Publications by authors named "Oliver Werz"

305 Publications

The Natural Combination Medicine Traumeel (Tr14) Improves Resolution of Inflammation by Promoting the Biosynthesis of Specialized Pro-Resolving Mediators.

Pharmaceuticals (Basel) 2021 Nov 3;14(11). Epub 2021 Nov 3.

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Philosophenweg 14, 07743 Jena, Germany.

The resolution of inflammation is an integral part of the acute inflammatory response and eventually leads to the return to homeostasis. It is supported by specialized pro-resolving mediators (SPMs) that act as immunoresolvents via specific G-protein-coupled receptors. In contrast to classical non-steroidal anti-inflammatory drugs (NSAIDs) that suppress the formation of pro-inflammatory lipid mediators such as prostaglandins, novel pharmacotherapeutic concepts propose to foster the biosynthesis of beneficial SPMs. Here, we demonstrate that the natural combination medicine Traumeel (Tr14) improves resolution of inflammation by promoting SPM formation. Tr14 enhanced the biosynthesis of 12-/15-lipoxygenase (LOX) products and of SPMs in zymosan-induced mouse peritonitis as well as in human monocyte-derived macrophages challenged with . Importantly, in the peritonitis model, Tr14 supported the recruitment of innate leukocytes and the efferocytotic capacity of macrophages, and positively influenced the inflammation resolution index. Taken together, we suggest that based on these properties Tr14 may possess therapeutic potential as an enhancer for the resolution of inflammatory processes.
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http://dx.doi.org/10.3390/ph14111123DOI Listing
November 2021

Natural chalcones elicit formation of specialized pro-resolving mediators and related 15-lipoxygenase products in human macrophages.

Biochem Pharmacol 2021 Nov 8:114825. Epub 2021 Nov 8.

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, 07743 Jena, Germany. Electronic address:

Specialized pro-resolving mediators (SPMs) comprise lipid mediators (LMs) produced from polyunsaturated fatty acids (PUFAs) via stereoselective oxygenation particularly involving 12/15-lipoxygenases (LOXs). In contrast to pro-inflammatory LMs such as leukotrienes formed by 5-LOX and prostaglandins formed by cyclooxygenases, the SPMs have anti-inflammatory and inflammation-resolving properties. Although glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) that block prostaglandin production are still prime therapeutics for inflammation-related diseases despite severe side-effects, novel concepts focus on SPMs as immunoresolvents for anti-inflammatory pharmacotherapy. Here, we studied the natural chalcone MF-14 and the corresponding dihydrochalcone MF-15 from Melodorum fruticosum, for modulating the biosynthesis of LM including leukotrienes, prostaglandins, SPM and their 12/15-LOX-derived precursors in human monocyte-derived macrophage (MDM) M1- and M2-like phenotypes. In MDM challenged with Staphylococcus aureus-derived exotoxins both compounds (10 µM) significantly suppressed 5-LOX product formation but increased the biosynthesis of 12/15-LOX products, especially in M2-MDM. Intriguingly, in resting M2-MDM, MF-14 and MF-15 strikingly evoked generation of 12/15-LOX products and of SPMs from liberated PUFAs, along with translocation of 15-LOX-1 to membranous compartments. Enhanced 12/15-LOX product formation by the chalcones was evident also when exogenous PUFAs were supplied, excluding increased substrate supply as sole underlying mechanism. Rather, MF-14 and MF15 stimulate the activity of 15-LOX-1, supported by experiments with HEK293 cells transfected with either 5-LOX, 15-LOX-1 and 15-LOX-2. Together, the natural chalcone MF-14 and the dihydrochalcone MF-15 favorably modulate LM biosynthesis in human macrophages by suppressing pro-inflammatory leukotrienes but stimulating formation of SPMs by differential interference with 5-LOX and 15-LOX-1.
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http://dx.doi.org/10.1016/j.bcp.2021.114825DOI Listing
November 2021

Encapsulation of the Anti-inflammatory Dual FLAP/sEH Inhibitor Diflapolin Improves the Efficiency in Human Whole Blood.

J Pharm Sci 2021 Oct 29. Epub 2021 Oct 29.

Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany; Division of Pharmaceutical Technology, Department for Chemistry and Pharmacy, Friedrich-Alexander-University Erlangen-Nürnberg, Cauerstrasse 4, 91058 Erlangen, Germany. Electronic address:

Diflapolin is a dual FLAP/sEH inhibitor with potent anti-inflammatory efficiency in cellular assays and experimental in vivo studies. Despite these outstanding characteristics, its high lipophilicity and plasma protein binding hamper the bioactivity in blood. To overcome these limitations, diflapolin was encapsulated in poly(lactic-co-glycolic acid) nanoparticles to develop an efficient and biocompatible drug delivery system. Two different cosolvent approaches were tested showing the possibility to exchange dimethyl sulfoxide in the organic phase by the sustainable 400 g/mol poly(ethylene glycol). A particle size of 220 nm and the amorphous encapsulation of diflapolin in high amounts rendered the nanoparticles appropriate for the intended application. Excellent biocompatibility of the nanoparticles was demonstrated in an ex ovo hen's egg model. The potent suppression of FLAP-dependent 5-lipoxygenase product formation by the nanoparticles in human whole blood, superior to the free drug, makes them to a promising drug delivery system to improve the bioactivity of diflapolin.
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http://dx.doi.org/10.1016/j.xphs.2021.10.030DOI Listing
October 2021

Specialized pro-resolving mediators: biosynthesis and biological role in bacterial infections.

FEBS J 2021 Nov 6. Epub 2021 Nov 6.

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, Jena, Germany.

