Publications by authors named "Mohamed E Shaker"

25 Publications

  • Page 1 of 1

Ingestion of mannose ameliorates thioacetamide-induced intrahepatic oxidative stress, inflammation and fibrosis in rats.

Life Sci 2021 Oct 9:120040. Epub 2021 Oct 9.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address:

Background And Aims: The monosaccharide mannose has gained recent interest for its beneficial effect against certain inflammatory disorders. Nevertheless, the influence of mannose on experimentally-induced liver fibrosis and the ensued inflammation is still not fully clear to date.

Main Methods: The current study investigated the outcomes of treating rats with mannose (0.2 ml of 20% w/v, oral gavage) 30 min before the twice weekly intoxication with thioacetamide (TAA) (200 mg/kg, intraperitoneal) for a total period of 8 weeks.

Key Findings: The data indicated that mannose markedly dampened TAA-induced liver fibrosis, as indicated by lowering the fibrotic bridges shown by Masson's trichrome staining. This effect was consistent with reducing TAA-induced hepatocellular injury, as evidenced biochemically (serum ALT and AST activities) and pathologically (necroinflammation score). These hepatoprotective effects mediated by mannose were attributed to i) reversing TAA-induced rise in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) expressions in the liver, ii) limiting TAA-induced release of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), iii) impairing TAA-induced activation of hepatic stellate cells by downregulating α-smooth muscle actin expression (α-SMA) and, and importantly, iv) dampening TAA-induced fibrogenesis driven by transforming growth factor-β1 (TGF-β1) and connective tissue growth factor (CTGF).

Significance: Mannose may be an auspicious candidate for preventing oxidative stress, inflammation and fibrogenesis in the liver.
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http://dx.doi.org/10.1016/j.lfs.2021.120040DOI Listing
October 2021

A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights.

Molecules 2021 Jan 14;26(2). Epub 2021 Jan 14.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf Province, Saudi Arabia.

Background: Cyclin-dependent kinases (CDKs) regulate mammalian cell cycle progression and RNA transcription. Based on the structural analysis of previously reported CDK2 inhibitors, a new compound with 3-hydrazonoindolin-2-one scaffold () was well designed, synthesized, and biologically evaluated as a promising anti-breast cancer hit compound.

Methods: The potential anti-cancerous effect of was evaluated using cytotoxicity assay, flow cytometric analysis of apoptosis and cell cycle distribution, ELISA immunoassay, in vitro CDK2/cyclin A2 activity, and molecular operating environment (MOE) virtual docking studies.

Results: The results revealed that exhibits pronounced CDK2 inhibitory activity and cytotoxicity in human breast cancer MCF-7 cell line. The cytotoxicity of was found to be intrinsically mediated apoptosis, which in turn, is associated with low Bcl-2 expression and high activation of caspase 3 and p53. Besides, blocked the proliferation of the MCF-7 cell line and arrested the cell cycle at the G2/M phase. The docking studies did not confirm which one of geometric isomers ( and ) is responsible for binding affinity and intrinsic activity of . However, the molecular dynamic studies have confirmed that the -isomer has more favorable binding interaction and thus is responsible for CDK2 inhibitory activity.

Discussion: These findings displayed a substantial basis of synthesizing further derivatives based on the 3-hydrazonoindolin-2-one scaffold for favorable targeting of breast cancer.
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http://dx.doi.org/10.3390/molecules26020412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830330PMC
January 2021

Inhibition of Bruton tyrosine kinase by acalabrutinib dampens lipopolysaccharide/galactosamine-induced hepatic damage.

Biomed Pharmacother 2020 Nov 17;131:110736. Epub 2020 Sep 17.

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

Bruton tyrosine kinase (BTK) sits at the crossroads of adaptive and innate immunities. Nevertheless, the detailed role of BTK activation in hepatic inflammatory disorders is still elusive to date. Accordingly, we investigated the impact of blocking BTK activation by acalabrutinib (ACB) on lipopolysaccharide/galactosamine (LPS/D-GaIN)-induced deleterious manifestations in the liver. This was achieved by pretreating mice with ACB (6, 12 or 24 mg/kg, oral) 2 h before challenge with LPS/D-GaIN (70 μg/kg and 700 mg/kg, respectively, i.p.) for 6 h. The results showed that ACB (6 and 12 mg/kg) (i) curbed LPS/D-GaIN-induced rise in biochemical (serum ALT, AST and LDH) and histological (necrosis, degeneration and congestion scores) indices of hepatocellular injury; (ii) attenuated LPS/D-GaIN-induced elevation in parameters of hepatocellular apoptosis (cleaved caspase 3) and proliferation (PCNA); and (iii) importantly, mitigated LPS/D-GaIN-induced recruitment and infiltration of the inflammatory cells to the liver evidenced by lowering elevated serum MCP-1 concentration and hepatic F4/80 immunostaining. These effects were linked to ACB dose-dependent inhibition of NF-κB nuclear translocation that subsequently reduced LPS/D-GaIN-mediated release of TNF-α, IL-1β and IL-22 in the blood circulation. However, a dose of 12 mg/kg of ACB elevated the hepatic TNF-α, IL-1β and IL-22 concentrations that arose from a compensatory activation of ERK and JNK. Inhibition of BTK also attenuated LPS/D-GaIN-induced overexpression of CD98, which is another contributor alongside cytokines for monocyte recruitment. Therapeutically, targeting BTK by ACB is an efficient approach for hitting multiple points with one agent that can dampen hepatocellular injury, death, immune cell recruitment and inflammation cascade.
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http://dx.doi.org/10.1016/j.biopha.2020.110736DOI Listing
November 2020

The NEDD8-activating enzyme inhibition with MLN4924 sensitizes human cancer cells of different origins to apoptosis and necroptosis.

