Individual resolvin E family members work distinctly and in a coordinated manner in the resolution of inflammation.

Three main E-type resolvins (RvEs): RvE1, RvE2, and RvE3, have roles in the resolution of inflammation as anti-inflammatory activities. To investigate the roles of each RvE in the resolution of inflammation, timing of interleukin (IL)- 10 release and IL-10 receptor expressions, and phagocytosis evoked by each RvE in differentiated human monocytes, macrophage-like U937 cells were examined. Here, we show that RvEs enhance the expression of IL-10, and IL-10 receptor-mediated signaling pathways and IL-10-mediated-signaling-independent resolution of inflammatory effects by activating the phagocytotic function. Thus, RvE2 mainly evoked an IL-10-mediated anti-inflammatory function, whereas RvE3 principally activated phagocytotic activity of macrophages, which may be involved in tissue repair. On the other hand, RvE1 showed both functions, although not prominent but rather acting as a relief mediator that takes over the RvE2 function and passes over to the RvE3 function. Therefore, each RvE may act as an important role/stage-specific mediator in a coordinated manner with other RvEs in the processes of the resolution of inflammation.

Intranasal Administration of Resolvin E1 Produces Antidepressant-Like Effects via BDNF/VEGF-mTORC1 Signaling in the Medial Prefrontal Cortex.

Intracerebroventricular infusion of resolvin E1 (RvE1), a bioactive metabolite derived from eicosapentaenoic acid, exerts antidepressant-like effects in a mouse model of lipopolysaccharide (LPS)-induced depression; these effects are blocked by systemic injection of rapamycin, a mechanistic target of rapamycin complex 1 (mTORC1) inhibitor. Additionally, local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) produces antidepressant-like effects. To evaluate the potential of RvE1 for clinical use, the present study examined whether treatment with RvE1 via intranasal (i.n.) route, a non-invasive route for effective drug delivery to the brain, produces antidepressant-like effects in LPS-challenged mice using tail suspension and forced swim tests. Intranasal administration of RvE1 significantly attenuated LPS-induced immobility, and these antidepressant-like effects were completely blocked by an AMPA receptor antagonist or L-type voltage-dependent Ca2+ channel blocker. The antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 were blocked by intra-mPFC infusion of a neutralizing antibody (nAb) for brain-derived neurotrophic factor (BDNF) or vascular endothelial growth factor (VEGF). Intra-mPFC infusion of rapamycin completely blocked the antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 as well as those of intra-mPFC infusion of BDNF and VEGF. Moreover, i.n. RvE1 produced antidepressant-like effects via mTORC1 activation in the mPFC of a mouse model of repeated prednisolone-induced depression. Intra-dorsal DG infusion of BDNF and VEGF nAbs, but not rapamycin, blocked the antidepressant-like effects of i.n. RvE1. These findings suggest that i.n. administration of RvE1 produces antidepressant-like effects through activity-dependent BDNF/VEGF release in the mPFC and dorsal DG, and mTORC1 activation in the mPFC, but not in the dorsal DG. Thus, RvE1 can be a promising candidate for a novel rapid-acting antidepressant.

Design and Synthesis of Cyclopropane Congeners of Resolvin E3, an Endogenous Pro-Resolving Lipid Mediator, as Its Stable Equivalents.

Resolvins are pro-resolving lipid mediators with highly potent anti-inflammatory effects. Because of their polyunsaturated structures, however, they are unstable to oxygen as a drug prototype. To address this issue, we designed and synthesized CP-RvE3 as oxidatively stable congeners of RvE3 by replacing the cis-olefin with a cis-cyclopropane to avoid the unstable bisallylic structure. Although the oxidative stabilities of CP-RvE3 were not improved, ß-CP-RvE3 was 3.7 times more metabolically stable than RvE3. Thus, we identified ß-CP-RvE3 as a metabolically stable equivalent.

Resolvin E3 ameliorates high-fat diet-induced insulin resistance via the phosphatidylinositol-3-kinase/Akt signaling pathway in adipocytes.

Obesity-associated type 2 diabetes mellitus is associated with the development of insulin resistance. Among several metabolites, resolvins that are metabolites of eicosapentaenoic acid have been shown to exert insulin-sensitizing effects; however, the role of resolvin E3 (RvE3) in glucose metabolism has not been studied. In this study, the effect of RvE3 on glucose metabolism in mice with high-fat diet-induced obesity and 3T3L1 adipocytes was studied. C57BL/6 mice fed a high-fat diet were administered RvE3, for which insulin tolerance, oral glucose tolerance tests, and the homeostasis model assessment of insulin resistance, were performed. RvE3 treatment significantly improved insulin sensitivity and glucose tolerance and regulated protein kinase B (Akt) phosphorylation in the adipose tissue. Moreover, RvE3 treatment enhanced the insulin-stimulated glucose transporter 4 (Glut4) translocation, glucose uptake, phosphatidylinositol-3-kinase (PI3K) activity, and Akt phosphorylation in 3T3L1 adipocytes, whereas a PI3K inhibitor inhibited the enhanced insulin-stimulated glucose uptake induced by RvE3. These findings indicate that RvE3 likely improves insulin sensitivity, resulting in the upregulation of glucose uptake in adipocytes by activating the PI3K/Akt signaling pathways. Collectively, the findings of this study show that RvE3 may play a role in glucose homeostasis and could be used as a potential therapeutic target for developing treatments for obesity-associated diabetes.

