Pulsed Electromagnetic Field as a Non-Invasive Alternative or Complementary Treatment in β-Thalassemia

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to be a suitable treatment strategy for inflammatory and tissuespecific gene expression related conditions such as alzheimer, arthritis, bacterial infection and wound healing in diabetic cases and its results demonstrated a significant improvement in the treatment of the patients [5]. The other effects of PEMF are its role in promoting angiogenesis in bone marrow by the overexpression of angiopoietin-2 mRNA [6], and up-regulation of osteogenic factors in human calvarial bone cell cultures which are critical factors in fracture healing [7,8]. It also can increase tendon-specific gene transcription scleraxis (SCX) (+95 %) and type I collagen (COL1A1) (+97 %) in human tendon cells culture model [9].
Angiopoietin-2 up-regulation which caused by PEMF treatment can promote endothelial cell migration by loosening their intercellular contacts, and fibroblast growth factor-2 in the mice bone marrow.
These findings suggest that PEMF induces an angiogenesis-prone environment in the bone marrow without having invasive effects including the induction of hypoxic conditions or inflammation [6].
Dose-dependent upregulation in the expression of SCX, and COL1A1 after PEMF treatment of tendon cells (TCs) is particularly important since PEMF stimulates cell proliferation with a consequent positive effect on tendon recovery. The other observation after PEMF treatment is a small, but significant, increase of IL-1β [9]. IL-1β induces the production of IL-6, a multifunctional Th2 cytokine which exhibits immunoregulatory functions in tissues and plays an essential role in tissue healing, as it is involved in cell proliferation and survival [9,10]. Thus, the increase of IL-6 correlates with the amount of cell viability and proliferation observed after PEMF treatment. On the other hand, IL-6 also has a stimulatory effect on IL-10 production [9]. IL-10 is not only the most effective antiinflammatory Th2 cytokine but it also affects connective tissue cells such as fibroblasts and chondrocytes [11]. In tenocytes, upregulation of IL-10 correlates with the healing increase in murine models [12]. The role of IL-10 in tissue repair involves the regeneration of extracellular matrix, especially in elevating elastin [13] and a significant increase in the vascular endothelial growth factor (VEGF). This is in accordance with the observed increase of IL-6, which is the main vascular endothelial growth factor (VEGF) promoter [9]. PEMF promotes angiogenesis in bone marrow, by the overexpression of angiopoietin-2 mRNA [6]. Thus, PEMF positively influences proliferation, tendon-specific marker expression, and the release of anti-inflammatory cytokines and angiogenic factor in a healthy human TCs culture model in a dose-dependent manner [9]. Diabetic peripheral neuropathy (DPN) studies in animal models, demonstrated that the restitution of nerve function induced by PEMF stimulation will lead to down-regulation of VEGF.
This down regulation, in turn, causes less damage to peripheral nerve fibers. It is suggested that PEMF might have direct corrective effects in relieving peripheral neuropathic symptoms in diabetic rats with DPN [14]. PEMF stimulation of human bone marrow stromal cells (HBMSCs), in lumbar spinal fusion, affects cell cycle regulation, cell structure, and growth receptors or kinase pathways.
In the differentiation and mineralization stages, PEMF regulated preosteoblast gene expression, the growth factor-beta (TGF-β) transformation signaling pathway and microRNA 21 (miR21) activity are highly regulated.
PEMF can affect bone metabolism by activation of the TGF-β signaling pathway and stimulation of microRNA 21-5p (miR21-5p) expression in human bone marrow stromal cells (HBMSCs) [15]. In the process of bone lesions repair, PEMF stimulation alone is able to motivate the expression of osteogenic genes that can lead to the higher expression levels of the osteocalcin (Ocn) mRNA in mesenchymal stem cells (MSCs) followed by MSCs proliferation. PEMFs also affect the molecular currents and cause a specific transmembrane signaling which will promote osteogenic differentiation [16]. PEMF is able to modulate both microRNA (miRNAs) that functions in RNA silencing and post-transcriptional regulation of gene expression and mRNA that is involved in the Alzheimer's disease (AD) related pathways, which will lead to the rebalancing of the pathways' deregulation occurring in the AD. In an ex vivo human peripheral blood mononuclear cells (PBMCs) study, a quantitative reduction of β-secretase, following by PEMF exposure, confirmed the protective role of the electromagnetic field whose action would counteract the formation of β-amyloid.
Expression values of miR-107 and miR-335-5p that are the negative regulator of enzyme beta-secretase 1 (BACE1) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, respectively decrease after PEMF exposure, and the same trend can be observed for the expression of miR-26b-5p, which is involved in brain signaling and synaptic plasticity. This possible effect of PEMF exposure confirms the capacity of the electromagnetic field to stimulate both tissue regeneration and brain signaling [17]. According to previous studies, cell stress signals induce γ-globin gene expression and this induction is a part of physiological stress response in erythroid cells [4]. It was shown that K562 cells and erythroid cells from cord blood progenitors in comparison to the adult cells have absent or lower levels of both KLF1 and BCL11A that are essential in the β-globin expression. These types of cells also express predominantly (mainly) γ, with a low level of β-globin.
There are increasing data to show that KLF1 also regulates many other erythroid genes and hence plays a critical and central role in erythropoiesis [3].

Conclusion
The usual treatment for β-thalassemia that is a combination of blood transfusions and iron chelation therapy has severe side effects that make it necessary for patients to use other medications and procedures like iron chelation therapy. In the pursuit of alternative treatment studies have shown that using heat-shock (HS), UV-and X-irradiation therapy can trigger stress signals that will cause a chain of reaction to activate transcription factors such as KLF1 and BCL11A-XL. These signals can stimulate β-globin production. Other alternatives like pulsed electromagnetic field It also proves to be effective in restitution of nerve function in DPN studies to relieve peripheral neuropathic symptoms and HBMSCs stimulation via TGF-β signaling pathway and miR21 activity. Other studies also showed promising therapeutic effects of this treatment on both tissue regeneration and brain signaling. Since all of these effects were reported without having side effects such as the induction of hypoxic conditions or inflammation and based on its noninvasive, low-cost, non-cytotoxic nature, we hypothesize to use it for activating cell stress signaling pathways to initiate and increase β-globin expression as a cellular stress response gene. This objective will need future studies to evaluate its effectiveness in thalassemic patients and also provide information to optimize and standardize its experimental protocol.