Publications by authors named "Abdelhadi Shebl"

22 Publications

  • Page 1 of 1

Targeting autophagy to modulate hepatic ischemia/reperfusion injury: A comparative study between octreotide and melatonin as autophagy modulators through AMPK/PI3K/AKT/mTOR/ULK1 and Keap1/Nrf2 signaling pathways in rats.

Eur J Pharmacol 2021 Feb 9;897:173920. Epub 2021 Feb 9.

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

Hepatic ischemia-reperfusion (HIR) injury is a common pathophysiological process in many clinical settings. This study was designed to compare the protective role of octreotide (somatostatin analogue, OCT) and melatonin (N-acetyl-5-methoxytryptamine, MLT) through the modulation of autophagy against HIR injury in rats. Male albino rats were divided into sham, HIR, OCT at three doses (50, 75, and 100 μg/kg), MLT, MLT + OCT75, compound C (AMPK inhibitor, CC), and CC + OCT75 groups. Ischemia was induced for 30 min followed by 24 h reperfusion. Biochemical, histopathological, immunohistochemical, lipid peroxidation, ELISA, qPCR, and western blot techniques were performed in our study. Liver autophagy was restored by OCT at doses (50 or 75 μg/kg) as indicated by elevating the expressions of Beclin-1, ATG7, and LC3 accompanied by the reduction of p62 expression through induction of AMPK/S317-ULK1 and inhibition of PI3K/AKT/mTOR/S757-ULK1 signaling pathways. As well, OCT maintained the integrity of the Keap1-Nrf2 system for the normal hepatic functions via controlling the Keap1 turnover through autophagy in a p62-dependent manner, resulting in upholding a series of anti-oxidant and anti-inflammatory cascades. These effects were abolished by compound C. On the other hand, MLT showed a decrease in the autophagy markers via inhibiting AMPK/pS317-ULK1 and activating PI3K/AKT/mTOR/pS757-ULK1 pathways. Autophagy inhibition with MLT markedly reversed the hepatoprotective effects of OCT75 after HIR injury. Finally, our results proved for the first time that OCT75 was more effective than MLT as it was sufficient to induce protective autophagy in our HIR model, which led to the induction of Nrf2-dependent AMPK/autophagy pathways.
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http://dx.doi.org/10.1016/j.ejphar.2021.173920DOI Listing
February 2021

Octreotide and melatonin alleviate inflammasome-induced pyroptosis through inhibition of TLR4-NF-κB-NLRP3 pathway in hepatic ischemia/reperfusion injury.

Toxicol Appl Pharmacol 2021 01 29;410:115340. Epub 2020 Nov 29.

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

Background And Aim: The Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB)/NLRP3 inflammasome signaling pathway is essential in the pathogenesis of hepatic ischemia/ reperfusion (HIR) injury. Pyroptosis is a proinflammatory programmed cell death that is related to several diseases. Thus, the purpose of this study was to examine whether pretreatment with octreotide (somatostatin analogue, OCT) at different doses or OCT at 75μg/kg combined with melatonin (N-acetyl-5-methoxytryptamine, MLT) can alleviate HIR injury via targeting NLRP3 inflammasome-induced pyroptosis in a TLR4/MyD88/NF-κB dependent manner.

Methods: Rats were randomized into sham, HIR, OCT (50, 75, and 100 µg/kg), MLT, and MLT + OCT75 groups. Ischemia was induced via occlusion of the portal triad for 30 min followed by 24 h reperfusion.

Results: OCT pretreatment at doses (50 or 75 μg/kg), MLT alone, and MLT + OCT75 significantly ameliorated the biochemical with histopathological changes, oxidative stress, inflammation, apoptosis, then augmented anti-oxidant and anti-apoptotic markers through downregulation of HMGB1, TLR4, MyD88, TRAF-6, p-IκBα (S32), p-NF-κBp65 (S536), NLRP3, ASC, caspase-1(p20), and GSDMD-N expressions compared with HIR group.

Conclusion: OCT at doses (50 or 75 µg/kg) showed for the first time a hepatoprotective effect against HIR injury via inhibiting TLR4-NLRP3-mediated pyroptosis in rats. As well, OCT75 was more effective than OCT50 or MLT alone, and its effect was not enhanced after the addition of MLT, through downregulation of TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway.
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http://dx.doi.org/10.1016/j.taap.2020.115340DOI Listing
January 2021

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

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

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

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

Atypical Central Neurocytoma: An Investigation of Prognostic Factors.

