Christian D Muller | Université de Strasbourg (original) (raw)

Papers by Christian D Muller

Current Drug Discovery Technologies, 2005

The aim of reverse pharmacognosy is to find new biological targets for natural compounds by virtu... more The aim of reverse pharmacognosy is to find new biological targets for natural compounds by virtual or real screening and identify natural resources that contain the active molecules. To demonstrate the applicability of this concept, we report here a study on -viniferin, an active ingredient for cosmetic development. Nevertheless, this natural substance is weakly defined in terms of biological properties. SELNERGY, an inverse docking computer software, was used to identify putative binding biological targets for -viniferin. Among the 400 screened proteins two targets were retained. For cosmetic application, cyclic nucleotide phosphodiesterase 4 (PDE4) was the most interesting candidate. Moreover, other PDE subtypes (1,2,3,5 and 6) were not retained, indicating a selectivity for PDE4. The experimental binding tests on the 6 subtypes of PDE revealed a significant selectivity of -viniferin for the PDE4 subtype. This selectivity was confirmed by evaluation of -viniferin on the secretion of TNF-and Interleukin-8. Our data demonstrated that -viniferin possesses anti-inflammatory properties by inhibiting PDE4 subtype. In conclusion, reverse pharmacognosy and its inverse docking component cannot only be integrated into a program for new lead discovery but is also a useful approach to find new applications for identified compounds.

Cellular Signalling, 2011

Cyclic nucleotide phosphodiesterase PDE1 Tumor suppressor p73 Epigenetic integrator UHRF1

Expert Opinion on Drug Discovery, 2010

Mediators of Inflammation, 2009

Crohn's disease (CD) is a multifactorial chronic inflammatory bowel disease of unknown cause. The... more Crohn's disease (CD) is a multifactorial chronic inflammatory bowel disease of unknown cause. The aim of the present study was to explore if mRNA over-expression of SSTR5 and CCR7 found in CD patients could be correlated to respective protein expression. When compared to healthy donors, SSTR5 was over-expressed 417 ± 71 times in CD peripheral blood mononuclear cells (PBMCs). Flow cytometry experiments showed no correlation between mRNA and protein expression for SSTR5 in PBMCs. In an attempt to find a reason of such a high mRNA expression, SSTR5 present on CD PBMCs were tested and found as biologically active as on healthy cells. In biopsies of CD intestinal tissue, SSTR5 was not over-expressed but CCR7, unchanged in PBMCs, was overexpressed by 10 ± 3 times in the lamina propria. Confocal microscopy showed a good correlation of CCR7 mRNA and protein expression in CD intestinal biopsies. Our data emphasize flow and image cytometry as impossible to circumvent in complement to molecular biology so to avoid false interpretation on receptor expressions. Once confirmed by further large-scale studies, our preliminary results suggest a role for SSTR5 and CCR7 in CD pathogenesis.

Anti-cancer Drugs, 1992

Multidrug resistance (MDR) of tumor cells may result from overexpression of P-glycoprotein (Pgp) ... more Multidrug resistance (MDR) of tumor cells may result from overexpression of P-glycoprotein (Pgp) but may be down-modulated by resistance-modifying agents (RMAs). The cyclosporin SDZ PSC 833 and the cyclopeptolide SDZ 280-446 were found to be the strongest RMAs known to date for restoring the sensitivity of MDR cells to anticancer drugs, as well as for restoring their retention of daunomycin, a fluorescent anthracycline. Using rhodamine-123 (Rhod-123), another fluorescent probe of Pgp function which also differentiates sensitive and MDR cells, several RMAs were compared for their capacity to inhibit Pgp function. At variance with the data obtained with the daunomycin probe, a series of RMAs did not detectably restore Rhod-123 retention by the MDR cells. With the remaining RMAs, achieving the same levels of Rhod-123 retention required 3 times lower RMA concentrations when the RMA was added to the MDR cells for both the initial uptake and the efflux of Rhod-123 rather than for its uptake only. Nevertheless, the data emphasized the large superiority of SDZ PSC 833 and SDZ 280-446 over all other RMAs.

