Role of the cutaneous extraneuronal cholinergic system in the pathogenesis of psoriasis: a case-control study.

BACKGROUND: Although during recent years there have been considerable advances in elucidating the mechanisms of psoriasis pathogenesis, its full understanding is still distant. A cholinergic dysfunction has been proposed in the pathophysiology of some inflammatory and autoimmune diseases, including psoriasis. AIM: To determine tissue levels of acetylcholine (ACh) and its muscarinic and nicotinic receptors (mAChR and nAChR) in psoriasis vulgaris lesions in comparison with normal control skin. METHODS: This case-control study included 30 patients with psoriasis vulgaris and 30 controls. A 4-mm punch skin biopsy was taken from the psoriatic plaques of patients and normal skin of controls. ACh level was measured in tissues using the colorimetric method, while mAChR and nAChR gene expression was determined by real-time PCR. RESULTS: The level of ACh was significantly higher in patients (mean ± SD: 5.95 ± 2.69) than in controls (1.12 ± 0.34) (P < 0.001). mAChR and nAChR expressions were significantly higher in patients compared with the controls (P < 0.001). A significant positive correlation was detected between the expression of nAChR in patients and the duration of psoriasis (r = 0.46, P = 0.01), and the body mass index of the patients correlated positively with both nAChR (r = 0.40, P = 0.027) and mAChR expression (r = 0.448, P = 0.013). CONCLUSION: Abnormalities in the cutaneous extraneuronal cholinergic system could be involved in the pathogenesis of psoriasis. The high expression of nAChRs in patients with longer disease durations might represent an attempt by the body to regulate the inflammatory cascade in psoriatic lesions. The high expression of mAChR in psoriatic lesions may provide a link between psoriasis and obesity.

Cross-talk between apelin and vasopressin in response to different osmotic stimuli in type 2 diabetic rats.

Apelin, a peptide hormone that has been linked to insulin resistance, obesity and glucose metabolism, coexists with arginine vasopressin (AVP) in hypothalamic magnocellular neurons that control body fluid homeostasis. The significant correlation between serum glucose and serum osmolarity in uncontrolled DM indicates the need for adequate compensation, but how apelin and AVP contribute to this is still unsettled. This study aims to investigate the interaction between apelin and AVP in osmotic regulation in type 2 diabetes mellitus (T2DM), and to explore the underlying mechanism. Forty-eight adult male albino rats were divided into six groups: control (isotonic, ip 0.9% NaCl; hypotonic, ip distilled water; hypertonic, ip 2% NaCl) groups and T2DM (isotonic, hypotonic, hypertonic) groups. Serum levels of AVP, apelin, Na, glucose, serum and urine osmolarity were measured; kidney samples were taken for Aquaporin 2 channels (AQP2) and epithelial sodium channel gamma subunit (ENaCγ) gene expression. Hypothalamic tissue sections were used for immunohistochemical staining of apelin and AVP. Both in control and diabetic groups serum apelin, showed a significant negative correlation with serum AVP (r=-0.533, p≤ 0.001). Serum apelin and AVP were inversely proportional to their hypothalamic protein expression. Serum apelin and AVP were significantly higher in diabetic rats (P= 0.001) yet their percentage change in response to hypo and hyper-osmotic stimuli (1.5±0.7, -0.34±0.15 and -0.38±0.13, 1.95±0.36, respectively) was less pronounced when compared to control rats (3.28±0.52, -0.59±0.12 and -0.45±0.13, 2.58±0.93, respectively). Na and ENaCγ levels significantly increased in hypertonic rats, while AQP2 gene expression significantly increased in hypotonic rats. Both apelin and AVP reacted to osmotic stimuli in T2DM but with less sensitivity than in control rats. In spite of its abnormal increased levels in diabetic rats, apelin maintained its role through counteracting AVP action.

Study of the prevalence of 5 HT-2C receptor gene polymorphisms in Egyptian patients with lifelong premature ejaculation.

