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Phoenixin-14 (PNX) is a neuropeptide that has been shown to prevent oxidative damage and stimulates insulin secretion. We investigated the effects of PNX on pancreatic injury induced by streptozotocin (STZ), and nicotinamide (NAD). Male Sprague-Dawley rats, in control (C) and diabetic (STZ) groups, were treated with either saline, or PNX (0.45 nmol/kg, or 45 nmol/kg) daily for 3 days 1 week after STZ injection. Fasting blood glucose (FBG) and gastric emptying rate (GER) were measured. Tissue and blood samples were collected. PNX treatments prevented pancreatic damage and β cell loss. Increased luminol and lucigenin levels in the pancreas, ileum and liver tissues of STZ groups were alleviated by PNX treatment in pancreatic and ileal tissues. PNX0.45 decreased FBG without any change in insulin blood level and pancreatic mRNA. GER increased in all diabetic rats while PNX0.45 delayed GER only in the C group. PNX diminishes pancreatic damage and lowers FBG by reducing oxidative load.

Ankylosing Spondylitis is an autoimmune disease leading to inflammation in the joints and ligaments of the spine. ERAP1 is a major risk factor for AS and ERAP1 mutations may result in structural changes that alter the trimming efficiency, thereby altering the immune response. The underlying structural mechanisms of AS pathogenesis have not yet been fully elucidated. This study investigated ERAP1/ERAP2 allotypes using Molecular Dynamics in both monomeric and dimeric forms. ERAP1's domain IV has been found to be a favorable region for dimerization. Different allotype dimers exhibited different stability characteristics. Furthermore, the effects of allotypic variation were more pronounced in Hap2-/Hap8-coupled dimer structures and were more distinct in heterodimers. An analysis of the interchain region revealed that both H-bonding and electrostatic interactions between chains of Hap2–N392 heterodimer structures were lower than those between Hap2–Hap2 revealing that allotypic variations played a significant role in stabilizing and destabilizing dimer structures.

Objective: The aim of this study is to determine the perceptions, attitudes, and behaviour of medical students and lecturers regardingthe lectures and their effects on students’ learning behaviour.Materials and Methods: This was a qualitative study including multi-methods. Researchers observed lecture ambiance and activitiesin two courses. Lectures were observed and slide-presentations were evaluated. Additionally, in-depth and focus group interviewswere conducted.Results: Two researchers attended and observed 75 lectures. The average number of attendees was 51.21. Eighty percent of lecturers didnot introduce any activities to attract attention and prepare students for the lecture. Only 12% of lectures were taught interactively. Ofthe evaluated 43 (69.80%) slide-presentations, sufficient association or integration was not made between clinical and basic sciences.Conclusion: This study revealed that the lectures created negative feelings and thoughts in students and lecturers, and led toundesirable attitudes and behaviour. It is essential to focus on giving interactive lectures which aim at developing reasoning, decisionmaking,and evaluation competencies. The most significant factors determining students’ attendance and appraisal of the lectureswere related to the preparation of the lecturers, the intensity of the content, integration between basic science and clinical science,and the presentation skills.

New findings What is the central question of this study? Could different hormonally active substances, including oestrogen receptor (ER) agonists, protect against oxidative brain damage and memory impairment induced by a single epileptic seizure in rats? If so, which signalling mechanisms are involved in their anti-inflammatory effects? What is the main finding and its importance? Chronic administration of oestrogen, progesterone, ER modulators/agonists or blockade of testosterone exhibited anti-inflammatory and antioxidant actions on single seizure-induced neuronal injury, while ER agonists additionally improved memory function and up-regulated CREB signalling and hippocampal GABA(A)α1 receptor density, suggesting that ERα or ERβ receptor activation may be beneficial in protecting against seizure-related oxidative brain injury and cognitive dysfunction. Abstract The susceptibility to epileptic seizures is dependent on sex as well as fluctuations in oestrogen levels, while exogenous oestrogen was shown to have no effect or to facilitate or to inhibit seizure activity. Oestrogen receptors (ERs) mediate antioxidant and anti-inflammatory actions in several inflammatory models, but the involvement of ERs in seizure-induced neuronal injury has not been evaluated previously. In order to assess the effects of resveratrol, progesterone, oestradiol (E2), an anti-testosterone (cyproterone acetate; CPA), a selective ER modulator (tamoxifen; TMX) and ERα/ERβ agonists (propyl pyrazole triol (PPT), diarylpropionitrile (DPN)) on oxidative brain damage and memory impairment due to epileptic seizure, male Wistar rats (n = 120) received one of the treatment choices either in drinking water or intraperitoneally for 31 days, and epileptic seizure was induced on the 28th day by injection of a single-dose of pentylenetetrazole (45 mg kg-1 ). The results demonstrate that chronic pretreatment with resveratrol, progesterone, E2, CPA or TMX suppressed most of the inflammatory parameters indicative of oxidative neuronal injury, while treatment with the ER agonists DPN or PPT were found to be even more effective in limiting the oxidative damage. Treatment with DPN resulted in the up-regulation of cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) expression, while PPT up-regulated expression of CREB without affecting BDNF levels. Moreover, both ER agonists provided protection against seizure-induced memory loss with a concomitant increase in hippocampal GABA(A)α1-positive cells. In conclusion, ER agonists, and more specifically ERβ agonist, appear to provide maximum protection against seizure-induced oxidative brain injury and associated memory dysfunction by up-regulating the expression of CREB, BDNF and GABA(A)α1 receptors.

