bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive Fluctuations and Cognitive Test Performance Among Institutionalized Persons With Dementia
Authors: Mainland Brian J. , Herrmann Nathan , Mallya Sasha , Fiocco Alexandra J. , Sin Gwen-Li , Shulman Kenneth I. , Ornstein Tisha J.
Published: July 2017

Objective:

To examine the nature and frequency of cognitive fluctuations (CFs) among institutionalized persons with dementia.

Method:

A clinical interview and a medical chart review were conducted, and 55 patients were assigned a specific dementia diagnosis. The Severe Impairment Battery (SIB) was administered to assess cognitive function, and the Dementia Cognitive Fluctuation Scale (DCFS) was administered to each patient’s primary nurse to determine the presence and severity of CFs.

Results:

A simple linear regression model was conducted with DCFS as the predictor variable and SIB total score as the dependent variable. The overall model was significant, suggesting that score on the DCFS significantly predicted SIB total score. Additionally, greater severity of CFs predicted poorer performance in the areas of orientation, language, and praxis.

Conclusions:

Results suggest that CFs exert a clinically significant influence over patients’ cognitive abilities and should be considered as a source of excess disability.
α-Tocopherol and Atherosclerosis
Authors: Kaul Nalini , Devaraj Sridevi , Jialal Ishwarlal
Published: July 2017

Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. There is compelling evidence incriminating oxidative stress in the pathogenesis of the atherosclerotic lesion. Several lines of evidence suggest that antioxidants, especially α-tocopherol, have potential beneficial effects with regard to cardiovascular disease. In vitro, α-tocopherol has been shown to inhibit platelet adhesion and aggregation and smooth muscle cell proliferation, exert anti-inflammatory effects on monocytes, and improve endothelial function. Also, supplementation with α-tocopherol has been shown to decrease lipid peroxidation, platelet aggregation, and pro-inflammatory activity of monocytes. However, clinical trials with α-tocopherol supplementation to date have been equivocal. Thus, although mounting in vitro evidence and animal models provide a sound scientific basis for α-tocopherol supplementation, further clinical trials are required before a definitive recommendation can be made with respect to the primary and secondary prevention of heart disease.
Hormonal and Neurotransmitter Roles for Angiotensin in the Regulation of Central Autonomic Function
Authors: Ferguson Alastair V. , Washburn David L.S. , Latchford Kevin J.
Published: July 2017

In this review we present the case for both hormonal and neurotransmitter actions of angiotensin II (ANG) in the control of neuronal excitability in a simple neural pathway involved in central autonomic regulation. We will present both single-cell and whole-animal data highlighting hormonal roles for ANG in controlling the excitability of subfornical organ (SFO) neurons. More controversially we will also present the case for a neurotransmitter role for ANG in SFO neurons in controlling the excitability of identified neurons in the paraventricular nucleus (PVN) of the hypothalamus. In this review we highlight the similarities between the actions of ANG on these two populations of neurons in an attempt to emphasize that whether we call such actions “hormonal” or “neurotransmitter” is largely semantic. In fact such definitions only refer to the method of delivery of the chemical messenger, in this case ANG, to its cellular site of action, in this case the AT1 receptor. We also described in this review some novel concepts that may underlie synthesis, metabolic processing, and co-transmitter actions of ANG in this pathway. We hope that such suggestions may lead ultimately to the development of broader guiding principles to enhance our understanding of the multiplicity of physiological uses for single chemical messengers.
Biological Effects of Long-Term Caloric Restriction: Adaptation with Simultaneous Administration of Caloric Stress Plus Repeated Immobilization Stress in Rats
Authors: Gursoy Erdal , Cardounel Arturo , Hu Yan , Kalimi Mohammed
Published: July 2017

In the present study, we have established the biological effects during 8 weeks of (i) caloric restriction (Cal) and (ii) simultaneous administration of Cal plus 2 hr daily immobilization stress using male Sprague-Dawley rats. Animals were divided into three equal groups: (i) ad libitum fed, (ii) 30% restriction of food intake of the ad libitum diet, and (iii) 30% restriction of food intake plus 2 hr daily immobilization stress. Caloric-restricted animals gained only 30% of the total body weight of the unrestricted animals but received 70% of the food of those rats. Cal animals showed a significant loss in their relative liver and thymus weight and a significant gain in their relative adrenal and testis weight as compared to the control animals. Cal animals had almost 2-fold higher levels of plasma corticosterone levels with a dramatic decrease in the total glucocorticoid receptor (GR) levels in the liver, thymus, heart, and testis as compared to ad libitum fed control animals. Interestingly, Cal animals showed higher levels of lipid peroxidation in both the liver and heart, indicating increased oxidative activities in these tissues when compared with the control animals. In addition, Cal animals had increased heat shock protein 70 (HSP 70) content in the testis. Surprisingly, hardly any significant differences were observed in either total body weight gain, organ weights, Plasma corticosterone levels, or lipid peroxidation between Cal animals and Cal plus immobilization-stressed animals. The results obtained suggest that (i) several stress-related responses such as inhibition of total body weight gain, increased adrenal weight, decreased thymus weight, increased plasma corticosterone, and lipid peroxidation levels in the liver and heart are associated with Cal, but (ii) no additional effects were observed on the parameters that were measured when two stress regimens were given simultaneously, suggesting that animals subjected to two stress regimens can protect themselves by controlling their stress-related thresholds of response through adaptation.
Food Restriction-like Effects of Dietary Dehydroepiandrosterone. Hypothalamic Neurotransmitters and Metabolites in Male C57BL/6 and (C57BL/6 × DBA/2)F1 Mice
Authors: Catalina Fernando , Speciale Samuel G. , Kumar Vinay , Milewich Leon , Bennett Michael
Published: July 2017

