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ABSTRACT: As HCV lymphotropism was ascertained, this study was carried out to verify the possible involvement of the spleen in HCV-related chronic hepatitis.
A cross-sectional study was conducted on 97 HCV infected patients attending for treatment with interferon, categorised as follows; before treatment (group I, n=49), non-responders (group II, n=18), responders (group III, n=18) and group IV (n=12) including patients with HCV RNA below detection limit after 24weeks of treatment. A control group of healthy blood donors (n=19) was enrolled in our study. Conventional ultrasonography was carried out on all participants. Splenic volume was measured and compared between the groups, and its relationship to HCV RNA concentration was investigated.
It was found that the splenic volume of patients of both groups I and II is significantly greater than that of the control group (p-values : 0.004 and 0.009, respectively) and, of patients of both groups III and IV. The latter are not significantly greater than that of the control group (p-value: 0.8 and 0.6, respectively). A significant positive relationship was detected between the splenic volume and the HCV RNA concentration in group I (r=0.56, p-value=0.00) but this is insignificant in group II. There is no significant relationship between the splenic longitudinal diameter and the HCV RNA concentration in any of the studied groups.
The splenic volume positively correlated with HCV RNA concentration in HCV positive patients, but this become insignificant in non-responders to interferon therapy. The successful response to interferon therapy matches with near normal splenic volume whilst non-responders to Interferon therapy matches with increased splenic volume. The change in the viral load leads to a corresponding change in the splenic volume and does not affect the splenic longitudinal diameter.
Arab Journal of Gastroenterology 06/2012; 13(2):58-64.
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Mohamed Talaat Abdel Aziz,
Tarek Motawi,
Ameen Rezq,
Taymour Mostafa,
Hanan H Fouad,
Hanan H Ahmed,
Laila Rashed, Dina Sabry,
Amira Senbel,
A Al-Malki,
Raghda El-Shafiey
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ABSTRACT: Curcumin is involved in erectile signaling via elevation of cyclic guanosine monophosphate (cGMP).
Assessment of the effects of water-soluble curcumin in erectile dysfunction (ED).
One hundred twenty male white albino rats were divided into: 1st and 2nd control groups with or without administration of Zinc protoporphyrin (ZnPP), 3rd and 4th diabetic groups with or without ZnPP, 5th diabetic group on single oral dose of pure curcumin, 6th diabetic group on pure curcumin administered daily for 12 weeks, 7th and 8th diabetic groups on single dose of water-soluble curcumin administered with or without ZnPP, 9th and 10th diabetic groups on water-soluble curcumin administered daily for 12 weeks with or without ZnPP. All curcumin dosage schedules were administered after induction of diabetes.
Quantitative gene expression of endothelial nitric oxide synthase (eNOS), neuronal NOS (nNOS), inducible NOS (iNOS), heme oxygenase-1 (HO-1), nuclear transcription factor-erythroid2 (Nrf2), NF-Кβ, and p38. Cavernous tissue levels of HO and NOS enzyme activities, cGMP and intracavernosal pressure (ICP).
Twelve weeks after induction of diabetes, ED was confirmed by the significant decrease in ICP. There was a significant decrease in cGMP, NOS, HO enzymes, a significant decrease in eNOS, nNOS, HO-1 genes and a significant elevation of NF-Кβ, p38, iNOS genes. Administration of pure curcumin or its water-soluble conjugate led to a significant elevation in ICP, cGMP levels, a significant increase in HO-1 and NOS enzymes, a significant increase in eNOS, nNOS, HO-1, and Nrf2 genes, and a significant decrease in NF-Кβ, p38, and iNOS genes. Water-soluble curcumin showed significant superiority and more prolonged duration of action. Repeated doses regimens were superior to single dose regimen. Administration of ZnPP significantly reduced HO enzyme, cGMP, ICP/ mean arterial pressure (MAP), HO-1 genes in diabetic groups.
Water-soluble curcumin could enhance erectile function with more effectiveness and with more prolonged duration of action.
Journal of Sexual Medicine 04/2012; 9(7):1815-33. · 3.55 Impact Factor
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ABSTRACT: This work aimed to study the homing evidence and the reparative effect of mesenchymal stem cells (MSCs) in the healing process of induced osteoarthritis in experimental animal model (donkeys).
