Nanoparticles for active combination radio mitigating agents of zinc coumarate and zinc caffeinate in a rat model.

Zinc coumarate and zinc caffeinate nanoparticles (ZnCoNPs, ZnCaNPs) affect different biological processes. This study aimed to evaluate the mitigating action of ZnCoNPs in combination with ZnCaNPs against liver damage induced by gamma rays (γ-rays). Rats were exposed to 7 Gy of γ-rays and then injected intraperitoneally (i.p) with ZnCoNPs [2U/rat/day (5 mg/kg)] and ZnCaNPs [2U/rat/day (15 mg/kg)] for 7 consecutive days. The results showed that irradiated rats treated with ZnCoNPs (5 mg/kg/body weight) in combination with ZnCaNPs (15 mg/kg/body weight) for 7 days had a significant increases in body weight, antioxidant levels, T helper cell 4 (cluster of differentiation 4 (CD4)), and T cytotoxic cell 8 (cluster of differentiation 8 (CD8)), associated with a marked decrease in lipid peroxidation (LP), nitric oxide(NOx), total free radicals concentrate (TFRC), and DNA fragmentation. There were positive alterations in the morphological state, hematological parameters and the cell cycle phases. Additionally, the histopathological study demonstrated an improvement in the liver tissue of irradiated rats after treatment. Thus, ZnCoNPs and ZnCaNPs could be used as natural mitigating agents to reduce the hazards of ionizing radiation.

Effect of Low-Level Laser on Some Metals Related to Redox State and Histological Alterations in the Liver and Kidney of Irradiated Rats.

Low-level laser therapy (LLLT) is a type of medicine that uses laser light at low levels to activate the cellular chromophores and the initiation of cellular signaling. This study aimed to evaluate the photomodulation effect of LLL against ionizing radiation (IR)-induced metal disorders related to redox state in the liver and kidney of male rats. Rats were divided into 4 groups (control, LLLT, IR (7Gy), IR+LLLT). The results showed that LLLT 870 nm one time for 3 days post-irradiation revealed redistribution of iron (Fe), copper (Cu), zinc (Zn),calcium (Ca), magnesium (Mg), manganese (Mn), and selenium (Se) in the liver and kidney tissues. Moreover, LLLT attenuated the oxidative stress manifested by a marked reduction of hydrogen peroxide (H2O2), 4-hydroxynonenal (4-HNE), total oxidant state (TOS), and oxidative stress index (OSI) associated with a significant increase in total antioxidant status (TAS), glutathione (GSH) content, and glutathione peroxide (GPx), glutathione reductase (GRx), superoxide dismutase(SOD), and catalase (CAT) activities. Moreover, LLLT displayed an increase in glutathione-S-transferase (GSH-T) and ceruloplasmin activities and a decrease in the activity of gamma-glutamyl transferase (γ-GT). Besides, LLLT significantly attenuated the histological changes in the liver and kidney tissues, denoted by a reduction in the necrotic and degenerative changes of hepatocytes and an improvement in the corpuscles and tubules of the kidney. In conclusion, LLLT could be used as an adjuvant treatment post-exposure to radiation, while it is not beneficial to use it on the normal tissue.

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

Nanoparticle is a microscopic particle that has been existed in a wide range of biotechnological purposes. Zinc oxide nanoparticles (ZnO-NPs) have fewer environmental hazards and have shown positive impacts in the medical field. This work aimed to observe the effects of low and high doses of ZnO-NPs on heart injury induced by ionizing radiation (IR). Animals were irradiated by 8 Gy of gamma rays and ZnO-NPs (10 and 300 mg/Kg/day) were orally delivered to rats 1 hour after irradiation. Animals were dissected on 15th day postirradiation. Data showed that the oxidative damage resulted from radiation exposure, appeared by marked increments in the malondialdehyde (MDA) content and the level and protein expression of thioredoxin-interacting protein (TXNIP) with a noticeable decline in the level and expression of thioredoxin 1 (Trx-1) and thioredoxin reductase (TrxR), as well as glutathione (GSH) level and the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Moreover, radiation-induced inflammation, manifested by a noticeable elevation in the level of tumor necrotic factor-alpha (TNF-α), interleukin-18 (IL-18), and C-reactive protein (CRP). Additionally, endothelial dysfunction marked with a high level of asymmetric dimethylarginine (ADMA), total nitrite/nitrate (NOx), intercellular adhesion molecule 1 (ICAM-1), homocysteine (Hcy), creatine kinase (CK-MB), cardiac troponin-I (cTn-I), and lactate dehydrogenase (LDH). In addition, a decrease of zinc (Zn) level in the cardiac tissue was recorded. ZnO-NPs treatment (10 mg/kg) mitigated the oxidative stress and inflammation effects on the cardiovascular tissue through the positive modulations in the studied parameters. In contrast, ZnO-NPs treatment (300 mg/kg) induced cardiovascular toxicity of normal rats and elevated the deleterious effects of radiation. In conclusion, ZnO-NPs at a low dose could mitigate the adverse effects on cardiovascular tissue induced by radiation during its applications, while the high dose showed morbidity and mortality in normal and irradiated rats.

