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1.
Acta Pharmaceutica Sinica ; (12): 2352-2363, 2022.
Article in Chinese | WPRIM | ID: wpr-937036

ABSTRACT

Using the concepts and methods of epigenetics and metabolomics, to investigate the overall action molecular mechanism of Chrysanthemi indici C (CIC), the anti-hepatitis B virus (HBV) active extracts from Flos chrysanthemi indici. The inhibitory effects of CIC on proliferation and hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg) and HBV-DNA of HepG2.2.15 cells were detected by CCK-8 and antigen kit. The DNA methyltransferases (DNMTs)/ten-eleven-translocation-2 (TET2) equilibrium was detected by ELISA. Illumina 850K methylation chip, pyrosequencing and qPCR were used to determine the action pathway and target of CIC by GO and KEGG analysis. Cell metabolites were extracted with 80% methanol, and the changes of differential metabolites, differential metabolic pathways and cell microenvironment were detected by LC-MS and other metabolomics methods. The results showed that CIC could inhibit the proliferation, HBsAg, HBeAg and HBV-DNA of HepG2.2.15 cells obviously, down-regulate DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3a (DNMT3a) and DNA methyltransferase 3b (DNMT3b), up-regulate TET2, and restore the balance of DNMTs/TET2. The action targets of CIC were phospholipase C gamma 2 (PLCG2), phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2), 5-hydroxytryptamine receptor 2B (HTR2B), nerve growth factor (NGF), mainly involved in lipid metabolism, inflammation mediated regulation of transient receptor potential (TRP), phospholipase D signaling and advanced glycation end product-receptor for AGE (AGE-RAGE) signaling in diabetic complications pathways. CIC could significantly affect fatty acid metabolism and had great influence on phenolic acid, alkaloid and lipid metabolites in cell microenvironment. These results suggest that the action mechanism of CIC may be the synergistic action of multiple pathways and multiple targets, including related inflammatory pathways, immune pathways and lipid metabolism, through regulating epigenetic expression balance and restoring the balance of cell microenvironment.

2.
Article in Chinese | WPRIM | ID: wpr-932424

ABSTRACT

Objective:To study the expression of methyltransferase-like protein 14 (METTL14) in epithelial ovarian cancer and its clinical significance, and to explore the effect of METTL14 expression on the proliferation, invasion and migration of ovarian cancer cells.Methods:Immunohistochemistry (IHC) was used to detect METTL14 expression in tumor tissue samples, and analyze the relationships among METTL14 expression, clinicopathological factors, and prognosis in ovarian cancer. Lentiviral vectors and small interfering RNA (siRNA) were used to up-regulate and down-regulate the METTL14 expression in ovarian cancer cell lines A2780 and SKOV3, respectively. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was used to detect the N6-methyladenosine (m6A) content in ovarian cancer cells. Cell counting kit-8 (CCK-8), wound healing assay, and transwell assay were used to examine the function of METTL14 expression in the cells.Results:(1) The IHC score of METTL14 protein was 6.2±3.7 in 20 samples of ovarian cancer tissues and 3.3±2.5 in 15 samples of normal ovarian tissues, and the difference was statistically significant ( t=-2.64, P=0.012). Among the patients who suffered from ovarian cancer, there were 69 cases with high expression of METTL14 protein (IHC score≥6), accounting for 57.0% (69/121), and the cases with low expression of METTL14 protein (IHC score<6) accounting for 43.0% (52/121). Compared with the patients with low expression of METTL14, the patients with high expression of METTL14 had later stages, higher rates of lymph node metastasis, abdominal metastasis, and more ascite amount. The differences were statistically significant (all P<0.05). The overall survival rate was significantly lower in patients with high METTL14 expression than the low expression ( P=0.009). (2) LC-MS/MS data showed that the relative expression of m6A in A2780 and SKOV3 cells in the lentivirus (LV)-METTL14 group were 0.213±0.024 and 0.181±0.018, which were significantly higher than those in the LV-normal control (NC) group (0.109±0.022 and 0.128±0.020; all P<0.05). While the relative expression of m6A in A2780 and SKOV3 cells in the si-METTL14 group were 0.063±0.012 and 0.069±0.015, which were significantly lower than the expression in si-NC group of 0.108±0.014 and 0.121±0.014 (all P<0.05). CCK-8 assay showed that the absorbance values were significantly lower in the si-METTL14 group compared with the si-NC group at 36, 48, 60 hours (all P<0.05); while were significantly increased in the LV-METTL14 group compared with the LV-NC group at 48, 60 hours (all P<0.01). Scratch wound assays showed that the migration rate of the si-METTL14 group was lower than those of the si-NC group, while the LV-METTL14 group were higher than the LV-NC group by 24 hours, the differences were statistically significant (all P<0.01). Cell migration and invasion were detected by transwell migration and invasion assays. After cultivated for 24 hours, the invasion cell number and the migration cell number in the si-METTL14 group were less than those in the si-NC group. While the invasion cell number and the migration cell number in the LV-METTL14 group were more than those in the LV-NC group, respectively. The differences were statistically significant (all P<0.01). Conclusion:Patients with high METTL14 expression have a worse prognosis in ovarian cancer, which may increase the m6A modification of ovarian cancer cells and promote cells proliferation, invasion and migration.