We investigated the prevalence of 5HT2C receptor gene polymorphisms in Egyptian patients with lifelong premature ejaculation. A total of 350 participants were enrolled in a prospective study. Two hundred and forty-five cases with lifelong premature ejaculation joined this study, in addition to 105 controls. We instructed the partners of the cases to measure the IELT of the first intercourse only using a stopwatch for 1 month. Genotyping was carried out at the end of the study. The results showed that the majority of the patients and controls were Cys/Cys. A highly significant statistical association was found between the studied gene polymorphisms and IELT among cases (p-values = .009). The study emphasised the potential role of 5HT2C receptor gene polymorphisms in patients with lifelong premature ejaculation.

In vitro evaluation of the human gingival fibroblast/gingival mesenchymal stem cell dynamics through perforated guided tissue membranes: cell migration, proliferation and membrane stiffness assay.

BACKGROUND: Migration of gingival fibroblasts/gingival mesenchymal stem cells through macro-perforated barrier membranes may allow them to participate positively in periodontal regeneration. The optimal guided tissue membrane perforation diameter that could favor maximum cell migration into the defect area and at the same time act as an occlusive barrier for gingival epithelium and its associated gingival extracellular matrix component is not yet identified. MATERIAL AND METHODS: Cultured human gingival fibroblasts/gingival mesenchymal stem cells were placed in the upper chambers of 12-well collagen-coated polytetrafluoroethylene transwells, which were manually perforated with 0.2, 0.4 and 0.7 mm sized pores. The lower chambers of the transwells received blood clot as an attraction medium. The number of cells that have migrated to the lower chambers was calculated. Proliferation of these cells was evaluated using MTT assay. Scanning electron microscopy images were obtained for the lower surfaces of the transwell membranes. Perforated bovine collagen membranes (Tutopatch® ) were subjected to mechanical testing to determine the tensile strength and modulus of elasticity. RESULTS: Group 3 (0.7 mm) showed significantly higher values for cell migration and proliferation. All groups showed a small degree of extracellular matrix migration through membrane perforations. Scanning electron microscopy evaluation revealed variable numbers of cells in fibrin matrices located mainly around the pore edges. There were non-significant differences between groups regarding mechanical properties. CONCLUSIONS: The present study demonstrated that macro-membrane perforations of 0.2, 0.4 and 0.7 mm are suitable pore diameters that could maintain membrane stiffness and allow for cellular migration. However, these membrane perforation diameters did not allow for total gingival connective tissue isolation.

MicroRNAs in cutaneous lichen planus.

Lichen planus (LP) is a chronic, inflammatory, papulosquamous, autoimmune disease. The pathogenesis of LP appears to be complex, with interactions between genetic, environmental and lifestyle factors. MicroRNAs (miRNAs) are short RNAs encoded in both protein coding and noncoding areas of the genome, and have been found to be involved in the pathogenesis of some inflammatory skin diseases. The aim of this study was to map the levels of miRNA (miR-)-203 and miR-125b in cutaneous LP to evaluate their possible role in the pathogenesis of the disease. In total, 40 patients with classic cutaneous LP and 40 age- and sex- matched healthy controls (HCs) were enrolled in this study. Punch biopsies (4 mm) were taken from cutaneous LP lesions of patients and from normal skin of HCs. miRNA-203 and miRNA-125b mRNA expression was estimated by reverse transcription PCR. Our analysis revealed a significantly (P < 0.001 for both) lower expression of both miR-203 and miR-125b mRNA in the LP than in the HC biopsies. No relationship was found between expression of miR-203 or miR-125b and either age, sex, presence of mucosal lesions or positivity for HCV antibodies. miR-125b and miR-203 could be involved in the pathogenesis of cutaneous LP.

Toll-like receptor (TLR)7 expression in mycosis fungoides and psoriasis: a case-control study.