Acute inflammation caused by bacterial infections is an essential biological defence mechanism of the host in order to neutralize and clear the invaders and to return to homeostasis. Despite its protective function, inflammation may become persistent and uncontrolled, resulting in chronic diseases and tissue destruction as consequence of the unresolved inflammatory process. Therefore, spatiotemporal induction of endogenous inflammation resolution programs that govern bacterial clearance as well as tissue repair and regeneration, are of major importance in order to enable tissues to restore functions. Lipid mediators that are de-novo biosynthesized from polyunsaturated fatty acids (PUFAs) mainly by lipoxygenases and cyclooxygenases, critically regulate the initiation, the maintenance but also the resolution of infectious inflammation and tissue regeneration. The discovery of specialized pro-resolving mediators (SPMs) generated from omega-3 PUFAs stimulated intensive research in inflammation resolution, especially in infectious inflammation elicited by bacteria. SPMs are immunoresolvents that actively terminate inflammation by limiting neutrophil influx, stimulating phagocytosis, bacterial killing and clearance as well as efferocytosis of apoptotic neutrophils and cellular debris by macrophages. Moreover, SPMs prevent collateral tissue damage, promote tissue repair and regeneration and lower antibiotic requirement. Here, we review the biosynthesis of SPMs in bacterial infections and cover specific mechanisms of SPMs that govern the resolution of bacteria-initiated inflammation.
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http://dx.doi.org/10.1111/febs.16266DOI Listing
November 2021

Proteomic and lipidomic profiling of demyelinating lesions identifies fatty acids as modulators in lesion recovery.

Cell Rep 2021 Oct;37(4):109898

Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany. Electronic address:

After demyelinating injury of the central nervous system, resolution of the mounting acute inflammation is crucial for the initiation of a regenerative response. Here, we aim to identify fatty acids and lipid mediators that govern the balance of inflammatory reactions within demyelinating lesions. Using lipidomics, we identify bioactive lipids in the resolution phase of inflammation with markedly elevated levels of n-3 polyunsaturated fatty acids. Using fat-1 transgenic mice, which convert n-6 fatty acids to n-3 fatty acids, we find that reduction of the n-6/n-3 ratio decreases the phagocytic infiltrate. In addition, we observe accelerated decline of microglia/macrophages and enhanced generation of oligodendrocytes in aged mice when n-3 fatty acids are shuttled to the brain. Thus, n-3 fatty acids enhance lesion recovery and may, therefore, provide the basis for pro-regenerative medicines of demyelinating diseases in the central nervous system.
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http://dx.doi.org/10.1016/j.celrep.2021.109898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567315PMC
October 2021

The Trace Element Selenium Is Important for Redox Signaling in Phorbol Ester-Differentiated THP-1 Macrophages.

Int J Mol Sci 2021 Oct 14;22(20). Epub 2021 Oct 14.

Department of Nutritional Physiology, Institute of Nutritional Sciences, Friedrich Schiller University Jena, 07743 Jena, Germany.

Physiological selenium (Se) levels counteract excessive inflammation, with selenoproteins shaping the immunoregulatory cytokine and lipid mediator profile. How exactly differentiation of monocytes into macrophages influences the expression of the selenoproteome in concert with the Se supply remains obscure. THP-1 monocytes were differentiated with phorbol 12-myristate 13-acetate (PMA) into macrophages and (i) the expression of selenoproteins, (ii) differentiation markers, (iii) the activity of NF-κB and NRF2, as well as (iv) lipid mediator profiles were analyzed. Se and differentiation affected the expression of selenoproteins in a heterogeneous manner. GPX4 expression was substantially decreased during differentiation, whereas GPX1 was not affected. Moreover, Se increased the expression of selenoproteins H and F, which was further enhanced by differentiation for selenoprotein F and diminished for selenoprotein H. Notably, LPS-induced expression of NF-κB target genes was facilitated by Se, as was the release of COX- and LOX-derived lipid mediators and substrates required for lipid mediator biosynthesis. This included TXB, TXB, 15-HETE, and 12-HEPE, as well as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Our results indicate that Se enables macrophages to accurately adjust redox-dependent signaling and thereby modulate downstream lipid mediator profiles.
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http://dx.doi.org/10.3390/ijms222011060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539332PMC
October 2021

Candida albicans-induced leukotriene biosynthesis in neutrophils is restricted to the hyphal morphology.

FASEB J 2021 10;35(10):e21820

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Greifswald University, Greifswald, Germany.

Neutrophils are the most abundant leukocytes in circulation playing a key role in acute inflammation during microbial infections. Phagocytosis, one of the crucial defence mechanisms of neutrophils against pathogens, is amplified by chemotactic leukotriene (LT)B , which is biosynthesized via 5-lipoxygenase (5-LOX). However, extensive liberation of LTB can be destructive by over-intensifying the inflammatory process. While enzymatic biosynthesis of LTB is well characterized, less is known about molecular mechanisms that activate 5-LOX and lead to LTB formation during host-pathogen interactions. Here, we investigated the ability of the common opportunistic fungal pathogen Candida albicans to induce LTB formation in neutrophils, and elucidated pathogen-mediated drivers and cellular processes that activate this pathway. We revealed that C. albicans-induced LTB biosynthesis requires both the morphological transition from yeast cells to hyphae and the expression of hyphae-associated genes, as exclusively viable hyphae or yeast-locked mutant cells expressing hyphae-associated genes stimulated 5-LOX by [Ca ] mobilization and p38 MAPK activation. LTB biosynthesis was orchestrated by synergistic activation of dectin-1 and Toll-like receptor 2, and corresponding signaling via SYK and MYD88, respectively. Conclusively, we report hyphae-specific induction of LTB biosynthesis in human neutrophils. This highlights an expanding role of neutrophils during inflammatory processes in the response to C. albicans infections.
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http://dx.doi.org/10.1096/fj.202100516RRDOI Listing
October 2021

Untangling the web of 5-lipoxygenase-derived products from a molecular and structural perspective: The battle between pro- and anti-inflammatory lipid mediators.

Biochem Pharmacol 2021 Nov 3;193:114759. Epub 2021 Sep 3.

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University Jena, 07743 Jena, Germany.

