Yoon Jae Kim

Oxidative stress in inflammation‐based gastrointestinal tract diseases: Challenges and opportunities

Oxygen free radicals in excessively high amounts are all very reactive chemically and can impose a detrimental influence on living organisms by provoking “oxidative stress” that can damage major cellular constituents. The latter includes the cell membrane, cytoplasmic proteins, and nuclear DNA. Conversely, nitric oxide (NO), superoxide anion, and related reactive oxygen species (ROS) when present in low amounts play an important role as regulatory mediators in signaling processes, through which, paradoxically, many ROS‐mediated responses can protect the cells against oxidative stress by induction of “redox homeostasis.” Therefore, diseases associated with free radical overproduction are provoked by “blazed ROS productions” far beyond the hosts capacity to quench. Free radicals have been implicated in the pathogenesis of diverse gastrointestinal (GI) diseases including gastroesophageal reflux disease (GERD), gastritis, enteritis, colitis and associated cancers as well as pancreatitis and liver cirrhosis. This article provides an overview of the role of oxidative stress in inflammation‐based GI tract diseases, including reflux esophagitis, Helicobacter pylori‐associated gastritis, non‐steroidal anti‐inflammatory drug‐induced enteritis, ulcerative colitis, and associated colorectal cancer. The challenging issue that ROS can contribute to diverse gastrointestinal dysfunction, or manifest dual roles in cancer promotion or cancer suppression will also be discussed for the opportunity to enhance understanding of inflammation‐based GI diseases.

Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer

Background:  The aim of this phase II study was to determine the efficacy of gemcitabine plus cisplatin chemotherapy in patients with advanced biliary tract cancer.

Bisphenol A exposure during adulthood causes augmentation of follicular atresia and luteal regression by decreasing 17β-estradiol synthesis via downregulation of aromatase in rat ovary.

Background: Bisphenol A (BPA) has been detected in human body fluids, such as serum and ovarian follicular fluids. Several reports indicated that BPA exposure is associated with the occurrence of several female reproductive diseases resulting from the disruption of steroid hormone biosynthesis in the adult ovary. Objective: We hypothesized that long-term exposure to low concentrations of BPA disrupts 17β-estradiol (E2) production in granulosa cells via an alteration of steroidogenic proteins in ovarian cells. Methods: Adult female rats received BPA for 90 days by daily gavage at doses of 0, 0.001, or 0.1 mg/kg body weight. We determined serum levels of E2, testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). We also analyzed the expressions of steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase isomerase (3β-HSD), and aromatase cytochrome P450 (P450arom) in the ovary. Results: Exposure to BPA significantly decreased E2 serum concentration, which was accompanied by augmented follicular atresia and luteal regression via increase of caspase-3–associated apoptosis in ovarian cells. After BPA exposure, P450arom and StAR protein levels were significantly decreased in granulosa cells and theca-interstitial (T-I) cells, respectively. However, P450scc and 3β-HSD protein levels remained unchanged. The increase in LH levels appeared to be associated with the decreased synthesis of T in T-I cells after BPA exposure via homeostatic positive feedback regulation. Conclusions: BPA exposure during adulthood can disturb the maintenance of normal ovarian functions by reducing E2. The steroidogenic proteins StAR and P450arom appear to be targeted by BPA.

Prevention of Colitis-Associated Carcinogenesis with Infliximab

The emergence of infliximab was an epochal event in the treatment of inflammatory bowel disease (IBD). Because colitis-associated cancers arose in the setting of chronic inflammation, during which “inflammation-dysplasia-carcinoma sequence” prevails and anti-inflammatory agents can prevent carcinogenesis, we hypothesized whether infliximab can prevent colitic cancer in animal models for which C57BL/6 mice were exposed to 15 cycles of dextran sulfate sodium (DSS), with each cycle consisting of 0.7% DSS for 1 week followed by sterilized water for 10 days. Infliximab (4 mg/kg i.v.) was given on the 1st, 3rd, and 7th weeks or 25th, 27th, and 31st weeks of cycle according to “step-up” versus “top-down” strategy. Molecular change about inflammation and carcinogenesis was compared between groups. Multiple colorectal tumors developed in 75% to 80% of control mice, whereas only 16.7% of mice treated with infliximab on the 1st, 3rd, and 7th weeks developed colon tumors. Significant decreases in tumor necrosis factor-α level, mast cell number, and the expression of inflammatory cytokines were observed in top-down strategy using infliximab. The expression and activity of matrix metalloproteinase-9 (MMP-9) and MMP-11 were significantly decreased in mice treated with infliximab accompanied with attenuated numbers of “β-catenin–accumulated crypts.” In animal group where infliximab was administered at later stage of 25th, 27th, and 31st weeks, no reduction in tumorigenesis was noted. These biological effects of infliximab were further explored in in vitro experiment using Raw264.7 and Jurkat T cells. Conclusively, earlier and intensive therapy with infliximab should be considered for either mitigating clinical course or preventing ultimate development of colitic cancer in high-risk IBD patients. Cancer Prev Res; 3(10); 1314–33. ©2010 AACR.

