The Emerging Role of Circular RNA Homeodomain Interacting Protein Kinase 3 and Circular RNA 0046367 through Wnt/Beta-Catenin Pathway on the Pathogenesis of Nonalcoholic Steatohepatitis in Egyptian Patients.

Background: Non-alcoholic fatty liver disease is a major problem worldwide that needs non-invasive biomarkers for early diagnosis and treatment response assessment. We aimed to assess the correlation between circRNA-HIPK3 and miRNA-29a expression and its role as miRNA-29a sponge, as well as the correlation between circRNA-0046367 and miRNA-34a expression and its role as miRNA-34a sponge and their effect on regulation of the Wnt/ß catenin pathway, which may provide a new target for treatment of non-alcoholic steatohepatitis. Methods: the research was performed on 110 participants: group (I): fifty-five healthy donors served as controls and group (II): fifty-five patients with fatty liver pattern on abdominal ultrasound. Lipid profile and liver functions were assessed. RT-PCR was performed to assess the RNAs: circRNA-HIPK3, circRNA-0046367, miRNA-29a, miRNA-34a and Wnt mRNA gene expression. ELISA was performed to determine ß-catenin protein levels. Results: miRNA-34a and circRNA-HIPK3 expression were significantly greater, while miRNA-29a and circRNA-0046367 expression were significantly less, in patients than in controls. Wnt/ß-catenin regulated by miRNA-29a and miRNA-34a showed a significant decrease that leads to its abnormal effect on lipid metabolism. Conclusions: our results imply that miRNA-29a can be investigated as a target for circRNA-HIPK3, while miRNA-34a can be investigated as a target for circRNA-0046367, and that circRNA-HIPK3 and circRNA-0046367 may have emerging roles that can affect the pathogenesis of nonalcoholic steatohepatitis through the Wnt/ß-catenin pathway and thus be used as therapeutic targets for the disease.

Correction to: The effect of exosomes derived from mesenchymal stem cells in the treatment of induced type 1 diabetes mellitus in rats.

In the original publication of the article, the reference citation style in the article was published incorrectly. The journal follows 'Name and Year' style for references. However, they were cited in numbering style incoherent to the references given in the Reference section which were placed in alphabetical order.

The effect of exosomes derived from mesenchymal stem cells in the treatment of induced type 1 diabetes mellitus in rats.

AIM: The aim of the current study was to evaluate the therapeutic and regenerative effects of MSCs derived exosomes in the treatment of type 1 DM and to compare its effects with MSCs themselves. The experiment was done on forty albino rats grouped as follows, group (1): Ten healthy rats, group (2): Ten induced type 1 DM rats, group (3): Ten induced type 1 DM rats received exosomes intraperitoneally, and group (4): Ten induced type 1 DM rats received MSCs intraperitoneally. Serum glucose and plasma insulin levels were assessed weekly. QRT-PCR was done to assess regeneration of pancreatic beta cells by measuring insulin, Pdx1, Smad2, Smad3 and TGFß genes. Additionally, histopathological and immune-histochemical examinations were done to confirm pancreatic tissue regeneration. RESULTS: Regarding the assessed genes (insulin, Pdx1, Smad2, Smad3 and Tgfß) gene expression in MSCs treated group showed significant increase compared to diabetic group (p value < 0.001) and gene expression in exosomes treated group was increased significantly compared to diabetic and MSCs treated groups (p value < 0.001). Histopathological and immune-histochemical examination revealed regeneration of pancreatic islets in both treated groups. CONCLUSION: MSCs Derived exosomes showed superior therapeutic and regenerative results than MSCs themselves.

Neupogen and mesenchymal stem cells are the novel therapeutic agents in regeneration of induced endometrial fibrosis in experimental rats.

