No abstract

Disulfide-bridged binuclear ruthenium complexes, [{RuCl(P(OMe) 3 ) 2 } 2 (µ-Cl) 2 (µ-S 2 )] ( 1), [{RuCl-(P(OMe) 3 ) 2 }(µ-Cl) 2 (µ-S 2 ){Ru(CH 3 CN)(P(OMe) 3 ) 2 ] + ([2] + ), [{Ru(CH 3 CN) , and [{Ru(CH 3 CN) 3 (P(OMe) 3 ) 2 } 2 (µ-S 2 )] 4+ ([5] 4+ ), have been synthesized, and their crystal structures have been solved. Compounds 1, [2] + , and [4] 2+ have a triply bridged Ru III (µ-Cl) 2 (µ-S 2 )Ru III core, in which the S 2 2ligand bridges the two Ru atoms in a cis configuration. Compounds [3] 3+ and [5] 4+ have a singly bridged trans-RuSSRu core, whereby [3] 3+ corresponds to a one-electron reduced form of [5] 4+ . Compound [3] 3+ is the first example of a well-characterized mixed-valent compound with a trans-MSSM core, where M is any metal. All the compounds have intense absorption bands at around 700 nm, which can be explained for [3] 3+ and [5] 4+ as a π-π* transition of the distinct trans-RuSSRu core. Resonance Raman spectroscopy of 1, [2] + , and [3] 3+ and comparison with several literature values for cis-RuSSRu compounds show that only [3] 3+ exhibits a strong ν(S-S) Raman band, when excited by λ e ) 647.1 nm, whereas all the others show strong to medium ν-(Ru-S) and very weak ν(S-S) bands. The ESR spectrum of [3] 3+ shows a rhombic signal with g 1 ) 2.12, g 2 ) 2.05, and g 3 ) 1.995. This anisotropy is unusually small, compared to most mononuclear and binuclear Ru(III) compounds with various ligands. Analysis of the g values by use of the matrix of spin-orbit coupling Hamiltonian has revealed a very small spin-orbit coupling constant of 100 cm -1 , which is a result of the extensive covalency of the metal-disulfide bond. The X-ray photoelectron spectrum of [3] 3+ did not give any of the expected double peaks of the Ru(II) and Ru(III) components; the observed peaks are Ru 3d 5/2 281.0 eV, 3P 3/2 462.4 eV, S(S 2 2-) 2P 3/2 162.7 eV. Compound [3] 3+ does not give any intervalence-transition band in the longer-wavelength visible to near-IR region, other than the UV-vis band similarly observed in the one-electron oxidized compound [5] 4+ . These characteristics are reasonably understood, if [3] 3+ is regarded as a mixed-valent complex with valence-averaged ground state (class III of the Robin and Day classification).

A favorable effect of an inhibitor of the sodium–glucose cotransporter 2 (SGLT2i) on mortality of diabetic patients was recently reported, although mechanisms underlying that effect remained unclear. Here, we examine SGLT2i effects on survival of diabetic mice and assess factors underlying these outcomes. To examine SGLT2i treatment effects in a model of severe diabetes, we fed genetically diabetic db/db mice a high-fat diet and then assessed outcomes including diabetic complications between SGLT2i TA-1887-treated and control mice. We also compare effects of SGLT2i TA-1887 with those of lowering blood glucose levels via insulin treatment. Untreated db/db mice showed remarkable weight loss, or cachexia, while TA-1887-treated mice did not but rather continued to gain weight at later time points and decreased mortality. TA-1887 treatment prevented pancreatic beta cell death, enhanced preservation of beta cell mass and endogenous insulin secretion, and increased insulin sensitivity. Moreover, TA-1887 treatment attenuated inflammation, oxidative stress, and cellular senescence, especially in visceral white adipose tissue, and antagonized endothelial dysfunction. Insulin treatment of db/db mice also prevented weight loss and antagonized inflammation and oxidative stress. However, insulin treatment had less potent effects on survival and prevention of cellular senescence and endothelial dysfunction than did TA-1887 treatment. SGLT2i treatment prevents diabetic cachexia and death by preserving function of beta cells and insulin target organs and attenuating complications. SGLT2i treatment may be a promising therapeutic strategy for type 2 diabetes patients with morbid obesity and severe insulin resistance.