Publications by authors named "Dalia H El-Kashef"

20 Publications

  • Page 1 of 1

Anti-fibrotic activity of sitagliptin against concanavalin A-induced hepatic fibrosis. Role of Nrf2 activation/NF-κB inhibition.

Int Immunopharmacol 2021 Aug 25;100:108088. Epub 2021 Aug 25.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia.

Sitagliptin is known for its anti-diabetic activity though it has other pleiotropic pharmacological actions. Its effect against concanavalin A (Con A)-induced hepatic fibrosis has not been investigated yet. Our target was to test whether sitagliptin can suppress the development of Con A-induced hepatic fibrosis and if so, what are the mechanisms involved? Con A (6 mg/kg) was injected once weekly to male Swiss albino mice for four weeks. Sitagliptin was daily administered concurrently with Con A. Results have shown the potent hepatoprotective activity of sitagliptin against Con A-induced hepatitis and fibrosis. That was evident through the amelioration of hepatotoxicity serum parameters (ALT, AST, ALP, and LDH) and the increase in the level of serum albumin in sitagliptin treated mice. Simultaneously, there was amendment of the Con A-induced hepatic lesions and repression of fibrosis in sitagliptin-treated animals. Hydroxyproline, collagen content and the immuno-expression of the fibrotic markers, TGF-β and α-SMA were depressed upon sitagliptin treatment. Sitagliptin suppressed Con A-induced oxidative stress and increased antioxidants. RT-PCR analysis showed enhancement of mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes (GCLc, GCLm, NQO-1, HO-1) by sitagliptin. Furthermore, sitagliptin ameliorated the level and immuno-expression of nuclear factor kappa-B (NF-κB) alongside the immuno-expression of the inflammatory cytokine, TNF-α. Taken together, this study demonstrates the hepatoprotective activity of sitagliptin which may be in part related to enhancement of Nrf2 signaling pathway and inhibition of NF-κB which interact inflammatory response in liver. Sitagliptin might be a new candidate to suppress hepatitis-associated fibrosis.
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http://dx.doi.org/10.1016/j.intimp.2021.108088DOI Listing
August 2021

Flavocoxid halts both intestinal and extraintestinal alterations in acetic acid-induced colitis in rats.

Environ Sci Pollut Res Int 2021 Aug 25. Epub 2021 Aug 25.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disorder mainly affecting the colon and rectum. The present investigation was undertaken to evaluate the potential protective effect of flavocoxid, a dual COX and LOX inhibitor, in colitis model in rats. UC was induced by instillation of 2 ml of 4% acetic acid (AA) into the colon using a pediatric catheter in rats, and flavocoxid (10 and 20 mg·kg) was given once daily for 7 days before induction of colitis. Rats were sacrificed; sera were collected; colons and livers were isolated and then analyzed by biochemical, macroscopic, and histopathological examination. Pretreatment with flavocoxid (10 and 20 mg·kg) significantly reduced serum levels of alanine transaminase (ALT) (43.7 ± 7 and 76.2 ± 7.3 vs. 288.7 ± 31.4 in AA group) and aspartate transaminase (AST) (179.5 ± 22.2 and 200.5 ± 14 vs. 392.7 ± 35.6 in AA group) (p>0.05). Also, it decreased malondialdehyde (MDA) and nitric oxide (NOx) levels in both colonic and hepatic tissues. Moreover, flavocoxid effectively elevated colonic and hepatic reduced glutathione (GSH) level and superoxide dismutase (SOD) activity when compared to AA group (p>0.05). Additionally, flavocoxid significantly decreased levels of tumor necrosis factor-α (TNF-α) (878.2 ± 13.4 and 560.1 ± 2.9 vs. 1378.1 ± 31 in AA group) in colonic tissues and (701 ± 6.9 and 442.5 ± 8.2 vs. 1501 ± 9.4 in AA group) in hepatic tissues, nuclear factor kappa B (NF-κBp65) (493.8 ± 6.8 and 368.7 ± 3.1 vs. 659.2 ± 9.4 in AA group) in colonic tissues and (358 ± 5.1 and 163.5 ± 7.8 vs. 732.5 ± 4.5 in AA group) in hepatic tissues, myeloperoxidase (MPO) (15.7 ± 0.3 and 13 ± 0.2 vs. 20.9 ± 0.5 in AA group) in colonic tissues and (20.4 ± 0.3 and 16.3 ± 0.3 vs. 23.9 ± 1.2 in AA group) in hepatic tissues, and inducible nitric oxide synthase (iNOS) (12.5 ± 0.3 and 10 ± 0.2 vs. 16 ± 0.1 in AA group) in colonic tissues and (14.1 ± 0.04 and 11.5 ± 0.08 vs. 17.8 ± 0.1 in AA group) in hepatic tissues (p>0.05). Furthermore, it down-regulated Bax and caspase-3 expression in colonic and hepatic tissues upon comparison with AA group. Collectively, flavocoxid conferred a protective impact against acetic acid-induced colitis in rats via attenuating oxidative stress, inflammation, and apoptosis.
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http://dx.doi.org/10.1007/s11356-021-16092-7DOI Listing
August 2021

Molsidomine alleviates acetic acid-induced colitis in rats by reducing oxidative stress, inflammation and apoptosis.

