Diagnosis of pancreatic malignancies using an overnight-stored pancreatic juice cell block specimen.

BACKGROUND AND AIMS: Pancreatic juice cytology is useful for diagnosing pancreatic duct strictures and cystic lesions. However, some cases cannot be diagnosed using cytology. This study aimed to evaluate the utility of the overnight-stored pancreatic juice cell block (CB) method for diagnosing pancreatic disease. METHODS: This retrospective study included 32 patients who presented with pancreatic duct strictures or cystic lesions between 2018 and 2024. The sensitivity, specificity, and accuracy of the CB method and single/multiple pancreatic juice cytology were compared to evaluate the utility of the CB. RESULT: An endoscopic nasopancreatic drainage tube was placed in the main pancreatic duct, and pancreatic juice was collected to create a CB specimen. The median amount of pancreatic juice collected was 180(30-200) mL, and the median number of cytological examinations was three(2-8). Of the 32 cases, 13 were malignant, and 19 were benign (non-malignant). The sensitivity was significantly higher for the CB method (62 %) than for single cytology(15 %, P = 0.0414), and there was no significant difference between CB and multiple cytology(54 %, P = 1.0). The specificity and accuracy were not significantly different between the CB method and single or multiple cytology. When multiple cytology and CB were combined, sensitivity improved to 77 %. The pathological findings of the CB specimens were similar to the surgical specimens, including immunohistochemistry. CONCLUSION: The overnight-stored pancreatic juice CB method was more effective than single cytology, with similar sensitivities to multiple cytology and can also be used for immunohistochemistry. The pancreatic juice CB method is useful for pancreatic juice assessment.

A Novel Mouse Model of Intrahepatic Cholangiocarcinoma Induced by Azoxymethane.

Cholangiocarcinoma is the second most common primary cancer of the liver and has a poor prognosis. Various animal models, including carcinogen-induced and genetically engineered rodent models, have been established to clarify the mechanisms underlying cholangiocarcinoma development. In the present study, we developed a novel mouse model of malignant lesions in the biliary ducts induced by the administration of the carcinogen azoxymethane to obese C57BLKS/J-db/db mice. A histopathological analysis revealed that the biliary tract lesions in the liver appeared to be an intrahepatic cholangiocarcinoma with higher tumor incidence, shorter experimental duration, and a markedly increased incidence in obese mice. Molecular markers analyzed using a microarray and a qPCR indicated that the cancerous lesions originated from the cholangiocytes and developed in the inflamed livers. These findings indicated that this is a novel mouse model of intrahepatic cholangiocarcinoma in the context of steatohepatitis. This model can be used to provide a better understanding of the pathogenic mechanisms of cholangiocarcinoma and to develop novel therapeutic strategies for this malignancy.

Induction of MYCN-amplified neuroblastoma differentiation through NMYC suppression using PPAR-γ antagonist.

Neuroblastomas are the most common extracranial solid tumors in children and have a unique feature of neuronal differentiation. Peroxisome proliferator-activated receptor (PPAR)-γ is reported to have neuroprotective effects in addition to having antitumor effects in various cancers. Thus, we aimed to clarify the role of PPAR-γ agonist and antagonist in malignant neuroblastomas, which also possess neuronal features. In MYCN-amplified neuroblastoma CHP212 cells, treatment with the PPAR-γ antagonist GW9662 induced growth inhibition in a dose-dependent manner. In addition, the PPAR-γ antagonist treatment changed cell morphology with increasing expression of the neuronal differentiation marker tubulin beta 3 (TUBB3) and induced G1 phase arrest and apoptosis in MYCN-amplified neuroblastoma. Notably, the PPAR-γ antagonist treatment significantly decreased expression of NMYC, B-cell lymphoma 2 (BCL2) and bromodomain-containing protein 4 (BRD4). It is implied that BRD4, NMYC, BCL2 suppression by the PPAR-γ antagonist resulted in cell growth inhibition, differentiation, and apoptosis induction. In our in vivo study, the PPAR-γ antagonist treatment induced CHP212 cells differentiation and resultant tumor growth inhibition. Our results provide a deeper understanding of the mechanisms of tumor cell differentiation and suggest that PPAR-γ antagonist is a new therapeutic and prevention option for neuroblastomas.

PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features.

To examine effects of PP6 gene (Ppp6c) deficiency on pancreatic tumor development, we developed pancreas-specific, tamoxifen-inducible Cre-mediated KP (KRAS(G12D) plus Trp53-deficient) mice (cKP mice) and crossed them with Ppp6cflox / flox mice. cKP mice with the homozygous Ppp6c deletion developed pancreatic tumors, became emaciated and required euthanasia within 150 days of mutation induction, phenotypes that were not seen in heterozygous or wild-type (WT) mice. At 30 days, a comparative analysis of genes commonly altered in homozygous versus WT Ppp6c cKP mice revealed enhanced activation of Erk and NFκB pathways in homozygotes. By 80 days, the number and size of tumors and number of precancerous lesions had significantly increased in the pancreas of Ppp6c homozygous relative to heterozygous or WT cKP mice. Ppp6c-/- tumors were pathologically diagnosed as pancreatic ductal adenocarcinoma (PDAC) undergoing the epithelial-mesenchymal transition (EMT), and cancer cells had invaded surrounding tissues in three out of six cases. Transcriptome and metabolome analyses indicated an enhanced cancer-specific glycolytic metabolism in Ppp6c-deficient cKP mice and the increased expression of inflammatory cytokines. Individual Ppp6c-/- cKP mice showed weight loss, decreased skeletal muscle and adipose tissue, and increased circulating tumor necrosis factor (TNF)-α and IL-6 levels, suggestive of systemic inflammation. Overall, Ppp6c deficiency in the presence of K-ras mutations and Trp53 gene deficiency promoted pancreatic tumorigenesis with generalized cachexia and early death. This study provided the first evidence that Ppp6c suppresses mouse pancreatic carcinogenesis and supports the use of Ppp6c-deficient cKP mice as a model for developing treatments for cachexia associated with pancreatic cancer.

A Biscuit Containing Fucoxanthin Prevents Colorectal Carcinogenesis in Mice.

Fucoxanthin (Fx) is a critical pigment required for photosynthesis in brown algae and microalgae. Fx is also a dietary marine carotenoid that with potent anticancer activity in vitro and in vivo. Some popular light meals for increased satiety, such as biscuits, cereals, and crackers, are frequently fortified with micronutrients for human health benefits. However, data on the anticancer potential of Fx-supplemented light meals in humans and animal models remain limited. In the present study, we investigated the anticancer effects of a Fx-supplemented biscuit using a carcinogenic murine azoxymethane/dextran sodium sulfate (AOM/DSS) model. We observed that periodic administration of biscuits containing 0.3% Fx (Fx-biscuit) at an interval of 3 days (each 15 h) per week for 15 weeks significantly inhibited colorectal carcinogenesis in AOM/DSS mice. Comprehensive gene analysis demonstrated that the Fx-biscuit significantly altered the expression of 138 genes in the colorectal mucosal tissue of the mice. In particular, the expression of heat shock protein 70 (HSP70) genes, Hspa1b (-35.7-fold) and Hspa1a (-34.9-fold), was markedly downregulated. HSP70 is a polyfunctional chaperone protein that is involved in cancer development. Compared to the control-biscuit group, the number of cells with markedly high fluorescence for HSP70 protein (HSP70high) in colorectal mucosal crypts and adenocarcinomas significantly reduced by 0.3- and 0.2-fold, respectively, in the Fx-biscuit group. Our results suggested that Fx-biscuit possesses chemopreventive potential in the colorectal cancer of AOM/DSS mice via the downregulation of HSP70.

[Paratesticular Low-Grade Fibromyxoid Sarcoma: A Case Report].

