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Article: Intrauterine growth restriction leads to a high-corticosterone producing offspring: An implication for pulmonary infection susceptibility

Gil, Noemi L. / Azevedo, Gabriela A. / Balbino, Aleksandro M. / Silva, Marina M. / Carvalho, Maria Helena C. / Akamine, Eliana H. / Keller, Alexandre C. / Landgraf, Richardt G. / Landgraf, Maristella A.

Life sciences. 2021 Sept. 15, v. 281

2021

Abstract: Although intrauterine growth restriction (IUGR) impairs immune system homeostasis and lung development, its relationship with the susceptibility to pulmonary infections remains unclear. Thus, this study aimed to investigate the impact of IUGR on acute ... ...

Abstract	Although intrauterine growth restriction (IUGR) impairs immune system homeostasis and lung development, its relationship with the susceptibility to pulmonary infections remains unclear. Thus, this study aimed to investigate the impact of IUGR on acute lung inflammatory response induced by bacterial stimulus.Pregnant female Wistar rats were subjected to 50% caloric-protein food restriction during gestation. To mimic bacterial lung infection, adult male offspring (12 weeks old) were challenged with a single lipopolysaccharide (LPS) intranasal instillation, and 6 h later, we assessed the acute inflammatory response. Normal birth weight (NBW) animals represent the control group.LPS instillation increased the protein levels in the airways of both the NBW and low birth weight (LBW) groups, indicating vascular leakage. LBW animals exhibited a lower number of neutrophils, reduced production of interleukin-6 and macrophage-inflammatory protein-2 and decreased upregulation of intercellular adhesion molecule-1 gene expression in lung tissues. Further analysis revealed that the LBW group produced lower levels of prostaglandin-E₂ and failed to secrete leukotriene-B₄ upon LPS stimulation, which correlated with impaired cyclooxygenase-2 and 5-lipoxygenase expression. These results were probably associated with their inability to upregulate the expression of Toll-like receptor-4 and downstream signaling proteins, such as nuclear factor kappa-B, in the lungs. The LBW group also exhibited abnormal airway thickening and high corticosterone levels under basal conditions.This study suggests that IUGR-induced foetal programming in LBW offspring threatens HPA axis physiology and corticosterone biodisponibility, and impairs the innate response to bacterial antigens, increasing future susceptibility to pulmonary infection.
Keywords	Toll-like receptor 4 ; adults ; corticosterone ; females ; gene expression ; homeostasis ; inflammation ; intercellular adhesion molecule-1 ; interleukin-6 ; lipopolysaccharides ; low birth weight ; lungs ; males ; neutrophils ; pregnancy ; progeny ; prostaglandin synthase
Language	English
Dates of publication	2021-0915
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2021.119764
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Article ; Online: Intrauterine growth restriction leads to a high-corticosterone producing offspring: An implication for pulmonary infection susceptibility.

Gil, Noemi L / Azevedo, Gabriela A / Balbino, Aleksandro M / Silva, Marina M / Carvalho, Maria Helena C / Akamine, Eliana H / Keller, Alexandre C / Landgraf, Richardt G / Landgraf, Maristella A

Life sciences

2021 Volume 281, Page(s) 119764

Abstract: Aims: Although intrauterine growth restriction (IUGR) impairs immune system homeostasis and lung development, its relationship with the susceptibility to pulmonary infections remains unclear. Thus, this study aimed to investigate the impact of IUGR on ... ...

