Role of Adipocyte Na,K‐ATPase Oxidant Amplification Loop in Neurodegeneration

Abstract Despite significant progress in the treatment of myeloma, multiple myeloma (MM) remains an incurable hematological malignancy due to cell adhesion-mediated drug resistance (CAM-DR) phenotype. However, data on the molecular mechanisms underlying the CAM-DR remains scanty. Here, we identified a miRNA-mRNA regulatory network in myeloma cells that are directly adherent to bone marrow stromal cells (BMSCs). Our data showed that the BMSCs up-regulated miR-30a-5p and down-regulated BCL2L11 at both mRNA and protein level in the myeloma cells. Besides, luciferase reporter genes demonstrated direct interaction between miR-30a-5p and BCL2L11 gene. Moreover, the BMSCs activated NF-ΚB signaling pathway in myeloma cells and the NF-κB P65 was shown to directly bind the miR-30a-5p promoter region. Moreover, suppression of the miR-30a-5p or upregulation of the BCL2L11 promoted apoptosis of the myeloma cells independent of the BMSCs, thus suggesting clinical significance of miR-30a-5p inhibitor and PLBCL2L11 plasmid in CAM-DR. Together, our data demonstrated the role of P65-miR-30a-5p-BCL2L11 loop in CAM-DR myeloma cells. These findings give new insights into the role of tumor microenvironment in the treatment of patients with myeloma.

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Hydrogen Sulfide Impairs Meiosis Resumption in Xenopus laevis Oocytes

Cells ◽

10.3390/cells9010237 ◽

2020 ◽

Vol 9 (1) ◽

pp. 237

Author(s):

Armance Gelaude ◽

Sylvain Slaby ◽

Katia Cailliau ◽

Matthieu Marin ◽

Arlette Lescuyer-Rousseau ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Xenopus Laevis ◽

Xenopus Laevis Oocytes ◽

Oocyte Meiosis ◽

M Phase ◽

Dependent Inhibition ◽

Mercaptopyruvate Sulfurtransferase ◽

Amplification Loop ◽

Dose Dependent Inhibition

The role of hydrogen sulfide (H2S) is addressed in Xenopus laevis oocytes. Three enzymes involved in H2S metabolism, cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase, were detected in prophase I and metaphase II-arrested oocytes and drove an acceleration of oocyte meiosis resumption when inhibited. Moreover, meiosis resumption is associated with a significant decrease in endogenous H2S. On another hand, a dose-dependent inhibition was obtained using the H2S donor, NaHS (1 and 5 mM). NaHS impaired translation. NaHS did not induce the dissociation of the components of the M-phase promoting factor (MPF), cyclin B and Cdk1, nor directly impacted the MPF activity. However, the M-phase entry induced by microinjection of metaphase II MPF-containing cytoplasm was diminished, suggesting upstream components of the MPF auto-amplification loop were sensitive to H2S. Superoxide dismutase and catalase hindered the effects of NaHS, and this sensitivity was partially dependent on the production of reactive oxygen species (ROS). In contrast to other species, no apoptosis was promoted. These results suggest a contribution of H2S signaling in the timing of amphibian oocytes meiosis resumption.

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The Complex Mcl-1/Bim Regulates the Sensitivity of Human Myeloma Cells to Melphalan.

Blood ◽

10.1182/blood.v106.11.357.357 ◽

2005 ◽

Vol 106 (11) ◽

pp. 357-357

Author(s):

Patricia Gomez-Bougie ◽

Lisa Oliver ◽

Emmanuelle Menoret ◽

Steven Le Gouill ◽

Régis Bataille ◽

...

Keyword(s):

Multiple Myeloma ◽

Small Molecules ◽

Caspase 3 ◽

Multi Drug Resistance ◽

Cytochrome C Release ◽

Myeloma Cells ◽

Caspase Cleavage ◽

Amplification Loop ◽

Apoptotic Cascade

Abstract Multiple myeloma is a fatal plasma-cell malignancy that evolves mainly in the bone marrow. Melphalan is widely used to treat patients with Multiple Myeloma, however its mechanism of action remains poorly documented. Thus, we studied the effect of this drug on the molecules of the Bcl-2 family. We showed that melphalan induces a drastic down-regulation of the anti-apoptotic proteins Mcl-1L and Bcl-xL and the pro-apoptotic BimEL in human melphalan-sensitive myeloma cells while the most potent pro-apoptotic Bim isoforms, L and S, are less affected. Interestingly, the disappearance of Mcl-1L and BimEL is associated with the generation of the respective cleaved forms, described as pro-apoptotic. We determined that the cleaved forms were generated by caspase cleavage since the addition of zVADfmk inhibited their formation. Indeed, we observed that caspase 3 activation occurred as early as Mcl-1 cleavage. Recently, we demonstrated that Mcl-1, the major anti-apoptotic molecule for myeloma cells, neutralizes the pro-apoptotic Bim molecule through endogenous complex formation and therefore, preventing the activation of death effectors. In this study, we demonstrate that melphalan disrupts the Mcl-1/Bim complex while the Bcl-2/Bim complex is not affected. In turn, the disappearance of full length Mcl-1 allows the release of Bim isoforms, particularly L and S, which can exert their pro-apoptotic function. In addition, we demonstrate both Bax activation and cytochrome c release, supporting the role of free Bim as a major initiator of the mitochondrial apoptotic cascade. Thus, we propose that in myeloma cells melphalan induces the disruption of Mcl-1/Bim complex resulting in the release of Bim from Mcl-1 sequestration and therefore leading to the initiation of the apoptotic process. Moreover, the cleaved 26kDa pro-apoptotic Mcl-1 and the 19kDa and 12kDa of Bim, generated during melphalan treatment could contribute to the amplification loop of apoptosis. MM remains a fatal disease which develops multi-drug resistance, including melphalan. A potential therapeutic approach could be the disruption of the Mcl-1/Bim complexes by the BH3 small molecules that might target those complexes leading to the release of sequestered Bim.

