bluuebunny/crossref_metadata_2025 huggingface dataset:
Congestive Heart Failure in Copper-Deficient Mice
Authors: Elsherif Laila , Ortines Raymond V. , Saari Jack T. , Kang Y. James
Published: January 2017

Copper Deficiency (CuD) leads to hypertrophic cardiomyopathy in various experimental models. The morphological, electrophysiological, and molecular aspects of this hypertrophy have been under investigation for a long time. However the transition from compensated hypertrophy to decompensated heart failure has not been investigated in the study of CuD. We set out to investigate the contractile and hemodynamic parameters of the CuD mouse heart and to determine whether heart failure follows hypertrophy in the CuD heart. Dams of FVB mice were fed CuD or copper-adequate (CuA) diet starting from the third day post delivery and the weanling pups were fed the same diet for a total period of 5 weeks (pre- and postweanling). At week 4, the functional parameters of the heart were analyzed using a surgical technique for catheterizing the left ventricle. A significant decrease in left ventricle systolic pressure was observed with no significant change in heart rate, and more importantly contractility as measured by the maximal rate of left ventricular pressure rise (+dP/dt) and decline (−dP/dt) were significantly depressed in the CuD mice. However, left ventricle end diastolic pressure was elevated, and relaxation was impaired in the CuD animals; the duration of relaxation was prolonged. In addition to significant changes in the basal level of cardiac function, CuD hearts had a blunted response to the stimulation of the β-adrenergic agonist isoproterenol. Furthermore, morphological analysis revealed increased collagen accumulation in the CuD hearts along with lipid deposition. This study shows that CuD leads to systolic and diastolic dysfunction in association with histopathological changes, which are indices commonly used to diagnose congestive heart failure.
Ascorbic Acid Blocks the Growth Inhibitory Effect of Tumor Necrosis Factor-α on Endothelial Cells
Authors: Saeed Rubina W. , Peng Tina , Metz Christine N.
Published: January 2017

Impaired endothelial cell proliferation has been proposed to be an early, critical defect contributing to the development of atherosclerosis. Recent studies show that high plasma tumor necrosis factor (TNF)-α levels and low serum ascorbic acid (AA) levels correlate with atherosclerosis severity. Additionally, AA has been reported to have potential beneficial effects in preventing atherosclerosis. Based on these studies, we investigated the role of AA (≤ 1mM) on TNF-α-mediated vascular endothelial cell growth inhibition in vitro. In accordance with previous reports, we found that TNF-α alone inhibited endothelial cell proliferation. Further studies revealed that AA alone enhanced endothelial cell proliferation and that AA blocked endothelial cell growth inhibition induced by TNF-α. By contrast, we observed no effect of AA on endothelial cell activation or nuclear entry of nuclear factor-κB in response to TNF-α. The protective effect of AA on endothelial cell proliferation was not simply the result of its antioxidant activity but did correlate with collagen IV expression by endothelial cells. AA pre-treatment of proliferating endothelial cells promoted retinoblastoma protein (Rb) phosphorylation and decreased p53 levels when compared to untreated cells. Furthermore, the addition of AA to TNF-α-treated proliferating endothelial cells blocked both the inhibition of retinoblastoma protein phosphorylation and enhanced p53 expression induced by TNF-α. Consistent with these results, we found that AA protects endothelial cells against TNF-α-induced apoptosis. These studies highlight the potential therapeutic role of AA in promoting endothelial cell proliferation during inflammatory conditions, such as atherosclerosis and cardiovascular disease.
Animal Model Systems for the Study of Alcohol Teratology
Authors: Cudd Timothy A.
Published: January 2017

The incidence of fetal alcohol syndrome has not been declining even though alcohol has been established as a teratogen and significant efforts have been made to educate women not to abuse alcohol during pregnancy. In addition to further educational efforts, strategies to prevent or mitigate the damages of prenatal alcohol exposure are now under development. Animal models will play a significant role in the effort to develop these strategies. Because prenatal alcohol exposure causes damage by multiple mechanisms, depending on dose, pattern, and timing of exposure, and because no species of animal is the same as the human, the choice of which animal model to use is complicated. To choose the best animal model, it is necessary to consider the specific scientific question that is being addressed and which model system is best able to addressthe question. Animal models that are currently in use include nonhuman primates, rodents (rats, mice, guinea pigs), large animal models (pig and sheep), the chick, and simple animals, including fish, insects, and round worms. Each model system has strengths and weaknesses, depending on the question being addressed. Simple animal models are useful in exploring basic science questions that relate to molecular biology and genetics that cannot be explored in higher-order animals, whereas higher-order animal models are useful in studying complex behaviors and validating basic science findings in an animal that is more like the human. Substantial progress in this field will require the judicious use of multiple scientific approaches that use different animal model systems.
Alcohol Teratogenesis: Mechanisms of Damage and Strategies for Intervention
Authors: Goodlett Charles R. , Horn Kristin H. , Zhou Feng C.
Published: January 2017

