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The implication of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in the striking process of liver regeneration has been previously reported. However, their exact roles and downstream signals have not been utterly revealed. Therefore, the present study was conducted to explore whether inhibition of cyclooxygenase-2 (COX-2)-derived PGE2 by celecoxib and blocking of TXA2 action by seratrodast could alter the progression of liver regeneration after 70% partial hepatectomy (PHx) in rats. Celecoxib (20 mg/kg/day) and seratrodast (2 mg/kg/day) were given orally 1 h before PHx and then daily till the end of experiment (1, 3, or 7 days after the operation). Interestingly, celecoxib-treated rats showed a further increase in interleukin-6, p65 nuclear factor κB, and phosphorylated signal transducer and activator of transcription 3 as compared with PHx control rats. Furthermore, the liver contents of growth factors as well as β-catenin and cyclin D1protein expressions were also enhanced by celecoxib. Accordingly, celecoxib significantly improved hepatic proliferation as indicated by the increase in Ki67 expression and liver index. Contrariwise, seratrodast hindered the normal regeneration process and completely abolished the proliferative effect of celecoxib. In conclusion, TXA2 has a major role in liver regeneration that could greatly mediate the triggering effect of celecoxib on hepatocytes proliferation following PHx.

JNJ7777120, a histamine H4 receptor antagonist, was shown to be effective in different experimental settings of allergic inflammation, including contact hypersensitivity. Toll-like receptors (TLRs) are thought to function as a link between innate and adaptive immune responses to various haptens. Here, we studied the suppression of TLR signaling as a possible mechanism by which JNJ7777120 exerts its anti-inflammatory effects against the chemical hapten, fluorescein isothiocyanate (FITC). The potential anti-oxidant effect of JNJ7777120 in this model was also examined. Mice subjected to FITC sensitization and challenge showed significantly elevated plasma immunoglobulin E (IgE) level, ear interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-α), and thiobarbituric acid reactive substance (TBARS) contents as well as increased myeloid differentiation factor 88 (MyD88) gene expression, nuclear factor-kappa B p65 (NF-κB p65), and phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) protein expression. This was accompanied by enhanced ear myeloperoxidase (MPO) and eosinophil peroxidase (EPO) activities as well as diminished glutathione (GSH) content and superoxide dismutase (SOD) activity. JNJ7777120 treatment perceivably reversed these effects, denoting profound anti-inflammatory and anti-oxidant character of JNJ7777120 which was confirmed by its mitigation of FITC-induced pathological changes in mouse ear. JNJ7777120 additionally enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), providing a novel mechanism by which JNJ7777120 functions as an anti-oxidant in this model. To conclude, JNJ7777120 afforded a remarkable amendment of FITC skin insult by virtue of its anti-inflammatory and anti-oxidant effects; the mechanistic basis of these effects may include modulation of TLR and Nrf2 pathways.

Background Lipopolysaccharide (LPS), a component of the outer membrane of Gram-negative bacteria, is involved in the pathogenesis of sepsis. LPS administration induces systemic inflammation that mimics many of the initial clinical features of sepsis and has deleterious effects on several organs including the liver and eventually leading to septic shock and death. The present study aimed to investigate the protective effect of magnesium (Mg), a well known cofactor in many enzymatic reactions and a critical component of the antioxidant system, on hepatic damage associated with LPS-induced endotoxima in mice. Methods Mg (20 and 40 mg/kg, po ) was administered for 7 consecutive days. Systemic inflammation was induced 1 h after the last dose of Mg by a single dose of LPS (2 mg/kg, ip ) and 3 h thereafter plasma was separated, animals were sacrificed and their livers were isolated. Results LPS-treated mice suffered from hepatic dysfunction revealed by histological observation, elevation in plasma transaminases activities, C-reactive protein content and caspase-3, a critical marker of apoptosis. Liver inflammation was evident by elevation in liver cytokines contents (TNF-α and IL-10) and MPO activity. Additionally, oxidative stress was manifested by increased liver lipoperoxidation, glutathione depletion, elevated total nitrate/nitrite (NO x ) content and glutathione peroxidase (GPx) activity. Pretreatment with Mg largely mitigated these alternations. Conclusion Pretreatment with Mg protects the liver from the acute injury which occurs shortly after septicemia.