Twenty-seven donkeys were equally divided into 3 groups based on the observation period after induction of arthritis (3, 6 and 9 weeks) to achieve different degrees of osteoarthritis. Each group was subdivided into three subgroups of three animals each based on the follow-up period (1, 2 and 6 months) after treatment. The induction was done through intra-articular (IA) injection of 2 ml of Amphotericin-B in both carpal joints. MSCs were harvested in a separate procedure, labeled with green fluorescent protein (GFP) using monster GFP vector and suspended in hyaluronic acid for IA injection. Treatment approaches consisted of cell-treatment using MSCs suspended in 3 ml of hyaluronic acid (HA) for the right carpal joint; and using the same amount of (HA) but without MSCs for the left contralateral carpal joint to serve as a control. Animals were assessed clinically and radiologically before and after treatment. Synovial fluid was also evaluated. Histopathologically; articular cartilage structural changes, reduction of articular cartilage matrix staining, osteophyte formation, and subchondral bone plate thickening were graded. Data was summarized using median and percentile for scores of histopathologic grading. Comparison between groups was done using non-parametric Mann Whitney test.
The reparative effect of MSCs was significant both clinically and radiologically in all treated groups (P < 0.05) compared to the control groups. Fluorescence microscopy of sections of the cell-treated joints of all animals indicated that the GFP-transduced injected cells have participated effectively in the reparative process of the damaged articular surface and have integrated within the existing articular cartilage. The cells were associated with the surface of the cartilage and, were also detected in the interior.
Homing was confirmed by the incorporation of injected GFP-labeled MSCs within the repaired newly formed cartilage. Significant recovery proves that the use of IA injection of autologous MSCs is a viable and a practical option for treating different degrees of osteoarthritis.
BMC Musculoskeletal Disorders 11/2011; 12:259. · 1.58 Impact Factor
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ABSTRACT: This study was intended to verify the likelihood of homing of intra-articularily injected mesenchymal stem cells (MSCs) and its involvement in the healing process of experimentally induced, acute and chronic, partial chondral defects in dogs.
Partial thickness chondral defects were created on the lateral femoral condyle of stifle joint in domestic mongrel dogs. MSCs were harvested in a separate procedure, labelled with green fluorescent protein (GFP) using monster GFP vector and suspended in buffer phosphate solution for intra-articular (IA) injection. Dogs were divided into three groups. Group I, served as the control. The dogs in the two cell-treated groups received a single IA injection of MSCs one day (Group II) and one month (Group III) after creating the defect. Sacrifice was scheduled at 2 and 8 weeks post-surgery for group I, and 2 and 8 weeks post-treatment, for the cell-treated groups. Morphological, histological, and fluorescence analysis was performed.
Recovery was significant both clinically and histologically in the two cell-treated groups (Group II and III) compared to the control (Group I), (p<0.001). In the meantime, Group-II showed better results at 8 weeks than Group III (p=0.01). Homing was confirmed by the incorporation of injected GFP-labelled MSCs within the newly formed cartilage.
The obtained results prove that the use of IA injection of autologous MSCs is a viable option for treating partial cartilage defects. Cell labelling gave evidence to the certainty of cell homing within the neocartilage of all treated cases and the participation in the reparative process.
Clinical and experimental rheumatology 03/2011; 29(2):275-84. · 2.15 Impact Factor
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ABSTRACT: The present study was conducted to evaluate the tumor suppressive effects of bone marrow derived mesenchymal stem cells (MSCs) in an experimental hepatocellular carcinoma (HCC) model in rats and to investigate the possible role of Wnt signaling in hepato-carcinogenesis.
Ninety rats were included in the study and were divided equally into: Control group, rats which received MSCs only, rats which received MSCs vehicle only, HCC group induced by diethylnitroseamine (DENA) and CCl(4), rats which received MSCs after HCC induction, rats which received MSCs before HCC induction. Histopathological examination and gene expression of Wnt signaling target genes by real time, reverse transcription-polymerase chain reaction (RT-PCR) in rat liver tissue, in addition to serum levels of ALT, AST and alpha fetoprotein were performed in all groups.