Long‐term follow up of gallbladder polyps

Background and Aim:  The management of gallbladder polyps (GBP) is directly linked to the early diagnosis of gallbladder cancer (GBC). This study aimed to evaluate the malignant risk of GBP.

Benzo[a]pyrene reduces testosterone production in rat Leydig cells via a direct disturbance of testicular steroidogenic machinery.

Background: Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon (PAH), is a ubiquitous environmental pollutant that is currently suspected of being an endocrine disruptor. The testis is an important target for PAHs, yet insufficient attention has been paid to their effects on steroidogenesis in Leydig cells. Objective: We hypothesized that long-term exposure to low concentrations of B[a]P might disrupt testosterone production in Leydig cells via an alteration of steroidogenic proteins. Results: Oral exposure to B[a]P reduced serum and intratesticular fluid testosterone levels in rats. However, we did not observe serious testicular atrophy or azoospermia, although spermatogonial apoptosis was significantly increased. Compared with control cells, Leydig cells primed with B[a]P in vivo produced less testosterone in response to human chorionic gonadotropin (hCG) or dibutyl cyclic adenosine monophosphate in vitro. Of note, the reduction of testosterone levels was accompanied by decreased expression of steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD), as well as increased levels of cytochrome P450 side chain cleavage (P450scc), in Leydig cells. The up-regulation of P450scc expression after exposure to B[a]P appears to be associated with a compensatory mechanism for producing the maximum amount of pregnenolone with the minimum amount of transported cholesterol by StAR; the down-regulation of 3β-HSD may occur because B[a]P can negatively target 3β-HSD, which is required for testosterone production. Conclusions: B[a]P exposure can decrease epididymal sperm quality, possibly by disturbing testosterone levels, and StAR may be a major steroidogenic protein that is targeted by B[a]P or other PAHs.

A Pilot Study of Sequential Capsule Endoscopy Using MiroCam and PillCam SB Devices with Different Transmission Technologies.

BACKGROUND/AIMS Studies have investigated the use of different types of radiofrequency capsules for comparison or sequential capsule endoscopy, but none have compared the MiroCam device - which utilizes a novel data transmission technology - with other capsules. This study compared the feasibility of sequential capsule endoscopy using the MiroCam and PillCam SB devices, which employ different transmission technologies. METHODS Patients with diseases requiring capsule endoscopy were enrolled. After a 12-hour fast, one randomly selected capsule was swallowed. The second capsule was swallowed once fluoroscopy had indicated that the first capsule had migrated below the gastric outlet. RESULTS The total operating time in 24 patients was 702+/-60 min (mean+/-SD) for the MiroCam and 446+/-28 min for the PillCam SB (p<0.0001). The rate of a complete examination to the cecum was 83.3% for the MiroCam and 58.3% for the PillCam SB (p=0.031). Diagnostic yields for the MiroCam, PillCam SB, and sequential capsule endoscopy were 45.8%, 41.7%, and 50.0%, respectively. The agreement rate between the two capsules was 87.5%, with a kappa value of 0.74. Electrical interference in data transmission between the two capsules was not observed, but temporary visual interferences were observed in seven patients (29.2%). CONCLUSIONS Sequential capsule endoscopy with the MiroCam and PillCam SB produced slight but nonsignificant increases in the diagnostic yield, and the two capsules did not exhibit electrical interference. A larger trial is necessary for elucidating the usefulness of sequential capsule endoscopy.