Dehydroepiandrosterone (DHEA) is a precursor of sex hormones in mammals. Dietary DHEA serves to prevent or inhibit various diseases and also lengthens life spans of animals. Moreover, dietary DHEA inhibits food intake in certain strains of mice. We administered DHEA (0.45% w/w of food) to C57BL/6 (B6) and (B6 x DBA/2)F1 (BDF1) mice for 5 weeks. Food intake was inhibited in both strains of mice during the first week. Thereafter, B6, but not BDF1, mice consumed less food. Because hypothalamic serotonin and/or dopamine regulate appetite, satiety and other behaviors, the hypothesis tested was that hypothalamic concentration of serotonin, dopamine and/or their metabolites are affected differentially in B6 and BDF1 mice fed DHEA. In another study, mice were fed the AIN-76A diet with or without DHEA for 1 and 7 days or were pair-fed to DHEA-fed mice for 7 days. On Day 1 of DHEA feeding (acute effects) hypothalamic levels of serotonin, dopamine, and metabolites were unchanged in B6 mice, but levels of dopamine were increased and levels of dopamine metabolites were decreased in BDF1 mice. On Day 7 of DHEA feeding, levels of serotonin were increased in BDF1 but not B6 mice. On Day 7 of pair-feeding there were decreased levels of hypothalamic dopamine metabolites in BDF1 but not B6 mice. Paraventricular nuclei of BDF1 mice had decreased levels of serotonin but not of dopamine in all groups. Serum levels of DHEA and its metabolite, 5-androstene-3β,17β-diol, correlated significantly only with serotonin concentrations in BDF1 mice. The salient findings of these experiments are that DHEA inhibits food intake to a greater extent in B6 than in BDF1 mice. However, alterations of hypothalamic neurotransmitters were greater in BDF1 than in B6 mice. Because BDF1 and B6 mice share B6 genes, relevant gene(s) derived from DBA/2 mice might mediate the different responses detected.
Bisphenol a Inhibits Testicular Functions and Increases Luteinizing Hormone Secretion in Adult Male Rats
Authors: Tohei Atsushi , Suda Satoshi , Taya Kazuyoshi , Hashimoto Takao , Kogo Hiroshi
Published: July 2017

Effects of a xenoblotic estrogen, bisphenol A (BPA), on reproductive functions were investigated using adult male rats. BPA was dissolved into sesame oil and injected sc every day (1 mg/rat) for 14 days. Animals were killed by decapitation after the final administration of BPA, and the trunk blood, pituitary, and testes were collected. Plasma concentrations of prolactin were dramatically Increased and pituitary contents of prolactin were slightly increased in the BPA group compared to the control group. Plasma concentrations of testosterone were decreased and plasma concentrations of LH were increased in BPA-treated rats compared to control rats. Testicular contents of inhibin were decreased in BPA-treated rats compared to control rats, although plasma concentrations of inhibin were not changed after administration of BPA. The testicular response to hCG for progesterone and testosterone release was decreased in BPA-treated rats. Administration of BPA did not change the pituitary response to luteinizing hormone-releasing hormone (LH-RH) in castrated male rats treated with testosterone. Male sexual behavior also was not changed as a result of BPA treatment. These results suggest that BPA directly inhibits testicular functions and the increased level of plasma LH is probably due to a reduction in the negative feedback regulation by testosterone. The testis is probably a more sensitive site for BPA action than the hypothalamus–pitultary axis.
Stable Isotopes of Minerals as Metabolic Tracers in Human Nutrition Research
Authors: Patterson Kristine Y. , Veillon Claude
Published: July 2017

Enriched stable isotopes used as tracers have proven to be valuable in studies of the absorption and metabolism of minerals. Unlike radioisotopes, they can be used in high-risk population groups such as infants, children, and pregnant or lactating women. Estimates of mineral absorption can be made from the oral administration of a single tracer or from two tracers, one given orally and the other intravenously (IV). It is possible to determine the metabolism of the mineral with modeling based on the amount of the tracer or tracers in different biological samples. One of the key decisions in studies of this type is determining which enriched isotope and what amount to use. An example is given of calculations to estimate and compare the amounts of tracers needed for an absorption study. Methods for calculating the amounts of tracer in oral and IV doses are presented, and limits of detection and quantitation are discussed in terms of percent of enrichment and related to isotope ratio measurement precision. A general review of the use of mass spectrometric instruments for quantifying various stable isotopes is given.
The Role of Adjuvants in the Efficacy of a Peptide Vaccine for Myasthenia Gravis
Authors: McAnally James L. , Xu Likang , Villain Matteo , Blalock J. Edwin
Published: July 2017

Myasthenia gravis (MG) and its animal model, experimental autoimmune (EA) MG, are caused by interference with neuromuscular transmission by autoantibodies against the nicotinic acetylcholine receptor (AChR) on muscle. Previously, we have shown that two peptides, denoted RhCA 67-16 and RhCA 611-001, designed to be complementary in structure to the main immunogenic region and the dominant Lewis rat T cell epitope (α-chain residues 100-116) of the AChR, respectively, are effective vaccines that prevent EAMG in rats by inducing anti-idiotypic/clonotypic antibodies (Ab) and lowering levels of AChR Ab. These studies employed keyhole limpet hemocyanin (KLH) as a carrier and complete Freunds adjuvant (CFA). In advance of a clinical trial the present study tested the efficacy of RhCA 611-001 when combined with different adjuvants that are approved for use in humans. Adjuvants chosen for comparison were incomplete Freunds adjuvant (IFA) and aluminum hydroxide (Alum). As a second goal we evaluated diphtheria toxin (DT) as an alternative carrier protein to KLH. Alum was found to be an effective adjuvant, particularly when used with the peptide conjugated to DT. This combination of carrier and adjuvant provided protection against EAMG comparable with that observed with CFA and KLH. Using enzyme-linked immunosorbent assays for Ab against RhCA 611-001, it was found that disease protection is qualitatively, but not quantitatively, related to the anti-peptide Ab response. Our results demonstrate a vaccine formulation that should be useful in the first soon-to-be-conducted clinical trials of peptide vaccines to specifically correct aberrant T and B cell responses in an autoimmune disease.
Blood Glutathione and Cysteine Concentrations in Twin Children
Authors: Lang Calvin A. , Matheny Adam P. , Mastropaolo Walter , Liu Marcia C.
Published: July 2017

