Publications by authors named "Dalaal M Abdallah"

42 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187628PMC
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 28;148:105082. Epub 2021 May 28.

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 Jul 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
July 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

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 paradox of dipeptidyl peptidase IV inhibition in enterocytic differentiation and epithelial-mesenchymal transition in rat cholestatic sepsis.

Toxicol Appl Pharmacol 2020 05 11;394:114956. Epub 2020 Mar 11.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt; School of Pharmacy, NewGiza University, Giza, Egypt.

Proper enterocytic proliferation/differentiation, besides providing adequate adherens junctions (AJ) integrity, are responsible for strengthening of the gut barrier that acts as a first line defense against endotoxemia. However, the preferential role of the underlying PI3K/Akt (PKB) axis in triggering enterocytic proliferation/differentiation signaling and AJ assembly is still obscure in sepsis. Additionally, the potential involvement of dipeptidyl peptidase (DPP)-IV in cholestatic sepsis has not yet been reported. Common bile duct ligation (CBDL) insult was performed in adult male Sprague-Dawley rats except for sham operated animals; three doses of vildagliptin (VLD3, 10 and 30 mg/kg/d; p.o) were administered for 10 consecutive days post CBDL. VLD3/10/30 dose-dependently decreased DPP-IV and elevated GLP-1, IGF-1, PI3K, pS473-Akt (PKB), pS9-GSK-3β, pS133-CREB and cyclin-D1. VLD3/10 reduced fever, portal/aortic endotoxin and IgG, body weight loss as well as ileal NF-κB, TNF-α, MPO, TBARS, subepithelial/pericryptal and submucosal collagen deposition, vimentin immunoreactivity, N-cadherin, Zeb1 and pY654-β-catenin but increased E-cadherin, NPSH and colon/spleen indices - effects that were quite the opposite of VLD30. Accordingly, maintaining proper enterocytic proliferation/differentiation and phosphorylation inputs consequent to adequate DPP-IV inhibition is integral to AJ assembly in cholestatic sepsis; however, perturbed signals by excessive suppression of the enzyme activity induce toxic effects manifested as AJ disassembly and EMT, hence gut leakage and overt endotoxemia.
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http://dx.doi.org/10.1016/j.taap.2020.114956DOI Listing
May 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

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

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

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

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

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

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

Paradoxical cardiotoxicity of intraperitoneally-injected epigallocatechin gallate preparation in diabetic mice.

Sci Rep 2018 05 18;8(1):7880. Epub 2018 May 18.

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

Numerous clinical and bioavailability studies addressed epigallocatechin gallate (EGCG) beneficial effects; however, our previous work revealed EGCG-induced nephrotoxicity in the presence of diabetes. In this study, the potential myocardial toxicity of EGCG preparation (100 mg/kg/day, IP; 4 days) in diabetic mice injected with streptozotocin (STZ; 150 mg/kg, IP) was investigated. Diabetic mice receiving EGCG preparation showed electrocardiographic changes in addition to elevation of both serum creatine kinase-MB and troponin-I levels accompanied by microscopic myocardial damage. Additionally, myocardial NADPH oxidase, lipid peroxides and nitrotyrosine were increased in the vicinity of decreases of nuclear factor erythroid 2-related factor 2, hemeoxygenase-1, reduced glutathione, total antioxidant capacity, glutathione peroxidase and reductase and heat shock protein 90. Moreover, in diabetic mice, EGCG preparation increased myocardial nuclear factor-kappa B and tumor necrosis factor-alpha in addition to pronounced overexpression of inducible nitric oxide synthase and active caspase-3. Therefore, this study substantiates that EGCG-mediated deterioration compromises diabetes-induced cardiotoxicity to solidify our previous report for its potential nephrotoxicity in the same experimental setting.
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http://dx.doi.org/10.1038/s41598-018-25901-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959847PMC
May 2018

Angiotensin 1-7 ameliorates 6-hydroxydopamine lesions in hemiparkinsonian rats through activation of MAS receptor/PI3K/Akt/BDNF pathway and inhibition of angiotensin II type-1 receptor/NF-κB axis.