Abstract	Aims: Although intrauterine growth restriction (IUGR) impairs immune system homeostasis and lung development, its relationship with the susceptibility to pulmonary infections remains unclear. Thus, this study aimed to investigate the impact of IUGR on acute lung inflammatory response induced by bacterial stimulus. Materials and methods: Pregnant female Wistar rats were subjected to 50% caloric-protein food restriction during gestation. To mimic bacterial lung infection, adult male offspring (12 weeks old) were challenged with a single lipopolysaccharide (LPS) intranasal instillation, and 6 h later, we assessed the acute inflammatory response. Normal birth weight (NBW) animals represent the control group. Key findings: LPS instillation increased the protein levels in the airways of both the NBW and low birth weight (LBW) groups, indicating vascular leakage. LBW animals exhibited a lower number of neutrophils, reduced production of interleukin-6 and macrophage-inflammatory protein-2 and decreased upregulation of intercellular adhesion molecule-1 gene expression in lung tissues. Further analysis revealed that the LBW group produced lower levels of prostaglandin-E Significance: This study suggests that IUGR-induced foetal programming in LBW offspring threatens HPA axis physiology and corticosterone biodisponibility, and impairs the innate response to bacterial antigens, increasing future susceptibility to pulmonary infection.
MeSH term(s)	Animals ; Arachidonic Acid/metabolism ; Corticosterone/biosynthesis ; Disease Susceptibility ; Female ; Fetal Growth Retardation ; Hypothalamo-Hypophyseal System/metabolism ; Lipopolysaccharides/administration & dosage ; Lung/drug effects ; Lung/metabolism ; Male ; NF-kappa B/metabolism ; Pituitary-Adrenal System/metabolism ; Pneumonia, Bacterial/immunology ; Pregnancy ; Prenatal Exposure Delayed Effects ; Rats ; Rats, Wistar ; Toll-Like Receptor 4/metabolism
Chemical Substances	Lipopolysaccharides ; NF-kappa B ; Tlr4 protein, rat ; Toll-Like Receptor 4 ; Arachidonic Acid (27YG812J1I) ; Corticosterone (W980KJ009P)
Language	English
Publishing date	2021-06-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2021.119764
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Article ; Online: Reactive oxygen species: players in the cardiovascular effects of testosterone.

Tostes, Rita C / Carneiro, Fernando S / Carvalho, Maria Helena C / Reckelhoff, Jane F

American journal of physiology. Regulatory, integrative and comparative physiology

2015 Volume 310, Issue 1, Page(s) R1–14

Abstract: Androgens are essential for the development and maintenance of male reproductive tissues and sexual function and for overall health and well being. Testosterone, the predominant and most important androgen, not only affects the male reproductive system, ... ...

Abstract	Androgens are essential for the development and maintenance of male reproductive tissues and sexual function and for overall health and well being. Testosterone, the predominant and most important androgen, not only affects the male reproductive system, but also influences the activity of many other organs. In the cardiovascular system, the actions of testosterone are still controversial, its effects ranging from protective to deleterious. While early studies showed that testosterone replacement therapy exerted beneficial effects on cardiovascular disease, some recent safety studies point to a positive association between endogenous and supraphysiological levels of androgens/testosterone and cardiovascular disease risk. Among the possible mechanisms involved in the actions of testosterone on the cardiovascular system, indirect actions (changes in the lipid profile, insulin sensitivity, and hemostatic mechanisms, modulation of the sympathetic nervous system and renin-angiotensin-aldosterone system), as well as direct actions (modulatory effects on proinflammatory enzymes, on the generation of reactive oxygen species, nitric oxide bioavailability, and on vasoconstrictor signaling pathways) have been reported. This mini-review focuses on evidence indicating that testosterone has prooxidative actions that may contribute to its deleterious actions in the cardiovascular system. The controversial effects of testosterone on ROS generation and oxidant status, both prooxidant and antioxidant, in the cardiovascular system and in cells and tissues of other systems are reviewed.
MeSH term(s)	Age Factors ; Animals ; Cardiovascular Diseases/epidemiology ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/physiopathology ; Cardiovascular Diseases/prevention & control ; Cardiovascular System/metabolism ; Cardiovascular System/physiopathology ; Female ; Hormone Replacement Therapy/adverse effects ; Humans ; Male ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Risk Factors ; Sex Factors ; Signal Transduction ; Testosterone/adverse effects ; Testosterone/deficiency ; Testosterone/metabolism
Chemical Substances	Reactive Oxygen Species ; Testosterone (3XMK78S47O)
Language	English
Publishing date	2015-11-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	603839-6
ISSN	1522-1490 ; 0363-6119
ISSN (online)	1522-1490
ISSN	0363-6119
DOI	10.1152/ajpregu.00392.2014
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Article ; Online: H2O2 generated from mitochondrial electron transport chain in thoracic perivascular adipose tissue is crucial for modulation of vascular smooth muscle contraction.

Costa, Rafael M / Filgueira, Fernando P / Tostes, Rita C / Carvalho, Maria Helena C / Akamine, Eliana H / Lobato, Nubia S

Vascular pharmacology

2016 Volume 84, Page(s) 28–37

Abstract: The perivascular adipose tissue (PVAT) releases a variety of factors that affect vascular function. PVAT in the thoracic aorta shares characteristics with the brown adipose tissue, including a large amount of mitochondria. PVAT-derived factors influence ... ...

