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Plant sterols are found in fruits and vegetables. Their cholesterol-lowering effect is well documented. Our study aimed at comparing antiproliferative effects of 7ß-hydroxysitosterol (7ß-OHsito) versus 7ß-hydroxycholesterol (7ß-OHchol) on the human colon cancer cell line Caco-2. When cells were exposed for 32?h to 60?µM 7ß-OHsito or to 30?µM 7ß-OHchol, both compounds caused 50%growth inhibition. Cells treated with 7ß-OHsito showed enhanced caspase-9 and -3 activities followed by DNA fragmentation. In contrast, 7ß-OHchol did not activate caspase-3 and activation of caspase-9 and DNA fragmentation were delayed. The treatment of cells with the caspase inhibitor Z-VAD.fmk retarded the 7ß-OHsito-induced apoptotic process but not that triggered by 7ß-OHchol. Our data suggest that the two compounds in spite of their structural similarities target different cellular pathways, which lead to cell death.Cell Death and Differentiation (2005) 12, 128-135. doi:10.1038/sj.cdd.4401530 Published online 19 November 2004 [ABSTRACT FROM AUTHOR]

Intestinal morphology and brush border hydrolase activities were determined along the small intestine of young adult (three months, n = 10), mature (12 months, n = 10), and senescent (29 months, n = 15) rats. The intestinal segments of the senescent rats contained higher mucosal mass and protein content (p less than 0.05) compared with the young and mature animals. A significant reduction of villus height and crypt depth (p less than 0.05) was found in the proximal intestine during aging. A 35% increase in villus height (p less than 0.05) without changes in crypt depth, was observed in the distal ileum in senescent rats. The activities of sucrase and isomaltase were significantly increased during aging in the duodenum and jejunum (p less than 0.05). Lactase and aminopeptidase activities which showed only minor changes between young and mature animals were significantly enhanced in senescent animals (p less than 0.05) with aminopeptidase exhibiting a three-fold increase in activity in the proximal ileum. The results when combined with those of previous studies suggest that in the aged animal, the increased level of intestinal hydrolase activities may be the consequence of prolonged cellular maturation along the villi in the proximal intestine, and of adaptation to increased concentrations of intraluminal substrates in the distal intestine. [ABSTRACT FROM PUBLISHER]

La cataracte demeure la première cause de cécité dans les pays en voie de développement posant un problème de santé publique. Le but de cette étude est de faire le bilan d'une activité de chirurgie avancée de la cataracte par la technique dite de à phacoalternative à ou par tunnélisation. Il s'agissait d'une étude prospective de base réalisée au Burkina Faso portant sur la chirurgie de la cataracte par la technique de tunnélisation. L'âge moyen de nos patients atteints de cataracte était de 62,47 , 12,77 ans avec un sex-ratio de 0,98. La majorité des patients opérés (82,82 %) étaient des cultivateurs et des ménagères. L'acuité visuelle de loin était réduite à la perception lumineuse dans 68,70% des cas. La profondeur moyenne de la chambre antérieure était de 2,98 , 0,53 mm. L'épaisseur moyenne du cristallin était de 3,55 , 0,75 mm. La longueur axiale moyenne de l'lèil de nos patients opérés de la cataracte était de 22,88 , 0,90 mm. La puissance réfractive moyenne estimée de la cornée était de 43,21 , 2,03 dioptries chez nos patients. La puissance moyenne estimée de l'implant intra oculaire (IOL) utilisé était de23,11 , 2,35D. La majorité (79,6%) de nos patients avait une bonne acuité visuelle après la chirurgie de la cataracte par tunnélisation. La chirurgie de la cataracte par tunnélisation est une technique révolutionnaire adaptée aux pays pauvres d'Afrique. Elle permet une lutte efficace à moindre coûtcontre la cécité par cataracte dans nos régions. La tunnélisation est une technique chirurgicale adaptée pour lutter efficacement contre la cécité due à la cataracte en Afrique.