Arachidonic acid (AA) is the precursor to leukotrienes (LT), potent mediators of the inflammatory response. In the 35 + years since cysteinyl-LTs were reported to mediate antigen-induced constriction of bronchi in tissue from asthma patients, numerous cellular responses evoked by the LTs, such as chemoattraction and G protein-coupled receptor (GPCR) activation, have been elucidated and revealed a potential for 5-lipoxygenase (5-LOX) as a promising drug target that goes beyond asthma. We describe herein early work identifying 5-LOX as the key enzyme that initiates LT biosynthesis and the discovery of its membrane-embedded helper protein required to execute the two-step reaction that transforms AA to the progenitor leukotriene A (LTA). 5-LOX must traffic to the nuclear membrane to interact with its partner and undergo a conformational change so that AA can enter the active site. Additionally, the enzyme must retain the hydroperoxy-reaction intermediate for its final transformation to LTA. Each of these steps provide a unique target for inhibition. Next, we describe the recent structures of GPCRs that recognize metabolites of the 5-LOX pathway and thus provide target alternatives. We also highlight the role of 5-LOX in the biosynthesis of anti-inflammatory lipid mediators (LM), the so-called specialized pro-resolving mediators (SPM). The involvement of 5-LOX in the biosynthesis of LM with opposing functions undoubtedly complicates the continuing search for 5-LOX inhibitors as therapeutic leads. Finally, we address the recent discovery of how some allosteric 5-LOX inhibitors promote oxygenation at the 12/15 carbon on AA to generate mediators that resolve, rather than promote, inflammation.
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http://dx.doi.org/10.1016/j.bcp.2021.114759DOI Listing
November 2021

Controlled Release of the α-Tocopherol-Derived Metabolite α-13'-Carboxychromanol from Bacterial Nanocellulose Wound Cover Improves Wound Healing.

Nanomaterials (Basel) 2021 Jul 28;11(8). Epub 2021 Jul 28.

Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Am Klinikum 1, 07747 Jena, Germany.

Inflammation is a hallmark of tissue remodeling during wound healing. The inflammatory response to wounds is tightly controlled and well-coordinated; dysregulation compromises wound healing and causes persistent inflammation. Topical application of natural anti-inflammatory products may improve wound healing, in particular under chronic pathological conditions. The long-chain metabolites of vitamin E (LCM) are bioactive molecules that mediate cellular effects via oxidative stress signaling as well as anti-inflammatory pathways. However, the effect of LCM on wound healing has not been investigated. We administered the α-tocopherol-derived LCMs α-13'-hydroxychromanol (α-13'-OH) and α-13'-carboxychromanol (α-13'-COOH) as well as the natural product garcinoic acid, a δ-tocotrienol derivative, in different pharmaceutical formulations directly to wounds using a splinted wound mouse model to investigate their effects on the wounds' proinflammatory microenvironment and wound healing. Garcinoic acid and, in particular, α-13'-COOH accelerated wound healing and quality of the newly formed tissue. We next loaded bacterial nanocellulose (BNC), a valuable nanomaterial used as a wound dressing with high potential for drug delivery, with α-13'-COOH. The controlled release of α-13'-COOH using BNC promoted wound healing and wound closure, mainly when a diabetic condition was induced before the injury. This study highlights the potential of α-13'-COOH combined with BNC as a potential active wound dressing for the advanced therapy of skin injuries.
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http://dx.doi.org/10.3390/nano11081939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398652PMC
July 2021

Incidence and severity of G6PI-induced arthritis are not increased in genetically distinct mouse strains upon aging.

Arthritis Res Ther 2021 08 24;23(1):222. Epub 2021 Aug 24.

Institute of Immunology, University Hospital Jena, Leutragraben 3, 07743, Jena, Germany.

Background: The incidence of rheumatoid arthritis is correlated with age. In this study, we analyzed the association of the incidence and severity of glucose-6-phosphate isomerase (G6PI)-induced arthritis with age in two different mouse strains.

Methods: Young and very old mice from two different arthritis-susceptible wild-type mouse strains were analyzed after a single subcutaneous injection of G6PI s.c. The metabolism and the function of synoviocytes were analyzed in vitro, the production of bioactive lipid mediators by myeloid cells and synoviocytes was assessed in vitro and ex vivo by UPLC-MS-MS, and flow cytometry was used to verify age-related changes of immune cell composition and function.

Results: While the severity of arthritis was independent from age, the onset was delayed in old mice. Old mice showed common signs of immune aging like thymic atrophy associated with decreased CD4 effector T cell numbers. Despite its decrease, the effector T helper (Th) cell compartment in old mice was reactive and functionally intact, and their Tregs exhibited unaltered suppressive capacities. In homeostasis, macrophages and synoviocytes from old mice produced higher amounts of pro-inflammatory cyclooxygenase (COX)-derived products. However, this functional difference did not remain upon challenge in vitro nor upon arthritis reactions ex vivo.

Conclusion: While old mice show a higher baseline of inflammatory functions, this does not result in increased reaction towards self-antigens in arthritis-susceptible mouse strains. Together, our data from two different mouse strains show that the susceptibility for G6PI-induced arthritis is not age-dependent.
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http://dx.doi.org/10.1186/s13075-021-02596-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383389PMC
August 2021

Effect of Crystallinity on the Properties of Polycaprolactone Nanoparticles Containing the Dual FLAP/mPEGS-1 Inhibitor BRP-187.

Polymers (Basel) 2021 Jul 31;13(15). Epub 2021 Jul 31.

Laboratory of Organic Chemistry and Macromolecular Chemistry (IOMC), Friedrich Schiller University, Humboldtstraße 10, 07743 Jena, Germany.

