scholarly journals Increased reactive oxygen species and exhaustion of quiescent CD34-positive bone marrow cells may contribute to poor graft function after allotransplants

Oncotarget ◽  
2016 ◽  
Vol 7 (21) ◽  
pp. 30892-30906 ◽  
Author(s):  
Yuan Kong ◽  
Yang Song ◽  
Yue Hu ◽  
Min-Min Shi ◽  
Yu-Tong Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Graft Function ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Poor Graft Function ◽  
Marrow Cells

scholarly journals (–)-Epigallocatechin-3-gallate induces apoptosis and differentiation in leukaemia by targeting reactive oxygen species and PIN1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fernanda Isabel Della Via ◽  
Rodrigo Naoto Shiraishi ◽  
Irene Santos ◽  
Karla Priscila Ferro ◽  
Myriam Janeth Salazar-Terreros ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Reactive Oxygen ◽  
Promyelocytic Leukaemia ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Nb4 Cells ◽  
Neutrophil Differentiation ◽  
Marrow Cells

Abstract(–)-Epigallocatechin-3-gallate (EGCG), the major active polyphenol extracted from green tea, has been shown to induce apoptosis and inhibit cell proliferation, cell invasion, angiogenesis and metastasis. Herein, we evaluated the in vivo effects of EGCG in acute myeloid leukaemia (AML) using an acute promyelocytic leukaemia (APL) experimental model (PML/RARα). Haematological analysis revealed that EGCG treatment reversed leucocytosis, anaemia and thrombocytopenia, and prolonged survival of PML/RARα mice. Notably, EGCG reduced leukaemia immature cells and promyelocytes in the bone marrow while increasing mature myeloid cells, possibly due to apoptosis increase and cell differentiation. The reduction of promyelocytes and neutrophils/monocytes increase detected in the peripheral blood, in addition to the increased percentage of bone marrow cells with aggregated promyelocytic leukaemia (PML) bodies staining and decreased expression of PML-RAR oncoprotein corroborates our results. In addition, EGCG increased expression of neutrophil differentiation markers such as CD11b, CD14, CD15 and CD66 in NB4 cells; and the combination of all-trans retinoic acid (ATRA) plus EGCG yield higher increase the expression of CD15 marker. These findings could be explained by a decrease of peptidyl-prolyl isomerase NIMA-interacting 1 (PIN1) expression and reactive oxygen species (ROS) increase. EGCG also decreased expression of substrate oncoproteins for PIN1 (including cyclin D1, NF-κB p65, c-MYC, and AKT) and 67 kDa laminin receptor (67LR) in the bone marrow cells. Moreover, EGCG showed inhibition of ROS production in NB4 cells in the presence of N-acetyl-L-cysteine (NAC), as well as a partial blockage of neutrophil differentiation and apoptosis, indicating that EGCG-activities involve/or are in response of oxidative stress. Furthermore, apoptosis of spleen cells was supported by increasing expression of BAD and BAX, parallel to BCL-2 and c-MYC decrease. The reduction of spleen weights of PML/RARα mice, as well as apoptosis induced by EGCG in NB4 cells in a dose-dependent manner confirms this assumption. Our results support further evaluation of EGCG in clinical trials for AML, since EGCG could represent a promising option for AML patient ineligible for current mainstay treatments.

scholarly journals N-Acetylcysteine As a Therapeutic for JAK2V617F Myeloproliferative Neoplasms

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1786-1786
Author(s):  
Brianna Craver ◽  
Gajalakshmi Ramanathan ◽  
Laura Mendez Luque ◽  
Summer Hoang ◽  
Kenza Elalaoui ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Myeloproliferative Neoplasms ◽  
Oxygen Species ◽  
Wild Type ◽  
Healthy Donors ◽  
Marrow Cells