Arch Biochem Biophys 2020 09 25;691:108513. Epub 2020 Jul 25.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, 72341, Saudi Arabia.

Objectives: MLN4924 is an inhibitor of NEDD8-activating enzyme (NAE) that interferes with the cullin-RING ubiquitin ligase complexes formation and the nuclear factor kappa B (NF-κB) activation. Here, we investigated the cytotoxic effect of MLN4924 and its ability to sensitize a broad range of cancer cells of different origins to tumour necrosis factor-α (TNF)-induced cell death alongside unravelling its mechanism of action.

Materials And Methods: Cell viability and caspases processing were determined after MLN4924 treatment either alone or with zVAD-fmk (pan caspase inhibitor), necrostatin-1 (nec-1, RIPK1 inhibitor) and necrosulfonamide (NSA, MLKL inhibitor). Moreover, MLN4924 ability to potentiate TNF-induced cell death was evaluated in 24 cell lines of different cancer origins. The impact of NAE inhibition with MLN4924 on TNF-induced apoptosis and necroptosis was evaluated using zVAD-fmk and nec-1, respectively.

Results: MLN4924 alone was able to induce cell death in different cell lines that was attributed to apoptosis induction. Also, MLN4924 sensitized different cancer cell lines to TNF-induced cell death. MLN4924/TNF-induced cell death was apoptosis and necroptosis dependent that may be attributed to MLN4924 inhibition of NF-κB pathway activation.

Conclusions: Targeting NAE and NF-κB pathway with MLN4924 represents a substantial approach to enhance the sensitivity of diverse types of cancer cells. Moreover, the broad in vitro screening of MLN4924 anticancer activity provides a valuable guidance for elucidating the susceptible cancer types for the prospective clinical application of MLN4924.
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http://dx.doi.org/10.1016/j.abb.2020.108513DOI Listing
September 2020

The selective c-Met inhibitor capmatinib offsets cisplatin-nephrotoxicity and doxorubicin-cardiotoxicity and improves their anticancer efficacies.

Toxicol Appl Pharmacol 2020 07 22;398:115018. Epub 2020 Apr 22.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

The incorporation of mesenchymal-epithelial transition factor (c-Met) inhibitors with conventional chemotherapeutics may increase the anticancer efficacy of chemotherapeutic agents, but bears the risk of enhancing the adverse effects. To test the hypothesis, co-administration of the novel c-Met inhibitor capmatinib with cisplatin (CIS) or doxorubicin (DOX) was investigated on nephrotoxicity and cardiotoxicity induced by these agents in mice, as well as their in vitro cytotoxicities. The results demonstrated that capmatinib in vivo offered protection against nephrotoxicity and cardiotoxicity by both CIS and DOX, respectively. The underlying mechanisms behind capmatinib protective effect were found to be i) limiting excessive generation of reactive oxygen species by decreasing the level of lipid peroxidation and nitrosative stress products; and ii) suppressing overproduction of pro-inflammatory mediators like TNF-α and IL-6 that coincided with less inflammatory cell infiltration as denoted by lower levels of serum MCP-1 and Ly6G immunostaining. Besides, capmatinib effectively improved the in vivo anticancer efficacy of both CIS and DOX against solid tumors. In vitro, capmatinib increased the apoptotic activity of DOX against cancerous cells, but did not affect that of CIS. This effect might be linked to capmatinib and DOX abilities to lower IL-12(p40) that has an inhibitory effect on IL-12(p70)/IFN-γ-mediated apoptotic activity. In conclusion, the favorable effects of capmatinib can be applied clinically to decrease the toxicity of DOX and CIS chemotherapeutic agents.
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http://dx.doi.org/10.1016/j.taap.2020.115018DOI Listing
July 2020

The c-Met inhibitor capmatinib alleviates acetaminophen-induced hepatotoxicity.

Int Immunopharmacol 2020 Apr 14;81:106292. Epub 2020 Feb 14.

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

Acetaminophen (APAP)-induced hepatotoxicity comes among the most frequent humans' toxicities caused by drugs. So far, therapeutic interventions for such type of drug-induced toxicity are still limited. In the current study, we examined the influence of capmatinib (Cap), a novel c-Met inhibitor, on APAP-induced hepatotoxicity in mice when administered 2 h prior, 2 h post and 4 h post APAP-challenge. The results revealed that Cap administration significantly attenuated APAP-induced liver injury when administered only 2 h prior and post APAP-administration. Cap hepatoprotective effect was mediated by lowering the excessive formation of lipid peroxidation and nitrosative stress products caused by APAP. Besides, Cap attenuated APAP-induced overproduction and release of proinflammatory mediators like TNF-α, IL-1β, IL-17A, IL-6, and MCP-1. Cap treatment also led to avoidance of APAP-subsequent repair by abating APAP-induced elevation of hepatic IL-22 and PCNA expressions. In conclusion, c-Met receptor inhibition may be a potential strategy for alleviating APAP-hepatotoxicity, especially when administered in the early phase of intoxication.
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http://dx.doi.org/10.1016/j.intimp.2020.106292DOI Listing
April 2020

Impact of interferon β-1b, interferon β-1a and fingolimod therapies on serum interleukins-22, 32α and 34 concentrations in patients with relapsing-remitting multiple sclerosis.

J Neuroimmunol 2019 12 6;337:577062. Epub 2019 Sep 6.

