Publications by authors named "Hanan S El-Abhar"

55 Publications

Peganum harmala enhanced GLP-1 and restored insulin signaling to alleviate AlCl-induced Alzheimer-like pathology model.

Sci Rep 2021 Jun 8;11(1):12040. Epub 2021 Jun 8.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Peganum harmala (P. harmala) is a folk medicinal herb used in the Sinai Peninsula (Egypt) as a remedy for central disorders. The main constituents, harmine and harmaline, have displayed therapeutic efficacy against Alzheimer's disease (AD); however, the P. harmala potential on sensitizing central insulin to combat AD remains to be clarified. An AD-like rat model was induced by aluminum chloride (AlCl; 50 mg/kg/day for six consecutive weeks; i.p), whereas a methanolic standardized P. harmala seed extract (187.5 mg/kg; p.o) was given to AD rats starting 2 weeks post AlCl exposure. Two additional groups of rats were administered either the vehicle to serve as the normal control or the vehicle + P. harmala seed extract to serve as the P. harmala control group. P. harmala enhanced cognition appraised by Y-maze and Morris water maze tests and improved histopathological structures altered by AlCl. Additionally, it heightened the hippocampal contents of glucagon-like peptide (GLP)-1 and insulin, but abated insulin receptor substrate-1 phosphorylation at serine 307 (pS307-IRS-1). Besides, P. harmala increased phosphorylated Akt at serine 473 (pS473-Akt) and glucose transporter type (GLUT)4. The extract also curtailed the hippocampal content of beta amyloid (Aβ)42, glycogen synthase (GSK)-3β and phosphorylated tau. It also enhanced Nrf2, while reduced lipid peroxides and replenished glutathione. In conclusion, combating insulin resistance by P. harmala is a novel machinery in attenuating the insidious progression of AD by enhancing both insulin and GLP-1 trajectories in the hippocampus favoring GLUT4 production.
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http://dx.doi.org/10.1038/s41598-021-90545-4DOI Listing
June 2021

Vitamin D and rosuvastatin obliterate peripheral neuropathy in a type-2 diabetes model through modulating Notch1, Wnt-10α, TGF-β and NRF-1 crosstalk.

Life Sci 2021 Jun 5;279:119697. Epub 2021 Jun 5.

Pharmacology, Toxicology, and Biochemistry Department, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt; Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Aims: Vitamin D and rosuvastatin are well-known drugs that mediate beneficial effects in treating type-2 diabetes (T2D) complications; however, their anti-neuropathic potential is debatable. Hence, our study investigates their neurotherapeutic potential and the possible underlying mechanisms using a T2D-associated neuropathy rat model.

Main Methods: Diabetic peripheral neuropathy (DPN) was induced with 8 weeks of administration of a high fat fructose diet followed by a single i.p. injection of streptozotocin (35 mg/kg). Six weeks later, DPN developed and rats were divided into five groups; viz., control, untreated DPN, DPN treated with vitamin D (cholecalciferol, 3500 IU/kg/week), DPN treated with rosuvastatin (10 mg/kg/day), or DPN treated with combination vitamin D and rosuvastatin. We determined their anti-neuropathic effects on small nerves (tail flick test); large nerves (electrophysiological and histological examination); neuronal inflammation (TNF-α and IL-18); apoptosis (caspase-3 activity and Bcl-2); mitochondrial function (NRF-1, TFAM, mtDNA, and ATP); and NICD1, Wnt-10α/β-catenin, and TGF-β/Smad-7 pathways.

Key Findings: Two-month treatment with vitamin D and/or rosuvastatin regenerated neuronal function and architecture and abated neuronal inflammation and apoptosis. This was verified by the inhibition of the neuronal content of TNF-α, IL-18, and caspase-3 activity, while augmenting Bcl-2 content in the sciatic nerve. These treatments inhibited the protein expressions of NICD1, Wnt-10α, β-catenin, and TGF-β; increased the sciatic nerve content of Smad-7; and enhanced mitochondrial biogenesis and function.

Significance: Vitamin D and/or rosuvastatin alleviated diabetes-induced neuropathy by suppressing Notch1 and Wnt-10α/β-catenin; modulating TGF-β/Smad-7 signaling pathways; and enhancing mitochondrial function, which lessened neuronal degeneration, demyelination, and fibrosis.
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http://dx.doi.org/10.1016/j.lfs.2021.119697DOI Listing
June 2021

Dimethyl fumarate abridged tauo-/amyloidopathy in a D-Galactose/ovariectomy-induced Alzheimer's-like disease: Modulation of AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, Adiponectin/Adipo1R, and NF-κB/IL-1β/ROS trajectories.

Neurochem Int 2021 May 27:105082. Epub 2021 May 27.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Κasr El-Aini Str., 11562, Cairo, Egypt.

Since the role of estrogen in postmenauposal-associated dementia is still debatable, this issue urges the search for other medications. Dimethyl fumarate (DMF) is a drug used for the treatment of multiple sclerosis and has shown a neuroprotective effect against other neurodegenerative diseases. Accordingly, the present study aimed to evaluate the effect of DMF on an experimental model of Alzheimer disease (AD) using D-galactose (D-Gal) administered to ovariectomized (OVX) rats, resembling a postmenopausal dementia paradigm. Adult 18-month old female Wistar rats were allocated into sham-operated and OVX/D-Gal groups that were either left untreated or treated with DMF for 56 days starting three weeks after sham-operation or ovariectomy. DMF succeeded to ameliorate cognitive (learning/short- and long-term memory) deficits and to enhance the dampened overall activity (NOR, Barnes-/Y-maze tests). These behavioral upturns were associated with increased intact neurons (Nissl stain) and a reduction in OVX/D-Gal-mediated hippocampal CA1 neurodegeneration and astrocyte activation assessed as GFAP immunoreactivity. Mechanistically, DMF suppressed the hippocampal contents of AD-surrogate markers; viz., apolipoprotein (APO)-E1, BACE1, Aβ42, and hyperphosphorylated Tau. Additionally, DMF has augmented the neuroprotective parameters p-AKT, its downstream target CREB and BDNF. Besides, it activated AMPK, and enhanced SIRT-1, as well as antioxidant defenses (SOD, GSH). On the other hand, DMF inhibited the transcription factor NF-κB, IL-1β, adiponectin/adiponectin receptor type (AdipoR)1, GSK-3β, and MDA. Accordingly, in this postmenopausal AD model, DMF treatment by pursuing the adiponectin/AdipoR1, AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, and APO-E1 quartet hampered the associated tauo-/amyloidopathy and NF-κB-mediated oxidative/inflammatory responses to advance insights into its anti-amnesic effect.
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http://dx.doi.org/10.1016/j.neuint.2021.105082DOI Listing
May 2021

Pentoxifylline treatment alleviates kidney ischemia/reperfusion injury: Novel involvement of galectin-3 and ASK-1/JNK & ERK1/2/NF-κB/HMGB-1 trajectories.