There are multiple mechanisms by which alcohol can damage the developing brain, but the type of damage induced will depend on the amount and developmental timing of exposure, along with other maternal and genetic factors. This article reviews current perspectives on how ethanol can produce neuroteratogenic effects by its interactions with molecular regulators of brain development. The current evidence suggests that alcohol produces many of its damaging effects by exerting specific actions on molecules that regulate key developmental processes (e.g., L1 cell adhesion molecule, alcohol dehydrogenase, catalase), interfering with the early development of midline serotonergic neurons and disrupting their regulatory-signaling function for other target brain structures, interfering with trophic factors that regulate neurogenesis and cell survival, or inducing excessive cell death via oxidative stress or activation of caspase-3 proteases. The current understanding of pathogenesis mechanisms suggests several strategic approaches to develop rational molecular prevention. However, the development of behavioral and biologic treatments for alcohol-affected children is crucial because it is unlikely that effective delivery of preventative interventions can realistically be achieved in ways to prevent prenatal damage in at-risk pregnancies. Toward that end, behavioral training that promotes experience-dependent neuroplasticity has been effective in a rat model of cerebellar damage induced by alcohol exposure during the period of brain development that is comparable to that of the human third trimester.
A BRIEF COMMUNICATION
Authors: Murdoch William J. , Van Kirk Edward A. , Alexander Brenda M.
Published: January 2017

A cause-effect relationship between ovulation and common (surface) epithelial ovarian cancer has been suspected for many years. The ovarian surface epithelium apparently becomes exposed to genotoxins that are generated during the ovulatory process. Intensive egg-laying hens readily develop ovarian carcinomatosis. Indeed, elevated levels of potentially mutagenic 8-oxo-guanine adducts were detected in avian ovarian epithelial cells isolated from the apical surfaces and perimeters of pre-and postovulatory follicles, respectively. Internucleosomal DNA fragmentation indicative of apoptosis was evident in ovarian surface epithelial cells associated with the formative site of ovulation (stigma line) and regressive ruptured follicles. It is conceivable that a genetically altered progenitor cell with unrepaired DNA but not committed to death (i.e., a unifocal “escape”) could give rise to a transformed phenotype. Hence, the high rate of ovarian cancer in egg-laying hens could be the consequence of genomic damages to the ovarian surface epithelium associated with incessant ovulations, thereby increasing the likelihood of mutation and clonal expansion.
Tomatoes, Lycopene Intake, and Digestive Tract and Female Hormone-Related Neoplasms
Authors: Vecchia Carlo La
Published: January 2017

Tomato consumption showed a consistent inverse relation with the risk of digestive tract neoplasms in Italy in an integrated series of studies conducted in the 1980s. Another series of case-control studies was conducted between 1992 and 1999 in different areas of Italy. Cases were patients below age 80 with incident, histologically confirmed cancer of the oral cavity and pharynx (n = 754), esophagus (n = 304), colorectum (n = 1953), breast (n = 2529), and ovary (n = 1031). The comparison group involved, overall, over 5000 patients below age 80 with acute, non-neoplastic, nonhormone-related diseases, unrelated to long-term diet modifications and admitted to the same network of hospitals. Information was collected in hospital by trained interviewers using a validated food frequency questionnaire, including 78 foods or groups of foods, various alcoholic beverage, and fat-intake pattern. The multivariate relative risk (RR) of oral, pharyngeal, and esophageal cancer decreased across subsequent levels of lycopene intake to reach 0.7 (95% confidence interval [CI] 0.4–1.0) for oral and pharyngeal, and 0.7 (95% CI 0.4–1.1) for esophageal cancer in the highest quintile of intake. Both trends in risk were of borderline statistical significance. With reference to colorectal, breast, and ovarian cancer, although no consistent association was observed for lycopene (RR = 1.0 for colorectal, 1.2 for breast, and 1.1 for ovary in the highest quintile), tomato Intake was inversely and significantly related with colorectal cancer (RR = 0.8). The inverse relation between lycopene and upper digestive tract neoplasms was not explained by alcohol or tobacco, sociodemographic factors, or total energy Intake. The interpretation of such an inverse relation, however, remains open to discussion because it may be related to an effect of lycopene due to its antioxidant effect and/or a potential role of lycopene in decreasing Insulin growth factor I, which is a promoter in the process of carcinogenesis.
Lycopene and the Lung
Authors: Arab Lenore , Steck-Scott Susan , Fleishauer Aaron T.
Published: January 2017

