SLC30A8, CDKAL1, TCF7L2, KCNQ1 and IGF2BP2 are Associated with Type 2 Diabetes Mellitus in Iranian Patients.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a serious public health issue with significantly increasing rates across the world. The genome-wide association studies (GWAS) have previously manifested involved genes that remarkably enhance the risk of T2DM. In this study, the association of common variants with T2DM risk has been identified among Iranian population from Tehran province of Iran. METHODS: Here, the association of refSNPs with T2DM risk was examined on peripheral blood samples of 268 individuals including control group and patients with T2DM using the tetra amplification refractory mutation system (ARMS) methods and direct genomic DNA sequencing. RESULTS: Our study demonstrated that SLC30A8 rs13266634 (T/C), CDKAL1 rs10946398 (A/C), TCF7L2 rs7903146 (C/T), KCNQ1 rs2237892 (T/C), and IGF2BP2 rs1470579 (A/C) polymorphisms are significantly associated with type 2 diabetes, but no significant association was identified for FTO rs8050136 and MTNR1B rs10830963 polymorphisms. CONCLUSION: The prediction of refSNPs is remarkably needed for pharmacogenetics and pharmacogenomic approaches, in which the information would be useful for clinicians to optimize therapeutic strategies and adverse drug reactions in patients with T2DM.

The Importance of Small Non-Coding RNAs in Human Reproduction: A Review Article.

BACKGROUND: MicroRNAs (miRNA) play a key role in the regulation of gene expression through the translational suppression and control of post-transcriptional modifications. AIM: Previous studies demonstrated that miRNAs conduct the pathways involved in human reproduction including maintenance of primordial germ cells (PGCs), spermatogenesis, oocyte maturation, folliculogenesis and corpus luteum function. The association of miRNA expression with infertility, polycystic ovary syndrome (PCOS), premature ovarian failure (POF), and repeated implantation failure (RIF) was previously revealed. Furthermore, there are evidences of the importance of miRNAs in embryonic development and implantation. Piwi-interacting RNAs (piRNAs) and miRNAs play an important role in the post-transcriptional regulatory processes of germ cells. Indeed, the investigation of small RNAs including miRNAs and piRNAs increase our understanding of the mechanisms involved in fertility. In this review, the current knowledge of microRNAs in embryogenesis and fertility is discussed. CONCLUSION: Further research is necessary to provide new insights into the application of small RNAs in the diagnosis and therapeutic approaches to infertility.

[Corrigendum] Antiproliferative effects of imatinib mesylate on ZR­75­1 and MDA­MB­231 cell lines via PDGFR­ß, PDGF­BB, c­Kit and SCF expression.

An interested reader drew to our attention that the above study appeared to contain a high level of overlap with an article by the same authors published in the journal Drug Design, Development and Therapy [Kadivar A, Kamalidehghan B, Akbari Javar H, Karimi B, Sedghi R and Noordin MI: Antiproliferation effect of imatinib mesylate on MCF7, T­47D tumorigenic and MCF 10A nontumorigenic breast cell lines via PDGFR­ß, PDGF­BB, c­Kit and SCF genes. Drug Des Devel Ther 11: 469­481, 2017]. Following an internal investigation and also in liaison with the authors, it was established that, although the studies were conducted along broadly similar lines, the papers contained entirely different data involving two different subsets of cell lines; the submission to Drug Des Devel Ther aimed to explore the effects of imatinib mesylate on three different groups, with each group being represented by a cell line, whereas the submission to Int J Mol Med explored the effectiveness of imatinib mesylate in breast cancer cell lines. In spite of this, considering the relatedness of the articles and the fact that the paper to Drug Des Devel Ther was submitted first and published while the Int J Mol Med paper was passing through the peer­review process, the authors concede that they should have properly referenced their paper submitted to Drug Des Devel Ther in the Int J Mol Med paper. Note that the publishers of Drug Des Devel Ther, with whom we were liaising, agreed with the decision to issue a Corrigendum for this paper that acknowledges the article published in Drug Des Devel Ther. The authors regret their failure to acknowledge the related paper in this instance, and apologize to the readership for this oversight. [the original article was published in International Journal of Molecular Medicine 14: 414­424, 2018; DOI: 10.3892/ijmm.2018.3590].

A comprehensive overview on osteoporosis and its risk factors.

