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9. Modulation of nucleotide metabolism by picornaviruses

Author

Nouwen, Lonneke V., primary, Breeuwsma, Martijn, additional, Zaal, Esther A., additional, van de Lest, Chris H. A., additional, Buitendijk, Inge, additional, Zwaagstra, Marleen, additional, Balić, Pascal, additional, Filippov, Dmitri V., additional, Berkers, Celia R., additional, and van Kuppeveld, Frank J. M., additional

Published
2024
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10. Synovial fluid extracellular vesicles as arthritis biomarkers: the added value of lipid-profiling and integrated omics

Author

Varela, Laura, van de Lest, Chris H.A., René van Weeren, P., Wauben, Marca H.M., Varela, Laura, van de Lest, Chris H.A., René van Weeren, P., and Wauben, Marca H.M.

Abstract

Arthritis, a diverse group of inflammatory joint disorders, poses great challenges in early diagnosis and targeted treatment. Timely intervention is imperative, yet conventional diagnostic methods are not able to detect subtle early symptoms. Hence, there is an urgent need for specific biomarkers that discriminate between different arthritis forms and for early diagnosis. The pursuit of such precise diagnostic tools has prompted a growing interest in extracellular vesicles (EVs). EVs, released by cells in a regulated fashion, are detectable in body fluids, including synovial fluid (SF), which fills the joint space. They provide insights into the intricate molecular landscapes of arthritis, and this has stimulated the search for minimally invasive EV-based diagnostics. As such, the analysis of EVs in SF has become a focus for identifying EV-based biomarkers for joint disease endotyping, prognosis, and progression. EVs are composed of a lipid bilayer and a wide variety of different cargo types, of which proteins and RNAs are widely investigated. In contrast, membrane lipids of EVs, especially the abundance, presence, or absence of specific lipids and their contribution to the biological activity of EVs, are largely overlooked in EV research. Furthermore, the identification of specific combinations of different EV components acting in concert in EVs can fuel the definition of composite biomarkers. We here provide a state-of-the-art overview of the knowledge on SF-derived EVs with emphasis on lipid analysis and we give an example of the added value of integrated proteomics and lipidomics analysis in the search for composite EV-associated biomarkers.

Published
2024

11. Modulation of nucleotide metabolism by picornaviruses

Author

Nouwen, Lonneke V, Breeuwsma, Martijn, Zaal, Esther A, van de Lest, Chris H A, Buitendijk, Inge, Zwaagstra, Marleen, Balić, Pascal, Filippov, Dmitri V, Berkers, Celia R, van Kuppeveld, Frank J M, Nouwen, Lonneke V, Breeuwsma, Martijn, Zaal, Esther A, van de Lest, Chris H A, Buitendijk, Inge, Zwaagstra, Marleen, Balić, Pascal, Filippov, Dmitri V, Berkers, Celia R, and van Kuppeveld, Frank J M

Abstract

Viruses actively reprogram the metabolism of the host to ensure the availability of sufficient building blocks for virus replication and spreading. However, relatively little is known about how picornaviruses-a large family of small, non-enveloped positive-strand RNA viruses-modulate cellular metabolism for their own benefit. Here, we studied the modulation of host metabolism by coxsackievirus B3 (CVB3), a member of the enterovirus genus, and encephalomyocarditis virus (EMCV), a member of the cardiovirus genus, using steady-state as well as 13C-glucose tracing metabolomics. We demonstrate that both CVB3 and EMCV increase the levels of pyrimidine and purine metabolites and provide evidence that this increase is mediated through degradation of nucleic acids and nucleotide recycling, rather than upregulation of de novo synthesis. Finally, by integrating our metabolomics data with a previously acquired phosphoproteomics dataset of CVB3-infected cells, we identify alterations in phosphorylation status of key enzymes involved in nucleotide metabolism, providing insight into the regulation of nucleotide metabolism during infection.

Published
2024

12. Early activation of hepatic stellate cells induces rapid initiation of retinyl ester breakdown while maintaining lecithin: Retinol acyltransferase (LRAT) activity

Author

Haaker, Maya W, Goossens, Vera, Hoogland, Nina A N, van Doorne, Hidde, Wang, Ziqiong, Jansen, Jeroen W A, Kaloyanova, Dora V, van de Lest, Chris H A, Houweling, Martin, Vaandrager, A Bas, Helms, J Bernd, Haaker, Maya W, Goossens, Vera, Hoogland, Nina A N, van Doorne, Hidde, Wang, Ziqiong, Jansen, Jeroen W A, Kaloyanova, Dora V, van de Lest, Chris H A, Houweling, Martin, Vaandrager, A Bas, and Helms, J Bernd

