Peroxisome proliferator-activated receptor gamma and spermidine/spermine N(1)-acetyltransferase gene expressions are significantly correlated in human colorectal cancer

BACKGROUND: The peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that regulates adipogenic differentiation and glucose homeostasis. Spermidine/spermine N(1)-acetyltransferase (SSAT) and ornithine decarboxylase (ODC) are key enzymes involved in the metabolism of polyamines, compounds that play an important role in cell proliferation. While the PPARγ role in tumour growth has not been clearly defined, the involvement of the altered polyamine metabolism in colorectal carcinogenesis has been established. In this direction, we have evaluated the PPARγ expression and its relationship with polyamine metabolism in tissue samples from 40 patients operated because of colorectal carcinoma. Since it is known that the functional role of K-ras mutation in colorectal tumorigenesis is associated with cell growth and differentiation, polyamine metabolism and the PPARγ expression were also investigated in terms of K-ras mutation. METHODS: PPARγ, ODC and SSAT mRNA levels were evaluated by reverse transcriptase and real-time PCR. Polyamines were quantified by high performance liquid chromatography (HPLC). ODC and SSAT activity were measured by a radiometric technique. RESULTS: PPARγ expression, as well as SSAT and ODC mRNA levels were significantly higher in cancer as compared to normal mucosa. Tumour samples also showed significantly higher polyamine levels and ODC and SSAT activities in comparison to normal samples. A significant and positive correlation between PPARγ and the SSAT gene expression was observed in both normal and neoplastic tissue (r = 0.73, p < 0.0001; r = 0.65, p < 0.0001, respectively). Moreover, gene expression, polyamine levels and enzymatic activities were increased in colorectal carcinoma samples expressing K-ras mutation as compared to non mutated K-ras samples. CONCLUSION: In conclusion, our data demonstrated a close relationship between PPARγ and SSAT in human colorectal cancer and this could represent an attempt to decrease polyamine levels and to reduce cell growth and tumour development. Therefore, pharmacological activation of PPARγ and/or induction of SSAT may represent a therapeutic or preventive strategy for treating colorectal cancer

The NOX toolbox: validating the role of NADPH oxidases in physiology and disease

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis

Effect of atenolol pre-treatment in heart damage in a model of intestinal ischemia-reperfusion

Purpose: To investigate the effects of atenolol in inflammatory mediator and oxidative stress in a myocardial injury by intestinal ischemia/reperfusion in rat model. Methods: Adult Wistar male rats were randomly (n= 8), anesthetized and divided in: Sham: submitted to operation only; group SS+ IR: intravenous saline infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); group AT+ IR: intravenous atenolol infusion (2 mg/kg) following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); and group AT+ I+ AT+ R: intravenous atenolol infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and in the time 45 minutes other atenolol doses were administrated and the artery was open for 120 minutes (reperfusion), all animals were submitted to muscular relaxation for mechanical ventilation. In the end of experiment the animals were euthanized and the hearts tissue were morphology analyzed by histology and malondialdehyde by ELISA, and the plasma were analyzed for tumor necrosis factor-alpha by ELISA. Results: The group SS+ IR demonstrated the higher malondialdehyde levels when compared with the atenolol treated-groups (p= 0.001) in the heart tissue. The tumor necrosis factoralpha level in plasma decrease in the treated groups when compared with SS+ IR group (p= 0.001). Histology analyses demonstrate pyknosis, edema, cellular vacuolization, presence of inflammatory infiltrate and band contraction in the heart tissue of the rats. Conclusion: Atenolol significantly reduce the degree of cardiac damage after intestinal ischemia-reperfusion.FAPESPUniv Fed Sao Paulo, UNIFESP, Postgrad Program Translat Med, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Surg, Div Anesthesia Pain & Intens Med, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Postgrad Program Pharmacol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Pharmacol, Sao Paulo, SP, BrazilUNESP, Vet Med Sch, Aracatuba, SP, BrazilUniv Fed Sao Paulo, Dept Surg, Div Cardiol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Postgrad Program Translat Med, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, UNIFESP, Postgrad Program Translat Med, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Surg, Div Anesthesia Pain & Intens Med, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Postgrad Program Pharmacol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Pharmacol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Dept Surg, Div Cardiol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Postgrad Program Translat Med, Sao Paulo, SP, BrazilWeb of Scienc

