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| 2. |
- Egecioglu, Emil, 1977, et al.
(author)
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Growth hormone receptor deficiency in mice results in reduced systolic blood pressure and plasma renin, increased aortic eNOS expression, and altered cardiovascular structure and function
- 2007
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In: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 292:5
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Journal article (peer-reviewed)abstract
- To study the role of the growth hormone receptor (GHR) in the development of cardiovascular structure and function, female GHR gene-disrupted or knockout (KO) and wild-type (WT) mice at age 18 wk were used. GHR KO mice had lower plasma renin levels (12 ± 2 vs. 20 ± 4 mGU/ml, P < 0.05) and increased aortic endothelial NO synthase (eNOS) expression (146%, P < 0.05) accompanied by a 25% reduction in systolic blood pressure (BP, 110 ± 4 vs. 147 ± 3 mmHg, P < 0.001) compared with WT mice. Aldosterone levels were unchanged, whereas the plasma potassium concentration was elevated by 14% ( P < 0.05) in GHR KO. Relative left ventricular weight was 14% lower in GHR KO mice ( P < 0.05), and cardiac dimensions as analyzed by echocardiography were similarly reduced. Myograph studies revealed a reduced maximum contractile response in the aorta to norepinephrine (NE) and K+ ( P < 0.05), and aorta media thickness was decreased in GHR KO ( P < 0.05). However, contractile force was normal in mesenteric arteries, whereas sensitivity to NE was increased ( P < 0.05). Maximal acetylcholine-mediated dilatation was similar in WT and GHR KO mice, whereas the aorta of GHR KO mice showed an increased sensitivity to acetylcholine ( P < 0.05). In conclusion, loss of GHR leads to low BP and decreased levels of renin in plasma as well as increase in aortic eNOS expression. Furthermore, GHR deficiency causes functional and morphological changes in both heart and vasculature that are beyond the observed alterations in body size. These data suggest an important role for an intact GH/IGF-I axis in the maintenance of a normal cardiovascular system.
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| 3. |
- Ong, L. K., et al.
(author)
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Growth Hormone Improves Cognitive Function After Experimental Stroke
- 2018
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In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 49:5, s. 1257-1266
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Journal article (peer-reviewed)abstract
- Background and Purpose-Cognitive impairment is a common outcome for stroke survivors. Growth hormone (GH) could represent a potential therapeutic option as this peptide hormone has been shown to improve cognition in various clinical conditions. In this study, we evaluated the effects of peripheral administration of GH at 48 hours poststroke for 28 days on cognitive function and the underlying mechanisms. Methods-Experimental stroke was induced by photothrombotic occlusion in young adult mice. We assessed the associative memory cognitive domain using mouse touchscreen platform for paired-associate learning task. We also evaluated neural tissue loss, neurotrophic factors, and markers of neuroplasticity and cerebrovascular remodeling using biochemical and histology analyses. Results-Our results show that GH-treated stroked mice made a significant improvement on the paired-associate learning task relative to non-GH-treated mice at the end of the study. Furthermore, we observed reduction of neural tissue loss in GH-treated stroked mice. We identified that GH treatment resulted in significantly higher levels of neurotrophic factors (IGF-1 [insulin-like growth factor-1] and VEGF [vascular endothelial growth factor]) in both the circulatory and peri-infarct regions. GH treatment in stroked mice not only promoted protein levels and density of presynaptic marker (SYN-1 [synapsin-1]) and marker of myelination (MBP [myelin basic protein]) but also increased the density and area coverage of 2 major vasculature markers (CD31 and collagen-IV), within the peri-infarct region. Conclusions-These findings provide compelling preclinical evidence for the usage of GH as a potential therapeutic tool in the recovery phase of patients after stroke. Visual Overview-An online visual overview is available for this article.
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| 4. |
- Patience, M. J., et al.
(author)
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Photothrombotic Stroke Induces Persistent Ipsilateral and Contralateral Astrogliosis in Key Cognitive Control Nuclei
- 2015
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In: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 40:2, s. 362-371
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Journal article (peer-reviewed)abstract
- While astrocytes are recognised to play a central role in repair processes following stroke, at this stage we do not have a clear understanding of how these cells are engaged during the chronic recovery phase. Accordingly, the principal aim of this study was to undertake a quantitative multi-regional investigation of astrocytes throughout the recovery process. Specifically, we have induced experimental vascular occlusion using cold-light photothrombotic occlusion of the somatosensory/motor cortex in adult male C57B6 mice. Four weeks following occlusion we collected, processed, and immunolabelled tissue using an antibody directed at the glial fibrillary acidic protein (GFAP), an astrocyte specific cytoskeletal protein marker. We investigated GFAP changes in 13 regions in both the contra- and ipsi-lateral hemispheres from control and occluded animals. Specifically, we examined the infra-limbic (A24a), pre-limbic (A25), anterior cingulate (A32), motor (M1 and M2) cortices, the forceps minor fibre tract, as well the shell of the accumbens, thalamus, cingulate cortex (A29c), hippocampus (CA1-3) and lateral hypothalamus. Tissue from occluded animals was compared against sham treated controls. We have identified that the focal occlusion produced significant astrogliosis (p < 0.05), as defined by a marked elevation in GFAP expression, within all 13 sites assessed within the ipsilateral (lesioned) hemisphere. We further observed significant increases in GFAP expression (p < 0.05) in 9 of the 13 contralesional sites examined. This work underscores that both the ipsilateral and contralesional hemispheres, at sites distal to the infarct, are very active many weeks after the initial occlusion, a finding that potentially has significant implications for understanding and improving the regeneration of the damaged brain.