Abstract

Lechthin:retinol acyltrasnferase (LRAT) is the main enzyme producing retinyl esters (REs) in quiescent hepatic stellate cells (HSCs). When cultured on stiff plastic culture plates, quiescent HSCs activate and lose their RE stores in a process similar to that in the liver following tissue damage, leading to fibrosis. Here we validated HSC cultures in soft gels to study RE metabolism in stable quiescent HSCs and investigated RE synthesis and breakdown in activating HSCs. HSCs cultured in a soft gel maintained characteristics of quiescent HSCs, including the size, amount and composition of their characteristic large lipid droplets. Quiescent gel-cultured HSCs maintained high expression levels of Lrat and a RE storing phenotype with low levels of RE breakdown. Newly formed REs are highly enriched in retinyl palmitate (RP), similar to freshly isolated quiescent HSCs, which is associated with high LRAT activity. Comparison of these quiescent gel-cultured HSCs with activated plastic-cultured HSCs showed that although during early activation the total RE levels and RP-enrichment are reduced, levels of RE formation are maintained and mediated by LRAT. Loss of REs was caused by enhanced RE breakdown in activating HSCs. Upon prolonged culturing, activated HSCs have lost their LRAT activity and produce small amounts of REs by DGAT1. This study reveals unexpected dynamics in RE metabolism during early HSC activation, which might be important in liver disease as early stages are reversible. Soft gel cultures provide a promising model to study RE metabolism in quiescent HSCs, allowing detailed molecular investigations on the mechanisms for storage and release.

Published
2024

13. Modulation of nucleotide metabolism by picornaviruses

Author

Virologie, Afd Chemical Biology and Drug Discovery, Veterinaire biochemie, Equine Musculoskeletal Biology, CS_Locomotion, Faculteit Diergeneeskunde, Sub Biomol.Mass Spectrometry & Proteom., Infectious Diseases and Immunology - Virology, Cell Biology, Metabolism & Cancer - Metabolomics, Nouwen, Lonneke V, Breeuwsma, Martijn, Zaal, Esther A, van de Lest, Chris H A, Buitendijk, Inge, Zwaagstra, Marleen, Balić, Pascal, Filippov, Dmitri V, Berkers, Celia R, van Kuppeveld, Frank J M, Virologie, Afd Chemical Biology and Drug Discovery, Veterinaire biochemie, Equine Musculoskeletal Biology, CS_Locomotion, Faculteit Diergeneeskunde, Sub Biomol.Mass Spectrometry & Proteom., Infectious Diseases and Immunology - Virology, Cell Biology, Metabolism & Cancer - Metabolomics, Nouwen, Lonneke V, Breeuwsma, Martijn, Zaal, Esther A, van de Lest, Chris H A, Buitendijk, Inge, Zwaagstra, Marleen, Balić, Pascal, Filippov, Dmitri V, Berkers, Celia R, and van Kuppeveld, Frank J M

Published
2024

14. Proteome and phospholipidome interrelationship of synovial fluid-derived extracellular vesicles in equine osteoarthritis: An exploratory 'multi-omics' study to identify composite biomarkers

Author

IOV Facs, Dep Clinical Sciences, Equine Musculoskeletal Biology, CS_Locomotion, Veterinaire biochemie, Celbiologie, Cell Biology, Metabolism & Cancer - Cellbiology, Cell Biology, Metabolism & Cancer - Metabolomics, Research Department OH - Biomolecular Health Sciences, Locomotion - Equine Sciences, Clarke, Emily, Varela, Laura, Jenkins, Rosalind E, Lozano-Andrés, Estefanía, Cywińska, Anna, Przewozny, Maciej, van Weeren, P René, van de Lest, Chris H A, Peffers, Mandy, Wauben, Marca H M, IOV Facs, Dep Clinical Sciences, Equine Musculoskeletal Biology, CS_Locomotion, Veterinaire biochemie, Celbiologie, Cell Biology, Metabolism & Cancer - Cellbiology, Cell Biology, Metabolism & Cancer - Metabolomics, Research Department OH - Biomolecular Health Sciences, Locomotion - Equine Sciences, Clarke, Emily, Varela, Laura, Jenkins, Rosalind E, Lozano-Andrés, Estefanía, Cywińska, Anna, Przewozny, Maciej, van Weeren, P René, van de Lest, Chris H A, Peffers, Mandy, and Wauben, Marca H M

Published
2024

18. Lipidome profiling of human and equine neutrophil-derived extracellular vesicles and their potential contribution to the ensemble of synovial fluid-derived extracellular vesicles during joint inflammation

Author

Varela, Laura, primary, Mol, Sanne, additional, Taanman-Kueter, Esther W., additional, Ryan, Sarah E., additional, Taams, Leonie S., additional, de Jong, Esther, additional, van Weeren, P. René, additional, van de Lest, Chris H.A., additional, and Wauben, Marca H.M., additional

Published
2023
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19. Inhibition of polyploidization in Pten-deficient livers reduces steatosis