World Neurosurg 2021 Feb 19;146:e184-e193. Epub 2020 Oct 19.

Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Objective: Central neurocytoma is a rare nervous tissue benign neoplasm. A subset of central neurocytoma has unfamiliar aggressive tendency: so-called atypical central neurocytoma (ACN). This retrospective study aims to analyze the prognostic factors and the impact of various therapy tools on atypical central neurocytoma.

Methods: Twenty-two patients diagnosed with ACN between January 2009 and March 2018 were included. Data collected included the patient's age, gender, tumor location, presenting symptoms, and treatment received. Patients were followed up to detect recurrence and to assess survival.

Results: Median overall survival was 57 months, with a 5-year survival of 35%. Better survival was observed for patients <35 years old (66 vs. 47 months; P = 0.061) and patients with gross total resection over subtotal resection or biopsy (76, 45, and 22 months, respectively; P < 0.0001). Patients with a tumor located in the posterior half of the lateral ventricle had better survival, with no statistical significance (P = 0.053). Multivariate analysis showed prognostic significance with the extent of resection (P = 0.000). Progression-free survival ranged from 6 to 82 months, with a median value of 38 months and showed a significant relation with subtotal resection compared with biopsy (P = 0.006). Recurrence was less in patients who received radiotherapy and was statistically significant (P = 0.007).

Conclusions: Long-term survival is possible for patients with atypical central neurocytomas treated with surgery and postoperative radiation. Multivariate analysis confirmed that gross total resection was an independent prognostic factor for survival. Adjuvant radiotherapy reduces tumor recurrence, especially after incomplete surgery.
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http://dx.doi.org/10.1016/j.wneu.2020.10.068DOI Listing
February 2021

Rectal prolapse but it is not just a rectal prolapse.

J Paediatr Child Health 2020 Sep 5. Epub 2020 Sep 5.

Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman.

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http://dx.doi.org/10.1111/jpc.15133DOI Listing
September 2020

Recurrent mandibular ameloblastoma in soft tissue and rib graft 17 years after initial presentation.

J Egypt Natl Canc Inst 2020 Jan 6;32(1). Epub 2020 Jan 6.

Surgical Oncology Unit, Oncology Center Mansoura University (OCMU), Mansoura, Egypt.

Background: Ameloblastoma is the commonest odontogenic tumour of epithelial origin with a high incidence for developing local recurrence. We present a patient who developed local recurrence in both soft tissue and bone graft 17 years after the initial presentation.

Case Presentation: A 75-year-old female with a previous history of right hemimandibulectomy and rib reconstruction for ameloblastoma in 1999 presented to our centre with a large cystic mouth floor swelling, biopsy from which revealed recurrent ameloblastoma. The patient underwent excision of the recurrent mass en bloc with the cystic swelling through oral and cervical approaches. The patient was discharged after 5 days with an uneventful postoperative course and with a free 2-year follow-up from further recurrence.

Conclusion: Ameloblastoma is a locally aggressive tumour for which wide local excision with adequate margins is the best management approach. Recurrence of ameloblastoma even after adequate resection is not uncommon, and its management is considered a surgical challenge. A very long time may pass between the initial presentation and the development of recurrence.
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http://dx.doi.org/10.1186/s43046-019-0012-1DOI Listing
January 2020

Male Breast Huge Malignant Phyllodes.

