Search

Scope The long-chain metabolites of (LCM) vitamin E are proposed as the active regulatory metabolites of vitamin E providing, with their anti-inflammatory properties, an explanatory approach for the inconsistent effects of vitamin E on inflammatory-driven diseases. We examined the modulation of cytokine expression and release from macrophages, a fundamental process in many diseases, to gain insights into the anti-inflammatory mechanisms of the α-tocopherol-derived LCM α-13′-COOH. Methods and results Suppressed gene expression of C–C motif chemokine ligand 2 (Ccl2), tumor necrosis factor (Tnf), and interleukin (Il) 6 in response to lipopolysaccharides by 24 h pre-treatment with α-13′-COOH in RAW264.7 macrophages was revealed using quantitative reverse transcription PCR. Further, reduced secretion of IL1β and CCL2 was found in this setup using flow cytometry. In contrast, 1 h pre-treatment suppressed only CCL2. Consequent gene expression analysis within 24 h of α-13′-COOH treatment revealed the induction of mitogen-activated protein kinases (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) negative feedback regulators including the ‘master regulators’ dual-specificity phosphatase 1 (Dusp1/Mkp1) and tumor necrosis factor induced protein 3 (Tnfaip3/A20). Approaches with immunoblots and chemical antagonists suggest a feedback induction via activation of extracellular-signal regulated kinase (ERK), p38 MAPK and NFκB pathways. Conclusions CCL2 is suppressed in murine macrophages by α-13′-COOH and the indirect suppression of MAPK and NFκB pathways is likely a relevant process contributing to anti-inflammatory actions of α-13′-COOH. These results improve the understanding of the effects of α-13′-COOH and provide a basis for new research strategies in the context of inflammatory diseases.

Specialized pro-resolving mediators (SPM), primarily produced in innate immune cells, exert crucial bioactions for resolving inflammation. Among various lipoxygenases (LOX), 15-LOX-1 is key for SPM biosynthesis, but cellular activation principles of 15-LOX-1 are unexplored. It was shown that 3-O-acetyl-11-keto-β-boswellic acid (AKBA) shifts 5-LOX regiospecificity from 5- to 12-lipoxygenation products. Here, it is demonstrated that AKBA additionally activates cellular 15-LOX-1 via an allosteric site accomplishing robust SPM formation in innate immune cells, particularly in M2 macrophages. Compared to ionophore, AKBA-induced LOX activation is Ca

The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH).

5-Lipoxygenase (LO) catalyzes the first steps in the formation of pro-inflammatory leukotrienes (LT) that are pivotal lipid mediators contributing to allergic reactions and inflammatory disorders. Based on its key role in LT biosynthesis, 5-LO is an attractive drug target, demanding for effective and selective inhibitors with efficacy in vivo, which however, are still rare. Encouraged by the recent identification of the catechol 4-(3,4-dihydroxyphenyl)dibenzofuran 1 as 5-LO inhibitor, simple structural modifications were made to yield even more effective and selective catechol derivatives. Within this new series, the two most potent compounds 3,4-dihydroxy-3'-phenoxybiphenyl (6b) and 2-(3,4-dihydroxyphenyl)benzo[b]thiophene (6d) potently inhibited human 5-LO in cell-free (IC

Excitons dominate the light absorption and re-emission spectra of monolayer transition-metal dichalcogenides (TMD). Microscopic investigations of the excitonic response in TMD almost invariably extract information from the radiative recombination step, which only constitutes one part of the picture. Here, by exploiting imaging spectroscopic ellipsometry (ISE), we investigate the spatial dependence of the dielectric function of chemical vapor deposition (CVD)-grown WS2 flakes with a microscopic lateral resolution, thus providing information about the spatially varying, exciton-induced light absorption in the monolayer WS2. Comparing the ISE results with imaging photoluminescence spectroscopy data, the presence of several correlated features was observed, along with the unexpected existence of a few uncorrelated characteristics. The latter demonstrates that the exciton-induced absorption and emission features are not always proportional at the microscopic scale. Microstructural modulations across the flakes, having a different influence on the absorption and re-emission of light, are deemed responsible for the effect.