Cancer Letters, 2004

Suicide gene therapy could be an attractive addition to the treatment of ovarian carcinomas, for ... more Suicide gene therapy could be an attractive addition to the treatment of ovarian carcinomas, for which acquired chemoresistance frequently results in treatment failure. Here we show that transfection of the HSV-tk gene, followed by incubation with up to 1 mM ganciclovir fails to induce cell death in SKOV3 chemoresistant human ovarian carcinoma cells. However, co-transfection of HSV-tk with Cip1/Waf1 encoding the p21(cip1/waf1) inhibitor of cdks, allows 100 microM ganciclovir to eradicate the population of tumor cells. Potentiation of a drug by co-transfer of HSV-tk with Cip1/Waf1could thus represent another therapeutic approach for tumours that are resistant to conventional therapy.

Biochemical and Biophysical Research Communications, 2004

CrohnÕs disease is a chronic intestinal inflammatory process. In modern therapy, TNF-a inhibition... more CrohnÕs disease is a chronic intestinal inflammatory process. In modern therapy, TNF-a inhibition is the main goal. The aim here is to characterize the effects of Celastrol, a pentacyclic-triterpene, on the secretion of inflammatory cytokines by LPS-activated human cells. Celastrol dose-dependently inhibited the secretion of all tested pro-inflammatory cytokines with IC 50 in the nanomolar range. Effect not related to glucocorticoid receptor activity is shown by competition experiments with the steroid antagonist RU486. Celastrol inhibited the pro-inflammatory cytokine secretion from mucosal inflammatory biopsies from CrohnÕs disease patients.

Biological Invasions, 2010

The dissemination of Hemimysis anomala (H. anomala) in Europe and more recently in North America ... more The dissemination of Hemimysis anomala (H. anomala) in Europe and more recently in North America highlights the problem of proliferation of invasive species able to form large colonies. Concern relates mainly to competition for food, in particular the zooplankton that H. anomala feeds on at the juvenile stage and that could be lacking for many other species, like young fish. A recent study describes the spread of H. anomala towards the south of France by the Rhône River (Wittmann and Ariani in Biol Invasions, 7 pp, 2008). We have also found it near the Marne east of Paris, as well as in an increasing number of rivers and gravel pits in Alsace. We confirm here that H. anomala is very prolific, reproducing three times a year, in March/April, June/ July and September/October. During the winter, we observed gatherings of thousands of individuals in open water from mid-December until March/April, with females carrying eggs in March when water reaches 7-8°C. The tracking of the population of H. anomala in an Alsatian gravel pit during three consecutive years shows a marked reduction in the number of individuals after a period of strong growth, which could be explained by substantial predation by perch and other predators. Finally, the ecological impact of the establishment of H. anomala was evaluated indirectly by the study of alevin and hydra populations, chosen for their nutritional dependence on zooplankton. Combined with the decrease of the H. anomala population observed over the period studied, our data suggest that a major impact on the aquatic community by H. anomala is unlikely at least in the studied area. Statements in this article were all recorded and corresponding sequences presented on http://riedbleu.free.fr/films_Hemimysis.html.

Recent Patents on Inflammation & Allergy Drug Discovery, 2007

Crohn's disease is a complex multifactorial disorder characterized by the alternation of a cytoki... more Crohn's disease is a complex multifactorial disorder characterized by the alternation of a cytokine-driven Tlymphocyte-depending inflammation of the intestinal mucosa, and "off" periods, where patients are completely asymptomatic. Although all the causative factors have not been clearly identified, the continuously growing understanding of the major abnormalities of the inflammatory and immune response leading to the often debilitating symptoms reported by Crohn's disease patients, improves our capacity to characterize new potential therapeutic targets with the subsequent hope to discover new (more efficient and less toxic) drugs. Saying that, in the recent years, tumor necrosis factor-alpha undoubtedly emerges as a key cytokine involved in Crohn's disease pathogenesis, and constant efforts have been made to control tumor necrosis factor-alpha deleterious effects in Crohn's disease. This review schematically summarizes the current understanding of tumor necrosis factor-alpha's role in Crohn's disease pathogenesis as well as the present and the future treatment strategies which may be helpful in patients by inhibiting tumor necrosis factor-alpha production and effects. Beside drugs under investigation, several original approaches are described or mentioned, most of them leading to recent patents such as polyclonal anti-TNF-alpha antibodies from avian origin, allowing potentially oral administration, or combination strategies such as vitamin D and anti-TNF-alpha antibodies or methotrexate and anti-TNF-alpha antibodies, or decoy oligodeoxynucleotides interfering with the binding of nuclear factor-κB to its target genes promoters.