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| 5. |
- Sanchez-Bezanilla, S., et al.
(author)
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Growth Hormone Increases BDNF and mTOR Expression in Specific Brain Regions after Photothrombotic Stroke in Mice
- 2022
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In: Neural Plasticity. - : Hindawi Limited. - 2090-5904 .- 1687-5443. ; 2022
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Journal article (peer-reviewed)abstract
- Aims. We have shown that growth hormone (GH) treatment poststroke increases neuroplasticity in peri-infarct areas and the hippocampus, improving motor and cognitive outcomes. We aimed to explore the mechanisms of GH treatment by investigating how GH modulates pathways known to induce neuroplasticity, focusing on association between brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the peri-infarct area, hippocampus, and thalamus. Methods. Recombinant human growth hormone (r-hGH) or saline was delivered (0.25 mu l/hr, 0.04 mg/day) to mice for 28 days, commencing 48 hours after photothrombotic stroke. Protein levels of pro-BDNF, total-mTOR, phosphorylated-mTOR, total-p70S6K, and phosporylated-p70S6K within the peri-infarct area, hippocampus, and thalamus were evaluated by western blotting at 30 days poststroke. Results. r-hGH treatment significantly increased pro-BDNF in peri-infarct area, hippocampus, and thalamus (p < 0.01). r-hGH treatment significantly increased expression levels of total-mTOR in the peri-infarct area and thalamus (p < 0.05). r-hGH treatment significantly increased expression of total-p70S6K in the hippocampus (p < 0.05). Conclusion. r-hGH increases pro-BDNF within the peri-infarct area and regions that are known to experience secondary neurodegeneration after stroke. Upregulation of total-mTOR protein expression in the peri-infarct and thalamus suggests that this might be a pathway that is involved in the neurorestorative effects previously reported in these animals and warrants further investigation. These findings suggest region-specific mechanisms of action of GH treatment and provide further understanding for how GH treatment promotes neurorestorative effects after stroke.
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| 6. |
- Walser, M., et al.
(author)
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Local overexpression of GH and GH/IGF1 effects in the adult mouse hippocampus
- 2012
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In: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 215:2, s. 257-268
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Journal article (peer-reviewed)abstract
- GH therapy improves hippocampal functions mainly via circulating IGF1. However, the roles of local GH and IGF1 expression are not well understood. We investigated whether transgenic (TG) overexpression in the adult brain of bovine GH (bGH) under the control of the glial fibrillary acidic protein (GFAP) promoter affected cellular proliferation and the expression of transcripts known to be induced by systemic GH in the hippocampus. Cellular proliferation was examined by 5-bromo-2'-deoxyuridine immunohistochemistry. Quantitative PCR and western blots were performed. Although robustly expressed, bGH-Tg did not increase either cell proliferation or survival. However, bGH-Tg modestly increased Igf1 and Gfap mRNAs, whereas other GH-associated transcripts were unaffected, i.e. the GH receptor (Ghr), IGF1 receptor (Igf1r), 2',3'-cyclic nucleotide 3'-phosphodiesterase (Cnp), ionotropic glutamate receptor 2a (Nr2a (Grin2a)), opioid receptor delta (Dor), synapse-associated protein 90/postsynaptic density-95-associated protein (Sapap2 (Dlgap2)), haemoglobin beta (Hbb) and glutamine synthetase (Gs (Glul)). However, IGF1R was correlated with the expression of Dor, Nr2a, Sapap2, Gs and Gfap. In summary, although local bGH expression was robust, it activated local IGF1 very modestly, which is probably the reason for the low response of previous GH-associated response parameters. This would, in turn, indicate that hippocampal GH is less important than endocrine GH. However, as most transcripts were correlated with the expression of IGF1R, there is still a possibility for endogenous circulating or local GH to act via IGF1R signalling. Possible reasons for the relative bio-inactivity of bGH include the bell-shaped dose-response curve and cell-specific expression of bGH. Journal of Endocrinology (2012) 215, 257-268
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| 7. |
- Arcopinto, M., et al.
