Characterization of a novel FADS2 transcript variant: implications for D6D activity regulation in cells

Delta-6-desaturase (D6D) activity is deficient in MCF-7 and other cancer cell lines, but it is not explained by FADS2 gene mutations. This deficient activity was not ameliorated by induction of the FADS2 gene; therefore, we hypothesized that some of the induced FADS2 transcript variants (tv) may play a negative regulatory role. FADS2_tv1 is the reference FADS2 tv, coding for full-length D6D isoform 1 (D6D-iso1), and alternative transcriptional start sites result in FADS2_tv2 and FADS2_tv3 variants encoding D6D-iso2 and D6D-iso3 isoforms, respectively, which lack the catalytically critical N-terminal domain. In MCF-7 cells, FADS2_tv2 and FADS2_tv3 were expressed at significantly higher levels than FADS2_tv1. Overexpression of FADS2_tv2 in HEK293 cells confirmed that D6D-iso2 is non-functional, and co-transfection demonstrated a dominant-negative role for D6D-iso2 in D6D-iso1 activity regulation. FADS2_tv2 was expressed at higher levels than FADS2_tv1 in HeLa, MDA-MB-435, MCF-10 A, and HT-29 cells, but at lower levels in A549, MDA-MB-231, and LNCaP cells. Overexpression studies indicated roles for FADS2 variants in proliferation and apoptosis regulation, which were also cell-line specific. Increased FADS2_tv2 expression provides a new mechanism to help explain deficient D6D activity in MCF-7 and other cancer cell lines, but it is not a hallmark of malignant cells.

Evaluation of Ginkgo biloba and Flunixin in BIM Gene Expression and Viability of Ovarian Cancer Cell A2780s

Background: Ovarian cancer is the deadliest gynecologic cancer. Studies on the therapeutic properties of Ginkgo biloba and flunixin showed that these drugs, singly or in combination with other drugs, have anti-cancer activities. Different genes are involved in apoptosis regulation. The BIM gene is one of the most important regulators of this process. BIM has different roles, including cell cycle regulation, apoptosis induction, deoxyribonucleic acid recombination, chromosomal segregation, and cell aging. Methods: This study evaluated the viability percentage of the A2780s cell line with Ginkgo biloba and flunixin at different concentrations, compared to that of the control group. Then, the half-maximal inhibitory concentration (IC50) values of Ginkgo biloba and flunixin were determined within 24 h. Then, the expression of the BIM gene was evaluated using a real-time polymerase chain reaction (PCR). Results: The IC50 results showed that Ginkgo biloba and flunixin significantly reduced cell life (P < 0.01) depending on time and concentration. The results of real-time PCR showed that cell treatment with Ginkgo biloba and flunixin significantly increased BIM expression. Conclusions: The results of this experiment indicated that BIM gene expression was increased in cancer cells treated with Ginkgo biloba and flunixin, compared to that reported for control cells. Therefore, with further research in the future, these compounds can be used for the development of ovarian anti-cancer drugs.

Therapeutic Potential of Isoflavones with an Emphasis on Daidzein

Daidzein is a phytoestrogen isoflavone found in soybeans and other legumes. The chemical composition of daidzein is analogous to mammalian estrogens, and it could be useful with a dual-directional purpose by substituting/hindering with estrogen and estrogen receptor (ER) complex. Hence, daidzein puts forth shielding effects against a great number of diseases, especially those associated with the control of estrogen, such as breast cancer, diabetes, osteoporosis, and cardiovascular disease. However, daidzein also has other ER-independent biological activities, such as oxidative damage reduction acting as an antioxidant, immune regulator as an anti-inflammatory agent, and apoptosis regulation, directly linked to its potential anticancer effects. In this sense, the present review is aimed at providing a deepen analysis of daidzein pharmacodynamics and its implications in human health, from its best-known effects alleviating postmenopausal symptoms to its potential anticancer and antiaging properties.