Background: Plasminogen activator inhibitor-1 (PAI-1) antagonists are known for their neuroprotective effects. In this study, it was aimed to investigate the possible protective effects of PAI-1 antagonists in a rat mild traumatic brain injury (TBI) model.Method: Sprague Dawley male rats were grouped as sham (n=7), TBI (n=9), TBI + PAI-1 antagonist (5 and 10 mg/kg TM5441 and TM5484; n=6-7). Under anesthesia, TBI was induced by dropping a metal 300-gram weight from a height of 1 meter on the skull. Before and 24-hour after trauma neurological examination, tail suspension, Y-maze, novel object recognition tests were performed. Twenty-four hours after TBI, the rats were decapitated and activities of myeloperoxidase, nitric oxide release, luminol- and lucigenin-enhanced chemiluminescence were measured. Also, interleukin-1b, interleukin-6, tumor necrosis factor, interleukin-10, tumor growth factor-b, caspase-3, cleaved caspase-3, and PAI levels were measured with the ELISA method in the brain tissue. Brain injury was graded histopathologically following hematoxylin-eosin staining. Western blot and immunohistochemical investigation for low-density lipoprotein receptor, matrix metalloproteinase-3 and nuclear factor-kB were also performed. Data were analyzed using GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA) and expressed as means ± SEM. Values of p < 0.05 were considered to be statistically significant.Results: Higher levels of myeloperoxidase activity in the TBI group (pConclusion: PAI antagonists, especially TM5441, has antioxidant and anti-inflammatory properties against mild TBI in the acute period. Behavioral test results were also improved after PAI antagonist treatment after mild TBI.

Cancer as the leading cause of death worldwide has many issues that still need to be addressed. Since the alterations on the glycan compositions or/and structures (i.e., glycosylation, sialylation, and fucosylation) are common features of tumorigenesis, glycomics becomes an emerging field examining the structure and function of glycans. In the past, cancer studies heavily relied on genomics and transcriptomics with relatively little exploration of the glycan alterations and glycoprotein biomarkers among individuals and populations. Since glycosylation of proteins increases their structural complexity by several orders of magnitude, glycome studies resulted in highly dynamic biomarkers that can be evaluated for cancer diagnosis, prognosis, and therapy. Glycome not only integrates our genetic background with past and present environmental factors but also offers a promise of more efficient patient stratification compared with genetic variations. Therefore, studying glycans holds great potential for better diagnostic markers as well as developing more efficient treatment strategies in human cancers. While recent developments in glycomics and associated technologies now offer new possibilities to achieve a high-throughput profiling of glycan diversity, we aim to give an overview of the current status of glycan research and the potential applications of the glycans in the scope of the personalized medicine strategies for cancer. WOS:000628899900003 33404348 Q2

Aims: This study aims to evaluate medical students’ knowledge, thoughts, and awareness of the COVID-19 pandemic. Metho- ds: A questionnaire consisting of 31 questions was prepared for this descriptive study. In the questionnaire, medical students’ knowledge, attitudes and behaviors during the COVID-19 pandemic were investigated. Categorical variables are demonstrated as numbers and percentages, whereas continuous variables are presented as minimum, maximum, and mean values. Results: A total of 575 participants completed the questionnaire. The mean participant age was 21.7 years. Fifty-two percent of participants knew about the coronaviridae family before the outbreak and 38.8% were informed about COVID-19 in their medical schools. Of the students, 99.7% stated that the first case’s origin was in China. Eighty percent of the participants stated that droplet spread is the transmission route of COVID-19. The most common opinion about the incubation period of the SARS CoV-2 was two to twelve days. Being older than 65 years old, having a comorbidity, being immunosuppressed, or working in the healthcare sector were the most particular risk factors to get infected. The majority of the participants follow the vaccine developments from social media, radio and television. According to 75.83% of the participants, all people should wear a mask in daily life for protection. Conclusion: The epidemiology and diagnostic factors of COVID-19 are well known by medical students. To minimize informa- tion pollution and raise awareness, medical students should be educated about pandemic and management of it. Further evalu- ation with various methods and more participants may help to better understand the awareness of the COVID-19 pandemic in medical students.

AIM: To identify the copy number variations that are specific to myxopapillary ependymomas (MPEs) of the cauda equina. MATERIAL and METHODS: The patient cohort included five patients who underwent resection of histologically confirmed MPEs. Tumor samples collected during surgery and stored in liquid nitrogen as well as corresponding blood samples collected were analyzed. Genomic DNA from the venous blood and tumor samples was obtained using standard techniques and hybridized to a Cytoscan 750K Array in accordance with the manufacturer's introductions. RESULTS: As a novel finding, amplification on chromosome 14q32.33 was detected in all tumor and blood samples, except one tumor sample. All tumor tissues also showed amplification on chromosomes 5, 7, 9, and 16. CONCLUSION: Although further studies with larger cohorts are required to identify genes involved in MPE tumorigenesis and to validate our results, these findings provide a basis for advanced molecular biological and genetic studies of MPEs.

Objectives: The purpose of this study was to investigate possible protective effects of St. John's wort in the hepatic ischemia/reperfusion injury. Material and Methods: The hepatic artery, portal vein, and bile duct were all clamped for 45 minutes to induce ischemia in rats, and after that reperfusion for 1 hour. SJW was administrated orally, once a day for 3 days before ischemia/reperfusion. The aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor, and interleukin levels were measured in the serum samples. Luminol chemiluminescence, lucigenin luminol chemiluminescence levels; myeloperoxidase. The sodium-potassium ATPase (Na+/K+ ATPase) activity was determined in the liver tissue, and caspase-3 and caspase-9 activity with the bcl-2/bax ratio were measured by the western blot analysis. Results: The St. John's wort administration recovered the aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor, and IL-1 beta levels serum parameters meaningfully, while ischemia/reperfusion caused an increase in luminol chemiluminescence, lucigenin luminol chemiluminescence, myeloperoxidase, caspase-3, and caspase-9 activity and led to a decrease in the B-cell lymphoma-2/bcl-2-associated X protein (bcl-2/bax) ratio and the Na+/K+ ATPase activity. Conclusion: The obtained results indicate protective effects of St. John's wort on the ischemia/reperfusion injury through various mechanisms, and we are able to suggest that St. John's wort can clinically create a new therapeutic principle.

