bluuebunny/crossref_metadata_2025 huggingface dataset:
μ-1 Opioid Receptor Stimulation Decreases Body Temperature in Conscious, Unrestrained Neonatal Rats
Authors: Colman Atalie S. , Miller John H.
Published: July 2017

The influence of μ-selective opioid agonists on neonatal thermoregulatory mechanisms has received little attention. Opioid treatment in adult subjects can cause either hyper- or hypothermia, depending on the experimental conditions, the strain of rat used, and the dose and route of administration of the drug. The present study assessed the effect of two μ opioid agonists on body temperature in neonatal Wistar rats aged 2 to 13 days. Rat pups were administered either saline or one of the two μ-selective opioid agonists, dermorphin (0.4 mg/kg) or fentanyl (0.06 mg/kg), by subcutaneous injection. Continuous rectal temperatures were measured both prior to and following drug or saline injection in freely moving, conscious animals. Ambient temperature in a plethysmograph chamber was maintained within or close to the thermoneutral zone for pups (32°C). To distinguish between μ-1 and μ-2 effects, all animals received either saline or 10 mg/kg of the irreversible μ-1 antagonist naloxonazine (NALZ) 1 day prior to agonist administration. NALZ on its own had no effect on body temperature. Dermorphin and fentanyl both caused a fall in body temperature in pups of all age groups. The temperature decreases ranged from 0.8°-2.2°C. These opioid-Induced changes were inhibited by NALZ pretreatment. Although there was no evidence for endogenous μ-1 opioid activity, this study indicated that stimulation of μ-1 opioid receptors causes a decrease in body temperature in conscious, unrestrained neonatal rats under or close to thermoneutral conditions.
Chronic and Intermittent Hypoxia Induce Different Degrees of Myocardial Tolerance to Hypoxia-Induced Dysfunction
Authors: Milano Giuseppina , Corno Antonio F. , Lippa Silvio , Segesser Ludwig K. von , Samaja Michele
Published: July 2017

Chronic hypoxia (CH) is believed to induce myocardial protection, but this is in contrast with clinical evidence. Here, we test the hypothesis that repeated brief reoxygenation episodes during prolonged CH improve myocardial tolerance to hypoxia-induced dysfunction. Male 5-week-old Sprague-Dawley rats (n = 7–9/group) were exposed for 2 weeks to CH (F1O2 = 0.10), intermittent hypoxia (IH, same as CH, but 1 hr/day exposure to room air), or normoxia (N, F1O2 = 0.21). Hearts were isolated, Langendorff perfused for 30 min with hypoxic medium (Krebs-Henseleit, PO2 = 67 mmHg), and exposed to hyperoxia (PO2 = 670 mmHg). CH hearts displayed higher end-diastolic pressure, lower rate-pressure product, and higher vascular resistance than IH. During hypoxic perfusion, anaerobic mechanisms recruitment was similar in CH and IH hearts, but less than in N. Thus, despite differing only for 1 hr daily exposure to room air, CH and IH induced different responses in animal homeostasis, markers of oxidative stress, and myocardial tolerance to reoxygenation. We conclude that the protection in animals exposed to CH appears conferred by the hypoxic preconditioning due to the reoxygenation rather than by hypoxia per se.
Estrogen-Dependent Growth of a Rat Pituitary Tumor Involves, But Does Not Require, a High Level of Vascular Endothelial Growth Factor
Authors: Cracchiolo Danny , Swick Jason W. , McKiernan Lucy , Sloan Erica , Raina Supriya , Sloan Charles , Wendell Douglas L.
Published: July 2017

Long-term (10-week) treatment of Fischer 344 (F344) rats with the synthetic estrogen diethylstilbestrol (DES) increases the level of vascular endothelial growth factor (VEGF) in the pituitary. This is concurrent with the development of a large tumor of the pituitary of F344 rats. A role for VEGF in estrogendependent pituitary tumor growth is also supported by the fact that pituitary VEGF level is not increased by estrogen treatment in rats of the tumor-resistant Brown Norway (BN) strain. However, VEGF is not increased by estrogen treatment in an F1hybrid of F344 and BN, even though F1hybrid rats do form pituitary tumors in response to estrogen. Quantitative trait locus (QLT) mapping reveals that control of estrogen-dependent VEGF expression is linked to the Edpm5 QTL, which was previously identified as a QTL for estrogen-dependent pituitary tumor growth. In contrast, the QTL Edpm2-1 and Edpm9-2, which have been shown to each have a significant effect on estrogendependent pituitary mass of a magnitude similar to Edpm5, do not have any effect on VEGF level. Taken together, our results support the association of VEGF expression with growth of the estrogen-Induced rat pituitary tumor, as has been reported by others, but they also indicate that there is significant pathways of growth regulation that are independent of high-level VEGF expression.
Quantitative Trait Loci Influencing Hepatic Copper in Rats
Authors: de Wolf I.D. , Bonné A.C.M. , Fielmich-Bouman X.M. , Oost B.A. van , Beynen A.C. , Zutphen L.F.M. van , Lith H.A. van
Published: July 2017

Significant differences in liver copper content have been observed between rat inbred strains. To define loci controlling this trait, the offspring (n = 190) from an (LEW/OlaHsd × BC/CpbU) F2-intercross was genetically analyzed. From each F2animal, liver copper content was determined and genomic DNA was screened with polymorphic DNA markers. We found a major quantitative trait locus (QTL) for liver copper content in females on chromosome 2 and in males on chromosome 10. Both QTLs accounted for approximately 20% of the genetic variance. In addition, suggestive linkage for liver copper content was found on rat chromosomes 1, 8, 10, 12, 14, and 19. The regions on these chromosomes contain genes that are responsible for 9.0–15.5% of the genetic variance of liver copper content.
Differential Development of Aldehyde Dehydrogenase in Fore- and Glandular Stomach in Postnatal Rats
Authors: Picchiottino Christa , Lee Ping C.
Published: July 2017

