Thioredoxin mitigates radiation-induced hematopoietic stem cell injury in mice

Abstract

Background: Radiation exposure poses a significant threat to public health. Hematopoietic injury is one of the major manifestations of acute radiation sickness. Protection and/or mitigation of hematopoietic stem cells (HSCs) from radiation injury is an important goal in the development of medical countermeasure agents (MCM). We recently identified thioredoxin (TXN) as a novel molecule that has marked protective and proliferative effects on HSCs. In the current study, we investigated the effectiveness of TXN in rescuing mice from a lethal dose of total body radiation (TBI) and in enhancing hematopoietic reconstitution following a lethal dose of irradiation. Methods: We used in-vivo and in-vitro methods to understand the biological and molecular mechanisms of TXN on radiation mitigation. BABL/c mice were used for the survival study and a flow cytometer was used to quantify the HSC population and cell senescence. A hematology analyzer was used for the peripheral blood cell count, including white blood cells (WBCs), red blood cells (RBCs), hemoglobin, and platelets. Colony forming unit (CFU) assay was used to study the colongenic function of HSCs. Hematoxylin and eosin staining was used to determine the bone marrow cellularity. Senescence-associated β-galactosidase assay was used for cell senescence. Western blot analysis was used to evaluate the DNA damage and senescence protein expression. Immunofluorescence staining was used to measure the expression of γ-H2AX foci for DNA damage.

Nrf2‐modulation by seleno‐hormetic agents and its potential for radiation protection

“…47,48 In agreement with this idea, studies have shown that pharmacologic suppression of oxidative stress by the treatment with superoxide dismutase (SOD) mimics, thioredoxin and catalase could alleviate or mitigate IR-induced HSC injury. [49][50][51] These results demonstrate the potential of redox-modulating agents for protection of radiation-induced toxicities.…”

“…Mechanistic studies suggest that increased levels of reactive oxygen species (ROS) and sustained oxidative stress may play a crucial role in IR‐induced long‐term hematopoietic stem cell (HSC) injury . In agreement with this idea, studies have shown that pharmacologic suppression of oxidative stress by the treatment with superoxide dismutase (SOD) mimics, thioredoxin and catalase could alleviate or mitigate IR‐induced HSC injury . These results demonstrate the potential of redox‐modulating agents for protection of radiation‐induced toxicities.…”

Impact of zinc oxide nanoparticles on thioredoxin‐interacting protein and asymmetric dimethylarginine as biochemical indicators of cardiovascular disorders in gamma‐irradiated rats

“…While TXNIP considers as an endogenous physiological suppression factor for Trx‐1 protein expression and activity resulting in increased ROS production and OS, causing cellular apoptosis. Trx‐1 might reduce hydrogen peroxide and scavenges free radicals that resulted from radiation . Additionally, Trx‐1 implicated in the cardiovascular homeostasis by preventing cell redox state impairment that modifies multiple cellular pathways .…”

“…Differences between means were considered significant (a1b1) at P ≤ .05, highly significant (a2b2) at P ≤ .01 and very highly significant (a3b3) at P ≤ .001 [Color figure can be viewed at wileyonlinelibrary.com] ROS production and OS, causing cellular apoptosis. Trx-1 might reduce hydrogen peroxide and scavenges free radicals that resulted from radiation 42. Additionally, Trx-1 implicated in the cardiovascular homeostasis by preventing cell redox state impairment that modifies multiple cellular pathways 43.…”

Interleukin-33 regulates hematopoietic stem cell regeneration after radiation injury

“…Moreover, IR doses beyond 3.5 Gy can lead to BM failure owing to a severe injury to hematopoietic stem cells (HSCs) that can transform into long-term BM damage on complete ablation of HSC reserves and functions [6]. Hence, recovery and survival following exposure to myeloablative doses of total body irradiation (TBI) is primarily dependent on the maintenance of HSC homeostasis, self-renewal capability and their ability to stimulate requisite levels of immune compartments [7, 8].…”