Search

Mona Mohamed El-Naa,1 Mohamed Othman,2,3 Sheren Younes4,5 1Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA), 6 October City, Egypt; 2Preparatory Year College, University of Hail, Hail, Kingdom of Saudi Arabia; 3Faculty of Biotechnology, October University for Modern Science and Arts (MSA), 6 October City, Egypt; 4Pathology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt; 5College of Medicine, Princess Nora Bint Abdulrahman University, Riyadh, Kingdom of Saudi ArabiaAbstract: Sildenafil is the first phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. However, recent studies have been suggesting an antitumor effect of sildenafil. The current study assessed the aforementioned activity of sildenafil in vivo and in vitro in solid-tumor-bearing mice and in a human cell line MCF-7, respectively. Moreover, we investigated the impact of sildenafil on cisplatin antitumor activity. The solid tumor was induced by inoculation of Ehrlich ascites carcinoma cells in female mice. The tumor-bearing mice were assigned randomly to control (saline), sildenafil (sildenafil 5 mg/kg/d, PO daily for 15 days), cisplatin (cisplatin 7.5 mg/kg, IP once on the 12th day of Ehrlich ascites carcinoma inoculation), and combination therapy (cisplatin and sildenafil) groups. The tumor volume was measured at the end of the treatment period along with the following parameters: angiogenin, vascular endothelial growth factor, tumor necrosis factor-α, Ki-67, caspase-3, DNA-flow cytometry analysis, and histopathological examination. The study results showed that sildenafil has significantly decreased the tumor volume by 30.4%, angiogenin and tumor necrosis factor-α contents, as well as vascular endothelial growth factor expression. Additionally, caspase-3 level significantly increased with sildenafil treatment, whereas Ki-67 expression failed to show any significant changes. Furthermore, the cell cycle analysis revealed that sildenafil was capable of improving the category of tumor activity from moderate to low proliferative. Sildenafil induced necrosis in the tumor. Moreover, the drug of interest showed cytotoxic activity against MCF-7 in vitro as well as potentiated cisplatin antitumor activity in vivo and in vitro. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating the antitumor effect of conventional chemotherapeutic agents such as cisplatin. These effects might be related to antiangiogenic, antiproliferative, and apoptotic activities of sildenafil.Keywords: sildenafil, phosphodiesterase-5, breast cancer, angiogenesis, proliferation, apoptosis

Stress is a condition affecting different body systems. Curcumin (CUR) is a natural compound that has various pharmacological benefits. However, its poor oral bioavailability limits its therapeutic value. This study aimed to formulating curcumin loaded chitosan nanoparticles (CS.CUR.NPs) and investigate its gastroprotective and neuroprotective effects in rats subjected to cold restraint stress (CRS), in reference to conventional oral CUR preparation, and explore its underlying mechanism. Treated groups received either CUR or CS.CUR.NPs (100 mg∕kg) orally for 14 days before exposure to CRS. CRS elicited marked behavioral changes and gastric ulcer accompanied by histopathological abnormalities of the brain and stomach along with elevation of pain score. CUR and CS.CUR.NPs improved stress-induced gastric ulcer, cognitive performance, and pain sensation. Mechanistically, CRS disrupts oxidative and inflammatory status of the brain as manifested by high malondialdehyde and IL-6 and low total antioxidant capacity and IL-10, along with high C-reactive protein level. CRS decreased nuclear factor erythroid 2-related factor2 (Nrf2) and increased nuclear factor-kappa B (NF-κB) expressions. Furthermore, brain levels of unphosphorylated signal transducer and activator of transcription3 (U-STAT3) and glial fibrillary acidic protein (GFAP) were upregulated with stress. CUR and CS.CUR.NPs provided beneficial effects against harmful consequences resulting from stress with superior beneficial effects reported with CS.CUR.NPs. In conclusion, these findings shed light on the neuroprotective effect of CUR and CS.CUR.NPs against stress-induced neurobehavioral and neurochemical