Background: Radiographic severity of ankylosing spondylitis (AS) shows such great variance that some patients never develop syndesmophytes throughout the entire disease span, whereas some develop bamboo spine relatively early. Objective: To study the association between ERAP1, IL23R and PTGER4 single nucleotide polymorphisms (SNPs) and radiographic severity in AS patients. Methods: rs27044 and rs30187 (ERAP1), rs11209032 (IL23R) and rs10440635 (PTGER4) SNPs were genotyped in 235 AS patients fulfilling the modified New York criteria. Patients were classified as mild- and severe-AS according to modified Stoke AS spinal score (mSASSS). Mild-AS is defined as having mSASSS of “0” following at least 10 years of disease duration. Severe-AS is defined as having mSASSS of >20 (patients with mild vertebral changes (i.e. squaring or erosions) were omitted for clear stratification) regardless of disease duration. Results: The genotype distributions and allele frequencies of ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNPs were similar in mild- (n=171, mSASSS=0, 55.6% HLA-B27 positive) and severe-AS patients (n=64, mSASSS=48.5±17.8, 73.4% HLA-B27 positive). After adjustment for clinical differences between groups (gender, disease duration, HLA-B27 and smoking status) by logistic regression analysis, none of the alleles in the investigated SNPs were found to be associated with radiographic severity of AS. Conclusion: In radiographically well-categorized AS patients, ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNPs are not found to be associated with radiographic severity of AS.

BACKGROUND: The insulin-like growth factor binding protein5 (IGFBP5) is often dysregulated in human cancers and considered neither a tumor suppressor nor an oncogene. OBJECTIVE: We aim to examine the reason of the changeable gene regulation of IGFBP5 in the case of methylation in breast cancer. METHODS: We used methyl-specific polymerase (MSP) chain reaction to detect CpG methylation of IGFBP5 promoter and exon-I in breast cancer and adjacent tissues. Gene expression is evaluated by quantative polymerase chain reaction (qPCR). RESULTS: IGFBP5 methylation was detected in 24 of 58 (41%) and 54 of 56 (96.5%) promoter and exon-I site respectively in tumor tissues. In adjacent tissues 17 of 58 (29%) and 53 of 56 (96.5%) was methylated. IGFBP5 expression was higher estrogene receptor (ER)(+) than ER(-) patients (p = 0:0549). Beside, we found a positive correlation between the expression of IGFBP5 and G2 tumor grade (p = 0:0131). However, no correlation was observed between IGFBP5 expression and age, menopause or the presence of lymph node metastasis (p > 0:05). CONCLUSIONS: In summary, our results showed that IGFBP5 promoter and exon-I methylation did not have any differences between tumor and adjacent tissues so that IGFBP5 methylation did not change IGFBP5 gene regulation in breast cancer. This is the first study investigating the IGFBP5 gene methylation in breast cancer. © 2016 - IOS Press and the authors.

Objective: In the present study, it was aimed to study the antioxidant effects of spironolactone (SPL) to determine its possible protective effects in hepatic ischemia reperfusion injury. Material and Methods: Hepatic artery, portal vein, and bile duct of Wistar albino rats were clamped for 45 minutes under anesthesia to form an ischemia period. Then reperfusion was allowed and the rats were decapitated 60 minutes later. SPL (20 mg/kg, p.o.) or SF was orally administered for 30 minutes before ischemia. Rats in the control arm underwent sham surgery and were administered isotonic saline. Liver function was studied by measuring aspartate aminotransferase (AST), alanine aminotransferase (ALT), tumor necrosis factor-alpha (TNF-alpha), and interleukin 1beta (IL-1 beta) levels. Malondialdehyde (MDA), glutathione (GSH), luminol, and lucigenin levels, myeloperoxidase (MPO) and Na+-K+- ATPase enzyme activities were analyzed to study tissue injury under light microscope. Results: While IR increased AST, ALT, TNF-alpha, and IL-1 beta levels and MDA, luminol, and lusigenin levels and MPO activities, it caused a decrease in GSH levels and Na+K+-ATPase activity. Spironolactone administration significantly improved these values. Conclusion: Protective effects of SPL against ischemia/reperfusion injury via various mechanisms suggest that this agent may become a novel treatment agent in clinical practice.

Background Cells detaching from the primary tumor site are metastasis initiator cells, and the detection of CTC, known as liquid biopsy, is an important test of biomarkers of cancer progression. We investigated the molecular characterization of circulating tumor cells (CTCs), profiled the plasma microRNA (miR) content, and analyzed the relationship with the clinical outcomes by sampling the peripheral blood from patients with locally advanced breast cancer before and after neoadjuvant chemotherapy. Patients and Methods Markers of breast cancer, epithelial–mesenchymal transition (EMT), drug resistance, and stem cells were used for CTC isolation and characterization. Plasma miR profiles were obtained from selected patients with CTC positivity determined using next-generation sequencing. Results The proportion of CTC, EMT, and stem cell marker positivity was 16.7%, 8.3%, and 25% before and 18.2%, 15.2%, and 9.1% after treatment, respectively. A significant correlation was found between the pretreatment CTCs and ALDH1 positivity (P = .0245). These CTCs with stemness properties were observed in most hormone receptor–positive, human epidermal growth factor receptor 2–negative cases and were also present with a high incidence in cases of early metastasis. miR-146b-5p and miR-199a-5p, which are involved in metastasis, invasion, and EMT, were accompanied by CTC positivity, and miR-4646-3p was associated with the development of early metastasis. Conclusions Molecular characterization of CTCs and miR profiling of serial samples from patients with locally advanced breast cancer during neoadjuvant chemotherapy appears to be a very useful in predicting cure and clinical course and might be a key to developing new targeted therapies.

Telomeres are the tandem repeats (TTAGGG) present at the ends of the chromosomes that ensure chromosome stability and protect chromosomes from degradation. Telomeres in somatic human cells shorten after every cellular division and are linked to the cellular senescence. In this study we have investigated telomere length and expression of shelterin genes in aborted fetus material from idiopathic recurrent pregnancy losses. Telomere length was measured using Telomere Restriction Fragment Length (TRF) analysis. The gene expression levels for important shelterin complex proteins (TRF1, TRF2, POT1, and TPP1) were determined by Real-time Quantitative Reverse Transcriptase PCR (qRT-PCR). Our results demonstrated down regulation of TRF2 and TPP1 and a strong decline in average telomere length in abort material from women suffering from idiopathic recurrent pregnancy loss. We suggest that shorter telomere length and downregulation of the major shelterin components TRF2 and TPP1 leading to "telomere uncapping", might play a critical role in recurrent pregnancy loss.