Abstract Chronic inflammation is common in MPN and drives disease progression and worsens symptom burden. It has been reported that JAK2V617F hematopoietic stem and progenitor cells (HSPCs) exhibit elevated basal oxidative stress compared to wild-type cells. However, JAK2V617F HSCs have a differential response than normal HSPCs upon stimulation with pro-inflammatory cytokines or lipopolysaccharide (LPS) invivo and in vitro. Specifically, JAK2V617F HSPCs do not significantly increase reactive oxygen species, exit quiescence, or increase DNA damage following LPS exposure (Blood 2017 130:4211). Therefore, we hypothesized that oxidative stress is important for differential responses of wild-type and JAK2V617F HSCs to inflammation. To compare cell responses to oxidative stress, we treated bone marrow cells from JAK2V617F knock-in and wild-type mice ex vivo with L-buthionine-S,R-sulfoximine (BSO), which reduces glutathione levels, then measured the impact on myeloid colony formation in methylcellulose. JAK2V617F knock-in bone marrow cells are resistant to oxidative stress-induced reduction in colony formation compared to wild-type bone marrow cells. This data suggests that JAK2V617F myeloid progenitors produce less reactive oxygen species in response to BSO or that these cells are resistant to oxidative stress-induced cell death. Next, we tested the effect of the anti-oxidant n-acetylcysteine (NAC) in a JAK2V617F knock-in mouse model. All hematopoietic cells in this model express JAK2V617F, these mice develop elevated blood counts, splenomegaly, and die suddenly at approximately 2-3 months of age. Surprisingly, addition of NAC (2g/L) in the drinking water extended the lifespan of JAK2V617F-knock in mice (p<0.02, n=6-12). However, aspirin (16mg/L) in drinking water did not extend the lifespan of JAK2V617F-knock in mice. NAC did not alter peripheral blood counts in either JAK2V617F-knock in or wild-type mice, which suggests that NAC's utility in JAK2V617F is not through cytoreduction but is due to its ability to reduce oxidative stress or thrombosis. Additionally, NAC had no effect on thrombin-induced platelet activation, which was assayed by P-selectin expression, phosphatidylserine exposure, and platelet-leukocyte aggregation via flow cytometry. There is a positive correlation between leukocytosis and thrombotic risk in MPN patients. Additionally, MPN patients and mice exhibit elevated neutrophil extracellular trap (NET) formation compared to healthy controls, which contributes to the increased thrombosis in MPN. To test the effect of antioxidants on NET formation in vitro, we treated neutrophils from MPN patients or healthy donors with phorbol myristate acetate concurrently with antioxidants (NAC or ferulic acid) and assayed the presence of extracellular DNA using a SYTOX Green nucleic acid stain. Unstimulated neutrophils from MPN patients exhibited sporadic NET formation while neutrophils from healthy donors did not. Additionally, NAC and ferulic acid reduced DNA release, which is indicative of NET formation. Taken together, these data demonstrate that JAK2V617F progenitors are resistant to oxidative stress-induced cell death. Furthermore, reduction of oxidative stress with n-acetylcysteine in vivo prevented NET-induced thrombosis in JAK2V617F knock-in mice as well as in vitro in normal and MPN neutrophils. These data provide a rationale for investigating the utility of n-acetylcysteine as a therapeutic in myeloproliferative neoplasms. Disclosures No relevant conflicts of interest to declare.

Polymorphism nt7778G/T In Mitochondrial ATP8 Gene Promotes Protective Effect On Reactive Oxygen Species Level In Murine Hematopoietic Cells During Aging

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1196-1196 ◽  
Author(s):  
Christin Kretzschmar ◽  
Catrin Roolf ◽  
Katrin Timmer ◽  
Gudrun Knübel ◽  
Anett Sekora ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Bone Marrow ◽  
Point Mutation ◽  
Respiratory Chain ◽  
Bone Marrow Cells ◽  
Hematopoietic Cells ◽  
Reactive Oxygen ◽  
Time Span ◽  
Oxygen Species ◽  
Atp Levels