A 36-year-old man presented with painless swelling in the right side scrotum. Ultrasonography showed a hypoechoic tumor with mosaic pattern. Plain computed tomograghy (CT) revealed a 67 mm scrotal cystic lesion with low density area. We suspected an intrascrotal tumor and performed right side radical orchiectomy. The removed sample was yellow clear and elastic hard. A 7 cm multilocular cystic tumor was present on the head side of the normal testis. The cut-surface and the contents of the mass revealed a jelly-like viscous liquid. On the microscopic examination, the tumor was composed of mucinous stroma and spindle-shaped atypical cells with hyperchromatic oval nuclei and eosinophilic cytoplasm. There was a characteristic network of blood vessesls with hyperhyalinization in the myxoid zones. Immunohistochemically, CDK4, MDM2, AE1/AE3, S-100, Alpha-SMA and desmin were negative, but MUC4 showed focal cytoplasmic positivity in the neoplastic cells. In the reverse transcription polymerase chain reaction assay, no FUS-CREB3L2/FUS-CREB3L1 fusion transcripts were identified although the detectable messages of the housekeeping genes were noted. The tumour was finally diagnosed as a paratesticular low-grade fibromyxoid sarcoma. Postoperative course was uneventful and no recurrence or metastasis was seen four months after the operation.

Alteration of fecal microbiota by fucoxanthin results in prevention of colorectal cancer in AOM/DSS mice.

Fucoxanthin (Fx), a marine carotenoid found in edible brown algae, is well known for having anticancer properties. The gut microbiota has been demonstrated as a hallmark for colorectal cancer progression in both humans and rodents. However, it remains unclear whether the gut microbiota is associated with the anticancer effect of Fx. We investigated the chemopreventive potency of Fx and its effect on gut microbiota in a mouse model of inflammation-associated colorectal cancer (by azoxymethane/dextran sulfate sodium treatment). Fx administration (30 mg/kg bw) during a 14 week period significantly inhibited the multiplicity of colorectal adenocarcinoma in mice. The number of apoptosis-like cleaved caspase-3high cells increased significantly in both colonic adenocarcinoma and mucosal crypts. Fx administration significantly suppressed Bacteroidlales (f_uc; g_uc) (0.3-fold) and Rikenellaceae (g_uc) (0.6-fold) and increased Lachnospiraceae (g_uc) (2.2-fold), compared with those of control mice. Oral administration of a fecal suspension obtained from Fx-treated mice, aimed to enhance Lachnospiraceae, suppress the number of colorectal adenocarcinomas in azoxymethane/dextran sulfate sodium-treated mice with a successful increase in Lachnospiraceae in the gut. Our findings suggested that an alteration in gut microbiota by dietary Fx might be an essential factor in the cancer chemopreventive effect of Fx in azoxymethane/dextran sulfate sodium-treated mice.

Ppp6c haploinsufficiency accelerates UV-induced BRAF(V600E)-initiated melanomagenesis.

According to TCGA database, mutations in PPP6C (encoding phosphatase PP6) are found in c. 10% of tumors from melanoma patients, in which they coexist with BRAF and NRAS mutations. To assess PP6 function in melanoma carcinogenesis, we generated mice in which we could specifically induce BRAF(V600E) expression and delete Ppp6c in melanocytes. In these mice, melanoma susceptibility following UVB irradiation exhibited the following pattern: Ppp6c semi-deficient (heterozygous) > Ppp6c wild-type > Ppp6c-deficient (homozygous) tumor types. Next-generation sequencing of Ppp6c heterozygous and wild-type melanoma tumors revealed that all harbored Trp53 mutations. However, Ppp6c heterozygous tumors showed a higher Signature 1 (mitotic/mitotic clock) mutation index compared with Ppp6c wild-type tumors, suggesting increased cell division. Analysis of cell lines derived from either Ppp6c heterozygous or wild-type melanoma tissues showed that both formed tumors in nude mice, but Ppp6c heterozygous tumors grew faster compared with those from the wild-type line. Ppp6c knockdown via siRNA in the Ppp6c heterozygous line promoted the accumulation of genomic damage and enhanced apoptosis relative to siRNA controls. We conclude that in the presence of BRAF(V600E) expression and UV-induced Trp53 mutation, Ppp6c haploinsufficiency promotes tumorigenesis.