WOS:000215712700012 Purpose: The present study was conducted to characterize the possible therapeutic effects of glucagon-like peptide (GLP)-1 and GLP-2 against oxidative damage in the ileum and colon of irradiated rats. Methods and materials: Sprague-Dawley rats of both sexes received either a single dose of GLP-1 (0.1 nmol/kg, intraperitoneally, ip; n = 6) 10 min before abdominal irradiation (IR) or two consecutive doses of GLP-2 (7 nmol/kg, ip; n = 6) at 30 and 10 min before IR, while another group was administered vehicle (n = 6) 10 min before IR. Control rats (n = 6) received vehicle treatment without IR. On the fourth day of IR, samples from ileum and colon were removed for histological analysis, for the determination of myeloperoxidase (MPO) activity, malondialdehyde (MDA) and glutathione (GSH) levels, as well as DNA fragmentation ratio, an index of apoptosis. Results: IR-induced oxidative injury in the colonic tissue of vehicle-treated rats, evidenced by elevated MDA levels and MPO activity, as well as depleted colonic GSH levels, was reversed by GLP-2, while GLP-1 reduced IR-induced elevations in colonic MDA levels. IR-induced injury with elevated ileal MDA levels was reduced by GLP-1, while replenishment in GSH was observed in GLP-2-treated rats. Conclusion: Current findings suggest that GLP-1 and GLP-2 appear to have protective roles in the irradiation-induced oxidative damage of the gut by inhibiting neutrophil infiltration and subsequent activation of inflammatory mediators that induce lipid peroxidation. Copyright (C) 2015, The Egyptian Society of Radiation Sciences and Applications. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license.

The functional role of IGFBP5 in breast cancer is complicated. Experimental and bioinformatics studies have shown that IGFBP5 is targeted by miR-140-5p and miR-193b, although this has not yet been proven in clinical samples. The aim of this study was to evaluate the expression of miR-140-5p and miR-193b in breast cancer and adjacent normal tissue and assess its correlation with IGFBP5 and the clinicopathological characteristics of the tumors. IGFBP5 protein expression was analyzed immunohistochemically and IGFBP5, miR-140 and miR-193b mRNA expression levels were analyzed with real-time RT-PCR. Tumor tissue had higher miR-140-5p expression than adjacent normal tissue (p = 0.015). Samples with no immunohistochemical staining for IGFBP5 showed increased miR-140-5p expression (p = 0.009). miR-140-5p expression was elevated in invasive ductal carcinomas (p = 0.002), whereas basal-like tumors had decreased expression of miR-140-5p compared to other tumors (p = 0.008). Lymph node-positive samples showed an approximately 13-fold increase in miR-140-5p expression compared to lymph node-negative tissue (p = 0.049). These findings suggest that miR-140-5p, but not miR-193b, could be an important determinant of IGFBP5 expression and clinical phenotype in breast cancer patients. Further studies are needed to clarify the expressional regulation of IGFBP5 by miR-140-5p.

Objective Observed low prevalence of SLE among familial Mediterranean fever (FMF) patients in several large cohorts suggests a possible protective effect of the MEFV mutations from SLE. In contrast, SLE patient carriers for the common MEFV mutations had rather complex disease expression with an increased frequency of febrile episodes and pleurisy and a decreased renal complication rate. Our aim was to investigate the prevalence of MEFV gene mutations in patients with SLE and their effect on organ involvement in a well-defined group of biopsy-proven SLE nephritis patients. Material and method The prevalence of four MEFV gene mutations (M694V, M680I, V726A and E148Q) was investigated in 114 SLE patients and effect on disease severity was analyzed in patients with biopsy-proven SLE nephritis. Results None of the SLE patients fulfilled the revised Tel-Hashomer criteria. Fourteen of 114 SLE patients (12.2%) were found to carry at least one MEFV mutation. A single patient in the SLE-Nephritis group was compound heterozygous for M694V/M680I mutations and only one patient in the SLE-Mild group was homozygous for E148Q mutation. Carrier frequency was similar to controls in SLE patients (12.2 vs 18.8%, p = 0.34). After the exclusion of the less penetrant E148Q mutation, re-analysis revealed an association between exon 10 mutations and SLE nephritis ( p = 0.050, odds ratio (OR) = 4.16, 95% confidence interval (CI) = 1.04–16.6). Carrier rate for the E148Q mutation decreased in the SLE group (controls vs. SLE = 20/186 vs. 3/114, p = 0.08) and E148Q mutation was absent in SLE nephritis (controls vs. SLE nephritis = 20/186 vs. 0/47, p = 0.016, OR = 11.69, 95% CI = 0.69–197.13). Conclusions Carrier rate for the studied MEFV mutations was slightly lower in the SLE group, which is in agreement with previous observations that FMF may confer some protection from SLE. Exon 10 mutations were associated with SLE nephritis after the exclusion of the E148Q mutation. The significance of the E148Q as a disease-causing mutation is controversial, and whether E148Q substitution is a polymorphism generally affecting inflammatory pathways is not addressed in the current literature. In this regard, absence of the E148Q mutation in SLE nephritis may serve as a clue for further investigation into its role as a general modulatory polymorphism for inflammation. This clarification is necessary to conclude whether other more penetrant MEFV gene mutations confer susceptibility to nephritis in SLE.

