| 1. |
- Bergqvist, Filip, et al.
(författare)
-
Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells
- 2019
-
Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Pharmacological inhibition of microsomal prostaglandin E synthase (mPGES)-1 for selective reduction in prostaglandin E-2 (PGE(2)) biosynthesis is protective in experimental models of cancer and inflammation. Targeting mPGES-1 is envisioned as a safer alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs). Herein, we compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1 beta-induced A549 lung cancer cells using mass spectrometry. Inhibition of mPGES-1 decreased PGE(2) production and increased PGF(2 alpha) and thromboxane B-2 (TXB2) formation, while inhibition of COX-2 decreased the production of all three prostanoids. Our proteomics results revealed that CIII downregulated multiple canonical pathways including eIF2, eIF4/P70S6K, and mTOR signaling, compared to NS-398 that activated these pathways. Moreover, pathway analysis predicted that CIII increased cell death of cancer cells (Z = 3.8, p = 5.1E-41) while NS-398 decreased the same function (Z = -5.0, p = 6.5E-35). In our lipidomics analyses, we found alterations in nine phospholipids between the two inhibitors, with a stronger alteration in the lysophospholipid (LPC) profile with NS-398 compared to CIII. Inhibition of mPGES-1 increased the concentration of sphinganine and dihydroceramide (C16:0D hCer), while inhibition of COX-2 caused a general decrease in most ceramides, again suggesting different effects on cell death between the two inhibitors. We showed that CIII decreased proliferation and potentiated the cytotoxic effect of the cytostatic drugs cisplatin, etoposide, and vincristine when investigated in a live cell imaging system. Our results demonstrate differences in protein and lipid profiles after inhibition of mPGES-1 or COX-2 with important implications on the therapeutic potential of mPGES-1 inhibitors as adjuvant treatment in cancer. We encourage further investigations to illuminate the clinical benefit of mPGES-1 inhibitors in cancer.
|
|
| 2. |
- Kehoe, Laura, et al.
(författare)
-
Make EU trade with Brazil sustainable
- 2019
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 3. |
- Raouf, Joan, et al.
(författare)
-
Targeted lipidomics analysis identified altered serum lipid profiles in patients with polymyositis and dermatomyositis
- 2018
-
Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 20
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Polymyositis (PM) and dermatomyositis (DM) are severe chronic autoimmune diseases, characterized by muscle fatigue and low muscle endurance. Conventional treatment includes high doses of glucocorticoids and immunosuppressive drugs; however, few patients recover full muscle function. One explanation of the persistent muscle weakness could be altered lipid metabolism in PM/DM muscle tissue as we previously reported. Using a targeted lipidomic approach we aimed to characterize serum lipid profiles in patients with PM/DM compared to healthy individuals (HI) in a cross-sectional study. Also, in the longitudinal study we compared serum lipid profiles in patients newly diagnosed with PM/DM before and after immunosuppressive treatment. Methods: Lipidomic profiles were analyzed in serum samples from 13 patients with PM/DM, 12 HI and 8 patients newly diagnosed with PM/DM before and after conventional immunosuppressive treatment using liquid chromatography tandem mass spectrometry (LC-MS/MS) and a gas-chromatography flame ionization detector (GC-FID). Functional Index (FI), as a test of muscle performance and serum levels of creatine kinase (s-CK) as a proxy for disease activity were analyzed. Results: The fatty acid (FA) composition of total serum lipids was altered in patients with PM/DM compared to HI; the levels of palmitic (16: 0) acid were significantly higher while the levels of arachidonic (20: 4, n-6) acid were significantly lower in patients with PM/DM. The profiles of serum phosphatidylcholine and triacylglycerol species were changed in patients with PM/DM compared to HI, suggesting disproportionate levels of saturated and polyunsaturated FAs that might have negative effects on muscle performance. After immunosuppressive treatment the total serum lipid levels of eicosadienoic (20: 2, n-6) and eicosapentaenoic (20: 5, n-3) acids were increased and serum phospholipid profiles were altered in patients with PM/DM. The correlation between FI or s-CK and levels of several lipid species indicate the important role of lipid changes in muscle performance and inflammation. Conclusions: Serum lipids profiles are significantly altered in patients with PM/DM compared to HI. Moreover, immunosuppressive treatment in patients newly diagnosed with PM/DM significantly affected serum lipid profiles. These findings provide new evidence of the dysregulated lipid metabolism in patients with PM/DM that could possibly contribute to low muscle performance.
|
|
| 4. |
|
|
| 5. |
- Öhlund, Gunnar, et al.
(författare)
-
Apex predator induces predator-rich ecosystem state innorthern lakes
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Large predators are disappearing from ecosystems around the world. If predator speciesfacilitate each other’s existence through niche construction, this development could causecascading predator collapses and reduce ecosystem resilience. However, the importance offacilitation for the assembly and function of predator communities remains poorly understood.Here, we show that a large piscivorous fish, the northern pike (Esox lucius), enables theformation of a numerous and diverse predator community by inducing a dwarf ecotype ofEuropean whitefish (Coregonus lavaretus). Pike increases the standing biomass of prey-sized(<200mm) whitefish with a factor of 12.6, allowing small-gaped fish species (Percafluviatilis, Lota lota, Salvelinus alpinus and Salmo trutta) to go from small-growinggeneralists, to large-growing piscivores. Similarly, a guild of piscivorous birds (Gavia arctica,G. stellata, Sterna paradisaea, S. hirundo, Mergus serrator and M. merganser) shift from amixed diet to relying mainly on whitefish prey in presence of pike. Through this regime shift,the functional piscivore biomass in the non-pike fish community increases with a factor of14.2, and the density- and species richness of piscivorous birds increase with factors of 2.08and 2.16, respectively. Our results demonstrate how feedbacks between presence/absence ofimportant predators and the phenotype of prey may keep complex ecosystems in predator-richor predator-depleted states.
|
|
| 6. |
- Öhlund, Gunnar, 1977-, et al.
(författare)
-
Ecological speciation in European whitefish is driven by a large‐gaped predator
- 2020
-
Ingår i: Evolution Letters. - : John Wiley & Sons. - 2056-3744. ; 4:3, s. 243-256
-
Tidskriftsartikel (refereegranskat)abstract
- Lake‐dwelling fish that form species pairs/flocks characterized by body size divergence are important model systems for speciation research. Although several sources of divergent selection have been identified in these systems, their importance for driving the speciation process remains elusive. A major problem is that in retrospect, we cannot distinguish selection pressures that initiated divergence from those acting later in the process. To address this issue, we studied the initial stages of speciation in European whitefish (Coregonus lavaretus) using data from 358 populations of varying age (26–10,000 years). We find that whitefish speciation is driven by a large‐growing predator, the northern pike (Esox lucius). Pike initiates divergence by causing a largely plastic differentiation into benthic giants and pelagic dwarfs: ecotypes that will subsequently develop partial reproductive isolation and heritable differences in gill raker number. Using an eco‐evolutionary model, we demonstrate how pike's habitat specificity and large gape size are critical for imposing a between‐habitat trade‐off, causing prey to mature in a safer place or at a safer size. Thereby, we propose a novel mechanism for how predators may cause dwarf/giant speciation in lake‐dwelling fish species.
|
|
