The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity.

Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the benzyl ester of gypsogenin (1c), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (PT1-PT6), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (GP1-GP5) were synthesized. All of the synthesized compounds were purified and charachterized by different spectroscopic methods. Cytotoxicity of the parent triterpenes and the synthesized compounds against CML cell line K562 was examined; revealing three promising compounds PT5, GP2 and GP5 (IC50 5.46, 4.78 and 3.19 µM, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, PT5 was identified to have in vitro activity (IC50 = 1.44 µM) against ABL1 kinase, about sixfold of 1c, which was justified by molecular docking. The in vitro activities of GP2 and GP5 are less than PT5, hence they were supposed to possess other more mechanisms of cytotoxicity. In general, our design and derivatizations resulted in enhancing the activity against ABL1 kinase and CML cells.

The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities.

The discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC50 value of 9.3 µM. In contrast, the IC50 against normal peripheral blood mononuclear cells was 276.0 µM, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABL1) (IC50=8.7 µM), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and 1c was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppressed signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors.

Serum and aqueous xanthine oxidase levels, and mRNA expression in anterior lens epithelial cells in pseudoexfoliation.

PURPOSE: The aim of this study was to determine serum and aqueous xanthine oxidase (XO) levels, and mRNA expression in anterior lens epithelial cells in pseudoexfoliation (PEX). METHODS: In this prospective study, serum, aqueous and anterior lens capsules were taken from 21 patients with PEX and 23 normal subjects who had undergone routine cataract surgery. Serum and aqueous XO levels were analyzed using the colorimetric method. mRNA expression of XO in anterior lens epithelial cells was evaluated using reverse transcription polymerase chain reaction analysis. RESULTS: Serum XO levels (means ± standard deviations) were 207.0 ± 86.1 IU/mL and 240.6 ± 114.1 IU/mL in the normal and PEX groups, respectively (p = 0.310). Aqueous XO levels (means ± standard deviations) were 65.5 ± 54.3 IU/mL in the normal group and 130.5 ± 117.4 IU/mL in the PEX group (p = 0.028). There was a 2.9 fold decrease in mRNA expression in anterior lens epithelial cells of PEX, which is significantly lower than the normal group (p = 0.01). CONCLUSIONS: Higher aqueous XO levels lacking associated different serum XO suggests higher oxidative stress in the aqueous. Higher aqueous XO levels in PEX with decreased mRNA expression in anterior lens epithelial cells indicate possible overexpression of XO in other structures related to the aqueous.

Clinical and cytogenetic results of a large series of amniocentesis cases from Turkey: report of 6124 cases.

AIM: The aim of this study was to document the clinical and cytogenetic results of a large series of amniocentesis (AS) cases from Turkey. MATERIAL AND METHODS: Second-trimester amniocentesis cases performed in Suleymaniye Maternity Hospital for Research and Training between January 2007 and December 2011 were included. RESULTS: During this period, 6124 AS were performed. Indications were increased risk in maternal serum screening (MSS) (56%), advanced maternal age (29%) and pathologic ultrasound finding (11.5%). Most frequent MSS abnormality was abnormal triple test result (58%). Overall culture success rate was 98.8%. Chromosomal abnormality was detected in 215 (3.6%) of the 6052 cytogenetic results (74.9% numerical, 25.1% structural). Most frequent numerical chromosomal abnormality was trisomy 21 (61.9%). Clinically insignificant polymorphisms were the most frequent structural changes (n = 571). Most frequent polymorphism was increase in heterochromatin region in the 1st chromosome (n = 158). Advanced maternal age had a positive predictive value of 5.2%. Among the MSS tests, the combined test had the highest positive predictive value (5.2%). CONCLUSIONS: In our study, abnormal MSS (and among these, abnormal triple test result) was the most frequent indication for amniocentesis. Our overall culture success rate was 98.8%. Frequency of major chromosomal abnormality was 3.2% and trisomy 21 was the most frequent abnormality.

The effects of hypericin on ADAMTS and p53 gene expression in MCF-7 breast cancer cells.

