Guy Haegeman

Guy Haegeman
Ghent University | UGhent · Department of Physiology

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187
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Publications (187)
Article
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Background: Cholangiocarcinoma (CCA) is a fatal cancer with high resistance to anticancer drugs. The development of new drugs or compounds to be used alone or in combination with currently available chemotherapeutic agents to improve the treatment of CCA is needed. Compound A (CpdA), which is a small plant-derived glucocorticoid receptor modulator...
Article
Full-text available
Genome-wide Illumina InfiniumMethylation 450 K DNA methylation analysis was performed on blood samples from clinical atherosclerosis patients (n = 8) and healthy donors (n = 8) in the LVAD study (NCT02174133, NCT01799005). Multiple differentially methylated regions (DMR) could be identified in atherosclerosis patients, related to epigenetic control...
Article
Withaferin A (WA), a natural phytochemical derived from the plant Withania somnifera, is a well-studied bioactive compound exerting a broad spectrum of health promoting effects. To gain better insight in the potential therapeutic capacity of WA, we evaluated the transcriptional effects of WA on primary human umbilical vein endothelial cells (HUVECs...
Article
Full-text available
Background: Glucocorticoids are effective anti-inflammatory drugs widely used in dermatology and for the treatment of blood cancer patients. Unfortunately, chronic treatment with glucocorticoids results in serious metabolic and atrophogenic adverse effects including skin atrophy. Glucocorticoids act via the glucocorticoid receptor (GR), a transcri...
Article
Full-text available
Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids...
Article
Full-text available
Glucocorticoids are among the most effective anti-inflammatory drugs, and are widely used for cancer therapy. Unfortunately, chronic treatment with glucocorticoids results in multiple side effects. Thus, there was an intensive search for selective glucocorticoid receptor (GR) activators (SEGRA), which retain therapeutic potential of glucocorticoids...
Article
Full-text available
Nowadays, epigenetic mechanisms involving DNA methylation, histone modifications and microRNA regulation emerge as important players in cardiovascular disease (CVD). Epigenetics may provide the missing link between environment, genome and disease phenotype and be responsible for the strong interindividual variation in disease risk factors underlyin...
Article
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In this study a series of curcumin analogues were evaluated for their ability to inhibit the activation of NF-κΒ, a transcription factor at the crossroads of cancer-inflammation. Our novel curcumin analogue BAT3 was identified to be the most potent NF-κB inhibitor and EMSA assays clearly showed inhibition of NF-κB/DNA-binding in the presence of BAT...
Article
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Corticosteroid-binding globulin (CBG), a negative acute phase protein produced primarily in the liver, is responsible for the transport of glucocorticoids (GCs). It also modulates the bioavailability of GCs, as only free or unbound steroids are biologically active. Fluctuations in CBG levels therefore can directly affect GC bioavailability. This st...
Article
The transcription factor NF-κB is one of the main players involved in inflammatory responses during which NF-κB becomes rapidly activated. However to maintain homeostasis, this NF-κB activation profile is only transient. Nevertheless deregulation of NF-κB activity is often observed and can lead to chronic inflammatory diseases as well as cancer. Th...
Article
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With more than 150,000 species, parasitoids are a large group of hymenopteran insects that inject venom into and then lay their eggs in or on other insects, eventually killing the hosts. Their venoms have evolved into different mechanisms for manipulating host immunity, physiology and behavior in such a way that enhance development of the parasitoi...
Article
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In a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA me...
Article
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The proinflammatory cytokine Tumour Necrosis Factor (TNF)-α is implicated in a variety of skeletal muscle pathologies. Here, we have investigated how in vitro cotreatment of skeletal muscle C2C12 cells with β-agonists modulates the TNF-α-induced inflammatory program. We observed that C2C12 myotubes express functional TNF receptor 1 (TNF-R1) and β2-...
Article
Several bamboo species have been used in traditional medicine for the treatment of inflammatory conditions. The present study evaluates the in vitro anti-inflammatory properties of the traditionally used bamboo species Phyllostachys nigra (Lodd.) Munro and Sasa veitchii (Carr.) Rehder to explore their future research opportunities and therapeutic p...
Article
Full-text available
Compound A possesses glucocorticoid receptor (GR)-dependent anti-inflammatory properties. Just like classical GR ligands, Compound A can repress NF-κB-mediated gene expression. However, the monomeric Compound A-activated GR is unable to trigger glucocorticoid response element-regulated gene expression. The heat shock response potently activates hea...
