Mansour, S. M., S. A. A. El-Aal, H. S. El-Abhar, K. A. Ahmed, and M. M. Awny, "Repositioning of Ticagrelor: Renoprotection mediated by modulating renin-angiotensin system, inflammation, autophagy and galectin-3", European Journal of Pharmacology, vol. 918:174793, issue 5, 2022.
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Soubh, A. A., A. A. El-Gazar, E. A. Mohamed, A. S. Awad, and H. S. El-Abhar, "Further insights for the role of Morin in mRTBI: Implication of non-canonical Wnt/PKC-α and JAK-2/STAT-3 signaling pathways", Int Immunopharmacol, vol. 100, pp. 108123, 2021.
Abdel Moneim, L. M., M. W. Helmy, and H. S. El-Abhar, "Co-targeting of endothelin- and vitamin D receptors: a novel strategy to ameliorate cisplatin-induced nephrotoxicity.", Pharmacological reports : PR, vol. 71, issue 5, pp. 917-925, 2019 Sep. Abstract

BACKGROUND: Although modulation of the vitamin D receptor (VDR) and endothelin- receptor (ETR) has previously been reported to offer renoprotection against cisplatin-induced nephrotoxicity, the possible interaction between the ET-1 and vitamin D pathways remains obscure. Therefore, the present study addressed the possible interaction between these signalling pathways using BQ-123 (a selective ETR blocker) and alfacalcidol (a vitamin D3 analogue) separately or in combination.

METHODS: Male Sprague-Dawley rats were divided into the following groups: control (DMSO orally), cisplatin (single dose of 6mg/kg ip; nephrotoxicity model), cisplatin + BQ-123 (1 mg/kg BQ-123 ip 1 h before and 1 day after cisplatin), cisplatin + alfacalcidol (50 ng/kg alfacalcidol orally 5 days before and 14 days after cisplatin), and cisplatin + BQ-123+alfacalcidol. Nephrotoxicity was evaluated 96 h and 14 days following cisplatin administration.

RESULTS: Both BQ-123 and alfacalcidol counteracted cisplatin-induced nephrotoxic changes. Specifically, they reduced serum creatinine and urea levels; renal tumour necrosis factor-alpha (TNF-ct), transforming growth factor-betal (TGF-pl), and phosphorylated nuclear factor-kappa B (pNF-KB) content; and caspase-3 activity. They downregulated ET-1 and ETR expression and ameliorated cisplatin-induced acute tubular necrosis. In addition, the treatments have increased VDR and endothelin- receptor (ETR) expression; however, BQ-123 did not affect ETR. The effect of the combination regimen surpassed that of each drug alone.

CONCLUSION: These findings highlight the potential cross-talk between vitamin D and ET-1 pathways and pave the way for future preclinical/clinical studies to explore further mechanisms involved in this crosstalk.

Gowayed, M. A., K. Rothe, M. Rossol, A. S. Attia, U. Wagner, C. Baerwald, H. S. El-Abhar, and R. Refaat, "The role of α7nAChR in controlling the anti-inflammatory/anti-arthritic action of galantamine.", Biochemical pharmacology, vol. 170, pp. 113665, 2019 Dec. Abstract

OBJECTIVE: The evolution of the "cholinergic anti-inflammatory pathway" and the fact that the α 7 subunit of the nicotinic acetylcholine receptor (α7nAChR) is present in the spleen, joint and on the surface of lymphocytes, opened up the prospective in this study of targeting the α7nAChR by the anticholinesterase and cholinergic drug, galantamine, to control inflammation in rheumatoid arthritis (RA).

METHODS: Twelve-adjuvant arthritic rats were exposed to the selective α7nAChR blocker methylcaconitine citrate 15 min before galantamine treatment. As control, six adjuvant arthritic rats were treated with galantamine and six others were untreated. After five days TNF-α levels were assessed in spleen and joints, while reduced glutathione was measured in blood and joint tissue. In the second part, magnetically sorted CD4 + T cells from peripheral blood mononuclear cells of RA patients and healthy donors were used to sort CD4 + CD25 - primary T cells (Tresp) and CD4 + CD25 + CD127low Tregs. The suppressive function of Tregs was investigated after incubation with galantamine using flow cytometry. Cell culture supernatants were analyzed for TNF-α and IL-10 levels after three days incubation period of Tregs with Tresp. The effect of galantamine on Tregs was then blocked by α-Bungarotoxin and the same assay has been repeated.

