Catharina Reker-Smit's research while affiliated with University of Groningen and other places
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Publications (53)
Understanding how cells process nanoparticles is crucial to optimize nanomedicine efficacy. However, characterizing cellular pathways is challenging, especially if non-canonical mechanisms are involved. In this Article a genome-wide forward genetic screening based on insertional mutagenesis is applied to discover receptors and proteins involved in...
Receptor activator for NF-kappa beta (RANK) ligand (RANKL) is found in lung tissue and elevated in lung diseases like chronic obstructive pulmonary disease (COPD), cystic fibrosis and silica-induced pulmonary fibrosis. RANKL is a well-known stimulator of bone tissue degradation, which may explain the association between these lung diseases and oste...
Nanoparticles of different properties, such as size, charge, and rigidity, are used for drug delivery. Upon interaction with the cell membrane, because of their curvature, nanoparticles can bend the lipid bilayer. Recent results show that cellular proteins capable of sensing membrane curvature are involved in nanoparticle uptake; however, no inform...
Administration of temperature-responsive drug carriers that release anticancer drugs at high temperatures can benefit hyperthermia therapies because of the synergistic effect of anticancer drug molecules and high temperature on killing the cancer cells. In this study, we design and characterize a new temperature-responsive nanocarrier based on a na...
Introduction
Differentially polarized macrophages, especially YM1+ and MHCII+ macrophages, play an important role in asthma development. The origin of these polarized macrophages has not been elucidated yet. We therefore aimed to investigate how proliferation, monocyte recruitment, and/or switching of polarization states contribute to this specific...
Nanosized drug carriers enter cells via active mechanisms of endocytosis but the pathways involved are often not clarified. Cells possess several mechanisms to generate membrane curvature during uptake. However, the mechanisms of membrane curvature generation for nanoparticle uptake have not been explored so far. Here, we combined different methods...
Background/aims:
Osteoprotegerin (OPG) is a profibrotic mediator produced by myofibro-blasts under influence of transforming growth factor β (TGFβ). Its expression in experimental models of liver fibrosis correlates well with disease severity and treatment responses. The regulation of OPG in liver tissue is largely unknown and we therefore set out...
The formation of the biomolecule corona on the surface of nanoparticles upon exposure to biological fluids critically influences nanocarrier performance in drug delivery. It has been shown that in some cases corona proteins can mediate specific nanoparticle interactions with cell receptors. Within this context, in order to identify corona proteins...
Corona formation in biological fluids strongly affects nanomedicine interactions with cells. However, relatively less is known on additional effects from the free proteins in solution. Within this context, this study aims to gain a better understanding of nanomaterial–cell interactions in different biological fluids and, more specifically, to disen...
Backgrounds
Osteoprotegerin (OPG) is a profibrotic mediator produced by myofibroblasts under influence of transforming growth factor β (TGFβ). Its expression in experimental models of liver fibrosis correlates well with disease severity and treatment responses. The regulation of OPG in liver tissue is largely unknown and we therefore set out to elu...
Zwitterionic molecules are used as an alternative to PEGylation to reduce protein adsorption on nanocarriers. Nonetheless, little is known on the effect of zwitterionic modifications on the mechanisms cells use for nanocarrier uptake. In this study, the uptake mechanism of liposomes containing zwitterionic or negatively-charged lipids was character...
Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question of whether OPG expression responds to treatment. Therefore, we aimed to elucidate the fibrotic regulation of OPG production and its possi...
Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question whether OPG expression responds to treatment. Therefore, we aimed to elucidate the regulation of OPG production and its biological activi...
Nano-sized objects, such as nanoparticles and other drug carriers used in nanomedicine, once in contact with biological environments are modified by adsorption of biomolecules on their surface. The presence of this corona strongly affects the following interactions at cell and organism levels. It has been shown that corona proteins can be recognize...
Aim: In this work we illustrate limits and challenges associated with the use of pharmacological inhibitors to study how nanomedicines enter cells and show how such limits can be overcome. Materials & methods: We selected a panel of six common pharmacological inhibitors and a model nanoparticle-cell system. We tested eventual toxicity by measuring...
Rho-kinase (ROCK) activation in hepatic stellate cells (HSC) is a key mechanism promoting liver fibrosis and portal hypertension (PTH). Specific delivery of ROCK-inhibitor Y-27632 (Y27) to HSC targeting mannose-6-phosphate-receptors reduces portal pressure and fibrogenesis. In decompensated cirrhosis, presence of ascites is associated with reduced...
Exchange protein activated by cAMP (Epac-1) is an important signaling mechanism for cAMP-mediated effects but factors that change Epac-1 levels are unknown. Such factors are relevant because it has been postulated that Epac-1 directly affects fibrogenesis. Prostaglandin E2 (PGE2) is a well-known cAMP-activator and we therefore studied the effects o...
