Essam, R. M., L. A. Ahmed, R. M. Abdelsalam, and A. S. El-Khatib, "Phosphodiestrase-1 and 4 inhibitors ameliorate liver fibrosis in rats: Modulation of cAMP/CREB/TLR4 inflammatory and fibrogenic pathways.", Life sciences, 2019. Abstract

BACKGROUND: Phosphodiestrase (PDE) enzymes are suggested to play a leading role in fibrogenesis of liver where studies showed the possible implication of PDE 1 & 4 in liver injury proposing them as possible targets for treating liver fibrosis.

AIM: The present study was designed to investigate, for the first time, the possible therapeutic effects of selective inhibitors of PDE-1 (vinpocetine) and PDE-4 (roflumilast) in liver fibrosis induced by diethylnitrosamine (DEN) in rats.

MAIN METHODS: Rats were given DEN (100 mg/kg, i.p.) once weekly for 6 weeks to induce liver fibrosis. Vinpocetine (10 mg/kg/day) or roflumilast (0.5 mg/kg/day) was then orally administered for 2 weeks.

KEY FINDINGS: Vinpocetine significantly suppressed the contents of hydroxyproline, transforming growth factor-beta 1 (TGF-β1), nuclear factor-kappa B (NF-κB) whereas roflumilast normalized them. Moreover, tumor necrosis factor-alpha (TNF-α) content and protein expressions of toll-like receptor 4 (TLR4) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly decreased whereas cAMP response element binding (CREB) protein expression was significantly elevated by both treatments. Additionally, vinpocetine and roflumilast up-regulated the gene expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) receptor where roflumilast showed better results. PDE1 and 4 activities were inhibited by vinpocetine and roflumilast, respectively. The superior results offered by roflumilast could be related to the higher cAMP level obtained relative to vinpocetine.

SIGNIFICANCE: Our study manifested the up-regulation of PDE enzymes (1 & 4) in liver fibrosis and addressed the therapeutic role of vinpocetine and roflumilast as PDEIs through a cAMP-mediated TLR4 inflammatory and fibrogenic signaling pathways.

El Khashab, I. H., R. M. Abdelsalam, A. I. Elbrairy, and A. S. Attia, "Chrysin attenuates global cerebral ischemic reperfusion injury via suppression of oxidative stress, inflammation and apoptosis.", Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, vol. 112, pp. 108619, 2019 Feb 20. Abstract

Global cerebral ischemia is a leading cause of mortality worldwide. Several biomechanisms play a role in the pathology of cerebral ischemia reperfusion damage, such as oxidative stress, inflammation, apoptosis and excitotoxicity. Chrysin, a natural flavonoid with many important biological activities, was investigated in the present study for its possible neuroprotective properties in a rat model of global ischemia reperfusion. Male Wistar rats were allocated into three groups: sham-operated, ischemia/reperfusion, and chrysin (30 mg/kg) groups. All animals were subjected to ischemia for 15 min followed by reperfusion for 60 min, except for the sham-operated group. Rats were decapitated, then both hippocampi were rapidly excised to evaluate several biomarkers that reflect ischemic injury. The obtained results showed that pre-treatment with chrysin attenuated ischemia-induced oxidative stress by: (i) restoring the glutathione level; and (ii) depressing the levels/activities of thiobarbituric acid reactive substances, the hippocampal NADPH, as well as the xanthine oxidase. Exposure to chrysin also suppressed the inflammation accompanying the ischemia/reperfusion (I/R) damage, through increasing the interleukin-10 level, while decreasing the levels of both interleukin-6 and tumour necrosis factor-alpha. Moreover, an increase in Bcl2 and a decrease in both BAX and Hsp90 levels were recorded following chrysin exposure, which was also accompanied with elevated glutamate and aspartate levels. In conclusion, chrysin has demonstrated an anti-ischemic potential, through attenuation of the mechanisms underlying I/R injury. These data add to the knowledge on the significance of natural flavonoids as neuroprotective agents.

