Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt

Xing, Bin; Xin, Tao; Hunter, Randy L.; Bing, Guoying

doi:10.1186/1742-2094-5-4

Cited by 107 publications

(78 citation statements)

References 69 publications

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“…To measure the total NO generated, nitrate is enzymatically converted to nitrite by nitrate reductase, and this is measured as a colored azo dye product. The assay quantifies the total NO produced and has been used to measure NO generation by microglial cells in mesencephalic cultures (44).…”

Section: Measurement Of Nitric Oxide Generation In the Anmentioning

confidence: 99%

Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia

MohanKumar

Kasturi²,

Shin

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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MohanKumar SM, Kasturi BS, Shin AC, Balasubramanian P, Gilbreath ET, Subramanian M, MohanKumar PS. Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia. Am J Physiol Regul Integr Comp Physiol 300: R693-R699, 2011. First published December 22, 2010 doi:10.1152/ajpregu.00481.2010.-Estrogens are known to cause hyperprolactinemia, most probably by acting on the tuberoinfundibular dopaminergic (TIDA) system of the hypothalamus. Dopamine (DA) produced by TIDA neurons directly inhibits prolactin secretion and, therefore, to stimulate prolactin secretion, estrogens inhibit TIDA neurons to decrease DA production. However, the mechanism by which estrogen produces this effect is not clear. In the present study, we used a paradigm involving chronic exposure to low levels of estradiol-17␤ (E2) to mimic prolonged exposures to environmental and endogenous estrogens. We hypothesized that chronic exposure to low levels of E2 induces oxidative stress in the arcuate nucleus (AN) of the hypothalamus that contains TIDA neurons and causes nitration of tyrosine hydroxylase (TH), the ratelimiting enzyme in the synthesis of DA. This results in a significant decrease in DA and consequently, hyperprolactinemia. To investigate this, adult, intact female cycling rats were implanted with slow-release E2 pellets (20 ng/day) for 30, 60, or 90 days and were compared with old (16 -18 mo old) constant estrous (OCE) rats. Chronic E2 exposure significantly increased the expression of glial fibrillary acidic protein and the concentrations of interleukin-1␤ (IL-1␤) and nitrate in the AN that contains perikarya of TIDA neurons and increased nitration of TH in the median eminence (ME) that contains the terminals. These levels were comparable to those seen in OCE rats. We observed a significant decrease in DA concentrations in the ME and hyperprolactinemia in an exposure-dependent manner similar to that seen in OCE rats. It was concluded that chronic exposure to low levels of E2 evokes oxidative stress in the AN to inhibit TIDA neuronal function, most probably leading to hyperprolactinemia. prolactin; nitration; tyrosine hydroxylase ESTROGENS ARE PLEIOTROPIC hormones and have been shown to have several beneficial effects: Estrogen therapy can prevent bone loss (27) and decrease the risk of coronary disease (45). Estrogens can also provide neuroprotection during ischemic brain injury and Alzheimer's disease and are believed to improve memory in postmenopausal women (13,40,43). In rats, both acute (5) and subchronic treatment (16, 23) with moderate to high doses of estradiol are known to increase prolactin (PRL) levels. PRL levels also increase during aging, specifically after rats have been in the constant estrous state for 4 or 5 mo (10). This increase in PRL levels is known to promote mammary and pituitary tumor formation (15,17). Estrogen is known to act directly on the pituitary gland and also inhibit hypothalamic dopamine (DA) to stimulate PRL release (10). While seve...

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Section: Measurement Of Nitric Oxide Generation In the Anmentioning

confidence: 99%

Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia

MohanKumar

Kasturi²,

Shin

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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“…While some reports have shown that activation of the PI3K pathway serves as a negative regulator of inflammation, 62,63 others have reported that activation of Akt contributes to the inflammatory phenotype in immune cells. 37 Furthermore, as constitutive activation of PI3K results in SLE-like disease, 64,65 it has been suggested that targeting Akt activation in the setting of SLE may have therapeutic effects.…”

