In vivo insulin mimetic effects of pV compounds: role for tissue targeting in determining potency

Bevan, A. Paul; Burgess, J. W.; Yale, JF; Drake, Paul L.; Lachance, Dominic; Baquiran, Gerardo; Shaver, Alan; Posner, Barry I.

doi:10.1152/ajpendo.1995.268.1.e60

Cited by 42 publications

(40 citation statements)

References 24 publications

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“…We hypothesized that transient incubation of neonatal mouse ovaries in vitro with bpV(pic), a PTEN inhibitor (7)(8)(9), allows the activation of dormant follicles. Ovaries containing mainly primordial follicles were obtained from neonatal mice at day 3 of age.…”

Section: Resultsmentioning

confidence: 99%

Activation of dormant ovarian follicles to generate mature eggs

Kawamura

Cheng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

379

340

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Although multiple follicles are present in mammalian ovaries, most of them remain dormant for years or decades. During reproductive life, some follicles are activated for development. Genetically modified mouse models with oocyte-specific deletion of genes in the PTEN-PI3K-Akt-Foxo3 pathway exhibited premature activation of all dormant follicles. Using an inhibitor of the Phosphatase with TENsin homology deleted in chromosome 10 (PTEN) phosphatase and a PI3K activating peptide, we found that short-term treatment of neonatal mouse ovaries increased nuclear exclusion of Foxo3 in primordial oocytes. After transplantation under kidney capsules of ovariectomized hosts, treated follicles developed to the preovulatory stage with mature eggs displaying normal epigenetic changes of imprinted genes. After in vitro fertilization and embryo transfer, healthy progeny with proven fertility were delivered. Human ovarian cortical fragments from cancer patients were also treated with the PTEN inhibitor. After xeno-transplantation to immune-deficient mice for 6 months, primordial follicles developed to the preovulatory stage with oocytes capable of undergoing nuclear maturation. Major differences between male and female mammals are unlimited number of sperm and paucity of mature oocytes. Thus, short-term in vitro activation of dormant ovarian follicles after stimulation of the PI3K-Akt pathway allows the generation of a large supply of mature female germ cells for future treatment of infertile women with a diminishing ovarian reserve and for cancer patients with cryo-preserved ovaries. Generation of a large number of human oocytes also facilitates future derivation of embryonic stem cells for regenerative medicine.

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Section: Resultsmentioning

confidence: 99%

Activation of dormant ovarian follicles to generate mature eggs

Kawamura

Cheng

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

379

340

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“…In view of this, experiments were done to determine whether bpV(phen) (21) could modulate the course of the infection in a murine leishmaniasis model (32). Infection by L. major, the causative agent of cutaneous leishmaniasis, was inhibited by 60% (p Ͻ 0.05) in bpV(phen)-treated BALB/c mice (Fig.…”

Section: Attenuation Of Mø and Other Host Immune Functions Bymentioning

confidence: 99%

“…19). It was demonstrated that a number of chemically defined pV derivatives, each containing an oxo ligand, one or two peroxo anions in the inner coordination sphere of vanadium, and an ancillary ligand, were equally potent PTP inhibitors stable in aqueous solution (20) that can activate the insulin receptor kinase and mimic insulin biological action in vivo (21). Moreover, they have the capacity to inhibit the proliferation of nervous cell lines in vitro (22) and activate the response of immune cells (23).…”

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confidence: 99%

Modulation of Interferon-γ-induced Macrophage Activation by Phosphotyrosine Phosphatases Inhibition

Olivier¹,

Romero-Gallo²,

Matte³

et al. 1998

Journal of Biological Chemistry

111

127

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Phagocyte functions are markedly inhibited after infection with the intracellular protozoan parasite Leishmania. This situation strongly favors the installation and propagation of this pathogen within its mammalian host. Previous findings by us and others have established that alteration of several signaling pathways (protein kinase C-, Ca 2؉ -and protein-tyrosine kinasesdependent signaling events) were directly responsible for Leishmania-induced macrophage (MØ) dysfunctions. Here we report that modulation of phosphotyrosine-dependent events with a protein tyrosine phosphatases (PTP) inhibitor, the peroxovanadium (pV) compound bpV(phen) (potassium bisperoxo(1,10-phenanthroline)oxovanadate(V i )), can control hostpathogen interactions by different mechanisms. We observed that the inhibition of parasite PTP resulted in an arrest of proliferation and death of the latter in coincidence with cyclin-dependent kinase (CDK1) tyrosine 15 phosphorylation. Moreover the treatment of MØ with bpV(phen) resulted in an increased sensitivity to interferon-␥ stimulation, which was reflected by enhanced nitric oxide (NO) production. This enhanced IFN-␥-induced NO generation was accompanied by a marked increase of inducible nitric oxide synthase (iNOS) mRNA gene and protein expression. Finally we have verified the in vivo potency of bpV(phen) over a 6-week period of daily administration of a sub-toxic dose. The results revealed its effectiveness in controlling the progression of visceral and cutaneous leishmaniasis. Therefore PTP inhibition of Leishmania and MØ by the pV compound bpV(phen) can differentially affect these eukaryotic cells. This strongly suggests that PTP plays an important role in the progression of Leishmania infection and pathogenesis. The apparent potency of pV compounds along with their relatively simple and versatile structure render them attractive pharmacological agents for the management of parasitic infections.

