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Objectives: The aim of this study was to explore the relationship between cognitive dysfunction, neurodegeneration, and genetic factors among multiple sclerosis (MS) patients.Methods: Fifty patient...

Background and Objective: The liver is responsible for metabolism and detoxification of the most of components that enter the body. Once the liver became injured, its efficient treatment with famous chemical drugs was limited. Therefore, interest concerned the use of alternative medicines for the treatment of hepatic disease has been arisen. The present study was aimed to investigate the therapeutic effect of the two types of stem cells against chromosomal aberrations in bone marrow (BM) cells of rats treated with carbon tetrachloride (CCl4). Design and Method: BM-derived mesenchymal stem cells (MSCs) were isolated and propagated in culture for 2 weeks and were characterized morphologically. Human umbilical cord blood (UCB) cells were obtained after full-term caesarean delivery from healthy donors. Low-density mononuclear cells were separated over Ficoll-Paque, and CD34+ hematopoietic cells were isolated using a magnetic cell sorter. Rats were divided into 4 groups: control, CCl4, CCl4 plus MSC, and CCl4 plus CD34+. Liver tissue was examined histopathologically for all groups. Results: The results of the present study indicated a significant increase (p ＜ 0.05) in the number of metaphases with different types of chromosomal aberrations in CCl4 group. Treatment of the animals with BM-MSCs and UCB-CD34+ cells improved both genotoxicity and histopathological changes induced by CCl4.

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. 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 stannus mesoporphyrin (SnMP), and third one received a combined 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, SnMP inhibited 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, Drummond G, and Olszanecki R. Effect of hemin and carbon monoxide releasing molecule (CORM-3) on cGMP in rat penile tissue. J Sex Med 2008;5:336-343.

Aim: To access beta-endorphin levels in serum as well as seminal plasma in different infertile male groups. Methods: Beta-endorphin was estimated in the serum and seminal plasma by enzyme-linked immunosorbent assay (ELISA) method in 80 infertile men equally divided into four groups: non-obstructive azoospermia (NOA), obstructive azoospermia (OA), congenital bilateral absent vas deferens (CBVAD) and asthenozoospermia. The results were compared to those of 20 normozoospermic proven fertile men. Results: There was a decrease in the mean levels of betaendorphin in the seminal plasma of all successive infertile groups (mean ± SD: NOA 51.30 ± 27.37, OA 51.88 ± 9.47, CBAVD 20.36 ± 13.39, asthenozoospermia 49.26 ± 12.49 pg/mL, respectively) compared to the normozoospermic fertile control (87.23 ± 29.55 pg/mL). This relation was not present in mean serum level of beta-endorphin between four infertile groups (51.09 ± 14.71, 49.76 ± 12.4, 33.96 ± 7.2, 69.1 ± 16.57 pg/mL, respectively) and the fertile control group (49.26 ± 31.32 pg/mL). The CBVAD group showed the lowest seminal plasma mean level of betaendorphin. Testicular contribution of seminal beta-endorphin was estimated to be approximately 40%. Seminal betaendorphin showed significant correlation with the sperm concentration (r = 0.699, P = 0.0188) and nonsignificant correlation with its serum level (r = 0.375, P = 0.185) or with the sperm motility percentage (r = 0.470, P = 0.899). Conclusion: The estimation of beta-endorphin alone is not conclusive to evaluate male reproduction as there are many other opiates acting at the hypothalamic pituitary gonadal axis. (Asian J Androl 2006 Nov; 8: 709–712)

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.

Changes in gene expression and the enzymatic activity of inducible nitric oxide synthase (iNOS), heme oxygenase isoenzymes 1 and 2 (HO-1 and HO-2) and cyclic GMP (cGMP) tissue levels in the corpora cavernosa (CC) were investigated experimentally in sixty Sprague-Dawley rats subjected to either HO or NOS inducers or inhibitors. They were divided into 5 groups (n = 12/group): Control group, L-arginine group which received L-arginine as NOS inducer, L-nitroarginine methyl ester (L-NAME) group which received L-NAME as NOS inhibitor, Hemin group which received hemin as HO inducer and Zn protoporphyrin (ZnPP) group which received ZnPP as HO inhibitor. The results of this study demonstrated that there was co-induction as well as co-repression of iNOS and HO-1 gene expression using either the inducers or inhibitors of both enzymes, whereas HO-2 gene expression was found to be upregulated by the use of L-arginine only in L-arginine rat group. HO-2 gene expression was not changed by the use of either HO inducer, suppressor or NOS suppressor. cGMP tissue levels in CC was significantly elevated in rats receiving HO inducer (hemin) as well as in those receiving NOS inducer (arginine) as compared with the control group, with a significant elevation in cGMP levels in hemin group as compared with L-arginine group. The use of hemin appears to be more efficient and dominates the use of arginine in inducing HO activity as well as cGMP tissue levels. These data indicate that HO and its product carbon monoxide (CO) are supervising nitric oxide as a signaling molecule in erectile function. On the other hand, There was a significant decrease in cGMP levels in HO inhibitor and in NOS inhibitor groups with a significant decrease in its levels in ZnPP group as compared with L-NAME group. HO enzymatic activity was significantly elevated in the hemin group, whereas it was significantly decreased in ZnPP and in arginine rat groups in comparison with the other groups. NOS activity was significantly elevated in arginine group and in ZnPP group and it was significantly decreased in L-NAME and in hemin rat groups in comparison with the other rat groups. Conclusion: The use of either NOS or HO inducers can equally enhance erectile function via upregulation of gene expression of the two signaling genes involved in erection as well as through upregulation of the tissue levels of cGMP, the mediator of vasodilatation. Our data indicate that HO/CO system is supervising and dominating nitric oxide as a signaling molecule in erectile function. Thus, induction of HO may have therapeutic implications for management of erectile dysfunction.