Kanser Gelişimi ve Progresyonunda miRNA’LAR VE miRNA Gen Varyasyonları

MicroRNAs (miRNAs) are short non-coding RNA class and perform regulatory functions at the post transcriptional level as tumor suppressors or oncogenes. miRNAs are effective in cell differentiation, cell proliferation and apoptosis regulation in normal development processes. miRNA gene variations associated with gene silencing mechanisms, , pri-miRNA, pre-miRNA, mat-miRNA gene variations, genetic cariations in target sites of miRNAs have been identified. Significant changes may occur in miRNA expression levels as a result of genetic variations defined in miRNA genes. Therefore, it is thought that genetic variations in miRNA genes may be biomarkers that can play an important role in cancer formation, prognosis and progression. MiRNA function disorder due to miRNA-mediated dysregulation in target genes that may occur as a result of miRNA gene variations in the diagnosis and progression of various types of cancer should be evaluated. In addition, determining miRNAs and miRNA gene variations in target genes that affect drug behavior in increasing the effectiveness of drugs is very important in terms of developing new treatment methods and different therapeutic strategies for various cancer types. In this review, it is aimed to examine the potential roles of miRNAs and miRNA gene variations in cancer development, progression and treatment.

Epigenetic Markers Are Associated With Differences in Isocyanate Biomarker Levels in Exposed Spray-Painters

Isocyanates are respiratory and skin sensitizers that are one of the main causes of occupational asthma globally. Genetic and epigenetic markers are associated with isocyanate-induced asthma and, before asthma develops, we have shown that genetic polymorphisms are associated with variation in plasma and urine biomarker levels in exposed workers. Inter-individual epigenetic variance may also have a significant role in the observed biomarker variability following isocyanate exposure. Therefore, we determined the percent methylation for CpG islands from DNA extracted from mononuclear blood cells of 24 male spray-painters exposed to 1,6-hexamethylene diisocyanate (HDI) monomer and HDI isocyanurate. Spray-painters’ personal inhalation and skin exposure to these compounds and the respective biomarker levels of 1,6-diaminohexane (HDA) and trisaminohexyl isocyanurate (TAHI) in their plasma and urine were measured during three repeated industrial hygiene monitoring visits. We controlled for inhalation exposure, skin exposure, age, smoking status, and ethnicity as covariates and performed an epigenome-wide association study (EWAS) using likelihood-ratio statistical modeling. We identified 38 CpG markers associated with differences in isocyanate biomarker levels (Bonferroni &lt; 0.05). Annotations for these markers included 18 genes: ALG1, ANKRD11, C16orf89, CHD7, COL27A, FUZ, FZD9, HMGN1, KRT6A, LEPR, MAPK10, MED25, NOSIP, PKD1, SNX19, UNC13A, UROS, and ZFHX3. We explored the functions of the genes that have been published in the literature and used GeneMANIA to investigate gene ontologies and predicted protein-interaction networks. The protein functions of the predicted networks include keratinocyte migration, cell–cell adhesions, calcium transport, neurotransmitter release, nitric oxide production, and apoptosis regulation. Many of the protein pathway functions overlap with previous findings on genetic markers associated with variability both in isocyanate biomarker levels and asthma susceptibility, which suggests there are overlapping protein pathways that contribute to both isocyanate toxicokinetics and toxicodynamics. These predicted protein networks can inform future research on the mechanism of allergic airway sensitization by isocyanates and aid in the development of mitigation strategies to better protect worker health.

Epigenetic Deregulation of Apoptosis in Cancers

Cancer cells possess the ability to evade apoptosis. Genetic alterations through mutations in key genes of the apoptotic signaling pathway represent a major adaptive mechanism of apoptosis evasion. In parallel, epigenetic changes via aberrant modifications of DNA and histones to regulate the expression of pro- and antiapoptotic signal mediators represent a major complementary mechanism in apoptosis regulation and therapy response. Most epigenetic changes are governed by the activity of chromatin modifying enzymes that add, remove, or recognize different marks on histones and DNA. Here, we discuss how apoptosis signaling components are deregulated at epigenetic levels, particularly focusing on the roles of chromatin-modifying enzymes in this process. We also review the advances in cancer therapies with epigenetic drugs such as DNMT, HMT, HDAC, and BET inhibitors, as well as their effects on apoptosis modulation in cancer cells. Rewiring the epigenome by drug interventions can provide therapeutic advantage for various cancers by reverting therapy resistance and leading cancer cells to undergo apoptotic cell death.