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Hanan Salah

Basic information

Name : Hanan Salah
Title: Professor
Google Schoolar Link
Personal Info: Dr. Hanan Salah, Professor in Pharmacology and Toxicology and Biochemistry Department. She has got her masters and PhD from Cairo University.

Education

Certificate Major University Year
PhD 2003
Masters 1988
Bachelor Pharmaceutical Sciences 1982

Researches /Publications

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 - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Israa M Abd El-Fatah, Heba M A Abdelrazek, Sherehan M Ibrahim, Dalaal M Abdallah

01/09/2021

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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Prasugrel anti-ischemic effect in rats: Modulation of hippocampal SUMO2/3-IкBα/Ubc9 and SIRT-1/miR-22 trajectories - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Asmaa A Gomaa, Dalaal M Abdallah, Azza S Awad, Ayman A Soubh

01/09/2021

The beneficial role of prasugrel, a P2Y12 receptor blocker, in several neurointerventional procedures has been reviewed clinically. Beyond its antiplatelet capacity, the potential neuroprotective mechanisms of prasugrel are poorly addressed experimentally. Relevant to the imbalance between neuro-inflammation and neuroprotective pathways in cerebral ischemia/reperfusion (I/R), our study evaluated the anti-ischemic potential of prasugrel treatment through tackling novel targets. Male Wistar rats were allocated into 2 sets; set 1 (I/R 60 min/3 days) to assess the neurological deficits/biochemical impact of prasugrel and set 2 (I/R 60 min/5 days) for evaluating short memory/morphological/immunoreactive changes. Each set comprised 4 groups designated as sham, sham + prasugrel, I/R, and I/R + prasugrel. Post-administration of prasugrel for 3 and 5 days reduced neurological deficit scores and improved the spontaneous activity/short term spatial memory using the Y-maze paradigm. On the molecular level, prasugrel turned off SUMO2/3-inhibitory kappa (Iκ)Bα, Ubc9 and nuclear factor kappa (NF-κ)B. Besides, it inhibited malondialdehyde (MDA) and inactivated astrocytes by downregulating the glial fibrillary acidic protein (GFAP) hippocampal immune-expression. Conversely, it activated its target molecule cAMP, protein kinase (PK)A, and cAMP response element-binding protein (CREB) to enhance the brain-derived nuclear factor (BDNF) hippocampal content. Additionally, cAMP/PKA axis increased the hippocampal content of deacetylator silent information regulator 1 (SIRT1) and the micro RNA (miR)-22 gene expression. The crosstalk between these paths partakes in preserving hippocampal cellularity. Accordingly, prasugrel, regardless inhibiting platelets activity, modulated other cellular components; viz., SUMO2/3-IκBα/Ubc9/NF-κB, cAMP/PKA related trajectories, CREB/BDNF and SIRT1/miR-22 signaling, besides inhibiting GFAP and MDA to signify its anti-ischemic potential.

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Vitamin D and rosuvastatin obliterate peripheral neuropathy in a type-2 diabetes model through modulating Notch1, Wnt-10α, TGF-β and NRF-1 crosstalk - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Engie S El-Sawaf, Samira Saleh, Dalaal M Abdallah, Kawkab A Ahmed

01/08/2021

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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Pentoxifylline treatment alleviates kidney ischemia/reperfusion injury: Novel involvement of galectin-3 and ASK-1/JNK & ERK1/2/NF-κB/HMGB-1 trajectories - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Hagar M El-Sadek, Muhammad Y Al-Shorbagy, Magdy M Awny, Dalaal M Abdallah

01/07/2021

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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Neuroprotective role of galantamine with/without physical exercise in experimental autoimmune encephalomyelitis in rats - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Mohamed A El-Emam, Samar El Achy, Dalaal M Abdallah, Mennatallah A Gowayed

01/07/2021

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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Epac-1/Rap-1 signaling pathway orchestrates the reno-therapeutic effect of ticagrelor against renal ischemia/reperfusion model - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Bassant M El-Mokadem, Dalaal M Abdallah, Azza S Awad, Ayman A Soubh