Abstract: The aim of this present study was (i) to identify the proteins from a Streptococcus infantarius cell wall partially purified fraction triggering in vitro proinflammatory and in vivo procarcinogenic responses, (ii) to clone the partial genes encoding 3 of these identified proteins and to express them in a fused form in Escherichia coli. [Copyright &y& Elsevier]

Background: Adults with cystic fibrosis (CF) must continuously manage their condition, while working for a living, and want a normal life. Adherence rates to treatments/medications are less than optimal. Existing theory offers little to explain adherence rates. The purpose of this study was to develop a theory to further the understanding of how people with CF manage their condition in an adherence-driven health care system., Methods: Constructivist Grounded Theory methodology was used to conduct 27 semistructured interviews with adults with CF, family members, and health care providers. Data collection and analysis were simultaneous, using constant comparative methods, initial and focused coding, and category identification and reduction to develop a theory., Results: Doing what works to balance life and CF is the theory generated from this study. The main concern of participants was to be seen as normal. The theory depicts what participants with CF and their family members do about their concerns and involves 4 interrelated processes: working overtime, receiving support, passing as normal, and facing disease progression., Conclusion: Participants did not relate to the term nonadherent; rather they described working overtime to manage CF, to work, and to have a normal life. Health care provider and researcher perspectives on adherence differ from those of people with CF. Engaging adults with CF and health care providers in a dialogue in which expectations are shared may lead to individualized treatment regimens that work, because adults with CF will do what works., (Copyright © 2019 by Daedalus Enterprises.)

Background: The progression of cystic fibrosis (CF) in patients with the rare mutation P67L was examined to determine if it induced a milder form of CF compared to the common severe ΔF508 mutation., Methods: Parameters of lung function, level of bacterial infection, nutritional status and hospitalization were used to represent CF progression. Age at diagnosis and pancreatic status were used to assess CF presentation. Analysis of data from the CF Canada Registry collected over a 15-year period included 266 ΔF508/ΔF508 homozygote patients from CF clinics in Atlantic Canada and 26 compound heterozygote patients with the rare P67L mutation from clinics across Canada., Results: Late age at diagnosis, high incidence of pancreatic sufficiency, maintained Body Mass Index (BMI) with age, delayed life-threatening bacterial infection, and fewer days in hospital were observed for P67L heterozygote patients included in this study. Although the decline of lung function did not differ from ΔF508 homozygotes, the fact that a greater proportion of P67L heterozygotes live to an older age suggests that lung function is not the primary factor determining CF progression for P67L heterozygote patients., Conclusion: The P67L mutation is associated with a mild disease, even when combined with the severe ΔF508 mutation., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The flavonolignan silibinin, the major biologically active compound of the milk thistle (Silybum marianum), has been shown to possess anticancer properties in a variety of epithelial cancers. The present study investigated the potential of silibinin as a chemopreventive agent in colon carcinogenesis. The rat azoxymethane (AOM)-induced colon carcinogenesis model was used because of its molecular and clinical similarities to sporadic human colorectal cancer. One week after AOM injection (post-initiation), Wistar rats received daily intragastric feeding of 300 mg silibinin/kg body weight per day until their sacrifice after 7 weeks of treatment. Silibinin-treated rats exhibited a 2-fold reduction in the number of AOM-induced hyperproliferative crypts and aberrant crypt foci in the colon compared to AOM-injected control rats receiving the vehicle. Silibinin-induced apoptosis in the colon mucosal cells was demonstrated by flow cytometry after propodium iodide staining and by colorimetric measurement of caspase-3 activity. Mechanisms involved in silibinin-induced apoptosis included the downregulation of the anti-apoptotic protein Bcl-2 and upregulation of the pro-apoptotic protein Bax, inverting the Bcl-2/Bax ratio to <1. This modulation already takes place at the mRNA expression level as shown by real-time RT-PCR. Furthermore, silibinin treatment significantly (P<0.01) decreased the genetic expression of biomarkers of the inflammatory response such as IL1β, TNFα and their downstream target MMP7, all of them shown to be upregulated during colon carcinogenesis. The downregulation of MMP7 protein was confirmed by western blot analysis. The present findings show the ability of silibinin to shift the disturbed balance between cell renewal and cell death in colon carcinogenesis in rats previously injected with the carcinogen AOM. Silibinin administered via intragastric feeding exhibited potent pro-apoptotic, anti-inflammatory and multi-targeted effects at the molecular level. The effective reduction of preneoplastic lesions by silibinin supports its use as a natural agent for colon cancer chemoprevention.