RESULTS & CONCLUSION: Selective α7nAChR blockade interrupted the anti-inflammatory effect of galantamine in the spleen and joints of arthritic rats. In healthy donors, galantamine could strengthen the suppressive activity of Tregs; while in RA patients it did not modulate the function of Tregs significantly. Further studies are necessary to investigate whether modulation of the cholinergic nervous system, especially α7nAChR, could have impact on the disturbed immune system in RA, which may open up a new treatment option of autoimmune diseases.

El-Gazar, A. A., A. A. Soubh, E. A. Mohamed, A. S. Awad, and H. S. El-Abhar, "Morin post-treatment confers neuroprotection in a novel rat model of mild repetitive traumatic brain injury by targeting dementia markers, APOE, autophagy and Wnt/β-catenin signaling pathway.", Brain research, vol. 1717, pp. 104-116, 2019 Aug 15. Abstract

Exposure to repetitive brain trauma has gained attention for its similarity to sport-related trauma. The traumatic brain injury (TBI) is strongly associated with neurodegenerative pathology that affects cognition, memory and behavior. The current study developed a novel mild repetitive traumatic brain injury (mRTBI) model to highlight some of the possible molecular pathological mechanisms compared to those of single trauma. Additionally, the study investigated the potential post-traumatic neuroprotective effect of Morin and/or MK-801. mRTBI was induced by weight drop model once daily for 5 days using Sprague-Dawley male rats. Animals were classified into control, mild TBI, mRTBI-5, mRTBI-7, mRTBI-5+DMSO, mRTBI-5+DMSO, mRTBI-5+Morin, mRTBI-5+MK801, and mRTBI-5+Morin+MK801. All treatments, especially the combination regimen, abated the cortical contents/protein expression of dementia markers (APO-E, Aβ, p(thr231)Tau, and p(Ser33)β-catenin), inflammatory markers (p(Ser536)NF-κBp65, and TNF-α, IL-6), and caspase-3 activity. Moreover, treatments enhanced the protein expression of Wnt-1 and autophagy-related markers (LC3BII/I and Beclin-1), besides the tissue content of the anti-apoptotic marker Bcl-2. These results entailed an improvement in the behavioral outcome, histological structure, and neuronal survival. In conclusion, the study proved that mRTBI impairs memory and alters APO-E/Aβ/p(thr231)Tau via the modulation of Wnt/β-catenin trajectory, autophagy, apoptosis, and inflammation. Additionally, post-treatment with Morin and/or MK-801 ameliorated these alterations, especially the combined regimen. It is also worth mentioning that Morin alone showed the finest behavioral improvements relative to the normal group. These results are summarized in Fig. 1.

Elsayed, I., M. W. Helmy, and H. S. El-Abhar, "Inhibition of SRC/FAK cue: A novel pathway for the synergistic effect of rosuvastatin on the anti-cancer effect of dasatinib in hepatocellular carcinoma.", Life sciences, vol. 213, pp. 248-257, 2018 Nov 15. Abstract

PURPOSE: Statins extended their hypocholestremic effect to show a promising anticancer activity. Hepatocellular carcinoma (HCC), the third common cause of cancer-related death, responded positively to statins. Some in-vitro studies reveal the rosuvastatin antitumor effect, but barely in-vivo studies. Hence, we evaluated the antitumor potential of rosuvastatin in a HCC model, the possible signaling cues involved, and whether it augments the dasatinib anticancer effect.

METHOD: For the in-vitro study, the IC and the combination (CI)/dose reduction (DRI) indices were determined for HCC cell line (HepG2) treated with dasatinib and/or rosuvastatin. For the in-vivo study, mice with diethylnitrosamine-induced HCC were treated for 21 days with dasatinib and/or rosuvastatin (10 and 20 mg/kg, respectively). The p-focal adhesion kinase/p-rous sarcoma oncogene cellular homolog (p-FAK/p-Src) cascade and its downstream molecules were assessed.

RESULTS: The in-vitro study confirmed the synergistic effect of rosuvastatin with dasatinib, which entailed the in-vivo results. The two drugs decreased the p-FAK/p-Src cue along with p-Ras/c-Raf, p-STAT-3, and p-Akt levels to enhance apoptosis by an increase in caspase-3 level and a decline in survivin level. Additionally, they inhibited HGF, VEGF, and the MMP-9. Moreover, the different treatments downregulated the expression of proliferative cell nuclear antigen (PCNA) and Ki-67. The best effect was mediated by the combination regimen that surpassed the effect of either drug alone.