3.
Acta Pharmaceutica Sinica B ; (6): 2709-2718, 2021.
Article in English | WPRIM | ID: wpr-888882

ABSTRACT

Protein arginine methyltransferases (PRMTs) have been implicated in the progression of many diseases. Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery. Herein, we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a

4.
Chinese Journal of Biotechnology ; (12): 1869-1886, 2021.
Article in Chinese | WPRIM | ID: wpr-887769

ABSTRACT

Methyltransferases (MTs) constitute a large group of enzymes that catalyze the transfer of a methyl moiety, most frequently from S-adenosyl-L-methionine, to their substrates. It plays an essential role in regulation of gene expression and synthesis of many natural compounds. Owing to its broad substrate spectrum, MTs make important contributions to diversify the spectrum of products through methylation modifications. Recently, great progress has been made in application of MTs for the biosynthesis of various natural products including phenylpropane compounds, fragrances, hormones and antibiotics, which is summarized in this review. Moreover, we highlighted the strategies of using MTs for efficient production and for expanding the diversity of these methylated natural products, and discussed the current challenges and future prospects in this area.


Subject(s)
Biological Products , Methylation , Methyltransferases/metabolism
5.
Journal of Clinical Hepatology ; (12): 2210-2214, 2021.
Article in Chinese | WPRIM | ID: wpr-904872

ABSTRACT

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has relatively high incidence and mortality rates. Abnormal modification of N6-methyladenosine (m6A) may promote the development and progression of HCC. This article describes the structure and function of m6A and summarizes the mechanism of action of methylase complexes which decide the function of m6A in HCC, including methyltransferases (writers), demethylases (erasers), and m6A-binding proteins (readers). It is pointed out that more in-depth studies are needed to clarify the diverse and specific role of methylase complexes in HCC, so as to help them become the new targets for the prevention and treatment of HCC in the future.

6.
Article in Chinese | WPRIM | ID: wpr-861639

ABSTRACT

Multiple myeloma (MM) is a malignant clonal disease of the plasma cells in bone marrow. Despite the progress of MM treatment, almost all patients will relapse or become resistant to the prescribed drugs. As such, new treatment targets are urgently needed. As well as genetic defects and bone marrow microenvironment disorders, increasing evidence shows that epigenetic regulation plays an important role in MM. Studies have shown that mutations in epigenetic factors are often related to genomic instability, drug resistance and disease progression. These mutations have been found to increase after treatment, particularly histone methylation and DNA methylation modifying enzymes. Here, we reviewed the progress in histone methylation modification in MM, in particular the role of histone methyltransferases (HMTs) and histone demethylases (HDMs) in the development of MM.

7.
Cancer Research and Clinic ; (6): 627-630, 2021.
Article in Chinese | WPRIM | ID: wpr-912935

ABSTRACT

RNA N6-methyladenosine (m6A) modification is an important gene expression regulation mechanism of eukaryotes. The m6A modification mainly mediates the methylation of adenosine N6. It is a reversible epigenetic modification that not only occurs in messenger RNA (mRNA), but also occurs in non-coding RNA (ncRNA). In addition, RNA m6A modification participates in many physiological and pathological processes, and also plays an important role in the occurrence and development of tumors. This article reviews the role of RNA m6A modification in malignant tumors of the digestive system.