Many foods contain the unsaturated aldehyde, hexadlenal (HX). Human exposure is thus unavoidable. HX feeding to rodents caused cancers only in the forestomach. Aldehyde dehydrogenases (ALDH) are key enzymes in the metabolism of aldehydes. We examined the distribution of ALDH using HX as the substrate (HXDH) along the GI tract of adolescent rats and found that their stomachs have high levels of HXDH activity and the enzyme preferred HX > 9-cis-retinal > acetyl aldehyde > formyl aldehyde. We also followed the postnatal development of the stomach. At birth, the forestomach represented 40–50% of the total stomach weight. Both fore- and glandular stomach gained weight, with the glandular portion gaining at a faster rate. By 21 days, the forestomach was 24–28% of the total weight and decreased slightly to an adult level of 22–24%. Gastric HXDH is low from birth to 14 days of age. HXDH activity increased thereafter, reaching higher levels at 21 days and peaking around 30–36 days of age. The activity then decreased to the adult level. The fore- and glandular stomach had the same level of HXDH activity in the newborn and at 7 and 14 days of age. At weaning, HXDH activity was higher (3×) in the forestomach than in the glandular stomach. In adults, the forestomach still had 2× the HXDH activity compared to the glandular stomach. Zymograms showed similar isozyme patterns of HXDH but with different ratios of the three major forms between the forestomach and the glandular stomach. Results indicate a differential development of HXDH between the fore- and glandular stomach that might be related to the higher sensitivity of the forestomach to HX feeding.
Cardiotonic Steroids: Potential Endogenous Sodium Pump Ligands with Diverse Function11
Authors: Dmitrieva Renata I. , Doris Peter A.
Published: July 2017

The highly conserved cardiotonic steroid (CS) binding site present on the ubiquitous membrane sodium pump, sodium, potassium-ATPase, appears to have been conserved by no force other than its capacity to bind CS: a family that includes plant-derived cardiac glycosides and putative endogenous vertebrate counterparts. Binding of ligand is inhibited by increased extracellular potassium. This implies functional coordination because inhibition of the sodium pump would be counterproductive when extracellular potassium is elevated. The interesting biology of the CS binding site continues to stimulate investigations into the identity of endogenous ligands, their role as pump regulators at the cellular level, and as mediators of body fluid balance and blood pressure regulation. In addition to inhibition of sodium and potassium transport, there is considerable recent evidence suggesting that the sodium pump may act as a cell signaling receptor activated by CS binding and responding by coordination of intracellular signaling pathways that can be dependent on and also independent of the reduction in transmembrane ion flux resulting directly from pump inhibition. This signaling may influence cell survival, growth, and differentiation. Recent insight into the biology of pump regulation by CS is reviewed.
Determinants Affecting Physical Activity Levels In Animal Models1
Authors: Tou Janet C.L. , Wade Charles E.
Published: July 2017

Weight control is dependent on energy balance. Reduced energy expenditure (EE) associated with decreased physical activity is suggested to be a major underlying cause in the increasing prevalence of weight gain and obesity. Therefore, a better understanding of the biological determinants involved in the regulation of physical activity is essential. To facilitate interpretation in humans, it is helpful to consider the evidence from animal studies. This review focuses on animal studies examining the biological determinants influencing activity and potential implications to human. It appears that physical activity is influenced by a number of parameters. However, regardless of the parameter involved, body weight appears to play an underlying role in the regulation of activity. Furthermore, the regulation of activity associated with body weight appears to occur only after the animal achieves a critical weight. This suggests that activity levels are a consequence rather than a contributor to weight control. However, the existence of an inverse weight-activity relationship remains inconclusive. Confounding the results are the multifactorial nature of physical activity and the lack of appropriate measuring devices. Furthermore, many determinants of body weight are closely interlocked, making it difficult to determine whether a single, combination, or interaction of factors is important for the regulation of activity. For example, diet-induced obesity, aging, lesions to the ventral medial hypothalamus, and genetics all produce hypoactivity. Providing a better understanding of the biological determinants involved in the regulation of activity has important implications for the development of strategies for the prevention of weight gain leading to obesity and subsequent morbidity and mortality in the human population.
Prior Increase in Metallothionein Levels is Required to Prevent Doxorubicin Cardiotoxicity1
Authors: Sun Xiuhua , Kang Y. James
Published: July 2017

Many studies have shown that metallothionein (MT) can be increased significantly by different oxidative insults in multiple organ systems. However, the increase in MT production often falls to protect against oxidative tissue injury. On the other hand, recent studies using a cardiac-specific, MT-overexpressing, transgenic mouse model have shown that MT protects against oxidative heart injury. Thus, the present study was undertaken to test the hypothesis that prior increase in MT levels is required to prevent oxidative injury. Oxidative heart injury was induced by doxorubicin (DOX), an important anticancer drug that causes severe cardiotoxicity through oxidative stress. Cardiac-specific, MT-overexpressing, transgenic mice and wild-type (WT) FVB mice were treated with OOX at 20 mg/kg. Four days after the treatment, MT concentrations were markedly elevated in the WT mouse heart. The elevated MT concentrations were comparable with those found in the transgenic mouse heart, which did not show further MT elevation in response to DOX challenge. Severe oxidative injury occurred in the heart of WT mice, including myocardial lipid peroxidation, morphological changes as examined by electron microscopy, high levels of serum creatine kinase activity, and decreased total glutathione concentrations in the heart. However, all of these pathological changes were significantly inhibited in the MT-transgenic mice. Therefore, this study demonstrates that there is a correlation between MT induction and oxidative stress in the DOX-treated mouse heart. However, MT can protect the heart from oxidative injury only if it is present prior to induction of oxidative stress.
Ectopic Expression of CXCR5/BLR1 Accelerates Retinoic Acid- and Vitamin D3-Induced Monocytic Differentiation of U937 Cells
Authors: Battle Traci E. , Yen Andrew
Published: July 2017