The human lung, due to the oxidative and ozone stress to which it is exposed, is particularly vulnerable to oxidative damage. Concentrations of dietary antioxidants in the lung epithelial lining and lining fluids may provide protection against oxidative damage. A randomized clinical trial was conducted to study the effects of supplemental, carotenoid-rich vegetable Juice (V-8) on lung function macrophage levels of carotenoids and in moderating ozone-induced lung damage. Healthy young adults (n = 23) were exposed to 0.4 ppm ozone in a chamber for 2 hr after either 2 weeks of antioxidant supplementation (including one can of V-8 juice daily) or placebo. Mean lung concentrations of lycopene increased by 12%, and lung epithelial cell DNA damage as measured by the Comet Assay decreased 20% In supplemented subjects. No change in peripheral blood lymphocyte DNA damage was observed as evidenced by no change in mean comet area or length in supplemented or placebo subjects. We were not able to separate the effects of lycopene from other carotenoids or antioxidants administered in this study; however, lycopene is the predominant carotenold in V-8 (it represents 88% of total carotenoids). A review of the epidemiologic literature providing evidence for the effect of lycopene (diet or serum) or tomatoes on the risk of lung cancer reveals 27 observational epidemiologic studies (18 case-control and nine cohort studies) reporting relative risk (RR) estimates. RR estimates for cohort studies ranged from 0.63 to 1.24 (mean RR = 0.93, SD = 0.16). Odds ratios (OR) for case-control studies ranged from 0.27 to 0.93 (mean OR = 0.61, SD = 0.16). Both plasma levels (RR = 1.01, OR = 0.37) and estimated intakes of lycopene from dietary sources (mean RR = 0.93, RR range = 0.80–1.05; mean OR = 0.67, OR range = 0.27–0.93) were examined. Seventeen studies, three of which were cohorts, reported their results at the level of tomato consumption rather than, or in addition to, lycopene consumption (mean RR = 0.89, RR range = 0.63–1.24; mean OR = 0.61, OR range = 0.37–0.80). The published epidemiologic literature shows an Interaction between study design and the relationship between lycopene and/or tomatoes and risk of lung cancer. Overall, cohort studies did not show an association, whereas case-control studies showed a decreased risk with greater consumption of lycopene and tomatoes. Altough lycopene can be found in the human lung, and there is evidence, albeit weak, for a protective association with lung cancer, its biologic role remains to be elucidated.
Overview of Mechanisms of Action of Lycopene
Authors: Heber David , Lu Qing-Yi
Published: January 2017

Dietary intakes of tomatoes and tomato products containing lycopene have been shown to be associated with decreased risk of chronic diseases such as cancer and cardiovascular diseases in numerous studies. Serum and tissue lycopene levels have also been inversely related to the risk of lung and prostate cancers. Lycopene functions as a very potent antioxidant, and this is clearly a major important mechanism of lycopene action. In this regard, lycopene can trap singlet oxygen and reduce mutagenesis in the Ames test. However, evidence is accumulating for other mechanisms as well. Lycopene at physiological concentrations can inhibit human cancer cell growth by interfering with growth factor receptor signaling and cell cycle progression specifically in prostate cancer cells without evidence of toxic effects or apoptosis of cells. Studies using human and animal cells have identified a gene, connexin 43, whose expression is upregulated by lycopene and which allows direct intercellular gap junctional communication (GJC). GJC is deficient in many human tumors and its restoration or upregulation is associated with decreased proliferation. The combination of low concentrations of lycopene with 1, 25-dihydroxyvitamin D3 exhibits a synergistic effect on cell proliferation and differentiation and an additive effect on cell cycle progression in the HL-60 promyelocyte leukemia cell line, suggesting some interaction at a nuclear or subcellular level. The combination of lycopene and lutein synergistically interact as antioxidants, and this may relate to specific positioning of different carotenoids in membranes. This review will focus on the growing body of evidence that carotenoids have unexpected biologic effects in experimental systems, some of which may contribute to their cancer preventive properties in models of carcinogenesis. Consideration of solubility In vitro, comparison with doses achieved in humans by dietary means, interactions with other phytochemicals, and other potential mechanisms such as stimulation of xenoblotic metabolism, inhibition of cholesterogenesis, modulation of cyclooxygenase pathways, and inhibition of inflammation will be considered. This review will point out areas for future research where more evidence is needed on the effects of lycopene on the etiology of chronic disease.
Regulation of Signaling Protein Function and Trafficking by the hsp90/hsp70-Based Chaperone Machinery
Authors: Pratt William B. , Toft David O.
Published: January 2017

Nearly 100 proteins are known to be regulated by hsp90. Most of these substrates or “client proteins” are involved in signal transduction, and they are brought into complex with hsp90 by a multlprotein hsp90/hsp70-based chaperone machinery. In addition to binding substrate proteins at the chaperone site(s), hsp90 binds cofactors at other sites that are part of the heterocomplex assembly machinery as well as immunophllins that connect assembled substrate·hsp90 complexes to protein-trafficking systems. In the 5 years since we last reviewed this subject, much has been learned about hsp90 structure, nucleotide-binding, and cochaperone interactions; the most important concept is that ATP hydrolysis by an intrinsic ATPase activity results in a conformational change in hsp90 that is required to induce conformational change in a substrate protein. The conformational change induced in steroid receptors is an opening of the steroid-binding cleft so that it can be accessed by steroid. We have now developed a minimal system of five purified proteins—hsp90, hsp70, Hop, hsp40, and p23—that assembles stable receptor·hsp90 heterocomplexes. An hsp90·Hop·hsp70·hsp40 complex opens the cleft in an ATP-dependent process to produce a receptor·hsp90 heterocomplex with hsp90 in its ATP-bound conformation, and p23 then interacts with the hsp90 to stabilize the complex. Stepwise assembly experiments have shown that hsp70 and hsp40 first interact with the receptor in an ATP-dependent reaction to produce a receptor·hsp70·hsp40 complex that is “primed” to be activated to the steroid-binding state in a second ATP-dependent step with hsp90, Hop, and p23. Successful use of the five-protein system with other substrates Indicates that it can assemble signal protein-hsp90 heterocomplexes whether the substrate is a receptor, a protein kinase, or a transcription factor. This purified system should facilitate understanding of how eukaryotlc hsp70 and hsp90 work together as essential components of a process that alters the conformations of substrate proteins to states that respond in signal transduction.
Maternal Hyperglycemia Leads to Gender-Dependent Deficits in Learning and Memory in Offspring
Authors: Kinney B.A. , Rabe M.B. , Jensen R.A. , Steger R.W.
Published: January 2017

