A new approach of nano-metformin as a protector against radiation-induced cardiac fibrosis and inflammation via CXCL1/TGF-Β pathway.

The present work investigates the potential role of metformin nanoparticles (MTF-NPs) as a radio-protector against cardiac fibrosis and inflammation induced by gamma radiation via CXCL1/TGF-ß pathway. Lethal dose fifty of nano-metformin was determined in mice, then 21 rats (male albino) were equally divided into three groups: normal control (G1), irradiated control (G2), and MTF-NPs + IRR (G3). The possible protective effect of MTF-NPs is illustrated via decreasing cardiac contents of troponin, C-X-C motif Ligand 1 (CXCL1), tumor growth factor ß (TGF-ß), protein kinase B (AKT), and nuclear factor-κB (NF-κB). Also, the positive effect of MTF-NPs on insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) in heart tissues using immunohistochemical technique is illustrated in the present study. Histopathological examination emphasizes the biochemical findings. The current investigation suggests that MTF-NPs might be considered as a potent novel treatment for the management of cardiac fibrosis and inflammation in patients who receive radiotherapy or workers who may be exposed to gamma radiation.

MitoQ and its hyaluronic acid-based nanopreparation mitigating gamma radiation-induced intestinal injury in mice: alleviation of oxidative stress and apoptosis.

Perturbations produced by ionizing radiation on intestinal tissue are considered one of highly drastic challenges in radiotherapy. Animals were randomized into five groups. The first group was allocated as control, and the second was subjected to whole body γ-irradiation (10 Gy). The third was administered HA NP (17.6 mg/kg/day; i.p.) and then irradiated. The fourth one received MitoQ (2 mg/kg/day; i.p.) and then irradiated. The last group received MitoQ/HA NP (2 mg/kg/day; i.p.) for 5 days prior to irradiation. Mice were sacrificed a week post-γ-irradiation for evaluation. MitoQ/HA NP ameliorated mitochondrial oxidative stress as indicated by rising (TAC) and glutathione peroxidase and decreasing malondialdehyde, showing its distinguished antioxidant yield. That impacted the attenuation of apoptosis, which was revealed by the restoration of the anti-apoptotic marker and lessening proapoptotic caspase-3. Inflammatory parameters dwindled via treatment with MitoQ/HA NP. Moreover, this new NP exerts its therapeutic action through a distinguished radioprotective pathway (Hmgb1/TLR-4.) Subsequently, these antioxidants and their nanoparticles conferred protection to intestinal tissue as manifested by histopathological examination. These findings would be associated with its eminent antioxidant potential through high mitochondria targeting, enhanced cellular uptake, and ROS scavenging. This research underlines MitoQ/HA NP as a new treatment for the modulation of intestinal damage caused by radiotherapy modalities.

Evaluation of Glycogen Synthase Kinase Pathway for Assessing the Antidepressant-like Effect of Glucosamine as a Radioprotector in Rats: Behavioral and Biochemical Studies.

Radiotherapy is a very important tool in the treatment of cancer; nevertheless, its side effects are a hindrance to its use. The present study is designed to evaluate glucosamine effects against radiation-induced brain oxidative stress and depression-like effect in rats. Four groups of female Wister rats were used as control, irradiated (4 × 2 Gy), glucosamine (1 g/kg P.O), and glucosamine + irradiated group. The behavioral responses are estimated. The brain hippocampi of the rats are separated to evaluate oxidative stress biochemical parameters and glycogen synthase kinase pathway in addition to the biogenic amines. Irradiation exposure led to disturbances in the behavioral assessments (forced swimming test, light-dark box, and open field test) and a significant decrease in brain GSH, neurotransmitters (serotonin, norepinephrine, and dopamine), phosphatidylinositol 3 kinase (PI3K), and phosphorylated protein kinase-B (p-AKT) levels. Additionally, MDA and ROS levels increased significantly post-irradiation along with the phosphorylated glycogen synthase kinase (p-GSK3). Glucosamine administration before irradiation caused improvement in the behavioral valuations and the biochemical parameters in the brain as well. Glucosamine might be used as a radioprotector to improve brain function and as an antidepressant drug. It could be promising as a future therapy in managing depression occurring during radiotherapy.

Novel iodoquinazolinones bearing sulfonamide moiety as potential antioxidants and neuroprotectors.