J Pharmacol Sci 2021 Jul 9;146(3):136-148. Epub 2021 Apr 9.

Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, 84518, Egypt.

Despite the documented renoprotective effect of pentoxifylline (PTX), a non-selective phosphodiesterase-4 inhibitor, the studies appraised only its anti-inflammatory/-oxidant/-apoptotic capacities without assessment of the possible involved trajectories. Here, we evaluated the potential role of galectin-3 and the ASK-1/NF-κB p65 signaling pathway with its upstream/downstream signals in an attempt to unveil part of the cascades involved in the renotherapeutic effect using a renal bilateral ischemia/reperfusion (I/R) model. Rats were randomized into sham-operated, renal I/R (45 min/72 h) and I/R + PTX (100 mg/kg; p.o). Post-treatment with PTX improved renal function and abated serum levels of cystatin C, creatinine, BUN and renal KIM-1 content, effects that were reflected on an improvement of the I/R-induced renal histological changes. On the molecular level, PTX reduced renal contents of galectin-3, ASK-1 with its downstream molecule JNK and ERK1/2, as well as NF-κB p65 and HMGB1. This inhibitory effect extended also to suppress neutrophil infiltration, evidenced by diminishing ICAM-1 and MPO, as well as inflammatory cytokines (TNF-α/IL-18), oxidative stress (MDA/TAC), and caspase-3. The PTX novel renotherapeutic effect involved in part the inhibition of galectin-3 and ASK-1/JNK and ERK1/2/NF-κB/HMGB-1 trajectories to mitigate renal I/R injury and to provide basis for its anti-inflammatory, antioxidant, and anti-apoptotic impacts.
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http://dx.doi.org/10.1016/j.jphs.2021.03.011DOI Listing
July 2021

Epac-1/Rap-1 signaling pathway orchestrates the reno-therapeutic effect of ticagrelor against renal ischemia/reperfusion model.

Biomed Pharmacother 2021 Jul 3;139:111488. Epub 2021 May 3.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, Egypt.

Despite the renal expression of PY, the purinergic receptor for adenosine diphosphate, few data are available to discuss the renotherapeutic potential of ticagrelor, one of its reversible blockers. Indeed, the tonic inhibitory effect of this receptor has been linked to the activation of exchange protein activated by cyclic adenosine monophosphate-1 (Epac-1) protein through the cyclic adenosine monophosphate cascade. Epac-1 is considered a crossroad protein, where its activation has been documented to manage renal injury models. Hence, the current study aimed to investigate the possible therapeutic effectiveness of ticagrelor, against renal ischemia/reperfusion (I/R) model with emphasis on the involvement of Epac-1 signaling pathway using R-CE3F4, a selective Epac-1 blocker. Accordingly, rats were randomized into four groups; viz., sham-operated, renal I/R, I/R post-treated with ticagrelor for 3 days, and ticagrelor + R-CE3F4. Treatment with ticagrelor ameliorated the I/R-mediated structural alterations and improved renal function manifested by the reduction in serum BUN and creatinine. On the molecular level, ticagrelor enhanced renal Epac-1 mRNA expression, Rap-1 activation (Rap-1-GTP) and SOCS-3 level. On the contrary, it inhibited the protein expression of JAK-2/STAT-3 hub, TNF-α and MDA contents, as well as caspase-3 activity. Additionally, ticagrelor enhanced the protein expression/content of AKT/Nrf-2/HO-1 axis. All these beneficial effects were obviously antagonized upon using R-CE3F4. In conclusion, ticagrelor reno-therapeutic effect is partly mediated through modulating the Epac-1/Rap-1-GTP, AKT/Nrf-2/HO-1 and JAK-2/STAT-3/SOCS-3 trajectories, pathways that integrate to afford novel explanations to its anti-inflammatory, anti-oxidant, and anti-apoptotic potentials.
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http://dx.doi.org/10.1016/j.biopha.2021.111488DOI Listing
July 2021

Neuroprotective role of galantamine with/without physical exercise in experimental autoimmune encephalomyelitis in rats.

Life Sci 2021 Apr 6;277:119459. Epub 2021 Apr 6.

Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt.

Aims: The fact that physical activity besides central cholinergic enhancement contributes in improving neuronal function and spastic plasticity, recommends the use of the anticholinesterase and cholinergic drug galantamine with/without exercise in the management of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS).

Materials And Methods: Sedentary and 14 days exercised male Sprague Dawley rats were subjected to EAE. Hereafter, exercised rats continued on rotarod for 30 min for 17 consecutive days. At the onset of symptoms (day 13), EAE sedentary/exercised groups were subdivided into untreated and post-treated with galantamine. The disease progression was assessed by EAE score, motor performance, and biochemically using cerebrospinal fluid (CSF). Cerebellum and brain stem samples were used for histopathology and immunohistochemistry analysis.

Key Findings: Galantamine decreased EAE score of sedentary/exercised rats and enhanced their motor performance. Galantamine with/without exercise inhibited CSF levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6), and Bcl-2-associated X protein (Bax), besides caspase-3 and forkhead box P3 (Foxp3) expression in the brain stem. Contrariwise, it has elevated CSF levels of brain derived neurotrophic factor (BDNF) and B-cell lymphoma (Bcl-2) and enhanced remyelination of cerebral neurons. Noteworthy, exercise boosted the drug effect on Bcl-2 and Bax.

Significance: The neuroprotective effect of galantamine against EAE was associated with anti-inflammatory and anti-apoptotic potentials, along with increasing BDNF and remyelination. It also normalized regulatory T-cells levels in the brain stem. The impact of the add-on of exercise was markedly manifested in reducing neuronal apoptosis.
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http://dx.doi.org/10.1016/j.lfs.2021.119459DOI Listing
April 2021

Novel peripheral role of Nurr-1/GDNF/AKT trajectory in carvedilol and/or morin hydrate hepatoprotective effect in a model of hepatic ischemia/reperfusion.

Life Sci 2021 May 17;273:119235. Epub 2021 Feb 17.

Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), 11835 Cairo, Egypt.

Although the central role of Nurr-1/GDNF has been reviewed amply, scarce data are available on their peripheral impact. Carvedilol and morin hydrate have previously conferred their hepatic anti-fibrotic action.