BACKGROUND: Toll-like receptors (TLRs) have been implicated in various dermatological diseases. TLR agonists have the capacity to potently activate the innate immune cells of patients with advanced, refractory, cutaneous T-cell lymphoma (CTCL). AIM: To detect TLR7 gene expression in mycosis fungoides (MF) (a neoplastic skin condition) and to compare it with psoriasis (an inflammatory skin condition) in an attempt to clarify the pathogenic role played by TLR7 in both conditions. METHODS: This case-control study enrolled 28 patients with MF: 30 patients with psoriasis, and 30 age- and sex-matched healthy controls (HCs). A 4-mm punch skin biopsy was obtained from lesional skin of patients and from normal skin of HCs for detection of TLR7 gene expression using real-time PCR. RESULTS: Mean TLR7 level in patients with MF (0.4 ± 0.23) was significantly lower than in patients with psoriasis (1.49 ± 0.46) and in HCs (1.22 ± 0.44) (P < 0.001), and mean TLR7 level in patients with psoriasis was significantly higher than in HCs (P < 0.03). Based on MF staging, 21.4% of patients had stage Ia, 28.6% had stage Ib, 28.6% had stage IIa and 21.4% had stage IIb disease. Comparing the TLR7 levels in relation to MF staging revealed the lowest mean value was in stage IIb and highest mean value in stage Ia, and this was significant (P < 0.001). CONCLUSION: Disturbed innate immunity might play a role in the pathogenesis of neoplastic and inflammatory skin conditions. TLR7 could be useful as a prognostic factor in MF.

Possible role of proenkephalin in psoriasis.

BACKGROUND: Psoriasis is a common chronic skin disease that can also affect the mucous membranes and joints. It is multifactorial in origin, occurring in genetically predisposed individuals, and triggered by various endogenous and exogenous factors. Proenkephalin (PENK) is an endogenous opioid polypeptide hormone that acts on specific opiate receptors found on nerve and mucosal cells, and on various cells in the immune system. PENK receptors are expressed on skin cells, and their activation can regulate keratinocyte and melanocyte activities. PENK expression has been found to be increased in keratinocytes in psoriatic skin, and together with its inflammatory basis, this suggests that PENK may be regulated by inflammatory stimuli. AIM: To assess the possible role of PENK in the pathogenesis of psoriasis and to assess if it is related to the severity of psoriatic lesions. METHODS: Serum and tissue PENK levels were estimated in 20 patients with psoriasis vulgaris, and compared with those of 20 healthy controls (HCs). RESULTS: PENK levels were found to be significantly increased both in serum and in psoriatic lesions in patients compared with HCs. No significant correlation was found between PENK levels and patient age, disease duration or disease severity (Psoriasis Area and Severity Index). CONCLUSION: Our results support the role of PENK in the aetiopathogenesis of psoriasis, and indicate that giving anti-PENK drugs in addition to current antipsoriatic therapies might be of value in treating this common chronic skin disease.

The role of cyclooxygenase-2 and prostaglandin E2 in the pathogenesis of cutaneous lichen planus.

BACKGROUND: Lichen planus (LP) is an inflammatory disease of the skin and mucous membranes. Autoimmunity has been suggested as a possible cause of this disease. The cyclooxygenase enzymes (COX-1, COX-2) are the key enzymes in the conversion of arachidonic acid into prostaglandins. Prostaglandin E2 (PGE2), a key product of COX-2, has an immunomodulatory role. AIM: To map levels of COX-2 and PGE2 in cutaneous LP lesions and evaluate their role in the pathogenesis of the disease. METHODS: In total, 31 patients with classic cutaneous LP and 30 age- and sex-matched healthy controls were enrolled. Skin biopsies were taken from the lesional and nonlesional skin of patients, and from the normal skin of controls. COX-2 mRNA expression was detected by real-time reverse transcription quantitative PCR, and PGE2 was detected by ELISA in skin biopsies from patients and controls. RESULTS: Our analysis revealed a significantly higher expression of COX-2 mRNA and PGE2 in the LP skin biopsies compared with the control biopsies (P < 0.001 and P < 0.001, respectively). Lesional biopsies showed significantly higher expression of COX-2 mRNA and PGE2 compared with nonlesional biopsies. The levels of COX-2 and PGE2 were not found to be correlated with age, sex or disease duration. CONCLUSIONS: COX-2 and its product PGE2 are strongly expressed in LP skin lesions, indicating that they have a role in the pathogenesis of LP through their immunomodulatory effects.

Seminal plasma oxytocin and oxidative stress levels in infertile men with varicocele.

