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It has been documented that stress or glucocorticoids have conflicting effects on memory under different conditions. However, it is not fully understood why stress can either impair or enhance memory. Here, we have examined the performance of six age groups of Wistar rats in a water maze spatial task to evaluate the effects of stress under different conditions. We found that the impairment or enhancement effect of an 'elevated platform' (EP) stress on memory was dependent on previous stress experience and on age. EP stress impaired memory retrieval in water maze naive animals, but enhanced rather than impaired memory retrieval in young water maze stress-experienced animals. Furthermore, exogenously applied corticosterone or foot shock stress before water maze training prevented the impairment of memory retrieval that should be induced by treatment with corticosterone or foot shock before the 'probe trial'. Again, memory retrieval was enhanced in young animals under these conditions, and this enhancement can be prevented by the glucocorticoid receptor antagonist RU 38486. Thus, glucocorticoid receptor activation not only induced impairment of memory but also increased the capacity of young animals to overcome a later stress. The present findings suggest that the effect of stress on memory can be switched from impairment to enhancement dependent on both stress experience and age.
Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming 82071, USA
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Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming 82071, USA
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Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming 82071, USA
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Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming 82071, USA
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Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming 82071, USA
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Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming 82071, USA
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Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming 82071, USA
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Department of Zoology and Physiology, University of Wyoming, Laramie, Wyoming 82071, USA
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The level of the obese gene product leptin is often positively correlated with body weight, supporting the notion that hyperleptinemia contributes to obesity-associated cardiac dysfunction. However, a link between leptin levels and cardiac function has not been elucidated. This study was designed to examine the role of leptin deficiency (resulting from a point mutation of the leptin gene) in cardiomyocyte contractile function. Mechanical properties and intracellular Ca2 + transients were evaluated in ventricular myocytes from lean control and leptin-deficient ob/ob obese mice at 12 weeks of age. Cardiac ultrastructure was evaluated using transmission electron microscopy. ob/ob mice were overtly obese, hyperinsulinemic, hypertriglycemic, hypoleptinemic and euglycemic. Ultrastructural examination revealed swelling and disorganization of cristae in mitochondria from ob/ob mouse ventricular tissues. Cardiomyocytes from ob/ob mice displayed reduced expression of the leptin receptor Ob-R, larger cross-sectional area, decreased peak shortening and maximal velocity of shortening/relengthening, and prolonged relengthening but not shortening duration compared with lean counterparts. Consistent with mechanical characteristics, myocytes from ob/ob mice displayed reduced intracellular Ca2 + release upon electrical stimulus associated with a slowed intracellular Ca2 + decay rate. Interestingly, the contractile aberrations seen in ob/ob myocytes were significantly improved by in vitro leptin incubation. Contractile dysfunction was not seen in age- and gender-matched high fat-induced obese mice. These results suggested that leptin deficiency contributes to cardiac contractile dysfunction characterized by both systolic and diastolic dysfunction, impaired intracellular Ca2 + hemostasis and ultrastructural derangement in ventricular myocytes.
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In oncogenic osteomalacia (OOM), a tumor produces an unknown substance that inhibits phosphate reabsorption in the proximal tubules. This causes urinary phosphate wasting and, as a consequence, hypophosphatemic osteomalacia. To characterize this poorly understood biological tumor activity we generated aqueous extracts from several OOM tumors. Extracts from three of four tumors inhibited, dose- and time-dependently, (32)P-orthophosphate uptake by opossum kidney (OK) cells; maximum inhibition was about 45% of untreated control. Further characterization revealed that the factor is resistant to heat and several proteases, and that it has a low molecular weight. The tumor extracts also stimulated cAMP accumulation in OK cells, but not in osteoblastic ROS 17/2.8 and UMR106 cells, or in LLC-PK1 kidney cells expressing the parathyroid hormone (PTH)/PTH-related peptide receptor or the PTH-2 receptor. HPLC separation of low molecular weight fractions of the tumor extracts revealed that the flow-through of all three positive tumor extracts inhibited (32)P uptake and stimulated cAMP accumulation in OK cells. Additionally, a second peak with inhibitory activity on phosphate transport, but without cAMP stimulatory activity, was identified in the most potent tumor extract. We have concluded that several low molecular weight molecules with the ability to inhibit phosphate transport in OK cells can be found in extracts from OOM tumors. It remains uncertain, however, whether these are related to the long-sought phosphaturic factor responsible for the phosphate wasting seen in OOM patients.
