Ribosomal protein S3 associates with the TFIIH complex and positively regulates nucleotide excision repair.

In mammalian cells, the bulky DNA adducts caused by ultraviolet radiation are mainly repaired via the nucleotide excision repair (NER) pathway; some defects in this pathway lead to a genetic disorder known as xeroderma pigmentosum (XP). Ribosomal protein S3 (rpS3), a constituent of the 40S ribosomal subunit, is a multi-functional protein with various extra-ribosomal functions, including a role in the cellular stress response and DNA repair-related activities. We report that rpS3 associates with transcription factor IIH (TFIIH) via an interaction with the xeroderma pigmentosum complementation group D (XPD) protein and complements its function in the NER pathway. For optimal repair of UV-induced duplex DNA lesions, the strong helicase activity of the TFIIH complex is required for unwinding damaged DNA around the lesion. Here, we show that XP-D cells overexpressing rpS3 showed markedly increased resistance to UV radiation through XPD and rpS3 interaction. Additionally, the knockdown of rpS3 caused reduced NER efficiency in HeLa cells and the overexpression of rpS3 partially restored helicase activity of the TFIIH complex of XP-D cells in vitro. We also present data suggesting that rpS3 is involved in post-excision processing in NER, assisting TFIIH in expediting the repair process by increasing its turnover rate when DNA is damaged. We propose that rpS3 is an accessory protein of the NER pathway and its recruitment to the repair machinery augments repair efficiency upon UV damage by enhancing XPD helicase function and increasing its turnover rate.

A Case-Control Study of Fluoridation and Osteosarcoma.

Public health policy decisions in the United States have resulted in 62.4% of the population having access to fluoridated water. The purpose of this study was to examine the association between community water fluoridation and osteosarcoma. A secondary data analysis was performed with data collected from 2 separate but linked studies. Patients for phase 1 and phase 2 were selected from US hospitals via a matched case-control study design. For both phases, cases included patients diagnosed with osteosarcoma, and controls were patients diagnosed with other bone tumors or nonneoplastic conditions. In phase 1, cases (n = 209) and controls (n = 440) were patients of record in the participating orthopedic departments from 1989 to 1993. In phase 2, cases (n = 108) and controls (n = 296) were incident patients who were identified and treated by orthopedic physicians from 1994 to 2000. This analysis included all patients who met eligibility criteria on whom we had complete data on covariates, exposures, and outcome. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs for the association of community water fluoridation with osteosarcoma. A modestly significant interaction existed between fluoridation living status and bottled water use (P = 0.047). The adjusted OR for osteosarcoma and ever having lived in a fluoridated area for nonbottled water drinkers was 0.51 (95% CI, 0.31 to 0.84; P = 0.008). In the same comparison, the adjusted OR for bottled water drinkers was 1.86 (95% CI, 0.54 to 6.41; P = 0.326). Findings from this study demonstrated that community water fluoridation is not associated with an increased risk for osteosarcoma.

Association of Periodontitis with Oral Cancer: A Case-Control Study.

The association between oral squamous cell carcinoma (OSCC) and periodontitis in large hospital cases with cohort controls has yet to be evaluated. The aim of this study was to investigate the association of periodontitis with OSCC across tumor location and tumor-node-metastasis (TNM) stage among Koreans ( N = 424). OSCC cases ( n = 146) were recruited from Seoul National University Dental Hospital and matched by age, sex, and smoking to controls ( n = 278) from the Yangpyeong health and periodontal cohort in Korea. OSCC was diagnosed through biopsy and radiographs, including computed tomography and magnetic resonance imaging. Tumor location and TNM stage were classified after the surgery. Periodontitis was defined by alveolar bone loss with panoramic radiographs following the guidelines of the Fifth European Workshop in Periodontology. Alcohol intake, education, physical activity, obesity by body mass index, hypertension by blood pressure, diabetes by plasma glucose, and hypercholesterolemia by plasma cholesterol were considered as confounders. Information about age, sex, smoking, alcohol intake, education, and physical activity was obtained through interview; body mass index and blood pressure, through physical examination; and preoperative glucose and cholesterol, through laboratory tests. Bivariate analysis was applied with Fisher's exact chi-square test. Multivariable conditional logistic regression models were applied to evaluate the adjusted association of periodontitis with OSCC after controlling for confounders. Subgroup analyses were explored by OSCC and periodontitis. Participants with periodontitis were 3.7 times more likely to have OSCC (adjusted odds ratio [aOR] = 3.66, 95% CI = 1.46 to 9.23) than participants without periodontitis. The differences in periodontitis were not statistically significant across TNM stages of OSCC ( P > 0.05) and its location ( P > 0.05). The link was highlighted among males (aOR = 6.55), elders aged >60 y (aOR = 4.98), and those with more tooth loss (aOR = 9.99). Our data showed that periodontitis was independently associated with OSCC. Thus, the risk of OSCC could be modulated by reducing periodontitis.