Development of redox potential-driven fermentation process for recombinant protein expression.

OBJECTIVES: A redox potential-driven fermentation, maintaining dissolved oxygen at a prescribed level while simultaneously monitoring the changes of fermentation redox potential, was developed to guide the cultivation progress of recombinant protein expression. RESULTS: A recombinant E. coli harboring prolinase-expressing plasmid (pKK-PepR2) was cultivated using the developed process. Two distinct ORP valleys were noticeable based on recorded profile. The first ORP valley is equivalent to the timing for the addition of inducing agent, and the second ORP valley serves to guide the timing for cell harvesting. The final prolinase activity is 0.172 µmol/mg/min as compared to that of 0.154 µmol/mg/min where the optical density was employed to guide the timing of inducer addition and an empirically determined length of the cultivation. CONCLUSION: The developed process can be further modified to become an automatic operation.

Fucoxanthin Prevents Pancreatic Tumorigenesis in C57BL/6J Mice That Received Allogenic and Orthotopic Transplants of Cancer Cells.

Fucoxanthin (Fx) is a marine carotenoid with anti-inflammatory and anti-cancer properties in various animal models of carcinogenesis. However, there is currently no information on the effects of Fx in animal models of pancreatic cancer. We investigated the chemopreventive effects of Fx in C57BL/6J mice that received allogenic and orthotopic transplantations of cancer cells (KMPC44) derived from a pancreatic cancer murine model (Ptf1aCre/+; LSL-krasG12D/+). Using microarray, immunofluorescence, western blot, and siRNA analyses, alterations in cancer-related genes and protein expression were evaluated in pancreatic tumors of Fx-administered mice. Fx administration prevented the adenocarcinoma (ADC) development of pancreatic and parietal peritoneum tissues in a pancreatic cancer murine model, but not the incidence of ADC. Gene and protein expressions showed that the suppression of chemokine (C-C motif) ligand 21 (CCL21)/chemokine receptor 7 (CCR7) axis, its downstream of Rho A, B- and T-lymphocyte attenuator (BTLA), N-cadherin, αSMA, pFAK(Tyr397), and pPaxillin(Tyr31) were significantly suppressed in the pancreatic tumors of mice treated with Fx. In addition, Ccr7 knockdown significantly attenuated the growth of KMPC44 cells. These results suggest that Fx is a promising candidate for pancreatic cancer chemoprevention that mediates the suppression of the CCL21/CCR7 axis, BTLA, tumor microenvironment, epithelial mesenchymal transition, and adhesion.

Protein quality and physicochemical properties of commercial cricket and mealworm powders.

The pressing need for protein supply growth gives rise to alternative protein sources, such as insect proteins. Commercial cricket and mealworm powders were examined for their protein quality, surface charge and functional attributes. Both insect powders had similar proximate compositions with protein and ash contents of ~ 66% db (dry weight basis) and 5% db, respectively, however cricket powder contained more lipid (16.1%, db) than mealworm powder (13.7%, db). Mealworm protein had an amino acid score of 0.71 and was first limiting in lysine, whereas cricket protein was first limiting in tryptophan with an amino acid score of 0.85. In vitro protein digestibility values of 75.7% and 76.2%, and in vitro protein digestibility corrected amino acid scores of 0.54 and 0.65, were obtained for mealworm and cricket powders, respectively. Zeta potential measurements gave isoelectric points near pH 3.9 for both insect powders. Mealworm and cricket powders had water hydration capacities of 1.62 g/g and 1.76 g/g, respectively, and oil holding capacities of 1.58 g/g and 1.42 g/g, respectively. Both insect proteins had low solubility (22-30%) at all pHs (3.0, 5.0, and 7.0) measured. Cricket powder had a foaming capacity of 82% and foam stability of 86%, whereas mealworm powder was non-foaming. Values for commercial pea and faba bean protein concentrates were reported for comparative purposes. The insect proteins had similar protein quality as the pulse proteins and had higher solubility at pH 5.0 but were much less soluble at pH 7.0.