Glutathione and cysteine are major antioxidants in blood that are associated with health and longevity. To ensure their measurement, careful attention to avoid auto-oxidation is necessary to stabilize the samples. Since no report of these compounds has been reported in children, our goal was to determine their levels of reduced and oxidized glutathione (GSH and GSSG) and cysteine (Cys and CSSC), To this end, 140 healthy children, ages 2 to 9 years from the Louisville Twin Study were studied. Blood samples were collected and analyzed for GSH, GSSG, Cys, and CSSC by our HPLC dual electrochemical method. The results showed that GSH and total GSH (GSH + GSSG) levels for monozygotic (MZ) twins were significantly higher (P < 0.001) than levels for dizygotic (DZ) twins. However, the opposite occurred for Cys and total Cys (Cys + CSSC) in that the levels were significantly higher for DZ twins than for MZ twins. (P < 0.005-0.013). In spite of this marked difference in zygosity, the withinpair correlations for twin pairs used for estimating heritability suggested that there was a major environmental influence for total GSH and total Cys. Finally. GSH levels were significantly lower for young (2–9 years) children than adults (P < 0.001).
Genetics of Arterial Prothrombotic Risk States
Authors: Williams Marlene S. , Bray Paul F.
Published: July 2017

Coronary artery disease is a leading cause of death worldwide and the largest killer of men and women in the United States. The pathophysiology of myocardial infarction is multifactorial, and numerous physiologic systems converge to dictate the formation of the two fundamental lesions, thrombosis and atherosclerosis. In this review we address genetic aspects of arterial thrombosis and the key thrombotic factors that have been associated with the increased risk for its development. Specifically, we consider components of coagulation, fibrinolysis, and Platelet adhesive receptors, and we review the genetic epidemiology and in vitro laboratory data regarding their risk for the acute coronary syndromes. In combination with traditional risk factor assessment, in the near future these inherited markers can be used to manage patients with vascular disease through a better utilization of invasive or expensive diagnostic testing, as well as pharmacologic intervention.
Suppression of the Development of Experimentally Induced Uterine Adenomyosis by a Novel Matrix Metalloproteinase Inhibitor, ONO-4817, in Mice
Authors: Mori Takao , Yamasaki Shinichi , Masui Fujiko , Matsuda Manabu , Sasabe Haruko , Zhou Ying-Fang
Published: July 2017

The inhibitory effects of a novel, orally active matrix metalloproteinase (MMP) inhibitor, ONO-4817, on the development of uterine adenomyosis induced experimentally by pituitary grafting were examined in mice. Mice were given transplants of isologous anterior pituitary glands (PGs) into the right uterine lumen at 7 weeks of age and were fed chow containing 0.1% to 1.0% ONO-4817 from 8 to 14 weeks of age. Mice treated with 0.3% or 1.0% ONO-4817 showed a significantly lower incidence of the development of adenomyosis than vehicle-treated mice. To evaluate the inhibitory effects of ONO-4817 on the progression of the invasion of the adenomyotic tissues, mice receiving PG grafts at 7 weeks of age were treated with 1.0% ONO-4817 from 13 to 17 weeks of age. The degree of pathological progression of adenomyosis was graded from 1 to 5 in increments of 1. The degree of the progression of the lesion was less in the uteri exposed to ONO-4817 (2.71 ± 0.93) than in the uteri not exposed to the inhibitor (4.33 ± 0.75). Finally, the invasiveness of endometrial stromal cells obtained from adenomyotic uteri into Matrigel consisting mainly of type IV collagen and laminin was examined using an invasion assay. The assay showed that the treatment with ONO-4817 markedly suppressed the invasion of the stromal cells of the adenomyotic uteri into the gel. These results indicate that ONO-4817 may be an effective inhibitor of the development of adenomyosis.
High Glucose Concentrations Induce Oxidative Damage to Mitochondrial DNA in Explanted Vascular Smooth Muscle Cells
Authors: Li Muyao , Absher P. Marlene , Liang Ping , Russell James C. , Sobel Burton E. , Fukagawa Naomi K.
Published: July 2017

Oxidative stress is considered to be one of the mechanisms leading to atherosclerosis. It occurs in response to injury or to altered metabolic state. Alterations in cell growth (proliferation or apoptosis) can also contribute to the pathogenesis of atherosclerosis and is influenced by oxidative stress. Smooth muscle cells (SMC) from aortic explants of JCR:LA-cp homozygous cp/cp corpulent rats who are genetically predisposed to develop atherosclerosis exhibit increased SMC proliferation, which can be attenuated by exercise and food restriction. This study was conducted to characterize the effects fo oxidative stress and high glucose media on cell growth and its relationship to mitochondrial DNA integrity and gene expression in explanted aortic SMC from corpulent and lean JCR:LA-cp rats. The results show that SMC from the cp/cp rat appear to be resistant to oxidant-induced cell death and that they accumulate mitochondrial DNA mutations, probably as a result of a reduction in apoptosis. These data suggest that susceptibility to age- and glucose-related atherosclerosis may be related to alterations in redox signaling.
Differing Effects of Endocrine-Disrupting Chemicals on Basal and FSH-Stimulated Progesterone Production in Rat Granulosa-Luteal Cells
Authors: Nejaty Hedieh , Lacey Michael , Whitehead Saffron A.
Published: July 2017

