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E
Saleh, D. O., S. A. El-Awdan, S. M. Nofel, W. I. El-Eraky, A. S. el-Khatib, and S. A. Kenawy, "ESTROGENS IMPROVE THE CARDIOVASCULAR ALTERATIONS IN FRUCTOSE-INDUCED INSULIN RESISTANT OVARIECTOMIZED RATS", Int. J. Pharm. Pharm. Sci, vol. 7, issue 7, pp. 241-247, 2015.
H
El-Mezayen, N. S., W. F. El-Hadidy, W. M. El-Refaie, T. I. Shalaby, M. M. Khattab, and A. S. El-Khatib, "Hepatic stellate cell-targeted imatinib nanomedicine versus conventional imatinib: A novel strategy with potent efficacy in experimental liver fibrosis.", Journal of controlled release : official journal of the Controlled Release Society, vol. 266, pp. 226-237, 2017 Nov 28. Abstract

Liver fibrosis is a global health problem without approved treatment. Imatinib inhibits two key profibrotic pathways; platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) and thus can be used to treat liver fibrosis. However, conventional imatinib therapy is hampered by low concentration at target tissue and increased toxicity to other tissues especially heart, lung and liver. Since hepatic stellate cells (HSCs) are the main contributors to liver fibrosis pathogenesis and sole hepatic vitamin A (V) storage cells, they can be actively targeted by coupling liposomes to V. In this study, novel V-coupled imatinib-loaded liposomes (ILC) were prepared and optimized regarding V-coupling efficiency, imatinib entrapment efficiency, and particle size. Preferential accumulation of the selected formula in liver was proved by tracing intraperitoneally (i.p.)-injected V-coupled liposomes loaded with Nile Red (LCNR) to rats with CCl-induced liver fibrosis using live animal imaging. Co-localization of LCNR with immunofluorescently-labeled PDGFR-β in frozen liver tissue sections confirmed HSCs targeting. ILC bio-distribution, following single i.p. injection, revealed 13.5 folds higher hepatic accumulation than conventional imatinib in addition to limited bio-distribution to other organs including heart and lung reflecting diminished adverse effects. ILC therapy resulted in a potent inhibition of phosphorylated PDGFR-β expression when compared to conventional imatinib. Subsequently, there was a statistically significant improvement in liver function tests and reversal of hepatotoxicity along with liver fibrosis. Anti-fibrotic effect was evident from histopathologic Ishak score reduction as well as normalization of the level of profibrotic mediators (hydroxyproline, TGF-B and matrix metalloproteinase-2). Thus, HSC-targeted imatinib therapy shows outstanding anti-fibrotic effects with reduced cytotoxicity compared to conventional imatinib. It can represent a promising novel approach for liver fibrosis treatment.

O
El-Mezayen, N. S., W. F. El-Hadidy, W. M. El-Refaie, T. I. Shalaby, M. M. Khattab, and A. S. El-Khatib, "Oral vitamin-A-coupled valsartan nanomedicine: High hepatic stellate cell receptors accessibility and prolonged enterohepatic residence.", Journal of controlled release : official journal of the Controlled Release Society, vol. 283, pp. 32-44, 2018 Aug 10. Abstract

So far, liver fibrosis still has no clinically-approved treatment. The loss of stored vitamin-A (V) in hepatic stellate cells (HSCs), the main regulators to hepatic fibrosis, can be applied as a mechanism for their targeting. Valsartan is a good candidate for this approach; it is a marketed oral-therapy with inverse- and partial-agonistic activity to the over-expressed angiotensin-II type1 receptor (AT1R) and depleted nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ), respectively, in activated HSCs. However, efficacy on AT1R and PPAR-γ necessitates high drug permeability which is lacking in valsartan. In the current study, liposomes were used as nanocarriers for valsartan to improve its permeability and hence efficacy. They were coupled to V and characterized for HSCs-targeting. Tracing of orally-administered fluorescently-labeled V-coupled liposomes in normal rats and their fluorescence intensity quantification in different organs convincingly demonstrated their intestinal entrapment. On the other hands, their administration to rats with induced fibrosis revealed preferential hepatic, and less intestinal, accumulation which lasted up to six days. This indicated their uptake by intestinal stellate cells that acted as a depot for their release over time. Confocal microscopical examination of immunofluorescently-stained HSCs in liver sections, with considerable formula accumulation, confirmed HSCs-targeting and nuclear uptake. Consequently, V-coupled valsartan-loaded liposomes (VLC)-therapy resulted in profound re-expression of hepatic Mas-receptor and PPAR-γ, potent reduction of fibrogenic mediators' level and nearly normal liver function tests. Therefore, VLC epitomizes a promising antifibrotic therapy with exceptional extended action and additional PPAR-γ agonistic activity.

S
Saleh, D. O., A. R. Bayoumi, W. I. El-Eraky, and A. S. El-Khatib, "Streptocin-induced vascular and biochemical changes in rats: Effects of rosiglitazone vs. metformin", Bulletin of Faculty of Pharmacy, Cairo University, vol. 51, pp. 131-138, 2013.
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