This study was conducted to evaluate the effect of mesenchymal stem cells (MSCs) and a novel curcumin derivative (NCD) on HepG2 cells (hepatoma cell line) and to investigate their effect on Notch1 signaling pathway target genes. HepG2 cells were divided into HepG2 control group, HepG2 cells treated with MSC conditioned medium (MSCs CM), HepG2 cells treated with a NCD, HepG2 cells treated with MSCs CM and NCD, and HepG2 cells treated with MSCs CM (CM of MSCs pretreated with a NCD). Expression of Notch1, Hes1, VEGF, and cyclin D1 was assessed by real-time, reverse transcription-polymerase chain reaction (RT-PCR) in HepG2 cells. In addition, HepG2 proliferation assay was performed in all groups. Notch1 and its target genes (Hes1 and cyclin D1) were downregulated in all treated groups with more suppressive effect in the groups treated with both MSCs and NCD. Also, treated HepG2 cells showed significant decrease in cell proliferation rate. These data suggest that modulation of Notch1 signaling pathway by MSCs and/or NCD can be considered as a therapeutic target in HCC.

Introduction Curcumin is involved in erectile signaling via elevation of cyclic guanosine monophosphate (cGMP). Aim Assessment of the effects of water‐soluble curcumin in erectile dysfunction (ED). Methods 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. Main Outcome Measures 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). Results 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. Conclusion Water‐soluble curcumin could enhance erectile function with more effectiveness and with more prolonged duration of action. Abdel Aziz MT, Motawi T, Rezq A, Mostafa T, Fouad HH, Ahmed HH, Rashed L, Sabry D, Senbel A, Al‐Malki A, and El‐Shafiey R. Effects of a water‐soluble curcumin protein conjugate vs. pure curcumin in a diabetic model of erectile dysfunction. J Sex Med 2012;9:1832–1850.

Introduction Curcumin is an inducer of heme oxygenase enzyme-1 (HO-1) that is involved in erectile signaling via elevating cyclic guanosine monophosphate (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 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. Main Outcome Measure Cavernous tissue HO enzyme activity, cGMP, and ICP. Results 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. Conclusion Water-soluble long-acting curcumin derivative could mediate erectile function via upregulating cavernous tissue cGMP. Abdel Aziz MT, El Asmer MF, Rezq A, Kumosani TA, Mostafa S, Mostafa 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 erectile signaling

N-methyl-d-aspartate (NMDA) receptor antagonists appear to enhance the anticonvulsant activity of antiepileptic drugs in several models of epilepsy. Therefore, the current study evaluates the modulatory effect of magnesium (Mg(2+)), a non-competitive NMDA receptor antagonist, on a subprotective dose of valproate (VPA) against pentylenetetrazol (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (60mg/kg, i.p.). The other three groups were pretreated with Mg(2+) (40mg/kg, p.o., 4weeks), single subprotective dose of VPA (100mg/kg, i.p.), or Mg(2+) with VPA, before PTZ injection. PTZ provoked clonic convulsions, reduced GABA content, deranged brain redox status, and elevated nitric oxide (NO). Neither the subprotective dose of VPA nor Mg(2+) alone guarded against clonic seizures invoked by PTZ, an effect that was achieved only by their combination and supported by a significant delay in seizure latency. Moreover, VPA leveled off glycine and aspartate, exerted no effect on glutamate, and unexpectedly reduced GABA and taurine levels. Mg(2+) alone or in combination showed the same pattern on the aforementioned amino acids, except for taurine. All regimens restored glutathione (GSH) and total antioxidant capacity (TAC); however, only VPA normalized NO level. This study demonstrates that Mg(2+) could enhance the antiepileptic efficacy of a subprotective dose of VPA, possibly by improving redox balance and modulation of some brain amino acids.

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.

Introduction Activation of the renin‐angiotensin system which is common in diabetes mellitus might affect heme oxygenase (HO‐1) gene expression. Aim 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 Asmer MF, Mostafa T, Atta H, Mahfouz S, Fouad H, Rashed L, Sabry D, Hassouna A, Abdel Aziz AT, Senbel A, and Demery A. Effects of losartan, HO‐1 inducers or HO‐1 inhibitors on erectile signaling in diabetic rats.

Introduction 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. Aim To assess CO signaling pathway for erectile function by reviewing published studies. Methods A systematic review of published studies on this affair based on Pubmed and Medical Subject Heading databases, with search for all concerned articles. Main Outcome Measures Documentation of positive as well as negative criteria of CO/HO signaling focused on penile tissue. Results 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. Conclusion 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. Abdel Aziz MT, Mostafa T, Atta H, Wassef MA, Fouad HH, Rashed LA, and Sabry D. Putative role of carbon monoxide signaling pathway in penile erectile function.