This study aimed to assess seminal plasma oxytocin (OT) and oxidative stress (OS) levels in infertile men with varicocele (Vx). A total of 131 men were divided into fertile men (n = 20), fertile men with Vx (n = 17), infertile men without Vx (n = 40) and infertile men with Vx (n = 54). OT, malondialdehyde (MDA) and glutathione peroxidase (GPx) were estimated in seminal plasma. Mean levels of seminal OT, MDA were significantly decreased, and the mean level of GPx was significantly increased in fertile men with/without Vx compared with infertile men with/without Vx. Mean levels of OT, MDA were increased, and mean level of GPx was significantly decreased in Vx grade III cases compared with Vx grades I, II cases and in bilateral Vx cases compared with unilateral Vx. There was significant negative correlation between seminal OT with sperm count, sperm motility, seminal GPx and significant positive correlation with sperm abnormal forms, seminal MDA. It is concluded that seminal OT is significantly decreased in fertile men with/without Vx compared with infertile men with/without Vx. Seminal OT demonstrated significant negative correlation with sperm count, sperm motility, seminal GPx and significant positive correlation with sperm abnormal forms, seminal MDA. Seminal OT is associated with Vx grade and its bilaterality.

Glutathione-S-transferase-oxidative stress relationship in the internal spermatic vein blood of infertile men with varicocele.

This study aimed to assess glutathione-S-transferase (GST) enzyme- oxidative stress (OS) relationship in the internal spermatic vein (ISV) of infertile men associated with varicocele (Vx). Ninety five infertile oligoasthenoteratozoospemic (OAT) men associated with Vx were subjected to history taking, clinical examination and semen analysis. During inguinal varicocelectomy, GST, malondialdehyde (MDA) and glutathione peroxidase (GPx) were estimated in the blood samples drawn from ISV and median cubital veins. The mean levels of GST, GPx were significantly decreased and the mean level of GPx was significantly increased in the ISV compared with the peripheral blood. The mean level of GST and GPx in the ISV was significantly decreased, and the mean level of MDA was significantly increased in Vx grade III compared with Vx grade II cases. There was nonsignificant difference in the mean level of GST in the ISV in unilateral Vx cases compared with bilateral Vx cases. There was significant positive correlation of GST with sperm count, sperm motility, GPx and significant negative correlation with sperm abnormal forms, MDA. It is concluded that ISV of infertile men associated with Vx has decreased levels of GST compared with peripheral venous circulation that is correlated with both OS and Vx grade.

Transplantation of bone marrow-derived mesenchymal stem cells ameliorated dopamine system impairment in a D-galactose-induced brain ageing in rats.

BACKGROUND: Ageing is the primary risk factor for Parkinson's disease. Progressive motor and coordination decline that occurs with ageing has been linked to nigrostriatal dysfunction. Few studies have investigated the efficacy of mesenchymal stem cells in ameliorating the structural and functional alterations in the ageing nigrostriatal system. This study is the first to evaluate the effects of intravenous injection of bone marrow-derived mesenchymal stem cells (BMMSCs) in a D-galactose- induced rat model of nigrostriatal ageing. MATERIALS AND METHODS: BMMSCs were intravenously injected once every 2 weeks for 8 weeks. The transplanted cells survived, migrated to the brain, and differentiated into dopaminergic neurones and astrocytes. RESULTS: BMMSC transplantation improved locomotor activity, restored dopaminergic system function, preserved atrophic dopaminergic neurones in the substantia nigra, exerted antioxidative effects, and restored neurotrophic factors. CONCLUSIONS: Our findings demonstrate the efficacy of BMMSC injection in a nigrostriatal ageing rat model, and suggest that these cells may provide an effective therapeutic approach for the ageing nigrostriatal system.

DNA polymorphisms and tissue cyclooxygenase-2 expression in oral lichen planus: a case-control study.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disorder defined as a precancerous condition. Special attention has been paid to the expression of cyclooxygenase-2 (COX-2) and its potential role in development of oral squamous cell carcinoma. The identification of single nucleotide polymorphisms that affect gene function or expression and contribute to disease predisposition has become a major area of investigation toward understanding the mechanisms for cancer. OBJECTIVE: The objective of this study is to investigate the association between the COX-2 765G>C gene polymorphism, tissue COX-2 expression and the development of OLP as a chronic inflammatory condition. METHODS: This study was done on 50 patients with OLP and 50 healthy controls. COX-2 activity was assessed by measuring tissue prostaglandin E (PGE)2 levels by enzyme immunometric assay kit. COX-2 765G>C gene polymorphism was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by restricted fragment length polymorphism (RFLP). RESULTS: OLP patients showed statistically significant higher mean PGE2 than the control group. We did not observe any statistically significant differences in genotype distribution or allele frequency between the patients and the control group (P > 0.05). Odds ratio showed no statistically significant association between COX-2 765G>C polymorphism and lichen planus. CONCLUSION: The present evidence thus indicates that variation in the COX-2 gene is unlikely to be of relevance to the aetiology of OLP. As this is the first report concerning the COX-2 -765G>C gene polymorphism and the risk of OLP, additional studies with larger sample size will be required to confirm these findings.