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

Interleukins (ILs)-22, 32α and 34 were monitored in the sera of relapsing-remitting multiple sclerosis (RRMS) patients at different time intervals with or without interferon β-1b, interferon β-1a and fingolimod treatments. The results showed that sera of untreated RRMS patients were statistically higher in concentration of IL-22 (P < .001), but not IL-32α and IL-34, than those of healthy individuals. Interestingly, interferon β-1b, interferon β-1a and fingolimod treatments led to a significant decrease of serum concentrations of ILs-22 and 32α, but not 34, at 6 and 12 months of treatment, compared to their initial concentrations before initiating therapy. The correlation analysis revealed that the changes of serum IL-22 (r = 0.814) and, to a lesser extent, IL-32α (r = 0.381) concentrations were positively correlated with those of expanded disability status score. In conclusion, serum IL-22 concentration may be a potential marker for MS disease severity and efficacy of treatment.
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http://dx.doi.org/10.1016/j.jneuroim.2019.577062DOI Listing
December 2019

Synthesis and In Vitro Antiproliferative Activity of New 1-Phenyl-3-(4-(pyridin-3-yl)phenyl)urea Scaffold-Based Compounds.

Molecules 2018 Jan 31;23(2). Epub 2018 Jan 31.

Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology & Information, 11571 Cairo, Egypt.

A new series of 1-phenyl-3-(4-(pyridin-3-yl)phenyl)urea derivatives were synthesized and subjected to in vitro antiproliferative screening against National Cancer Institute (NCI)-60 human cancer cell lines of nine different cancer types. Fourteen compounds - were synthesized with three different solvent exposure moieties (4-hydroxylmethylpiperidinyl and trimethoxyphenyloxy and 4-hydroxyethylpiperazine) attached to the core structure. Substituents with different π and σ values were added on the terminal phenyl group. Compounds - with a 4-hydroxymethylpiperidine moiety showed broad-spectrum antiproliferative activity with higher mean percentage inhibition values over the 60-cell line panel at 10 µM concentration. Compound elicited lethal rather than inhibition effects on SK-MEL-5 melanoma cell line, 786-0, A498, RXF 393 renal cancer cell lines, and MDA-MB-468 breast cancer cell line. Two compounds, and showed promising mean growth inhibitions and thus were further tested at five-dose mode to determine median inhibitory concentration (IC) values. The data revealed that urea compounds and are the most active derivatives, with significant efficacies and superior potencies than paclitaxel in 21 different cancer cell lines belonging particularly to renal cancer and melanoma cell lines. Moreover, and had superior potencies than gefitinib in 38 and 34 cancer cell lines, respectively, particularly colon cancer, breast cancer and melanoma cell lines.
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http://dx.doi.org/10.3390/molecules23020297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017049PMC
January 2018

Serum and aqueous humor concentrations of interleukin-27 in diabetic retinopathy patients.

Int Ophthalmol 2018 Oct 24;38(5):1817-1823. Epub 2017 Jul 24.

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

Purpose: Interleukin (IL)-27 has been reported to possess anti- and proinflammatory properties in several immune related-disorders, but its role in diabetic retinopathy is still elusive. Here, we aimed to (i) evaluate IL-27 concentrations in serum and aqueous humor of diabetic patients with or without retinopathy and (ii) test whether IL-27 is correlated with some risk factors of diabetic retinopathy.

Methods: The study comprised 60 diabetic patients with and without retinopathy along with 20 healthy controls. Serum and aqueous humor concentrations of IL-27 were assessed by ELISA.

Results: The mean of IL-27 concentration in aqueous humor in patients with diabetic retinopathy (6.7 ± 2.7 ng/L) was significantly elevated in comparison with either diabetic patients without retinopathy (4.6 ± 0.5 ng/L) or healthy control group (4.1 ± 0.8 ng/L). Besides, IL-27 concentration in aqueous humor was positively correlated with serum glucose, lipid profile and glycated hemoglobin (HbA1c).

Conclusions: Based on this study, IL-27 is implicated in the pathogenesis of diabetic retinopathy and positively correlates with the disorder progression.
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http://dx.doi.org/10.1007/s10792-017-0655-7DOI Listing
October 2018

Repression of acetaminophen-induced hepatotoxicity by a combination of celastrol and brilliant blue G.

Toxicol Lett 2017 Jun 21;275:6-18. Epub 2017 Apr 21.

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

The sterile inflammatory response is an eminent contributor to acetaminophen (APAP)-hepatotoxicity in humans. Recent advances unraveled an axial role of the NLRP3-inflammasome in APAP-post injury inflammation. Nevertheless, the role of signaling events preceded the NLRP3-inflammasome activation, like the transcription factor NF-κB and the purinergic receptor P2X7, is still unclear and needs further elucidation. Here, we investigated the pharmacological inhibition of these upstream signaling molecules by celastrol and brilliant blue G (BBG) (separately or simultaneously) in APAP-hepatotoxicity in mice. The results indicated that both celastrol and BBG pretreatments, especially when combined together, curbed APAP-induced hepatocellular injury (ALT, AST and LDH) and death (necrosis and apoptosis). The underlying mechanisms of protection of such combination against APAP-challenge were attributed to their efficient cooperation in: i) preventing the consumption of hepatic antioxidants (reduced glutathione and superoxide dismutase); ii) limiting the overproduction of lipid peroxidation aldehydes (malondialdehyde and 4-hydroxynonenal) and total nitrate/nitrite products; iii) attenuating the inflammatory cells accumulation in the liver, as evidenced by reducing the number of F4/80 positive cells/field in immunostaining and myeloperoxidase activity; iv) reversing the dysregulation in production of pro-inflammatory (TNF-α, IL-17A and IL-23) and anti-inflammatory (IL-10) cytokines; and v) enhancing the reparative capacity of injured hepatocytes, as demonstrated by increasing the percentage of PCNA positive hepatocytes per field of immunostaining. In conclusion, this murine study elicits a potential clinical applicability and therapeutic utility of celastrol and BBG combination in human cases of APAP-overdose hepatotoxicity.
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http://dx.doi.org/10.1016/j.toxlet.2017.04.012DOI Listing
June 2017

The novel c-Met inhibitor capmatinib mitigates diethylnitrosamine acute liver injury in mice.

