Skin Extracellular Matrix Breakdown Following Paclitaxel Therapy in Patients with Chemotherapy-Induced Peripheral Neuropathy.

The chemotherapeutic agent paclitaxel causes peripheral neuropathy, a dose-limiting side effect, in up to 68% of cancer patients. In this study, we investigated the impact of paclitaxel therapy on the skin of breast cancer patients with chemotherapy-induced peripheral neuropathy (CIPN), building upon previous findings in zebrafish and rodents. Comprehensive assessments, including neurological examinations and quality of life questionnaires, were conducted, followed by intraepidermal nerve fiber (IENF) density evaluations using skin punch biopsies. Additionally, RNA sequencing, immunostaining for Matrix-Metalloproteinase 13 (MMP-13), and transmission electron microscopy provided insights into molecular and ultrastructural changes in this skin. The results showed no significant difference in IENF density between the control and CIPN patients despite the presence of patient-reported CIPN symptoms. Nevertheless, the RNA sequencing and immunostaining on the skin revealed significantly upregulated MMP-13, which is known to play a key role in CIPN caused by paclitaxel therapy. Additionally, various genes involved in the regulation of the extracellular matrix, microtubules, cell cycle, and nervous system were significantly and differentially expressed. An ultrastructural examination of the skin showed changes in collagen and basement membrane structures. These findings highlight the presence of CIPN in the absence of IENF density changes and support the role of skin remodeling as a major contributor to CIPN.

Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition.

Osteosarcomas are immune-resistant and metastatic as a result of elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT). Although vitamin D has anti-cancer effects, its effectiveness and mechanism of action against osteosarcomas are poorly understood. In this study, we assessed the impact of vitamin D and its receptor (VDR) on NMD-ROS-EMT signaling in in vitro and in vivo osteosarcoma animal models. Initiation of VDR signaling facilitated the enrichment of EMT pathway genes, after which 1,25(OH)2D, the active vitamin D derivative, inhibited the EMT pathway in osteosarcoma subtypes. The ligand-bound VDR directly downregulated the EMT inducer SNAI2, differentiating highly metastatic from low metastatic subtypes and 1,25(OH)2D sensitivity. Moreover, epigenome-wide motif and putative target gene analysis revealed the VDR's integration with NMD tumorigenic and immunogenic pathways. In an autoregulatory manner, 1,25(OH)2D inhibited NMD machinery genes and upregulated NMD target genes implicated in anti-oncogenic activity, immunorecognition, and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH)2D sensitization via non-canonical SOD2 nuclear-to-mitochondrial translocalization leading to overall ROS suppression. In a mouse xenograft metastasis model, the therapeutically relevant vitamin D derivative calcipotriol inhibited osteosarcoma metastasis and tumor growth shown for the first time. Our results uncover novel osteosarcoma-inhibiting mechanisms for vitamin D and calcipotriol that may be translated to human patients.

The impact of vitamin D on cancer: A mini review.

In this review, we summarize the most recent advances in vitamin D cancer research to provide molecular clarity, as well as its translational trajectory across the cancer landscape. Vitamin D is well known for its role in regulating mineral homeostasis; however, vitamin D deficiency has also been linked to the development and progression of a number of cancer types. Recent epigenomic, transcriptomic, and proteomic studies have revealed novel vitamin D-mediated biological mechanisms that regulate cancer cell self-renewal, differentiation, proliferation, transformation, and death. Tumor microenvironmental studies have also revealed dynamic relationships between the immune system and vitamin D's anti-neoplastic properties. These findings help to explain the large number of population-based studies that show clinicopathological correlations between circulating vitamin D levels and risk of cancer development and death. The majority of evidence suggests that low circulating vitamin D levels are associated with an increased risk of cancers, whereas supplementation alone or in combination with other chemo/immunotherapeutic drugs may improve clinical outcomes even further. These promising results still necessitate further research and development into novel approaches that target vitamin D signaling and metabolic systems to improve cancer outcomes.

Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition.