Aim: Thus, our aim was to unveil the potential hepatoprotective role of carvedilol (CR) and/or morin hydrate (MH) using a hepatic 70% partial warm ischemia/reperfusion (I/R) rat model.

Main Method: Rats were allocated into sham-operated, hepatic I/R, and I/R preceded by oral administration of CR (10 and 30 mg/kg; CR/CR), MH (30 mg/kg), or CR + MH for one week.

Key Findings: On the molecular level, pretreatment with CR and/or MH increased the hepatic contents of Nurr-1, GDNF, and the protein expression of active/p-AKT. On the other hand, they inactivated GSK3β and NF-κB to increase the antioxidant enzymes (GPx, SOD, CAT). All regimens also enhanced the autophagy/lysosomal function and boosted the protein expression of beclin-1, LC3II, and TFEB. Moreover, their antiapoptotic effect was signified by increasing the anti-apoptotic molecule Bcl2 and inhibiting Bax, Bax/Bcl2 ratio, and caspase-3, effects that were confirmed by the TUNEL assay. These improvements were reflected on liver function, as they decreased serum aminotransferases and liver structural alterations induced by I/R. Despite its mild impact, CR showed marked improvements when combined with MH; this synergistic interaction overrides the effect of either regimen alone.

Significance: In conclusion, CR, MH, and especially the combination regimen, conferred hepatoprotection against I/R via activating the Nurr-1/GDNF/AKT trajectory to induce autophagy/lysosomal biogenesis, inhibit GSK3β/NF-кB hub and apoptosis, and amend redox balance.
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http://dx.doi.org/10.1016/j.lfs.2021.119235DOI Listing
May 2021

The interrupted cross-talk of inflammatory and oxidative stress trajectories signifies the effect of artesunate against hepatic ischemia/reperfusion-induced inflammasomopathy.

Toxicol Appl Pharmacol 2020 12 30;409:115309. Epub 2020 Oct 30.

Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), 11835 Cairo, Egypt.

The antimalarial drug artesunate (Art) has proven its beneficial effects against ischemia/reperfusion (I/R) injury in diverse organs, but its potential role against hepatic I/R is still obscure. This study, hence, examined whether treatment with Art alone or in combination with rapamycin (Rapa), an mTOR inhibitor, can ameliorate hepatic I/R injury via targeting the NLRP3 inflammasome signaling pathway. Rats were divided into hepatic sham- and I/R-operated rats. The latter were either left untreated (I/R group) or treated with Art, Rapa, or their combination. On the molecular level, all treatment regimens succeeded to hinder inflammasome assembly and activation, assessed as NLRP3, ASC, cleaved caspase-1, caspase-11, N-terminal cleaved gasdermin-D (GSDMD-N), IL-1β, and IL-18. This effect was associated by the inhibition in the harmful signaling pathways HMGB1/RAGE and TLR4/MyD88/TRAF6 to inactivate the transcription factor NF-κB and the production of its pro-inflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α. Additionally, this effect entailed the inhibition of ICAM-1/MPO/ROS cascade, which in turn hampered cell demise induced by apoptosis, manifested as correction of the imbalanced Bcl2/Bax, as well as pyroptosis (LDH, cleaved caspase-1, caspase-11, GSDMD-N, IL-1β, and IL-18), and necrosis. The corrected pathways were reflected on the improved liver function (serum ALT, AST, and LDH) and microscopical hepatic architecture. Noteworthy, the effect of Art on all parameters exceeded significantly that of Rapa and even improved the effect of the latter in the combination group. In conclusion, our results suggest novel roles for Art in abating functional and structural I/R-induced hepatic abnormalities via several traversing cross-talking pathways that succeeded to abate NLRP3 inflammasome and cell death.
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http://dx.doi.org/10.1016/j.taap.2020.115309DOI Listing
December 2020

MiR-200a inversely correlates with Hedgehog and TGF-β canonical/non-canonical trajectories to orchestrate the anti-fibrotic effect of Tadalafil in a bleomycin-induced pulmonary fibrosis model.

Inflammopharmacology 2021 Feb 10;29(1):167-182. Epub 2020 Sep 10.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza, 12566, Egypt.

Few reports have documented the ability of phosphodiesterase-5 inhibitors (PDE-5-Is) to ameliorate idiopathic pulmonary fibrosis (IPF) mainly by their anti-inflammatory/antioxidant capacities, without unveiling the possible molecular mechanisms involved. Because of the recent role of miR-200 family and Sonic Hedgehog (SHH) trajectory in IPF, we have studied their impact on the anti-fibrotic potential of tadalafil against bleomycin-induced pulmonary fibrosis. Animals were allocated into normal-control, bleomycin-fibrotic control, and bleomycin post-treated with tadalafil or dexamethasone, as the reference drug. On the molecular level, tadalafil has reverted the bleomycin effect on all the assessed parameters. Tadalafil upregulated the gene expression of miR-200a, but decreased the smoothened (SMO) and the transcription factors glioma-associated oncogene homolog (Gli-1, Gli-2), members of SHH pathway. Additionally, tadalafil ebbed transforming growth factor (TGF)-β, its canonical (SMAD-3/alpha smooth muscle actin [α-SMA] and Snail), and non-canonical (p-Akt/p-Forkhead box O3 (FOXO3) a) pathways. Besides, a strong negative correlation between miR-200a and the analyzed pathways was proved. The effect of tadalafil was further confirmed by the improved lung structure and the reduced Ashcroft score/collagen deposition. The results were comparable to that of dexamethasone. In conclusion, our study has highlighted the involvement of miR-200a in the anti-fibrotic effect of tadalafil with the inhibition of SHH hub and the pro-fibrotic pathways (TGF-β/ SMAD-3/α-SMA, Snail and p-AKT/p-FOXO3a). Potential anti-fibrotic effect of tadalafil. Modulation of miR200a/SHH/canonical and non-canonical TGF-β trajectories. → : stimulatory effect; ┴: inhibitory effect.
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http://dx.doi.org/10.1007/s10787-020-00748-wDOI Listing
February 2021

Diabetes and CYP2C19 Polymorphism Synergistically Impair the Antiplatelet Activity of Clopidogrel Compared With Ticagrelor in Percutaneous Coronary Intervention-treated Acute Coronary Syndrome Patients.

J Cardiovasc Pharmacol 2020 10;76(4):478-488

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; and.

