scholarly journals The Two Faces of Ascorbate: Prooxidant Activity and Radio-Sensitisation

2021 ◽  
Author(s):  
◽  
Georgia Carson
Keyword(s):  
Dna Damage ◽  
Alternative Therapy ◽  
High Dose ◽  
Intravenous Injections ◽  
Unique Nature ◽  
Therapy Option ◽  
The Brain

<p>Although not recommended by mainstream oncologists, intravenous injections of pharmacological ascorbate are currently an alternative therapy option for cancer patients. Research has not yet determined whether high-dose ascorbate interacts favourably with radiation therapy to increase DNA damage, and therefore cell death in cancer. Some studies suggest that ascorbate can act as a prooxidant and increase the cytotoxic effect of irradiation in vitro. Glioblastoma multiforme (GBM) is a primary brain astrocytoma that is highly therapy resistant, so patients would be advantaged if ascorbate radiosensitised their cancer.  In this investigation, flow cytometry and single cell gel electrophoresis (comet tail assay) were used to measure three indicators of DNA damage in GBM cells in response to ascorbate and irradiation, and were contrasted with immunofluorescence-revealed DNA damage from an intracranial mouse model of GBM.   The pro-oxidant, radiosensitisation role of ascorbate was confirmed, as measured by H2AX, 8OHdG, and DSBs in vitro. With all three of these markers of DNA damage, combinations of irradiation and ascorbate had increased damage compared with individual treatments. However preliminary in vivo evidence indicates that increased DNA damage did not occur in an animal model of GBM, and in fact ascorbate may protect from DNA damage in an in vivo context.  These findings complement previous results from our lab, and serve to fill in gaps in knowledge specifically around the DNA damaging effects of ascorbate. The unique nature of the brain environment, as enclosed by the blood brain barrier, prevents translation of data from other non-brain cancer studies, as such, this investigation also contributes to the exploration of a much needed avenue of research. Considering the context of ascorbate treatment as a potentially harmful currently used adjuvant, it is imperative to confirm or disprove its efficacy in a clinically relevant environment.</p>

scholarly journals The Two Faces of Ascorbate: Prooxidant Activity and Radio-Sensitisation

2021 ◽  
Author(s):  
◽  
Georgia Carson
Keyword(s):  
Dna Damage ◽  
Alternative Therapy ◽  
High Dose ◽  
Intravenous Injections ◽  
Unique Nature ◽  
Therapy Option ◽  
The Brain

<p>Although not recommended by mainstream oncologists, intravenous injections of pharmacological ascorbate are currently an alternative therapy option for cancer patients. Research has not yet determined whether high-dose ascorbate interacts favourably with radiation therapy to increase DNA damage, and therefore cell death in cancer. Some studies suggest that ascorbate can act as a prooxidant and increase the cytotoxic effect of irradiation in vitro. Glioblastoma multiforme (GBM) is a primary brain astrocytoma that is highly therapy resistant, so patients would be advantaged if ascorbate radiosensitised their cancer.  In this investigation, flow cytometry and single cell gel electrophoresis (comet tail assay) were used to measure three indicators of DNA damage in GBM cells in response to ascorbate and irradiation, and were contrasted with immunofluorescence-revealed DNA damage from an intracranial mouse model of GBM.   The pro-oxidant, radiosensitisation role of ascorbate was confirmed, as measured by H2AX, 8OHdG, and DSBs in vitro. With all three of these markers of DNA damage, combinations of irradiation and ascorbate had increased damage compared with individual treatments. However preliminary in vivo evidence indicates that increased DNA damage did not occur in an animal model of GBM, and in fact ascorbate may protect from DNA damage in an in vivo context.  These findings complement previous results from our lab, and serve to fill in gaps in knowledge specifically around the DNA damaging effects of ascorbate. The unique nature of the brain environment, as enclosed by the blood brain barrier, prevents translation of data from other non-brain cancer studies, as such, this investigation also contributes to the exploration of a much needed avenue of research. Considering the context of ascorbate treatment as a potentially harmful currently used adjuvant, it is imperative to confirm or disprove its efficacy in a clinically relevant environment.</p>

scholarly journals LINC-PINT impedes DNA repair and enhances radiotherapeutic response by targeting DNA-PKcs in nasopharyngeal cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
You-hong Wang ◽  
Zhen Guo ◽  
Liang An ◽  
Yong Zhou ◽  
Heng Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Cancer ◽  
Noncoding Rnas ◽  
Dependent Protein Kinase ◽  
Damage Repair ◽  
Dependent Protein ◽  
Cancer Tissues

AbstractRadioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

The use of siRNA as a pharmacological tool to assess a role for the transcription factor NF-IL6 in the brain under in vitro and in vivo conditions during LPS-induced inflammatory stimulation

2017 ◽  
Vol 28 (6) ◽  
Author(s):  
Jelena Damm ◽  
Joachim Roth ◽  
Rüdiger Gerstberger ◽  
Christoph Rummel
Keyword(s):  
Transcription Factor ◽  
Brain Cells ◽  
Nuclear Factor ◽  
Si Rna ◽  
The Brain ◽  
Deficient Mice ◽  
Transcription Factor Nuclear Factor

AbstractBackground:Studies with NF-IL6-deficient mice indicate that this transcription factor plays a dual role during systemic inflammation with pro- and anti-inflammatory capacities. Here, we aimed to characterize the role of NF-IL6 specifically within the brain.Methods:In this study, we tested the capacity of short interfering (si) RNA to silence the inflammatory transcription factor nuclear factor-interleukin 6 (NF-IL6) in brain cells underResults:In cells of a mixed neuronal and glial primary culture from the ratConclusions:This approach was, thus, not suitable to characterize the role NF-IL6 in the brain

scholarly journals SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair

2019 ◽  
Vol 5 (3) ◽  
pp. eaav1118 ◽  
Author(s):  
Ming Tang ◽  
Zhiming Li ◽  
Chaohua Zhang ◽  
Xiaopeng Lu ◽  
Bo Tu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Repair ◽  
Class Iii ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Repair ◽  
Damage Response ◽  
Late Stages

The activation of ataxia-telangiectasia mutated (ATM) upon DNA damage involves a cascade of reactions, including acetylation by TIP60 and autophosphorylation. However, how ATM is progressively deactivated after completing DNA damage repair remains obscure. Here, we report that sirtuin 7 (SIRT7)–mediated deacetylation is essential for dephosphorylation and deactivation of ATM. We show that SIRT7, a class III histone deacetylase, interacts with and deacetylates ATM in vitro and in vivo. In response to DNA damage, SIRT7 is mobilized onto chromatin and deacetylates ATM during the late stages of DNA damage response, when ATM is being gradually deactivated. Deacetylation of ATM by SIRT7 is prerequisite for its dephosphorylation by its phosphatase WIP1. Consequently, depletion of SIRT7 or acetylation-mimic mutation of ATM induces persistent ATM phosphorylation and activation, thus leading to impaired DNA damage repair. Together, our findings reveal a previously unidentified role of SIRT7 in regulating ATM activity and DNA damage repair.

scholarly journals DR5 Knockout Mice Are Compromised in Radiation-Induced Apoptosis

2005 ◽  
Vol 25 (5) ◽  
pp. 2000-2013 ◽  
Author(s):  
Niklas Finnberg ◽  
Joshua J. Gruber ◽  
Peiwen Fei ◽  
Dorothea Rudolph ◽  
Anka Bric ◽  
...  
Keyword(s):  
Cell Death ◽  
Null Mouse ◽  
Organ Specific ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
The Brain ◽  
Necrosis Factor

ABSTRACT DR5 (also called TRAIL receptor 2 and KILLER) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called TRAIL and Apo2 ligand). DR5 is a transcriptional target of p53, and its overexpression induces cell death in vitro. However, the in vivo biology of DR5 has remained largely unexplored. To better understand the role of DR5 in development and in adult tissues, we have created a knockout mouse lacking DR5. This mouse is viable and develops normally with the exception of having an enlarged thymus. We show that DR5 is not expressed in developing embryos but is present in the decidua and chorion early in development. DR5-null mouse embryo fibroblasts expressing E1A are resistant to treatment with TRAIL, suggesting that DR5 may be the primary proapoptotic receptor for TRAIL in the mouse. When exposed to ionizing radiation, DR5-null tissues exhibit reduced amounts of apoptosis compared to wild-type thymus, spleen, Peyer's patches, and the white matter of the brain. In the ileum, colon, and stomach, DR5 deficiency was associated with a subtle phenotype of radiation-induced cell death. These results indicate that DR5 has a limited role during embryogenesis and early stages of development but plays an organ-specific role in the response to DNA-damaging stimuli.