Int Immunopharmacol 2021 Oct 27;99:108005. Epub 2021 Jul 27.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address:

Ulcerative colitis (UC) is a subcategory of intestinal inflammatory bowel disease characterized by up-regulation of proinflammatory cytokines and oxidative stress. The current study was designed to assess the probable protective effect of the nitric oxide (NO) donor, molsidomine, in experimental colitis model in rats. Rats were haphazardly classified into four groups: control, acetic acid, acetic acid + molsidomine (1 mg/kg) and acetic acid + molsidomine (2 mg/kg). Molsidomine (1 and 2 mg/kg/day) was administered by intra-peritoneal injection for 7 days prior to induction of UC. On the 8th day, colitis was induced by intra-rectal instillation of 2 ml of (4% v/v) acetic acid in normal saline using a pediatric plastic catheter. The rats were sacrificed 1 day following colitis induction, blood samples were obtained; colons and livers were isolated then underwent macroscopic, biochemical, histopathological and immunohistochemical examination. Pretreatment with molsidomine significantly reduced disease activity index, colon mass index, colonic macroscopic and histological damage. Besides, molsidomine significantly reduced the serum levels of alanine transaminase (ALT) (58.7 ± 8.9 & 59.7 ± 8 vs 288.75 ± 31.4 in AA group) and aspartate transaminase (AST) (196.2 ± 37.4 & 204 ± 30 vs 392.7 ± 35.6 in AA group). Moreover, molsidomine effectively decreased malondialdehyde (MDA) and total nitrate/nitrite (NOx) contents, and up regulated the enzymatic activity of superoxide dismutase (SOD) and glutathione level (GSH) in colonic and hepatic tissues. With regard to anti-inflammatory mechanisms, molsidomine suppressed tumor necrosis factor-alpha (TNF-α) (792.5 ± 16.7 & 448 ± 12.1 vs 1352.5 ± 45.8 in AA group) in colonic tissues and (701 ± 19 & 442.5 ± 22.5 vs 1501 ± 26 in AA group) in hepatic tissues as well as nuclear transcription factor kappa B (NF-kB/p65) levels (416.2 ± 4.1 & 185.5 ± 14.2 vs 659.2 ± 11.5 in AA group) in colonic tissues and (358 ± 6.2 & 163.5 ± 9.6 vs 732.5 ± 5.5 in AA group) in hepatic tissues. In addition, molsidomine significantly decreased inducible nitric oxide synthase (iNOS) levels (8.1 ± 0.1 & 4.9 ± 0.1 vs 16 ± 0.1 in AA group) in colonic tissues and (8.6 ± 0.3 & 6.1 ± 0.1 vs 17.8 ± 0.1 in AA group) in hepatic tissues, and myeloperoxidase (MPO) contents (10.5 ± 0.4 & 6.6 ± 0.3 vs 20.9 ± 0.6 in AA group) in colonic tissues and (13.1 ± 0.2 & 6.3 ± 0.06 vs 23.9 ± 1.4 in AA group) in hepatic tissues at p > 0.05. Furthermore, it suppressed apoptosis by reducing expression of Caspase 3 and Bax in colonic and hepatic tissues. Therefore, molsidomine might be a promising candidate for the treatment of UC.
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http://dx.doi.org/10.1016/j.intimp.2021.108005DOI Listing
October 2021

Nicorandil mitigates folic acid-induced nephrotoxicity in mice: Role of iNOS and eNOS.

J Biochem Mol Toxicol 2021 Apr 6;35(4):e22692. Epub 2021 Jan 6.