Osteoporosis is a bone disorder with remarkable changes in bone biologic material and consequent bone structural distraction, affecting millions of people around the world from different ethnic groups. Bone fragility is the worse outcome of the disease, which needs long term therapy and medical management, especially in the elderly. Many involved genes including environmental factors have been introduced as the disease risk factors so far, of which genes should be considered as effective early diagnosis biomarkers, especially for the individuals from high-risk families. In this review, a number of important criteria involved in osteoporosis are addressed and discussed.

Inhibition of human prostate cancer (PC-3) cells and targeting of PC-3-derived prostate cancer stem cells with koenimbin, a natural dietary compound from Murraya koenigii (L) Spreng.

BACKGROUND: Inhibition of prostate cancer stem cells (PCSCs) is an efficient curative maintenance protocol for the prevention of prostate cancer. The objectives of this study were to assess the efficiency of koenimbin, a major biologically active component of Murraya koenigii (L) Spreng, in the suppression of PC-3 cells and to target PC-3-derived cancer stem cells (CSCs) through apoptotic and CSC signaling pathways in vitro. MATERIALS AND METHODS: The antiproliferative activity of koenimbin was examined using MTT, and the apoptotic detection was carried out by acridine orange/propidium iodide (AO/PI) double-staining and multiparametric high-content screening (HCS) assays. Caspase bioluminescence assay, reverse transcription polymerase chain reaction (RT-PCR), and immunoblotting were conducted to confirm the expression of apoptotic-associated proteins. Cell cycle analysis was investigated using flow cytometry. Involvement of nuclear factor-kappa B (NF-κB) was analyzed using HCS assay. Aldefluor™ and prostasphere formation examinations were used to evaluate the impact of koenimbin on PC-3 CSCs in vitro. RESULTS: Koenimbin remarkably inhibited cell proliferation in a dose-dependent manner. Koenimbin induced nuclear condensation, formation of apoptotic bodies, and G0/G1 phase arrest of PC-3 cells. Koenimbin triggered the activation of caspase-3/7 and caspase-9 and the release of cytochrome c, decreased anti-apoptotic Bcl-2 and HSP70 proteins, increased pro-apoptotic Bax proteins, and inhibited NF-κB translocation from the cytoplasm to the nucleus, leading to the activation of the intrinsic apoptotic pathway. Koenimbin significantly (P<0.05) reduced the aldehyde dehydrogenase-positive cell population of PC-3 CSCs and the size and number of PC-3 CSCs in primary, secondary, and tertiary prostaspheres in vitro. CONCLUSION: Koenimbin has chemotherapeutic potential that may be employed for future treatment through decreasing the recurrence of cancer, resulting in the improvement of cancer management strategies and patient survival.

Brain Lipopolysaccharide Preconditioning-Induced Gene Reprogramming Mediates a Tolerance State in Electroconvulsive Shock Model of Epilepsy.

There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS). A total of 60 male Sprague Dawley rats were randomly assigned to five groups: control, vehicle (single and chronic), and LPS PC (single and chronic). We first recorded the data regarding the behavioral and histological changes. We further investigated the alterations of gene and protein expression of important mediators in relation to TLR4 and inflammatory signaling pathways. Interestingly, significant increased presence of NFκB inhibitors [Src homology 2-containing inositol phosphatase-1 (SHIP1) and Toll interacting protein (TOLLIP)] was observed in LPS-preconditioned animals. This result was also associated with over-expression of IRF3 activity and anti-inflammatory markers, along with down-regulation of pro-inflammatory mediators. Summarizing, the analysis revealed that PC with LPS prior to seizure induction may have a neuroprotective effect possibly by reprogramming the signaling response to injury.

Antiproliferative effects of imatinib mesylate on ZR­75­1 and MDA­MB­231 cell lines via PDGFR­ß, PDGF­BB, c­Kit and SCF expression.