Author

Moreno, Eva, Matondo, Augustine B, Bongiovanni, Laura, van de Lest, Chris H A, Molenaar, Martijn R, Toussaint, Mathilda J M, van Essen, Saskia C, Houweling, Martin, Helms, J Bernd, Westendorp, Bart, de Bruin, Alain, Cell Biology, Metabolism and Cancer, Pathobiologie, CS_Locomotion, Veterinaire biochemie, Equine Musculoskeletal Biology, Dep Biomolecular Health Sciences, Cell Biology, Metabolism and Cancer, Pathobiologie, CS_Locomotion, Veterinaire biochemie, Equine Musculoskeletal Biology, and Dep Biomolecular Health Sciences

Subjects
EXPRESSION, PTEN, GENES, Hepatology, Liver Neoplasms, Peroxisome Proliferator-Activated Receptors, PTEN Phosphohydrolase, non-alcoholic fatty liver disease, FATTY LIVER, hepatocellular carcinoma, polyploidization, Lipids, HEPATOCYTE PLOIDY, atypical E2Fs, Mice, Phosphatidylinositol 3-Kinases, FUSION, Liver, conditional knockout mice, Hepatocytes, steatosis, Animals, E2F8, Proto-Oncogene Proteins c-akt, SUPPRESSION
Abstract

The tumour suppressor PTEN is a negative regulator of the PI3K/AKT signalling pathway. Liver-specific deletion of Pten in mice results in the hyper-activation PI3K/AKT signalling accompanied by enhanced genome duplication (polyploidization), marked lipid accumulation (steatosis) and formation of hepatocellular carcinomas. However, it is unknown whether polyploidization in this model has an impact on the development of steatosis and the progression towards liver cancer. Here, we used a liver-specific conditional knockout approach to delete Pten in combination with deletion of E2f7/8, known key inducers of polyploidization. As expected, Pten deletion caused severe steatosis and liver tumours accompanied by enhanced polyploidization. Additional deletion of E2f7/8 inhibited polyploidization, alleviated Pten-induced steatosis without affecting lipid species composition and accelerated liver tumour progression. Global transcriptomic analysis showed that inhibition of polyploidization in Pten-deficient livers resulted in reduced expression of genes involved in energy metabolism, including PPAR-gamma signalling. However, we find no evidence that deregulated genes in Pten-deficient livers are direct transcriptional targets of E2F7/8, supporting that reduction in steatosis and progression towards liver cancer are likely consequences of inhibiting polyploidization. Lastly, flow cytometry and image analysis on isolated primary wildtype mouse hepatocytes provided further support that polyploid cells can accumulate more lipid droplets than diploid hepatocytes. Collectively, we show that polyploidization promotes steatosis and function as an important barrier against liver tumour progression in Pten-deficient livers.

Published
2022
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20. Proteome and phospholipidome interrelationship of synovial fluid-derived extracellular vesicles in equine osteoarthritis: An exploratory ‘multi-omics’ study to identify composite biomarkers

Author

Clarke, Emily J, primary, Varela, Laura, additional, Jenkins, Rosalind E, additional, Lozano−Andrés, Estefanía, additional, Cywińska, Anna, additional, Przewozny, Maciej, additional, van Weeren, P. René, additional, van de Lest, Chris H.A., additional, Peffers, Mandy, additional, and Wauben, Marca H.M., additional

Published
2023
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21. Acute joint inflammation induces a sharp increase in the number of synovial fluid EVs and modifies their phospholipid profile

Author

CS_Locomotion, Equine Musculoskeletal Biology, Veterinaire biochemie, Celbiologie, IOV Facs, Dep Clinical Sciences, Cell Biology, Metabolism & Cancer - Metabolomics, Cell Biology, Metabolism & Cancer - Cellbiology, Research Department OH - Biomolecular Health Sciences, Locomotion - Equine Sciences, Varela, Laura, van de Lest, Chris H A, Boere, Janneke, Libregts, Sten F W M, Lozano-Andrés, Estefania, van Weeren, P René, Wauben, Marca H M, CS_Locomotion, Equine Musculoskeletal Biology, Veterinaire biochemie, Celbiologie, IOV Facs, Dep Clinical Sciences, Cell Biology, Metabolism & Cancer - Metabolomics, Cell Biology, Metabolism & Cancer - Cellbiology, Research Department OH - Biomolecular Health Sciences, Locomotion - Equine Sciences, Varela, Laura, van de Lest, Chris H A, Boere, Janneke, Libregts, Sten F W M, Lozano-Andrés, Estefania, van Weeren, P René, and Wauben, Marca H M

