Dyslipidemia initiates keratinocytes proliferation through upregulation of lncRNA NEAT in psoriasis patients.

BACKGROUND: Psoriasis is a chronic inflammatory immune-mediated and hyper proliferative skin disorder that has underlying genetic factors. Psoriasis can result from interaction of cytokines between keratinocytes and T-lymphocytes. NEAT is a lncRNA involved in immune modulation and has been previously studied in cancers. This study aims to clarify the unprecedented role of NEAT in psoriasis pathogenesis. METHODS: The study was conducted on 50 healthy control subjects and 50 psoriasis patients. Blood samples from all participants were collected for analysis of their lipid profile. qRT-PCR was done for lncRNA NEAT, TNF-α, VEGF genes expression. The levels of ROS and caspase-3 were estimated by ELISA. ROC analysis was done to detect the diagnostic value of lncRNA NEAT gene expression. RESULTS: Dyslipidemia is more prevalent among psoriasis patients. A significant up regulation in lncRNA NEAT, TNF-α, VEGF genes expression (p value˂0.001) in psoriasis patients in addition to significant increase in ROS and caspase-3 levels (p value˂0.001) in compare to controls. Additionally, a positive significant correlation between TNF-α, ROS, NEAT, caspase-3 and dyslipidemia. NEAT had an area under the curve (AUC) of 0.931 (95% CI 0.844-0.978, p < 0.001). CONCLUSION: Dyslipidemia is an initiating signal in psoriasis pathogenesis that creates a state of chronic inflammation and oxidative stress. This state induces keratinocytes proliferation and release of NEAT with subsequent caspase-3 activation to counteract the proliferating cells. NEAT could be considered as a good diagnostic biomarker for psoriasis.

Nicorandil mitigates amiodarone-induced pulmonary toxicity and fibrosis in association with the inhibition of lung TGF-ß1/PI3K/Akt1-p/mTOR axis in rats.

The long-term side effect of the antiarrhythmic drug, amiodarone (AMIO), such as lung toxicity, remains a critical clinical issue. The previous knowledge denotes diverse antioxidant, anti-inflammatory, and antifibrotic properties of the anti-anginal drug, nicorandil (NI). Therefore, we aimed to investigate the possible protective effect of NI on pulmonary tissue remodelling following AMIO-induced lung toxicity. The included rats were assigned into four equal groups (n = 8): (1) control, (2) control group that received NI 10 mg kg-1  day-1 , (3) model group that received AMIO in a dose of 60 mg kg-1  day-1 , and (4) treated group (AMIO-NI) that were treated with AMIO plus NI as shown above. Drug administration continued for 10 weeks. AMIO resulted in deteriorated (p < 0.001) pulmonary functions accompanied by respiratory acidosis. AMIO showed an obvious histological injury score with intense collagen deposition, disturbed nitric oxide synthase enzymes (NOS/iNOS), and increased alpha smooth muscle actin expression. Furthermore, AMIO upregulated the transforming growth factor (TGF-ß1)/phosphoinositide-3 kinase (PI3K)-Akt1-p/mammalian target of rapamycin (mTOR) axis, which determined the possible mechanism of AMIO on pulmonary remodelling. NI treatment significantly (p < 0.001) prevented the AMIO-induced lung toxicity, as well as inhibited the TGF-ß1/PI3K/Akt1-p/mTOR axis in the lung tissue of rats. The results were confirmed by an in-vitro study. CONCLUSION: The current results revealed that NI was effective in preserving the lung structure and functions. Amelioration of the oxidative stress and modulation of TGF-ß1/PI3K/Akt1-p/mTOR have been achieved. This study suggests NI administration as a preventive therapy from the serious pulmonary fibrosis side effect of AMIO.

Cardioprotective effects of amiodarone in a rat model of epilepsy-induced cardiac dysfunction.

