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2020
Aziz, A. M. T. A., H. M. E. Zahed, S. H. Ahmed, B. E. A. Khaled, and E. H. Nadwa, "Cumulative Effect of Mesenchymal Stem Cells and Heme Oxygenase-1 Inducer in Ameliorating Induced Liver Toxicity in Rats.", Journal of Chemical Health Risks , 2020. Abstract

Liver diseases are most commonly occurring nowadays, that’s why we are in argent need to develop new strategies in treatment. to evaluate the role of MSCs in regenerating liver cells and to clarify the anti-inflammatory role of HO-1 either alone or as a combined therapy with MSCs. 72 rats were divided into seven groups (n=10 rats/group) as follows, group1: control rats, group 2: CCL4, group 3: CCL4 that received MSCs group 4: CCL4 that received HO-1 inhibitor, group 5: CCL4 that received HO-1 inducer, group 6: CCL4 that received combined MSCs and HO-1 inhibitor , and group 7: CCL4 that received combined MSCs and HO-1 inducer. All groups were evaluated histopathologically with assessment of liver functions. The combined MSCs and HO-1 inducer group showed the highest significant results in ALT (p-value ˂0.05), albumin (p-value ˂0.05), HO-1 activity (p-value ˂0.0001), and genes expression compared to other groups. This is due to the cumulative anti-inflammatory role of both MSCs and HO-1 together with the ability of MSCs to increase the HO-1 expression with further reduction in inflammation and fibrosis. MSCs and HO-1 inducer provide promising tool in treatment of liver disease.
Key words: MSCs; liver fibrosis; HO-1 inducer; HO-1 inhibitor.

Aziz, A. M. T. A., H. M. E. Zahed, S. H. Ahmed, and W. Fathy, "Occupational Exposure to Heavy Metal Initiate Carcinogenesis Though BRAF/KRAS Over Expression and DNA Methylation.", Journal of Chemical Health Risks , 2020. Abstract

Colorectal cancer (CRC) is a leading cause of death especially in industries worker.
The aim of this study: is to identify the role of heavy elements exposure on CRC DNA methylation.
Methods: The study was conducted on 25 CRC patients. Biopsies were taken by colonoscopy from malignant tissue and adjacent normal tissues for comparative assessment of BRAF/KRAS, methylated MLH1 and MGMT between the normal and malignant tissues by using real time PCR. In an attempt to identify wither heavy metal like Lead, Aluminum and Mn have a role in cancer development or not, we compared their levels in the serum of 25 CRC patients and 25 normal volunteers by using atomic absorption.
Results: The expressions of BRAF/KRAS, methylated MLH1 and MGMT were significantly higher in malignant tissues compared to normal tissues (p value<0.001). Additionally, the levels of lead and aluminum but not Mn were significantly higher in CRC patients compared to normal controls (p value<0.001). Lead and Aluminum were positively correlated with all studied parameters.
Conclusion: Heavy metals act as starting signals for carcinogenesis through DNA methylation.
Keywords: Colorectal cancer; Heavy metals; DNA methylation.

2019
Aziz, A. M. T. A., AMANY A. ABOU-ELALLA, and W. Fathy, "AMYLOID A INITIATED CARCINOGENESIS IN CHRONIC HCV PATIENTS BY UP¬REGULATING LNCRNA HOTAIR.", The Arab Journal of Laboratory Medicine, vol. 44, issue 2, pp. 493-501, 2019. Abstractamyloid_a_initiated_carcinogenesis_in_chronic_hcv_patients_by_upregulating_lncrna_hotair.pdf