Diabetes and CYP2C19 loss of function (LOF) alleles are associated with the variable antiplatelet activity of the prodrug clopidogrel. We conducted a randomized trial (NCT03613857) to compare the combined and individualized effects of diabetes and CYP2C19 polymorphisms on the antiplatelet reactivity of clopidogrel versus ticagrelor in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Patients (948, 1 year follow-up 943) were randomly allocated in a 1:1 ratio to receive either clopidogrel or ticagrelor, after PCI; patients were subdivided into 8 subgroups according to the diabetes and/or CYP2C19 allele status. The study outcomes were recurrent ACS, maximum platelet aggregation (MPA), high platelet reactivity index (PRI), and incidence of major bleeding events. Diabetic patients with LOF alleles taking clopidogrel had the highest recurrent ACS rate (6 of 33 patients) versus all other study groups (P < 0.05). However, both drugs had similar proportions of recurrent ACS in all other subgroups. Similarly, both PRI and MPA were significantly higher in the diabetic patients having LOF alleles and receiving clopidogrel versus all their study groups (P < 0.05). Nevertheless, ticagrelor caused higher rates of major bleeding versus clopidogrel (P < 0.001). PCI-treated ACS patients with diabetes and CYP2C19 LOF alleles are at a higher risk of recurrent ACS and high PRI/MPA, when treated with clopidogrel versus ticagrelor, but almost comparable outcomes are recorded in the absence of 1 or the 2 risk factors.
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http://dx.doi.org/10.1097/FJC.0000000000000881DOI Listing
October 2020

Modulation of endoplasmic reticulum stress response in gut-origin encephalopathy: Impact of vascular endothelial growth factor receptor-2 manipulation.

Life Sci 2020 Jul 8;252:117654. Epub 2020 Apr 8.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, P.O. Box 11835, Egypt.

Background: Septic encephalopathy, the most frequent complication of sepsis, is orchestrated by a complex interplay of signals that leads to high mortality rates among intensive care unit patients. However, the role of the vascular endothelial growth factor receptor-2 (VEGFR2) in endoplasmic reticulum stress response (ERSR), during septic encephalopathy, is still elusive.

Aim: This study was aimed to examine the effect of an in-house designed/synthesized VEGFR2 antagonist, named WAG4S, on septic encephalopathy using cecal ligation and perforation (CLP).

Main Methods: Rats were intraperitoneally injected with WAG-4S (1 mg/kg/d) for 7 days post-CLP.

Key Findings: In septic animals, VEGFR2 antagonism declined the expression of cortical p-VEGFR2 and p-mammalian target of rapamycin complex-1 (p-mTORC1). It also worsened the behavioral and histopathological alterations beyond CLP. However, and contrary to CLP, WAG-4S decreased the p-protein kinase R-like ER kinase (p-PERK) and eukaryotic initiation factor-2α (p-eIF2α) expression. Moreover, VEGFR2 blockade upregulated the mRNA expression of activating transcription factor-4 (ATF4), binding immunoglobulin protein/glucose-regulated protein-78 (Bip/GRP78), growth arrest and DNA damage-34 (GADD34) and spliced X-box binding protein-1 (XBP1s) above CLP. Similarly, it boosted inositol requiring enzyme-1α (IRE1α) activation and redox imbalance. In the same context, WAG-4S augmented the protein levels of CLP-induced ERSR apoptotic markers, namely C/EBP homologous protein (CHOP/GADD153), c-jun N-terminal kinase (JNK) and caspase-3.

Significance: In conclusion, the PERK/eIF2α axis inhibition, during septic encephalopathy, is VEGFR2-independent, whereas the activated IRE1α/XBP1s/CHOP/JNK/caspase-3 cue promotes the ERSR execution module through VEGFR2 inhibition. This has turned VEGFR2 into a potential therapeutic target for ameliorating such an ailment.
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http://dx.doi.org/10.1016/j.lfs.2020.117654DOI Listing
July 2020

The dual reno- and neuro-protective effects of dimethyl fumarate against uremic encephalopathy in a renal ischemia/reperfusion model.

Pharmacol Rep 2020 Aug 5;72(4):969-983. Epub 2020 Mar 5.

Department of Pharmacology and Toxicology, Faculty Pharmacy, Cairo University, Kasr El-Aini Str, Cairo, 11562, Egypt.

Background: Dimethyl fumarate (DMF), a Nrf2 activator approved for multiple sclerosis (MS) in 2013, showed promising antioxidant and anti-inflammatory effects against cerebral injury. However, its mechanistic maneuver in renal ischemia/reperfusion (I/R) injury and its associated uremic encephalopathy has not been previously highlighted.

Methods: To fulfill this aim, rats were divided into 4 groups; sham-operated, renal I/R, and 14 days pretreated DMF (15 and 25 mg/kg/day, orally).

Results: The small molecule drug reduced renal I/R-induced elevation in serum creatinine and blood urea nitrogen, the renal content of interleukin (IL)-18 and its pro-activator caspase-1. The DMF antioxidant potential was confirmed by the increased renal Nrf2 mRNA expression/content associated wit an enhanced total antioxidant capacity and an inhibition of lipid peroxidation. This character entailed the suppression of the assessed inflammatory markers, such as nuclear factor (NF)-κB, p38 mitogen-activated protein kinase, and tumor necrosis factor-α. Remotely, DMF protected against uremic encephalopathy signified by the suppressed cortical/hippocampal contents of glial fibrillary acidic protein through suppressing 2 trajectories, the NF-κB/inducible nitric oxide synthase/nitric oxide/guanylyl cyclase/cyclic guanosine monophosphate and IL-6/signal transducer and activator of transcription 3. Moreover, the open field test revealed an enhanced locomotor activity in DMF pretreated rats, reflecting counter ability against functional and behavioral effects of acute uremic encephalopathy.

Conclusion: The current study advocates the novel DMF dual protection potential against renal I/R insult and its remote brain injury to compensate uremic encephalopathy and acute kidney injury as well.
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http://dx.doi.org/10.1007/s43440-020-00076-4DOI Listing
August 2020

Olmesartan attenuates type 2 diabetes-associated liver injury: Cross-talk of AGE/RAGE/JNK, STAT3/SCOS3 and RAS signaling pathways.

Eur J Pharmacol 2020 May 14;874:173010. Epub 2020 Feb 14.

Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industry, Future University, Cairo, Egypt.