Recovery of glucose from dried distiller's grain with solubles, using combinations of solid-state fermentation and insect culture.

A bioethanol by-product, dried distiller's grains with solubles (DDGS) contains high levels of cellulose and starch. We hypothesized that combinations of solid-state fermentation (SSF) and digestion by black soldier fly larvae (BSFL) (Hermetia illucens) could increase the recovery of glucose from this by-product by concentrating and loosening the cellulose matrix through their activities. DDGS was individually fermented with Aspergillus niger, Aspergillus fumigatus, Trichoderma koningii, Phanerochaete chrysosporium, or Lactobacillus plantarum. The fermented DDGS was fed to BSFL, and glucose recoveries from spent feeds were conducted. SSF increases lipid and protein contents, supporting BSFL growth, and weakens the cellulosic matrix. BSFL use nutrients in SSF-DDGS, further concentrating and weakening the cellulose, i.e., DDGS is halved without changing the cellulose contents. For example, Lactobacillus plantarum SSF with BSFL culture concentrates the cellulose content from 9.7% to 26.5% of spent feed. Glucose recovery was determined using three sequential processes (free glucose determination, weak-acid hydrolysis of amorphous cellulose, and enzymatic hydrolysis of micronized crystalline cellulose). Total glucose obtained from 100 g of DDGS increased from 4.8 to 10.7 g. These results show that the combinations of SSF and BSFL could provide additional fermentable sugars (and insect biomass) from bioethanol by-products, suggesting a high productivity from the same feedstock.

Effect of Lactobacillus plantarum Fermentation on the Surface and Functional Properties of Pea Protein-Enriched Flour.

The effect of Lactobacillus plantarum fermentation on the functional and physicochemical properties of pea protein-enriched flour (PPF) was investigated. Over the course of the fermentation the extent of hydrolysis increased continuously until reaching a maximum degree of hydrolysis of 13.5% after 11 h. The resulting fermented flour was then adjusted to either pH=4 or 7 prior to measuring the surface and functional attributes as a function of fermentation time. At pH=4 surface charge, as measured by zeta potential, initially increased from +14 to +27 mV after 1 h of fermentation, and then decreased to +10 mV after 11 h; whereas at pH=7 the charge gradually increased from -37 to -27 mV over the entire fermentation time. Surface hydrophobicity significantly increased at pH=4 as a function of fermentation time, whereas at pH=7 fermentation induced only a slight decrease in PPF surface hydrophobicity. Foam capacity was highest at pH=4 using PPF fermented for 5 h whereas foam stability was low at both pH values for all samples. Emulsifying activity sharply decreased after 5 h of fermentation at pH=4. Emulsion stability improved at pH=7 after 5 h of fermentation as compared to the control. Oil-holding capacity improved from 1.8 g/g at time 0 to 3.5 g/g by the end of 11 h of fermentation, whereas water hydration capacity decreased after 5 h, then increased after 9 h of fermentation. These results indicate that the fermentation of PPF can modify its properties, which can lead towards its utilization as a functional food ingredient.

Effect of Fermentation on the Protein Digestibility and Levels of Non-Nutritive Compounds of Pea Protein Concentrate.