Seven polycaprolactones (PCL) with constant hydrophobicity but a varying degree of crystallinity prepared from the constitutional isomers ε-caprolactone (εCL) and δ-caprolactone (δCL) were utilized to formulate nanoparticles (NPs). The aim was to investigate the effect of the crystallinity of the bulk polymers on the enzymatic degradation of the particles. Furthermore, their efficiency to encapsulate the hydrophobic anti-inflammatory drug BRP-187 and the final in vitro performance of the resulting NPs were evaluated. Initially, high-throughput nanoprecipitation was employed for the εCL and δCL homopolymers to screen and establish important formulation parameters (organic solvent, polymer and surfactant concentration). Next, BRP-187-loaded PCL nanoparticles were prepared by batch nanoprecipitation and characterized using dynamic light scattering, scanning electron microscopy and UV-Vis spectroscopy to determine and to compare particle size, polydispersity, zeta potential, drug loading as well as the apparent enzymatic degradation as a function of the copolymer composition. Ultimately, NPs were examined for their potency in vitro in human polymorphonuclear leukocytes to inhibit the BRP-187 target 5-lipoxygenase-activating protein (FLAP). It was evident by Tukey's multi-comparison test that the degree of crystallinity of copolymers directly influenced their apparent enzymatic degradation and consequently their efficiency to inhibit the drug target.
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http://dx.doi.org/10.3390/polym13152557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347491PMC
July 2021

Mitochondrial Fusion Mediated by Mitofusin 1 Regulates Macrophage Mycobactericidal Activity by Enhancing Autophagy.

Infect Immun 2021 10 9;89(11):e0030621. Epub 2021 Aug 9.

Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen Universitygrid.263488.3 School of Medicine, Shenzhen, Guangdong, China.

A mitochondrion, as a highly dynamic organelle, continuously changes morphology and position during its life cycle. Mitochondrial dynamics, including fission and fusion, play a critical role in maintaining functional mitochondria for ATP production, which is directly linked to host defense against Mycobacterium tuberculosis infection. However, how macrophages regulate mitochondrial dynamics during M. tuberculosis infection remains elusive. In this study, we found that M. tuberculosis infection induced mitochondrial fusion by enhancing the expression of mitofusin 1 (), which resulted in increased ATP production. Silencing of inhibited mitochondrial fusion and subsequently reduced ATP production, which, in turn, severely impaired macrophages' mycobactericidal activity by inhibiting autophagy. Impairment of mycobactericidal activity and autophagy was replicated using oligomycin, an inhibitor of ATP synthase. In summary, our study revealed that MFN1-mediated mitochondrial fusion is essential for macrophages' mycobactericidal activity through the regulation of ATP-dependent autophagy. The MFN1-mediated metabolism pathway might be a target for the development of a host direct therapy (HDT) strategy against tuberculosis.
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http://dx.doi.org/10.1128/IAI.00306-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8519288PMC
October 2021

Analysis of Boswellic Acid Contents and Related Pharmacological Activities of Frankincense-Based Remedies That Modulate Inflammation.

Pharmaceuticals (Basel) 2021 Jul 10;14(7). Epub 2021 Jul 10.

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany.

Extracts of frankincense, the gum resin of species, have been extensively used in traditional folk medicine since ancient times and are still of great interest as promising anti-inflammatory remedies in Western countries. Despite their common therapeutic use and the intensive pharmacological research including studies on active ingredients, modes of action, bioavailability, pharmacokinetics, and clinical efficacy, frankincense preparations are available as nutraceuticals but have not yet approved as a drug on the market. A major issue of commercially available frankincense nutraceuticals is the striking differences in their composition and quality, especially related to the content of boswellic acids (BAs) as active ingredients, mainly due to the use of material from divergent species but also because of different work-up and extraction procedures. Here, we assessed three frequently used frankincense-based preparations for their BA content and the interference with prominent pro-inflammatory actions and targets that have been proposed, that is, 5-lipoxygenase and leukotriene formation in human neutrophils, microsomal prostaglandin E synthase-1, and inflammatory cytokine secretion in human blood monocytes. Our data reveal striking differences in the pharmacological efficiencies of these preparations in inflammation-related bioassays which obviously correlate with the amounts of BAs they contain. In summary, high-quality frankincense extracts display powerful anti-inflammatory effectiveness against multiple targets which can be traced back to BAs as bioactive ingredients.
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http://dx.doi.org/10.3390/ph14070660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308689PMC
July 2021

Structure-based screening for the discovery of 1,2,4-oxadiazoles as promising hits for the development of new anti-inflammatory agents interfering with eicosanoid biosynthesis pathways.

Eur J Med Chem 2021 Nov 13;224:113693. Epub 2021 Jul 13.

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084, Fisciano, Italy. Electronic address:

The multiple inhibition of biological targets involved in pro-inflammatory eicosanoid biosynthesis represents an innovative strategy for treating inflammatory disorders in light of higher efficacy and safety. Herein, following a multidisciplinary protocol involving virtual combinatorial screening, chemical synthesis, and in vitro and in vivo validation of the biological activities, we report the identification of 1,2,4-oxadiazole-based eicosanoid biosynthesis multi-target inhibitors. The multidisciplinary scientific approach led to the identification of three 1,2,4-oxadiazole hits (compounds 1, 2 and 5), all endowed with IC values in the low micromolar range, acting as 5-lipoxygenase-activating protein (FLAP) antagonists (compounds 1 and 2), and as a multi-target inhibitor (compound 5) of arachidonic acid cascade enzymes, namely cyclooxygenase-1 (COX-1), 5-lipoxygenase (5-LO) and microsomal prostaglandin E synthase-1 (mPGES-1). Moreover, our in vivo results demonstrate that compound 5 is able to attenuate leukocyte migration in a model of zymosan-induced peritonitis and to modulate the production of IL-1β and TNF-α. These results are of interest for further expanding the chemical diversity around the 1,2,4-oxadiazole central core, enabling the identification of novel anti-inflammatory agents characterized by a favorable pharmacological profile and considering that moderate interference with multiple targets might have advantages in re-adjusting homeostasis.
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http://dx.doi.org/10.1016/j.ejmech.2021.113693DOI Listing
November 2021

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation.

J Med Chem 2021 08 19;64(15):11496-11526. Epub 2021 Jul 19.