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Assembly and regulation of the complement amplification loop in blood: the role of C3b-C3b-IgG complexes

Molecular Immunology ◽

10.1016/s0161-5890(99)00104-2 ◽

1999 ◽

Vol 36 (13-14) ◽

pp. 837-842 ◽

Cited By ~ 18

Author(s):

Emiliana Jelezarova ◽

Hans U Lutz

Keyword(s):

Amplification Loop

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LuxS Mediates Iron-Dependent Biofilm Formation, Competence, and Fratricide in Streptococcus pneumoniae

Infection and Immunity ◽

10.1128/iai.05644-11 ◽

2011 ◽

Vol 79 (11) ◽

pp. 4550-4558 ◽

Cited By ~ 59

Author(s):

Claudia Trappetti ◽

Adam J. Potter ◽

Adrienne W. Paton ◽

Marco R. Oggioni ◽

James C. Paton

Keyword(s):

Streptococcus Pneumoniae ◽

Biofilm Formation ◽

Extracellular Dna ◽

Wild Type ◽

Nasopharyngeal Colonization ◽

Content Type ◽

Planktonic Form ◽

Dna Release ◽

Amplification Loop

ABSTRACTDuring infection,Streptococcus pneumoniaeexists mainly in sessile biofilms rather than in planktonic form, except during sepsis. The capacity to form biofilms is believed to be important for nasopharyngeal colonization as well as disease pathogenesis, but relatively little is known about the regulation of this process. Here, we investigated the effect of exogenous iron [Fe(III)] as well as the role ofluxS(encoding S-ribosylhomocysteine lyase) on biofilm formation byS. pneumoniaeD39. Fe(III) strongly enhanced biofilm formation at concentrations of ≥50 μM, while Fe(III) chelation with deferoxamine was inhibitory. Importantly, Fe(III) also upregulated the expression ofluxSin wild-type D39. AluxS-deficient mutant (D39luxS) failed to form a biofilm, even with Fe(III) supplementation, whereas a derivative overexpressingluxS(D39luxS+) exhibited enhanced biofilm formation capacity and could form a biofilm without added Fe(III). D39luxSexhibited reduced expression of the major Fe(III) transporter PiuA, and the cellular [Fe(III)] was significantly lower than that in D39; in contrast, D39luxS+ had a significantly higher cellular [Fe(III)] than the wild type. The release of extracellular DNA, which is an important component of the biofilm matrix, also was directly related toluxSexpression. Similarly, genetic competence, as measured by transformation frequency as well as the expression of competence genescomD,comX,comW,cglA, anddltAand the murein hydrolasecbpD, which is associated with fratricide-dependent DNA release, all were directly related toluxSexpression levels and were further upregulated by Fe(III). Moreover, mutagenesis ofcbpDblocked biofilm formation. We propose that competence, fratricide, and biofilm formation are closely linked in pneumococci, and thatluxSis a central regulator of these processes. We also propose that the stimulatory effects of Fe(III) on all of these parameters are due to the upregulation ofluxSexpression, and that LuxS provides for a positive Fe(III)-dependent amplification loop by increasing iron uptake.

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Role of dactinomycin in the improved survival of children with Wilms' tumor

JAMA ◽

10.1001/jama.195.12.1005 ◽

1966 ◽

Vol 195 (12) ◽

pp. 1005-1009 ◽

Cited By ~ 18

Author(s):

D. J. Fernbach

Keyword(s):

Wilms Tumor

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Role of the allergist in diagnosis and management of patients with uveitis

JAMA ◽

10.1001/jama.195.3.167 ◽

1966 ◽

Vol 195 (3) ◽

pp. 167-172 ◽

Cited By ~ 2

Author(s):

T. E. Van Metre

Keyword(s):

Diagnosis And Management

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The power of norms to sway fused group members

Behavioral and Brain Sciences ◽

10.1017/s0140525x18001644 ◽

2018 ◽

Vol 41 ◽

Cited By ~ 1

Author(s):

Winnifred R. Louis ◽

Craig McGarty ◽

Emma F. Thomas ◽

Catherine E. Amiot ◽

Fathali M. Moghaddam

Keyword(s):

Evolutionary Anthropology ◽

Normative Systems ◽

Violent Extremism ◽

Identity Fusion ◽

Group Members

AbstractWhitehouse adapts insights from evolutionary anthropology to interpret extreme self-sacrifice through the concept of identity fusion. The model neglects the role of normative systems in shaping behaviors, especially in relation to violent extremism. In peaceful groups, increasing fusion will actually decrease extremism. Groups collectively appraise threats and opportunities, actively debate action options, and rarely choose violence toward self or others.

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Elaborating the role of reflection and individual differences in the study of folk-economic beliefs

Behavioral and Brain Sciences ◽

10.1017/s0140525x18000274 ◽

2018 ◽

Vol 41 ◽

Author(s):

Kevin Arceneaux

Keyword(s):

Decision Making ◽

Individual Differences ◽

Cognitive Processes ◽

Evolutionary History ◽

Behavioral Responses ◽

History Of ◽

Economic Beliefs

AbstractIntuitions guide decision-making, and looking to the evolutionary history of humans illuminates why some behavioral responses are more intuitive than others. Yet a place remains for cognitive processes to second-guess intuitive responses – that is, to be reflective – and individual differences abound in automatic, intuitive processing as well.

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