Cardiac dysfunction is one of the leading causes of death in epilepsy. The anti-arrhythmic drug, amiodarone, is under investigation for its therapeutic effects in epilepsy. We aimed to evaluate the possible effects of amiodarone on cardiac injury during status epilepticus, as it can cause prolongation of the QT interval. Five rat groups were enrolled in the study; three control groups (1) Control, (2) Control-lithium and (3) Control-Amio, treated with 150 mg/kg/intraperitoneal amiodarone, (4) Epilepsy model, induced by sequential lithium/pilocarpine administration, and (5) the epilepsy-Amio group. The model group expressed a typical clinical picture of epileptiform activity confirmed by the augmented electroencephalogram alpha and beta spikes. The anticonvulsive effect of amiodarone was prominent, it diminished (p < 0.001) the severity of seizures and hence, deaths and reduced serum noradrenaline levels. In the model group, the electrocardiogram findings revealed tachycardia, prolongation of the corrected QT (QTc) interval, depressed ST segments and increased myocardial oxidative stress. The in-vitro myocardial performance (contraction force and - (df/dt)max ) was also reduced. Amiodarone decreased (p < 0.001) the heart rate, improved ST segment depression, and myocardial contractility with no significant change in the duration of the QTc interval. Amiodarone preserved the cardiac histological structure and reduced the myocardial injury markers represented by serum Troponin-I, oxidative stress and IL-1. Amiodarone pretreatment prevented the anticipated cardiac injury induced during epilepsy. Amiodarone possessed an anticonvulsive potential, protected the cardiac muscle and preserved its histological architecture. Therefore, amiodarone could be recommended as a protective therapy against cardiac dysfunction during epileptic seizures with favourable effect on seizure activity.

Nicorandil prevents the nephrotoxic effect of cyclosporine-A in albino rats through modulation of HIF-1α/VEGF/eNOS signaling.

Despite that cyclosporine-A (CsA) is a widely used immunosuppressive drug, its nephrotoxic effect limits its long-term administration. Herein we tried to investigate its renal effect on endothelial dysfunction targeting the hypoxia-inducible factor (HIF-1α) / vascular endothelial growth factor (VEGF) / endothelial nitric oxide synthase (eNOS) pathway and the possible modulation by nicorandil. Eight groups of adult male Wistar rats were included: (1) control; (2) vehicle group (received oil); (3) glibenclamide 5 mg·kg-1·day-1 administered orally; (4) nicorandil 10 mg·kg-1·day-1 administered orally; (5) CsA 25 mg·kg-1·day-1 administered orally; (6) combined administration of CsA and nicorandil; (7) glibenclamide was added to CsA; and (8) both CsA and nicorandil were combined with glibenclamide. The treatment continued for six weeks. Combined nicorandil with CsA improved renal function deterioration initiated by CsA. CsA decreased the renal expression levels (P < 0.001) of HIF-1α, eNOS, and VEGF, inducing endothelial dysfunction and triggering inflammation, and upregulated the profibrotic marker transforming growth factor (TGF-ß). Nicorandil fixed the disturbed HIF-1α/VEGF/eNOS signaling. Nicorandil corrected the renal functions, confirmed by the improved histological glomerular tuft retraction that was obvious in the CsA group, without significant influence by glibenclamide. Proper protection from CsA-induced nephrotoxicity was achieved by nicorandil. Nicorandil reversed the disturbed HIF-1α/VEGF/eNOS pathway created by CsA.

Hepatoprotective effect of gallic acid against type 2-induced diabetic liver injury in male rats through modulation of fetuin-A and GLP-1 with involvement of ERK1/2/NF-κB and Wnt1/ß-catenin signaling pathways.

Gallic acid is a phenolic compound with biological and pharmacological activities. Therefore, our study aimed to examine whether gallic acid has a beneficial effect against type 2-induced diabetic hepatic injury in rats and attempt to discover its possible intracellular pathways. Adult male rats were subdivided into six groups: Control, DM (diabetes mellitus), GA (gallic acid)+DM, DM+GA, DM+MET (metformin) and DM+GA+MET. Type 2 diabetes mellitus (T2DM) induced a significant increase in the blood glucose, HOMA-IR, liver enzymes, fetuin-A, hepatic triglycerides content with diminished serum insulin and hepatic glycogen content associated with impairment of cellular redox balance. Administration of gallic acid successfully restored all these alterations which was confirmed by marked improvement of the histopathological changes of the liver. Significantly, gallic acid increased the expression of glucagon-like peptide-1 (GLP-1) immunoreactive cells in the terminal ileum with negative correlation observed between fetuin-A and GLP-1 cells. Furthermore, our results discovered that gallic acid could diminish the DM-induced hepatic damage via upregulated hepatic mRNA expression of GLUT-4, Wnt1 and ß-catenin with inhibitory effects on the elevated expression of ERK1/2/NF-κB. In conclusion, this study suggests that gallic acid provides a significant protection against T2DM-mediated liver injury. The use of gallic acid with traditional anti-diabetic drug enhanced its efficiency compared with traditional drug alone.