In healthy lungs, many macrophages are characterized by IL-10 production, and few are characterized by expression of IFN regulatory factor 5 (formerly M1) or YM1 and/or CD206 (formerly M2), whereas in asthma, this balance shifts toward few producing IL-10 and many expressing IFN regulatory factor 5 or YM1/CD206. In this study, we tested whether red...
Macrophages have been found to both promote liver fibrosis and contribute to its resolution by acquiring different phenotypes based on signals from the micro-environment. The best-characterized phenotypes in the macrophage spectrum are labeled M1 (classically activated) and M2 (alternatively activated). Until now the in situ localization of these p...
M6PHSA carrier does not affect collagen deposition in livers of CCl4 mice. Representative pictures of immunohistochemical stainings for collagen I and collagen III on liver sections of C57Bl/6 mice, after one injection of CCl4 and treated with M6PHSA carrier. Original magnification 400×.
(TIF)
Transforming growth factor-β (TGF-β) is a major pro-fibrotic cytokine, causing the overproduction of extracellular matrix molecules in many fibrotic diseases. Inhibition of its type-I receptor (ALK5) has been shown to effectively inhibit fibrosis in animal models. However, apart from its pro-fibrotic effects, TGF-β also has a regulatory role in the...
Aim:
Interleukin-10 (IL-10) is a cytokine with potent antifibrotic and anti-inflammatory properties. However, IL-10 has a very short plasma half-life in vivo. This prompted the question whether a short intravenous treatment might have prolonged effects on more chronic processes like sclerosis.
Methods:
Glomerulosclerosis was induced by anti-Thym...
One of the pathways activated during liver fibrosis is the Rho kinase pathway, which regulates activation, migration, and contraction of hepatic stellate cells (HSC). Inhibition of this kinase by the Rho kinase inhibitor Y27632 [(+)-(R)-trans- 4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride] has been shown to reduce fibrosis in...
Rho-kinase regulates activation of hepatic stellate cells (HSC) during liver fibrosis, but the ubiquitous presence of this kinase may hinder examination of its exact role and the therapeutic use of inhibitors. We therefore coupled the Rho-kinase inhibitor Y27632 to a drug carrier that binds the mannose-6-phosphate insulin-like growth factor II (M6P...
![Fig.1. A gammacamera analysis showed a high level of [ 123 I]IL-10 in...](profile/Leonie-Beljaars/publication/40841838/figure/fig7/AS:650036606165056@1531992212741/A-gammacamera-analysis-showed-a-high-level-of-123-IIL-10-in-the-kidneys-K-after-iv_Q320.jpg)
![Fig.1. A gammacamera image of [ 123 I]IL-10 and [ 123 I]M6PIL-10...](profile/Leonie-Beljaars/publication/40841838/figure/fig13/AS:650036606156892@1531992212893/A-gammacamera-image-of-123-IIL-10-and-123-IM6PIL-10-distribution-in-BDL-1-rats_Q320.jpg)
In the present study, we examined the effects of IL-10 after 24 h in a model of acute glomerulonephritis (GN). One hour after the anti-Thy 1 antibody administration, a single i.v. dose of IL-10 was administered to rats. Normal rats, control nephritic rats and nephritic rats treated with IL-10, were sacrificed 24 h after administration of antibody....
In the present study, we examined the effects of IL-10 after 24 h in a model of acute glomerulonephritis (GN). One hour after the anti-Thy 1 antibody administration, a single i.v. dose of IL-10 was administered to rats. Normal rats, control nephritic rats and nephritic rats treated with IL-10, were sacrificed 24 h after administration of antibody....
Liver fibrosis is associated with proliferation of hepatic stellate cells (HSCs) and their transformation into myofibroblastic cells that synthesize scar tissue. Several studies indicate that induction of apoptosis in myofibroblastic cells may prevent fibrogenesis. Gliotoxin (GTX) was found to induce apoptosis of hepatic cells and caused regression...
In fibrotic livers, collagen producing hepatic stellate cells (HSC) represent a major target for antifibrotic therapies. We designed liposomes with surface-coupled mannose 6-phosphate (M6P) modified human serum albumin (HSA) to target HSC via the M6P receptor. In this study we determined the pharmacokinetics and target specificity of M6P-HSA-liposo...
Liver fibrosis is characterized by excessive proliferation and activation of hepatic stellate cells (HSC), a process in which platelet-derived growth factor (PDGF) plays an important role. Inhibition of liver fibrosis via specific delivery of a PDGF kinase inhibitor to HSC might therefore be an attractive strategy. The HSC-selective carrier mannose...
