White matter lesions in an unselected cohort of the elderly: astrocytic, microglial and oligodendrocyte precursor cell responsesHyperintense lesions are frequently identified in T2-weighted magnetic resonance images (MRI) in the ageing brain. The pathological correlate and pathogenesis of white matter lesions (WML) remain unclear, and it is uncertain whether pathology and pathogenesis differ in periventricular lesions (PVL) compared with deep subcortical lesions (DSCL). Therefore we characterized astrocytic, microglial and oligodendrocyte responses in PVL and DSCL and compared them with control white matter using immunohistochemistry. Both PVL and DSCL were associated with severe myelin loss and increased microglia (P = 0.069 and P < 0.001), compared with nonlesional aged brain. Clasmatodendritic astroglia, immunoreactive for the serum protein fibrinogen, were present in 67% of PVL examined and 42% of DSCL. Compared with control and DSCL cases, more MAP-2 +13 positive remyelinating oligodendrocytes (P = 0.003 and P = 0.035) and platelet-derived growth factor alpha receptor positive reactive astrocytes (P < 0.001) were present in the perilesional white matter of PVL. In addition to a role for hypoperfusion, our data suggest that dysfunction of the blood-brain barrier may also contribute to the pathogenesis of a proportion of cerebral WML associated with ageing, and that attempts at remyelination are only associated with PVL and not DSCL.
A nomenclature is described for restriction endonucleases, DNA methyltransferases, homing endonucleases and related genes and gene products. It provides explicit categories for the many different Type II enzymes now identi®ed and provides a system for naming the putative genes found by sequence analysis of microbial genomes.
There is a growing body of literature that recognizes the importance of plasma treated water (PTW) for inactivation of microorganism. However, very little attention has been paid to the role of reactive nitrogen species (RNS) in deactivation of bacteria. The aim of this study is to explore the role of RNS in bacterial killing, and to develop a plasma system with increased sterilization efficiency. To increase the concentration of reactive oxygen and nitrogen species (RONS) in solution, we have used vapor systems (DI water/HNO3 at different wt%) combined with plasma using N2 as working gas. The results show that the addition of the vapor system yields higher RONS contents. Furthermore, PTW produced by N2 + 0.5 wt% HNO3 vapor comprises a large amount of both RNS and ROS, while PTW created by N2 + H2O vapor consists of a large amount of ROS, but much less RNS. Interestingly, we observed more deactivation of E. Coli with PTW created by N2 + 0.5 wt% HNO3 vapor plasma as compared to PTW generated by the other plasma systems. This work provides new insight into the role of RNS along with ROS for deactivation of bacteria.
Melittin (MEL), a small peptide component of bee venom, has been reported to exhibit anti-cancer effects in vitro and in vivo. However, its clinical applicability is disputed because of its non-specific cytotoxicity and haemolytic activity in high treatment doses. Plasma-treated phosphate buffered saline solution (PT-PBS), a solution rich in reactive oxygen and nitrogen species (RONS) can disrupt the cell membrane integrity and induce cancer cell death through oxidative stress-mediated pathways. Thus, PT-PBS could be used in combination with MEL to facilitate its access into cancer cells and to reduce the required therapeutic dose. The aim of our study is to determine the reduction of the effective dose of MEL required to eliminate cancer cells by its combination with PT-PBS. For this purpose, we have optimised the MEL threshold concentration and tested the combined treatment of MEL and PT-PBS on A375 melanoma and MCF7 breast cancer cells, using in vitro, in ovo and in silico approaches. We investigated the cytotoxic effect of MEL and PT-PBS alone and in combination to reveal their synergistic cytological effects. To support the in vitro and in ovo experiments, we showed by computer simulations that plasma-induced oxidation of the phospholipid bilayer leads to a decrease of the free energy barrier for translocation of MEL in comparison with the non-oxidized bilayer, which also suggests a synergistic effect of MEL with plasma induced oxidation. Overall, our findings suggest that MEL in combination with PT-PBS can be a promising combinational therapy to circumvent the non-specific toxicity of MEL, which may help for clinical applicability in the future.
Glioblastoma multiforme (GBM) is the most frequent and aggressive primary malignant brain tumor in adults. Current standard radiotherapy and adjuvant chemotherapy with the alkylating agent temozolomide (TMZ) yield poor clinical outcome. This is due to the stem-like properties of tumor cells and genetic abnormalities in GBM, which contribute to resistance to TMZ and progression. In this study, we used cold atmospheric plasma (CAP) to enhance the sensitivity to TMZ through inhibition of antioxidant signaling (linked to TMZ resistance). We demonstrate that CAP indeed enhances the cytotoxicity of TMZ by targeting the antioxidant specific glutathione (GSH)/glutathione peroxidase 4 (GPX4) signaling. We optimized the threshold concentration of TMZ on five different GBM cell lines (U251, LN18, LN229, U87-MG and T98G). We combined TMZ with CAP and tested it on both TMZ-sensitive (U251, LN18 and LN229) and TMZ-resistant (U87-MG and T98G) cell lines using two-dimensional cell cultures. Subsequently, we used a three-dimensional spheroid model for the U251 (TMZ-sensitive) and U87-MG and T98G (TMZ-resistant) cells. The sensitivity of TMZ was enhanced, i.e., higher cytotoxicity and spheroid shrinkage was obtained when TMZ and CAP were administered together. We attribute the anticancer properties to the release of intracellular reactive oxygen species, through inhibiting the GSH/GPX4 antioxidant machinery, which can lead to DNA damage. Overall, our findings suggest that the combination of CAP with TMZ is a promising combination therapy to enhance the efficacy of TMZ towards the treatment of GBM spheroids.
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