scholarly journals Cefazolin and Imipenem Enhance AmpC Expression and Resistance in NagZ-Dependent Manner in Enterobacter Cloacae

2021 ◽  
Author(s):  
Xianggui Yang ◽  
Zhenguo Wang ◽  
Xuejing Yu ◽  
Yuanxiu Zhong ◽  
Fuying Wang ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Target Genes ◽  
Ectopic Expression ◽  
Enterobacter Cloacae ◽  
Opportunistic Pathogen ◽  
Resistance Mechanisms ◽  
Induction Effect ◽  
Dependent Manner ◽  
Critical Determinant ◽  
2Nd Generation

Abstract Background: Enterobacter cloacae (EC) is a commonly occurring opportunistic pathogen and is responsible for causing various infections in humans. Owing to its inducible chromosomal AmpC β-lactamase (AmpC), EC is inherently resistant to the 1st- and 2nd- generation cephalosporins. However, whether β-lactams antibiotics enhance EC resistance remains unclear.Results: In this study, we found that subinhibitory concentrations (SICs) of cefazolin (CFZ) and imipenem (IMP) are able to advance the expression of AmpC and improve its resistance towards β - lactams through NagZ in EC clinical isolate. Our work indicate that AmpC manifested a substantial upregulation in EC in response to SICs of CFZ and IMP. In nagZ knockout EC (ΔnagZ), we found that the resistance to β - lactam antibiotics was rather weakened and the effect of CFZ and IMP on induction of AmpC was completely abrogated. Ectopic expression of NagZ can rescue the induction effect of CFZ and IMP on AmpC and enhance resistance in ΔnagZ. More importantly, CFZ and IMP have the potential to bring about the target genes expressions of AmpR in a NagZ-dependent manner.Conclusions: Our findings show that NagZ is a critical determinant for CFZ and IMP to promote AmpC expression and improve resistance and that CFZ and IMP should be used with caution since they may aggravate EC resistance. At the same time, this study further improves our understanding of resistance mechanisms in EC.

scholarly journals Association of two resistance mechanisms in a clinical isolate of Enterobacter cloacae with high-level resistance to imipenem.

1991 ◽  
Vol 35 (6) ◽  
pp. 1093-1098 ◽  
Author(s):  
E H Lee ◽  
M H Nicolas ◽  
M D Kitzis ◽  
G Pialoux ◽  
E Collatz ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Enterobacter Cloacae ◽  
Resistance Mechanisms ◽  
High Level ◽  
Level Resistance

scholarly journals HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Meng Yu ◽  
Toshinori Ozaki ◽  
Dan Sun ◽  
Haotian Xing ◽  
Baojun Wei ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Cells ◽  
Target Genes ◽  
Ectopic Expression ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Down Regulation ◽  
Expression Levels ◽  
Bladder Cancer Cells

Abstract Background Chemo-resistance of bladder cancer has been considered to be one of the serious issues to be solved. In this study, we revealed pivotal role of miR-424 in the regulation of CDDP sensitivity of bladder cancer cells. Methods The cytotoxicity of cisplatin and effect of miR-424 were assessed by flow cytometry and TUNEL. Transcriptional regulation of miR-424 by HIF-1α was assessed by Chromatin immunoprecipitation (ChIP). Effect of miR-424 on expression of UNC5B, SIRT4 (Sirtuin4) and apoptotic markers was measured by QRT-PCR and/or Western blot. The regulation of miR-424 for UNC5B and SIRT4 were tested by luciferase reporter assay. The 5637-inoculated nude mice xenograft model was used for the in vivo study. The clinical significance of miR-424 was demonstrated mainly through data mining and statistical analysis of TCGA. Results In this study, we have found for the first time that cisplatin (CDDP) induces the expression of miR-424 in a HIF-1α-dependent manner under normoxia, and miR-424 plays a vital role in the regulation of CDDP resistance of bladder cancer cells in vitro. Mechanistically, we have found that UNC5B and SIRT4 are the direct downstream target genes of miR-424. CDDP-mediated suppression of xenograft bladder tumor growth was prohibited by the addition of miR-424, whereas ectopic expression of UNC5B or SIRT4 partially restored miR-424-dependent decrease in CDDP sensitivity of bladder cancer 5637 and T24 cells. Moreover, knockdown of UNC5B or SIRT4 prohibited CDDP-mediated proteolytic cleavage of PARP and also decreased CDDP sensitivity of these cells. Consistently, the higher expression levels of miR-424 were closely associated with the poor clinical outcome of the bladder cancer patients. There existed a clear inverse relationship between the expression levels of miR-424 and pro-apoptotic UNC5B or SIRT4 in bladder cancer tissues. Conclusions Collectively, our current results strongly suggest that miR-424 tightly participates in the acquisition/maintenance of CDDP-resistant phenotype of bladder cancer cells through down-regulation of its targets UNC5B and SIRT4, and thus combination chemotherapy of CDDP plus HIF-1α/miR-424 inhibition might have a significant impact on hypoxic as well as normoxic bladder cancer cells.

