scholarly journals Chronic exposure of humans to high level natural background radiation leads to robust expression of protective stress response proteins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
S. Nishad ◽  
Pankaj Kumar Chauhan ◽  
R. Sowdhamini ◽  
Anu Ghosh
Keyword(s):  
Molecular Mechanisms ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Background Radiation ◽  
Human Peripheral Blood ◽  
Indian Subcontinent ◽  
Occupational Exposures ◽  
Healthy Humans ◽  
Ppi Networks ◽  
High Level

AbstractUnderstanding exposures to low doses of ionizing radiation are relevant since most environmental, diagnostic radiology and occupational exposures lie in this region. However, the molecular mechanisms that drive cellular responses at these doses, and the subsequent health outcomes, remain unclear. A local monazite-rich high level natural radiation area (HLNRA) in the state of Kerala on the south-west coast of Indian subcontinent show radiation doses extending from ≤ 1 to ≥ 45 mGy/y and thus, serve as a model resource to understand low dose mechanisms directly on healthy humans. We performed quantitative discovery proteomics based on multiplexed isobaric tags (iTRAQ) coupled with LC–MS/MS on human peripheral blood mononuclear cells from HLNRA individuals. Several proteins involved in diverse biological processes such as DNA repair, RNA processing, chromatin modifications and cytoskeletal organization showed distinct expression in HLNRA individuals, suggestive of both recovery and adaptation to low dose radiation. In protein–protein interaction (PPI) networks, YWHAZ (14-3-3ζ) emerged as the top-most hub protein that may direct phosphorylation driven pro-survival cellular processes against radiation stress. PPI networks also identified an integral role for the cytoskeletal protein ACTB, signaling protein PRKACA; and the molecular chaperone HSPA8. The data will allow better integration of radiation biology and epidemiology for risk assessment [Data are available via ProteomeXchange with identifier PXD022380].

scholarly journals Hypoxia-Induced Intracellular and Extracellular Heat Shock Protein gp96 Increases Paclitaxel-Resistance and Facilitates Immune Evasion in Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Tian Tian ◽  
Jiguang Han ◽  
Jian Huang ◽  
Shangziyan Li ◽  
Hui Pang
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Immune Evasion ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Paclitaxel Resistance ◽  
Mesenchymal Transition ◽  
Paclitaxel Treatment

BackgroundsHypoxia contributes to cancer progression, drug resistance and immune evasion in various cancers, including breast cancer (BC), but the molecular mechanisms have not been fully studied. Thus, the present study aimed to investigate this issue.MethodsThe paclitaxel-sensitive BC (PS-BC) cells were administered with continuous low-dose paclitaxel treatment to establish paclitaxel-resistant BC (PR-BC) cells. Exosomes were isolated/purified by using the commercial kit, which were observed by Transmission electron microscopy (TEM). Cell viability was measured by MTT assay, cell apoptosis was determined by flow cytometer (FCM). Gene expressions were respectively measured by Real-Time qPCR, Western Blot and immunofluorescence staining assay. The peripheral mononuclear cells (PBMCs) derived CD8+ T cells were obtained and co-cultured with gp96-containing exosomes, and cell proliferation was evaluated by EdU assay. ELISA was employed to measure cytokine secretion in CD8+ T cells’ supernatants.ResultsHSP gp96 was significantly upregulated in the cancer tissues and plasma exosomes collected from BC patients with paclitaxel-resistant properties. Also, continuous low-dose paclitaxel treatment increased gp96 levels in the descendent PR-BC cells and their exosomes, in contrast with the parental PS-BC cells. Upregulation of gp96 increased paclitaxel-resistance in PS-BC cells via degrading p53, while gp96 silence sensitized PR-BC cells to paclitaxel treatments. Moreover, PR-BC derived gp96 exosomes promoted paclitaxel-resistance in PS-BC cells and induced pyroptotic cell death in the CD8+ T cells isolated from human peripheral blood mononuclear cells (pPBMCs). Furthermore, we noticed that hypoxia promoted gp96 generation and secretion through upregulating hypoxia-inducible factor 1 (HIF-1), and hypoxia increased paclitaxel-resistance and accelerated epithelial-mesenchymal transition (EMT) in PS-BC cells.ConclusionsHypoxia induced upregulation of intracellular and extracellular gp96, which further degraded p53 to increase paclitaxel-sensitivity in BC cells and activated cell pyroptosis in CD8+ T cells to impair immune surveillance.

scholarly journals Investigation of low-dose ritonavir on human peripheral blood mononuclear cells using gene expression whole genome microarrays

Genomics ◽  
2010 ◽  
Vol 96 (1) ◽  
pp. 57-65 ◽  
Author(s):  
Saliha Yilmaz ◽  
Marta Boffito ◽  
Sophie Collot-Teixeira ◽  
Ferruccio De Lorenzo ◽  
Laura Waters ◽  
...  
Keyword(s):  
Gene Expression ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Whole Genome ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

scholarly journals Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma

2020 ◽  
Vol 8 (2) ◽  
pp. e000807
Author(s):  
Xiran He ◽  
Yang Du ◽  
Zhijie Wang ◽  
Xin Wang ◽  
Jianchun Duan ◽  
...  
Keyword(s):  
Squamous Cell ◽  
Lung Carcinoma ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Type I ◽  
Squamous Cell Lung Carcinoma ◽  
Antigen Uptake ◽  
Cell Lung Carcinoma