01/07/2021

Despite the renal expression of P2Y12, 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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Peganum harmala enhanced GLP-1 and restored insulin signaling to alleviate AlCl 3-induced Alzheimer-like pathology model - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Rofida A Saleh, Tarek F Eissa, Dalaal M Abdallah, Muhammed A Saad

01/06/2021

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 (AlCl3; 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 AlCl3 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 AlCl3. 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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Novel peripheral role of Nurr-1/GDNF/AKT trajectory in carvedilol and/or morin hydrate hepatoprotective effect in a model of hepatic ischemia/ reperfusion - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Nermein F El Sayed, Dalaal M Abdallah, Azza S Awad, Kawkab A Ahmed

01/05/2021

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; CR10/CR30), MH (30 mg/kg), or CR10 + 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, CR10 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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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 - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Suzan M Mansour, Ayman A Soubh

01/02/2021

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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The interrupted cross-talk of inflammatory and oxidative stress trajectories signifies the effect of artesunate against hepatic ischemia/reperfusion-induced inflammasomopathy - 01/1

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Mai El-Sayed Ghoneim, Dalaal M Abdallah, Abdelhadi Mohamed Shebl

01/12/2020

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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Diabetes and CYP2C19 Polymorphism Synergistically Impair the Antiplatelet Activity of Clopidogrel Compared With Ticagrelor in Percutaneous Coronary Intervention-treated Acute Coronary Syndrome Patients - 01/1

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Mina W Mohareb, Mohamed AbdElghany, Hala F Zaki

01/10/2020

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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Activated ROCK/Akt/eNOS and ET-1/ERK pathways in 5-fluorouracil-induced cardiotoxicity: modulation by simvastatin - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Radwa Nasser Muhammad, Nada Sallam

01/09/2020

5-Fluorouracil (5-FU) is used in the treatment of different solid tumors; however, its use is associated with rare, but serious cardiotoxicity. Nevertheless, the involvement of ROCK/NF-κB, Akt/eNOS and ET-1/ERK1/2 trajectories in the cardiotoxic effect and in the potential cardioprotective upshot of simvastatin has been elusive. Male Wistar rats were allocated into 5-FU (50 mg/kg/week; i.p, 6 weeks), simvastatin (15 mg/kg/day; p.o, 8 weeks) treated groups and simvastatin + 5-FU, besides the normal control group. 5-FU-induced cardiotoxicity boosted the serum level of N-terminal pro-brain (B-type) natriuretic peptide (NT-proBNP), aortic contents of endothelin (ET)-1 and thromboxane (TX) A2, as well as cardiac contents of NADPH oxidases (Nox), cyclooxygenase (COX)-2, malondialdehyde (MDA), phosphorylated Akt (p-Akt), phosphorylated extracellular signal-regulated kinase (p-ERK)1/2 and the protein expressions of rho-kinase (ROCK) and caspase-3. On the other hand, it suppressed cardiac reduced glutathione (GSH) and phosphorylated endothelial nitric oxide synthase (p-eNOS). Contrariwise, co-administration with simvastatin overcame these disturbed events and modulated the ROCK/NF-κB, Akt/eNOS and ET-1/ERK1/2 signaling pathways. This study highlights other mechanisms than coronary artery spasm in the 5-FU cardiotoxicity and reveals that NT-proBNP is a potential early marker in this case. Moreover, the cross-talk between ROCK/ NF-κB, ROS/COX-2/TXA2, Akt/eNOS and ET-1/ERK1/2 pathways contributes via different means to upsetting the vasoconstriction/vasodilatation equilibrium as well as endothelial cell function and finally leads to cardiomyocyte stress and death-the modulation of these trajectories offers simvastatin its potential cardio-protection against 5-FU.