A Stereoselective Synthesis of Fused Carbocycles with a cis-1,2-Diol Moiety by Desymmetrization: SmI2-Mediated Pinacol Coupling of meso-Cyclic 1,3-Diones.

Samarium diiodide (SmI2)-mediated desymmetrization of a meso-cyclic 1,3-dione pinacol coupling is described. The reaction proceeds with high stereoselectivity to provide fused carbocyclic compounds with three contiguous stereogenic centers featuring an all-carbon quaternary center and a cis-1,2-diol moiety.

The antidepressant-like effect of resolvin E1 in repeated prednisolone-induced depression model mice.

Resolvin E1 (RvE1) is an anti-inflammatory lipid mediator derived from eicosapentaenoic acid. We previously demonstrated that intracerebroventricular (i.c.v.) and intra-medial prefrontal cortex (mPFC) infusions of RvE1 produce antidepressant-like effects in a lipopolysaccharide-induced depression mouse model. To further confirm the antidepressant-like effect of RvE1, the present study examined whether RvE1 ameliorated depression-like behavior induced by repeated injections of prednisolone (PSL), a synthetic glucocorticoid, in male ICR mice. We first ascertained whether repeated subcutaneous treatment with PSL (50 mg/kg, once a day) affected locomotor activity and anxiety-like behavior in the open field test (OFT; after a 5-day PSL treatment) and induced depression-like behavior in the tail suspension test (TST; after a 6-day PSL treatment) and forced swim test (FST; after a 7-day PSL treatment). Repeated PSL injections significantly increased immobility in the FST, which was not ameliorated by acute desipramine treatment (30 mg/kg, i.p.), but not in the TST, without affecting locomotor activity and anxiety-like behavior in the OFT. Subsequently, we investigated the therapeutic effects of i.c.v. (1 ng) and intra-mPFC (50 pg/side) infusions of RvE1 in the repeated PSL-induced depression mouse model using the OFT and FST after 5- and 6-day PSL treatments, respectively. The repeated PSL-induced increase in immobility in the FST was significantly attenuated by both i.c.v. and intra-mPFC infusions of RvE1 without affecting the locomotor activity and anxiety-like behavior. In addition, a single i.c.v. infusion of RvE1 immediately before the first or fourth injection of PSL also attenuated PSL-induced depression-like behavior in the FST, suggesting the preventive effect of RvE1. These results indicate that RvE1 produces antidepressant-like effects in a mouse model of repeated PSL-induced depression.

Resolvin E1 Attenuates Chronic Pain-Induced Depression-Like Behavior in Mice: Possible Involvement of Chemerin Receptor ChemR23.

The antidepressant effect of eicosapentaenoic acid-derived bioactive lipid, resolvin E1 (RvE1), was examined in a murine model of chronic pain-induced depression using a tail suspension test. Because RvE1 reportedly possesses agonistic activity on a chemerin receptor ChemR23, we also examined the antidepressant effect of chemerin. Two weeks after surgery for unilateral spared nerve injury to prepare neuropathic pain model mice, immobility time was measured in a tail suspension test. Chronic pain significantly increased immobility time, and this depression-like behavior was attenuated by intracerebroventricular injection of RvE1 (1 ng) or chemerin (500 ng). These results demonstrate that RvE1 exerts an antidepressant effect in a murine model of chronic pain-induced depression, which is likely to be via ChemR23. RvE1 and its receptor may be promising targets to develop novel antidepressants.

Total Synthesis of Thuggacin cmc-A and Its Structure Determination.

The first total synthesis of thuggacin cmc-A and the determination of the absolute structure are described. The thuggacin family of antibiotics is of great interest due to the antibiotic activity against Mycobacterium tuberculosis. Based on the assumption that seven stereogenic centers in thuggacin cmc-A would share the same stereochemistry as thuggacin-A, all stereogenic centers of thuggacin cmc-A were strictly constructed in a stereocontrolled manner. The total synthesis allowed its stereostructure to be fully confirmed.

Synthesis of Resolvin E1 and Its Conformationally Restricted Cyclopropane Congeners with Potent Anti-Inflammatory Effect.