Biochem Pharmacol 2018 05 8;151:126-134. Epub 2018 Feb 8.

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

MAS receptor (MASR), expressed in several brain areas, conferred neuroprotection against neurodegenerative disorders when activated by angiotensin (Ang) 1-7; however, its role in Parkinson's disease (PD) remains elusive. Intra-striatal post-administration of Ang1-7, using a 6-hydroxydopamine (OHDA) PD model, improved motor performance and muscle coordination. On the molecular level, Ang1-7 upregulated the striatal expression of MASR and caused upsurge in its downstream targets (p-PI3K/p-Akt/p-CREB/BDNF) to phosphorylate TrKB, which in a positive feedback upregulates MASR. Moreover, Ang1-7 increased substantia nigral tyrosine hydroxylase (TH) expression and striatal dopamine (DA) content to indicate the preservation of the dopaminergic neuronal signal. This effect extended to inhibit the striatal expression of Ang II type-1 receptor (AT-1R) to hold the neurodegenerative effect and to boost Ang1-7 anti-inflammatory/antioxidant effects by abating NADPH oxidase, along with lipid peroxidation. Indeed, Ang1-7 was able to decrease p-MAPK p38/NF-κB p65 to level the inflammatory and oxidative stress events off. The Ang1-7-mediated activation of MASR cue and the suppression of the AT-1R cascade were partially reversed by the intrastartial injection of A-779, a MASR antagonist. The current data suggests a novel therapeutic potential for the Ang1-7 against neurotoxicity associated motor impairment related to PD. The anti-parkinsonian effect of Ang1-7, is in part, mediated by its binding to MASR and the initiation of PI3K/Akt/CREB/BDNF/TrKB cue to increase DA synthesis, besides the downregulation/inhibition of AT-1R/MAPK p38/NF-κB p65/NADPH oxidase pathway.
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http://dx.doi.org/10.1016/j.bcp.2018.01.047DOI Listing
May 2018

Renoprotective effects of montelukast in an experimental model of cisplatin nephrotoxicity in rats.

J Biochem Mol Toxicol 2017 Dec 13;31(12). Epub 2017 Sep 13.

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

Renal toxicity is one of the most severe complications that can occur with cisplatin (CIS) administration in cancer patients. Montelukast (ML) renoprotective outcome contrary to CIS-drawn nephrotoxicity remains obscure. Therefore, adult male Sprague-Dawley rats were orally given ML (10 and 20 mg/kg/day) 5 days before and after single CIS (5 mg/kg; i.p.) treatment. ML returned blood urea nitrogen, as well as serum creatinine and gamma glutamyl transferase that were elevated by CIS to normal level. The improved kidney function tests corroborated the attenuation of CIS renal injury at the microscopical level. It also reduced serum/renal nitric oxide and renal hemeoxygenase-1. Meanwhile, ML hindered the raised levels of serum endothelin-1, serum and renal tumor necrosis factor-α, and monocyte chemoattractant protein-1. These effects were associated by deceased caspase-3 expression in kidney after ML treatment. In conclusion, ML guards against CIS-induced nephrotoxicity via anti-inflammatory and antiapoptotic properties.
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http://dx.doi.org/10.1002/jbt.21979DOI Listing
December 2017

The potential curative effect of rebamipide in hepatic ischemia/reperfusion injury.

Naunyn Schmiedebergs Arch Pharmacol 2017 Jul 30;390(7):691-700. Epub 2017 Mar 30.