8.
J Biosci ; 2020 Jan; : 1-17
Article | IMSEAR | ID: sea-214358

ABSTRACT

Epigenetic regulation through post-translational modification of histones, especially methylation, is wellconserved in evolution. Although there are several insect genomes sequenced, an analysis with a focus on theirepigenetic repertoire is limited. We have utilized a novel work-flow to identify one or more domains as highpriority domain (HPD), if present in at least 50% of the genes of a given functional class in the referencegenome, namely, that of Drosophila melanogaster. Based on this approach, we have mined histone methyltransferases and demethylases from the whole genome sequence of Aedes aegypti (Diptera), the pea aphidAcyrthosiphon pisum, the triatomid bug Rhodnius prolixus (Hemiptera), the honeybee Apis mellifera (Hymenoptera), the silkworm Bombyx mori (Lepidoptera) and the red flour beetle Tribolium castaneum(Coleoptera). We identified 38 clusters consisting of arginine methyltransferases, lysine methyltransferases anddemethylases using OrthoFinder, and the presence of HPD was queried in these sequences using InterProScan.This approach led us to identify putative novel members and currently inaccurate ones. Other than the highpriority domains, these proteins contain shared and unique domains that can mediate protein–protein interaction. Phylogenetic analysis indicates that there is different extent of protein sequence similarity; averagesimilarity between histone lysine methyltransferases varies from 41% (for active mark) to 48% (for repressivemark), arginine methyltransferases is 51%, and demethylases is 52%. The method utilized here facilitatesreliable identification of desired functional class in newly sequenced genomes

9.
Tumor ; (12): 137-145, 2020.
Article in Chinese | WPRIM | ID: wpr-848212

ABSTRACT

[ABSTRACT] SET domain-containing protein 2 (SETD 2), an epigenetic gene encoding a tri-methyltransferase of histone H3 lysine 36 (H3K36), has been found to be recurrently mutated in a variety of malignancies in the past few decades. SETD2 mutation was firstly identified in solid tumors including renal clear cell carcinoma, glioma and breast cancer, then recently found in multiple hematological malignancies. Increasing evidences have revealed that SETD2 played a pivotal role in regulating the functions of hematopoietic stem cells and the normal development of hematopoietic system. Inactivating mutations of SETD2 can promote the pathogenesis of myeloid, lymphoid leukemia and lymphoma as well as the development of therapeutic resistance. Further elucidation of the molecular mechanisms underlying SETD2-associated hematological malignancies and drug resistance is of great significance for the innovations of diagnosis and treatment methods. In this review, the progress of SETD2 in hematological malignancies are elaborated.

10.
Article in Chinese | WPRIM | ID: wpr-798968

ABSTRACT

Epigenetic modification is one of the important causes for the occurrence and development of cancers. Enhancer of zeste homolog 2 (EZH2) , as an important member of the epigenetic suppressor polycomb group (PcG) , can tri-methylate lysine at amino acid position 27 of histone H3 gene, and participates in the regulation of cell cycle, cell aging and cell differentiation. Recently, overexpression or mutation of EZH2 has been detected in a variety of solid tumors and B-cell lymphomas. However, the expression status and action mechanism of EZH2 in some T-cell lymphomas are still unclear, and its action mechanisms in different tumors are not completely consistent, which need further study.

11.
Article in Chinese | WPRIM | ID: wpr-870225

ABSTRACT

Epigenetic modification is one of the important causes for the occurrence and development of cancers.Enhancer of zeste homolog 2 (EZH2),as an important member of the epigenetic suppressor polycomb group (PcG),can tri-methylate lysine at amino acid position 27 of histone H3 gene,and participates in the regulation of cell cycle,cell aging and cell differentiation.Recently,overexpression or mutation of EZH2 has been detected in a variety of solid tumors and B-cell lymphomas.However,the expression status and action mechanism of EZH2 in some T-cell lymphomas are still unclear,and its action mechanisms in different tumors are not completely consistent,which need further study.