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

Folic acid (FA)-induced acute kidney injury (AKI) is a commonly used model in experimental animals for studying renal injury. This study aimed to investigate the probable protecting impact of nicorandil against FA-induced renal dysfunction. A mouse model was executed by a single injection of FA (250 mg/kg). Nicorandil was orally administrated in two doses (50 and 100 mg/kg) for 10 days. Nicorandil repressed the progression of FA-induced AKI as evidenced by the improvement of histopathological alterations and the substantial decrease of serum levels of creatinine, urea, blood urea nitrogen, malondialdehyde (MDA), and urinary protein levels. Moreover, nicorandil resulted in a profound reduction in oxidative stress as manifested by decreased MDA and increased reduced glutathione and superoxide dismutase in renal tissue. Notably, nicorandil suppressed FA-induced inflammation; it reduced renal levels of nuclear factor-κB, tumor necrosis factor-α, and interleukin-6. Furthermore, nicorandil decreased renal levels of nitric oxide, inducible nitric oxide synthase, and increased endothelial nitric oxide synthase. Lastly, nicorandil efficiently decreased expression of the proapoptotic protein (Bax) and caspase 3. Nicorandil confers dose-dependent protection against FA-induced AKI by alleviating oxidative stress, inflammation besides modulating nitric oxide synthase and reducing apoptosis.
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http://dx.doi.org/10.1002/jbt.22692DOI Listing
April 2021

Tiron alleviates MPTP-induced Parkinsonism in mice via activation of Keap-1/Nrf2 pathway.

J Biochem Mol Toxicol 2021 Mar 28;35(3):e22685. Epub 2020 Dec 28.

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

Parkinsonism is a neurodegenerative disease that is common all over the world. This study aimed at exploring the neuroprotective effect of tiron against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. MPTP (30 mg/kg, intraperitoneally [ip]) was injected in mice daily for 5 consecutive days. Mice were treated with tiron (140 and 280 mg/kg, ip) or levodopa (8.4 mg/kg, orally) for 10 consecutive days starting 5 days before MPTP injection. At the end of the experiment, behavioral tests were conducted to assess the neuroprotective effect of tiron. Moreover, oxidative stress was assessed via measuring antioxidant enzyme, such as catalase, and lipid peroxidation was evaluated as malondialdehyde. Neuronal damage was also detected by histopathological examination and via estimating hippocampal levels of dopamine, γ-aminobutyric acid, and nuclear factor erythroid-derived 2-like 2. In addition, the expression of Kelch-like ECH-associated protein 1 and heme oxygenase-1 was assessed by immunohistochemistry. Compared with the blank control group and the positive control group, the inhibitory effect of tiron on MPTP-induced neurodegenerative injury was statistically significant.
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http://dx.doi.org/10.1002/jbt.22685DOI Listing
March 2021

Saroglitazar attenuates renal fibrosis induced by unilateral ureteral obstruction via inhibiting TGF-β/Smad signaling pathway.

Life Sci 2020 Jul 27;253:117729. Epub 2020 Apr 27.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address:

Obstructive nephropathy is a common clinical case that causes chronic kidney disease and ultimately progresses to end-stage renal disease. The activation of peroxisome proliferator-activated receptor-α (PPAR-α) reduces tubulointerstitial fibrosis and inflammation associated with obstructive nephropathy.

Aims: This study was carried out to investigate the potential effect of saroglitazar, dual PPAR-α/γ agonist, in alleviating renal fibrosis induced by unilateralureteral obstruction (UUO).

Main Methods: Twenty-four male Sprague Dawley rats were haphazardly divided into four groups of six rats each, including sham operated group, vehicle- or saroglitazar-treated UUO and saroglitazar groups. Rats received oral gavage of saroglitazar (3 mg/kg/day) for 13 days. On day 14, all rats were sacrificed; blood and renal tissues were collected.

Key Findings: Saroglitazar inhibited UUO-induced oxidative stress; it decreased the elevated levels of MDA and nitric oxide and increased levels of GSH and SOD in renal tissue. Moreover, saroglitazar repressed UUO-induced inflammation; it decreased the renal levels of nuclear factor kappa B (NF-κB) and interleukin-6 (IL-6). Furthermore, saroglitazar inhibited the accumulation of extracellular matrix via decreasing collagen, hydroxylproline and matrix metalloproteinase-9 (MMP-9) levels. Saroglitazar also decreased the expression of both the alpha smooth muscle actin (α-SMA) and tumor growth factor-beta (TGF-β). These effects were in parallel with reduction in mothers against decapentaplegic homolog 3 (smad3) expression and plasminogen activator inhibitor-1 (PAI-1) levels.

Significance: Collectively, the protective impact of saroglitazar might be attributed to its antioxidant, anti-inflammatory and anti-fibrotic effects against UUO-induced tubulointerstitial fibrosis through its regulatory effect on TGF-β1/Smad3 signaling pathway.
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http://dx.doi.org/10.1016/j.lfs.2020.117729DOI Listing
July 2020

Montelukast ameliorates Concanavalin A-induced autoimmune hepatitis in mice via inhibiting TNF-α/JNK signaling pathway.

Toxicol Appl Pharmacol 2020 04 25;393:114931. Epub 2020 Feb 25.

Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madina Al-Munawwarah, 30001, Saudi Arabia. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt. Electronic address:

Background: Concanavalin A (ConA) is a well-established model to induce autoimmune hepatitis (AIH) in mice which mimics pathological alterations that occur in human. The pathogenesis of ConA-induced AIH involves many signaling pathways. Montelukast is a leukotriene receptor antagonist that is mainly used in the management of asthma. The antioxidant, anti-inflammatory and anti-apoptotic effects of montelukast have been reported in previous studies. Lately, montelukast has been documented to confer protection against various inflammatory diseases. Up to date, no study has explored the effect of montelukast on AIH induced by ConA.

Aim And Method: This study aims to detect the protective effects of montelukast (10 mg/kg) on ConA (20 mg/kg)- induced AIH in mice and to demonstrate its hepatoprotective mechanisms. Hepatic function, histological changes, oxidative stress, inflammation, autophagy, and apoptotic markers were investigated.

Results: Hepatic function and histological data revealed that treatment with montelukast significantly attenuated ConA-induced hepatic damage. Montelukast significantly reduced JNK level and NFκB p65 expression, and inhibited proinflammatory cytokines (TNF-α and IL-6) as well as oxidative stress (MDA, NO, and GSH). Moreover, inflammatory cells (CD4+ infiltration and the levels of apoptotic markers (Bax and caspase-3) besides autophagy biomarkers (Beclin1 and LC3) were reduced.

Conclusion: Our results suggest that montelukast could be a potential therapeutic drug against the ConA-induced AIH through its anti-oxidant, anti-inflammatory, anti- autophagy as well as anti-apoptotic properties.
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http://dx.doi.org/10.1016/j.taap.2020.114931DOI Listing
April 2020

Krill oil alleviates oxidative stress, iron accumulation and fibrosis in the liver and spleen of iron-overload rats.

Environ Sci Pollut Res Int 2020 Feb 10;27(4):3950-3961. Epub 2019 Dec 10.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

Krill oil (KO) is a recent supplement which is rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These fatty acids are found in both krill oil and fish oil. In krill oil, they esterified to phospholipids, but in fish oil, they are esterified to triacylglycerols. The target of this study was to investigate whether KO could help against iron overload-induced toxicity in liver and spleen. Rats were randomly assigned into 3 categories: control rats, rats received iron in a drinking water for 8 weeks followed by either vehicle or KO (40 mg/kg) treatment for an extra 8 weeks. Extent of hepatic and splenic injury was assessed via biochemical, histopathological and immunohistochemical evaluations. KO effectively improved the microscopic features of liver and spleen. Moreover, it decreased the increased levels of serum transaminases, ALP, LDH, iron, and ferritin and increased albumin serum level as well. In addition, it restored the balance between oxidants and antioxidants in the hepatic and splenic tissues. Furthermore, it decreased HO-1 levels, upregulated the production of Nrf2, and limited the expression of MMP9. These findings altogether suggest that KO might be a new candidate for treatment of iron overload-induced toxicity. Graphical abstract Graphical abstract.
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http://dx.doi.org/10.1007/s11356-019-06983-1DOI Listing
February 2020

Protective role of pirfenidone against experimentally-induced pancreatitis.

Pharmacol Rep 2019 Oct 9;71(5):774-781. Epub 2019 Apr 9.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt; Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, Saudi Arabia. Electronic address:

Background: Pirfenidone (PFD) is an orally active antifibrotic agent that has anti-inflammatory activity in diverse animal models. Its effect against acute pancreatitis (AP) has not been elucidated. Hence, the present investigation was carried out to assess the potential protective role of PFD against l-arginine-induced AP in mice.

Methods: AP was induced in adult male Swiss albino mice via intraperitoneal injections of l-arginine (4 g/kg, twice each 1 h apart). PFD (250 mg/kg, orally) was administered one day before and on the day of l-arginine challenge. Twenty-four hours after l-arginine injection, the severity of AP was evaluated using biochemical and histological analyses. Indices of oxidative stress, inflammation and apoptosis were evaluated using ELISA and immunohistochemistry (IHC).

Results: PFD suppressed the development of l-arginine-induced AP as revealed by the improvement of histopathological lesions of pancreatic specimen and the significant reduction of serum amylase and lipase levels. Notably, PFD reduced the lipid peroxidation and enhanced the antioxidants such as reduced glutathione (GSH) and superoxide dismutase (SOD) in pancreatic tissue. Importantly, PFD suppressed AP-associated elevation of inflammatory cytokines along with depression of nuclear factor kappa-B (NF-κB) immuno-expression in pancreatic tissue. Lastly, PFD efficiently ameliorated AP-induced elevation of the pro-apoptotic protein (Bax) and increased AP-induced reduction of the anti-apoptotic protein (Bcl2).