Obstructive jaundice (OJ) can be defined as cessation of bile flow into the small intestine due to benign or malignant changes. Nesfatin-1, recently discovered anorexigenic peptide derived from nucleobindin-2 in hypothalamic nuclei, was shown to have anti-inflammatory and antiapoptotic effects. This study is aimed to investigate the therapeutic effects of nesfatin-1 on OJ in rats. Twenty-four adult male Wistar-Hannover rats were randomly assigned to three groups: sham (n = 8), control (n = 8), and nesfatin (n = 8). After bile duct ligation, the study groups were treated with saline or nesfatin-1, for 10 days. Afterward, blood and liver tissue samples were obtained for biochemical analyses, measurement of cytokines, determination of the oxidative DNA damage, DNA fragmentation, and histopathologic analyses. Alanine aminotransferase and gamma-glutamyl transferase levels were decreased after the nesfatin treatment; however, these drops were statistically non-significant compared to control group (p = 0.345, p = 0.114). Malondialdehyde levels decreased significantly in nesfatin group compared to control group (p = 0.032). Decreases in interleukin-6 and tumor necrosis factor-α levels from the liver tissue samples were not statistically significant in nesfatin group compared to control group. The level of oxidative DNA damage was lower in nesfatin group, however this result was not statistically significant (p = 0.75). DNA fragmentation results of all groups were similar. Histopathological examination revealed that there was less neutrophil infiltration, edema, bile duct proliferation, hepatocyte necrosis, basement membrane damage, and parenchymal necrosis in nesfatin compared to control group. The nesfatin-1 treatment could alleviate cholestatic liver damage caused by OJ due to its anti-inflammatory and antioxidant effects.

Background Thermal injury may cause distant organ inflammation and multiorgan failure. Oxytocin (OT), a nonapeptide, modulates the immune and inflammatory processes. Materials and Methods To investigate the effects of oxytocin on burn-induced tissue injury, Sprague-Dawley rats were subjected to a partial thickness burn. Immediately after burn, half of the burned rats were placed single in the cages, while others were caged in groups. All the rats then were treated with either OT (5 μg/kg, s.c) or saline twice daily for 5 d. The control rats had no burn injury and received no treatments. On day 5, the rats were decapitated, tissue and serum samples were obtained to score the severity of damage and to assay TNF-α levels. Results Burn trauma resulted in oxidative ileal damage, as evidenced by increased apoptotic rate, increased neutrophil recruitment, and enhanced lipid peroxidation. OT treatment depressed the TNF-α level and alleviated dermal degeneration, while attenuating ileal damage. Although a higher degree of skin damage was observed in the animals kept isolated following burn injury, keeping the rats in groups did not affect the level of TNF-α or the severity of dermal or ileal injury, but abolished the burn-induced elevations in ileal lipid peroxidation and myeloperoxidase activity. Moreover, OT treatment reduced the ileal apoptosis when applied to rats housed in groups, while the treatment did not alter apoptotic ratio in the isolated rats. Conclusion Oxytocin can be considered as a potential agent in treating burn-induced distant organ injury.

The neuroprotective effect of alpha lipoic acid (ALA; 100 mg/kg, po), a dithiol antioxidant, on experimentally induced subarachnoid hemorrhage (SAH) was assessed in Wistar albino rats. Neurological examination scores recorded at the 48th h of SAH induction were increased in SAH groups, which were accompanied with significant increases in the formation of reactive oxygen species, DNA fragmentation ratios, malondialdehyde levels and myeloperoxidase activity, while significant decreases in the brain glutathione content and Na(+), K(+)-ATPase activity were observed. On the other hand, ALA treatment reversed all these biochemical indices as well as SAH-induced histopathological alterations. Increased brain edema, impaired blood-brain-barrier permeability and neurological scores were also improved by ALA treatment. The results demonstrate that ALA exerts neuroprotective effects via the enhancement of endogenous antioxidant enzyme activity, the inhibition of neutrophil accumulation and free radical generation, suggesting a therapeutic potential in reducing secondary injury after SAH in patients.

To evaluate the role of ALA treatment on the healing of acetic acid-induced gastric ulcer, rats were given ALA (35 mg/kg/day) or saline for 3 days before the induction of ulcer and the treatment was continued twice daily for 2 days (early) or 10 days (late) until they were decapitated. Gastric ulcer index, microscopic score, elevated DNA fragmentation and chemiluminescence levels of the saline-treated ulcer groups were all reduced by ALA treatment. Likewise, ALA treatment inhibited chemiluminescence levels in both early and late ulcer groups. Marked reduction in glutathione levels of the saline-treated early ulcer group was reversed by ALA treatment, while ALA treatment was effective in depressing gastric myeloperoxidase activity in the late ulcer group. In conclusion, ALA treatment shows protective role in the healing of acetic acid-induced gastric injury in rats via the suppression of neutrophil accumulation, preservation of endogenous glutathione, inhibition of reactive oxidant generation and apoptosis.

Mechanisms of burn-induced skin and remote organ injury involve oxidant generation and the release of pro-inflammatory cytokines. In this study the possible antioxidant and anti-inflammatory effects of ghrelin were evaluated in a rat model of thermal trauma. Wistar albino rats were exposed to 90 degrees C bath for 10 s to induce thermal trauma. Ghrelin, was administered subcutaneously (10 ng/kg/day) after the burn injury and repeated twice daily. Rats were decapitated at 6 h and 48 h after burn injury and blood was collected for the analysis of pro-inflammatory cytokines (TNF-alpha and IL-1beta), lactate dehydrogenase (LDH) activity and antioxidant capacity (AOC). In skin, lung and stomach tissue samples malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) and Na(+)-K(+)-ATPase activity were measured in addition to the histological analysis. DNA fragmentation ratio in the gastric mucosa was also evaluated. Burn injury caused significant increase in both cytokine levels, and LDH activity, while plasma AOC was found to be depleted after thermal trauma. On the other hand, in tissue samples the raised MDA levels, MPO activity and reduced GSH levels, Na(+)-K(+)-ATPase activity due to burn injury were found at control levels in ghrelin-treated groups, while DNA fragmentation in the gastric tissue was also reduced. According to the findings of the present study, ghrelin possesses a neutrophil-dependent anti-inflammatory effect that prevents burn-induced damage in skin and remote organs and protects against oxidative organ damage.

