Regulation of radiation-induced liver damage by modulation of SIRT-1 activity: In vivo rat model.

Silent information regulator 1 (SIRT-1), a nicotinamide adenine dinucleotide-dependent deacetylase, was found to regulate cell apoptosis, inflammation, and oxidative stress response in living organisms. Therefore, the role of SIRT-1 in regulating forkhead box O/poly ADP-ribose polymerase-1 (FOXO-1/PARP-1) signaling could provide the necessary validation for developing new pharmacological targets for the promotion or inhibition of SIRT-1 activity toward radiation sensitivity. In the present study, the SIRT-1 signaling pathway is being investigated to study the possible modulatory effect of resveratrol (RSV, SIRT-1 activator) versus nicotinamide (NAM, SIRT-1 inhibitor) in case of liver damage induced by whole-body gamma irradiation. Rats were exposed to 6 Gy gamma radiation after being pretreated with either RSV (10 mg/kg/day) or NAM (100 mg/kg/day) for 5 days, and subsequent examining hepatic morphological changes and apoptotic markers were assessed. The expression of SIRT-1, FOXO-1, and cleaved PARP-1 in the liver was analyzed. RSV improved radiation-induced apoptosis, mitochondrial dysfunction, and inflammation signified by low expression of caspase-3, lactate dehydrogenase, complex-I activity, myeloperoxidase, and total nitric oxide content. RSV increased the expression of SIRT-1, whereas cleaved PARP-1 and FOXO-1 were suppressed. These protective effects were suppressed by inhibition of SIRT-1 activity using NAM. These findings suggest that RSV can attenuate radiation-induced hepatic injury by reducing apoptosis and inflammation via SIRT-1 activity modulation.

Effectiveness of deferiprone-loaded nanocarrier in experimentally induced rhabdomyolysis: A dose-comparison study.

Herein, the efficacy of free deferiprone (DFP) and DFP-loaded starch/polyethylene glycol/polyacrylic acid (St/PEG/PAAc) nanogel [Nano-DFP] in modulating the biochemical changes induced by glycerol model of rhabdomyolysis (RBD) in male rats was investigated. In this respect, gamma radiation-induced crosslinking was used to produce St/PEG/PAAc nanogel particles, and then, it was used as a nanocarrier for DFP as an attempt to overcome the poor bioavailability and short half-life of DFP. St/PEG/PAAc nanogel was characterized by Fourier transform infrared, dynamic light scattering and Transmission electron microscopy. Free DFP was administered to rats in two doses; 25 and 50 mg following RBD induction, while the loaded nanogel was administered at a dose of 25 mg. The liver and kidney functions were then fully assessed in association with the histological tissue examination of both organs and the femur muscle. Both doses of DFP significantly antagonized the RBD-induced changes in most of the assessed organs functions. The higher dose of DFP, however, showed a statistically more pronounced modulation of RBD effects on each of kidney, liver and skeletal muscles. Nano-DFP; at 25 mg dose, resulted in a statistically significant correction of most of the RBD-related biomarkers with a comparable magnitude to the higher DFP dose rather than the corresponding lower one.

Anti-inflammatory and analgesic effect of LD-RT and some novel thiadiazole derivatives through COX-2 inhibition.

Generally, highly selective COX-2 inhibitors cause cardiovascular side effects. Celecoxib is the highly marketed coxib, so there is still a need for the synthesis of COX-2 inhibitors with less adverse effects. Moreover, low-dose radiotherapy (LD-RT) is clinically used for the treatment of inflammatory diseases. The present study aimed to investigate the analgesic and anti-inflammatory activity of a novel series of 1,3,4-thiadiazole derivatives alone or combined with LD-RT with a single dose of 0.5 Gy. Initially, in vitro COX-1/COX-2 inhibition assays were performed, identifying the sulfonamide-containing compounds 5-10 as the most potent candidates, with IC50 values in the range of 0.32-0.37 µM and the highest selectivity indices. These compounds and celecoxib were subjected to in vivo examination after their safety was assessed through the acute toxicity test. Treatment with compounds 5-10 inhibited carrageenan-induced edema by nearly 47-56%, which was nearly equivalent to celecoxib. Compounds 7 and 8 and celecoxib showed an analgesic activity of 64.15%, 49.05%, and 84.90%, respectively, whereas compounds 5, 6, 9, and 10 did not show any analgesic activity unless combined with LD-RT. Ulcerogenic activity, histological paw examination, and docking studies were performed. Compounds 5-10 were nearly similar to celecoxib, showing normal histological features with no ulcerogenic activity.

Design and synthesis of novel pyridazinoquinazoline derivatives as potent VEGFR-2 inhibitors: In vitro and in vivo study.