Olmesartan (OLM), an angiotensin receptor blocker, was tested against diabetes/insulin resistance (IR) models associated with renal/cardiovascular complications. Methods: we tested its potential role against diabetes-induced hepatic hitches using an IR/type2 diabetic (IR/D) model induced by high fat/high fructose diet for 7 weeks ​+ ​a single sub-diabetogenic dose of streptozotocin (35mg/kg; i.p). IR/D rats were orally treated with OLM (10 ​mg/kg), pioglitazone (PIO; 5 or 10 ​mg/kg) or their combinations for 4 consecutive weeks. OLM alone opposed the detrimental effects of IR/D; it significantly improved metabolic parameters, liver function, and abated hepatic oxidative stress, and inflammatory cytokine interleukin-6 (IL-6) and its upstream mediator nuclear factor kappa B. Consequently, OLM turned off the downstream cue p-Jak2/STAT3/SOCS3. Moreover, it suppressed the elevated AGE/RAGE/p-JNK pathway and increased the PPARγ/adiponectin cue to signify its anti-inflammatory and anti-oxidant capacity (GSH, MDA). Nevertheless, co-administration of OLM to PIO showed a synergistic improvement in all the aforementioned parameters in a dose dependent manner. Additionally, OLM with PIO provoked a surge in hepatic PPARγ and adiponectin (5 and 6 folds) with a sharp decrease of about 85% in the NF-κB/IL-6/p-STAT3/SCOS3 pathway. These effects were confirmed by the histopathological study. In conclusion, OLM and its combination with PIO enhanced insulin sensitivity and guarded against hepatic complications associated with type 2 diabetes probably via modulating various inter-related pathways; namely, metabolic alteration, renin-angiotensin system, inflammatory trajectories, as well as oxidative stress. This study manifests the potential synergistic effects of OLM as an adjuvant therapy to the conventional antidiabetic therapies.
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http://dx.doi.org/10.1016/j.ejphar.2020.173010DOI Listing
May 2020

Alanyl-glutamine Heals Indomethacin-induced Gastric Ulceration in Rats Via Antisecretory and Anti-apoptotic Mechanisms.

J Pediatr Gastroenterol Nutr 2019 12;69(6):710-718

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Objectives: Alanylglutamine (AG) is a dipeptide that fuels enterocytes and has a coadjuvant role during gut healing. The current study aimed to investigate the potential ulcer-healing effect of AG in indomethacin-induced gastropathy.

Methods: Animals (n = 10 rats/group) were randomly allocated into 5 groups. Gastric ulcerated rats were administered AG, AG + dexamethasone, or pantoprazole after indomethacin exposure.

Results: Comparable to pantoprazole, AG inhibited H-KATPase pump, and elevated the pH of gastric juice. Moreover, the dipeptide increased the serum/mucosal contents of glucagon-like peptide-1 (GLP-1), pS473-Akt, and cyclin-D1. On the contrary, AG abated serum tumor necrosis factor-α and gastric mucosal content of pS45-β catenin, pS9-GSK3β, pS133-CREB, pS536-NF-κB, H2O2, claudin-1, and caspase-3. The administration of dexamethasone before AG hampered its effect on almost all the measured parameters.

Conclusions: AG confers its antiulcerogenic/antisecretory potentials by repressing the proton pump to increase the gastric juice pH via boosting p-CREB, p-Akt, p-GSK-3β, and GLP-1. Also, it inhibits apoptosis through suppressing nuclear factor-kappa B/tumor necrosis factor-α/H2O2/claudin-1 cue. This trajectory contributes to loosen the tight junction priming AG-mediated GLP-1/β-catenin/cyclin-D1 that results in pronounced increase in gastric mucosa proliferation. Therefore, the crosstalk between multiple pathways orchestrates the action of AG against gastric ulceration.
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http://dx.doi.org/10.1097/MPG.0000000000002474DOI Listing
December 2019

Mesenchymal stem cells in chemotherapy-induced peripheral neuropathy: A new challenging approach that requires further investigations.

J Tissue Eng Regen Med 2020 01 2;14(1):108-122. Epub 2019 Dec 2.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Chemotherapeutic drugs may disrupt the nervous system and cause chemotherapy-induced peripheral neuropathy (CIPN) as side effects. There are no completely successful medications for the prevention or treatment of CIPN. Many drugs such as tricyclic antidepressants and anticonvulsants have been used for symptomatic treatment of CIPN. Unfortunately, these drugs often give only partial relief or have dose-limiting side effects. Thus, the treatment of CIPN becomes a challenge because of failure to regenerate and repair the injured neurons. Mesenchymal stem cell (MSC) therapy is a new attractive approach for CIPN. Evidence has demonstrated that MSCs play important roles in reducing oxidative stress, neuroinflammation, and apoptosis, as well as mediating axon regeneration after nerve damage in several experimental studies and some clinical trials. We will briefly review the pathogenesis of CIPN, traditional therapies used and their drawbacks as well as therapeutic effects of MSCs, their related mechanisms, future challenges for their clinical application, and the additional benefit of their combination with pharmacological agents. MSCs-based therapies may provide a new therapeutic strategy for patients suffering from CIPN where further investigations are required for studying their exact mechanisms. Combined therapy with pharmacological agents can provide another promising option for enhancing MSC therapy success while limiting its adverse effects.
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http://dx.doi.org/10.1002/term.2972DOI Listing
January 2020

Correlation between angiotensin 1-7-mediated Mas receptor expression with motor improvement, activated STAT3/SOCS3 cascade, and suppressed HMGB-1/RAGE/NF-κB signaling in 6-hydroxydopamine hemiparkinsonian rats.

Biochem Pharmacol 2020 01 25;171:113681. Epub 2019 Oct 25.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Κasr El-Aini Str., 11562 Cairo, Egypt.

In the current investigation, a Parkinson's disease (PD) model was established by a single direct right intrastriatal injection of the 6-hydroxydopamine (OHDA) in male Wistar rats followed by 7 daily unilateral injection of angiotensin (Ang) 1-7 in the striatum. To confirm the putative role of Mas receptor (MasR), the selective antagonist A779 was also injected intrastriatally prior to Ang 1-7 injections and a correlation analysis was performed between MasR expression and the assessed parameters. Ang 1-7 upregulated MasR expression to correlate strongly with the improved rotarod (r = 0.95, p = 0.003) and spontaneous activity task (r = 0.99, p < 0.0001). This correlation extends to involve other effects of Ang 1-7, such as the increased striatal dopamine content (r = 0.98, p = 0.0005), substantia nigra pars compacta tyrosine hydroxylase immune-reactivity (r = 0.97, p = 0.001), active pY705-STAT3 (r = 0.99, p < 0.0001) and SOCS3 (r = 0.99, p < 0.0001). Conversely, Ang 1-7 inhibited inflammatory markers to correlate negatively with NF-κBp65 (r = -0.99, p < 0.0003) and its downstream targets, high mobility group box-1 (HMGB-1; r = -0.97, p = 0.002), receptor for advanced glycation end products (RAGE; r = -0.98, p = 0.0004), and TNF-α (r = -0.99, p < 0.0003), besides poly-ADP-ribose polymerase-1 (r = -0.99, p = 0.0002). In confirmation, the pre-administration of the selective MasR antagonist, A779, partially attenuated Ang 1-7-induced alterations towards 6-OHDA neurodegeneration. Collectively, our findings support a novel role for the anti-inflammatory capacity of the MasR axis to prove potential therapeutic relevance in PD via the upregulation/activation of MasR-dependent STAT3/SOCS3 cascade to negatively control the HMGB-1/RAGE/NF-κB axis hindering PD associated neuro-inflammation along with DA depletion and motor deficits.
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http://dx.doi.org/10.1016/j.bcp.2019.113681DOI Listing
January 2020

The role of α7nAChR in controlling the anti-inflammatory/anti-arthritic action of galantamine.