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 Dracaena cambodiana, 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 2S,γS-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 E2 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 in vivo 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., Graphical abstract From a library of Vietnamese plant extracts, we identified the 2S,γS-isomer of 8-methylsocotrin-4′-ol (compound 2) as a promising anti-inflammatory drug candidate. The biflavonoid induces a lipid mediator class switch from pro-inflammatory leukotrienes to specialized pro-resolving lipid mediators and relieves inflammation in vitro and in vivo.Image 1

Two-dimensional semiconductors are gaining increasing interest for their potential application in several fields. In particular, when combined with graphene into vertical van der Waals heterostructures, they have demonstrated unique properties, such as large spin-orbit coupling at the valence band maximum and ultrafast charge transfer. An understanding of the WS2 stability on epitaxial graphene in ambient conditions is crucial for the development of potential applications. In this work, we study the environmental aging related degradation of WS2 monolayers directly synthesized on top of epitaxial graphene. We experimentally demonstrate that the oxidation of the WS2 monolayers on epitaxial graphene starts from the flake edges, being attributed to a local high concentration of defects. The oxidation leads to the complete deterioration of the semiconducting material in less than 120 days. In addition, we demonstrate that the oxidation mechanism is accelerated on epitaxial graphene in comparison to that on insulating sapphire substrate. First-principles theoretical analysis reveals that the oxidation mechanism is strongly promoted by the presence of sulfur vacancies and is further accelerated by transfer of electron density from the substrate, whereas it is slowed down by depletion of electron density from the support. Our exhaustive approach sheds light on the oxidative process promoted by defects and not self-limited to the oxidation of the monolayer edges.

Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO), two key enzymes involved in pro-inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4-thiazolidinedione-based mPGES-1/5-LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent-based chemical route for the decoration of the 2,4-thiazolidinedione core, a large library of virtual compounds was built (∼2.0×104 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid- and low- micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4-thiazolidinedione central core, facilitating the identification of novel anti-inflammatory agents endowed with a promising and safer pharmacological profile.

Hexagonal boron nitride (hBN), sometimes referred to as white graphene, receives growing interest in the scientific community, especially when combined into van der Waals (vdW) homo- and heterostacks, in which novel and interesting phenomena may arise. hBN is also commonly used in combination with two-dimensional (2D) semiconducting transition metal dichalcogenides (TMDCs). The realization of hBN-encapsulated TMDC homo- and heterostacks can indeed offer opportunities to investigate and compare TMDC excitonic properties in various stacking configurations. In this work, we investigate the optical response at the micrometric scale of mono- and homo-bilayer WS2 grown by chemical vapor deposition and encapsulated between two single layers of hBN. Imaging spectroscopic ellipsometry is exploited to extract the local dielectric functions across one single WS2 flake and detect the evolution of excitonic spectral features from monolayer to bilayer regions. Exciton energies undergo a redshift by passing from hBN-encapsulated single layer to homo-bilayer WS2, as also confirmed by photoluminescence spectra. Our results can provide a reference for the study of the dielectric properties of more complex systems where hBN is combined with other 2D vdW materials into heterostructures and are stimulating towards the investigation of the optical response of other technologically-relevant heterostacks.

Staphylococcus aureus causes severe infections associated with inflammation, such as sepsis or osteomyelitis. Inflammatory processes are regulated by distinct lipid mediators (LMs) but how their biosynthetic pathways are orchestrated in S. aureus infections is elusive. We show that S. aureus strikingly not only modulates pro-inflammatory, but also inflammation-resolving LM pathways in murine osteomyelitis and osteoclasts as well as in human monocyte-derived macrophages (MDMs) with different phenotype. Targeted LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed massive generation of LM with distinct LM signature profiles in acute and chronic phases of S. aureus-induced murine osteomyelitis in vivo. In human MDM, S. aureus elevated cyclooxygenase-2 (COX-2) and microsomal prostaglandin E

We demonstrate a graphene-MoS2 architecture integrating multiple field-effect transistors (FETs), and we independently probe and correlate the conducting properties of van der Waals coupled graphene-MoS2 contacts with those of the MoS2 channels. Devices are fabricated starting from high-quality single-crystal monolayers grown by chemical vapor deposition. The heterojunction was investigated by scanning Raman and photoluminescence spectroscopies. Moreover, transconductance curves of MoS2 are compared with the current-voltage characteristics of graphene contact stripes, revealing a significant suppression of transport on the n-side of the transconductance curve. On the basis of ab initio modeling, the effect is understood in terms of trapping by sulfur vacancies, which counterintuitively depends on the field effect, even though the graphene contact layer is positioned between the backgate and the MoS2 channel.