Osteosarcomas are immune-resistant and metastatic as a result of elevated nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT). Although vitamin D has anti-cancer effects, its effectiveness and mechanism of action against osteosarcomas are poorly understood. In this study, we assessed the impact of vitamin D and its receptor (VDR) on the NMD-ROS-EMT signaling axis in in vitro and in vivo osteosarcoma animal models. Initiation of VDR signaling facilitated the enrichment of EMT pathway genes, after which 1,25(OH) 2 D, the active vitamin D derivative, inhibited the EMT pathway in osteosarcoma subtypes. The ligand-bound VDR directly downregulated the EMT inducer SNAI2 , differentiating highly metastatic from low metastatic subtypes and 1,25(OH) 2 D sensitivity. Moreover, epigenome-wide motif and putative target gene analysis revealed the VDR’s integration with NMD tumorigenic and immunogenic pathways. In an autoregulatory manner, 1,25(OH) 2 D inhibited NMD machinery genes and upregulated NMD target genes implicated in anti-oncogenic activity, immunorecognition, and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH) 2 D sensitization via non-canonical SOD2 nuclear-to-mitochondrial translocalization leading to overall ROS suppression. In a mouse xenograft metastasis model, the therapeutically relevant vitamin D derivative calcipotriol inhibited osteosarcoma metastasis and tumor growth shown for the first time. Our results uncover novel osteosarcoma-inhibiting mechanisms for vitamin D and calcipotriol that may be translated to human patients.

Longitudinal RNA Sequencing of Skin and DRG Neurons in Mice with Paclitaxel-Induced Peripheral Neuropathy.

Paclitaxel-induced peripheral neuropathy is a condition of nerve degeneration induced by chemotherapy, which afflicts up to 70% of treated patients. Therapeutic interventions are unavailable due to an incomplete understanding of the underlying mechanisms. We previously discovered that major physiological changes in the skin underlie paclitaxel-induced peripheral neuropathy in zebrafish and rodents. The precise molecular mechanisms are only incompletely understood. For instance, paclitaxel induces the upregulation of MMP-13, which, when inhibited, prevents axon degeneration. To better understand other gene regulatory changes induced by paclitaxel, we induced peripheral neuropathy in mice following intraperitoneal injection either with vehicle or paclitaxel every other day four times total. Skin and dorsal root ganglion neurons were collected based on distinct behavioural responses categorised as "pain onset" (d4), "maximal pain" (d7), "beginning of pain resolution" (d11), and "recovery phase" (d23) for comparative longitudinal RNA sequencing. The generated datasets validate previous discoveries and reveal additional gene expression changes that warrant further validation with the goal to aid in the development of drugs that prevent or reverse paclitaxel-induced peripheral neuropathy.

Coordinated NADPH oxidase/hydrogen peroxide functions regulate cutaneous sensory axon de- and regeneration.

Tissue wounding induces cutaneous sensory axon regeneration via hydrogen peroxide (H2O2) that is produced by the epithelial NADPH oxidase, Duox1. Sciatic nerve injury instead induces axon regeneration through neuronal uptake of the NADPH oxidase, Nox2, from macrophages. We therefore reasoned that the tissue environment in which axons are damaged stimulates distinct regenerative mechanisms. Here, we show that cutaneous axon regeneration induced by tissue wounding depends on both neuronal and keratinocyte-specific mechanisms involving H2O2 signaling. Genetic depletion of H2O2 in sensory neurons abolishes axon regeneration, whereas keratinocyte-specific H2O2 depletion promotes axonal repulsion, a phenotype mirrored in duox1 mutants. Intriguingly, cyba mutants, deficient in the essential Nox subunit, p22Phox, retain limited axon regenerative capacity but display delayed Wallerian degeneration and axonal fusion, observed so far only in invertebrates. We further show that keratinocyte-specific oxidation of the epidermal growth factor receptor (EGFR) at a conserved cysteine thiol (C797) serves as an attractive cue for regenerating axons, leading to EGFR-dependent localized epidermal matrix remodeling via the matrix-metalloproteinase, MMP-13. Therefore, wound-induced cutaneous axon de- and regeneration depend on the coordinated functions of NADPH oxidases mediating distinct processes following injury.