Abstract	The perivascular adipose tissue (PVAT) releases a variety of factors that affect vascular function. PVAT in the thoracic aorta shares characteristics with the brown adipose tissue, including a large amount of mitochondria. PVAT-derived factors influence both endothelial and smooth muscle function via several signaling mechanisms including the release/generation of reactive nitrogen and oxygen species. Considering the importance of reactive oxygen species (ROS) on vascular function and that mitochondria are an important source of ROS, we hypothesized that mitochondria-derived ROS in the PVAT modulates vascular reactivity. Vascular reactivity to norephinephrine (NE) was evaluated in thoracic aortic rings, with or without endothelium and/or PVAT, from male Wistar rats. Mitochondrial uncoupling, as well as hydrogen peroxide (H2O2) removal, increased the contraction in vessels surrounded by PVAT. PVAT stimulated with NE exhibited increased protein expression, determined by Western blot analysis, of manganese superoxide dismutase (Mn-SOD) and decreased protein expression of catalase. Ultimately, NE increased superoxide anion (O2(-)) generation in PVAT via increases in intracellular calcium. These results clearly demonstrate that mitochondrial electron transport chain (mETC) in PVAT contributes to modulation of aortic muscle contraction by generating higher amounts of O2(-) that is, in turn, dismutated to hydrogen peroxide, which then acts as a pivotal signaling molecule regulating vascular smooth muscle contraction.
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Aorta, Thoracic/metabolism ; Electron Transport/physiology ; Hydrogen Peroxide/metabolism ; Male ; Mitochondria/metabolism ; Muscle Contraction/physiology ; Muscle, Smooth, Vascular/metabolism ; Rats ; Rats, Wistar ; Reactive Nitrogen Species/metabolism ; Reactive Oxygen Species/metabolism ; Superoxides/metabolism ; Vasoconstriction
Chemical Substances	Reactive Nitrogen Species ; Reactive Oxygen Species ; Superoxides (11062-77-4) ; Hydrogen Peroxide (BBX060AN9V)
Language	English
Publishing date	2016-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2082846-9
ISSN	1879-3649 ; 1537-1891 ; 1879-3649
ISSN (online)	1879-3649 ; 1537-1891
ISSN	1879-3649
DOI	10.1016/j.vph.2016.05.008
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Article: Detrimental Effects of Testosterone Addition to Estrogen Therapy Involve Cytochrome P-450-Induced 20-HETE Synthesis in Aorta of Ovariectomized Spontaneously Hypertensive Rat (SHR), a Model of Postmenopausal Hypertension.

Costa, Tiago J / Ceravolo, Graziela S / Echem, Cinthya / Hashimoto, Carolina M / Costa, Beatriz P / Santos-Eichler, Rosangela A / Oliveira, Maria Aparecida / Jiménez-Altayó, Francesc / Akamine, Eliana H / Dantas, Ana Paula / Carvalho, Maria Helena C

Frontiers in physiology

2018 Volume 9, Page(s) 490

Abstract: Postmenopausal period has been associated to different symptoms such as hot flashes, vulvovaginal atrophy, hypoactive sexual desire disorder (HSDD) and others. Clinical studies have described postmenopausal women presenting HSDD can benefit from the ... ...

Abstract	Postmenopausal period has been associated to different symptoms such as hot flashes, vulvovaginal atrophy, hypoactive sexual desire disorder (HSDD) and others. Clinical studies have described postmenopausal women presenting HSDD can benefit from the association of testosterone to conventional hormonal therapy. Testosterone has been linked to development of cardiovascular diseases including hypertension and it also increases cytochrome
Language	English
Publishing date	2018-05-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2018.00490
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Article ; Online: Intrauterine and lactational exposure to fluoxetine enhances endothelial modulation of aortic contractile response in adult female rats.

Higashi, Carolina M / Sartoretto, Simone M / Echem, Cinthya / Lucchetti, Bruno F C / Carvalho, Maria Helena C de / Pelosi, Gislaine G / Pinge-Filho, Phileno / Gerardin, Daniela C C / Moreira, Estefânia G / Akamine, Eliana H / Ceravolo, Graziela S