Conclusions: PFD protected against l-arginine-induced AP in mice through anti-oxidative, anti-inflammatory and anti-apoptotic properties.
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http://dx.doi.org/10.1016/j.pharep.2019.04.005DOI Listing
October 2019

Hepatoprotective effect of celecoxib against tamoxifen-induced liver injury via inhibiting ASK-1/JNK pathway in female rats.

Life Sci 2019 Aug 14;231:116573. Epub 2019 Jun 14.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Hepatotoxicity is a common side effect encountered with tamoxifen (TAM) administration. Due to the great value of TAM in breast cancer treatment, hepato-protection is seriously recommended.

Aims: The present study investigated the hepato-protective effect of celecoxib (CX) against TAM-induced hepatotoxicity in rats.

Main Methods: Female rats were injected with TAM (45 mg/kg, i.p.) for 7 days and given CX (15 mg/kg, orally) 7 days before TAM injection, then continued for the following 7 days.

Key Findings: Administration of CX for 14 days conferred significant hepatoprotection against TAM-induced hepatotoxicity indexed by decreased liver/body weight ratio, boosted cytoprotection and substantial reduction in serum LDH activity besides functional hepatic improvement; marked decrease in ALT, AST and ALP with significant elevation in serum albumin. Oxidant/antioxidants hemostasis was improved upon CX treatment with profound decrease in hepatic MDA content and elevation of GSH and SOD levels. Furthermore, hepatic content of NO decreased along with significant decrease in ASK-1, JNK and Bax levels as well as TNFα and caspase3 expression. Finally, CX administration resulted in obvious diminution of TAM-induced necrotic and apoptotic alterations.

Significance: Celecoxib might be used in combination with TAM in treatment protocol of breast to prevent liver injury induced by TAM and further clinical studies might be needed to approve this notion.
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http://dx.doi.org/10.1016/j.lfs.2019.116573DOI Listing
August 2019

Sitagliptin ameliorates thioacetamide-induced acute liver injury via modulating TLR4/NF-KB signaling pathway in mice.

Life Sci 2019 Jul 9;228:266-273. Epub 2019 May 9.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Sitagliptin is an oral hypoglycemic drug that acts by selective inhibition of dipeptidyl peptidase-4 (DDP-4) enzyme.

Aim: This study scrutinized the hepatoprotective impact of sitagliptin) against thioacetamide (TAA)-induced liver damage in mice.

Main Methods: Male mice were injected with TAA (500 mg/kg) then treated with sitagliptin (20 mg/kg) orally for 5 days.

Key Findings: Histopathological results of TAA group revealed severe degree of centrolobular hepatic necrosis. Additionally, biochemical findings showed marked elevation in the serum transaminases and gamma glutamyl transpeptidase (GGT) levels in TAA group. Injection of TAA significantly disrupted oxidant/antioxidants hemostasis of the hepatic tissues. Also, TAA markedly increased the expression of nuclear factor kappa-B (NF-KB); and enhanced Toll like receptor 4 (TLR4) as well as NLPR3 inflammosome production. Moreover, there was an elevation in the hepatic levels of tumor necrosis factor-alpha (TNF-α) and interleukin -1 beta (IL-1β) besides increased immunoexpression of Bcl-2-associated X protein (Bax) as well as caspase 3. In contrast, treatment with sitagliptin significantly attenuated TAA-induced histopathological, biochemical and immunohistochemical alterations.

Significance: Our results suggest that the hepatoprophylactic impact of sitagliptin might be arbitrated via modulating TLR4 and NK-KB signaling cascade followed by depression of inflammation besides apoptosis.
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http://dx.doi.org/10.1016/j.lfs.2019.05.019DOI Listing
July 2019

Nicorandil ameliorates pulmonary inflammation and fibrosis in a rat model of silicosis.

Int Immunopharmacol 2018 Nov 14;64:289-297. Epub 2018 Sep 14.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address:

Nicorandil, an antianginal and potassium channel opener agent, has different useful impacts on cardiovascular and respiratory systems. Its effect against silicosis has not been discussed yet, therefore, this is an attempt to decide whether nicorandil can reduce silica-induced lung injury in rats. Silica model was induced by intranasal instillation of silica dust once. Rats were given nicorandil for 56 days after exposure to silica. Results showed that nicorandil significantly alleviated silica-induced inflammation as it decreased the elevated levels of total and differential cell counts, pulmonary edema (revealed by decreased lung/body weight ratio and W/D weight ratio), LDH and total protein levels in BALF. Notably, nicorandil decreased collagen deposition as evidenced by reduction in levels of hydroxyproline and collagen in lung tissues as well as obvious alleviation in silica-induced fibrosis in histopathological findings. Nicorandil effectively reduced the increased expression of NF-κB and iNOS and decreased MPO levels in lung tissues. Moreover, nicorandil abolished oxidative and nitrosative stress via reducing levels of pulmonary MDA and NOx concomitant with elevating levels of pulmonary GSH and SOD. Meanwhile, nicorandil decreased the levels of TNF-α and TGF-β, up regulated Nrf-2 and HO-1 levels in BALF suggesting antioxidant, anti-inflammatory and antifibrotic properties. In summary, nicorandil can confer protection against silica-induced lung inflammation and fibrosis. This impact might be due to its ability to down regulate the production of inflammatory and fibrotic cytokines in addition to restoring oxidant/antioxidant balance.
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http://dx.doi.org/10.1016/j.intimp.2018.09.017DOI Listing
November 2018

Agmatine attenuates rhabdomyolysis-induced acute kidney injury in rats in a dose dependent manner.

Life Sci 2018 Sep 17;208:79-86. Epub 2018 Jul 17.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address:

Acute kidney injury (AKI) is a serious disorder that accompanies rhabdomyolysis (RM). The underlying mechanisms as well as protective approaches need to be investigated. This study was targeted to explore the prophylactic effect of agmatine (AGM), an endogenous metabolite of l-arginine against RM-induced AKI. A rat model was elucidated by 50% glycerol (10 ml/kg, im). Glycerol induced functional and structural alterations in the kidney. Pretreatment with AGM significantly ameliorated RM through decreasing total creatinine kinase (CK) and creatine kinase-MB (CK-MB) levels. AGM alleviated functional changes evidenced by decreased serum levels of creatinine (Cr), blood urea nitrogen (BUN) and decreased urinary levels of albumin and proteins. Moreover, AGM decreased renal levels of malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β), neutrophil gelatinase-associated lipocalin (NGAL), inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-κB) and myeloperoxidase (MPO). Furthermore, AGM significantly increased renal levels of reduced glutathione (GSH), superoxide dismutase (SOD), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Structural abnormalities confirmed by histopathological examination were also attenuated. AGM confers a dose-dependent protection against RM-induced AKI by preventing muscle degradation, alleviating oxidative stress and inhibiting production of cytokines and inflammation.
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http://dx.doi.org/10.1016/j.lfs.2018.07.019DOI Listing
September 2018

Venlafaxine mitigates cisplatin-induced nephrotoxicity via down-regulating apoptotic pathway in rats.

Chem Biol Interact 2018 Jun 29;290:110-118. Epub 2018 May 29.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address:

The antidepressant venlafaxine, a norepinephrine and serotonin reuptake inhibitor, is recently identified for its anti-inflammatory role against many experimental models. In this study, the effect of venlafaxine against cisplatin-induced nephrotoxicity and bladder rings hypersensitivity towards acetylcholine were explored. Single injection of cisplatin (7 mg/kg, ip) in Sprague-Dawley rats instigated nephrotoxicity evidenced by hindering renal function (changes in kidney/body weight ratio, serum creatinine, BUN, albumin and urinary total protein levels which were supported by histopathology). In addition, cisplatin caused a profound oxidative stress, inflammation and apoptosis. Treatment with venlafaxine (50 mg/kg, po) managed to alleviate the nephrotoxicity indices and rehabilitate the antioxidant parameters (MDA, GSH, SOD and CAT) in addition to retaining NOx levels to the normal levels. Moreover, venlafaxine caused a decline in LDH and NF-κB levels supporting its anti-inflammatory effect. Additionally, the antiapoptotic effect was demonstrated by increasing Bcl-2, suppressing p53 and Bax renal levels, decreasing caspase-3 expression and by flow cytometry (annexin V and PI) that showed an increase in viable cells and a decrease in early apoptotic and necrotic cells. Furthermore, venlafaxine ameliorated bladder rings hyperreactivity to acetylcholine and improved histopathologic findings. In brief, venlafaxine ameliorated nephrotoxicity and bladder rings hyperreactivity caused by cisplatin through acting as an antioxidant, anti-inflammatory and antiapoptotic agent.
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http://dx.doi.org/10.1016/j.cbi.2018.05.015DOI Listing
June 2018

Protective effect of pristimerin against LPS-induced acute lung injury in mice.

Int Immunopharmacol 2018 Jun 2;59:31-39. Epub 2018 Apr 2.

Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawwarah, 30001, Saudi Arabia; Pharmacology and Toxicology Dept., Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address:

Pristimerin (Pris) is a triterpenoid derivative obtained from Celastraceae and Hippocrateaceae families. This compound has been extensively tested for its potent anti-cancer activity against different types of tumors. However, its effects against acute lung injury (ALI) remain to be investigated. This study explored the efficacy of Pris to protect against lipopolysaccharide (LPS)-induced ALI and its possible pathways. Results have shown that Pris possesses potent protective activity against LPS-induced acute lung damage. It significantly decreased pulmonary edema as presented by significant decrease in lung W/D ratio and in protein content. Pris attenuated LPS-induced inflammatory cell infiltration into the lung tissue and suppressed the activity of myeloperoxidase in lung. LPS-induced histopathological lesions were significantly improved via Pris pretreatment. Pris exhibited not only inhibition of LPS-induced oxidative stress, but also enhancement of the suppressed antioxidant capacity of the lung tissue. The anti-inflammatory activity of Pris against LPS-induced ALI was clearly evident via attenuation of the levels of pro-inflammatory cytokines namely, tumor necrosis factor-α and interleukin-6. Similarly, Pris inhibited LPS-induced elevation of pro-apoptotic protein, Bax, and caspase-3. Pris also increased the diminished level of Bcl2 induced by LPS. Collectively, Pris exerted protective activity against LPS-induced ALI via anti-oxidant, anti-inflammatory and anti-apoptotic pathways.
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http://dx.doi.org/10.1016/j.intimp.2018.03.033DOI Listing
June 2018

Nicorandil alleviates ovalbumin-induced airway inflammation in a mouse model of asthma.

Environ Toxicol Pharmacol 2018 Apr 19;59:132-137. Epub 2018 Mar 19.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address:

Nicorandil is an antianginal drug that has anti-inflammatory property. This study aimed to investigate the effects of nicorandil on allergic asthma induced by ovalbumin (OVA) in mice in comparison with dexamethasone. Mice were sensitized to OVA (on days 0 and 7) and challenged with OVA three times (on days 14, 15 and 16). Nicorandil was given orally for 5 days 1 h before OVA treatment in days of challenge. Progression of asthma was accompanied by significant elevation in the lung/body weight index, LDH, total protein, IL-13 and NF-κB levels besides inflammatory cell counts in BALF; Also pulmonary MDA and NO contents were significantly increased but GSH and SOD levels were decreased. Histopathological alterations in lung tissues were also observed. In contrast, nicorandil treatment significantly alleviated OVA-induced lung injury. In conclusion, our results proposed that nicorandil is equivalent to dexamethasone in ameliorating allergic asthma by restoring oxidant/antioxidant balance and reducing inflammation.
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http://dx.doi.org/10.1016/j.etap.2018.03.012DOI Listing
April 2018

Role of venlafaxine in prevention of cyclophosphamide-induced lung toxicity and airway hyperactivity in rats.

Environ Toxicol Pharmacol 2018 Mar 27;58:70-76. Epub 2017 Dec 27.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt. Electronic address:

Cyclophosphamide (CP) is a drug used in chemotherapy and management of neoplastic diseases. This study aimed to investigate the prophylactic impacts of venlafaxine against CP-induced lung toxicity in rats. Rats were assigned randomly into 3 groups; control, CP (150 mg/kg) and CP/venlafaxine (50 mg/kg). On the end day, rats were sacrificed then bronchoalveolar fluid (BALF) and lungs were harvested. CP produced significant decrease in animal body weights and significant increase in lung/body weight ratio; levels of LDH, total protein, total and differential cell counts in BALF in comparison with control group. Moreover, significant elevation incontents of MDA, NOx, TNF-α and IL-1β and significant decline in GSH, SOD activities were observed in lung tissues. CP increased the response of tracheal zigzag to ACh. Histopathological results showed that CP increased inflammation and fibrosis in lung tissues. Venlafaxine restored most parameters to the normal levels. This protective effect of venlafaxine could be linked to its ability to reduce oxidative stress and inflammation.
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http://dx.doi.org/10.1016/j.etap.2017.12.020DOI Listing
March 2018

Agmatine improves renal function in gentamicin-induced nephrotoxicity in rats.

Can J Physiol Pharmacol 2016 Mar 31;94(3):278-86. Epub 2015 Aug 31.

a Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

The present study was designed to explore the possible protective effects of agmatine, a known nitric oxide (NO) synthase inhibitor, against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of agmatine on gentamicin-induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was evaluated. Twenty-four male Wistar albino rats were randomly divided into 3 groups, namely control, gentamicin (100 mg/kg, i.p.), and gentamicin plus agmatine (40 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood and urine samples and kidneys were taken. Administration of agmatine significantly decreased kidney/body mass ratio, serum creatinine, lactate dehydrogenase (LDH), renal malondialdehyde (MDA), myeloperoxidase (MPO), NO, and tumor necrosis factor-alpha (TNF-α) while it significantly increased creatinine clearance and renal superoxide dismutase (SOD) activity when compared with the gentamicin-treated group. Additionally, agmatine ameliorated tissue morphology as evidenced by histological evaluation and reduced the responses of isolated bladder rings to ACh. Our study indicates that agmatine administration with gentamicin attenuates oxidative-stress associated renal injury by reducing oxygen free radicals and lipid peroxidation, restoring NO level and inhibiting inflammatory mediators such as TNF-α.
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http://dx.doi.org/10.1139/cjpp-2015-0321DOI Listing
March 2016

Protective effect of allicin against gentamicin-induced nephrotoxicity in rats.