Reawakening GDNF's regenerative past in mice and humans.

The ability of an animal to regenerate lost tissue and body parts has obviously life-saving implications. Understanding how this ability became restricted or active in specific animal lineages will help us understand our own regeneration. According to phylogenic analysis, the glial cell line-derived neurotrophic factor (GDNF) signaling pathway, but not other family members, is conserved in axolotls, a salamander with remarkable regenerative capacity. Furthermore, comparing the pro-regenerative Spiny mouse to its less regenerative descendant, the House mouse, revealed that the GDNF signaling pathway, but not other family members, was induced in regenerating Spiny mice. According to GDNF receptor expression analysis, GDNF may promote hair follicle neogenesis - an important feature of skin regeneration - by determining the fate of dermal fibroblasts as part of new hair follicles. These findings support the idea that GDNF treatment will promote skin regeneration in humans by demonstrating the GDNF signaling pathway's ancestral and cellular nature.

Vitamin D Modulation of Mitochondrial Oxidative Metabolism and mTOR Enforces Stress Adaptations and Anticancer Responses.

The relationship between the active form of vitamin D3 (1,25-dihydroxyvitamin D, 1,25(OH)2D) and reactive oxygen species (ROS), two integral signaling molecules of the cell, is poorly understood. This is striking, given that both factors are involved in cancer cell regulation and metabolism. Mitochondria (mt) dysfunction is one of the main drivers of cancer, producing more mitochondria, higher cellular energy, and ROS that can enhance oxidative stress and stress tolerance responses. To study the effects of 1,25(OH)2D on metabolic and mt dysfunction, we used the vitamin D receptor (VDR)-sensitive MG-63 osteosarcoma cell model. Using biochemical approaches, 1,25(OH)2D decreased mt ROS levels, membrane potential (ΔΨmt), biogenesis, and translation, while enforcing endoplasmic reticulum/mitohormetic stress adaptive responses. Using a mitochondria-focused transcriptomic approach, gene set enrichment and pathway analyses show that 1,25(OH)2D lowered mt fusion/fission and oxidative phosphorylation (OXPHOS). By contrast, mitophagy, ROS defense, and epigenetic gene regulation were enhanced after 1,25(OH)2D treatment, as well as key metabolic enzymes that regulate fluxes of substrates for cellular architecture and a shift toward non-oxidative energy metabolism. ATACseq revealed putative oxi-sensitive and tumor-suppressing transcription factors that may regulate important mt functional genes such as the mTORC1 inhibitor, DDIT4/REDD1. DDIT4/REDD1 was predominantly localized to the outer mt membrane in untreated MG-63 cells yet sequestered in the cytoplasm after 1,25(OH)2D and rotenone treatments, suggesting a level of control by membrane depolarization to facilitate its cytoplasmic mTORC1 inhibitory function. The results show that 1,25(OH)2D activates distinct adaptive metabolic responses involving mitochondria to regain redox balance and control the growth of osteosarcoma cells. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

GDNF neurotrophic factor signalling determines the fate of dermal fibroblasts in wound-induced hair neogenesis and skin regeneration.

We propose that GDNF, a glial cell line-derived neurotrophic factor, can promote hair follicle neogenesis and skin regeneration after wounding by directing the fate of dermal fibroblasts. Our hypothesis is largely based on detailed GDNF and receptor analysis during skin regenerative stages, as well as the induction of GDNF receptors after wounding between the pro-regenerative spiny mouse (genus Acomys) and its less-regenerative descendant, the house mouse (Mus musculus). To characterize the GDNF-target cells, we will conduct a series of lineage-tracing experiments in conjunction with single-cell RNA and assay for transposase-accessible chromatin sequencing experiments. The heterogenetic dynamics of skin regeneration have yet to be fully defined, and this research will help to advance the fields of regenerative medicine and biology. Finally, we believe that stimulating the GDNF signalling pathway in fibroblasts from less-regenerative animals, such as humans, will promote skin regeneration, morphogenesis and scarless wound healing.