Histopathological examination of liver tissue from animals which received DENA-CCl(4) only, revealed the presence of anaplastic carcinoma cells and macro-regenerative nodules type II with foci of large and small cell dysplasia. Administration of MSCs into rats after induction of experimental HCC improved the histopathological picture which showed minimal liver cell damage, reversible changes, areas of cell drop out filled with stem cells. Gene expression in rat liver tissue demonstrated that MSCs downregulated β-catenin, proliferating cell nuclear antigen (PCNA), cyclin D and survivin genes expression in liver tissues after HCC induction. Amelioration of the liver status after administration of MSCs has been inferred by the significant decrease of ALT, AST and Alpha fetoprotein serum levels. Administration of MSCs before HCC induction did not show any tumor suppressive or protective effect.
Administration of MSCs in chemically induced HCC has tumor suppressive effects as evidenced by down regulation of Wnt signaling target genes concerned with antiapoptosis, mitogenesis, cell proliferation and cell cycle regulation, with subsequent amelioration of liver histopathological picture and liver function.
Journal of Experimental & Clinical Cancer Research 01/2011; 30:49. · 2.15 Impact Factor
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ABSTRACT: OBJECTIVE: To test the hypothesis that platelet-rich fibrin glue (PR-FG) can be used clinically as a scaffold to deliver autologous culture-expanded bone marrow mesenchymal stem cells (BM-MSCs) for cartilage repair and to report clinical results 1 y after implantation of MSCs PR-FG. PATIENTS AND METHODS: Autologous BM-MSCs were culture expanded, placed on PR-FG intraoperatively, and then transplanted into 5 full-thickness cartilage defects of femoral condyles of 5 patients and covered with an autologous periosteal flap. Patients were evaluated clinically at 6 and 12 mo by the Lysholm and Revised Hospital for Special Surgery Knee (RHSSK) scores and radiographically by x-rays and magnetic resonance imaging (MRI) at the same time points. Repair tissue in 2 patients was rated arthroscopically after 12 mo using the International Cartilage Repair Society (ICRS) Arthroscopic Score. STUDY DESIGN: Case series; level of evidence 4. RESULTS: All patients' symptoms improved over the follow-up period of 12 mo. Average Lysholm and RHSSK scores for all patients showed statistically significant improvement at 6 and 12 mo postoperatively (P < 0.05). There was no statistically significant difference between the 6 and 12 mo postoperative clinical scores (P = 0.18). ICRS arthroscopic scores were 8/12 and 11/12 (nearly normal) for the 2 patients who consented to arthroscopy. MRI of 3 patients at 12 mo postoperatively revealed complete defect fill and complete surface congruity with native cartilage, whereas that of 2 patients showed incomplete congruity. CONCLUSION: Autologous BM-MSC transplantation on PR-FG as a cell scaffold may be an effective approach to promote the repair of articular cartilage defects of the knee in human patients.
Cartilage 10/2010; 1(4):253-261.
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ABSTRACT: The present study was performed to estimate the frequency of methylated p16INK4A in the sera of patients with hepatitis C virus (HCV)-related chronic active hepatitis (CAH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC) and to evaluate the role of p16INK4A as a tumor marker of HCC.
The sera of 17 CAH, 20 LC, and 25 HCC patients were examined in this study. The methylation status of p16INK4A was evaluated by methylation-specific PCR of the serum samples.
Methylated p16INK4A was detected in 47.1% (8/17) of the CAH patients, 5% (4/20) of the LC patients, and in 92% (23/25) of the HCC patients. HBV markers were detected in (4/25) of HCC patients; all had methylated p16INK4A. No association was demonstrated between p16INK4A methylation and serum AFP level in the HCC group.
The results of this study indicate that aberrant DNA methylation contributes to hepatocarcinogenesis and it may be an early event during hepatocarcinogenesis. As the status of p16INK4A methylation was not associated with serum AFP level, it may have a complementary role with AFP as a tumor marker of HCC.
Medical science monitor: international medical journal of experimental and clinical research 09/2010; 16(9):CR410-5. · 1.70 Impact Factor
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ABSTRACT: 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 incubation 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.
