| 1. |
- Beck, Carole, et al.
(författare)
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PARP3, a new therapeutic target to alter Rictor/mTORC2 signaling and tumor progression in BRCA1-associated cancers
- 2019
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Ingår i: Cell Death and Differentiation. - : Nature Publishing Group. - 1350-9047 .- 1476-5403. ; 26:9, s. 1615-1630
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Tidskriftsartikel (refereegranskat)abstract
- PARP3 has been shown to be a key driver of TGF beta-induced epithelial-to-mesenchymal transition (EMT) and sternness in breast cancer cells, emerging as an attractive therapeutic target. Nevertheless, the therapeutic value of PARP3 inhibition has not yet been assessed. Here we investigated the impact of the absence of PARP3 or its inhibition on the tumorigenicity of BRCA1-proficient versus BRCA1-deficient breast cancer cell lines, focusing on the triple-negative breast cancer subtype (TNBC). We show that PARP3 knockdown exacerbates centrosome amplification and genome instability and reduces survival of BRCA1-deficient TNBC cells. Furthermore, we engineered PARP3(-/- )BRCA1-deficient or BRCA1-proficient TNBC cell lines using the CRISPR/nCas9(D10A) gene editing technology and demonstrate that the absence of PARP3 selectively suppresses the growth, survival and in vivo tumorigenicity of BRCA1-deficient TNBC cells, mechanistically via effects associated with an altered Rictor/mTORC2 signaling complex resulting from enhanced ubiquitination of Rictor. Accordingly, PARP3 interacts with and ADP-ribosylates GSK3 beta, a positive regulator of Rictor ubiquitination and degradation. Importantly, these phenotypes were rescued by re-expression of a wild-type PARP3 but not by a catalytic mutant, demonstrating the importance of PARP3's catalytic activity. Accordingly, reduced survival and compromised Rictor/mTORC2 signaling were also observed using a cell-permeable PARP3-specific inhibitor. We conclude that PARP3 and BRCA1 are synthetic lethal and that targeting PARP3's catalytic activity is a promising therapeutic strategy for BRCA1-associated cancers via the Rictor/mTORC2 signaling pathway.
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| 2. |
- Chaskiel, Lea, et al.
(författare)
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Interleukin-1 reduces food intake and body weight in rat by acting in the arcuate hypothalamus
- 2019
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Ingår i: Brain, behavior, and immunity. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0889-1591 .- 1090-2139. ; 81, s. 560-573
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Tidskriftsartikel (refereegranskat)abstract
- A reduction in food intake is commonly observed after bacterial infection, a phenomenon that can be reproduced by peripheral administration of Gram-negative bacterial lipopolysaccharide (LPS) or interleukin-lbeta (IL-1 beta), a pro-inflammatory cytokine released by LPS-activated macrophages. The arcuate nucleus of the hypothalamus (ARH) plays a major role in food intake regulation and expresses IL-1 type 1 receptor (IL-1R1) mRNA. In the present work, we tested the hypothesis that IL-1R1 expressing cells in the ARH mediate IL-1 beta and/or LPS-induced hypophagia in the rat. To do so, we developed an IL-1 beta-saporin conjugate, which eliminated IL-R1 expressing neurons in the hippocampus, and micro-injected it into the ARH prior to systemic IL-1 beta and LPS administration. ARH IL-1 beta-saporin injection resulted in loss of neuropeptide Y-containing cells and attenuated hypophagia and weight loss after intraperitoneal IL-1 beta, but not LPS, administration. In conclusion, the present study shows that ARH NPY-containing neurons express functional IL-1R1s that mediate peripheral IL-1 beta-, but not LPS-, induced hypophagia. Our present and previous findings indicate that the reduction of food intake after IL-1 beta and LPS are mediated by different neural pathways.
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| 3. |
- Lasselin, Julie, et al.
(författare)
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Lipopolysaccharide Alters Motivated Behavior in a Monetary Reward Task : a Randomized Trial
- 2017
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 42:4, s. 801-810
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation-induced sickness is associated with a large set of behavioral alterations; however, its motivational aspects remain poorly explored in humans. The present study assessed the effect of lipopolysaccharide (LPS) administration at a dose of 2 ng/kg of body weight on motivation in 21 healthy human subjects in a double-blinded, placebo (saline)-controlled, cross-over design. Incentive motivation and reward sensitivity were measured using the Effort Expenditure for Rewards Task (EEfRT), in which motivation for high-effort/high-reward trials vs low-effort/low-reward trials are manipulated by variations in reward magnitude and,probability to win. Because of the strong interactions between sleepiness and motivation, the role of sleepiness was also determined. As expected, the probability to win predicted the choice to engage in high-effort/high-reward trials; however, this occurred at a greater extent after LPS than after saline administration. This effect was related to the level of sleepiness. Sleepiness increased motivation to choose the high-effort/high-reward mode of response, but only when the probability to win was the highest. LPS had no effect on reward sensitivity either directly or via sleepiness. These results indicate that systemic inflammation induced by LPS administration causes motivational changes in young healthy subjects, which are associated with sleepiness. Thus, despite its association with energy-saving behaviors, sickness allows increased incentive motivation when the effort is deemed worthwhile.