Biochem Pharmacol 2019 12 10;170:113665. Epub 2019 Oct 10.

Department of Pharmacology, Medical Research Institute, University of Alexandria, Egypt.

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.
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http://dx.doi.org/10.1016/j.bcp.2019.113665DOI Listing
December 2019

Novel repair mechanisms in a renal ischaemia/reperfusion model: Subsequent saxagliptin treatment modulates the pro-angiogenic GLP-1/cAMP/VEGF, ANP/eNOS/NO, SDF-1α/CXCR4, and Kim-1/STAT3/HIF-1α/VEGF/eNOS pathways.

Eur J Pharmacol 2019 Oct 19;861:172620. Epub 2019 Aug 19.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address:

The reno-protective effects of antidiabetic dipeptidyl peptidase (DPP)-4 inhibitors have been studied regarding their antioxidant and anti-inflammatory properties. However, the potential ability of saxagliptin to ameliorate renal injury by enhancing neovascularization has not been elucidated. To address this issue, saxagliptin (10 and 30 mg/kg) was administered to Wistar rats after the induction of renal ischaemia/reperfusion (I/R). Our results showed that saxagliptin operated through different axes to ameliorate I/R injury. By inhibiting DPP-4, saxagliptin maintained stromal cell-derived factor-1α expression and upregulated its chemokine receptor CXCR4 to trigger vasculogenesis through the enhanced migration of endothelial progenitor cells (EPCs). Additionally, this compound rescued the levels of glucagon-like peptide-1 and its downstream mediator cAMP to increase vascular endothelial growth factor (VEGF) and CXCR4 levels. Moreover, saxagliptin stimulated atrial natriuretic peptide/endothelial nitric oxide synthase to increase nitric oxide levels and provoke angiogenesis and renal vasodilation. In addition to inhibiting DPP-4, saxagliptin increased the renal kidney injury molecule-1/pY705-STAT3/hypoxia-inducible factor-1α/VEGF pathway to enhance angiogenesis. Similar to other gliptins, saxagliptin exerted its anti-inflammatory and antioxidant effects by suppressing the renal contents of p (S536)-nuclear factor-κB p65, tumour necrosis factor-α, monocyte chemoattractant protein-1, myeloperoxidase, and malondialdehyde while boosting the glutathione content. These events improved the histological structure and function of the kidney, as evidenced by decreased serum creatinine, blood urea nitrogen, and cystatin C and increased serum albumin. Accordingly, in addition to its anti-inflammatory and antioxidant activities, saxagliptin dose-dependently ameliorated I/R-induced renal damage by enhancing neovascularization through improved tissue perfusion and homing of bone marrow-derived EPCs to mediate repair processes.
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http://dx.doi.org/10.1016/j.ejphar.2019.172620DOI Listing
October 2019

Co-targeting of endothelin- and vitamin D receptors: a novel strategy to ameliorate cisplatin-induced nephrotoxicity.

Pharmacol Rep 2019 Oct 25;71(5):917-925. Epub 2019 Apr 25.

Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

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 6 mg/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-α), transforming growth factor-beta1 (TGF-β1), and phosphorylated nuclear factor-kappa B (pNF-κB) 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 cross-talk.
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http://dx.doi.org/10.1016/j.pharep.2019.04.018DOI Listing
October 2019

Cilostazol against 2,4,6-trinitrobenzene sulfonic acid-induced colitis: Effect on tight junction, inflammation, and apoptosis.

JGH Open 2019 Aug 29;3(4):281-289. Epub 2019 Mar 29.

Department of Pharmacology and Toxicology, Faculty of Pharmacy Cairo University Cairo Egypt.

Background: Inflammatory bowel diseases are immunologically mediated disorders of gastrointestinal tract, characterized by dysregulated immune responses that result in a chronic intestinal inflammation. The antiplatelet cilostazol (CS), a phosphodiesterase-III inhibitor, exerted a beneficial effect on several models of gastrointestinal diseases; however, the full mechanism of action in this context has not been unveiled.

Aim: The current study aimed to elucidate the potential role of CS in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model.

Methods: Male Wistar rats were divided into a sham group and groups treated with sulfasalazine (500 mg/kg), CS (50 and 100 mg/kg), and a combination (sulfasalazine/CS 50 mg/kg). All treatments were administered orally 15 days, with TNBS rectal administration on the 11th day.

Results: TNBS-produced colitis manifested as a decrease in the epithelial junctional adhesion molecule-A (JAM-A) and as an increase in trefoil factor-3, ulcerative area, and colon mass index, parameters that collaborate with the gross macroscopic changes in colon tissue. In addition, TNBS increased hemeoxygenase-1, nuclear factor-kappa B, P-selectin, and myeloperoxidase, as well as the apoptotic ratio of Bax/Bcl-2. Administration of CS alone, especially at the high dose level, attenuated the severity of TNBS-induced colitis in a sulfasalazine-comparable manner. In addition, a better effect was mediated by the combination regimen, which succeeded in normalizing most of the measured parameters.

Conclusion: CS protected the colon against TNBS through its anti-inflammatory and antiapoptotic effects along with maintaining cellular tight junctions (TJs). Furthermore, CS can be beneficial as an add-on drug with the conventional treatments of colitis.
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http://dx.doi.org/10.1002/jgh3.12148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684512PMC
August 2019

Chenodeoxycholic Acid Ameliorates AlCl-Induced Alzheimer's Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats.

Molecules 2019 May 24;24(10). Epub 2019 May 24.

Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.

Insulin resistance is a major risk factor for Alzheimer's disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl 50 mg/kg/day i.p) and CDCA-treated group (AlCl + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aβ). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl-treated rats, which highlights its potential in AD management.
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http://dx.doi.org/10.3390/molecules24101992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571973PMC
May 2019

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 Res 2019 08 16;1717:104-116. Epub 2019 Apr 16.