The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC50s of 0.41 ± 0.01 and 0.43 ± 0.10 μM for 5-LOX and sEH, respectively). When challenged in vivo in zymosan-induced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents.

We demonstrate a graphene–MoS2 architecture integrating multiple field-effect transistors (FETs), and we independently probe and correlate the conducting properties of van der Waals coupled graphene–MoS2 contacts with those of the MoS2 channels. Devices are fabricated starting from high-quality single-crystal monolayers grown by chemical vapor deposition. The heterojunction was investigated by scanning Raman and photoluminescence spectroscopies. Moreover, transconductance curves of MoS2 are compared with the current–voltage characteristics of graphene contact stripes, revealing a significant suppression of transport on the n-side of the transconductance curve. On the basis of ab initio modeling, the effect is understood in terms of trapping by sulfur vacancies, which counterintuitively depends on the field effect, even though the graphene contact layer is positioned between the backgate and the MoS2 channel.

In tumors, cancer cells coexist and communicate with macrophages that can promote tumorigenesis via pro-inflammatory signals. Lipid mediators (LMs), produced mainly by cyclooxygenases (COXs) or lipoxygenases (LOs), display a variety of biological functions with advantageous or deleterious consequences for tumors. Here, we investigated how the communication between human monocyte-derived M2-like macrophages (MDM) and cancer cells affects LM biosynthesis using LM metabololipidomics. Coculture of human MDM with human A549 epithelial lung carcinoma cells, separated by a semipermeable membrane, increased LM formation by MDM upon subsequent activation. Strongest effects were observed on 5-LO-derived LM. While expression of the 5-LO pathway was not altered, p38 MAPK and the downstream MAPKAPK-2 that phosphorylates and stimulates 5-LO were more susceptible for activation in MDM upon precedent coculture with A549 cells as compared to monocultures. Accordingly, the p38 MAPK inhibitor Skepinone-L selectively prevented this increase in 5-LO product formation. Also, 5-LO-/15-LO-derived LM including lipoxin A4, resolvin D2 and D5 were elevated after coculture with A549 cells, correlating to increased 15-LO-1 protein levels. In contrast to cancer cells, coincubation with non-transformed human umbilical vein endothelial cells (HUVEC) did not affect LM production in MDM. Vice versa, MDM increased COX-2 protein expression and COX-mediated prostanoid formation in cancer cells. Conclusively, our data reveal that the communication between MDM and cancer cells can strikingly modulate the biosynthetic capacities to produce bioactive LM with potential relevance for tumor biology.

Precursor-directed biosynthesis was used to introduce selected aryl carboxylic acids into the pseudochelin pathway, which had recently been assembled in Myxococcus xanthus. Overall, 14 previously undescribed analogues of the natural products myxochelin B and pseudochelin A were generated and structurally characterized. A subset of 10 derivatives together with their parental molecules were evaluated for their activity toward human 5-lipoxygenase. This testing revealed pseudochelin A as the most potent 5-lipoxygenase inhibitor among the naturally occurring compounds, whereas myxochelin A is the least active. Replacement of the catechol moieties in myxochelin B and pseudochelin A affected the bioactivity to different degrees.

Nonsteroidal anti-inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5-lipoxygenase (LOX), or the 5-LOX–activating protein (FLAP). These and related enzymes act in conjunction with marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to Escherichia coli, produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography–tandem mass spectrometry–based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on-target actions, we found that: 1) COX or 15-LOX-1 inhibitors elevate inflammatory leukotriene levels, 2) FLAP and 5-LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, 3) zileuton blocks resolution-initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and 4) that the 15-LOX-1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation-resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.—Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.-E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome.

Tripterygium wilfordii 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 (IC50 = 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.