Despite numerous studies aimed at verifying the anti-tumour activity of aspirin on colon carcinogenesis little is known on the molecular targets involved in the anti-carcinogenic properties of this drug. We investigated the long-term administration of low dose of aspirin in a model of experimental colon carcinogenesis in rats. Adult Wistar rats received an intraperitoneal injection of azoxymethane (AOM) once a week for two weeks in order to initiate colon carcinogenesis. One week after AOM injection, rats received daily 0.01% aspirin (6 mg/kg body weight) in drinking water for 10 months. Compared to AOM control rats, aspirin treatment for 10 months caused a 50% reduction of the number of aberrant crypt foci associated with a 50% reduction of prostaglandin E2 (PGE2) concentration and suppressed by 80% tumour formation in the colon. RT-PCR quantitative analysis showed that aspirin treatment reduced significantly (P<0.01) the AOM-triggered increase in mRNA levels of soluble inflammatory mediators (TNFalpha and IL-1beta) and metalloproteinases (MMP3 and MMP7). Conversely, we detected an increased expression level of alpha-defensin-5 (Rd-5, 2 fold) and lipocalin-2 (LCN2, 4 fold), two markers of the innate immunity system. The expression of apoptosis-related genes such as death receptors and their ligands were reduced by aspirin and the Bcl-2/Bax transcript ratio droped, Bcl-2 expression being reduced to the level found in saline control rats. The present study identifies new molecular targets triggered by aspirin in the colonic mucosa and may support the use of non-toxic low dose of aspirin in long-term treatments as a prophylactic approach against colon carcinogenesis.

We aimed to establish a reliable procedure allowing the follow-up of tumor development by computed tomographic (CT) colonography in an animal model of colon carcinogenesis in order to assess the chemopreventive efficacy of aspirin and difluoromethylornithine (DFMO) given in combination. Fischer rats received an intraperitoneal injection (25 mg/kg) of dimethylhydrazine (DMH) once a week for two weeks in order to initiate colon carcinogenesis. Five months after the last injection of DMH, a first CT colonography was performed and rats were then randomly separated into two groups (control and experimental). The experimental group received a 0.1% mixture of aspirin and DFMO in drinking water. CT colonography was performed at 6, 7 and 8 months. Data showed a precise correlation between location and size of tumors found at autopsy and those detected by CT colonography at 8 months. All tumors were also detected on the CT views obtained previously. Animals of the aspirin/DFMO group exhibited an inactivation of ornithine decarboxylase, a key enzyme in polyamine biosynthesis, and a two-fold reduction in the prostaglandin E2 content of the colonic mucosa (p<0.01). In rats with tumors at the start of the aspirin/DFMO treatment, a significant slow-down of tumor development was observed. In contrast, in rats where no tumors were detected at the start of the treatment, tumor formation was inhibited. Our data show that CT colonography represents a reliable method to assess in a living animal the efficacy of chemopreventive agents.

The pro-apoptotic ability of (Z)-3,5,4'-Tri-O-methyl-resveratrol (R3) was investigated in vitro on the human lymphoblastoid cell line TK6 and its p53-knockout counterpart (NH32). In both cell lines, R3 induced the stimulation of caspase-3. Although R3 induced growth inhibition and apoptosis of both cell lines, two distinct mechanisms were observed. The p53-knockout NH32 cells were shown to override the G2/M phase checkpoint with development of hyperdiploid cells, whereas TK6 cells accumulated at G2/M. As p53 function is often altered in human cancer cells, these results show that the pro-apototic effects of R3 against tumor cells are independent of their p53 status.