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, 07743 Jena, Germany.

Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E synthase-1. Compound is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8365602PMC
August 2021

From Vietnamese plants to a biflavonoid that relieves inflammation by triggering the lipid mediator class switch to resolution.

Acta Pharm Sin B 2021 Jun 20;11(6):1629-1647. Epub 2021 Apr 20.

Michael Popp Institute and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck 6020, Austria.

Chronic inflammation results from excessive pro-inflammatory signaling and the failure to resolve the inflammatory reaction. Lipid mediators orchestrate both the initiation and resolution of inflammation. Switching from pro-inflammatory to pro-resolving lipid mediator biosynthesis is considered as efficient strategy to relieve chronic inflammation, though drug candidates exhibiting such features are unknown. Starting from a library of Vietnamese medical plant extracts, we identified isomers of the biflavanoid 8-methylsocotrin-4'-ol from , which limit inflammation by targeting 5-lipoxygenase and switching the lipid mediator profile from leukotrienes to specialized pro-resolving mediators (SPM). Elucidation of the absolute configurations of 8-methylsocotrin-4'-ol revealed the 2,-isomer being most active, and molecular docking studies suggest that the compound binds to an allosteric site between the 5-lipoxygenase subdomains. We identified additional subordinate targets within lipid mediator biosynthesis, including microsomal prostaglandin E synthase-1. Leukotriene production is efficiently suppressed in activated human neutrophils, macrophages, and blood, while the induction of SPM biosynthesis is restricted to M2 macrophages. The shift from leukotrienes to SPM was also evident in mouse peritonitis and accompanied by a substantial decrease in immune cell infiltration. In summary, we disclose a promising drug candidate that combines potent 5-lipoxygenase inhibition with the favorable reprogramming of lipid mediator profiles.
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http://dx.doi.org/10.1016/j.apsb.2021.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245855PMC
June 2021

Learning from Nature: From a Marine Natural Product to Synthetic Cyclooxygenase-1 Inhibitors by Automated De Novo Design.

Adv Sci (Weinh) 2021 08 27;8(16):e2100832. Epub 2021 Jun 27.

Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, Zurich, 8093, Switzerland.

The repertoire of natural products offers tremendous opportunities for chemical biology and drug discovery. Natural product-inspired synthetic molecules represent an ecologically and economically sustainable alternative to the direct utilization of natural products. De novo design with machine intelligence bridges the gap between the worlds of bioactive natural products and synthetic molecules. On employing the compound Marinopyrrole A from marine Streptomyces as a design template, the algorithm constructs innovative small molecules that can be synthesized in three steps, following the computationally suggested synthesis route. Computational activity prediction reveals cyclooxygenase (COX) as a putative target of both Marinopyrrole A and the de novo designs. The molecular designs are experimentally confirmed as selective COX-1 inhibitors with nanomolar potency. X-ray structure analysis reveals the binding of the most selective compound to COX-1. This molecular design approach provides a blueprint for natural product-inspired hit and lead identification for drug discovery with machine intelligence.
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http://dx.doi.org/10.1002/advs.202100832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373093PMC
August 2021

14,17,18-Trihydroxy-Eicosatetraenoic Acid: A Novel Pro-Resolving Lipid Mediator from Marine Microalgae.

ACS Pharmacol Transl Sci 2021 Jun 27;4(3):1188-1194. Epub 2021 May 27.

Institute for Inorganic and Analytical Chemistry, Department of Instrumental Analytics/Bioorganic Analytics, Friedrich Schiller University Jena, Lessingstraße 8, 07743 Jena, Germany.

Specialized pro-resolving mediators (SPMs) are enzymatically oxygenated derivatives of polyunsaturated fatty acids that function as central immunoregulators in mammals. Among them are resolvins (Rvs) that stimulate the clearance of harmful stimuli and limit pro-inflammatory processes. Because of their beneficial features and their high potency, SPMs are promising molecules for anti-inflammatory therapy. Besides mammals, also marine algae form lipid mediators such as prostaglandins and leukotrienes. In particular, microalgae are attractive candidates for the production of bioactive high-value metabolites. Here, we identified the diatom as a prolific producer of SPMs. The diatom forms RvE3 and novel structurally related eicosanoids, including 14/,17,18-trihydroxy-eicosatetraenoic acid, which displays inflammation-resolving and anti-inflammatory bioactivities. This pro-resolving compound might enable advancements in anti-inflammatory therapy in mammals.
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http://dx.doi.org/10.1021/acsptsci.1c00057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205247PMC
June 2021

ATP/IL-33-triggered hyperactivation of mast cells results in an amplified production of pro-inflammatory cytokines and eicosanoids.

Immunology 2021 11 30;164(3):541-554. Epub 2021 Jun 30.

Institute of Immunology, Jena University Hospital, Jena, Germany.

IL-33 and ATP are alarmins, which are released upon damage of cellular barriers or are actively secreted upon cell stress. Due to high-density expression of the IL-33 receptor T1/ST2 (IL-33R), and the ATP receptor P2X7, mast cells (MCs) are one of the first highly sensitive sentinels recognizing released IL-33 or ATP in damaged peripheral tissues. Whereas IL-33 induces the MyD88-dependent activation of the TAK1-IKK2-NF-κB signalling, ATP induces the Ca -dependent activation of NFAT. Thereby, each signal alone only induces a moderate production of pro-inflammatory cytokines and lipid mediators (LMs). However, MCs, which simultaneously sense (co-sensing) IL-33 and ATP, display an enhanced and prolonged activation of the TAK1-IKK2-NF-κB signalling pathway. This resulted in a massive production of pro-inflammatory cytokines such as IL-2, IL-4, IL-6 and GM-CSF as well as of arachidonic acid-derived cyclooxygenase (COX)-mediated pro-inflammatory prostaglandins (PGs) and thromboxanes (TXs), hallmarks of strong MC activation. Collectively, these data show that co-sensing of ATP and IL-33 results in hyperactivation of MCs, which resembles to MC activation induced by IgE-mediated crosslinking of the FcεRI. Therefore, the IL-33/IL-33R and/or the ATP/P2X7 signalling axis are attractive targets for therapeutical intervention of diseases associated with the loss of integrity of cellular barriers such as allergic and infectious respiratory reactions.
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http://dx.doi.org/10.1111/imm.13386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517600PMC
November 2021

Beneficial Modulation of Lipid Mediator Biosynthesis in Innate Immune Cells by Antirheumatic Glycosides.

