction, carbonylation, nitrosylation, glycosylation, ubiquitination/deubiquitination, SUMOylation etc. which can modulate its catalytic activity, stability, subcellular localization, and also binding affinity for substrate proteins. This short review highlights the regulation of SIRT1 post-translational modifications and their pathophysiologic implications.

PURPOSE: Inflammation acts as a driving force for the development of cancer. Multiple lines of evidence suggest that nonsteroidal anti-inflammatory drugs, especially those that specifically target cyclooxygenase-2 (COX-2), are effective in preventing certain cancers. The present study was aimed at investigating the antitumor promoting potential of celecoxib in chemically induced mouse skin tumorigenesis, as well as elucidating the underlying molecular mechanisms. MATERIALS AND METHODS: To study the antitumor promoting effects of celecoxib, we used the classical two-stage mouse skin tumorigenesis model that involves initiation with a single application of 7,12-dimethylbenz[alpha]anthracene (DMBA) followed by promotion with repeated applications of 12-O-tetradecanoylphorbol-13-acetate (TPA). The effects of celecoxib on the expression of COX-2, vascular endothelial growth factor (VEGF), p65 and the different isoforms of CCAAT/enhancer binding protein (C/EBP) were examined by performing Western blot analysis. Electrophoretic mobility gel shift assay was used to examine the effects of celecoxib on the TPA-induced DNA binding activities of various transcription factors. RESULTS: Our study revealed that topical application of celecoxib (10 micromol) significantly reduced the multiplicity of papillomas in DMBA-initiated and TPA-promoted mouse skin. Pretreatment with celecoxib also diminished the expression of COX-2 and VEGF in the mouse skin papillomas. Pretreatment with celecoxib attenuated DNA binding of transcription factor (C/EBP) in the TPA-stimulated mouse skin. Moreover, celecoxib suppressed the TPA-induced nuclear expression of C/EBPdelta, but not C/EBPbeta, in mouse skin in vivo. CONCLUSION: Our study demonstrates the inhibitory effects of celecoxib on mouse skin tumor promotion, which was associated with a decreased expression of COX-2 and VEGF, as well as inhibition of C/EBP activation.
Animals ; Blotting, Western ; Carcinogenesis ; Carrier Proteins ; Chemoprevention ; Cyclooxygenase 2 ; DNA ; Inflammation ; Mice* ; NF-kappa B ; Papilloma ; Protein Isoforms ; Skin* ; Transcription Factors ; Vascular Endothelial Growth Factor A ; Celecoxib

BACKGROUND: Baicalein is a bioactive flavone that is originally extracted from the root of Scutellaria baicalensis Georgi. This plant has long served as Chinese herbal medicine in the management of multiple diseases including inflammatory bowel diseases. Although it has been revealed that baicalein inhibits experimental colitis in mice, the molecular mechanisms still remain largely unrecognized. METHODS: The experimental colitis was induced in mice by 3% dextran sulfate sodium (DSS) in drinking water. The mice were given baicalein (10 or 25 mg/kg) by gavage for 7 days before and after DSS administration. Expression of COX-2 and inducible nitric oxide synthase (iNOS) and molecules involved in NF-κB signaling, such as inhibitor of κBα (IκBα), pIκBα, p65, and phospho-p65 was examined by Western blot analysis in the tissue of the mouse colon. Activity of IκB kinase β (IKKβ) was assessed by measuring the relative amount of radioactive γ-phosphate of ATP transferred to the IκBα substrate protein. The expression and phosphorylation of STAT3 and its target gene cyclin D1 were also measured. RESULTS: Baicalein prominently mitigated the severity of DSS-induced colitis in mice. It inhibited the expression of COX-2 and iNOS. Moreover, baicalein attenuated activity and phosphorylation of IKKβ and subsequent degradation of IκBα. Baicalein suppressed the phosphorylation and nuclear translocation of p65, resulting in a reduced DNA binding activity of NF-κB. Baicalein also suppressed the phosphorylation of STAT3 and expression of cyclin D1. Baicalein exhibited the synergistic effect on inhibition of COX-2 induced by DSS with curcumin, an ingredient of turmeric. CONCLUSIONS: Protective effects of baicalein on DSS-induced colitis are associated with suppression of NF-κB and STAT3 signaling pathways, which may contribute to its cancer preventive effects on colon carcinogenesis.
Adenosine Triphosphate ; Animals ; Asian Continental Ancestry Group ; Blotting, Western ; Carcinogenesis ; Colitis ; Colon ; Curcuma ; Curcumin ; Cyclin D1 ; Cyclooxygenase 2 ; Dextran Sulfate ; Dextrans ; DNA ; Drinking Water ; Herbal Medicine ; Humans ; Inflammatory Bowel Diseases ; Mice ; Nitric Oxide Synthase Type II ; Phosphorylation ; Phosphotransferases ; Plants ; Scutellaria baicalensis

BACKGROUND: BRCA1 mutated breast cancer cells exhibit the elevated cell proliferation and the higher metastatic potential. G protein-coupled receptor 30 (GPR30) has been shown to regulate growth of hormonally responsive cancers, such as ovarian and breast cancers, and high expression of GPR30 is found in estrogen receptor (ER)-negative breast cancer cells. ER-negative breast cancer patients often have a mutation in the tumor suppressor gene, BRCA1. This study explored antiproliferative effects of genistein, a chemopreventive isoflavone present in legumes, and underlying molecular mechanisms in triple negative breast cancer cells with or without functionally active BRCA1.METHODS: Expression of BRCA1, GPR30 and Nrf2 was measured by Western blot analysis. Reactive oxygen species (ROS) accumulation was monitored by using the fluorescence-generating probe, 2’,7’-dichlorofluorescein diacetate. The effects of genistein on breast cancer cell viability and proliferation were assessed by the MTT, migration and clonogenic assays.RESULTS: The expression of GPR30 was dramatically elevated at both transcriptional and translational levels in BRCA1 mutated breast cancer cells compared to cells with wild-type BRCA1. Notably, there was diminished Akt phosporylation in GPR30 silenced cells. Treatment of BRCA1 silenced breast cancer cells with genistein resulted in the down-regulation of GPR30 expression and the inhibition of Akt phosphorylation as well as the reduced cell viability, migration and colony formation. Genistein caused cell cycle arrest at the G₂/M phase in BRCA1-mutant cells through down-regulation of cyclin B1 expression. Furthermore, BRCA1-mutant breast cancer cells exhibited higher levels of intracellular ROS than those in the wild-type cells. Genistein treatment lowered the ROS levels through up-regulation of Nrf2 expression.CONCLUSIONS: Lack of functional BRCA1 activates GPR30 signaling, thereby stimulating Akt phosphorylation and cell proliferation. Genistein induces G2/M phase arrest by down-regulating cyclin B1 expression, which is attributable to its suppression of GPR30 activation and Akt phosphorylation in BRCA1 impaired breast cancer cells.
Blotting, Western ; Breast Neoplasms ; Breast ; Cell Cycle Checkpoints ; Cell Proliferation ; Cell Survival ; Cyclin B1 ; Down-Regulation ; Estrogens ; Fabaceae ; Genes, Tumor Suppressor ; Genistein ; Humans ; Phosphorylation ; Reactive Oxygen Species ; Triple Negative Breast Neoplasms ; Up-Regulation