PURPOSE: The purpose of this study was to determine the effects of hypericin on MCF-7 (Michigan Cancer Foundation- 7) breast cancer cells, as it is known to exert an antitumor effect on the expression and regulation of ADAMTS1, 3, 10 and the p53 gene in breast cancer cells. METHODS: MFC-7 cells were cultured and subjected separately to various doses (1, 5 and 7.5 µg /mL) hypericin. After 24 hrs, RNA was isolated and transcribed into cDNA. Expression analysis was performed by real time (RT)-PCR and cell survival was determined by the XTT assay. RESULTS: While the expression of ADAMTS1 in MFC-7 cells decreased to 0.04-fold after exposure to 1 µg /mL hypericin, the expression increased by 5.6- and 36-fold with 5 and 7.5 µg/mL, respectively. Furthermore, ADAMTS3 expression in MCF7 cells increased 3.9-fold with the use of 5 µg /mL of hypericin. These concentrations of hypericin did not lead to significant changes in the expression of ADAMTS10 and the p53 gene. Viability of cancer cells as evaluated by the XTT assay showed that hypericin concentration of 7.5 µg /mL led to increased apoptosis of cancer cells. CONCLUSION: The increase in ADAMTS1 expression may prevent metastasis or facilitate the development of an adjuvant factor with tumor-suppressive effects. Hypericin may therefore exert its antitumor and apoptotic effects in MFC-7 cells via ADAMTS1 and ADAMTS3.

SYBR green dye-based probe-free SNP genotyping: introduction of T-Plex real-time PCR assay.

Single-nucleotide polymorphism (SNP) genotyping is widely used in genetic association studies to characterize genetic factors underlying inherited traits. Despite many recent advances in high-throughput SNP genotyping, inexpensive and flexible methods with reasonable throughput levels are still needed. Real-time PCR methods for discovering and genotyping SNPs are becoming increasingly important in various fields of biology. In this study, we introduce a new, single-tube strategy that combines the tetra-primer ARMS PCR assay, SYBR Green I-based real-time PCR, and melting-point analysis with primer design strategies to detect the SNP of interest. This assay, T-Plex real-time PCR, is based on the T(m) discrimination of the amplified allele-specific amplicons in a single tube. The specificity, sensitivity, and robustness of the assay were evaluated for common mutations in the FV, PII, MTHFR, and FGFR3 genes. We believe that T-Plex real-time PCR would be a useful alternative for either individual genotyping requests or large epidemiological studies.

Frequency of MEFV mutation and genotype-phenotype correlation in cases with dysmenorrhea.

AIM: We aimed to investigate the relation between mutations and polymorphisms playing roles in the onset of clinical findings of Familial Mediterranean Fever (FMF) and clinical phenotypic reflections manifesting with painful episodes, such as dysmenorrhea. MATERIAL AND METHODS: A total of 1000 female patients who had not responded well to non-steroidal anti-inflammatory drugs in the menstrual period, and who had presented to the emergency room with the complaint of recurrent pain episodes were included in the study. All the patients were Turkish women living in Istanbul. In this study, the mutations most frequently seen in the Mediterranean Fever Gene (MEFV), namely M694V, E148Q, M680I(G/C), V726A, P369S, R761H, A744S, M694I, K695R, F479L, M680I(G/A), and I692del were examined using the DNA sequence analysis following DNA isolation. RESULTS: The number of individuals who had a mutation in at least one allele for FMF was 511 out of 1000 patients. Of these 511 patients, homozygous mutations were found in 21% (n = 109), compound heterozygous mutations were found in 27% (n = 136), and heterozygous mutations were found in 52% (n = 266). The most frequent homozygous genotype seen in our study population was M694V/M694V. The most common compound heterozygote genotypes were M694V/M680I, M694V/V726A, M694V/E148Q, and M680I/V726A; and 11.7% (n = 60) of the families in whom mutations were found had consanguinity. CONCLUSION: Women who present to the emergency room with the complaint of dysmenorrhea that is irresponsive to non-steroidal anti-inflammatory drugs may have several types of MEFV mutations that are responsible for FMF.

Left Ventricular Systolic Dysfunction Related to Adrenal Insufficiency in a Case due to Autoimmune Polyendocrine Syndrome Type 1 with a Novel Variant.