Angiology 08/2010; 61(6):557-66. · 1.51 Impact Factor
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Mohamed Talaat Abdel Aziz,
Mohammed F El Asmer,
Ameen Rezq,
Taha Abdullah Kumosani,
Samya Mostafa,
Taymour Mostafa,
Hazem Atta,
Mohamed Abdel Aziz Wassef,
Hanan H Fouad,
Laila Rashed, Dina Sabry,
Amira A Hassouna,
Amira Senbel,
Ahmed Abdel Aziz
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ABSTRACT: Curcumin is an inducer of heme oxygenase enzyme-1 (HO-1) that is involved in erectile signaling via elevating cyclic guanosine monophosphate (cGMP)levels.
To assess the effect of oral administration of a water-soluble long-acting curcumin derivative on erectile signaling.
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 curcumin derivative (2 mg/kg), subgroup 3 received the long-acting curcumin 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 subgroups already mentioned and were sacrificed after 24 hours, 48 hours, and 1 week. Group 4 (N = 72) was subjected to intracavernosal pressure (ICP) measurements 1 hour following oral administration of the same previous doses in the same rat subgroups.
Cavernous tissue HO enzyme activity, cGMP, and ICP.
In group 2, there was a significant progressive maintained elevation of HO activity and cGMP tissue levels starting from the first hour in subgroups 3 and 4, whereas, the rise in HO activity and cGMP started from second hour regarding the other 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 curcumin derivative exhibited more significant potentiation of intracavernosal pressure as compared to control and to the pure curcumin.
Water-soluble long-acting curcumin derivative could mediate erectile function via upregulating cavernous tissue cGMP.
Journal of Sexual Medicine 08/2010; 7(8):2714-22. · 3.55 Impact Factor
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ABSTRACT: a b s t r a c t : Background and study aims: Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in most types of chronic liver diseases. Non-alcoholic fatty liver disease (NAFLD) can be asso-ciated with progressive hepatic fibrosis. In this study we evaluated the effect of pentoxifylline (PTX) on serum hyaluronic acid (HA) levels as a marker of fibrosis. Patients and methods: In this study we included 30 subjects (14 males and 16 females), divided into three groups. The NAFLD group included 20 patients with fatty livers as shown by ultrasound examination. Patients were randomised into a placebo group of 10 patients who received a placebo, and a pentoxifyl-line PTX group of 10 patients who received pentoxifylline at 400 mg/day for 6 months. The control group included 10 normal individuals. Results: In the NAFLD group the mean value of the base line serum HA was 133 ± 150.48, while in the control group it was 33.5 ± 10.01; the difference between the groups was statistically significant (p < 0.001). The mean value of the base line serum HA in the PTX treated group was 169.5 ± 156.19, while after 6 months of treatment it was 59 ± 44.34, with a statistically significant difference (p = 0.007). In the placebo treated group the mean value of the base line serum HA was 96.5 ± 143.004, while after 6 months of treatment it was 59.7 ± 44.29; this difference was not statistically significant (p = 0.594). Conclusion: Our results showed that, when administered for 6 months, PTX caused a significant decline in HA levels, which may be an index reflecting improvement of hepatic fibrosis. Further investigations should be conducted with a large number of patients to confirm our results and correlate this with his-tological findings.
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Mohamed Talaat Abdel Aziz,
Mohamed Farid El Asmer,
Taymour Mostafa,
Hazem Atta,
Soheir Mahfouz,
Hanan Fouad,
Laila Rashed, Dina Sabry,
Amira Hassouna,
Ahmed Talaat Abdel Aziz,
Amira Senbel,
Ahmed Demery
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ABSTRACT: Activation of the renin-angiotensin system which is common in diabetes mellitus might affect heme oxygenase (HO-1) gene expression.
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.
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]).
HO enzyme activity, HO-1 gene expression, cyclic guanosine monophosphate (cGMP) assay, intracavernosal pressure (ICP), and cavernous tissue sinusoids surface area.
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.
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.