Hassan, N. F., S. A. Nada, A. Hassan, M. R. El-Ansary, M. Y. Al-Shorbagy, and R. M. Abdelsalam, "Saroglitazar Deactivates the Hepatic LPS/TLR4 Signaling Pathway and Ameliorates Adipocyte Dysfunction in Rats with High-Fat Emulsion/LPS Model-Induced Non-alcoholic Steatohepatitis.", Inflammation, 2019 Feb 09. Abstract

The most epidemic liver disorder non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with hepatocellular damage. Recently, it is predictable to be the extensive cause for liver transplantation. The absence of an approved therapeutic agent for NASH is the reason for investigating saroglitazar (SAR) which showed promising effects as a dual PPAR-α/γ agonist in recent studies on NASH. Here, we aimed to investigate the effect of SAR on NASH induced in rats by the administration of high-fat emulsion (HFE) and small doses of lipopolysaccharides (LPS) for 5 weeks. Rats were divided into three groups: negative control group (saline and standard rodent chow), model group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p)), and SAR-treated group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p.) + SAR(4 mg/kg/day, oral gavage) starting at week 3.Treatment with SAR successfully ameliorated the damaging effects of HFE with LPS, by counteracting body weight gain and biochemically by normalization of liver function parameters activity, glucose, insulin, homeostasis model of assessment (HOMA-IR) score, lipid profile levels, and histopathological examination. Significant changes in adipokine levels were perceived, resulting in a significant decline in serum leptin and tumor necrosis factor-α (TNF-α) level concurrent with adiponectin normalization. The positive effects observed for SAR on NASH are due to the downregulation of the LPS/TLR4 pathway, as indicated by the suppression of hepatic Toll-like receptor 4 (TLR4), NF-κB, TNF-α, and transforming growth factor-β1 (TGF-β1) expression. In conclusion, this work verified that SAR ameliorates NASH through deactivation of the hepatic LPS/TLR4 pathway and inhibition of adipocyte dysfunction.

Atwa, A., R. Hegazy, R. M. Abdelsalam, N. Yassin, and S. A. Kenawy, "Protective Effects of the Third Generation Vasodilatory Βeta-Blocker Nebivolol against D-Galactosamine-Induced Hepatorenal Syndrome in Rats", Macedonian journal of medical sciences, vol. 5, issue 7, pp. 880, 2017.
A.M., G., E. A. H.S., and A. R.M., "CILOSTAZOL HEPATOPROTECTIVE EFFECT AGAINST ISCHEMIA/REPERFUSION: INVOLVEMENT OF GSK-3β, CYCLIN D1 and WNT/β-CATENIN PATHWAY", Journal of Pharmacology Research, vol. 4, issue 1, pp. 75-81, 2014.
Mahdi, Z. K., R. M. Abdelsalam, and A. M. Agha, "Resveratrol alleviates oxidative stress and inflammation in the hippocampus of rats subjected to global cerebral ischemia/reperfusion: Comparison with vitamin E", African journal of Pharmacy and Pharmacology, vol. 8, issue 27, pp. 727-736, 2014.
El-Ridy, M. S., A. A. Elbary, T. Essam, R. M. A. EL-Salam, and A. A. A. Kassem, "Niosomes as a potential drug delivery system for increasing the efficacy and safety of nystatin.", Drug development and industrial pharmacy, vol. 37, issue 12, pp. 1491-508, 2011 Dec. Abstract

