scholarly journals Wnt/β-catenin signaling as an emerging potential key pharmacological target in cholangiocarcinoma

2020 ◽  
Vol 40 (3) ◽  
Author(s):  
Guo-Feng Zhang ◽  
Ling Qiu ◽  
Shu-Li Yang ◽  
Jia-Cheng Wu ◽  
Tong-Jun Liu
Keyword(s):  
Signaling Pathways ◽  
Nuclear Translocation ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Regulatory Subunit ◽  
Wnt Ligands ◽  
Liver Kinase B1 ◽  
Gsk 3Β

Abstract Cholangiocarcinoma (CCA) is a fatal malignant tumor of biliary epithelial cells involving intra- or extra-hepatic bile ducts. The prognosis of CCA is generally poor due to its diagnosis at the late stages. The currently employed chemotherapeutic agents do not increase the survival rate in patients with unresectable CCA. Accordingly, there is a need to identify new therapeutic agents for the effective management of intra- and extra-hepatic CCA. Clinical as well as preclinical studies have suggested the key role of the activation of Wnt/β-catenin signaling pathway in the induction and progression of CCA. There is an up-regulation of different Wnt ligands including Wnt2, Wnt3, Wnt5, Wnt7 and Wnt10 along with redistribution of β-catenin (more expression in the nucleus and lesser on the cell surface due to nuclear translocation of β-catenin) in different types of malignant biliary tumors. Apart from the role of this pathway in the induction and progression of CCA, this pathway is also involved in inducing multidrug resistance by inducing the expression of P-glycoprotein efflux pump on the cancer cells. These deleterious effects of Wnt/β-catenin signaling are mediated in association with other signaling pathways involving microRNAs (miRNAs), PI3K/AKT/PTEN/GSK-3β, retinoic acid receptors (RARs), dickkopf-1 (DKK1), protein kinase A regulatory subunit 1 α (PRKAR1A/PKAI), (SLAP), liver kinase B1 (LKB1) and CXCR4. The selective inhibitors of Wnt/β-catenin signaling may be potentially employed to overcome multidrug-resistant, fatal CCA. The present review discusses the role of Wnt/β-catenin along with its relation with other signaling pathways in the induction and progression of CCA.

Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase/Akt-mediated pathway in mouse β-cells

2007 ◽  
Vol 293 (3) ◽  
pp. E645-E655 ◽  
Author(s):  
Subbiah Pugazhenthi ◽  
Leonid Akhov ◽  
Gopalan Selvaraj ◽  
Maorong Wang ◽  
Jawed Alam
Keyword(s):  
Signaling Pathways ◽  
Heme Oxygenase ◽  
Nuclear Translocation ◽  
Regulatory Subunit ◽  
Luciferase Reporter ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mrna Levels ◽  
Phase 2 ◽  
Β Cells

Curcumin (diferuloylmethane), a component of turmeric, has been shown to have therapeutic properties. Induction of phase 2 detoxifying enzymes is a potential mechanism through which some of the actions of curcumin could proceed. Heme oxygenase-1 (HO-1), an antioxidant phase 2 enzyme, has been reported to have cytoprotective effects in pancreatic β-cells. Curcumin on further purification yields demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC). The objective of the present study was to determine the mechanism by which these purified curcuminoids induce HO-1 in MIN6 cells, a mouse β-cell line. Demethoxy curcuminoids induced HO-1 promoter linked to the luciferase reporter gene more effectively than curcumin. The induction was dependent on the presence of antioxidant response element (ARE) sites containing enhancer regions (E1 and E2) in HO-1 promoter and nuclear translocation of nuclear factor-E2-related factor (Nrf2), the transcription factor that binds to ARE. Curcuminoids stimulated multiple signaling pathways that are known to induce HO-1. Inhibition of specific signaling pathways with pharmacological inhibitors and cotransfection experiments suggested the involvement of phosphotidylinositol 3-kinase and Akt. Real-time quantitative RT-PCR analysis showed significant elevation in the mRNA levels of HO-1 and two other phase 2 enzymes, the regulatory subunit of glutamyl cysteine ligase, which is needed for the synthesis of glutathione, and NAD(P)H:quinone oxidoreductase, which detoxifies quinones. DMC and BDMC induced the expression of HO-1 and translocated Nrf2 to nucleus in β-cells of mouse islets. Our observations suggest that demethoxy curcuminoids could be used to induce a cellular defense mechanism in β-cells under conditions of stress as seen in diabetes.