Background Hyperglycemia induces activation of the c-Jun N-terminal kinase (JNK) pathway, which suppresses insulin gene expression and reduces DNA binding of pancreatic and duodenal homeobox factor (PDX)-1. This study aims to investigate the effects of a novel curcumin derivative (NCD) on JNK signaling pathway on insulin synthesis and secretion in streptozotocin (STZ)-treated rat pancreatic islets in vitro. Methods Isolated rat pancreatic islets were divided into five groups: untreated control group; group treated with NCD (10 μM); group exposed to STZ (5 mM); group treated with NCD (10 μM) and then exposed to STZ (5 mM); and group exposed to STZ (5 mM) and then treated with NCD (10 μM). The pancreatic islets from all groups were used for DNA fragmentation assays and quantitative assessments of the JNK, Pdx1, glucose transporter-2 (GLUT2), heme oxygenase (HO)-1, transcription factor 7-like 2 (TCF7L2), and glucagon-like peptide (GLP)-1 gene expression levels. The intracellular calcium, zinc, and the phosphorylated and total JNK protein levels were assessed. The insulin (secreted/total) and C-peptide levels were examined in islet culture medium. Results NCD protected pancreatic islets against STZ-induced DNA damage, improved total insulin (P = 0.001), secreted insulin (P = 0.001), and C-peptide levels (P = 0.001), normalized mRNA expressions of insulin, Pdx1, and GLUT2 (P = 0.0001), and significantly elevated calcium and zinc levels (P = 0.0001). All effects were significant when islets were treated with NCD before STZ (P = 0.05). JNK gene overexpression and JNK protein levels induced by STZ were significantly inhibited after NCD treatment of islets ( P = 0.0001). NCD-treated islets showed significantly elevated gene expressions of HO-1, TCF7L2, and GLP-1 (P = 0.0001), and these upregulated gene expressions were more significantly elevated with NCD treatment before STZ than after STZ (P = 0.05). Conclusions NCD improved insulin synthesis and secretion in vitro in isolated pancreatic islets treated with STZ through inhibition of the JNK pathway, up-regulation of the gene expressions of HO-1, TCF7L2, and GLP-1 and enhancing effects on calcium and zinc levels.

Introduction Vitamin D is one of the important hormones involved in Ca homeostasis. It is also essential for the prevention of osteoporosis and fractures. Vitamin D is important for maintaining many physiologic functions, such as optimal balance, muscle strength, and innate immunity. Vitamin D deficiency is associated with an increased risk for several types of cancer, as well as autoimmune and cardiovascular disorders. As the influence of diet on vitamin D status is minimal and most circulating vitamin D is derived from exposure to sunlight, elderly populations are greatly affected; they have marked limitations that hinder their exposure to sunlight as well as their feeding and nutritional habits. Objectives of the study The aim of this study was to assess vitamin D status in Egyptian geriatric, homebound, nursing home residents, and ambulatory elderly individuals. Patients and methods This study was carried out on 90 elderly male and female individuals divided into three groups: the first group included 30 homebound elderly individuals, the second group included 30 elderly individuals living in nursing homes, and the third group included 30 community-dwelling ambulatory elderly individuals. Results There were high statistically significant difference in the vitamin D levels between the groups studied, being the highest in group III, 158 (18–240) nmol/l, and the lowest in group II, 16 (4–194) nmol/l. Statistically significant differences were found in sun exposure, with good exposure in 60% of the individuals in group III. There were also statistically significant differences in the intake of vitamin D in diet, with good intake in 64.30% of the individuals in group III. Also, we found the highest waist circumference in group II (98.68±20.73 cm). Vitamin D showed a significant positive correlation with serum calcium in group II (ρ=0.199) and a positive correlation with aspartate transaminase (AST) in group III (ρ=0.418). Conclusion Elderly Egyptian individuals in nursing houses are at risk of developing vitamin D deficiency because of lack of exposure to sunlight, dietary problems, and or central obesity.