The product of the blr1 gene is a CXC chemokine receptor (CXCR5) that regulates B lymphocyte migration and has been implicated in myelomonocytic differentiation. The U937 human leukemia cell line was used to study the role of blr1 in retinoic acid-regulated monocytic leukemia cell growth and differentiation. blr1 mRNA expression was induced within 12 hr by retinoic acid in U937 cells. To determine whether the early induction of blr1 might regulate inducible monocytic cell differentiation, U937 cells were stably transfected with blr1 (U937/blr1 cells). Ectopic expression of blr1 caused no significant cell cycle or differentiation changes, but caused the U937/blr1 cells to differentiate faster when treated with either retinoic acid or 1α,5-dihydroxyvitamin D3. Treated with retinoic acid, U937/blr1 cells showed a greater increase in the percentage of CD11b expressing cells than vector control cells. Retinoic acid also Induced a higher percentage of functionally differentiated blr1 transfectants as assessed by nitroblue tetrazolium reduction. U937/blr1 cells underwent moderate growth inhibition on treatment with retinoic acid. Similar results occurred with 1α,25-dihydroxyvitamin D3. Because blr1 was induced early during cell differentiation and because its overexpression accelerated monocytic differentiation, it may be Important for signals controlling cell differentiation.
Interactions of Caffeine and Restraint Stress During Pregnancy in Mice
Authors: Albina M. Luisa , Colomina M. Teresa , Sanchez Domenec J. , Torrente Margarita , Domingo Jose L.
Published: July 2017

The maternal and developmental toxicity of combined exposure to restraint stress and caffeine was assessed in mice. On gestational Days 0–18, three groups of plug-positive females (n = 13–15) were given by gavage caffeine at 30, 60, and 120 mg/kg/day. Three additional groups received the same caffeine doses and were restrained for 2 hr/day. Control groups included restrained and unrestrained plug-positive mice not exposed to caffeine. All animals in the group concurrently exposed to 120 mg/kg/day of caffeine and restraint died during the experimental period. In the remaining groups, cesarean sections were performed on Day 18 of gestation, and the fetuses were weighed and examined for external, internal, and skeletal malformations and variations. Although maternal and embryo/fetal toxicity were observed at all caffeine doses, the adverse maternal and developmental effects were significantly enhanced in the groups concurrently exposed to caffeine and restraint. It was especially remarkable at 60 and 120 mg/kg/day. The results of this study suggest that maternal and developmental toxic effects might occur if high amounts of caffeine were consumed by women under a notable stress during pregnancy.
Chronic Nitric Oxide Deficiency is Associated with Altered Leutinizing Hormone and Follicle-Stimulating Hormone Release in Ovariectomized Rats1
Authors: Barnes Maria J. , Lapanowski Karen , Rafols Jose A. , Lawson David M. , Dunbar Joseph C.
Published: July 2017

Nitric oxide (NO) synthase (NOS) has been found in the gonadotrophs and folliculo-stellate cells of the anterior pituitary. Previous observations from our laboratory suggest that NO may play a role in regulating gonadotropin secretion. Because estrogen secretion by the ovary can influence gonadotropin secretion, we investigated the hypothesis that chronic in vivo NO deficiency has a direct estrogen-independent effect on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Chronic NO deficiency was induced by adding an NOS inhibitor, N-nitro-L-arginine (L-NNA, 0.6 g/l) to the drinking water of ovariectomized (OVX) rats. The control OVX rats were untreated. After 6–8 weeks, the animals were sacrificed, and the pituitaries were removed and perfused continuously for 4 hr in the presence of pulsatile gonadotropin-releasing hormone (GnRH, 500 ng/pulse) every 30 min. S-Nitroso-l-acetyl penicillamine (SNAP, an NO donor, 0.1 mM) or l-nitro-arginine methyl ester (L-NAME, an NOS inhibitor, 0.1 mM) was added to the media and perfusate samples were collected at 10-min intervals. GnRH-stimulated LH and FSH levels were significantly lower in pituitaries from OVX/NO-deficient pituitaries compared with pituitaries from the OVX control group. The addition of SNAP significantly decreased LH and FSH secretion by pituitaries from OVX control animals, but significantly increased their secretion by pituitaries from the OVX/NO-deficient animals. L-NAME also suppressed LH and FSH secretion by pituitaries from the OVX control animals and stimulated their release by pituitaries from the NO-deficient/OVX animals. Immunohisto-chemistry of frontal sections through the hypothalamus demonstrated that OVX/NO deficiency is associated with increased GnRH in the median eminence. We conclude that NO has a chronic stimulatory effect on LH and FSH release and the subsequent altered secretory responsiveness to NO agonist or antagonist is the result of chronic NO suppression.
Transforming Growth Factor-β Signal Transduction and Progressive Renal Disease1
Authors: Cheng Jingfei , Grande Joseph P.
Published: July 2017

