Various stimuli, such as telomere dysfunction and oxidative stress, can induce irreversible cell growth arrest, which is termed 'cellular senescence'. This response is controlled by tumor suppressor proteins such as p53 and pRb. There is also evidence that senescent cells promote changes related to aging or age-related diseases. Here we show that p53 expression in adipose tissue is crucially involved in the development of insulin resistance, which underlies age-related cardiovascular and metabolic disorders. We found that excessive calorie intake led to the accumulation of oxidative stress in the adipose tissue of mice with type 2 diabetes-like disease and promoted senescence-like changes, such as increased activity of senescence-associated beta-galactosidase, increased expression of p53 and increased production of proinflammatory cytokines. Inhibition of p53 activity in adipose tissue markedly ameliorated these senescence-like changes, decreased the expression of proinflammatory cytokines and improved insulin resistance in mice with type 2 diabetes-like disease. Conversely, upregulation of p53 in adipose tissue caused an inflammatory response that led to insulin resistance. Adipose tissue from individuals with diabetes also showed senescence-like features. Our results show a previously unappreciated role of adipose tissue p53 expression in the regulation of insulin resistance and suggest that cellular aging signals in adipose tissue could be a new target for the treatment of diabetes (pages 996-967).

Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch-induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overloadinduced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.

Adding steroid to local anaesthetics in local infiltration analgesia reduced inflammation both locally and systemically, resulting in significant early pain relief and rapid recovery in total knee arthroplasty.

C NMR, and EPR studies of a series of low-spin (meso-tetraalkylporphyrinato)iron(III) complexes, [Fe(TRP)(L) 2 ]X where R ) n Pr, c Pr, and i Pr and L represents axial ligands such as imidazoles, pyridines, and cyanide, have revealed that the ground-state electron configuration of [Fe(T n PrP)(L) 2 ]X and [Fe(T c PrP)(L) 2 ]X is presented either as the common (d xy ) 2 (d xz ,d yz ) 3 or as the less common (d xz ,d yz ) 4 (d xy ) 1 depending on the axial ligands. The ground-state electron configuration of the isopropyl complexes [Fe(Ti-PrP)(L) 2 ]X is, however, presented as (d xz ,d yz ) 4 (d xy ) 1 regardless of the kind of axial ligands. In every case, the contribution of the (d xz ,d yz ) 4 (d xy ) 1 state to the electronic ground state increases in the following order: HIm < 4-Me 2 NPy < 2-MeIm < CN -< 3-MePy < Py < 4-CNPy. Combined analysis of the 13 C and 1 H NMR isotropic shifts together with the EPR g values have yielded the spin densities at the porphyrin carbon and nitrogen atoms. Estimated spin densities in [Fe(T i PrP)(4-CNPy) 2 ] + , which has the purest (d xz ,d yz ) 4 (d xy ) 1 ground state among the complexes examined in this study, are as follows: meso-carbon, +0.045; R-pyrrole carbon, +0.0088; β-pyrrole carbon, -0.00026; and pyrrole nitrogen, +0.057. Thus, the relatively large spin densities are on the pyrrole nitrogen and meso-carbon atoms. The result is in sharp contrast to the spin distribution in the (d xy ) 2 (d xz ,d yz ) 3 type complexes; the largest spin density is at the β-pyrrole carbon atoms in bis(1methylimidazole)(meso-tetraphenylporphyrinato)iron(III), [Fe(TPP)(1-MeIm) 2 ] + , as determined by Goff. The large downfield shift of the meso-carbon signal, δ +917.5 ppm at -50 °C in [Fe(T i PrP)(4-CNPy) 2 ] + , is ascribed to the large spin densities at these carbon atoms. In contrast, the large upfield shift of the R-pyrrole carbon signal, δ -293.5 ppm at the same temperature, is caused by the spin polarization from the adjacent mesocarbon and pyrrole nitrogen atoms.