Theo Nell

Differential induction of apoptosis and inhibition of the PI3-kinase pathway by saturated, monounsaturated and polyunsaturated fatty acids in a colon cancer cell model

Although numerous studies have shown that certain long chain fatty acids can induce apoptosis in cancer cells, the molecular mechanisms for this phenomenon are still poorly elucidated. The phosphoinositide 3-kinase (PI3-kinase) signaling pathway plays a pivotal role in the regulation of cell growth and can also contribute to tumorigenesis and cancer progression. The aims of the present study were three fold: (i) to investigate the potential chemopreventative/antiproliferative effect of various fatty acids in colon cancer cells (CaCo-2 cells) and normal colon epithelium cells (NCM460 cells); (ii) to investigate the mechanisms by which incubation with various fatty acids influences the PI3-kinase pathway in CaCo-2 cells; and (iii) to evaluate apoptosis in our cell model. Although all the fatty acids increased the viability of normal (NCM460) cells, only docosahexaenoic acid (DHA) significantly reduced cell viability and induced apoptosis in the cancer (CaCo-2) cells. Our results indicate that DHA is an effective chemotherapeutic agent to induce apoptosis in cancer cells and that this effect is mediated by the PI3-kinase signaling pathway.

Autophagy—A free meal in sickness-associated anorexia

ABSTRACT Activation of the immune system is metabolically costly, yet a hallmark of an infection is a reduction in appetite with a subsequent reduction in metabolite provision. What is the functional value of decreasing nutrient intake when an infection imposes large demands on metabolic parameters? Here, we propose that sickness-associated anorexia (SAA) upregulates the ancient process of autophagy systemically, thereby profoundly controlling not only immune- but also nonimmune-competent cells. This allows an advanced impact on the resolution of an infection through direct pathogen killing, enhancement of epitope presentation and the contribution toward the clearance of noxious factors. By rendering a ‘free meal,’ autophagy is thus most fundamentally harnessed during an anorexic response in order to promote both host tolerance and resistance. These findings strongly suggest a reassessment of numerous SAA-related clinical applications and a re-evaluation of current efforts in patient care.

Sickness-associated anorexia : mother nature’s idea of immunonutrition?

During an infection, expansion of immune cells, assembly of antibodies, and the induction of a febrile response collectively place continual metabolic strain on the host. These considerations also provide a rationale for nutritional support in critically ill patients. Yet, results from clinical and preclinical studies indicate that aggressive nutritional support does not always benefit patients and may occasionally be detrimental. Moreover, both vertebrates and invertebrates exhibit a decrease in appetite during an infection, indicating that such sickness-associated anorexia (SAA) is evolutionarily conserved. It also suggests that SAA performs a vital function during an infection. We review evidence signifying that SAA may present a mechanism by which autophagic flux is upregulated systemically. A decrease in serum amino acids during an infection promotes autophagy not only in immune cells, but also in nonimmune cells. Similarly, bile acids reabsorbed postprandially inhibit hepatic autophagy by binding to farnesoid X receptors, indicating that SAA may be an attempt to conserve autophagy. In addition, augmented autophagic responses may play a critical role in clearing pathogens (xenophagy), in the presentation of epitopes in nonprovisional antigen presenting cells and the removal of damaged proteins and organelles. Collectively, these observations suggest that some patients might benefit from permissive underfeeding.

The prevalence of the metabolic syndrome in a farm worker community in the Boland district, South Africa

BackgroundIn South Africa, not much is known about MetS in farm working communities. This study aimed to describe the prevalence of the MetS in a farm working population from the Boland winelands district of the Western Cape, South Africa.MethodsA cross-sectional study was followed among farm workers (aged 20–60 years) from surrounding wine estates. The questionnaires used described socio-demographic status, ethnic background, alcohol consumption, smoking, exercise and daily medication. Anthropometric assessments were performed and blood pressure measurements taken prior to blood sampling for serum insulin, glucose and fasting lipogram profiles.ResultsThe prevalence of the MetS was higher in women (46.3 vs 29.3%). Both men and women in the MetS group had a significantly higher waist circumferences (WC; p < 0.001 for both), whilst higher glucose levels were only significantly higher in the women (p < 0.001). Correlations showed significant differences between body mass index (BMI), WC and waist to hip ratio (W:H) and the different MetS risk factors.ConclusionsThe female population in this study showed higher prevalence rates for the individual risk factors and the MetS overall. There is an urgent need to develop culturally sensitive health promotion programs addressing risk factors for metabolic syndrome among farm workers.

Domesticating cancer : an evolutionary strategy in the war on cancer

Since cancer shares the same molecular machinery as the host, most therapeutic interventions that aim to target cancer would inadvertently also adversely affect the host. In addition, cancer continuously evolves, streamlining its host-derived genome for a new single-celled existence. In particular, short-term clinical success observed with most antineoplastic therapies directly relate to the fact that cancer is constantly evolving. However, the clonal evolution of cancer occasionally also render cancer cells uniquely susceptible to therapeutic interventions, as is exemplified by the clinical relevance of synthetic lethality. Synthetic lethality describes a situation where the simultaneous loss of function in two genes results in lethality, but where a loss of function in either single gene is tolerated. This observation suggests that the evolution of cancer, usually seen as a major clinical challenge, may also afford a key opportunity in lowering on-target toxicities accosted with chemotherapy. As an example, by subjecting cancer to specific selection regimes, cancer can in effect be placed on evolutionary trajectories leading to the development of “targetable” phenotypes such as synthetic lethal interactions. However, such a selection regime would have to overcome a range of obstacles such as on-target toxicity and the selection of an evolvable trait. Since the majority of cancer evolution manifests as a loss of function, we suggest that the induction of auxotrophic phenotypes (i.e., where an organism lose the ability to synthesize specific organic compounds required for growth and thus become dependent on it from dietary sources) may represent an attractive therapeutic option. As an example, animals can obtain vitamin C either by de novo synthesis or from their diet. However, since the maintenance of synthetic pathways is costly, such pathways are often lost if no longer necessary, resulting in the organism being auxotrophic toward the dietary compound. Similarly, increasing the maintenance cost of a redundant pathway in cancer cells is likely to select for clones that have lost such a redundant pathway. Inhibition of a pathway, while supporting the activity of a compensating pathway, may thus induce auxotrophism in cancer cells but not in genomic stable host cells.

Cancer tolerance, resistance, pathogenicity and virulence: deconstructing the disease state

Immunologists have recently taken note of the fact that a host not only resists infection, but also exhibits a capacity to manage the pathology associated with such infection - a concept referred to as tolerance. Here we explore how the tolerance/resistance (T/R) framework can be implemented within an oncological context and explore a number of implications. In particular, the T/R framework distinguishes between pathology manifesting from extensive tumor burden, versus cancers intrinsically expressing a more pathogenic phenotype. Consequently, the T/R framework provides novel methodology in studying the nature of cancer pathology and for marker identification. Additionally, this framework may aid in redefining the therapeutic end point under suitable circumstances: establishing cancer as a chronic, manageable disease.