Toxicol Lett 2016 Nov 21;261:13-25. Epub 2016 Aug 21.

Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

The receptor tyrosine kinase mesenchymal-epithelial transition factor (c-Met) sits at the interface between controlled cellular division of organogenesis and uncontrolled cellular division of carcinogenesis. c-Met contribution to the initial phases of liver injury and inflammation is still not resolved. Herein, we investigated the selective pharmacological intervention of c-Met by capmatinib (formerly known as INC280) in the diethylnitrosamine (DEN) acute liver injury model in mice. c-Met inhibition by capmatinib reduced DEN-induced elevation of the pro-inflammatory cytokines TNF-α, IL-1β, IL-17A, IL-23(p19/40) and IFN-γ, which correlated well with serum markers of hepatocellular injury (ALT, AST and LDH). The protective effects possessed by capmatinib were mainly mediated by inhibiting inflammatory cells infiltration to the liver. However, hematoxylin-eosin and bax-immunohistochemical stainings revealed that capmatinib (at a dose of 10, but not 5mg/kg) aggravated DEN-induced hepatocellular ballooning and apoptosis, respectively. These effects were concordant with hepatocellular overexpression of the amino acid transporter CD98. Such capmatinib effects arised mostly from exaggerating the elevation of the mutagenic lipid peroxide 4-HNE along with MDA that enhanced DEN-induced compensatory proliferation evidenced by PCNA expression. In conclusion, inhibition of c-Met activation by capmatinib may provide protection against liver injury, but may trigger undesirable elevation of the mutagenic 4-HNE.
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http://dx.doi.org/10.1016/j.toxlet.2016.08.015DOI Listing
November 2016

Inhibition of the JAK/STAT pathway by ruxolitinib ameliorates thioacetamide-induced hepatotoxicity.

Food Chem Toxicol 2016 Oct 18;96:290-301. Epub 2016 Aug 18.

Pathology Dept., Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.

In an attempt to explore the role of the JAK/STAT pathway in liver inflammation, we investigated the effect of intervening this pathway by ruxolitinib in thioacetamide (TAA)-induced hepatotoxicity. Ruxolitinib treatments were administered to male mice either before or after intoxication with TAA. The hepatic histopathological and serum biochemical assessment revealed that ruxolitinib pre-treatments dose-dependently reduced TAA-induced liver injury, caspase 3 cleavage and increase in number of hepatocytes positive for the pro-apoptotic Bax, as well as inflammatory cells positive for F4/80 and myeloperoxidase activity in the liver. Ruxolitinib pre-treatments also curbed TAA-induced rise in NF-κB nuclear expression and STAT3 phosphorylation. Ruxolitinib pre-treatments also lowered TAA-induced elevation of hepatic oxidative stress parameters (total nitrate/nitrite and 4-hydroxynonenal), but did not restore the hepatic antioxidant reduced glutathione. Interestingly, ruxolitinib, especially at a dose of 200 mg/kg, dampened the overproduction of pro-inflammatory cytokines (TNF-α, IL-1β, IFN-γ, IL-23 and IL-17A), which coincided with boosting the release of the anti-inflammatory cytokine IL-10. Ruxolitinib when used as a post-treatment (1 and 3 h after TAA-insult) could still spare the liver from injury and might be clinically applicable. In conclusion, the multimechanistic-hepatoprotective activity of ruxolitinib can be linked to its ameliorative properties on cellular death, oxidative stress and inflammation machinery.
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http://dx.doi.org/10.1016/j.fct.2016.08.018DOI Listing
October 2016

The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis.

Exp Biol Med (Maywood) 2016 12 28;241(18):2015-2022. Epub 2016 Jul 28.

3 Faculty of Pharmacy, Department of Microbiology and Immunology, Mansoura University, Mansoura 35516, Egypt.

The inhibitors of apoptosis proteins are implicated in promoting cancer cells survival and resistance toward immune surveillance and chemotherapy. Second mitochondria-derived activator of caspases (SMAC) mimetics are novel compounds developed to mimic the inhibitory effect of the endogenous SMAC/DIABLO on these IAPs. Here, we examined the potential effects of the novel SMAC mimetic BV6 on different human cancer cell lines. Our results indicated that BV6 was able to induce cell death in different human cancer cell lines. Mechanistically, BV6 dose dependently induced degradation of IAPs, including cIAP1 and cIAP2. This was coincided with activating the non-canonical NF -kappa B (NF-κB) pathway, as indicated by stabilizing NF-κB-inducing kinase (NIK) for p100 processing to p52. More interestingly, BV6 was able to sensitize some of the resistant cancer cell lines to apoptosis induced by the death ligands tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) that are produced by different cells of the immune system. Such cell death enhancement was mediated by inducing an additional cleavage of caspase-9 to augment that of caspase-8 induced by death ligands. This eventually led to more processing of the executioner caspase-3 and poly (ADP-ribose) polymerase (PARP). In conclusion, therapeutic targeting of IAPs by BV6 might be an effective approach to enhance cancer regression induced by immune system. Our data also open up the future possibility of using BV6 in combination with other antitumor therapies to overcome cancer drug resistance.
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http://dx.doi.org/10.1177/1535370216661779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102137PMC
December 2016

The novel TLR9 antagonist COV08-0064 protects from ischemia/reperfusion injury in non-steatotic and steatotic mice livers.