Vascular pharmacology

2018 Volume 108, Page(s) 67–73

MeSH term(s)	Animals ; Antidepressive Agents, Second-Generation/pharmacology ; Aorta, Thoracic/drug effects ; Aorta, Thoracic/metabolism ; Cyclooxygenase 1/metabolism ; Dose-Response Relationship, Drug ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Female ; Fluoxetine/pharmacology ; Gestational Age ; Lactation ; Male ; Membrane Proteins/metabolism ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type I/metabolism ; Nitric Oxide Synthase Type III/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; Rats, Wistar ; Sex Factors ; Signal Transduction/drug effects ; Vasoconstriction/drug effects ; Vasoconstrictor Agents/pharmacology ; Vasodilator Agents/pharmacology
Chemical Substances	Antidepressive Agents, Second-Generation ; Membrane Proteins ; Vasoconstrictor Agents ; Vasodilator Agents ; Fluoxetine (01K63SUP8D) ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase Type I (EC 1.14.13.39) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Nos1 protein, rat (EC 1.14.13.39) ; Nos3 protein, rat (EC 1.14.13.39) ; Cyclooxygenase 1 (EC 1.14.99.1) ; Ptgs1 protein, rat (EC 1.14.99.1)
Language	English
Publishing date	2018-04-11
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2082846-9
ISSN	1879-3649 ; 1537-1891 ; 1879-3649
ISSN (online)	1879-3649 ; 1537-1891
ISSN	1879-3649
DOI	10.1016/j.vph.2018.04.004
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Article ; Online: Equilin displays similar endothelium-independent vasodilator potential to 17β-estradiol regardless of lower potential to inhibit calcium entry.

Filgueira, Fernando P / Lobato, Núbia S / Nascimento, Denise L / Ceravolo, Graziela S / Giachini, Fernanda R C / Lima, Victor V / Dantas, Ana Paula / Fortes, Zuleica B / Webb, R Clinton / Tostes, Rita C / Carvalho, Maria Helena C

Steroids

2018 Volume 141, Page(s) 46–54

Abstract: Conjugated equine estrogens (CEE) have been widely used by women who seek to relieve symptoms of menopause. Despite evidence describing protective effects against risk factors for cardiovascular diseases by naturally occurring estrogens, little is known ... ...

Abstract	Conjugated equine estrogens (CEE) have been widely used by women who seek to relieve symptoms of menopause. Despite evidence describing protective effects against risk factors for cardiovascular diseases by naturally occurring estrogens, little is known about the vascular effects of equilin, one of the main components of CEE and not physiologically present in women. In this regard, the present study aims to compare the vascular effects of equilin in an experimental model of hypertension with those induced by 17β-estradiol. Resistance mesenteric arteries from female spontaneously hypertensive rats (SHR) were used for recording isometric tension in a small vessel myograph. As effectively as 17β-estradiol, equilin evoked a concentration-dependent relaxation in mesenteric arteries from female SHRs contracted with KCl, U46619, PDBu or ET-1. Equilin-induced vasodilation does not involve classical estrogen receptor activation, since the estrogen receptor antagonist (ICI 182,780) failed to inhibit relaxation in U46619-precontracted mesenteric arteries. Vasorelaxation was not affected by either endothelium removal or by inhibiting the release or action of endothelium-derived factors. Incubation with L-NAME (NOS inhibitor), ODQ (guanylyl cyclase inhibitor) or KT5823 (inhibitor of protein kinase G) did not affect equilin-induced relaxation. Similarly, indomethacin (COX inhibitor) or blockage of potassium channels with tetraethylammonium, glibenclamide, 4-aminopyridine, or ouabain did not affect equilin-induced relaxation. Inhibitors of adenylyl cyclase SQ22536 or protein kinase A (KT5720) also had no effects on equilin-induced relaxation. While 17β-estradiol inhibited calcium (Ca
MeSH term(s)	Animals ; Calcium/metabolism ; Endoplasmic Reticulum/drug effects ; Endoplasmic Reticulum/metabolism ; Equilin/pharmacology ; Estradiol/pharmacology ; Female ; Rats ; Rats, Inbred SHR ; Vasodilation/drug effects ; Vasodilator Agents/pharmacology
Chemical Substances	Vasodilator Agents ; Equilin (08O86EX0J4) ; Estradiol (4TI98Z838E) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2018-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80312-1
ISSN	1878-5867 ; 0039-128X
ISSN (online)	1878-5867
ISSN	0039-128X
DOI	10.1016/j.steroids.2018.11.006
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Article ; Online: Influence of aerobic training on the reduced vasoconstriction to angiotensin II in rats exposed to intrauterine growth restriction: possible role of oxidative stress and AT2 receptor of angiotensin II.

