Up-Regulation of A1M/α1-Microglobulin in Skin by Heme and Reactive Oxygen Species Gives Protection from Oxidative Damage

During bleeding the skin is subjected to oxidative insults from free heme and radicals, generated from extracellular hemoglobin. The lipocalin α1-microglobulin (A1M) was recently shown to have reductase properties, reducing heme-proteins and other substrates, and to scavenge heme and radicals. We investigated the expression and localization of A1M in skin and the possible role of A1M in the protection of skin tissue from damage induced by heme and reactive oxygen species. Skin explants, keratinocyte cultures and purified collagen I were exposed to heme, reactive oxygen species, and/or A1M and investigated by biochemical methods and electron microscopy. The results demonstrate that A1M is localized ubiquitously in the dermal and epidermal layers, and that the A1M-gene is expressed in keratinocytes and up-regulated after exposure to heme and reactive oxygen species. A1M inhibited the heme- and reactive oxygen species-induced ultrastructural damage, up-regulation of antioxidation and cell cycle regulatory genes, and protein carbonyl formation in skin and keratinocytes. Finally, A1M bound to purified collagen I (Kd = 0.96×10−6 M) and could inhibit and repair the destruction of collagen fibrils by heme and reactive oxygen species. The results suggest that A1M may have a physiological role in protection of skin cells and matrix against oxidative damage following bleeding

“Leaps of faith”: parents' and professionals' viewpoints on preparing adolescents on the autism spectrum for leaving school

Adolescents on the autism spectrum experience difficulty transitioning from secondary school to post-school activities, often due to transition planning processes that do not meet their unique needs. This study identified parents' and professionals' viewpoints on transition planning for adolescents on the autism spectrum. Interviews were completed with nine parents of adolescents on the autism spectrum and four professionals who worked with adolescents on the autism spectrum. A constant comparison approach was used to analyse the transcripts. Four themes were identified, reflecting parents' and professionals' viewpoints on how to meet the transition planning needs of adolescents on the autism spectrum. Supporting adolescents to grasp the big picture can enhance motivation to participate in transition planning. Autism can be an ‘invisible disability’; therefore, encouraging adolescents to be active participants and to be seen in transition planning ensures their individual needs are met. Encouraging adolescents to have high aspirations in transition planning develops their self-determination. Finally, to be prepared for the transition from school may reduce the adolescent's' anxiety. Adolescents on the autism spectrum face unique challenges in transition planning. The themes identified in this study provide insight into how parents and professionals might support adolescents with these challenges

Measurement properties of tools used to assess depression in adults with and without Autism Spectrum Conditions: a systematic review

Depression is the most commonly experienced mental health condition in adults with Autism Spectrum Conditions (ASC). However, it is unclear what tools are currently being used to assess depression in ASC, or whether tools need to be adapted for this group. This systematic review therefore aimed to identify tools used to assess depression in adults with and without ASC, and then evaluate these tools for their appropriateness and measurement properties. Medline, PsychINFO and Web of Knowledge were searched for studies of depression in: a) adults with ASC, without co-morbid intellectual disability; and b) adults from the general population without co-morbid conditions. Articles examining the measurement properties of these tools were then searched for using a methodological filter in PubMed, and the quality of the evidence was evaluated using the COSMIN checklist. Twelve articles were identified which utilised three tools to assess depression in adults with ASC, but only one article which assessed the measurement properties of one of these tools was identified and thus evaluated. Sixty-five articles were identified which utilised five tools to assess depression in general population adults, and 14 articles had assessed the measurement properties of these tools. Overall, two tools were found to be robust in their measurement properties in the general population – the Beck Depression Inventory (BDI-II), and the Patient Health Questionnaire (PHQ-9). Crucially only one study was identified from the COSMIN search, which showed weak evidence in support of the measurement properties of the BDI-II in an ASC sample. Implications for effective measurement of depression in ASC are discussed

Therapeutic opportunities of alpha-1-microglobulin A study in placenta, blood, skin and eye