Abscisic acid: a novel uterine stimulator in normal and diabetic rats.

Diabetes is usually associated with alterations in myometrial contractility with altered oxytocin responsiveness that increase the incidence of fetal and maternal morbidity and mortality. Pancreatic ß-cells release abscisic acid (ABA) in response to glucose, which in turn potentiates insulin secretion. The aim of the study was to find out the effect of ABA on the uterine contractility in normal and diabetic induced rats and tried to detect its possible underlying signaling pathway. Adult non-pregnant female rats were divided into normal nondiabetic group (n = 27) and diabetic group (n = 12). The effect of ABA on the normal and diabetic isolated myometrium was determined alone or after different blockers. Spontaneous diabetic myometrial contraction showed significant decrease and less responsiveness to oxytocin, KCL, and acetylcholine than nondiabetic samples. ABA showed 60% of oxytocin stimulatory effects on myometrial contraction in a dose-response manner in both groups. Meanwhile, this effect was decreased after blocking L-type calcium channels and completely abolished after blocking prostaglandin F (FP) and inositol trisphosphate (IP3) receptors. ABA is found to have an uterotonic effect that is mediated mainly via FP receptor through increasing the level of IP3. So, ABA by its novel effect could be beneficial as pre-labor prescription, especially in diabetic females.

Omega-3 polyunsaturated fatty acid docosahexaenoic acid and its role in exhaustive-exercise-induced changes in female rat ovulatory cycle.

Exhaustive exercises can cause delayed menarche or menstrual cycle irregularities in females. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are incorporated into a wide range of benefits in many physiological systems. Our work aimed to assess the role of ω-3 PUFA docosahexaenoic acid (DHA) on the deleterious effects of exhaustive exercise on the female reproductive system in rats. Virgin female rats were randomly divided into 4 groups (12 rats in each): control group, omega-3 group treated with DHA, exhaustive exercise group, and exhaustive exercised rats treated with DHA. Omega-3 was given orally to the rats once daily for 4 estrous cycles. Exhaustive exercises revealed lower levels in progesterone and gonadotropins together with histopathological decrease in number of growing follicles and corpora lutea. Moreover, the exercised rats showed low levels of ovarian antioxidants with high level of caspase-3 and plasma cortisol level that lead to disruption of hypothalamic-pituitary-gonadal axis. ω-3 PUFA DHA has beneficial effects on the number of newly growing follicles in both sedentary and exercised rats with decreasing the level of caspase-3 and increasing the antioxidant activity in ovaries. Exhaustive exercises can cause ovulatory problems in female rats that can be improved by ω-3 supplementation.

Mesenchymal stem cells-derived microvesicles versus platelet-rich plasma in the treatment of monoiodoacetate-induced temporomandibular joint osteoarthritis in Albino rats.

Temporomandibular joint osteoarthritis (TMJ-OA) is a serious disease, designated by severe joint pain and dysfunction. Limitations of current therapeutics have led to an increased interest in regenerative strategies. Recently, the non-surgical treatment of OA has seen increased use of biologic injectable therapies like mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP). Although these biotherapies represent an admirable effort, more studies are necessary to determine their efficacy. Thus, the aim of this study was to assess the curative potential of a single intra-articular injection of bone marrow MSCs-derived microvesicles (BM-MSCs-MVs) versus a single intra-articular injection of PRP in monoiodoacetate (MIA)-induced TMJ-OA model in Albino rats. Forty-eight male rats were used. A single intra-articular unilateral MIA injection was utilized to induce TMJ-OA. One week post induction, rats were sorted into 3 groups (16 rats each): group (I): received no treatment, groups (II) & (III): received BM-MSCs-MVs and PRP respectively. Scarification was done at 2 and 4 weeks from onset of treatment. Histological changes of the condylar TMJ were examined with H&E staining. Expression of IL-1ß, TNF-α, NF-κB, MMP-13, MMP-3, and collagen ΙΙ markers was detected using real-time PCR. Histologically, the osteoarthritic group exhibited degenerated condylar tissues which were aggravated at 4 weeks. Oppositely, a marked improvement in the condylar TMJ histology was noticed in both the BM-MSCs-MVs-and PRP-treated groups at both time intervals. Additionally, the treated groups showed a decrease in IL-1ß, TNF-α, NF-κB, MMP-13 and MMP-3 and an increase in collagen ΙΙ genes expression in contrast to the untreated group. Moreover, this difference was significant in the BM-MSCs-MVs group as compared to the PRP-treated group. Our results concluded that BM-MSCs-MVs as well as PRP treatments were able to target the key pathological features in OA, mainly inflammation and matrix degradation, and helped in restoring condylar structure in TMJ-OA rat model. However, BM-MSCs-MVs treatment exhibited more efficient therapeutic potential as compared to PRP treatment.

