Effects of Stem Cell Factor on Hypoxia-Inducible Factor 1 Alpha Accumulation in Human Acute Myeloid Leukaemia and LAD2 Mast Cells

Stem cell factor (SCF) is a hematopoietic growth factor that exerts its activity by signalling through the tyrosine kinase receptor known as Kit or CD117. SCF-Kit signalling is crucial for the survival, proliferation and differentiation of hematopoietic cells of myeloid lineage. Furthermore, since myeloid leukaemia cells express the Kit receptor, SCF may play an important role in myeloid leukaemia progression too. However, the mechanisms of this pathophysiological effect remain unclear. Recent evidence shows that SCF triggers accumulation of the inducible alpha subunit of hypoxia-inducible factor 1 (HIF-1) in hematopoietic cells—a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability. However, it is unknown how SCF impacts on HIF-1α accumulation in human myeloid leukaemia and mast cells. Here we show that SCF induces HIF-1α accumulation in THP-1 human myeloid leukaemia cells but not in LAD2 mast cells. We demonstrated that LAD2 cells have a more robust glutathione (GSH)-dependent antioxidative system compared to THP-1 cells and are therefore protected against the actions of ROS generated in an SCF-dependent manner. BSO-induced GSH depletion led to a significant decrease in HIF-1α prolyl hydroxylase (PHD) activity in THP-1 cells and to near attenuation of it in LAD2 cells. In THP-1 cells, SCF-induced HIF-1α accumulation is controlled via ERK, PI3 kinase/PKC-δ/mTOR-dependent and to a certain extent by redox-dependent mechanisms. These results demonstrate for the first time an important cross-talk of signalling pathways associated with HIF-1 activation—an important stage of the myeloid leukaemia cell life cycle

The DRUID study: racism and self-assessed health status in an indigenous population

BackgroundThere is now considerable evidence from around the world that racism is associated with both mental and physical ill-health. However, little is known about the mediating factors between racism and ill-health. This paper investigates relationships between racism and self-assessed mental and physical health among Indigenous Australians as well as potential mediators of these relationships.MethodsA total of 164 adults in the Darwin Region Urban Indigenous Diabetes (DRUID) study completed a validated instrument assessing interpersonal racism and a separate item on discrimination-related stress. Self-assessed health status was measured using the SF-12. Stress, optimism, lack of control, social connections, cultural identity and reactions/responses to interpersonal racism were considered as mediators and moderators of the relationship between racism/discrimination and self-assessed health status.ResultsAfter adjusting for socio-demographic factors, interpersonal racism was significantly associated with the SF-12 mental (but not the physical) health component. Stress, lack of control and feeling powerless as a reaction to racism emerged as significant mediators of the relationship between racism and general mental health. Similar findings emerged for discrimination-related stress.ConclusionsRacism/discrimination is significantly associated with poor general mental health among this indigenous population. The mediating factors between racism and mental health identified in this study suggest new approaches to ameliorating the detrimental effects of racism on health. In particular, the importance of reducing racism-related stress, enhancing general levels of mastery, and minimising negative social connections in order to ameliorate the negative consequences of racism

Racism as a determinant of health: a systematic review and meta-analysis

Despite a growing body of epidemiological evidence in recent years documenting the health impacts of racism, the cumulative evidence base has yet to be synthesized in a comprehensive meta-analysis focused specifically on racism as a determinant of health. This meta-analysis reviewed the literature focusing on the relationship between reported racism and mental and physical health outcomes. Data from 293 studies reported in 333 articles published between 1983 and 2013, and conducted predominately in the U.S., were analysed using random effects models and mean weighted effect sizes. Racism was associated with poorer mental health (negative mental health: r = -.23, 95% CI [-.24,-.21], k = 227; positive mental health: r = -.13, 95% CI [-.16,-.10], k = 113), including depression, anxiety, psychological stress and various other outcomes. Racism was also associated with poorer general health (r = -.13 (95% CI [-.18,-.09], k = 30), and poorer physical health (r = -.09, 95% CI [-.12,-.06], k = 50). Moderation effects were found for some outcomes with regard to study and exposure characteristics. Effect sizes of racism on mental health were stronger in cross-sectional compared with longitudinal data and in non-representative samples compared with representative samples. Age, sex, birthplace and education level did not moderate the effects of racism on health. Ethnicity significantly moderated the effect of racism on negative mental health and physical health: the association between racism and negative mental health was significantly stronger for Asian American and Latino(a) American participants compared with African American participants, and the association between racism and physical health was significantly stronger for Latino(a) American participants compared with African American participants.<br /