12.
Colomb. med ; 50(1): 40-45, Jan.-Mar. 2019. tab, graf
Article in English | LILACS | ID: biblio-1001852

ABSTRACT

Abstract Case Description: We report the case of a one-year-old girl who was diagnosed with Wiedemann-Steiner Syndrome based on the identification of a novel de novo frameshift mutation in the KMT2A gene by whole exome sequencing and supported by her clinical features. Clinical Findings: KMT2A mutations cause Wiedemann-Steiner Syndrome, a very rare genetic disorder characterized by congenital hypertrichosis, short stature, intellectual disability, and distinct facial features. Treatment and Outcome: Whole exome sequencing identified a novel frameshift variant: c. 4177dupA (p.Ile1393Asnfs * 14) in KMT2A; this change generates an alteration of the specific binding to non-methylated CpG motifs of the DNA to the protein. The genotype and phenotype of the patient were compared with those of earlier reported patients in the literature. Clinical Relevance: In diseases with low frequency, it is necessary to establish a genotype-phenotype correlation that allows the establishment of therapeutic and follow-up goals. The phenotype comparation with other reported cases did not show differences attributable to sex or age among patients with Wiedemann-Steiner Syndrome. Whole exome sequencing allows identifying causality in conditions with high clinical and genetic heterogeneity like hypertrichosis.


Resumen Descripción del caso: Se reporta el caso de una paciente femenina de un año de edad, diagnosticada con Síndrome de Wiedemann-Steiner basado en la identificación de una nueva variante patogénica de novo de tipo frameshift en el gen KMT2A Mediante secuenciación de exoma usando el enfoque de trio, sumado a sus características clínicas. Hallazgos clínicos: las mutaciones en KMT2A causan el Síndrome de Wiedemann-Steiner, un desorden genético muy raro caracterizado por hipertricosis congénita, talla baja, retardo mental variable y fenotipo facial distintivo, los cuales se encuentran en la paciente reportada. Resultado: La Secuenciación de exoma completo encontró una variante de tipo frameshift: c.4177dupA (p. Ile1393Asnfs * 14) en KMT2A, este cambio a nivel génico genera una alteración de la unión específica a motivos CpG no metilados del DNA a la proteína. El genotipo y el fenotipo de la paciente fue comparado con los pacientes reportados previamente en la literatura. Relevancia clínica: En enfermedades con baja frecuencia como la aquí reportada es necesario establecer correlaciones genotipo-fenotipo que permitan establecer planes terapéuticos y de seguimiento. El análisis realizado no evidenció diferencias atribuibles a sexo o edad entre los pacientes diagnosticados con Síndrome de Weidemann-Steiner. La secuenciación de exoma permitió identificar causalidad en este caso, cuya característica principal de hipertricosis se asocia con alta heterogeneidad clínica y genética.


Subject(s)
Female , Humans , Infant , Abnormalities, Multiple/diagnosis , Histone-Lysine N-Methyltransferase/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Hypertrichosis/congenital , Intellectual Disability/genetics , Phenotype , Syndrome , Abnormalities, Multiple/genetics , Genotype , Hypertrichosis/genetics , Mutation
13.
Practical Oncology Journal ; (6): 357-360, 2019.
Article in Chinese | WPRIM | ID: wpr-752868

ABSTRACT

N6-methyladenine(m6 A),a major RNA methylation modification,affects the development and progression of hu-man cancer through a variety of mechanisms. The m6 A modification also affects multiple aspects of RNA metabolism,ranging from RNA processing,nuclear export,RNA translation to decay. In this review,the basic concepts of m6 A methylation,regulation of m6 A methyltransferase complex and m6 A demethylases in several cancers and some m6 A performed the biological function of the modifica-tion as m6 A-binding proteins are introduced. In addition,the dual role of m6 A methylation and its potential in clinical application are summarized in this review.