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The dual reno- and neuro-protective effects of dimethyl fumarate against uremic encephalopathy in a renal ischemia/reperfusion model - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Diaa Ragab, Dalaal M Abdallah

01/08/2020

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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Modulation of endoplasmic reticulum stress response in gut-origin encephalopathy: Impact of vascular endothelial growth factor receptor-2 manipulation - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Doaa A Zaky, Walaa Wadie, Wagdy M Eldehna, Ahmed M El Kerdawy, Dalaal M Abdallah

01/07/2020

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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Olmesartan attenuates type 2 diabetes-associated liver injury: Cross-talk of AGE/RAGE/JNK, STAT3/SCOS3 and RAS signaling pathways - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Nesma M E Abo El-Nasr, Dalia Osama Saleh, Sawsan S Mahmoud, Salwa M Nofal, Rania M Abdelsalam, Marwa M Safar

01/05/2020

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 PIO10 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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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 - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Mostafa A Rabie, Mai A Abd El Fattah, Noha N Nassar, Dalaal M Abdallah

01/01/2020

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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Mesenchymal stem cells in chemotherapy-induced peripheral neuropathy: A new challenging approach that requires further investigations - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Khaled F Al-Massri, Lamiaa A Ahmed

01/01/2020

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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Chenodeoxycholic acid ameliorates AlCl3-induced Alzheimer’s disease neurotoxicity and cognitive deterioration via enhanced insulin signaling in rats - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Firas H. Bazzari , Dalaal M. Abdallah

01/05/2019

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 (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + 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 (Aβ42). 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 AlCl3-treated rats, which highlights its potential in AD managemen

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Raspberry keto ne and Garcinia Cambogia rebalanced disrupted insulin resistance and leptin silencing in rats fed high fat fructose diet - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Dalaal M. Abdallah

01/02/2019

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.

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Activation of α7 nicotinic acetylcholine receptor ameliorates zymosan-induced acute kidney injury in BALB/c mice - 01/1

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Muhammad Y. Al-Shorbagy, Dalaal M. Abdallah, Sherehan M. Ibrahim

01/11/2018

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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Galantamine anti-colitic effect: Role of alpha-7 nicotinic acetylcholine receptor in modulating Jak/STAT3, NF-κB/HMGB1/RAGE and p-AKT/Bcl-2 pathways - 01/0

HANAN SALAHELDIN HAMDY MAHMOUD HAMDY ELABHAR

Shakeeb A. Wazea, Walaa Wadie, Ashraf K. Bahgat

01/03/2018

Vagal stimulation controls systemic inflammation and modulates the immune response in different inflammatory conditions, including inflammatory bowel diseases (IBD). The released acetylcholine binds to alpha-7 nicotinic acetylcholine receptor (α7 nAChR) to suppress pro-inflammatory cytokines. This provides a new range of potential therapeutic approaches for controlling inflammatory responses. The present study aimed to assess whether galantamine (Galan) anti-inflammatory action involves α7 nAChR in a 2,4,6-trinitrobenzene sulfonic acid (TNBS) model of colitis and to estimate its possible molecular pathways. Rats were assigned into normal, TNBS, sulfasalazine (Sulfz), Galan treated (10 mg/kg), methyllycaconitine (MLA; 5.6 mg/kg), and MLA + Galan groups. Drugs were administered orally once per day (11 days) and colitis was induced on the 8th day. Galan reduced the TNBS-induced ulceration, colon mass index, colonic MDA, neutrophils adhesion and infiltration (ICAM-1/MPO), inflammatory mediators (NF-κB, TNF-α, HMGB1, and RAGE), while increased the anti-apoptotic pathway (p-Akt/Bcl-2). Mechanistic study revealed that Galan increased the anti-inflammatory cytokine IL-10, phosphorylated Jak2, while reduced the inflammation controller SOCS3. However, combining MLA with Galan abrogated the beneficial anti-inflammatory/anti-apoptotic signals. The results of the present study indicate that Galan anti-inflammatory/-apoptotic/ -oxidant effects originate from the stimulation of the peripheral α7 nAChR, with the involvement of the Jak2/SOCS3 signaling pathway

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