Previous studies have shown that the phytoestrogen, genistein, inhibits basal and forskolin-stimulated progesterone synthesis in rat granulosa-luteal cells. Genistein, however, not only binds and activates the estrogen receptor (ER), but is also a potent inhibitor of tyrosine kinase. In these studies we have compared the effects of estradiol, two other phytoestrogens, apigenin and coumarin, the pesticide, [2-(chlorphenyl)-2-(4-chlorphenyl)-1,1,1-trichlorethan] (2,4′DDT), and the industrial chemical, 4-octyl-phenol, on basal and follicle stimulating hormone (FSH)-stimulated progesterone production in the same experimental system. Only a supraphysiological dose of estradiol (10–5 M) significantly inhibited basal and forskolin-stimulated progesterone production in granulosa-luteal cells, but had no effect on FSH-stimulated production. In contrast, apigenin, DDT, and octyl-phenol stimulated basal progesterone production at doses around 10–8 to 10–7 M, but this effect was reversed at higher doses. Coumarin was without effect. Like basal production, the two phytoestrogens had opposing effects on FSH-stimulated progesterone production. Genistein at 10–5 M was inhibitory, while apigenin significantly potentiated the response at 19–7 M. In contrast, DDT had no effect on the FSH-induced response, though 10–7 M octyl-phenol nearly doubled the response. While all these chemicals are known to interact with the estrogen receptor to a greater or lesser extent, these studies suggest that like genistein, these different endocrine-disrupting chemicals may have other actions apart from those on the estrogen receptor.
Inheritance of Resistance to Promotion of Preneoplastic Liver Lesions in Copenhagen Rats
Authors: Wood Geoffrey A. , Sarma Dittakavi S.R. , Archer Michael C.
Published: July 2017

Previously, we have shown that Copenhagen (Cop) rats are highly resistant to the induction of putative preneoplastic, glutathione S-transferase 7-7- (GST 7-7) positive liver lesions following treatment with a modified resistant hepatocyte (RH) protocol. The objective of this study was to determine if resistance is inherited in a dominant or recessive manner and to derive an estimate of the number of genetic loci involved. We crossed male and female Cop rats with F344 rats to produce F1 offspring. Backcross rats were generated using female F1 rats and either Cop or F344 males, resulting in B1c and B1f generations, respectively. The male rats from all these crosses were initiated with diethylnitrosamine (200 mg/kg) at 7 to 8 weeks of age and were promoted 3 weeks later with the RH protocol (2-acetylaminofluorene and a two-thirds partial hepatectomy). The rats were sacrificed 3 weeks after the partial hepatectomy and their livers were sectioned and stained for GST 7-7-positive lesions. The susceptibility of F1 rats was in between Cop and F344 rats, having 21.7% ± 2.0% (mean ± SEM) of their liver volume occupied by lesions versus 4.2% ± 0.8% for Cop and 53.0% ± 5.8% for F344 rats. As expected, B1c rats had a volume of liver occupied by lesions that was in between the F1 and Cop rats at 13.5% ± 1.6%. Surprisingly, B1f rats were similar to B1c rats in their resistance (9.1% ± 2.1%). These results point to a complex, polygenic inheritance pattern that can be explained by a minimum of four loci, one of which shows recessive epistasis.
Recent Advances in Membrane Microdomains: Rafts, Caveolae, and Intracellular Cholesterol Trafficking
Authors: Schroeder Friedhelm , Gallegos Adalberto M. , Atshaves Barbara P. , Storey Stephen M. , Mcintosh Avery L. , Petrescu Anca D. , Huang Huan , Starodub Olga , Chao Hsu , Yang Huiqin , Frolov Andrey , Kier Ann B.
Published: July 2017

Cellular cholesterol homeostasis is a balance of influx, catabolism and synthesis, and efflux. Unlike vascular lipoprotein cholesterol transport, intracellular cholesterol trafficking is only beginning to be resolved. Exogenous cholesterol and cholesterol ester enter cells via the low-density lipoprotein (LDL) receptor/lysosomal and less so by nonvesicular, high-density lipoprotein (HDL) receptor/caveolar pathways. However, the mechanism(s) whereby cholesterol enters the lysosomal membrane, translocates, and transfers out of the lysosome to the cell interior are unknown. Likewise, the steps whereby cholesterol enters the cytofacial leaflet of the plasma membrane caveolae, rapidly translocates, leaves the exofacial leaflet, and transfers to extracellular HDL are unclear. Increasing evidence obtained with model and isolated cell membranes, transfected cells, genetic mutants, and gene-ablated mice suggests that proteins such as caveolin, sterol carrier protein-2 (SCP-2), Niemann-Pick C1 protein, steroidogenic acute regulatory protein (StAR), and other intracellular proteins mediate intracellular cholesterol transfer. While these proteins bind cholesterol and/or interact with cholesterol-rich membrane microdomains (e.g., caveolae, rafts, and annuli), their relative contributions to direct molecular versus vesicular cholesterol transfer remain to be resolved. The formation, regulation, and role of membrane microdomains in regulating cholesterol uptake/efflux and trafficking are unclear. Some cholesterol-binding proteins exert opposing effects on cellular cholesterol uptake/efflux, transfer of cholesterol out of the lysosomal membrane, and/or intracellular cholesterol trafficking to select membranous organelles. Resolving these cholesterol pathways and the role of membrane cholesterol microdomains is essential to our understanding not only of processes that affect cholesterol metabolism, but also of the abnormal regulation that may lead to disease (diabetes, obesity, atherosclerosis, neutral lipid storage, Niemann-Pick C, congenital lipoid adrenal hyperplasia, etc.).
Leptin-Deficient Mice Commence Hypersecreting Insulin in Response to Acetylcholine between 1 and 2 Weeks of Age
Authors: Lee Joo-Won , Romsos Dale R.
Published: July 2017