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“…1A) provides the opportunity to more fully characterize the action of peroxovanadium within the cell. The action of vanadium can also be modified by organic ligands that facilitate cellular targeting and biochemical specificity (20,21); for example, we found that BMOV (Fig. 1B) induced apoptosis in B cell lineages but enhanced the activation of T cell lineages (15).…”

mentioning

confidence: 97%

Role of Oxidative Stress in the Action of Vanadium Phosphotyrosine Phosphatase Inhibitors

Krejsa

Nadler

Esselstyn

et al. 1997

Journal of Biological Chemistry

141

105

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The role of intracellular oxidative stress in the mechanism of action of phosphotyrosine phosphatase (PTP) inhibitors was studied using three vanadiumbased compounds. Sodium orthovanadate (Na 3 VO 4 ), sodium oxodiperoxo(1,10-phenanthroline)vanadate(V) (pV(phen), and bis(maltolato)-oxovanadium(IV) (BMOV) differentially induced oxidative stress in lymphocytes. Treatment with pV(phen), which caused intracellular oxidation, induced strong protein tyrosine phosphorylation compared with Na 3 VO 4 and BMOV. Syk family kinases and the mitogen-activated protein kinase erk2 were rapidly activated by pV(phen) but not by BMOV or Na 3 VO 4 . In contrast, both BMOV and pV(phen) strongly activated NF-B. The antioxidant pyrrolidine dithiocarbamate (PDTC) greatly diminished the intracellular oxidation and protein phosphotyrosine accumulation induced by pV(phen). Pretreatment of cells with PDTC reduced and delayed the activation of Syk kinases and erk2. However, NF-B activation by pV(phen) was markedly enhanced in lymphocytes pretreated with PDTC, and another antioxidant, N-acetylcysteine, did not prevent the activation of NF-B by BMOV. These results indicate a role for oxidative stress in the biological effects of some PTP inhibitors, whereas NF-B activation by PTP inhibitors is mediated by mechanisms independent of intracellular redox status.Lymphocyte signal transduction requires the activation of protein tyrosine kinases (PTKs), 1 with subsequent assembly of signaling complexes, generation of second messengers, activation of transcription factors, and gene expression (1, 2). The balance of protein tyrosine phosphorylation within the cell is controlled by the relative activities of the PTKs and PTPs in the signaling network (3). Besides dephosphorylating a variety of PTK substrates, PTPs have been shown to directly modulate the activities of PTKs (4, 5). Thus PTPs serve a crucial function in lymphocytes by controlling both the initiation and termination of receptor-based signals.The inhibition of PTPs reveals PTK substrates on which phosphotyrosine accumulates in the absence of receptor engagement (6). Some of these substrates are key phosphoproteins in lymphocyte signal transduction pathways, suggesting that PTKs involved in transmission of receptor signals are activated by the absence of PTP regulation (6 -9). However, many of the PTP inhibitors used thus far to explore lymphocyte signal transduction pathways are redox-active compounds. For example, phenylarsine oxide, a thiol-reactive compound, and H 2 O 2 , which generates hydroxyl radicals, both act as potent PTP inhibitors (6, 10). The role of intracellular oxidation in the mechanism of action of PTP inhibitors is unknown, a question this study addresses.Vanadium-based PTP inhibitors, which have been extensively studied as insulin mimetic agents, stimulate glucose uptake and fatty acid synthesis in adipocytes and mimic receptor-based signals in lymphocytes (11-15). The widely used PTP inhibitor pervanadate is a peroxovanadium compound generated by reaction of H 2 O 2 wi...

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In vivo insulin mimetic effects of pV compounds: role for tissue targeting in determining potency

Cited by 42 publications

References 24 publications

Activation of dormant ovarian follicles to generate mature eggs

Activation of dormant ovarian follicles to generate mature eggs

Modulation of Interferon-γ-induced Macrophage Activation by Phosphotyrosine Phosphatases Inhibition

Role of Oxidative Stress in the Action of Vanadium Phosphotyrosine Phosphatase Inhibitors

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