Department of Pharmacology & Toxicology, Cairo University, Cairo, Egypt.

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.
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http://dx.doi.org/10.1016/j.brainres.2019.04.003DOI Listing
August 2019

Pharmacological Interventions to Attenuate Alzheimer's Disease Progression: The Story So Far.

Curr Alzheimer Res 2019 ;16(3):261-277

Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in the elderly. Up to date, the available pharmacological options for AD are limited to cholinesterase inhibitors and memantine that may only provide modest symptomatic management with no significance in slowing down the disease progression. Over the past three decades, the increased interest in and the understanding of AD major pathological hallmarks have provided an insight into the mechanisms mediating its pathogenesis, which in turn introduced a number of hypotheses and novel targets for the treatment of AD. Initially, targeting amyloid-beta and tau protein was considered the most promising therapeutic approach. However, further investigations have identified other major players, such as neuroinflammation, impaired insulin signalling and defective autophagy, that may contribute to the disease progression. While some promising drugs are currently being investigated in human studies, the majority of the previously developed medical agents have come to an end in clinical trials, as they have failed to illustrate any beneficial outcome. This review aims to discuss the different introduced approaches to alleviate AD progression; in addition, provides a comprehensive overview of the drugs in the development phase as well as their mode of action and an update of their status in clinical trials.
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http://dx.doi.org/10.2174/1567205016666190301111120DOI Listing
June 2020

Mesenchymal stem cells therapy enhances the efficacy of pregabalin and prevents its motor impairment in paclitaxel-induced neuropathy in rats: Role of Notch1 receptor and JAK/STAT signaling pathway.

Behav Brain Res 2019 03 10;360:303-311. Epub 2018 Dec 10.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address:

Peripheral neuropathy is a common adverse effect observed during the use of paclitaxel (PTX) as chemotherapy. The present investigation was directed to estimate the modulatory effect of bone marrow derived mesenchymal stem cells (BM-MSCs) on pregabalin (PGB) treatment in PTX-induced peripheral neuropathy. Neuropathic pain was induced in rats by injecting PTX (2 mg/kg, i.p) 4 times every other day. Rats were then treated with PGB (30 mg/kg/day, p.o.) for 21 days with or without a single intravenous administration of BM-MSCs. At the end of experiment, behavioral and motor abnormalities were assessed. Animals were then sacrificed for measurement of total antioxidant capacity (TAC), nerve growth factor (NGF), nuclear factor kappa B p65 (NF-κB p65), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and active caspase-3 in the sciatic nerve. Moreover, protein expressions of Notch1 receptor, phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK) were estimated. Finally, histological examinations were performed to assess severity of sciatic nerve damage and for estimation of BM-MSCs homing. Combined PGB/BM-MSCs therapy provided an additional improvement toward reducing PTX-induced oxidative stress, neuro-inflammation, and apoptotic markers. Interestingly, BM-MSCs therapy effectively prevented motor impairment observed by PGB treatment. Combined therapy also induced a significant increase in cell homing and prevented PTX-induced sciatic nerve damage in histological examination. The present study highlights a significant role for BM-MSCs in enhancing treatment potential of PGB and reducing its motor side effects when used as therapy in the management of peripheral neuropathy.
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http://dx.doi.org/10.1016/j.bbr.2018.12.013DOI Listing
March 2019

Raspberry ketone and Garcinia Cambogia rebalanced disrupted insulin resistance and leptin signaling in rats fed high fat fructose diet.

Biomed Pharmacother 2019 Feb 7;110:500-509. Epub 2018 Dec 7.

Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt (FUE), 11835, Cairo, Egypt.

Aim: Obesity is a continually growing pandemic leading to many diseases that affect the overall quality of life. The widely marketed Garcinia cambogia (GC) and Raspberry ketone (RK) were used in this study. Despite their known dietetic effect, however, the metabolomic/signaling pathways involved in this effect are not fully elucidated. Hence, our study comprehends the possible trajectories of their combination against obesity and insulin resistance in addition to exploring their combination merit.

Materials And Methods: Adult male Wistar rats were divided into 5 groups; viz., normal diet (ND), high fat fructose diet (HFFD), HFFD+GC (600mg/kg), HFFD+RK (55mg/kg) and HFFD+GC+RK. To assess our aim, we determined their effect on body weight, IPGTT, glucose homeostasis (glucose, insulin, HOMA IR), lipid profile parameters and SREBP-1c, oxidative stress markers, insulin and leptin signaling pathways (p-IRS-1/p-AKT/GLUT-4, and leptin/STAT-3), as well as liver and adipose tissue histopathology.

Results: GC/RK combinationcaused weight loss, corrected the disturbed glucose and insulin homeostasis, raised serum levels of HDL anddecreased all other lipid profile parameters. They also increased Nrf-2 expression, ad GSH, as well as p-IRS-1/p-Akt/GLUT-4 cue, while they decreased MDA, leptin/STAT-3 and SREBP-1c content compared to the HFFD group. Furthermore, the GC/RK combination abolished apoptosis, fatty changes and inflammation in hepatocytes and decreased sclerotic blood vessels and congestion in adipose tissue.

Conclusion: Our study highlights the involvement ofp-IRS-1/p-Akt/GLUT-4, leptin/STAT-3 and SREBP-1c signaling trajectories in the beneficial combination of GC and RK, besides, the efficient rebalance of the redox status, insulin resistance and tissue fat deposition confirmed histopathologically.
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http://dx.doi.org/10.1016/j.biopha.2018.11.079DOI Listing
February 2019

Activation of α7 Nicotinic Acetylcholine Receptor Ameliorates Zymosan-Induced Acute Kidney Injury in BALB/c Mice.

Sci Rep 2018 11 14;8(1):16814. Epub 2018 Nov 14.

Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Giza, Egypt.

Zymosan, a natural compound, provokes acute peritonitis and multiple organ dysfunction that affects the kidney, beside other organs via exaggerated inflammatory response. The aim of the present study is to test the role of cholinergic anti-inflammatory pathway (CAP) in alleviating acute kidney injury (AKI) induced by zymosan in BALB/c mice, using galantamine, a cholinesterase inhibitor, known to act via α7 nicotinic acetylcholine receptor (α7 nAChR) to stimulate CAP. Galantamine verified its anti-inflammatory effect by elevating acetylcholine (ACh) level, while abating the interleukin-6/ janus kinase 2 (Y1007/1008)/ signal transducer and activator of transcription 3 (Y705) (IL-6/ pY(1007/1008)-JAK2/ pY705-STAT3) inflammatory axis, with a consequent inhibition in suppressor of cytokine signaling 3 (SOCS3). This effect entails also the nuclear factor-kappa B (p65)/ high mobility group box protein-1/ (NF-κB (p65)/ HMGB-1) signaling pathway. Furthermore, the reno-curattive effect of galantamine was associated by a reduction in plasma creatinine (Cr), cystatin (Cys)-C, IL-18, and renal neutrophil gelatinase-associated lipocalin (NGAL), as well as an improved histopathological structure. Blocking the α7 nAChR by methyllycaconitine abolished the beneficial effect of galantamine to document the involvement of this receptor and the CAP in the amelioration of AKI induced by zymosan.
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http://dx.doi.org/10.1038/s41598-018-35254-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235888PMC
November 2018

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 Sci 2018 Nov 5;213:248-257. Epub 2018 Oct 5.

Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Electronic address:

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.
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http://dx.doi.org/10.1016/j.lfs.2018.10.002DOI Listing
November 2018

Anti-fibrotic impact of Carvedilol in a CCl-4 model of liver fibrosis via serum microRNA-200a/SMAD7 enhancement to bridle TGF-β1/EMT track.

Sci Rep 2018 09 25;8(1):14327. Epub 2018 Sep 25.

Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Circulating microRNAs (miRNAs) play a role in modulating the prevalence of fibrosis and have been a target of the cardiac anti-fibrotic effect of Carvedilol. However, the impact of miRNAs on the hepatoprotective effect of this non-selective β-blocker has not been yet elucidated. Hence, the current goal is to evaluate the potential role of circulating miR-200a in the hepatic anti-fibrotic pathway of Carvedilol. Male Wistar rats were randomized into normal, CCl (2 ml/kg, i.p, twice weekly for 8 weeks), and CCl + Carvedilol (10 mg/kg, p.o, daily). Carvedilol over-expressed the circulating miR-200a to modulate epithelial mesenchymal transition (EMT) markers (vimentin, E-Cadherin). In turn, Carvedilol increased SMAD7 gene expression and protein content to attenuate the pro-fibrogenic marker transforming growth factor β1 (TGF-β1) and the inflammatory markers (p-38 MAPK and p-S536-NF-κB p65). The anti-fibrotic potential was reflected on the decreased expression of the mesenchymal product and EMT marker α-SMA, besides the improved histopathological examination, and the fibrosis scores/collagen quantification to enhance liver functions (AST, ALT, ALP, and AST/platelet ratio index; APRI). In conclusion, circulating miR-200a/SMAD7/TGF-β1/EMT/MAPK axis is crucial in the hepatic anti-fibrotic mechanism of Carvedilol.
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http://dx.doi.org/10.1038/s41598-018-32309-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156520PMC
September 2018

Pregabalin and lacosamide ameliorate paclitaxel-induced peripheral neuropathy via inhibition of JAK/STAT signaling pathway and Notch-1 receptor.

Neurochem Int 2018 11 15;120:164-171. Epub 2018 Aug 15.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt. Electronic address:

Anticonvulsant drugs such as pregabalin (PGB) and lacosamide (LCM), exhibit potent analgesic effects in diabetic neuropathy; however, their possible role/mechanisms in paclitaxel (PTX)-induced peripheral neuropathy have not been elucidated, which is the aim of the present study. Neuropathic pain was induced in rats by injecting PTX (2 mg/kg, i. p) on days 0, 2, 4 and 6. Forty eight hours after the last dose of PTX, rats were treated orally with 30 mg/kg/day of either PGB or LCM for 21 days. Both therapies improved thermal hyperalgesia and cold allodynia induced by PTX. Interestingly, LCM therapy showed no motor impairment that was observed upon using PGB, as demonstrated using rotarod test. Treatment with PGB or LCM restored the sciatic nerve content of the depleted total antioxidant capacity (TAC) and nerve growth factor (NGF), and lessened the elevated contents of nuclear factor kappa B p65 (NF-kB p65), tumor necrosis factor-α (TNF-α), and active caspase-3. On the molecular level, the drugs reduced the protein expression of Notch1 receptor, phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK), and the trajectory interleukin-6/phosphorylated janus kinase 2/phosphorylated signal transducer and activator of transcription 3 (IL-6/p-JAK2/p-STAT3). Therefore, the current study demonstrated a pivotal role for LCM in the management of PTX-induced peripheral neuropathy similar to PGB, but without motor adverse effects via the inhibition of oxidative stress, inflammation and apoptosis, as well as IL-6/JAK/STAT pathway and Notch1 receptor over-expression.
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http://dx.doi.org/10.1016/j.neuint.2018.08.007DOI Listing
November 2018

Novel Trajectories of Bromocriptine Antidiabetic Action: Leptin-IL-6/ JAK2/p-STAT3/SOCS3, p-IR/p-AKT/GLUT4, PPAR-γ/Adiponectin, Nrf2/PARP-1, and GLP-1.

Front Pharmacol 2018 18;9:771. Epub 2018 Jul 18.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Bromocriptine (BC), a sympatholytic dopaminergic D2 receptor agonist, has been comprehensively used in clinic to treat Parkinson's disease (PD) and prolactinomas. Besides, BC represents a novel therapeutic option in type 2 diabetes (T2DM); however, the precise mechanisms are not completely unveiled. Hence, the objective of the current work is to clarify the potential molecular pathways of the insulin sensitizing effect of BC in the skeletal muscle of diabetic rats and to evaluate its possible interaction with sitagliptin (SG) as an add-on therapy. Here experimental model impersonates unhealthy dietary habit and T2DM was adopted, in which rats were fed high caloric diet of fat and fructose for 6 weeks followed by a single sub-diabetogenic dose of streptozotocin (STZ) (35 mg/kg; HF/Fr/STZ). Diabetic rats were treated with BC, SG at two dose levels (SG10 and SG20) and combination of BC + SG10 for 2 weeks. BC successfully corrected glucose/lipid profile, as well as leptin and GLP-1. On the muscular molecular level, BC curtailed the inflammatory signal IL-6/JAK2/-STAT3/SOCS3, while enhanced the PPAR-γ/adiponectin signaling, resulting in activation of the insulin signaling pathway (-IR/-AKT/GLUT4). Moreover, BC confirmed its antioxidant capabilities by altering Nrf2 and PARP-1; the study also highlighted novel mechanisms for SG as well. On almost all tested parameters/pathways, the combination regimen surpassed each drug alone to reach a comparable level to the high dose of SG. In conclusion, our finding shed some light on novel anti-diabetic mechanisms of BC. The study also points to the potential use of BC as an adds-on to standard anti-diabetic therapies.
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http://dx.doi.org/10.3389/fphar.2018.00771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058031PMC
July 2018