Journal of Sexual Medicine 10/2009; 6(12):3254-64. · 3.55 Impact Factor
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ABSTRACT: Erectile response depends on nitric oxide (NO) generated by NO synthase (NOS) enzyme of the nerves and vascular endothelium in the cavernous tissue. NO activates soluble guanylate cyclase (sGC), leading to the production of cyclic guanosine monophosphate (cGMP). cGMP activates cGMP-dependent protein kinase that activates Ca(2+)/ATPase pump that activates Ca(2+)/K efflux pump extruding Ca(2+) across the plasma membrane with consequent smooth muscle cell relaxation. A role similar to that of NOS/NO signaling has been postulated for carbon monoxide (CO) produced in mammals from heme catabolism by heme oxygenase (HO) enzyme.
To assess CO signaling pathway for erectile function by reviewing published studies.
A systematic review of published studies on this affair based on Pubmed and Medical Subject Heading databases, with search for all concerned articles.
Documentation of positive as well as negative criteria of CO/HO signaling focused on penile tissue.
The concept that HO-derived CO could play a role in mediating erectile function acting in synergism with, or as a potentiator for, NOS/NO signaling pathway is gaining momentum. CO/HO signaling pathway has been shown to partially mediate the actions of oral phosphodiesterase type 5 inhibitors. In addition, it was shown that the use of CO releasing molecules potentiated cavernous cGMP levels. However, increased CO production or release was reported to be associated, in some studies, with vasoconstriction.
This review sheds a light on the significance of cavernous tissue CO signaling pathway that may pave the way for creation of therapeutic modalities based on this pathway.
Journal of Sexual Medicine 02/2009; 6(1):49-60. · 3.55 Impact Factor
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ABSTRACT: 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.
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 streptozotocin (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.
Diabetic rats which received MSCs showed significantly 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.
Rat bone marrow harbors cells that have the 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, MSC transplantation can improve cardiac function in DM.<
Medical science monitor: international medical journal of experimental and clinical research 12/2008; 14(11):BR249-55. · 1.70 Impact Factor
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ABSTRACT: 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.
To assess cavernous tissue HO activity and cyclic guanosine monophosphate (cGMP) levels in response to oral phosphodiesterase type 5 (PDE5) inhibitors.
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 subdivided into three equal subgroups, received the same dose of each drug added to the NO inhibitor, L-nitroarginine methylester. Eight rats from each group/subgroup were sacrificed at 0.5, 1, 2, 3, 4, 6, 18, 24, and 36 hours, respectively.
HO enzyme activity assay and cGMP tissue levels in dissected rat cavernous tissues.
Both cavernous tissue HO enzyme activity and cGMP 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).
The effects of PDE5 inhibitors in cavernous tissue are partly mediated through HO enzyme activity.
Journal of Sexual Medicine 08/2008; 5(7):1636-45. · 3.55 Impact Factor
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ABSTRACT: To assess the role of HO-1 in HCC progression and to study the expression of apoptotic factors represented by TNF-alpha, and Fas-L versus antiapoptotic and angiogenic factors represented by HO-1, TGF-beta, HGF, and VEGF in HCC compared to non cancerous cirrhotic liver.
Liver biopsies were taken from twelve patients with grade II HCC confined to the liver and twelve patients with non cancerous liver cirrhosis (served as control). RT-PCR of previous genes was evaluated.
HO-1, VEGF, HGF, and TNF-alpha genes were significantly increased (P<0.05) in HCC compared to control. Fas-L showed a significant decrease (P<0.05) in HCC compared to control. TGF-beta was higher in HCC than control but the difference was not statistically significant (P>0.05). HGF showed significant positive correlation with HO-1 (r=0.8217, P=0.001).
HCC is associated with increased expression of VEGF, HGF, and TGF-beta, and with suppression of Fas-L. In addition, HO-1 is highly significantly expressed in HCC. The significant positive correlation between HO-1 and HGF was first reported in Egyptian human liver biopsies, and this suggests that it may play a role in the progression of hepatocellular carcinoma.
Clinical biochemistry 08/2008; 41(12):1008-14. · 2.02 Impact Factor
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ABSTRACT: Heme oxygenase (HO) enzyme catalyzes the rate limiting step in oxidative degradation of heme to biliverdin and carbon monoxide (CO). CO has been shown to share many properties with nitric oxide (NO), including activation of guanyl cyclase, signal transduction, and gene regulation.