Imatinib mesylate is an anti­neoplastic targeted chemotherapeutic agent, which can inhibit tyrosine kinase receptors, including BCR­ABL, platelet­derived growth factor receptors (PDGFRs) and c­Kit. Cellular processes, including differentiation, proliferation and survival are regulated by these receptors. The present study aimed to evaluate the antiproliferative effects of imatinib mesylate, and its effects on apoptotic induction and cell cycle arrest in breast cancer cell lines. In addition, the study aimed to determine whether the effects of this drug were associated with the mRNA and protein expression levels of PDGFR­ß, c­Kit, and their corresponding ligands PDGF­BB and stem cell factor (SCF), which may potentially modulate cell survival and proliferation. To assess the antiproliferative effects of imatinib mesylate, an MTS assay was conducted following treatment of cells with 2­10 µM imatinib mesylate for 96, 120 and 144 h; accordingly the half maximal inhibitory concentration of imatinib mesylate was calculated for each cell line. In addition, the proapoptotic effects and cytostatic activity of imatinib mesylate were investigated. To evaluate the expression of imatinib­targeted genes, PDGFR­ß, c­Kit, PDGF­BB and SCF, under imatinib mesylate treatment, mRNA expression was detected using semi­quantitative polymerase chain reaction and protein expression was detected by western blot analysis in ZR­75­1 and MDA­MB­231 breast carcinoma cell lines. Treatment with imatinib mesylate suppressed cell proliferation, which was accompanied by apoptotic induction and cell cycle arrest in the investigated cell lines. In addition, PDGFR­ß, PDGF­BB, c­Kit and SCF were expressed in both breast carcinoma cell lines; PDGFR­ß and c­Kit, as imatinib targets, were downregulated in response to imatinib mesylate treatment. The present results revealed that at least two potential targets of imatinib mesylate were expressed in the two breast carcinoma cell lines studied. In conclusion, the antiproliferative, cytostatic and proapoptotic effects of imatinib mesylate may be the result of a reduction in the expression of c­Kit and PDGFR tyrosine kinase receptors, thus resulting in suppression of the corresponding ligand PDGF­BB. Therefore, imatinib mesylate may be considered a promising target therapy for the future treatment of breast cancer.

Prevalence of the CYP2C19*2 (681 G>A), *3 (636 G>A) and *17 (­806 C>T) alleles among an Iranian population of different ethnicities.

Polymorphisms in the cytochrome P (CYP) 450 family may cause adverse drug responses in individuals. Cytochrome P450 2C19 (CYP2C19) is a member of the CYP family, where the presence of the 681 G>A, 636 G>A and 806 C>T polymorphisms result in the CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles, respectively. In the current study, the frequency of the CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles in an Iranian population cohort of different ethnicities were examined and then compared with previously published frequencies within other populations. Allelic and genotypic frequencies of the CYP2C19 alleles (*2, *3 and *17) were detected using polymerase chain reaction (PCR)­restriction fragment length polymorphism analysis, PCR­single­strand conformation polymorphism analysis and DNA sequencing from blood samples of 1,229 unrelated healthy individuals from different ethnicities within the Iranian population. The CYP2C19 allele frequencies among the Iranian population were 21.4, 1.7, and 27.1% for the CYP2C19*2, CYP2C19*3 and CYP2C19*17 alleles, respectively. The frequency of the homozygous A/A variant of the CYP2C19*2 allele was significantly high and low in the Lur (P<0.001) and Caspian (P<0.001) ethnicities, respectively. However, the frequency of the homozygous A/A variant of the CYP2C19*3 allele was not detected in the Iranian cohort in the current study. The frequency of the heterozygous G/A variant of the CYP2C19*3 allele had the significantly highest and lowest frequency in the Fars (P<0.001) and Lur (P<0.001) groups, respectively. The allele frequency of the homozygous T/T variant of the CYP2C19*17 allele was significantly high in the Caspian (P<0.001) and low in the Kurd (P<0.05) groups. The frequency of the CYP2C19 alleles involved in drug metabolism, may improve the clinical understanding of the ethnic differences in drug responses, resulting in the advancement of the personalized medicine among the different ethnicities within the Iranian population.

Comparative analysis of essential oil composition of Iranian and Indian Nigella sativa L. extracted using supercritical fluid extraction and solvent extraction.

The objective of this study was to compare the oil extraction yield and essential oil composition of Indian and Iranian Nigella sativa L. extracted by using Supercritical Fluid Extraction (SFE) and solvent extraction methods. In this study, a gas chromatography equipped with a mass spectrophotometer detector was employed for qualitative analysis of the essential oil composition of Indian and Iranian N. sativa L. The results indicated that the main fatty acid composition identified in the essential oils extracted by using SFE and solvent extraction were linoleic acid (22.4%-61.85%) and oleic acid (1.64%-18.97%). Thymoquinone (0.72%-21.03%) was found to be the major volatile compound in the extracted N. sativa oil. It was observed that the oil extraction efficiency obtained from SFE was significantly (P<0.05) higher than that achieved by the solvent extraction technique. The present study showed that SFE can be used as a more efficient technique for extraction of N. Sativa L. essential oil, which is composed of higher linoleic acid and thymoquinone contents compared to the essential oil obtained by the solvent extraction technique.