Chirurgia (Bucur) 2019 Jul-Aug;114(4):512-517

Phyllodes tumors are rare breast tumors. The best treatment is wide local excision with 1 cm safety margin unless metastatic. The three pathological types (benign, borderline and malignant were reported in men. A 73year-old male with huge left breast swelling extending from the clavicle to the left hypochondriac region. Core needle biopsy suggested malignant phyllodes tumor. Postcontrast CT revealed a huge mass seen at the left anterolateral chest wall measuring about (22 x 25 x 26 cm). Simple mastectomy was performed en bloc with the tumor. The microscopic examination led to the diagnosis of high grade malignant phyllodes. IHC showed diffuse positive vimentin, CD10 and negative CK in the neoplastic cells. The patient lost follow up for three months.Then he was presented with fungating local recurrence with bilateral metastatic pulmonary. The patient underwent palliative excision. After the second surgery, he was prepared for palliative chemoradiotherapy but the patient died one month later at home. Very few cases of phyllodes tumor were reported in men. Pathologically, phyllodes tumors are subdivided into three types: benign, borderline and malignant according to mitotic frequency, nature of margins, stromal growth, cellularity and atypia. Malignant phyllodes tumors tend to spread via hematological route mainly to the lung, then to the bone. Phyllodes tumors even benign type tend to recur even after complete excision with higher tendency for malignant cases. Wide local excision is the standard of care for phyllodes tumors with or without adjuvant radiotherapy in malignant lesions- with no proved value for chemotherapy or hormonal therapy.
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http://dx.doi.org/10.21614/chirurgia.114.4.514DOI Listing
October 2019

Role of ERCC1 expression in colorectal adenoma-carcinoma sequence and relation to other mismatch repair proteins expression, clinicopathological features and prognosis in mucinous and non-mucinous colorectal carcinoma.

Indian J Pathol Microbiol 2019 Jul-Sep;62(3):405-412

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

Background: There are several DNA repair pathways that protect cellular DNA from injury, such as nucleotide excision repair (NER) and mismatch repair (MMR). The protein product of the excision repair cross-complementation group 1 (ERCC1) gene plays a pivotal role in NER. The exact relationship between MMR proteins and ERCC1 is not well known in colorectal carcinoma (CRC).

Aim Of The Study: To investigate expression of ERCC1 and MMR proteins in colorectal mucinous carcinoma (MA) and non-mucinous carcinoma (NMA) using tissue microarray technique.

Material And Methods: We studied tumor tissue specimens from 150 patients with colorectal mucinous (MA) and non-mucinous adenocarcinoma (NMA). Tissue microarrays were constructed using modified mechanical pencil tips technique and immunohistochemistry for ERCC1, MLH1, MSH2, MSH6, and PMS2.

Results: NMA showed a significantly more frequent aberrant cytoplasmic expression than MA while MA showed a more frequent intact nuclear expression than NMA. There were no significant differences between the NMA and MA groups in the expression of MMR proteins. In NMA cases, ERCC1 expression was significantly related to MMR status while was not significantly related in MA cases. ERCC1 expression was not significantly related to overall and disease-free survival in both NMA and MA groups.

Conclusion: this study is the first to investigate the relation between MMR status and ERCC1 expression in colorectal MA and NMA. ERCC1 expression was significantly related to MMR status only in NMA cases. Hence, the current study emphasizes that further research about the relation between various DNA repair pathways is needed.
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http://dx.doi.org/10.4103/IJPM.IJPM_684_18DOI Listing
December 2019

Effect of omega-3 fatty acids administered as monotherapy or combined with artemether on experimental Schistosoma mansoni infection.

Acta Trop 2019 Jun 22;194:62-68. Epub 2019 Mar 22.

Department of Medical Parasitology, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt.

Schistosomiasis is on the top list of endemic diseases in sub-Saharan Africa. Praziquantel is the drug of choice for treatment of human schistosomiasis. Yet, the sole dependence on the drug raises concerns about the potential for increased drug resistance, which would subsequently result in searching for alternative preventive chemotherapy options, ideally among natural compounds. Therefore, we conducted this work to assess the effect of omega-3 polyunsaturated fatty acids [(ω-3) PUFAs] monotherapy or combined therapy with artemether (ART) against Schistosoma mansoni infection in a mouse model. A total of 42 mice were divided into 4 groups and infected with 50 ± 5 S. mansoni cercariae for 10 weeks. Mice were treated orally with either (ω-3) PUFAs as 273 mg/ kg, 4 times/ week throughout the experiment, ART as a single dose of 400 mg/ kg, 3 weeks post-infection, or combined ART + (ω-3) PUFAs using the same respective treatment regimen, while infected untreated mice were served as controls. The study explored that combined administration of (ω-3) PUFAs and ART has the best schistosomicidal efficacy as it significantly reduced liver and spleen indices, worm count, egg burdens, and granulomas count as well as diameter. Besides, the combined regimen was associated with a significant decrease in both hepatic nitric oxide and serum interleukin-4 level. The results highlighted the possibility of using (ω-3) PUFA combined with ART as a novel anti-schistosomal combination therapy. However, further researches should be conducted to clarify the possible synergistic mechanism/s between the two natural compounds.
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http://dx.doi.org/10.1016/j.actatropica.2019.02.027DOI Listing
June 2019

Potential Role for a Panel of Immunohistochemical Markers in the Management of Endometrial Carcinoma.