Geraniol, a natural component of plant essential oils, has antiproliferative effects on human colon cancer cells. To obtain more insight into its mechanism of action, we studied its effect on the resting membrane potential and on the expression of proteins involved in cell signaling pathways. Since geraniol is a well known inhibitor of mevalonate metabolism, the effect of mevalonate supplementation on geraniol-triggered growth inhibition was also determined. Geraniol (400 microM) induced membrane depolarization with a decrease of membrane resistance due to local perforation of the cell membrane. Incubation of Caco-2 cells with geraniol (400 microM) for 6 h caused a 60% reduction of protein kinase C (PKC) activity. After 16 h of incubation, geraniol decreased by 50% the amount of active forms of p44/p42 extracellular signal-regulated protein kinases (ERK). Mevalonate supplementation did not reverse inhibition of cell growth by geraniol. These results indicate that the antiproliferative effect of geraniol on Caco-2 cells was not related to a limitation of the mevalonate pool but was directly linked to the perturbation of cell membrane function leading to the reduction of PKC activity and to the decreased expression of p44/p42 ERK active forms.

Differentiation of human colonic cancer cells at confluency has been correlated to their increased resistance to chemotherapeutic agents. The aim of this study was to determine whether blocking Caco-2 cell differentiation could sensitize the cells to 5-fluorouracil (5-FU) treatment. We show that in cells at confluency, geraniol (400 microM) prevented the formation of brush-border membranes and inhibited the expression of intestinal hydrolases (sucrase, lactase, alkaline phosphatase). The antiproliferative effect of geraniol (400 microM) together with 5-FU (5 microM) was twice that of 5-FU alone. The cytotoxicity induced by 5-FU was enhanced in the presence of geraniol, as shown by a 50% increase of lactate dehydrogenase release in the culture medium. These effects are related to enhanced intracellular accumulation of 5-FU in the presence of geraniol as shown by a 2-fold increase in intracellular 5-[6-(3)H]FU (1.5 microCi/ml). It is concluded that geraniol sensitizes colonic cancer cells to 5-FU treatment, by increasing the cytotoxicity of the drug, and that this results from the facilitated transport of 5-FU and the blockade of the morphological and functional differentiation of the cancer cells.

Food irradiation is acknowledged as a safe process to improve food quality by reducing microbial contamination. Information on the toxicological potential of 2-alkylcyclobutanones (2-ACBs), radiolytic derivatives of triglycerides found exclusively in irradiated food, is scarce. Wistar rats received daily a solution of highly pure 2-tetradecylcyclobutanone (2-tDCB) or 2-(tetradec-5-enyl)-cyclobutanone (2-tDeCB) at a concentration of 0.005% in 1% ethanol as drinking fluid, while control animals received 1% ethanol. All animals received a single intraperitoneal injection of the chemical carcinogen azoxymethane (AOM) at Weeks 3 and 4. At 3 mo after AOM injection, no significant changes were observed in the total number of preneoplastic lesions in the colon of AOM controls and 2-ACB-treated animals. After 6 mo, the total number of tumors in the colon was threefold higher in the 2-ACB-treated animals than in the AOM controls. The colon of four of six AOM control rats exhibited only one small tumor ( &6 mm3). Multiple tumors were observed in four and three of six animals treated with 2-tDCB or 2-tDeCB, respectively. Medium (6 < S < 25 mm3) and larger (>25 mm3) tumors were detected only in 2-ACB-treated animals. This is the first demonstration that a compound found exclusively in irradiated dietary fats may promote colon carcinogenesis in animals treated with a chemical carcinogen.