RvE1 (1) is an endogenous lipid mediator with very potent anti-inflammatory activity, which is due to the inhibition of neutrophil chemotaxis and inflammatory cytokine production and the promotion of macrophage phagocytosis. On the basis of the conformational analysis of RvE1, we designed its four cyclopropane congeners (2a-d), in which the conformationally flexible terminal C1-C4 moiety of RvE1 was rigidified by introducing stereoisomeric cyclopropanes. The four congeners and also RvE1 were efficiently synthesized via a common synthetic route. The evaluation of the anti-inflammatory effects of the compounds in mice resulted in the identification of trans-ß-CP-RvE1 (2d), which was significantly more active than RvE1, as a potential lead for anti-inflammatory drugs of a novel mechanism of action.

Synthesis of Resolvin E3, a Proresolving Lipid Mediator, and Its Deoxy Derivatives: Identification of 18-Deoxy-resolvin E3 as a Potent Anti-Inflammatory Agent.

We synthesized RvE3 and its deoxy derivatives, 17-deoxy-RvE3 and 18-deoxy-RvE3, by a common route via Sonogashira coupling as a key step. The evaluation of their anti-inflammatory activities revealed that 18-deoxy-RvE3 was remarkably more potent than the parent RvE3 and significantly active at a 300 fg dose in mice; additionally, 17-deoxy-RvE3 was significantly less potent than the parent RvE3. For the first time, we found that the 17-hydroxy group of RvE3 is very important for anti-inflammatory activity.

Formal Synthesis of (-)-Haliclonin A: Stereoselective Construction of an Azabicyclo[3.3.1]nonane Ring System by a Tandem Radical Reaction.

A formal synthesis of (-)-haliclonin A, isolated from the marine sponge Haliclona sp. in Korea, is described. The key feature of the synthesis includes the highly stereoselective tandem radical reaction to construct the azabicyclo[3.3.1]nonane core and the enantioselective formation of an all-carbon quaternary center via the Pd-mediated deracemization.

Catalytic Asymmetric Total Synthesis of Exiguolide.

The catalytic asymmetric total synthesis of (-)-exiguolide, a complex 20-membered macrolide embedded with a bis(tetrahydropyran) motif, is reported. The convergent synthesis involves the construction of the C1-C11 tetrahydropyran segment via catalytic asymmetric allylation and Prins cyclization, and the formation of the C12-C21 phosphonate segment via catalytic asymmetric cyclocondensation reaction and Johnson-Claisen rearrangement. The synthesis of 15-epi-exiguolide is also described.

Design and Synthesis of Benzene Congeners of Resolvin E2, a Proresolving Lipid Mediator, as Its Stable Equivalents.

Resolvins (Rvs) are highly potent anti-inflammatory lipid mediators that are chemically and biologically unstable because of their polyunsaturated structures. To address this issue, we designed benzene congeners of RvE2, i.e., o-, m-, and p-BZ-RvE2s, as stable equivalents of RvE2 by replacing the unstable skipped diene moiety with a benzene ring on the basis of computational conformation studies and synthesized these congeners via a short common route through two Stille couplings. o-BZ-RvE2 exhibited more potent anti-inflammatory activity and much higher metabolic stability than RvE2. Thus, o-BZ-RvE2 was identified as a stable equivalent of RvE2, which is useful as a lead for anti-inflammatory drugs with a new mechanism of action as well as a biotool for investigating RvE2-mediated inflammation resolving pathways.

New entry to the enantioselective formation of substituted cyclohexenes bearing an all-carbon quaternary stereogenic center.

Enantioselective formation of cyclohexene derivatives bearing an all-carbon quaternary stereogenic center is described. The racemic cyclohexenes are readily transformed to chiral substituted cyclohexenes in good yield with excellent enantioselectivity and diastereoselectivity by a palladium-mediated deracemization. The resulting products are promising synthetic intermediates of biologically active natural products. This protocol provides us with a new entry to the concise and scalable synthesis of multifunctionalized compounds.

Resolvin E3 attenuates allergic airway inflammation via the interleukin-23-interleukin-17A pathway.