J Pathol Transl Med 2019 May 28;53(3):164-172. Epub 2019 Feb 28.

Department of Obstetrics and Gynecology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

Background: In order to improve the efficacy of endometrial carcinoma (EC) treatment, identifying prognostic factors for high risk patients is a high research priority. This study aimed to assess the relationships among the expression of estrogen receptors (ER), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), Ki-67, and the different histopathological prognostic parameters in EC and to assess the value of these in the management of EC.

Methods: We examined 109 cases of EC. Immunohistochemistry for ER, PR, HER2, and Ki-67 were evaluated in relation to age, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and grade, depth of infiltration, cervical and ovarian involvement, lymphovascular space invasion (LVSI), and lymph node (LN) metastasis.

Results: The mean age of patients in this study was 59.8 ± 8.2 years. Low ER and PR expression scores and high Ki-67 expression showed highly significant associations with non-endometrioid histology (p = .007, p < .001, and p < .001, respectively) and poor differentiation (p = .007, p < .001, and p <. 001, respectively). Low PR score showed a significant association with advanced stage (p = .009). Low ER score was highly associated with LVSI (p = .006), and low PR scores were associated significantly with LN metastasis (p = .026). HER2 expression was significantly related to advanced stages (p = .04), increased depth of infiltration (p = .02), LVSI (p = .017), ovarian involvement (p = .038), and LN metastasis (p = .038). There was a close relationship between HER2 expression and uterine cervical involvement (p = .009). Higher Ki-67 values were associated with LN involvement (p = .012).

Conclusions: The over-expression of HER2 and Ki-67 and low expression of ER and PR indicate a more malignant EC behavior. An immunohistochemical panel for the identification of high risk tumors can contribute significantly to prognostic assessments.
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http://dx.doi.org/10.4132/jptm.2019.02.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527935PMC
May 2019

Syndecan-1 could be added to hormonal receptors and HER2/neu in routine assessment of invasive breast carcinoma, relation of its expression to prognosis and clinicopathological parameters.

Pathol Res Pract 2019 May 2;215(5):977-982. Epub 2019 Feb 2.

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

Introduction: Syndecan-1 is heparan sulfate proteoglycans (HSPGs) that is used as coreceptors for signaling of growth factors. The comprehensive effect of syndecan-1 is to augment receptor stimulation at little ligand concentrations. THE GOAL OF THIS RESEARCH: is to study syndecan-1 expression in breast carcinoma and its value in predicting the prognosis in comparison to other clinicopathological parameters. MATERIAL &METHODS: immunohistochemistry study for syndecan-1 is done on 103 cases of invasive breast carcinoma. Its expression is assessed and correlated to other clinicopathological parameters and prognosis.

Results: overexpression was significantly related to high histologic grade (p = 0.001), large tumor size (p = 0.043), HER2-positive status (p = 0.001), and ER&PR-negative status (p = 0.001). It was also have a negative impact on the overall survival (p=0.012) and disease free survival (p = 0.009). Syndecan-1 expression showed weak positive correlation with Her 2 expression (Correlation Coefficient (co): 0.332, p = 0.001).

Conclusion: syndecan-1 is a good predictor of poor overall survival and recurrence/ metastasis free survival. It is associated with aggressive phenotype as HER2 enriched and Triple negative rather than luminal subtypes of breast carcinoma. So it can be added to the hormonal receptors and HER 2 assay in the routine management of invasive breast cancer after confirmation on a more larger study.
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http://dx.doi.org/10.1016/j.prp.2019.02.003DOI Listing
May 2019

Expression levels of β-catenin and galectin-3 in meningioma and their effect on brain invasion and recurrence: a tissue microarray study.