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

Rebamipide (Reba), a gastroprotective drug, has signified its hepatoprotective activity; however, its possible post-therapeutic intervention in hepatic ischemia/reperfusion (I/R) remains elusive. Consequently, the intent of this study was to test Reba modulatory effect on nuclear factor (NF)-κB signaling in hepatic I/R model. Rats were randomized into sham, I/R, Reba 60, and Reba100 (60 and 100 mg/kg, respectively) groups. Ischemia was induced for 30 min followed by 3-day reperfusion to set up a model of partial (70%) warm hepatic ischemia. Post-treatment with Reba reduced the serum level of alanine transaminase, improved histopathological alterations of the liver, and elevated hepatic adenosine triphosphate. It also lowered hepatic lipid peroxides and increased both total antioxidant capacity and nitric oxide. Besides, Reba decreased tumor necrosis factor-α, interferon-γ, intercellular adhesion molecule-1, myeloperoxidase, prostaglandin E, cyclooxygenase-2 expression/content, and caspase-3 activity. Reba also upregulated the gene expression/content of sirtuin 1 (SIRT-1), while it downregulated that of high mobility group box (HMGB)1 and reduced the expression/content of NF-κB p65/pS536-NF-κB and the content of pT180/Y182-p38MAPK. Reba provided tenable hepato-therapeutic mechanisms to mitigate events concomitant with hepatic I/R via inhibition of NF-κB p65 and modulation of its influential signals (SIRT-1, HMGB1, p38MAPK) associated with its antiinflammatory, antioxidant, and antiapoptotic impacts.
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http://dx.doi.org/10.1007/s00210-017-1370-7DOI Listing
July 2017

Trigonelline and vildagliptin antidiabetic effect: improvement of insulin signalling pathway.

J Pharm Pharmacol 2017 Jul 8;69(7):856-864. Epub 2017 Mar 8.

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

Objectives: Trigonelline (TRG) is known to have an antidiabetic efficacy; however, its mechanism is not entirely elucidated.

Methods: Hence, its effect on insulin signaling, besides its effectiveness in combination with vildagliptin (VLD) in a Type 2 diabetes model has been tested.

Key Findings: TRG (50 mg/kg; p.o) lowered serum glucose, fructosamine, insulin, and HOMA-IR index and increased insulin sensitivity in soleus muscle via augmenting insulin receptor autophosphorylation (IR-PH), pT308-Akt, and glucose transporter 4 (GLUT4). Additionally, it reduced muscle advanced glycation end products and lipid peroxides with increased glutathione. TRG showed an anti-lipidemic effect lowering serum and/or muscle total cholesterol, triglycerides, and FFAs to decrease body weight, and visceral/epididymal indices. Furthermore, VLD (3 and 10 mg/kg, p.o) increased IR-PH, pT308-Akt, and GLUT4 to improve insulin signaling. The combined effect of TRG with the low dose of VLD was mostly confined to the reduction of the aberrant lipid profile.

Conclusions: The beneficial effect of TRG on insulin sensitivity and glucose/ lipid homeostasis is mediated by the enhancement of the insulin signaling and antioxidant property. Moreover, the positive impact of VLD on pT308-Akt is an integral part in insulin signaling, and hence its antidiabetic effect.
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http://dx.doi.org/10.1111/jphp.12713DOI Listing
July 2017

Nephro-toxic effects of intraperitoneally injected EGCG in diabetic mice: involvement of oxidative stress, inflammation and apoptosis.

Sci Rep 2017 01 18;7:40617. Epub 2017 Jan 18.

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

Epigallocatechin gallate (EGCG) has been studied for its beneficial effects. However, some case reports have associated EGCG supplementation with hepato-toxicity. In the present study, we investigated the possible nephro-toxic effects of EGCG in diabetic mice. Streptozotocin (150 mg/kg, i.p.) was injected in mice for diabetes induction. EGCG (100 mg/kg/day, i.p.) was then given for 4 days. The administration of EGCG to diabetic mice caused 60% mortality with no death recorded in other groups. Blood samples were collected for estimation of serum cystatin C, neutrophil gelatinase-associated lipocalin and blood urea nitrogen. Animals were then sacrificed and kidneys were rapidly excised for estimation of oxidative stress markers (NADPH oxidase, reduced glutathione, total antioxidant capacity, nuclear factor erythroid 2-related factor 2, heat shock protein 90, hemeoxygenase-1), as well as inflammatory markers (nuclear factor kappa-B and tumor necrosis factor-α). Administration of EGCG to diabetic mice showed significant elevation in serum cystatin C and neutrophil gelatinase-associated lipocalin, marked increase in oxidative stress and inflammatory states in addition to marked over expression of active caspase-3. Histopathological examination confirmed EGCG induced renal damage in diabetic mice. In conclusion, despite of its well known favorable effects, EGCG could paradoxically exhibit nephro-toxic effect in the presence of diabetes.
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http://dx.doi.org/10.1038/srep40617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241811PMC
January 2017

Geraniol ameliorates TNBS-induced colitis: Involvement of Wnt/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways.