Background and objectives Autogenous bone grafts is considered to be the best choice for reconstructive surgery. Adipose Derived Stromal Cells (ASCs) represents a promising tool for new clinical concepts in supporting cellular therapy. The goal of our study was to investigate bone regeneration following application of autologous ASCs with or without Platelet-Rich Plasma (PRP) at dehiscence-type defects in alveolar bone in dogs. Methods and results Standardized buccal dehiscence defects (4× 3×3 mm) were surgically created in eighteen dogs, the defects were grafted with either ASCs -PRP, ASCs alone, or without grafting material. Three months later; a bone core was harvested from grafted and non grafted sites for histological, histochemical and histomorphometric assessment. There was no evidence of inflammation or adverse tissue reaction with either treatment. Defects grafted with ASCs-PRP showed a significantly higher result (p≤ 0.05), with a mean area % of spongy bone and compact bone of (64.96±5.37 and 837.62±24.95), compared to ASCs alone (47.65±1.43 and 661.92±12.65) and without grafting (33.55± 1.74 and 290.85±7.27) respectively. The area % of lamellated bone increased significantly reaching its highest level in group A followed by group B. Also a significant increase in area % of neutral mucopolysaccharides and calcified reactivity of Masson|s Trichrome stain in groups A and B compared to group C was obtained. Conclusions Our results suggest that, the addition of PRP to ASCs enhances bone formation after 3 months and may be clinically effective in accelerating postsurgical healing in both periodontal and maxillofacial surgical applications.

Human umbilical cord blood (UCB) cells have many advantages as grafts for cell transplantation. Here, we transplant UCB cells into injured liver fibrosis, investigated the hepatic potential of UCB cells both in vitro and in vivo. a CCl4 rat model with liver fibrosis was prepared. Human (UCB) CD34(+) stem cell was separated with MACS (magnetic cell sorting). Cells were cultured with and without hepatic differentiation medium. Rats were divided into 3 groups; group (1): control healthy, group (2): CCl4 injected rats and group 3: CCl4/CD34(+)injected rats with human differentiated and undifferentiated cells through intrahepatic (IH) and intravenous (IV) routes. A significant elevation was detected in serum albumin in CCl4/CD34(+) compared to the CCl4 group (p

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.

This work aimed to assess heme oxygenase (HO) enzyme activity relationship with different human semen parameters. One hundred and twenty men were divided according to their sperm count and clinical examination into: obstructive azoospermia (n = 20), nonobstructive azoospermia (NOA) (n = 25), oligozoospermia (n = 35) and normozoospermia (n = 40). Semen analysis, western blot for HO-1 and HO-2, and estimation of seminal plasma HO enzyme activity chemically in the form of bilirubin concentration were carried out. Seminal plasma HO enzyme activity was very low in OA specimens, low in NOA, moderate in oligozoospermia while higher in normozoospermia (mean +/- SD; 6.26 +/- 2.2, 81.4 +/- 35.5, 283.8 +/- 90.1, 657.4 +/- 227.6 pmol ml(-1) min(-1)) with significant differences. Western blot analysis demonstrated HO-2 expression in all studied groups whereas HO-1 was highly expressed in fertile normozoospermic group compared with other groups. There was positive correlation between seminal plasma HO enzyme activity and sperm concentration, sperm motility percentage, motile spermatozoa ml(-1) and sperm normal morphology per cent. It is concluded that HO enzyme activity in the human seminal plasma is related to spermatogenesis and sperm-motility processes.

We assessed survivin (an inhibitor of apoptosis) protein in the seminal plasma of infertile and fertile males.Seminal plasma survivin was estimated by enzyme-linked immunosorbent assay in 23 healthy fertile volunteers, 22 men with oligo-asthenozoospermia, 37 with nonobstructive azoospermia and 12 with obstructive azoospermia. Histopathology and testicular sperm extraction were done in testicular tissue biopsies from obstructive azoospermia and nonobstructive azoospermia cases.Mean seminal survivin was highest in fertile controls, less in oligo-asthenozoospermic cases and low in nonobstructive azoospermia cases with significant differences. In obstructive azoospermia cases seminal plasma survivin was absent. Seminal survivin positively correlated with sperm concentration and total sperm motility, and negatively correlated with the percent of sperm abnormal forms. Seminal survivin was detectable in nonobstructive azoospermia cases in which testicular sperm extraction was successful but absent in such cases when testicular sperm extraction was unsuccessful.Seminal survivin is testicular in origin. It is related to spermatogenesis and sperm motility processes. Seminal survivin was related to successful testicular sperm extraction in nonobstructive azoospermia cases.