Inhibition of hepatic stellate cell (HSC) proliferation is a relevant strategy to inhibit liver fibrosis. Coupling of antiproliferative drugs to the HSC-selective drug carrier mannose-6-phosphate-modified human serum albumin (M6PHSA) may lead to cell-selective inhibition of HSC proliferation. We coupled the antiproliferative drug doxorubicin (DOX)...
Cytokines are considered a promising immunotherapy for chronic diseases, because of their potency and fundamental roles in pathological processes. However, their therapeutic use is limited because of their poor pharmacokinetics and pleiotropic effects in various organs. These problems may be overcome by cell-specific delivery of the cytokine. This...
In the fibrotic liver, hepatic stellate cells (HSC) produce large amounts of collagen and secrete variety of mediators that promote development of fibrosis in this organ. Therefore, these cells are considered an attractive target for antifibrotic therapies. We incorporated the bioactive lipid dilinoleoylphosphatidylcholine (DLPC) into the membrane...
Delivery of apoptosis-inducing compounds to hepatic stellate cells (HSC) may be an effective strategy to reverse liver fibrosis. The aim of this study was therefore to examine the selective targeting of the apoptosis-inducing drug 15-deoxy-delta12,14-prostaglandin J2 (15dPGJ2) with two different HSC-carriers: human serum albumin modified with the s...
Hepatic stellate cell (HSC) proliferation is a key event in liver fibrosis; therefore, pharmacological intervention with antiproliferative drugs may result in antifibrotic effects. In this article, the antiproliferative effect of three cytostatic drugs was tested in cultured rat HSC. Subsequently, the antifibrotic potential of the most potent drug...
In designing a versatile liposomal drug carrier to hepatic stellate cells (HSC), the interaction of mannose 6-phosphate human serum albumin (M6P-HSA) liposomes with cultured cells was studied.
M6P-HSA was covalently coupled to the liposomal surface and the uptake and binding of 3H-labelled M6P-HSA liposomes by primary rat HSC and liver endothelial...
Targeting of antifibrotic drugs to hepatic stellate cells (HSC) is a promising strategy to block fibrotic processes leading to liver cirrhosis. For this purpose, we utilized the neo-glycoprotein mannose-6-phosphate-albumin (M6PHSA) that accumulates efficiently in HSC during liver fibrosis. Pentoxifylline (PTX), an antifibrotic compound that inhibit...
Suc-HSA is a potent HIV-inhibitor with possible application in man. To facilitate the assessment of dosing regimens for future phase I clinical studies, we predicted the pharmacokinetic properties of Suc-HSA in man. Slices prepared from rat, monkey and human liver were incubated with succinylated albumin, and the maximum uptake rate V(m) and Michae...
Hepatic stellate cell (HSC) activation and proliferation are key events in the pathology of liver fibrosis. Inhibiting these parameters, therefore, is a relevant option to treat liver fibrosis pharmacologically. The immunosuppressive drug mycophenolic acid (MPA) has been shown to inhibit proliferation and activation of various types of fibroblasts....
![Fig.1. A gammacamera analysis showed a high level of [ 123 I]IL-10 in...](profile/Leonie-Beljaars/publication/8139970/figure/fig7/AS:667198544695311@1536083937901/A-gammacamera-analysis-showed-a-high-level-of-123-IIL-10-in-the-kidneys-K-after-iv_Q320.jpg)
![Fig.1. A gammacamera image of [ 123 I]IL-10 and [ 123 I]M6PIL-10...](profile/Leonie-Beljaars/publication/8139970/figure/fig13/AS:667198548897794@1536083938030/A-gammacamera-image-of-123-IIL-10-and-123-IM6PIL-10-distribution-in-BDL-1-rats_Q320.jpg)
Because interleukin-10 (IL-10) seems a promising new antifibrotic drug, we investigated the pharmacokinetic and biodistribution profile of this potent therapeutic cytokine in rats with extensive liver fibrosis (BDL-3). IL-10 receptor expression was also determined in relation to these aspects.
To study the pharmacokinetic and biodistribution of IL-...
Lactoferrin is an antimicrobial agent, that, amongst other viruses, inhibits cytomegalovirus (CMV). In this study, we addressed the mechanism(s) by which lactoferrin interacts with CMV and its target cells to inhibit infection. We also studied the antiviral activity of lactoferrin in vivo in rat CMV models with and without immune suppression. We ca...
![Fig.1. A gammacamera analysis showed a high level of [ 123 I]IL-10 in...](profile/Leonie-Beljaars/publication/268296312/figure/fig1/AS:669533467590657@1536640626055/A-gammacamera-analysis-showed-a-high-level-of-123-IIL-10-in-the-kidneys-K-after-iv_Q320.jpg)
Abstract Purpose:T o evaluate effects of liposomes containing the bioactive lipid dilinoleoylphos- phatidylcholine (DLPC) on hepatic stellate cells (HSC) activation and liver fibrosis. Methods: To target DLPC-liposomes to HSC, human serum albumin modified with mannose 6-phosphate (M6P-HSA) was coupled to the surface of these liposomes. In vitro, th...