Introduction: Primary adrenal insufficiency associated with cardiomyopathy has been rarely reported in children. We report a case of left ventricular (LV) systolic dysfunction related to adrenal insufficiency with autoimmune polyendocrine syndrome type 1 (APS1). Case Presentation: A 7-year-old girl presented with a loss of consciousness. She had hyperpigmentation over joints and enamel hypoplasia. Laboratory tests showed hypoglycemia, hyponatremia, hypocalcemia, and hyperphosphatemia. Endocrine evaluations revealed low serum parathyroid hormone, low cortisol, and high ACTH. Echocardiography showed moderate to severe mitral regurgitation and LV systolic dysfunction. Serum pro-brain natriuretic peptide (pro-BNP) level was high (2,348 pg/mL). Adrenal insufficiency, hypoparathyroidism, and enamel dysplasia suggested APS1. A novel homozygous variant in the AIRE gene, NM_000383, p.Cys322Arg (c.964T>C) confirmed the diagnosis. Calcium, calcitriol, and hydrocortisone treatments were started. Serum pro-BNP level returned to normal, and LV systolic function improved. Conclusion: Here, we present a case of adrenal insufficiency and hypoparathyroidism associated with LV systolic dysfunction whose cardiac findings improved completely with hydrocortisone and calcitriol treatments. Our case is the second reported case of APS1 presenting with LV dysfunction.

Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability.

Genetic heterogeneity, reduced penetrance, and variable expressivity, the latter including asymmetric body axis plane presentations, have all been described in families with congenital limb malformations (CLMs). Interfamilial and intrafamilial heterogeneity highlight the complexity of the underlying genetic pathogenesis of these developmental anomalies. Family-based genomics by exome sequencing (ES) and rare variant analyses combined with whole-genome array-based comparative genomic hybridization were implemented to investigate 18 families with limb birth defects. Eleven of 18 (61%) families revealed explanatory variants, including 7 single-nucleotide variant alleles and 3 copy number variants (CNVs), at previously reported "disease trait associated loci": BHLHA9, GLI3, HOXD cluster, HOXD13, NPR2, and WNT10B. Breakpoint junction analyses for all three CNV alleles revealed mutational signatures consistent with microhomology-mediated break-induced replication, a mechanism facilitated by Alu/Alu-mediated rearrangement. Homozygous duplication of BHLHA9 was observed in one Turkish kindred and represents a novel contributory genetic mechanism to Gollop-Wolfgang Complex (MIM: 228250), where triplication of the locus has been reported in one family from Japan (i.e., 4n = 2n + 2n versus 4n = 3n + 1n allelic configurations). Genes acting on limb patterning are sensitive to a gene dosage effect and are often associated with an allelic series. We extend an allele-specific gene dosage model to potentially assist, in an adjuvant way, interpretations of interconnections among an allelic series, clinical severity, and reduced penetrance of the BHLHA9-related CLM spectrum.

The Relationship between Genotype and Phenotype in Primary Ciliary Dyskinesia Patients.

OBJECTIVES: Primary ciliary dyskinesia (PCD) is a chronic genetic disease that affects the respiratory tract, characterized by different clinical and laboratory features. It has a very difficult diagnosis, and high morbidity. In recent years, with the advances in genetics, the rate of diagnosis has increased considerably. In this study, it was aimed to evaluate the relationship between PCD patients' clinical, radiological and laboratory features and genetic analysis. METHODS: The study included 14 children who were diagnosed with PCD between 2015-2019 and underwent exome analysis. Diagnostic ages, body mass indexes (BMI)- Z score, clinical and radiological findings, pulmonary function tests, sputum culture reproduction and gene analysis were evaluated and compared. RESULTS: Six of the patients (43%) were girls and 8 (57%) were boys, and the median age at the time of diagnosis was 9 (min-max: 3-16) years. Genetic analysis revealed pathogenic mutations in DNAH5 (n=4, 29%), DNAH11 (n=2, 14%), RSPH4A (n=2, 14%), CCDC40 (n=2, 14%), DNAH9 (n=1, 7%), HYDIN (n=1, 7%), DNAH1 (n=1, 7%), and ARMC4 (n=1, 7%). Although not statistically significant, it was found that the diagnosis age was lower and the BMI Z-score was lower in CCDC40 mutations. Growth parametres were normal in DNAH5, DNAH11, RSPH4A and ARMC4 pathogenic variants. No significant correlation was found between genetic analysis and clinical features, culture reproduction and pulmonary function tests of the patients. CONCLUSION: It is thought that more detailed information about the possible clinical features and prognosis of the disease can be obtained by genetic examinations of PCD. However, clinical trials with higher patient numbers are still needed.

Is There an Association Between Nasal Polyposis and ADAMTS Genes Expressions?

