NADPH oxidases of the NADPH oxidase (NOX) family are dedicated reactive oxygen species-generating enzymes that broadly and specifically regulate redox-sensitive signalling pathways that are involved ...in cancer development and progression. They act at specific cellular membranes and microdomains through the activation of oncogenes and the inactivation of tumour suppressor proteins. In this Review, we discuss primary targets and redox-linked signalling systems that are influenced by NOX-derived ROS, and the biological role of NOX oxidases in the aetiology of cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Oxidative stress has been linked to the pathogenesis of the major complications of diabetes in the kidney, the heart, the eye or the vasculature. NADPH oxidases of the Nox family are a major source ...of ROS (reactive oxygen species) and are critical mediators of redox signalling in cells from different organs afflicted by the diabetic milieu. In the present review, we provide an overview of the current knowledge related to the understanding of the role of Nox in the processes that control cell injury induced by hyperglycaemia and other predominant factors enhanced in diabetes, including the renin-angiotensin system, TGF-β (transforming growth factor-β) and AGEs (advanced glycation end-products). These observations support a critical role for Nox homologues in diabetic complications and indicate that NADPH oxidases are an important therapeutic target. Therefore the design and development of small-molecule inhibitors that selectively block Nox oxidases appears to be a reasonable approach to prevent or retard the complications of diabetes in target organs. The bioefficacy of these agents in experimental animal models is also discussed in the present review.
Oxidative stress is implicated in human diseases. Some of the oxidative pathways are harbored in the mitochondria. NAD(P)H oxidases have been identified not only in phagocytic but also in somatic ...cells. Nox4 is the most ubiquitous of these oxidases and is a major source of reactive oxygen species (ROS) in many cell types and in kidney tissue of diabetic animals. We generated specific Nox4 antibodies, and found that Nox4 localizes to mitochondria. (i) Immunoblot analysis in cultured mesangial cells and kidney cortex revealed that Nox4 is present in crude mitochondria, in mitochondria-enriched heavy fractions, and in purified mitochondria; (ii) immunofluorescence confocal microscopy also revealed that Nox4 localizes with the mitochondrial marker Mitotracker; and (iii) the mitochondrial localization prediction program MitoProt indicated that the probability score for Nox4 is identical to mitochondrial protein cytochrome c oxidase subunit IV. We also show that in purified mitochondria, siRNA-mediated knockdown of Nox4 significantly reduces NADPH oxidase activity in pure mitochondria and blocks glucose-induced mitochondrial superoxide generation. In a rat model of diabetes, mitochondrial Nox4 expression is increased in kidney cortex. Our data provide evidence that a functional Nox4 is present and regulated in mitochondria, indicating the existence of a previously undescribed source of ROS in this organelle.
The molecular mechanisms that couple glycolysis to cancer drug resistance remain unclear. Here we identify an ATP-binding motif within the NADPH oxidase isoform, NOX4, and show that ATP directly ...binds and negatively regulates NOX4 activity. We find that NOX4 localizes to the inner mitochondria membrane and that subcellular redistribution of ATP levels from the mitochondria act as an allosteric switch to activate NOX4. We provide evidence that NOX4-derived reactive oxygen species (ROS) inhibits P300/CBP-associated factor (PCAF)-dependent acetylation and lysosomal degradation of the pyruvate kinase-M2 isoform (PKM2). Finally, we show that NOX4 silencing, through PKM2, sensitizes cultured and ex vivo freshly isolated human-renal carcinoma cells to drug-induced cell death in xenograft models and ex vivo cultures. These findings highlight yet unidentified insights into the molecular events driving cancer evasive resistance and suggest modulation of ATP levels together with cytotoxic drugs could overcome drug-resistance in glycolytic cancers.
Sports participation can confer a range of physical and psychosocial benefits and, for refugee and migrant youth, may even act as a critical mediator for achieving positive settlement and engaging ...meaningfully in Australian society. This group has low participation rates however, with identified barriers including costs; discrimination and a lack of cultural sensitivity in sporting environments; lack of knowledge of mainstream sports services on the part of refugee-background settlers; inadequate access to transport; culturally determined gender norms; and family attitudes. Organisations in various sectors have devised programs and strategies for addressing these participation barriers. In many cases however, these responses appear to be ad hoc and under-theorised. This article reports findings from a qualitative exploratory study conducted in a range of settings to examine the benefits, challenges and shortcomings associated with different participation models. Interview participants were drawn from non-government organisations, local governments, schools, and sports clubs. Three distinct models of participation were identified, including short term programs for refugee-background children; ongoing programs for refugee-background children and youth; and integration into mainstream clubs. These models are discussed in terms of their relative challenges and benefits and their capacity to promote sustainable engagement and social inclusion for this population group.