Mesenchymal Stem Cells Treatment Aggravates Tumor Growth Regardless Its Route of Administration: An In vivo Study.

OBJECTIVES: to clarify the effect of MSCs in cancer growth and to detect whether the rout of administration (either locally inside the tumor tissue or systemic )could affect the outcome of treatment or not. METHODS: Eighteen female mice were involved in the study. All mice were subcutaneously inoculated with Ehrlich tumor cells into the right flank. After three week of tumor growth; the mice were divided randomly in to three groups six mice for each ; group I: untreated Erlish tumor group; group II: Erlish tumor treated by local injection of 1 x106 MSCs/week inside the tumor tissue, group III: Erlish tumor treated by systemic injection of 1 x106 MSCs iv in tail vein/week. Tumor growth was recorded .After 4 weeks of stem cells injection, all rats were sacrificed by cervical dislocation and tumor tissues were collected for histopathological study. inflammatory cytokine TNF was assessed by ELISA, lncRNA MALAT ,NFKB and MMP2 genes expression were assessed by Quantitative RT-PCR. RESULTS: Erlish tumor was developed as a well-defined capsule composed by connective tissue infiltrated by inflammatory and neoplastic cells surrounded the tumors. The tumor growth regarding size and weight of tumor tissue was significantly aggravated after both local and systemic treatment MSCs (p value =0.007, 0.001) respectively. Inflammatory cytokines  TNF and NFKB were significantly elevated (p value <0.0001), lncRNA MALAT, MMP2 expressions were significantly induced (p value <0.0001), after MSCs treatment with more significant increase in those treated by local intratumor injection of MSCs compared to those treated by systemic MSCs(p value <0.0001). CONCLUSION: Ehrlich tumor model is feasible and easily monitored tumor model. Although MSCs have anti-inflammatory effect and the ability to regenerate the damaged tissue; it could aggravate tumor growth as it exploited by cancer cells for behave of tumor cells.

Combined Systemic Intake of K-ATP Opener (Nicorandil) and Mesenchymal Stem Cells Preconditioned With Nicorandil Alleviates Pancreatic Insufficiency in a Model of Bilateral Renal Ischemia/Reperfusion Injury.

We used nicorandil, a K-ATP channel opener, to study the role of these channels in the amelioration of renal ischemia/reperfusion (I/R)-induced pancreatic injury, and the possible involvement of PI3K/Akt/mTOR signaling pathway. Forty-two male Wistar rats were included in this study, six were sacrificed for extraction of bone marrow mesenchymal stem cells (BM-MSCs) and conducting the in-vitro work, the others were included in vivo study and equally divided into six groups. Group 1 (sham control), but groups 2-6 were subjected to bilateral renal I/R: Group 2 (I/R); Group 3 (I/R-NC), treated with nicorandil; Group 4 (I/R-MSCs), treated with BM-MSCs; Group 5 (I/R-MSCC), treated with nicorandil-preconditioned BM-MSCs; Group 6 (I/R-NC-MSCC), treated with both systemic nicorandil and preconditioned BM-MSCC. Renal injury and subsequent pancreatic damage were detected in the I/R group by a significant increase in serum urea, creatinine, fasting glucose, and pancreatic enzymes. The pancreatic tissues showed a reduction in cellularity and a significant decrease in the expression of the cell survival pathway, PI3K/Akt/mTOR, in the I/R group compared to the control. Preconditioning MSCs with nicorandil significantly enhanced the proliferation assay and decreased their apoptotic markers. Indeed, combined systemic nicorandil and nicorandil-preconditioning maintained survival of MSC in the pancreatic tissue and amelioration of apoptotic markers and pancreatic TNF-α production. Histologically, all treated groups revealed better pancreatic architecture, and increased area % of anti-insulin antibody and CD31, which were all best observed in the NC-MSCC group. Thus, using K-ATP channel opener was efficient to enhance PI3K/Akt/mTOR expression levels (in vivo and in vitro).

