Environmental factors in causing human cancers: emphasis on tumorigenesis

The environment and dietary factors play an essential role in the etiology of cancer. Environmental component is implicated in ~80?% of all cancers; however, the causes for certain cancers are still unknown. The potential players associated with various cancers include chemicals, heavy metals, diet, radiation, and smoking. Lifestyle habits such as smoking and alcohol consumption, exposure to certain chemicals (e.g., polycyclic aromatic hydrocarbons, organochlorines), metals and pesticides also pose risk in causing human cancers. Several studies indicated a strong association of lung cancer with the exposure to tobacco products and asbestos. The contribution of excessive sunlight, radiation, occupational exposure (e.g., painting, coal, and certain metals) is also well established in cancer. Smoking, excessive alcohol intake, consumption of an unhealthy diet, and lack of physical activity can act as risk factors for cancer and also impact the prognosis. Even though the environmental disposition is linked to cancer, the level and duration of carcinogen-exposure and associated cellular and biochemical aspects determine the actual risk. Modulations in metabolism and DNA adduct formation are considered central mechanisms in environmental carcinogenesis. This review describes the major environmental contributors in causing cancer with an emphasis on molecular aspects associated with environmental disposition in carcinogenesis.     

Evaluation of supercritical fluid engineered budesonide powder for respiratory delivery using nebulisers

Objectives Currently, suspensions prepared from micronised drug substances are the only delivery system marketed for nebulisation of steroids, and reported inconsistent or low bioavailability arising from their use provides a rationale for researching alternative formulations. Supercritical fluid processing of drug substances to obtain respirable‐sized particles has been used over the last decade to formulate dry powder inhalers. We aimed thus to process budesonide powder to improve its deposition characteristics. Methods In an attempt to overcome the limitations of nebuliser suspensions when prepared from micronised drug particles, budesonide powder was processed using a supercritical fluid based process and suspended using Tween 80 as a surfactant to provide an aqueous nebuliser formulation. The in‐vitro characteristics of the emitted dose on nebulisation for the prepared suspension were then compared to a commercially available suspension formulation of budesonide using a jet and a vibrating mesh nebuliser. Key findings The results showed a significant improvement of the in‐vitro deposition properties of the suspension containing supercritical fluid engineered budesonide particles. Conclusions The results indicated the benefit of such materials compared with traditionally micronised drug powders.     

Coronary risk factor management in the framework of a community hospital-based ambulatory exercise training program

Ischemic heart disease is a chronic illness that causes major mortality and morbidity. Angiographic studies have shown the effectiveness of exercise programs, in combination with aggressive lipid management, in reversing or slowing the progression of atherosclerotic coronary disease. Despite these studies, participation in supervised programs that combine exercise and risk-factor management is limited. The authors measured the ability of a community hospital-based ambulatory cardiac rehabilitation program to recruit patients and to facilitate reduction of risk factors that have been demonstrated to influence progression of disease. Patients were recruited from a single community hospital for an ambulatory exercise training and cardiac risk-factor management program, and clinical and laboratory data was collected periodically. Recruited patients participated in a minimum 3-month period of training and counseling by a multidisciplinary team with follow-up measurements of weight, lipid profile, blood pressure, and exercise capacity. Thirty-two percent of the eligible hospitalized patients were successfully recruited into the program. Dropout rates over the initial 3 months were low (25%). Improvement in low-density lipoprotein cholesterol level (-4.5%), high-density lipoprotein cholesterol level (+7%), body mass index (-2%), systolic blood pressure (-3%), and maximum metabolic equivalents (+25%) were comparable to levels achieved in studies showing angiographic stabilization and/or regression of disease. Implementation of a community hospital-based risk management exercise program is an effective method for improving the long-term management of patients with chronic ischemic heart disease.     