Thread lifting: a minimally invasive surgical technique for long-standing facial paralysis.

BACKGROUND: Chronic facial paralysis induces degenerative facial muscle changes on the involved side, thus, making the individual seem as older than their actual age. Furthermore, contralateral facial hypertrophy aggravates facial asymmetry. A thread-lifting procedure has been used widely for correction of a drooping or wrinkled face due to the aging process. In addition, botulinum toxin injection can be used to reduce facial hypertrophy. The aim of study was to evaluate the effectiveness of thread lifting with botulinum toxin injection for chronic facial paralysis. METHODS: A total 34 of patients with chronic facial paralysis were enrolled from March to October 2014. Thread lifting for elevating loose facial muscles on the ipsilateral side and botulinum toxin A for controlling the facial muscle hypertrophy on the contralateral side were conducted. Facial function was evaluated using the Sunnybrook grading system and dynamic facial asymmetry ratios 1 year after treatment. RESULTS: All 34 patients displayed improved facial symmetry and showed improvement in Sunnybrook scores (37.4 vs. 83.3) and dynamic facial asymmetry ratios (0.58 vs 0.92). Of the 34 patients, 28 (82.4%) reported being satisfied with treatment. CONCLUSION: The application of subdermal suspension with a reabsorbable thread in conjunction with botulinum toxin A to optimize facial rejuvenation of the contralateral side constitutes an effective and safe procedure for face lifting and rejuvenation of a drooping face as a result of long-lasting facial paralysis.

Higher risk of hepatocellular carcinoma in chronic hepatitis B vs chronic hepatitis C after achievement of virologic response.

It is unclear whether the achievement of virologic response modifies the risk of hepatocellular carcinoma (HCC) differently in chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Our aim was to compare the risk of HCC between patients with CHB and CHC who achieved virological response. We analysed data from patients with CHB treated with entecavir (n=2000) or CHC treated with peg-interferon and ribavirin (n=733) at a tertiary hospital from 2004 to 2011. Virological response was defined as serum HBV DNA<15 IU/mL at 1 year of treatment for CHB or the achievement of sustained virologic response for CHC. Virological response was achieved in 1520 patients with CHB (76.0%) and 475 patients with CHC (64.8%). During the median follow-up period of 6 years, 228 patients with CHB (11.4%) and 59 patients with CHC (8.0%) developed HCC. Among patients with virological response, CHB was independently associated with a significantly higher incidence of HCC (hazard ratio, 2.17; 95% CI, 1.30-3.63; P=.003) than CHC. Among patients without virological response, there were no differences in HCC incidence between the two cohorts (P=.52). In patients with cirrhosis at baseline, the incidence of HCC did not differ between the two cohorts even after achieving virological response (P>.99). In conclusion, patients with CHB treated with entecavir were associated with a higher risk of HCC compared to patients with CHC treated with peg-interferon and ribavirin after achieving virological response. However, the risk of HCC did not differ between the two cohorts if the patients had cirrhosis at baseline, even if virological response was achieved.

Massive epistaxis due to pseudoaneurysm of the sphenopalatine artery: a rare post-operative complication of orthognathic surgery.