Background: Hepatitis C virus (HCV) infection is a worldwide health problem and is one of the main causes of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). HCC is one of the most common cancers worldwide and has a poor prognosis. Long noncoding RNAs (lncRNAs) have been identified as playing critical roles in cancer development and progression.
Aim: we investigated a novel diagnostic /prognostic biomarkers and effective therapeutic targets for HCCs.
Subjects &Method: 90 subjects were included in the study as follows. Group 1: 20 normal control subjects. Group 2:35 HCV patients. Group 3: 35 patients developed HCC on top of HCV. Serum analysis for studied groups for biochemical marker and amyloid A were assessed by ELISA. In addition, lncRNA HOTAIR expression was assessed by real time PCR.
Results: serum amyloid A is significantly higher in HCV and HCC compared to control. While no significant difference between HCV and HCC patients was found. While HOTAIR level was higher in HCC compared to HCV.
Conclusion: elevated serum amyloid A predispose to the occurrence of HCC in chronic HCV patients then HOTAIR induce tumor progression.
Key words: Amyloid A, HCV, HCC and lncRNA HOTAIR.

Abdel Aziz, A. T., and A. A. Abou-Elalla, "DNA Methylation biomarkers for Body Fluid Identification.", The Arab Journal of Laboratory Medicine, vol. 44, issue 3, pp. 633-641, 2019. Abstractdna__methylation_biomarkers_for_body_fluid_identification.pdf

Background: Identification of body fluid in medicine is important. DNA methylation profiling is a promising new tool for distinguishing between different types of body fluids.
Aim: In this study, 4 epigenetic markers were selected (MGMT, LINE-1, MT2A AND FGF7) which were expected to show differential DNA methylation profiles among various body fluids.
Subjects and methods: Peripheral blood (n=52), saliva (n=52), semen (n=26) and menstrual blood samples (n=26) were collected. DNA extraction, bisulfite treatment and the methylation pattern comparisons between the different body fluids at different age and sex groups were carried out using quantitative real time PCR.
Results: MGMT epigenetic marker shows a differential methylation pattern in blood compared with other body fluids, FGF7 marker displayed a differential methylation pattern in semen. Methylation profile of LINE-1 successfully differentiated saliva from the other 3 biofluids. Hypermethylation was estimated for MT2A in saliva and semen. However, MT2A showed no significant difference between menstrual blood and other body fluids rendering them indistinguishable.
Conclusion: LINE-1, FGF7 and MGMT could be useful markers for body fluid identification.
Keywords: Body fluid identification, MGMT, LINE-1, MT2A, FGF7.

Aziz, A. M. T. A., and S. Hassan, "THERAPEUTIC EFFECT OF METFORMIN ON THE SQUAMOUS CELL CARCINOMA CELL LINE.", The Arab Journal of Laboratory Medicine, vol. 44, issue 2, pp. 503-513, 2019. Abstracttherapeutic_effect_of_metformin_on_the_squamous_cell_carcinoma_cell_line.pdf

Background: Understanding the actions of metformin on cell cycle, and particularly its effect on mitochondrial functions and cycle regulators, is important in the context of interest in ‘repurposing’ the compound for possible applications as a chemotherapeutic and/or chemopreventive agent in oncology.
Aim: This research was conducted to study the effect of metformin drug on the proliferation of cells in squamous cell carcinoma cell line (HEp-2) and the effect of metformin on the expression of cyclin D1 and mitochondrial COX1 genes.
Material and methods: MTT assay was applied to assess the rate of proliferation of cells in squamous cell carcinoma cell line HEp-2 before and after application of metformin in concentrations 5, 10, and 20 mmol for a period of 24, 48, and 72 hours. We assessed the quantitative expression of two genes mitochondrial COX1 and cyclinD1 using RT- PCR amplification and statistical analysis were performed on.
Results: The results of the present study showed that metformin significantly decreased both the proliferation of cells and the expression of both genes in a dose and time dependent manner. The cells showed significant decreased proliferation, with a significant positive direct linear correlation between both genes over the whole period.
Conclusion: It was concluded from this study that metformin affects the viability of cells through cell cycle arrest and apoptosis, there was an increase in mitochondrial COX1 and cyclin D1 genes in cancer cells where metformin significantly decreased their expression and hence is strongly recommended as an effective anticancer agent.
Key words: Metformin, squamous carcinoma cells.