Possible curative role of curcumin and silymarin against nephrotoxicity induced by gamma-rays in rats.

Curcumin (CUR) and silymarin (SLM) are powerful antioxidant and anti-inflammatory compounds with beneficial protective effects against renal diseases. The purpose of this study was to evaluate the efficacy of CUR and SLM alone or in combination on radiation (IR) induced kidney injury. The results showed that CUR and SLM alone or in combination attenuated the oxidative stress denoted by a reduction in the level of malondialdehyde (MDA), hydrogen peroxide (H2O2) and advanced oxidation protein products (AOPP) along with a marked increase of glutathione GSH content and total antioxidant capacity (TAC). Additionally, a significant decrease in the level of blood urea nitrogen (BUN), creatinine, Cystatin-C (CYT-C), neutrophil gelatinase-associated lipocalin (N-GAL) and Kidney Injury Molecule-1 (Kim-1) was recorded. Moreover, the treatment resulted in a remarkable decline in the serum levels of interleukin-18(IL-18), tumor necrosis factor- alpha (TNF-α), C reactive protein (CRP), BCL2 associated X protein (Bax), Factor-related Apoptosis (FAS) and the activity of Caspase-3 associated by an increase of B-cell CLL/lymphoma 2 (Bcl2) level. The results were confirmed with the histopathological examination. Kidney of irradiated showed glomerular atrophy, massive necrotic changes of expanded tubules with hyaline cast inside some tubules and apoptotic changes were recorded in some renal tubules. While irradiated rats treated with CUR and SLM exhibited marked preservation of the cellular structure of their kidney tissue. In conclusion, the combination of CUR and SLM could be more potent than a single agent on the biochemical and histological changes of the irradiated rat renal tissue.

Differential effect of Taraxacum officinale L. (dandelion) root extract on hepatic and testicular tissues of rats exposed to ionizing radiation.

Exposure to high doses of radiation negatively impacts on human organs. Dandelion (Taraxacum officinale ) L. has been used as a traditional folk. This study was to investigate the effect of dandelion root extract (DRE) on radiation -induced hepatic and testicular tissues injury. Animals were exposed to 8.5 Gy of gamma radiation applied as a shot dose and DRE (200 mg/kg/day), was orally supplemented to rats 14 days before and after irradiation. The results showed that DRE administration attenuated oxidative stress in the liver and testis denoted by a significant reduction in the level of MDA and PCO with a marked elevation in GSH and the activity of SOD, CAT and Gpx. Moreover, DRE administration showed positive modulation in the activity of PNPase, GLDH and GSH-Ts. Additionally, these alterations were associated with a significant decrease in the activity of ALT, AST, ALP, and LDH with a marked increase of AL level. Further, elevated levels of testosterone, LH and inhibin B, as well as StAR and P450scc gene expression and Zn level with a decrease of FSH level were noticed. Also, DRE reduced the level of IL-1ß, TNF-α, and caspase-3. Also administration of DRE significance diminished the histopathological changes in the hepatic and testicular tissues, denoted by a reduction in the necrotic and degenerative changes of hepatocytes or fibrinoid necrosis of congested central vein and improving the seminiferous tubules and interstitial tissue between the tubules of the testis. In conclusion, treatment with DRE pre-irradiation is effective on both liver and testicular tissues of rats. Meanwhile, in the case of post-radiation administration, DRE was more effective on testicular tissue than liver. So we suggest that it is better to use the dandelion before exposure to radiation rather than after it.

Mitigating effect of biotin against irradiation-induced cerebral cortical and hippocampal damage in the rat brain tissue.