scholarly journals TBLR1 as an androgen receptor (AR) coactivator selectively activates AR target genes to inhibit prostate cancer growth

2013 ◽  
Vol 21 (1) ◽  
pp. 127-142 ◽  
Author(s):  
Garrett Daniels ◽  
Yirong Li ◽  
Lan Lin Gellert ◽  
Albert Zhou ◽  
Jonathan Melamed ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Target Genes ◽  
Ectopic Expression ◽  
Growth Suppression ◽  
Cancer Growth ◽  
Dependent Manner ◽  
Prostate Cancer Cells ◽  
Dependent Growth

Androgen receptor (AR), a steroid hormone receptor, is critical for prostate cancer growth. However, activation of AR by androgens can also lead to growth suppression and differentiation. Transcriptional cofactors play an important role in this switch between proliferative and anti-proliferative AR target gene programs. Transducin β-like-related protein 1 (TBLR1), a core component of the nuclear receptor corepressor complex, shows both corepressor and coactivator activities on nuclear receptors, but little is known about its effects on AR and prostate cancer. We characterized TBLR1 as a coactivator of AR in prostate cancer cells and determined that the activation is dependent on both phosphorylation and 19S proteosome. We showed that TBLR1 physically interacts with AR and directly occupies the androgen-response elements of the affected AR target genes in an androgen-dependent manner. TBLR1 is primarily localized in the nucleus in benign prostate cells and nuclear expression is significantly reduced in prostate cancer cells in culture. Similarly, in human tumor samples, the expression of TBLR1 in the nucleus is significantly reduced in the malignant glands compared with the surrounding benign prostatic glands (P<0.005). Stable ectopic expression of nuclear TBLR1 leads to androgen-dependent growth suppression of prostate cancer cells in vitro and in vivo by selective activation of androgen-regulated genes associated with differentiation (e.g. KRT18) and growth suppression (e.g. NKX3-1), but not cell proliferation of the prostate cancer. Understanding the molecular switches involved in the transition from AR-dependent growth promotion to AR-dependent growth suppression will lead to more successful treatments for prostate cancer.

scholarly journals The Role of microRNAs in Cholangiocarcinoma

2021 ◽  
Vol 22 (14) ◽  
pp. 7627
Author(s):  
Tingting Shi ◽  
Asahiro Morishita ◽  
Hideki Kobara ◽  
Tsutomu Masaki
Keyword(s):  
Cell Cycle Progression ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Survival Rates ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Mesenchymal Transition ◽  
Diagnosis And Prognosis ◽  
Related Risk