Life Sci 2015 Sep 10;136:142-50. Epub 2015 Jul 10.

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

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.
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http://dx.doi.org/10.1016/j.lfs.2015.07.004DOI Listing
September 2015

Geraniol, alone and in combination with pioglitazone, ameliorates fructose-induced metabolic syndrome in rats via the modulation of both inflammatory and oxidative stress status.

PLoS One 2015 13;10(2):e0117516. Epub 2015 Feb 13.

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

Geraniol (GO) potent antitumor and chemopreventive effects are attributed to its antioxidant and anti-inflammatory properties. In the current study, the potential efficacy of GO (250 mg/kg) in ameliorating metabolic syndrome (MetS) induced by fructose in drinking water was elucidated. Moreover, the effect of pioglitazone (5 and 10 mg/kg; PIO) and the possible interaction of the co-treatment of GO with PIO5 were studied in the MetS model. After 4 weeks of treatment, GO and/or PIO reduced the fasting blood glucose and the glycemic excursion in the intraperitoneal glucose tolerance test. GO and PIO5/10 restrained visceral adiposity and partly the body weight gain. The decreased level of peroxisome proliferator activated receptor (PPAR)-γ transcriptional activity in the visceral adipose tissue of MetS rats was increased by single treatment regimens. Though GO did not affect MetS-induced hyperinsulinemia, PIO5/10 lowered it. Additionally, GO and PIO5/10 suppressed glycated hemoglobin and the receptor for advanced glycated end products (RAGE). These single regimens also ameliorated hyperuricemia, the disrupted lipid profile, and the elevated systolic blood pressure evoked by MetS. The rise in serum transaminases, interleukin-1β, and tumor necrosis factor-α, as well as hepatic lipid peroxides and nitric oxide (NO) was lowered by the single treatments to different extents. Moreover, hepatic non-protein thiols, as well as serum NO and adiponectin were enhanced by single regimens. Similar effects were reached by the combination of GO with PIO5; however, a potentiative interaction was noted on fasting serum insulin level, while synergistic effects were reflected as improved insulin sensitivity, as well as reduced RAGE and triglycerides. Therefore, GO via the transcriptional activation of PPAR-γ reduces inflammation and free radical injury produced by MetS. Thereby, these effects provide novel mechanistic insights on GO management of MetS associated critical risk factors. Moreover, the co-administration of GO to PIO5 exalted the antidiabetic drug anti-MetS efficacy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117516PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332632PMC
January 2016

Saxagliptin: a novel antiparkinsonian approach.

Neuropharmacology 2015 Feb;89:308-17

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

The emergence of glucagon-like peptide-1 as a crucial contender in modifying neurodegenerative diseases in the preclinical studies has instigated interest in investigating the antiparkinsonian effect of dipeptidyl peptidase (DPP)-4 inhibition. Notably, saxagliptin (SAX), the DPP-4 inhibitor, recently showed efficacy in ameliorating streptozotocin-induced Alzheimer's disease; however, its effect on Parkinson's disease (PD) has not yet been elucidated. In a rat rotenone (ROT) model, SAX prominently improved motor performance as well as muscle coordination and corrected akinesia. Moreover, SAX preserved substantia nigra pars compacta tyrosine hydroxylase (TH) immunoreactivity while halting the reduction in the striatal TH, dopamine (DA) and complex I. Meanwhile, SAX prevented the ROT-induced increment of striatal DPP-4 and the decline in cAMP, ATP/ADP and brain-derived neurotropic factor levels. Improvement in striatal energy level was associated with partial hindrance of ROT-induced body weight reduction. In addition, through its anti-inflammatory potential, SAX decreased the ROT-induced nuclear factor-κΒ, inducible nitric oxide synthase, tumor necrosis factor-α, intracellular adhesion molecule-1 and myeloperoxidase. The antiapoptotic marker B-cell lymphoma-2 was enhanced by SAX, versus reduction in caspase-3 and its intrinsic apoptotic activator cytochrome C. Furthermore, SAX amended alterations induced by ROT in the thiobarbituric acid reactive substances and the transcriptional factor Nrf-2 level. In conclusion, SAX can be introduced as a novel approach for the management of PD based on the remarkable improvement in motor functions denoting antiparkinsonian efficacy via antioxidant, anti-inflammatory, antiapoptotic, neuroprotective and neurorestorative mechanisms. These effects were linked to DPP-4 inhibition, reduced neurodegeneration and enhanced DA synthesis.
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http://dx.doi.org/10.1016/j.neuropharm.2014.10.007DOI Listing
February 2015