OBJECTIVE: Nasal polyposis (NP) is an inflammatory chronic disease in which polyps are located in the nose or paranasal sinuses. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) genes have roles in vascular biology, inflammation, tissue morphogenesis, and pathophysiological remodeling. Therefore, some members of the ADAMTS gene family may contribute to pathogenesis of NPs. This study aimed to detect the potential relation between NP and the expression levels of ADAMTS 5, 8, and 9 genes. MATERIALS AND METHODS: This study consisted of nasal polyp tissues from 34 patients in whom nasal polyps had been diagnosed clinically, and healthy nasal mucosal tissues from 14 controls. RNA was isolated from the nasal polyps and normal nasal mucosal tissue in each subject. The expression levels of ADAMTS 5, 8, and 9 genes in the patients and controls were detected by quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) method. RESULTS: The expression levels of ADAMTS 5 and 9 genes were significantly decreased in NP tissues. In contrast, the expression levels of ADAMTS 8 genes were also decreased in NP tissues, but they were not significantly different from those in the normal nasal tissues. CONCLUSION: An association was detected between the expression levels of ADAMTS genes and NP. ADAMTS 5 and 9 genes may have an effect on the formation of NP.

A New Series of Antileukemic Agents: Design, Synthesis, In Vitro and In Silico Evaluation of Thiazole-Based ABL1 Kinase Inhibitors.

BACKGROUND: After the approval of imatinib, more than 25 antitumor agents targeting kinases have been approved, and several promising candidates are at various stages of clinical evaluation. OBJECTIVES: Due to the importance of the thiazole scaffold in targeted anticancer drug discovery, the goal of this work is to identify new thiazolyl hydrazones as potent ABL1 kinase inhibitors for the management of Chronic Myeloid Leukemia (CML). METHODS: New thiazolyl hydrazones (2a-p) were synthesized and investigated for their cytotoxic effects on the K562 CML cell line. Compounds 2h, 2j and 2l showed potent anticancer activity against K562 cell line. The cytotoxic effects of these compounds on other leukemia (HL-60, MT-2 and Jurkat) and HeLa human cervical carcinoma cell lines were also investigated. Furthermore, their cytotoxic effects on Mitogen-Activated Peripheral Blood Mononuclear Cells (MA-PBMCs) were evaluated to determine their selectivity. Due to its selective and potent anticancer activity, compound 2j was benchmarked for its apoptosis-inducing potential on K562 cell line and inhibitory effects on eight different Tyrosine Kinases (TKs), including ABL1 kinase. In order to investigate the binding mode of compound 2j into the ATP binding site of ABL1 kinase (PDB: 1IEP), a molecular docking study was conducted using MOE 2018.01 program. The QikProp module of Schrödinger's Molecular modelling package was used to predict the pharmacokinetic properties of compounds 2a-p. RESULTS: 4-(4-(Methylsulfonyl)phenyl)-2-[2-((1,3-benzodioxol-4-yl)methylene)hydrazinyl]thiazole (2j) showed antiproliferative activity against K562 cell line with an IC50 value of 8.87±1.93 µM similar to imatinib (IC50= 6.84±1.11µM). Compound 2j was found to be more effective than imatinib on HL-60, Jurkat and MT-2 cells. Compound 2j also showed cytotoxic activity against HeLa cell line similar to imatinib. The higher selectivity index value of compound 2j than imatinib indicated that its antiproliferative activity was selective. Compound 2j also induced apoptosis in K562 cell line more than imatinib. Among eight TKs, compound 2j showed the strongest inhibitory activity against ABL1 kinase enzyme (IC50= 5.37±1.17µM). According to molecular docking studies, compound 2j exhibited high affinity to the ATP binding site of ABL1 kinase, forming significant intermolecular interactions. On the basis of in silico studies, this compound did not violate Lipinski's rule of five and Jorgensen's rule of three. CONCLUSION: Compound 2j stands out as a potential orally bioavailable ABL1 kinase inhibitor for the treatment of CML.

Primary hypogonadism, partial alopecia, and Mullerian hypoplasia: report of a third family and review.

Two sisters presented with partial alopecia, primary hypergonadotropic hypogonadism and Mullerian hypoplasia associated with mild mental retardation, microcephaly, flat occiput, sparse eyebrows, absence of breast tissue, absent ovaries, mild-moderate dorsal kyphosis, thin upper lip and unilateral sensorioneural deafness in one of them. They were the product of a Turkish consanguineous marriage. The clinical course for our patients is similar to two families reported by Al-Awadi et al. [Al-Awadi et al. (1985) Am J Med Genet 22:619-622] and Megarbane et al. [Megarbane et al. (2003) Am J Med Genet Part A 119A:214-217]. This report supports the literature by proposing an autosomal recessive syndrome which was firstly reported by Al-Awadi et al. [Al-Awadi et al. (1985) Am J Med Genet 22:619-622]. This condition may be due to a founder mutation.