Abdel Aziz, A. T., and W. Fathy., "Vitamin D supplementation potentiate antiviral SOC therapy in chronic HCV patients.", The Arab Journal of Laboratory Medicine, vol. 44, issue 3, pp. 683-689, 2019. Abstractvitamin_d_supplementation_potentiate_antiviral_soc_therapy_in_chronic_hcv_patients..pdf

Background: HCV is major health problem worldwide, that can lead to hepatic fibrosis, decompensation, and hepatocellular carcinoma. The current standard of care therapy (SOC) for chronic HCV is pegylated interferon/ribavirin (Peg-IFN/ RBV). It has been reported that vitamin D has immune-modulatory effect and alleviates the inflammatory diseases in addition to its role in bone homeostasis. The aim of this study is to evaluate the effect of combined vitamin D supplementation and SOC therapy in chronic HCV patients.
Methods: One hundred chronic HCV patients were classified into two groups (Group 1): 50 patients received the SOC therapy (Group 2): 50 patients received the SOC therapy + vitamin D3. During the treatment course, Vitamin D, liver function were evaluated in 6, 12, 24 and 48 weeks.
Results: vitamin D deficiency was found in both groups at basal time of the study, which then elevated up on treatment. The patients received vitamin D turn HCV RNA negative after 12 weeks of treatment, while those in group1 became negative after 48 weeks. Vitamin D supplementation has positive impact on treatment outcome where sustained viral response (SVR) was achieved in nearly all patients in group 2.
Conclusion: vitamin D accelerate the antiviral treatment effect and has positive impact on sustained viral response.
Key words: vitamin D, HCV, Interferon therapy.

2018
Aziz, A. M. T. A., and H. M. E. Zahed, "THE DUAL ROLE OF VITAMIN D IN OSTEOPOROSIS TREATMENT ", THE EGYPTIAN JOURNAL OF MEDICAL SCIENCES , vol. 39, issue 1, pp. 85-93 , 2018. Abstractthe_dual_role_of_vitamin_d_in_osteoporosis_treatment.pdf

Background: Osteoporosis is a condition characterized by low bone mass and increased bone fragility, and increase the risk of fractures. Osteoporosis is attributed to interaction between endocrine, metabolic and mechanical factors. proinflammatory cytokines are involved in the regulation of osteoblasts and osteoclasts. There is growing evidence that vitamin D3 deficiency could be a contributing factor in the development of different chronic diseases and their complications. Vitamin D plays an im-portant role in normal calcium and bone homeostasis though stimulation of new bone formation and suppression of the production of pro-inflammatory cytokines.
Methods: fifty rats were included in the experiment and were divided in to five groups of ten rats in each group as the following:
group1: control group; group2: induced osteoporosis group; group3: induced osteoporosis received vitamin D for one month; group4: induced osteoporosis received vitamin D for two months; group 5: induced osteoporosis received vitamin D for three months. Serum samples were collected for estimation of inflammatory cytokines (IL1, IL 6, and TNF) and inflammatory cytokines (IL10 and IL13) and bone marker (RANKL, os-teocalcin, and ALP) by ELISA technique.
Results: vitamin D treatment suppress the inflammation and im-prove the immune system in addition to stimulation of new bone formation through inhibition of RANKL and stimulation of osteocalcin and ALP.
Conclusion: vitamin D can be considered an effective therapeutic agent for osteoporosis.

