# Low Dose Ionising Radiation-Induced Hormesis: Therapeutic Implications to Human Health
## 4 The Phenomena of LDIR
### Bystander Effects  
A large number of published studies have described the biological effects of LDIR, seen not only in irradiated cells but also in non-irradiated cells or non-targeted cells, arising as a consequence of radiation events which induce various signalling pathways [67; 68; 69; 70; 71]. This phenomenon is known as the bystander effect (BE), invoking biological effects through intercellular communications. Cell-to-cell interaction via gap junctions, protein mediators and signalling molecules released into a medium play a significant role in the BE, be it protective or detrimental, depending on the different cell types and their different responses [66; 72]. Nitric oxide (NO), a signalling molecule, has been reported to play a role in the bystander response, inducing an increase in radioresistance in non-irradiated human wild-type p53 glioblastoma cells co-cultured with the medium of the cells irradiated with accelerated carbon-ion beams and/or X-ray irradiation [73; 74]. Moreover, it has  
Figure 3: The underlying mechanisms for the phenomena of low dose ionising radiation. also been shown that an NO-mediated bystander response stimulates cell proliferation and micronucleus (MN) formation in nonirradiated human salivary gland tumour cells irradiated with 290 MeV/u carbon ions, dependent on the LET used [75]. On the other hand, [PERSON] et al. (2007) and colleagues, [PERSON] et al. (2011) have demonstrated a natural anticancer mechanism through the bystander effect, by showing the LDIR of both low and high LET stimulates anti-carcinogenic effects in irradiated non-transformed cell (fibroblasts, 208F rat cells) by releasing several signalling species such as cytokines and ROS/reactive nitrogen species (RNS) that eventually lead to apoptosis in the transformed 208 Fsrc3 cancerous cells [76; 77]. The transformed 208 Fsrc3 cells were stably transfected with the src oncogene, resulting in excessive nicotinamide adenine dinucleotide phosphate (NADPH)-mediated superoxide anion generation in order to maintain its transformed state and proliferation. The data showed that the irradiation of non-transformed cells with low doses of 2 mGy \(\gamma\)-rays and 0.29 mGy \(\alpha\)-particles was sufficient to stimulate transformed cell apoptosis through the activation of the transforming growth factor beta (TGF-\(\beta\)) signalling pathway. The activated TGF-\(\beta\) in turn stimulates the production of peroxidase and NO, resulting in a selective removal mechanism for the transformed cells; the membrane-bound NADPH oxidase is constitutively expressed and superoxide anion is produced as the targeting ROS/RNS-induced apoptosis signalling pathway [76; 77]. Conversely, the release of peroxidase and NO by surrounding non-transformed cells are known to play a pivotal role in eliminating transformed cells through the classical intercellular induction of the apoptosis pathway, hypochlorous acid (HOCI) and NO/peroxynitrite signalling [78]. However, the BE has also been proposed as a risk-enhancing phenomenon, resulting in more harmful effects from irradiated cells to its neighbouring cells via cell-to-cell interactions [79; 80]. It has been suggested that the irradiated cells may exert its bystander effect to distress the adjacent cells (extracellular) by activating a series of cellular signalling cascades such as interleukin-8, which correspond to an increased production of ROS [81], and the TGF\(\beta\)1 (cytokine) pathway, activated by radiation, orchestrates multicellular response to damage triggering inflammatory and immune response [82]; and chemokines (CCL5 and CCL11) that influence the immune system [83] by recruiting leucocytes such as T cells, macrophages, eosinophils and basophils, a tumour promoter inflammatory mediator [84; 85]. Studies have demonstrated that a high frequency of chromosomal aberrations and micronucleus formation were observed in the bystander effect induced by \(\alpha\)-particles (\({}^{241}\)Am) in human blood lymphocytes [86].