Endometrial fibrosis is the presence of intrauterine adhesions (IUAs) after any uterine surgery or curettage and it results in infertility and recurrent pregnancy loss. We evaluated the role of human mesenchymal stem cells (hMSCs) as a therapeutic agent of endometrial fibrosis. We also compared the effect of MSCs with the effect of estrogen and neupogen either each alone or as a combined therapy with MSCs. This experimental study was performed on 84 albino rats which were divided into seven groups (n=12 rats/group) as follows, group1: normal control rats, group 2: induced fibrosis, group 3: induced fibrosis that received oral estrogen, group 4: induced fibrosis that received hMSCs, group 5: induced fibrosis that received hMSCs and estrogen, group 6: induced fibrosis that received neupogen, and group 7: induced fibrosis that received hMSCs and neupogen. The extent of fibrosis, vascularization, and inflammation were evaluated by; qRT-PCR for interleukin 1 (IL-1), interleukin 6 (IL-6), TNF, vascular endothelial growth factor (VEGF), transforming growth factor-ß (TGF-ß), and RUNX; ELISA for connective tissue growth factor (CTGF); Western blotting for collagen-I; immunohistochemistry examination for VEGF and RUNX-2; and histopathological assessment. In therapeutic groups either by hMSCs alone or combined with estrogen or neupogen; fibrosis and inflammation (IL-1, IL-6, TNF, TGF-ß, RUNX, CTGF, and collagen-I) were significantly decreased but vascularization (VEGF) was significantly increased (P<0.05) compared with induced fibrosis group. The most significant result was obtained in fibrosis that received combined therapy of hMSCs and neupogen (P=0.000). Stem cells and neupogen are a highly effective alternative regenerative agents in endometrial fibrosis.

The association between RANKL and Osteoprotegerin gene polymorphisms with breast cancer.

Breast cancer is the most common cause of cancer death among women (522,000 deaths in 2012). Imbalance between RANKL and OPG is observed in many cancers, including breast cancer. Consequently, SNPs in the genes of RANKL and OPG may be involved in breast cancer development. This study included 276 subjects. Group I (n = 100) healthy females as a control group, group II (n = 96) breast cancer patients without bone metastases, and group III (n = 80) breast cancer patients with bone metastases. RANKL rs9533156, OPG rs2073618, and OPG rs2073617 SNPs and their serum protein levels were studied for a possible association with breast cancer development. The allele frequency [(OR: 4.832 CI 2.18-10.71, P = 0.001) and genotype distribution (P = 0.001)] of OPG SNP rs2073618 showed a highly significant difference between breast cancer patients and healthy controls. The allele C is more common in breast cancer patients. The allele frequency [(OR: 0.451 CI 0.232-0.879, P = 0.018) and genotype distribution (P = 0.003)] of RANKL SNP rs9533156 differed significantly between breast cancer patients and healthy controls. The allele T is more common in breast cancer patients. The allele frequency [(OR: 0.36 CI 0.184-0.705, P = 0.002) and genotype distribution (P = 0.011)] of OPG SNP rs2073617 differed significantly between breast cancer patients and healthy controls. The allele T is more common in breast cancer patients. The C allele of OPG SNP rs2073618 may be associated with breast cancer development. No association was found between any of the SNPs and the serum protein levels of RANKL and OPG.

Bronchial aspirates glucose level as indicator for methicillin-resistant Staphylococcus aureus (MRSA) in intubated mechanically ventilated patients.

This study evaluated if the level of glucose in bronchial aspirate serves as indicator for the risk of MRSA infection in intubated mechanically ventilated ICU patients. A total of 50 critically ill patients was enrolled and were under tight glycemic control to abolish the effect of hyperglycemia on bronchial secretion, if they were expected to require mechanical ventilation for more than 48 hours. Bronchial aspirates were detected for glucose and sent twice weekly for microbiological analysis and whenever an MRSA was expected. The results showed that all the patients had glucose tested in bronchial aspirates. Glucose was detected in bronchial aspirates of 28 of the 50 patients. Glucose in bronchial aspirates in these patients ranged between (2.9-5.1 mmol/l). MRSA was detected in 22 patients where 28 were MRSA free of the MRSA patients 19 had positive glucose where glucose was positive in 28 patients of them 19 (86.4%) where MRSA positive to 9 with no MRSA (32.1%).The risk of having MRSA present markedly increased significantly in the presence of glucose: (p value .001).

Comparative diagnostic study of biomarkers using FibroMax™ and pathology for prediction of liver steatosis in patients with chronic hepatitis C virus infection: an Egyptian study.