Excitons dominate the light absorption and re-emission spectra of monolayer transition-metal dichalcogenides (TMD). Microscopic investigations of the excitonic response in TMD almost invariably extract information from the radiative recombination step, which only constitutes one part of the picture. Here, by exploiting imaging spectroscopic ellipsometry (ISE), we investigate the spatial dependence of the dielectric function of chemical vapor deposition (CVD)-grown WS2 flakes with a microscopic lateral resolution, thus providing information about the spatially varying, exciton-induced light absorption in the monolayer WS2. Comparing the ISE results with imaging photoluminescence spectroscopy data, the presence of several correlated features was observed, along with the unexpected existence of a few uncorrelated characteristics. The latter demonstrates that the exciton-induced absorption and emission features are not always proportional at the microscopic scale. Microstructural modulations across the flakes, having a different influence on the absorption and re-emission of light, are deemed responsible for the effect.

Out of the different structural phases of molybdenum ditelluride (MoTe2), the distorted octahedral 1T′ possesses great interest for fundamental physics and is a promising candidate for the implementation of innovative devices such as topological transistors. Indeed, 1T′-MoTe2 is a semimetal with superconductivity, which has been predicted to be a Weyl semimetal and a quantum spin Hall insulator in bulk and monolayer form, respectively. Large instability of monolayer 1T′-MoTe2 in environmental conditions, however, has made its investigation extremely challenging so far. In this work, we demonstrate homogeneous growth of large single-crystal (up to 500 μm) monolayer 1T′-MoTe2via chemical vapor deposition (CVD) and its stabilization in air with a scalable encapsulation approach. The encapsulant is obtained by electrochemically delaminating CVD hexagonal boron nitride (hBN) from copper foil, and it is applied on the freshly grown 1T′-MoTe2via a top-down dry lamination step. The structural and electrical properties of encapsulated 1T′-MoTe2 have been monitored over several months to assess the degree of degradation of the material. We find that when encapsulated with hBN, the lifetime of monolayer 1T′-MoTe2 successfully increases from a few minutes to more than a month. Furthermore, the encapsulated monolayer can be subjected to transfer, device processing, and heating and cooling cycles without degradation of its properties. The potential of this scalable heterostack is confirmed by the observation of signatures of low-temperature phase transition in monolayer 1T′-MoTe2 by both Raman spectroscopy and electrical measurements. The growth and encapsulation methods reported in this work can be employed for further fundamental studies of this enticing material as well as facilitate the technological development of monolayer 1T′-MoTe2.

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 IC50 = 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.

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 (27a), 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 E2 synthase-1. Compound 27a 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 27a 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 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead.

Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13′-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8–49 nM) that inhibit 5-lipoxygenase in human leukocytes. α-T-13′-COOH accumulates in immune cells and inflamed murine exudates, selectively inhibits the biosynthesis of 5-lipoxygenase-derived lipid mediators in vitro and in vivo, and efficiently suppresses inflammation and bronchial hyper-reactivity in mouse models of peritonitis and asthma. Together, our data suggest that the immune regulatory and anti-inflammatory functions of α-tocopherol depend on its endogenous metabolite α-T-13′-COOH, potentially through inhibiting 5-lipoxygenase in immune cells.

Leukotrienes (LTs) and prostaglandin (PG)E2, produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous studies revealed that the benzenesulfonamide scaffold displays efficient 5-LO-inhibitory properties. Here, we structurally optimized benzenesulfonamides which led to an N-phenylbenzenesulfonamide derivative (compound 47) with potent inhibitory activities (IC50 = 2.3 and 0.4 μM for isolated 5-LO and 5-LO in intact cells, respectively). Compound 47 prevented the interaction of 5-LO with its activating protein (FLAP) at the nuclear envelope in transfected HEK293 cells as shown by in situ proximity ligation assay. Comprehensive assessment of the LM profile produced by human macrophages revealed the ability of 47 to selectively down-regulate pro-inflammatory LMs (i.e. LTs and PGE2) in M1 but to enhance the formation of pro-resolving LMs (i.e. resolvins and maresins) in M2 macrophages. Moreover, 47 strongly inhibited LT formation and cell infiltration in two in vivo models of acute inflammation (i.e., peritonitis and air pouch sterile inflammation in mice). Together, 47 represents a novel LT biosynthesis inhibitor with an attractive pharmacological profile as anti-inflammatory drug that also promotes the biosynthesis of pro-resolving LM.

