Receptor Gamma Signaling Pathways Research Articles

Atorvastatin protects against postoperative neurocognitive disorder via a peroxisome proliferator-activated receptor-gamma signaling pathway in mice.

ObjectivePostoperative neurocognitive disorder (PND) is a main complication that is commonly seen postoperatively in elderly patients. The underlying mechanism remains unclear, although neuroinflammation has been increasingly observed in PND. Atorvastatin is a pleiotropic agent with proven anti-inflammatory effects. In this study, we investigated the effects of atorvastatin on a PND mouse model after peripheral surgery.Material and methodsThe mice were randomized into five groups. The PND models were established, and an open field test and fear condition test were performed. Hippocampal inflammatory cytokine expression was determined using ELISA. Peroxisome proliferator-activated receptor-gamma (PPARγ) expression in the hippocampus was tested using qRT-PCR and western blot analysis.ResultsOn day 1 after surgery, inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6 showed a significant increase in the hippocampus, with prominent cognitive impairment. Atorvastatin treatment improved cognitive function in the mouse model, attenuated neuroinflammation, and increased PPARγ expression in the hippocampus. However, treatment with the PPARγ antagonist GW9662 partially reversed the protective effects of atorvastatin.ConclusionsThese results indicated that atorvastatin improves several hippocampal functions and alleviates inflammation in PND mice after surgery, probably through a PPARγ-involved signaling pathway.

Breast Cancer Genetic and Molecular Subtype Impacts Response to Omega-3 Fatty Acid Ethyl Esters

ABSTRACTEpidemiological studies have correlated frequent omega-3 (n-3) fatty acid consumption with a lower risk for breast cancer; however, recent prospective studies have been less conclusive. Efforts in the preventive setting have focused on the use of n-3 fatty acids, and the pharmaceutical ethyl esters (EE) of these natural compounds, for high-risk patient populations. Limited understanding of specific mechanisms by which these agents function has hampered identification of the cancer subtype(s) that would gain the greatest therapeutic benefit. In this study, we investigated the in vitro effects of n-3 EEs in four distinct breast cancer subtypes and explored how they affect not only breast cancer cell survival but also modulate the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and peroxisome proliferator-activated receptor gamma signaling pathways. Similar to the high variance in response observed in human studies, we found that the effectiveness of n-3 EEs depends on the molecular characteristics of the MCF-7, CAMA-1, MDA-MB-231, and SKBR3 breast cancer cell lines and is closely associated with the suppression of NF-κB. These data strongly suggest that the use of n-3 fatty acids and their pharmaceutical ether esters in the prevention and therapeutic setting should be guided by specific tumor characteristics.

Homeodomain interacting protein kinase 2 is downregulated through the peroxisome proliferator-activated receptor gamma signaling pathway in an insulin-resistant population.

Homeodomain interacting protein kinase 2 (HIPK2), the highly conserved nuclear serine/threonine kinase, is known to act as a co-repressor through interacting with a number of transcription factors. Notably, HIPK2 inhibits cell growth through the activation of p53. However, its in vivo function in insulin resistance is still unknown. Recently, the discovery by Sjolund et al.1 has implicated HIPK2 as a central modulator of adipogenesis. They found that deletion of HIPK2 in mice gave rise to decreased adipogenesis and increased insulin-sensitivity independence of the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. According to their result, we hypothesize that the expression of HIPK2 in the insulin-resistant population might be upregulated. To testify our supposition, we analyzed the publicly available expression data from two human insulin-resistant expression data in GEO datasets that use the same platform. Contrary to our deduction, the HIPK2 gene was downregulated in the insulin-resistant population (Figure ​(Figure11a,b). Figure 1 Decreased expression of homeodomain interacting protein kinase 2 (HIPK2) in an insulin resistant population was associated with the peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway. (a,b) Expression of HIPK2 detected ... PPARγ is the key transcription factor in adipogenesis, as well as glucose and fatty acid metabolism, and alterations in the pathway lead to insulin resistance and type 2 diabetes mellitus2. According to the report by Sjolund et al.1, the function of HIPK2 was not mediated by a PPARγ-dependent mechanism1. However, we identified that some downstream targets of PPARγ, which Sjolund et al. mentioned, were downregulated in adipocytes in insulin-resistant people, which is synchronously expressed with HIPK2 messenger ribonucleic acid expression (Figure ​(Figure1c).1c). Some transcription cofactors of PPARγ shown by GeneMANIA (http://www.genemania.org/) were also downregulated in the adipocytes of the insulin-resistant population (Figure ​(Figure11d). Rosiglitazone (Rosi), a member of the thiazolidinediones and an agonist of PPARγ, works as an insulin sensitizer in type 2 diabetes mellitus3. The present results showed that HIPK2 messenger ribonucleic acid expression was significantly increased in the presence of both Rosi and overexpressed PPARγ in murine marrow-derived U-33 cells, indicating a tendency of increased HIPK2 expression after administration of insulin sensitizer (Figure ​(Figure1e).1e). In agreement with this, several other articles published the same results that HIPK2 expression was elevated after administration of insulin sensitizer, rosiglitazone and troglitazone (Table S1), suggested by The Comparative Toxicogenomics Database (http://ctdbase.org/). Taken together, despite of Sjolund et al. discovery that HIPK2 deletion in mice induces increased insulin sensitivity and was not mediated by the PPARγ pathway, our data suggest that downexpression of HIPK2 was discovered in a population that suffered from decreased insulin sensitivity (insulin resistance) through the PPARγ-dependent pathway. This discrepancy might be caused by the following reasons: (i) metabolic differences between humans and murine; (ii) the discovery by Sjolund et al. was carried out on skeletal muscle, where the present results were shown in adipocytes; and (iii) our discovery was the result of a subset of humans, accordingly, the discovery by Sjolund et al. was based on a few HIPK2 knockout mice, the two studies all await further verification. Furthermore, we also showed that administration of insulin sensitizer could promote the elevated expression of HIPK2, thus providing a benefit for treatment of insulin resistance.

