Browsing by Author "Lang, Dirk"

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    Effect of maternal separation on stress-related proteins measured in a 6-hydroxydopamine rat model of Parkinson’s disease
    (2014) Tomes, Hayley Sarah; Russell, Vivienne A; Lang, Dirk
    The developing central nervous system is especially vulnerable and research has implicated early life stress (ELS) as a potentiating factor to cell death in a rat model of Parkinson’s disease (PD). PD is a movement disorder resulting from the selective degeneration of dopamine neurons in the substantia nigra pars compacta (SNc). Dopamine neurons have been shown to exhibit mitochondrial dysfunction, oxidative stress and misfolded protein aggregation in patients with PD. Since ELS has been shown to negatively affect the nigrostriatal pathway and mitochondrial function, developmental stress may create a vulnerable microenvironment which results in a greater rate of cell death during the development of PD. Many proteins play a role in establishing a positive microenvironment that is neuroprotective, and may be good candidates for the mechanism by which ELS potentiates neurodegeneration in the PD rat model. This study aimed to investigate whether the finding that ELS increases neuronal susceptibility to 6-hydroxydopamine(6-OHDA)-induced degeneration of dopamine neurons occurs through dysregulation of the oxidative stress-related heat shock protein (HSP)25, or plasticity-related proteins, chondroitin sulphate proteoglycans (CSPGs) or Nogo-A.
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    Exogenous Vimentin Supplementation Transiently Affects Early Steps during HPV16 Pseudovirus Infection
    (2021-12-10) Carse, Sinead; Lang, Dirk; Katz, Arieh A; Schäfer, Georgia
    Understanding and modulating the early steps in oncogenic Human Papillomavirus (HPV) infection has great cancer-preventative potential, as this virus is the etiological agent of virtually all cervical cancer cases and is associated with many other anogenital and oropharyngeal cancers. Previous work from our laboratory has identified cell-surface-expressed vimentin as a novel HPV16 pseudovirus (HPV16-PsVs)-binding molecule modulating its infectious potential. To further explore its mode of inhibiting HPV16-PsVs internalisation, we supplemented it with exogenous recombinant human vimentin and show that only the globular form of the molecule (as opposed to the filamentous form) inhibited HPV16-PsVs internalisation in vitro. Further, this inhibitory effect was only transient and not sustained over prolonged incubation times, as demonstrated in vitro and in vivo, possibly due to full-entry molecule engagement by the virions once saturation levels have been reached. The vimentin-mediated delay of HPV16-PsVs internalisation could be narrowed down to affecting multiple steps during the virus’ interaction with the host cell and was found to affect both heparan sulphate proteoglycan (HSPG) binding as well as the subsequent entry receptor complex engagement. Interestingly, decreased pseudovirus internalisation (but not infection) in the presence of vimentin was also demonstrated for oncogenic HPV types 18, 31 and 45. Together, these data demonstrate the potential of vimentin as a modulator of HPV infection which can be used as a tool to study early mechanisms in infectious internalisation. However, further refinement is needed with regard to vimentin’s stabilisation and formulation before its development as an alternative prophylactic means.
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    St John's Wort (Hypericum perforatum L.) photomedicine: hypericin-photodynamic therapy induces metastatic melanoma cell death
    (Public Library of Science, 2014) Kleemann, Britta; Loos, Benjamin; Scriba, Thomas J; Lang, Dirk; Davids, Lester M
    Hypericin, an extract from St John's Wort ( Hypericum perforatum L. ), is a promising photosensitizer in the context of clinical photodynamic therapy due to its excellent photosensitizing properties and tumoritropic characteristics. Hypericin-PDT induced cytotoxicity elicits tumor cell death by various mechanisms including apoptosis, necrosis and autophagy-related cell death. However, limited reports on the efficacy of this photomedicine for the treatment of melanoma have been published. Melanoma is a highly aggressive tumor due to its metastasizing potential and resistance to conventional cancer therapies. The aim of this study was to investigate the response mechanisms of melanoma cells to hypericin-PDT in an in vitro tissue culture model. Hypericin was taken up by all melanoma cells and partially co-localized to the endoplasmic reticulum, mitochondria, lysosomes and melanosomes, but not the nucleus. Light activation of hypericin induced a rapid, extensive modification of the tubular mitochondrial network into a beaded appearance, loss of structural details of the endoplasmic reticulum and concomitant loss of hypericin co-localization. Surprisingly the opposite was found for lysosomal-related organelles, suggesting that the melanoma cells may be using these intracellular organelles for hypericin-PDT resistance. In line with this speculation we found an increase in cellular granularity, suggesting an increase in pigmentation levels in response to hypericin-PDT. Pigmentation in melanoma is related to a melanocyte-specific organelle, the melanosome, which has recently been implicated in drug trapping, chemotherapy and hypericin-PDT resistance. However, hypericin-PDT was effective in killing both unpigmented (A375 and 501mel) and pigmented (UCT Mel-1) melanoma cells by specific mechanisms involving the externalization of phosphatidylserines, cell shrinkage and loss of cell membrane integrity. In addition, this treatment resulted in extrinsic (A375) and intrinsic (UCT Mel-1) caspase-dependent apoptotic modes of cell death, as well as a caspase-independent apoptotic mode that did not involve apoptosis-inducing factor (501 mel). Further research is needed to shed more light on these mechanisms.