Oliveira, Vanessa / Akamine, Eliana Hiromi / Carvalho, Maria Helena C / Michelini, Lisete Compagno / Fortes, Zuleica Bruno / Cunha, Tatiana Sousa / do Carmo Franco, Maria

PloS one

2014 Volume 9, Issue 11, Page(s) e113035

Abstract: Intrauterine growth restriction (IUGR) is associated with impaired vascular function, which contributes to the increased incidence of chronic disease. The aim of this study was to investigate whether aerobic training improves AngII-induced ... ...

Abstract	Intrauterine growth restriction (IUGR) is associated with impaired vascular function, which contributes to the increased incidence of chronic disease. The aim of this study was to investigate whether aerobic training improves AngII-induced vasoconstriction in IUGR rats. Moreover, we assess the role of superoxide dismutase (SOD) isoforms and NADPH oxidase-derived superoxide anions in this improvement. Female Wistar rats were randomly divided into two groups on day 1 of pregnancy. A control group was fed standard chow ad libitum, and a restricted group was fed 50% of the ad libitum intake throughout gestation. At 8 weeks of age, male offspring from both groups were randomly assigned to 4 experimental groups: sedentary control (SC), trained control (TC), sedentary restricted (SRT), and trained restricted (TRT). The training protocol was performed on a treadmill and consisted of a continuous 60-min session 5 days/week for 10 weeks. Following aerobic training, concentration-response curves to AngII were obtained in endothelium-intact aortic rings. Protein expression of SOD isoforms, AngII receptors and the NADPH oxidase component p47phox was assessed by Western blot analysis. The dihydroethidium was used to evaluate the in situ superoxide levels under basal conditions or in the presence of apocynin, losartan or PD 123,319. Our results indicate that aerobic training can prevent IUGR-associated increases in AngII-dependent vasoconstriction and can restore basal superoxide levels in the aortic rings of TRT rats. Moreover, we observed that aerobic training normalized the increased p47phox protein expression and increased MnSOD and AT2 receptor protein expression in thoracic aortas of SRT rats. In summary, aerobic training can result in an upregulation of antioxidant defense by improved of MnSOD expression and attenuation of NADPH oxidase component p47phox. These effects are accompanied by increased expression of AT2 receptor, which provide positive effects against Ang II-induced superoxide generation, resulting in attenuation of AngII-induced vasoconstriction.
MeSH term(s)	Angiotensin II/metabolism ; Animals ; Female ; Fetal Growth Retardation/physiopathology ; Gene Expression Regulation/physiology ; Male ; NADPH Oxidases/metabolism ; Oxidative Stress/physiology ; Physical Conditioning, Animal/physiology ; Pregnancy ; Rats ; Receptor, Angiotensin, Type 2/metabolism ; Superoxide Dismutase/metabolism ; Vasoconstriction/physiology
Chemical Substances	Receptor, Angiotensin, Type 2 ; Angiotensin II (11128-99-7) ; Superoxide Dismutase (EC 1.15.1.1) ; NADPH Oxidases (EC 1.6.3.-)
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0113035
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Article ; Online: Leptin downregulates LPS-induced lung injury: role of corticosterone and insulin.

Landgraf, Maristella A / Silva, Reinaldo C / Corrêa-Costa, Matheus / Hiyane, Meire I / Carvalho, Maria Helena C / Landgraf, Richardt G / Câmara, Niels O S

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology

2014 Volume 33, Issue 3, Page(s) 835–846

Abstract: Background/aims: We investigated the effects of leptin in the development of lipopolysaccharide (LPS)-induced acute lung inflammation (ALI) in lean mice.: Methods: Mice were administered leptin (1.0µg/g) or leptin (1.0µg/g) followed by LPS (1.5µg/g) ... ...