Transforming growth factor-β (TGF-β) superfamily members are multifunctional growth factors that play pivotal roles in development and tissue homeostasis. Recent studies have underscored the importance of TGF-β in regulation of cell proliferation and extracellular matrix synthesis and deposition. TGF-β signaling is initiated by ligand binding to a membrane-associated receptor complex that has serine/threonine kinase activity. This receptor complex phosphorylates specific Smad proteins, which then transduce the ligand-activated signal to the nucleus. Smad complexes regulate target gene transcription either by directly binding DNA sequences, or by complexing with other transcription factors or co-activators. There is extensive crosstalk between the TGF-β signaling pathway and other signaling systems, including the mitogen-activated protein kinase pathways. The importance of TGF-β in regulation of cell growth has been emphasized by recent observations that mutations of critical elements of the TGF-β signaling system are associated with tumor progression in patients with many different types of epithelial neoplasms. TGF-β has emerged as a predominant mediator of extracellular matrix production and deposition in progressive renal disease and in other forms of chronic tissue injury. In this overview, recent advances in our understanding of TGF-β signaling, cell cycle regulation by TGF-β, and the role of TGF-β in progressive renal injury are highlighted.
Role of Nociceptin/Orphanin FQ in the Physiologic and Pathologic Control of the Cerebral Circulation
Authors: Armstead William M.
Published: July 2017

Nociceptin/orphanin FQ is a newly described member of the opioid family. Previous minireviews in this series have described the contribution of important factors, including opioids, in the regulation of the cerebral circulation during physiologic and pathologic conditions. The present review extends these initial comments to an opioid whose vascular actions have only very recently been appreciated. In particular, this review discusses the contribution of nociceptin/orphanin FQ to impaired cerebral hemodynamics after cerebral hypoxia/ischemia and traumatic brain injury.
Is Metabolic Syndrome X an Inflammatory Condition?
Authors: Das Undurti N.
Published: July 2017

It is suggested that metabolic syndrome X is a low-grade systemic Inflammatory condition.
Acetaminophen in the Post-ischemia Reperfused Myocardium
Authors: Golfetti Roseli , VanDyke Knox , Rork Tyler , Spiler Norell , Merrill Gary
Published: July 2017

Acetaminophen was administered acutely at the onset of reperfusion after 20 min of low-flow, global myocardial ischemia in isolated, perfused guinea pig hearts (Langendorff) to evaluate its influence in the postischemia, reperfused myocardium. Similarly prepared hearts were treated with vehicle or with uric acid (another phenol for comparison). Functionally, acetaminophen-treated hearts (0.35 mM) achieved significantly greater recovery during reperfusion. For example, left ventricular developed pressures at 40 min reperfusion were 38 ± 3, 27 ± 3, and 20 ± 2 in the presence of acetaminophen (P < 0.05, relative to the other two groups), vehicle, and uric acid, respectively. Coronary perfusion pressures and calculated coronary vascular resistances, in the acetaminophen-treated hearts, were significantly lower at the same time (e.g., coronary perfusion pressures in the three groups, respectively, were 40 ± 2 [P < 0.05], 51 ± 3, and 65 ± 12 mm Hg). Under baseline, control conditions, creatine kinase ranged from 12–15 units/liter in the three groups. It increased to 35–40 units/liter (P < 0.05) during ischemia but was significantly reduced by acetaminophen during reperfusion (e.g., 5.3 ± 0.8 units/liter at 40 min). Oxidant-mediated chemiluminescence in all three treatment groups during baseline conditions and ischemia was similar (i.e., approximately 1.5–2.0 min for peak luminescence to reach its half maximal value). It took significantly more time during reperfusion for the oxidation of luminol in the presence of acetaminophen (>20 min, P < 0.05) than in its absence (3–8 min in uric acid- and vehicle-treated hearts). These results suggest that administration of acetaminophen (0.35 mM), at the onset of reperfusion, provides anti-oxidant–mediated cardioprotection in the postischemia, reperfused myocardium.
Leptin-Induced Changes in Body Composition in High Fat-Fed Mice1
Authors: Harris Ruth B.S. , Mitchell Tiffany D. , Hebert Sadie
Published: July 2017

Female C57BL/6J mice were adapted to 10% or 45% kcal fat diets for 8 weeks. Continuous intraperitoneal infusion of 10 μg of leptin/day from a miniosmotic pump transiently inhibited food intake in low fat-fed but not high fat-fed mice. In contrast, both low and high fat-fed leptin-infused mice were less fat than their phosphate-buffered saline (PBS) controls after 13 days. Leptin infusion inhibited insulin release but did not change glucose clearance in low fat-fed mice during a glucose tolerance test. A single intraperitoneal injection of 30 μg of leptin inhibited 24-hr energy intake and inhibited weight gain in both low and high fat-fed mice. Insulin responsiveness was improved in high fat-fed mice during an insulin sensitivity test due to an exaggerated elevation of circulating insulin concentrations. Thus, leptin infusion reduced adiposity independently of energy intake in high fat-fed mice and improved insulin sensitivity in low fat-fed mice, whereas leptin injections, which produced much greater, but transient, increases in serum leptin concentration, inhibited energy intake in both low and high fat-fed mice.
Induction of Glutamate Dehydrogenase in the Ovine Fetal Liver by Dexamethasone Infusion during Late Gestation1
Authors: Timmerman M. , Wilkening R.B. , Regnault T.R.H.
Published: July 2017

