Peroxisome proliferator-activated receptor gamma-dependent activation of p21 in Panc-28 pancreatic cancer cells involves Sp1 and Sp4 proteins

1,1-Bis(3'-indolyl)-1-(p-trifluoromethylphenyl)methane (DIM-C-pPhCF3) and troglitazone activate peroxisome proliferator-activated receptor gamma (PPARgamma) in Panc-28 pancreatic cancer cells and also inhibit cell proliferation. DIM-C-pPhCF3 was more active than troglitazone and was used as a model to investigate the mechanism of PPARgamma-dependent inhibition of Panc-28 cell growth. DIM-C-pPhCF3 significantly inhibited G0/G1-->S phase progression, as determined by FACS analysis, and this was associated with decreased retinoblastoma protein phosphorylation and increased p21 protein and mRNA expression, but no change in p27 or cyclin D1. PPARgamma antagonists blocked DIM-C-pPhCF3-induced growth inhibition and induction of p21 protein, and similar inhibitory effects were observed in Panc-28 cells transfected with a construct (pWWP) containing a -2325 to +8 p21 promoter insert. Deletion analysis of the p21 promoter indicated that PPARgamma-dependent activation of p21 promoter constructs by DIM-C-pPhCF3 required GC-rich sites 3 and 4 in the proximal region (-124 to -60) of the p21 promoter. The results of RNA interference and protein expression/DNA binding assays suggest that DIM-C-pPhCF3 induced p21 expression through a novel mechanism that involves PPARgamma interactions with both Sp1 and Sp4 proteins bound to the proximal GC-rich region of the p21 promoter.     

3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha

3-Methylcholanthrene (3MC) is an aryl hydrocarbon receptor (AhR) agonist, and it has been reported that 3MC induces estrogenic activity through AhR-estrogen receptor alpha (ER alpha) interactions. In this study, we used 3MC and 3,3',4,4',5-pentachlorobiphenyl (PCB) as prototypical AhR ligands, and both compounds activated estrogen-responsive reporter genes/gene products (cathepsin D) in MCF-7 breast cancer cells. The estrogenic responses induced by these AhR ligands were inhibited by the antiestrogen ICI 182780 and by the transfection of a small inhibitory RNA for ER alpha but were not affected by the small inhibitory RNA for AhR. These results suggest that 3MC and PCB directly activate ER alpha, and this was confirmed in a competitive ER alpha binding assay and in a fluorescence resonance energy transfer experiment in which PCB and 3MC induced CFP-ER alpha/YFP-ER alpha interactions. In a chromatin immunoprecipitation assay, PCB and 3MC enhanced ER alpha (but not AhR) association with the estrogen-responsive region of the pS2 gene promoter. Moreover, in AhR knockout mice, 3MC increased uterine weights and induced expression of cyclin D1 mRNA levels. These results show that PCB and 3MC directly activate ER alpha-dependent transactivation and extend the number of ligands that activate both AhR and ER alpha.     

In vitro and In vivo evaluation of positively charged liposaccharide derivatives as oral absorption enhancers for the delivery of anionic drugs

Oral delivery of hydrophilic, ionisable drugs remains a major challenge in drug development and a number of active pharmaceuticals fail to reach the market of oral drugs because of a lack of absorption and/or stability issues. One possible approach to improving the bioavailability of such drug candidates is to increase their lipophilicity, which is a key parameter in the permeation across cell membranes. However, modifying the chemical structure by adding lipid residues often results in changes in activity. With ionised molecules, ion‐pairing can be considered to associate charged lipid moieties with the parent drug without altering its structure and therefore activity. This study presents the results of in vitro and in vivo evaluation of a series of synthetic, positively charged liposaccharide derivatives combined with an anionic model drug, piperacillin. The antimicrobial activity, plasma stability, Caco‐2 cell permeability and oral absorption of the conjugates were assessed. Increases in apparent permeability were observed in vitro for three of the tested formulations, while retaining the antibacterial activity of the drug. However, the in vivo intestinal absorption of piperacillin formulated with the liposaccharide derivatives was found unchanged, possibly due to molecular dissociation, early degradation or structural differences between the intestinal epithelium and cultured monolayers. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2333–2342, 2010     

1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways

1,1-Bis(3'-indolyl)-1-(p-t-butylphenyl)methane (DIM-C-pPhtBu) is a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, and treatment of SKOV3 ovarian cancer cells with this compound (5 micromol/L) inhibits cell proliferation, whereas up to 15 micromol/L rosiglitazone had no effect on cell growth. DIM-C-pPhtBu also inhibits G0-G1 to S phase cell cycle progression and this is linked, in part, to PPARgamma-dependent induction of the cyclin-dependent kinase inhibitor p21. DIM-C-pPhtBu induces PPARgamma-independent down-regulation of cyclin D1 and we therefore further investigated activation of receptor-independent pathways. DIM-C-pPhtBu also induced apoptosis in SKOV3 cells and this was related to induction of glucose-related protein 78, which is typically up-regulated as part of the unfolded protein response during endoplasmic reticulum (ER) stress. Activation of ER stress was also observed in other ovarian cancer cell lines treated with DIM-C-pPhtBu. In addition, DIM-C-pPhtBu induced CCAAT/enhancer binding protein homologous protein through both ER stress and c-jun NH2-terminal kinase-dependent pathways, and CCAAT/enhancer binding protein homologous protein activated death receptor 5 and the extrinsic pathway of apoptosis. These results show that DIM-C-pPhtBu inhibits growth and induces apoptosis in ovarian cancer cells through both PPARgamma-dependent and PPARgamma-independent pathways, and this complex mechanism of action will be advantageous for future clinical development of these compounds for treatment of ovarian cancer.     

