2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities

Kandadi, Machender R.; Rajanna, Prabhakar; Unnikrishnan, M.K.; Boddu, Sai P.; Hua, Yinan; Ji, Li Li; Du, Min; Ren, Jun; Nair, Sreejayan

doi:10.1016/j.bcp.2009.09.018

Cited by 12 publications

(7 citation statements)

References 32 publications

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“…After three washes in TBS-T, immunoreactive bands were detected using the super signal west Dura Extended Duration Substrate (Pierce, Milwaukee, WI). The intensity of bands was measured using a Bio-Rad densitometer [17]. …”

Section: Methodsmentioning

confidence: 99%

RETRACTED: Influence of gestational overfeeding on myocardial proinflammatory mediators in fetal sheep heart

Kandadi

Hua

Zhu

et al. 2013

The Journal of Nutritional Biochemistry

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Maternal overnutrition is associated with predisposition of offspring to cardiovascular disease in later life. Since maternal overnutrition may promote fetal and placental inflammatory responses, we hypothesized that maternal overnutrition/obesity increases expression of fetal cardiac proinflammatory mediators and alter cardiac morphometry. Multiparous ewes were fed either 150% of National Research Council (NRC) nutrient recommendations (overfed) or 100% of NRC requirement (control) from 60 days prior to mating to gestation day 75 (D75), when ewes were euthanized. An additional cohort of overfed and control ewes were necropsied on D135. Cardiac morphometry, histology, mRNA and protein expression of TLR4, iNOS, IL-1a, IL-1b, IL-6, IL-18, CD-14, CD-68, M-CSF and protein levels of phosphorylated I-κB and NF-κB were examined. Immunohistochemistry was performed to assess neutrophil and monocyte infiltration. Crown rump length, left and right ventricular free wall weights as well as left and right ventricular wall thickness were significantly increased in D75 fetuses of overfed mothers. Hematoxylin and eosin staining revealed irregular myofiber orientation and increased interstitial space in fetal ventricular tissues born to overfed mothers. Oil red O staining exhibited marked lipid droplet accumulation in the overfed fetuses. Overfeeding significantly enhanced TLR-4, IL-1a, IL-1b IL-6 expression, promoted phosphorylation of IκB, decreased cytoplasmic NF-κB levels and increased neutrophil and monocyte infiltration. Collectively, these data suggest that maternal overfeeding prior to and throughout gestation leads to inflammation in the fetal heart and alters fetal cardiac morphometry.

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Section: Methodsmentioning

confidence: 99%

RETRACTED: Influence of gestational overfeeding on myocardial proinflammatory mediators in fetal sheep heart

Kandadi

Hua

Zhu

et al. 2013

The Journal of Nutritional Biochemistry

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“…Ex vivo [ 3 H]-2-deoxy-glucose-uptake assay was performed as previously described [35]. Briefly, gastrocnemius muscles were dissected out from mice, incubated in Krebs–Ringer phosphate HEPES buffer (KRPH buffer; 10 mM phosphate buffer, pH 7.4, 1 mM MgSO4, 1 mMCaCl2, 136 mM NaCl, 4.7 mM KCl, 10 mM HEPES (pH 7.6)) for 30 min in an atmosphere containing 5% CO 2 and then incubated for 30 min at 37°C in the presence of 2-deoxy-[ 3 H]-glucose (0.2 µCi) and 100 nmol/l insulin.…”

Section: Methodsmentioning

confidence: 99%

Protein Tyrosine Phosphatase 1B and Insulin Resistance: Role of Endoplasmic Reticulum Stress/Reactive Oxygen Species/Nuclear Factor Kappa B Axis

