Effect of novel porphyrazine photosensitizers on normal and tumor brain cells

Photodynamic therapy (PDT) is a clinically approved procedure for targeting tumor cells. Though several different photosensitizers have been developed, there is still much demand for novel photosensitizers with improved properties. In this study we aim to characterize the accumulation, localization and dark cytotoxicity of the novel photosensitizers developed in-house derivatives of porphyrazines (pz I-IV) in primary murine neuronal cells, as well as to identify the concentrations at which pz still effectively induces death in glioma cells yet is nontoxic to nontransformed cells. The study shows that incubation of primary neuronal and glioma cells with pz I-IV leads to their accumulation in both types of cells, but their rates of internalization, subcellular localization and dark toxicity differ significantly. Pz II was the most promising photosensitizer. It efficiently killed glioma cells while remaining nontoxic to primary neuronal cells. This opens up the possibility of evaluating pz II for experimental PDT for glioma

Dimebon Does Not Ameliorate Pathological Changes Caused by Expression of Truncated (1–120) Human Alpha-Synuclein in Dopaminergic Neurons of Transgenic Mice

Background: Recent clinical studies have demonstrated that dimebon, a drug originally designed and used as a non-selective antihistamine, ameliorates symptoms and delays progress of mild to moderate forms of Alzheimer’s and Huntington’s diseases. Although the mechanism of dimebon action on pathological processes in degenerating brain is elusive, results of studies carried out in cell cultures and animal models suggested that this drug might affect the process of pathological accumulation and aggregation of various proteins involved in the pathogenesis of proteinopathies. However, the effect of this drug on the pathology caused by overexpression and aggregation of alpha-synuclein, including Parkinson’s disease (PD), has not been assessed. Objective: To test if dimebon affected alpha-synuclein-induced pathology using a transgenic animal model. Methods: We studied the effects of chronic dimebon treatment on transgenic mice expressing the C-terminally truncated (1–120) form of human alpha-synuclein in dopaminergic neurons, a mouse model that recapitulates several biochemical, histopathological and behavioral characteristics of the early stage of PD. Results: Dimebon did not improve balance and coordination of aging transgenic animals or increase the level of striatal dopamine, nor did it prevent accumulation of alpha-synuclein in cell bodies of dopaminergic neurons. Conclusion: Our observations suggest that in the studied model of alpha-synucleinopathy dimebon has very limited effect on certain pathological alterations typical of PD and related diseases

Chlorophyll-deficient mutants of Chlamydomonas reinhardtii that accumulate magnesium protoporphyrin IX

Two Chlamydomonas reinhardtii mutants defective in CHLM encoding Mg-protoporphyrin IX methyltransferase (MgPMT) were identified. The mutants, one with a missense mutation (chlM-1) and a second mutant with a splicing defect (chlM-2), do not accumulate chlorophyll, are yellow in the dark and dim light, and their growth is inhibited at higher light intensities. They accumulate Mg-protoporphyrin IX (MgProto), the substrate of MgPMT and this may be the cause for their light sensitivity. In the dark, both mutants showed a drastic reduction in the amounts of core proteins of photosystems I and II and light-harvesting chlorophyll a/b-binding proteins. However, LHC mRNAs accumulated above wild-type levels. The accumulation of the transcripts of the LHC and other genes that were expressed at higher levels in the mutants during dark incubation was attenuated in the initial phase of light exposure. No regulatory effects of the constitutively 7- to 18-fold increased MgProto levels on gene expression were detected, supporting previous results in which MgProto and heme in Chlamydomonas were assigned roles as second messengers only in the transient activation of genes by light

Quantitative Microscopy Reveals Centromeric Chromatin Stability, Size, and Cell Cycle Mechanisms to Maintain Centromere Homeostasis

The deposited item is a book chapter and is part of the series "Centromeres and Kinetochores" published by the publisher Springer Verlag. The deposited book chapter is a post-print version and has been submitted to peer reviewing. There is no public supplementary material available for this publication. This publication hasn't any creative commons license associated.Centromeres are chromatin domains specified by nucleosomes containing the histone H3 variant, CENP-A. This unique centromeric structure is at the heart of a strong self-templating epigenetic mechanism that renders centromeres heritable. We review how specific quantitative microscopy approaches have contributed to the determination of the copy number, architecture, size, and dynamics of centromeric chromatin and its associated centromere complex and kinetochore. These efforts revealed that the key to long-term centromere maintenance is the slow turnover of CENP-A nucleosomes, a critical size of the chromatin domain and its cell cycle-coupled replication. These features come together to maintain homeostasis of a chromatin locus that directs its own epigenetic inheritance and facilitates the assembly of the mitotic kinetochore.There are no funders and sponsors indicated explicitly in the document.info:eu-repo/semantics/publishedVersio

CenH3 evolution in diploids and polyploids of three angiosperm genera

BACKGROUND: Centromeric DNA sequences alone are neither necessary nor sufficient for centromere specification. The centromere specific histone, CenH3, evolves rapidly in many species, perhaps as a coevolutionary response to rapidly evolving centromeric DNA. To gain insight into CenH3 evolution, we characterized patterns of nucleotide and protein diversity among diploids and allopolyploids within three diverse angiosperm genera, Brassica, Oryza, and Gossypium (cotton), with a focus on evidence for diversifying selection in the various domains of the CenH3 gene. In addition, we compare expression profiles and alternative splicing patterns for CenH3 in representatives of each genus. RESULTS: All three genera retain both duplicated CenH3 copies, while Brassica and Gossypium exhibit pronounced homoeologous expression level bias. Comparisons among genera reveal shared and unique aspects of CenH3 evolution, variable levels of diversifying selection in different CenH3 domains, and that alternative splicing contributes significantly to CenH3 diversity. CONCLUSIONS: Since the N terminus is subject to diversifying selection but the DNA binding domains do not appear to be, rapidly evolving centromere sequences are unlikely to be the primary driver of CenH3 sequence diversification. At present, the functional explanation for the diversity generated by both conventional protein evolution in the N terminal domain, as well as alternative splicing, remains unexplained. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12870-014-0383-3) contains supplementary material, which is available to authorized users

The effect of dithiocarbamates on neurotoxic action of 1-methyl-4- phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on mitochondrial respiration chain

The neurotoxin MPTP induces in human and in some laboratory animals parkinsonism-like neurological disorder, biochemically characterized by selective and irreversible decrease of dopamine content in striatum. The terminal step in the mechanism of neurotoxic action of MPTP is the inhibition of mitochondrial respiratory chain by pyridinium metabolite (MPP+) resulting in energy depletion and nervous cells death. Earlier it was shown that some chemical compounds, in particular diethyldithiocarbamate (DTC), can potentiate MPTP neurotoxicity. In the present work we have studied the influence of DTC derivatives on MPTP neurotoxic effect in vive and on MPP+ inhibition of mitochondrial respiration (both on intact mitochondria and on submitochondrial particles) in vitro. It was revealed that DTC alone change mitochondrial membrane state by respiratory chain uncoupling and inhibition. DTC and MPP+ mutually potentiate inhibition of electron transport as well. The combined effect of DTC plus MPP+ action on mitochondria respiration reflects the sum of reciprocally leveling and potentiating factors and can explain the order of efficacy of MPTP-neurotoxicity potentiation in vive in series of close DTC derivatives.</p