# Low Dose Ionising Radiation-Induced Hormesis: Therapeutic Implications to Human Health
## 3 LDIR-Induced Hormetic Effects
In another study, at a \(\gamma\)-irradiation dose of 50 cGy compared to 4 Gy, it was shown that LDIR effectively alleviates amyloid-\(\beta\)1-42 (A\(\beta\)42)-induced cell death via regulating AKT and p38 pathways in drosophila Alzheimer disease (AD) models, suggesting a potential hormetic effect in treating AD [51]. This concurred with the findings of [PERSON] et al. (2009) who analysed the transcriptome profiles of mouse brain tissue, previously whole-body irradiated with 10 cGy. They identified nine neural signalling pathways that are concordant in the irradiated mouse brain tissue, in the aging unirradiated human brain, and in Alzheimer's disease patients brain tissue. They indicated that 10 cGy exposure-induced molecular response involved the down-regulation of neural pathways associated with cognitive dysfunctions that were similarly down-regulated in normal human aging and Alzheimer's disease [52]. The underlying molecular mechanism of the hormetic effect is commonly associated with the increase in antioxidant activity, and accordingly, in the immune system. In Wistar rats, [PERSON] et al. (2019) have investigated LDIR exposures at a dose of 20 cGy (moderately low dose [4]), with the rats subsequently sacrificed 6 h and 24 h post-irradiation. Significant elevations of endogenous antioxidant activities such as catalase and glutathione-S-transferase were noted, accompanied by an increase in whole blood lymphocytes and eosinophils, indicative of an immune defence mechanism [53]. This sub-lethal radiation dose has been known to trigger a protective mechanism against stronger toxicity in subsequent stress events. In a recent study, thiocyanate (SCN\({}^{-}\)), a biomolecule that acts as a natural antioxidant in the immune system, was found to be increased in the saliva of 10 healthy orthodontic patients (age 12-17 years) subsequent to exposure to LDIR effective doses of 0.174-0.256 mSv, delivered during cone beam computed tomography (CBCT), inferring that LDIR may exert protective effects by activating the natural antioxidant system [54]. In addition, LDIR (0.1 Gy, \(\gamma\)-radiation) has also demonstrated a bio-positive effect in reducing the transformation of thyroid cancer cells by restoring the thyroid metabolising genes expression, PAX8 and suppressing thyroid cancer carcinogenesis by inhibiting STAT3-miR-330-5p pathways in both cells and a mouse model [55]. Moreover, other experimental studies have demonstrated that the hormetic effects of LDIR only occur in normal cells or tissues and not in malignant cells [56; 57; 58]. Furthermore, LDIR could also induce cell proliferation in normal cells via the Mitogen-Activated Protein Kinase (MAPK)/ERK signalling pathway, while p53 activation in cancer cells could induce cell cycle arrest or apoptosis, as shown in Figure 3.  
Reviews of the beneficial effects of LDIR, also addressing the risk of carcinogenesis and the need for a re-assessment of the LNT model, have been published over the past 20 years and beyond, mainly by [PERSON] and [PERSON] [32; 33; 59; 60]. Not only have these reviews provoked controversy between evidence supporting an hormetic dose response versus the LNT risk model, but they have increasingly revived interest in exploring the evidence base for bio-positive effects of LDIR. A number of reviews have summarised the bio-positive effects of LDIR in epidemiological, animal model, and clinical studies [61; 62; 63]. These papers also discussed the underlying protective mechanisms of LDIR such as enhanced DNA repairs, increased protein folding and the upregulation of oxidative stress enzyme activities, resulting in induced cellular effects such as adaptive response, immunological activity and bystander effects. However, these reviews are not comprehensive nor exhaustive. There is a lack of description and discussion of studies involving bystander effects, adaptive response, hypersensitivity, radioresistance and genomic instability, matters now deliberated in this article.