(author)
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Hormone replacement therapy in heart failure
- 2015
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In: Current Opinion in Cardiology. - : Ovid Technologies (Wolters Kluwer Health). - 0268-4705. ; 30:3, s. 277-284
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Research review (peer-reviewed)abstract
- Purpose of review Despite major advances in medical treatments, survival rates of chronic heart failure (CHF) have not significantly changed in the past 50 years, making it imperative to search for novel pathophysiological mechanisms and therapeutic targets. In this article, we summarize the current knowledge regarding the possibility to treat such anabolic deficiencies with hormone replacement therapy (HRT). Mounting evidence supports the concept that CHF is a disease characterized not only by excessive neurohormonal activation but also by a reduced anabolic drive that carries functional and prognostic significance. The recent demonstration of overall beneficial effects of HRT in CHF may pave the way to slow the disease progression in patients with coexisting CHF and hormone deficiencies. The hypothesis is to identify a considerable subset of CHF patients also affected with hormone deficiency and to treat them with HRT. Single or multiple HRT may in theory be performed in CHF. Such a novel approach may improve left ventricular architecture, function, and physical capacity as well as quality of life. Larger randomized, controlled trials are needed to confirm this working hypothesis.
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| 8. |
- Evans, William J, et al.
(author)
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Effect of recombinant human growth hormone on exercise capacity in patients with HIV-associated wasting on HAART.
- 2005
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In: The AIDS reader. - 1053-0894. ; 15:6
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Journal article (peer-reviewed)abstract
- Over 700 patients with HIV-associated wasting while receiving HAART were randomly assigned to double-blind treatment for 12 weeks with recombinant human growth hormone (rhGH) daily or on alternate days, or to placebo. Maximum exercise intensity increased by a median of 2.35kJ in the alternate-days group and 2.60 kJ in the daily group but decreased by 0.25kJ in the placebo group. The median difference between the daily and placebo groups was 2.85 kJ (P < .0001). These improvements suggest that rhGH treatment may enable patients with wasting to perform activities of daily living that would be exhausting without rhGH treatment.
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| 9. |
- Johannsson, Gudmundur, 1960, et al.
(author)
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Long-term cardiovascular effects of growth hormone treatment in GH-deficient adults. Preliminary data in a small group of patients.
- 1996
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In: Clinical endocrinology. - 0300-0664. ; 45:3, s. 305-14
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Journal article (peer-reviewed)abstract
- The long-term cardiovascular effects of GH administration in adults are of major clinical importance, given the increasing use of such treatment. We have evaluated long-term cardiovascular effects of recombinant human GH (rhGH) substitution in GH deficient men.S.c. rhGH 0.5 U/kg/week or placebo was administered in a 6-month double-blind, cross-over study, followed (after a year without substitution) by a 42-month period of open GH substitution.We evaluated 7 GH-deficient men serially and compared the results with 21 men matched in terms of age and height.Investigations included exercise tests and Doppler-echocardiography to determine exercise capacity and cardiovascular performance.Heart rate and systolic blood pressure at rest increased with GH substitution to the level of the controls, as did diastolic blood pressure after an initial reduction. Age-adjusted exercise capacity increased during the study and we found no evidence of ischaemic heart disease on exercise ECG. Stroke volume increased with GH substitution, thereby normalizing the initially reduced cardiac index. There was no significant change in left atrial or ventricular internal dimensions, systolic function as measured by fractional shortening, or diastolic function as measured by isovolumic relaxation time and left ventricular filling (A/E ratio). However, a lower atrial emptying index than that seen among controls might indicate some diastolic disturbance and there was a definite increase in left ventricular wall thickness compared with controls (to 25.1 +/- 1.5 vs 19.7 +/- 0.4 mm, P < 0.001).We found that GH substitution in GH-deficient adults had a beneficial effect on physical performance and cardiac output. The concomitant increase in left ventricular mass index might be an effect of an excessive substitution dose.
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| 10. |
- Jones, K. A., et al.
(author)
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Chronic stress exacerbates neuronal loss associated with secondary neurodegeneration and suppresses microglial-like cells following focal motor cortex ischemia in the mouse
- 2015
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In: Brain Behavior and Immunity. - : Elsevier BV. - 0889-1591. ; 48, s. 57-67
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Journal article (peer-reviewed)abstract
- Post-stroke patients describe suffering from persistent and unremitting levels of distress. Using an experimental model of focal cortical ischemia in adult male C57BL/6 mice, we examined whether exposure to chronic stress could modify the development of secondary thalamic neurodegeneration (STND), which is commonly reported to be associated with impaired functional recovery. We were particularly focused on the modulatory role of microglia-like cells, as several clinical studies have linked microglial activation to the development of STND. One month following the induction of cortical ischemia we identified that numbers of microglial-like cells, as well as putative markers of microglial structural reorganization (Iba-1), complement processing (CD11b), phagocytosis (CD68), and antigen presentation (MHC-II) were all significantly elevated in response to occlusion. We further identified that these changes co-occurred with a decrease in the numbers of mature neurons within the thalamus. Occluded animals that were also exposed to chronic stress exhibited significantly lower levels of Iba-1 positive cells and a reduced expression of Iba-1 and CD11b compared to the 'occlusion-alone' group. Interestingly, the dampened expression of microglial/monocyte markers observed in stressed animals was associated with significant additional loss of neurons. These findings indicate that the process of STND can be negatively modified, potentially in a microglial dependent manner, by exposure to chronic stress. (C) 2015 Elsevier Inc. All rights reserved.
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