Novel Application of Proton Pump Inhibitor for the Prevention of Colitis-Induced Colorectal Carcinogenesis beyond Acid Suppression

Colitis-associated cancers arise in the setting of chronic inflammation wherein an “inflammation-dysplasia-carcinoma” sequence prevails. Based on our previous findings in which the proton pump inhibitor could impose significant levels of anti-inflammatory, antiangiogenic, and selective apoptosis induction beyond gastric acid suppression, we investigated whether omeprazole could prevent the development of colitis-associated cancer in a mouse model induced by repeated bouts of colitis. Omeprazole, 10 mg/kg, was given i.p. all through the experimental periods for colitis-associated carcinogenesis. Molecular changes regarding inflammation and carcinogenesis were compared between control groups and colitis-associated cancer groups treated with omeprazole in addition to chemopreventive outcome. Nine of 12 (75.0%) mice in the control group developed multiple colorectal tumors, whereas tumors were noted in only 3 of 12 (25.0%) mice treated with daily injections of omeprazole. The cancer-preventive results of omeprazole treatment was based on significant decreases in the levels of nitric oxide, thiobarbituric acid–reactive substance, and interleukin-6 accompanied with attenuated expressions of tumor necrosis factor-α, inducible nitric oxide synthase, and cyclooxygenase-2. The expressions of matrix metalloproteinase (MMP)-9, MMP-11, and MT1-MMMP were significantly decreased in mice treated with omeprazole in accordance with significant decreases in the number of β-catenin–accumulated crypts. A significant induction of apoptosis was observed in tumor tissue treated with omeprazole. Omeprazole could block the trophic effect of gastrin in colon epithelial cells. The significant anti-inflammatory, antioxidative, and antimutagenic activities of omeprazole played a cancer-preventive role against colitis-induced carcinogenesis, and our novel in vivo evidence is suggestive of chemopreventive action independent of gastric acid suppression. Cancer Prev Res; 3(8); 963–74. ©2010 AACR.

Ellipticine induces apoptosis in human endometrial cancer cells: The potential involvement of reactive oxygen species and mitogen-activated protein kinases

Ellipticine, an alkaloid isolated from Apocyanaceae plants, has been shown to exhibit antitumor activity in several human malignant tissues including breast, thyroid, and ovarian cancers. The antitumor activity of ellipticine is thought to be primarily mediated by the induction of DNA damage through the inhibition of topoisomerase II and formation of DNA adducts. The human endometrium is known to express topoisomerase II. However, the apoptogenic activity of ellipticine and the mechanisms underlying its action have not been investigated in endometrial cancer cells. In the present study, exposure to ellipticine (1-10μM) was shown to induce apoptosis in RL95-2 human endometrial cancer cells. Ellipticine-induced cell death was associated with the accumulation of cells in the G2/M phase of the cell cycle and was accompanied by depolarization of the mitochondrial membrane potential, release of cytochrome c and apoptosis-inducing factor (AIF) from the mitochondrial membrane, and caspase activation. The production of intracellular reactive oxygen species (ROS) was increased and sustained at high levels during ellipticine treatment. Subsequent to ROS accumulation, extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were activated in ellipticine-treated cells. Release of AIF from the mitochondria appeared to be affected by caspases, ROS, and ERK. The present data show that the treatment of RL95-2 cells with ellipticine induces apoptosis, ellipticine-induced apoptosis is mediated by ROS and the activation of MAPKs, and release of AIF is involved in a caspase-independent pathway. These results demonstrate the potential of ellipticine as a therapeutic strategy for the treatment of human endometrial cancers.

Hepatoid Carcinoma of the Pancreas Combined with Neuroendocrine Carcinoma

Hepatoid carcinoma is a primary extrahepatic carcinoma whose morphology, immunohistochemistry, and behavior are similar to those of hepatocellular carcinoma. The most common sites of extrahepatic carcinoma are the stomach and ovary, but nine cases of hepatocellular differentiation of the pancreas have been reported in the literature. We report another case of hepatoid carcinoma of the pancreas that was associated with the development of a pancreatic endocrine carcinoma in a 46-year-old man. Serum alpha-fetoprotein (AFP) was elevated to 262.49 IU/mL and radiological examinations revealed a mass measuring 7.5 cm in diameter in the head of the pancreas. He underwent a conventional Whipple operation, and light microscopy showed adenocarcinoma that was immunopositive for AFP, hepatocyte antigen, cytokeratin, chromogranin, synaptophysin, and alpha-1 antichymotrypsin. Although hepatoid differentiation was not shown unequivocally histologically, other immunohistochemistry findings supported the diagnosis of hepatoid carcinoma combined with neuroendocrine carcinoma. The patient was healthy and had no evidence of recurrence at 4 months after the surgery. This report describes why hepatoid carcinoma should be considered as a differential diagnosis of a pancreatic mass, especially when serum AFP is elevated.