Biomolecules 2021 05 17;11(5). Epub 2021 May 17.

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, 07743 Jena, Germany.

glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation and immune responses and are strongly linked to RA. The mechanism by which TWG affects LM networks in RA treatment remains elusive. Employing LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed striking modulation of LM pathways by TWG in human monocyte-derived macrophage (MDM) phenotypes. In inflammatory M1-MDM, TWG (30 µg/mL) potently suppressed agonist-induced formation of 5-LOX products which was confirmed in human PMNL and traced back to direct inhibition of 5-LOX (IC = 2.9 µg/mL). TWG also efficiently blocked thromboxane formation in M1-MDM without inhibiting other prostanoids and COX enzymes. Importantly, in anti-inflammatory M2-MDM, TWG (30 µg/mL) induced pronounced formation of specialized pro-resolving mediators (SPM) and related 12/15-LOX-derived SPM precursors, without COX and 5-LOX activation. During MDM polarization, TWG (1 µg/mL) decreased the capacity to generate pro-inflammatory 5-LOX and COX products, cytokines and markers for M1 phenotypes. Together, suppression of pro-inflammatory LM but SPM induction may contribute to the antirheumatic properties of TWG.
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http://dx.doi.org/10.3390/biom11050746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155965PMC
May 2021

Identification of 2-(thiophen-2-yl)acetic Acid-Based Lead Compound for mPGES-1 Inhibition.

Front Chem 2021 7;9:676631. Epub 2021 May 7.

Dipartimento di Farmacia, University degli Studi di Salerno, Fisciano, Italy.

We report the implementation of our /synthesis pipeline by targeting the glutathione-dependent enzyme mPGES-1, a valuable macromolecular target in both cancer therapy and inflammation therapy. Specifically, by using a virtual fragment screening approach of aromatic bromides, straightforwardly modifiable by the Suzuki-Miyaura reaction, we identified 3-phenylpropanoic acid and 2-(thiophen-2-yl)acetic acid to be suitable chemical platforms to develop tighter mPGES-1 inhibitors. Among these, compounds and showed selective inhibitory activity against mPGES-1 in the low micromolar range in accordance with molecular modeling calculations. Moreover, and exhibited interesting IC values on A549 cell lines compared to CAY10526, selected as reference compound. The most promising compound induced the cycle arrest in the G/G phase at 24 h of exposure, whereas at 48 and 72 h, it caused an increase of subG/G fraction, suggesting an apoptosis/necrosis effect.
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http://dx.doi.org/10.3389/fchem.2021.676631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144515PMC
May 2021

Endogenous vitamin E metabolites mediate allosteric PPARγ activation with unprecedented co-regulatory interactions.

Cell Chem Biol 2021 10 13;28(10):1489-1500.e8. Epub 2021 May 13.

Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt 60438, Germany. Electronic address:

Vitamin E exhibits pharmacological effects beyond established antioxidant activity suggesting involvement of unidentified mechanisms. Here, we characterize endogenously formed tocopherol carboxylates and the vitamin E mimetic garcinoic acid (GA) as activators of the peroxisome proliferator-activated receptor gamma (PPARγ). Co-stimulation of PPARγ with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARγ-GA complex adopted a fully active conformation and interestingly contained two bound GA molecules with one at an allosteric site. A co-regulator interaction scan demonstrated an unanticipated co-factor recruitment profile for GA-bound PPARγ compared with canonical PPARγ agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARγ modulation as an alternative avenue to PPARγ targeting and suggest contributions of PPARγ activation by α-13-tocopherolcarboxylate to the pharmacological effects of vitamin E.
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http://dx.doi.org/10.1016/j.chembiol.2021.04.019DOI Listing
October 2021

Aging drives organ-specific alterations of the inflammatory microenvironment guided by immunomodulatory mediators in mice.

FASEB J 2021 05;35(5):e21558

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Jena, Germany.

Aging is accompanied by chronic, low-grade systemic inflammation, termed inflammaging, a main driver of age-associated diseases. Such sterile inflammation is typically characterized by elevated levels of pro-inflammatory mediators, such as cytokines, chemokines and reactive oxygen species causing organ damage. Lipid mediators play important roles in the fine-tuning of both the promotion and the resolution of inflammation. Yet, it remains unclear how lipid mediators fit within the concept of inflammaging and how their biosynthesis and function is affected by aging. Here, we provide comprehensive signature profiles of inflammatory markers in organs afflicted with inflammation of young and old C57BL/6 mice. We reveal an organ-specific footprint of inflammation-related cytokines, chemokines and lipid mediators, which are distinctively affected by aging. While some organs are characterized by a pronounced pro-inflammatory microenvironment and impaired resolution during aging, others display elevated levels of pro-resolving mediators or an overall decrease in inflammatory signaling. Our results demonstrate that it proves difficult to establish a unifying concept for alterations of immunomodulatory mediators as consequence of aging and that organ specificity needs to be considered. Moreover, our data imply that inclusion of lipid mediators into the concept of inflammaging provides a comprehensive tool to characterize the inflammatory microenvironment during aging on a broader and yet, more detailed scope.
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http://dx.doi.org/10.1096/fj.202002684RDOI Listing
May 2021

Simple heteroaryl modifications in the 4,5-diarylisoxazol-3-carboxylic acid scaffold favorably modulates the activity as dual mPGES-1/5-LO inhibitors with in vivo efficacy.