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 (P0.05) in HCC compared to control. Fas-L showed a significant decrease (P0.05) in HCC compared to control. TGF-beta was higher in HCC than control but the difference was not statistically significant (P0.05). 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.

Schistosomiasis is characterized by a unique form of periportal fibrosis and not cirrhosis. Heme oxygenase (HO-1) is a stress inducible molecule that could modulate the fibrogenic process in the murine model of schistosoma mansoni. In this study, the extent of heme oxygenase-1 gene expression was evaluated by RT-PCR in liver tissues of thirty mice infested with schistosoma mansoni after the 2nd, 4th, 6th, 8th and 10th weeks of infestation. Furthermore, the gene expression of some fibrogenic and antifibrogenic factors [pro α2 (I) collagen, laminin β1, transforming growth factor β (TGF-β), platelet derived growth factor (PDGF) and hepatocyte growth factor (HGF)], apoptotic factors (Fas L) and the transcriptional factor nuclear factor-κB (NF-κB) were also evaluated in liver tissues of the same animals by RT-PCR techniques. The PCR bands densities were semi-quantitated using Biometra gel documentation system. The present study showed that the gene expression of HO-1 coincided with the expression of NF-κB. Both were induced from the 2nd week post infestation and their PCR band density remained high till the 8th week with a slight decline at the 10th week. The gene expression of HO-1 paralleled the levels of HO activity. On the other hand, increase in gene expression of HGF and Fas L was detected only in the 2nd and the 4th weeks post infestation. This may suggest a down regulation of Fas L and HGF by the sustained increase in gene expression of HO-1 and/or NF-κB. Meanwhile, there is increase in the gene expression of the profibrogenic cytokines PDGF and TGF-β, starting in the 4th week (PDGF) and 6th week (TGF-β). They were however expressed at low levels at the 2nd and 4th weeks, respectively. Thus a direct effect of HO-1 on the expression of these cytokines cannot be sharply delineated. However, the expression of these cytokines preceded and then paralleled pro α2 (1) collagen gene expression, indicating their role in the fibrogenic process. Laminin gene expression increased from the 6th week and remained highly expressed till the 10th weeks. Thus the similar patterns of gene expression of HO-1 and NF-κB at the selected stages in murine schistosomiasis and the accompanying down regulation of the Fas L suggest that, as a stress inducible protein, HO-1 might be part of the protective mechanisms elicited by the acute phase response in Schistosoma mansoni infection possibly by protecting the cells against the consequences of oxidative stress (i.e. apoptotic and necrotic pathways). HO-1 gene expression may play a role in the modulation of the immunopathology of schistosomiasis and hence, indirectly influence fibrogenesis and prevent cirrhosis.

systemic endotoxemia and its relation to the fibrotic process were studied in two forms of hepatic disorders in experimental animals. The first was bilharzial liver disease, and the second was CCl4-induced cirrhosis. Endotoxin results were correlated with total hepatic collagen and tissue fibronectin, which are two indices of the fibrotic process. In schistosome-infested hamsters, early significant progressive elevation of plasma endotoxin was detected 6 weeks post-infestation and was correlated with significantly elevated total hepatic collagen and tissue fibronectin. In rats with CCl4-induced cirrhosis, significant rise in plasma endotoxin, total hepatic collagen, and tissue fibronectin was observed at the 10th week after injections. We noticed that removal of intestinal endotoxins by neomycin administration, induction of endotoxin tolerance, or enhancement of macrophage functions by interferon (IFN) injections resulted in significant lower levels of systemic endotoxemia and fibrogenesis in both rats and hamsters.

Background Curcumin exhibits anti-diabetic activities, induces heme-oxygenase-1 (HO-1) and is an inhibitor of transcriptional co-activator p300. A novel water soluble curcumin derivative (NCD) has been developed to overcome low invivo bioavailability of curcumin. We evaluated the effect of the NCD on signaling mechanisms involved in cardiomyocyte hypertrophy and studied whether its action is mediated via inducible HO-1. Materials and methods Rats were divided into controls, controls receiving NCD, diabetic, diabetic receiving NCD, diabetic receiving pure curcumin, diabetic receiving HO inhibitor, zinc protoporphyrin IX (ZnPP IX) and diabetic receiving NCD and ZnPP IX. NCD and curcumin were given orally. After 45 days, cardiac physiologic parameters, plasma glucose, insulin, glycated hemoglobin (GHb), HO-1 gene expression and HO activity in pancreas and cardiac tissues were assessed. Gene expression of p300, atrial natriuretic peptide (ANP) and myocyte enhancer factor 2 (MEF2A and MEF2C) were studied. Results NCD and curcumin decreased plasma glucose, GHb and increased insulin levels significantly in diabetic rats. This action may be partially mediated by induction of HO-1 gene. HO-1 gene expression and HO activity were significantly increased in diabetic heart and pancreas. Diabetes upregulated the expression of ANP, MEF2A, MEF2C and p300. NCD and curcumin prevented diabetes-induced upregulation of these parameters and improved left ventricular function. The effect of the NCD was better than the same dose of curcumin.