scholarly journals The synergistic role of ATP-dependent drug efflux pump and focal adhesion signaling pathways in vinorelbine resistance in lung cancer

2018 ◽  
Vol 7 (2) ◽  
pp. 408-419 ◽  
Author(s):  
Takao Nakanishi ◽  
Toshi Menju ◽  
Shigeto Nishikawa ◽  
Koji Takahashi ◽  
Ryo Miyata ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Efflux Pump ◽  
Drug Efflux ◽  
Drug Efflux Pump

scholarly journals Multidrug resistant Acinetobacter baumannii--the role of AdeABC (RND family) efflux pump in resistance to antibiotics.

2008 ◽  
Vol 46 (3) ◽  
Author(s):  
Piotr Wieczorek ◽  
Paweł Sacha ◽  
Tomasz Hauschild ◽  
Marcin Zórawski ◽  
Małgorzata Krawczyk ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Resistance To Antibiotics

Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype

Blood ◽  
1992 ◽  
Vol 80 (6) ◽  
pp. 1528-1536 ◽  
Author(s):  
RJ Arceci ◽  
K Stieglitz ◽  
BE Bierer
Keyword(s):  
Efflux Pump ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Drug ◽  
Cytotoxic Agents ◽  
Cross Resistance ◽  
Clinical Role ◽  
Reversal Agents ◽  
P Glycoprotein ◽  
Mdr Reversal

Abstract The multidrug-resistant (MDR) phenotype is characterized in vitro by the resistance displayed by cell lines to a broad spectrum of natural product cytotoxic agents. This high level of cross-resistance is due to the increased expression of a membrane glycoprotein termed P- glycoprotein. Encoded in humans by the mdr1 gene, P-glycoprotein functions as an energy-dependent efflux pump of these cytotoxic agents. In this report, we demonstrate that the newly characterized immunosuppressant FK506 and its structural analogue, rapamycin, are capable of functioning as MDR reversal agents. FK506 and rapamycin increase both intracellular, cytotoxic drug (daunomycin) accumulation, and the cytotoxicity of chemotherapeutic agents in multidrug-resistant cells. The increase in cytotoxic drug accumulation is observed at concentrations of FK506 and rapamycin 1,000-fold greater than the concentrations required for FK506 and rapamycin to inhibit T-lymphocyte activation and similar to those shown to be effective for other MDR reversal agents such as cyclosporine A (CsA) and verapamil. The effect of FK506 or rapamycin on both intracellular accumulation and cytotoxicity of daunomycin is additive. This is supported by the ability of FK506 and rapamycin to directly compete the binding of the photoaffinity analogue 125I-iodoaryl azidoprazosin to the P- glycoprotein. The data demonstrate that FK506 and rapamycin represent a new class of structurally distinct molecules that can function as MDR reversal agents and suggest a previously unidentified, potential clinical role for these compounds.

scholarly journals Antistaphylococcal and Antibiotic Resistance Modulatory Activities of Thirteen Cameroonian Edible Plants against Resistant Phenotypes

2018 ◽  
Vol 2018 ◽  
pp. 1-12
Author(s):  
Brice E. N. Wamba ◽  
Armelle T. Mbaveng ◽  
Paul Nayim ◽  
Joachim K. Dzotam ◽  
Ornella J. T. Ngalani ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Efflux Pump ◽  
Efflux Pumps ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Edible Plants ◽  
Bacterial Strains ◽  
Efflux Pump Inhibitor ◽  
Dacryodes Edulis