Glucocorticoids near term are known to upregulate many important enzyme systems prior to birth. Glutamate dehydrogenase (GDH) is a mitochondrial enzyme that catalyzes both the reversible conversion of ammonium nitrogen into organic nitrogen (glutamate production) and the oxidative deamination of glutamate resulting in 2-oxoglutarate. The activity of this enzyme is considered to be of major importance in the development of catabolic conditions leading to gluconeogenesis prior to birth. Ovine hepatic GDH mRNA expression and activity were determined in near-term (130 days of gestation, term 147 ± 4 days) control and acutely dexamethasone-treated (0.07 mg–1 hr–1 for 26 hr) fetuses. Dexamethasone infusion had no effect on placental or fetal liver weights. Dexamethasone infusion for 26 hr significantly increased hepatic GDH mRNA expression. This increased GDH mRNA expression was accompanied by an increase in hepatic mitochondrial GDH activity, from 30.0 ± 7.4 to 58.2 ± 8.1 U GDH/U CS (citrate synthase), and there was a significant correlation between GDH mRNA expression and GDH activity. The generated ovine GDH sequence displayed significant similarity with published human, rat, and murine GDH sequence. These data are consistent with the in vivo studies that have shown a redirection of glutamine carbon away from net hepatic glutamate release and into the citric acid cycle through the forward reaction catalyzed by GDH, i.e., glutamate to oxoglutarate.
Effects of Docosahexaenoic Acid on Vascular Pathology and Reactivity in Hypertension
Authors: Engler Marguerite M. , Engler Mary B. , Pierson Diane M. , Molteni Loredana Brizio , Molteni Agostino
Published: July 2017

Previous studies have shown that docosahexaenoic acid (DHA) has an antihypertensive effect in spontaneously hypertensive rats (SHR). To investigate possible mechanisms for this effect, vascular pathology and reactivity were determined in SHR treated with dietary DHA. SHR (7 weeks) were fed a purified diet with either a combination of corn/soybean oils or a DHA-enriched oil for 6 weeks. Histological evaluation of heart tissue, aorta, coronary, and renal arteries was performed. Vascular responses were determined in isolated aortic rings. Contractile responses to agonists, including norepinephrine (10–9to 10–4M), potassium chloride (5–55 mM), and angiotensin II (5 × 10–7M) were assessed. Vasorelaxant responses to acetylcholine (10–9to 10–4M), sodium nitroprusside (10–9to 10–6M), papaverine ((10–5to (10–4M), and methoxyverapamil (D600, 1–100 μM) were determined. DHA-fed SHR had significantly reduced blood pressure (P < 0.001) and vascular wall thicknesses in the coronary, thoracic, and abdominal aorta compared with controls (P < 0.05) Contractile responses to agonists mediated by receptor stimulation and potassium depolarization were not altered in DHA-fed SHR. Endothelial-dependent relaxations to acetylcholine were not altered which suggests endothelial-derived nitric oxide production/release is not affected by dietary DHA. Other mechanisms of vascular relaxation, including intracellular cyclic nucleotides, cGMP, and cAMP were not altered by dietary DHA because aortic relaxant responses to sodium nitroprusside and papaverine were similar in control and DHA-fed SHR. No significant differences were seen in relaxant responses to the calcium channel blocker, D600, or contractile responses to norepinephrine in the absence of extracellular calcium. These results suggest that dietary DHA does not affect mechanisms related to extracellular calcium channels or intracellular calcium mobilization. Moreover, the contractile and vasorelaxant responses are not differentially altered with dietary DHA in this in vivo SHR model. The findings demonstrate that dietary DHA reduces systolic blood pressure and vascular wall thickness in SHR. This may contribute to decrease arterial stiffness and pulse pressure, in addition to the antihypertensive properties of DHA. The antihypertensive properties of DHA are not related to alterations in vascular responses.
Inhibitory Effects of Progesterone on Plasma Membrane Fluidity and Tumorigenic Potential of Ovarian Epithelial Cancer Cells
Authors: McDonnel Anna C. , Kirk Edward A. Van , Isaak Dale D. , Murdoch William J.
Published: July 2017

The lethality of common (surface) epithelial ovarian cancer is contingent on its metastatic capacity. Dissemination of the neoplasia throughout the abdominal cavity has been associated with secretion of proteolytic enzymes from vesicles shed by ovarian cancer cells. We report that the lipophilic steroid hormone progesterone decreases the fluid dynamics of plasma membranes of human SKOV-3 adenocarcinoma cells. The decrease in membrane fluidity was related to an inhibition in vitro of exocytotic vesicle release, cellular invasiveness into Matrigel, and colony formation in three-dimensional collagen matrix. Tumorigenesis was suppressed by progesterone in immunocompromised nude mice inoculated intraperitoneally with SKOV-3 cells. Progestins could therefore be of benefit in the prevention and(or) treatment of early-stage ovarian carcinomatosis.
Insulin Resistance and Its Contribution to Colon Carcinogenesis
Authors: Komninou Despina , Ayonote Alexis , Richie John P. , Rigas Basil
Published: July 2017

