Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant ...cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.
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•SIRT6 KO mice accumulate L1 cDNA, triggering interferon response via cGAS pathway•Wild-type aged mice accumulate L1 cDNA and display type I interferon response•Reverse-transcriptase inhibitors rescue type I interferon response and DNA damage•Reverse-transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice
Simon et al. show that LINE1 retrotransposon elements are derepressed in aged and progeroid mice. Cytoplasmic accumulation of LINE1 cDNA copies induced a type I interferon response, through the cGAS DNA sensing pathway, resulting in pathological inflammation. Inhibiting L1 replication significantly improved the health and lifespan of aged mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An observation of neutron-antineutron oscillations (n-nover ¯), which violate both B and B-L conservation, would constitute a scientific discovery of fundamental importance to physics and cosmology. ...A stringent upper bound on its transition rate would make an important contribution to our understanding of the baryon asymmetry of the Universe by eliminating the postsphaleron baryogenesis scenario in the light quark sector. We show that one can design an experiment using slow neutrons that in principle can reach the required sensitivity of τ_{n-nover ¯}∼10^{10} s in the oscillation time, an improvement of ∼10^{4} in the oscillation probability relative to the existing limit for free neutrons. The improved statistical accuracy needed to reach this sensitivity can be achieved by allowing both the neutron and antineutron components of the developing superposition state to coherently reflect from mirrors. We present a quantitative analysis of this scenario and show that, for sufficiently small transverse momenta of n/nover ¯ and for certain choices of nuclei for the n/nover ¯ guide material, the relative phase shift of the n and nover ¯ components upon reflection and the nover ¯ annihilation rate can be small enough to maintain sufficient coherence to benefit from the greater phase space acceptance the mirror provides.
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Targeted Radionuclide Therapy of Human Tumors Gudkov, Sergey V; Shilyagina, Natalya Yu; Vodeneev, Vladimir A ...
International Journal of Molecular Sciences,
12/2015, Volume:
17, Issue:
1
Journal Article, Book Review
Peer reviewed
Open access
Targeted radionuclide therapy is one of the most intensively developing directions of nuclear medicine. Unlike conventional external beam therapy, the targeted radionuclide therapy causes less ...collateral damage to normal tissues and allows targeted drug delivery to a clinically diagnosed neoplastic malformations, as well as metastasized cells and cellular clusters, thus providing systemic therapy of cancer. The methods of targeted radionuclide therapy are based on the use of molecular carriers of radionuclides with high affinity to antigens on the surface of tumor cells. The potential of targeted radionuclide therapy has markedly grown nowadays due to the expanded knowledge base in cancer biology, bioengineering, and radiochemistry. In this review, progress in the radionuclide therapy of hematological malignancies and approaches for treatment of solid tumors is addressed.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We investigated the dynamic properties of the organism state fluctuations along individual aging trajectories in a large longitudinal database of CBC measurements from a consumer diagnostics ...laboratory. To simplify the analysis, we used a log-linear mortality estimate from the CBC variables as a single quantitative measure of the aging process, henceforth referred to as dynamic organism state indicator (DOSI). We observed, that the age-dependent population DOSI distribution broadening could be explained by a progressive loss of physiological resilience measured by the DOSI auto-correlation time. Extrapolation of this trend suggested that DOSI recovery time and variance would simultaneously diverge at a critical point of 120 - 150 years of age corresponding to a complete loss of resilience. The observation was immediately confirmed by the independent analysis of correlation properties of intraday physical activity levels fluctuations collected by wearable devices. We conclude that the criticality resulting in the end of life is an intrinsic biological property of an organism that is independent of stress factors and signifies a fundamental or absolute limit of human lifespan.