Cancer Biol Med 2017 Aug;14(3):319-326

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

Objective: Meningiomas are neoplasms that arise from the meninges of the central nervous system (CNS). They constitute about 25.6% of CNS tumors diagnosed in Egypt. Some morphological variants of meningiomas display aggressive behavior, leading to brain-invasive growth pattern. Although meningiomas are usually treated by complete surgical excision, the risk of postoperative recurrence remains. Hence, additional biomarkers for predicting aggressive behavior must be discovered. This study aims to explore the clinical and biological relevance of the protein expression levels of β-catenin and galectine-3 in meningioma and to understand the pathobiology of this neoplasm.

Methods: This retrospective study was carried out on 153 cases of meningioma by using tissue microarrays and immunohistochemistry for β-catenin and galectine-3.

Results: High β-catenin expression was significantly associated with transitional and meningiotheliomatous meningiomas, low tumor grade, low recurrence rate, and low incidence of brain invasion. Meanwhile, high galectin-3 expression was associated with brain invasion, recurrence, high tumor grade, and tumor type. Logistic regression analysis indicated that among all variables included in the model, β-catenin and galactin-3 expression levels were significant predictors of tumor recurrence (P<0.001).

Conclusions: Galectin-3 and β-catenin are involved in meningioma recurrencebut not in brain invasion. These molecules could be important potential therapeutic targets and predictors for meningiomas.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2017.0024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570608PMC
August 2017

Antifibrotic effect of diethylcarbamazine combined with hesperidin against ethanol induced liver fibrosis in rats.

Biomed Pharmacother 2017 May 14;89:1196-1206. Epub 2017 Mar 14.

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

Chronic alcohol consumption leads to extracellular matrix hyperplasia and liver fibrosis with a great role of hepatic stellate cell (HSC) activation in this process. The present study was designed to investigate the possible protective effects of diethylcarbamazine (DEC) (50mg/kg, acting as an anti-inflammatory drug, interferes with the arachidonic acid metabolism) when administrated in combination with hesperidin (HDN) (200mg/kg, a flavanone glycoside with potent antioxidant and anti-inflammatory activities) against alcoholic liver fibrosis in wistar rats compared to silymarin (Sil) (100mg/kg). Liver fibrosis was induced in rats using ethanol (EtOH) (1ml/100g/day, p.o.) twice a week for seven weeks. Then, tissue and blood samples were collected to assess the protective effect of DEC+HDN combination. Our results indicated that DEC when combined with HDN blunted EtOH-induced necroinflammation and elevation of liver injury parameters in serum. Besides, attenuated EtOH- induced liver fibrosis, as demonstrated by hepatic histopathology scoring and 4-hydroxyproline content. The mechanisms behind these beneficial effects of both DEC and HDN were also elucidated. These include (1) counteracting hepatic oxidative stress and augmenting hepatic antioxidants; (2) inhibiting the activation of NF-κB as indicated by preventing release of hepatic IL6; (3) preventing the activation of hepatic stellate cells (HSCs), as denoted by reducing a-smooth muscle actin (a-SMA) expression in the liver; and (4) inhibiting the fibrogenesis response of HSCs, as indicated by inhibiting serum transforming growth factor-b1 (TGF-b1). Our study indicates a novel hepatoprotective effect when DEC was co-administered with HDN against liver fibrosis.
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http://dx.doi.org/10.1016/j.biopha.2017.03.013DOI Listing
May 2017

Combination of Sitagliptin and Silymarin ameliorates liver fibrosis induced by carbon tetrachloride in rats.

Biomed Pharmacother 2017 May 20;89:98-107. Epub 2017 Feb 20.

Department of Pathology, Faculty of Medicine, El-Mansoura University, El-Mansoura, Egypt.