In order to determine the impact of fermentation on protein quality, pea protein concentrate (PPC) was fermented with Lactobacillus plantarum for 11 h and total phenol and tannin contents, protease inhibitor activity, amino acid composition and in vitro protein digestibility were analyzed. Phenol levels, expressed as catechin equivalents (CE), increased on dry mass basis from 2.5 at 0 h to 4.9 mg CE per 1 g of PPC at 11 h. Tannin content rose from 0.14 at 0 h to a maximum of 0.96 mg CE per 1 g of PPC after 5 h, and thereafter declined to 0.79 mg/g after 11 h. After 9 h of fermentation trypsin inhibitor activity decreased, however, at all other fermentation times similar levels to the PPC at time 0 h were produced. Chymotrypsin inhibitor activity decreased from 3.7 to 1.1 chymotrypsin inhibitory units (CIU) per mg following 11 h of fermentation. Protein digestibility reached a maximum (87.4%) after 5 h of fermentation, however, the sulfur amino acid score was reduced from 0.84 at 0 h to 0.66 at 11 h. This reduction in sulfur content altered the in vitro protein digestibility-corrected amino acid score from 67.0% at 0 h to 54.6% at 11 h. These data suggest that while fermentation is a viable method of reducing certain non-nutritive compounds in pea protein concentrate, selection of an alternative bacterium which metabolises sulfur amino acids to a lesser extent than L. plantarum should be considered.

Egg proteins: fractionation, bioactive peptides and allergenicity.

Eggs are an important source of macro and micronutrients within the diet, comprised of proteins, lipids, vitamins, and minerals. They are constituted by a shell, the white (containing 110 g kg-1 proteins: ovalbumin, ovotransferrin, ovomucoid, lysozyme and ovomucin), and the yolk (containing 150-170 g kg-1 proteins: lipovitellins, phosvitin, livetins, and low-density lipoproteins). Owing to their nutritional value and biological characteristics, both the egg white and yolk proteins are extensively fractionated using different techniques (e.g., liquid chromatography, ultrafiltration, electrophoresis, and chemical precipitation), in which liquid chromatography is the most commonly used technique to obtain individual proteins with high protein recovery and purity to develop novel food products. However, concerns over allergenic responses induced by certain egg proteins (e.g., ovomucoid, ovalbumin, ovotransferrin, lysozyme, α-livetin, and lipoprotein YGP42) limit their widespread use. As such, processing technologies (e.g., thermal processing, enzymatic hydrolysis, and high-pressure treatment) are investigated to reduce the allergenicity by conformational changes. In addition, biological activities (e.g., antioxidant, antimicrobial, antihypertensive, and anticancer activities) associated with egg peptides have received more attention, in which enzyme hydrolysis is demonstrated as a promising way to break polypeptides sequences and produce bioactive peptides to provide nutritional and therapeutic benefits for human health. © 2018 Society of Chemical Industry.

Nonproliferative and Proliferative Lesions of the Rat and Mouse Endocrine System.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative among the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the endocrine organs (pituitary gland, pineal gland, thyroid gland, parathyroid glands, adrenal glands and pancreatic islets) of laboratory rats and mice, with color photomicrographs illustrating examples of the lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for endocrine lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Crystallographic structure of recombinant Lactococcus lactis prolidase to support proposed structure-function relationships.

Lactococcus lactis prolidase (Xaa-Pro dipeptidase; EC.3.4.13.9) is unique from other prolidases by showing allosteric behaviour, substrate inhibition, and metal-dependent substrate specificity. We have previously shown several critical residues for these characteristics using site-directed mutagenesis and amino acid sequence-based models. In this present study, the three-dimensional structure of recombinant L. lactis prolidase was determined by X-ray crystallography at 2.25Å resolution in order to provide evidences of the proposed mechanism. Three molecules are located in the crystal asymmetric unit where molecule A forms a dimer with molecule B, while molecule C forms a dimer with molecule C' in the adjacent asymmetric unit. Of all the three molecules, molecule C is less defined and incomplete. While this fact compromises the overall quality of the refined model, the functional interpretation of the structure is not compromised since the biologically-functional homodimeric configuration of L. lactis prolidase is represented by well-defined molecules A and B. The refined model confirmed that there is a twelve-residue (residues 32-43) loop structure from one subunit over the active site of the other subunit, proving the existence of the putative loop structure in our previous study. This loop is three amino acids longer than the loops of prolidases of Pyrococcus furious (1pv9) and Pyrococcus horikoshii OT3 (1wy2). The crystal structure shows the loop structure can form two states ("open" and "closed" states) through interaction between the loop and active site proximity. It supports the proposed formation of allosteric site by the loop and Arg 293.