The insulin resistance-colon cancer hypothesis, stating that insulin resistance may be associated with the development of colorectal cancer, represents a significant advance in colon cancer, as it emphasizes the potential for this cancer to become a modifiable disease. The fact that the incidence of insulin resistance has been increasing in the United States and much of the rest of the Western world where colon cancer remains the second leading cause of cancer death makes the exploration of the interrelationship of these conditions a subject of high priority. Here, we review the salient features of insulin resistance, defined as impaired biological response to the action of insulin. Recent epidemiological studies, evaluating potential associations between colon cancer risk and diabetes mellitus, dietary intake and metabolic factors, and IGF levels in several clinical settings, provide strong support of the insulin resistance-colon cancer hypothesis (without establishing causality). Mechanistically, insulin resistance has been associated with hyperinsulinemia, increased levels of growth factors including IGF-1, and alterations in NF-κB and peroxisome proliferator-activated receptor signaling, which may promote colon cancer through their effects on colonocyte kinetics. It is a reasonable expectation that in the not too distant future, critical interventions to the already mapped molecular sequence of events, which link two apparently disparate entities, combined with lifestyle changes could abrogate the development of colon cancer.
Effects of Resistance versus Aerobic Training on Coronary Artery Disease Risk Factors
Authors: Banz William J. , Maher Margaret A. , Thompson Warren G. , Bassett David R. , Moore Wayne , Ashraf Muhammad , Keefer Daniel J. , Zemel Michael B.
Published: July 2017

Individuals exhibiting “the metabolic syndrome” have multiple coronary artery disease risk factors, including insulin resistance, hyperlipidemia, hypertension, and android obesity. We performed a randomized trial to compare the effects of aerobic and resistance training regimens on coronary risk factors. Twenty-six volunteers who exhibited android obesity and at least one other risk factor for coronary artery disease were randomized to aerobic or resistance training groups. Body mass index, waist-to-hip ratio, glucose, insulin, body composition, 24-hr urinary albumin, fibrinogen, blood pressure, and lipid profile were measured at baseline and after 10 weeks of exercise training. Both groups showed a significant reduction in waist-to-hip ratio and the resistance training group also showed a reduction in total body fat. There was no significant change in mean arterial blood pressure in either group. Fasting plasma glucose, insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were unchanged in both groups. High-density lipoprotein (HDL) cholesterol increased (13%) with aerobic training only. Plasma fibrinogen was increased (28% and 34%, P < 0.02) in both groups and both groups showed a significant decrease (34% and 28%, P < 0.03) in microalbuminuria after their respective training regimen. In conclusion, resistance training was effective in improving body composition of middle-aged obese sedentary males. Only aerobic training was effective in raising HDL cholesterol. More studies are warranted to assess the effects of exercise on plasma fibrinogen and microalbuminuria.
Intestinal Pathophysiology in Autism
Authors: White John F.
Published: July 2017

Autism is a life-long developmental disorder affecting as many as 1 in 500 children. The causes for this profound disorder are largely unknown. Recent research has uncovered pathology in the gastrointestinal tract of autistic children. The pathology, reported to extend from the esophagus to the colon, is described here along with other studies pointing to a connection between diet and the severity of symptoms expressed in autism. The evidence that there is impaired intestinal permeability in autism is reviewed, and various theories are discussed by which a leaky gut could develop. Lastly, some possible ways in which impaired gastrointestinal function might influence brain function are discussed.
Asbestos-Induced Pulmonary Toxicity: Role of DNA Damage and Apoptosis
Authors: Upadhyay Daya , Kamp David W.
Published: July 2017

Asbestos causes asbestosis and various malignancies by mechanisms that are not clearly defined. Here, we review the accumulating evidence showing that asbestos is directly genotoxic by inducing DNA strand breaks (DNA-SB) and apoptosis in relevant lung target cells. Although the exact mechanisms by which asbestos causes DNA damage and apoptosis are not firmly established, some of the implicated mechanisms include the generation of iron-derived reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), alteration in the mitochondrial function, and activation of the death receptor pathway. We focus on the accumulating evidence implicating ROS. DNA repair mechanisms have a key role in limiting the extent of DNA damage. Recent studies show that asbestos activates DNA repair enzymes such as apurinic/apyrimidinic endonuclease (APE) and poly (ADP-ribose) polymerase (PARP). Asbestos-induced neoplastic transformation may result in the setting where DNA damage overwhelms DNA repair in the face of a persistent proliferative signal. Strategies aimed at limiting asbestos-induced oxidative stress may reduce DNA damage and, as such, prevent malignant transformation.
Neurodevelopmental Disorders after Thimerosal-Containing Vaccines: A Brief Communication
Authors: Geier Mark R. , Geier David A.
Published: July 2017

We were initially highly skeptical that differences in the concentrations of thimerosal in vaccines would have any effect on the incidence rate of neurodevelopmental disorders after childhood immunization. This study presents the first epidemiologic evidence, based upon tens of millions of doses of vaccine administered in the United States, that associates increasing thimerosal from vaccines with neurodevelopmental disorders. Specifically, an analysis of the Vaccine Adverse Events Reporting System (VAERS) database showed statistical increases in the incidence rate of autism (relative risk [RR] = 6.0), mental retardation (RR = 6.1), and speech disorders (RR = 2.2) after thimerosal-containing diphtheria, tetanus, and acellular pertussis (DTaP) vaccines in comparison with thimerosal-free DTaP vaccines. The male/female ratio indicated that autism (17) and speech disorders (2.3) were reported more in males than females after thimerosal-containing DTaP vaccines, whereas mental retardation (1.2) was more evenly reported among male and female vaccine recipients. Controls were employed to determine if biases were present in the data, but none were found. It was determined that overall adverse reactions were reported in similar-aged populations after thimerosal-containing DTaP (2.4 ± 3.2 years old) and thimerosal-free DTaP (2.1 ± 2.8 years old) vaccinations. Acute control adverse reactions such as deaths (RR = 1.0), vasculitis (RR = 1.2), seizures (RR = 1.6), ED visits (RR = 1.4), total adverse reactions (RR = 1.4), and gastroenteritis (RR = 1.1) were reported similarly after thimerosal-containing and thimerosal-free DTaP vaccines. An association between neurodevelopmental disorders and thimerosal-containing DTaP vaccines was found, but additional studies should be conducted to confirm and extend this study.
Enhancement of Repopulation and Hematopoiesis of Bone Marrow Cells in Irradiated Mice by Oral Administration of PG101, a Water-Soluble Extract fromLentinus lepideus
Authors: Jin Mirim , Jeon Hyang , Jung Hyung Jin , Kim Bongcheol , Shin Sung Seup , Choi Jeong June , Lee Jong Kyu , Kang Chang-Yuil , Kim Sunyoung
Published: July 2017