Liver fibrosis is a common pathological condition that occurs in most conditions associated with chronic liver injury. Silymarin is a herbal product widely used for its hepatoprotective effect. Sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP4-I), is clinically used as an oral antidiabetic agent. This study was designed to investigate the effects of Sitagliptin, Silymarin, and their combination on established liver fibrosis in carbon tetrachloride (CCl) rat model. Male albino rats received intraperitoneal injections of CCl three times a week for 7 weeks, as well as daily oral treatments of Sitagliptin (100mg/kg) or Silymarin (100mg/kg) or their combination during the 7 weeks of intoxication. Hepatic fibrotic changes were evaluated by measuring hepatic enzymes (ALT, AST, ALP, and GGT) and markers of fibrosis (transforming growth factor β1 (TGF-β1), tissue 4-hydroxyproline level, histopathological score), oxidative stress (MDA, GSH, and NOx levels), inflammation (interleukin-6) as well as markers of HSCs activation (α-smooth muscle actin (α-SMA) expression). The injected rats with CCl for 7 weeks resulted in a marked elevation of hepatic fibrotic changes and reduction of GSH level, while the combination therapy showed a significant decrease in the former one and a significant increase in the later. In conclusion, this study shows that the combination therapy is more beneficial than monotherapy in ameliorating liver fibrosis in rats. Our findings suggest that Sitagliptin alone or in combination with Silymarin may introduce a new strategy for treating liver fibrosis in humans.
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http://dx.doi.org/10.1016/j.biopha.2017.02.010DOI Listing
May 2017

Febuxostat exerts dose-dependent renoprotection in rats with cisplatin-induced acute renal injury.

Naunyn Schmiedebergs Arch Pharmacol 2016 Aug 23;389(8):819-30. Epub 2016 May 23.

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

The aim of the present study was to investigate possible renoprotective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against cisplatin (CIS)-induced acute kidney injury in rats. Male Sprague Dawley rats were randomly assigned into four groups of six rats each, as follows: normal control; CIS, received a single intraperitoneal injection of CIS (7.5 mg/kg); [febuxostat 10 + CIS] and [febuxostat 15 + CIS], received febuxostat (10 and 15 mg/kg/day, respectively, orally) for 14 days, starting 7 days before CIS injection. At the end of experiment, 24-h urine output was collected and serum was separated for biochemical assessments. Kidney tissue homogenate was prepared for determination of oxidative stress-related parameters, nitric oxide (NO), and tumor necrosis factor-α (TNF-α). Moreover, histological alterations of kidney tissues were evaluated. Serum creatinine, blood urea, and urinary total protein were significantly elevated, while serum albumin and creatinine clearance were significantly reduced, in CIS-intoxicated rats, indicating depressed renal function. CIS administration also elicited renal oxidative stress, evidenced by increased malondialdehyde content and depleted levels of reduced glutathione and superoxide dismutase activity. Moreover, enhancement of renal levels of the pro-inflammatory TNF-α indicated renal inflammation. CIS-administered rats also showed increased serum lactate dehydrogenase activity and reduced renal NO bioavailability. Febuxostat dose-dependently improved or restored these changes to near-normal (e.g., mean ± SD of serum creatinine levels in control, CIS, [febuxostat 10 + CIS] and [febuxostat 15 + CIS] groups were 0.78 ± 0.19, 3.28 ± 2.0 (P < 0.01 versus control group), 1.03 ± 0.36 (P < 0.01 versus CIS group), and 0.93 ± 0.21 (P < 0.01 versus CIS group) mg/dl, respectively, and blood urea levels for the different groups were 36.80 ± 4.36, 236.10 ± 89.19 (P < 0.0001 versus control group), 114.50 ± 78.63 (P < 0.05 versus CIS group), and 60.91 ± 14.30 (P < 0.001 versus CIS group) mg/dl, respectively). Histological analysis of renal tissues also demonstrated that febuxostat offered a dose-dependent renoprotection. The present study suggests that antioxidant, anti-inflammatory, and cytoprotective mechanisms potentially mediate the renoprotective effects of febuxostat in CIS-administered rats, presenting febuxostat as a promising combinatorial strategy for cancer patients undergoing CIS chemotherapy.
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http://dx.doi.org/10.1007/s00210-016-1258-yDOI Listing
August 2016

Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner.

Naunyn Schmiedebergs Arch Pharmacol 2016 Mar 28;389(3):269-78. Epub 2015 Dec 28.

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

The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose-dependent protection by febuxostat against LPS-induced lung inflammation in rats.
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http://dx.doi.org/10.1007/s00210-015-1202-6DOI Listing
March 2016

Phenethyl isothiocyanate potentiates anti-tumour effect of doxorubicin through Akt-dependent pathway.