2017
Abdel Aziz, A. T., and M. Elnahaas, "IN VITRO HUMAN ADULT MESENCHYMAL STEM CELLS DIFFERENTIATION STUDY. ", THE EGYPTIAN JOURNAL OF MEDICAL SCIENCES , vol. 38, issue 1, pp. 171-184, 2017. Abstractin_vitro_human_adult_mesenchymal_stem_cells_differentiation_study.pdf

Background: Stem cell therapy is an exciting and upcoming branch of tissue engineering with application in different fields of medicine. The most commonly used type of stem cells, mesenchymal stem cells (MSCs), can be easily isolated from bone marrow and cultured in vitro. MSCs are non-hematopoietic stem cells with the capacity to differentiate into tissues of both mesenchymal and non-mesenchymal origin. Research has shown the importance of growth factors in guiding and modulating the differentiation of MSCs in order to obtain the required cell type.
Aim of work: We aimed to investigate the differentiation potential of bone marrow MSCs into osteoblastic, chon-drogenic, hepatocyte-like cells and β-islets of pancreas like cells.
Methods: Human bone marrow MSCs from a healthy donor were cultured in vitro and propagated to reach confluence 80-90%. Confluent MSCs were differentiated into osteoblasts, chon-drocytes, hepatocyte-like cells and β-islets of pancreas like cells. This evidence was achieved by addition of several growth factors to confluent MSCs that enhanced their differentiation. We investigated the morphological changes, specific histological staining of differentiated MSCs and gene expression of osteoblasts, chondrocytes, hepatocyte and β-islets of pancreas-specific markers.
Results: MSCs morphologically changed from undifferentiated shape to differentiated osteoblasts, chondrocytes, hepatocyte and β-islets of pancreas. Differentiation confirmed by osteoblasts staining with Alzarin red, chondrocytes staining with Alcian blue and β-islets of pancreas staining with Ditizone. Specific genes expression for osteonectin, collagen II, albumin and insulin were detected to confirm osteoblasts, chondrocyes, hepatocyte and β-islets of pancreas respectively.
Conclusion: Human MSCs can be differentiated into partially functional osteoblasts, chondrocytes, hepatocyte-like cells and β-islets of pancreas. Thus, they could be a potential source for cell therapy in medical disorders. Ultimately, there is a need for randomised controlled trials on human populations to apply these findings to a clinical setting.

2010
Aziz, M. T. A., M. F. El-Asmar, E. E. Nadi, M. A. Wassef, H. H. Ahmed, L. A. Rashed, E. M. Obaia, D. Sabry, A. Hassouna, and A. T. Abdel Aziz, "The Effect of curcumin on insulin release in rat-isolated pancreatic islets.", Angiology, vol. 61, issue 6, pp. 557-566, 2010. Abstractthe_effect_of_curcumin_on_insulin_release_in_rat-isolated_pancreatic_islets..pdf

Curcumin exerts a hypoglycemic action and induces heme-oxygenase-1 (HO-1). We evaluated the effect of curcumin on isolated islets of Langerhans and studied whether its action on insulin secretion is mediated by inducible HO-1. Islets were isolated from rats and Divided into control islets, islets incubated in different curcumin concentrations, islets incubated in hemin, islets incubated in curcumin and HO inhibitor, stannous mesoporphyrin (SnMP), islets incubated in hemin and SnMP, islets incubated in SnMP only, and islets incubated in 16.7 mmol/L glucose. Heme-oxygenase activity, HO-1 expression, and insulin estimation was assessed. Insulin secretion, HO-1 gene expression and HO activity were significantly increased in islets incubated in curcumin, hemin, and glucose compared with controls. This increase in insulin secretion was significantly decreased by incubated of islets in SnMP. The action of curcumin on insulin secretion from the isolated islets may be, in part, mediated through increased HO-1 gene expression.
Keyword: curcumin, pancreatic islets, heme oxygenase, insulin secretion.