Leptin-deficient Lepob/Lepob mice develop hyperinsulinemia early in life, before they begin to overeat or develop insulin resistance. Pancreatic islets from these young mice do not yet hypersecrete insulin in response to glucose, but they hyperrespond to acetylcholine. Islets from 4-day, and 1-, 2-, and 4-week-old mice were used in the present study to determine when leptin-deficient mice first hypersecrete insulin In response to acetylcholine. This relative hypersecretion of insulin from islets of leptin-deficient mice occurred between 1 and 2 weeks of age. The divergence in insulin secretion occurred at this time because islets from lean, leptin-sufficient mice became relatively less responsive to acetylcholine between 1 and 2 weeks of age, whereas islets from leptin-deficient mice maintained a high responsiveness to acetylcholine during development. Leptin addition to islets isolated from 4-day, and 2-, and 4-week-old leptin-deficient mice rapidly (i.e., within 30 min) suppressed acetylcholine-induced insulin secretion at each stage of development. In contrast, islets from 4-day, and 2- and 4-week-old leptin-sufficient mice became progressively less responsive to leptin with development. Leptin targets pancreatic islets early in development to specifically constrain the overall capacity for acetylcholine-induced insulin secretion, and to acutely modulate this secretion.
Adrenoceptors, Uncoupling Proteins, and Energy Expenditure
Authors: Collins Sheila , Cao Wenhong , Daniel Kiefer W. , Dixon Tonya M. , Medvedev Alexander V. , Onuma Hiroki , Surwit Richard
Published: July 2017

Interest in the biology of adipose tissue has undergone a revival in recent years with the discovery of a host of genes that contribute to the regulation of satiety and metabolic rate. The catecholamines have long been known to be key modulators of adipose tissue lipolysis and the hydrolysis of triglyceride energy stores. However, more recent efforts to understand the role of Individual adrenergic receptor subtypes expressed in adipocytes and their signal transduction pathways have revealed a complexity not previously appreciated. Combined with this interest in the modulation of adipocyte metabolism is a renewed focus upon brown adipose tissue and the mechanisms of whole body thermogenesis in general. The discovery of novel homologs of the brown fat uncoupling protein (UCP) such as UCP2 and UCP3 has provoked intensive study of these mitochondrial proteins and the role that they play in fuel metabolism. The story of the novel UCPs has proven to be intriguing and still incompletely understood. Here, we review the status of adipose tissue from inert storage depot to endocrine organ, Interesting signal transduction pathways triggered by β-adrenergic receptors in adipocytes, the potential of these receptors for discriminating and coordinated metabolic regulation, and current views on the role of UCP2 and UCP3 based on physiological studies and gene knockout models.
Prevention of Radiation-Induced Nephropathy and Fibrosis in a Model of Bone Marrow Transplant by an Angiotensin II Receptor Blocker
Authors: Molteni Agostino , Moulder John E. , Cohen Eric P. , Fish Brian L. , Taylor Joan M. , Veno Patricia A. , Wolfe Lisa F. , Ward William F.
Published: July 2017

Nephropathy, interstitial pneumopathy, and renal and lung fibrosis are major complications of bone marrow transplantation (BMT). This study evaluated the antifibrotic property of an angiotensin II (A2) type-1 receptor blocker (L-159,809) and compared it with those of Captopril and Enalapril, two angiotensin-converting enzyme (ACE) inhibitors, in a rat model of BMT. Male WAG/Rij/MCW rats received a preparative regimen of 60 mg/kg body wt of cytoxan (i.p., Days 9 and 8) and 18.5 Gy of total body irradiation (TBI) in six twice daily fractions (Days 2, 1, and 0) followed immediately (Day 0) by BMT. Modifiers were given in drinking water from Day 10 until autopsy, 8 weeks after BMT. Rats treated with TBI plus cytoxan alone developed severe nephropathy. Trichrome staining showed marked collagen deposition in glomeruli, renal interstitium, and renal arteries and arterioles (especially in their adventitia). Collagen deposition and renal damage were markedly reduced by the three modifiers. Of the three, L-158,809-treated rats had slightly thinner vessels and slightly less collagen than nonirradiated normal controls. The study shows the effectiveness of these drugs in the protection of the renal parenchyma from the development of radiation-induced fibrosis. It also indicates a role for angiotensin II in the modulation of collagen synthesis.
Inhibition of Ganglionic Long-Term Potentiation Decreases Blood Pressure in Spontaneously Hypertensive Rats
Authors: Alkadhi Karim A. , Otoom Sameer A. , Tanner Felicia L. , Sockwell Deanna , Hogan Yvonne H.
Published: July 2017