PG101 is a water-soluble extract from Lentinus lepideus. It is a potential biological response modifier that activates selective cytokines in vitro, mainly by controlling cellular transcription factor NF-κB. Effects of PG101 were tested on bone marrow cells in irradiated mice. Mice were irradiated with a dose of 6 Gy and were given PG101 by gavages daily for 24 days. In PG101-treated mice, the number of colony-forming cells, including colony-forming units (CFU)-granulocytes/macrophages (GM) and erythroid burst-forming units (BFU-E), were increased to almost the levels seen in nonirradiated control as early as 8 days after irradiation. Two-color flow cytometric analysis using antibodies to ER-MP12 and ER-MP20 suggested that in the bone marrow cell population, PG101 increased the number of granulocytes (ER-MP12-20med) and myeloid progenitors (ER-MP12+20+). Analysis of surface c-Kit and Gr-1 proteins in bone marrow cells indicated that PG101 might induce differentiation of progenitor cells to granulocytes and/or proliferation of the committed cells. Lastly, oral administration of PG101 highly increased serum levels of GM-CSF, IL-6, and IL-1β. Interestingly, the level of TNF-α was elevated by irradiation in control mice, but was maintained at the background level in PG101-treated mice, suggesting that PG101 might effectively suppress TNF-α-related pathologic conditions. Our results strongly suggest the great potential of PG101 as an immune enhancer during radiotherapy and/or chemotherapy.
Recent Insights into the Role of the Innate Immune System in the Development of Alcoholic Liver Disease
Authors: Nagy Laura E.
Published: July 2017

The innate immune system is responsible for the rapid, initial response of the organism to potentially dangerous stresses, including pathogens, tissue injury, and malignancy. Pattern-recognition receptors of the toll-like receptor (TLR) family expressed by macrophages provide a first line of defense against microbial invasion. Activation of these receptors results in a stimulus-specific expression of genes required to control the infection, including the production of inflammatory cytokines and chemokines, followed by the recruitment of neutrophils to the site of infection. The early stages in the development of alcoholic liver disease (ALD) follow a pattern characteristic of an innate immune response. Kupffer cells, the resident macrophages in the liver, are activated in response to bacterial endotoxins (lipopolysaccharide, LPS), leading to the production of inflammatory and fibrogenic cytokines, reactive oxygen species, as well as the recruitment of neutrophils to the liver. One mechanism by which chronic ethanol can turn the highly regulated innate immune response into a pathway of disease is by disrupting the signal transduction cascades mediating the innate Immune response. Recent studies have identified specific modules in the TLR-4 signaling cascade that are disrupted after chronic ethanol exposure, including CD14 and the mitogen-activated protein kinase family members, ERK1/2 and p38. Enhanced activation of these TLR-4 dependent signaling pathways after chronic ethanol likely contributes to the development of alcoholic liver disease.
Caspase-Dependent and -Independent Panc-1 Cell Death Due to Actinomycin D and MK 886 are Additive but Increase Clonogenic Survival
Authors: Anderson Kenning M. , Alrefai Waddah , Bonomi Philip , Seed Thomas M. , Dudeja Pradeep , Hu Yunming , Harris Jules E.
Published: July 2017

In human panc-1 pancreatic cancer cells, actinomycin D (act D) induces a type 1 (apoptotic, extrinsic, death domain, receptor-dependent, and caspase-positive) form of programmed cell death (PCD) and MK 886, a 5-Iipoxygenase inhibitor serving among other functions as a surrogate for increasing oxidative stress, a type 2 form, defined as an intrinsic, mitochondria-dependent, autophagic form of cellular suicide. Using both agents simultaneously should allow for examination of their interaction in cells able to express either form of PCD. Activation of both forms might result in synergistic, additive, null, or inhibitory effects on the reduction in proliferation, PCD, and clonogenicity of surviving cells. Co-culture of panc-1 cells with act D and MK 886, which both inhibit their proliferation, had an additive effect on increasing the development of these forms of PCD, as determined by morphology, a nucleosome assay, and flow cytometry. Initially, laddering on agarose detected with propidium iodide, present in act D, and act D plus MK 886-treated cells was partially obscured by randomly degraded DNA. With the use of the more sensitive SYBR green dye and reduced exposure of detached cells to 37°C, a limited laddering of DNA from MK 886-treated cells was also detected. Caspase activity was present in act-D-cultured cells but was absent in cells cultured with MK 886. Combined culture reduced caspase activity in act D-treated cells, consistent with interference from type 2 of type 1 PCD. Removal after 48 hr of act D or MK 886 allowed regrowth of residual cells, the latter agent to a greater extent than the former. In combination, the number of clones was increased compared with act D alone. These features distinguish two forms of PCD. In therapeutic settings in which the modes of cell death have not been identified, unintentional activation of several cellular suicide pathways with “crosstalk” between them occurs. Their intentional simultaneous activation and responses, as modulated by the history of cells in or out of cycle, could reduce the intended therapeutic outcome with survival of additional clonogenic cells due to various forms of mutual interference.
Exposure to Flaxseed or Its Purified Lignan during Suckling Inhibits Chemically Induced Rat Mammary Tumorigenesis
Authors: Chen Jianmin , Tan Kah Poh , Ward Wendy E. , Thompson Lilian U.
Published: July 2017