Long-lived luminescence in the blue region was found to occur in deionized water saturated with atmospheric gases following mechanical shaking. Luminescence intensity decreased exponentially after ...the cessation of stress. During vigorous mechanical shaking, we observed gas bubbles in solution, and the liquid-gas interface area increased noticeably. At the same time, the concentration of molecular oxygen decreased, which could not be attributed to the water warming up with exposure to mechanical stress. However, deaerated water rapidly became saturated with gases following mechanical stress. The recommendation that cell culture media should be mixed after they are removed from the fridge in order to allow saturation with oxygen is probably misleading. It was shown that gases existed in water both in the form of individual molecules and nanobubbles. Mechanical stress did not influence the number or size of nanobubbles. While gas nanobubbles were absent in freshly prepared deaerated water, they appeared following exposure to mechanical stress. In addition, in mechanically treated gas-saturated water, there was seemingly an equilibrium shift towards the decomposition of carbonic acid to water and carbon dioxide. At the same time, the pH of water tended to increase immediately after mechanical stress. It was demonstrated that reactive oxygen species (ROS) form in gas-saturated water under mechanical stress (30 Hz, amplitude of 5 mm). The relative generation rate of hydrogen peroxide and of the hydroxyl radical was 1 nM/min and 0.5 nM/min, respectively. It was found that with an increase in the frequency of mechanical action (
), the rate of ROS generation increased in proportion to
. The major pathways for hydrogen peroxide generation are probably associated with the formation of singlet oxygen and its further reduction, and the alternative pathway is the formation of hydrogen peroxide as a result of hydroxyl radical recombination.
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In recent decades, studies on the functional features of Se nanoparticles (SeNP) have gained great popularity due to their high biocompatibility, stability, and pronounced selectivity. A large number ...of works prove the anticarcinogenic effect of SeNP. In this work, the molecular mechanisms regulating the cytotoxic effects of SeNP, obtained by laser ablation, were studied by the example of four human cancer cell lines: A-172 (glioblastoma), Caco-2, (colorectal adenocarcinoma), DU-145 (prostate carcinoma), MCF-7 (breast adenocarcinoma). It was found that SeNP had different concentration-dependent effects on cancer cells of the four studied human lines. SeNP at concentrations of less than 1 μg/mL had no cytotoxic effect on the studied cancer cells, with the exception of the A-172 cell line, for which 0.5 μg/mL SeNP was the minimum concentration affecting its metabolic activity. It was shown that SeNP concentration-dependently caused cancer cell apoptosis, but not necrosis. In addition, it was found that SeNP enhanced the expression of pro-apoptotic genes in almost all cancer cell lines, with the exception of Caco-2 and activated various pathways of adaptive and pro-apoptotic signaling pathways of UPR. Different effects of SeNP on the expression of ER-resident selenoproteins and selenium-containing glutathione peroxidases and thioredoxin reductases, depending on the cell line, were established. In addition, SeNP triggered Ca2+ signals in all investigated cancer cell lines. Different sensitivity of cancer cell lines to SeNP can determine the induction of the process of apoptosis in them through regulation of the Ca2+ signaling system, mechanisms of ER stress, and activation of various expression patterns of genes encoding pro-apoptotic proteins.
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The study is aimed at elucidating the effect of selenium nanoparticles (SeNPs) on the death of cells in the primary culture of mouse cerebral cortex during oxygen and glucose deprivation (OGD). A ...primary cell culture of the cerebral cortex containing neurons and astrocytes was subjected to OGD and reoxygenation to simulate cerebral ischemia-like conditions in vitro. To evaluate the neuroprotective effect of SeNPs, cortical astrocytes and neurons were incubated for 24 h with SeNPs, and then subjected to 2-h OGD, followed by 24-h reoxygenation. Vitality tests, fluorescence microscopy, and real-time PCR have shown that incubation of primary cultured neurons and astrocytes with SeNPs at concentrations of 2.5-10 µg/ml under physiological conditions has its own characteristics depending on the type of cells (astrocytes or neurons) and leads to a dose-dependent increase in apoptosis. At low concentration SeNPs (0.5 µg/ml), on the contrary, almost completely suppressed the processes of basic necrosis and apoptosis. Both high (5 µg/ml) and low (0.5 µg/ml) concentrations of SeNPs, added for 24 h to the cells of cerebral cortex, led to an increase in the expression level of genes Bcl-2, Bcl-xL, Socs3, while the expression of Bax was suppressed. Incubation of the cells with 0.5 µg/ml SeNPs led to a decrease in the expression of SelK and SelT. On the contrary, 5 µg/ml SeNPs caused an increase in the expression of SelK, SelN, SelT, SelP. In the ischemic model, after OGD/R, there was a significant death of brain cells by the type of necrosis and apoptosis. OGD/R also led to an increase in mRNA expression of the Bax, SelK, SelN, and SelT genes and suppression of the Bcl-2, Bcl-xL, Socs3, SelP genes. Pre-incubation of cell cultures with 0.5 and 2.5 µg/ml SeNPs led to almost complete inhibition of OGD/R-induced necrosis and greatly reduced apoptosis. Simultaneously with these processes we observed suppression of caspase-3 activation. We hypothesize that the mechanisms of the protective action of SeNPs involve the activation of signaling cascades recruiting nuclear factors Nrf2 and SOCS3/STAT3, as well as the activation of adaptive pathways of ESR signaling of stress arising during OGD and involving selenoproteins SelK and SelT, proteins of the Bcl-2 family ultimately leading to inactivation of caspase-3 and inhibition of apoptosis. Thus, our results demonstrate that SeNPs can act as neuroprotective agents in the treatment of ischemic brain injuries.