Biochem Pharmacol 2016 07 6;112:90-101. Epub 2016 May 6.

Section of Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, CT 06520, USA; Section of Digestive Diseases, Department of Veterans Affairs Connecticut Healthcare, West Haven, CT 06516, USA. Electronic address:

Ischemia/reperfusion (I/R) injury constitutes a major reason for failure of liver surgeries and transplantation. I/R injury is more severe in steatotic livers and limits their use in transplantation. Here, we present a novel and selective Toll-like receptor 9 (TLR9) antagonist COV08-0064 and test its potential to protect from I/R-induced injury in normal and steatotic livers. The in vivo effects of COV08-0064 pretreatment were investigated on normal chow diet (NCD) and high fat diet (HFD)-fed mice subjected to segmental (70%) warm hepatic I/R. Also, the in vitro effects of COV08-0064 were elucidated in murine macrophages and dendritic cells. Mice on a HFD had pronouncedly greater hepatic I/R injury than mice on a NCD. COV08-0064-pretreatment to both NCD and HFD-fed mice reduced hepatic I/R injury. COV08-0064-pretreatment was associated with less production of the liver inflammatory cytokines and mediators TNF-α, IL-1β, IL-6, NLRP3, iNOS and MCP-1. These manifestations were preceded with inhibition of JNK and ERK phosphorylation and TLR9 cleavage in the liver. COV08-0064 enhanced the hepatic expression of the endogenous anti-inflammatory cytokines IL-10 and IL-1Ra at the early phase I/R injury. In vitro, COV08-0064 selectively blocked mRNA upregulation of TNF-α, IL-1β, NLRP3 and MCP-1 in macrophages and IFN-β mRNA in dendritic cells induced by the TLR9 agonist CpG-ODN. These effects were concordant with inhibition of JNK, ERK, IκBα and IKKα/β phosphorylation. In conclusion, TLR9 signaling inhibition by COV08-0064 may be an effective approach in liver surgeries including transplantation to limit I/R-injury and overcome the shortages in the donor pool by incorporating steatotic livers.
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http://dx.doi.org/10.1016/j.bcp.2016.05.003DOI Listing
July 2016

Polymorphisms of glutathione S-transferase π 1 and toll-like receptors 2 and 9: Association with breast cancer susceptibility.

Oncol Lett 2016 Mar 28;11(3):2182-2188. Epub 2016 Jan 28.

Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.

Polymorphisms in antioxidant enzymes and innate immune receptors have been implicated in the development of various types of cancer. The present study aimed to investigate whether polymorphisms of glutathione S-transferase π 1 (GSTP1) and toll-like receptors (TLRs) 2 and 9 are associated with susceptibility to breast cancer among females. The study was conducted on 72 Egyptian female patients with breast cancer, along with 100 healthy volunteers. Polymorphisms of GSTP1 (codon 105 Ile/Val) and TLR9 rs187084 (1237T/C) genes were assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism, while the -196 to -174 deletion/insertion (del/ins) polymorphism of TLR2 was detected by PCR. The results indicated a decrease in GSTP1 Val allele frequency in breast cancer patients compared with healthy controls, at rates of 22.9 vs. 32.5%, respectively. In addition, the breast cancer group demonstrated a decreased TLR9 C allele frequency compared with the control group, at rates of 36.1 vs. 51.5%, respectively (P=0.0047). A non-significant difference was detected in the frequency of the TLR2 -196 to -174 del allele in breast cancer patients when compared to normal controls. In conclusion, these results suggested that the GSTP1 Val and TLR9 1237C alleles, but not TLR2 -196 to -174 del, are likely to be associated with breast cancer development among females.
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http://dx.doi.org/10.3892/ol.2016.4159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774482PMC
March 2016

Therapeutic Opportunities in Damage-Associated Molecular Pattern-Driven Metabolic Diseases.

Antioxid Redox Signal 2015 Dec 27;23(17):1305-15. Epub 2015 Jul 27.

1 Section of Digestive Diseases, Department of Internal Medicine, Yale University , New Haven, Connecticut.

Significance: Sterile inflammation is a common finding present in various metabolic disorders. This type of inflammation is mediated by damage-associated molecular patterns (DAMPs) that are released upon cellular injury to activate pattern recognition receptors on innate immune cells and amplify organ damage.

Recent Advances: In the last decade, DAMPs, such as high-mobility group protein B1, nucleic acids (DNA, RNA), adenosine triphosphate, and other metabolites, were found to contribute to the inflammatory response in diabetes, gout, obesity, steatohepatitis, and atherosclerosis. Varied receptors, including Toll-like receptors (TLRs), the purinergic P2X(7) receptors, and nucleotide-binding domain, and leucine-rich repeat protein 3 (NLRP3)-inflammasome sense DAMPs and DAMP-like molecules and release the proinflammatory cytokines, interleukin (IL)-1β and IL-18.

Critical Issues: Available therapeutic approaches that interfered with the signaling of TLRs, P2X(7), NLRP3-inflammasome, and IL-1β showed encouraging results in metabolic diseases, which will be also highlighted in this review.

