Inhibition of the neuronal NFκB pathway attenuates bortezomib-induced neuropathy in a mouse model

© 2016 Elsevier B.V. Bortezomib is a proteasome inhibitor with a remarkable antitumor activity, used in the clinic as first line treatment for multiple myeloma. One hallmark of bortezomib mechanism of action in neoplastic cells is the inhibition of nuclear factor kappa B (NFκB), a transcription factor involved in cell survival and proliferation. Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity that often requires adjustment of treatment and affects patient's prognosis and quality of life. Since disruption of NFκB pathway can also affect neuronal survival, we assessed the role of NFκB in bortezomib-induced neuropathy by using a transgenic mouse that selectively provides blockage of the NFκB pathway in neurons. Interestingly, we observed that animals with impaired NFκB activation developed significantly less severe neuropathy than wild type animals, with particular preservation of large myelinated fibers, thus suggesting that neuronal NFκB activation plays a positive role in bortezomib induced neuropathy and that bortezomib treatment might induce neuropathy by inhibiting NFκΒ in non-neuronal cell types or by targeting other signaling pathways. Therefore, inhibition of NFκB might be a promising strategy for the cotreatment of cancer and neuropathy

Promoting remyelination through cell transplantation therapies in a model of viral-induced neurodegenerative disease.

Multiple sclerosis (MS) is a central nervous system (CNS) disease characterized by chronic neuroinflammation, demyelination, and axonal damage. Infiltration of activated lymphocytes and myeloid cells are thought to be primarily responsible for white matter damage and axonopathy. Several United States Food and Drug Administration-approved therapies exist that impede activated lymphocytes from entering the CNS thereby limiting new lesion formation in patients with relapse-remitting forms of MS. However, a significant challenge within the field of MS research is to develop effective and sustained therapies that allow for axonal protection and remyelination. In recent years, there has been increasing evidence that some kinds of stem cells and their derivatives seem to be able to mute neuroinflammation as well as promote remyelination and axonal integrity. Intracranial infection of mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in immune-mediated demyelination and axonopathy, making this an excellent model to interrogate the therapeutic potential of stem cell derivatives in evoking remyelination. This review provides a succinct overview of our recent findings using intraspinal injection of mouse CNS neural progenitor cells and human neural precursors into JHMV-infected mice. JHMV-infected mice receiving these cells display extensive remyelination associated with axonal sparing. In addition, we discuss possible mechanisms associated with sustained clinical recovery. Developmental Dynamics 248:43-52, 2019. © 2018 Wiley Periodicals, Inc

European Red List of Habitats Part 1. Marine habitats

The European Red List of Habitats provides an overview of the risk of collapse (degree of endangerment) of marine, terrestrial and freshwater habitats in the European Union (EU28) and adjacent regions (EU28+), based on a consistent set of categories and criteria, and detailed data and expert knowledge from involved countries1. A total of 257 benthic marine habitat types were assessed. In total, 19% (EU28) and 18% (EU28+) of the evaluated habitats were assessed as threatened in categories Critically Endangered, Endangered and Vulnerable. An additional 12% were Near Threatened in the EU28 and 11% in the EU28+. These figures are approximately doubled if Data Deficient habitats are excluded. The percentage of threatened habitat types differs across the regional seas. The highest proportion of threatened habitats in the EU28 was found in the Mediterranean Sea (32%), followed by the North-East Atlantic (23%), the Black Sea (13%) and then the Baltic Sea (8%). There was a similar pattern in the EU28+. The most frequently cited pressures and threats were similar across the four regional seas: pollution (eutrophication), biological resource use other than agriculture or forestry (mainly fishing but also aquaculture), natural system modifications (e.g. dredging and sea defence works), urbanisation and climate change. Even for habitats where the assessment outcome was Data Deficient, the Red List assessment process has resulted in the compilation of a substantial body of useful information to support the conservation of marine habitats

Study of the role of cell specific NF-κB activation during inflammation and demyelination in neurodegenerative diseases of the central nervous system using transgenic mice