Transient splanchnic vasoconstriction following major burns causes oxidative and/or nitrosative damage in gastrointestinal tissues due to ischemia, which is followed by reperfusion injury. Oxytocin (OT), a hypothalamic nonapeptide, possesses antisecretory and antiulcer effects, facilitates wound healing and is involved in immune and inflammatory processes. To assess the possible protective effect of oxytocin (OT) against burn-induced gastric injury, Sprague–Dawley rats (250–300 g) were randomly divided into three groups as control (n = 8), OT-treated burn (n = 8) and saline-treated burn (n = 8) groups. Under anesthesia, the shaved dorsal skin of rats was exposed to 90 °C water for 10 s to induce burn injury covering 30% of total body surface area in a standardized manner. Either oxytocin (5 μg/kg) or saline was administered subcutaneously immediately after and at 24 h following burn, and the rats were decapitated at 48 h. Serum samples were assayed for TNF-alpha, and stomach was taken for the determination of malondialdehyde (MDA), myeloperoxidase (MPO) activity, DNA fragmentation rate (%) and histopathological examination. MDA and MPO were assayed for products of lipid peroxidation and as an index of tissue neutrophil infiltration, respectively. When compared to control group, burn caused significant increases in gastric MDA and MPO activity and increased microscopic damage scores at 48 h (p < 0.001). Oxytocin treatment reversed the burn-induced elevations in MDA and MPO levels and reduced the gastric damage scores (p < 0.001, p < 0.01), while TNF-alpha levels, which were increased significantly at 48th h after injury (p < 0.001), were abolished with OT treatment (p < 0.001). The results of this study suggest that oxytocin may provide a therapeutic benefit in diminishing burn-induced gastric inflammation by depressing tissue neutrophil infiltration and decreasing the release of inflammatory cytokines, but requires further investigation as a potential therapeutic agent in ameliorating the systemic effects of severe burn.

Background/Aims: This investigation elucidates the role of free radicals in ethanol-induced gastric mucosal erosion and the protective effect of lipoic acid. Methods: After overnight fasting, Wistar albino rats were orally treated with 1 ml of absolute ethanol to induce gastric erosion. Lipoic acid (100 mg/kg) was given orally for 3 days before ethanol administration. Mucosal damage was evaluated 1 h after ethanol administration by macroscopic examination and histological analysis. Additional tissue samples were taken for measurement of malondialdehyde, glutathione (GSH), and myeloperoxidase activity. Production of reactive oxidants and oxidant-induced DNA fragmentation and Na+,K+-ATPase activity were also assayed in the tissue samples. Results: Generation of reactive oxygen species and lipid peroxidation associated with neutrophil infiltration play an important role in the pathogenesis of gastric mucosal damage induced by ethanol. Furthermore, oxidants depleted tissue GSH stores and impaired membrane structure as Na+,K+-ATPase activity was inhibited. On the other hand, lipoic acid treatment reversed all these biochemical indices as well as the histopathological changes induced by ethanol. Conclusion: These data suggest that lipoic acid administration effectively counteracts the deleterious effect of ethanol-induced gastric mucosal injury and attenuates gastric damage through its antioxidant effects.

Udgivelsesdato: 2007-Nov There is increasing evidence suggesting that stem cells are susceptive to carcinogenesis and, consequently, can be the origin of many cancers. Recently, the neoplastic potential of stem cells has been supported by many groups showing the existence of subpopulations with stem cell characteristics in tumor biopsies such as brain and breast. Evidence supporting the cancer stem cell hypothesis has gained impact due to progress in stem cell biology and development of new models to validate the self-renewal potential of stem cells. Recent evidence on the possible identification of cancer stem cells may offer an opportunity to use these cells as future therapeutic targets. Therefore, model systems in this field have become very important and useful. This review will focus on the state of knowledge on cancer stem cell research, including cell line models for cancer stem cells. The latter will, as models, help us both in the identification and characterization of cancer stem cells and in the further development of therapeutic strategies including tissue engineering

The present study was designed to determine the possible protective effects of Ginkgo biloba extract (EGb) against oxidative organ damage induced by irradiation (IR). Sprague-Dawley rats were exposed to whole-body IR (800 cGy) after a 15-day pretreatment with either saline or EGb (50 mg/kg/day), intraperitoneally, and treatments were repeated immediately after the IR. Then the rats were decapitated at either 6 h or 72 h after IR, where EGb or saline injections were repeated once daily. Lung, liver, kidney and ileum samples were obtained for the determination of malondialdehyde, glutathione levels, myeloperoxidase activity and collagen contents, while oxidant-induced DNA fragmentation was evaluated in the ileal tissues. All tissues were also examined microscopically and assayed for the production of reactive oxidants using chemiluminescence (CL). Lactate dehydrogenase (LDH)-an indicator of tissue damage and TNF-alpha were assayed in serum samples. In the saline-treated irradiation groups, glutathione levels were decreased significantly, while the malondialdehyde levels, myeloperoxidase activity and collagen content were increased in the tissues (p < 0.01-0.001), which were in parallel with the increases in luminol and lucigenin CL values. In the EGb treated-IR groups, all of these oxidant responses were prevented significantly (p < 0.05-0.01). LDH and TNF-alpha levels, which were increased significantly (p < 0.01-0.001) following IR, were decreased (p < 0.05-0.001) with EGb treatment. In conclusion, the present data demonstrate that EGb, through its free radical scavenging and antioxidant properties, attenuates irradiation-induced oxidative organ injury, suggesting that EGb may have a potential benefit in enhancing the success of radiotherapy.

A 19-year-old woman presented with pain at the lateral side of the fifth toe of her left foot, which was separated from the adjacent toe. Initial examination suggested dislocation of the fifth metatarsophalangeal joint due to a past fracture. Radiographs showed a mass arising from the proximal phalanx of the little toe, with no medullary and cortical continuity. Excisional biopsy of the mass was performed, and a histologic diagnosis of bizarre parosteal osteochondromatous proliferation of bone (Nora’s lesion) was made. (J Am Podiatr Med Assoc 96(2): 158–161, 2006)

Traumatic injury to the central nervous system results in the delayed dysfunction and neuronal death. Impaired mitochondrial function, generation of reactive oxygen species (ROS), and lipid peroxidation occur soon after traumatic spinal cord injury (SCI), while the activation of compensatory molecules that neutralize ROS occurs at later time points. The aim of the current study was to investigate the putative neuroprotective effect of the COX2 inhibitor meloxicam in a rat model of SCI. In order to induce SCI, a standard weight-drop method that induced a moderately severe injury (100 g/cm force) at T10, was used. Injured animals were given either 2 mg/kg meloxicam or saline 30 min postinjury by intraperitoneal injection. At seven days postinjury, neurological examination was performed and rats were decapitated. Spinal cord samples were taken for histological examination or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and DNA fragmentation. Formation of ROS in spinal cord tissue samples was monitored by using a chemiluminescence (CL) technique. SCI caused a significant decrease in spinal cord GSH content, which was accompanied with significant increases in CL, MDA levels, MPO activity, and DNA damage. On the other hand, meloxicam treatment reversed all these biochemical parameters as well as SCI-induced histopathological alterations. Furthermore, impairment of the neurological functions due to SCI was improved by meloxicam treatment. The present study suggests that meloxicam, reduces SCI-induced oxidative stress and exerts neuroprotection by inhibiting lipid peroxidation, GSH depletion, and DNA fragmentation.