Geraniol and other monoterpenes found in essential oils of fruits and herbs have been suggested to represent a new class of agents for cancer chemoprevention. As a first step in clarifying the mode of action of geraniol on colon carcinogenesis, we studied its effects on the growth of a human colon cancer cell line (Caco-2). Geraniol (400 microM) caused a 70% inhibition of cell growth, with cells accumulating in the S transition phase of the cell cycle, and concomitant inhibition of DNA synthesis. No signs of cytotoxicity or apoptosis were detected. Geraniol caused a 50% decrease of ornithine decarboxylase activity, a key enzyme of polyamine biosynthesis, which is enhanced in cancer growth. This led to a 40% reduction of the intracellular pool of putrescine. Geraniol also activated the intracellular catabolism of polyamines, indicated by enhanced polyamine acetylation. These observations indicate that polyamine metabolism is presumably a target in the antiproliferative properties of geraniol.

A possible link between the corticoid-elicited premature expression of intestinal sucrase-isomaltase (SI) and endogenous changes in polyamine metabolism was investigated in preweaned rats. Starvation at postnatal day 12 caused a precocious expression of SI mRNA and activity. A rapid upsurge of serum corticosterone was observed during the first hour of isolation, occurring in parallel with a transient enhancement of ornithine decarboxylase (ODC) expression and followed by an increase in mucosal polyamine content. Administration of the antiglucocorticoid RU-38486 completely prevented the starvation-evoked stimulation of ODC. The treatment of the sucklings with RU-38486 or with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ODC, dramatically reduced the amount of SI mRNA. When exogenous hydrocortisone (HC) was administered to 12-day-old sucklings nourished by their dam, an important accumulation of ODC mRNA was observed in the intestinal mucosa 4 h after treatment. Sucklings receiving HC and treated concomitantly with either RU-38486 or DFMO exhibited a reduced amount of ODC mRNA and a dramatic decline in both SI mRNA and activity. Altogether these data support the view that the premature induction of SI expression is dependent on changes in ODC expression and polyamine metabolism that can be elicited either by endogenous changes or by exogenously administered glucocorticoids.

The polyamines are involved in repair processes after intestinal ischemia. Arginine and ornithine, both precursors of polyamines were therefore expected to exert beneficial effects on mucosal barrier dysfunction. Arginine may also generate NO and there is support for the view that NO may be beneficial after an ischemic insult. Male Wistar rats were given, by gavage, isonitrogenous solutions of L-arginine (0.5 g/kg) or L-ornithine (0.7 g/kg) 17 and 2 h before ischemia. Controls received an isonitrogenous solution of casein hydrolysate (1 g/kg). Transient intestinal ischemia was produced in anesthetized rats by occluding the superior mesenteric artery for 90 min. Intestinal morphology, hydrolase activities, polyamine and cGMP contents, and cell proliferation rates were determined 4 h after reperfusion. Administration of arginine or ornithine did not prevent ischemic damage but accelerated morphological repair, enhanced cell proliferation, and polyamine content was observed. Arginine was significantly more effective than ornithine. Formation of cGMP was enhanced after arginine administration. NG-nitroarginine methylester, an inhibitor of NO synthase, prevented the arginine effects on mucosal repair. We conclude that arginine-derived NO is an important mediator in the restitution of intestinal mucosa by minimizing cell injury during reperfusion.