Prevention of Colorectal Cancer by Targeting Obesity-Related Disorders and Inflammation.

Colorectal cancer is a major healthcare concern worldwide. Many experimental and clinical studies have been conducted to date to discover agents that help in the prevention of this disease. Chronic inflammation in colonic mucosa and obesity, and its related metabolic abnormalities, are considered to increase the risk of colorectal cancer. Therefore, treatments targeting these factors might be a promising strategy to prevent the development of colorectal cancer. Among a number of functional foods, various phytochemicals, including tea catechins, which have anti-inflammatory and anti-obesity properties, and medicinal agents that ameliorate metabolic disorders, might also be beneficial in the prevention of colorectal cancer. In this review article, we summarize the strategies for preventing colorectal cancer by targeting obesity-related disorders and inflammation through nutraceutical and pharmaceutical approaches, and discuss the mechanisms of several phytochemicals and medicinal drugs used in basic and clinical research, especially focusing on the effects of green tea catechins.

p53 Expression as a Diagnostic Biomarker in Ulcerative Colitis-Associated Cancer.

Ulcerative colitis (UC) is defined as an idiopathic inflammatory disorder primarily involving the mucosa and submucosa of the colon. UC-associated colon cancers (also known as colitic cancers) develop through the inflammation-dysplasia sequence, which is a major problem affecting the prognosis of patients with UC. It is therefore very important to detect malignancy from UC at an early stage. As precancerous lesions arising in UC, there are pathological adenomatous changes, basal cell changes, in situ anaplasia, clear cell changes, and pan-cellular change. It is considered that the mutation of the p53 gene plays a crucial role, and the protein expression of p53 in dysplastic crypts may serve as a good biomarker in the early stages of UC-associated colon carcinogenesis. Immunohistochemistry for p53 is a very valuable diagnostic tool in UC-associated colon cancers. However, protein expression of p53 is not always universal, and additional methods may be required to assess p53 status in UC-associated colon cancers.

Preventive Effects of Pentoxifylline on the Development of Colonic Premalignant Lesions in Obese and Diabetic Mice.

Obesity and its related metabolic abnormalities, including enhanced oxidative stress and chronic inflammation, are closely related to colorectal tumorigenesis. Pentoxifylline (PTX), a methylxanthine derivative, has been reported to suppress the production of tumor necrosis factor (TNF)-α and possess anti-inflammatory properties. The present study investigated the effects of PTX on the development of carcinogen-induced colorectal premalignant lesions in obese and diabetic mice. Male C57BL/KsJ-db/db mice, which are severely obese and diabetic, were administered weekly subcutaneous injections of the colonic carcinogen azoxymethane (15 mg/kg body weight) for four weeks and then received drinking water containing 125 or 500 ppm PTX for eight weeks. At the time of sacrifice, PTX administration markedly suppressed the development of premalignant lesions in the colorectum. The levels of oxidative stress markers were significantly decreased in the PTX-treated group compared with those in the untreated control group. In PTX-administered mice, the mRNA expression levels of cyclooxygenase (COX)-2, interleukin (IL)-6, and TNF-α, and the number of proliferating cell nuclear antigen (PCNA)-positive cells in the colonic mucosa, were significantly reduced. These observations suggest that PTX attenuated chronic inflammation and oxidative stress, and prevented the development of colonic tumorigenesis in an obesity-related colon cancer model.