Background. In this study, 18 methanol extracts from Cameroonian edible plants were tested for their antibacterial activities against 26 strains ofS. aureus; the role of efflux pumps in the resistance of tested bacteria and the antibiotic resistance-modulating activities against selected multidrug-resistant (MDR) phenotypes were also investigated.Methods. Broth microdilution assay was used to evaluate the antibacterial activity, the role of efflux pumps, and the antibiotic resistance-modulating effects of plant extracts.Results. Extracts fromDacryodes edulisseeds (DES) andDacryodes edulisbark (DEB) were active against all 26 tested bacterial strains, within the minimal inhibitory concentration (MIC) range of 256–1024 µg/mL. MIC values varied from 64 to 1024 µg/mL against 96.2% of the 26 tested bacteria forPhaseolus vulgarisleaves (PVL), 92.3% forAzadirachta indicabark (AIB),Dacryodes edulisleaves (DEL), andRicinodendron heudelotiileaves (RHL). The lowest MIC value of 64 µg/mL was obtained with the extract fromCucurbita maximabeans (CMB) against MRSA4 strain and fromUapaca guineensisbark (UGB) against MRSA9 strain. Bacterial efflux pump inhibitor (EPI), carbonyl cyanidem-chlorophenyl hydrazone (CCCP), improved the activity of DES and UGB as well as that of extracts fromHibiscus esculentusleaves (HEL) andUapaca guineensisleaves (UGL) against resistantS. aureusstrains. Antibiotic-modulating effects against more than 70% of theS. aureusstrains tested were obtained when RHL (at MIC/2) was combined with CIP, ERY, and KAN (88.89%), CHL (88.89%), TET (77.78%), and STR (88.89%).Conclusion. The present study demonstrated that the 13 tested plants had antistaphylococcal effects and that DES, HEL, UGL, and UGB could be used in combination with EPI to combat resistance toStaphylococcus aureus. Also, it demonstrated that some studied extracts and mostly RHL could be used as antibiotic resistance modulators to fight against resistant strains ofS. aureus.

scholarly journals Regulation of the Nrf2 Pathway by Glycogen Synthase Kinase-3β in MPP+-Induced Cell Damage

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1377 ◽  
Author(s):  
Güliz Armagan ◽  
Elvin Sevgili ◽  
Fulya Tuzcu Gürkan ◽  
Fadime Aydın Köse ◽  
Tuğçe Bilgiç ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Cellular Damage ◽  
Glycogen Synthase Kinase 3Β ◽  
Nrf2 Pathway ◽  
Gsk 3Β

Recently, nuclear translocation and stability of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) have gained increasing attention in the prevention of oxidative stress. The present study was aimed to evaluate the regulatory role of glycogen synthase kinase-3β (GSK-3β) inhibition by tideglusib through the Nrf2 pathway in a cellular damage model. Gene silencing (siRNA-mediated) was performed to examine the responses of Nrf2-target genes (i.e., heme oxygenase-1, NAD(P)H:quinone oxidoreductase1) to siRNA depletion of Nrf2 in MPP+-induced dopaminergic cell death. Nrf2 and its downstream regulated genes/proteins were analyzed using Real-time PCR and Western Blotting techniques, respectively. Moreover, free radical production, the changes in mitochondrial membrane potential, total glutathione, and glutathione-S-transferase were examined. The possible contribution of peroxisome proliferator-activated receptor gamma (PPARγ) to tideglusib-mediated neuroprotection was evaluated. The number of viable cells and mitochondrial membrane potential were increased following GSK-3β enzyme inhibition against MPP+. HO-1, NQO1 mRNA/protein expressions and Nrf2 nuclear translocation significantly triggered by tideglusib. Moreover, the neuroprotection by tideglusib was not observed in the presence of siRNA Nrf2. Our study supports the idea that GSK-3β enzyme inhibition may modulate the Nrf2/ARE pathway in cellular damage and the inhibitory role of tideglusib on GSK-3β along with PPARγ activation may be responsible for neuroprotection.

scholarly journals Characterization of Posttranslationally Modified Multidrug Efflux Pumps Reveals an Unexpected Link between Glycosylation and Antimicrobial Resistance

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
Sherif Abouelhadid ◽  
John Raynes ◽  
Tam Bui ◽  
Jon Cuccui ◽  
Brendan W. Wren
Keyword(s):  
Antimicrobial Resistance ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Gram Negative ◽  
Content Type ◽  
Multidrug Efflux Pumps ◽  
Pump Activity