Published
2023

24. Hyperlipidemia elicits an atypical, Th1 like CD4+ T cell response: a key role for VLDL

Author

van Os, Bram W, primary, Vos, Winnie G, additional, Bosmans, Laura A, additional, van Tiel, Claudia M, additional, Lith, Sanne C, additional, den Toom, Myrthe, additional, Beckers, Linda, additional, Levels, Johannes H M, additional, van Wouw, Suzanne A E, additional, Zelcer, Noam, additional, Zaal, Esther A, additional, Berkers, Celia R, additional, van de Lest, Chris H A, additional, Helms, J Bernd, additional, Weber, Christian, additional, Atzler, Dorothee, additional, de Winther, Menno P J, additional, Baardman, Jeroen, additional, and Lutgens, Esther, additional

Published
2023
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30. Reporting of anaesthesia and pain management in preclinical large animal models of articular cartilage repair - A long way to go

Author

Fugazzola, Maria C, Wever, Kimberley E, van de Lest, Chris, de Grauw, Janny, Salvatori, Daniela, Fugazzola, Maria C, Wever, Kimberley E, van de Lest, Chris, de Grauw, Janny, and Salvatori, Daniela

Abstract

Animal models continue to be used to investigate cartilage repair strategies. Adequate anaesthesia and pain management are essential in order to guarantee acceptable animal welfare as well as reproducible experimental results. This systematic review evaluates reporting of anaesthesia and pain management in surgical large animal models (horse, pig, dog, goat and sheep) of (osteo)chondral repair. Manuscripts published between 2015 and 2020 were included after a comprehensive search strategy. Data were evaluated using descriptive statistics and qualitative review. Out of 223 eligible studies, 220 studies contained incomplete information on anaesthetic and pain management. Pre-, intra- and post-operative analgesia were not mentioned in 68%, 94%, and 64% of manuscripts respectively. A total of 176 studies reported that animals underwent general anaesthesia during surgery. Surprisingly, 30% of these articles did not provide any detail on anaesthetic management, while 37% reported using inhalant, hypnotic or sedative drugs only, without mention of analgesics. Pain monitoring was not reported in 87% of manuscripts. The vast majority of preclinical large animal studies on cartilage repair did not meet veterinary clinical standards for anaesthesia and analgesia, and failed to report according to the ARRIVE international guidelines. In light of serious welfare, ethical and translational validity concerns, improvement is urgently needed.

Published
2022

31. Campylobacter jejuni permeabilizes the host cell membrane by short chain lysophosphatidylethanolamines

Author

Cao, Xuefeng, van de Lest, Chris H A, Huang, Liane Z X, van Putten, Jos P M, Wösten, Marc M S M, Cao, Xuefeng, van de Lest, Chris H A, Huang, Liane Z X, van Putten, Jos P M, and Wösten, Marc M S M

Abstract

Lysophospholipids (LPLs) are crucial for regulating epithelial integrity and homeostasis in eukaryotes, however the effects of LPLs produced by bacteria on host cells is largely unknown. The membrane of the human bacterial pathogen Campylobacter jejuni is rich in LPLs. Although C. jejuni possesses several virulence factors, it lacks traditional virulence factors like type III secretion systems, present in most enteropathogens. Here, we provide evidence that membrane lipids lysophosphatidylethanolamines (lysoPEs) of C. jejuni are able to lyse erythrocytes and are toxic for HeLa and Caco-2 cells. Lactate dehydrogenase (LDH) release assays and confocal microscopy revealed that lysoPE permeabilizes the cells. LysoPE toxicity was partially rescued by oxidative stress inhibitors, indicating that intracellular reactive oxygen species may contribute to the cell damage. Our results show that especially the short-chain lysoPEs (C:14) which is abundantly present in the C. jejuni membrane may be considered as a novel virulence factor.

Published
2022

32. Reporting of anaesthesia and pain management in preclinical large animal models of articular cartilage repair - A long way to go

Author

CS_Locomotion, Equine Musculoskeletal Biology, Veterinaire biochemie, Anesthesiologie, Anatomie en fysiologie, CS_Cancer, Fugazzola, Maria C, Wever, Kimberley E, van de Lest, Chris, de Grauw, Janny, Salvatori, Daniela, CS_Locomotion, Equine Musculoskeletal Biology, Veterinaire biochemie, Anesthesiologie, Anatomie en fysiologie, CS_Cancer, Fugazzola, Maria C, Wever, Kimberley E, van de Lest, Chris, de Grauw, Janny, and Salvatori, Daniela

Published
2022

33. Campylobacter jejuni permeabilizes the host cell membrane by short chain lysophosphatidylethanolamines

Author

Infectiebiologie, Equine Musculoskeletal Biology, Veterinaire biochemie, CS_Locomotion, Cao, Xuefeng, van de Lest, Chris H A, Huang, Liane Z X, van Putten, Jos P M, Wösten, Marc M S M, Infectiebiologie, Equine Musculoskeletal Biology, Veterinaire biochemie, CS_Locomotion, Cao, Xuefeng, van de Lest, Chris H A, Huang, Liane Z X, van Putten, Jos P M, and Wösten, Marc M S M