BACKGROUND: Steatosis is common in patients with hepatitis C virus (HCV) infection and may be a major determinant of progression of liver injury. This study evaluated FibroMax™ for noninvasive diagnosis of steatosis in patients with chronic HCV. METHODS: This cross-sectional study included 44 patients naïve to treatment who were referred to our hepatology clinic for assessment of fitness for antiviral therapy. Chronic HCV infection was diagnosed by viral markers. Investigations included assessment of abdominal ultrasonography, liver biopsy, calculation of body mass index, and biomarker parameters in serum using FibroMax. RESULTS: Histopathology of liver biopsies showed steatosis in 30 of 44 (68%) patients. FibroMax results were positively correlated with viral load by quantitative polymerase chain reaction and histopathological findings. Body mass index was significantly higher in steatotic patients (P = 0.003) and was significantly associated with the results on FibroMax (P = 0.005). CONCLUSION: FibroMax was correlated with histopathology and body mass index in patients with HCV. Abdominal ultrasonography could not be used as a single tool to diagnose steatosis with HCV. Steatosis is correlated with viral load, which suggests a direct viral effect. We recommend FibroMax assessment in a larger number of patients to assess its applicability in patients with HCV and steatosis.

Osteopontin gene polymorphisms as predictors for the efficacy of interferon therapy in chronic hepatitis C Egyptian patients with genotype 4.

This study aimed to determine the relationship between osteopontin gene polymorphisms and its protein level and the efficacy of interferon-based therapies in Hepatitis C virus (HCV) patients. Hundreds HCV patients genotype 4, treated with pegylated interferon alfa-2b plus ribavirin and 60 healthy subjects were enrolled. All individuals were subjected to clinical and laboratory parameters, including hepatitis markers and HCV quantitation by real-time polymerase chain reaction. Single nucleotide polymorphisms (SNPs) of osteopontin (OPN) gene (nucleotide -155, -443 and -1748) were analysed by direct sequencing in addition to estimation of serum level of OPN. SNP at -443 (C/C versus C/T, T/T) was found to represent predictors for treatment response by univariate logistic regression analysis. OPN serum level was independent predictors for treatment response by both univariate and multivariate logistic regression analysis. SNP at nucleotide -443 and serum OPN protein levels could be used as useful markers to predict the efficacy of treatment.

Relationship of BsmI polymorphism of vitamin D receptor gene with left ventricular hypertrophy and atherosclerosis in hemodialysis patients.

BACKGROUND: Left ventricular hypertrophy (LVH) is a common manifestation of cardiovascular disease and has an important prognostic value in patients with end-stage renal disease (ESRD). Vitamin D receptor (VDR) has been intensively investigated, and one of these (BsmI) already has been associated with survival in the dialysis population. OBJECTIVE: The aim of this study was to investigate the role of VDR polymorphism (BsmI) on the development of ventricular hypertrophy and atherosclerosis in hemodialysis patients. Subject and methods. The subjects were 80 patients with end-stage renal disease on maintenance hemodialysis, and 40 healthy controls. Clinical and laboratory parameters, including genetic variation in VDR gene (BsmI), were assessed. In addition, echocardiography and intima-media thickness were performed for all subjects. RESULTS: There was no significant difference in the distribution of BsmI genotypes either in patients or in the control group. The frequency of the B allele of BsmI polymorphism (41.6%) in dialysis patients was similar to that of healthy control subjects (39.2%). Patients with BB genotype had significantly lower serum concentrations of 25-hydroxy vitamin D compared to both Bb and bb genotypes. The number of B alleles was positively correlated with left ventricular mass index (LVMI), but not with intima-media thickness. CONCLUSION: These results suggest that the B alleles of the BsmI polymorphism could be considered as novel markers of altered vitamin D signaling in ESRD patients, and this alteration in BB genotype produces an increase in left ventricle mass.

Serum procalcitonin as a predicting value in severity and prognosis of CAP in sickle cell-patients.

The Pneumonia Severity Index (PSI) and CURB-65 predict outcomes in community acquired pneumonia but have limitations. The study evaluated if procalcitonin in community-acquired pneumonia provides prognostic information with the PSI and CURB-65 in sickle cell adult patients. Twenty sickle cell positive adult patients with a clinical and radiographic diagnosis of community acquired pneumonia were scored using PSI and CRUB-65, and measured procalcitonin levels. They were 12 female 60% and 8 males 40% with mean of age 46.0 +/- 10.26 and were stratified with PSI, CRUB65 and sampled for procalcitonin level for PSI class I (3) patients 15%, class II (10) patients 50%, class III (3) patients 15%, class IV (one) patient 5% and class V (3) patients 15% with mean of 2.55 +/- 1.276 were CRUB65 0 (2) patients 10% 1 (11) patients 55% two (3) patients 15%, three (4) patients 20% with mean of 1.45 +/- 0.94 proclacitonin >0.25 (8) patients 40% and >0.50 were (12) patients 60% with mean of 1.098 +/- 1.346.