Aziz, M. T. A., M. F. E. Asmar, A. Rezq, T. A. Kumosani, S. moustafa, T. Moustafa, H. Atta, M. A. A. Wassef, H. H. Fouad, L. Rashed, et al., "Novel Water-Soluble Curcumin Derivative Mediating Erectile Signaling.", The journal of sexual medicine, vol. 7, pp. 2714-2722, 2010. Abstractnovel_water-soluble_curcumin_derivative_mediating_erectile_signaling..pdf

Introduction: Curcumin is an inducer of heme oxygenase Enzyme-1 (HO-1) that is involved in erectile signaling via elevating cycle guanosine monophsphate (cGMP) levels.
Aim: To assess the effect of oral administration of a water soluble long-acting curcumin derivative on erectile signaling.
Methods: Two hundred and thirty six male white albino rats were divided into four groups; group 1 (N = 20) includes control. Group 2 (N = 72) was equally divided into four subgroups; subgroup 1 received pure curcumin (10 mg/kg), subgroup 2 received the long-acting cucumin derivative (2 mg/kg), subgroup 3 received the long-acting cucumin derivative (10 mg/kg), and subgroup 4 received sildenafil (4 mg/kg). Subgroups were sacrificed after the first, second, and third hour. Group 3 (N = 72) was equally divided into the same four groups already mentioned and were sacrificed after 24 hours, 48 hours, and 1 week. Group 4 (N = 72) was subjected to intracavernosal presser (ICP)measurements 1 hour following oral administration of the same previous doses in the same rat subgroups.
Main Outcome Measure. cavernous tissue HO enzyme activity, cGMP, and ICP.
Result. In group 2 there was a significant progressive maintained elevation of HO activity and cGMP tissue levels starting from the first hour in subgroup 3 and 4,whereas, the rise in HO activity and cGMP started from second hour regarding the ather rat subgroups. Sildenafil effect decreased after 3 hours. In group 3, there was a significant maintained elevation of HO activity and cGMP tissue levels extended to 1 week as compared to controls for all rat subgroups that received both forms of curcumin. In group 4, long-acting cucumin derivative exhibited more significant potentiation of intracavernosal pressure as compared to control and to the pure curcumin.
Conclusion. Water-soluble long-acting curcumin derivative could mediate erectile function via upregulating cavernous tissue cGMP. Abdel Aziz MT, El Asmar MF, Rezq A, kumosani TA, Moustafa S, Moustafa T, Atta H, Abdel Aziz Wassef M, Fouad HH, Rashed L, Sabry D, HAssouna AA, Senbel A, and Abdel Aziz A. Novel Water-Soluble Curcumin Derivative Mediating Erictile Signaling.
Keywords. Diferuloylmethane; cGMP; Heme Oxygenase; Carbon Monoxide System; Erectile Function; Erectile Dysfunction; Corpus Cavernosum; Intracavernosal Pressure.

2009
MT, A. A., E. A. MF, M. T, A. H, M. S, F. H, R. L, S. D, H. A, A. A. AT, et al., "Effect of Losartan, HO-1 Inducers or HO-1 inhibitors on Erectile Signaling in Diabetic Rats.", The journal of sexual medicine, vol. 6, issue 12, pp. 3254–3264, 2009. Abstracteffect_of_losartan__ho-1_inducers_or_ho-1_inhibitors_on_erectile_signaling_in_diabetic_rats..pdf