Iodized Salt Consumption in Sudan: Present Status and Future Directions

Iodine Deficiency Disorders (IDD) Control Programme in Sudan adopted salt iodization as the long-term strategy in 1994. In 2000, it was found that less than 1% of households were using adequately-iodized salt. The objectives of this study were to: (i) study the coverage and variation of different geographical regions of Sudan regarding access to and use of iodized salt, (ii) explore the possible factors which influence the use of iodized salt, (iii) develop recommendations to help in the implementation of the Universal Salt Iodization (USI) strategy in Sudan. This paper is based on the Sudan Household Health Survey (SHHS) dataset. A total sample of 24,507 households was surveyed, and 18,786 cooking salt samples were tested for iodine levels with rapid salt-testing kits. Nationally, the percentage of households using adequately-iodized salt increased from less than 1% in 2000 to 14.4%, with wide variations between states. Access to iodized salt ranged from 96.9% in Central Equatoria to 0.4% in Gezira state. Population coverage with iodized salt in Sudan remains very low. The awareness and political support for USI programme is very weak. National legislation banning the sale of non-iodized salt does not exist. Utilization of the already-existing laws, like the National Standardization and Metrology Law (2008), to develop a compulsory national salt specification, will accelerate the USI in Sudan.Key words: Iodine deficiency disorders, Salt legislations, Universal Salt Iodization, Sudan     

Thyrotropin modulates receptor-mediated processing of the atrial natriuretic peptide receptor in cultured thyroid cells.

In a prior study of atrial natriuretic peptide (ANP) binding to cultured thyroid cells, we reported that at 4 C, more than 95% of bound ANP is recovered on cell membranes, with negligible ANP internalization observed. Since ANP binding was inhibited by TSH, we have further studied TSH effects on postbinding ANP processing to determine whether this phenomenon reflects enhanced endocytosis of the ANP-receptor complex. An ANP chase study was initiated by binding [125I] ANP to thyroid cells at 4 C for 2 h, followed by incubation at 37 C. ANP processing was then traced by following 125I activity at various time intervals in three fractions: cell surface membranes, incubation medium, and inside the cells. Radioactivity released into medium represented processed ANP rather than ANP dissociated from surface membranes, since prebound [125I]ANP could not be competitively dissociated by a high concentration of ANP (1 mumol/L) at 37 C. Chase study results showed that prebound ANP quickly disappeared from cell membranes down to 34% by 30 min. Internalized ANP peaked at 10 min, with 21% of initial prebound ANP found inside the cells. At the same time, radioactivity recovered in incubation medium sharply increased between 10-30 min from 8% to 52%. Preincubation of cells with chloroquine (which blocks degradation of the ANP-receptor complex by inhibiting lysosomal hydrolase) caused a 146% increase in internalized [125I]ANP by 30 min (39% compared to 15% control), while medium radioactivity decreased from 52% to 16%, suggesting that processing of the receptor complex is mediated via lysosomal enzymes. In chase studies employing cells pretreated with chloroquine, TSH stimulated the internalization rate of ANP-receptor complex. By 30 min, TSH significantly reduced the membrane-bound ANP, and the decrease was inversely correlated to the increase in internalized radioactivity. In the absence of ANP ligand, TSH also modulated receptor translocation, resulting in decreased receptor number on surface membrane. However, TSH did not affect ANP degradation on the basis of analysis by immunoprecipitation and high performance liquid chromatography. Taken together, these data suggest that TSH downregulates ANP receptor on thyroid cell surface membranes, and that an ANP degradative pathway exists which is not mediated through receptor binding.     

Design, synthesis, and biological evaluation studies of novel quinazolinone derivatives as anticonvulsant agents

In view of their expected anticonvulsant activity, some novel derivatives of 6,8-diiodo-2-methyl-3-substituted-quinazolin-4(3H)-ones (4–14) were synthesized, evaluated for their anticonvulsant activity by the maximal electroshock-induced seizure and subcutaneous pentylenetetrazole tests. The neurotoxicity was assessed using rotorod test. All the tested compounds showed considerable anticonvulsant activity in at least one of the anticonvulsant tests. Compounds 5, 6, and 8 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test when compared with the reference drugs. The obtained results showed that the most potent compounds could be useful as a template for future design, optimization, and investigation to produce more active analogs.     