deficits and protection against stress-associated gastric ulcer. Moreover, we explored a potential crosslink between neuroinflammation, U-STAT3, NF-κB, and GFAP in brain dysfunction resulted from CRS., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The use of doxorubicin (DOX) to treat various tumors is limited by its cardiotoxicity. This study aimed to investigate and compare the cardioprotective effects of nicotinamide (NAM) and alfacalcidol (1α(OH)D 3 ), against DOX-induced cardiotoxicity. Sprague Dawley male rats received DOX (5 mg/kg, i.p.) once/week for four consecutive weeks. Treated groups received either NAM (600 mg/kg, p.o.) for 28 consecutive days or 1α(OH)D 3 (0.5 ug/kg, i.p.) once/week for four consecutive weeks. DOX elicited marked cardiac tissue injury manifested by elevated serum cardiotoxicity indices, conduction and histopathological abnormalities. Both NAM and 1α(OH)D 3 successfully reversed all these changes. From the mechanistic point of view, DOX provoked intense cytosolic and mitochondrial calcium (Ca 2+ ) overload hence switching on calpain1 (CPN1) and mitochondrial-mediated apoptotic cascades as confirmed by upregulating Bax and caspase-3 while downregulating Bcl-2 expression. DOX also disrupted cardiac bioenergetics as evidenced by adenosine triphosphate (ATP) depletion and a declined ATP/ADP ratio. Moreover, DOX upregulated the Ca 2+ sensor; calmodulin kinase II gamma (CaMKII-δ) which further contributed to cardiac damage. Interestingly, co-treatment with either NAM or 1α(OH)D 3 reversed all DOX associated abnormalities by preserving Ca 2+ homeostasis, replenishing ATP stores and obstructing apoptotic events. Additionally, DOX prompted nuclear factor kappa B (NF-κB) dependent inflammatory responses and subsequently upregulated interleukin-6 (IL-6) expression. Co-treatment with NAM or 1α(OH)D 3 effectively obstructed these inflammatory signals. Remarkably, NAM showed superior beneficial cardioprotective properties over 1α(OH)D 3 . Both NAM and 1α(OH)D 3 efficiently attenuated DOX-cardiomyopathy mainly via preserving Ca 2+ homeostasis and diminishing apoptotic and inflammatory pathways. NAM definitely exhibited effective cardioprotective capabilities over 1α(OH)D 3 ., (Copyright © 2021. Published by Elsevier Masson SAS.)

Tissue factor (TF) is a blood coagulation factor that has several roles in many non-coagulant pathways involved in different pathological conditions such as angiogenesis, inflammation and fibrogenesis. Coagulation and inflammation are crosslinked with liver fibrosis where protease-activated receptor1 (PAR1) and toll-like receptor4 (TLR4) play a key role. Antisense oligodeoxynucleotides are strong modulators of gene expression. In the present study, antisense TF oligodeoxynucleotides (TFAS) was evaluated in treating liver fibrosis via suppression of TF gene expression. Liver fibrosis was induced in rats by a single administration of N-diethyl nitrosamine (DEN, 200 mg/kg; i. p.) followed by carbon tetrachloride (CCl4, 3 ml/kg; s. c.) once weekly for 6 weeks. Following fibrosis induction, liver TF expression was significantly upregulated along with liver enzymes activities and liver histopathological deterioration. Alpha smooth muscle actin (α-SMA) and transforming growth factor-1beta (TGF-1β) expression, tumor necrosis factor-alpha (TNF-α) and hydroxyproline content and collagen deposition were significantly elevated in the liver. Blocking of TF expression by TFAS injection (2.8 mg/kg; s. c.) once weekly for 6 weeks significantly restored liver enzymes activities and improved histopathological features along with decreasing the elevated α-SMA, TGF-1β, TNF-α, hydroxyproline and collagen. Moreover, TFAS decreased the expression of both PAR1 and TLR4 that were induced by liver fibrosis. In conclusion, we reported that blockage of TF expression by TFAS improved inflammatory and fibrotic changes associated with CCl4+DEN intoxication. In addition, we explored the potential crosslink between the TF, PAR1 and TLR4 in liver fibrogenesis. These findings offer a platform on which recovery from liver fibrosis could be mediated through targeting TF expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shouman, Abdelsalam, Tawfick, Kenawy and El-Naa.)