Cyclic guanosine monophosphate (cGMP) levels can be regulated by heme oxygenase-1 and 2 (HO-1 and HO-2)-derived carbon monoxide (CO).Assessment of the effect of upregulating CO in rat corpora cavernosa (CC) on cavernous cGMP.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 stannus mesoporphyrin (SnMP), and third one received a combined hemin, CORM-3, and SnMP.In CC, HO-1 and HO-2 gene expression, Northern blot and Western blot, cGMP levels, and HO enzyme activity.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, SnMP inhibited the enhancing effect of CORM-3 and HO on erectile signaling molecules; i.e., HO-1 gene, enzyme activity, and cGMP.CORM-3- or hemin-mediated CO release could increase cavernous tissue cGMP.

To study the effect of mesenchymal stem cells (MSC) on experimental liver fibrosis in rats.MSC were derived from bone marrow obtained from femoral and tibial bones of male albino rats. MSC were separated, grown, and propagated in culture for 4 weeks and were characterized morphologically and by detection of CD29 by RT-PCR. They were then infused into the tail vein of female rats that received CCl4 injection to induce liver fibrosis. Rats were divided into 4 groups: control, CCl4, CCl4 plus MSC, and MSC. Liver tissue was examined histopathologically and liver functions (ALT and serum albumin) were estimated for all groups. Y-chromosome gene (sry) was assessed by PCR in liver tissue of the female rats to confirm uptake of the male stem cells. Hydroxyproline content in liver tissue was assessed by chemical methods and expression of the collagen gene (type I) was detected as a marker for liver fibrosis. Results of the present study showed that MSC have a significant antifibrotic effect as evidenced by the significant decrease in liver collagen gene expression as well as the decrease in hydroxyproline content in the CCl4/MSC group (p0.001) compared to the CCl4 group. The Y-chromosome gene (sry) was detected by RT-PCR in the CCl4/MSC group, but was not detected in control group and other groups. The CD29 gene was expressed in MSC culture, and this confirmed the efficiency of isolation and propagation of MSC in culture. With regard to liver function, there was also a significant improvement and elevation of serum albumin in the CCl4/MSC group compared to the CCl4 group (p0.05). As regard to the liver enzyme ALT, there was a decrease of its level in the CCl4/MSC group compared to the CCl4 group. However, this was statistically nonsignificant (p0.05). In conclusion, MSC have a potential therapeutic effect against the fibrotic process through their effect in minimizing collagen deposition in addition to their capacity to differentiate into hepatocytes.

Background: Major components of the renin-angiotensin system (RAS) such as angiotensin II (Ang-II), angiotensin converting enzyme (ACE), ACE2, Ang-II type 1 receptors (AT1R) and Ang-II type 2 receptors (AT2R) have been identified in human and rodent heart cells. Over-activation of this system has been reported to play a key role in diabetes. Methods: 72 male albino rats were divided into the following groups each containing 18 rats. Group 1:Control group, Group 2: Type 2 diabetic control rats, Group 3: Angiotensin Receptor Blocker (ARB)-protected diabetic rats and Group 4: Angiotensin Converting Enzyme Inhibitor (ACEI)- protected diabetic rats. At the end of experiment , half the number of rats in all groups was sacrificed and the heart excised and perfused according to the Langendorff technique. Mechanical performance of the left ventricle of the heart was determined by the systolic pressure, the diastolic pressure, the heart rate and the peak rate of maximum left ventricular pressure rise (dp/dt). These mechanical performances were monitored during pre-ischemic; ischemic and post-ischemic reperfusion phases. From the other group of rats (n=9), tissue was extracted from the heart for estimation of AT2R and ACE2 gene expression. Results: Treatment with ARBs and ACEIs significantly lowered blood glucose, insulin levels and homeostasis model assessment insulin resistance index (HOMA IR) compared to untreated diabetic rats. However, values did not return to control values. ARBs and ACEI improved myocardial performance and percentage recovery following ischemia reperfusion. The cardio protective effect was more pronounced in the ARBs group. This positively correlated with increased AT2R and ACE2 expression in all studied groups. However, there was no significant correlation between the level of AT2R and ACE2 expression in cardiac tissue. Conclusion: The use of ARBs and ACEIs in type 2 DM significantly offered cardio-protection against ischemia-reperfusion injury either through improving the diabetic condition or by increasing the expression of AT2R and/or ACE2 in cardiac tissue.

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.

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.