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For centuries, Berberine has been used in the treatment of enteritis in China, and it is also known to have anti-hyperglycemic effects in type 2 diabetic patients. However, as Berberine is insoluble and rarely absorbed in gastrointestinal tract, the mechanism by which it works is unclear. We hypothesized that it may act locally by ameliorating intestinal barrier abnormalities and endotoxemia. A high-fat diet combined with low-dose streptozotocin was used to induce type 2 diabetes in male Sprague Dawley rats. Berberine (100 mg/kg) was administered by lavage to diabetic rats for 2 weeks and saline was given to controls. Hyperinsulinemia and insulin resistance improved in the Berberine group, although there was no significant decrease in blood glucose. Berberine treatment also led to a notable restoration of intestinal villi/mucosa structure and less infiltration of inflammatory cells, along with a decrease in plasma lipopolysaccharide (LPS) level. Tight junction protein zonula occludens 1 (ZO1) was also decreased in diabetic rats but was restored by Berberine treatment. Glutamine-induced glucagon-like peptide 2 (GLP2) secretion from ileal tissue decreased dramatically in the diabetic group but was restored by Berberine treatment. Fasting insulin, insulin resistance index, plasma LPS level, and ZO1 expression were significantly correlated with GLP2 level. In type 2 diabetic rats, Berberine treatment not only augments GLP2 secretion and improves diabetes but is also effective in repairing the damaged intestinal mucosa, restoring intestinal permeability, and improving endotoxemia. Whether these effects are mechanistically related will require further studies, but they certainly support the hypothesis that Berberine acts via modulation of intestinal function.
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Heat–alkali treatment of synthetic α- and β-melanocyte-stimulating hormones (MSH), known to cause racemization of amino acids within the peptides, results in prolongation of the darkening (melanophore dispersion) effect of these hormones on frog and lizard skins in vitro. Skins remain darkened for hours or even days if supramaximal concentrations of the racemized hormones are used. This response can be partially reversed by melatonin or noradrenaline. Heat–alkali treatment of α-MSH at either 60 or 97 °C results in a retardation of the response of the skins to the racemized peptides. In contrast, the response of frog skins to heat–alkali-treated β-MSH is immediately enhanced and potentiated. Heat–alkali treatment also prolongs and potentiates the activity of synthetic [des-acetyl]-α-MSH (in contrast to the retardation effect on the natural acetylated peptide). These data suggest a role for the N-acetyl group in the retardation phenomenon. The activity of synthetic [2-d-tyrosine]-α-MSH is much lower than that of α-MSH itself, indicating that heat–alkali treatment of the hormone may produce either potentiation or partial inactivation of the peptide, depending on the site of racemization.
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Department of Minimally Invasive Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Department of Nutrition, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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KIIT School of Biotechnology, KIIT University, Bhubaneswar, India
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Adipokine leptin regulates neuroendocrine circuits that control energy expenditure, thermogenesis and weight loss. However, canonic regulators of leptin secretion, such as insulin and malonyl CoA, do not support these processes. We hypothesize that epiregulin (EREG), a growth factor that is secreted from fibroblasts under thermogenic and cachexia conditions, induces leptin secretion associated with energy dissipation. The effects of EREG on leptin secretion were studied ex vivo, in the intra-abdominal white adipose tissue (iAb WAT) explants, as well as in vivo, in WT mice with diet-induced obesity (DIO) and in ob/ob mice. These mice were pair fed a high-fat diet and treated with intraperitoneal injections of EREG. EREG increased leptin production and secretion in a dose-dependent manner in iAb fat explants via the EGFR/MAPK pathway. After 2 weeks, the plasma leptin concentration was increased by 215% in the EREG-treated group compared to the control DIO group. EREG-treated DIO mice had an increased metabolic rate and core temperature during the active dark cycle and displayed cold-induced thermogenesis. EREG treatment reduced iAb fat mass, the major site of leptin protein production and secretion, but did not reduce the mass of the other fat depots. In the iAb fat, expression of genes supporting mitochondrial oxidation and thermogenesis was increased in EREG-treated mice vs control DIO mice. All metabolic and gene regulation effects of EREG treatment were abolished in leptin-deficient ob/ob mice. Our data revealed a new role of EREG in induction of leptin secretion leading to the energy expenditure state. EREG could be a potential target protein to regulate hypo- and hyperleptinemia, underlying metabolic and immune diseases.