Radiation-induced brain injury is common and mainly occurs in patients receiving radiotherapy for malignant head and neck tumors. The brain is oversensitive to oxidant injury induced by radiation. Biotin is a member of the vitamin B complex family and its deficiency has been associated with neurogenesis impairment in animals and humans. The present study was undertaken to investigate the mitigating effect of biotin on the cerebral cortical and hippocampal damage induced by radiation exposure. Animals were exposed to radiation in the presence or absence of biotin and sacrificed on day 10. The results demonstrated that the administration of biotin 2 mg to irradiated rats had no significant effect on the radiation-induced damage of the cerebral cortex and the hippocampus, while the administration of biotin 6 mg has significantly attenuated oxidative stress in the hippocampus, manifested by a reduction of 4-hydroxynonenal (4HNE), total nitrate/nitrite (NOx), and xanthine oxidase (XO) levels associated with an elevation of glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities. In addition, biotin decreased the pro-inflammatory cytokines (interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and tumor necrotic factor alpha (TNF-α)), caspase-3, poly(ADP-ribose) polymerase 1 (PARP1) level, and PARP1 gene expression. Moreover, biotin 6 mg treatment diminished serum S100 protein (S100B) and neuron-specific enolase (NSE) levels. In conclusion, biotin treatment at high dose post-irradiation has efficiently neutralized the effect of free radicals in the hippocampal region of rats. Thus, it could be applicable as a radio-mitigator for reducing or delayed radiation-induced brain injury in patients post-radiotherapy.

The effect of naringenin on the role of nuclear factor (erythroid-derived 2)-like2 (Nrf2) and haem oxygenase 1 (HO-1) in reducing the risk of oxidative stress-related radiotoxicity in the spleen of rats.

The present study was to evaluate the radiomitigative effect of naringenin (NRG) on the modulation of ionizing radiation (IR)-induced spleen injury. Rats were exposed to 12 Gy (3Gy/two times/week). NRG (50mg/Kg), was orally given one hour after the first radiation dose, and daily continued during the irradiation period. Rats were sacrificed 1 day after the last dose of radiation. NRG showed a significant decrease of malondialdehyde, hydrogen peroxide with a significant elevation of superoxide dismutase, catalase and glutathione peroxidase activities and glutathione content. Moreover, NRG confirmed the intracellular defense mechanisms through activation of nuclear factor (erythroid-derived 2)-like2 (Nrf2) and haem oxygenase-1 (HO-1) levels and their protein expression. In addition, NRG deactivated the nuclear factor-κB (NF-κB) and reduced the pro-inflammatory cytokines. Further, NRG showed positive modulation in the haematological values (WBCs, RBCs, Hb, Hct% and PLt). In conclusion, these results suggested that NRG reversed the IR-induced redox-imbalance in the rat spleen.

Modulating effect of tiron on the capability of mitochondrial oxidative phosphorylation in the brain of rats exposed to radiation or manganese toxicity.

The brain is an important organ rich in mitochondria and more susceptible to oxidative stress. Tiron (sodium 4,5-dihydroxybenzene-1,3-disulfonate) is a potent antioxidant. This study aims to evaluate the effect of tiron on the impairment of brain mitochondria induced by exposure to radiation or manganese (Mn) toxicity. We assessed the capability of oxidative phosphorylation (OXPHOS) through determination of mitochondrial redox state, the activity of electron transport chain (ETC), and Krebs cycle as well as the level of adenosine triphosphate (ATP) production. Rats were exposed to 7 Gy of γ-rays or injected i.p. with manganese chloride (100 mg/kg), then treated with tiron (471 mg/kg) for 7 days. The results showed that tiron treatment revealed positive modulation on the mitochondrial redox state manifested by a marked decrease of hydrogen peroxide (H2O2), malondialdehyde (MDA), and total nitrate/nitrite (NOx) associated with a significant increase in total antioxidant capacity (TAC), glutathione (GSH) content, manganese superoxide dismutase (MnSOD), and glutathione peroxidase (GPx) activities. Moreover, tiron can increase the activity of ETC through preventing the depletion in the activity of mitochondrial complexes (I, II, III, and IV), an elevation of coenzyme Q10 (CoQ10) and cytochrome c (Cyt-c) levels. Additionally, tiron showed a noticeable increase in mitochondrial aconitase (mt-aconitase) activity as the major component of Krebs cycle to maintain a high level of ATP production. Tiron also can restore mitochondrial metal homeostasis through positive changes in the levels of calcium (Ca), iron (Fe), Mn, and copper (Cu). It can be concluded that tiron may be used as a good mitigating agent to attenuate the harmful effects on the brain through the inhibition of mitochondrial injury post-exposure to radiation or Mn toxicity.