Genotoxic effect of albendazole in pediatric patients with hepatic hydatid disease.

OBJECTIVE: Hydatid disease occurs throughout the world and is treated with both surgery and medical administration of albendazole. Some adverse effects of albendazole are known. However, its genotoxic effect on humans has not been reported yet. In this study, we aimed to investigate the genotoxic effect of albendazole on human lymphocytes in vivo. METHODS: The study involved 14 children (eight males and six females) who had undergone operations for hepatic hydatid disease. The ages of the patients ranged from 6 to 13 years. Genotoxicity of albendazole was evaluated as the frequency of sister chromatid exchange (SCE) and micronucleated cells in the patient's lymphocytes. Prior to and after albendazole treatment, blood samples were obtained from these patients for SCE and micronucleus (MN) studies. SCE and MN frequencies of the patients were measured separately before and after albendazole treatment. RESULTS: All patient SCE values increased significantly after albendazole administration (p<0.001). Similarly, MN frequencies in all the patients increased significantly following albendazole treatment (p<0.001). CONCLUSION: This study revealed that both SCE and MN frequencies are higher after albendazole treatment. The results suggest that albendazole may be genotoxic to human lymphocytes in vivo.

Clinical and prognostic importance of chromosomal abnormalities, Y chromosome microdeletions, and CFTR gene mutations in individuals with azoospermia or severe oligospermia.

AIM: To illustrate the importance of genetic screening in the assessment of fertility and the correct diagnosis in patients with azoospermia or severe oligospermia. MATERIALS AND METHODS: This study examined 500 patients with reproductive failure, having fewer than 5 million sperm/mL detected in at least 2 consecutive spermiograms, who presented at a medical genetics polyclinic between 2008 and 2012. Metaphase preparations obtained from cell cultures were stained by trypsin-Giemsa banding. After DNA isolation, Y chromosome loci, including AZFa (SY84, SY86), AZFb (SY127, SY134), AZFc (SY254 SY255), and AZFd, were amplified by polymerase chain reaction using specific primers. Thirty-five patients with congenital unilateral absence of the vas deferens or congenital bilateral absence of the vas deferens (CBAVD) and a positive cystic fibrosis family history were evaluated for cystic fibrosis transmembrane conductance regulator gene mutations. RESULTS: No chromosomal abnormalities were noted in 440 (88%) of the 500 patients, whereas structural or numerical chromosomal abnormalities were detected in 60 patients (12%). Individuals with Y deletions made up 5.6% (n = 28) of the study sample. Three patients with no AZF deletion or chromosomal abnormality, but with CBAVD, were heterozygous for I148T, G1130A, or IVS3 406- 3T>C mutations. CONCLUSION: This study shows that genetic testing can make an important contribution to the treatment of patients planning in vitro fertilization due to azoospermia or severe oligospermia.

Protective effects of montelukast and Hypericum perforatum against intestinal ischemia-reperfusion injury in hamsters.

AIM: To evaluate the effects of montelukast and Hypericum perforatum against ischemia/reperfusion (I/R)-induced intestinal damage. MATERIALS AND METHODS: Twenty-eight hamsters were divided into 4 groups following midline abdominal laparotomy: control group (n = 7), I/R group (n = 7), montelukast and I/R (MIR) group (n = 7), and Hypericum perforatum and I/R (HPIR) group (n = 7). After 60 min of ischemia through obstruction of the superior mesenteric artery, 24 h of reperfusion was maintained. Ten minutes prior to the reperfusion period, the MIR group received 7 mg/kg of intraperitoneal montelukast and the HPIR group received 7 mg/kg of intraperitoneal Hypericum perforatum. Malondialdehyde, glutathione, myeloperoxidase, and cardiotrophin-1 levels were measured from blood samples. A semiquantitative histological evaluation was performed. RESULTS: Montelukast and Hypericum perforatum significantly reduced malondialdehyde levels and increased glutathione levels compared to the I/R group (P < 0.008). A statistically significant difference was also found between the I/R group and MIR and HPIR groups in terms of myelqperoxidase levels (P < 0.008). The MIR and HPIR groups showed increased cardiotrophin- 1 levels compared to the control and I/R groups (P < 0.008 for all). The MIR and HPIR groups showed significantly lower histological scores compared to the I/R group (P = 0.03 and P = 0.007, respectively). CONCLUSION: This study demonstrated the preventive effects of montelukast and Hypericum perforatum on I/R-induced intestinal injury.