13 research outputs found
A Novel Class of Small Molecule Inhibitors of HDAC6
Histone deacetylases (HDACs) are a family of enzymes
that play
significant roles in numerous biological processes and diseases. HDACs
are best known for their repressive influence on gene transcription
through histone deacetylation. Mapping of nonhistone acetylated proteins
and acetylation-modifying enzymes involved in various cellular pathways
has shown protein acetylation/deacetylation also plays key roles in
a variety of cellular processes including RNA splicing, nuclear transport,
and cytoskeletal remodeling. Studies of HDACs have accelerated due
to the availability of small molecule HDAC inhibitors, most of which
contain a canonical hydroxamic acid or benzamide that chelates the
metal catalytic site. To increase the pool of unique and novel HDAC
inhibitor pharmacophores, a pharmacological active compound screen
was performed. Several unique HDAC inhibitor pharmacophores were identified <i>in vitro</i>. One class of novel HDAC inhibitors, with a central
naphthoquinone structure, displayed a selective inhibition profile
against HDAC6. Here we present the results of a unique class of HDAC6
inhibitors identified using this compound library screen. In addition,
we demonstrated that treatment of human acute myeloid leukemia cell
line MV4-11 with the selective HDAC6 inhibitors decreases levels of
mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation,
all of which are associated with the inhibitor’s selective
toxicity against leukemia
A Novel Class of Small Molecule Inhibitors of HDAC6
Histone deacetylases (HDACs) are a family of enzymes
that play
significant roles in numerous biological processes and diseases. HDACs
are best known for their repressive influence on gene transcription
through histone deacetylation. Mapping of nonhistone acetylated proteins
and acetylation-modifying enzymes involved in various cellular pathways
has shown protein acetylation/deacetylation also plays key roles in
a variety of cellular processes including RNA splicing, nuclear transport,
and cytoskeletal remodeling. Studies of HDACs have accelerated due
to the availability of small molecule HDAC inhibitors, most of which
contain a canonical hydroxamic acid or benzamide that chelates the
metal catalytic site. To increase the pool of unique and novel HDAC
inhibitor pharmacophores, a pharmacological active compound screen
was performed. Several unique HDAC inhibitor pharmacophores were identified <i>in vitro</i>. One class of novel HDAC inhibitors, with a central
naphthoquinone structure, displayed a selective inhibition profile
against HDAC6. Here we present the results of a unique class of HDAC6
inhibitors identified using this compound library screen. In addition,
we demonstrated that treatment of human acute myeloid leukemia cell
line MV4-11 with the selective HDAC6 inhibitors decreases levels of
mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation,
all of which are associated with the inhibitor’s selective
toxicity against leukemia
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Mitochondrial GTP Links Nutrient Sensing to β Cell Health, Mitochondrial Morphology, and Insulin Secretion Independent of OxPhos
Mechanisms coordinating pancreatic β cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of β cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and β cell health
Mitochondrial dysfunction in inherited renal disease and acute kidney injury
Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by tubular defects, but glomerular, tubulointerstitial and cystic diseases have also been described. For example, defects in coenzyme Q10 (CoQ10) biosynthesis and the mitochondrial DNA 3243 A>G mutation are important causes of focal segmental glomerulosclerosis in children and in adults, respectively. Although they sometimes present with isolated renal findings, mitochondrial diseases are frequently associated with symptoms related to central nervous system and neuromuscular involvement. They can result from mutations in nuclear genes that are inherited according to classic Mendelian rules or from mutations in mitochondrial DNA, which are transmitted according to more complex rules of mitochondrial genetics. Diagnosis of mitochondrial disorders involves clinical characterization of patients in combination with biochemical and genetic analyses. In particular, prompt diagnosis of CoQ10 biosynthesis defects is imperative because of their potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes to the physiopathology of tissue injury, whereas mitochondrial biogenesis has an important role in the recovery of renal function. Potential therapies that target mitochondrial dysfunction or promote mitochondrial regeneration are being developed to limit renal damage during AKI and promote repair of injured tissue