The effect of starvation and refeeding on the developmental pattern of intestinal sucrase-isomaltase (SI) was analyzed in preweaned rats. Starvation at postnatal day 12 caused a precocious expression of SI activity and mRNA. Alkaline phosphatase activity was slightly reduced, and no significant change was observed for aminopeptidase and lactase activities. Immunostaining showed that SI molecules appear in cells at the base of the villus. Sucrase expression was further increased by prolonged food deprivation, whereas enzyme activity as well as the amount of SI mRNA dropped to reach the low level found in control sucklings when 48 h-starved pups were refed by returning them to their dams. During the refeeding period, the enterocytes that were committed to produce SI by starvation continued to express the enzyme while migrating up the villi. However, the new epithelial cells arising from the crypts no longer synthesized the disaccharidase. The starvation-evoked appearance of SI was preceded by a transient burst of expression of the protooncogene c-fos, an event that may be correlated to the ontogenic rise of c-fos mRNA observed before weaning. However, in contrast to the normal weaning condition, SI induction by starvation occurred without obvious increase of epithelial cell proliferation and turnover. During the starvation and refeeding period, patterns of sucrase activity and SI mRNA paralleled the serum level of glucocorticoids.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptive responses of brush border hydrolases and crypt cell proliferation were measured in the jejunum and ileum of 4-mo-old adult and 28-mo-old senescent male Wistar rats. Responses were measured after rats were deprived of food and then refed with a normoprotein diet (17% protein) or an isoenergetic high protein diet (70% protein). The young rats deprived of food then refed for 18 h with the high protein diet showed better body weight recovery than did old animals. Withholding food for 48 h induced a more pronounced drop of sucrase activity in the intestine of the old rats relative to young rats. Refeeding the high protein diet caused a better recovery of sucrase activity in the jejunum of young rats relative to senescent rats. In the aged animals, sucrase activity in the jejunum remained significantly lower after refeeding both diets. Compared with nourished controls, aged rats showed enzyme activity to be completely restored in the ileum. The high protein diet increased aminopeptidase activity in the jejunum and ileum of young rats, in contrast to the senescent rats in which the increase of enzyme activity was restricted to the ileum. In the jejunum of aged rats, the cell migration rate from crypt base to villus tip was reduced after refeeding, but no age-related changes were observed in the ileum. Our results indicate that the jejunum of senescent rats exhibits reduced adaptive capacities that may be partly compensated by enhanced ileal functions.

The effect of glucocorticoids and thyroid hormones on lactase expression was investigated along the small intestine of rats. In sucklings thyroxine injections promoted a precocious drop of enzyme activity but not of mRNA. Hydrocortisone did neither modify lactase activity nor its mRNA expression. In adults decreasing the amount of thyroid hormones led to a slight and reversible increase of the lactase mRNA content whereas lactase activity rised more dramatically. Thus, thyroid hormones in contrast to corticoids, are involved in the posttranscriptional control of lactase during the suckling period. Yet, none of these hormones might induced the modification of the longitudinal distribution of the lactase mRNA that occurred at weaning.

The expression of lactase was compared in the jejunum and colon of the rat at the levels of enzyme activity and protein and RNA content. We found that the enzyme proteins and the corresponding mRNAs share common features and are encoded by a single gene in both intestinal segments. In the jejunum, large amounts of lactase mRNA and proteins were detected during postnatal development as well as in adult rats, despite the 10-fold decline in lactase specific activity which occurs at weaning. In contrast, in the colon the expression of lactase was restricted to early postnatal development. In the colon, the enzymic activity of lactase and the amounts of protein and mRNA followed parallel development profiles with a peak at day 4 after birth. Injections of thryoxine or epidermal growth factor into neonates led to small modifications in the expression of lactase in the jejunum. On the other hand, these treatments caused a large decline in lactase activity in the colon that paralleled a decrease in the amount of lactase protein and mRNA. These data indicate that the expression of lactase is mainly regulated at the post-transcriptional level in the jejunum, whereas it is controlled at the pretranslational level in the colon.

Intestinal hydrolase activities were studied during postnatal development in the offspring of rats exposed to 20% ethanol during gestation; alcohol was withdrawn at birth. Controls received water during gestation. Sucrase, lactase, glucoamylase and aminopeptidase activities were determined 2 and 4 weeks after birth in the proximal jejunum. Offspring prenatally exposed to ethanol showed a deficit in body weight and lower aminopeptidase activity during the suckling period (2 weeks). These effects were reversible by 4 weeks when alcohol was withdrawn at birth. The prenatal exposure to ethanol did not change the pattern of sucrase maturation in the intestine of offsprings. The activities of lactase and glucoamylase were not modified following prenatal exposure to ethanol. In conclusion, exposure to ethanol during gestation caused decreased abilities for the intestine of the offspring to digest protein.