Abstract Mitochondria are complex cell compartments characterized by a nuclear genome independent own genome referred to as mitochondrial genome (mtDNA). MtDNA encodes 13 proteins which are part of the five enzyme complexes of the mitochondrial respiratory chain. The respiratory chain is responsible for ATP synthesis and is the main source of reactive oxygen species (ROS) in the cell. During cellular aging, mutations in mtDNA accumulate leading potentially to respiratory chain deficiency. Due to the lack of DNA repair mechanisms within the mitochondrion itself, the mtDNA is especially vulnerable towards ROS. Until now it is not fully understood whether intracellular ROS levels increase with aging in all cell types, and whether this process is due to a potential impaired function of the respiratory chain. Thus, the influence of mtDNA mutations on oxidative stress and aging of hematopoietic cells remains to be investigated. Herein, we compared two conplastic mouse strains differing in one point mutation in the mtDNA affecting the respiratory chain. The C5BL/6Ntac-mtFVB/NJ (mtFVB) strain carries a point mutation at nt7778G/T leading to a D>Y replacement in ATP8 protein, while the control stain C5BL/6Ntac-mtAKR (mtAKR) does not. The targeted protein is part of the F0sub unit of complex V in the respiratory chain and we hypothesize that the mutation affects the transport of protons within the complex V. In our study, we analyzed bone marrow cells of both strains at four different aging stages (3 to 24 months) for ROS and ATP levels by DCFH-fluorescence and luminescence staining, respectively. Additionally, the subpopulations of bone marrow cells were analyzed by flow cytometric immunophenotyping. Further, blood counts of the mice treated with a single dose of 5 Fluorouracil (5-FU, 150mg/kg BW, i.p.) were performed every 3 days during a total time span of 21 days. The mtAKR strain showed increasing levels of ROS ranging from 7.1 x 103 to 12 x 103 relative fluorescence units (RFU) and decreasing levels of ATP (from 0.99 to 0.36 µM) during the measurement time points 3 to 24 months. In comparison, the mtFVB strain showed a significant decrease in ROS levels ranging from 5.5 x 103 to 2.4 x 103 RFU and a significant increase of ATP levels (from 0.23 to 0.64 µM) during the same period. Hematopoietic cells of aged mtFVB mice (24 months) contained significantly more ATP than cells of mtAKR mice. Analysis of bone marrow cell composition of both strains showed an increase of hematopoietic stem cells (LSK cells: lineage-, sca-1+, c-kit+) during experimental time span from 3 to 24 months (mtAKR: from 2.13 to 2.81 % of lineage- cells, mtFVB: from 2.13 to 3.52 %). However, only in the mtFVB strain this increase was significant. Interestingly, the amount of LSK cells was significant higher in mtFVB compared to the mtAKR strain (mtFVB: 2.36 %, mtAKR: 1.23 %) at 6 months. Furthermore, erythroide cells (Ter119+) in mtAKR increased with aging (from 25.22 % to 32.69 %), while the mtFVB strain showed a decreased rate (from 25.88 % to 18.9 %). Blood counts of 3 months old mtFVB mice treated with 5-FU were similar to those of the mtAKR strain in the myelosuppression phase after application, but demonstrated higher regeneration peaks at day 15 in white blood cells (mtAKR: 20.24 x 103/µl, mtFVB: 25.72 x 103/µl), platelets (mtAKR: 2016 x 103/µl, mtFVB: 2848 x 103/µl), neutrophilic (mtAKR: 0.8 x 103/µl, mtFVB: 2.36 x 103/µl) and eosinophilic granulocytes (mtAKR: 0.28 x 103/µl, mtFVB: 0.76 x 103/µl) and lymphocytes (mtAKR: 17.12 x 103/µl, mtFVB: 21.84 x 103/µl). The mtDNA polymorphism in complex V of the respiratory chain in mtFVB strain influences the development of ROS and ATP levels in hematopoietic cells during aging, and seems to have a protective impact concerning ROS and ATP levels in aged mice. Furthermore, the capability of LSK cells to expand with age seems to be enhanced in mtFVB strain. Moreover, the regeneration capacity after 5-FU myelosuppression seems also to be increased in 3 months old mice. Disclosures: No relevant conflicts of interest to declare.