Sociodemographic Factors Associated With Tobacco Smoking Among Intermediate and Secondary School Students in Jazan Region of Saudi Arabia

ABSTRACT

Background: The objectives of this study were to (i) determine the prevalence of and characteristics associated with tobacco smoking; (ii) identify the factors associated with tobacco smoking; and (iii) evaluate the association between tobacco smoking and khat chewing among intermediate and secondary school students in Jazan Region, Saudi Arabia. Methods: A cross-sectional study was conducted with a representative sample (N = 4100) of intermediate and secondary school students in Jazan Region. The data were collected using a pretested modified version of the global youth tobacco survey questionnaire. Results: A total of 3923 students from 72 intermediate and secondary schools for males and females in Jazan Region, Saudi Arabia, were included in this study. The ever having smoked prevalence was 17.3%, and the current smoking prevalence was 10.7%. The most important independent predictors of smoking were academic performance (odds ratio [OR]: 5.32), having friends who used khat (OR: 3.23), and having friends who used tobacco (OR: 2.88). Conclusions: Understanding the factors and predictors associated with tobacco use are crucial to identifying high-risk groups to design tobacco prevention and control programs. For the first time, a strong and statistically significant association was identified between tobacco smoking and khat chewing among intermediate and secondary school students in Jazan Region. Because the use of khat is increasingly spreading outside of its traditional areas to Europe and America, this finding may have an important impact on tobacco control efforts internationally.     

Cultural competence springs up in the desert: the story of the center for cultural competence in health care at Weill Cornell Medical College in Qatar

The authors describe the factors that led Weill Cornell Medical College in Qatar (WCMC-Q) to establish the Center for Cultural Competence in Health Care from the ground up, and they explore challenges and successes in implementing cultural competence training.Qatar's capital, Doha, is an extremely high-density multicultural setting. When WCMC-Q's first class of medical students began their clinical clerkships at the affiliated teaching hospital Hamad Medical Corporation in 2006, the complicated nature of training in a multicultural and multilingual setting became apparent immediately. In response, initiatives to improve students' cultural competence were undertaken. Initiatives included launching a medical interpretation program in 2007; surveying the patients' spoken languages, examining the effect of an orientation program on interpretation requests, and surveying faculty using the Tool for Assessing Cultural Competence Training in 2008; implementing cultural competence training for students and securing research funding in 2009; and expanding awareness to the Qatar community in 2010. These types of initiatives, which are generally highly valued in U.S. and Canadian settings, are also apropos in the Arabian Gulf region.The authors report on their initial efforts, which can serve as a resource for other programs in the Arabian Gulf region.     

Impact of negative pressure wound drainage compared with natural wound drainage after thyroid tumour surgery: A meta-analysis

We conducted a meta-analysis to compare the effectiveness of negative pressure wound drainage to that of spontaneous wound drainage after thyroid tumour surgery. A thorough analysis of the literature up to July 2022 revealed that, of the 1234 patients who used surgery for thyroid tumours, 615 used negative pressure wound drainage and 619 used natural wound drainage. To measure the influence of negative pressure wound drainage in comparison to natural wound drainage following thyroid tumour surgery, mean difference (MD) and odds ratio (OR) with 95% confidence intervals (CIs) were measured using the contentious and dichotomous approaches with a random or fixed-effect model. Subjects who used negative pressure wound drainage had significantly higher averages for drained material (OR, 12.52; 95% CI, 6.78-18.26, P = 0.001), shorter drain placement times (MD, −1.06; 95% CI, 1.57 to −0.55, P = .001), lower rates of infection at the surgical site (OR, 0.17; 95% CI, 0.05-0.60, P = .006), higher rates of wound healing (OR, 5.91; 95% CI, 1.56-22.34, P = .009), and lower rate of wound seroma (OR, 0.21; 95% CI, 0.10-0.42, P < .001) in subjects after thyroid tumour surgery in comparison to subjects who used natural wound drainage after thyroid tumour surgery. Those who used negative pressure wound drainage had significantly higher averages of drained material, shorter drain placement times, lower rates of wound infection at the surgical site, higher rates of wound healing, and lower rates of wound seroma. Care must be used when analysing the results because of the small sample size of 7 of the 13 studies included in the meta-analysis and the lack of studies in several comparisons.