Advances in biological regulation
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Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disorder that is characterized by the selective death of motor neurons. While the fundamental cause of the disorder is still unclear, the first identified risk gene, Cu,Zn superoxide dismutase (SOD1), has led to the proposal of several mechanisms that are relevant to its pathogenesis. ⋯ Yet to what extent SOD1 contributes to neurotoxicity in ALS cases generally is unknown. This review discusses the toxic mechanisms of mutant SOD1 (SOD1(mut)) and misfolded SOD1(WT) in the context of ALS as well as the potential implication of these mechanisms in SOD1 mutation-negative ALS.
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Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase that functions via two multiprotein complexes, namely mTORC1 and mTORC2, each characterized by different binding partners that confer separate functions. mTORC1 function is tightly regulated by PI3-K/Akt and is sensitive to rapamycin. mTORC2 is sensitive to growth factors, not nutrients, and is associated with rapamycin-insensitivity. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is thought to modulate growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases such as Akt and SGK. Recent evidence has suggested that mTORC2 may play an important role in maintenance of normal as well as cancer cells by virtue of its association with ribosomes, which may be involved in metabolic regulation of the cell. ⋯ In recent years, new pharmacologic agents have been developed which can inhibit these complexes via ATP-binding mechanism, or dual inhibition of the canonical PI3-K/Akt/mTOR signaling pathway. These compounds include WYE-354, KU-003679, PI-103, Torin1, and Torin2, which can target both complexes or serve as a dual inhibitor for PI3-K/mTOR. This investigation describes the mechanism of action of pharmacological agents that effectively target mTORC1 and mTORC2 resulting in suppression of growth, proliferation, and migration of tumor and cancer stem cells.
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Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by alveolar epithelial cell injury, accumulation of fibroblasts/myofibroblasts and deposition of extracellular matrix proteins. Levels of sphingosine-1-phosphate (S1P), a naturally occurring bioactive lipid, are elevated in bronchoalveolar fluids and lung tissues from IPF patients and animal models of pulmonary fibrosis. However, the in vivo contribution of S1P, regulated by its synthesis catalyzed by Sphingosine kinases (SphKs) 1 & 2 and catabolism by S1P phosphatases and S1P lyase (S1PL), in the pathogenesis of pulmonary fibrosis is not well defined. ⋯ Over-expression of S1PL attenuated bleomycin-induced TGF-β secretion and S1P mediated differentiation of human lung fibroblasts through regulation of autophagy. Administration of SphK1 inhibitor 8 days post-bleomycin challenge reduced bleomycin-induced mortality and pulmonary fibrosis. Our results suggest that SphK1 and S1PL play critical roles in the pathology of lung fibrosis and may be novel therapeutic targets.