Introduction. Activation of the renin-angiotensin system which is common in diabetes mellitus might affect heme oxygenase (HO-1) gene expression.
Aims. Assessment of the effects of administration of angiotensin II (Ang II) receptor antagonist (losartan) with HO-1 inducer or inhibitor on erectile signaling in diabetic rats.
Materials and Methods. Seventy male rats were divided equally into seven groups; healthy controls, streptozotocin induced diabetic rats, rats on citrate buffer, diabetic rats on losartan, diabetic rats on HO-1 inducer (cobalt protoporphyrin [CoPP]), diabetic rats on losartan and CoPP, and diabetic rats on losartan and HO-1 inhibitor (stannus mesoporphyrin [SnMP]).
Main Outcome Measure. HO enzyme activity, HO-1 gene expression, cyclic guanosine monophosphate (cGMP) assay, intracavernosal pressure (ICP), and cavernous tissue sinusoids surface area.
Results. HO-1 gene expression, HO enzymatic activity, and cGMP were significantly decreased in the cavernous tissue of diabetic rats. These parameters were significantly elevated with the use of CoPP that restored the normal control levels of HO enzyme activity. Administration of losartan exhibited a significant enhancing effect on these parameters compared with the diabetic group, but not restored to the control levels, whereas administration of CoPP combined with losartan led to the restoration of their normal levels. ICP demonstrated significant decline in diabetic rats. The use of CoPP and / or losartan led to its significant improvement compared with diabetic rats. Administration of either losartan and/or CoPP led to a significant increase in the cavernous sinusoids surface area of diabetic rats. Administration of losartan with SnMP significantly decreased the enhancing effect of losartan on the studied parameters.
Conclusion. The decline in erectile function in diabetes mellitus could be attributed to the downregulation of HO-1 gene expression. HO-1 induction added to ang II receptor antagonist could improve erectile function. Abdel Aziz MT, El Asmar MF, Mostafa T, Atta H, Mahfouz S, Fouad H, Rashed L, Sabry D, Hassouna A, Abdel Aziz AT, Senbel A and Demery A6. Effect of Losartan, HO-1 Inducers or HO-1 inhibitors on Erectile Signaling in Diabetic Rats.
Key Words. Losartan; HO-1 inducer; HO-1 inhibitor; Erectile Signaling; Diabetes.

2008
Aziz, M. T. A., M. F. E. – Asmar, M. Haidara, H. M. Atta, N. K. Roshdy, L. A. Rashed, D. Sabry, M. A. Youssef, A. T. Abdel Aziz, and M. Moustafa, "Effect of Bone marrow derived Mesenchymal Stem Cells on cardiovascular complications in diabetic rats.", Med Sci Monit, vol. 14, issue 11, pp. 249-255, 2008. Abstracteffect_of_bone_marrow_derived_mesenchymal_stem_cells_on_cardiovascular_complications_in_diabetic_rats..pdf

Background : The purpose of this study was to investigate the effect of mesenchymal stem cells (MSCs) on cardiovascular complications of type 1 diabetes mellitus (DM) in rats.
Material/Methods : MSCs were derived from the bone marrow of male albino rats. The MSCs were characterized morphologically and by RT-PCR for CD29 expression. They were then infused into female rats which were made diabetic by IP injection of streptozocin(STZ) .The rats were divided into control, STZ,and STZ plus MSC groups. Serum insulin, glucose, and fibrinogen were estimated in all groups and the Y-chromosome gene sry was detected by PCR in pancreatic and cardiac tissues. Physiological cardiovascular functions (heart rate, systolic blood pressure) were assessed by a Langendorff apparatus.
Results: Diabetic rats which received MSCs showed signicantly lower serum glucose and increased serum insulin levels compared with the STZ group. Improvement of cardiovascular performance was also observed in the STZ/MSC group compared with the STZ group. The sry gene was detected by PCR in the pancreatic and cardiac tissues of the STZ/MSC group.
Conclusions: Rate bone marrow harbors cells that capacity to differentiate into functional insulin-producing cells capable of controlling blood glucose level in diabetic rats. This may provide a source of cell-based therapy for DM. Furthermore, MCS transplantation can improve cardiac function in DM.
Key words: mesenchymal stem cells, insulin, Diabetes mellitus, cardiovascular complications.

MT, A. A., E. - A. MF, M. T, A. H, F. HH, R. NK, R. LA, O. EA, Sabry DA, A. A. AT, et al., "Effect of hemin and carbon monoxide releasing molecule (CORM-3) on cGMP in rat penile tissue.", The Journal of Sexual Medicine, vol. 5, issue 2, pp. 336-343, 2008. Abstracteffect_of_hemin_and_carbon_monoxide_releasing_molecule_corm-3_on_cgmp_in_rat_penile_tissue..pdf