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| 4. |
- Paul, Elisabeth, 1991-, et al.
(författare)
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Peripheral and central kynurenine pathway abnormalities in major depression
- 2022
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Ingår i: Brain, behavior, and immunity. - : Academic Press Inc - Elsevier Science. - 0889-1591 .- 1090-2139. ; 101, s. 136-145
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Tidskriftsartikel (refereegranskat)abstract
- Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an index of metabolic disturbance associated with atypical depression. Plasma levels of picolinic acid (PIC), the kynurenic/quinolinic acid ratio (KYNA/QUIN), and PIC/QUIN were lower in MDD, but QUIN levels were increased. In the CSF, we found lower PIC in MDD. Confirming previous work, MDD patients had lower hippocampal, and amygdalar volumes. Hippocampal and amygdalar volumes were correlated positively with plasma KYNA/QUIN ratio in MDD patients. BMI was increased in the MDD group relative to the control group. Moreover, BMI was inversely correlated with plasma and CSF PIC and PIC/QUIN, and positively correlated with plasma QUIN levels in MDD. Our results partially confirm previous peripheral KP findings and extend them to the CSF in MDD. We present the novel finding that abnormalities in KP metabolites are related to metabolic disturbances in depression, but the relation between KP metabolites and depression-associated brain atrophy might not be as direct as previously hypothesized.
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| 5. |
- Raizen, David M., et al.
(författare)
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Beyond the symptom : the biology of fatigue
- 2023
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Ingår i: Sleep. - : Oxford University Press. - 0161-8105 .- 1550-9109. ; 46:9
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Tidskriftsartikel (refereegranskat)abstract
- A workshop titled “Beyond the Symptom: The Biology of Fatigue” was held virtually September 27–28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue.The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.
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| 6. |
- Sundgren Andersson, Anna, 1969-
(författare)
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On Fever Mechanisms & Preoptic Signalling
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fever, a 1-4 °C elevation of the body temperature, is part of the systemic inflammatory response to infection or tissue damage, and it is believed to be a potent host defence. The underlying physiological mechanisms of the febrile response are one of the two main objectives in this thesis, where studies conducted in whole animals (rats and mice), chiefly aimed at clarifying the cytokine cascade in fever. The other principal objective of this thesis was to gain a general understanding on the signalling properties of neurons in the thermoregulatory region of the brain, the preoptic area, through electrophysiological investigations in vitro of ion channels and impulse firing behaviour of medial preoptic neurons of rat. From these studies it was concluded that:The endogenous pyrogen tumour necrosis factor _ (TNF_) injected intraperitoneally causes fever independent of interleukin-1_ (IL-1_), but dependent on interleukin-6 (IL-6) in the central nervous system. The TNF__induced fever is triggered through release endoperoxides, since pre-administration of the cyclooxygenase inhibitor indomethacin, efficiently blocks the increased body temperature.An intraperitoneal injection of lipopolysaccharide (LPS) induces fever that is independent on central IL-1 binding to its receptors, since occupancy of central IL-1 receptors of the IL-1 receptor antagonist (IL-1ra), is unable to block the febrile response.The temperature in the central nervous system and in the peritoneum are similar during the febrile response with respect to onset, temporal characteristics and fever amplitude.The neurons of the medial preoptic nucleus respond to glutamate application with currents that can be attributed to ion channels of the AMPA-receptor type as well as of the NMDA-receptor type. The functional characteristics of these channels comprise fast activation and desensitization of the AMPA-receptor channel, as well as glycine dependency, Mg2+dependent outward rectification and slow desensitization kinetics of the NMDA-receptor channel.The medial preoptic neurons display two types of Ca2+ spikes, that result in two types of firing behaviour. First, low-threshold spikes depend on T-type Ca2+ channels and are generated from membrane potentials < -75 mV. They may induce short bursts of fast Na+ spikes. Second, high-threshold spikes can be generated from more depolarized levels, and depend on Ca2+channels that are mainly of the L, N and P -types. One role of these channels is to sustain long-burst firing.Medial preoptic neurons spontaneously fire with several types of temporal firing patterns. Apart from burst firing, neurons are silent or discharge regularly as well as irregularly. The type of firing pattern can be manipulated with steady current injection and possibly also by PGE2.
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