Worldwide, Hepatocellular Carcinoma (HCC) endures to be a prominent cause of cancer death. Treatment of HCC follows multiple therapies which are not entirely applicable for treatment of all patients. HCC usually arises contextual to chronic liver diseases and is often discovered at later stages which makes treatment options more complex. The present study aimed at design, synthesis & evaluation of new pyridazinoquinazoline derivatives as potential nontoxic anti-hepatocellular carcinoma (HCC) agents, through inhibition of Vascular endothelial growth factor -2 (VEGFR-2). Novel Pyridazino[3, 4, 5-de]quinazoline derivatives (2-6) were designed & synthesized. Their structures were confirmed via spectral and microanalytical data. They were tested for their in vitro VEGFR-2 inhibition & anticancer activity against human liver cancer cell line (HEPG-2). Molecular docking was investigated into VEGFR-2 site. In vivo studies of VEGRF-2 inhibition and the anti-apoptotic effect of the new compounds were determined in liver of irradiated rats. Toxicity of synthesized compounds was also assessed. The results showed that compounds 3-6 have significant antitumor activity and proved to be non-toxic. The ethoxy aniline derivative 6, exhibited the highest activity both in vitro and in vivo compared to the reference drug used, sorafenib. Compound 6 could be considered a promising nontoxic anti HCC agent and this could be partially attributed to its VEGFR-2 inhibition. Future preclinical investigation would be carried out to confirm the specific and exact mechanism of action of these derivatives especially compound 6 as an effective pharmaceutical agent after full toxicological and pharmacological assessment.

Ubiquinol attenuates γ-radiation induced coronary and aortic changes via PDGF/p38 MAPK/ICAM-1 related pathway.

Endothelial vascular injury is one of the most pivotal disorders emerging during radiotherapy. It is crucial to rely on strong antioxidants to defend against vascular damage. The current study was carried out to investigate the ameliorative effect of ubiquinol (Ubq) against gamma (γ)-radiation induced aortic and coronary changes, with highlighting its role in suppression of p38 mitogen activated protein kinase (MAPK). Exposure to γ-radiation was adopted as a potent detrimental model that induces vascular tissue damage. Concisely, male albino rats were irradiated at a dose level of 7 Gy and treated daily with Ubq (10 mg/kg/day, p.o.) for 7 days pre-and post-irradiation. At the end of the experiment, lipid profile, 8-hydroxydeoxyguanosine (8-OHdG), gene expression of intercellular adhesion molecule (ICAM-1), platelet derived growth factor (PDGF), p38 MAPK and matrix metalloproteinase-9 (MMP-9) were estimated. Exposure to radiation significantly deteriorates aortic and coronary tissues. Conversely, administration of Ubq significantly reduced serum t-cholesterol, LDL and triglycerides (p = 0.001). In addition, Ubq prevented oxidative DNA damage (8-OHdG) (p = 0.1) and reduced serum MMP-9 (p = 0.001) which contributed to the endothelial cells damage. The positive impact of Ubq was more apparent in suppression of both PDGF (p = 0.001) and p38 MAPK (p = 0.1) protein concentrations, leading subsequently in reduction of ICAM-1 (p = 0.001) gene expression. As a conclusion, vascular endothelial damage brought on by γ-radiation is one of the leading causes of coronary and aortic deteriorations which could be successfully mitigated by Ubq.

Micellar solubilization enhances the anti-inflammatory effect of xanthohumol.

BACKGROUND: Xanthohumol is known to exert anti-inflammatory properties but has poor oral bioavailability. Using advanced micellization technology, it has been possible to markedly enhance its bioavailability. PURPOSE: In the present study, we compared the chronic anti-inflammatory activities of native and micellar xanthohumol in the rat adjuvant arthritis model, using diclofenac as a reference drug. METHODS: Adjuvant arthritis was induced by injecting Freund's complete adjuvant into the right hind paw of rats and monitoring paw volume over 3 weeks. The drugs were given daily for 3 weeks, starting from the day of adjuvant inoculation. Serum was collected at the end of the experiment to measure inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. RESULTS: Micellar solubilized xanthohumol showed a better anti-inflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α, interleukin-6 and C-reactive protein, myloperoxidase and lipid peroxidation markers. CONCLUSION: The findings confirm that micellar solubilization of xanthohumol enhances its anti-inflammatory activity, probably as a result of improving its bioavailabilty. The solubilized xanthohumol may prove to be a promising adjuvant tool for anti-inflammatory treatment and a potential anti-inflammatory alternative to synthetic drugs.

Intestinal injury can be effectively prevented by Dunaliella salina in gamma irradiated rats.