Burdens, resources, health and wellbeing of nurses working in general and specialised palliative care in Germany - results of a nationwide cross-sectional survey study.

BACKGROUND: Palliative care in Germany is divided into general (GPC) and specialised palliative care (SPC). Although palliative care will become more important in the care sector in future, there is a large knowledge gab, especially with regard to GPC. The aim of this study was to identify and compare the burdens, resources, health and wellbeing of nurses working in GPC and SPC. Such information will be helpful for developing prevention programs in order to reduce burdens and to strengthen resources of nurses. METHODS: In 2017, a nationwide cross-sectional survey was conducted. In total, 437 nurses in GPC and 1316 nurses in SPC completed a questionnaire containing parts of standardised instruments, which included parts of the Copenhagen Psychosocial Questionnaire (COPSOQ), the Patient Health Questionnaire (PHQ-2), the Resilience Scale (RS-13) Questionnaire, a single question about back pain from the health survey conducted by the Robert Koch Institute as well as self-developed questions. The differences in the variables between GPC and SPC nurses were compared. RESULTS: SPC nurses reported higher emotional demands as well as higher burdens due to nursing care and the care of relatives while GPC nurses stated higher quantitative demands, i.e. higher workload. SPC nurses more often reported organisational and social resources that were helpful in dealing with the demands of their work. Regarding health, GPC nurses stated a poorer health status and reported chronic back pain as well as a major depressive disorder more frequently than SPC nurses. Furthermore, GPC nurses reported a higher intention to leave the profession compared to SPC nurses. CONCLUSIONS: The findings of the present study indicate that SPC could be reviewed as the best practice example for nursing care in Germany. The results may be used for developing target group specific prevention programs for improving health and wellbeing of nurses taking the differences between GPC and SPC into account. Finally, interventional and longitudinal studies should be conducted in future to determine causality in the relationship of burdens, resources, health and wellbeing.

Arbeitsbedingungen von Pflegekräften in der allgemeinen Palliativversorgung in Deutschland.

Working conditions of nurses in general palliative care in Germany - A cross-sectional survey Abstract. Background: Most terminally ill people are treated within general palliative care including outpatient care, nursing homes and hospitals. In contrast, only a small number is treated within specialised palliative care. Nursing research within the framework of palliative care focuses on the latter. AIM: To investigate the working conditions of nurses working in general palliative care and to analyse potential differences between nurses in outpatient care, in nursing homes and in hospitals. METHODS: A cross-sectional survey was conducted among nurses working in outpatient care, in nursing homes and in hospitals. The questionnaire included questions about working conditions, parts of the Copenhagen Psychosocial Questionnaire and self-developed questions. Descriptive and bivariate analyses were conducted. RESULTS: 437 questionnaires entered final analyses (response rate 16.7 %). On average, nurses spend 20 % of their working time with palliative care. Every fourth nurse (n = 104) express the wish for an additional qualification in palliative care. The following demands are reported: confrontation with pain, death and dying, as well as care of relatives. 59 % (n = 249) of the nurses evaluate the quality of palliative care as good / very good. CONCLUSIONS: Nurses are faced with demands, which so far had only been a subject of discussion within the framework of the specialised palliative care. Further steps for action, in particular the additional qualification in palliative care for nurses, should be discussed.

The relationship between workload and burnout among nurses: The buffering role of personal, social and organisational resources.