Introduction. Cyclic guanosine monophosphate (cGMP) levels can be regulated by heme oxygenase-1 and 2 (HO-1 and HO-2)-derived carbon monoxide (co).
Aims. Assessment of the effect of upregulating CO in rat corpora cavernosa (CC) on cavernous cGMP.
Methods. Three experimental groups were studied: first group (N = 40), short term HO induction over 2 weeks by injection of intraperitoneal increasing doses of hemin; the second group (N = 40) was subjected to intracavernosal injection of CO donor, CORM-3, or its inactive form (iCORM-3) over 2 weeks; the third group (N = 60) was subdivided into three subgroups: the first one received a combined hemin and CORM-3, the second one received hemin and its inhibitor stannous mesoporphyrin (SnMP), and third one received a combind hemin, CORM-3, and SnMP.
Main outcome Measures. In CC, HO-1 and HO-2 gene expression, Northern blot and Western blot, cGMP levels, and HO enzyme activity.
Results. In the first group maximum induction of HO-1 gene expression, HO enzyme activity, and cGMP occurred with 4-mg hemin dose with a successive increase over 2 weeks. In the second group, CORM-3 increased cGMP by twofold compared with iCORM-3, and also increased HO-1 protein. In the third group, SnMPinhibited the enhancing effect of CORM-3 and HO on erectile signaling molecules;i.e., HO-1 gene, enzyme activity, and cGMP.
Conclusions. CORM-3- or hemin-mediated CO release could increase cavernous tissue cGMP. Abdel Aziz MT, El-Asmar MF, Mostafa T, Atta H, Fouad HH, Roshdy NK, Rashed LA, Obaia EA, Sabry DA, Abdel Aziz AT, Druummond G and Olszanecki R. Effect of hemin and carbon monoxide releasing molecule (CORM-3) on cGMP in rat penile tissue.
J Sex Med. 2008 Feb; 5(2): 336-43.
Key Words. Erectile Dysfunction; HO-1;HO-2; Corpus cavernosum; NO;CO; cGMP.

Aziz, T. A. M., T. Mostafa, H. Atta, L. Rashed, S. A. Marzouk, E. M. Obaia, D. Sabry, A. A. Hassouna, A. M. El-Shehaby, and A. A. T. Aziz, "The Role of PDE5 Inhibitors in Heme Oxygenase-cGMP Relationship in Rat Cavernous Tissues.", The Journal of Sexual Medicine, vol. 5, issue 7, pp. 1636–1645, 2008. Abstractthe_role_of_pde5_inhibitors_in_heme_oxygenase-cgmp_relationship_in_rat_cavernous_tissues..pdf

Introduction. Heme Oxygenase (HO) enzyme catalyzes Oxidative degradation of heme to biliverdin and carbon monoxide (CO). CO shares many properties with nitric oxide (NO) including the activation of soluble guanyl cyclase.
Aim. To assess cavernous tissue HO activity and cyclic guanosine monophosphate (cGMP) levels in response to oral phosphodiesterse type 5 (PDE5) inhibitors.
Methods. Seven hundred twenty male Sprague-Dawley rats, divided into six groups, were investigated. Group 1, controls; Group 2 received sildenafil citrate orally; Group 3 received vardenafil hydrochloride; and Group 4 received tadalafil. Group 5 was subdivided into three equal subgroups, received the same dose of each drug added to the HO inhibitor, Zn protoporphyrin.Group 6 was subedivided into three equal subgroups, received the same dose of each drug added to the NO inhibitor, L-nitroarginine methylester. Either rats from each group / subgroup were sacrificed at 0.5, 1, 2, 3, 4, 6, 18, 24 and 36 hours, respectively.
Main Outcome Measures. HO enzyme activity assay and cGMP tissue levels in dissected rat cavernous tissues.
Results. Both cavernous tissue HO enzyme activity and cGMP tissue levels were increased significantly in sildenafil-,vardenafil-, and tadalafil-treated rats compared with the controls, with significant decreases after either HO or NO inhibition.Cavernous tissue HO enzyme activity and cGMP showed a positive significant correlation (r = 0.854,P < 0.001).
Conclusion. The effects of PDE5 inhibitors in cavernous tissue are partly mediated through HO enzyme activity.
Keywords. Heme Oxygenase; cGMP; sildenafil; Vardenafil; Tadalafil; PDE5 inhibitors.