Dunaliella salina (D. salina) is one of the most common microalgae that is used as human food. It is isolated from the salty lakes in El-Fayoum and Lake of Bardawil-Sinai in Egypt and can withstand very high concentrations of salt: The potentiality of D. salina, a unicellular biflagellate green alga to protect against intestinal injury induced after radiation exposure was studied. D. salina was given orally in doses of 100 and 200 mg/kg to male Wistar rats for 5 days before exposure to 6 Gray (Gy) gamma radiation and continued for a further two days. Rats were sacrificed 24 h later and intestinal segments were dissected out. One segment was examined histologically and another was used to prepare homogenates to assess relevant biochemical parameters reflecting intestinal injury. Radiation exposure led to a rise in the histological damage score, an increase in tissue tumor necrosis factor (TNF-α), interleukin (IL-1ß) and thiobarbituric acid reactive substances (TBARS) but a reduction in tissue reduced glutathione (GSH) and in serum citrulline. Pretreatment with either dose of D. salina effectively reduced the severity of intestinal mucositis induced by gamma radiation.

Anti-apoptotic effect of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase, against multiple organ damage induced by gamma irradiation in rats.

PURPOSE: This study aimed to investigate the effect of 3-aminobenzamide (3-AB) in doses of 5, 10 and 15 mg/kg on the inhibition of Poly (ADP-ribose) polymerase (PARP) when combined with ionizing radiation (IR). MATERIAL AND METHODS: Rats were treated intraperitonealy, one hour prior to irradiation at a dose level of 6 Gray (Gy) and were sacrificed 24 hours after irradiation. Control groups were run concurrently. RESULTS: IR led to an increase of thiobarbituric acid reactive substance (TBARS), nitrite as well as a decrease in total antioxidant capacity associated increase in myeloperoxidase (MPO) with the expression of cyclooxygenase-2 (COX-2). Moreover, IR caused an increase in serum lactate dehydrogenase (LDH) activity and cytosolyic Ca+2 associated with an expression of Caspase-3 as well as a decline in complex-I activity and adenosine triphosphate (ATP) level. Pretreatment with 5 and 10 mg/kg of 3AB guarded against the changes in all the measured parameters, conversely the dose of 15 mg/kg showed no effect on the damage induced by irradiation in the selected tissues. Moreover, 3AB has a dose-dependent effect on viability of Vero cells. CONCLUSION: The selected low doses of 3AB rather than the higher dose (15 mg/kg) protected against radiation-induced multiple organ damage.

Micellar solubilisation enhances the antiinflammatory activities of curcumin and boswellic acids in rats with adjuvant-induced arthritis.

OBJECTIVE: Native extracts of curcumin and boswellia are known to exert antiinflammatory properties but have poor bioavailability when given orally. Using advanced micellation technology, it has been possible to produce stable solubilisates of these extracts with markedly enhanced bioavailability. In the present study, we compared the chronic antiinflammatory activities of native and micellar curcumin in the rat adjuvant arthritis model, using diclofenac as a reference drug. METHODS AND PROCEDURES: Adjuvant arthritis was induced by injecting Freund's complete adjuvant (FCA) into the right hind paw of rats and monitoring paw volume over 3 wk. The drugs were given daily for 3 wk, starting from the day of adjuvant inoculation. The serum was collected at end of the experiment for the assay of inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. RESULTS: Solubilized curcumin showed better antiinflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), myeloperoxidase (MPO), and lipid peroxidation markers. The combination of curcumin and boswellia solubilisates synergistically produced an even more potent therapeutic effect. CONCLUSION: The findings confirm that micellar solubilisation of curcumin and boswellia not only increases their bioavailability, but also enhances their biological activity. Micellar curcumin, in particular in combination with micellar boswellia, may thus represent a promising concomitant tool for antiinflammatory treatment and a potential antiinflammatory alternative to synthetic drugs.

Platelet-rich plasma-induced feedback inhibition of activin A/follistatin signaling: A mechanism for tumor-low risk skin rejuvenation in irradiated rats.

BACKGROUND: Platelet-rich plasma (PRP) is a source of natural growth factors and is emerging as a treatment modality to mitigate radiotherapy- induced adverse effects. Activin A (ACTA) is a member of the transforming growth factor-ß (TGF-ß) superfamily, which has been shown to modulate the inflammatory response and macrophages polarization between different phenotypes. The aim of this study is to determine the value of PRP in preventing radiation-induced malignancies in light of the cross-talk between PRP and activin A type II receptors (ActR-IIA)/follistatin (FST) signaling pathways where the inflammatory responses at 2 different time points were evaluated. MATERIAL AND METHODS: Male albino rats were exposed to radiation and given PRP over the course of 6 days. Rats were sacrificed on day 7 or day 28 post radiation. RESULTS: Quantitative real-time reverse transcriptase polymerase chain reaction (QRT-PCR) and western-blot showed that after 7 days of administrating of PRP, ActR-IIA/FST signaling was markedly induced and was associated with the expressions of inflammatory, natural killer and M1 macrophages markers, TNF-α, IL-1ß, IFN-γ and IL-12. By contrast, on day 28 of PRP administration, ActR-IIA/FST signaling and the expressions of proinflammatory cytokines were downregulated in parallel with inducing M2 macrophages phenotype as indicated by arginase-1, IL-10 and dectin-1. CONCLUSION: The suppression of inflammation and induction of M2 macrophages phenotype in response to PRP administration were found significantly linked to ActR-IIA/FST signaling downregulation. Furthermore, the specific M2 macrophage subtype was found to express dectin-1 receptors which have high affinity for tumor cells thereby is expected to reduce the potential for developing tumors after radiotherapy.