Background: Nymphaea alba L. represents an interesting field of study. Flowers have antioxidant and hepatoprotective effects, rhizomes constituents showed cytotoxic activity against liver cell carcinoma, while several Nymphaea species have been reported for their hepatoprotective effects. Leaves of N. alba have not been studied before. Therefore, in this study, in-depth characterization of the leaf phytoconstituents as well as its antioxidant and hepatoprotective activities have been performed where N. alba leaf extract was evaluated as a possible therapeutic alternative in hepatic disorders., Methods: The aqueous ethanolic extract (AEE, 70%) was investigated for its polyphenolic content identified by high-resolution electrospray ionisation mass spectrometry (HRESI-MS/MS), while the petroleum ether fraction was saponified, and the lipid profile was analysed using gas liquid chromatography (GLC) analysis and compared with reference standards. The hepatoprotective activity of two doses of the extract (100 and 200 mg/kg; P.O.) for 5 days was evaluated against CCl 4 -induced hepatotoxicity in male Wistar albino rats, in comparison with silymarin. Liver function tests; aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT) and total bilirubin were performed. Oxidative stress parameters; malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (TAC) as well as inflammatory mediator; tumour necrosis factor (TNF)-α were detected in the liver homogenate. Histopathological examination of the liver and immunohistochemical staining of caspase-3 were performed RESULTS: Fifty-three compounds were tentatively identified for the first time in N.alba leaf extract, where ellagitannins represent the main identified constituents. Nine hydrocarbons, two sterols and eleven fatty acids were identified in the petroleum ether extract where, palmitic acid and linolenic acids represented the major saturated and unsaturated fatty acid respectively. N.alba AEE significantly improved the liver function, oxidative stress parameters as well as TNF-α in addition to the amelioration of histopathological features of the liver and a profound decrease in caspase-3 expression., Conclusion: These results shed light on the hepatoprotective effect of N. alba that is comparable with that of silymarin. The antioxidant activities of N. alba extract in addition to the inhibition of crucial inflammatory mediator, as TNF-α, might be the possible hepatoprotective mechanisms.

Objectives: Peroxisome proliferator activated receptor-gamma (PPAR-γ) has been shown to play an important role in the control of immunological and inflammatory responses. This study aims at investigating the potential role of rosiglitazone, a strong PPAR-γ agonist in a murine model of bronchial asthma., Methods: Adult male guinea pigs were administered ovalbumin 100 mg/kg subcutaneous (SC) and 100 mg/kg intraperitoneal (IP). Treatment with rosiglitazone [5 mg/kg/day, per oral (PO)] was assessed for 21 days. On day 21, the animals were challenged with the same dose of ovalbumin. The forced expiratory volume in 1 s (FEV1 ) to forced vital capacity (FVC), FEV1 /FVC, was measured using a spirometer to diagnosis lung obstruction. Serum levels of interleukin-5 (IL-5) and immunoglobulin E (IgE) were assessed. The activity of superoxide dismutase (SOD) and catalase and the level of reduced glutathione (GSH) were determined in lung tissue homogenates., Key Findings: Our results demonstrated that treatment with rosiglitazone resulted in a statistically significant improvement in lung function and histopathological features. Significant decrease in the serum levels of IL-5 and IgE were observed. The activity of SOD and catalase as well as the GSH level were significantly increased in the lung tissues of treated animals compared with untreated asthmatic animals. Serum IgE concentrations and IL-5 levels were directly correlated to each other and inversely correlated to the SOD, GSH and catalase levels in the all studied guinea pigs., Conclusions: Our results provide evidence that the PPAR-γ agonist rosiglitazone may have potential in the development of therapies for bronchial asthma., (© 2015 Royal Pharmaceutical Society.)

