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Transitioning from a differentiated state to a higher-order of plasticity, by partial rather than full reactivation of pluripotency genes, might be a better approach in regenerative medicine. Hydrogen sulfide plays a crucial role in the maintenance and differentiation of mesenchymal stem cells (MSC) that have the potential to differentiate to a diverse group of mesenchymally derived cells. It was shown that these cells show a heavy reliance on cystathionine-β-synthase (CBS)-derived hydrogen sulfide (H 2 S) during differentiation. We have found that expression and activity of 3-mercaptopyruvate sulfurtransferase (MPST), one of three enzymes that hat regulates H 2 S biosynthesis, is significantly lower in MSC as compared with lineage-restricted dermal fibroblasts. Here, we tested the hypothesis that suppression of MPST in dermal fibroblasts might induce plasticity-related changes and broaden the transdifferentiation potency. Inactivation of MPST with phenylpyruvate (PP) or by siRNA silencing led to diminished H 2 S production associated with increased production of reactive oxygen species (ROS) and lactic acid. Accumulation of α-ketoglutarate (α-KG), a key metabolite required for the expression of ten-eleven translocation hydroxylase (TET), was associated with stimulated transcription of pluripotency related genes including OCT4, KLF4, SOX2, and NANOG. Suppression of TET1 gene and inhibition of glycolysis with glucose analog, 2-desoxy-d-glucose, or hexokinase II inhibitor significantly reduced expression of pluripotency genes following MPST inactivation or knockdown. MPST disruption promoted the conversion of fibroblasts into adipocytes as evidenced by a significant increase in expression of adipocyte-specific genes, PPARγ, and UCP1, and intracellular accumulation of oil Red-O positive fat droplets. Inhibition of glycolysis inhibited these changes. Under induced differentiation conditions, fibroblasts with disrupted MPST show the potency to differentiate to white adipogenic lineage. Thus, MPST inactivation or silencing enhances the plasticity of dermal fibroblasts in a TET1 and glycolysis dependent manner and promotes adipogenic transdifferentiation., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Recently, we reported that cancer cells that recover from a potentially lethal damage gain new phenotypic features comprised of mitochondrial structural remodeling associated with increased glycolytic dependency and drug resistance. Here, we demonstrate that a subset of cancer cells, upon recovery from a potentially lethal damage, undergo dedifferentiation and express genes, which are characteristic of undifferentiated stem cells. While these cells are competent in maintaining differentiated progeny of tumor, they also exhibit transdifferentiation potential. Dedifferentiation is characterized by accumulation of hydrogen sulfide (H2S), which triggers up-regulation of nicotinamide phosphoribosyltransferase (Nampt) accompanied by changes in the redox state. The molecular events triggered by Nampt include elevated production of NAD(+) and up-regulation of H2S producing enzymes, cystathionine beta synthase (CBS) and cystathionase (CTH) with 3-mercaptopyruvate sulfurtransferase (MST) being detectable only in 3D spheroids. Suppression of Nampt, or inactivation of H2S producing enzymes, all reduce H2S production and reverse the ability of cells to dedifferentiate. Moreover, H2S induced stem cell markers in parental cancer cells in a manner similar to that observed in damage recovered cells. These data suggest of existence of a positive feedback loop between H2S and Nampt that controls dedifferentiation in cancer cells that recover from a potentially lethal damage., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Hyperhomocysteinemia occurs in chronic- and end-stage kidney disease at the time when dialysis or transplant becomes indispensable for survival. Excessive accumulation of homocysteine (Hcy) aggravates conditions associated with imbalanced homeostasis and cellular redox thereby resulting in severe oxidative stress leading to oxidation of reduced free and protein-bound thiols. Thiol modifications such as N-homocysteinylation, sulfination, cysteinylation, glutathionylation, and sulfhydration control cellular responses that direct complex metabolic pathways. Although cysteinyl modifications are kept low, under Hcy-induced stress, thiol modifications persist thus surpassing cellular proteostasis. Here, we review mechanisms of redox regulation and show how cysteinyl modifications triggered by excess Hcy contribute development and progression of chronic kidney disease. We discuss different signaling events resulting from aberrant cysteinyl modification with a focus on transsulfuration., (© 2015 Elsevier Inc. All rights reserved.)