Protective effect of the herbal preparation, STW 5, against intestinal damage induced by gamma radiation in rats.

PURPOSE: STW 5 (marketed as Iberogast(®), Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany) is a herbal preparation reported to possess anti-inflammatory properties and antioxidant activity. We investigated the effect of STW 5 against intestinal injury induced after whole body exposure to ionizing radiation (IR). MATERIALS AND METHODS: Intestinal mucositis was induced in rats by irradiation at a level of 6 Gy. STW 5 (5 ml/kg) was delivered orally for 5 days before irradiation and 2 days after. Rats were sacrificed, jejunum homogenates were tested to assess biochemical parameters indicating intestinal injury and jejunum segments were exposed to semi-quantitative histological examination. RESULTS: IR led to an increase in overall damage severity (ODS) score associated with a significant rise in tumor necrosis factor (TNF-α) and thiobarbituric acid reactive substances (TBARS) by 46% and 50% (p ≤ 0.05), respectively, whereas the reduced glutathione (GSH), sucrase and alkaline phosphatase enzyme activities were significantly decreased by 68%, 76% and 25% (p ≤ 0.05), respectively, in intestinal homogenates. IR led to a reduction of plasma citrulline. Pre-treatment with STW 5 guarded against the changes in ODS score and in all parameters measured. CONCLUSION: Pre-treatment with STW 5 has the potential to decrease the severity of radiation-induced mucositis.

Propolis aqueous extract preserves functional integrity of murine intestinal mucosa after exposure to ionizing radiation.

The ability of a specially prepared water propolis extract (PWE) to preserve the functional activity of the intestinal mucosa after radiation exposure was studied. PWE was given orally (650 mg/kg) to rats five days prior to irradiation by 6 Gy and continued for further two days. Rats were sacrificed 24h later, intestinal segments were examined histologically and homogenates were used to assess relevant biochemical parameters reflecting intestinal injury. Irradiation led to a rise in the histological damage score, a rise in tissue TNF-α and TBARS, and a decrease in sucrase, alkaline phosphatase, GSH and cholecystokinin as well as a decrease in plasma citrulline. The findings reflect a decrease in intestinal functional activity. PWE preserved the intestinal integrity and largely protected against the changes induced in the histology damage score and all parameters measured, possibly as a result of the antioxidant and anti-inflammatory action of its caffeic acid content.

Effect of selective COX-2 inhibitor, celecoxib on adjuvant-induced arthritis model in irradiated rats.

PURPOSE: The potential value of celecoxib was compared to a standard non-steroidal anti-inflammatory drug (NSAID), diclofenac in the adjuvant-induced arthritis (AIA) model in rats as a model of chronic inflammation under the influence of ionising radiation. MATERIAL AND METHODS: Various inflammatory mediators and biochemical parameters were measured in the arthritic rats under the influence of ionising radiation. RESULTS: Exposure of the animals to a radiation dose of 2 Gy before inoculation of the adjuvant led to a marked increase in the paw volume reaching ca. 70% more than that in non-irradiated ones as well as a significant increase in the levels of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) as an index of cyclooxygenase-2 (COX-2) activity, thromboxane B2 (TXB2) as an index of cyclooxygenase-1 (COX-1) activity and plasma level of malondialdehyde (MDA). The blood glutathione (GSH) level was not affected by the dose of irradiation used while superoxidedismutase (SOD) activity was reduced. Treatment with celecoxib in a dose of 5 mg/kg was effective in decreasing the elevated levels of IL-6, IL-1ß, TNF-α, PGE2 whereas it lacked any effect on TXB2 level since it had hardly any effect on COX-1 enzyme. Both drugs at the selected dose levels showed no effect on level of MDA, GSH and SOD activity. CONCLUSION: Irradiation of animals caused a marked change in the inflammatory response in AIA model of inflammation. Both celecoxib and diclofenac were nearly equipotent in suppressing the inflammatory response in both normal and irradiated rats. Accordingly, since the inhibition of COX-1 by traditional NSAID is thought to have undesirable side-effects on proliferating tissues, it would seem preferable to use selective COX-2 inhibitors to limit such deleterious effect.