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Hou X.,Omaha Veterans Affairs Medical Center | Hou X.,Olson Center for Womens Health | Arvisais E.W.,Olson Center for Womens Health | Davis J.S.,Omaha Veterans Affairs Medical Center | And 2 more authors.
Endocrinology | Year: 2010

LH stimulates the production of cAMP in luteal cells, which leads to the production of progesterone, a hormone critical for the maintenance of pregnancy. The mammalian target of rapamycin (MTOR) signaling cascade has recently been examined in ovarian follicles where it regulates granulosa cell proliferation and differentiation. This study examined the actions of LH on the regulation and possible role of the MTOR signaling pathway in primary cultures of bovine corpus luteum cells. Herein, we demonstrate that activation of the LH receptor stimulates the phosphorylation of the MTOR substrates ribosomal protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1. The actions of LH were mimicked by forskolin and 8-bromo-cAMP. LH did not increase AKT or MAPK1/3 phosphorylation. Studies with pathway-specific inhibitors demonstrated that the MAPK kinase 1 (MAP2K1)/MAPK or phosphatidylinositol 3-kinase/AKT signaling pathways were not required for LH-stimulated MTOR/S6K1 activity. However, LH decreased the activity of glycogen synthase kinase 3B (GSK3B) and AMP-activated protein kinase (AMPK). The actions of LH on MTOR/S6K1 were mimicked by agents that modulated GSK3B and AMPK activity. The ability of LH to stimulate progesterone secretion was not prevented by rapamycin, a MTOR inhibitor. In contrast, activation of AMPK inhibited LH-stimulated MTOR/S6K1 signaling and progesterone secretion. In summary, the LH receptor stimulates a unique series of intracellular signals to activate MTOR/S6K1 signaling. Furthermore, LH-directed changes in AMPK and GSK3B phosphorylation appear to exert a greater impact on progesterone synthesis in the corpus luteum than rapamycin-sensitive MTOR-mediated events. Copyright © 2010 by The Endocrine Society. Source

Carlson M.A.,University of Nebraska Medical Center | Carlson M.A.,Omaha Veterans Affairs Medical Center | Chakkalakal D.,Orthopedic Research Laboratory | Chakkalakal D.,Creighton University
PLoS ONE | Year: 2011

Background: In clinical surgery, the vertical midline abdominal incision is popular but associated with healing failures. A murine model of the ventral vertical midline incision was developed in order to study the healing of this incision type. Methodology/Principal Findings: The strength of the wild type murine ventral abdominal wall in the midline was contained within the dermis; the linea alba made a negligible contribution. Unwounded abdominal wall had a downward trend (nonsignificant) in maximal tension between 12 and 29 weeks of age. The incision attained 50% of its final strength by postoperative day 40. The maximal tension of the ventral vertical midline incision was nearly that of unwounded abdominal wall by postwounding day 60; there was no difference in unwounded vs. wounded maximal tension at postwounding day 120. Conclusions/Significance: After 120 days of healing, the ventral vertical midline incision in the wild type mouse was not significantly different from age-matched nonwounded controls. About half of the final incisional strength was attained after 6 weeks of healing. The significance of this work was to establish the kinetics of wild type incisional healing in a model for which numerous genotypes and genetic tools would be available for subsequent study. Source

Desouza C.V.,Omaha Veterans Affairs Medical Center | Desouza C.V.,University of Nebraska Medical Center | Gupta N.,University of Nebraska Medical Center | Patel A.,University of Nebraska Medical Center
Clinical Therapeutics | Year: 2015