In a search for new antioxidants, a set of new iodoquinazolinone derivatives bearing benzenesulfonamide moiety and variable acetamide pharmacophores 5-17 were designed and synthesized. The structures of the synthesized compounds were confirmed based on spectral data. Compounds 5-17 were screened using in vitro assay for their antioxidant potential and acetylcholinesterase (AChE) inhibitory activity. The 2-(6-iodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-ylthio)-N-(pyrazin-2-yl) acetamide 14 was the most active scaffold with potent AChE inhibitory activity. Compound 14 showed relative safety with a median lethal dose of 300 mg/kg (LD50 = 300 mg/kg), in an acute toxicity study. The possible antioxidant and neuroprotective activities of 14 were evaluated in irradiated mice. Compound 14 possessed in vivo AChE inhibitory activity and was able to modify the brain neurotransmitters. It was able to cause mitigation of gamma radiation-induced oxidative stress verified by the decline in Myeloperoxidase (MPO) and increase of glutathione (GSH) levels. Also, 14 restored the alterations in behavioral tests. Molecular docking of 14 was performed inside MPO and AChE active sites and showed the same binding interactions as that of the co-crystallized ligands considering the binding possibilities and energy scores. These findings would support that 14 could be considered a promising antioxidant with a neuromodulatory effect.

MitoQ combats tumor cell progression in Ehrlich ascites carcinoma mice: A crosstalk between mitochondrial oxidative status, mitophagy, and NF-κB signaling.

Despite the clinical advances in cancer treatment, the high mortality rate is still a great challenge, requiring much effort to find new and efficient cancer therapies. AIMS: The present evidence investigated the potential antiproliferative impact of the mitochondrial-targeted antioxidant, Mitoquinol (MitoQ), on a mouse model of Ehrlich ascites carcinoma (EAC). MAIN METHODS: Mice-bearing tumors were administered two doses of MitoQ (0.3 mg & 0.5 mg/kg; i.p daily) or doxorubicin (2 mg/kg; i.p daily) for 20 days. KEY FINDINGS: EAC mice revealed exacerbated mitochondrial reactive oxygen species (mtROS) and impaired mitochondrial membrane potential (△Ψm). Dysfunctional mitophagy was observed in EAC mice, along with boosting aerobic glycolysis. In addition, tumor cells exhibited higher proliferation rates, thereby stimulating cell cycle, invasion, and angiogenesis biomarkers together with suppressing proapoptotic proteins, events that might be correlated with activation of NF-κB signaling. The administration of MitoQ combated tumor cell survival and dissemination in EAC mice as evidenced by reducing tumor volumes and weights and increasing the number of necrotic areas in histopathological assessment. MitoQ also repressed tumor cell cycle, invasion, and angiogenesis via preventing cyclin D1 mRNA, MMP-1, and CD34 levels as well as VEGF protein expression. These observations were associated with the abrogation of mtROS overproduction and enhancement of the mitophagy proteins, PINK1/Parkin levels, followed by inhibition of NADH dehydrogenase. Notably, NF-κB signaling was modulated. SIGNIFICANCE: This study suggests that MitoQ combated tumor cell survival and progression in EAC mice by maintaining mtROS and restoring mitophagy, thereby attenuation of NF-κB activation.

Nrf2 and NF-қB interplay in tamoxifen-induced hepatic toxicity: A promising therapeutic approach of sildenafil and low-dose γ radiation.

Tamoxifen-induced hepatotoxicity is an inevitable side effect during breast cancer treatment. Low-dose gamma irradiation (IRR) shows many beneficial effects by stimulating various biological processes. This study evaluates the possible effect of sildenafil and low-dose gamma radiation on liver damages as new treatment strategies. Group I (control), group II: (tamoxifen), group III: (tamoxifen + Sildenafil), group IV: (tamoxifen+ irradiation) and group V: (tamoxifen +Sildenafil + irradiation). Rats were sacrificed after 5 h from tamoxifen injection. Results showed that tamoxifen caused elevation in serum AST, ALT and ALP as well hepatic ROS, iNOS, MDA, Keap-1 and NF-Kb, in addition to diminution in hepatic Nrf2 and HO-1. Exposure to low-dose gamma radiation and sildenafil amended the alterations in the measured parameters in serum and tissue. Moreover, all results were confirmed by histopathological examination. In conclusion, sildenafil and low-dose gamma radiation can mitigate the toxicity induced by tamoxifen in liver tissues. Hence, this treatment could be further evaluated as a new approach for alleviating various liver disorders.

Development of gamma irradiated SSD-embedded hydrogel dyed with prodigiosin as a smart wound dressing: Evaluation in a MDR infected burn rat model.

Burn wounds are prone to infections and cause a large amount of death worldwide. Although burn wound is sterile at the beginning but due to the risk factors such as prolonged hospital stay, immune suppression and burn affecting large surface area, it turns to infected burn. This study aims to examine the possible protective properties of silver sulfadiazine embedded in alginate macromolecule to prepare hydrogel. The prepared hydrogel dyed with prodigiosin was used as a smart wound dressing to treat burn wounds that were infected with S. aureus and E. coli. Rats were divided into four groups: (1) control group, (2) burn-infected with S. aureus and E. coli group, (3) burn-infected treated with silver nitrate cream group and (4) burn-infected gamma irradiated silver sulfadiazine-embedded hydrogel dyed with prodigiosin. The biochemical results verified the histopathological results and our findings showed that silver sulfadiazine-embedded hydrogel dyed with prodigiosin is an effective product in compared with silver nitrate cream.