Osteoblast-Targeted Overexpression of TAZ Increases Bone Mass In Vivo

Osteoblasts are derived from mesenchymal progenitors. Differentiation to osteoblasts and adipocytes is reciprocally regulated. Transcriptional coactivator with a PDZ-binding motif (TAZ) is a transcriptional coactivator that induces differentiation of mesenchymal cells into osteoblasts while blocking differentiation into adipocytes. To investigate the role of TAZ on bone metabolism in vivo, we generated transgenic mice that overexpress TAZ under the control of the procollagen type 1 promoter (Col1-TAZ). Whole body bone mineral density (BMD) of 6- to 19-week-old Col-TAZ mice was 4% to 7% higher than that of their wild-type (WT) littermates, whereas no difference was noticed in Col.1-TAZ female mice. Microcomputed tomography analyses of proximal tibiae at 16 weeks of age demonstrated a significant increase in trabecular bone volume (26.7%) and trabecular number (26.6%) with a reciprocal decrease in trabecular spacing (14.2%) in Col1-TAZ mice compared with their WT littermates. In addition, dynamic histomorphometric analysis of the lumbar spine revealed increased mineral apposition rate (42.8%) and the serum P1NP level was also significantly increased (53%) in Col.1-TAZ mice. When primary calvaria cells were cultured in osteogenic medium, alkaline phosphatase (ALP) activity was significantly increased and adipogenesis was significantly suppressed in Col1-TAZ mice compared with their WT littermates. Quantitative real-time polymerase chain reaction analyses showed that expression of collagen type 1, bone sialoprotein, osteocalcin, ALP, osterix, and Runx2 was significantly increased in calvaria cells from Col1-TAZ mice compared to their WT littermates. In vitro, TAZ enhanced Runx2-mediated transcriptional activity while suppressing the peroxisome proliferator-activated receptor gamma signaling pathway. TAZ also enhanced transcriptional activity from 3TP-Lux, which reflects transforming growth factor-beta (TGF-β)-mediated signaling. In addition, TAZ enhanced TGF-β-dependent nuclear translocation of Smad2/3 and Smad4. Taken together, these results suggest that TAZ positively regulates bone formation in vivo, which seems to be mediated by enhancing both Runx2 and TGF-β signaling.

The 9-Cis Retinoic Acid Signaling Pathway and Its Regulation of Prostaglandin-Endoperoxide Synthase 2 During In Vitro Maturation of Pig Cumulus Cell-Oocyte Complexes and Effects on Parthenogenetic Embryo Production1

The addition of 9-cis retinoic acid to the oocyte maturation culture medium has a beneficial effect on in vitro fertilized embryos. However, the mechanism of this activity is not known. Therefore, this study was done to elucidate the effect of 9-cis retinoic acid on parthenogenetic embryo production and its signaling pathway and molecular function during in vitro maturation of porcine cumulus cell-oocyte complexes (COCs). Concentrations of 0, 5, 50, and 500 nM 9-cis retinoic acid were added to the in vitro maturation medium, and the embryos were assessed after parthenogenetic activation. Cumulus cells and oocytes from the in vitro matured COCs were separated and subjected to RT-PCR and real-time RT-PCR for detecting retinoic acid receptors and measuring expression of prostaglandin-endoperoxide synthase1 and 2. The addition of 5 nM 9-cis retinoic acid to the maturation medium was beneficial for parthenogenetic embryo production. The effect of 9-cis retinoic acid was exerted directly through the oocytes via the retinoic acid receptor alpha and retinoid X receptor gamma signaling pathways and indirectly through the cumulus cells by the retinoic acid receptor beta and gamma and retinoid X receptor alpha and beta signaling pathways. The addition of 5 nM 9-cis retinoic acid-stimulated cumulus cells reaches full expansion by suppressing their excessive expression of prostaglandin-endoperoxide synthase 2. This study shows that 9-cis retinoic acid can exert its beneficial effect on parthenogenetic embryo production in pigs by multidimensional pathways affecting oocyte maturation.

Effect of maternal food restriction on fetal rat lung lipid differentiation program

Although "fetal programming" has been extensively studied in many organs, there is only limited information on pulmonary effects in the offspring following intrauterine growth restriction (IUGR). We aimed to determine the effects of nutrient restriction on the lung structure and lung lipid differentiation programs in offspring using an animal mode of maternal food restriction (MFR). We utilized a rodent model of 50% MFR from day 10 of gestation to term and then using lung morphology, Western blotting, Real Time RT-PCR and Oil Red O staining, lung structure and development of the offspring were examined at postnatal days (p) 1, p21, and 9 months (9M). At postnatal day 1, MFR pups weighed significantly less compared to control pups, but at p21 and 9M, they weighed significantly more. However, lung weight, expressed as a percentage of body weight between the two groups was not different at all time-points examined. The MFR group had significantly decreased alveolar number and significantly increased septal thickness at p1 and 9M, indicating significantly altered lung structure in the MFR offspring. Furthermore, although at p1, compared to the control group, lung lipid accumulation was significantly decreased in the MFR group, at 9M, it was significantly increased. There were significant temporal changes in the parathyroid hormone-related protein/peroxisome proliferator-activated receptor gamma signaling pathway and surfactant synthesis. We conclude that MFR alters fetal lung lipid differentiation programming and lung morphometry by affecting specific epithelial-mesenchymal signaling pathways, offering the possibility for specific interventions to overcome these effects.