OBJECTIVE: To introduce pseudoaneurysm of the sphenopalatine artery as the possible aetiology of acute massive epistaxis in patients with a history of orthognathic surgery accompanied by Le Fort I osteotomy. METHODS: Case report and literature review. RESULTS: This paper reports a case of acute life-threatening epistaxis following Le Fort I osteotomy. Computed tomography and angiography showed a pseudoaneurysm of the sphenopalatine artery, which was successfully treated by endovascular embolisation. CONCLUSION: Although a pseudoaneurysm of the sphenopalatine artery following Le Fort I osteotomy is extremely rare, it should be considered as the possible aetiology of acute massive epistaxis in patients with a history of orthognathic surgery accompanied by Le Fort I osteotomy.

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest.

The largest energy consumer in the cell is the ribosome biogenesis whose aberrancy elicits various diseases in humans. It has been recently revealed that p53 induction, along with cell cycle arrest, is related with abnormal ribosome biogenesis, but the exact mechanism still remains unknown. In this study, we have found that aberrant ribosome biogenesis activates two parallel cellular pathways, c-Myc and ASK1/p38, which result in p53 induction and G1 arrest. The c-Myc stabilizes p53 by rpL11-mediated HDM2 inhibition, and ASK1/p38 activates p53 by phosphorylation on serine 15 and 33. Our studies demonstrate the relationship between these two pathways and p53 induction. The changes caused by impaired ribosomal stress, such as p53 induction and G1 arrest, were completely disappeared by inhibition of either pathway. These findings suggest a monitoring mechanism of c-Myc and ASK1/p38 against abnormal ribosome biogenesis through controlling the stability and activity of p53 protein.

In-vivo-induced antigenic determinants of Fusobacterium nucleatum subsp. nucleatum.

Fusobacterium nucleatum plays a pivotal role in dental plaque biofilm formation and is known to be involved in chronic inflammatory systemic disease. However, limited knowledge of F. nucleatum genes expressed in vivo interferes with our understanding of pathogenesis. In this study, we identified F. nucleatum genes induced in vivo using in-vivo-induced antigen technology (IVIAT). Among 30,000 recombinant clones screened, 87 reacted reproducibly with pooled sera from 10 patients with periodontitis. The clones encoded for 32 different proteins, of which 28 could be assigned to their functions, which were categorized in translation, transcription, transport, energy metabolism, cell envelope, cellular process, fatty acid and phospholipid metabolism, transposition, cofactor biosynthesis, amino acid biosynthesis, and DNA replication. Putative virulence factors detected were ABC transporter, butyrate-acetoacetate CoA-transferase, hemin receptor, hemolysin, hemolysin-related protein, LysR family transcriptional regulator, serine protease, and transposase. Analysis of immune responses to the in-vivo-induced (ivi) antigens in five patients demonstrated that most were reactive to these proteins, confirming results with pooled sera. IVIAT-identified F. nucleatum genes in this study may accelerate the elucidation of F. nucleatum-mediated molecular pathogenesis.

An orally active cathepsin K inhibitor, furan-2-carboxylic acid, 1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide (OST-4077), inhibits osteoclast activity in vitro and bone loss in ovariectomized rats.

Human cathepsin K, a cysteine proteinase of the papain family, has been recognized as a potential drug target for the treatment of osteoporosis. The predominant expression of cathepsin K in osteoclasts has rendered the enzyme into a major target for the development of novel antiresorptive drugs. Now, we report the pharmacological properties of OST-4077 [furan-2-carboxylic acid (1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide] as a novel selective cathepsin K inhibitor. Human and rat cathepsin K were inhibited in vitro by OST-4077 with the IC50 values of 11 and 427 nM, respectively. OST-4077 suppressed bone resorption induced by rabbit osteoclasts (IC50, 37 nM) but did not affect bone mineralization or cellular alkaline phosphatase activity in MC3T3-E1 cells. Parathyroid hormone-induced bone resorption was inhibited in a dose-dependent manner in thyroparathyroidectomized rats gavaged with a single dose of OST-4077 (ED50, 69 mg/kg). When given orally twice daily for 4 weeks to 3-month-old ovariectomized (OVX) rats, OST-4077 dose-dependently prevented bone loss, as monitored by bone densitometry, ash content, and urinary excretion of deoxypyridinoline. No change in serum osteocalcin in the OVX rats by OST-4077 suggested that bone formation might not be affected by the agent. In summary, OST-4077 selectively inhibited bone resorbing activities of osteoclasts and prevented bone loss induced by estrogen deficiency but did not affect bone formation. OST-4077, an orally active selective human cathepsin K inhibitor, may have the therapeutic potential for the treatment of diseases characterized by excessive bone loss including osteoporosis.