Previous studies have shown that feeding flaxseed (FS) or its lignan secoisolariciresinol diglucoside (SDG) to rat dams during lactation enhances the differentiation of rat mammary gland in the female offspring. This study determined whether exposure to a diet with 10% FS or SDG (equivalent to the amount in 10% FS) during suckling could protect against 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced rat mammary tumorigenesis later in life. Dams were fed the AIN-93G basal diet (BD) throughout pregnancy. After delivery, dams were randomized to continue on BD or were fed BD supplemented with 10% FS or SDG during lactation. Three-day urine of dams was analyzed for mammalian lignans. After weaning, all offspring were fed BD. At postnatal Days 49 to 51, during proestrus phase, offspring were gavaged with 5 mg of DMBA. At Week 21 post-DMBA administration, compared with the BD group, the FS and SDG groups had significantly lower (P < 0.05) tumor incidence (31.3% and 42.0% lower, respectively), total tumor load (50.8% and 62.5% lower, respectively), mean tumor size (43.9% and 67.7% lower, respectively), and tumor number (46.9% and 44.8% lower, respectively) per rat. There was a significant decreasing trend (P < 0.05) in final tumor weights in rats fed FS or SDG. The high urinary lignan excretion in dams fed with FS or SDG corresponded with the reduced tumor development. The FS and SDG groups did not differ significantly in tumor indices, indicating that the effect of FS is primarily due to its SDG. There were no significant changes in selective reproductive indices measured among dams and offspring. In conclusion, exposure to FS or SDG during suckling suppressed DMBA-induced rat mammary tumorigenesis, suggesting that exposure to lignans at this early stage of mammary gland development reduces susceptibility to mammary carcinogenesis later in life without adverse effects on selective reproductive Indices in dams or offspring.
Copper, Zinc-Superoxide Dismutase Protein but not mRNA is Lower in Copper-Deficient Mice and Mice Lacking the Copper Chaperone for Superoxide Dismutase
Authors: Prohaska Joseph R. , Geissler Jacqueline , Brokate Bruce , Broderius Margaret
Published: July 2017

Cu, Zn-superoxide dismutase (SOD1) is an abundant metalloenzyme important in scavenging superoxide ions. Cu-deficient rats have lower SOD1 activity and protein, possibly because apo-SOD1 is degraded faster than holo-SOD1. Previous work with mice lacking the Cu chaperone for SOD1 (CCS) indicated a drastic loss of SOD1 activity but not protein, suggesting an accumulation of apo-SOD1. We produced dietary Cu deficiency in mice to clarify this issue. Compared with Cu-deficient rats, reduction in liver SOD1 activity and protein was much less than Cu-deficient mouse dams and offspring. However, after perinatal Cu deficiency, 4-week-old mouse pups had lower levels of SOD1 activity and protein in liver and heart, but not brain, compared with Cu-adequate controls. Reduction in brain Cu was greater than liver. In CCS –t– mice, there was severe reduction in liver, heart, and brain SOD1 activity and protein. In fact, the reduction in activity was similar to the loss of protein. Neither Cu-deficient mouse liver nor CCS -/- mouse liver had altered SOD1 mRNA levels compared with control values. These results in mice are comparable with rats and suggest a posttranscriptional mechanism for reduction of SOD1 protein when Cu is limiting in SOD1.
Soy Protein with or Without Isoflavones, Soy Germ and Soy Germ Extract, and Daidzein Lessen Plasma Cholesterol Levels in Golden Syrian Hamsters
Authors: Song Tongtong , Lee Sun-Ok , Murphy Patricia A. , Hendrich Suzanne
Published: July 2017

Dietary isolated soy protein (ISP, containing approximately equal amounts of daidzein and genistein), ethanol-extracted ISP (ISP (–)), soygerm or soygerm extract (containing large amounts of daidzein and glycitein and little genistein) and the isoflavone, daidzein, were hypothesized to lessen plasma cholesterol in comparison with casein. Sixty male and 60 female golden Syrian hamsters (6–8 weeks of age) were randomly assigned to six treatments fed for 10 weeks. Four of the experimental diets (ISP, daidzein, soygerm, and soygerm extract) contained 1.3 mmol total isoflavones/kg. The ISP (–) diet contained 0.013 mmol isoflavone/kg, whereas the casein diet contained no isoflavones. Hamsters fed ISP, ISP (–), daidzein, soygerm, and soygerm extract had significantly less plasma total cholesterol (by 16%–28%), less non-HDL cholesterol (by 15%–50%) and less non-HDL/HDL cholesterol ratios compared with hamsters fed casein ( P < 0.01). For male hamsters, there were no differences among treatments in plasma HDL concentrations. Female hamsters fed ISP (–) had significantly greater HDL levels ( P < 0.01) than females fed casein or daidzein. Triglyceride concentration was significantly less in hamsters fed ISP (–) compared with the casein-fed females. Because soy protein with or without isoflavones, soygerm and soygerm extract, and daidzein lessened plasma cholesterol to an approximately equal extent, soy protein alone, varying mixtures of isoflavones, and other extractable components of soy are responsible for cholesterol-lessening effects of soy foods, mainly due to their effects to lessen LDL cholesterol.