A comprehensive introduction to the genetic basis of non-syndromic hearing loss in the Saudi Arabian population.

BACKGROUND: Hearing loss is a clinically and genetically heterogeneous disorder. Mutations in the DFNB1 locus have been reported to be the most common cause of autosomal recessive non-syndromic hearing loss worldwide. Apart from DFNB1, many other loci and their underlying genes have also been identified and the basis of our study was to provide a comprehensive introduction to the delineation of the molecular basis of non-syndromic hearing loss in the Saudi Arabian population. This was performed by screening DFNB1 and to initiate prioritized linkage analysis or homozygosity mapping for a pilot number of families in which DFNB1 has been excluded. METHODS: Individuals from 130 families of Saudi Arabian tribal origin diagnosed with an autosomal recessive non-syndromic sensorineural hearing loss were screened for mutations at the DFNB1 locus by direct sequencing. If negative, genome wide linkage analysis or homozygosity mapping were performed using Affymetrix GeneChip® Human Mapping 250K/6.0 Arrays to identify regions containing any known-deafness causing genes that were subsequently sequenced. RESULTS: Our results strongly indicate that DFNB1 only accounts for 3% of non-syndromic hearing loss in the Saudi Arabian population of ethnic ancestry. Prioritized linkage analysis or homozygosity mapping in five separate families established that their hearing loss was caused by five different known-deafness causing genes thus confirming the genetic heterogeneity of this disorder in the kingdom. CONCLUSION: The overall results of this study are highly suggestive that underlying molecular basis of autosomal recessive non-syndromic deafness in Saudi Arabia is very genetically heterogeneous. In addition, we report that the preliminary results indicate that there does not seem to be any common or more prevalent loci, genes or mutations in patients with autosomal recessive non-syndromic hearing loss in patients of Saudi Arabian tribal origin.

Prophylactic effect of aquatic extract of stevia on acetic acid induced-ulcerative colitis in male rats: a possible role of Nrf2 and PPARγ.

OBJECTIVES: Ulcerative colitis (UC) is a non-specific intestinal inflammatory disease. Several studies demonstrated that inflammation and oxidative stress play significant role in the pathogenesis of this disease. This study aimed to determine the protective effect and possible mechanism by which stevia affects the course of experimentally induced colitis. METHODS: Male rats were received stevia 20, 40, 80 mg/kg/day before induction of colitis by intra-rectal administration of 2 mL of 4% acetic acid, AA. Macroscopic and histopathological examination of the colon were done. Colonic content of catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH), myeloperoxidase (MPO) and thiobarbituric acid reactive substances (TBARS) activities and serum levels of interleukin (IL)1- ß and tumor necrosis factor (TNF)-α were assessed. Real time-PCR (RT-PCR) was done to determine the expression of NF-κB, Nrf2 and PPARγ genes. Spontaneous contraction and effects of increasing concentrations of acetylcholine and stevia have been studied on the isolated colonic segments. RESULTS: Stevia ameliorated colitis not only histopathologically but also it decreased the level of TNF-α, IL-1ß, TBARS, MPO and the expression of NF-κB which were significantly increased in the AA group. The concentration of GSH, SOD, CAT and expression of Nrf2 and PPARγ were significantly increased with stevia. Moreover, stevia showed a relaxant effect on the colonic contractility which was increased in AA group. These all effects of stevia were more prominent with its highest dose. CONCLUSION: Our results explored that, stevia acts protectively against UC by its anti-inflammatory and antioxidant properties which mediated by up-regulation of Nrf2 and PPARγ with downregulation of NF-κB. We suggest that stevia has the potential for treatment of chronic inflammatory diseases, such as UC.

Impact of DAXX and ATRX expression on telomere length and prognosis of breast cancer patients.

BACKGROUND: Telomere stability is one of the hallmarks of cancer that promotes cellular longevity, the accumulation of genetic alterations, and tumorigenesis. The loss of death domain-associated protein (DAXX) and α-thalassemia/mental retardation X-linked protein (ATRX) plays a role in telomere lengthening and stability. This study aims to evaluate the prognostic significance of telomere length (TL) and its association with DAXX and ATRX proteins in breast cancer (BC). Our study used the FISH technique to detect peptide nucleic acid (PNA) in the peripheral blood cells of a cohort of BC patients (n = 220) and a control group of apparently healthy individuals (n = 100). Expression of DAXX and ATRX proteins was evaluated using immunohistochemistry (IHC) in all BC tissues. RESULTS: Patients with a shorter TL had worse disease-free survival (DFS) and overall survival (OS). There were significant associations between shorter TL and advanced disease stages, lymph node metastasis, and positive HER2/neu expression. DAXX protein expression was significantly correlated with TL. Lower DAXX expression was significantly with shorter DFS. CONCLUSION: Assessing TL can be used as a worthy prognostic indicator in BC patients. Specifically, short TL had a poor impact on the prognosis of BC patients. Low DAXX expression is associated with poor outcomes in BC. Further mechanistic studies are warranted to reveal the underlying mechanisms of these associations.

Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model.

BACKGROUND: Mesenchymal stem cells (MSCs) have diverse functions in regulating injury and inflammation through the secretion of extracellular vesicles (EVs). METHODS: In this study, we investigated the systemic administration of extracellular vesicles derived from human umbilical cord mesenchymal stem cells (UCMSCs-EVs) as a therapeutic agent for intrauterine adhesions (IUAs) caused by endometrial injury. Additionally, we investigated the therapeutic impact of both UCMSCs-EVs and estrogen either separately or in combination in a rat model. The inflammation, vascularization, proliferation, and extent of fibrosis were assessed by a histopathological and immunohistochemical assessment using transforming growth factor (TGF)-ß as a fibrotic marker and vascular endothelial growth factor (VEGF) as a vascular marker. Additionally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 (inflammatory cytokines), CD140b (a marker of endometrial stem cells), and RUNX2 (an antifibrotic factor). Finally, Western blotting was used to evaluate collagen I and ß-actin expression. RESULTS: The therapeutic groups treated with either UCMSCs-EVs alone or combined with estrogen exhibited a significant decrease in inflammation and fibrosis (TNF-α, TGF-ß, IL-1, IL-6, RUNX2, and collagen-I) as well as a significant decrease in vascularization (VEGF) compared with the untreated rats with IUAs. The most significant results were obtained in animals with IUAs that received a combined therapy of UCMSCs-EVs and estrogen. CONCLUSIONS: We conclude that the synergistic action of human UCMSCs-EVs combined with estrogen provides a highly effective alternative regenerative agent in IUA treatment.

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.

Twenty novel mutations in BCKDHA, BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease.

Maple syrup urine disease (MSUD), an autosomal recessive inborn error of metabolism due to defects in the branched-chain α-ketoacid dehydrogenase (BCKD) complex, is commonly observed among other inherited metabolic disorders in the kingdom of Saudi Arabia. This report presents the results of mutation analysis of three of the four genes encoding the BCKD complex in 52 biochemically diagnosed MSUD patients originating from Saudi Arabia. The 25 mutations (20 novel) detected spanned across the entire coding regions of the BCKHDA, BCKDHB and DBT genes. There were no mutations found in the DLD gene in this cohort of patients. Prediction effects, conservation and modelling of novel mutations demonstrated that all were predicted to be disease-causing. All mutations presented in a homozygous form and we did not detect the presence of a "founder" mutation in any of three genes. In addition, prenatal molecular genetic testing was successfully carried out on chorionic villus samples or amniocenteses in 10 expectant mothers with affected children with MSUD, molecularly characterized by this study.

Spectrum of Mutations in 60 Saudi Patients with Mut Methylmalonic Acidemia.

Defects in the human gene encoding methylmalonyl-CoA mutase enzyme (MCM) give rise to a rare autosomal recessive inherited disorder of propionate metabolism termed mut methylmalonic acidemia (MMA). Patients with mut MMA have been divided into two subgroups: mut0 with complete loss of MCM activity and mut- with residual activity in the presence of adenosylcobalamin (AdoCbl). The disease typically presents in the first weeks or months of life and is clinically characterized by recurrent vomiting, metabolic acidosis, hyperammonemia, lethargy, poor feeding, failure to thrive and neurological deficit. To better elucidate the spectrum of mutations causing mut MMA in Saudi patients, we screened a cohort of 60 Saudi patients affected by either forms of the disease for mutations in the MUT gene. A total of 13 different mutations, including seven previously reported missense changes and six novel mutations, were detected in a homozygous state except for two compound heterozygous cases. The six novel mutations identified herein consist of three nonsense, two missense and one frameshift, distributed throughout the whole protein. This study describes for the first time the clinical and mutational spectrum of mut MMA in Saudi Arabian patients.