Pregnancy in the diabetic woman has long been associated with an increased risk of congenital malformation in the offspring. However, little is known about the effects of maternal diabetes on development of the central nervous system. To begin to gain an understanding of this problem, diabetes was induced in adult female Sprague-Dawley rats by injection with streptozotocin. Only animals with serum glucose levels greater than 200 mg/dl were used. Diabetic and control females were bred, and all newborn pups were cross-fostered to nondiabetic mothers. At 60 days of age, pups were tested in an elevated plus-maze to assess differences in emotionality and anxiety. There were no significant differences between offspring of diabetic dams and controls on this measure. All pups were then housed individually, put on food restriction, and maintained at 85% of their ad libitum weight. They were then trained in a Lashley III maze, which assesses learning and retention capability. The female offspring of diabetic dams performed poorer than controls, a finding that was supported by inhibitory avoidance data from a separate group of animals. All animals were then trained in a radial-arm maze. Results failed to find differences between experimental and control animals. It was concluded that the diabetic intrauterine environment has gender-specific effects on central nervous system development.
Leptin Administration Normalizes Insulin Secretion from Islets of Lepob/LepobMice by Food Intake-Dependent and -Independent Mechanisms
Authors: Lee Joo-Won , Romsos Dale R.
Published: January 2017

Leptin-deficient Lepob/Lepobmice exhibit elevations in plasma insulin early in development. The present study tested the hypothesis that absence of leptin during neonatal development permanently programs islets from these mice to hypersecrete insulin. Administration of leptin for 8 days to young adult Lepob/Lepobmice normalized their food intake, plasma Insulin concentration, and insulin secretion in response to glucose, acetylcholine, and leptin. Restriction of food intake per se of Lepob/Lepobmice lowered, but did not normalize, plasma insulin concentrations. Food-restricted Lepob/Lepobmice continued to hypersecrete insulin in response to glucose, but islets from these mice did not hyperrespond to acetylcholine or respond to leptin as occurs in ad libitum-fed Lepob/Lepobmice. We conclude that neonatal leptin deficiency does not permanently program islets from mice to hypersecrete insulin. The hyperphagia associated with leptin deficiency contributes substantially to the hypersecretion of Insulin, but leptin also appears to have more direct effects on regulation of insulin secretion.
Stretch-Activated Atrial Natriuretic Peptide Secretion in Atria with Heat Shock Protein 70 Overexpression
Authors: Kim Suhn Hee , Koh Gou Young , Cho Kyung Woo , Park Woong-Yang , Seo Jeong-Sun
Published: January 2017

The mechanical overload of the heart is known to induce the expression of atrial natriuretic peptide (ANP) and heat-shock protein 70 (HSP70) in the heart. However, the relationship between these two substances remains unknown. In the present study, we characterized ANP secretion from mouse atria and examined a possible role that HSP70 may play in the regulation of ANP synthesis and secretion by using atria in transgenic mice in which HSP70 was overexpressed. We generated transgenic mice harboring the human HSP70 gene under the transcriptional control of human myosin heavy-chain promoter. In these mice, the transgene was overexpressed in the heart. Both atrial ANP messenger RNA and its concentration in the HSP70 transgenic mice were measured; these were not significantly different from those in wild-type mice. In isolated perfused non-beating atria, basal secretion of ANP was similar in both groups. When atrial volume was increased by changing atrial pressure, extracellular fluid (ECF) translocation and ANP secretion proportionately increased. Changes in atrial volume and ECF translocation and ANP secretion were positively correlated. However, these parameters did not significantly differ between the two groups. Endothelin-1 (ET-1), the strongest paracrine stimulus of ANP secretion, accentuated stretch-activated ANP secretion without significantly changing mechanically stimulated ECF translocation, as compared with that in the wild-type mice. The increased ANP secretion due to ET-1 in the transgenic mice was similar to that in the wild-type mice. The results suggest that both atrial stretching and ET-1 are important stimuli to ANP secretion from mouse atria, and the responsiveness of the ANP system to those stimuli are unlikely coupled to the pathway involving HSP70.
Leukemia Cells and the Cytokine Network: Therapeutic Prospects
Authors: Moqattash Satei , Lutton John D.
Published: January 2017

The network and balance of cytokines is of major importance in maintaining proper homeostasis of hematopoiesis. Abnormalities in this network may result in a variety of blood disorders; however, the role of this network is not clear in leukemia. The use of antineoplastic agents has improved the survival rate of some types of leukemia, and adjunctive therapy with cytokines may be helpful. Chemotherapeutic approaches are no longer the best choice because cytotoxicity may affect normal and leukemic cells, and leukemic cells may develop resistance to the chemotherapeutic agent. Induction of differentiation to a mature phenotype and the control of apoptotic-gene expression have provided other possible alternative therapies. Combined effects of cytokines and vitamin derivatives such as retinoic acid (RA) and 1, 25 dihydroxyvitamin D3 (VD3) were found more beneficial than any of these agents individually. These agents exhibit cooperative effects, potentiate each other's effects, or both. Therefore, understanding the hematopoietic actions of these agents, their interactions with their receptors, and their differentiation signaling pathways may result In the design of new therapies. However, the role of cytokines in apoptosis is controversial because in some cases they were found to increase tumor cell resistance to apoptosis-inducing agents. Recent studies in the molecular biology of gene regulation, transcription factors, and repressors have led to new possible approaches such as differentiation therapy for the treatment of leukemia. In addition, the development of drugs that act on the molecular level such as imatinib is just the beginning of a new era in molecular targeted therapy in which the drug acts specifically on the leukemic cell. There are many possible combinations of cytokines, retinoids, and VD3, and perhaps the best therapeutic combination is yet to be described. This minireview is an update on the role of cytokines and the therapeutic potential of combinations with agents such as RA, VD3, and other chemotherapeutic agents.
Repletion of Copper-Deficient Rats with Dietary Copper Restores Duodenal Hephaestin Protein and Iron Absorption
Authors: Reeves Philip G. , Demars Lana C.S.
Published: January 2017