Cell Biochem Funct 2015 Dec 8;33(8):541-51. Epub 2015 Nov 8.

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

The present study aims to investigate the in vivo and in vitro anti-tumour properties of phenethyl isothiocyanate (PEITC) alone and in combination with doxorubicin (Dox). The anti-tumour activity was evaluated in vitro by MTT assay using cultured human breast cancer cell line (MCF-7) and human hepatoma cell line (HepG-2) cell lines. In vivo, Ehrlich solid tumour model was used. Tumour volume, weight and antioxidant parameters were determined. Immunohistochemistry analysis for active (cleaved) caspase-3 was also performed. We tested the effect of PEITC treatment on pAkt/Akt ratio, NF-κB p65 DNA binding activity and caspase-9 enzyme activity in both MCF-7 and HepG-2 cell lines. Effect of PEITC treatment on cell migration was assessed by wound healing assay. PEITC and/or Dox treatment significantly inhibited solid tumour volume and tumour weight when compared with control mice. PEITC treatment significantly reduced oxidative stress caused by Dox treatment as indicated by significant increase in total antioxidant capacity and decrease in malondialdehyde level. Microscopic examination of tumour tissues showed a significant increase in active (cleaved) caspase-3 expression in PEITC and/or Dox treated groups. PEITC showed a dose-dependent inhibition of MCF-7 and HepG-2 cellular viability. PEITC inhibited Akt and NF-κB activation and increased caspase-9 activity in a dose-dependent manner. PEITC treatment effectively inhibited both MCF-7 and HepG-2 cell migration. We can conclude that PEITC acts via multiple molecular targets to elicit anti-carcinogenic activity. PEITC/Dox combination therapy might be a potential novel strategy, which may benefit patients with breast and liver cancers.
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http://dx.doi.org/10.1002/cbf.3153DOI Listing
December 2015

CXCL10 antagonism and plasma sDPPIV correlate with increasing liver disease in chronic HCV genotype 4 infected patients.

Cytokine 2013 Aug 7;63(2):105-12. Epub 2013 May 7.

Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France; Faculty of Medicine, Aim Shams University, Cairo, Egypt.

Egypt has the highest prevalence of hepatitis C virus infection worldwide. CXCL10 is a potent chemoattractant that directs effector lymphocytes to sites of inflammation. It has been reported that plasma CXCL10 is processed by dipeptidylpeptidase IV (DPPIV) thus leading to the generation of an antagonist form. Using Luminex-based immunoassays we determined the concentration of different forms of CXCL10 (total, agonist, and antagonist). We also evaluated plasma soluble DPPIV (sDPPIV) concentration and plasma dipeptidylpeptidase (DPP) activity. Using flow cytometry and immunohistochemistry, we analyzed the distribution of lymphocyte subsets. Plasma CXCL10 was elevated in chronic HCV patients, however the agonist form was undetectable. Increased sDPPIV concentration and DPP activity supported the NH2-truncation of CXCL10. Finally, we demonstrated an increased frequency of CXCR3(+) cells in the peripheral blood, and low numbers of CXCR3(+) cells within the lobular regions of the liver. These findings generalize the observation of chemokine antagonism as a mechanism of immune modulation in chronic HCV patients and may help guide the use of new therapeutic immune modulators.
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http://dx.doi.org/10.1016/j.cyto.2013.04.016DOI Listing
August 2013

Bilharzial endocervical polyp.

Indian J Pathol Microbiol 2012 Jul-Sep;55(3):377-8

Department of Pathology, Mansoura University, Mansoura, Egypt.

Schistosomiasis still represents a major threat to women's health in many developing countries. The frequency in developed countries is increasing among immigrants and tourists who have a history of freshwater exposure in endemic areas. This is a case of 43-year-old immunocompetent Egyptian woman presented by abnormal vaginal bleeding. The gynecological examination revealed an endocervical polyp measuring 3 x 2 x 1 cm. Polypectomy was done. Histopathological examination revealed several granulomas containing viable eggs of Schistosoma hematobium. Schistosomiasis is rarely presented with endocervical polyp. In developing countries, schistosomiasis may be considered in differential diagnosis of patient with endocervical polyp.
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http://dx.doi.org/10.4103/0377-4929.101750DOI Listing
February 2013

An inexpensive method of small paraffin tissue microarrays using mechanical pencil tips.