Four novel ARSA gene mutations with pathogenic impacts on metachromatic leukodystrophy: a bioinformatics approach to predict pathogenic mutations.

Metachromatic leukodystrophy (MLD) disorder is a rare lysosomal storage disorder that leads to severe neurological symptoms and an early death. MLD occurs due to the deficiency of enzyme arylsulfatase A (ARSA) in leukocytes, and patients with MLD excrete sulfatide in their urine. In this study, the ARSA gene in 12 non-consanguineous MLD patients and 40 healthy individuals was examined using polymerase chain reaction sequencing. Furthermore, the structural and functional effects of new mutations on ARSA were analyzed using SIFT (sorting intolerant from tolerant), I-Mutant 2, and PolyPhen bioinformatics software. Here, 4 new pathogenic homozygous mutations c.585G>T, c.661T>A, c.849C>G, and c.911A>G were detected. The consequence of this study has extended the genotypic spectrum of MLD patients, paving way to a more effective method for carrier detection and genetic counseling.

Antiproliferation effect of imatinib mesylate on MCF7, T-47D tumorigenic and MCF 10A nontumorigenic breast cell lines via PDGFR-ß, PDGF-BB, c-Kit and SCF genes.

Recent cancer molecular therapies are targeting main functional molecules to control applicable process of cancer cells. Attractive targets are established by receptor tyrosine kinases, such as platelet-derived growth factor receptors (PDGFRs) and c-Kit as mostly irregular signaling, which is due to either over expression or mutation that is associated with tumorigenesis and cell proliferation. Imatinib mesylate is a selective inhibitor of receptor tyrosine kinase, including PDGFR-ß and c-Kit. In this research, we studied how imatinib mesylate would exert effect on MCF7 and T-47D breast cancer and MCF 10A epithelial cell lines, the gene and protein expression of PDGFR-ß, c-Kit and their relevant ligands platelet-derived growth factor (PDGF)-BB and stem cell factor (SCF). The MTS assay was conducted in therapeutic relevant concentration of 2-10 µM for 96, 120 and 144 h treatment. In addition, apoptosis induction and cytostatic activity of imatinib mesylate were investigated with the terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL and cell cycle assays, respectively, in a time-dependent manner. Comparative real-time PCR and Western blot analysis were conducted to evaluate the expression and regulation of imatinib target genes and proteins. Our finding revealed that imatinib mesylate antiproliferation effect, apoptosis induction and cytostatic activity were significantly higher in breast cancer cell lines compared to MCF 10A. This effect might be due to the expression of PDGFR-ß, PDGF-BB, c-Kit and SCF, which was expressed by all examined cell lines, except the T-47D cell line which was not expressed c-Kit. However, examined gene and proteins expressed more in cancer cell lines. Therefore, imatinib mesylate was more effective on them. It is concluded that imatinib has at least two potential targets in both examined breast cancer cell lines and can be a promising drug for targeted therapy to treat breast cancer.

Apoptotic induction and inhibition of NF-κB signaling pathway in human prostatic cancer PC3 cells by natural compound 2,2'-oxybis (4-allyl-1-methoxybenzene), biseugenol B, from Litsea costalis: an in vitro study.