Cholangiocarcinoma (CCA), an aggressive malignancy, is typically diagnosed at an advanced stage. It is associated with dismal 5-year postoperative survival rates, generating an urgent need for prognostic and diagnostic biomarkers. MicroRNAs (miRNAs) are a class of non-coding RNAs that are associated with cancer regulation, including modulation of cell cycle progression, apoptosis, metastasis, angiogenesis, autophagy, therapy resistance, and epithelial–mesenchymal transition. Several miRNAs have been found to be dysregulated in CCA and are associated with CCA-related risk factors. Accumulating studies have indicated that the expression of altered miRNAs could act as oncogenic or suppressor miRNAs in the development and progression of CCA and contribute to clinical diagnosis and prognosis prediction as potential biomarkers. Furthermore, miRNAs and their target genes also contribute to targeted therapy development and aid in the determination of drug resistance mechanisms. This review aims to summarize the roles of miRNAs in the pathogenesis of CCA, their potential use as biomarkers of diagnosis and prognosis, and their utilization as novel therapeutic targets in CCA.

scholarly journals Characterization of resistance mechanisms of Enterobacter cloacae Complex co-resistant to carbapenem and colistin

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shixing Liu ◽  
Renchi Fang ◽  
Ying Zhang ◽  
Lijiang Chen ◽  
Na Huang ◽  
...  
Keyword(s):  
Lipid A ◽  
Efflux Pump ◽  
Resistance Mechanism ◽  
Carbapenem Resistance ◽  
Enterobacter Cloacae ◽  
Resistance Mechanisms ◽  
Colistin Resistance ◽  
Carbapenem Resistant ◽  
Horizontal Spread

Abstract Background The emergence of carbapenem-resistant and colistin-resistant ECC pose a huge challenge to infection control. The purpose of this study was to clarify the mechanism of the carbapenems and colistin co-resistance in Enterobacter cloacae Complex (ECC) strains. Results This study showed that the mechanisms of carbapenem resistance in this study are: 1. Generating carbapenemase (7 of 19); 2. The production of AmpC or ESBLs combined with decreased expression of out membrane protein (12 of 19). hsp60 sequence analysis suggested 10 of 19 the strains belong to colistin hetero-resistant clusters and the mechanism of colistin resistance is increasing expression of acrA in the efflux pump AcrAB-TolC alone (18 of 19) or accompanied by a decrease of affinity between colistin and outer membrane caused by the modification of lipid A (14 of 19). Moreover, an ECC strain co-harboring plasmid-mediated mcr-4.3 and blaNDM-1 has been found. Conclusions This study suggested that there is no overlap between the resistance mechanism of co-resistant ECC strains to carbapenem and colistin. However, the emergence of strain co-harboring plasmid-mediated resistance genes indicated that ECC is a potential carrier for the horizontal spread of carbapenems and colistin resistance.

scholarly journals A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Qian Liu ◽  
Lijuan Guo ◽  
Hongyan Qi ◽  
Meng Lou ◽  
Rui Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Dna Synthesis ◽  
Ectopic Expression ◽  
Building Blocks ◽  
Small Subunit ◽  
S Phase ◽  
Clinical Samples ◽  
Dependent Manner

AbstractRibonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.

scholarly journals Disassembly of theStaphylococcus aureushibernating 100S ribosome by an evolutionarily conserved GTPase

2017 ◽  
Vol 114 (39) ◽  
pp. E8165-E8173 ◽  
Author(s):  
Arnab Basu ◽  
Mee-Ngan F. Yap
Keyword(s):  
Opportunistic Pathogen ◽  
Dependent Manner ◽  
Bacterial Survival ◽  
Temperature Dependent ◽  
Bacterial Phyla ◽  
Evolutionarily Conserved ◽  
Bona Fide ◽  
70S Ribosome ◽  
Relationship Of ◽  
Dissociation Factor