Section: Egcg Inhibits Inflammation In Lupus Mesangial Cells a Peairsmentioning

confidence: 99%

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

et al. 2010

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Epigallocatechin-3-gallate (EGCG), a bioactive component of green tea, has been reported to exert anti-inflammatory effects on immune cells. EGCG is also shown to activate the metabolic regulator, adenosine 5'-monophosphate-activated protein kinase (AMPK). Reports have also indicated that EGCG inhibits the immune-stimulated phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. The PI3K/Akt/mTOR pathway has been implicated in mesangial cell activation in lupus. Mesangial cells from MRL/lpr lupus-like mice are hyper-responsive to immune stimulation and overproduce nitric oxide (NO) and other inflammatory mediators when stimulated. In our current studies, we sought to determine the mechanism by which EGCG attenuates immune-induced expression of pro-inflammatory mediators. Cultured mesangial cells from MRL/lpr mice were pre-treated with various concentrations of EGCG and stimulated with lipopolysaccharide (LPS)/interferon (IFN)-c. EGCG activated AMPK and blocked LPS/ IFN-c-induced inflammatory mediator production (iNOS expression, supernatant NO and interleukin-6). Interestingly, EGCG attenuated inflammation during AMPK inhibition indicating that the anti-inflammatory effect of EGCG may be partially independent of AMPK activation. Furthermore, we found that EGCG effectively inhibited the immune-stimulated PI3K/Akt/mTOR pathway independently of AMPK, by decreasing phosphorylation of Akt, suggesting an alternate mechanism for EGCG-mediated anti-inflammatory action in mesangial cells. Taken together, these studies show that EGCG attenuated inflammation in MRL/lpr mouse mesangial cells via the PI3K/Akt/mTOR pathway. Our findings suggest a potential therapeutic role for the use of EGCG to regulate inflammation and control autoimmune disease.

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“…3 and 4). Rosiglitazone acts predominantly through the PPAR␥ pathway (22); however, non-PPAR␥ related effects in response to rosiglitazone treatment have been reported (19,22,41). Therefore, to determine if rosiglitazone is eliciting its protective effects on mitochondrial function in this model through PPAR␥ activation, we measured mitochondrial potential in striatal cells preincubated for 24 h with rosiglitazone, in the presence or absence of GW9662 (Fig.…”

Section: Gw9662 Prevents Mitochondrial Function Improvement Induced Bmentioning

confidence: 99%

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

Quintanilla

Jin

Fuenzalida

et al. 2008

Journal of Biological Chemistry

118

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Peroxisome proliferator-activated receptor-␥ (PPAR␥) is a member of the PPAR family of transcription factors. Synthetic PPAR␥ agonists are used as oral anti-hyperglycemic drugs for the treatment of non-insulin-dependent diabetes. However, emerging evidence indicates that PPAR␥ activators can also prevent or attenuate neurodegeneration. Given these previous findings, the focus of this report is on the potential neuroprotective role of PPAR␥ activation in preventing the loss of mitochondrial function in Huntington disease (HD). For these studies we used striatal cells that express wild-type (STHdh Q7/Q7 ) or mutant (STHdh Q111/Q111 ) huntingtin protein at physiological levels. Treatment of mutant cells with thapsigargin resulted in a significant decrease in mitochondrial calcium uptake, an increase in reactive oxygen species production, and a significant decrease in mitochondrial membrane potential. PPAR␥ activation by rosiglitazone prevented the mitochondrial dysfunction and oxidative stress that occurred when mutant striatal cells were challenged with pathological increases in calcium. The beneficial effects of rosiglitazone were likely mediated by activation of PPAR␥, as all protective effects were prevented by the PPAR␥ antagonist GW9662. Additionally, the PPAR␥ signaling pathway was significantly impaired in the mutant striatal cells with decreases in PPAR␥ expression and reduced PPAR␥ transcriptional activity. Treatment with rosiglitazone increased mitochondrial mass levels, suggesting a role for the PPAR␥ pathway in mitochondrial function in striatal cells. Altogether, this evidence indicates that PPAR␥ activation by rosiglitazone attenuates mitochondrial dysfunction in mutant huntingtin-expressing striatal cells, and this could be an important therapeutic avenue to ameliorate the mitochondrial dysfunction that occurs in HD.

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Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt

Abstract: Background: Previous studies have suggested that peroxisome proliferator activated receptor-gamma (PPAR-γ)-mediated neuroprotection involves inhibition of microglial activation and decreased expression and activity of

Cited by 107 publications

References 69 publications

Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia

Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

Rosiglitazone Treatment Prevents Mitochondrial Dysfunction in Mutant Huntingtin-expressing Cells

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