Novel iodinated quinazolinones bearing sulfonamide as new scaffold targeting radiation induced oxidative stress.

Reactive oxygen species (ROS) play an integral role in the pathogenesis of most diseases. This work presents the design and synthesis of fourteen new diiodoquinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail and evaluation of their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) using its classical target NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The N-(2-chloropyridin-3-yl)-2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio) acetamide 17 was the most potent NQO1 inducer (CD = 25 µM) with free radical scavenging activity (IC50 = 28 µM) and in vivo median lethal dose (LD50) of 500 mg/Kg. The possible radioprotective activity of compound 17 was evaluated in (7 Gy) irradiated mice. Compound 17 showed a reduction in radiation induced oxidative stress as evidenced by the lower levels of ROS, malondialdehyde (MDA) and NQO1 in liver tissues. Moreover, compound 17 showed improvement in the complete blood count (CBC) of irradiated mice and decreased mortality over 30 days following irradiation. Additionally, docking studies inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, confirmed that 17 revealed the same interactions with the key amino acids as those of the co-crystallized ligand. This study identifies 17 as a novel antioxidant that protects against the harmful effect of radiation.

Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety.

Fifteen new quinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail were synthesized. The structures assigned to the products were concordant with the microanalytical and spectral data. Compounds 4-18 were screened for their ability to induce the antioxidant enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1) in cells, a classical target for transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). The 2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-trimethoxyphenyl) acetamide 15 showed the most potent NQO1 inducer activity in vitro. Compound 15 had low toxicity in mice (LD50 = 500 mg/kg). It also reduced the damaging effects of gamma radiation, as assessed by the levels of Nrf2, NQO1, reactive oxygen species (ROS) and malondialdehyde (MDA) in liver tissues. In addition, compound 15 showed amelioration in the complete blood count of irradiated mice and enhanced survival over a period of 30 days following irradiation. Molecular docking of 15 inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, showed the same binding interactions as that of the co-crystallized ligand considering the binding possibilities and energy scores. These findings suggest that compound 15 could be considered as a promising antioxidant and radiomodulatory agent.

Low dose γ radiation enhances antidepressant effect of resveratrol: Behavioral and neurochemical studies.

The low dose of radiation (LDR) has received growing attention for its beneficial neuroprotective effect. This study was designed to investigate the enhancing effect of LDR on the antidepressant potential of resveratrol against diazepam-induced depression in mice. Female mice divided into five groups; control, diazepam (2 mg/kg), LDR (0.5Gy) + diazepam, resveratrol (20 mg/kg) + diazepam, LDR + resveratrol+diazepam. Mice received diazepam showed depressive symptoms as evidenced by decreased locomotor activity in the open field and increased immobility time in the forced swimming and tail suspension tests integrated with a marked decline in biogenic amines (serotonin, norepinephrine, and dopamine) in brain tissues. These effects were ameliorated by LDR or resveratrol administration demonstrating an antidepressant activity. Interestingly, LDR triggered the antidepressant effect of resveratrol as it restored the changes in behavioral tests, neurotransmitters, and neuro-histoarchitecture. In conclusion, these findings suggested that LDR could be considered as a novel adjuvant that augmented the resveratrol antidepressant effect and might serve as a potential therapeutic approach for depression.

Antioxidant activity of novel quinazolinones bearing sulfonamide: Potential radiomodulatory effects on liver tissues via NF-κB/ PON1 pathway.

In order to discover new antioxidants, fifteen novel quinazolinone derivatives bearing benzenesulfonamide moiety with variable heterocyclic tail, were synthesized and their structures were established on the basis of spectral data. All the synthesized compounds were screened for their antioxidant potential using DPPH assay in comparison to ascorbic acid. The N-(pyrazin-2-yl)-2-[(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio]acetamide 16 was the most active scaffold in this series with greater scavenging activity than that of ascorbic acid. In vivo acute toxicity study of compound 16 indicates its relative safety with a median lethal dose of 200 mg/kg. The possible antioxidant and hepatoprotective activities of compound 16 were evaluated in irradiated mice. Compound 16 caused mitigation of gamma radiation-induced oxidative stress verified by the decline in MDA, ROS and NF-κB levels. Moreover, SOD and PON1 activities, as well as Zn2+ levels, were improved in liver tissues. Furthermore, molecular docking of compound 16 inside the active site of SOD and PON1 demonstrated the same binding interactions as that of the co-crystallized ligands considering the binding possibilities and energy scores. These findings support that compound 16 may represent a structural lead for developing new antioxidants and hepatoprotective agents.

