Inflammatory arthritis disrupts gut resolution mechanisms, promoting barrier breakdown by Porphyromonas gingivalis.

Rheumatoid arthritis is linked with altered host immune responses and severe joint destruction. Recent evidence suggests that loss of gut homeostasis and barrier breach by pathobionts, including Porphyromonas gingivalis, may influence disease severity. The mechanism(s) leading to altered gut homeostasis and barrier breakdown in inflammatory arthritis are poorly understood. In the present study, we found a significant reduction in intestinal concentrations of several proresolving mediators during inflammatory arthritis, including downregulation of the gut-protective mediator resolvin D5n-3 DPA (RvD5n-3 DPA). This was linked with increased metabolism of RvD5n-3 DPA to its inactive 17-oxo metabolite. We also found downregulation of IL-10 expression in the gut of arthritic mice that was coupled with a reduction in IL-10 and IL-10 receptor (IL-10R) in lamina propria macrophages. These changes were linked with a decrease in the number of mucus-producing goblet cells and tight junction molecule expression in the intestinal epithelium of arthritic mice when compared with naive mice. P. gingivalis inoculation further downregulated intestinal RvD5n-3 DPA and Il-10 levels and the expression of gut tight junction proteins. RvD5n-3 DPA, but not its metabolite 17-oxo-RvD5n-3 DPA, increased the expression of both IL-10 and IL-10R in macrophages via the upregulation of the aryl hydrocarbon receptor agonist l-kynurenine. Administration of RvD5n-3 DPA to arthritic P. gingivalis-inoculated mice increased intestinal Il-10 expression, restored gut barrier function, and reduced joint inflammation. Together, these findings uncover mechanisms in the pathogenesis of rheumatoid arthritis, where disruption of the gut RvD5n-3 DPA-IL-10 axis weakens the gut barrier, which becomes permissive to the pathogenic actions of the pathobiont P. gingivalis.

Ocular pharmacokinetics of moxifloxacin after topical treatment of animals and humans.

The ocular penetration and pharmacokinetics of moxifloxacin in comparison to other fluoroquinolones (ofloxacin, ciprofloxacin, gatifloxacin, norfloxacin, levofloxacin, and lomefloxacin) have been determined by in vitro and ex vivo techniques, as well as in animal and human studies. This article reviews the original pharmacokinetics work performed by Alcon and other studies reported in the ocular fluoroquinolone literature. The results consistently demonstrate higher maximum concentrations for moxifloxacin relative to the other fluoroquinolones in ocular tissues with levels well above its minimum inhibitory concentrations for relevant ocular pathogens. This superior performance is due to the unique structure of moxifloxacin that combines high lipophilicity for enhanced corneal penetration with high aqueous solubility at physiological pH. The latter property creates a high concentration gradient at the tear film/corneal epithelial interface providing a driving force for better ocular penetration for moxifloxacin. In addition, the higher concentration of moxifloxacin in VIGAMOX (i.e., 0.5% vs. 0.3%) allows more antibiotic to be available to ocular tissues. It is clear from the array of studies summarized in this report that moxifloxacin penetrates ocular tissues better (two- to three-fold) than gatifloxacin, ciprofloxacin, ofloxacin, or levofloxacin. This consistent, enhanced penetration of topical moxifloxacin offers powerful advantages for ophthalmic therapy.

New Metallacarborane Chemistry: Molybdenum and Tungsten Carbonyl Multidecker Sandwiches. Cluster Dimers Linked via Metal-Metal Bonds(1).

This article reports the synthesis, characterization, and chemistry of the first molybdenum and tungsten complexes bearing small carborane ligands, including novel M-M-linked dicluster species. The reaction of the nido-2,3-Et(2)C(2)B(4)H(4)(2)(-) dianion with (RCN)(3)M(CO)(3) reagents (M = Mo, W; R = Me, Et) gave the (Et(2)C(2)B(4)H(4))M(CO)(3)(2)(-) anions, which were isolated as lithium (12-crown-4) salts 1b (M = Mo) and 2b (M = W). Treatment of 1b and 2b with Ph(4)PX (X = Cl, Br, I) followed by triflic acid afforded the dimeric products [(Et(2)C(2)B(4)H(4))Mo(CO)(2)](2)(&mgr;-X)(2) (X = Cl (3a), Br (3b), I (3c)) and the corresponding tungsten dimers 4a-c, all of which are red or orange air-stable crystalline solids. X-ray crystallography on 3b revealed a geometry without precedent in small metallacarborane dimers, in which two MC(2)B(4) pentagonal pyramidal clusters are linked via an intercluster metal-metal bond. From NMR and other spectroscopic evidence, the remaining dimeric products 3a, 3c, and 4a-c are proposed to have structures similar to 3b. Decapitation of 3b with HCl/EtOAc in THF gave red solid [(Et(2)C(2)B(3)H(5))Mo(CO)(2)](2)(&mgr;-Br)(2) (5), which is proposed to have two open planar C(2)B(3) end rings and, hence, is a potential building block for linear polymers via deprotonation and metal-ion-stacking reactions. Compound 3b was also generated in a different reaction, involving the nido-Et(2)C(2)B(4)H(5)(-) anion and [Mo(CO)(4)Br](2)[&mgr;-Br](2) which also produced the bis(carboranyl)molybdenum complex (Et(2)C(2)B(4)H(4))(2)Mo(CO)(2) (6), a nearly colorless solid for which a bent sandwich structure is postulated. The reaction of the nido-cobaltacarborane anion CpCo(Et(2)C(2)B(3)H(4))(-) with [Mo(CO)(4)Cl](2)[&mgr;-Cl](2) in toluene gave two isolable products, red CpCo(Et(2)C(2)B(3)H(3))Mo(CO)(4) (7) and dark red [CpCo(Et(2)C(2)B(3)H(3))](2)Mo(CO)(2) (8), which have, respectively, triple-decker and bent-tetradecker sandwich structures based on X-ray crystallographic structure determinations. The reaction of CpCo(Et(2)C(2)B(3)H(4))(-) with [Mo(CO)(4)Br](2)[&mgr;-Br](2) in toluene gave 8 and a known fused-cluster complex Cp(2)Co(2)(Et(4)C(4)B(6)H(6)) (9). Treatment of the CpCo(Et(2)C(2)B(3)H(4))(-) anion with [W(CO)(4)Br](2)[&mgr;-Br](2) afforded red crystalline CpCo(Et(2)C(2)B(3)H(3))W(CO)(4) (10), which on reaction with PhLi followed by Me(3)OBF(4) gave 11, a B(5)-benzyl derivative of 10. X-ray diffraction analyses established triple-decker sandwich structures for both compounds. The new products were characterized by multinuclear NMR, IR, UV-vis, and mass spectroscopy, and elemental analysis, supplemented by electrochemical data on 3b, 8, and 11.