14.
Acta Pharmaceutica Sinica B ; (6): 794-808, 2019.
Article in English | WPRIM | ID: wpr-774942

ABSTRACT

Histone lysine specific demethylase 1 (LSD1) has been recognized as an important modulator in post-translational process in epigenetics. Dysregulation of LSD1 has been implicated in the development of various cancers. Herein, we report the discovery of the hit compound (IC = 3.93 μmol/L) and further medicinal chemistry efforts, leading to the generation of compound (IC = 49 nmol/L, and = 16 nmol/L), which inhibited LSD1 reversibly and competitively with H3K4me2, and was selective to LSD1 over MAO-A/B. Docking studies were performed to rationalize the potency of compound . Compound also showed strong antiproliferative activity against four leukemia cell lines (OCL-AML3, K562, THP-1 and U937) as well as the lymphoma cell line Raji with the IC values of 1.79, 1.30, 0.45, 1.22 and 1.40 μmol/L, respectively. In THP-1 cell line, significantly inhibited colony formation and caused remarkable morphological changes. Compound induced expression of CD86 and CD11b in THP-1 cells, confirming its cellular activity and ability of inducing differentiation. The findings further indicate that targeting LSD1 is a promising strategy for AML treatment, the triazole-fused pyrimidine derivatives are new scaffolds for the development of LSD1/KDM1A inhibitors.

15.
Article in Chinese | WPRIM | ID: wpr-756469

ABSTRACT

Objective The primary goal of this work is to discuss the molecular mechanism of multi-drug resistant Pseudomonas spp. resistance to carbapenam and aminoglycoside antibiotics. Methods From June 2012 to March 2013, six strains of P. aeruginosa and P. putida producing carbapenemasefrom 4 different district were collected. Species identification was performed using VITEK-2 compact system and by sequencing of 16S rDNA amplicons. Minimum inhibitory concentrations were determined by E-test method. Production of carbapenemase were detected by Carba NP method. Carbapenemase genes and aminoglycoside 16s rRNAmethylase genes were screened by PCR, and their subtypes combined with their immediate genetic context were worked out by assemble the sequence of overlapped PCR amplicons. SpeI-PFGE (Pulse field gel electrophoresis after SpeI enzyme digestion) were conducted to evaluate their clonal relatedness. S1-PFGE (Pulse field gel electrophoresis after S1 enzyme digestion) were conducted to conform the relatedness of plasmids they carried. Results Three multidrug resistant P. aeruginosa and three P. putida, were all positive for Carba NP test and conformed producing class B carbapenemase. PCR screening followed by sequencing confirmed carriage of blaIMP-45 and armA, which confer resistance to β-lactams (except aztreonam) and aminoglycosides. These two genes co-located in a Tn1548-associatedregion. SpeI-PFGE disclosed that these isolates were not clonal closely related to each other, except two P. aeruginosa isolates were clonal related. S1-PFGE results showed that these isolates all carried plasmids of large size (300-600 kb). Conclusions This study showed that Pseudomonas spp. isolates co-carried blaIMP-45 and armA were disseminated in clinical settings. Spread of these genes may attribute to horizontal gene transfer of related entities.

16.
Chinese Journal of Digestion ; (12): 332-336, 2019.
Article in Chinese | WPRIM | ID: wpr-756294

ABSTRACT

Objective To investigate the relationship between aberrant expression of interleukin 6 (IL-6) and gene methylation in patients with ulcerative colitis (UC),and to clarify the mechanism of epigenetics in UC.Methods From March 2017 to March 2018,a total of 59 UC patients admitted to the Department of Gastroenterology,General Hospital Affiliated to Tianjin Medical University were enrolled,and at the same time 58 normal individuals who received health checkups were selected as healthy controls.Blood samples and colonic mucosa specimens of UC group and healthy control group were collected.DNA methyltransferase (DNMT) activity,methylation level of CpG locus in IL-6 promoter region and expression level of IL-6 were detected.Chi-square test and student's t test were performed for statistical analysis.Results The methylation level and IL-6 expression level examination were completed in 24 and 30 cases of UC group,respectively;which were detected in 21 and 20 cases of healthy control group,respectively.The activity of DNMT of UC group was significantly lower than that of healthy control group ((16.48 ± 6.17) OD · h-1 · mg-1 vs.(62.48 ± 33.88) OD · h-1 ·mg-1),and the difference was statistically significant (t =3.707,P < 0.05).The ratios of methylation,partial methylation and non-methylation of UC group were 31.2% (15/48),50.0% (24/48) and 18.8% (9/48),respectively,and those of healthy control group were 58.3% (35/60),21.7% (13/60) and 20.0% (12/60),and the difference between the two groups was statistically significant (x2 =10.495,P < 0.05).The positive expression rate of IL-6 in intestinal mucosa of UC group was higher than that of healthy control group (100.0%,21/21 vs.25.0%,5/20),and the difference was statistically significant (x2 =24.837,P <0.05).The serum IL-6 level of UC group was higher than that of healthy control group ((1 075.02 ±661.95) ng/L vs.(583.43 ± 425.10) ng/L),and the difference was statistically significant (t =3.245,P < 0.05).Conclusion The decrease of DNMT activity in the intestinal mucosa of UC patients may reduce the methylation level of IL-6 gene promoter region,which is correlated with the increased level of IL-6 expression in the intestinal mucosa and serum,and involve in the inflammatory process of UC.