Published
2022

34. Inhibition of polyploidization in Pten-deficient livers reduces steatosis

Author

Cell Biology, Metabolism and Cancer, Pathobiologie, CS_Locomotion, Veterinaire biochemie, Equine Musculoskeletal Biology, Dep Biomolecular Health Sciences, Moreno, Eva, Matondo, Augustine B, Bongiovanni, Laura, van de Lest, Chris H A, Molenaar, Martijn R, Toussaint, Mathilda J M, van Essen, Saskia C, Houweling, Martin, Helms, J Bernd, Westendorp, Bart, de Bruin, Alain, Cell Biology, Metabolism and Cancer, Pathobiologie, CS_Locomotion, Veterinaire biochemie, Equine Musculoskeletal Biology, Dep Biomolecular Health Sciences, Moreno, Eva, Matondo, Augustine B, Bongiovanni, Laura, van de Lest, Chris H A, Molenaar, Martijn R, Toussaint, Mathilda J M, van Essen, Saskia C, Houweling, Martin, Helms, J Bernd, Westendorp, Bart, and de Bruin, Alain

Published
2022

37. Bicarbonate-Stimulated Membrane Reorganization in Stallion Spermatozoa

Author

Maitan, Paula Piccolo, Bromfield, Elizabeth G, Hoogendijk, Romy, Leung, Miguel Ricardo, Zeev-Ben-Mordehai, Tzviya, van de Lest, Chris H, Jansen, Jeroen W A, Leemans, Bart, Guimarães, José Domingos, Stout, Tom A E, Gadella, Bart M, Henning, Heiko, Sub Structural Biochemistry, Equine Musculoskeletal Biology, Veterinaire biochemie, dB&C FR-RMSC RMSC, dES RMSC, IOV MS, Voortplanting paard, dES/dFAH FR, FAH klinische reproductie, dB&C FR-RMSC FR, Structural Biochemistry, CS_Fertility, Sub Structural Biochemistry, Equine Musculoskeletal Biology, Veterinaire biochemie, dB&C FR-RMSC RMSC, dES RMSC, IOV MS, Voortplanting paard, dES/dFAH FR, FAH klinische reproductie, dB&C FR-RMSC FR, Structural Biochemistry, and CS_Fertility

Subjects
capacitation, QH301-705.5, Acrosome reaction, Cell and Developmental Biology, chemistry.chemical_compound, spermatozoa, lipid, Capacitation, Membrane fluidity, Biology (General), education, membrane, Original Research, equine, Sperm plasma membrane, Phosphatidylethanolamine, education.field_of_study, urogenital system, Chemistry, Cell Biology, Soluble adenylyl cyclase, Sperm, Cell biology, fertilization, bicarbonate (HCO3−), adenylyl cyclase, Outer acrosomal membrane, Developmental Biology
Abstract

Classical in vitro fertilization (IVF) is still poorly successful in horses. This lack of success is thought to be due primarily to inadequate capacitation of stallion spermatozoa under in vitro conditions. In species in which IVF is successful, bicarbonate, calcium, and albumin are considered the key components that enable a gradual reorganization of the sperm plasma membrane that allows the spermatozoa to undergo an acrosome reaction and fertilize the oocyte. The aim of this work was to comprehensively examine contributors to stallion sperm capacitation by investigating bicarbonate-induced membrane remodelling steps, and elucidating the contribution of cAMP signalling to these events. In the presence of capacitating media containing bicarbonate, a significant increase in plasma membrane fluidity was readily detected using merocyanine 540 staining in the majority of viable spermatozoa within 15 min of bicarbonate exposure. Specific inhibition of soluble adenylyl cyclase (sAC) in the presence of bicarbonate by LRE1 significantly reduced the number of viable sperm with high membrane fluidity. This suggests a vital role for sAC-mediated cAMP production in the regulation of membrane fluidity. Cryo-electron tomography of viable cells with high membrane fluidity revealed a range of membrane remodelling intermediates, including destabilized membranes and zones with close apposition of the plasma membrane and the outer acrosomal membrane. However, lipidomic analysis of equivalent viable spermatozoa with high membrane fluidity demonstrated that this phenomenon was neither accompanied by a gross change in the phospholipid composition of stallion sperm membranes nor detectable sterol efflux (p > 0.05). After an early increase in membrane fluidity, a significant and cAMP-dependent increase in viable sperm with phosphatidylserine (PS), but not phosphatidylethanolamine (PE) exposure was noted. While the events observed partly resemble findings from the in vitro capacitation of sperm from other mammalian species, the lack of cholesterol removal appears to be an equine-specific phenomenon. This research will assist in the development of a defined medium for the capacitation of stallion sperm and will facilitate progress toward a functional IVF protocol for horse gametes.

