A quantitative LC–MS/MS method for determination of thiazolidinedione mitoNEET ligand NL-1 in mouse serum suitable for pharmacokinetic studies

Pedada, Kiran K.; Zhou, Xiang; Jogiraju, Harini; Carroll, Richard T.; Geldenhuys, Werner J.; Lin, Li; Anderson, David J.

doi:10.1016/j.jchromb.2013.11.048

Cited by 7 publications

(3 citation statements)

References 30 publications

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“…Resulting Ct values were normalized to those for CSCs without NL-1 treatment. NL-1 was not used in the whole animal because of its very short half-life [21], and our goal to confine the effects of the drugs to the cells we were administering.…”

Section: Methodsmentioning

confidence: 99%

Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress

et al. 2015

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Ischemic heart disease (IHD) is a leading cause of death worldwide, and regenerative therapies through exogenous stem cell delivery hold promising potential. One limitation of such therapies is the vulnerability of stem cells to the oxidative environment associated with IHD. Accordingly, manipulation of stem cell mitochondrial metabolism may be an effective strategy to improve survival of stem cells under oxidative stress. MitoNEET is a redox-sensitive, mitochondrial target of thiazolidinediones (TZDs), and influences cellular oxidative capacity. Pharmacological targeting of mitoNEET with the novel TZD, mitoNEET Ligand-1 (NL-1), improved cardiac stem cell (CSC) survival compared to vehicle (0.1 % DMSO) during in vitro oxidative stress (H2O2). 10 μM NL-1 also reduced CSC maximal oxygen consumption rate (OCR) compared to vehicle. Following treatment with dexamethasone, CSC maximal OCR increased compared to baseline, but NL-1 prevented this effect. Smooth muscle α-actin expression increased significantly in CSC following differentiation compared to baseline, irrespective of NL-1 treatment. When CSCs were treated with glucose oxidase for 7 days, NL-1 significantly improved cell survival compared to vehicle (trypan blue exclusion). NL-1 treatment of cells isolated from mitoNEET knockout mice did not increase CSC survival with H2O2 treatment. Following intramyocardial injection of CSCs into Zucker obese fatty rats, NL-1 significantly improved CSC survival after 24 h, but not after 10 days. These data suggest that pharmacological targeting of mitoNEET with TZDs may acutely protect stem cells following transplantation into an oxidative environment. Continued treatment or manipulation of mitochondrial metabolism may be necessary to produce long-term benefits related to stem cell therapies.

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Section: Methodsmentioning

confidence: 99%

Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress

et al. 2015

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“…After confirming leukemic cell engraftment by IVIS luminescent imaging, the mice were treated with 1 mg/kg NL-1 every day for 5 days. The dose was based on our previous pharmacokinetic study (Pedada et al, 2014). Out of the 10 mice, one control mouse did not show tumor progression after engraftment and was not included in the study.…”

Section: Development Of a Chemotherapy-resistant All Cellmentioning

confidence: 99%

The MitoNEET Ligand NL-1 Mediates Antileukemic Activity in Drug-Resistant B-Cell Acute Lymphoblastic Leukemia

Geldenhuys

Nair

Piktel

et al. 2019

J Pharmacol Exp Ther

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Disease relapse in B-cell acute lymphoblastic leukemia (ALL), either due to development of acquired resistance after therapy or because of de novo resistance, remains a therapeutic challenge. In the present study, we have developed a cytarabine (Ara-C)resistant REH cell line (REH/Ara-C) as a chemoresistance model. REH/Ara-C 1) was not crossresistant to vincristine or methotrexate; 2) showed a similar proliferation rate and cell surface marker expression as parental REH; 3) demonstrated decreased chemotaxis toward bone marrow stromal cells; and 4) expressed higher transcript levels of cytidine deaminase (CDA) and mito-NEET (CISD1) than the parental REH cell line. Based on these findings, we tested NL-1, a mitoNEET inhibitor, which induced a concentration-dependent decrease in cell viability with a comparable IC 50 value in REH and REH/Ara-C. Furthermore, NL-1 decreased cell viability in six different ALL cell lines and showed inhibitory activity in a hemosphere assay. NL-1 also impaired the migratory ability of leukemic cells, irrespective of the chemoattractant used, in a chemotaxis assay. More importantly, NL-1 showed specific activity in inducing death in a drug-resistant population of leukemic cells within a coculture model that mimicked the acquired resistance and de novo resistance observed in the bone marrow of relapsed patients. Subsequent studies indicated that NL-1 mediates autophagy, and inhibition of autophagy partially decreased NL-1-induced tumor cell death. Finally, NL-1 showed antileukemic activity in an in vivo mouse ALL model. Taken together, our study demonstrates that mitoNEET has potential as a novel antileukemic drug target in treatment refractory or relapsed ALL.