Preventive effects of bone marrow-derived mesenchymal stem cell transplantation in a D-galactose-induced brain aging in rats.

BACKGROUND: Aging is a complex process accompanied by numerous morphological, functional, and metabolic impairments in the brain, and a critical risk factor involved in the increasing incidence of neurodegenerative diseases. Few studies have evaluated the efficacy of different sources of mesenchymal stem cells (MSCs) in ameliorating the early morphological and functional alterations in the aging brain. This study, for the first time, evaluated the potential efficacy of intravenous injection of bone marrow-derived mesenchymal stem cells (BMMSCs) in a D-galactose-induced rat model of brain aging. MATERIALS AND METHODS: BMMSCs (1 × 106) were intravenously injected into brain aging model rats once every 2 weeks for 8 weeks. RESULTS: The transplanted cells survived and migrated to the brain, and differentiated into astrocytes and neurons, including choline acetyltransferase neurons. BMMSC transplantation improved locomotor activity and cognitive functions, restored cholinergic system function, protected atrophic cholinergic neurons in the basal forebrain, induced antioxidative effects and restored neurotrophic factors, and modulated hippocampal synaptic plasticity by upregulating PSD95 and Egr1 expression. CONCLUSIONS: Our findings demonstrated the efficacy of BMMSC injection in an aging rat model and suggest that these cells may be developed into an effective cell therapy for the aging brain.

The extent of involvement of ouabain, hippocampal expression of Na+/K+-ATPase, and corticosterone/melatonin receptors ratio in modifying stress-induced behavior differs according to the stressor in context.

The aim of this study was to assess the effect of two types of stressors, regarding the extent of involvement of ouabain (OUA), hippocampal sodium/potassium ATPase (NKA) expression, and the hippocampal corticosterone receptors (CR)/melatonin receptors (MR) expression ratio, on the behavioral and cardiovascular responses and on the hippocampal cornu ammonis zone 3 (CA3) and dentate gyrus (DG). Thirty adult male Wistar albino rats aged 7-8 months were exposed to either chronic immobilization or a disturbed dark/light cycle and treated with either ouabain or vehicle. In the immobilized group, in the absence of hippocampal corticosterone (CORT) changes, rats were non-responsive to stress, despite experiencing increased pulse rate, downregulated hippocampal sodium/potassium pump, and enhanced hippocampal CR/MR expression ratio. Prolonged darkness precipitated a reduced upright attack posture, with elevated CORT against hippocampal MR downregulation. Both immobilization and, to a lesser extent, prolonged darkness stress resulted in histopathological and ultrastructural neurodegenerative changes in the hippocampus. OUA administration did not change the behavioral resilience in restrained rats, despite persistence of the underlying biochemical derangements, added to decreased CORT. On the contrary, with exposure to short photoperiods, OUA reverted the behavior towards a combative reduction of inactivity, with unvaried CR/MR and CORT, while ameliorating hippocampal neuro-regeneration, with co-existing NKA and MR repressions. Therefore, the extent of OUA, hippocampal NKA expression, and CR/MR expression, and subsequent behavioral and cardiac responses and hippocampal histopathology, differ according to the type of stressor, whether immobilization or prolonged darkness.

Stem cell therapy targets the neointimal smooth muscle cells in experimentally induced atherosclerosis: involvement of intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM).