Workload in the nursing profession is high, which is associated with poor health. Thus, it is important to get a proper understanding of the working situation and to analyse factors which might be able to mitigate the negative effects of such a high workload. In Germany, many people with serious or life-threatening illnesses are treated in non-specialized palliative care settings such as nursing homes, hospitals and outpatient care. The purpose of the present study was to investigate the buffering role of resources on the relationship between workload and burnout among nurses. A nationwide cross-sectional survey was applied. The questionnaire included parts of the Copenhagen Psychosocial Questionnaire (COPSOQ) (scale 'quantitative demands' measuring workload, scale 'burnout', various scales to resources), the resilience questionnaire RS-13 and single self-developed questions. Bivariate and moderator analyses were performed. Palliative care aspects, such as the 'extent of palliative care', were incorporated to the analyses as covariates. 497 nurses participated. Nurses who reported 'workplace commitment', a 'good working team' and 'recognition from supervisor' conveyed a weaker association between 'quantitative demands' and 'burnout' than those who did not. On average, nurses spend 20% of their working time with palliative care. Spending more time than this was associated with 'burnout'. The results of our study imply a buffering role of different resources on burnout. Additionally, the study reveals that the 'extent of palliative care' may have an impact on nurse burnout, and should be considered in future studies.

Health and intention to leave the profession of nursing - which individual, social and organisational resources buffer the impact of quantitative demands? A cross-sectional study.

BACKGROUND: The aim of this study was to analyse the buffering effect of individual, social and organisational resources on health and intention to leave the profession in the context of burden due to quantitative job demands. METHODS: In 2017, a cross-sectional survey was carried out anonymously among nurses in palliative care in Germany. One thousand three hundred sixteen nurses responded to the questionnaire (response rate 38.7%), which contained, amongst others, questions from the German version of the Copenhagen Psychosocial Questionnaire (COPSOQ). Moderator analyses were conducted to investigate the buffering effect of different resources on health ('self-rated health' and 'burnout') and 'intention to leave' in the context of quantitative demands. RESULTS: 'Self-rated health' was significantly buffered by the resources 'recognition through salary' (p = 0.001) and 'good working team' (p = 0.004). Additionally, buffering effects of the resources 'workplace commitment' and 'good working team' on 'burnout' (p = 0.001 and p = 0.006, respectively) as well as of the resources 'degree of freedom', 'meeting relatives after death of patients', 'recognition from supervisor' and 'possibilities for development' on 'intention to leave' (p = 0.014, p = 0.012, p = 0.007 and p = 0.036, respectively) were observed. CONCLUSIONS: The results of our study can be used to develop and implement job (re) design interventions with the goal of reducing the risk of burnout and enhancing job satisfaction among nurses in palliative care. This includes for example adequate payment, communication training and team activities or team events to strengthen the team as well as the implementation of some rituals (such as meeting relatives after the death of patients). As our study was exploratory, the results should be confirmed in further studies.

Paclitaxel-induced peripheral neuropathy is caused by epidermal ROS and mitochondrial damage through conserved MMP-13 activation.

Paclitaxel induces peripheral neuropathy as a side effect of cancer treatment. The underlying causes are unclear, but epidermal, unmyelinated axons have been shown to be the first to degenerate. We previously utilized an in vivo zebrafish model to show that the epidermal matrix-metalloproteinase 13 (MMP-13) induces degeneration of unmyelinated axons, whereas pharmacological inhibition of MMP-13 prevented axon degeneration. However, the precise functions by which MMP-13 is regulated and affects axons remained elusive. In this study, we assessed mitochondrial damage and reactive oxygen species (ROS) formation as possible inducers of MMP-13, and we analyzed MMP-13-dependent damage. We show that the small ROS, H2O2, is increased in basal keratinocytes following treatment with paclitaxel. Cytoplasmic H2O2 appears to derive, at least in part, from mitochondrial damage, leading to upregulation of MMP-13, which in turn underlies increased epidermal extracellular matrix degradation. Intriguingly, also axonal mitochondria show signs of damage, such as fusion/fission defects and vacuolation, but axons do not show increased levels of H2O2. Since MMP-13 inhibition prevents axon degeneration but does not prevent mitochondrial vacuolation, we suggest that vacuolization occurs independently of axonal damage. Finally, we show that MMP-13 dysregulation also underlies paclitaxel-induced peripheral neuropathy in mammals, indicating that epidermal mitochondrial H2O2 and its effectors could be targeted for therapeutic interventions.

Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems.