Disasters are an important public health issue; however, there is scarce evidence to date on what happens when communities and populations experience more than one disaster. This scoping review ...identifies literature on the effects of multiple disasters published until Aug 2, 2021, 1425 articles were identified, of which 150 articles were included. We analysed direct and indirect public health implications of multiple disasters. Our analysis suggests that exposure to multiple disasters can affect mental health, physical health, and wellbeing, with some evidence that the potential risks of multiple disaster exposure exceed those of single disaster exposure. We also identified indirect public health implications of multiple disaster exposure, related to changes in health-care facilities, changes in public risk perception, and governmental responses to multiple disasters. We present findings on community recovery and methodological challenges to the study of multiple disasters, and directions for future research.
Hypoxia-inducible factor (HIF)-1 mediates hypoxia- and chronic kidney disease-induced fibrotic events. Here, we assessed whether HIF-1 blockade attenuates the manifestations of diabetic nephropathy ...in a type 1 diabetic animal model, OVE26. YC-1 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole, an HIF-1 inhibitor, reduced whole kidney glomerular hypertrophy, mesangial matrix expansion, extracellular matrix accumulation, and urinary albumin excretion as well as NOX4 protein expression and NADPH-dependent reactive oxygen species production, while blood glucose levels remained unchanged. The role of NOX oxidases in HIF-1-mediated extracellular matrix accumulation was explored in vitro using glomerular mesangial cells. Through a series of genetic silencing and adenoviral overexpression studies, we have defined GLUT1 as a critical downstream target of HIF-1α mediating high glucose-induced matrix expression through the NADPH oxidase isoform, NOX4. Together, our data suggest that pharmacological inhibition of HIF-1 may improve clinical manifestations of diabetic nephropathy.
Reproductive coercion (RC), generally considered a form of intimate partner violence (IPV), refers to perpetrator behaviours and actions that are intended to interfere with and control the autonomous ...decision-making of a person regarding their reproductive health. To date there are few studies that document RC as experienced by immigrant and refugee women. In this article, we explore cases of RC as described by women who were part of a larger qualitative study investigating violence against immigrant and refugee women in southern Australia. The study aimed to identify the types of RC detailed in immigrant and refugee women’s narratives, and to illustrate the contexts in which these experiences occurred. Analysis followed Baxter and Jack’s (2008) case study methodology; whereby particular “cases” are used to describe a phenomenon in context. Thirteen women from seven countries described experiences that fit definitions of RC. The cases describe various types of RC including violence during pregnancy with the intent of causing miscarriage, forced abortion, contraception sabotage and forced pregnancy. As well as intimate partners, some women described multiple perpetrators being complicit in their experience of RC, especially in regard to controlling women’s access to, and interactions with health services. More information is needed about immigrant and refugee women’s experiences of RC, and how vulnerability to multi-perpetrator violence affects health service access. In particular knowledge about how multi-perpetrator RC can affect consent processes for women who already face barriers to health care requires attention. Further research is required to address knowledge gaps about appropriate prevention and advocacy work about RC in refugee and migrant communities, and what training is needed for professionals in the family violence sector, women’s health services, women’s organisations, multicultural and ethno-specific services.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective:Although disasters are a major cause of mental health problems and typically affect large numbers of people and communities, little is known about how social structures affect mental health ...after a disaster. The authors assessed the extent to which mental health outcomes after disaster are associated with social network structures.Method:In a community-based cohort study of survivors of a major bushfire disaster, participants (N=558) were assessed for probable posttraumatic stress disorder (PTSD) and probable depression. Social networks were assessed by asking participants to nominate people with whom they felt personally close. These nominations were used to construct a social network map that showed each participant’s ties to other participants they nominated and also to other participants who nominated them. This map was then analyzed for prevailing patterns of mental health outcomes.Results:Depression risk was higher for participants who reported fewer social connections, were connected to other depressed people, or were connected to people who had left their community. PTSD risk was higher if fewer people reported being connected with the participant, if those who felt close to the participant had higher levels of property loss, or if the participant was linked to others who were themselves not interconnected. Interestingly, being connected to other people who in turn were reciprocally close to each other was associated with a lower risk of PTSD.Conclusions:These findings provide the first evidence of disorder-specific patterns in relation to one’s social connections after disaster. Depression appears to co-occur in linked individuals, whereas PTSD risk is increased with social fragmentation. These patterns underscore the need to adopt a sociocentric perspective of postdisaster mental health in order to better understand the potential for societal interventions in the wake of disaster.
Ethical complexities associated with research involving vulnerable and marginalized population groups are well recognized, while practical solutions to these challenges are somewhat less well ...described. In this article we focus on strategies for addressing interrelated practical, methodological and ethical issues which may arise during research with refugee-background participants considered vulnerable. The article draws on a study exploring the impact of social networks and support on the resettlement experiences of newly-arrived migrant youth of refugee background in Australia. Three key sets of issues are discussed: developing research processes that maximize the benefits of involvement for participants while reducing potential harms; enhancing capacities for participants to give informed consent; and adapting research methods to heighten their relevance to the circumstances of participants’ lives and enhance their engagement in the research. We argue that promoting ethical practice and methodological validity are mutually reinforcing objectives and illustrate how processes of ethical reflexivity were applied to resolve methodological challenges, promote autonomy and capacity of research participants and enhance the potential for outcomes to be rigorous and useful.
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