The bacterial hibernating 100S ribosome is a poorly understood form of the dimeric 70S particle that has been linked to pathogenesis, translational repression, starvation responses, and ribosome turnover. In the opportunistic pathogenStaphylococcus aureusand most other bacteria, hibernation-promoting factor (HPF) homodimerizes the 70S ribosomes to form a translationally silent 100S complex. Conversely, the 100S ribosomes dissociate into subunits and are presumably recycled for new rounds of translation. The regulation and disassembly of the 100S ribosome are largely unknown because the temporal abundance of the 100S ribosome varies considerably among different bacterial phyla. Here, we identify a universally conserved GTPase (HflX) as a bona fide dissociation factor of theS. aureus100S ribosome. The expression levelshpfandhflXare coregulated by general stress and stringent responses in a temperature-dependent manner. While all tested guanosine analogs stimulate the splitting activity of HflX on the 70S ribosome, only GTP can completely dissociate the 100S ribosome. Our results reveal the antagonistic relationship of HPF and HflX and uncover the key regulators of 70S and 100S ribosome homeostasis that are intimately associated with bacterial survival.

fMLP induces Hsp27 expression, attenuates NF-κB activation, and confers intestinal epithelial cell protection

2007 ◽  
Vol 292 (4) ◽  
pp. G1070-G1078 ◽  
Author(s):  
Ryan M. Carlson ◽  
Stephan R. Vavricka ◽  
Jyrki J. Eloranta ◽  
Mark W. Musch ◽  
Donna L. Arvans ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Intestinal Epithelial Cell ◽  
Target Genes ◽  
Bacterial Flora ◽  
Epithelial Cell Line ◽  
Dependent Manner ◽  
Intestinal Epithelial ◽  
Cell Protection ◽  
Hsp27 Expression ◽  
Tnf Α

Sustained expression of cytoprotective intestinal epithelial heat shock proteins (Hsps), particularly Hsp27, depends on stimuli derived from bacterial flora. In this study, we examined the role of the bacterial chemotactic peptide fMLP in stimulating colonic epithelial Hsp expression at concentrations encountered in a physiological milieu. Treatment of the polarized human intestinal epithelial cell line Caco2bbe with physiological concentrations of fMLP (10–100 nM) induced expression of Hsp27, but not Hsp72, in a time- and concentration-dependent manner. Induction of Hsp27 by fMLP was specific since the fMLP analogs MRP and MLP were not effective. Hsp27 induction by fMLP was blocked by the fMLP-receptor antagonist BOC-FLFLF and was blocked when the dipeptide transporter PepT1, an entry pathway for fMLP, was silenced. fMLP activated both the p38 and ERK1/2 MAP kinase pathways in Caco2bbe cells, but not the SAPK/JNK pathway. The p38 inhibitor SB203580, but not the MEK-1 inhibitor PD98059, blocked Hsp27 induction by fMLP. fMLP treatment inhibited actin depolymerization and decreased transepithelial resistance caused by the oxidant monochloramine, and this inhibition was reversed by silencing Hsp27 expression. fMLP pretreatment also inhibited activation of proinflammatory transcription factor NF-κB by TNF-α in Caco2bbe cells, reducing induction of NF-κB target genes by TNF-α both in human intestinal biopsies and Caco2bbe cells. In conclusion, fMLP may contribute to the maintenance of intestinal homeostasis by mediating physiological expression of Hsp27, enhancing cellular protection, and negatively regulating the inflammatory response.

scholarly journals Draft Genome Sequences of Two Enterobacter cloacae subsp. cloacae Strains Isolated from Australian Hematology Patients with Bacteremia

2017 ◽  
Vol 5 (33) ◽  
Author(s):  
Lex E. X. Leong ◽  
David Shaw ◽  
Lito Papanicolas ◽  
Diana Lagana ◽  
Ivan Bastian ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Draft Genome ◽  
Enterobacter Cloacae ◽  
Opportunistic Pathogen ◽  
Healthy Individuals ◽  
Genome Sequences ◽  
Content Type ◽  
Extended Spectrum ◽  
Genes Encoding

ABSTRACT Enterobacter cloacae is a common member of the gut microbiota in healthy individuals. However, it is also an opportunistic pathogen, capable of causing bacteremia. We report the draft genomes of two Enterobacter cloacae subspecies cloacae strains isolated from hematology patients with bacteremia. Both isolates carry genes encoding extended-spectrum β-lactamases.

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