Article
Like most neurotransmitters, serotonin possesses a simple structure. However, the pharmacological consequences are more complex and diverse. Serotonin is involved in numerous functions in the human body including the control of appetite, sleep, memory and learning, temperature regulation, mood, behavior, cardiovascular function, muscle contraction,...
Data
CpdA can elevate Hsp70 gene expression levels in MCF7 cells. (A) MCF7 cells were pretreated with solvent or CpdA (10µM) for 8 h. Total RNA was reverse transcribed and HSPA1A and housekeeping GAPDH mRNA levels were determined via semi-quantitative PCR visualized on a 2% agarose gels. The displayed bands were detected from one single gel. (B) MCF7 ce...
Data
Hsp70 is required to allow the anti-inflammatory activity of Compound A. A549 cells were transfected with siControl or siRNA targeting HSPA1A and HSPA1B (siHsp70). 41h post transfection, cells were pretreated with Solv or CpdA (10µM) for 2h, after which ensued a 6h TNF (2000IU/ml) treatment. Total RNA extracts were prepared. Purified mRNA was subje...
Data
Control of CHX functionality. A549 cells, starved for 48h, were left untreated or were treated for 7h with cycloheximide (CHX) (20µg/ml). Total cell protein extracts were subjected to Western blot analysis detecting β-catenin and an aspecific band serves as a loading control. (TIF)
Data
Compound A diminishes IκBα degradation and NF-κB translocation. (A) L929sA cells, starved for 48h, were pretreated for 2h with solvent (Solv), DEX (1µM) or CpdA (10µM), after which TNF (2000IU/ml) was added as indicated. Western blot analysis of total cells lysates detects IκBα protein, with NF-κB p65 as loading control. This figure is representati...
Data
Compound A augments Hsp70 gene expression. A549 cells, were treated with solvent or CpdA 10µM for the indicated time period. Total cellular mRNA was subjected to RT-qPCR detecting gene expression levels for HSPA2 or HSPA6 (as indicated), normalized using housekeeping 36B4 and β-actin mRNA levels. The Solv condition was set as 1 and results recalcul...
Data
CpdA does not elevate the Hsp70 protein level in L929sA cells. L929sA cells were treated with solvent or CpdA (10µM) for 4h,8h or 24h or heat-shocked at 43°C for 2h, after which cells were left to recover at 37°C for 2h (HS+Rec). Total cell protein lysates were analyzed via Hsp70 ELISA. Statistical analysis (ANOVA with Tukey’s multiple comparison p...
Data
Heat shock stimulates HSF1 heat shock granules, but CpdA does not. A549 cells, starved for 48h in Optimem, were treated with solvent (Solv) for 60 minutes or CpdA (10µM) for 30 or 60 minutes. Alternatively, cells were heat-shocked (HS) at 43°C for 30 minutes. Via indirect immunofluorescence using an α-HSF1 Ab, endogenous HSF1 was visualized (green)...
Data
All materials and methods, as described in the manuscript are also valid for the supporting information figures S1-S10 and tables S1 and S2. Additional materials en methods to understand the supporting information figures and tables are added as a supporting file. (DOCX)
Data
Both Compound A and heat shock diminish IL6 gene expression. (A) A549 cells, starved for 48h, were pretreated for 1.5h with solvent (Solv), DEX (1µM), CpdA (10µM) or subjected to heat shock treatment (1h at 43°C and 30′ recovery at 37°C), ensued with TNF (2000IU/ml) for 5.5h. Isolated total RNA was subjected to RT-qPCR assaying IL6 mRNA levels, nor...
Data
CpdA does not augment the HSF1 level, nor does it shift the band hight. (A) A549 cells were treated with Solv, CpdA (10µM) or DEX (1µM) for 2, 4, 6 or 24 hours. Alternatively, cells were heat-shocked at 43°C for 2h, after which cells were left to recover at 37°C for 2h (HS+Rec). Total cell protein extracts were subjected to Western blot analysis de...
Data
Detailed siRNA information (Dharmacon, Thermo Fischer). (DOCX)
Data
Compound A does not block translation. (A) PC-3 cells were starved for 48h in 0% DMEM, after which these cells were treated with solvent for 48h or Compound A (CpdA) (10µM) for 2h, 6h, 24h or 48h. Total cell protein extracts were subjected to Western blot analysis detecting β-catenin. Tubulin detection served as a loading control. (B) L929sA cells,...
Data
List of identified heat shock proteins and their corresponding peptides. HEK293T cells were transfected with Flag-hGRα via calcium phosphate and following stimulation with either solvent (NI) or 10µM CpdA (CpdA), immunoprecipitated using Flag beads (plasmid and methodology described in [7]. Two identical set-ups were done in parallel, yet, using tw...