In this PhD study we investigated the contribution of the TNF-NFκB signaling axis, and particularly the differential contribution of solTNF and tmTNF ligands, to demyelination and remyelination in a cuprizone-induced (CPZ) model of MS, using selective and non-selective TNF inhibitors as well as mice deficient in TNF (Tnf-/-). We show that XPro1595, a novel dominant negative mutant of solTNF which functions as selective inhibitor of solTNF while preserving the beneficial functions of tm TNF, has the ability to cross the blood brain barrier, even in naïve mice, and can therefore be used for investigating the role of solTNF in the CNS under physiological and disease conditions. Treatment of mice with XPro1595 does not prevent the development of CPZ induced demyelination, neuroinflammation or axonal damage, but promotes remyelination and protects axons against further damage. Overall, this study stresses the critical importance of TNF-NF-κB signaling in CNS protection and repair mechanisms. Due to the complexity of this system, it has been imperative to identify the TNF ligands and receptors, as well as cellular targets of protective TNF function. Selective inhibitors of solTNF, that have the ability to cross the blood brain barrier, therefore represent promising therapeutics for the treatment of progressive MS and a wide range of other neurodegenerative diseases.Στην συγκεκριμένη διατριβή διερευνήσαμε τη συνεισφορά του μονοπατιού TNF-NFκB και ειδικότερα τις διαφορετικές επιδράσεις των tmTNF και solTNF στην απομυελίνωση και επαναμυελίνωση σε ένα ζωικό μοντέλο για την ΣΚΠ, αυτό της επαγόμενης από το cuprizone (CPZ) απομυελίνωσης. Χρησιμοποιήσαμε εκλεκτικούς και μη εκλεκτικούς αναστολείς του TNF ή επίμυες από τους οποίους απουσιάζει πλήρως ο TNF (Tnf-/-). Δείξαμε ότι το XPro1595, ένα κυρίαρχο αρνητικό ανάλογο του solTNF που τον αναστέλλει εκλεκτικά διατηρώντας τις ευεργετικές ιδιότητες του tmTNF, έχει την ικανότητα να διαπερνά τον αιματοεγκεφαλικό φραγμό ακόμη και σε υγιείς επίμυες. Η ιδιότητα αυτή του XPro1595 το καθιστά κατάλληλο εργαλείο για τη μελέτη του ρόλου του solTNF τοπικά στο ΚΝΣ υπό φυσιολογικές και παθολογικές καταστάσεις. Η χορήγηση του XPro1595 σε αγρίου τύπου επίμυες δεν παρεμπόδισε την εξέλιξη της επαγόμενης από το CPZ απομυελίνωσης, της νευροφλεγμονής, και του νευροεκφυλισμού, αλλά επήγαγε την επαναμυελίνωση και παρεμπόδισε περαιτέρω εκφυλισμό των αξόνων. Συνολικά, η μελέτη αυτή δίνει έμφαση στην σημασία της TNF-NF-κB σηματοδότησης στην προστασία και την αποκατάσταση του ΚΝΣ. Λόγω της πολυπλοκότητας του συστήματος αυτού, είναι επιτακτική η ανάγκη να προσδιοριστούν οι ακριβείς μηχανισμοί πρόσδεσης του TNF στους υποδοχείς του, καθώς και τα κύτταρα στόχοι της προστατευτικής του δράσης. Οι εκλεκτικοί αναστολείς του solTNF , που έχουν την ικανότητα να διασχίζουν τον αιματοεγκεφαλικό φραγμό, αποτελούν ελπιδοφόρα προσέγγιση για την θεραπεία της προοδευτικής ΣΚΠ και ενός ευρέως φάσματος νευροεκφυλιστικών ασθενειών

Upplevelser av cytostatikabehandling vid bröstcancer : En litteraturstudie av patografier