To elucidate the putative neuroprotective effects of ghrelin in subarachnoid hemorrhage (SAH)-induced brain injury, Wistar albino rats (n = 54) were divided into sham-operated control, saline-treated SAH, and ghrelin-treated (10 microg/kg/d IP) SAH groups. The rats were injected with blood (0.3 mL) into the cisterna magna to induce SAH, and were sacrificed 48 h after the neurological examination scores were recorded. In plasma samples, neuron-specific enolase (NSE), S-100beta protein, TNF-alpha, and IL-1beta levels were evaluated, while forebrain tissue samples were taken for the measurement of malondialdehyde (MDA), glutathione (GSH), reactive oxygen species levels, myeloperoxidase (MPO), Na(+)-K(+)-ATPase activity, and DNA fragmentation ratio. Brain tissue samples containing the basilar arteries were obtained for histological examination, while cerebrum and cerebellum were removed for the measurement of blood-brain barrier (BBB) permeability and brain water content. The neurological scores were impaired at 48 h after SAH induction, and SAH caused significant decreases in brain GSH content and Na(+)-K(+)-ATPase activity, and increases in chemiluminescence, MDA levels, and MPO activity. Compared with the control group, the protein levels of NSE, S-100beta, TNF-alpha, and IL-1beta in plasma were also increased, while ghrelin treatment prevented all SAH-induced alterations observed both biochemically and histopathologically. The results demonstrate that ghrelin alleviates SAH-induced oxidative brain damage, and exerts neuroprotection by maintaining a balance in oxidant-antioxidant status, by inhibiting proinflammatory mediators, and preventing the depletion of endogenous antioxidants evoked by SAH.

Background: Oxidative stress is a mediator of secondary injury to the spinal cord following trauma. Objective: To investigate the putative neuroprotective effect of a-lipoic acid (LA), a powerful antioxidant, in a rat model of spinal cord injury (SCI). Methods: Wistar albino rats were divided as control, vehicle-treated SCI, and LA-treated SCI groups. To induce SCI, a standard weight-drop method that induced a moderately severe injury (100 g/cm force) at T10 was used. Injured animals were given either 50 mg/kg LA or saline at 30 minutes postinjury by intraperitoneal injection. At 7 days postinjury, neurologic examination was performed, and rats were decapitated. Spinal cord samples were taken for histologic examination or determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and DNA fragmentation. Formation of reactive oxygen species in spinal cord tissue samples was monitored by using a chemiluminescence (CL) technique. Results: SCI caused a significant decrease in spinal cord GSH content, which was accompanied with significant increases in luminol CL and MDA levels, MPO activity, and DNA damage. Furthermore, LA treatment reversed all these biochemical parameters as well as SO-induced histopathologic alterations. Conversely, impairment of the neurologic function caused by SCI remained unchanged. Conclusion: The present study suggests that LA reduces SCI-induced oxidative stress and exerts neuroprotection by inhibiting lipid peroxidation, glutathione depletion, and DNA fragmentation.

The present study was undertaken to determine whether resveratrol (RVT) could ameliorate ionizing radiation-induced oxidative injury. After a 10-days pre-treatment with RVT (10 mg/kg/day p.o.), rats were exposed to whole-body IR (800 cGy) and the RVT treatment was continued for 10 more days after the irradiation. Irradiation caused a significant decrease in glutathione level, while malondialdehyde levels, myeloperoxidase activity and collagen content were increased in the liver and ileum tissues. Similarly, plasma lactate dehydrogenase and pro-inflammatory cytokine levels, 8-hydroxy-2'-deoxyguanosine and leukocyte apoptosis were elevated, while antioxidant-capacity was reduced in the irradiated rats as compared with the control group. Furthermore, Na(+), K(+)-ATPase activity was inhibited and DNA fragmentation was increased in the ileal tissues. Resveratrol treatment reversed all these biochemical indices, as well as histopathological alterations induced by irradiation. In conclusion, supplementing cancer patients with adjuvant therapy of resveratrol may have some benefit for a more successful radiotherapy.

Background Ankylosing spondylitis (AS) is an inflammatory disease predominantly affecting spine which may lead to syndesmophyte formation and disability. However, the new bone formation and the radiographic severity of AS shows great variance that some patients never develop syndesmophytes throughout the entire disease duration, whereas some develop spinal fusion. The genetic determinants of this variance has not been identified yet in a well-defined mild-radiograhic AS and severe-radiographic AS. Objectives To determine the association between ERAP1 , IL23R and PTGER4 polymorphisms and radiographic severity of AS and secondly to identify clinical characteristics associated with severe radiographic AS. Methods rs27044 and rs30187 ( ERAP1 gene), rs11209032 ( IL23R gene) and rs10440635 ( PTGER4 gene) single nucleotide polymorphisms (SNP) were genotyped in total of 199 AS patients (F/M: 83/116, mean age: 42.1±11.0 years, 62.8% HLA-B27 [+]) fulfilling the 1984 modified New York criteria for AS. Patients were classifed as severe-radiographic AS and mild-radiographic AS according to modified Stoke AS spinal score (m-SASSS). Mild AS is defined as having m-SASSS of “0” despite ≥10 years of disease duration. Whereas severe AS is defined as having m-SASSS of >20 (without counting scores “1”) regardless of the disease duration. Results Fifty eight patients (F/M=9/49, mean age 50.7±9.3, disease duration 21.9±7.0 years) were classified as severe AS, 141 patients (F/M=74/67, mean age 38.3±9.1, disease duration 13.6±4.9 years) were classified as mild AS. Severe group had significantly higher m-SASSS scores (48.5±18.3 vs 0) ( P ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNP genotypes between severe and mild AS (Table 2). The genotype frequencies did not change when severe and mild AS patients were categorized according to gender or HLA-B27 status. Concerning clinical and demographic characteristics, it was found that majority of severe AS patients were males (84.5%) and severe AS patients had significantly higher coxofemoral joint involvement (43.1% vs 22.2%, P =0.003), uveitis (25.9% vs 12.8%, P =0.024), anti-TNF usage (70.7% vs 39.7, P P =0.026) compared to mild AS. In multi-variate analysis male gender (OR=0.19, 95% CI [0.087-0.42], P P =0.033) were independently associated with severe AS. Conclusions Our data with a well-defined categorization of mild and severe-radiographic AS underline that ERAP1 rs27044 and rs30187, IL23R rs11209032 and PTGER4 rs10440635 SNPs are not associated with radiographic severity of AS. Whereas male gender and coxofemoral joint involvement are associated with severe-radiographic AS. Disclosure of Interest None declared