Paclitaxel (Brand name Taxol) is widely used in the treatment of common cancers like breast, ovarian and lung cancer. Although highly effective in blocking tumor progression, paclitaxel also causes peripheral neuropathy as a side effect in 60-70% of chemotherapy patients. Recent efforts by numerous labs have aimed at defining the underlying mechanisms of paclitaxel-induced peripheral neuropathy (PIPN). In vitro models using rodent dorsal root ganglion neurons, human induced pluripotent stem cells, and rodent in vivo models have revealed a number of molecular pathways affected by paclitaxel within axons of sensory neurons and within other cell types, such as the immune system and peripheral glia, as well skin. These studies revealed that paclitaxel induces altered calcium signaling, neuropeptide and growth factor release, mitochondrial damage and reactive oxygen species formation, and can activate ion channels that mediate responses to extracellular cues. Recent studies also suggest a role for the matrix-metalloproteinase 13 (MMP-13) in mediating neuropathy. These diverse changes may be secondary to paclitaxel-induced microtubule transport impairment. Human genetic studies, although still limited, also highlight the involvement of cytoskeletal changes in PIPN. Newly identified molecular targets resulting from these studies could provide the basis for the development of therapies with which to either prevent or reverse paclitaxel-induced peripheral neuropathy in chemotherapy patients.

Analyzing chemotherapy-induced peripheral neuropathy in vivo using non-mammalian animal models.

Non-mammalian models of CIPN remain relatively sparse, but the knowledge gained from the few published studies suggest that these species have great potential to serve as a discovery platform for new pathways and underlying genetic mechanisms of CIPN. These models permit large-scale genetic and pharmacological screening, and they are highly suitable for in vivo imaging. CIPN phenotypes described in rodents have been confirmed in those models, and conversely, genetic players leading to axon de- and regeneration under conditions of chemotherapy treatment identified in these non-mammalian species have been validated in rodents. Given the need for non-traditional approaches with which to identify new CIPN mechanisms, these models bear a strong potential due to the conservation of basic mechanisms by which chemotherapeutic agents induce neurotoxicity.

[Burdens and resources of nurses working in the specialist palliative care: an explorative cross-sectional study]. / Belastungen und Ressourcen von Pflegekräften der spezialisierten Palliativversorgung.

Burdens and resources of nurses working in the specialist palliative care: an explorative cross-sectional study Abstract. Background: For Germany, there are no studies so far which compare the burdens and the resources of nurses working in the specialized palliative care settings. AIM: The aim of this study was to analyse and compare burdens and resources of nurses working in palliative care wards, inpatient hospices and in specialized outpatient palliative care services. METHOD: In 2015, nurses from the referred settings in Rhineland-Palatinate were invited to complete a self-developed questionnaire on burdens and resources. Contingency tables, Kruskal-Wallis tests and regressions were calculated. RESULTS: 149 nurses (response rate: 34.5 %) participated in the survey. Nurses working in palliative care wards indicated higher values in all types of burdens than nurses working in hospices and specialized outpatient palliative care. Nurses in palliative care wards and hospices reported emotional burdens as the most stressful factor, while nurses working in specialized outpatient care services expressed the highest levels of burdens in patient-related areas. An association between the experienced amount of burdens and having acquired an additional qualification in palliative care was determined (adjusted Odds Ratio (aOR) for burden due to organizational conditions: 2.56, CI: 1.06 - 6.19; aOR for burden due to support for family members: 2.99, CI: 1.06 - 8.46). The three settings in our study differ in terms of the availability of the resources family, group supervision and additional qualifications. CONCLUSIONS: This study provides an insight into the burdens and the resources of nurses working in palliative care wards, hospices and specialized outpatient palliative care services in Rhineland-Palatinate, Germany. Future preventative measures should be tailored to the respective settings.

Oxidative stress-dependent MMP-13 activity underlies glucose neurotoxicity.