Published
2021
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39. Outer Membrane Vesicles Protect Gram-Negative Bacteria against Host Defense Peptides

Author

Balhuizen, Melanie D, van Dijk, Albert, Jansen, Jeroen W A, van de Lest, Chris H A, Veldhuizen, Edwin J A, Haagsman, Henk P, Moleculaire afweer, dI&I I&I-3, IOV MS, Equine Musculoskeletal Biology, Veterinaire biochemie, dB&C FR-RMSC RMSC, dES RMSC, Immunologie, Moleculaire afweer, dI&I I&I-3, IOV MS, Equine Musculoskeletal Biology, Veterinaire biochemie, dB&C FR-RMSC RMSC, dES RMSC, and Immunologie

Subjects
0301 basic medicine, Gram-negative bacteria, antibiotic resistance, Swine, 030106 microbiology, Antimicrobial peptides, Microbiology, 03 medical and health sciences, Extracellular Vesicles, antimicrobial peptides, Antibiotic resistance, Escherichia coli, Animals, Humans, Molecular Biology, Innate immune system, Minimum bactericidal concentration, biology, Chemistry, host defense peptides, Antimicrobial, biology.organism_classification, QR1-502, Anti-Bacterial Agents, 030104 developmental biology, Bacterial outer membrane, Gram-Negative Bacterial Infections, Bacteria, outer membrane vesicles, Antimicrobial Cationic Peptides, Bacterial Outer Membrane Proteins, Research Article
Abstract

Host defense peptides (HDPs) are part of the innate immune system and constitute a first line of defense against invading pathogens. They possess antimicrobial activity against a broad spectrum of pathogens. However, pathogens have been known to adapt to hostile environments. Therefore, the bacterial response to treatment with HDPs was investigated. Previous observations suggested that sublethal concentrations of HDPs increase the release of outer membrane vesicles (OMVs) in Escherichia coli. First, the effects of sublethal treatment with HDPs CATH-2, PMAP-36, and LL-37 on OMV release of several Gram-negative bacteria were analyzed. Treatment with PMAP-36 and CATH-2 induced release of OMVs, but treatment with LL-37 did not. The OMVs were further characterized with respect to morphological properties. The HDP-induced OMVs often had disc-like shapes. The beneficial effect of bacterial OMV release was studied by determining the susceptibility of E. coli toward HDPs in the presence of OMVs. The minimal bactericidal concentration was increased in the presence of OMVs. It is concluded that OMV release is a means of bacteria to dispose of HDP-affected membrane. Furthermore, OMVs act as a decoy for HDPs and thereby protect the bacterium. IMPORTANCE Antibiotic resistance is a pressing problem and estimated to be a leading cause of mortality by 2050. Antimicrobial peptides, also known as host defense peptides (HDPs), and HDP-derived antimicrobials have potent antimicrobial activity and high potential as alternatives to antibiotics due to low resistance development. Some resistance mechanisms have developed in bacteria, and complete understanding of bacterial defense against HDPs will aid their use in the clinic. This study provides insight into outer membrane vesicles (OMVs) as potential defense mechanisms against HDPs, which will allow anticipation of unforeseen resistance to HDPs in clinical use and possibly prevention of bacterial resistance by the means of OMVs.

Published
2021

40. Sustained Intra-Articular Release and Biocompatibility of Tacrolimus (FK506) Loaded Monospheres Composed of [PDLA-PEG1000]-b-[PLLA] Multi-Block Copolymers in Healthy Horse Joints

Author

Cokelaere, Stefan M., primary, Groen, Wilhelmina M.G.A.C., additional, Plomp, Saskia G.M., additional, de Grauw, Janny C., additional, van Midwoud, Paul M., additional, Weinans, Harrie H., additional, van de Lest, Chris H.A., additional, Tryfonidou, Marianna A., additional, van Weeren, P. René, additional, and Korthagen, Nicoline M., additional

Published
2021
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41. Dataset of the phospholipidome and transcriptome of Campylobacter jejuni under different growth conditions

Author

Cao, Xuefeng, Brouwers, Jos F H M, van Dijk, Linda, van de Lest, Chris H A, Parker, Craig T, Huynh, Steven, van Putten, Jos P H, Kelly, David J, Wösten, Marc M S M, dB&C FR-RMSC FR, dB&C FR-RMSC RMSC, Equine Musculoskeletal Biology, Veterinaire biochemie, dES RMSC, Infectiebiologie, dI&I I&I-2, dB&C FR-RMSC FR, dB&C FR-RMSC RMSC, Equine Musculoskeletal Biology, Veterinaire biochemie, dES RMSC, Infectiebiologie, and dI&I I&I-2

Subjects
Phospholipid, Human pathogen, RNA-Seq, lcsh:Computer applications to medicine. Medical informatics, Campylobacter jejuni, Transcriptome, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Growth phase, Microaerophile, Oxygen concentration, LC-MS/MS, lcsh:Science (General), Gene, Phospholipids, 030304 developmental biology, Data Article, Phospholipidome, 0303 health sciences, Multidisciplinary, biology, biology.organism_classification, chemistry, Biochemistry, lcsh:R858-859.7, RNA-seq, 030217 neurology & neurosurgery, Bacteria, lcsh:Q1-390
Abstract