Copper (Cu) deficiency in rats reduces the relative concentration of duodenal hephaestin (Hp), reduces Iron (Fe) absorption, and causes anemia. An experiment was conducted to determine whether these effects could be reversed by dietary Cu repletion. Five groups of eight weanling male rats each were used. Group 1 was fed a Cu-adequate diet (5.0 mg Cu/kg; CuA) and Group 2 was fed a Cu-deflcient diet (0.25 mg Cu/kg; CuD) for 28 days. The rats were fed 1.0 g each of their respective diets labeled with59Fe (37 kBq/g), and the amount of label retained was measured one week later by whole-body-counting (WBC). Group 3 was fed a CuA diet and Groups 4 and 5 were fed a CuD diet for 28 days. Group 5 was then fed the CuA dlet for another week while Groups 3 and 4 continued on their previous regimens. Rats In Groups 3, 4, and 5 were fed 1.0 g of diet labeled with59Fe, and the amount of label retained was measured by WBC one week later. Rats were killed and duodenal enterocytes Isolated for Hp protein analysis, whole blood was analyzed for hematological parameters, and various organs for59Fe content. CuD rats absorbed less (P <0.05) Fe than CuA rats, the relative amount of duodenal Hp was less (P <0.05) In CuD rate, and the CuD rats developed anemia. After the CuD rats had been repleted with Cu for one week, Fe retention rose to values even higher (P <0.05) than those in CuA rats. After two weeks, the relative amount of duodenal Hp was higher (P <0.05) than normal, and most signs of anemia were reversed. Liver59Fe was elevated In CuD rats, but was restored to normal upon Cu repletion. These findings suggest a strong association between duodenal Hp abundance and Fe absorption In the CuD rat, and that reduced Fe absorption Is an important factor in the cause of anemia.
Hypothalamic Neuronal Histamine Modulates Febrile Response but Not Anorexia Induced by Lipopolysaccharide
Authors: Chiba Seiichi , Itateyama Emi , Oka Kyoko , Masaki Takayuki , Sakata Toshiie , Yoshimatsu Hironobu
Published: January 2017

This study examined the contribution of hypothalamic neuronal histamine (HA) to the anorectic and febrlle responses induced by lipopolysaccharide (LPS), an exogenous pyrogen, and the endogenous pyrogens interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Intraperitoneal (ip) Injection of LPS, IL-1β, or TNF-α suppressed 24-hr cumulative food intake and increased rectal temperature in rats.

To analyze the histamlnergic contribution, rats were pre-treated with intracerebroventricular (icv) injection of 2.44 mmol/ kg or ip injection of 244 mmol/kg of α-fluoromethylhistidine (FMH), a suicide inhibitor of histidine decarboxylase (HDC), to deplete Neural HA. The depletion of neural HA augmented the febrile response to ip Injection of LPS and IL-1ß and alleviated the anorectic response to ip injection of IL-1ß. However, the depletion of neural HA did not modify the LPS-lnduced anorectic response or TNF-α-induced febrile and anorectic responses. Consistent with these results, the rate of hypothalamic HA turnover, assessed by the accumulation of tele-methylhistamine (t-MH), was elevated with ip injections of LPS and IL-1ß, but unaffected by TNF-α at equivalent doses. This suggests that (I) LPS and IL-1ß activate hypothalamic neural HA turnover; (II) hypothalamic neural HA suppresses the LPS- and IL-1β-induced febrile responses and accelerates the IL-1ß-induced anorectic response; and (iii) TNF-α modulates the febrile and anorectic responses via a neural HA-independent pathway. Therefore, hypothalamic neural HA is Involved in the IL-1ß-dominant pathway, rather than the TNF-α-dominant pathway, preceding the systemic Inflammatory response induced by exogenous pyrogens, such as LPS. Further research on this is needed.
Effects of Vesl/Homer Proteins on Intracellular Signaling
Authors: Duncan R. Scott , Hwang Sung-Yong , Koulen Peter
Published: January 2017