Resveratrol attenuates intestinal injury in irradiated rats via PI3K/Akt/mTOR signaling pathway.

Radiation-induced enteritis is one of the greatest challenges in radiotherapy. The current study was designed to evaluate the ameliorative effect of resveratrol, which exhibits anti-inflammatory property, against radiation-induced intestinal injury in rats and to explore the underlying mechanism. Rats were exposed to a single dose of 5 Gy. Resveratrol (20 mg/kg/day) was orally administered to irradiated rats over 3 weeks. Results showed that resveratrol ameliorated the intestinal oxidative stress parameters; malondialdehyde (MDA) content, glutathione (GSH) level, and catalase (CAT) activity compared to irradiated group. Furthermore, resveratrol reduced the contents of inflammatory cytokines; tumor necrosis factor α (TNF-α), nuclear factor-kappa (NF-κB), and interleukin 1ß (IL-1ß) in intestine. Western blotting analysis revealed that resveratrol down-regulated the proteins expression of phosphoinositide 3-kinases (PI3K), protein kinase B (Akt) as well as the mammalian target of rapamycin (mTOR) in intestinal tissues of irradiated rats and thus reduced the inflammatory mediator production. These results were confirmed by histopathological investigation. In conclusion, resveratrol attenuated intestinal inflammation following irradiation via modulating PI3K/Akt/mTOR pathway and thereby could be a promising adjuvant in radiotherapy.

MitoQ ameliorates testicular damage induced by gamma irradiation in rats: Modulation of mitochondrial apoptosis and steroidogenesis.

AIMS: The deleterious effect of gamma radiation on testicular tissue is a challenging problem in nuclear medicine. This study investigated the potential radioprotective effect of mitoquinol (MitoQ), a mitochondria-targeted antioxidant, against testicular damage induced by gamma irradiation in rats. MAIN METHODS: Rats were allocated into four groups. The first group served as the control, the second group received MitoQ (2 mg / kg / day; i.p.) for seven days, the third group was exposed to gamma radiation (5 Gy as a single dose) and the last group received MitoQ prior to irradiation. Rats were sacrificed. Then, sperm analyses and the serum testosterone were determined. Moreover, evaluation of mitochondrial oxidative stress parameters (SOD, GSH and GPx) as well as apoptosis indicators (cytochrome-c, Bax, Bcl-2 and caspase-3) was performed. Additionally, analysis of steroidogensis biomarkers (StAR, 3ß-HSD and 17ß-HSD) and histopathological investigations were carried out. KEY FINDINGS: MitoQ replenished mitochondrial SOD, GPx and GSH indicating its strong antioxidant effect in addition to its energy preservation manifested by the elevated ATP. MitoQ inhibited the intrinsic apoptosis via diminution of Bax, cytochrome-c and caspase-3 and alleviation of Bcl-2. This antioxidant conferred protection to steroidogenesis as verified by the increase in testosterone and the up-regulation of StAR, 3ß-HSD and 17ß-HSD expression; these effects might be correlated with its antioxidant/anti-apoptotic potential. Histopathological and sperm analyses corroborated the biochemical findings. SIGNIFICANCE: This study identifies MitoQ as a novel agent for the management of testicular toxicity induced by gamma irradiation.

Metformin modulates cardiac endothelial dysfunction, oxidative stress and inflammation in irradiated rats: A new perspective of an antidiabetic drug.

Cardiovascular disease is one of the most pivotal disorders after radiotherapy. The aim of this study investigates the possible protective effect of metformin against gamma radiation-induced heart damage in male rats. Group 1 (control) received saline, group 2 was whole body gamma-irradiated 5 Gy, group 3 was orally administered metformin 50 mg/kg/day for 2 weeks, group 4 received metformin 50 mg/kg/day for 1 week, then exposed to whole-body gamma radiation at a dose of 5 Gy and continued with metformin for further 1 week. The results revealed that the administration of metformin to irradiated rats significantly ameliorated the changes in cardiac biomarkers (LDH and CK-MB) compared with irradiated group. Heart catalase and SOD activities showed normal level when compared with the irradiated group. Also, NF-κB, IL-6 and TNF- α levels were markedly decreased compared with the corresponding values of irradiated group. Consequently, metformin reduced E-selectin as well ICAM and VCAM-1. These results confirmed by histopathological examination. In conclusion, concomitant administration of metformin during radiotherapy acts as a potent heart protector from oxidative stress, inflammatory mediators and endothelial dysfunction induced damages. Results thus hold a great promise for a new implication of an antidiabetic drug (metformin) as adjunct to radiotherapy.