The Protective Effect of DiDang Tang Against AlCl ₃-Induced Oxidative Stress and Apoptosis in PC12 Cells Through the Activation of SIRT1-Mediated Akt/Nrf2/HO-1 Pathway

Oxidative stress and ferrous metabolism are important in the pathogenesis in Parkinson's disease. In dopaminergic neurons, several stress proteins are upregulated under oxidative stress. To clarify this mechanism, we investigated hemin-related signal transduction and the induction of oxidative stress-related proteins in SH-SY5Y cells. We identified phosphatidylinositol 3-kinase (PI3K) and Nrf2 as important molecules in the induction of heme oxygenase-1, thioredoxin, and peroxiredoxin-I. PI3K-related signal controlled Nrf2 activation, and consequently, PI3K inhibitors blocked the nuclear translocation of Nrf2 and induction of stress proteins. These observations suggest that PI3K and Nrf2 are key molecules in maintaining suitable conditions under oxidative stress and ferrous metabolism.

Apart from regulating somatic growth and metabolic processes, accumulating evidence suggests that the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is involved in the regulation of brain growth, development, and myelination. In addition, both GH and IGF-I affect cognition and biochemistry in the adult brain. Some of the effects of GH are attributable to circulating IGF-I, while others may be due to IGF-I produced locally within the brain. Some of the shared effects in common to GH and IGF-I may also be explained by cross-talk between the GH and IGF-I transduction pathways, as indicated by recent data from other cell systems. Otherwise, it also seems that GH may act directly without involving IGF-I (either circulating or locally). Plasticity in the central nervous system (CNS) may be viewed as changes in the functional interplay between the major cell types, neurons, astrocytes, and oligodendrocytes. GH and IGF-I affect all three of these cell types in several ways. Apart from the neuroprotective effects of GH and IGF-I posited in different experimental models of CNS injury, IGF-I has been found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. It appears that the MAPK signaling pathway is required for IGF-I—stimulated proliferation in vitro, whereas the PI3K/Akt or MAPK/Erk signaling pathway appears to mediate antiapoptotic effects. The increase of IGF-I on endothelial cell phenotype may explain the increase in cerebral arteriole density observed after GH treatment. The functional role of GH and IGF-I in the adult brain will be reviewed with reference to neurotransmitters, glucose metabolism, cerebral blood flow, gap junctional communication, dendritic arborization, exercise, enriched environment, depression, learning, memory, and aging.Briefly, these findings suggest that IGF-I functions as a putative regenerative agent in the adult CNS. Hitherto less studied regarding in these aspects, GH may have similar effects, especially as it is the main regulator of IGF-I in vivo. Some of the positive cognitive features of GH treatment are likely attributable to the mechanisms reviewed here.

Cardiac hypertrophy is a multifactorial disease characterized by multiple molecular alterations. One of these alterations is change in the activity of Akt, which plays a central role in regulating a variety of cellular processes ranging from cell survival to aging. Akt activation is mainly achieved by its binding to phosphatidylinositol (3,4,5)-triphosphate. This results in a conformational change that exposes the kinase domain of Akt for phosphorylation and activation by its upstream kinase, 3-phosphoinositide-dependent protein kinase 1, in the cell membrane. Recent studies have shown that sirtuin isoforms, silent information regulator (SIRT) 1, SIRT3, and SIRT6, play an essential role in the regulation of Akt activation. Although SIRT1 deacetylates Akt to promote phosphatidylinositol (3,4,5)-triphosphate binding and activation, SIRT3 controls reactive oxygen species-mediated Akt activation, and SIRT6 transcriptionally represses Akt at the level of chromatin. In the first part of this review, we discuss the mechanisms by which sirtuins regulate Akt activation and how they influence other post-translational modifications of Akt. In the latter part of the review, we summarize the implications of sirtuin-dependent regulation of Akt signaling in the control of major cellular processes such as cellular growth, angiogenesis, apoptosis, autophagy, and aging, which are involved in the initiation and progression of several diseases.