The clustering of signaling molecules at specialized cellular sites allows cells to effectively convert extracellular signals into intracellular signals and to produce a concerted functional output with specific temporal and spatial patterns. A prime example for these molecules and their effects on cellular signaling are the postsynaptic density proteins of the central nervous system. Recently, one group of these proteins, the Vesl/Homer protein family has received increased attention because of its unique molecular properties that allow both the clustering end functional modulation of a plethora of different binding Proteins. Within multlprotein signaling complexes, Vesl/Homer Proteins influence proteins as diverse as metabotropic glutamate receptors; transient receptor potential channels; intracellular calcium channels; the scaffolding protein, Shank; small GTPases; transcription factors; and cytoskeletal proteins. Furthermore, interaction with such functionally relevant proteins also links Vesl/Homer proteins indirectly to an even larger group of cellular effector proteins, putting the Vesl/Homer Proteins at the crossroads of several critical intracellular signaling processes. In addition to the initial reports of Vesl/Homer protein expression in the central nervous system, members of this protein family have now been identified in other excitable cells in various muscle types and in a large number of nonexcitable cells. The widespread expression of Vesl/Homer proteins in different organs and their functional importance in cellular protein signaling complexes is further evidenced by their conservation in organisms from Drosoohila to humans.
Impaired Deformability of Copper-Deficient Neutrophils
Authors: Gordon Sharon A. , Lominadze David , Saari Jack T. , Lentsch Alex B. , Schuschke Dale A.
Published: January 2017

We have previously shown that dietary copper deficiency augments neutrophil accumulation in the lung microvasculature. The current study was designed to determine whether a diet deficient in copper promotes neutrophil chemoattraction within the lung vasculature or if it alters the mechanical properties of the neutrophil, thus restricting passage through the microvessels. Sprague-Dawley rats were fed purified diets that were either copper adequate (6.3 μg Cu/g diet) or copper deficient (0.3 μg Cu/g diet) for 4 weeks. To assess neutrophil chemoattraction, bronchoalveolar lavage fluid was assayed for the neutrophil chemokine macrophage inflammatory protein-2 (MIP-2) by enzyme-linked immunosorbent assay. Neutrophil deformability was determined by measuring the pressure required to pass Isolated neutrophils through a 5-μm polycarbonate filter. The MIP-2 concentration was not significantly different between the dietary groups (Cu adequate, 435.4 ± 11.9 pg/ml; Cu deficient, 425.6 ± 14.8 pg/ml). However, compared with controls, more pressure was needed to push Cu-deficient neutrophils through the filter (Cu adequate, 0.150 ± 0.032 mm Hg/sec; Cu deficient, 0.284 0.037 mm Hg/sec). Staining of the filamentous actin (F-actin) with FITC-Phalloldin showed greater F-actin polymerization and shape change in the Cu-deficient group. These results suggest that dietary copper deficiency reduces the deformability of neutrophils by promoting F-actin polymerization. Because most neutrophils must deform during passage from arterioles to venules in the lungs, we propose that copper-deficient neutrophils accumulate in the lung because they are less deformable.
New Insight into the Mechanism of Cardiovascular Dysfunction in the Elderly: Transfer Function Analysis
Authors: Guo Hong , Schaller Frederic , Tierney Nancy , Smith Scott A. , Shi Xiangrong
Published: January 2017

This study sought to test the hypothesis that alterations in the relationships between (i) mean arterial pressure (MAP) and heart rate (HR), (ii) cardiac output (CO) and MAP, and (Hi) total Peripheral resistance (TPR) and MAP variability contribute to the diminished dynamic control of cardiovascular function with advanced age. Six-minute hemodynamic data were continuously recorded in 11 elderly (70 ± 2 years) and 11 young (26 ± 1 year) healthy volunteers under supine resting condition and during lower body negative pressure–induced orthostatic challenge. The data were converted using fast Fourier transform, and the ratio of cross-spectra to auto-spectra between two signals (i.e., MAP-HR, CO-MAP, TPR-MAP) was computed for transfer function analysis. In the low-frequency ranges (LF; 0.04–O.14 Hz) and high-frequency ranges (0.15–0.30 Hz), the gain and coherence of the transfer function describing the relationship between MAP-HR signals were significantly greater in younger than in older adults. The phase degree was significantly >0 in both groups under all conditions, suggesting that the MAP variability preceded the HR variability. In contrast, the coherence between CO-MAP signals in both age groups was <0.5, indicating that the beat-to-beat MAP variability was not significantly related to the CO signals. However, the transfer function gain and coherence of TPR-MAP signals were significantly greater in the young group (coherence ≥0.5 in the LF range), suggesting a more effective dynamic vasomotor control. In conclusion, the oscillations in CO-MAP signals are not significantly synchronized or not related in a simply linear fashion in both age groups. The MAP variability is more related to the oscillation of TPR signals in the young group only. Advanced age not only diminishes MAP-HR transfer function gain, but also weakens its coherence. Thus, alterations in the relationship between MAP-HR variability and TPR-MAP variability may significantly contribute to the diminished dynamic control of cardiovascular function manifest in the elderly.
Electric Activity of the Testicular Tunica Albuginea During Ejaculation: A Canine Study
Authors: Shafik Ahmed , Sibai Olfat El , Shafik Ali A.
Published: January 2017