Abstract	Background/aims: We investigated the effects of leptin in the development of lipopolysaccharide (LPS)-induced acute lung inflammation (ALI) in lean mice. Methods: Mice were administered leptin (1.0µg/g) or leptin (1.0µg/g) followed by LPS (1.5µg/g) intranasally. Additionally, some animals were given LPS (1.5µg/g) or saline intranasally alone, as a control. Tissue samples and fluids were collected six hours after instillation. Results: We demonstrated that leptin alone did not induce any injury. Local LPS exposure resulted in significant acute lung inflammation, characterized by a substantial increase in total cells, mainly neutrophils, in bronchoalveolar lavages (BAL). We also observed a significant lymphocyte influx into the lungs associated with enhanced lung expression of chemokines and cytokines (KC, RANTES, TNF-α, IFN-γ, GM-CSF and VEGF). LPS-induced ALI was characterized by the enhanced expression of ICAM-1 and iNOS in the lungs. Mice that received LPS showed an increase in insulin levels. Leptin, when administered prior to LPS instillation, abolished all of these effects. LPS induced an increase in corticosterone levels, and leptin potentiated this event. Conclusion: These data suggest that exogenous leptin may promote protection during sepsis, and downregulation of the insulin levels and upregulation of corticosterone may be important mechanisms in the amelioration of LPS-induced ALI.
MeSH term(s)	Acute Lung Injury/chemically induced ; Acute Lung Injury/drug therapy ; Acute Lung Injury/metabolism ; Acute Lung Injury/pathology ; Animals ; Corticosterone/pharmacology ; Cytokines/biosynthesis ; Insulin/pharmacology ; Intercellular Adhesion Molecule-1/biosynthesis ; Leptin/pharmacology ; Lipopolysaccharides/toxicity ; Male ; Mice ; Nitric Oxide Synthase Type II/biosynthesis
Chemical Substances	Cytokines ; Icam1 protein, mouse ; Insulin ; Leptin ; Lipopolysaccharides ; Intercellular Adhesion Molecule-1 (126547-89-5) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Nos2 protein, mouse (EC 1.14.13.39) ; Corticosterone (W980KJ009P)
Language	English
Publishing date	2014-03-21
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1067572-3
ISSN	1421-9778 ; 1015-8987
ISSN (online)	1421-9778
ISSN	1015-8987
DOI	10.1159/000358656
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Article ; Online: Metformin reduces the Walker-256 tumor development in obese-MSG rats via AMPK and FOXO3a.

de Queiroz, Eveline A I F / Akamine, Eliana H / de Carvalho, Maria Helena C / Sampaio, Sandra C / Fortes, Zuleica B

Life sciences

2014 Volume 121, Page(s) 78–87

Abstract: Aims: Studies have associated obesity with a wide variety of cancers. Metformin, an anti-diabetic drug, has recently received attention as a potentially useful therapeutic agent for treating cancer. Therefore, the objective of this study was to analyze ... ...

Abstract	Aims: Studies have associated obesity with a wide variety of cancers. Metformin, an anti-diabetic drug, has recently received attention as a potentially useful therapeutic agent for treating cancer. Therefore, the objective of this study was to analyze the mechanisms involved in the increase in tumor development and the reduction of it by metformin in obesity using an experimental breast tumor model. Material and methods: Newborn male Wistar rats were subcutaneously injected with 400mg/kg monosodium glutamate (MSG) (obese) or saline (control) at 2, 3, 4, 5 and 6 days of age. After 16 weeks, 1 × 10(7) Walker-256 tumor cells were subcutaneously injected in the right flank of the rats and concomitantly the treatment with metformin 300 mg/kg/15 days, via gavage, started. The rats were divided into 4 groups: control tumor (CT), control tumor metformin (CTM), obese-MSG tumor (OT) and obese-MSG tumor metformin (OTM). On the 18th week the tumor development and metformin effect were analyzed. Key findings: Tumor development was higher in OT rats compared with CT rats. Activation of insulin-IR-ERK1/2 pathway and an anti-apoptotic effect might be the mechanisms involved in the higher development of tumor in obesity. The effect of metformin reducing the tumor development in obese rats might involve increased mRNA expression of pRb and p27, increased activity of AMPK and FOXO3a and decreased expression of p-ERK1/2 (Thr202/Tyr204) in Walker-256 tumor. Significance: Our data allow us to suggest that metformin, reducing the stimulatory effect of obesity on tumor development, has a potential role in the management of cancers.
MeSH term(s)	Animals ; Carcinoma 256, Walker/drug therapy ; Carcinoma 256, Walker/pathology ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Female ; Food Additives ; Forkhead Box Protein O3 ; Forkhead Transcription Factors/metabolism ; Hypoglycemic Agents/therapeutic use ; Male ; Mammary Neoplasms, Experimental/drug therapy ; Mammary Neoplasms, Experimental/metabolism ; Mammary Neoplasms, Experimental/pathology ; Metformin/therapeutic use ; Obesity/chemically induced ; Obesity/complications ; Obesity/pathology ; Rats ; Rats, Wistar ; Signal Transduction/drug effects ; Sodium Glutamate
Chemical Substances	FOXO3 protein, rat ; Food Additives ; Forkhead Box Protein O3 ; Forkhead Transcription Factors ; Hypoglycemic Agents ; Metformin (9100L32L2N) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Sodium Glutamate (W81N5U6R6U)
Language	English
Publishing date	2014-12-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2014.11.028
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