Purpose Within the past decade, many new classes of drugs have received approval from the US Food and Drug Administration for treatment of type 2 diabetes mellitus, including glucagon-like peptide-1agonists, dipeptidyl peptidase-4 inhibitors, and the sodium-glucose cotransporter-2 inhibitors. Many trials have been performed, and several more are currently ongoing to evaluate these drugs. This review addresses the broad therapeutic and pleiotropic effects of these drugs. The review also discusses the role of these drugs in the treatment paradigm for type 2 diabetes and identifies patients who would be suitable candidates for treatment with these drugs. Methods In this comprehensive evidence-based review, the following databases were searched from 1990 to the present: PubMed/MEDLINE, Scopus, CINAHL, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Portal, and the American Diabetes Association and European Association for the Study of Diabetes abstract databases. Randomized clinical trials (RCTs) were only included for the main therapeutic and cardiovascular (CV) effects of these drug classes. For pleiotropic effects, RCTs were included unless no RCTs exist, in which case other studies as specified in the detailed Methods section were included. Findings All 3 drug classes are effective in lowering hemoglobin A1c between 0.4% and 1.4%, depending on the drug class and population selected. These drug classes have beneficial effects on CV risk factors, such as weight, lipids, and blood pressure, in addition to lowering blood glucose levels. The CV tolerability of some drugs has been evaluated and found to be neutral; however, most trials are currently ongoing to assess CV tolerability. There are no concrete guidelines to determine where these drugs fit in the diabetes management paradigm, and there are ongoing trials to determine the best combination drug with metformin. Implications These 3 drug classes will potentially increase the armamentarium against hyperglycemia. However, the specific combinations with other antidiabetic drugs and populations that will best benefit from these drugs are still being tested. Future research is also being conducted on the use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors in patients with type 1 diabetes. Source

Gaffo A.L.,University of Alabama at Birmingham | Roseman J.M.,University of Alabama at Birmingham | Jacobs Jr. D.R.,University of Minnesota | Jacobs Jr. D.R.,University of Oslo | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Objective: To investigate if beer, liquor (spirits), wine and total alcohol intakes have different associations with serum urate (SU) concentrations at different ages in a cohort of young men and women. Methods: Data from 3123 participants at baseline and follow-up at 20 years were used, with balanced proportions of Caucasians and African Americans. The relationships of SU with categories of beer, liquor, wine and total alcohol intake referent to no intake were examined in sex-specific, cross-sectional analyses. Results: Mean age (SD) at the beginning of follow-up was 25.1 (3.6) years. Compared with non-drinkers, signifi cant associations between higher SU concentrations and greater beer intake were observed among men and women, with more pronounced and consistent associations for women. An association between greater liquor intake and higher SU concentrations was only seen for men at the year 20 evaluation. Wine intake was not associated with SU in either sex and total alcohol was associated with higher SU concentrations in both men and women. The magnitude of the associations between alcoholic beverages intake and SU was modest (≤0.03 mg/dl/alcoholic beverage serving). Conclusion: An association between higher SU concentrations and greater beer intake was consistent and pronounced among women, but also present in men. Despite the small magnitude of the increases in SU associated with alcohol intake, clinical implications in conditions such as cardiovascular disease and gout in young adults who are moderate and heavy drinkers cannot be ruled out. Source

Fu D.,University of Nebraska Medical Center | Lv X.,University of Nebraska Medical Center | Hua G.,University of Nebraska Medical Center | Hua G.,Huazhong Agricultural University | And 8 more authors.
Endocrine-Related Cancer | Year: 2014

The Hippo signaling pathway has been implicated as a conserved regulator of organ size in both Drosophila and mammals. Yes-associated protein (YAP), the central component of the Hippo signaling cascade, functions as an oncogene in several malignancies. Ovarian granulosa cell tumors (GCT) are characterized by enlargement of the ovary, excess production of estrogen, a high frequency of recurrence, and the potential for malignancy and metastasis. Whether the Hippo pathway plays a role in the pathogenesis of GCT is unknown. This study was conducted to examine the expression of YAP in human adult GCTs and to determine the role of YAP in the proliferation and steroidogenesis of GCT cells. Compared with age-matched normal human ovaries, GCT tissues exhibited higher levels of YAP expression. YAP protein was predominantly expressed in the nucleus of tumor cells, whereas the non-tumor ovarian stromal cells expressed very low levels of YAP. YAP was also expressed in cultured primary human granulosa cells and in KGN and COV434 GCT cell lines. siRNA-mediated knockdown of YAP in KGN cells resulted in a significant reduction in cell proliferation (P<0.001). Conversely, overexpression of wild type YAP or a constitutively active YAP (YAP1) mutant resulted in a significant increase in KGN cell proliferation and migration. Moreover, YAP knockdown reduced FSH-induced aromatase (CYP19A1) protein expression and estrogen production in KGN cells. These results demonstrate that YAP plays an important role in the regulation of GCTcell proliferation, migration, and steroidogenesis. Targeting the Hippo/YAP pathway may provide a novel therapeutic approach for GCT. © 2014 Society for Endocrinology. Source

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