Ellagic acid antiinflammatory and antiapoptotic potential mediate renoprotection in cisplatin nephrotoxic rats.

J Biochem Mol Toxicol 2014 Oct 10;28(10):472-9. Epub 2014 Jul 10.

Department of Pharmacology, National Organization for Drug Control and Research (NODCAR), Giza, Egypt.

Ellagic acid (EA) renoprotective effect against cisplatin (CIS)-induced nephrotoxicity remains elusive. Therefore, male Sprague-Dawley rats received CIS alone or EA (10 and 30 mg/kg, p.o.) for 5 days before and after CIS injection. CIS increased serum levels of blood urea nitrogen, creatinine, γ-glutamyl transferase, and reduced those of albumin and total protein. It also raised serum endothelin-1, as well as serum and renal nitric oxide, tumor necrosis factor-α, and monocyte chemoattractant protein-1. CIS enhanced the renal caspase-3, hemeoxygenase (HO)-1, nuclear factor-κB, and inducible nitric oxide. EA hampered CIS-induced nephrotoxicity manifested by an enhancement of the glomerular filtration rate which was associated by the reduction of inflammatory mediators and the apoptotic marker in the serum and/or kidney. The present study discloses that EA suppresses HO-1 and, its renoprotection is also linked to its anti-inflammatory and antiapoptotic properties, as well as the reduction of nitric oxide and endothelin-1.
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http://dx.doi.org/10.1002/jbt.21587DOI Listing
October 2014

Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease.

PLoS One 2014 15;9(5):e97193. Epub 2014 May 15.

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

Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097193PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022743PMC
January 2015

Cilostazol renoprotective effect: modulation of PPAR-γ, NGAL, KIM-1 and IL-18 underlies its novel effect in a model of ischemia-reperfusion.

PLoS One 2014 9;9(5):e95313. Epub 2014 May 9.

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

Cilostazol, a phosphodiesterase-III inhibitor, reportedly exhibits positive effects against ischemia/reperfusion (I/R)-induced injury in several models. However, its potential role against the renal I/R insult has not been elucidated. To test whether the PPAR-γ (of peroxisome proliferator activated receptor gamma) pathway is involved in the cilostazol effect, rats were randomized into sham, I/R, cilostazol (50 and 100 mg/kg per day, orally), pioglitazone (3 and 10 mg/kg per day, orally) and their combination at the low dose levels. Drugs regimens were administered for 14 days prior to the I/R induction. Pretreatment with cilostazol or pioglitazone provided significant protection against the I/R-induced renal injury as manifested by the attenuated serum levels of creatinine, blood urea nitrogen and cystatin C. Both drugs have also opposed the I/R-induced elevation in tissue contents/activity of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Κim-1), nuclear factor-κB, interleuκin-18, caspase-1, as well as malondialdehyde, iNOS, myeloperoxidase, ICAM-1 and VCAM-1. Nevertheless, the drugs increased both the PPAR-γ transcriptional activity and the content of glutathione. Furthermore, combining the two low doses of both drugs produced effects comparable to that of the high dose level of either drug, advocating the fortification of pioglitazone renoprotective effect when given concomitantly with cilostazol. In conclusion, cilostazol purveyed conceivable novel renoprotective mechanisms and alleviated incidents associated with acute renal injury either alone or in combination with pioglitazone partially via the elevation of PPAR-γ besides the amendment of the aforementioned biomarkers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095313PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015937PMC
October 2015