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- Zegeye, Mulugeta Melkie, 1986-
(författare)
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Interleukin-6 Signaling Pathways in Human Vascular Endothelial Cells : Molecular Mechanisms and Associations to Atherosclerosis
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Interleukin-6 is pleotropic cytokine produced by several types of cells including endothelial cells (ECs). IL-6 acts on target cells via two major signaling mechanisms known as classic signaling and trans-signaling. Whileactivation of IL-6 classic signaling is associated with homeostatic and tissue regeneration functions, the trans-signaling is linked to pro-inflammatory effects. Our studies reveal that ECs respond to both IL-6 classic- aswell as trans-singling pathways in distinct but also overlapping manner.While IL-6 classic-signaling activated JAK/STAT3 pathway, the trans-signaling additionally engaged PI3K/AKT and MAPK/ERK pathways. Further, IL-6 trans-singling, but not classic signaling, led to secretion of proinflammatory chemokine MCP-1 mainly via JAK/STAT3 and PI3K/AKTpathways. In addition, IL-6 trans-signaling regulate expression of angiogenesis related genes to subsequently impair endothelial tube formationability. Autocrine IL-6 classic-signaling, however, was vital to maintainthe angiogenic response of ECs. Further proteomic analyses showed thatIL-6 trans-signaling in ECs regulates secretion of several inflammatoryproteins and also shifts laminin secretion from LAMA4 to LAMA5, whichmight collectively favor binding and trans-endothelial migration of mononuclear cells. In human atherosclerotic plaques, we found that expression of LAMA4 and LAMA5 is altered compared to healthy vessels, andthat the alteration appears to be associated with immune cell content andstability of the plaque. Using plasma IL-6 binary complex, a novel biomarker, we showed a strong association between IL-6 trans-signalingand risk of future myocardial infarction (MI). In addition, we showed thatelevated plasma IL-6 binary complex mediates the association betweentraditional risk factors (hypertension and smoking) and MI, suggestingthat elevated plasma IL-6 binary complex concentration could partly explain the increased risk of MI in smokers and hypertensive participants.
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- Sakellari, Marianthi, 1987-
(författare)
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Functional analysis of the proteasome in eukaryotic organisms
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Proteasome degradation machinery is responsible for the turnover of a huge variety of normal and abnormal proteins, thus regulating a plethora of cellular processes. Aging is an inevitable biological process that is characterized by reduced proteasome function that leads to proteotoxic stress. Compound-related interventions, that ameliorate proteasome system collapse, retard aging process. In the present thesis, 18α-glycyrrhetinic acid (18α-GA), a natural compound with known proteasome activating properties in cells, was indicated to activate proteasome also in the multicellular organism Caenorhabditis elegans (C. elegans). Evaluation of the antiaging and protein anti-aggregation effects of this bioactive compound indicated that 18α-GA promoted longevity in nematodes through proteasome-and SKN-1-mediated activation and decelerated Alzheimer’sdisease progression and neuropathology both in nematodes and neuronal cells. Additionally, the crosstalk between protein synthesis and proteasome-mediated protein degradation was analyzed in eukaryotic organisms under various cellular conditions. Protein synthesis inhibition was observed to increase proteasome function and assembly in human primary embryonic fibroblasts, with heat shock protein chaperone machinery to contribute to the elevated proteasome assembly. Alternatively, protein synthesis inhibition increased the protein levels of specific proteasome subunits without influencing the proteasome activity in C. elegans. Furthermore, proteasome activation by means which have also pro-longevity effects decreased the protein synthesis rate both in human fibroblast cellsand nematodes. This thesis suggests: 1) that a diet-derived compound could act as a pro-longevity and anti-aggregation agent in the context of amulticellular organism and 2) the existence of a complex interplay between anabolic and catabolic processes under different cellular conditions, across species.
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- Eriksson, Leif A., 1964-, et al.
(författare)
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Tetrazole derivatives as cytochrome p450 inhibitors
- 2019
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Patent (populärvet., debatt m.m.)abstract
- According to the invention there is provided a compound of formula I, wherein R1 and R2 have meanings given in the description, which compounds are useful in the treatment of skin disorders and other diseases.
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