ABSTRACT The substantial rise in multidrug-resistant bacterial infections is a current global imperative. Cumulative efforts to characterize antimicrobial resistance in bacteria has demonstrated the spread of six families of multidrug efflux pumps, of which resistance-nodulation-cell division (RND) is the major mechanism of multidrug resistance in Gram-negative bacteria. RND is composed of a tripartite protein assembly and confers resistance to a range of unrelated compounds. In the major enteric pathogen Campylobacter jejuni, the three protein components of RND are posttranslationally modified with N-linked glycans. The direct role of N-linked glycans in C. jejuni and other bacteria has long been elusive. Here, we present the first detailed account of the role of N-linked glycans and the link between N-glycosylation and antimicrobial resistance in C. jejuni. We demonstrate the multifunctional role of N-linked glycans in enhancing protein thermostability, stabilizing protein complexes and the promotion of protein-protein interaction, thus mediating antimicrobial resistance via enhancing multidrug efflux pump activity. This affirms that glycosylation is critical for multidrug efflux pump assembly. We present a generalized strategy that could be used to investigate general glycosylation system in Campylobacter genus and a potential target to develop antimicrobials against multidrug-resistant pathogens. IMPORTANCE Nearly all bacterial species have at least a single glycosylation system, but the direct effects of these posttranslational protein modifications are unresolved. Glycoproteome-wide analysis of several bacterial pathogens has revealed general glycan modifications of virulence factors and protein assemblies. Using Campylobacter jejuni as a model organism, we have studied the role of general N-linked glycans in the multidrug efflux pump commonly found in Gram-negative bacteria. We show, for the first time, the direct link between N-linked glycans and multidrug efflux pump activity. At the protein level, we demonstrate that N-linked glycans play a role in enhancing protein thermostability and mediating the assembly of the multidrug efflux pump to promote antimicrobial resistance, highlighting the importance of this posttranslational modification in bacterial physiology. Similar roles for glycans are expected to be found in other Gram-negative pathogens that possess general protein glycosylation systems.

scholarly journals Exploring the Contribution of the AcrB Homolog MdtF to Drug Resistance and Dye Efflux in a Multidrug Resistant E. coli Isolate

Antibiotics ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 503
Author(s):  
Sabine Schuster ◽  
Martina Vavra ◽  
Ludwig Greim ◽  
Winfried V. Kern
Keyword(s):  
Fluorescent Dyes ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Coli Strain ◽  
Double Knockout ◽  
E Coli ◽  
Knockout Mutants ◽  
Antibiotic Agents ◽  
Single Knockout

In Escherichia coli, the role of RND-type drug transporters other than the major efflux pump AcrB has largely remained undeciphered (particularly in multidrug resistant pathogens), because genetic engineering in such isolates is challenging. The present study aimed to explore the capability of the AcrB homolog MdtF to contribute to the extrusion of noxious compounds and to multidrug resistance in an E. coli clinical isolate with demonstrated expression of this efflux pump. An mdtF/acrB double-knockout was engineered, and susceptibility changes with drugs from various classes were determined in comparison to the parental strain and its acrB and tolC single-knockout mutants. The potential of MdtF to participate in the export of agents with different physicochemical properties was additionally assessed using accumulation and real-time efflux assays with several fluorescent dyes. The results show that there was limited impact to the multidrug resistant phenotype in the tested E. coli strain, while the RND-type transporter remarkably contributes to the efflux of all tested dyes. This should be considered when evaluating the efflux phenotype of clinical isolates via dye accumulation assays. Furthermore, the promiscuity of MdtF should be taken into account when developing new antibiotic agents.

Berberine and/or zinc protect against methotrexate-induced intestinal damage: Role of GSK-3β/NRF2 and JAK1/STAT-3 signaling pathways

Life Sciences ◽  
2021 ◽  
pp. 119754
Author(s):  
Emad H.M. Hassanein ◽  
Esam Omar Kamel ◽  
Fares E.M. Ali ◽  
Marwa Abdel-Raheim Ahmed
Keyword(s):  
Signaling Pathways ◽  
Intestinal Damage ◽  
Gsk 3Β
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