2013

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Obesity-induced endoplasmic reticulum (ER) stress has been proposed as an important pathway in the development of insulin resistance. Protein-tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signaling and is tethered to the ER-membrane. The aim of the study was to determine the mechanisms involved in the crosstalk between ER-stress and PTP1B. PTP1B whole body knockout and C57BL/6J mice were subjected to a high-fat or normal chow-diet for 20 weeks. High-fat diet feeding induced body weight gain, increased adiposity, systemic glucose intolerance, and hepatic steatosis were attenuated by PTP1B deletion. High-fat diet- fed PTP1B knockout mice also exhibited improved glucose uptake measured using [3H]-2-deoxy-glucose incorporation assay and Akt phosphorylation in the skeletal muscle tissue, compared to their wild-type control mice which received similar diet. High-fat diet-induced upregulation of glucose-regulated protein-78, phosphorylation of eukaryotic initiation factor 2α and c-Jun NH2-terminal kinase-2 were significantly attenuated in the PTP1B knockout mice. Mice lacking PTP1B showed decreased expression of the autophagy related protein p62 and the unfolded protein response adaptor protein NCK1 (non-catalytic region of tyrosine kinase). Treatment of C2C12 myotubes with the ER-stressor tunicamycin resulted in the accumulation of reactive oxygen species (ROS), leading to the activation of protein expression of PTP1B. Furthermore, tunicamycin-induced ROS production activated nuclear translocation of NFκB p65 and was required for ER stress-mediated expression of PTP1B. Our data suggest that PTP1B is induced by ER stress via the activation of the ROS-NFκB axis which is causes unfolded protein response and mediates insulin resistance in the skeletal muscle under obese condition.

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“…2-Deoxy[ 3 H]glucose-uptake assay was performed as previously described [25]. Briefly, cells were incubated in Krebs–Ringer phosphate HEPES buffer for 30 min at 37°C in the presence of 2-deoxy[ 3 H]glucose (7,400 Bq) and 50 nmol/l of insulin.…”

Section: Methodsmentioning

confidence: 99%

Endoplasmic reticulum stress upregulates protein tyrosine phosphatase 1B and impairs glucose uptake in cultured myotubes

Panzhinskiy¹,

Hua²,

Culver³

et al. 2012

Diabetologia

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Aims/hypothesis Endoplasmic reticulum (ER) stress has been recognised as a common pathway in the development of obesity-associated insulin resistance. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of insulin signalling and is localised on the ER membrane. The aim of the study was to investigate the cross-talk between ER stress and PTP1B. Methods Leptin-deficient obese (ob/ob), Ptp1b (also known as Ptpn1) knockout and C57BL/6J mice were subjected to a high-fat or normal-chow diet for 20 weeks. ER stress was induced in cultured myotubes by treatment with tunicamycin. Immunohistochemistry and western blotting were used to assess proteins involved in the ER stress response. Myotube glucose uptake was determined by measuring 2-deoxy[3H]glucose incorporation. Results A high-fat diet induced ER stress and PTP1B expression in the muscle tissue of mice and these responses were attenuated by treatment with the ER chaperone tauroursodeoxycholic acid (TUDCA). Cultured myotubes exhibited increased levels of PTP1B in response to tunicamycin treatment. Silencing of Ptp1b with small interfering RNA (siRNA) or overexpression of Ptp1b with adenovirus construct failed to alter the levels of ER stress. Ptp1b knockout mice did not differ from the wild-type mice in the extent of tunicamycin-induced upregulation of glucose-regulated protein-78. However, tunicamycin-induced phosphorylation of eukaryotic initiation factor 2α and c-Jun NH2-terminal kinase-2 were significantly attenuated in the Ptp1b knockout mice. Treatment with TUDCA or silencing of PTP1B reversed tunicamycin-induced blunted myotube glucose uptake. Conclusions/interpretation Our data suggest that PTP1B is activated by ER stress and is required for full-range activation of ER stress pathways in mediating insulin resistance in the skeletal muscle.

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2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities

Cited by 12 publications

References 32 publications

RETRACTED: Influence of gestational overfeeding on myocardial proinflammatory mediators in fetal sheep heart

RETRACTED: Influence of gestational overfeeding on myocardial proinflammatory mediators in fetal sheep heart

Protein Tyrosine Phosphatase 1B and Insulin Resistance: Role of Endoplasmic Reticulum Stress/Reactive Oxygen Species/Nuclear Factor Kappa B Axis

Endoplasmic reticulum stress upregulates protein tyrosine phosphatase 1B and impairs glucose uptake in cultured myotubes

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