Role of GADD153 (growth arrest- and DNA damage-inducible gene 153) in vascular smooth muscle cell apoptosis

2001 ◽  
Vol 100 (3) ◽  
pp. 275-281 ◽  
Author(s):  
Michiya IGASE ◽  
Takafumi OKURA ◽  
Michitsugu NAKAMURA ◽  
Yasunori TAKATA ◽  
Yutaka KITAMI ◽  
...  
Keyword(s):  
Dna Damage ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Molecular Mechanisms ◽  
Growth Arrest ◽  
Cell Contact ◽  
Inducible Gene

GADD153 (growth arrest- and DNA damage-inducible gene 153) is expressed at very low levels in growing cells, but is markedly induced in response to a variety of cellular stresses, including glucose deprivation, exposure to genotoxic agents and other growth-arresting situations. Forced expression of GADD153 induces cell cycle arrest in many types of cells. It is also reported that GADD153 is directly associated with apoptosis. Recently we have reported that platelet-derived growth factor (PDGF)-BB induces apoptosis in cultured vascular smooth muscle cells (VSMC), but only when 100% confluency is reached. These results suggested that cell–cell contact inhibition (cell growth arrest) may be a critical factor for induction of VSMC apoptosis by PDGF-BB. In the present study, we explored the role of GADD153, one of a number of growth-arrest-related gene products, in the molecular mechanisms of VSMC apoptosis in vitro and in vivo. GADD153 was markedly induced at both the mRNA and protein levels, in parallel with the induction of VSMC apoptosis, after treatment with PDGF-BB. Moreover, overexpression of GADD153 in VSMC significantly reduced cell viability and induced apoptosis. In the carotid artery balloon injury model in rats, GADD153 protein was expressed in apoptotic VSMC which were positively stained by in situ DNA labelling. These results demonstrate an important role for GADD153 in the molecular mechanisms of VSMC apoptosis.

scholarly journals Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice

2009 ◽  
Vol 207 (1) ◽  
pp. 117-128 ◽  
Author(s):  
Fangfang Yin ◽  
Rebecca Banerjee ◽  
Bobby Thomas ◽  
Ping Zhou ◽  
Liping Qian ◽  
...  
Keyword(s):  
Host Defense ◽  
Hippocampal Slices ◽  
Interleukin 10 ◽  
Biological Processes ◽  
Listeria Monocytogenes Infection ◽  
The Brain ◽  
Deficient Mice

Progranulin (PGRN) is a widely expressed protein involved in diverse biological processes. Haploinsufficiency of PGRN in the human causes tau-negative, ubiquitin-positive frontotemporal dementia (FTD). However, the mechanisms are unknown. To explore the role of PGRN in vivo, we generated PGRN-deficient mice. Macrophages from these mice released less interleukin-10 and more inflammatory cytokines than wild type (WT) when exposed to bacterial lipopolysaccharide. PGRN-deficient mice failed to clear Listeria monocytogenes infection as quickly as WT and allowed bacteria to proliferate in the brain, with correspondingly greater inflammation than in WT. PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptible to deprivation of oxygen and glucose. With age, brains of PGRN-deficient mice displayed greater activation of microglia and astrocytes than WT, and their hippocampal and thalamic neurons accumulated cytosolic phosphorylated transactivation response element DNA binding protein–43. Thus, PGRN is a key regulator of inflammation and plays critical roles in both host defense and neuronal integrity. FTD associated with PGRN insufficiency may result from many years of reduced neutrotrophic support together with cumulative damage in association with dysregulated inflammation.

scholarly journals An overview on the interplay between nutraceuticals and gut microbiota

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4465 ◽  
Author(s):  
Adrian Catinean ◽  
Maria Adriana Neag ◽  
Dana Maria Muntean ◽  
Ioana Corina Bocsan ◽  
Anca Dana Buzoianu
Keyword(s):  
Health Status ◽  
Side Effects ◽  
Alternative Therapy ◽  
Animal Experiments ◽  
Health Benefits ◽  
Health Benefit ◽  
Synthetic Drugs