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Toll-like receptor 5 (TLR5) binding to bacterial flagellin activates signaling through the transcription factor NF-kB and triggers an innate immune response to the invading pathogen. To elucidate the ...structural basis and mechanistic implications of TLR5-flagellin recognition, we determined the crystal structure of zebrafish TLR5 (as a variable lymphocyte receptor hybrid protein) in complex with the D1/D2/D3 fragment of Salmonella flagellin, FliC, at 2.47 angstrom resolution. TLR5 interacts primarily with the three helices of the FliC D1 domain using its lateral side. Two TLR5-FliC 1:1 heterodimers assemble into a 2:2 tail-to-tail signaling complex that is stabilized by quaternary contacts of the FliC D1 domain with the convex surface of the opposing TLR5. The proposed signaling mechanism is supported by structure-guided mutagenesis and deletion analyses on CBLB502, a therapeutic protein derived from FliC.
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Chronic inflammation is a major cancer predisposition factor. Constitutive activation of the inflammation-driving NF-κB pathway commonly observed in cancer or developed in normal tissues because of ...persistent infections or endogenous tissue irritating factors, including products of secretion by senescent cells accumulating with age, markedly represses p53 functions. In its turn, p53 acts as a suppressor of inflammation helping to keep it within safe limits. The antagonistic relationship between p53 and NF-κB is controlled by multiple mechanisms and reflects cardinal differences in organismal responses to intrinsic and extrinsic cell stresses driven by these two transcription factors, respectively. This provides an opportunity for developing drugs to treat diseases associated with inappropriate activity of either p53 or NF-κB through targeting the opposing pathway. Several drug candidates of this kind are currently in clinical testing. These include anticancer small molecules capable of simultaneous suppression of p53 and activation of NF-κB and NF-κB-activating biologics that counteract p53-mediated pathologies associated with systemic genotoxic stresses such as acute radiation syndrome and side effects of cancer treatment.
This Article covers the influence of the concentration of gold nanoparticles on laser-induced water decomposition. It was established that addition of gold nanoparticles intensifies laser-induced ...water decomposition by almost 2 orders of magnitude. The water decomposition rate was shown to be maximal at a nanoparticle concentration around 1010 NP/mL, whereas a decrease or increase of nanoparticle concentration leads to a decrease of water decomposition rate. It was demonstrated that, if the concentration of nanoparticles in water-based colloid was less than 1010 NP/mL, laser irradiation of the colloid caused formation of molecular hydrogen, hydrogen peroxide, and molecular oxygen. If the concentration of nanoparticles exceeded 1011 NP/mL, only two products, molecular hydrogen and hydrogen peroxide, were formed. Correlations between the water decomposition rate and the main optical and acoustic parameters of optical breakdown-generated plasma were investigated. Variants of laser-induced decomposition of colloidal solutions of nanoparticles based on organic solvents (ethanol, propanol-2, butanol-2, diethyl ether) were also analyzed.
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