Int Immunopharmacol 2015 Dec 29;29(2):679-686. Epub 2015 Sep 29.

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

In this study, the modulator effect of allicin on the oxidative nephrotoxicity of gentamicin in the kidneys of rats was investigated by determining indices of lipid peroxidation and the activities of antioxidant enzymes, as well as by histological analyses. Furthermore, the effect of allicin on gentamicin induced hypersensitivity of urinary bladder rings to ACh was estimated. Twenty-four male Wistar albino rats were randomly divided into three groups, control, gentamicin (100mg/kg, i.p.) and gentamicin+allicin (50mg/kg, orally). At the end of the study, all rats were sacrificed and then urine, blood samples and kidneys were taken. Gentamicin administration caused a severe nephrotoxicity as evidenced by an elevated kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), serum lactate dehydrogenase (LDH) and proteinuria with a reduction in serum albumin and creatinine clearance as compared with control group. In addition, a significant increase in renal contents of malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NOx) and tumor necrosis factor-alpha (TNF-α) concomitantly with a significant decrease in renal reduced glutathione (GSH) and superoxide dismutase (SOD) activities was detected upon gentamicin injection. Exposure to gentamicin increased the sensitivity of isolated urinary bladder rings to ACh and induced acute renal tubular epithelial cells necrosis. Administration of allicin significantly decreased kidney/body weight ratio, serum creatinine, LDH, renal MDA, MPO, NOx and TNF-α while it significantly increased creatinine clearance, renal GSH content and renal SOD activity when compared to gentamicin-treated group. Additionally, allicin significantly reduced the responses of isolated bladder rings to ACh and ameliorated tissue morphology as evidenced by histological evaluation. Our study indicates that allicin exerted protection against structural and functional damage induced by gentamicin possibly due to its antioxidant, anti-inflammatory and immunomodulatory properties in addition to its ability to retaining nitric oxide level.
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http://dx.doi.org/10.1016/j.intimp.2015.09.010DOI Listing
December 2015

Flavocoxid attenuates gentamicin-induced nephrotoxicity in rats.

Naunyn Schmiedebergs Arch Pharmacol 2015 Dec 15;388(12):1305-15. Epub 2015 Aug 15.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, 35516, Mansoura, Egypt.

Gentamicin is a widely used antibiotic against serious and life-threatening infections; however, its usefulness is limited by the development of nephrotoxicity. The present study was designed to determine whether flavocoxid has a protective effect against gentamicin-induced nephrotoxicity in rats. For this purpose, we quantitatively evaluated gentamicin-induced renal structural and functional alterations using histopathological and biochemical approaches. Furthermore, the effect of flavocoxid on gentamicin induced hypersensitivity of urinary bladder rings to acetylcholine (ACh) was determined. Twenty-four male Wistar albino rats were randomly divided into three groups, namely control, gentamicin (100 mg/kg, i.p.) and gentamicin plus flavocoxid (20 mg/kg, orally). At the end of the study, all rats were sacrificed and then blood, urine samples and kidneys were collected for further analysis. Gentamicin administration caused a severe nephrotoxicity which was evidenced by an elevated renal somatic index (RSI), serum creatinine, blood urea nitrogen, serum lactate dehydrogenase, and protein in urine with a concomitant reduction in serum albumin and normalized creatinine clearance value as compared with the controls. Moreover, a significant increase in renal contents of malondialdehyde, myeloperoxidase, and tumor necrosis factor-alpha with a significant decrease in renal reduced glutathione and superoxide dismutase activities was detected upon gentamicin administration together with increasing the sensitivity of isolated urinary bladder rings to ACh. Exposure to gentamicin induced necrosis of renal tubular epithelial cells. Flavocoxid protected kidney tissue against the oxidative damage and the nephrotoxic effect caused by gentamicin treatment. In addition, flavocoxid significantly reduced the responses of isolated bladder rings to ACh. The results from our study indicate that flavocoxid supplement attenuates gentamicin-induced renal injury via the amelioration of oxidative stress and inflammation of renal tubular cells.
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http://dx.doi.org/10.1007/s00210-015-1164-8DOI Listing
December 2015
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