Bakgrund: Bröstcancer är en vanlig cancersjukdom som drabbar många människor runt om i världen och bedöms som ett globalt problem. Behandlingen består ofta av en kombination av behandlingsmetoder och många patienter behandlas med cytostatika. Behandling med cytostatika leder vanligen till många biverkningar och dessa kan uppträda från stora delar av kroppen. Varje persons upplevelse av behandlingen är unik och för att kunna bemöta människors olika behov och förbättra samt utöva en god personcentrerad vård behövs upplevelsen förstås utifrån den levda livsvärlden. Syfte: Syftet var att sammanställa kvinnors upplevelser av att genomgå cytostatikabehandling vid bröstcancer. Metod: Litteraturstudien baserades på fyra patografier och analyserades med en kvalitativ innehållsanalys enligt Graneheim och Lundman (2004). Resultat: Resultatet presenteras med tre huvudkategorier kroppsliga förändringar, emotionella förändringar samt vardagliga förändringar. Kroppsliga förändringar hade två underkategorier kroppen bryts ner och utseendet förändras. Kategorin emotionella förändringar hade två underkategorier måendet försämras och perspektiv förändras. Sista kategorin vardagliga förändringar hade tre underkategorier tillvaron förändras, bemötandet förändras och behovet av stöd ökar. Slutsats: Cytostatikabehandling vid bröstcancer leder till en stor påverkan och förändring på både individen och dennes vardag. Upplevelser av symtom skiljer sig vilket betonar vikten av att tillämpa en personcentrerad vård som ser till det unika hos varje individ. Med hjälp av livsvärldsperspektivet nås dessutom en djupare förståelse för hur cytostatikabehandlingen upplevs från ett inifrånperspektiv

Ekstrak Air J amur Ling Zhi (Ganoderma lucidum (Leysser) Karsten) Meningkatkan Persentase Sel Limfosit T CD8+ Relatif pada Tikus yang Dipejani Doxorubicin

Cancer therapy using chemotherapeutic agents associated with many adversed side effects, including immunosupressant. The use of immunostimulator together with chemotherapeutic agent (co-chemotherapy) can be the alternative method to solve that problem. Ganoderma lucidum (Ling Zhi) has been reported to have immunostimulatory activity. The aim of this research was to evaluate the immunostimulatory activity of water extract of G. Zucidum by determining the relative CD8+ T lymphocyte cell percentage in rats induced by doxorubicin. Extraction of plant material was carried out by infusion method. Sprague Dawley female rats were divided into six groups, they were doxorubicin as control, commercial product as comparing control, 100 mg/kgBW and 450 mg/kgBW extract treatment, extract control, and without treatment control. Relative CD8+ T lymphocyte cell percentages of blood samples were obtained by flow cytometry by using Multiset program. The data were analyzed statistically using paired sample t test and one way ANOVA continued by Post Hoc test. The result showed that the water extract of G. lucidum increased the relative CD8+ T lymphocyte cell percentage in rats induced by doxorubicin. The water extract of G. lucidum is promising to be developed as co-chemotherapy immunostimulatory agent.Pengobatan kanker dengan agen kemoterapi sering menimbulkan berbagai macam efek samping yang merugikan, termasuk imunosupresi. Penggunaan imunostimulan bersama dengan agen kemoterapi (ko-kemoterapi) dapat menjadi alternatif untuk mengatasinya. Ganoderma lucidum (jamur Ling Zhi) dilaporkan menunjukkan aktivitas imunostimulan. Penelitian ini bertujuan untuk mengevaluasi aktivitas imunostimulan ekstrak air G. lucidum dengan menentukan persentase sel limfosit T CD8+ relatif pada hewan uji yang dipejani doxorubicin. Ekstraksi bahan tanaman dilakukan dengan metode infusa. Tikus betina galur Sprague Dawley dibagi dalam 6 kelompok, yaitu kelompok kontrol doxorubicin, kontrol pembanding produk komersil, perlakuan ekstrak dosis 100 mg/kgBB dan 450 mg/kgBB, kontrol ekstrak, dan kontrol tanpa perlakuan. Persentase sel limfosit T CD8+ relatif dari sampel darah diukur dengan flow cytometry menggunakan program Multiset. Data dianalisis secara statistik dengan t test dan one way ANOVA, dilanjutkan Post Hoc test. Hasil penelitian menunjukkan bahwa ekstrak air G. lucidum mampu meningkatkan persentase sel limfosit T CD8+ relatif pada tikus yang dipejani doxorubicin. Ekstrak air G. lucidum menjanjikan untuk dikembangkan sebagai agen imunostimulan ko-kemoterapi