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Transcriptomics Lab, Division of Plant Biotechnology, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir, Shalimar, Srinagar, Jammu and Kashmir, India
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School of Medicine, Tsinghua University, Beijing, China
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Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, China
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Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Department of Urology, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
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Department of Urology, China-Japan Hospital of Jilin University, Changchun, Jilin, China
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Department of Biology, Southern University of Science and Technology School of Medicine, Shenzhen, Guangdong, China
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Department of Biology, Southern University of Science and Technology School of Medicine, Shenzhen, Guangdong, China
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University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
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Elongation factor, RNA polymerase II, 2 (ELL2) is an RNA Pol II elongation factor with functional properties similar to ELL that can interact with the prostate tumor suppressor EAF2. In the prostate, ELL2 is an androgen response gene that is upregulated in benign prostatic hyperplasia (BPH). We recently showed that ELL2 loss could enhance prostate cancer cell proliferation and migration, and that ELL2 gene expression was downregulated in high Gleason score prostate cancer specimens. Here, prostate-specific deletion of ELL2 in a mouse model revealed a potential role for ELL2 as a prostate tumor suppressor in vivo. Ell2-knockout mice exhibited prostatic defects including increased epithelial proliferation, vascularity and PIN lesions similar to the previously determined prostate phenotype in Eaf2-knockout mice. Microarray analysis of prostates from Ell2-knockout and wild-type mice on a C57BL/6J background at age 3 months and qPCR validation at 17 months of age revealed a number of differentially expressed genes associated with proliferation, cellular motility and epithelial and neural differentiation. OncoPrint analysis identified combined downregulation or deletion in prostate adenocarcinoma cases from the Cancer Genome Atlas (TCGA) data portal. These results suggest that ELL2 and its pathway genes likely play an important role in the development and progression of prostate cancer.
Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Bayer HealthCare, Biotechnology, 800 Dwight Way, Berkeley, California 94701, USA
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Type 2 diabetes is characterized by reduced insulin secretion from the pancreas and overproduction of glucose by the liver. Glucagon-like peptide-1 (GLP-1) promotes glucose-dependent insulin secretion from the pancreas, while glucagon promotes glucose output from the liver. Taking advantage of the homology between GLP-1 and glucagon, a GLP-1/glucagon hybrid peptide, dual-acting peptide for diabetes (DAPD), was identified with combined GLP-1 receptor agonist and glucagon receptor antagonist activity. To overcome its short plasma half-life DAPD was PEGylated, resulting in dramatically prolonged activity in vivo. PEGylated DAPD (PEG-DAPD) increases insulin and decreases glucose in a glucose tolerance test, evidence of GLP-1 receptor agonism. It also reduces blood glucose following a glucagon challenge and elevates fasting glucagon levels in mice, evidence of glucagon receptor antagonism. The PEG-DAPD effects on glucose tolerance are also observed in the presence of the GLP-1 antagonist peptide, exendin(9–39). An antidiabetic effect of PEG-DAPD is observed in db/db mice. Furthermore, PEGylation of DAPD eliminates the inhibition of gastrointestinal motility observed with GLP-1 and its analogues. Thus, PEG-DAPD has the potential to be developed as a novel dual-acting peptide to treat type 2 diabetes, with prolonged in vivo activity, and without the GI side-effects.
epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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epartment of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taiwan
Department of Physiology, Loyola University, Chicago, Illinois 60153, USA
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The 70 kDa heat shock protein family plays important cardiac protective roles against myocardial injuries. Reduced myocardial protection is a common feature of diabetic myocardium. This study was carried out to define the changes in the 70 kDa heat shock protein family in the myocardium in the of streptozotocin-diabetes rats, and to explore the mechanisms through which diabetes alters the abundance of Hsp70/Hsc70 in cardiac muscle. In the diabetic myocardium, the abundance of Hsc70 was significantly reduced. The abundance of Hsp70 was low in cardiac muscle and was not induced in the diabetic myocardium. Unlike Hsp60, Hsp70 and Hsc70 did not augment insulin-like growth factor-I receptor signaling in cardiac muscle cells. In cultured cardiomyocytes, insulin directly increased the abundance of Hsc70, whereas insulin could not modulate Hsp70. Treating diabetic rats with insulin restored myocardial Hsc70 level, but phlorizin treatment failed to restore myocardial Hsc70. These in vivo and in vitro studies showed that downregulation of Hsc70 in diabetic myocardium was secondary to insulin deficiency. Thus, insulin played a major role in maintaining adequate expression of Hsc70 in cardiac muscle.
Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Department of Discovery Technologies and
Department of CNS Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA
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Recent work has shown that neuromedin U (NmU), a peptide initially identified as a smooth muscle contractor, may play a role in regulating food intake and energy homeostasis. To further evaluate this putative function, we measured food intake, body weight, energy expenditure and glucose homeostasis in transgenic mice that ubiquitously overexpress murine proNmU. NmU transgenic mice were lighter and had less somatic and liver fat, were hypophagic, and had improved insulin sensitivity as judged by an intraperitoneal insulin tolerance test. Transgenic mice had higher levels of hypothalamic NPY, POMC and MCH mRNA. There was no difference in O2 consumption between genotypes; however, NmU transgenic mice displayed a modest increase in respiratory quotient during food deprivation and refeeding. There were no behavioral disturbances in the NmU transgenic mice that could account for the results (e.g. changes in locomotor activity). When placed on a high-fat diet, transgenic mice remained lighter than wild-type mice and ate less, but gained weight at a rate similar to wild-type mice. Despite the increased weight gain with high-fat feeding, glucose tolerance was significantly improved in the transgenic mice. These findings support the hypothesized role of NmU as an endogenous anorexigenic peptide.