Litsea is considered as an evergreen genus distributed in tropical and subtropical Asia; this genus belongs to the large family of Lauraceae. In this study, the cell-death metabolism of biseugenol B was investigated. Nuclear condensation, cell permeability, mitochondrial membrane potential (MMP) and release of cytochrome c have been detected in human prostate cancer cell line (PC3) treated with biseugenol B by high content screening (HCS). Fluorescent analysis was conducted to examine the reactive oxygen species formation. To determine the mechanism of cell death, the levels of Bcl-cell lymphoma (Bcl)-2 proteins, Bcl-2-associated X (Bax) protein and anti-apoptosis heat-shock protein 70 were tested by applying reverse transcription polymerase chain reaction and Western blot. Bioluminescent assays were also performed to assess the level of caspases such as 3/7, 8 and 9 during treatment. Furthermore, the involvement of nuclear factor kappa-B (NF-κB) was examined by Western blot and HCS. Biseugenol B showed significant cytotoxicity toward PC3 with no toxicity toward normal prostate cells (RWPE-1), which indicates that biseugenol B has qualities that induce apoptosis in tumor cells. The treatment of PC3 cells with biseugenol B provoked apoptosis with cell-death-transducing signals. Downregulation of Bcl-2 and upregulation of Bax regulated the MMP, which in turn caused the release of cytochrome c from mitochondria into cytosol. The release of cytochrome c activated caspase-9, which consequently activated caspase-3/7 with the cleaved poly(ADP-ribose) polymerase protein, thereby resulting in apoptosis alteration. Involvement of an extrinsic apoptosis pathway was exhibited by the increase in caspase-8, while the increase in caspase-3/7 and caspase-9 demonstrated involvement of an intrinsic apoptosis pathway. Meanwhile, no significant increase was observed in caspases 3/7, 8 or 9 in normal prostate cells (RWPE-1) after treatment with biseugenol B. Prevention of NF-κB translocation from the cytosol to the nucleus occurred in PC3 after treatment with biseugenol B. The results of our study reveal that biseugenol B triggers the apoptosis of PC3 cells via intrinsic and extrinsic apoptosis pathways and inhibition of NF-κB signaling pathway. Our findings suggest that biseugenol B is a potentially useful agent for prostate cancer treatment.

Identification of a new mutation in an Iranian family with hereditary multiple osteochondromas.

BACKGROUND: Hereditary multiple osteochondromas (HMO), previously named hereditary multiple exostoses (HME), is an autosomal dominant skeletal disorder characterized by the growth of multiple osteochondromas and is associated with bony deformity, skeletal growth reduction, nerve compression, restriction of joint motion, and premature osteoarthrosis. HMO is genetically heterogeneous, localized on at least three chromosomal loci including 8q24.1 (EXT1), 11p11-p13 (EXT2), and 19p (EXT3). The median age of diagnosis is 3 years; almost all affected individuals are diagnosed by age 12. The risk for malignant degeneration to osteochondrosarcoma increases with age, although the lifetime risk of malignant degeneration is low (~1%). METHODS AND RESULTS: This study was performed on an Iranian family with nine affected individuals from three consecutive generations. Here, the proband was an affected woman who received genetic counseling prior to pregnancy. All exons of the three genes were examined in the proband using polymerase chain reaction and sequencing methods (the last member of this family is a male with severe deformities and lesions, especially around his large joints). Exon 4 of EXT1 (c.1235 G>A) was changed in affected individuals. This mutation alters tryptophan to a premature stop codon on amino acid position 412 (p.Trp412x). CONCLUSION: The outcome of this study has extended the genotypic spectrum of Iranian patients with HMO, revealing a way for improving detection and genetic counseling in carriers.

Tribenzyltin carboxylates as anticancer drug candidates: Effect on the cytotoxicity, motility and invasiveness of breast cancer cell lines.

This study seeks to investigate the relationship between the structural modification and bioactivity of a series of tribenzyltin complexes with different ligands and substitutions. Complexation with the N,N-diisopropylcarbamothioylsulfanylacetate or isonicotinate ligands enhanced the anticancer properties of tribenzyltin compounds via delayed cancer cell-cycle progression, caspase-dependent apoptosis induction, and significant reduction in cell motility, migration and invasion. Halogenation of the benzyl ring improved the anticancer effects of the tribenzyltin compounds with the N,N-diisopropylcarbamothioylsulfanylacetate ligand. These compounds also demonstrated far greater anticancer effects and selectivity than cisplatin and doxorubicin, which provides a rationale for their further development as anticancer agents.

Anticancer activity of a monobenzyltin complex C1 against MDA-MB-231 cells through induction of Apoptosis and inhibition of breast cancer stem cells.