Role of betaine in liver injury induced by the exposure to ionizing radiation.

Oxidative stress, apoptosis, and fibrosis may play a major role in the development of radiation-induced liver damage. Betaine, a native compound widely present in beetroot, was reported to possess hepato-protective properties. The objective of this study was to investigate the influence of betaine on radiation-induced liver damage. Animals were exposed to 9 Gy applied in 3 doses of 3 Gy/wk. Betaine (400 mg/kg/d), was orally supplemented to rats after the first radiation dose, and daily during the irradiation period. Animals were sacrificed 1 day after the last dose of radiation. The results showed that irradiation has induced oxidative stress in the liver denoted by a significant elevation in malondialdehyde, protein carbonyl, and 8-hydroxy-2-deoxyguanosine with a significant reduction in catalase activity and glutathione (GSH) content. The activity of the detoxification enzyme cytochrome P450 (CYP450) increased while GSH transferase (GSH-T) decreased. The activity of the apoptotic marker caspase-3 increased concomitant with increased hyaluronic acid, hydroxyproline, laminin (LN), and collagen IV. These alterations were associated with a significant increase of gamma-glutamyl transferase, alkaline phosphatase and alanine and aspartate aminotransferase markers of liver dysfunction. Betaine treatment has significantly attenuated oxidative stress, decreased the activity of CYP450, enhanced GSH-T, reduced the activity of caspase-3, and the level of fibrotic markers concomitant with a significant improvement of liver function. In conclusion, betaine through its antioxidant activity and by enhancing liver detoxification and reducing apoptosis may alleviate the progression of liver fibrosis and exert a beneficial impact on radiation-induced liver damage.

Possible ameliorative effect of aqueous extract of date (Phoenix dactylifera) pits in rats exposed to gamma radiation.

PURPOSE: To evaluate the radioprotective efficacy of date (Phoenix dactylifera) pits extract (DPE) against γ-irradiation-induced liver damage in the male albino rats. For this study, 30-day survival, dose reduction factor (DRF), antioxidant status and some biochemical changes in the serum and hepatic tissue were evaluated. MATERIALS AND METHODS: To calculate 30-day survival, median lethal dose of 30 days (LD50/30) and DRF, DPE was orally administered to rats for 21 days before irradiation with different doses (5, 6, 8, 10 and 12 Gy) of γ-rays and the rats were observed for 30 days post-irradiation. To evaluate the radioprotective efficacy of DPE against γ-irradiation induced-liver tissue damage, animals were divided into four groups (eight animals in each group). (i) Control: rats not subjected to any treatment; (ii) DPE: DPE was orally administrated (1000 mg/kg body weight) for 21 days; (iii) RAD: rats' whole body exposed to 5 Gy of γ-rays; (iv) DPE + RAD: rats received DPE treatment for 21 days before γ-irradiation. Animals were sacrificed on the seventh day postexposure to radiation. RESULTS: The results showed that pretreatment prior to irradiation with DPE resulted in a significantly higher 30-day survival rate of rats after exposure to different doses of γ-irradiation. Furthermore, DPE treatment resulted in a significant improvement in the hepatic redox state, manifested by a marked increase of superoxide dismutase (SOD) and catalase (CAT) activities and glutathione content associated with a significant decrease of malondialdehyde (MDA) level. In addition, DPE exhibited hepatoprotective effect evidenced by a marked increase in serum levels of insulin, testosterone, high-density lipoprotein-cholesterol (HDL-c) and hepatic glucose 6 phosphate dehydrogenase (G6PHD) activity associated with a significant decrease in serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (γ-GT), glucose, total cholesterol (TC), triglycerides (TG), low density-lipoprotein cholesterol (LDL-c) and hepatic glucose 6 phosphatase (G6Pase) activity, compared with irradiated group. Moreover, DPE showed positive modulation in the levels of hepatic metals [(iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn)]. CONCLUSIONS: DPE treatment prior to gamma irradiation produced biochemical changes that could lead to a reduction in radiation-induced oxidative stress. Hence, we suggest that DPE may be useful as a new natural radioprotective agent.