17.
Article in Chinese | WPRIM | ID: wpr-804791

ABSTRACT

Objective@#To investigate the effects of Paraquat on neural stem cell proliferation in vitro and explore the its mechanism based on DNA methylation pathway.@*Methods@#Nestin, β-tubulin III, and glial fibrillary acidic protein (GFAP) were detected by indirect immunofluorescence assay to evaluate self renewal and differentiation potentia of ReNcell CX human neural stem. The cells were treated with terminal concentrations of 0, 5, 25, 50, and 100μmol/L PQ for 24 hours, and the cells were induced by 50 μmol/L PQ for different time (6, 12, 24, 48 h). Cell viability was determined by MTT assay. The proliferation of neural stem cells was evaluated using Sox2/Brdu and Nestin/Brdu double immunofluorescence staining. The global DNA methylation level was assayed by MethyflashTM methylated DNA Quantification kit. The expression levels of Dnmts mRNA and protein were analyzed by quantitative reverse transcription polymerase chain reaction(qRT-PCR) and Western blot, respectively.@*Results@#Immunofluorescence showed that nestin was primarily expressed in proliferative neural stem cell and peotein biomarkers (β-tubulin III, GFAP) for neuron and astrocyte were expressed in differentiated cells. MTT assay showed PQ induced cell survival rate decrease in a time and dose dependent manner. Double immunfluorescence staining of cells showed colocalization of Sox2 and Brdu. The percentage of Brdu/Sox2 positive cells was significantly lower in the PQ-exposed (25, 50, 100μmol/L PQ treatment) groups compared to control (P<0.05); Meanwhile, The percentage of Brdu/Nestin positive cells was also significantly lower in the PQ-exposed(50,100μmol/L PQ treatment) groups compared to control (P<0.05). The results of global DNA methylation revealed a significant decrease in PQ-exposed groups (P<0.05). Western blot showed that compared with control group, the protein and mRNA levels of Dnmt1, Dnmt3a in PQ-exposed group were significantly decreased (P<0.05), but there was a significant increase in expression level of Dnmt3b in 50, 100 μmol/L PQ-treated group(P<0.05).@*Conclusion@#Paraquat could inhibite the proliferation of human neural stem cells through reducing the level of DNA methylation reaction by suppressing the protein expression and transcription of DNA methylated transferase(Dnmts).

18.
Indian J Med Microbiol ; 2018 Mar; 36(1): 43-48
Article | IMSEAR | ID: sea-198751

ABSTRACT

Background: Acinetobacter baumannii has emerged as an important nosocomial pathogen, its ability to acquire resistance to carbapenems and aminoglycosides, has complicated their treatment regimen. The present study investigates the prevalence and diversity of aminoglycoside-modifying enzymes and 16S methyltransferases in A. baumannii isolates recovered from patients admitted in Intensive Care Unit (ICU) of a tertiary referral hospital in Northeastern India. Materials and Methods: We investigated the high-level aminoglycoside-resistance (HLAR) (gentamicin and amikacin minimum inhibitory concentration ? 512 ?g/ml) among 164 multidrug-resistant A. baumannii obtained from ICU. Genes encoding aminoglycoside-modifying enzymes, 16S methyltransferase and coexisting beta-lactamases were amplified. Horizontal transferability, plasmid stability and elimination assays were performed. Clonality and sequence types were evaluated by repetitive extragenic palindromic-polymerase chain reaction and multilocus sequence typing (MLST) respectively. Results: A total of 130 (79.2%) isolates were found to exhibit HLAR, with acquired aminoglycoside-resistance genes in 109 (83.8%) isolates along with coexisting extended-spectrum beta-lactamases and metallo-beta-lactamases. Genes aph (3') I, aph (3') VIa and armA were predominant and horizontally transferable. Plasmids were eliminated with single sodium dodecyl sulphate treatment. Seventeen haplotypes were found responsible for the infection. MLST revealed circulation of ST583 and ST188 in ICU. Conclusions: This study reveals the presence of aminoglycoside-resistance genes in combination with blaCTXM and blaNDM, which are highly stable and not frequently reported from this geographical region. Further, the study could predict limited treatment option and need for formulating infection control strategy.