Diagn Pathol 2011 Dec 1;6:117. Epub 2011 Dec 1.

Pathology department, faculty of medicine, Mansoura University, Egypt.

Background: Tissue microarray technology has provided a high throughput means of evaluating potential biomarkers in archival pathological specimens. This study was carried out in order to produce tissue microarray blocks using mechanical pencil tips without high cost.

Method: Conventional mechanical pencil tips (Rotring Tikky II Mechanical Pencil 1.0 mm) were used to cut out 1 mm wax cylinders from the recipient block, creating from 36 to 72 holes. Three cores of tumor areas were punched out manually by using the mechanical pencil tips from donor paraffin embedded tissue blocks and transferred to the holes of the paraffin tissue microarrays.

Results: This technique was easy and caused little damage to the donor blocks. We successfully performed H&E slides and immunodetection without substantial tissue cylinder loss.

Conclusion: Our mechanical pencil tip technique is the most inexpensive easy technique among the literature. It also takes a reasonable amount of time and reduces antibody consumption during immunohistochemistry.
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http://dx.doi.org/10.1186/1746-1596-6-117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3256120PMC
December 2011

Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice.

Inflammopharmacology 2011 Dec 23;19(6):307-16. Epub 2011 Sep 23.

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

The present study was designed to examine the potential preventive and curative effects of curcumin, resveratrol, imatinib, rosiglitazone, losartan and bosentan (BOS) on Schistosoma mansoni-induced liver fibrosis in mice. Induction of liver fibrosis was produced in male Swiss mice by subcutaneous injection of S. mansoni cercariae per mouse. Mice were left for 28 days before starting the experiment then mice were divided into two main groups. The first group was further subdivided into experimental groups and started drug treatment at day 28 after infection and continued for 2 weeks in order to evaluate the potential preventive effects of the mentioned drugs on S. mansoni-induced liver fibrosis. The second group of mice were left for 2 weeks and then treated with praziquantel for two consecutive days to eradicate the worms and so stop egg disposition and further fibrosis development. Mice were then subdivided into the experimental groups and drug treatment was started for 2 weeks to evaluate their efficacy to decrease the developed fibrosis. At the end of the experiment period, mice were killed and serum was collected for the estimation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin and albumin. Liver tissue was taken for the estimation of hepatic hydroxyproline content and histopathological examination to confirm the biochemical results. Results of the study indicate that curcumin and imatinib have potent antifibrotic activity both in suppressing and reversing S. mansoni-induced liver fibrosis, while resveratrol has beneficial effects only in suppressing the development of S. mansoni-induced liver fibrosis.
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http://dx.doi.org/10.1007/s10787-011-0092-6DOI Listing
December 2011

Frequency of central nervous system tumors in delta region, Egypt.

Indian J Pathol Microbiol 2011 Apr-Jun;54(2):299-306

Department of Pathology, Mansoura University, Mansoura, Egypt.

Unlabelled: INTRODUCTION AND AIM OF WORK: Central nervous system (CNS) tumors represent a major public health problem, and their epidemiological data in Egypt have been rather incomplete except for some regional reports. There are no available frequency-based data on CNS tumors in our locality. The objective of this study was to estimate the frequency of CNS tumors in east delta region, Egypt.

Materials And Methods: The data were collected during the 8-year period from January 1999 to December 2007 from Pathology Department, Mansoura University, and other referred pathology labs. Examination of HandE stained sections from retrieved paraffin blocks were done in all cases for histopathologic categorization of C.N.S. tumors. Immunohistochemical studies were applied to confirm final histopathologic diagnosis in problematic cases.

Results: Intracranial tumors represented 86.7% of cases in comparison to only 13.3% for spinal tumors. Gliomas were the CNS tumors of the highest frequency (35.2%), followed by meningioma (25.6%), pituitary adenoma (11.6%) and nerve sheath tumors (6.6%). 10.25% of tumors were of children <15 years.

Conclusion: This study provides the largest series of the relative frequency of CNS tumors in Delta region in Egypt till now and may help to give insight into the epidemiology of CNS tumors in our locality.
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http://dx.doi.org/10.4103/0377-4929.81607DOI Listing
August 2011