• Genomics & Informatics
• /
• v.21 no.2
• /
• pp.20.1-20.10
• /
• 2023

Aromatase inhibitors (AI) are drugs that are widely used in treating estrogen receptor (ER)-positive breast cancer patients. Drug resistance is a major obstacle to aromatase inhibition therapy. There are diverse reasons behind acquired AI resistance. This study aims at identifying the plausible cause of acquired AI resistance in patients administered with non-steroidal AIs (anastrozole and letrozole). We used genomic, transcriptomic, epigenetic, and mutation data of breast invasive carcinoma from The Cancer Genomic Atlas database. The data was then separated into sensitive and resistant sets based on patients' responsiveness to the non-steroidal AIs. A sensitive set of 150 patients and a resistant set of 172 patients were included for the study. These data were collectively analyzed to probe into the factors that might be responsible for AI resistance. We identified 17 differentially regulated genes (DEGs) among the two groups. Then, methylation, mutation, miRNA, copy number variation, and pathway analyses were performed for these DEGs. The top mutated genes (FGFR3, CDKN2A, RNF208, MAPK4, MAPK15, HSD3B1, CRYBB2, CDC20B, TP53TG5, and MAPK8IP3) were predicted. We also identified a key miRNA - hsa-mir-1264 regulating the expression of CDC20B. Pathway analysis revealed HSD3B1 to be involved in estrogen biosynthesis. This study reveals the involvement of key genes that might be associated with the development of AI resistance in ER-positive breast cancers and hence may act as a potential prognostic and diagnostic biomarker for these patients.

• Journal of the Korean Wood Science and Technology
• /
• v.46 no.5
• /
• pp.449-470
• /
• 2018

A review of research trends on wood surface protection for exterior use obtained the following conclusions: It has been reported that inorganic compounds such as chrome and copper used as wood preservatives can protect wood from weathering. It has been shown that precoating with hydrophobic substances such as wax and oil, UV absorbers, and HALS (Hindered Amine Light Stabilizers) enhances weathering resistance on the surface of ACQ-treated wood. Opaque coatings of paint/stains and semitransparent stains on the surface of preservative treated wood can increase the synergistic effects on prevention of weathering deterioration. Also the need for repainting periodically for the protection of the preservative treated wood surface has also been suggested. ZnO or $TiO_2$ of fine particles, metal ions such as Co, Cr, Fe, Mn, Ni and Ti, and UV absorbers such as tris-resorcinol triazine derivatives, triazine and benzotriazole were introduced as additives for preventing UV in the transparent coating on wood. Several reports showed that chemical modification such as methylation, acetylation, or alkylations have made some increases the effects of preventing weathering with the increasing weight gain of chemical formulas. In heat-treated wood, there were various contradictory reports on the resistance of weathering, and there were some other reports emphasizing the necessity of painting with UV resistance, which leads to the necessity of more advanced studies.

• Journal of Interdisciplinary Genomics
• /
• v.5 no.2
• /
• pp.29-31
• /
• 2023

Pseudohypoparathyroidism (PHP) is very rare and shows heterogeneity with impaired genetic components. PHP is characterized by parathyroid hormone resistance to target organ, related with a GNAS (guanine nucleotide-binding protein α-subunit) mutation and epimutation. PHP receptor is coupled with the stimulatory G protein which activates cyclic adenosine monophosphate formation. PHP type 1A is caused by inactivating mutations on the maternal allele of the GNAS whereas paternal allele mutations cause pseudopseudohypoparathyroidism. PHP type 1B is caused by abnormal patterns of methylation in differentially methylated region which can be divided into partial or complete. This disease has some difficulties to diagnose according to these different molecular alterations caused by complex genetic and epigenetic defects. According to this different molecular alterations, genetic confirmation must be done to discriminate their etiology.

• Korean Journal of Microbiology
• /
• v.52 no.3
• /
• pp.269-277
• /
• 2016

Erm proteins methylate the specific adenine residue ($A_{2058}$, E. coli numbering) on 23S rRNA to confer the $MLS_B$ (macrolidelincosamide-streptogramin B) antibiotic resistance on a variety of microorganisms ranging from antibiotic producers to pathogens. When phylogenetic tree is constructed, two main clusters come out forming each cluster of Actinobacteria and Firmicutes. Two representative Erm proteins from each cluster were selected and their in vitro methylation activities were compared. ErmS and ErmE from Actinobacteria cluster exhibited much higher activities than ErmB and ErmC' from Firmicutes: 9 fold difference when ErmC' and ErmE were compared and 13 fold between ErmS and ErmB. Most of the difference was observed and presumed to be caused by N-terminal and C-terminal extra region from ErmS and ErmE, respectively because NT59TE in which N-terminal end 59 amino acids was truncated from wild type ErmS exhibited only 22.5% of wild type ErmS activity. Meanwhile, even NT59TE showed three and 2.2 times more activity when it was compared to ErmB and C, respectively, suggesting core region from antibiotic producers contains extra structure enabling higher activity. This is suggested to be possible through the extra region of 197RWS199 (from both ErmS and ErmE), 261GVGGSLY267 (from ErmS), and 261GVGGNIQ267 (from ErmE) and 291SVV293 (from ErmS) and 291GAV293 (from ErmE) by multiple sequence alignment.