Smooth muscle cells (SMCs) are currently considered a central pivotal player in pathogenesis and development of atherosclerotic lesions. As consequence of vascular injury, SMCs migrate from the tunica media into the tunica intima layers where they contribute to neointimal formation by converting into foam cells and producing pro-inflammatory and oxidative stress markers. We targeted the replacement of neointimal SMCs by using the mesenchymal stem cells (MSCs) therapy in experimentally induced atherosclerosis in an attempt to improve the atherosclerotic lesion and its concomitant complications. Rats were divided into 4 groups (n=20). Control group: rats kept on a standard chow diet; atherosclerotic group: rats received the atherogenic diet; stem cells-treated group: rats were injected with CD34+ stem cells (6×106 cells in 0.5 mL PBS in rat tail vein) and maintained on the atherogenic diet; and resveratrol-treated group: rats were supplemented orally with resveratrol at a dose level 3 mg/kg per day and the atherogenic diet. After 12 weeks, rats were euthanized, blood samples were collected for separation of serum, and abdominal aortas were excised for further biochemical, molecular, and histopathological investigations. We used resveratrol, the well-established anti-atherosclerotic drug, as a benchmark to assess the efficacy of stem cell therapy. MSCs treatment revealed significant amelioration in both histopathological and biochemical patterns as evidenced by decreased foam cells formation, ICAM-1, VCAM, M-CSF, iNOS, COX-2, and TNF-α. We concluded that MSCs therapy significantly replaced the neointimal SMCs and decreased adhesion molecules as well as the oxidative and inflammatory markers in atherosclerosis.

The role of bone marrow-derived mesenchymal stem cells in treating formocresol induced oral ulcers in dogs.

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.

Therapeutic role of bone marrow mesenchymal stem cells in diabetic neuronal alternations of rat hippocampus.

BACKGROUND: As the hippocampus is the main brain region for many forms of learning and memory functions and is acutely sensitive to blood glucose changes, diabetes mellitus, which is a serious metabolic disease, is often accompanied by learning and memory deficits. Through scientific literatures, mesenchymal stem cells (MSCs) promote functional recovery in rats with traumatic brain injury, so the present work was conducted to study MSCs as a possible treatment for the diabetic neuronal degeneration and functional impairment of rat hippocampus. MATERIALS AND METHODS: It was carried out using male albino rats: non-diabetic control groups (4, 8, 12 weeks) (n = 15), diabetic groups by i.v. injection of streptozotocin for (4, 8, 12 weeks) (n = 15) and MSCs treatment to diabetic groups for (8, 12 weeks) (n = 10). Hippocampal learning and memory functions were assessed by the Morris Water Maze test and its results were statistically analysed. The rat hippocampal regions (CA1 and CA3) were subjected to histological, ultrastructural examination and morphometrical analyse of pyramidal neurons. RESULTS: Neurons of the diabetic groups showed disturbed function and architecture; shrunken hyperchromatic nuclei and vacuolated eosinophilic cytoplasm (apoptotic changes) also MSCs treatment improved hippocampal learning and memory functions plus its architectural changes; increasing populations and normal regular distribution. CONCLUSIONS: It can be concluded that diabetic hippocampal neuronal alternations and functional impairment can be ameliorated by MSCs treatment.

α-Lipoic acid and amlodipine/perindopril combination potentiate the therapeutic effect of mesenchymal stem cells on isoproterenol induced cardiac injury in rats.

Cardiac injury is a dangerous disease and become a greater issue in the forthcoming decades. The ultimate goal is to prevent the progression of heart failure and apoptotic processes. Cardiac tissue may regenerate itself but to certain extent depending on the number of resident stem cells that is limited. Thus, research had been focused on bone marrow derived stem cells (BM-MSCs) as a promising therapy in different types of tissues, including the heart. This study is designed not only to assess the therapeutic effect of BM-MSCs but also to improve their therapeutic effect in combination with antioxidant α-lipoic acid (ALA) and antihypertensive therapeutic drug form (AP) against isoproterenol-induced cardiac injury and compared with that of BM-MSCs alone. Cardiac injury was induced in 70 male rats by Isoproterenol (ISO was injected s.c. for four consecutive days). Experimental animals were divided into six ISO-treated groups beside a control non treated one. The six ISO-treated groups were divided into: ISO group, ISO+BM-MSCs group, ISO+ALA group, ISO+AP group, ISO+ALA+AP group and ISO+ALA+AP+BM-MSCs group, the last five groups were treated with the examined materials after one week of ISO injection. Isoproterenol significantly increased serum CK-MB, LDH activities, Troponin1 and TNF-α. Oxidative stress is evidenced by the increased MDA, NO and Caspase-3 activity associated with significant reduction of GSH content and SOD activity in cardiac tissue. Furthermore, mRNA expression of NFκB and iNOS were significantly up regulated and eNOS mRNA expression was down regulated. Administration of BM-MSCs, ALA and AP alone significantly mitigated the induced cardiac injury. Concomitant administration of ALA and AP after BM-MSCs induced a more pronounced improving effect on cardiac functions. In conclusion, the concomitant administration of ALA and AP after BM-MSCs infusion increases the cellular antioxidant levels of cardiac tissue that improves the repairing function of BM-MSCs.