Future Directions: It is important to understand the origination of DAMPs and how they contribute to the inflammatory response in metabolic disorders to develop selective and efficient therapeutics for intervention.
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http://dx.doi.org/10.1089/ars.2015.6383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685500PMC
December 2015

The novel Janus kinase inhibitor ruxolitinib confers protection against carbon tetrachloride-induced hepatotoxicity via multiple mechanisms.

Chem Biol Interact 2014 Sep 25;220:116-27. Epub 2014 Jun 25.

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

Therapeutic targeting of the JAK/STAT pathway, the principal signaling mechanism for numerous cytokines, might be an effective approach for limiting inflammation in different organs, including the liver. Therefore, we investigated whether targeting this pathway by the novel JAK inhibitor ruxolitinib could mitigate hepatic damage provoked by carbon tetrachloride (CCl4). Male mice received ruxolitinib treatments (75 and 150 mg/kg, oral) 2 h prior to intoxication with CCl4 (10 ml/kg of 0.3% v/v CCl4 solution in olive oil, intraperitoneal) for 24 h. Our results showed that ruxolitinib treatments dose-dependently alleviated CCl4-induced hepatic injury and necroinflammation, as indicated by biochemical markers of injury and histopathology. We unraveled also the mechanisms involved in these hepatoprotective effects. These comprise (i) reducing infiltration of neutrophils and macrophages, as demonstrated by reducing myeloperoxidase activity and F4/80 positive macrophages; (ii) abating apoptosis of hepatocytes, as denoted by decreasing hepatocytes positive for Bax protein; (iii) inhibiting elevation of TNF-α, IL-1β and IL-10; (iv) inhibiting NF-κB activation and translocation to the nucleus, as visualized immunohistochemically; (v) attenuating activation of the IL-23/IL-17 pathway via targeting IL-17, but not IL-23; (vi) antagonizing hepatic oxidative stress by increasing the antioxidant levels (reduced glutathione, glutathione-S-transferase and superoxide dismutase) and decreasing products of lipid peroxidation (malondialdehyde and 4-hydroxynonenal) and total nitrate/nitrite; and (vii) more interestingly, modulating hepatocyte regeneration according to the extent of damage, as quantified by PCNA-immunohistochemistry. In conclusion, our study sheds light on the therapeutic usefulness and the potential underlying mechanisms of the novel JAK inhibitor ruxolitinib in hepatic inflammatory disorders.
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http://dx.doi.org/10.1016/j.cbi.2014.06.017DOI Listing
September 2014

Celastrol ameliorates murine colitis via modulating oxidative stress, inflammatory cytokines and intestinal homeostasis.

Chem Biol Interact 2014 Mar 30;210:26-33. Epub 2013 Dec 30.

Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt.

Therapeutic agents that block the nuclear factor-kappa B (NF-κB) pathway might be beneficial for incurable inflammatory diseases, such as ulcerative colitis. Here, we investigated the effect of the novel NF-κB inhibitor celastrol on murine colitis. Colitis was induced in male mice by administration of 5% (w/v) dextran sulfate sodium (DSS) in drinking water for a period of 5 days, followed by a 2 day recovery period. Celastrol (2mg/kg, oral) was administered daily over the 1 week of the study. Our results indicated that treatment with celastrol attenuated DSS-induced colon shortening and neutrophil infiltration. Besides, celastrol ameliorated DSS-induced colon injury and inflammatory signs as visualized by histopathology. The mechanisms behind these beneficial effects of celastrol were also elucidated. These include (i) counteracting DSS-induced oxidative stress in the colon via decreasing lipid peroxidation products (malondialdehyde and 4-hydroxynonenal) and increasing the antioxidant levels (reduced glutathione, glutathione-S-transferase and superoxide dismutase); (ii) inhibiting DSS-induced activation of the NLRP3-inflammasome, as evidenced by decreased production of IL-1β and IFN-γ as indirect measure of IL-18 in the colon; (iii) targeting DSS-induced activation of the IL-23/IL-17 pathway by abating the elevation of IL-23 and IL-17A levels in the colon; (iv) augmenting the anti-inflammatory defense mechanisms via increasing IL-10 and TNF-α levels in the colon; (v) and more importantly, maintaining intestinal epithelial reconstitution and homeostasis via attenuating the overexpression of CD98 in colonic epithelial cells. In conclusion, our study provides novel insights into the beneficial effects of celastrol as a promising candidate for the treatment of ulcerative colitis in humans.
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http://dx.doi.org/10.1016/j.cbi.2013.12.007DOI Listing
March 2014

Modulation of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis by olmesartan and omega-3.

Chem Biol Interact 2014 Jan 18;207:81-91. Epub 2013 Oct 18.

