Somatostatin induces hyperpolarization in pancreatic islet α cells by activating a G protein-gated K+ channel

AbstractSomatostatin inhibits glucagon-secretion from pancreatic α cells but its underlying mechanism is unknown. In mouse α cells, we found that somatostatin induced prominent hyperpolarization by activating a K+ channel, which was unaffected by tolbutamide but prevented by pre-treating the cells with pertussis toxin. The K+ channel was activated by intracellular GTP (with somatostatin), GTPγS or Gβγ subunits. It was thus identified as a G protein-gated K+ (KG) channel. RT-PCR and immunohistochemical analyses suggested the KG channel to be composed of Kir3.2c and Kir3.4. This study identified a novel ionic mechanism involved in somatostatin-inhibition of glucagon-secretion from pancreatic α cells

SIRT1 negatively regulates the expression of Prl2C3,a senescence-associated protein

SIRT1 is a mammalian homologue of yeast longevity protein Sir2. SIRT1 deacetylates transcription factors, cofactors, and histones in an NAD+-dependent manner, and promotes cell survival, anti-oxidative function, and DNA repair. Although some studies have indicated that SIRT1 is involved in longevity, the function of SIRT1 for preventing aging and senescence is still unclear. In mouse embryonic fibroblasts (MEFs), we found that SIRT1 expression decreased by aging and IRT1 reciprocally regulated the expression level of Prl2C3, one of the prolactin-like peptides. In young MEFs, purified Prl2C3 inhibited the growth and increased the number of senescence-associated β galactosidase-positive cells with enlarged and flattened shapes. Moreover, immunostaining of human skin sections showed the expression of Prl2C3 in the basal cells of the epidermis. These results indicate that SIRT1 negatively regulates a senescence-associated protein rl2C3

Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome

The acetylase inhibitor spermidine and the sirtuin-1 activator resveratrol disrupt the antagonistic network of acetylases and deacetylases that regulate autophagy

SIRT1: A Novel Target for the Treatment of Muscular Dystrophies

Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy and is caused by mutations in the gene that encodes the cytoskeletal protein dystrophin. The treatment for DMD is limited to glucocorticoids, which are associated with multiple side effects. Thus, the identification of novel therapeutic targets is urgently needed. SIRT1 is an NAD+-dependent histone/protein deacetylase that plays roles in diverse cellular processes, including stress resistance and cell survival. Studies have shown that SIRT1 activation provides beneficial effects in the dystrophin-deficient mdx mouse, a model of DMD. SIRT1 activation leads to the attenuation of oxidative stress and inflammation, a shift from the fast to slow myofiber phenotype, and the suppression of tissue fibrosis. Although further research is needed to clarify the molecular mechanisms underlying the protective role of SIRT1 in mdx mice, we propose SIRT1 as a novel therapeutic target for patients with muscular dystrophies

Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress.

Excessive reactive oxygen species (ROS) induce apoptosis and are associated with various diseases and with aging. SIRT1 (sirtuin-1), an NAD+-dependent protein deacetylase, decreases ROS levels and participates in cell survival under oxidative stress conditions. SIRT1 modulates the transcription factors p53, a tumor suppressor and inducer of apoptosis, and the forkhead O (FOXO) family, both of which play roles for cell survival and cell death. In this study, we aimed to know which is working greatly among p53 and FOXOs transcription factors in SIRT1's cell protective functions under oxidative stress conditions. The antimycin A-induced increase in ROS levels and apoptosis was enhanced by SIRT1 inhibitors nicotinamide and splitomicin, whereas it was suppressed by a SIRT1 activator, resveratrol, and a SIRT1 cofactor, NAD+. SIRT1-siRNA abolished the effects of splitomicin and resveratrol. p53-knockdown experiment in C2C12 cells and experiment using p53-deficient HCT116 cells showed that splitomicin and resveratrol modulated apoptosis by p53-dependent and p53-independent pathways. In p53-independent cell protective pathway, we found that FOXO1, FOXO3a, and FOXO4 were involved in SOD2's upregulation by resveratrol. The knockdown of these three FOXOs by siRNAs completely abolished the SOD2 induction, ROS reduction, and anti-apoptotic function of resveratrol. Our results indicate that FOXO1, FOXO3a and FOXO4, are indispensable for SIRT1-dependent cell survival against oxidative stress, although deacetylation of p53 has also some role for cell protective function of SIRT1

Resveratrol Decreases Oxidative Stress by Restoring Mitophagy and Improves the Pathophysiology of Dystrophin-Deficient mdx Mice

We previously showed that treatment with resveratrol (3,5,4′-trihydroxy-trans-stilbene), an activator of the NAD+-dependent deacetylase SIRT1 at 4 g/kg food for 32 weeks, significantly decreased the muscular reactive oxygen species (ROS) levels and ameliorated the pathology of mdx mice, an animal model of Duchenne muscular dystrophy (DMD). Here, we treated mdx mice with various doses of resveratrol (0.04, 0.4, and 4 g/kg food) for 56 weeks and examined the effects on serum creatine kinase levels and physical activities. Because resveratrol promotes autophagy, we also investigated whether autophagy including mitochondrial autophagy (mitophagy) is involved in resveratrol’s effects. Autophagy/mitophagy-related genes and autophagic flux were downregulated in the muscle of mdx mice, and these phenomena were reversed by resveratrol with significant ROS reduction. Resveratrol at 4 g/kg food reduced the number of immature myofibers containing central nuclei and fine fibers < 400 μm2 and increased that of thicker myofibers in the quadriceps, suggesting that resveratrol decreased myofiber wasting and promoted muscular maturation. Accordingly, resveratrol at 0.4 g/kg food reduced the creatine kinase levels to one-third of those in untreated mdx mice and significantly increased the animals’ physical activities. In C2C12 myoblast cells, resveratrol promoted mitophagy and eliminated mitochondria containing high superoxide levels. The clearance of damaged mitochondria and ROS reduction by resveratrol was completely suppressed by an autophagy inhibitor (chloroquine) and by knocking down Atg5 or Pink1, essential genes for autophagy and mitophagy, respectively. Thus, resveratrol is a potential therapeutic agent for DMD, and the clearance of damaged mitochondria probably contributes to its action