The potential of fish or fish oil as supplier for eicosapentaenoic acid (EPA, C20:5n3) and docosahexaenoic acid (DHA, C22:6n3) for reducing cardiovascular risk factors and supporting therapy of chronic inflammatory diseases, has been investigated intensively, but our knowledge about the physiological effects of the individual compounds EPA and DHA are limited.In this double-blind pilot study, thirty-eight patients with defined RA were allocated to consume foods enriched with microalgae oil from Schizochytrium sp. (2.1 g DHA/d) or sunflower oil (placebo) for 10 weeks (cross-over), maintaining the regular RA medication during the study.In contrast to placebo, the daily consumption of DHA led to a decline in the sum of tender and swollen joints (68/66) from 13.9 ± 7.4 to 9.9 ± 7.0 (p = 0.010), total DAS28 from 4.3 ± 1.0 to 3.9 ± 1.2 (p = 0.072), and ultrasound score (US-7) from 15.1 ± 9.5 to 12.4 ± 7.0 (p = 0.160). The consumption of placebo products caused an increase of the n-6 PUFA linoleic acid and arachidonic acid (AA) in erythrocyte lipids (EL, p 0.05). The amount of DHA was doubled in EL of DHA-supplemented patients and the ratios of AA/EPA and AA/DHA dropped significantly. We speculate that the production of pro-inflammatory/non-resolving AA-derived eicosanoids might decrease in relation to anti-inflammatory/pro-resolving DHA- and EPA-derived lipid mediators. In fact, plasma concentrations of AA-derived thromboxane BThe study shows for the first time that supplemented microalgae DHA ameliorates disease activity in patients with RA along with a shift in the balance of AA- and DHA-derived lipid mediators towards an anti-inflammatory/pro-resolving state.

The artificial stacking of atomically thin crystals suffers from intrinsic limitations in terms of control and reproducibility of the relative orientation of exfoliated flakes. This drawback is particularly severe when the properties of the system critically depend on the twist angle, as in the case of the dodecagonal quasicrystal formed by two graphene layers rotated by 30$^\circ$. Here we show that large-area 30$^\circ$-rotated bilayer graphene can be grown deterministically by chemical vapor deposition on Cu, eliminating the need of artificial assembly. The quasicrystals are easily transferred to arbitrary substrates and integrated in high-quality hBN-encapsulated heterostructures, which we process into dual-gated devices exhibiting carrier mobility up to $10^5$ cm$^2$/Vs. From low-temperature magnetotransport, we find that the graphene quasicrystals effectively behave as uncoupled graphene layers, showing 8-fold degenerate quantum Hall states: this result indicates that the Dirac cones replica detected by previous photo-emission experiments do not contribute to the electrical transport., Comment: This is the unedited authors' version of the submitted article, published in its final form on Nano Letters 2020 https://doi.org/10.1021/acs.nanolett.0c00172 , 21 pages, 3 figures and supporting information

Paper is the ideal substrate for the development of flexible and environmentally sustainable ubiquitous electronic systems, which, combined with two-dimensional materials, could be exploited in many Internet-of-Things applications, ranging from wearable electronics to smart packaging. Here we report high-performance MoS2 field-effect transistors on paper fabricated with a “channel array” approach, combining the advantages of two large-area techniques: chemical vapor deposition and inkjet-printing. The first allows the pre-deposition of a pattern of MoS2; the second, the printing of dielectric layers, contacts, and connections to complete transistors and circuits fabrication. Average ION/IOFF of 8 × 103 (up to 5 × 104) and mobility of 5.5 cm2 V−1 s−1 (up to 26 cm2 V−1 s−1) are obtained. Fully functional integrated circuits of digital and analog building blocks, such as logic gates and current mirrors, are demonstrated, highlighting the potential of this approach for ubiquitous electronics on paper., Paper is a promising substrate for flexible and environmentally sustainable electronic devices. Here, the authors combine chemical vapor deposition of MoS2 with inkjet printing of a hexagonal boron nitride (hBN) dielectric and silver electrodes, to fabricate flexible MoS2 field-effect transistors on paper, and then combine the latter with printed graphene resistors and silver interconnects to create inverters, logic gates and current mirrors.