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

This study was designed to investigate the potential effects of omega-3, olmesartan and their combination on established hepatic fibrosis in the carbon tetrachloride (CCl4) rat model. Male Wistar rats received subcutaneous injections of CCl4 twice weekly for 12weeks, as well as daily oral treatments of olmesartan (1 and 3mg/kg), omega-3 (75 and 150mg/kg) and their combination during the last 4weeks of intoxication. Our results indicated that omega-3 and, to a lesser extent, olmesartan dose-dependently blunted CCl4-induced necroinflammation scoring and elevation of liver injury parameters in serum. Besides, omega-3 and, to a lesser extent, olmesartan treatments in a dose dependent manner attenuated CCl4-induced liver fibrosis, as demonstrated by hepatic histopathology scoring and 4-hydroxyproline content. The mechanisms behind these beneficial effects of both omega-3 and olmesartan were also elucidated. These include (1) counteracting hepatic oxidative stress and augmenting hepatic antioxidants; (2) preventing the activation of hepatic stellate cells (HSCs), as denoted by reducing α-smooth muscle actin (α-SMA) expression in the liver; (3) inhibiting the proliferation and chemotaxis of HSCs, as evidenced by downregulating platelet-derived growth factor receptors-β (PDGFR-β) expression in the liver; and (4) inhibiting the fibrogenesis response of HSCs, as indicated by inhibiting the secretion of transforming growth factor-β1 (TGF-β1). Unexpectedly, when olmesartan was co-administered with omega-3, it interfered with the hepatoprotective and anti-fibrotic activities of omega-3. In conclusion, this study introduces the first evidence regarding the pronounced anti-fibrotic activity of omega-3 and suggests that it may be beneficial in the treatment of hepatic fibrosis in humans.
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http://dx.doi.org/10.1016/j.cbi.2013.10.008DOI Listing
January 2014

Nilotinib interferes with the signalling pathways implicated in acetaminophen hepatotoxicity.

Authors:
Mohamed E Shaker

Basic Clin Pharmacol Toxicol 2014 Mar 23;114(3):263-70. Epub 2013 Oct 23.

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

Nilotinib, a second-generation tyrosine kinase inhibitor, has been recently approved for the treatment for chronic myeloid leukaemia. The objective of this study was to explore the potential effects of clinically relevant doses of nilotinib against acetaminophen (APAP)-induced hepatotoxicity in mice. To simulate the clinical application in human beings, nilotinib (25 and 50 mg/kg) was administered to mice 2 hr after APAP intoxication (500 mg/kg). The results indicated that nilotinib (25 mg/kg) (i) abolished APAP-induced liver injury and necro-inflammation, (ii) increased hepatic-reduced glutathione (GSH) and its related enzymes synthesis, (iii) suppressed hepatic oxidative/nitrosative stress cascades, (iv) decreased neutrophil accumulation in the liver, and (v) prevented the over-expression of B-cell lymphoma-2 (bcl-2), cyclin-D1 and stem cell factor receptor (c-Kit) proteins in the liver. Although nilotinib (50 mg/kg) acted through the same mechanisms, there was severe depletion in hepatic GSH content by nilotinib itself at that dose level, rather than the potent stimulation observed by using a dose of 25 mg/kg. Consequently, the mortality rate after 18 hr was 100% for nilotinib (50 mg/kg) + APAP (750 mg/kg) versus 60% for APAP (750 mg/kg) and 40% for nilotinib (25 mg/kg) + APAP (750 mg/kg) in the survival analysis experiment. In conclusion, nilotinib can counteract the hepatotoxicity produced by a non-lethal dose of APAP. However, there is a risk of aggravating the mortality for a lethal dose of APAP when nilotinib is co-administered at doses relatively high, or near to the clinical range because of hepatic GSH depletion and c-kit inhibition.
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http://dx.doi.org/10.1111/bcpt.12144DOI Listing
March 2014

Clomiphene citrate co-treatment with low dose urinary FSH versus urinary FSH for clomiphene resistant PCOS: randomized controlled trial.

J Assist Reprod Genet 2013 Nov 7;30(11):1477-85. Epub 2013 Sep 7.

Mansoura Integrated Fertility Center, Mansoura, Egypt.

Purpose: The aim of this study was to examine the effect of clomiphene citrate [CC] co-administration during the use of exogenous low-dose urinary FSH [uFSH] for induction of ovulation in CC-resistant infertile PCOS women.

Methods: In a randomised controlled setting, 174 CC-resistant infertile PCOS women were randomized into two parallel groups; Group I received CC 100 mg/day for 5 days plus uFSH 37.5 IU/day while group II received only uFSH 37.5 IU /day. Subsequent increments of uFSH by 37.5 IU/day were made according to response. Primary outcome was ovulation rate. Secondary outcomes were clinical pregnancy rates, number of follicles, endometrial thickness, and gonadotropins consumption.

Results: Our results have demonstrated that group I compared to group II had significantly higher ovulation rate per intention to treat [ITT] [72.4 % vs. 34.2 %, p < 0.001]. Clinical pregnancy and live birth rates were comparable between the two groups. Group I consumed significantly lower total FSH dose and needed significantly shorter stimulation duration compared to group II.

Conclusion: CC co-administered during low dose HP uFSH versus uFSH for CC-resistant PCOS yields significantly higher ovulation rate and less consumption of FSH.
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http://dx.doi.org/10.1007/s10815-013-0090-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879942PMC
November 2013

Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases.

Biochim Biophys Acta 2013 Aug 13;1833(8):1992-2003. Epub 2013 Mar 13.

Department of Internal Medicine, Yale University, New Haven, CT 06520, USA.