To assess the signaling pathways mediating cavernous tissues response to sildenafil citrate intake experimentally.
In dissected cavernous tissues; detection of HO-1, HO-2 and nueronal nitric oxide synthase (nNOS) gene expressions by reverse transcriptase polymerase chain reaction (RT-PCR), HO enzyme activity assay, HO-1, HO-2 protein detection by Western blot, cyclic guanosine monophosphate (cGMP) tissue levels by enzyme linked immunosorbent assay (ELISA) and histopathology.
Two hundred forty Sprague-Dawley rats divided into five equal groups were investigated: group (Gr) 1, controls received regular diet; Gr 2, received sildenafil citrate 4 mg/kg orally; Gr 3, received the same dose of sildenafil added to HO inducer, diferuloylmethane; Gr 4, received sildenafil added to HO inhibitor, zinc protoporphyrin, and Gr 5, received sildenafil kg orally by gastric tube. Gr 3 received the same dose of sildenafil added to HO inducer, added to nitric oxide synthase inhibitor, L-Nitroarginine methylester. Twelve rats from each group were sacrificed by cervical dislocation successively after 1/2, 1, 2, and 3 hours from the intake.
HO-2 gene expression was demonstrated in all groups. HO-1 was not expressed in controls, expressed in Gr 2, accentuated in Gr 3, and attenuated in Gr 4 and 5. These results were confirmed by Western blot. The nNOS was expressed in controls, increased in Gr 2 and 3, and decreased in Gr 4 and 5. HO enzyme activity and cGMP levels were significantly elevated in Gr 2, accentuated in Gr 3, and significantly decreased in Gr 4 and 5 compared to controls. Vasodilatations were observed in cavernous tissues of histopathologic sections of Gr 2 and increased in those of Gr 3.
Sildenafil citrate actions may be mediated by up-regulation of HO-1 gene expression.
Journal of Sexual Medicine 08/2007; 4(4 Pt 2):1098-107. · 3.55 Impact Factor
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ABSTRACT: To assess heme oxygenase-1 (HO-1) activity in the cavernous tissue of sildenafil citrate-treated rats.
One hundred and ninety-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-nitroarginine methyl ester (L-NAME). Twelve rats from each group were killed after 0.5 h, 1 h, 2 h and 3 h of drug administration. Then HO-1 activity, cGMP levels and NOS enzymatic activity in the cavernous tissues were estimated.
In cavernous tissue, HO-1 activity, 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).
The actions of PDE5 inhibitor sildenafil citrate in the cavernous tissue are partly mediated through the interdependent relationship between both HO-1 and NOS activities.
Asian Journal of Andrology 06/2007; 9(3):377-81. · 1.52 Impact Factor
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ABSTRACT: Human mesenchymal stem cells (hMSCs) are mostly studied for their potential clinical use. Little is known about the underlying molecular mechanisms that link hMSCs to the targeted inhibition of tumor cells. The present study was conducted to evaluate the tumor suppressive effects of human mesenchymal stem cells (hMSCs) on human hepatoma cell line (HepG2) and their signaling mechanisms. To fulfill this objective, the influence of hMSCs on genes concerned with apoptosis, mitogene-sis as well as on the proliferation of HepG2 cell line was investigated using either hMSCs-con-ditioned or using hMSCs and HepG2 co-culture conditioned media. Cell survival was evaluated using cell proliferation (MTT) assay kit. Gene expression of survivin, proliferating cell nuclear antigen (PCNA), β-Catenin, telom-erase and VEGF was assessed by real time reverse transcription-polymerase chain reac-tion (RT-PCR). HpG2 cells cultured with either hMSCs-conditioned media or with hMSCs&HepG2 co-culture conditioned media showed decreased proliferation and decreased expression of survivin, PCNA, β-Catenin and telomerase. However, both media had increased expression of VEGF. Treatment of HepG2 cells by either hMSCs conditioned media or by hMSCs and HepG2 co-culture con-dition media led to a significant decrease in cell proliferation and down regulation of genes concerned with antiapoptosis, mitogenesis, and cell proliferation. This indicates that hMSCs can suppress tumorigenesis through factors produced in their conditioned media.