BackgroundThe survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for the treatment of squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization of chemoimmunotherapy in order to enhance the efficacy of immune checkpoint inhibitors (ICIs) in SQCLC remains to be explored.MethodsCell lines, syngeneic immunocompetent mouse models, and patients’ peripheral blood mononuclear cells were used in order to comprehensively explore how to enhance ectopic lymphoid-like structures (ELSs) and upregulate the therapeutic targets of anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering SQCLC more sensitive to ICIs. In addition, molecular mechanisms underlying optimization were characterized.ResultsLow-dose chemotherapy contributed to an enhanced antigen exposure via the phosphatidylinositol 3-kinase/Akt/transcription factor nuclear factor kappa B signaling pathway. Improved antigen uptake and presentation by activated dendritic cells (DCs) was observed, thus invoking specific T cell responses leading to systemic immune responses and immunological memory. In turn, enhanced antitumor ELSs and PD-1/PD-L1 expression was observed in vivo. Moreover, upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and effectively synergized with anti-PD-1/PD-L1 mAbs. A possible mechanism underlying this synergy is the increase of activated type I macrophages, DCs, and cytotoxic CD8+ T cells, as well as the maintenance of intestinal gut microbiota diversity and composition. In contrast, when combining routine MTD chemotherapy with ICIs, the effects appeared to be additive rather than synergistic.ConclusionsWe first attempted to optimize chemoimmunotherapy for SQCLC by investigating different combinatorial modes. Compared with the MTD chemotherapy used in current clinical practice, upfront metronomic chemotherapy performed better with subsequent anti-PD-1/PD-L1 mAb treatment. This combination approach is worth investigating in other types of tumors, followed by translation into the clinic in the future.

scholarly journals Carcinogenesis induced by low-dose radiation

2017 ◽  
Vol 51 (4) ◽  
pp. 369-377 ◽  
Author(s):  
Igor Piotrowski ◽  
Katarzyna Kulcenty ◽  
Wiktoria Maria Suchorska ◽  
Agnieszka Skrobała ◽  
Małgorzata Skórska ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Dose ◽  
Atomic Bomb ◽  
Threshold Model ◽  
Occupational Exposures ◽  
High Dose ◽  
Low Dose Radiation ◽  
Oncologic Patients ◽  
Risk Of Cancer ◽  
Dose Radiation

AbstractBackgroundAlthough the effects of high dose radiation on human cells and tissues are relatively well defined, there is no consensus regarding the effects of low and very low radiation doses on the organism. Ionizing radiation has been shown to induce gene mutations and chromosome aberrations which are known to be involved in the process of carcinogenesis. The induction of secondary cancers is a challenging long-term side effect in oncologic patients treated with radiation. Medical sources of radiation like intensity modulated radiotherapy used in cancer treatment and computed tomography used in diagnostics, deliver very low doses of radiation to large volumes of healthy tissue, which might contribute to increased cancer rates in long surviving patients and in the general population. Research shows that because of the phenomena characteristic for low dose radiation the risk of cancer induction from exposure of healthy tissues to low dose radiation can be greater than the risk calculated from linear no-threshold model. Epidemiological data collected from radiation workers and atomic bomb survivors confirms that exposure to low dose radiation can contribute to increased cancer risk and also that the risk might correlate with the age at exposure.ConclusionsUnderstanding the molecular mechanisms of response to low dose radiation is crucial for the proper evaluation of risks and benefits that stem from these exposures and should be considered in the radiotherapy treatment planning and in determining the allowed occupational exposures.

scholarly journals A New Insight on the Radioprotective Potential of Epsilon-Aminocaproic Acid

Medicina ◽  
2020 ◽  
Vol 56 (12) ◽  
pp. 663
Author(s):  
Timur Saliev ◽  
Dinara Baiskhanova ◽  
Dmitriy Beznosko ◽  
Dinara Begimbetova ◽  
Bauyrzhan Umbayev ◽  
...  
Keyword(s):  
Low Dose ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Aminocaproic Acid ◽  
Free Radical Scavengers ◽  
Peripheral Blood Mononuclear ◽  
X Ray ◽  
Radiation Induced ◽  
Induced Apoptosis ◽  
Epsilon Aminocaproic Acid

Background and objectives: The aim of the study was to scrutinize the ability of epsilon-aminocaproic acid (EACA) to prevent radiation-induced damage to human cells. Materials and Methods: Human peripheral blood mononuclear cells (PBMCs) were exposed to ionizing radiation at three low doses (22.62 mGy, 45.27 mGy, and 67.88 mGy) in the presence of EACA at the concentration of 50 ng/mL. Results: EACA was able to prevent cell death induced by low-dose X-ray radiation and suppress the formation of reactive oxygen species (ROS). EACA also demonstrated a capacity to protect DNA from radiation-induced damage. The data indicated that EACA is capable of suppression of radiation-induced apoptosis. Comparative tests of antioxidative activity of EACA and a range of free radical scavengers showed an ability of EACA to effectively inhibit the generation of ROS. Conclusions: This study showed that the pretreatment of PBMCs with EACA is able to protect the cells from radiation-elicited damage, including free radicals’ formation, DNA damage, and apoptosis.

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