We have shown in previous studies that electric waves at rest could be recorded from the testicle and originate from the tunica albuginea (TA) and not from the testicular tissue. In the current study, we investigated the hypothesis that the electric activity of the TA increases during ejaculation. Three electrodes were sutured to the TAs of 11 anesthetized male dogs. The slow waves were recorded at rest and on inducing ejaculation by an ejaculator applied to the glans penis. Basal electric waves were recorded from the testicle. Each wave consisted of a negative followed by a positive deflection with a mean frequency of 6.2 ± 1.3 cycles/min, an amplitude of 0.59 ± 0.06 mV, and a conduction velocity of 5.2 ± 0.8 cm/sec. These wave variables showed a significant intermittent increase (P < 0.05) at intervals of 0.6–1.0 sees and occurred simultaneously with the bouts of ejaculation. The increase remained for 0.8–1.2 sees at each ejaculation bout. The number of bouts of increased electric waves varied from 3 to 5. Apparently, the TA is not an inert covering to the testicle, but it seems to have a functional activity. Recording resting electric waves of the TA presumably denotes that the TA possesses a resting tone that appears to support the testicular tissue. During ejaculation, the increased electric activity of the TA, which coincides with semen spurt episodes, presumably denotes TA contraction. The intermittent TA contractions seem to assist in massaging the testicular secretions to the epididymis and the vas deferens and augment testicular circulation. The effect of pathologic conditions of the TA on ejaculation needs to be studied.
Biology of a Novel Organic Solute and Steroid Transporter, OSTΑ-OSTβ
Authors: Ballatori Nazzareno
Published: January 2017

Using a comparative approach, recent studies have identified and functionally characterized a new type of organic solute and steroid transporter (OST) from skate, mouse, rat, and human genomes. In contrast to all other organic anion transporters identified to date, transport activity requires the coexpression of two distinct gene products, a predicted 340–amino acid, seven-transmembrane (TM) domain protein (OSTΑ) and a putative 128–amino acid, single-TM domain ancillary polypeptide (OSTβ). When OSTΑ and OSTβ are coexpressed in Xenopus oocytes, they are able to mediate transport of estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, taurocholate, digoxin, and prostaglandin E2, indicating a role in the disposition of key cellular metabolites or signaling molecules. OSTΑ and OSTβ are expressed at relatively high levels in intestine, kidney, and liver, but they are also expressed at lower levels in many human tissues. Indirect immunofluorescence microscopy revealed that intestinal OSTΑ and OSTβ proteins are localized to the baso-lateral membrane of mouse enterocytes. In MDCK cells, mouse OstΑ–Ostβ mediated the vectorial movement of taurocholate from the apical to the basolateral membrane, but not in the opposite direction, indicating basolateral efflux of bile acids. Overall, these findings indicate that OSTΑ-OSTβ is a heteromeric transporter that is localized to the basolateral membrane of specific epithelial tissues and serves to regulate the export and disposition of bile acids and structurally related compounds from the cell. If confirmed, this model would have important implications for the body's handling of various steroid-derived molecules and may provide a new pharmacologic target for altering sterol homeostasis.
Influence of Estrogen Administration on the Growth Response to Growth Hormone (GH) in GH-Deficient Mice
Authors: Fintini Danilo , Alba Maria , Salvatori Roberto
Published: January 2017

In women who are growth hormone (GH) deficient, exogenous estrogens increase the dosage of GH that is needed to normalize circulating levels of insulin-like growth factor (IGF-1). Serum IGF-1 derives mostly from the liver, and it is unknown whether the peripheral effects of GH are also impaired by estrogens. Because the ultimate effect of GH is longitudinal growth, we have investigated the influence of estrogen administration on the growth response to recombinant mouse GH therapy in prepubertal GH-deficient (GHD) GHRH knockout (GHRHKO) female mice. Twenty-four GHRHKO female mice (4 animals/group) were treated for 4 weeks (from the second to sixth week of age) with the following schedules: Group I, GH only (25 μg/day); Group II, subcutaneous (sc) ethynil estradiol (EE) (0.035 μg/day); Group III, GH + scEE; Group IV, oral (po) EE (0.035 μg/day); Group V, GH + poEE; Group VI, placebo. At the end of the treatment period, we measured uterine weight, total body weight (TBW), body length (nose-anus, N-A), and femur length. In addition, serum IGF-1 levels were measured. Uteri of mice treated with oral or scEE showed similar increases in weight. There was no difference in the increase in longitudinal growth parameters between mice treated with GH alone or with GH in association with oral or scEE. Serum IGF-1 decreased in animals treated with GH + scEE, compared with GH group, but no group was significantly different from placebo. These results show that subcutaneous or oral EE does not reduce the growth response to GH in female GHD mice.
Localization of Fertility Factor SP22 to Specific Cell Types Within the Anterior Pituitary Gland
Authors: Benoit Allison M. , Mccoy George L. , Blake Charles A.
Published: January 2017

Sperm protein 22 (SP22) was recently identified in the anterior pituitary gland (AP) of male Golden Syrian hamsters using ion trap mass spectrometry. SP22 has been implicated in apoptosis, androgen receptor function, fertility, and ontogeny of early-onset Parkinson's disease. However, the role of SP22 in the pituitary has not been investigated. We cloned the cDNA for full-length SP22 from AP and posterior lobe (posterior pituitary and intermediate lobe) of the pituitary gland in adult male rats and Golden Syrian hamsters, confirming the presence of SP22 mRNA in the AP and posterior lobe. Because gonadal steroids are important regulators of AP function, and SP22 is associated with androgen receptor function, we used Western blots to compare SP22 in the AP of intact and orchidectomized male rats given placebo or a low or high dose of testosterone. SP22 did not differ with treatment, indicating that AP SP22 concentration was not regulated by testosterone. To localize SP22 to specific cells of the AP, mirror-image paraffin sections were labeled against SP22 and either luteinizing hormone (LH)β, thyroid-stimulating hormone (TSH)β, prolactin, adrenocorticotropic hormone (ACTH), or growth hormone (GH) using peroxidase-conjugated secondary antibody. Additional sections were colabeled with SP22 and one of the AP hormones using fluorescent secondary antibodies. SP22 colocalized in somatotropes and thyrotropes in rat and hamster. We identified SP22 in a small percentage of corticotropes, gonadotropes, and lactotropes. This is the first report that SP22 mRNA is present specifically in the AP, and SP22 is localized primarily in somatotropes and thyrotropes. SP22 may help regulate AP function and be particularly important for the control of GH and TSH secretion.
Infectivity of Hepatic Strain Klebsiella pneumoniae in Diabetic Mice
Authors: Wu June Hsieh , Tsai Cheng Gie
Published: January 2017