• Journal of the Korean Wood Science and Technology
• /
• v.26 no.3
• /
• pp.53-62
• /
• 1998

In this research, 7 species of white rot fungi were used for determining the resistance against pentachlorophenol (PCP). Three fungi with good PCP resistance were selected for evaluating the biodegradability, and biodegradation mechanism by HPLC and GC/MS spectrometry. Among 7 fungi, there were significant differences on PCP resistance on 4 different PCP concentrations. In the concentrations of 50 and 100ppm ($\mu$g of PCP per g of 2% malt extract agar), most fungi were easily able to grow, and well suited to newly PCP-added condition, but in that of more than 250ppm, the mycelia growths of Ganoderma lucidum 20435, G. lucidum 20432, Pleurotus ostreatus, and Daldinia concentrica were significantly inhibited or even stopped by the addition of PCP to the culture. However, Trametes versicolor, Phanerochaete chrysosporium, and Inonotus cuticularis still kept growing at 250ppm, indicating the potential utilization of wood rot fungi to high concentrated PCP biodegradation. Particularly, P. chrysosporium even showed very rapid growth rate at more than 500ppm of PCP concentration. Three selected fungi based on the above results showed an excellent biodegradability against PCP. P. chrysosporium degraded PCP up to 84% on the first day of incubation, and during 7 days, most of added PCP were degraded. T. versicolor also showed more than 90% of biodegradability at 7th day, and even though the initial stage of degradation was very slow, I. cuticularis has been approached to 90% at 21 st day after incubation with dense growing pattern of mycelia. Therefore, the PCP biodegradability was definitely dependent on the rapid suitability of fungi to newly PCP-added condition. In addition, the PCP biodegradation by filtrates of P. chrysosporium, T. versicolor, and I. cuticularis was very minimal or limited, suggesting that the extracellular enzyme system may be not so significantly related to the PCP biodegradation. Among the biodegradation metabolites of PCP, the most abundant one was pentachloroanisole which resulted in a little weaker toxicity than PCP, and others were tetrachlorophenol, tetrachloro-hydroquinone, benzoic acid, and salicylic acid, suggesting that PCP may be biodegraded by several sequential reactions such as methylation, radical-induced oxidation, dechlorination, and hydroxylation.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.23
• /
• pp.10439-10444
• /
• 2015

Many chemotherapeutic agents have been successfully used to treat hepatocellular carcinoma (HCC); however, the development of chemoresistance in liver cancer cells usually results in a relapse and worsening of prognosis. It has been demonstrated that DNA methylation and histone modification play crucial roles in chemotherapy resistance. Currently, extensive research has shown that there is another potential mechanism of gene expression control, which is mediated through the function of short noncoding RNAs, especially for microRNAs (miRNAs), but little is known about their roles in cancer cell drug resistance. In present study, by taking advantage of miRNA effects on the resistance of human hepatocellular carcinoma cells line to cisplatin, it has been demonstrated that miR-340 were significantly downregulated whereas Nrf2 was upregulated in HepG2/CDDP (cisplatin) cells, compared with parental HepG2 cells. Bioinformatics analysis and luciferase assays of Nrf2-3'-untranslated region-based reporter constructor indicated that Nrf2 was the direct target gene of miR-340, miR-340 mimics suppressing Nrf2-dependent antioxidant pathway and enhancing the sensitivity of HepG2/CDDP cells to cisplatin. Interestingly, transfection with miR-340 mimics combined with miR-340 inhibitors reactivated the Nrf2 related pathway and restored the resistance of HepG2/CDDP cells to CDDP. Collectively, the results first suggested that lower expression of miR-340 is involved in the development of CDDP resistance in hepatocellular carcinoma cell line, at least partly due to regulating Nrf2-dependent antioxidant pathway.