Various flavonoid scaffold based derivatives viz furochalcones (3a-e, 6a-d and 9a-d), furoflavones (10a-d, 11a-d, 12a-d, 18a&b), flavones (21a-d), furoaurones (13a,b, 14a-d and 15a-d) and 7-styrylfurochromones (22a-d and 25a-e) were designed and synthesized. The novel compounds were evaluated for their antiproliferative activity against a panel of 60 cancer cell lines comprising 9 types of tumors. Ten compounds belonging to the major subgroups of flavonoids viz furochalcones (3a, 3d, 6b, 9a and 9b), furoflavones (12a and 12c), furoaurones (15d), styrylfurochromones (25b and 25e) showed very promising activity. These active compounds were also evaluated in vitro as kinase inhibitors against CDK2/cyclin E1, CDK4/cyclin D1 and GSK-3β and the best inhibition was displayed against GSK-3β with the allylfurochalcone derivative 9b exhibiting 80% decrease in GSK-3β catalytic activity. On the other hand, the styrylfurochromone 25e interestingly showed a 13% enhancement of GSK-3β catalytic power and a 12% reduction in CDK4/cyclin D1 activity. Finally, the in vivo anti-tumor activity of 25e was evaluated against breast cancer induced in mice. The results showed a profound anti-tumor effect of 25e that accompanies a significant increase and decrease in the levels of GSK-3β and cyclin D1, respectively., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Unlabelled: This study aims at investigating the anti-tumor effect of caffeic acid phenethyl ester (CAPE) against animal carcinogenesis. In order to substantiate this fact implanted tumor Ehrlich carcinoma cells were assessed in vivo to Swiss mice strain. We found that administrating of CAPE (15 mg/kg S.C.) showed that the tumor volume decreased significantly by 51%. As a result, it improved animal chances of survival and they became healthier. An anti-angiogenic effect of CAPE in vivo was observed, as determined by a significant serum matrix metalloproteinase (MMP-9) reduction (142.1 ng/ml), activation of endostatin serum level (1.9 ng/ml), as well as DNA fragmentation in tumor treated mice when compared with untreated ones., Conclusion: CAPE has a significant inhibitory effect on tumor in vivo. This inhibition may be related to its angiostatic and apoptotic effects. It also reduced angiogenic factors which may shift the equilibrium to the angiostatic effect of CAPE. These findings provide the possibility for the future use of CAPE as tumor therapy in human clinical trials., ((c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Cytokines and nitric oxide (NO) are involved in the pathogenesis of autoimmune diabetes mellitus (DM). Rosiglitazone is an insulin-sensitizing drug that is a ligand for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The anti-inflammatory and immunomodulating properties of PPAR-gamma have been documented. The aim of this study is to investigate the effectiveness of rosiglitazone in autoimmune DM and to clarify the possible mechanism(s) involved. Autoimmune DM was induced in adult male Balb/c mice by co-administration of cyclosporin A and multiple low doses of streptozotocin. Diabetic mice were treated daily with rosiglitazone (7 mg/kg, p.o.) for 21 days. Blood glucose level (BGL), serum insulin level and pancreatic levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and NO were measured. Histopathological examination and immunohistochemical determination of CD4 and CD8 T lymphocytes in the pancreatic islets were performed. In addition, analysis of pancreatic protein expression was carried out. The results showed that rosiglitazone treatment resulted in a significant decrease in the BGL and the pancreatic levels of TNF-alpha, IFN-gamma and NO compared to diabetic mice. The serum insulin level was significantly increased after rosiglitazone treatment compared to diabetic mice. The destroyed pancreatic islets were regenerated and became free from both CD4 and CD8 T cells after treatment. Furthermore, many changes in pancreatic protein expression were observed. These results suggest that rosiglitazone has a beneficial effect in the treatment of autoimmune diabetes, an effect that seemed to be a secondary consequence of its anti-inflammatory and immunomodulating properties and might be reflected at the level of protein expression.