Journal of Pharmacy and Pharmacology, 2009

Objectives Flavonoids are phenolic compounds found in most edible fruits and vegetables. Previous... more Objectives Flavonoids are phenolic compounds found in most edible fruits and vegetables. Previous studies have demonstrated their biological and beneficial effects on human health. However, their bioavailability and, in particular, their intestinal absorption mechanism have not yet been clearly identified. The aim of our work was to quantify and to characterize in vitro the nature of the transport of two flavonoids distinguished by their physicochemical and pharmacological properties: quercetin, a flavan-3-ol, and naringenin, a flavanone. Methods Differentiated and polarized Caco-2 human intestinal epithelial cell lines were used for this purpose. Key findings In our experimental conditions, quercetin and naringenin were poorly absorbed by Caco-2 cells. Quercetin was absorbed by passive diffusion and a pHdependent mechanism mediated by the organic anion transporting protein B (OATP-B). It was not a multidrug resistance associated protein (MRP)1 substrate, but was substrate of the MRP2 efflux transporter and not P-glycoprotein (P-gp). Intestinal permeability from the apical to the basolateral side was higher for naringenin than for quercetin, which was partly explained by naringenin's physicochemical characteristics. Naringenin, partially absorbed by passive diffusion, was also an ATP-dependent transport substrate mediated by MRP1, but was not an OATP-B substrate. However, naringenin was secreted via active P-gp and MRP2 efflux transporters. Conclusions The contribution of ATP-dependent efflux transporters (MRP2 and P-gp) to the permeability of these compounds in the apical side could explain their low bioavailability. In conclusion, knowledge of the absorption mechanism of these two flavonoids was used to determine the intake level that has a beneficial effect on human health and their putative role in food-drug interactions.

Clinical Nutrition, 2004

Background & aims: Studies have suggested that 100% long-chain triacylglycerols (LCTs) lipid emul... more Background & aims: Studies have suggested that 100% long-chain triacylglycerols (LCTs) lipid emulsions exhibit immunosuppressive effects, sometimes suspected to favor infectious complications in patients receiving parenteral nutrition. Newer emulsions, in particular olive oil-based emulsions, seem to have lesser immunosuppressive effects. We studied the in vitro effect of 100% LCTs (Intralipide s ), 50% LCTs-50% medium chain triacylglycerols (M ! edialipide s ), and 80% olive oil-based lipid emulsions (ClinOl ! eic s ) on inflammatory cytokines production by peripheral blood mononuclear cells (PBMCs).

Gut, 1996

Background-Increasing evidence points to a important role for inflammatory cytokines for the path... more Background-Increasing evidence points to a important role for inflammatory cytokines for the pathogenesis of Crohn's disease. Aim-To compare the secretion rate of tumour necrosis factor-a (TNF-a),

Journal of Clinical Immunology, 1996

Chronic inflammation in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) ... more Chronic inflammation in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) may be attributed partly to increased secretion of inflammatory cytokines. The aim of this study was to investigate simultaneously the spontaneous release patterns of tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), and interleukin-6 (IL-6) by organ cultures of inflamed mucosa from IBD patients. Organ cultures of involved IBD mucosa spontaneously produced increased amounts of TNF-α, IL-1β, and IL-6 compared to normal mucosa. The patterns of cytokine release between Crohn's disease and ulcerative colitis organ cultures were not significantly different. Increased inflammatory cytokine production by lamina propria mononuclear cells (LPMCs) and mucosa treated with EDTA suggests that these cytokines originate mainly from LPMCs. These results confirm the role of inflammatory cytokines in IBD and shed a new light on the role of TNF-α in IBD.