The Role of Reactive Oxygen Species in Tumor Treatment and its Impact on Bone Marrow Hematopoiesis

2020 ◽  
Vol 21 (5) ◽  
pp. 477-498
Author(s):  
Yongfeng Chen ◽  
Xingjing Luo ◽  
Zhenyou Zou ◽  
Yong Liang
Keyword(s):  
Reactive Oxygen Species ◽  
Bone Marrow ◽  
Oxidative Damage ◽  
Tumor Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Tumor Treatment ◽  
Normal Cells ◽  
Treatment And Prevention

Reactive oxygen species (ROS), an important molecule inducing oxidative stress in organisms, play a key role in tumorigenesis, tumor progression and recurrence. Recent findings on ROS have shown that ROS can be used to treat cancer as they accelerate the death of tumor cells. At present, pro-oxidant drugs that are intended to increase ROS levels of the tumor cells have been widely used in the clinic. However, ROS are a double-edged sword in the treatment of tumors. High levels of ROS induce not only the death of tumor cells but also oxidative damage to normal cells, especially bone marrow hemopoietic cells, which leads to bone marrow suppression and (or) other side effects, weak efficacy of tumor treatment and even threatening patients’ life. How to enhance the killing effect of ROS on tumor cells while avoiding oxidative damage to the normal cells has become an urgent issue. This study is a review of the latest progress in the role of ROS-mediated programmed death in tumor treatment and prevention and treatment of oxidative damage in bone marrow induced by ROS.

scholarly journals Fe3O4@GO magnetic nanocomposites protect mesenchymal stem cells and promote osteogenic differentiation of rat bone marrow mesenchymal stem cells

2020 ◽  
Vol 8 (21) ◽  
pp. 5984-5993
Author(s):  
He Zhang ◽  
Sirong Li ◽  
Yufeng Liu ◽  
Yijun Yu ◽  
Shichao Lin ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Reactive Oxygen ◽  
Magnetic Nanocomposites ◽  
Oxygen Species ◽  
Marrow Mesenchymal Stem Cells ◽  
Rat Bone

Fe3O4@GO/BMP2 protecting mesenchymal stem cells by regulating reactive oxygen species and promoting osteogenic differentiation of cells.

scholarly journals CCR-2 neutralization augments murine fresh BMC activation by Staphylococcus aureus via two distinct mechanisms: at the level of ROS production and cytokine response

2017 ◽  
Vol 23 (4) ◽  
pp. 345-372 ◽  
Author(s):  
Ajeya Nandi ◽  
Biswadev Bishayi
Keyword(s):  
Reactive Oxygen Species ◽  
Staphylococcus Aureus ◽  
Bone Marrow ◽  
P38 Mapk ◽  
Bone Marrow Cells ◽  
Cytokine Response ◽  
Ros Production ◽  
Oxygen Species ◽  
Murine Bone Marrow ◽  
Aureus Infection

CCR-2 signaling regulates recruitment of monocytes from the bone marrow into the bloodstream and then to sites of infection. We sought to determine whether CCL-2/CCR-2 signaling is involved in the killing of Staphylococcus aureus by murine bone marrow cells (BMCs). The intermittent link of reactive oxygen species (ROS)–NF-κB/p38–MAPK-mediated CCL-2 production in CCR-2 signaling prompted us to determine whether neutralization of CCR-2 augments the response of murine fresh BMCs (FBMCs) after S. aureus infection. It was observed that anti-CCR-2 Ab-treated FBMCs released fewer ROS on encountering S. aureus infection than CCR-2 non-neutralized FBMCs, also correlating with reduced killing of S. aureus in CCR-2 neutralized FBMCs. Staphylococcal catalase and SOD were also found to play a role in protecting S. aureus from the ROS-mediated killing of FBMC. S. aureus infection of CCR-2 intact FBMCs pre-treated with either NF-κB or p-38-MAPK blocker induced less CCL-2, suggesting that NF-κB or p-38-MAPK is required for CCL-2 production by FBMCs. Moreover, blocking of CCR-2 along with NF-κB or p-38-MAPK resulted in elevated CCL-2 production and reduced CCR-2 expression. Inhibition of CCR-2 impairs the response of murine BMCs to S. aureus infection by attenuation ROS production and modulating the cytokine response.

Sign in / Sign up

Export Citation Format

Share Document