The effect of nitro-oleic versus losartan in diabetic nephropathy: modulation of parathyroid hormone-related protein.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) involvement in the mechanisms related to angiotensin II (AngII)-induced renal injury has become an emerging concern. The current study was thus designed to compare the possible preventive and therapeutic effect of AngII antagonists, losartan and nitro-oleic (NO2-OA) acid, on diabetic nephropathy (DN) and evaluate their effect on PTHrP modulation as well as on the functional and histopathological parameters in the kidney of diabetic rats. MATERIALS AND METHODS: Forty eight adult male Sprague Dawley rats were divided into control group, DN group, pre-diabetic nephropathy (pre-DN) losartan group, pre-diabetic nephropathy nitro-oleic acid (pre-DN NO2-OA) group, post-diabetic nephropathy (post-DN) losartan and post-diabetic nephropathy nitro-oleic acid (post-DN NO2-OA) groups. At the end of the study, systolic blood pressure (SBP), serum fasting glucose, glomerular filtration rate (GFR), urea, urea albumin excretion (UAE), serum angiotensin, renal PTHrP gene expression and correlations between PTHrP and SBP, serum glucose, AngII and kidney functions were evaluated. Histo- logical examination, Masson's trichrome, periodic acid-Schiff staining as well as morphometric analysis and histopathological scoring for tubular and glomerular parameters have been carried out. RESULTS: Prophylactic losartan and NO2-OA were associated with improvement in SBP, serum glucose, urea, GFR, UAE, with reduction in serum AngII and PTHrP overexpression observed in diabetic kidney. Treatment with losartan and NO2-OA showed the same effect except that post-DN NO2-OA showed no significant effect regarding kidney function. Strong correlations were observed between PTHrP and SBP, serum glucose, AngII and kidney functions. Histopathological results revealed obvious improvement in glomerulosclerosis, vascular and tubular injury parameters in prophylactic groups especially with losartan. CONCLUSIONS: Both pre and post-DN losartan, NO2-OA may have a potential role in protection and regression of DN through reduction of PTHrP overexpression.

Effects of occupational exposure to aluminium on some oxidative stress and DNA damage parameters.

AIM: The aim of this work was to investigate the relationships between aluminium levels, oxidative status and DNA damage in workers occupationally exposed to aluminium. SUBJECTS AND METHODS: This study was conducted in a secondary aluminium smelter. It included 96 male workers occupationally exposed to aluminium fume and dust compared to 96 male nonexposed individuals. Full history and clinical examination were done for all participants. Laboratory investigations in the form of serum aluminium, total antioxidant capacity (TAC), urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and comet assay test were performed. RESULTS: Serum aluminium level ranged from 4 to 30 µg/L of median: 10 µg/L; urinary 8-OHdG ranged from 2.7 to 17.2 ng/mg creatinine of median: 7.6 ng/mg creatinine; comet tail length (CTL) ranged from 19.7 to 50.5 µm of median: 45 µm, were statistically significantly increased in the exposed group compared to nonexposed group. In exposed workers, a statistically significant positive correlations were found between serum aluminium level and urinary 8-OHdG ( r = 0.75, p < 0.001); aluminium level and CTL ( r = 0.71, p < 0.001); and urinary 8-OHdG and CTL ( r = 0.71, p < 0.001). There was a statistically significant negative correlation between serum aluminium and TAC ( r = -0.76, p < 0.001). CONCLUSION: Occupational exposure to aluminium in secondary aluminium smelters was related to the induction of oxidative stress and DNA damage. This may promote the development of adverse health hazards in the exposed workers.