Long-term potentiation of sympathetic ganglia (gLTP), a unique form of synaptic plasticity, is serotonin dependent and can be blocked with 5-HT3 receptor antagonists. Long-lasting enhancement of the basal tone of ganglionic transmission (as with gLTP) is expected to result in sustained increase in peripheral resistance that would lead to elevated blood pressure. We examined the possibility that in sympathetic ganglia, gLTP may be involved in the expression of stress-induced (neurogenic) form of hypertension. High blood pressure in spontaneously hypertensive rat (SHR), known to show exaggerated cardiovascular defense reactions to environmental stimuli, is partly due to a neurogenic factor. Chronic treatment of SHR and their normotensive counterpart, the Wistar Kyoto (WKY) rats with the 5-HT3 receptor antagonist tropisetron (ICS; 5 mg/kg/day), caused a marked decrease in the blood pressure of the SHR but not of WKY rats. Increasing the daily dose of ICS cumulatively (7 and 10 mg/kg) did not result in significant additional decrease in blood pressure of SHR, indicating that the drug blocks only the neurogenic component of hypertension in the SHR. electrophysiological procedures for indirectly testing for the presence of gLTP in ganglia excised from SHR suggest that gLTP has been previously expressed in these ganglia in vivo. This contrasts with the absence of gLTP in ganglia from normotensive rats. The results support contribution of gLTP to the expression of neurogenic hypertension.
High Glycemic Index Carbohydrate Diet Alters the Diurnal Rhythm of Leptin But Not Insulin Concentrations
Authors: Herrmann Tracy S. , Bean Michelle L. , Black Tracy M. , Wang Ping , Coleman Rosalind A.
Published: July 2017

Morning serum leptin values in humans are inconsistently altered by diet, and the molecular mechanisms controlling the diurnal leptin pattern remain unexplained. We determined whether leptin values after meals or the leptin diurnal pattern was altered by the type of carbohydrate (CHO) ingested in diets containing either 20% or 30% fat. In a randomized, crossover study design, nine healthy lean adults ate one of four isocaloric diets for 8 days. Diets contained 15% protein: A, high glycemic index (GI) CHO, 30% fat; B, low GI CHO, 30% fat; C, high GI CHO, 20% fat; and D, low GI CHO, 20% fat. Serum glucose, insulin, and leptin were measured at intervals on Day 8 for 24 hr, and on Day 9 during an oral glucose tolerance test (GTT). Although the 24-hr glucose and insulin profiles did not differ with the diets, diets A and C altered the serum leptin diurnal pattern. In contrast to the usual evening rise in leptin concentration, which begins after 2200 hr, diets A and C caused a rise in leptin beginning at 1300 hr. The area under the curve for leptin between 1230 and 2400 hr was 17% greater for diets A and C. During the GTT, leptin concentrations were similar for each diet. These results suggest that the pattern and amount of leptin secretion may be altered by high GI CHO or the simple sugar content of the diet, unrelated to differences in insulin concentration, that high GI foods may have little or no effect on serum insulin in the context of a mixed meal, and that a single 0800-hr leptin value may not be sufficient to reveal a diet-induced change in leptin secretion
Possible Role of Retinoids in Hepatitis B Virus-Associated Liver Damage
Authors: Mawson Anthony R. , Steele Timothy A.
Published: July 2017

Liver damage following hepatitis B virus (HBV) infection may be due to the action of retinoids as modulators of viral replication. The reduced rate of survival of liver grafts in patients with HBV infection could also be due to the continued presence of the virus, stimulated by retinoids in the graft tissue. Subject to obtaining empirical support for this hypothesis, the use of retinoid-blocking agents could be explored to reduce the risk of liver damage in HBV infection and to enhance the survival of liver grafts. Continued use of such agents may need to be used in conjunction with anti-viral modalities such as HBV hyperimmune globulin and lamivudine to prevent recurrent liver damage and to increase the long-term viability of the graft.
Retinoic Acid Combined with Neurotrophin-3 Enhances the Survival and Neurite Outgrowth of Embryonic Sympathetic Neurons
Authors: Plum Lori A. , Parada Luis F. , Tsoulfas Pantelis , Clagett-Dame Margaret
Published: July 2017

Both nerve growth factor (NGF) and neurotrophin-3 (NT-3) are necessary for the survival of embryonic sympathetic neurons in vivo. All-trans retinoic acid (atRA) has been shown to promote neurite outgrowth and long-term survival of chick embryonic sympathetic neurons cultured in the presence of NGF. The present study shows that atRA can also potentiate the survival and neurite outgrowth-promoting activities of NT-3. This was accomplished by enhancing the survival of existing neurons, as cell proliferation was unaffected by exposure to atRA. atRA also enhanced neurite outgrowth of the NT-3-treated cells; however, the neurites appeared thicker and less branched than cells treated with atRA in combination with NGF. Using a quantitative PCR assay, trkA and p75NTR mRNAs, but not trkC mRNA, were increased (~1.5- to 2-fold) after 72 and 48 hr of exposure of the cultures to atRA, respectively. The atRA-induced increase in trkA mRNA may play a role in the enhanced survival of neurons cultured in the presence of either NGF or NT-3, as both neurotrophins have been shown to signal through this receptor. The time course of these mRNA changes would indicate that atRA does not regulate the neurotrophin receptor mRNA directly, rather, intervening gene transcription is required. Thus, during development, atRA may play a role in fine-tuning embryonic responsiveness to both NT-3 and NGF.
Effects of Hypergravity Exposure on the Developing Central Nervous System: Possible Involvement of Thyroid Hormone
Authors: Sajdel-Sulkowska Elizabeth M. , Li Gui-Hua , Ronca April E. , Baer Lisa A. , Sulkowski Gregory M. , Koibuchi Noriyuki , Wade Charles E.
Published: July 2017