Background: Tumor necrosis factor-alpha (TNF-a) is a pro-inflammatory cytokine today identified a... more Background: Tumor necrosis factor-alpha (TNF-a) is a pro-inflammatory cytokine today identified as a key mediator of several chronic inflammatory diseases. TNF-a, initially synthesized as a membrane-anchored precursor (pro-TNF-a), is processed by proteolytic cleavage to generate the secreted mature form. TNF-a converting enzyme (TACE) is currently the first and single protease described as responsible for the inducible release of soluble TNF-a.

Cancer Gene Therapy, 2000

As a prerequisite to nonviral gene therapy approaches of ovarian carcinoma, we evaluated the poss... more As a prerequisite to nonviral gene therapy approaches of ovarian carcinoma, we evaluated the possibility of transfecting established tumor cell lines (SKOV3, IGROV1) as well as primary mesothelial and tumor cells by various polyethylenimine (PEI) derivatives. Several PEI-based vectors were able to effectively transfect these cells, as shown by high luciferase expression levels (10 8 to 10 9 relative light units per milligram of cell protein) that corresponded with 25-50% of green fluorescent protein-positive cells after 24 hours. However, unpredictable differences were observed among the vectors and cell types that a posteriori justified the screening procedure. We also showed that cells that were not transfected after the first experiment remained transfectable in a subsequent transfection experiment to a level similar to that of the initial population. This experiment does not support the emergence of a transfection-resistant cell population and opens the door to multiple therapeutic gene deliveries. Although efficacy and cell targeting still remain to be improved, PEI derivatives appear to be promising molecules for the development of nonviral gene therapy of ovarian carcinoma. Cancer Gene Therapy (2000) 7, 644 -652

Neurochemistry International, 1995

Ammonium acetate decreased in a concentration-dependent manner the phagocytic uptake of mannosyla... more Ammonium acetate decreased in a concentration-dependent manner the phagocytic uptake of mannosylated latex microspheres and of yeast by immortalized human microglia (CHME-5) and astroglioma (GL-15) cells. In both cell lines ammonium acetate affected also the secretion of certain cytokines. The most conspicuous effects were the following : in both cell lines ammonium acetate enhanced greatly the secretion of tumor necrosis factor-or in the absence of any other stimulus. In the human microglia cells ammonia decreased the constitutive secretion of interleukin-6, but it enhanced the stimulated (interleukin-l~t, tumor necrosis factor-or, y-interferon and y-interferon + tumor necrosis factor-c0 secretion ofinterleukin-8. In the astroglioma cell line, the stimulated release of tumor necrosis factor<t, interleukin-6 and interleukin-8 was diminished by ammonium acetate. The magnitude of the ammonia-effect depended on the stimulating agent (lipopolysaccharide, interleukin-lct, tumor necrosis factor<t, y-interferon). The results are discussed with regard to their potential importance in the pathogenesis of human diseases with elevated blood and brain ammonia concentrations.

Cytometry, 1994

Our laboratory recently developed a light microscopy staining technique that provides a mean to d... more Our laboratory recently developed a light microscopy staining technique that provides a mean to distinguish between yeast that are simply bound to the surface of macrophages and yeast that have actually been phagocytized by macrophages (7). We adapted this technique by using fluorescent probes in order to test phagocytic activity by flow cytometry. Thus we are able to distinguish unambiguously extracellular from intracellular yeast during phagocytosis with the fast rate of flow cytometry (-200 cells/s). The fluorescence quenching induced by a 1% tannic acid solution (wlv) can be applied to any FITC-labeled, heat-killed yeast cell or bacteria. The yeast cells already engulfed in the macrophage remain with their native fluorescence (internal and external pH equilibrated by 50 pM monensin 30 minI4"C) protected from the action of tannic acid, a nonmembrane permeable molecule. The results presented here validate this new technique. An application is presented showing the inhibition of endocytosis by cytochalasin-B.