19.
Mem. Inst. Oswaldo Cruz ; 113(12): e180392, 2018. tab, graf
Article in English | LILACS | ID: biblio-976235

ABSTRACT

OBJECTIVES The emergence of 16S rRNA methyltranferases (16 RMTAses) has jeopardised the clinical use of aminoglycosides. RmtB is one of the most frequently reported in Gram-negatives worldwide. In this study, we aimed to estimate the frequency of 16S RMTAses encoding genes in Enterobacteriaceae isolated in a three-month period from a tertiary Brazilian hospital. METHODS All Gram-negatives classified as resistant to amikacin, gentamicin, and tobramycin by agar screening were selected for analysis. The presence of 16SRMTases encoding genes was verified by polymerase chain reaction (PCR). Antimicrobial susceptible profile was determined by broth microdilution. The genetic relationship among these isolates was accessed by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Selected RmtB-producing isolates were characterised by whole genome sequencing (WGS) analysis. RESULTS Twenty-two of 1,052 (2.1%) Enterobacteriaceae were detected as producers of RmtB-1 [Klebsiella pneumoniae (n = 21) and Proteus mirabilis (n = 1)]. blaKPC-2 was identified among 20 RmtB-1-producing K. pneumoniae isolates that exhibited an identical PFGE and MLST (ST258) patterns. Two K. pneumoniae isolates, the A64216 (not harboring bla KPC-2), A64477 (harboring bla KPC-2) and one P. mirabilis isolate (A64421) were selected for WGS. rmtB-1 and bla KPC-2 genes were carried by distinct plasmids. While a plasmid belonging to the IncFIIk group harbored rmtB-1 in K. pneumoniae, this gene was carried by a non-typable plasmid in P. mirabilis. In the three analysed plasmids, rmtB-1 was inserted on a transposon, downstream a Tn2. CONCLUSION Our findings suggested that the rmtB-1 was harbored by plasmids distinct from those previously reported in Bolivia and China. It suggests that multiple mobilization events might have occurred in South America.


Subject(s)
Humans , Disease Outbreaks/statistics & numerical data , Enterobacteriaceae , Klebsiella pneumoniae , Genes, rRNA/genetics , Aminoglycosides/therapeutic use
20.
Tumor ; (12): 980-986, 2018.
Article in Chinese | WPRIM | ID: wpr-848339

ABSTRACT

Breast cancer is now the most common malignant tumor in Chinese women. Approximately 70% of breast cancers express estrogen receptor (ER) which plays a critical role in the development of breast cancer. Endocrine therapy has become one of the most effective treatments for ER-positive breast cancer. At present, the endocrine therapy drugs are mainly divided into three categories: selective ER modulators, selective ER down-regulators and aromatase inhibitors. The adjuvant endocrine therapy with these drugs can reduce the risk of breast cancer recurrence by nearly 40%. However, the resistance of tumor cells to endocrine therapy is a major factor limiting the success of breast cancer treatment. The known mechanisms of endocrine therapy resistance include the concentration of estrogen increased in tumor microenvironment, ER gene mutation, up-regulation of multiple molecular signal pathway, and epigenetic mechanisms. Overcoming endocrine therapy resistance is essential for further improving the benefit rate of endocrine therapy. In this review, the progresses of epigenetic mechanisms (including DNA methylation and histone modification) and epigenetic drugs (including DNAmethyltransferases inhibitors and histone deacetylases inhibitors) of endocrine therapy resistance in ER-positive breast cancer are introduced, in order to further understand the mechanism and therapeutics of endocrine therapy resistance in breast cancer.

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