The present study examined the effects of hypergravity exposure on the developing brain and specifically explored the possibility that these effects are mediated by altered thyroid status. Thirty-four timed-pregnant Sprague-Dawley rats were exposed to continuous centrifugation at 1.5 G (HG) from gestational Day 11 until one of three key developmental points: postnatal Day (P) 6, P15, or P21 (10 pups/dam: 5 males/5 females). During the 32-day centrifugation, stationary controls (SC, n = 25 dams) were housed in the same room as HG animals. Neonatal body, forebrain, and cerebellum mass and neonatal and maternal thyroid status were assessed at each time point. The body mass of centrifuged neonates was comparatively lower at each time point. The mass of the forebrain and the mass of the cerebellum were maximally reduced in hypergravity-exposed neonates at P6 by 15.9% and 25.6%, respectively. Analysis of neonatal plasma suggested a transient hypothyroid status, as indicated by increased thyroid stimulating hormone (TSH) level (38.6%) at P6, while maternal plasma TSH levels were maximally elevated at P15 (38.9%). Neither neonatal nor maternal plasma TH levels were altered, suggesting a moderate hypothyroid condition. Thus, continuous exposure of the developing rats to hypergravity during the embryonic and neonatal periods has a highly significant effect on the developing forebrain and cerebellum and neonatal thyroid status (P < 0.05, Bonferroni corrected). These data are consistent with the hypothesized role of the thyroid hormone in mediating the effect of hypergravity in the developing central nervous system and begin to define the role of TH in the overall response of the developing organism to altered gravity.
A Critical Review of the Nature of the Spongiform Encephalopathy Agent: Protein Theory Versus Virus Theory
Authors: Narang Harash
Published: July 2017

All spongiform encephalopathies (SEs) result in brain disorders brought about by a slow virus. Since the origin of bovine SE (BSE), the infectious nature of the disease has been firmly established. Tubulofilamentous particles/scrapie termed nemavirus (NVP) and scrapie-associated fibrils (SAF) are ultrastructural markers, whereas protease-resistant protein (PrPsc) is a protein marker. The PrP molecules aggregate to form SAF. Each NVP consists of three layers: an outer protein coat, an intermediate ssDNA layer, and inner PrP/SAF. Therefore, ssDNA and PrP/SAF are physically associated with each other. The existence of at least 20 stable strains of SEs implies that a nucleic acid molecule serves as the information molecule. Animals inoculated with PrPsc do not develop the clinical disease, however, ssDNA purified from scrapie-hamster brains by alkaline gel electrophoresis mixed with binding proteins before inoculation developed the clinical disease. It appears that an “accessory protein” coded by the ssDNA of the NVP interacts with normal PrPc molecules, resulting in their conversion to PrPsc/SAF. The pathogenesis process in the infected animal, with increasing incubation periods, reveals that larger amounts of normal PrP molecules are modified to form SAF. This interferes with the normal supply of PrP to cell membranes, which become disrupted and eventually fragment, resulting in the vacuoles typical of those found in the SEs. Critical review of scientific literature has demonstrated that the agent contains a DNA genome.
Induction of Metallothionein-I Protects Glomeruli from Superoxide-Mediated Increase in Albumin Permeability
Authors: Sharma Ram , Sharma Mukut , Datta Prasun K. , Savin Virginia J.
Published: July 2017

Metallothioneins (MT) are low-molecular-weight, heat-stable, cysteine-rich proteins with four isoforms. MT-I and MT-II are ubiquitous and are induced by oxidative, physical, and chemical stress. MT-I is an efficient scavenger of superoxide (O2) and hydroxyl ion (OH–). We have demonstrated that O2 and hypohalous acid can cause an increase in glomerular albumin permeability (Palb) in vitro. The purpose of this study was to document the protective effect of MT gene product on the O2-mediated increase in Palb. Glomeruli from Sprague-Dawley rats in 4% BSA medium were incubated for 4 hr at 37°C in duplicate tubes. Each set contained glomeruli alone or with 5 μM Cd++, 0.3 mM Spermine-NONOate (NO donor), 0.3 mM Sulfo-NONOate (nitrous oxide donor), 0.6 mM SNP (nonspecific NO donor) and SNP + carboxy-PTIO (10 mg/ml). After incubation, one set of tubes was used to isolate total RNA for the measurement of the mRNA levels of MT-I by reverse transcriptase polymerase chain reaction (RT-PCR). Duplicate tubes were incubated for an additional 10 min with 10 nM of O2, and Palb was measured using video microscopy. RT-PCR of total RNA from Cd++ and Spermine-NONOate treated glomeruli revealed a 2-fold induction of MT-I expression at the mRNA level. O2 caused a significant increase in Palb (0.8 ± 0.06 vs. control 0.0 ± 0.12, P < 0.05) and induction of MT-I in glomeruli by Cd++ or by Spermine-NONOate blocked this effect (0.21 ± 0.12 and 0.24 ± 0.19, respectively, P < 0.05 vs. O2). In contrast, Sulfo-NONOate and SNP did not induce mRNA for MT-I in glomeruli and did not provide protection against O2-mediated increase in Palb We conclude that MT-I gene products may play an important role in protecting the glomerular filtration barrier from the injury induced by reactive oxygen species in immune and/or nonimmune renal diseases
The Effect of Lysozyme on Elastase-Mediated Injury
Authors: Cantor Jerome O. , Shteyngart Bronislava , Cerreta Joseph M. , Turino Gerard M.
Published: July 2017