Sialic acid value in pleural effusion as a diagnostic marker of malignancy.

In differential diagnosis of pleural effusions, cytology is the most sensitive method. Since cytology findings are positive in half of such fluids, combined use of reliable tumor marker and cytology is a logical approach. Sialic acid and other tumor markers can be reliable substances associated with neoplasia. The present study measured sialic acid levels in pleural effusion and serum samples of patients with malignant and nonmalignant diseases to discriminate each other, and to diagnose malignant effusion in a simple, cheap and reliable way. Sixty patients with pleural effusion were enrolled in the study and classified into two groups, group (I) 30 patients with malignant pleural effusion, and group (II) 30 patients with nonmalignant pleural effusion. Pleural fluid (PF) and serum (S) levels of sialic acid were measured prior to any therapy; and PF/S sialic acid ratios were calculated. Pleural fluid and serum levels of sialic acid were significantly higher in malignant group compared to nonmalignant one. PF/S sialic acid ratio was higher in malignant group compared to nonmalignant group. In the malignant pleural effusion group, smokers showed a statistically significant higher pleural fluid and serum sialic acid levels as compared to nonsmokers. By using ROC curve, the cut off value of malignant pleural fluid sialic acid was 69.65 mg/dL, sensitivity was 70%, and specificity was 96%.

Elevated serum TRAIL levels in scleroderma patients and its possible association with pulmonary involvement.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to be involved in the pathophysiology of some autoimmune diseases as systemic lupus erythematosus, ankylosing spondylitis, and multiple sclerosis. The aim of this study was to assess serum TRAIL concentration in systemic sclerosis (SSc) patients and to investigate its possible association with various disease parameters. Thirty SSc patients as well as 25 rheumatoid arthritis (RA) patients and 25 healthy volunteers were included in the present study. Organ system involvement in SSc patients was investigated. Pulmonary function tests as well as chest high-resolution computed tomography (HRCT) were done to detect pulmonary involvement in our patients. TRAIL concentrations were measured in the sera of SSc patients, RA patients and healthy controls by enzyme-linked immunosorbent assay. Mean serum TRAIL levels were significantly higher in SSc patients than in the control RA patients and in healthy controls (p < 0.001) while they were not significantly different between patients with diffuse cutaneous SSc and patients with limited cutaneous scleroderma. Serum TRAIL levels were significantly higher in SSc patients with pulmonary involvement and were significantly correlated with HRCT scores. Serum TRAIL levels are significantly elevated in SSc patients and are associated with SSc-associated pulmonary involvement denoting a possible role of TRAIL in the pathogenesis of SSc. Further studies may be needed to confirm these findings and the possible use of TRAIL in detection and possibly treatment of SSc-associated pulmonary disease.

Correlations of urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and IL-8 with lupus nephritis.

OBJECTIVE: This case-controlled study was designed to correlate urinary biomarkers, TNF-like weak inducer of apoptosis (TWEAK), osteoprotegerin (OPG), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) levels, with renal involvement in a cohort of systemic lupus erythematosus (SLE) patients to examine their diagnostic performance. PATIENTS AND METHODS: In 73 SLE patients, and in 23 healthy volunteers, urinary levels of TWEAK, OPG, MCP-1, and IL-8 levels were measured. Disease activity was assessed by total SLE disease activity index, and renal activity by renal activity index (rSLEDAI), and both were correlated with urinary biomarkers. Sensitivity, specificity, and predictive values of individual biomarkers to predict lupus nephritis were also calculated. RESULTS: Significantly higher levels of urinary biomarkers were observed in SLE patients with lupus nephritis (LN) compared with those without LN (TWEAK, p < 0.001; MCP-1, p < 0.001; OPG, p < 0.001; IL-8, p < 0.032). Other significantly higher levels were observed in SLE patients with LN compared with control subjects (TWEAK, MCP-1, OPG, and IL-8 p < 0.001). Positive correlations were observed between rSLEDAI and TWEAK (r = 0.612 and p < 0.001), MCP-1 (r = 0.635 and p < 0.001), and OPG (r = 0.505 and p < 0.001). CONCLUSIONS: Urinary levels of TWEAK, OPG, and MCP-1 positively correlate with renal involvement as assessed by rSLEDAI with reasonable sensitivity, specificity, and predictive values to detect lupus nephritis while IL-8 was not significantly associated with global or rSLEDAI.

The role of PDE5 inhibitors in heme oxygenase-cGMP relationship in rat cavernous tissues.

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