Bioorg Chem 2021 07 24;112:104861. Epub 2021 Mar 24.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Yenimahalle, 06560 Ankara, Turkey. Electronic address:

Microsomal prostaglandin E synthase-1 (mPGES-1), 5-lipoxygenase (5-LO) and 5- lipoxygenase-activating protein (FLAP) are key for biosynthesis of proinflammatory lipid mediators and pharmacologically relevant drug targets. In the present study, we made an attempt to explore the role of small heteroaromatic fragments on the 4,5-diarylisoxazol-3-carboxylic acid scaffold, which are selected to interact with focused regions in the active sites of mPGES-1, 5-LO and FLAP. We report that the simple structural variations on the benzyloxyaryl side-arm of the scaffold significantly influence the selectivity against mPGES-1, 5-LO and FLAP, enabling to produce multi-target inhibitors of these protein targets, exemplified by compound 18 (IC mPGES-1 = 0.16 µM; IC 5-LO = 0.39 µM) with in vivo efficacy in animal model of inflammation. The computationally modeled binding structures of these new inhibitors for three targets provide clues for rational design of modified structures as multi-target inhibitors. In conclusion, the simple synthetic procedure, and the possibility of enhancing the potency of this class of inhibitors through structural modifications pave the way for further development of new multi-target inhibitors against mPGES-1, 5-LO and FLAP, with potential application as anti-inflammatory agents.
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http://dx.doi.org/10.1016/j.bioorg.2021.104861DOI Listing
July 2021

Biocompatible valproic acid-coupled nanoparticles attenuate lipopolysaccharide-induced inflammation.

Int J Pharm 2021 May 1;601:120567. Epub 2021 Apr 1.

Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University of Jena, Hans-Knöll-Straße 2, 07745 Jena, Germany. Electronic address:

Inflammatory diseases like sepsis are associated with dysregulated gene expression, often caused by an imbalance of epigenetic regulators, such as histone acetyltransferases (HATs) and histone deacetylases (HDACs), and consequently, altered epigenetic chromatin signatures or aberrant posttranslational modifications of signalling proteins and transcription factors. Thus, HDAC inhibitors (HDACi) are a promising class of anti-inflammatory drugs. Recently, an efficient drug delivery system carrying the class I/IIa selective HDACi valproic acid (VPA) was developed to circumvent common disadvantages of free drug administration, e.g. short half-life and side effects. The cellulose-based sulphated VPA-coupled (CV-S) nanoparticles (NPs) are rapidly taken up by cells, do not cause any toxic effects and are fully biocompatible. Importantly, VPA is intracellularly cleaved from the NPs and HDACi activity could be proven. Here, we demonstrate that CV-S NPs exhibit overall anti-inflammatory effects in primary human macrophages and are able to attenuate the lipopolysaccharide-induced inflammatory response. CV-S NPs show superior potential to free VPA to suppress the TLR-MyD88-NF-κB signalling axis, leading to decreased TNF-α expression and secretion.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120567DOI Listing
May 2021

Anti-inflammatory celastrol promotes a switch from leukotriene biosynthesis to formation of specialized pro-resolving lipid mediators.

Pharmacol Res 2021 05 31;167:105556. Epub 2021 Mar 31.

Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University, Philosophenweg 14, D-07743 Jena, Germany. Electronic address:

The pentacyclic triterpenoid quinone methide celastrol (CS) from Tripterygium wilfordii Hook. F. effectively ameliorates inflammation with potential as therapeutics for inflammatory diseases. However, the molecular mechanisms underlying the anti-inflammatory and inflammation-resolving features of CS are incompletely understood. Here we demonstrate that CS potently inhibits the activity of human 5-lipoxygenase (5-LOX), the key enzyme in pro-inflammatory leukotriene (LT) formation, in cell-free assays with IC = 0.19-0.49 µM. Employing metabololipidomics using ultra-performance liquid chromatography coupled to tandem mass spectrometry in activated human polymorphonuclear leukocytes or M1 macrophages we found that CS (1 µM) potently suppresses 5-LOX-derived products without impairing the formation of lipid mediators (LM) formed by 12-/15-LOXs as well as fatty acid substrate release. Intriguingly, CS induced the generation of 12-/15-LOX-derived LM including the specialized pro-resolving mediator (SPM) resolvin D5 in human M2 macrophages. Finally, intraperitoneal pre-treatment of mice with 10 mg/kg CS strongly impaired zymosan-induced LT formation and simultaneously elevated the levels of SPM and related 12-/15-LOX-derived LM in peritoneal exudates, spleen and plasma in vivo. Conclusively, CS promotes a switch from LT biosynthesis to formation of SPM which may underlie the anti-inflammatory and inflammation-resolving effects of CS, representing an interesting pharmacological strategy for intervention with inflammatory disorders.
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http://dx.doi.org/10.1016/j.phrs.2021.105556DOI Listing
May 2021

Discovery of N-amido-phenylsulfonamide derivatives as novel microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors.

Bioorg Med Chem Lett 2021 06 26;41:127992. Epub 2021 Mar 26.

Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Our previous research showed that N-carboxy-phenylsulfonyl hydrazide (scaffold A) could reduce LPS-stimulated PGE levels in RAW 264.7 macrophage cells by an inhibition of mPGES-1 enzyme. However, a number of scaffold A derivatives showed the drawbacks such as the formation of regioisomers and poor liver metabolic stability. In order to overcome these synthetic and metabolic problems, therefore, we decided to replace N-carboxy-phenylsulfonyl hydrazide (scaffold A) with N-carboxy-phenylsulfonamide (scaffold B) or N-amido-phenylsulfonamide frameworks (scaffold C) as a bioisosteric replacement. Among them, MPO-0186 (scaffold C) inhibited the production of PGE (IC: 0.24 μM) in A549 cells via inhibition of mPGES-1 (IC: 0.49 μM in a cell-free assay) and was found to be approximately 9- and 8-fold more potent than MK-886 as a reference inhibitor, respectively. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE production by blocking the PGH binding site of mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good liver metabolic stability and no significant inhibition observed in clinically relevant CYP isoforms except CYP2C19. This result provides a potential starting point for the development of selective and potent mPGES-1 inhibitor with a novel scaffold.
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http://dx.doi.org/10.1016/j.bmcl.2021.127992DOI Listing
June 2021

Sustainable preparation of anti-inflammatory atorvastatin PLGA nanoparticles.

