Diaryl pyrroles: A new series of anti-inflammatory agents

Zusammenfassung Die antiinflammatorischen Eigenschaften von verschiedenen Diaryl-pyrrol-Derivaten wurden untersucht. Es wurde festgestellt, dass eine repräsentative Verbindung, 2-Methyl-4, 5-bis(p-metoxyphenyl)-pyrrol, eine ausgeprägte Hemmung gegen das akute Ödem und die chronische Arthritis der Ratte zeigt.

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We thank Messrs.K. Wachi, Y. Umemuro andT. Kojima for their technical assistance.     

DiC14-amidine confers new anti-inflammatory properties to phospholipids

The inflammatory effect of unmethylated CpG DNA sequences represents a major obstacle to the use of cationic lipids for in vivo gene therapy. Although the mechanism of CpG-induced inflammatory response is rather well understood nowadays, few solutions have been designed to circumvent this effect in gene therapy experiments. Our previous work has shown that a refractory state towards inflammation can be elicited by preinjecting cationic liposomes. Here, we present evidence that diC14-amidine liposomes confer new anti-inflammatory properties to phospholipids from low-density lipoprotein (LDL) and even to synthetic phospholipids for which such an observation has not been reported so far. Whereas oxidation of LDL lipids was a prerequisite for any anti-inflammatory activity, lipid oxidation is no longer required in our experiments, suggesting that cationic lipids transport phospholipids through a different route and affect different pathways.This opens up new possibilities for manipulating inflammatory responses in gene therapy protocols but also in a general manner in immunological experiments. Received 12 November 2007; received after revision 4 December 2007; accepted 4 December 2007     

Novel macrophage polarization model: from gene expression to identification of new anti-inflammatory molecules

Plasticity is a well-known property of macrophages that is controlled by different changes in environmental signals. Macrophage polarization is regarded as a spectrum of activation phenotypes adjusted from one activation extreme, the classic (M1), to the other, the alternative (M2) activation. Here we show, in vitro and in vivo, that both M1 and M2 macrophage phenotypes are tightly coupled to specific patterns of gene expression. Novel M2-associated markers were characterized and identified as genes controlling the extracellular metabolism of ATP to generate pyrophosphates (PPi). Stimulation of M1 macrophages with PPi dampens both NLR and TLR signaling and thus mediates cytokine production. In this context extracellular PPi enhanced the resolution phase of a murine peritonitis model via a decrease in pro-inflammatory cytokine production. Therefore, our study reveals an additional level of plasticity modulating the resolution of inflammation.     

Glycine seed germination: Differential response to abscisic acid

Zusammenfassung In Keimen von Glycinensamen wurden unterschiedliche Reaktionen der Kulturvarianten (Cultivaren) zur Abscisinsäure (ABA) beobachtet. Die Unterschiede in Keimem können nicht der unterschiedlichen Wasser-oder ABA-Absorption zugeschrieben werden.     

Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin

Background

Persistent inflammation exacerbates the progression of Duchenne muscular dystrophy (DMD). The hormone, adiponectin (ApN), which is decreased in the metabolic syndrome, exhibits anti-inflammatory properties on skeletal muscle and alleviates the dystrophic phenotype of mdx mice. Here, we investigate whether ApN retains its anti-inflammatory action in myotubes obtained from DMD patients. We unravel the underlying mechanisms by studying the secretome and the early events of ApN.

Methods

Primary cultures of myotubes from DMD and control patients were treated or not by ApN after an inflammatory challenge. Myokines secreted in medium were identified by cytokine antibody-arrays and ELISAs. The early events of ApN signaling were assessed by abrogating selected genes.

Results

ApN retained its anti-inflammatory properties in both dystrophic and control myotubes. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNFα and IL-17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms. Earlier events of the ApN cascade involved AdipoR1, the main receptor for muscle, and the AMPK-SIRT1-PGC-1α axis leading, besides alteration of the myokine profile, to the upregulation of utrophin A (a dystrophin analog).

Conclusion

ApN retains its beneficial properties in dystrophic muscles by activating the AdipoR1-AMPK-SIRT1-PGC-1α pathway, thereby inducing a shift in the secretion of downstream myokines toward a less inflammatory profile while upregulating utrophin. ApN, the early events of the cascade and downstream myokines may be therapeutic targets for the management of DMD.

     

Vidalols A and B,new anti-inflammatory bromophenols from the Caribbean marine red algaVidalia obtusaloba

Chemical studies of the Caribbean red algaVidalia obtusaloba have resulted in the isolation of two new bromophenolic metabolites, vidalols A and B (1, 2). The new compounds were discovered as part of an organized effort to isolate new naturally-occurring anti-inflammatory agents with a focus upon those which may function through the inhibition of phospholipase A₂.     