2007
Aziz, T. A. M., F. A. M. Asmar, T. Moustafa, H. Atta, L. Rashed, D. Sabry, S. Ashour, and A. A. T. Aziz, "Assessment of heme oxygenase-1 (HO-1) activity in the cavernous tissues of sildenafil citrate-treated rats", Asian Journal of Andrology, vol. 9, issue 3, pp. 377–381, 2007. Abstractassessment_of_heme_oxygenase_1_ho_1_activity_in_the_cavernous_t.pdf

Aim: To assess heme oxygenase-1 (HO-1) activity in the cavernous tissues of sildenafil citrate-treated rats.
Methods: One hudred and ninty-two Sprague-Dawley male rats, divided into four equal groups, were investigated. Group 1 the control group, received regular animal chow; group 2 received sildenafil citrate by intragastric tube; group 3 received sildenafil and HO inhibitor (zinc protoporphyrin, ZnPP); and group 4 received sildenafil and nitric oxide synthase (NOS) inhibitor L-nitroaginine methyl ester (L-NAME).Twelve rats from each group were killed after 0.5 h, 1h, 2h and 3h of drug administration. Then HO-1 activity, cGMP levels and NOS enzymatic activity and cGMP concentration increased significantly in sildenafil-treated rats compared to other groups throughout the experiment. Rats receiving either HO or NOS inhibitors showed a significant decrease in these parameters. HO-1 cavernous tissue activity and NOS enzymatic activity demonstrated a positive significant correlation with cGMP levels (r = 0.646, r = 0.612 respectively; P < 0.001).
Conclusion. The action of PDE5 inhibitor sildenafil citrate in the cavernous tissue are partly mediated through the interdependent relationship between both HO-1 and NOS activities.
Keywords. Erectile Dysfunction; heme oxygenase; sildenafil citrate; nitric oxide synthase; carbon monoxide.

Aziz, A. M. T., T. Moustafa, H. Atta, L. Rashed, S. A. Marzouk, E. M. Obaia, D. Sabry, A. A. Hassouna, E. A. M. Shehaby, and A. A. T. Aziz, "Oral phosphodiesterase-5 inhibitors: Effect of heme oxygenase inhibition on cGMP signaling in rat cavernous tissue.", Andrologia, vol. 39, issue 2, pp. 66-70, 2007. Abstractoral_phosphodiesterase-5_inhibitors.pdf

Abstract
Summary. This Work postulated that heme oxygenase (HO) is partly responsible for con-trolling phosphodiesterase-5 inhibitor actions by modulating cyclic guanosine monophosphate (cGMP) cavernous tissue levels. Five hundred and four maleSprague-Dawley rats, divided into five groups, were investigated.Group 1 (n = 72) included controls, Group 2 (n = 72) received sildenafil citrate (ViagraR) Orally, Group 3 (n = 72) received vardenafil hydrochloride (LevitraR), group 4 (n = 72) received tadalafil (cialisR). Group 5 (n = 216), subdivided into three subgroups (A, B and C, 72 each), received the same dose of each drug with the HO inhibitor, Zn proptoporphyrin. Eight rats from each group / subgroup were killed at 0.5, 1, 2, 3, 4, 6, 18, 24 and 36 h when cGMP levels in the cavernous tissue were estimated. Cavernous tissue cGMP levels increased significantly in sildenafil, vardenafil and tadalafil-treated rats compared to the controls with significant decreases after HO inhibition. It is concluded that the effects of these PDE-5 inhibitors in rat cavernous tissue are partly mediated through HO activity via the cGMP signalling pathway.
Keywords. cGMP—erectile dysfunction—heme oxygenase—PDF inhibitors—sildenafil— tadalafil —vardenafil.

2002
1998
Tourism