Bone ingrowth on a smooth-surfaced hydroxyapatite-coated acetabular cup.

We studied 29 retrieved smooth-surfaced hydroxyapatite (HA)-coated acetabular cups that had been in situ for an average of 54.9 months. The outer surface of all cups carried two circular grooves dividing the smooth surface. The extent of bony in-growth and hydroxyapatite absorption was calculated using a computer imaging system (analySIS-pro 3.0, Soft Imaging System GmbH, Germany). Absorption of HA was seen in all 29 cups. The extent of absorption was, on average, 60.5%. Twenty-five cups showed bony in-growth covering an average of 13.8% of the cup surface. Thirteen cups showed bony in-growth on the smooth surface as well as the circular grooves. On 11 cups, the bony in-growth was confined to the grooves. We found that bony in-growth on the smooth-surfaced HA-coated acetabular cup was minimal. It occurred along the two circular grooves rather than on the smooth surfaces. We conclude that a macro-structure surface enhancing bony in-growth is necessary for the long-term survival of the studied cup.

Investigation of juxtasellar and cerebellopontine angle meningiomas and neurogenic tumours: two-phase helical CT.

We performed two-phase helical CT in 31 patients with juxtasellar region and cerebellopontine angle tumours to evaluate its usefulness in differentiating meningiomas from neurogenic tumours. After the intravenous injection of 90 ml contrast medium at 3 ml/s, axial helical images were obtained with delays of 30 and 120 s. After the delayed axial images, we acquired coronal images. Changes in attenuation were assessed visually and quantitatively (by comparing the attenuation in Hounsfield units). There were 17 meningiomas and 14 neurogenic tumours, all pathologically proven. Two-phase helical CT showed a decrease in attenuation in 15 (88%) meningiomas and an increase in 14 (100%) neurogenic tumours from early to delayed axial images. Coronal images showed a decrease in attenuation in all 17 meningiomas and an increase in 13 (93%) of the neurogenic tumours. The mean HU and their ratios were significantly different between meningiomas and neurogenic tumours.

Synthesis of novel D- and L-3'-deoxy-3'-C-hydroxymethyl nucleoside with exocyclic methylene as potential ribonucleotide reductase inhibitor.

D- and L-3'-Deoxy-3'-C-hydroxymethyl thymidine substituted with exocyclic methylene at 2'-position were synthesized, starting from D- and L-xylose as potential ribonucleotide reductase inhibitor, respectively, but they were found to be inactive against several tumor cell lines.

Novel nucleosides with vinyl fluoride or vinyl bromide moiety as open-chain analogs of neplanocin A.

Novel nucleosides with vinyl fluoride and vinyl bromide were designed, synthesized and evaluated their antiviral activities against poliovirus, HSV, HIV, and HBV.

Tripartite structure of Saccharomyces cerevisiae Dna2 helicase/endonuclease.

In order to gain insights into the structural basis of the multifunctional Dna2 enzyme involved in Okazaki fragment processing, we performed biochemical, biophysical and genetic studies to dissect the domain structure of Dna2. Proteolytic digestion of Dna2 using subtilisin produced a 127 kDa polypeptide that lacked the 45 kDa N-terminal region of Dna2. Further digestion generated two subtilisin-resistant core fragments of approximately equal size, 58 and 60 kDa. Surprisingly, digestion resulted in a significant (3- to 8-fold) increase in both ATPase and endonuclease activities compared to the intact enzyme. However, cells with a mutant DNA2 allele lacking the corresponding N-terminal region were severely impaired in growth, being unable to grow at 37 degrees C, indicating that the N-terminal region contains a domain critical for a cellular function(s) of Dna2. Analyses of the hydrodynamic properties of and in vivo complex formation by wild-type and/or mutant Dna2 lacking the N-terminal 45 kDa domain revealed that Dna2 is active as the monomer and thus the defect in the mutant Dna2 protein is not due to its inability to multimerize. In addition, we found that the N-terminal 45 kDa domain interacts physically with a central region located between the two catalytic domains. Our results suggest that the N-terminal 45 kDa domain of Dna2 plays a critical role in regulation of the enzymatic activities of Dna2 by serving as a site for intra- and intermolecular interactions essential for optimal function of Dna2 in Okazaki fragment processing. The possible mode of regulation of Dna2 is discussed based upon our recent finding that replication protein A interacts functionally and physically with Dna2 during Okazaki fragment processing.