Previous studies by this laboratory demonstrated that lysozyme is increased in human pulmonary emphysema, and that it preferentially binds to elastic fibers, which undergo degradation in this disease. In the current investigation, the relationship between lysozyme and elastic fiber injury was further examined, both In vitro and In vivo. The effect of exogenously administered egg-white lysozyme on pancreatic elastase-induced injury was determined using a biosynthetically radiolabeled extracellular matrix preparation mainly composed of elastic fibers. Although matrix treated with lysozyme showed attachment of the protein to elastic fibers, there was no significant increase in elastolysis compared with untreated controls following exposure to either 1 μg/ml or 100 ng/ml of pancreatic elastase. However, lysozyme did Impair the ability of hyaluronan (HA) to prevent elastase injury to elastic fibers. Matrix samples sequentially treated with lysozyme and HA, then incubated with 1 μg/ml or 100 ng/ml of pancreatic elastase, showed significantly Increased elastolysis compared with those treated with HA alone. Since HA is closely associated with elastic fibers In vivo, the ability of lysozyme to enhance elastolysis was further tested in an animal model of emphysema induced by intratracheal administration of porcine pancreatic elastase. Animals exposed to aerosolized lysozyme prior to elastase administration showed significantly increased airspace enlargement. The mean linear intercept of the lysozyme-treated animals was 123 μm compared with 75 μm for controls receiving aerosolized water (P < 0.0001). These findings suggest that lysozyme may not be an innocuous component of the inflammatory response associated with pulmonary emphysema, but may actually play a role in the pathogenesis of the disease.
Generation of Oxygen Free Radicals in Thyroid Cells and Inhibition of Thyroid Peroxidase
Authors: Sugawara Masahiro , Sugawara Yoshinobu , Wen Katherine , Giulivi Cecilia
Published: July 2017

We examined whether superoxide (O2-) is produced as a precursor of hydrogen peroxide (H2O2) in cultured thyroid cells using the cytochrome c method and the electron paramagnetic resonance (EPR) method. No O2- or its related radicals was detected in thyroid cells under the physiological condition. The presence of quinone, 2, 3-dimethoxy-1-naphthoqulnone (DMNQ), or 2-methyl-1, 4-naphthoqulnone (menadione), in the medium produced O2- and hydroxyl radicals (OH); the amount of H2O2 generation was also increased. Incubation of follicles with DMNQ or menadione inhibited iodine organification (a step of thyroid hormone formation) and its catalytic enzyme, thyroid peroxidase (TPO). This inhibition should be caused by reactive oxygen species because the two quinones, particularly DMNQ, exert their effect through the generation of reactive oxygen species. It is speculated that the site-specific inactlvatlon of TPO might have occurred at the heme-linked histidine residue of the TPO molecule, a critical amino acid for enzyme activity because OH• (vicious free radicals) can be formed at the iron-linked amino acid. TPO mRNA level and electrophoretlc mobility of TPO were not inhibited by quinones. Our study suggests that thyroid H2O2 is produced by divalent reduction of oxygen without O2- generation. If thyroid cells happen to be exposed to significant amount of reactive oxygen species, TPO and subsequent thyroid hormone formation are inhibited.
Systolic Elastance and Resistance in the Regulation of Cardiac Pumping Function in Early Streptozotocin-Diabetic Rats
Authors: Chang Kuo-Chu , Lo Huey-Ming , Tseng Yung-Zu
Published: July 2017

We determined the roles of maximal systolic elastance (Emax) and theoretical maximum flow (Qmax) in the regulation of cardiac pumping function in early streptozotocin (STZ)-diabetic fats. Physically, Emax can reflect the intrinsic contractility of the myocardium as an intact heart, and Qmax has an inverse relation to the systolic resistance of the left ventricle. Rats given STZ 65 mg/kg l.v. (n = 17) were divided into two groups, 1 week and 4 weeks after induction of diabetes, and compared with untreated age-matched controls (n = 15). Left ventricular (LV) pressure and ascending aortic flow signals were recorded to calculate Emax and Qmax, using the elastance-resistance model. After 1 or 4 weeks, STZ-diabetic animals show an increase in effective LV end-diastolic volume (Veed), no significant change in peak iso-volumic pressure (Pisomax), and a decline in effective arterial volume elastance (Ea). The maximal systolic elastance Emax is reduced from 751.5 ± 23.1 mmHg/ml in controls to 514.1 ± 22.4 mmHg/ml in 1- and 538.4 ± 33.8 mmHg/ml in 4-week diabetic rats. Since Emax equals PisomaxVeed, an increase in Veed with unaltered Pisomax may primarily act to diminish Emax so that the intrinsic contractility of the diabetic heart is impaired. By contrast, STZ-diabetic rats have higher theoretical maximum flow Qmax (40.9 ± 2.8 ml/s in 1- and 44.5 ± 3.8 ml/s in 4-week diabetic rats) than do controls (30.7 ± 1.7 ml/s). There exists an inverse relation between Qmax and Ea when a linear regression of Qmax on Ea is performed over all animals studied (r= 0.65, p < 0.01). The enhanced Qmax is indicative of the decline in systolic resistance of the diabetic rat heart. The opposing effects of enhanced Qmax and reduced Emax may negate each other, and then the cardiac pumping function of the early STZ-diabetic rat heart could be preserved before cardiac failure occurs.
Ethanol Modulates the Growth of Human Breast Cancer Cells In Vitro
Authors: Izevbigie Ernest B. , Ekunwe Stephen I. , Jordan Jenny , Howard Carolyn B.
Published: July 2017

The role of ethanol or its metabolites on breast neoplasm has not been characterized. We hypothesized that ethanol may alter the growth rate of human breast tumor epithelial cells by modulating putative growth-promoting signaling pathways such as p44/42 mitogen-activated protein kinases (MAPKs). The MCF-7 cell line, considered a suitable model, was used in these studies to investigate the effects of ethanol on [3H]thymidine incorporation, cell number, and p44/42 MAPK activities in the presence or absence of a MAPK or extracellular signal-regulated kinase ERK-1, and (MEK1) inhibitor (PD098059). Treatment of MCF-7 cells with a physiologically relevant concentration of ethanol (0.3% or 65 mM) increased p44/42 activities by an average of 400% (P < 0.02), and subsequent cell growth by 200% (P < 0.05) in a MEK1 inhibitor (PD098059)-sensitive fashion, thus suggesting that the Ras/MEK/MAPK signaling pathways are crucial for ethanol-induced MCF-7 cell growth.