BackgroundNowadays, growing attention was being given to the alternative ways to prevent or treat diseases. Nutraceuticals are used increasingly for this purpose. Many of these are being used as alternative therapy. Classic therapy with synthetic drugs, although very effective, has many side effects. The term “nutraceuticals” refers to the link between the nutritional and pharmaceutical domains. Also, lately, many studies have been done to investigate the role of microbiota in maintaining health. There is the hypothesis that some of the health benefits of nutraceuticals are due to their ability to change the microbiota. The aim of this review was to emphasize the link between the most commonly used nutraceuticals, the microbiota and the health benefits.MethodsWe selected the articles in PubMed, published up to July 2017, that provided information about most used nutraceuticals, microbiota and health benefits. In this review, we incorporate evidence from various types of studies, including observational,in vitroandin vivo, clinical studies or animal experiments.ResultsThe results demonstrate that many nutraceuticals change the composition of microbiota and can interfere with health status of the patients.DiscussionThere is evidence which sustains the importance of nutraceuticals in people’s health through microbiota but further studies are needed to complete the assessment of nutraceuticals in health benefit as a consequence of microbiota’s changing.

scholarly journals The effects of 6 hours of hypoxia on protein synthesis in rat tissues in vivo and in vitro

1985 ◽  
Vol 228 (1) ◽  
pp. 179-185 ◽  
Author(s):  
V R Preedy ◽  
D M Smith ◽  
P H Sugden
Keyword(s):  
Protein Synthesis ◽  
Gastric Emptying ◽  
Skeletal Muscles ◽  
Rat Tissues ◽  
Tissue Nitrogen ◽  
The Brain ◽  
H Protein

Rates of protein synthesis were measured in vivo in several tissues (heart, skeletal muscles, liver, tibia, skin, brain, kidney, lung) of fed rats exposed to O2/N2 (1:9) for 6 h starting at 08:00-11:00 h. Protein synthesis rates were depressed by 15-35% compared with normoxic controls in all of the tissues studied. The decreases were greatest in the brain and the skin. Although hypoxia inhibited gastric emptying, its effects on protein synthesis could probably not be attributed to its induction of a starved state, because protein-synthesis rates in brain and skin were not decreased by a 15-18 h period of starvation initiated at 23:00 h. Furthermore, we showed that protein synthesis was inhibited by hypoxia in the rat heart perfused in vitro, suggesting a direct effect. The role of hypoxia in perturbing tissue nitrogen balance in various physiological and pathological states is discussed.

scholarly journals Elucidating the role of leptin in systemic inflammation: a study targeting physiological leptin levels in rats and their macrophages

2017 ◽  
Vol 313 (5) ◽  
pp. R572-R582 ◽  
Author(s):  
Elizabeth A. Flatow ◽  
Evilin N. Komegae ◽  
Monique T. Fonseca ◽  
Camila F. Brito ◽  
Florin M. Musteata ◽  
...  
Keyword(s):  
Food Deprivation ◽  
Systemic Inflammation ◽  
Peritoneal Macrophages ◽  
Tnf Α ◽  
Macrophage Subpopulations ◽  
Limited Food ◽  
The Brain

To elucidate the role of leptin in acute systemic inflammation, we investigated how its infusion at low, physiologically relevant doses affects the responses to bacterial lipopolysaccharide (LPS) in rats subjected to 24 h of food deprivation. Leptin was infused subcutaneously (0–20 μg·kg−1·h−1) or intracerebroventricularly (0–1 μg·kg−1·h−1). Using hypothermia and hypotension as biomarkers of systemic inflammation, we identified the phase extending from 90 to 240 min post-LPS as the most susceptible to modulation by leptin. In this phase, leptin suppressed the rise in plasma TNF-α and accelerated the recoveries from hypothermia and hypotension. Suppression of TNF-α was not accompanied by changes in other cytokines or prostaglandins. Leptin suppressed TNF-α when infused peripherally but not when infused into the brain. Importantly, the leptin dose that suppressed TNF-α corresponded to the lowest dose that limited food consumption; this dose elevated plasma leptin within the physiological range (to 5.9 ng/ml). We then conducted in vitro experiments to investigate whether an action of leptin on macrophages could parallel our in vivo observations. The results revealed that, when sensitized by food deprivation, LPS-stimulated peritoneal macrophages can be inhibited by leptin at concentrations that are lower than those reported to promote cytokine release. It is concluded that physiological levels of leptin do not exert a proinflammatory effect but rather an anti-inflammatory effect involving selective suppression of TNF-α via an action outside the brain. The mechanism of this effect might involve a previously unrecognized, suppressive action of leptin on macrophage subpopulations sensitized by food deprivation, but future studies are warranted.

Sign in / Sign up

Export Citation Format

Share Document