Activation of heat shock factor 1 by pyrrolidine dithiocarbamate is mediated by its activities as pro-oxidant and thiol modulator.

Pyrrolidine dithiocarbamate (PDTC) is known to inhibit NF-kappa B, which plays a critical role(s) as an immediate early mediator of immune and inflammatory responses. Here we show that PDTC induces heat shock factor 1 (HSF1) activation and heat shock protein expression, while other antioxidants such as butylated hydroxytoluene (BHT), n-propylgallate (PG), ascorbic acid (AA), and N-acetyl-L-cysteine (NAC) do not. Since PDTC exerts other functions than antioxidant, e.g., a pro-oxidant, metal chelator, and thiol group modulator, we examined which of these activities is responsible for the PDTC-induced HSF1 activation. PDTC-induced HSF1 activation was not prevented by metal chelators, EDTAs, indicating that the metal chelating effect of PDTC is not linked to the HSF1 activation. PDTC increased intracellular GSSG level. In addition, PDTC-induced activation of HSF1 was significantly inhibited by NAC and a thiol-reducing agent dithiothreitol (DTT), while it was partially prevented by other antioxidants, AA, BHT, and PG. These results suggest that the activation of HSF1 by PDTC may be due to its activities as pro-oxidant and thiol group modulator rather than anti-oxidant.

The mechanism of action of coculture on embryo development in the mouse model: direct embryo-to-cell contact and the removal of deleterious components.

OBJECTIVE: To elucidate the mechanism for the mode of action of coculture by the use of a coculture system for mouse one-cell embryos with human oviductal epithelial cells. DESIGN: Prospective, controlled in vitro experimental study. SETTING: Academic research laboratory. ANIMAL(S): Female ICR strain mice aged between 6 and 8 weeks. INTERVENTION(S): Flushed one-cell embryos were cultured in human tubal fluid medium alone (control), in coculture system with human oviductal cells, in five kinds of conditioned media, and in a contactless coculture system using a cell-culture insert. MAIN OUTCOME MEASURE(S): The percentage of the embryos developed to hatching blastocyst stage and the level of superoxide anion in the supernatant from each culture condition. RESULT(S): The rates of embryo development to the hatching blastocyst stage were significantly higher in the coculture group (43%) than in the control group (none) (P <.05). The embryo development rate in the control group was similar to that of the embryos in the five kinds of conditioned media. The effects of coculture on embryo development disappeared in the contactless coculture group. The level of superoxide anion was significantly reduced in the coculture group compared to the control group. CONCLUSION(S): The present coculture system overcomes the two-cell block in vitro and improves the embryo development. The beneficial effect may be a result of direct cell-to-cell contact between the embryo and helper cells and the removal of deleterious components from medium, rather than a result of embryotrophic factors.

Implication of a small GTPase Rac1 in the activation of c-Jun N-terminal kinase and heat shock factor in response to heat shock.

Heat shock induces c-Jun N-terminal kinase (JNK) activation as well as heat shock protein (HSP) expression through activation of the heat shock factor (HSF), but its signal pathway is not clearly understood. Since a small GTPase Rac1 has been suggested to participate in the cellular response to stresses, we examined whether Rac1 is involved in the heat shock response. Here we show that moderate heat shock (39-41 degrees C) induces membrane translocation of Rac1 and membrane ruffling in a Rac1-dependent manner. In addition, Rac1N17, a dominant negative mutant of Rac1, significantly inhibited JNK activation by heat shock. Since Rac1V12 was able to activate JNK, it is suggested that heat shock may activate JNK via Rac1. Similar inhibition by Rac1N17 of HSF activation in response to heat shock was observed. However, inhibitory effects of Rac1N17 on heat shock-induced JNK and HSF activation were reduced as the heat shock temperature increased. Rac1N17 also inhibited HSF activation by l-azetidine-2-carboxylic acid, a proline analog, and heavy metals (CdCl)), suggesting that Rac1 may be linked to HSF activation by denaturation of polypeptides in response to various proteotoxic stresses. However, Rac1N17 did not prevent phosphorylation of HSF1 in response to these proteotoxic stresses. Interestingly, a constitutively active mutant Rac1V12 did not activate the HSF. Therefore, Rac1 activation may be necessary, but not sufficient, for heat shock-inducible HSF activation and HSP expression, or otherwise a signal pathway(s) involving Rac1 may be indirectly involved in the HSF activation. In sum, we suggest that Rac1 may play a critical role(s) in several aspects of the heat shock response.