Int J Pharm 2021 Apr 26;599:120404. Epub 2021 Feb 26.

Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy, Friedrich Schiller University Jena, Lessingstraße 8, 07743 Jena, Germany; Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743 Jena, Germany; Pharmaceutical Technology, Department for Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg, Cauerstrasse 4, 91058 Erlangen, Germany. Electronic address:

In the present study, the anti-inflammatory lipophilic drug atorvastatin was encapsulated in poly(D,L-lactide-co-glycolide) (PLGA) using a sustainable method in comparison to the standard emulsion-diffusion-evaporation technique. For the sustainable method the organic solvent ethyl acetate was fully replaced by 400 g/mol poly(ethylene glycol) (PEG 400). Both techniques led to the formation of nanoparticles with comparable sizes of about 170 to 247 nm depending on the polymer type, with monomodal size distribution and negative zeta potential. All nanoparticles demonstrated a high biocompatibility in a shell-less hen's egg model and displayed an anti-inflammatory effect in human monocytes. The use of PEG 400 resulted in plasticizing effects and a lower crystallinity of the PLGA nanoparticles as determined by differential scanning calorimetry and Raman spectroscopy, which correlated with a faster drug release. Interestingly, the particles prepared by the sustainable method showed a crystallinity and drug release kinetics similar to nanoparticles made of PEG-PLGA using the standard method. Conclusively, the sustainable method is a fast and easy to perform technique suitable to prepare atorvastatin-loaded PLGA nanoparticles avoiding toxic and environmentally damaging drawbacks frequently associated with classical organic solvents.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120404DOI Listing
April 2021

SARS-CoV-2 causes severe epithelial inflammation and barrier dysfunction.

J Virol 2021 Feb 26. Epub 2021 Feb 26.

Section of Experimental Virology, Institute of Medical Microbiology, Jena University Hospital, Hans-Knoell-Str. 2, D-07745, Jena, Germany

Infections with SARS-CoV-2 can be asymptomatic, but they can also be accompanied by a variety of symptoms that result in mild to severe coronavirus disease-19 (COVID-19) and are sometimes associated with systemic symptoms. Although the viral infection originates in the respiratory system, it is unclear how the virus can overcome the alveolar barrier, which is observed in severe COVID-19 disease courses. To elucidate the viral effects on the barrier integrity and immune reactions, we used mono-cell culture systems and a complex human chip model composed of epithelial, endothelial, and mononuclear cells. Our data show that SARS-CoV-2 efficiently infected epithelial cells with high viral loads and inflammatory response, including interferon expression. By contrast, the adjacent endothelial layer was neither infected nor did it show productive virus replication or interferon release. With prolonged infection, both cell types were damaged, and the barrier function was deteriorated, allowing the viral particles to overbear. In our study, we demonstrate that although SARS-CoV-2 is dependent on the epithelium for efficient replication, the neighboring endothelial cells are affected, e.g., by the epithelial cytokines or components induced during infection, which further results in the damage of the epithelial/endothelial barrier function and viral dissemination.SARS-CoV-2 challenges healthcare systems and societies worldwide in unprecedented ways. Although numerous new studies have been conducted, research to better understand the molecular pathogen-host interactions are urgently needed. For this, experimental models have to be developed and adapted. In the present study we used mono cell-culture systems and we established a complex chip model, where epithelial and endothelial cells are cultured in close proximity. We demonstrate that epithelial cells can be infected with SARS-CoV-2, while the endothelium did not show any infection signs. Since SARS-CoV-2 is able to establish viremia, the link to thromboembolic events in severe COVID-19 courses is evident. However, whether the endothelial layer is damaged by the viral pathogens or whether other endothelial-independent homeostatic factors are induced by the virus is essential for understanding the disease development. Therefore, our study is important as it demonstrates that the endothelial layer could not be infected by SARS-CoV-2 in our experiments, but we were able to show the destruction of the epithelial-endothelial barrier in our chip model. From our experiments we can assume that virus-induced host factors disturbed the epithelial-endothelial barrier function and thereby promote viral spread.
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http://dx.doi.org/10.1128/JVI.00110-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139673PMC
February 2021

Modified Bacterial Cellulose Dressings to Treat Inflammatory Wounds.

Nanomaterials (Basel) 2020 Dec 14;10(12). Epub 2020 Dec 14.

Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy, Friedrich Schiller University, Lessingstraße 8, 07743 Jena, Germany.

Natural products suited for prophylaxis and therapy of inflammatory diseases have gained increasing importance. These compounds could be beneficially integrated into bacterial cellulose (BC), which is a natural hydropolymer applicable as a wound dressing and drug delivery system alike. This study presents experimental outcomes for a natural anti-inflammatory product concept of boswellic acids from frankincense formulated in BC. Using esterification respectively (resp.) oxidation and subsequent coupling with phenylalanine and tryptophan, -modification of BC was tested to facilitate lipophilic active pharmaceutical ingredient (API) incorporation. Diclofenac sodium and indomethacin were used as anti-inflammatory model drugs before the findings were transferred to boswellic acids. By acetylation of BC fibers, the loading efficiency for the more lipophilic API indomethacin and the release was increased by up to 65.6% and 25%, respectively, while no significant differences in loading could be found for the API diclofenac sodium. -modifications could be made while preserving biocompatibility, essential wound dressing properties and anti-inflammatory efficacy. Eventually, in vitro wound closure experiments and evaluations of the effect of secondary dressings completed the study.
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http://dx.doi.org/10.3390/nano10122508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764978PMC
December 2020
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