In the present study, we examined the cytotoxic effects of Schiff base complex, [N-(3,5-dichloro-2-oxidobenzylidene)-4-chlorobenzyhydrazidato](o-methylbenzyl)aquatin(IV) chloride, and C1 on MDA-MB-231 cells and derived breast cancer stem cells from MDA-MB-231 cells. The acute toxicity experiment with compound C1 revealed no cytotoxic effects on rats. Fluorescent microscopic studies using Acridine Orange/Propidium Iodide (AO/PI) staining and flow cytometric analysis using an Annexin V probe confirmed the occurrence of apoptosis in C1-treated MDA-MB-231 cells. Compound C1 triggered intracellular reactive oxygen species (ROS) production and lactate dehydrogenase (LDH) releases in treated MDA-MB-231 cells. The Cellomics High Content Screening (HCS) analysis showed the induction of intrinsic pathways in treated MDA-MB-231 cells, and a luminescence assay revealed significant increases in caspase 9 and 3/7 activity. Furthermore, flow cytometric analysis showed that compound C1 induced G0/G1 arrest in treated MDA-MB-231 cells. Real time PCR and western blot analysis revealed the upregulation of the Bax protein and the downregulation of the Bcl-2 and HSP70 proteins. Additionally, this study revealed the suppressive effect of compound C1 against breast CSCs and its ability to inhibit the Wnt/ß-catenin signaling pathways. Our results demonstrate the chemotherapeutic properties of compound C1 against breast cancer cells and derived breast cancer stem cells, suggesting that the anticancer capabilities of this compound should be clinically assessed.

Monobenzyltin Complex C1 Induces Apoptosis in MCF-7 Breast Cancer Cells through the Intrinsic Signaling Pathway and through the Targeting of MCF-7-Derived Breast Cancer Stem Cells via the Wnt/ß-Catenin Signaling Pathway.

Monobenzyltin Schiff base complex, [N-(3,5-dichloro-2-oxidobenzylidene)-4-chlorobenzyhydrazidato](o-methylbenzyl)aquatin(IV) chloride, C1, is an organotin non-platinum metal-based agent. The present study was conducted to investigate its effects on MCF-7 cells with respect to the induction of apoptosis and its inhibitory effect against MCF-7 breast cancer stem cells. As determined in a previous study, compound C1 revealed strong antiproliferative activity on MCF-7 cells with an IC50 value of 2.5 µg/mL. Annexin V/propidium iodide staining coupled with flow cytometry indicated the induction of apoptosis in treated cells. Compound C1 induced apoptosis in MCF-7 cells and was mediated through the intrinsic pathway with a reduction in mitochondrial membrane potential and mitochondrial cytochrome c release to cytosol. Complex C1 activated caspase 9 as a result of cytochrome c release. Subsequently, western blot and real time PCR revealed a significant increase in Bax and Bad expression and a significant decrease in the expression levels of Bcl2 and HSP70. Furthermore, a flow cytometric analysis showed that treatment with compound C1 caused a significant arrest of MCF-7 cells in G0/G1 phase. The inhibitory analysis of compound C1 against derived MCF-7 stem cells showed a significant reduction in the aldehyde dehydrogenase-positive cell population and a significant reduction in the population of MCF-7 cancer stem cells in primary, secondary, and tertiary mammospheres. Moreover, treatment with C1 down-regulated the Wnt/ß-catenin self-renewal pathway. These findings indicate that complex C1 is a suppressive agent of MCF-7 cells that functions through the induction of apoptosis, cell cycle arrest, and the targeting of MCF-7-derived cancer stem cells. This work may lead to a better treatment strategy for the reduction of breast cancer recurrence.

Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells.

c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence.

Association of nuclear and mitochondrial genes with audiological examinations in Iranian patients with nonaminoglycoside antibiotics-induced hearing loss.

Mitochondrial DNA mutations play an important role in causing sensorineural hearing loss. The purpose of this study was to determine the association of the mitochondrial genes RNR1, MT-TL1, and ND1 as well as the nuclear genes GJB2 and GJB6 with audiological examinations in nonfamilial Iranians with cochlear implants, using polymerase chain reaction, DNA sequencing, and RNA secondary structure analysis. We found that there were no novel mutations in the mitochondrial gene 12S rRNA (MT-RNR1) in patients with and without GJB2 mutation (GJB2(+) and GJB2(-), respectively), but a total of six polymorphisms were found. No mutations were observed in tRNA(Leu) (() (UUR) ()) (MT-TL1). Furthermore, eight polymorphisms were found in the mitochondrial ND1 gene. Additionally, no mutations were observed in the nuclear GJB6 gene in patients in the GJB2(-) and GJB2(+) groups. The speech intelligibility rating and category of auditory perception tests were statistically assessed in patients in the GJB2(-) and GJB2(+) groups. The results indicated that there was a significant difference (P<0.05) between the categories of auditory perception score in the GJB2(-) group compared to that in the GJB2(+) group. Successful cochlear implantation was observed among individuals with GJB2 mutations (GJB2(+)) and mitochondrial polymorphisms compared to those without GJB2 mutations (GJB2(-)). In conclusion, the outcome of this study suggests that variation in the mitochondrial and nuclear genes may influence the penetrance of deafness. Therefore, further genetic and functional studies are required to help patients in making the best choice for cochlear implants.