The membrane phospholipid composition is not a stable bacterial characteristic but can change in response to altered environmental conditions. Here we provide the dataset of the phospholipidome and transcriptome of the microaerophilic human pathogen Campylobacter jejuni under different environmental conditions. These data have been used in Cao (2020), The unique phospholipidome of the enteric pathogen C. jejuni: Lysolipids are required for motility at low oxygen availability. Here the abundance of each phospholipid is shown during the growth of C. jejuni for 0-108 h under low and high oxygen conditions (0.3 vs 10% O2). The phospholipid data were obtained by applying high performance liquid chromatography tandem-mass spectrometry (LC-MS/MS). The transcriptomic data obtained by RNA-seq show the differential expressed genes between logarithmic and stationary grown bacteria. In addition, our data might serve as a reference information for further in-depth investigation to understand the relation between specific phospholipids and the activity of membrane associated proteins.

Published
2020

42. Sustained Intra-Articular Release and Biocompatibility of Tacrolimus (FK506) Loaded Monospheres Composed of [PDLA-PEG1000]-b-[PLLA] Multi-Block Copolymers in Healthy Horse Joints

Author

Cokelaere, Stefan M, Groen, Wilhelmina M G A C, Plomp, Saskia G M, de Grauw, Janny C, van Midwoud, Paul M, Weinans, Harrie H, van de Lest, Chris H A, Tryfonidou, Marianna A, van Weeren, P René, Korthagen, Nicoline M, Cokelaere, Stefan M, Groen, Wilhelmina M G A C, Plomp, Saskia G M, de Grauw, Janny C, van Midwoud, Paul M, Weinans, Harrie H, van de Lest, Chris H A, Tryfonidou, Marianna A, van Weeren, P René, and Korthagen, Nicoline M

Abstract

There is an increasing interest in controlled release systems for local therapy in the treatment of human and equine joint diseases, aiming for optimal intra-articular concentrations with no systemic side effects. In this study, the intra-articular tolerability and suitability for local and sustained release of tacrolimus (FK506) from monospheres composed of [PDLA-PEG1000 ]-b-PLLA multiblock copolymers were investigated. Unloaded and tacrolimus-loaded (18.4 mg tacrolimus/joint) mono-spheres were injected into the joints of six healthy horses, with saline and hyaluronic acid (HA) in the contralateral joints as controls. Blood and synovial fluid were analysed for the tacrolimus concentration and biomarkers for inflammation and cartilage metabolism. After an initial burst release, sustained intra-articular tacrolimus concentrations (>20 ng/mL) were observed during the 42 days follow-up. Whole-blood tacrolimus levels were below the detectable level (<0.5 ng/mL). A transient inflammatory reaction was observed for all substances, evidenced by increases of the synovial fluid white blood cell count and total protein. Prostaglandin and glycosaminoglycan release were increased in joints injected with unloaded monospheres, which was mitigated by tacrolimus. Both tacrolimus-loaded monospheres and HA transiently increased the concentration of collagen II cleavage products (C2C). A histologic evaluation of the joints at the endpoint showed no pathological changes in any of the conditions. Together, these results indicate the good biocompatibility of intra-articular applied tacrolimus-loaded monospheres combined with prolonged local drug release while minimising the risk of systemic side effects. Further evaluation in a clinical setting is needed to determine if tacrolimus-loaded monospheres can be beneficial in the treatment of inflammatory joint diseases in humans and animals.

Published
2021

43. Sustained intra-articular release and biocompatibility of tacrolimus (Fk506) loaded monospheres composed of [pdla-peg1000]-b-[plla] multi-block copolymers in healthy horse joints

Author

Zorgeenheid Orthopaedie Medisch, ORT Research, Regenerative Medicine and Stem Cells, Orthopaedie Onderzoek, Other research (not in main researchprogram), Cokelaere, Stefan M., Groen, Wilhelmina M.G.A.C., Plomp, Saskia G.M., de Grauw, Janny C., van Midwoud, Paul M., Weinans, Harrie H., van de Lest, Chris H.A., Tryfonidou, Marianna A., René van Weeren, P., Korthagen, Nicoline M., Zorgeenheid Orthopaedie Medisch, ORT Research, Regenerative Medicine and Stem Cells, Orthopaedie Onderzoek, Other research (not in main researchprogram), Cokelaere, Stefan M., Groen, Wilhelmina M.G.A.C., Plomp, Saskia G.M., de Grauw, Janny C., van Midwoud, Paul M., Weinans, Harrie H., van de Lest, Chris H.A., Tryfonidou, Marianna A., René van Weeren, P., and Korthagen, Nicoline M.