The objective of this study was to examine the potential radioprotective properties of propylthiouracil (PTU)-induced hypothyroidism against oxidative organ damage induced by irradiation. Sprague–Dawley rats were pre-treated with saline or PTU (10 mg/kg i.p.) for 15 days, and were then exposed to whole-body irradiation (800 cGy). A group of rats were decapitated at 6 h after exposure to irradiation, while another group was followed for 72 h after irradiation, during which saline or PTU injections were repeated once daily. Lung, liver, kidney and ileum samples were obtained for the determination of malondialdehyde (MDA; an index of lipid peroxidation) and glutathione (GSH, an antioxidant) levels, myeloperoxidase activity (MPO; an index of tissue neutrophil accumulation) and collagen contents, while oxidant-induced DNA fragmentation was evaluated in the ileal tissues. All tissues were also examined microscopically and assayed for the production of reactive oxidants using chemiluminescence (CL). Lactate dehydrogenase (LDH), an indicator of tissue damage, and tumour necrosis factor-α (TNFα) were assayed in serum samples. Irradiation caused a significant decrease in GSH level, which was accompanied by significant increases in MDA levels, MPO activity, CL levels and collagen content of the tissues studied (P

Background\ud \ud Mutations in the gene coding for the RNA component of telomerase, hTERC, have been found in autosomal dominant dyskeratosis congenita (DC) and aplastic anemia. Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal blood disorder associated with aplastic anemia and characterized by the presence of one or more clones of blood cells lacking glycosylphosphatidylinositol (GPI) anchored proteins due to a somatic mutation in the PIGA gene.\ud \ud Methods\ud \ud We searched for mutations in DNA extracted from PNH patients by amplification of the hTERC gene and denaturing high performance liquid chromatography (dHPLC). After a mutation was found in a potential transcription factor binding site in one patient electrophoretic mobility shift assays were used to detect binding of transcription factors to that site. The effect of the mutation on the function of the promoter was tested by transient transfection constructs in which the promoter is used to drive a reporter gene.\ud \ud Results\ud \ud Here we report the finding of a novel promoter mutation (-99C->G) in the hTERC gene in a patient with PNH. The mutation disrupts an Sp1 binding site and destroys its ability to bind Sp1. Transient transfection assays show that mutations in this hTERC site including C-99G cause either up- or down-regulation of promoter activity and suggest that the site regulates core promoter activity in a context dependent manner in cancer cells.\ud \ud Conclusions\ud \ud These data are the first report of an hTERC promoter mutation from a patient sample which can modulate core promoter activity in vitro, raising the possibility that the mutation may affect the transcription of the gene in hematopoietic stem cells in vivo, and that dysregulation of telomerase may play a role in the development of bone marrow failure and the evolution of PNH clones.

Amac: Epidemiyolojik calismalar ulseratif kolitin sigara kullanmayanlarda daha sik goruldugunu bildirmektedir. Bu calismada kolitle olusan oksidan hasar ve anksiyete uzerine nikotin on tedavisinin ve/veya kolit sonrasi tedavinin olasi yararli etkilerinin arastirilmasi amaclanmistir. Gerec ve Yontem: Wistar Albino (250-300 g) sicanlar (n=40), serum fizyolojik (SF) verilen, on-tedavili, tedavili ve on-tedavi+ tedavili kolit grubu ve kontrol grubu olmak uzere bese ayrildi. Kolit oncesi 15 gun ve kolit sonrasinda 3 gun sicanlara intraperitoneal SF ya da nikotin (0,1 mg/kg/gun) uygulandi. Kolon orneklerinde oksidan hasari belirlemek icin malondialdehid (MDA), miyeloperoksidaz (MPO) aktivitesi, glutatyon (GSH), superoksit dismutaz (SOD), katalaz ve DNA fragmantasyonu olcumleri ile histolojik skorlama yapildi. Delikli kutu testi ile anksiyete seviyeleri belirlendi. Sonuclar ANOVA ve Mann Whitney U testi ile analiz edildi. Bulgular: Kolitte artan anksiyetenin nikotin ile degismedigi gozlendi. SF verilen kolit grubunda kolon MPO ve MDA duzeyleri ile DNA fragmantasyonunun ve hasar skorunun kontrol grubuna kiyasla arttigi, nikotin verilen tum kolit gruplarinda ise bu hasar gostergelerinin anlamli sekilde dustugu gozlendi. Histolojik doku hasari skorunun nikotin uygulanan kolit grubunda daha az oldugu gozlendi. SOD, katalaz ve GSH duzeylerindeki azalmanin nikotin tedavisiyle anlamli sekilde arttigi gozlendi. Sonuc: Calismada asetik asitle olusturulan kolit modelinde, nikotin tedavisinin doku antioksidan kapasitesini arttirarak, inflamasyon sonucu notrofil gocunu ve membran hasarini azaltarak antioksidan etki olusturdugu gosterildi.