Variable expression pattern in Donnai-Barrow syndrome: Report of two novel LRP2 mutations and review of the literature.

Donnai-Barrow syndrome (DBS; MIM 222448) is characterized by typical craniofacial anomalies (major hypertelorism with bulging eyes), high grade myopia, deafness and low molecular weight proteinuria. The disorder results from mutations in the low density lipoprotein receptor-related protein 2 gene LRP2 that maps to chromosome 2q31.1. LRP2 encodes megalin, a multi-ligand endocytic receptor. Herein, we describe the clinical presentation of 4 patients from 2 unrelated Saudi families. Two novel LRP2 mutations, a homozygous nonsense mutation (c.4968C>G; p.Tyr1656*) and a missense mutation (c.12062G>A; p.Cys4021Tyr), were detected in the first and second family respectively. Interestingly, intrafamilial phenotypic variability was observed in one family, while DBS features were atypical in the second family. Differential diagnosis of DBS includes several syndromes associating hypertelorism with high grade myopia, and several syndromal forms of CDH, which are briefly summarized in this study.

Serum Resistin Level and Its Receptor Gene Expression in Liver Biopsy as Predictors for the Severity of Nonalcoholic Fatty Liver Disease.

BACKGROUND: Liver histology remains the gold standard for assessing nonalcoholic fatty liver disease (NAFLD). Noninvasive serological markers have been developed to evaluate steatosis to avoid biopsy. In NAFLD patients, serum resistin was higher than those in control lean and obese patients. OBJECTIVE OF THE STUDY: To investigate serum resistin and its receptor gene expression in liver biopsy as predictors for NAFLD severity. PATIENTS AND METHODS: This study was conducted on 54 obese patients, with suspected fatty liver by ultrasound (excluding diabetic, alcoholic, hepatitis C virus antibody (HCVAb) or hepatitis B surface antigen (HBsAg) positive patients). They were subjected to anthropometric measurements, laboratory studies including serum resistin, abdominal ultrasonography (US) and liver biopsy. The 15 lean subjects were included as a control group. According to biopsy results, patients were subdivided into nonalcoholic steatohepatitis (NASH) group (46 patients) and non-NASH group (8 patients). RESULTS: Significantly higher levels of resistin were detected in NAFLD patients compared to control subjects (p = 0.0001). Also, higher levels of resistin were recorded in NASH group compared to the non-NASH group; however, the difference was not statistically significant (p = 0.584). Serum alanine aspirate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) were higher in NASH patients than non-NASH group (p = 0.223, p = 0.005 and p = 0.006 respectively). Abdominal US showed high sensitivity in NAFLD diagnosis (sensitivity of sonar in detecting steatosis grade compared to biopsy was 61% in grade 1, 25% in grade 2 and 75% in grade 3). CONCLUSION: Serum resistin can be combined with other noninvasive markers to predict the presence of NASH as an alternative to liver biopsy.How to cite this article: Hegazy M, Abo-Elfadl S, Mostafa A, Ibrahim M, Rashed L, Salman A. Serum Resistin Level and Its Receptor Gene Expression in Liver Biopsy as Predictors for the Severity of Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2014;4(2):59-62.

What is the effect of ghrelin on rat uterine contractility in vitro?

BACKGROUND: Ghrelin, a recently isolated gastric hormone, is an endogenous ligand for growth hormone secretagogue receptors. There is novel evidence that ghrelin might be expressed in rat ovaries, placental tissues, and the uterus. It has been reported to have modulatory effects on smooth muscle contractility. In this study, we investigated the effects of ghrelin on spontaneous and oxytocin-induced contractions in the rat uterus in vitro and tried to detect its signaling pathway. METHODS: Myometrium strips were removed from virgin female albino Wister rats and placed in a jacketed tissue bath. After initiation of spontaneous contractions, ghrelin was added to the tissue bath alone or after administration of indomethacin or NG-nitro-L-arginine methyl ester (L-NAME) or propranolol HCl. Student's t-test was used for statistical analysis. RESULTS: Our results revealed an inhibitory effect of ghrelin on both spontaneous and oxytocin-induced myometrial contractions. This effect was not affected by the application of indomethacin or L-NAME but was blocked after propranolol HCl administration. CONCLUSIONS: Ghrelin has an inhibitory effect on basal and oxytocin-induced rat myometrial contractions in vitro, and this myometrial response to ghrelin might be mediated by ß-receptor signaling pathway.