Alarming high prevalence of overweight/obesity among Sudanese children

The objective of this study was to estimate the prevalence of obesity among schoolchildren in Khartoum state, Sudan. Multistage stratified random sampling methodology was used. Sampling included different residential areas within the state. A total of 1138 children between the ages of 10 and 18 years were involved in the study. More than 9% of the children were obese, 10.8% were overweight whereas combined overweight/obesity scored 20.5%. The prevalence of combined overweight/obesity among higher, middle and lower socioeconomic class children was 56.8, 27.3 and 3.1%, respectively. These figures, being higher than those reported among Nigerian and South African children, living in similar conditions, may refer to an emerging problem of overweight and obesity especially among children of the higher and middle class families. Adoption of national programs of promoting healthy food habits and physical activity among children is recommended.     

Interaction of the aryl hydrocarbon receptor ligand 6-methyl-1,3,8-trichlorodibenzofuran with estrogen receptor alpha

The polycyclic aromatic hydrocarbon 6-methyl-1,3,8-trichlorodibenzofuran (MCDF) is related to the industrial byproduct dioxin and is a weak agonist and partial antagonist at the aryl hydrocarbon receptor (AhR). Tamoxifen is used for the treatment and prevention of breast cancer and interferes with the interaction of estrogen with estrogen receptor alpha (ER). The combination of MCDF and tamoxifen lowered the effective dose of both drugs required to inhibit 7,12-dimethylbenz(a)anthracene-induced mammary tumor growth in rats and protected against the estrogenic effects of tamoxifen on the uterus in rats (A. McDougal et al., Cancer Res 2001;61:3902-7), pointing to the potential use of MCDF in breast cancer treatment. Potential AhR-ER cross-talk is evidenced by the antiestrogenic activity of MCDF and the degradative effect of MCDF on ER protein levels. Our studies confirmed that MCDF degraded the ER. MCDF displayed antiestrogenic activity at higher concentrations in MCF-7 human breast cancer cells, but MCDF alone (10(-6) M) stimulated the growth of MCF-7 cells. MCDF also activated an estrogen response element (ERE)-luciferase reporter and increased mRNA levels of the estrogen-responsive gene transforming growth factor (TGF)-alpha. The estrogenic effects of MCDF are ER dependent because they were blocked by the pure antiestrogen ICI 182,780. MCDF induced ER-coactivator interaction in glutathione S-transferase pull-down assays and the formation of an ER.ERE complex in gel mobility shift assays, further indicating that the estrogenic actions of MCDF are mediated by the ER. In addition, knockdown of the AhR with small interfering RNA did not affect MCDF-induced ERE-luciferase activity. Overall, these data support the conclusion that MCDF is a partial agonist at the ER. This study provides the first evidence for the direct interaction of the ER with MCDF and challenges the view that MCDF is simply an AhR-specific ligand.     

Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells

Sp proteins play an important role in angiogenesis and growth of cancer cells, and specificity protein 1 (Sp1) has been linked to vascular endothelial growth factor (VEGF) expression in pancreatic cancer cells. RNA interference was used to investigate the role of Sp family proteins on regulation of VEGF expression and proliferation of Panc-1 pancreatic cancer cells. Using a series of constructs containing VEGF promoter inserts, it was initially shown that Sp1 and Sp3 were required for transactivation, and this was primarily dependent on proximal GC-rich motifs. We also showed that Sp4 was expressed in Panc-1 cells, and RNA interference assays suggested that Sp4 cooperatively interacted with Sp1 and Sp3 to activate VEGF promoter constructs in these cells. However, the relative contributions of Sp proteins to VEGF expression were variable among different pancreatic cancer cell lines. Small inhibitory RNAs for Sp3, but not Sp1 or Sp4, inhibited phosphorylation of retinoblastoma protein, blocked G0/G1-->S-phase progression, and up-regulated p27 protein/promoter activity of Panc-1 cells; similar results were observed in other pancreatic cancer cells, suggesting that Sp3-dependent growth of pancreatic cancer cells is caused by inhibition of p27 expression.