Aims The aim of this study was to determine the possible usefulness of the assay of the aminoterminal propeptide of type III procollagen and fibronectin in detecting connective tissue changes associated with gynecologic malignancies. Study Design Serum aminoterminal propeptide of type III procollagen and plasma fibronectin were measured in 36 women with gynecologic malignancies, 20 women with benign gynecologic tumors and 10 healthy women serving as controls. Results A significant serum propeptide was significantly high In the group with gynecologic malignancies and normal in the benign tumor group. The serum propeptide levels were related to of disease stage and presence of ascites in patients with ovarian carcinoma but not in those with cervical or endometrial carcinoma. In the follow-up study, a favorable clinical response was associated with normalizing propeptide levels whereas in rapidly progressive disease the levels fell initially but rose again. In partial response with ultimate progression, the propeptide concentration decreased but remained clearly above the normal range. No difference in plasma fibronectin was found among the malignant tumor, benign tumor and control groups. Conclusions The present study indicates that the aminoterminal propeptide of type III procollagen could serve as an additional, non specific marker to follow the clinical behavior of gynecologic malignancies and consequently of connective tissue metabolism reflecting tumor matrix interaction.

J Oral Pathol Med (2010) 39: 281–289 Background: Mesenchymal stem cells (MSCs), a subpopulation of adult somatic stem cells, are an attractive stem cell source in regenerative medicine because of their multipotentiality. In this study, the effects of MSCs transplantation on oral ulcer healing were examined. Methods: Mesenchymal stem cells were isolated from bone marrow aspirates of dogs by dish adherence and expanded in culture. Oral ulcers were induced by topical application of formocresol in the oral cavity of dogs. Either autologous MSCs or vehicle (saline) was injected around the ulcer. The healing process of the ulcer was monitored clinically and histopathologically. Gene expression of vascular endothelial growth factor (VEGF) was detected in MSCs by reverse transcription-polymerase chain reaction. Expression of VEGF and collagen genes was detected in biopsies from all ulcers. Results: Mesenchymal stem cells expressed mRNA for VEGF MSCs transplantation significantly accelerated oral ulcer healing compared with controls. There was increased expression of both collagen and VEGF genes in MSCs-treated ulcers compared with controls. Conclusion: Mesenchymal stem cells transplantation may help accelerate oral ulcer healing, possibly through the induction of angiogenesis by VEGF together with increased intracellular matrix formation as detected by increased collagen gene expression.

Both heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) have been shown to be involved in the progression of atherosclerosis. The relationship between HO-1 and VEGF gene expression and their proteins in endothelial cells from human atherosclerotic arterial specimens was investigated.The study included seventeen human arterial specimens with early and six specimens with advanced atherosclerotic lesions. Ten specimens were obtained from healthy young adults undergoing arterial reconstruction for trauma and were considered as non-atherosclerotic control. HO-1 and VEGF expressions as well as HO activity and VEGF protein content were measured in isolated endothelial cells (ECs).HO-1 expression and activity (5.3+/-2.1 nmol bilirubin/mg protein/h) were only present in ECs from advanced atherosclerotic lesions. VEGF expression was more strongly expressed in ECs from advanced lesion compared with early lesions and was absent in healthy arteries. VEGF protein (1.35+/-0.69 ng/mg) was only detected in advanced lesions. A significant positive correlation (r=0.9, p0.01) exists between HO activity and VEGF protein content in ECs of advanced lesions.This study demonstrated that HO-1 expression and activity in ECs are present only in advanced atherosclerosis whereas, VEGF expression is present in early as well as in advanced atherosclerosis and the degree of its expression increases with severity of atherosclerosis. This study suggests an association between HO activity and VEGF protein in human ECs from advanced atherosclerotic lesions.