Self-induced decoherence: a new approach

According to Zurek, decoherence is a process resulting from the interaction between a quantum system and its environment; this process singles out a preferred set of states, usually called “pointer basis”, that determines which observables will receive definite values. This means that decoherence leads to a sort of selection which precludes all except a small subset of the states in the Hilbert space of the system from behaving in a classical manner: environment-induced-superselection—einselection—is a consequence of the process of decoherence. The aim of this paper is to present a new approach to decoherence, different from the mainstream approach of Zurek and his collaborators. We will argue that this approach offers conceptual advantages over the traditional one when problems of foundations are considered; in particular, from the new perspective, decoherence in closed quantum systems becomes possible and the preferred basis acquires a well founded definition.     

Sodium [o-[(2,6-dichlorophenyl)-amino]-phenyl]-acetate (gp 45 840), a new non-steroidal anti-inflammatory agent

Zusammenfassung gp 45 840, das Natriumsalz der [o-[(2,6-Dichlorphenyl)-amino]-phenyl]-essigsäure, besitzt pharmakodynamisch in verschiedenen Testsystemen am Tier eine ausgeprägte anti-inflammatorische, antinociceptive und antipyretische Aktivität. Das Präparat zeigt eine höhere Wirksamkeit als Phenylbutazon und ist ebenso aktiv wie Indomethacin; es übertrifft in seiner akuten therapeutischen Breite die beiden Vergleichspräparate.

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Preliminary results have been reported at the 5th International Congress on Pharmacology 1972.     

Glycine,strychnine and retinal inhibition

Résumé L'injection intravitréenne de glycine (3 mg) chez le lapin entraîne l'abolition des potentiels oscillatoires de l'ERG moyenné photopique, phénomène réversible en 20–24 h. La glycine exerce un effet inhibiteur, qui est annulé par la strychnine en faible dose.     

Glycine methoxyamide,acyclic analog of cycloserine

Zusammenfassung Methoxy-glycinamid, ein offenkettiges Isomeres von Cycloserin, wurde hergestellt. Seine physikalischen Eigenschaften sind von denjenigen des Cycloserins stark verschieden. Es besitzt keine antibiotische Eigenschaft mehr.     

Luffolide,a novel anti-inflammatory terpene from the spongeLuffariella sp.

Summary Luffolide (4) is a minor metabolite of the spongeLuffariella sp. from Palau. The structure of luffolide was determined by single crystal X-ray analysis. Luffolide is relatively unstable and undergoes a complex cyclization reaction to give the hexacyclic products5 and6. Luffolide (4) has some of the anti-inflammatory properties of manoalide (1): this may help to define the chemical reaction between manoalide (1) and phospholipase A₂.All crystallographic calculations were done on a PRIME 9950 computer operated by the Cornell Chemistry Computing Facility. Principal programs employed were: FOBS, a data reduction program by G.D. Van Duyne, Cornell University, 1987; MULTAN 80, and RANTAN 80, systems of computer programs for the automatic solution of crystal structures from X-ray diffraction data (locally modified to perform all Fourier calculations including Patterson syntheses) written by P. Main, S. E. Hull, L. Lessinger, G. Germain, J. P. Declercq and M. M. Woolfson, University of York, England, 1980 BDLS, an, anisotropic block diagonal least squares refinement written by K. Hirotsu, E. Arnold, and G. D. Van Duyne, Cornell University, 1987; PLUTO 78, a locally modified crystallographic illustration program by W. D. S. Motherwell, Cambridge Crystallographic Data Centre, 1978; and BOND, a program to calculate molecular parameters and prepare tables written by K. Hirotsu and G. Van Duyne, Cornell University, 1985.Acknowledgment. We thank the Government of the Republic of Palau for a scientific research permit. We thank Dr Klaus Rützler, Smithsonian Institution, Washington, D.C. for identifying the sponge and Mary Kay Harper for performing additional bioassays. This research was supported by grants from the Sea Grant College Programs of California [Projects R/MP-30 to DJF) and R/MP-31 (to RSJ)] and New York (to JC) and the National Institutes of Health (CA 24487 to JC).     

Cyanovirin-N: a sugar-binding antiviral protein with a new twist

Cyanovirin-N (CV-N), an 11-kDa protein from the cyanobacterium Nostoc ellipsosporum, is a highly potent virucidal agent that has generated interest as a lead natural product for the prevention and chemotherapy of human immunodeficiency virus infection. The antiviral activity of CV-N is mediated through specific, high-affinity interactions with the viral surface envelope glycoproteins. A number of structures of wild-type, mutant and sequence-shuffled CV-N have been solved by nuclear magnetic resonance and crystallography, showing that the protein exists as either a quasi-symmetric two-domain monomer or a domain-swapped dimer. Structures of several complexes of CV-N with oligosaccharides help in explaining the unique mode of high-affinity binding of these molecules to both forms of CV-N. RID="*" ID="*"Corresponding author.     

Lentinacin: a new hypocholesterolemic substance inLentinus edodes

Zusammenfassung Aus dem Speisepilz «Shiitake» (Lentinus edodes) wurde ein neues Adeninderivat isoliert und Lentinacin genannt. Seine chemische Struktur wurde mit 2(R), 3(R)-Dihydroxy-4-(9-adenyl)-buttersäure durch die vollständige Synthese identifiziert. Lentinacin senkt den Cholesterinspiegel bei Ratten.