Changes in gut bacterial populations and their translocation into liver and ascites in alcoholic liver cirrhotics

Background The liver is the first line of defence against continuously occurring influx of microbial-derived products and bacteria from the gut. Intestinal bacteria have been implicated in the pathogenesis of alcoholic liver cirrhosis. Escape of intestinal bacteria into the ascites is involved in the pathogenesis of spontaneous bacterial peritonitis, which is a common complication of liver cirrhosis. The association between faecal bacterial populations and alcoholic liver cirrhosis has not been resolved. Methods Relative ratios of major commensal bacterial communities (Bacteroides spp., Bifidobacterium spp., Clostridium leptum group, Enterobactericaea and Lactobacillus spp.) were determined in faecal samples from post mortem examinations performed on 42 males, including cirrhotic alcoholics (n = 13), non-cirrhotic alcoholics (n = 15), non-alcoholic controls (n = 14) and in 7 healthy male volunteers using real-time quantitative PCR (RT-qPCR). Translocation of bacteria into liver in the autopsy cases and into the ascites of 12 volunteers with liver cirrhosis was also studied with RT-qPCR. CD14 immunostaining was performed for the autopsy liver samples. Results Relative ratios of faecal bacteria in autopsy controls were comparable to those of healthy volunteers. Cirrhotics had in median 27 times more bacterial DNA of Enterobactericaea in faeces compared to the healthy volunteers (p = 0.011). Enterobactericaea were also the most common bacteria translocated into cirrhotic liver, although there were no statistically significant differences between the study groups. Of the ascites samples from the volunteers with liver cirrhosis, 50% contained bacterial DNA from Enterobactericaea, Clostridium leptum group or Lactobacillus spp.. The total bacterial DNA in autopsy liver was associated with the percentage of CD14 expression (p = 0.045). CD14 expression percentage in cirrhotics was significantly higher than in the autopsy controls (p = 0.004). Conclusions Our results suggest that translocation of intestinal bacteria into liver may be involved as a one factor in the pathogenesis of alcoholic liver cirrhosis.BioMed Central open acces

The effects of having more than one good reputation on distributor investments in the film industry

Reputations of organizations and its individual members are valuable resources that help new organizations to get access to investment capital. Reputations, however, can have different dimensions. In this paper, we argue that an individual’s reputation along a particular dimension will have a positive effect on the behavior of investors when it is role congruent. In addition, we argue that also scoring favorably on the role-incongruent dimension at the same time—or, in other words, engaging in reputational category spanning—will weaken the positive effect of the role-congruent reputation. Our empirical setting is the film industry where we study the effect of the two main dimensions of reputation in cultural industries, artistic and commercial, of both directors and producers on the size of the investment by distributors. In this study, artistic reputation is based on professional critics’ reviews and commercial reputation on box office performance of the films in which individuals were involved in the past. We find that the commercial reputation of a film producer based on past box office performance has a positive effect on the size of the investment by film distributors. In addition, we find that directors who at the same time combine both a favorable commercial as well as an artistic reputation actually receive a lower investment from film distributors

Conceptualising the role of evaluation systems in markets: the case of dominant evaluators

Evaluation is usually an internalized process that is intrinsic to the activities of market actors. Producers evaluate what goods to produce, intermediaries such as distributors and retailers evaluate what goods to promote and stock, while consumers evaluate what goods to buy. In some cases, however, a secondary evaluation market controlled by an external evaluator can emerge as a de-facto gatekeeper exerting a powerful influence over the activities of market actors in the primary market. This article develops a conceptual model of external evaluation that describes: (i) the factors common to primary markets that are dominated by evaluation markets; (ii) the characteristics common to dominant evaluators and their evaluation markets; and (iii) the dynamic processes through which an evaluator can become entrenched in a position of dominance over other market actors. This conceptual model is illustrated through examples drawn from three dominant evaluators and the markets they dominate

PI3K-dependent GSK3ß(Ser9)-phosphorylation is implicated in the intestinal epithelial cell wound-healing response.

We conclude that PI3K-mediated GSK3ß phosphorylation is involved in the intestinal epithelial wound-healing response. Phosphorylation of GSK3ß may be important for intestinal restitution by promoting cell motility in response to wounding