The present study was conducted to investigate if the mechanism of human heme oxygenase-1 (HO-1) mediated angiogenesis was through the induction of vascular endothelial growth factor (VEGF). Also, the effect of HO-1 on the expression of transforming growth factor beta (TGF-beta),was studied in the presence and absence of HO-1 inducers. Rat lung microvessel endothelial cell line transduced with human HO-1 gene was subjected to cell culture (six separate experiments). mRNA extraction and reverse transcriptase polymerase chain reaction (RT-PCR) experiments, were performed to evaluate the expression of HO-1, VEGF, and TGF-beta in the presence and absence of HO inducers including H(2)O(2), endotoxin and snake venom metalloproteinase with disintegrin like activity(SnMP). ELISA technique was performed to evaluate the levels of the studied growth factors. The results of the study showed over expression of VEGF in endothelial cells transduced with HO-1 compared to control non-transduced endothelial cells. On the other hand, the expression of TGF-beta and its protein level were markedly inhibited in HO-1 transduced endothelial cells compared to control non-transduced cells. Endotoxin and SnMP showed more prominent effect on the expression of VEGF and suppression of TGF-beta in HO-1 transduced endothelial cells, suggesting that their effect is most probably mediated through induction of HO-1.

Background Diabetes mellitus type 1 is an autoimmune disorder caused by lymphocytic infiltration and beta cells destruction. Curcumin has been identified as a potent inducer of heme-oxygenase-1 (HO-1), a redoxsensitive inducible protein that provides protection against various forms of stress. A novel water soluble curcumin derivative (NCD) has been developed to overcome low in vivo bioavailability of curcumin. The aim of the present work is to evaluate the anti diabetic effects of the “NCD” and its effects on diabetes-induced ROS generation and lipid peroxidation in experimental type- 1 diabetes mellitus. We also examine whether the up regulation of HO-1 accompanied by increased HO activity mediates these antidiabetic and anti oxidant actions. Materials and methods Rats were divided into control group, control group receiving curcumin derivative, diabetic group, diabetic group receiving curcumin derivative and diabetic group receiving curcumin derivative and HO inhibitor ZnPP. Type-1 diabetes was induced by intraperitoneal injection of streptozotocin. Curcumin derivative was given orally for 45 days. At the planned sacrification time (after 45 days), fasting blood samples were withdrawn for estimation of plasma glucose, plasma insulin and lipid profile . Animals were sacrificed; pancreas, aorta and liver were excised for the heme oxygenase - 1 expression, activity and malondialdehyde estimation. Results NCD supplementation to diabetic rats significantly lowered the plasma glucose by 27.5% and increased plasma insulin by 66.67%. On the other hand, the mean plasma glucose level in the control group showed no significant difference compared to the control group receiving the oral NCD whereas, NCD supplementation to the control rats significantly increased the plasma insulin by 47.13% compared to the control. NCD decreased total cholesterol, triglycerides, LDL cholesterol and increased HDL cholesterol levels. Also, it decreased lipid peroxides (malondialdehyde) in the pancreas, aorta and liver. Conclusion The (NCD) by its small dose possesses antidiabetic actions and that heme oxygenase induction seems to play an important role in its anti-diabetic effects. NCD also improves the lipid profile and oxidative status directly, proved by decreasing lipid peroxides (malondialdehyde) in pancreas, liver & aorta. The new water soluble curcumin derivative still retains the essential potencies of natural curcumin.

Background: Curcumin, a polyphenol from turmeric, has potent anticancer properties in human cancer cell lines. Nevertheless, its multitargeting clinical application in cancer and other diseases is hampered by

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, mitogenesis as well as on the proliferation of HepG2 cell line was investigated using either hMSCs-conditioned 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, telomerase and VEGF was assessed by real time reverse transcription-polymerase chain reaction (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 condition 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.

Chronic renal failure (CRF) is a common disease with high morbidity and mortality. The inadequacy of current treatment modalities and insufficiency of donor organs for cadaveric transplantation have driven a search for improved methods of dealing with renal failure. This raises the concept of cell-based therapy using mesenchymal stem cells (MSCs). The purpose of this work is to evaluate the effect of MSCs in rats with CRF and to detect the level of B-cell lymphoma 2 (Bcl-2) and basic fibroblast growth factor (bFGF) as possible antiapoptotic and anti-inflammatory paracrine mediators of MSCs action. This study was carried on female albino rats, which were divided into 3 groups, control group, CRF group and CRF/MSCs group. MSCs were derived from bone marrow of male albino rats and were characterized morphologically and by RT-PCR for CD29. Serum urea, creatinine, Na, K, systolic blood pressure and 24-hour urinary albumin were estimated for all groups, Y-chromosome gene (Sry) was detected by PCR in renal tissue. Also Bcl-2 and bFGF were examined by RT-PCR in renal tissue of all studied groups and the kidney was examined pathologically. The results of this work showed that CRF rats receiving MSCs showed significantly lowered serum urea, creatinine and urinary albumin levels compared to the CRF group. Also improvement of serum Na and K was observed in CRF/MSCs group compared to CRF group. As regard Bcl-2 and bFGF they were highly expressed in renal tissue of CRF/MSCs group compared to the CRF group. The (Sry) gene was detected by PCR in the renal tissue of CRF/MSCs group. These results demonstrate a potential of MSCs to ameliorate the kidney function in rats with CRF possibly through the antiapoptotic and anti-inflammatory paracrine mediators of MSCs.