Anti-inflammatory effect of the aqueous extract from Lonicera japonica flower is related to inhibition of NF-kappaB activation through reducing I-kappaBalpha degradation in rat liver.

We investigated the anti-inflammatory effects of aqueous extract from Lonicera japonica flower (AELJ), a traditional skin rash drug, in lipopolysaccharide (LPS)-induced rat liver sepsis. Immunoblot analysis showed that the level of nuclear factor (NF)-kappaBp65 was rapidly up-regulated and inhibitory (I)-kappaBalpha was down-regulated by LPS challenge. However, AELJ inhibited the increase of NF-kappaBp65 and degradation of I-kappaBalpha in the liver of LPS-challenged rats. Immunohistochemical analysis of rat hepatocytes showed that LPS-induced inflammatory responses, involving degradation of I-kappaBalpha and induction of NF-kappaBp65, tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS), are partially inhibited by pretreatment with AELJ. These results suggest that AELJ may act as a therapeutic agent for inflammatory disease through a selective regulation of NF-kappaB activation.

Direct binding of hepatitis B virus X protein and retinoid X receptor contributes to phosphoenolpyruvate carboxykinase gene transactivation.

The X gene product of the human hepatitis B virus (HBx), a major factor responsible for hepatitis and hepatocellular carcinoma, modulates transactivation by a variety of transcription factors. Herein, expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene was found to be regulated transcriptionally by HBx through two distinct promoter regions. The cAMP response element (CRE)-1 site within the proximal promoter region mediated the HBx-induced transactivation of the PEPCK gene through C/EBP alpha and ATF-2. A retinoid X receptor (RXR) response element within the distal promoter region also contributed to the HBx-induced transactivation. Consistent with these results, HBx directly interacted with RXR, and the interaction interfaces were localized to the transactivation domain of HBx and the ligand binding domain of RXR.

Uroguanylin treatment suppresses polyp formation in the Apc(Min/+) mouse and induces apoptosis in human colon adenocarcinoma cells via cyclic GMP.

The enteric peptides, guanylin and uroguanylin, are local regulators of intestinal secretion by activation of receptor-guanylate cyclase (R-GC) signaling molecules that produce cyclic GMP (cGMP) and stimulate the cystic fibrosis transmembrane conductance regulator-dependent secretion of Cl- and HCO3-. Our experiments demonstrate that mRNA transcripts for guanylin and uroguanylin are markedly reduced in colon polyps and adenocarcinomas. In contrast, a specific uroguanylin-R-GC, R-GCC, is expressed in polyps and adenocarcinomas at levels comparable with normal colon mucosa. Activation of R-GCC by uroguanylin in vitro inhibits the proliferation of T84 colon cells and elicits profound apoptosis in human colon cancer cells, T84. Therefore, down-regulation of gene expression and loss of the peptides may interfere with renewal and/or removal of the epithelial cells resulting in the formation of polyps, which can progress to malignant cancers of the colon and rectum. Oral replacement therapy with human uroguanylin was used to evaluate its effects on the formation of intestinal polyps in the Min/+ mouse model for colorectal cancer. Uroguanylin significantly reduces the number of polyps found in the intestine of Min/+ mice by approximately 50% of control. Our findings suggest that uroguanylin and guanylin regulate the turnover of epithelial cells within the intestinal mucosa via activation of a cGMP signaling mechanism that elicits apoptosis of target enterocytes. The intestinal R-GC signaling molecules for guanylin regulatory peptides are promising targets for prevention and/or therapeutic treatment of intestinal polyps and cancers by oral administration of human uroguanylin.