This thesis describes functional studies of the human protein alpha-1-microglobulin (A1M), with the aim of exploring its usefulness as a therapeutic agent in diseases where oxidative stress is a prominent feature. A1M is a 26 kDa plasma and tissue protein with reductase activity and radical- and heme-binding antioxidative functions. The research focus in this thesis has been to study the in vivo protective mechanisms against oxidative stress in tissue of placenta, blood, skin and eye. Oxidative stress in the tissues were induced by disease, surgery, culturing or addition of pro-oxidants. Damage by oxidative stress in the tissues with or without addition of A1M was analyzed by biochemical methods and electron microscopy. The results show that A1M inhibits trophoblast barrier leakage, morphological damage and gene-upregulation related to oxidative stress in placenta tissue suffering from hemoglobin-induced oxidative stress, while simultaneously stimulating upregulation of genes related to extracellular matrix re-building. Skin explants, keratinocyte cultures, and purified collagen showed similar damage when exposed to heme and reactive oxygen species. Also in the skin, the damage was inhibited by A1M and signs of repair observed. In the vitreous of eyes from patients with rhegmatogenous retinal detachment, a significant correlation between oxidative stress, A1M-concentrations and disease severity parameters was shown. A newly described retina culture method, with improved biomechanical tissue support, displayed a reduced oxidative stress and optimal mitochondrial structure. Finally, A1M was shown to inhibit and repair oxidation of low density lipoprotein of blood by the neutrophil enzyme myeloperoxidase, an early event of atherosclerosis. The results suggest that the inhibition mechanism involves binding and degradation of the essential heme-group of myeloperoxidase by A1M. Taken together, the results suggest that A1M has a potential as a therapeutic agent in some diseases associated with pathological oxidative stress

Vitreous levels of oxidative stress biomarkers and the radical-scavenger α(1)-microglobulin/A1M in human rhegmatogenous retinal detachment.

PURPOSE: To explore oxidative stress and the radical scavenger α(1)-microglobulin (A1M) in the vitreous body of human eyes with primary rhegmatogenous retinal detachment (RRD). METHODS: Levels of carbonyl groups, a marker of oxidative stress, and A1M were measured by ELISA and RIA in 14 vitreous samples derived from patients suffering from RRD, and compared with 14 samples from macula hole (MH) patients. Carbonyl group and A1M levels in RRD samples were statistically related to detachment characteristics. Analysis of total protein level, SDS-PAGE, and Western blotting of A1M was also performed. In a separate experiment, mRNA expression of A1M was measured by RT-PCR in rat retina explants. RESULTS: Levels of carbonyl groups and A1M varied widely in RRD vitreous samples, but were significantly higher in samples derived from eyes with large detachment area and macula-off status, while the presence of vitreous hemorrhage did not show any significant correlation. Compared with MH samples, RRD samples displayed significantly higher levels of A1M, whereas changes in total protein levels and carbonyl groups were not significant. Novel forms of A1M, not previously seen in plasma, were found in the vitreous body by Western blotting. Furthermore, A1M expression was seen in rat retina explants and was upregulated after 24 h of culturing. CONCLUSION: Oxidative stress is a prominent feature of human eyes with primary RRD, and is directly related to detachment severity. Affected eyes can launch a protective response in the form of the radical scavenger A1M possibly derived from the retina. The results thus indicate potential therapeutic cell loss prevention in RRD by employing the endogeneous radical scavenger A1M

A1M/α1-microglobulin is proteolytically activated by myeloperoxidase, binds its heme group and inhibits low density lipoprotein oxidation.

α1-microglobulin (A1M) is a 26 kDa plasma and tissue protein with reductase activity and radical- and heme-binding anti-oxidative functions. In addition, exposure of A1M to hemoglobin has been shown to induce proteolytic elimination of a C-terminal tetrapeptide yielding a heme-degrading form, truncated A1M (t-A1M). Myeloperoxidase (MPO), a heme-containing enzyme that catalyzes the production of free radicals and hypochlorite, is released by neutrophils during the inflammatory response to bacterial infections. MPO-induced low density lipoprotein (LDL)-oxidation in blood has been suggested as a causative factor in atherosclerosis. In this study we have hypothesized that A1M interacts with MPO in a similar mode as with hemoglobin, and is a regulator of its activity. The results show that A1M is proteolytically cleaved, with formation of t-A1M, after exposure to MPO, and that t-A1M contains iron and heme-degradation products. The reaction is dependent of pH, time and concentration of substrates and a pH-value around 7 is shown to be optimal for cleavage. Furthermore, A1M inhibits MPO- and hydrogen peroxide-induced oxidation of LDL. The results suggest that A1M may have a role as an inhibitor of the damaging effects of the neutrophil respiratory burst on bystander tissue components

Perfusion Of Human Placenta With Hemoglobin, Introduces Preeclampsia-Like Injuries That Are Prevented By Alpha 1-Microglobulin

Preeclamptic women have increased plasma levels of free fetal hemoglobin (HbF), increased gene expression of placental HbF and accumulation of free HbF in the placental vascular lumen. Free hemoglobin (Hb) is pro-inflammatory, and causes oxidative stress and tissue damage