BACKGROUND: A complication of diabetes is neuropathy, a condition of sensory axon degeneration that originates in the epidermis. The mechanisms remain unknown but reactive oxygen species (ROS) have been implicated in this condition. In this study, we assessed the role of ROS and a candidate downstream target, MMP-13 in glucose-induced sensory axon degeneration in zebrafish and mice. METHODS: The effects of glucose on metabolism and sensory axon degeneration were assessed using qPCR and live imaging. ROS were analyzed using pentafluorobenzene-sulfonyl fluorescein and activation of the NF-κB stress response was determined using Tg(NF-κB:GFP) zebrafish. The role of MMP-13 and ROS in glucose-dependent axon degeneration was determined in zebrafish following treatment with the antioxidant, N-acetylcysteine and the MMP-13 inhibitor, DB04760. Neuropathic mice fed on a high-fat/high-sugar diet were treated with the MMP-13 inhibitor, CL-82198 to assess sensory recovery. RESULTS: Glucose treatment of zebrafish induced metabolic changes that resemble diabetes. Sensory axon degeneration was mediated by ROS-induced MMP-13 and prevented upon antioxidant treatment or MMP-13 inhibition. MMP-13 inhibition also reversed neuropathy in diabetic mice. CONCLUSION: We demonstrate that zebrafish are suitable to study glucose-induced neurotoxicity. Given the effects in zebrafish and mice, MMP-13 inhibition may be beneficial in the treatment of human diabetic neuropathy.

[Factors Influencing Chronic Back Pain in Care Workers Attending to The Elderly in Germany]. / Einflussfaktoren auf chronische Rückenschmerzen bei Pflegekräften in der Altenpflege in Rheinland-Pfalz.

INTRODUCTION: The present study determined the lifetime prevalence of chronic back pain in care workers attending to the needs of elderly in Rhineland-Palatinate facilities and identified potential influencing factors. METHODS: In a cross-sectional survey, 155 care workers in 5 institutions for the elderly care were interviewed with a written questionnaire. Questions from different standardised questionnaires were combined with our own questions. We complemented the examination with 2 standardized exercise tests. The data were analysed using descriptive and bivariate as well as binary logistic regression analysis. RESULTS: The nurses (83.8%) were female, and the average age was 41 years. The lifetime prevalence of chronic back pain in female care workers was 50.8%. In male elderly care workers this was 20.0%. As potential influencing factors for chronic back pain, a bad subjective state of health and a weak endurance of back muscles could be identified. CONCLUSION: The lifetime prevalence of chronic back pain was higher in the care workers taking care of the elderly than in the data of the general population. Discussed risk factors for back pain such as too many tasks not directly associated with caretaking, time pressure or too many elderly residents turned out as not significant. However, the subjective state of health and the endurance of back muscles were related to back pain. Prospective studies, which focus on physical and psychological stress, strain and resources, are needed to understand the causality of the high lifetime prevalence of chronic back pain in care workers in homes for the elderly better.

IKKα regulates human keratinocyte migration through surveillance of the redox environment.

Although the functions of H2O2 in epidermal wound repair are conserved throughout evolution, the underlying signaling mechanisms are largely unknown. In this study we used human keratinocytes (HEK001) to investigate H2O2-dependent wound repair mechanisms. Scratch wounding led to H2O2 production in two or three cell layers at the wound margin within ∼30 min and subsequent cysteine modification of proteins via sulfenylation. Intriguingly, exogenous H2O2 treatment resulted in preferential sulfenylation of keratinocytes that adopted a migratory phenotype and detached from neighboring cells, suggesting that one of the primary functions of H2O2 is to stimulate signaling factors involved in cell migration. Based on previous findings that revealed epidermal growth factor receptor (EGFR) involvement in H2O2-dependent cell migration, we analyzed oxidation of a candidate upstream target, the inhibitor of κB kinase α (IKKα; encoded by CHUK), as a mechanism of action. We show that IKKα is sulfenylated at a conserved cysteine residue in the kinase domain, which correlates with de-repression of EGF promoter activity and increased EGF expression. Thus, this indicates that IKKα promotes migration through dynamic interactions with the EGF promoter depending on the redox state within cells.