Nonionic surfactant (NIS) vesicles (niosomes) formed from self-assembly of hydrated synthetic NIS monomers are capable of entrapping a variety of drugs and have been evaluated as an alternative to liposomes. Nystatin (NYS) is a polyene antifungal drug that has been used in the treatment of cutaneous, vaginal and oral fungal infections since the 1950s. The aim of this work is to encapsulate NYS in niosomes to obtain a safe and effective formula administered parenterally for neutropenic patients. NYS niosomes were prepared by the thin-film hydration method using Span 60 or Span 40 and cholesterol (CHOL). Stearylamine and dicetyl phosphate were added as the positive and negative charge-inducing agents (CIA), respectively. Two molar ratios were used, namely NIS/CHOL/CIA (1:1:0.1 and 2:1:0.25). Neutral and positively charged niosomes gave the highest encapsulation efficiencies. NYS niosomes were characterized using transmission electron microscopy, differential scanning calorimetry and dynamic light scattering. The release of neutral and negatively charged NYS niosomes was estimated, and it showed a slow sustained release profile. A 25-kGy γ-irradiation dose was sufficient to sterilize the investigated vesicles. NYS niosomes exerted less nephrotoxicity and hepatotoxicity in vivo, showed higher level of drug in vital organs and revealed pronounced efficacy in elimination of the fungal burden in experimental animals infected with Candida albicans compared with those treated with free NYS. Niosomal encapsulation thus provided means for parenteral administration of NYS, reducing its toxicity and making it a more active antifungal agent.

Abdelghany, T. M., R. M. Abdelsalam, A. S. Attia, and M. E. Elsayed, "Ramipril could attenuate thioacetamide-induced liver fibrosis in rats", the Faseb Journal, vol. abstract No.1267.1, 2016.
Asaad, M., R. M. Abdelsalam, S. A. Kenawy, and A. S. Attia, "Montelukast, a cysteinyl leukotriene receptor-1 antagonist protects against hippocampal injury induced by transient global cerebral ischemia and reperfusion in rats.", Neurochemical research, vol. 40, issue 1, pp. 139-50, 2015 Jan. Abstract

Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory and immune modulating lipid mediators involved in inflammatory diseases and were boosted in human brain after acute phase of cerebral ischemia. The antagonism of CysLTs receptors may offer protection against ischemic damage. Therefore it seemed interesting to study the possible neuroprotective effect of Montelukast, a CysLTR1 antagonist in global cerebral ischemia/reperfusion (IR) injury in rats. Global cerebral ischemia-reperfusion was induced by bilateral carotid artery occlusion for 15 min followed by 60 min reperfusion period. Animals were randomly allocated into three groups (n = 30 per group): Sham operated, I/R control and rats treated with montelukast (0.5 mg/kg, po) daily for 7 days then I/R was induced 1 h after the last dose of montelukast. After reperfusion rats were killed by decapitation, brains were removed and both hippocampi separated and the following biochemical parameters were estimated; lactate dehydrogenase activity, oxidative stress markers (lipid peroxides, nitric oxide and reduced glutathione), inflammatory markers (myeloperoxidase, tumor necrosis factor-alpha, nuclear factor kappa-B, interleukin-6 and interleukin-10), apoptotic biomarkers (caspase 3 and cytochrome C), neurotransmitters (glutamate, gamma aminobutyric acid), Cys-LTs contents and CysLT1 receptor expression; as well as total brain infarct size and histopathological examination of the hippocampus were assessed. Montelukast protected hippocampal tissue by reducing oxidative stress, inflammatory and apoptotic markers. Furthermore, it reduced glutamate and lactate dehydrogenase activity as well as infarct size elevated by I/R. These results were consistent with the histopathological findings. Montelukast showed a neuroprotective effects through antioxidant, anti-inflammatory and antiapoptotic mechanisms.

Badran, M. M., M. A. Hakeem, S. M. Abuel-Maaty, A. El-Malah, and R. M. Abdelsalam, "Design, synthesis, and molecular-modeling study of aminothienopyridine analogues of tacrine for Alzheimer's disease.", Archiv der Pharmazie, vol. 343, issue 10, pp. 590-601, 2010 Oct. Abstract

2-Amino-3-cyanothiophenes were successfully condensed with a number of cycloalkanones to afford tacrine analogues in a one-step reaction mediated with Lewis acid. The newly synthesized compounds have been tested for their ability to inhibit acetylcholine esterase (AChE) activity using tacrine as standard drug. Some of the tested compounds showed moderate inhibitory activity in comparison with tacrine, especially compounds 6a which displayed the highest inhibitory activity. Furthermore, molecular-modeling studies were performed in order to rationalize the obtained biological results.