Twenty-seven patients with vitiligo took (Meladinine 8-methoxypsoralen) for 2 to 12 years. They were selected from those patients who, in an attempt to get a more rapid repigmentary response, exceeded the advised doses by ingesting from 7–16 tablets (equivalent to 70–160 mg) per day. These regimens were well tolerated. Hepatic and renal function were not affected.

Background Several studies highlight curcumin’s benefit as a hypoglycemic agent, however; a limited number of reports present the importance of curcumin in improvement of pancreatic islets in diabetes. The aim of the present study is to evaluate the antidiabetic effect of a novel curcumin derivative and its effect on pancreatic islet regeneration in type I diabetes-induced by STZ. Materials and methods Rats were divided into diabetic rats and diabetic rats treated orally with the novel curcumin derivative (NCD) for 40 days. Fasting blood samples were withdrawn periodically from all rats to estimate plasma glucose, insulin and C-peptide for 10 months. Histopathology was performed to allow the assessment of pancreatic islet morphology. Insulin and CD105 were detected immunohistochemically. Results In diabetic rats, the plasma glucose, insulin and C-peptide levels remained within the diabetic range for about 4 months, after which a gradual decrease in glucose and increase in insulin and C-peptide was observed, which reached almost normal levels after 10 months. NCD treated diabetic rats showed significantly lowered plasma glucose and increased plasma insulin and C-peptide levels. This was followed by a further significant decrease in plasma glucose and increase in plasma insulin and C-peptide after two months from oral administration of the NCD. The plasma insulin and C-peptide continued to increase for ten months reaching levels significantly higher than the basal level. Histopathological examination of diabetic rat pancreas revealed absence of islets of Langerhans, minimal adipose tissue infiltration and localized lymphocytic infiltrates. However, after 6 months of induction of diabetes, rat pancreas showed the appearance of small well formed islets and positive insulin cells but no CD105 positive cells. NCD treated rats showed the appearance of primitive cell collections, large insulin positive cells and CD105 positive cells in the adipose tissue infiltrating the pancreatic tissues. This was followed by the gradual appearance of insulin positive cells in the islets while, CD 105 positive cells remained in the adipose tissue. After 5 and 10 months from the onset of diabetes, rat pancreas showed, well developed larger sized islets with disappearance of primitive cell collections and CD 105 positive cells. Also, insulin positive islets of variable size with disappearance of insulin positive cells in adipose tissue were detected. Conclusion The NCD possesses antidiabetic actions and enhanced pancreatic islets regeneration.

Background Stem cell therapy holds a great promise for the repair of injured tissues and organs, including the kidney. We studied the effect of mesenchymal stem cells (MSC) on experimental diabetic nephropathy (DN) in rats and the possible paracrine signals that mediate their action. Materials and methods Rats were divided into controls, DN rats, DN rats receiving MSCs. MSCs were given in a dose of (106cells) by intravenous injection. After 4 weeks, 24 h urinary albumin, serum urea and creatinine concentrations, transforming growth factor β (TGF β), tumor necrosis factor α (TNFα), B-cell lymphoma 2 (bcl2) and Bax gene expression and vascular endothelial growth factor (VEGF) were assessed. Histopathology staining was performed. Results MSC therapy significantly improved 24 h urinary albumin, serum urea and creatinine concentrations, increased angiogenic growth factor VEGF, and anti-apoptotic protein bcl2 while decreased the pro-inflammatory TNF-α, fibrogenic growth factor TGF β, and pro-apoptotic protein Bax. The histopathology examination showed patchy areas of minimal necrosis and degeneration in renal tubules.

Background 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. Methods 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. Results Histopathological examination of liver tissue from animals which received DENA-CCl4 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. Conclusions 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.