| 1. |
- Charmpilas, Nikolaos, et al.
(författare)
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Acyl-CoA-binding protein (ACBP) : a phylogenetically conserved appetite stimulator
- 2020
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889 .- 2041-4889. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Recently, we reported that, in mice, hunger causes the autophagy-dependent release of a protein called acyl-CoA-binding protein or diazepam binding inhibitor (ACBP/DBI) from cells, resulting in an increase in plasma ACBP concentrations. Administration of extra ACBP is orexigenic and obesogenic, while its neutralization is anorexigenic in mice, suggesting that ACBP is a major stimulator of appetite and lipo-anabolism. Accordingly, obese persons have higher circulating ACBP levels than lean individuals, and anorexia nervosa is associated with subnormal ACBP plasma concentrations. Here, we investigated whether ACBP might play a phylogenetically conserved role in appetite stimulation. We found that extracellular ACBP favors sporulation in Saccharomyces cerevisiae, knowing that sporulation is a strategy for yeast to seek new food sources. Moreover, in the nematode Caenorhabditis elegans, ACBP increased the ingestion of bacteria as well as the frequency pharyngeal pumping. These observations indicate that ACBP has a phylogenetically ancient role as a 'hunger factor' that favors food intake.
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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
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| 4. |
- Mangu, Jagadish, 1986-
(författare)
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Influence of gut microbiota on xenobiotic toxicity in a Caenorhabditis elegans model with a focus on arsenic and PFAS
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Exposure to environmental toxins presents a hazard to humans. Inorganic metalloid- arsenic (As), organic chemicals- per and poly-fluoroalkyl substances (PFAS) are frequently detected in the environment. Exposure to As and PFAS is associated with multiple adverse effects in humans and animals. However, little attention has been given to the interaction between host microbiota and pollutants. Gut microbiota interactions with the host and xenobiotics, is hy-pothesized to decrease xenobiotic toxicity. However, the role of microbiota on host responses during these exposure scenarios is poorly understood. Therefore, the aim was to study the influence of gut microbes on Caenorhabditis elegans responses using As and PFAS as environmental toxins. Specific objectives were to study the role of single microbes, and simple three microbe combinations with tractable diversity in nematode responses to As and PFAS. The study examined C. elegans physiological responses to As in the presence of single As resistant microbe Lysinibacillus sphaericus (Paper I) and simple 3-bacteria combinations (Paper IV). These studies showed that gut microbes decrease As toxicity and increase nematode survival through mediating host stress responses and fat metabolism. Combinations of microbes with toxins in microbiota also affect lifespan (Paper III). Furthermore, effects of PFAS mixtures were also analyzed on C. elegans and pathogen Staphylococcus aureus (Paper II); and role of gut microbe combinations during exposures to PFOS (Paper V). Exposure to PFAS/ PFOS increased virulence of pathogens and decreased host immunity, stress response and survival with opportunists; with non-pathogens C. elegans showed increased stress response and lived longer. These results emphasized that gut microbes contribute to alter xenobiotic toxicity in the host. Finally, this thesis presents novel insights into the role of gut microbes in modulating host physiological responses during As and PFAS exposures.
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| 5. |
- Papaevgeniou, Nikoletta, et al.
(författare)
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18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression in Caenorhabditis elegans and Neuronal Cultures
- 2016
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Ingår i: Antioxidants and Redox Signaling. - New Rochelle, USA : Mary Ann Liebert. - 1523-0864 .- 1557-7716. ; 25:16, s. 855-869
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Proteasomes are constituents of the cellular proteolytic networks that maintain protein homeostasis through regulated proteolysis of normal and abnormal (in any way) proteins. Genetically mediated proteasome activation in multicellular organisms has been shown to promote longevity and to exert protein antiaggregation activity. In this study, we investigate whether compound-mediated proteasome activation is feasible in a multicellular organism and we dissect the effects of such approach in aging and Alzheimer's disease (AD) progression.Results: Feeding of wild-type Caenorhabditis elegans with 18α-glycyrrhetinic acid (18α-GA; a previously shown proteasome activator in cell culture) results in enhanced levels of proteasome activities that lead to a skinhead-1- and proteasome activation-dependent life span extension. The elevated proteasome function confers lower paralysis rates in various AD nematode models accompanied by decreased Aβ deposits, thus ultimately decelerating the progression of AD phenotype. More importantly, similar positive results are also delivered when human and murine cells of nervous origin are subjected to 18α-GA treatment.Innovation: This is the first report of the use of 18α-GA, a diet-derived compound as prolongevity and antiaggregation factor in the context of a multicellular organism.Conclusion: Our results suggest that proteasome activation with downstream positive outcomes on aging and AD, an aggregation-related disease, is feasible in a nongenetic manipulation manner in a multicellular organism. Moreover, they unveil the need for identification of antiaging and antiamyloidogenic compounds among the nutrients found in our normal diet.
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| 6. |
- Tasdemir, Ezgi, et al.
(författare)
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Regulation of autophagy by cytoplasmic p53.
- 2008
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Ingår i: Nature cell biology. - : Springer Science and Business Media LLC. - 1476-4679 .- 1465-7392. ; 10:6, s. 676-87
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Tidskriftsartikel (refereegranskat)abstract
- Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.
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