• Korean Journal of Microbiology
• /
• v.50 no.3
• /
• pp.239-244
• /
• 2014

ErmSF is one of the four antibiotic resistance factor proteins expressed by Streptomyces fradiae, antibiotic tylosin producer, which renders $MLS_B$ (macrolide-lincosamide-streptogramin B) antibiotic resistance through dimethylating A2058 of 23S rRNA, thereby reducing the affinity of antibiotic to ribosome. Unlike other Erm proteins, ErmSF harbors long N-terminal end region. To investigate its role in enzyme activity, mutant ErmSF deleted of 1-38 amino acids was overexpressed and activity in vivo and in vitro was observed. In vitro enzymatic assay showed that mutant protein exhibited reduced activity by 20% compared to the wild type enzyme. Due to the reduced activity of the mutant protein, cells expressing mutant protein showed weaker resistance to erythromycin than cells with wild type enzyme. Presumably, the decrease in enzyme activity was caused by the hindrance in substrate binding and (or) product release, not by defect in the methyl group transfer occurred in active site.

• Korean Journal of Microbiology
• /
• v.43 no.3
• /
• pp.166-172
• /
• 2007

ERM proteins transfer the methyl group to $A_{2058}$ in 23S rRNA, which reduces the affinity of MLS (macrolide-lincosamide-streptogramin B) antibiotics to 23S rRNA, thereby confer the antibiotic resistance on micro-organisms ranging from antibiotic producers to pathogens and are classified into monomethyltransferase and dimethyltransferase. To investigate the differences between mono- and dimethyltransferase, tirD, a representative monomethylase gene was cloned in Escherichia coli from Streptomyces fradiae which contains ermSF, dimethylase gene as well to overexpress the TlrD for the first time. T7 promoter driven expression system successfully overexpress tlrD as a insoluble aggregate at $37^{\circ}C$ accumulating to around 55% of the total cell protein but unlike ErmSF, culturing at temperature as low as $18^{\circ}C$ did not make insoluble aggregate of protein into soluble protein. Coexpression of Thioredoxin and GroESL, chaperone was not helpful in turning into soluble protein either as in case of ErmSF. These results might suggest that differences between mono- and dimethylase could be investigated on the basis of the characteristics of protein structure. However, a very small amount of soluble protein which could not be detected by SDS-PAGE conferred antibiotic resistance on E. coli as in ErmSF which was expected from the activity exerted by monmethylase in a cell.

• Nutrition Research and Practice
• /
• v.14 no.2
• /
• pp.95-101
• /
• 2020

BACKGROUND/OBJECTIVES: Folate plays a critical role in DNA synthesis and methylation. Intracellular folate homeostasis is maintained by the enzymes folylpolyglutamate synthase (FPGS) and γ-glutamyl hydrolase (GGH). FPGS adds glutamate residues to folate upon its entry into the cell through a process known as polyglutamylation to enhance folate retention in the cell and to maintain a steady supply of utilizable folate derivatives for folate-dependent enzyme reactions. Thereafter, GGH catalyzes the hydrolysis of polyglutamylated folate into monoglutamylated folate, which can subsequently be exported from the cell. The objective of this review is to summarize the scientific evidence available on the effects of intracellular folate homeostasis-associated enzymes on cancer chemotherapy. METHODS: This review discusses the effects of FPGS and GGH on chemosensitivity to cancer chemotherapeutic agents such as antifolates, such as methotrexate, and 5-fluorouracil. RESULTS AND DISCUSSION: Polyglutamylated (anti)folates are better substrates for intracellular folate-dependent enzymes and retained for longer within cells. In addition to polyglutamylation of (anti)folates, FPGS and GGH modulate intracellular folate concentrations, which are an important determinant of chemosensitivity of cancer cells toward chemotherapeutic agents. Therefore, FPGS and GGH affect chemosensitivity to antifolates and 5-fluorouracil by altering intracellular retention status of antifolates and folate cofactors such as 5,10-methylenetetrahydrofolate, subsequently influencing the cytotoxic effects of 5-fluorouracil, respectively. Generally, high FPGS and/or low GGH activity is associated with increased chemosensitivity of cancer cells to methotrexate and 5-fluorouracil, while low FPGS and/or high GGH activity seems to correspond to resistance to these drugs. Further preclinical and clinical studies elucidating the pharmocogenetic ramifications of these enzyme-induced changes are warranted to provide a framework for developing rational, effective, safe, and customized chemotherapeutic practices.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.20 no.2
• /
• pp.44-49
• /
• 2020

Pseudohypoparathyroidism (PHP) is a disorder characterized by hypocalcemia and hyperphosphatemia due to end organ resistance to parathyroid hormone. PHP is caused by the deficiency of the α-subunit of the stimulatory G protein encoded by the GNAS gene, and this defect arises from genetic or imprinting disturbances. Sporadic PHP 1b shows two or more methylation defects of upstream of GNAS gene and some of them lead to loss of maternal GNAS imprints, therefore, only paternally derived GNAS gene is expressed. Here, we report a 10 year 9 month old boy presented with intermittent tetany who was finally diagnosed with PHP 1b caused by paternal uniparental disomy of chromosome 20q.