Besides urinary tract infection (UTI) and pneumonia, increased severe liver abscesses caused by Klebsiella pneumoniae (KP), especially in diabetic patients, have been observed in infections acquired in hospitals. This indicates that different KP strains with higher virulence have emerged in recent years. Our goal was to investigate the infectivity of KP isolates in mice from liver abscess or UTI patients. Mice were injected with streptozotocin to induce diabetes. Male ICR mice were infected with KpU1 (UTI strain CG3 for survival experiment only) and KpL1 (liver abscess strain CG5) by tail-vein injection of 5 × 104colony-forming units (CFU) bacterial suspension. The mice survival rates, cytokine level by enzyme-linked immunosorbent assay (ELISA), and bacterial presence in liver tissue by Giemsa stain were examined. The survival rates for the KpL1-infected animals were 28% and 0% in normal and diabetic groups, respectively, whereas, for the KpU1-infected mice, the rates were 100% and 75% during a 30-day observation. Nonsurviving KpL1-infected mice showed >105bacteria/ml blood and the bacteria appeared in the liver sinus area and inside liver cells. The KpL1-infected mice showed a tendency to increase the blood interleukin 1β (IL-1β) level in both nondiabetic and diabetic groups, whereas the tumor necrosis factor-Α (TNF-Α) level was significantly decreased in the KpL1-infected diabetic mice (P = 0.002). In conclusion, the KP strain from liver abscess showed a greater virulence in mice than the KP from UTI and was more virulent in diabetic than in nondiabetic mice. The infection with KP from liver abscess significantly decreased the blood TNF-Α level in diabetes mellitus (DM) mice and the blood IL-1β level tended to increase in both infected nondiabetic and diabetic groups. High blood bacterial count and appearance of bacteria in liver sinus and cells usually contribute to death of the animals.
The Choroid Plexus Removes β-Amyloid from Brain Cerebrospinal Fluid
Authors: Crossgrove Janelle S. , Li G. Jane , Zheng Wei
Published: January 2017

β-Amyloid (Aβ) concentration in the cerebrospinal fluid (CSF) of the brain may be regulated by the choroid plexus, which forms a barrier between blood and brain CSF. Aβ uptake from CSF was determined as its volume of distribution (VD) into isolated rat choroid plexus tissue. The VD of [125l]Aβ1–40 was corrected by subtraction of the VD of [14C]sucrose, a marker for extracellular space and diffusion. Aβ uptake into choroid plexus was time and temperature dependent. Uptake of [125l]Aβ was saturable. Aβ uptake was not affected by addition of transthyretin or apolipoprotein E3. In studies with primary culture monolayers of choroidal epithelial cells in Transwells, Aβ permeability across cells, corrected by [14C]sucrose, was greater from the CSF-facing membrane than from the blood-facing membrane. Similarly, cellular accumulation of [125l]Aβ was concentrative from both directions and was greater from the CSF-facing membrane, suggesting a bias for efflux. Overall, these results suggest the choroid plexus selectively cleanses Aβ from the CSF by an undetermined mechanism(s), potentially reducing Aβ from normal brains and the brains of Alzheimer's disease patients.
The Proteomics of Sickle Cell Disease: Profiling of Erythrocyte Membrane Proteins by 2D-DIGE and Tandem Mass Spectrometry
Authors: Kakhniashvili David G. , Griko Natalya B. , Bulla Lee A. , Goodman Steven R.
Published: January 2017

Quantitative changes in the red blood cell membrane proteome in sickle cell disease were analyzed using the two-dimensional fluorescence difference gel electrophoresis 2D-DIGE technique. From over 500 analyzed two-dimensional gel spots, we found 49 protein gel spots whose content in sickle cell membranes were changed by at least 2.5-fold as compared to control cells. In 38 cases we observed an increase and in 11 cases a decrease in content in the sickle cell membranes. The proteins of interest were identified by in-gel tryptic digestion followed by liquid chromatography in line with tandem mass spectrometry. From 38 analyzed gel spots, we identified 44 protein forms representing different modifications of 22 original protein sequences. The majority of the identified proteins fall into small groups of related proteins of the following five categories: actin accessory proteins—four proteins, components of lipid rafts—two proteins, scavengers of oxygen radicals—two proteins, protein repair participants—six proteins, and protein turnover components-three proteins. The number of proteins whose content in sickle RBC membrane is decreased is noticeably smaller, and most are either components of lipid rafts or actin accessory proteins. Elevated content of protein repair participants as well as oxygen radical scavengers may reflect the increased oxidative stress observed in sickle cells.