Increasing hepatic stellate cell (HSC) death is a very attractive approach for limiting liver fibrosis. Tyrosine kinase inhibitors have been shown to have anti-fibrotic properties, but the mechanisms are poorly understood. Here, we identified the mechanism of action of the second-generation tyrosine kinase inhibitor nilotinib in inducing HSC death. Human HSC line (LX-2) and rat HSCs were treated with nilotinib and its predecessor, imatinib, in the absence or presence of various blockers, known to interfere with death signaling pathways. Nilotinib, but not imatinib, induced progressive cell death of activated, but not quiescent, HSCs in a dose-dependent manner. Activated HSCs died through apoptosis, as denoted by increased DNA fragmentation and caspase activation, and through autophagy, as indicated by the accumulation of autophagic markers, light chain (LC)3A-II and LC3B-II. Although inhibition of caspases with Z-VAD-FMK suppressed nilotinib-induced HSCs' apoptosis, there was no increase in HSCs' survival, because autophagy was exacerbated. However, blocking the mitochondrial permeability transition pore (mPTP) opening with cyclosporin A completely abolished both apoptosis and autophagy due to nilotinib. Moreover, nilotinib treatment decreased the protein expression of histone deacetylases 1, 2 and 4. Interestingly, pretreament with C646, a selective p300/CBP histone acetyl transferase inhibitor, resulted in diverting nilotinib-induced apoptosis and autophagy towards necrosis. In conclusion, the identification of mPTP as a target of nilotinib in activated HSCs suggests coordination with histone deacetylases inhibition to induce apoptosis and autophagy. Thus, our study provides novel insights into the anti-fibrotic effects of nilotinib.
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http://dx.doi.org/10.1016/j.bbamcr.2013.02.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410771PMC
August 2013

Comparison of early treatment with low doses of nilotinib, imatinib and a clinically relevant dose of silymarin in thioacetamide-induced liver fibrosis.

Eur J Pharmacol 2011 Nov 8;670(2-3):593-600. Epub 2011 Sep 8.

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

Our previous study has already confirmed a promising anti-fibrotic activity especially for nilotinib; when given at a daily dose of 10 mg/kg during the last 4 weeks of thioacetamide (TAA)-induced liver fibrosis for 12 weeks in rats. Therefore, this study was carried out to compare the prophylactic potential of low dose of nilotinib to that of its predecessor, imatinib, and a clinically relevant dose of the standard hepatoprotective treatment, silymarin, in TAA-intoxication. Male Wistar rats received intraperitoneal injections of TAA (150 mg/kg, twice weekly) for 8 weeks, as well as oral treatments with imatinib (5 mg/kg/day), nilotinib (5 mg/kg/day) and silymarin (50 mg/kg/day) from the first day of TAA-intoxication. At the end of the study, chronic hepatic injury was evaluated by analysis of liver function tests in serum. Hepatic oxidative stress was assessed by measuring malondialdehyde, 4-hydroxynonenal, total nitrate/nitrite and reduced glutathione contents, as well as myeloperoxidase and superoxide dismutase activities. Hepatic fibrosis was evaluated by histopathology and collagen content. Our results suggest that the prophylactic potential of nilotinib (5 mg/kg/day), imatinib (5mg/kg/day) and silymarin (50 mg/kg/day) in TAA-intoxication for 8 weeks is lower than the late treatments of nilotinib (10 mg/kg/day), imatinib (10mg/kg/day) and silymarin (100 mg/kg/day) during the last 4 weeks of TAA-intoxication for 12 weeks in rats. Taken together, this study suggests that nilotinib may have higher anti-fibrotic activity when administered at a significant stage of fibrosis as a result of impairment of its metabolism in the fibrotic livers.
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http://dx.doi.org/10.1016/j.ejphar.2011.08.041DOI Listing
November 2011

Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis.

Toxicol Appl Pharmacol 2011 Apr 24;252(2):165-75. Epub 2011 Feb 24.

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

Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl(4)) rat model. Male Wistar rats received intraperitoneal injections of CCl(4) twice weekly for 8weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20mg/kg), nilotinib (10 and 20mg/kg) and silymarin (100mg/kg) during the last 4weeks of CCl(4)-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20mg/kg) was the most effective treatment to counteract CCl(4)-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10mg/kg), nilotinib (20mg/kg) and silymarin (100mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl(4)-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl(4)-induced fibrosis was ameliorated significantly by nilotinib (20mg/kg) and imatinib (20mg/kg). Unlike nilotinib, imatinib (20mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans.
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http://dx.doi.org/10.1016/j.taap.2011.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895503PMC
April 2011

Nilotinib counteracts thioacetamide-induced hepatic oxidative stress and attenuates liver fibrosis progression.

Fundam Clin Pharmacol 2011 Apr;25(2):248-57

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

The aim of this study was to evaluate and compare the effects of imatinib and nilotinib to that of silymarin on established liver fibrosis and oxidative stress in a thioacetamide (TAA) rat model. Male Wistar rats received intraperitoneal (i.p.) injections of TAA (150mg/kg, twice weekly) for 12weeks. Daily treatments with imatinib (10mg/kg), nilotinib (10mg/kg), and silymarin (100mg/kg) were administered orally during the last 4weeks of TAA-administration. At the end of the study, hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis. Hepatic oxidative stress was assessed by measuring malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), total nitrate/nitrite (NOx), and reduced glutathione (GSH) contents, as well as myeloperoxidase (MPO) and superoxide dismutase (SOD) activities. Nilotinib, silymarin and, to a lesser extent, imatinib treatments ameliorated TAA-induced hepatic oxidative stress and damage as indicated by hepatic MDA, 4-HNE, NOx, GSH, MPO and SOD levels, as well as liver function tests. Hepatic histopathology results revealed that nilotinib, imatinib, and silymarin treatments decreased the mean score of fibrosis in TAA-treated rats by 24, 14, and 3%, respectively. However, nilotinib and silymarin, but not imatinib, treatments decreased hepatic collagen content in TAA-treated rats by 17 and 36%, respectively. In conclusion, we demonstrated for the first time that nilotinib not only protected against hepatic oxidative stress, but also slowed down liver fibrosis progression. Thus, we provide the first evidence that nilotinib might be a promising anti-fibrotic drug.
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http://dx.doi.org/10.1111/j.1472-8206.2010.00824.xDOI Listing
April 2011
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