Citations
... We recently described a novel marker called osteoprotegerin (OPG) that is highly upregulated in lung tissue of patients with lung fibrosis and appears to be involved in regulating alveolar epithelial regeneration [9,10]. A large multicenter cohort study also found OPG to be a biomarker of progressive fibrosing interstitial lung disease [11]. ...
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... The nanocarrier is responsive to changes in temperature reported by Hemmatpour et al. [58]. The carrier is made from a natural and safe clay mineral, halloysite nanotubes, coated with a layer of Poly (N-isopropyl acrylamide) brushes. ...
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... However, it cannot be excluded that the CD206 + INOS − DN fraction may contain proinflammatory macrophages, given that macrophage fractions in bronchoalveolar lavage that lack the M1 marker CD40 and the M2 marker CD163 were reported to have a proinflammatory gene signature [8]. Moreover, the impaired function of nonpolarized macrophages has been implicated in various lung diseases such as COPD, asthma, and fibrosis [18][19][20][21]. Nevertheless, we observed a substantial shift from DN macrophages in FT toward an expanded population of M2 macrophages in OT. ...
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... Since the surface structure affects the interaction between nanoparticles and plasma proteins [26][27][28][29], modification of nanoparticles with specific molecules to recruit functional proteins has become the main strategy to achieve targeted delivery through repurposing protein corona function. Zhang et al. designed an amyloid-β [25][26][27][28][29][30][31][32][33][34][35] modified liposome to up-regulate the recruitment of apolipoprotein A-I, E and J (Apo A-I, Apo E and Apo J) in plasma proteins and improve its brain targeting efficiency [30]. ...
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... The canonical function of OPG is to regulate osteogenesis and is produced by osteoblasts to control osteoclast activity [13]. However, we have additionally shown that OPG is produced and secreted by lung broblasts under the in uence of the key pro brotic mediator transforming growth factor beta 1 (TGFβ1) [14]. Interestingly, our recent studies indicate that through its capturing of RANKL it can also inhibit alveolar epithelial repair [9,10]. ...
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... The coagulation and complement cascade has been intensively studied in the context of nanomedicine, and the presence of these proteins was found to increase particle phagocytosis of liposomes and PMMA nanoplastics [68,69]. The complement proteins found on serum-coated PS100 included proteins with a known role in phagocytosis or that have previously been related to nanoparticle uptake, such as plasminogen [70,71], complement factor C3 [69], complement factor H [68], coagulation factor XIII A [72], prothrombin [73], alpha-1-antitrypsin [73] and von Willebrand factor 74. ...
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... 2-4). Moreover, standard curves of phospholipid (DSPC) contained in three LNP formulations were respectively drawn, as the phospholipid component is commonly used for quantifying the whole LNP21,22 . Subsequently, clinically relevant doses of LNP including low dose (L-LNP, 0.009 mg phospholipids/kg), middle dose (M-LNP, 0.342 mg phospholipids/kg), and high dose (H-LNP, 2.358 mg phospholipids/kg) were calculated based on the corresponding equations (Supplementary Fig. 1d-f; see "Methods"). ...
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... OPG inhibited RANK activation by RANKL, reducing osteoclastogenesis [112,113]. OPG expression and production were regulated by cytokines such as IL-6 and TNFα [114], steroid hormones (17β estradiol) [115], transforming growth factor (TGFβ) [116], and bone morphogenetic proteins (BMPs) [117]. Glucocorticoids, prostaglandin E2, fibroblastic growth factor, and parathyroid hormone (PTH) were all known to suppress the expression of OPG [118]. ...
... In all the endocytosis experiments, endocytic inhibitors were incubated with MCF-7 cells for 24 h at 37 � C prior to the incubation with NPs for 2 h before flow cytometry analysis. Chlorpromazine is commonly used to inhibit clathrinmediated endocytosis, which is widely regarded as a major pathway to transport cargo through endocytosis [148][149][150][151] . Amiloride acts as an inhibitor of micropinocytosis by inhibiting Na þ /H þ exchange proteins on the cell membrane 152 . ...
... OPG was initially recognized for its role in bone turnover in which it prevents bone resorption and stimulates production of extracellular matrix in cartilage [18]. However, in recent years, an increasing number of studies have shown correlations between OPG and several fibrotic conditions including liver, vascular, cardiac, kidney and intestinal fibrosis [19][20][21][22][23][24][25][26][27][28][29]. This study, and our own previous studies [9,10] have now shown that this also appears to be the case for fibrosis in lung tissue and even wound healing. ...
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