Article
Full-text available
Glucocorticoids (GC) are potent drugs to treat rheumatoid arthritis, but exert adverse skeletal effects. Compound A (CpdA) is a selective GC receptor modulator with an improved risk/benefit profile in mouse models of inflammation and bone loss. Here, we tested whether CpdA also exerts bone-sparing effects under pro-inflammatory circumstances using...
Article
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Glucocorticoids (GCs) block inflammation via interference of the liganded glucocorticoid receptor (GR) with the activity of pro-inflammatory transcription factors NF-κB and AP-1, a mechanism known as transrepression. This mechanism is believed to involve the activity of GR monomers. Here, we explored how the GR monomer-favoring Compound A (CpdA) af...
Article
Epidemiological studies show that a flavanol-rich diet is associated with a decreased risk of cardiovascular disease (CVD). Experimental studies revealed that flavanols modulate signaling cascades, epigenetic profiles and consequently gene expression. In how far these modulations occur in humans upon flavanol intake is yet unclear. In a randomized...
Article
The 5-hydroxytryptamine (5-HT)7 receptor is the most recently identified serotonin receptor and is involved in a wide variety of central nervous system (CNS) functions, namely circadian rhythm, REM sleep, depression, thermoregulation, obsessive-compulsive disorder (OCD), anxiety, schizophrenia, epilepsy, nociception, migraine, sensation-seeking beh...
Article
The 5-hydroxytryptamine (5-HT)(7(a)) receptor is a G-protein-coupled receptor critically involved in human psychiatric and neurological disorders. In the present study, we evaluate the presence and the functional role of N-glycosylation of the human 5-HT(7) receptor. Western blot analysis of HEK293T cells transiently expressing the 5-HT(7(a)) recep...
Article
Full-text available
The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively mo...
Chapter
Full-text available
Cancer, as one of the non-communicable diseases, remains one of the leading causes of death around the world. Since immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conver...
Article
We have analyzed in molecular detail how kurarinone, a lavandulyl flavanone isolated from Sophora flavescens, suppresses nuclear factor-κB (NFκB)-driven interleukin-6 (IL6) expression and cancer cell growth. Interleukin-6 (IL6), involved in cancer-related inflammation, acts as an autocrine and paracrine growth factor, which promotes angiogenesis, m...
Article
It has been known for several decades that cyclic AMP (cAMP), a prototypical second messenger, transducing the action of a variety of G-protein-coupled receptor ligands, has potent immunosuppressive and anti-inflammatory actions. These actions have been attributed in part to the ability of cAMP-induced signals to interfere with the function of the...
Chapter
Glucocorticoids (GCs) block inflammation via interference of the Glucocorticoid Receptor (GR) with the pro-inflammatory transcription factors NF-κB and AP-1, a mechanism known as transrepression. GCs additionally control genes involved in metabolism via a transactivation mechanism. Hence, chronic, supraphysiological GC treatment in immune disorders...
Article
Almost a quarter of a century ago, interleukin-6 (IL-6) was discovered as an inflammatory cytokine involved in B cell differentiation. Today, IL-6 is recognized to be a highly versatile cytokine, with pleiotropic actions not only in immune cells, but also in other cell types, such as cells of the central nervous system (CNS). The first evidence imp...
Article
The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that can bind to glucocorticoids (GCs). Upon ligand binding, GR sheds its cytoplasmic chaperoning complex and translocates to the nucleus, where it can act as a ligand-dependent transcription factor, transactivating or transrepressing specific gene promoters. Often, GR inte...
Article
Full-text available
Glucocorticoids (GCs) are in widespread use to treat inflammatory bone diseases, such as rheumatoid arthritis (RA). Their anti-inflammatory efficacy, however, is accompanied by deleterious effects on bone, leading to GC-induced osteoporosis (GIO). These effects include up-regulation of the receptor activator of NF-κB ligand/osteoprotegerin (RANKL/O...
Article
The extracellular complex between the haematopoietic receptor Flt3 and its cytokine ligand (FL) is the cornerstone of signalling cascades that are central to early haematopoiesis and the immune system. Here, efficient protocols for the production of two ectodomain variants of human Flt3 receptor, Flt3D1-D5 and Flt3D1-D4, for structural studies are...
Article
Pharmacological and genetic tools targeting the 5-hydroxytryptamine (5-HT)7 receptor in preclinical animal models have implicated this receptor in diverse (patho)physiological processes of the central nervous system (CNS). Some data obtained with 5-HT7 receptor knockout mice, selective antagonists, and, to a lesser extent, agonists, however, are qu...