CONCLUSION: Our results highlighted some of the signals involved in rosuvastatin antitumor effect and nominate it as an adds-on therapy with dasatinib to yield a better effect in HCC through inhibiting the FAK/Src cascade.

Mahmoud-Awny, M., A. S. Attia, M. F. Abd-Ellah, and H. S. El-Abhar, "Mangiferin Mitigates Gastric Ulcer in Ischemia/ Reperfused Rats: Involvement of PPAR-γ, NF-κB and Nrf2/HO-1 Signaling Pathways.", PloS one, vol. 10, issue 7, pp. e0132497, 2015. Abstract

Mangiferin (MF), a xanthonoid from Mangifera indica, has been proved to have antisecretory and antioxidant gastroprotective effects against different gastric ulcer models; however, its molecular mechanism has not been previously elucidated. Therefore, the aim of this study was to test its modulatory effect on several signaling pathways using the ischemia/reperfusion model for the first time. Animals were treated with MF, omeprazole (OMP), and the vehicle. The mechanistic studies revealed that MF mediated its gastroprotective effect partly via inducing the expression of Nrf2, HO-1 and PPAR-γ along with downregulating that of NF-κB. Surprisingly, the effect of MF, especially the high dose, exceeded that mediated by OMP except for Nrf2. The molecular results were reflected on the biomarkers measured, where the antioxidant effect of MF was manifested by increasing total antioxidant capacity and glutathione, besides normalizing malondialdehyde level. Additionally, MF decreased the I/R-induced nitric oxide elevation, an effect that was better than that of OMP. In the serum, MF, dose dependently, enhanced endothelial nitric oxide synthase, while reduced the inducible isoform. Regarding the anti-inflammatory effect of MF, it reduced serum level of IL-1β and sE-selectin, effects that were mirrored on the tissue level of myeloperoxidase, the neutrophil infiltration marker. In addition, MF possessed an antiapoptotic character evidenced by elevating Bcl-2 level and reducing that of caspase-3 in a dose related order. As a conclusion, the intimated gastroprotective mechanisms of MF are mediated, partially, by modulation of oxidative stress, inflammation and apoptosis possibly via the Nrf2/HO-1, PPAR-γ/NF-κB signaling pathways.

Soubh, A. A., D. M. Abdallah, and H. S. El-Abhar, "Geraniol ameliorates TNBS-induced colitis: Involvement of Wnt/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways.", Life sciences, vol. 136, pp. 142-50, 2015 Sep 1. Abstract

AIMS: Geraniol, a natural component of plant essential oils, exhibits potent chemopreventive effects in the colon; however, its possible role/mechanisms in experimental colitis have not been elucidated, which is the aim of this study.

MAIN METHODS: To fulfill this goal, rats were treated for 11days with geraniol and/or sulfasalazine using a TNBS-induced colitis model.

KEY FINDINGS: Geraniol significantly hindered the colitis-clinical signs (weight loss, colon edema,ulcerative area, colon/spleen mass indices) and opposed the altered oxidative/nitrosative stress. It restored the depleted total antioxidant capacity and lessened the elevated levels of nitric oxide and lipid peroxide. TNBS induced apoptosis and inflammatory cell infiltration, whereas geraniol curtailed these effects by diminishing the levels of caspase-3, intercellular adhesion molecule-1, and myeloperoxidase. The anti-inflammatory effect was documented by inhibiting the colon contents of prostaglandin E2 and interleukin-1β. In order to delve into the anti-colitic signaling pathways, geraniol inhibited the content/expression of glycogen synthase kinase (GSK)-3β, β-catenin, p38 mitogen activated protein kinase (p38MAPK), and nuclear factor kappa B (NFκB), but upregulated that of peroxisome proliferator activated receptor γ (PPARγ). These effects were comparable to those of sulfasalazine, the standard drug, whereas its combination with geraniol mediated effects that surpassed either treatment alone.

SIGNIFICANCE: Geraniol in the current study improved experimental colitis partly via its antioxidant, anti-inflammatory, and immunosuppressive potentials, possibly by modulating the Wnt/GSK-3β/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways. The study also revealed that geraniol represents a valuable asset against colitis alone or in combination with the conventional anti-colitic therapies.