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“…Pioglitazone binding can then inhibit the transfer of [2Fe-2S] clusters making mitoNEET unable to dimerize and perform its necessary task. Additionally, through the use of mitoNEET knockout mice, it was shown that mitochondria without mitoNEET have a decreased oxidative capacity which suggests that this iron-containing protein may be pivotal in controlling the rate of mitochondrial respiration (Geldenhuys et al, 2011; Kusminski et al, 2012; Pedada et al, 2014; Wiley et al, 2007). Finally, a recent study has highlighted that mitoNEET is a redox-sensitive protein and can be reduced by biological thiols such as gluthathione (GSH), reversing the effect of mitoNEET oxidation (Landry and Ding, 2014) in accordance that GSH precursors can reverse mitochondrial dysfunction and afford neuroprotection following CNS injuries (Pandya et al, 2014; Patel et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Pioglitazone treatment following spinal cord injury maintains acute mitochondrial integrity and increases chronic tissue sparing and functional recovery

Patel

Cox

Gollihue

et al. 2017

Experimental Neurology

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Pioglitazone is an FDA-approved PPAR-γ agonist drug used to for treat diabetes, and it has demonstrated neuroprotective effects in multiple models of central nervous system (CNS) injury. Acute treatment after spinal cord injury (SCI) in rats is reported to suppress neuroinflammation, rescue injured tissues, and improve locomotor recovery. In the current study, we additionally assessed the protective efficacy of pioglitazone treatment on acute mitochondrial respiration, as well as functional and anatomical recovery after contusion SCI in adult male C57BL/6 mice. Mice received either vehicle or pioglitazone (10 mg/kg) at either 15 min or 3 hr after injury (75 kDyn at T9) followed by a booster at 24 hr post-injury. At 25 hr, mitochondria were isolated from spinal cord segments centered on the injury epicenters and assessed for their respiratory capacity. Results showed significantly compromised mitochondrial respiration 25 hr following SCI, but pioglitazone treatment that was initiated either at 15 min or 3 hr post-injury significantly maintained mitochondrial respiration rates near sham levels. A second cohort of injured mice received pioglitazone at 15 min post injury, then once a day for 5 days post-injury to assess locomotor recovery and tissue sparing over 4 weeks. Compared to vehicle, pioglitazone treatment resulted in significantly greater recovery of hind-limb function over time, as determined by serial locomotor BMS assessments and both terminal BMS subscores and gridwalk performance. Such improvements correlated with significantly increased grey and white matter tissue sparing, although pioglitazone treatment did not abrogate long-term injury-induced inflammatory microglia/macrophage responses. In sum, pioglitazone significantly increased functional neuroprotection that was associated with remarkable maintenance of acute mitochondrial bioenergetics after traumatic SCI. This sets the stage for dose-response and delayed administration studies to maximize pioglitazone’s efficacy for SCI while elucidating the precise role that mitochondria play in governing its neuroprotection; the ultimate goal to develop novel therapeutics that specifically target mitochondrial dysfunction.

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A quantitative LC–MS/MS method for determination of thiazolidinedione mitoNEET ligand NL-1 in mouse serum suitable for pharmacokinetic studies

Cited by 7 publications

References 30 publications

Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress

Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress

The MitoNEET Ligand NL-1 Mediates Antileukemic Activity in Drug-Resistant B-Cell Acute Lymphoblastic Leukemia

Pioglitazone treatment following spinal cord injury maintains acute mitochondrial integrity and increases chronic tissue sparing and functional recovery

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