Article
Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined β-adrenergic and TNF-receptor triggering induces synerg...
Article
Dopamine D4 receptors (D4Rs) are G protein-coupled receptors that play a role in attention and cognition. In the present study, we investigated the dimerization properties of this receptor. Western blot analysis of the human D4.2R, D4.4R and D4.7R revealed the presence of higher molecular weight immunoreactive bands, which might indicate the format...
Article
Dopamine D(2) and D(4) receptors partially codistribute in the dorsal striatum and appear to play a fundamental role in complex behaviors and motor function. The discovery of D(2)R-D(4.)(x)R (D(4.2)R, D(4.4)R or D(4.7)R) heteromers has been made in cellular models using co-immunoprecipitation, in situ Proximity Ligation Assays and BRET(1) technique...
Article
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Numerous clinical, physiopathological and epidemiological studies have underlined the detrimental or beneficial role of nutritional factors in complex inflammation related disorders such as allergy, asthma, obesity, type 2 diabetes, cardiovascular disease, rheumatoid arthritis and cancer. Today, nutritional research has shifted from alleviating nut...
Article
Glucocorticoids (GCs) regulate various physiological processes, including bone remodeling. Whereas physiological amounts of GCs are required for proper human osteoblast differentiation, prolonged exposure to GCs leads to substantial bone loss in vivo predominantly by inhibiting osteoblast functions. Compound A (CpdA) is a novel GC receptor modulato...
Article
The search for novel glucocorticoid receptor (GR) modulators with similar anti-inflammatory properties as conventional steroids, but with a reduction in the number or severity of the side effects has been a long-standing goal, and still remains a challenge today. The quest for these so-called 'dissociated GR ligands' is mainly based on the hypothes...
Chapter
Nuclear receptors can function as ligand-activated transcription factors but can even so cross-talk with other transcription factors. In this respect, NF-κB, a central regulator of both inflammation and tumorigenesis, can cross-react with and is negatively affected by these nuclear receptors. In current medicine, the nuclear receptor ligands for th...
Article
Glucocorticoids have been used since several decades in a variety of diseases in view of their potent anti-inflammatory properties. Nevertheless, the widespread use of glucocorticoids is hampered by the risk of side effects. Because the effects of glucocorticoids are mediated at large through interaction with the glucocorticoid receptor, which resu...
Article
In previous studies, we identified KLHL12 as a novel interaction partner of the dopamine D4 receptor that functions as an adaptor in a Cullin3-based E3 ubiquitin ligase complex to target the receptor for ubiquitination. In this study, we show that KLHL12 promotes poly-ubiquitination of the receptor by performing ubiquitination assays in eukaryotic...
Article
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While many botanicals have been used during thousands of years in various cultures for the treatment of several inflammatory conditions, wound healing or preserving skin beauty, their active ingredients and their mechanisms of action are less well characterized. It is known that throughout life, environmental conditions and dietary compounds influe...
Article
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Multidrug resistance (MDR) is a major obstacle in cancer treatment and is often the result of overexpression of the drug efflux protein, P-glycoprotein (P-gp), as a consequence of hyperactivation of NFkappaB, AP1 and Nrf2 transcription factors. In addition to effluxing chemotherapeutic drugs, P-gp also plays a specific role in blocking caspase-depe...
Article
Astrocytes are critical players in the innate immune response of the central nervous system. Upon encountering proinflammatory stimuli, astrocytes produce a plethora of inflammatory mediators. Here, we have investigated how beta(2)-adrenergic receptor activation modulates proinflammatory gene expression in astrocytes. We have observed that treatmen...
Article
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Compound A (CpdA), a dissociated glucocorticoid receptor modulator, decreases corticosteroid-binding globulin (CBG), adrenocorticotropic hormone (ACTH), and luteneinizing hormone levels in rats. Whether this is due to transcriptional regulation by CpdA is not known. Using promoter reporter assays we show that CpdA, like dexamethasone (Dex), directl...
Data
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Supplementary table 1. Summary of reports that have used phospho-specific antibodies to show phosphorylation of p65 at the ser276 residue. In the table the cell types in which p65 phosphorylation was investigated, and the antibody-based techniques used to study p65 phosphorylation, are indicated. All corresponding authors were contacted via E-mail...
Article
Dopamine is an important neurotransmitter that regulates several key functions in the brain, such as motor output, motivation and reward, learning and memory, and endocrine regulation. Dopamine does not mediate fast synaptic transmission, but rather modulates it by triggering slow-acting effects through the activation of dopamine receptors, which b...