Published
2021

44. Bicarbonate-Stimulated Membrane Reorganization in Stallion Spermatozoa

Author

Sub Structural Biochemistry, Equine Musculoskeletal Biology, Veterinaire biochemie, dB&C FR-RMSC RMSC, dES RMSC, IOV MS, Voortplanting paard, dES/dFAH FR, FAH klinische reproductie, dB&C FR-RMSC FR, Structural Biochemistry, CS_Fertility, Maitan, Paula Piccolo, Bromfield, Elizabeth G, Hoogendijk, Romy, Leung, Miguel Ricardo, Zeev-Ben-Mordehai, Tzviya, van de Lest, Chris H, Jansen, Jeroen W A, Leemans, Bart, Guimarães, José Domingos, Stout, Tom A E, Gadella, Bart M, Henning, Heiko, Sub Structural Biochemistry, Equine Musculoskeletal Biology, Veterinaire biochemie, dB&C FR-RMSC RMSC, dES RMSC, IOV MS, Voortplanting paard, dES/dFAH FR, FAH klinische reproductie, dB&C FR-RMSC FR, Structural Biochemistry, CS_Fertility, Maitan, Paula Piccolo, Bromfield, Elizabeth G, Hoogendijk, Romy, Leung, Miguel Ricardo, Zeev-Ben-Mordehai, Tzviya, van de Lest, Chris H, Jansen, Jeroen W A, Leemans, Bart, Guimarães, José Domingos, Stout, Tom A E, Gadella, Bart M, and Henning, Heiko

Published
2021

45. Outer Membrane Vesicles Protect Gram-Negative Bacteria against Host Defense Peptides

Author

Moleculaire afweer, dI&I I&I-3, IOV MS, Equine Musculoskeletal Biology, Veterinaire biochemie, dB&C FR-RMSC RMSC, dES RMSC, Immunologie, Balhuizen, Melanie D, van Dijk, Albert, Jansen, Jeroen W A, van de Lest, Chris H A, Veldhuizen, Edwin J A, Haagsman, Henk P, Moleculaire afweer, dI&I I&I-3, IOV MS, Equine Musculoskeletal Biology, Veterinaire biochemie, dB&C FR-RMSC RMSC, dES RMSC, Immunologie, Balhuizen, Melanie D, van Dijk, Albert, Jansen, Jeroen W A, van de Lest, Chris H A, Veldhuizen, Edwin J A, and Haagsman, Henk P

Published
2021

46. PMAP-36 reduces the innate immune response induced by Bordetella bronchiseptica-derived outer membrane vesicles

Author

Moleculaire afweer, dI&I I&I-3, Sub Molecular Microbiology, dB&C FR-RMSC FR, dB&C FR-RMSC RMSC, Equine Musculoskeletal Biology, Veterinaire biochemie, dES RMSC, Immunologie, Molecular Microbiology, Balhuizen, Melanie D., Versluis, Chantal M., Van Harten, Roel M., De Jonge, Eline F., Brouwers, Jos F., Van De Lest, Chris H.a., Veldhuizen, Edwin J.a., Tommassen, Jan, Haagsman, Henk P., Moleculaire afweer, dI&I I&I-3, Sub Molecular Microbiology, dB&C FR-RMSC FR, dB&C FR-RMSC RMSC, Equine Musculoskeletal Biology, Veterinaire biochemie, dES RMSC, Immunologie, Molecular Microbiology, Balhuizen, Melanie D., Versluis, Chantal M., Van Harten, Roel M., De Jonge, Eline F., Brouwers, Jos F., Van De Lest, Chris H.a., Veldhuizen, Edwin J.a., Tommassen, Jan, and Haagsman, Henk P.

Published
2021

47. Sustained Intra-Articular Release and Biocompatibility of Tacrolimus (FK506) Loaded Monospheres Composed of [PDLA-PEG1000]-b-[PLLA] Multi-Block Copolymers in Healthy Horse Joints

Author

CS_Locomotion, Equine Musculoskeletal Biology, Anesthesiologie, Veterinaire biochemie, Chirurgie, Dep Clinical Sciences, Cokelaere, Stefan M, Groen, Wilhelmina M G A C, Plomp, Saskia G M, de Grauw, Janny C, van Midwoud, Paul M, Weinans, Harrie H, van de Lest, Chris H A, Tryfonidou, Marianna A, van Weeren, P René, Korthagen, Nicoline M, CS_Locomotion, Equine Musculoskeletal Biology, Anesthesiologie, Veterinaire biochemie, Chirurgie, Dep Clinical Sciences, Cokelaere, Stefan M, Groen, Wilhelmina M G A C, Plomp, Saskia G M, de Grauw, Janny C, van Midwoud, Paul M, Weinans, Harrie H, van de Lest, Chris H A, Tryfonidou, Marianna A, van Weeren, P René, and Korthagen, Nicoline M

Published
2021

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