Producing and manipulating graphene on fab-compatible scale, while maintaining its remarkable carrier mobility, is key to finalize its technological application. We show that a large-scale approach (chemical vapor deposition on Cu followed by polymer-mediated semi-dry transfer) yields single-layer graphene crystals fully comparable, in terms of electronic transport, to micro-mechanically exfoliated flakes. hBN is used to encapsulate the graphene crystals $-$ without taking part to their detachment from the growth catalyst $-$ and study their intrinsic properties in field-effect devices. At room temperature, the electron-phonon coupling sets the mobility to $\sim1.3 \times10^5$ cm$^2$V$^{-1}$s$^{-1}$ at $\sim10^{11}$ cm$^{-2}$ concentration. At cryogenic temperatures, the mobility ($ > 6\times10^5$ cm$^2$V$^{-1}$s$^{-1}$ at $\sim10^{11}$ cm$^{-2}$) is limited by the devices' physical edges, and charge fluctuations $ < 7\times10^9$ cm$^{-2}$ are detected. Under perpendicular magnetic fields, we observe early onset of Landau quantization ($B\sim50$ mT) and signatures of electronic correlation, including the fractional quantum Hall effect., This is the unedited authors' version of the submitted article; 24 pages, 4 figures and supplementary information

SUMMARY The small intestine is responsible for nutrient absorption and one of the most important interfaces between the environment and the body. During aging, changes of the epithelium lead to food malabsorption and reduced barrier function, thus increasing disease risk. The drivers of these alterations remain poorly understood. Here, we compare the proteomes of intestinal crypts from mice across different anatomical regions and ages. We find that aging alters epithelial immunity, metabolism, and cell proliferation and is accompanied by region-dependent skewing in the cellular composition of the epithelium. Of note, short-term dietary restriction followed by refeeding partially restores the epithelium by promoting stem cell differentiation toward the secretory lineage. We identify Hmgcs2 (3-hydroxy-3-methylglutaryl-coenzyme A [CoA] synthetase 2), the rate-limiting enzyme for ketogenesis, as a modulator of stem cell differentiation that responds to dietary changes, and we provide an atlas of region- and age-dependent proteome changes of the small intestine., In Brief Using proteomics, Gebert et al. find that aging has region-specific effects on the small intestine epithelium of mice. These effects can be partially reversed by modulating ketone body signaling in intestinal stem cells via dietary interventions., Graphical Abstract

Androgen levels inversely correlate with the incidence, susceptibility and severity of asthma. However, whether male sex hormones such as 5α-dihydrotestosterone (DHT) have beneficial effects on asthma symptoms and/or could affect asthma susceptibility have not been investigated. DHT administration to female mice, during the sensitization phase, abrogates the sex bias in bronchial hyperreactivity. This effect correlates with inhibition of leukotriene biosynthesis in the lung. DHT significantly inhibits also other asthma-like features such as airway hyperplasia and mucus production in sensitized female mice. Conversely, DHT does not affect plasma IgE levels as well as CD3+CD4+ IL-4+ cell and IgE+c-Kit+ cell infiltration within the lung but prevents pulmonary mast cell activation. The in vitro study on RBL‐2H3 cells confirms that DHT inhibits mast cell degranulation. In conclusion, our data demonstrate that immunomodulatory effects of DHT on mast cell activation prevent the translation of allergen sensitization into clinical manifestation of asthma. © 2020 Androgen levels inversely correlate with the incidence, susceptibility and severity of asthma. However, whether male sex hormones such as 5α-dihydrotestosterone (DHT) have beneficial effects on asthma symptoms and/or could affect asthma susceptibility have not been investigated. DHT administration to female mice, during the sensitization phase, abrogates the sex bias in bronchial hyperreactivity. This effect correlates with inhibition of leukotriene biosynthesis in the lung. DHT significantly inhibits also other asthma-like features such as airway hyperplasia and mucus production in sensitized female mice. Conversely, DHT does not affect plasma IgE levels as well as CD3+CD4+ IL-4+ cell and IgE+c-Kit+ cell infiltration within the lung but prevents pulmonary mast cell activation. The in vitro study on RBL‐2H3 cells confirms that DHT inhibits mast cell degranulation. In conclusion, our data demonstrate that immunomodulatory effects of DHT on mast cell activation prevent the translation of allergen sensitization into clinical manifestation of asthma.

Monocytes are professional immune cells that produce abundant levels of pro-inflammatory eicosanoids including prostaglandins and leukotrienes during inflammation. Vacuolar (H

International audience

International audience