Growth hormone and aging

Les alteracions vasculars i degeneratives del sistema nerviós central (SNC) són dues de les causes més comunes de malaltia i de mort entre la gent gran; ambdues es correlacionen amb l'edat, amb la deficiència en GH, i poden afectar les funcions fisiològiques de la població d'edat avançada. Amb la finalitat de clarificar els efectes de la GH en el metabolisme, en els vasos i en el SNC, hem dut a terme un estudi in vivo utilitzant rates vellesWistar tractades crònicament amb GH. Les rates velles varen presentar un augment en el pes de greix i una disminució de l'índex específic de gravetat (SGI) (p < 0,05) en comparar-les amb les rates adultes no tractades. La GH va reduir el pes en greix (p < 0,05), i va mostrar també una tendència a augmentar l'SGI. Es va analitzar també la resposta de diverses substàncies vasoactives en els anells aòrtics, i es va demostrar una disminució de la vasodilatació per acetilcolina i isoprenalina (p < 0,05) en els animals vells. La contracció induïda per acetilcolina+L-NAME era més alta en els animals vells que en els adults. L'administració de GH millorava les respostes vasodilatadores (p < 0,05) mentre que tendia a reduïr les respostes vasoconstrictores. L'àrea aòrtica mitja augmentava també en les rates velles, mentre que la GH reduïa aquest paràmetre (p < 0,05). Les poblacions neuronals es reduïen en els hipocamps de les rates velles en comparar-les amb les joves. Aquesta reducció estava asociada a un augment dels nucleosomes i a una reducció de Bcl2 en el cervell. Les caspases 3 i 9 també varen augmentar. El tractament amb GH va augmentar significativament el nombre de neurones i va reduir els nucleosomes i les caspases i augmentar el Bcl2. En conclusió, el tractament perGHindueix l'aparició d'efectes beneficiosos en la composició del cos i ha restablert també les funcions cerebrals i vasculars en les rates velles.Vascular and degenerative alterations of the central nervous system (CNS) are two of the most common reasons for illness and death in elderly people; they exhibit an age-related GH deficiency that can affect their physiological functions. A study was conducted under chronic in vivo conditions using old Wistar rats, in order to clarify the effects of GH on the metabolism, vessels, and the CNS. The old rats showed an increased fat weight and a decreased Specific Gravity Index (SGI) (p < 0.05), as compared to the adult animals. GH reduced the fat weight (p < 0.05) and tended to increase the SGI (N.S.). The response to several vasoactive substances in aortic rings showed impaired vasodilatation to Acetylcholine and Isoprenaline (p < 0.05) in the old animals. Contraction, induced by Acetylcholine+ L-NAME, was higher in the old rats than in the adults. GH administration improved the vasodilatory responses (p < 0.05) and tended to reduce the constrictory responses. The aortic media area was increased in the old rats, and GH reduced this parameter (p < 0.05). The neuronal populations were reduced in the hippocampi of the old rats as compared to the young ones. This reduction was associated with an increase in nucleosomes and a reduction in Bcl2 in the brain. An increase was also detected in caspases 3 and 9. GH treatment was able to significantly enhance the number of neurons by reducing the nucleosomes and the caspases and by increasing Bcl2. In conclusion,GHtreatment was able to show beneficial effects on body composition and was able to restore both vascular and brain functions in the old rats

Zebrafish hoxd4a Acts Upstream of meis1.1 to Direct Vasculogenesis, Angiogenesis and Hematopoiesis

10.1371/journal.pone.0058857PLoS ONE83

Growth hormone responsive neural precursor cells reside within the adult mammalian brain

The detection of growth hormone (GH) and its receptor in germinal regions of the mammalian brain prompted our investigation of GH and its role in the regulation of endogenous neural precursor cell activity. Here we report that the addition of exogenous GH significantly increased the expansion rate in long-term neurosphere cultures derived from wild-type mice, while neurospheres derived from GH null mice exhibited a reduced expansion rate. We also detected a doubling in the frequency of large (i.e. stem cell-derived) colonies for up to 120 days following a 7-day intracerebroventricular infusion of GH suggesting the activation of endogenous stem cells. Moreover, gamma irradiation induced the ablation of normally quiescent stem cells in GH-infused mice, resulting in a decline in olfactory bulb neurogenesis. These results suggest that GH activates populations of resident stem and progenitor cells, and therefore may represent a novel therapeutic target for age-related neurodegeneration and associated cognitive decline

Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes

<p>Abstract</p> <p>Background</p> <p>Human hemangiosarcoma (HSA) tends to have a poor prognosis; its tumorigenesis has not been elucidated, as there is a dearth of HSA clinical specimens and no experimental model for HSA. However, the incidence of spontaneous HSA is relatively high in canines; therefore, canine HSA has been useful in the study of human HSA. Recently, the production of angiogenic growth factors and their receptors in human and canine HSA has been reported. Moreover, the growth-factor environment of HSA is very similar to that of pathophysiological angiogenesis, which some homeobox genes regulate in the transcription of angiogenic molecules. In the present study, we established 6 xenograft canine HSA tumors and detected the expression of growth factors, their receptors, and angiogenic homeobox genes.</p> <p>Methods</p> <p>Six primary canine HSAs were xenografted to nude mice subcutaneously and serially transplanted. Subsequently, the expressions of vascular endothelial growth factor (VEGF)-A, basic fibroblast growth factors (bFGF), flt-1 and flk-1 (receptors of VEGF-A), FGFR-1, and angiogenic homeobox genes HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 were investigated in original and xenograft tumors by histopathology, immunostaining, and reverse transcription polymerase chain reaction (RT-PCR), using canine-specific primer sets.</p> <p>Results</p> <p>Histopathologically, xenograft tumors comprised a proliferation of neoplastic cells that were varied in shape, from spindle-shaped and polygonal to ovoid; some vascular-like structures and vascular clefts of channels were observed, similar to those in the original tumors. The expression of endothelial markers (CD31 and vWF) was detected in xenograft tumors by immunohistochemistry and RT-PCR. Moreover, the expression of VEGF-A, bFGF, flt-1, flk-1, FGFR-1, HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 was detected in xenograft tumors. Interestingly, expressions of bFGF tended to be higher in 3 of the xenograft HSA tumors than in the other tumors.</p> <p>Conclusion</p> <p>We established 6 xenograft canine HSA tumors in nude mice and found that the expressions of angiogenic growth factors and their receptors in xenograft HSAs were similar to those in spontaneous HSA. Furthermore, we detected the expression of angiogenic homeobox genes; therefore, xenograft models may be useful in analyzing malignant growth in HSA.</p

Progesterone and its derivatives dihydroprogesterone and tetrahydroprogesterone reduce myelin fiber morphological abnormalities and myelin fiber loss in the sciatic nerve of aged rats

Previous studies indicate that steroid hormones may be protective for Schwann cells and promote the expression of myelin proteins in the sciatic nerve of adult rats. In this study, we have evaluated the effect of progesterone (P), dihydroprogesterone (DHP), tetrahydroprogesterone (THP), testosterone (T), dihydrotestosterone (DHT) and 5alpha-androstan-3alpha, 17beta-diol (3alpha-diol) on the morphological alterations of myelinated fibers in the sciatic nerve of 22-24-month-old male rats. The sciatic nerves of untreated old male rats, showed a general disorganization and a significant reduction in the density of myelinated fibers, compared to nerves from 3-month-old male rats. The effect of aging was particularly evident in myelinated fibers of small caliber (<5 microm in diameter). In addition, the sciatic nerves of old rats showed a significant increase in the number of fibers with myelin infoldings in the axoplasm and in the number of fibers with irregular shapes. Treatments of old rats with P, DHP and THP resulted in a significant increase in the number of myelinated fibers of small caliber, a significant reduction in the frequency of myelin abnormalities and a significant increase in the g ratio of small myelinated fibers. Furthermore, P treatment significantly reduced the frequency of myelinated fibers with irregular shapes. In contrast, treatments with T, DHT or 3alpha-diol did not significantly affect any of the morphological parameters examined. In conclusion, our data indicate that P, and its derivatives DHP and THP, are able to reduce aging-associated morphological abnormalities of myelin and aging-associated myelin fiber loss in the sciatic nerve. These data suggest that P, DHP and THP may represent useful therapeutic alternatives to maintain peripheral nerve integrity in aged animals

Non-neuronal cells in the nervous system: sources and targets of neuroactive steroids

Non-neuronal cells synthethize and metabolize steroid hormones and produce local neuroactive steroids that exert neuromodulatory and neurotrophic actions under physiological and pathological conditions. In the central nervous system, the steroids produced by non-neuronal cells, such as pregnenolone, dehydroepiandrosterone (DHEA), testosterone, estradiol, progesterone and other steroid metabolites, regulate synaptic function, affect anxiety, cognition, sleep and behavior and exert neuroprotective and reparative roles. In the peripheral nervous system, progesterone and progesterone derivatives producted by Schwann cells, promote myelin formation, the remyelination and regeneration of injured nerves. non-neuronal cells are also targets for steroids and mediate or partecipate in many of the actions of these substances in the nervouis system. These include: (i) the regulation of blood-brain barrier and cerebrovascular permeability by actions of steroid on endothelial cells; (ii) the regulation of synaptogenesis, synaptic plasticity, neuritic growth and neuroendocrine secretion by actions of steroids on astroglia and (iii) the regulation of neuronal survival and regeneration by actions of steroids on microglia, astroglia and Schwann cells