We investigated the effects of resolvin E (RvE) 1, RvE2, and RvE3 on IL-4- and IL-33-stimulated bone marrow-derived dendritic cells (BMDCs) from house dust mite (HDM)-sensitized mice. We also investigated the role of RvE3 in a murine model of HDM-induced airway inflammation. In vitro, BMDCs from HDM-sensitized mice were stimulated with IL-4 and IL-33 and then treated with RvE1, RvE2, RvE3, or vehicle. RvE1, RvE2, and RvE3 suppressed IL-23 release from BMDCs. In vivo, RvE3 administrated to HDM-sensitized and challenged mice in the resolution phase promoted a decline in total numbers of inflammatory cells and eosinophils, reduced levels of IL-23 and IL-17 in lavage fluid, and suppressed IL-23 and IL-17A mRNA expression in lung and peribronchial lymph nodes. RvE3 also reduced resistance in the lungs of HDM-sensitized mice. A NanoBiT ß-arrestin recruitment assay using human embryonic kidney 293 cells revealed that pretreatment with RvE3 suppressed the leukotriene B4 (LTB4)-induced ß-arrestin 2 binding to LTB4 receptor 1 (BLT1R), indicating that RvE3 antagonistically interacts with BLT1R. Collectively, these findings indicate that RvE3 facilitates the resolution of allergic airway inflammation, partly by regulating BLT1R activity and selective cytokine release by dendritic cells. Our results accordingly identify RvE3 as a potential therapeutic target for the management of asthma.-Sato, M., Aoki-Saito, H., Fukuda, H., Ikeda, H., Koga, Y., Yatomi, M., Tsurumaki, H., Maeno, T., Saito, T., Nakakura, T., Mori, T., Yanagawa, M., Abe, M., Sako, Y., Dobashi, K., Ishizuka, T., Yamada, M., Shuto, S., Hisada, T. Resolvin E3 attenuates allergic airway inflammation via the interleukin-23-interleukin-17A pathway.

STAT3 Activation Correlates with Adventitial Neutrophil Infiltration in Human Aortic Dissection.

Objective: Aortic dissection (AD) is a fatal disease that is caused by the rapid destruction of the aortic wall. Although recent studies in animal models indicate an important relationship between inflammation and tissue destruction, activation status of inflammatory signaling and its relation to the inflammatory cell infiltration are poorly characterized in human AD. Materials and Methods: We examined the activation of inflammatory signaling molecules NFκB and STAT3, and neutrophil infiltration in AD tissue samples that were obtained during the surgical repair within 24 h after AD onset. Results: Activation of NFκB was observed mainly in the intima both in AD samples and in aortic samples without AD. Activation of STAT3 was observed in AD samples, but not in the aortic sample without AD. Neutrophil infiltration was observed predominantly in the adventitial layer of AD samples. Histological analysis revealed that STAT3 was activated in cells other than neutrophils. Notably, STAT3 activation and neutrophil infiltration showed positive correlation in adventitial layer of AD tissue. Conclusion: These findings demonstrated that adventitial STAT3 activation was associated with neutrophil infiltration, suggesting their importance in AD pathogenesis.

Synthesis of oxytocin derivatives lipidated via a carbonate or carbamate linkage as a long-acting therapeutic agent for social impairment-like behaviors.

In the course of our studies of hydrophobic oxytocin (OT) analogues, we newly synthesized lipidated OT (LOT-4a-c and LOT-5a-c), in which a long alkyl chain (C14-C16) is conjugated via a carbonate or carbamate linkage at the Tyr-2 phenolic hydroxy group and a palmitoyl group at the terminal amino group of Cys-1. These LOTs did not activate OT and vasopressin receptors. Among the LOTs, however, LOT-4c, having a C16-chain via a carbonate linkage at the phenolic hydroxyl group of the Tyr-2, showed very long-lasting action for the recovery of impaired social behavior in CD38 knockout mice, a rodent model of autistic phenotypes, whereas the effect of OT itself rapidly diminished. These results indicate that LOT-4c may serve as a potential prodrug in mice.

Synthesis of 1,1,2-trisubstituted cyclopropane nucleosides in enantiomerically pure forms.

Due to the unique rigid and small steric feature of cyclopropane, cyclopropane nucleosides (CPNs) in which the ribose (deoxyribose) of nucleosides are replaced by a hydroxy-substituted cyclopropane, are of great biological interest. Novel 1,1,2-trisubstituted cyclopropane nucleosides were synthesized in enantiomerically pure forms as potential antiviral agents. In the synthesis, two cyclopropane tosylates, which were prepared from chiral cyclopropane lactones previously reported by us, were used effectively as common intermediates for the CPNs. These CPNs are also potentially useful as nucleoside units to incorporate into oligonucleotides in nucleic acids chemotherapy studies.

Synthesis of Enantiomerically Pure 1,2,3-Trisubstituted Cyclopropane Nucleosides Using Pd-Catalyzed Substitution via Directing Group-Mediated C(sp3)-H Activation as a Key Step.

A series of enantiomerically pure 1,2,3-trisubstituted cyclopropane nucleosides Ia-Id and IIa-IId of medicinal chemical interest was designed and synthesized. In the synthesis, a Pd-catalyzed substitution reaction via a directing group-mediated C(sp3)-H activation was effectively used to construct the 1,2,3-trisubstituted cyclopropane structure as a key step.