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Rutin (RUT) is a biologically active flavonoid that is reported to modulate radiation-induced brain dysfunctions. However, RUT's poor water solubility and low brain bioavailability limit its clinical use. To increase its brain bioavailability, RUT was loaded onto nanoplatforms based on chitosan/diacrylated pluronic (CS/DA-PLUR) nanogels synthesized by gamma radiation. The optimized formulation was investigated as a carrier system for RUT. Based on pilot experiments' results, the cranial radiation (CR) dose that induced cognitive dysfunction was selected. In the main experiment, rats were pre-treated orally with either free RUT or RUT-CS/DA-PLUR. Rats' cognitive and motor functions were assessed; 24 h later, rats were sacrificed, and the whole brain was separated for histopathological examination and biochemical estimation of brain content of acetylcholine esterase (AChE), neurotransmitters, oxidative stress markers, and interleukin-1β. CR produced prominent impairment in spatial and non-spatial learning memory, motor coordination, and muscular strength. Moreover, histopathological and biochemical alterations in brain contents of neurotransmitters, oxidative stress, and interleukin-1β were induced by CR. Conversely, RUT-CS/DA-PLUR, but not free RUT, successfully guarded against all the detrimental effects induced by CR. Based on the current findings, loading of RUT enhanced its bioavailability and therapeutic effectiveness by restoring the cognitive functions impaired by CR.

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.

Nicotine is an active pharmacological ingredient in cigarette smoke, which may negatively influence the male reproductive system and fertility. This study aims to investigate the effect of fractionated low-dose radiation (fractionated-LDR) and/or ellagic acid (EA) on nicotine-induced hormonal changes and testicular toxicity in rats. Nicotine was administrated orally (1 mg/kg) for 30 days, afterward, rats were treated with LDR (2 × 0.25 Gy/1-week interval), EA (10 mg/kg, 14 consecutive days p.o.), or a combination of both fractionated-LDR and EA. Rats were sacrificed 24 h after the last dose of treatment, then testes were dissected for histopathology examination, along with some biochemical parameters in serum and testicular tissue were evaluated. Nicotine-induced oxidative stress was evidenced by an increase in testicular thiobarbituric acid reactive substances (TBARS) and a decrease in reduced glutathione (GSH) content. Additionally, the activities of testicular androgenic enzymes were decreased, and the activity of serum lactate dehydrogenase (LDH) was significantly increased. The hormonal changes were verified by a noticeable reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone serum levels. Histological evaluation revealed that the testicular seminiferous tubules structure was distorted. On the contrary, fractionated-LDR plus EA attenuated the negative changes caused by nicotine observed through biochemical and histological findings. Accordingly, the exposure to fractionated-LDR combined with EA may be a promising candidate for treating hormonal changes and testicular toxicity caused by nicotine.

Transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) is an effective route of drug administration, as it directs the drug to the inflamed site with reduced incidence of systemic adverse effects such as gastric hemorrhage and ulcers. Tenoxicam (TNX) is a member of NSAIDs that are marketed only as oral tablets due to very poor absorption through the skin. The current study intended to formulate and characterize a hydrogel loaded with nanostructured lipid carriers (NLCs) to enhance the transdermal delivery of TNX. Six formulations of TNX were formulated by slight modifications of high shear homogenization and ultrasonication method. The selected formula was characterized for their particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE), in-vitro drug release and ex-vivo skin permeation studies. Moreover, the effectiveness of the developed formula was studied in-vivo using carrageenan-induced paw edema and hyperalgesia model in irradiated rats. Formula F4 was chosen from six formulations, as the average diameter was 679.4 ± 51.3 nm, PDI value of about 0.02, zeta potential of −4.24 mV, EE of 92.36%, globules nanoparticles without aggregations and absence of interactions in the developed formula. Additionally, the in-vivo study showed the efficacy of formula F4 (TNX-NLCs hydrogel) equivalent to oral TNX in reducing the exaggerated inflammatory response induced by carrageenan after irradiation. In conclusion, the present findings suggest that TNX-NLCs hydrogel could be a potential transdermal drug delivery system alternative to the oral formulation for the treatment of various inflammatory conditions.