Synthesis, structural characterization, and anticancer activity of a monobenzyltin compound against MCF-7 breast cancer cells.

A new monoorganotin Schiff base compound, [N-(3,5-dichloro-2-oxidobenzylidene)-4-chlorobenzyhydrazidato](o-methylbenzyl)aquatin(IV) chloride, (compound C1), was synthesized, and its structural features were investigated by spectroscopic techniques and single-crystal X-ray diffractometry. Compound C1 was exposed to several human cancer cell lines, including breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, ovarian adenocarcinoma cell lines Skov3 and Caov3, and prostate cancer cell line PC3, in order to examine its cytotoxic effect for different forms of cancer. Human hepatic cell line WRL-68 was used as a normal cell line. We concentrated on the MCF-7 cell line to detect possible underlying mechanism involvement of compound C1. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed the strongest cytotoxicity of compound C1 against MCF-7 cells, with a half maximal inhibitory concentration (IC50) value of 2.5±0.50 µg/mL after 48 hours treatment. The IC50 value was >30 µg/mL in WRL-68 cells. Induced antiproliferative activity of compound C1 for MCF-7 cells was further confirmed by lactate dehydrogenase, reactive oxygen species, acridine orange/propidium iodide staining, and DNA fragmentation assays. A significant increase of lactate dehydrogenase release in treated cells was observed via fluorescence analysis. Luminescent analysis showed significant growth in intracellular reactive oxygen species production after treatment. Morphological changes of necrosis and early and late apoptosis stages were observed in treated cells after staining with acridine orange/propidium iodide. DNA fragmentation was observed as a characteristic of apoptosis in treated cells. Results of the present study obviously reveal potential cytotoxic effects of compound C1 against human breast cancer MCF-7 cells.

Prevalence of the rs7903146C>T polymorphism in TCF7L2 gene for prediction of type 2 diabetes risk among Iranians of different ethnicities.

BACKGROUND: Pharmacogenetics is the study of genetic polymorphisms affecting responses to drug therapy. The common rs7903146 (C>T) polymorphism of the TCF7L2 gene has recently been associated with type 2 diabetes (T2D). In this study, prevalence of the rs7903146 (C>T) polymorphism in the TCF7L2 gene for prediction of T2D risk was examined in an Iranian population of different ethnicities. METHODS: The prevalence of rs7903146 (C>T) and the predicted phenotypes, including extensive metabolizers, intermediate metabolizers, and poor metabolizers were investigated in blood samples of 300 unrelated healthy individuals in an Iranian population, including Fars, Turk, Lure, and Kurd, using polymerase chain reaction restriction fragment length polymorphism and direct genomic DNA sequencing. RESULTS: The homozygous wild-type (C/C), heterozygous (C/T), and homozygous (T/T) allelic frequencies of rs7903146 (C>T) in the TCF7L2 gene were 29% (extensive metabolizers), 66.34% (intermediate metabolizers), and 4.66% (poor metabolizers), respectively. The C/C, C/T, and T/T genotypic frequencies of the rs7903146 (C>T) allele were significantly different (P<0.01) among Iranians of different ethnicities. The frequency of the homozygous T/T variant of the rs7903146 (C>T) allele was significantly low in the Lure (P<0.01) and high in the Fars (P<0.001) ethnicities. Additionally, the frequency of the T/T variant of the rs7903146 (C>T) allele in the South of Iran was the highest (P<0.04), while the East of Iran had the lowest frequency (P<0.01). CONCLUSION: The prediction of rs7903146 (C>T) is required in drug research and routine treatment, where the information would be helpful for clinicians to optimize therapy and adverse drug reactions and predict drug response in individuals at risk of T2D.