The Predominant Protective Effect of Tianeptine Over Other Antidepressants in Models of Neuronal Apoptosis: The Effect Blocked by Inhibitors of MAPK/ERK1/2 and PI3-K/Akt Pathways

Tianeptine (Tian) possesses neuroprotective potential, however, little is known about the effect of this drug in models of neuronal apoptosis. In the present study, we aimed (1) to compare the neuroprotective capacities of some antidepressants (ADs) in the models of staurosporine (St)- and doxorubicin (Dox)-evoked cell death, activating the intracellular and the extracellular apoptotic pathway, respectively; (2) to identify the Tian-modulated steps underlying its neuroprotective action; (3) to test the effect of various ADs against Dox-evoked cell damage in glia cells. Primary neuronal and glia cell cultures and retinoic acid-differentiated human neuroblastoma SH-SY5Y (RA-SH-SY5Y) cells were co-treated with imipramine, fluoxetine, citalopram, reboxetine, mirtazapine or Tian and St or Dox. The data showed the predominant neuroprotective effect of Tian over other tested ADs against St- and Dox-induced cell damage in primary neurons and in RA-SH-SY5Y cells. This effect was shown to be caspase-3-independent but connected with attenuation of DNA fragmentation. Moreover, neuroprotection elicited by Tian was blocked by pharmacological inhibitors of MAPK/ERK1/2 and PI3-K/Akt signaling pathways as well by inhibitor of necroptosis, necrostatin-1. Interestingly, the protective effects of all tested ADs were demonstrated in primary glia cells against the Dox-evoked cell damage. The obtained data suggests the glial cells as a common target for protective action of various ADs whereas in relation to neuronal cells only Tian possesses such properties, at least against St- and Dox-induced cell damage. Moreover, this neuroprotective effect of Tian is caspase-3-independent and engages the regulation of survival pathways (MAPK/ERK1/2 and PI3-K/Akt). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12640-013-9430-3) contains supplementary material, which is available to authorized users

Pan-Cancer Survey of Tumor Mass Dormancy and Underlying Mutational Processes

Tumor mass dormancy is the key intermediate step between immune surveillance and cancer progression, yet due to its transitory nature it has been difficult to capture and characterize. Little is understood of its prevalence across cancer types and of the mutational background that may favor such a state. While this balance is finely tuned internally by the equilibrium between cell proliferation and cell death, the main external factors contributing to tumor mass dormancy are immunological and angiogenic. To understand the genomic and cellular context in which tumor mass dormancy may develop, we comprehensively profiled signals of immune and angiogenic dormancy in 9,631 cancers from the Cancer Genome Atlas and linked them to tumor mutagenesis. We find evidence for immunological and angiogenic dormancy-like signals in 16.5% of bulk sequenced tumors, with a frequency of up to 33% in certain tissues. Mutations in the CASP8 and HRAS oncogenes were positively selected in dormant tumors, suggesting an evolutionary pressure for controlling cell growth/apoptosis signals. By surveying the mutational damage patterns left in the genome by known cancer risk factors, we found that aging-induced mutations were relatively depleted in these tumors, while patterns of smoking and defective base excision repair were linked with increased tumor mass dormancy. Furthermore, we identified a link between APOBEC mutagenesis and dormancy, which comes in conjunction with immune exhaustion and may partly depend on the expression of the angiogenesis regulator PLG as well as interferon and chemokine signals. Tumor mass dormancy also appeared to be impaired in hypoxic conditions in the majority of cancers. The microenvironment of dormant cancers was enriched in cytotoxic and regulatory T cells, as expected, but also in macrophages and showed a reduction in inflammatory Th17 signals. Finally, tumor mass dormancy was linked with improved patient survival outcomes. Our analysis sheds light onto the complex interplay between dormancy, exhaustion, APOBEC activity and hypoxia, and sets directions for future mechanistic explorations

Southern African Large Telescope Spectroscopy of BL Lacs for the CTA project

In the last two decades, very-high-energy gamma-ray astronomy has reached maturity: over 200 sources have been detected, both Galactic and extragalactic, by ground-based experiments. At present, Active Galactic Nuclei (AGN) make up about 40% of the more than 200 sources detected at very high energies with ground-based telescopes, the majority of which are blazars, i.e. their jets are closely aligned with the line of sight to Earth and three quarters of which are classified as high-frequency peaked BL Lac objects. One challenge to studies of the cosmological evolution of BL Lacs is the difficulty of obtaining redshifts from their nearly featureless, continuum-dominated spectra. It is expected that a significant fraction of the AGN to be detected with the future Cherenkov Telescope Array (CTA) observatory will have no spectroscopic redshifts, compromising the reliability of BL Lac population studies, particularly of their cosmic evolution. We started an effort in 2019 to measure the redshifts of a large fraction of the AGN that are likely to be detected with CTA, using the Southern African Large Telescope (SALT). In this contribution, we present two results from an on-going SALT program focused on the determination of BL Lac object redshifts that will be relevant for the CTA observatory

Finasteride inhibits the progesterone-induced spike-wave discharges in a genetic model of absence epilepsy

Item does not contain fulltextPreviously, it was found that progesterone aggravates spike-wave discharges (SWD) in WAG/Rij rats in a nongenomic way. In order to elucidate whether the regulatory effect of progesterone depends on its conversion to allopregnanolone, the effect of finasteride, a 5alpha-reductase inhibitor, on progesterone-induced increase in SWD was studied in the same model for absence epilepsy. Progesterone (10 and 20 mg/kg ip) dose-dependently increased the number of SWD (by 54% and 97%, respectively) during the first hour postinjection. Pretreatment of rats with finasteride (50 mg/kg sc) blocked the progesterone-induced enhancement of SWD. Finasteride alone had no effect on the number of SWD, up to 24 h following its administration. It is concluded that finasteride blocked the progesterone-induced increase in SWD, which indicates that this action of progesterone is mediated by its neuroactive metabolite allopregnanolone. (C) 2003 Elsevier Inc. All tights reserved

Progesterone-induced spike-wave discharges are inhibited by finasteride

Item does not contain fulltextPreviously, it was found that progesterone aggravates spike-wave discharges (SWD) in WAG/Rij rats in a non-genomic way. In order to elucidate whether the regulatory effect of progesterone depends on its conversion to allopregnanolone, the effect of finasteride, a 5?-reductase inhibitor, on progesterone-induced increase in SWD was studied in the same model for absence epilepsy. Progesterone (10 and 20 mg/kg, i.p.) dose-dependently increased the number of SWD (by 54 and 97 %, respectively) during the first hour post-injection. Pretreatment of rats with finasteride (50 mg/kg, s.c.) blocked the progesterone-induced enhancement of SWD. Finasteride alone had no effect on the number of SWD, up to 24 hours following its administration. It is concluded that finasteride blocked the progesterone-induced increase in SWD, which indicates that this action of progesterone is mediated by its neuroactive metabolite allopregnanolone