Aim of the work: Resveratrol (RSV) is a phytoalexin with potent anti-inflammatory and anti-oxidant properties; however, its low bioavailability is considered a major obstacle. Piperine (PIP), an alkaloid, has been widely used as an effective bio-enhancer with drugs associated with low bioavailability. The current study was directed to examine the role of PIP in enhancing the efficacy of RSV in adjuvant-induced arthritis (AIA) in rats. Materials and methods: Carrageenan-induced paw edema model was designed for RSV and PIP doses optimization. Afterward, in the AIA model, rats were immunized at day 0 by sub-plantar injection of Freund’s complete-adjuvant. RSV (50 mg/kg) and PIP (20 mg/kg) were orally administered concurrently once daily from day 14 for two weeks. A standard anti-inflammatory drug, diclofenac, was employed for treatment validation. The paw volume was measured every 4 days. On day 29, rats were sacrificed and serum tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NOx) were estimated. Ankles were dissected for histopathological examinations and immuno-histochemical expression of nuclear factor-kappa B p65 (NF-κB p65). Results: Co-administration of RSV and PIP significantly decreased the paw swelling and ameliorated the histopathological changes. In addition, the combined treatment highly reduced the serum TNF-α, IL-1β, TBARS and NOx. Besides, a nearly negative expression of NF-κB p65 in the synovial tissue was observed by co-administration of PIP with RSV. Results of the combination treatment were comparable to that of the diclofenac treatment. Conclusion: Co-administration of PIP enhanced the anti-inflammatory efficacy of RSV in the arthritic-induced rats. Keywords: Adjuvant-induced arthritis, Resveratrol, Piperine, Inflammation, Cytokines, Oxidative stress

Nicotine is an active pharmacological ingredient in cigarette smoke, which may negatively influence the male reproductive system and fertility. This study aims to investigate the effect of fractionated low-dose radiation (fractionated-LDR) and/or ellagic acid (EA) on nicotine-induced hormonal changes and testicular toxicity in rats. Nicotine was administrated orally (1 mg/kg) for 30 days, afterward, rats were treated with LDR (2 × 0.25 Gy/1-week interval), EA (10 mg/kg, 14 consecutive days p.o.), or a combination of both fractionated-LDR and EA. Rats were sacrificed 24 h after the last dose of treatment, then testes were dissected for histopathology examination, along with some biochemical parameters in serum and testicular tissue were evaluated. Nicotine-induced oxidative stress was evidenced by an increase in testicular thiobarbituric acid reactive substances (TBARS) and a decrease in reduced glutathione (GSH) content. Additionally, the activities of testicular androgenic enzymes were decreased, and the activity of serum lactate dehydrogenase (LDH) was significantly increased. The hormonal changes were verified by a noticeable reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone serum levels. Histological evaluation revealed that the testicular seminiferous tubules structure was distorted. On the contrary, fractionated-LDR plus EA attenuated the negative changes caused by nicotine observed through biochemical and histological findings. Accordingly, the exposure to fractionated-LDR combined with EA may be a promising candidate for treating hormonal changes and testicular toxicity caused by nicotine.

Purpose: Low dose radiation has been reported as an effective treatment for rheumatoid arthritis via multiple dose exposures. The present study was designed to increase the therapeutic efficacy of ...

Intestinal mucositis is a common side effect during radiotherapy that could be largely prevented by compounds possessing anti-inflammatory or anti-oxidant properties, including extracts of propolis containing a high proportion of flavonoids. A specially formulated aqueous extract of propolis (PWE) has been prepared in such a way to preclude the inclusion of flavonoids but contain mostly organic aromatic acids to study whether it would still protect against radiation-induced intestinal mucositis and to study the possible involvement of apoptotic pathways. Rats were exposed to a gamma radiation dose of 8 Gy from a Cesium-137 source in order to inflict intestinal mucositis. Three days before exposure, rats were given PWE orally and treatment continued for 2 more days. Twenty-four hours later, rats were sacrificed, the small intestine was excised, and sections were examined histologically. Different parameters for apoptosis, inflammation, and oxidative stress were determined in the serum and in intestinal homogenates. Radiation exposure led to histological and biochemical signs of intestinal damage. This was associated with an increase in apoptotic indicators and derangement in oxidative stress parameters. All deranged parameters were largely prevented by PWE. The findings provide evidence that the protective effect of PWE against intestinal radiation damage involves not only its anti-inflammatory and anti-oxidant effects but also its anti-apoptotic properties as well.

Compounds that prevent radiation-induced mucositis may offer new therapeutic strategies for maintaining intestinal integrity in patients undergoing radiotherapy. A specially formulated chamomile extract was studied with the hope of proving efficacy in this regard. Intestinal mucositis was induced in rats by exposing them to whole body gamma-irradiation. Rats were treated orally with the extract for 5 days before and 2 days after radiation exposure. One day later, rats were sacrificed. Histological examination of segments of small intestine showed shortening and fusion of villi, activation of mucus secreting glands, inflammatory cell infiltration of lamina propria, and mucosal atrophy. Intestinal homogenates showed an increase in tumor necrosis factor, a pro-inflammatory cytokine, and myeloperoxidase, an indicator of cellular infiltration, as well as in thiobarbituric acid reactive substances and a reduction in glutathione content. Intestinal injury was further evidenced by an increase in diamine oxidase and a reduction in citrulline levels in the serum. A rise in apoptosis was evidenced by an increase in cytosolic cytochrome c, caspase-3, and depletion of mitochondrial B-cell lymphoma-2/ Bax ratio. Most histological changes and associated derangement in related parameters were largely prevented by the chamomile extract, thus paving the way to a new therapeutic approach towards the management of radiation-induced intestinal mucositis.