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Growth Hormone (GH): Multiple Therapeutic Possibilities and Molecular Mechanisms of Action 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 17927

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Prof. Dr. Jesús Devesa

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Scientific Director of the Medical Center Foltra, Travesía de Montouto 24, 15886 Teo, Spain
Interests: growth hormone; growth hormone receptor; IGF-I; brain injury; stroke; cerebral palsy; hypoxia/ischemia; neurodegeneration; atherosclerosis; growth hormone and gonads; growth hormone and diabetes; growth hormone and cancer; growth hormone signaling pathway
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Dear Colleagues,

Classically, GH has been considered to be a pituitary hormone, with predominantly metabolic actions and an effect on the longitudinal growth of that organism until the end of puberty. However, today, we know that GH is expressed in virtually all tissues and organs of the human body, in which it plays a self/paracrine role—possibly, although it is not known—in cooperation with hormones from the plasma after being released by the pituitary gland. We also know that after interacting with its membrane receptor, GH is internalized together with the GHR, a mechanism that allows the GHR to be translocated to the nucleus of cells for inducing or blocking gene expression; we also know that, at least in rodents, internalized GH undergoes a proteolytic break (tissue, sex, and age-specific), giving rise to shorter peptides whose functions are still unknown. Since the beginning of the 2000s, when it was discovered that the GHR was upregulated in the brain of rodents after induced brain damage, interest in the possible actions of GH in the repair of the brain has continued to increase. The same is true with respect to the effects of the hormone on the vascular endothelium, where GH seems to have a beneficial effect, or in the gonads, where a local GH/IGF-I axis seems to play a key role in the physiological gonadal function. The effects of GH on the beta cells of the islets of Langerhans and diabetes need to be clarified, as well as the relationships between GH and cancer. Furthermore, GH signaling pathways in different tissues must be elucidated, and the same is true of the induction by GH of the expression of many different growth factors.
Giving an answer to these molecular mechanisms of action, still unknown or poorly understood, and the relationships between GH and other growth factors will provide a better understanding of the effects of this important hormone, for its therapeutic use in many different pathologies beyond its mere use for growth in GH-deficient children.
For these reasons, researchers are invited to submit their original research or reviews for this Special Issue of the International Journal of Molecular Sciences, entitled "Growth Hormone (GH): Multiple Possibilities and Molecular Mechanisms of Action", which will cover a selection of topics highlighting the role of GH and its molecular effects in health (included aging) and therapeutic possibilities.

Prof. Dr. Jesús Devesa
Guest Editor

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Keywords

Growth Hormone
cancer
GH/IGF-I axis
GH-deficient

Published Papers (6 papers)

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Research

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23 pages, 3365 KiB

Open AccessArticle

Neuroprotective and Regenerative Effects of Growth Hormone (GH) in the Embryonic Chicken Cerebral Pallium Exposed to Hypoxic–Ischemic (HI) Injury

by Juan David Olivares-Hernández, Martha Carranza, Jerusa Elienai Balderas-Márquez, David Epardo, Rosario Baltazar-Lara, José Ávila-Mendoza, Carlos G. Martínez-Moreno, Maricela Luna and Carlos Arámburo

Int. J. Mol. Sci. 2022, 23(16), 9054; https://doi.org/10.3390/ijms23169054 - 13 Aug 2022

Cited by 5 | Viewed by 1918

Abstract

Prenatal hypoxic–ischemic (HI) injury inflicts severe damage on the developing brain provoked by a pathophysiological response that leads to neural structural lesions, synaptic loss, and neuronal death, which may result in a high risk of permanent neurological deficits or even newborn decease. It is known that growth hormone (GH) can act as a neurotrophic factor inducing neuroprotection, neurite growth, and synaptogenesis after HI injury. In this study we used the chicken embryo to develop both in vitro and in vivo models of prenatal HI injury in the cerebral pallium, which is the equivalent of brain cortex in mammals, to examine whether GH exerts neuroprotective and regenerative effects in this tissue and the putative mechanisms involved in these actions. For the in vitro experiments, pallial cell cultures obtained from chick embryos were incubated under HI conditions (<5% O₂, 1 g/L glucose) for 24 h and treated with 10 nM GH, and then collected for analysis. For the in vivo experiments, chicken embryos (ED14) were injected in ovo with GH (2.25 µg), exposed to hypoxia (12% O₂) for 6 h, and later the pallial tissue was obtained to perform the studies. Results show that GH exerted a clear anti-apoptotic effect and promoted cell survival and proliferation in HI-injured pallial neurons, in both in vitro and in vivo models. Neuroprotective actions of GH were associated with the activation of ERK1/2 and Bcl-2 signaling pathways. Remarkably, GH protected mature neurons that were particularly harmed by HI injury, but was also capable of stimulating neural precursors. In addition, GH stimulated restorative processes such as the number and length of neurite outgrowth and branching in HI-injured pallial neurons, and these effects were blocked by a specific GH antibody, thus indicating a direct action of GH. Furthermore, it was found that the local expression of several synaptogenic markers (NRXN1, NRXN3, GAP-43, and NLG1) and neurotrophic factors (GH, BDNF, NT-3, IGF-1, and BMP4) were increased after GH treatment during HI damage. Together, these results provide novel evidence supporting that GH exerts protective and restorative effects in brain pallium during prenatal HI injury, and these actions could be the result of a joint effect between GH and endogenous neurotrophic factors. Also, they encourage further research on the potential role of GH as a therapeutic complement in HI encephalopathy treatments. Full article

(This article belongs to the Special Issue Growth Hormone (GH): Multiple Therapeutic Possibilities and Molecular Mechanisms of Action 2.0)

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21 pages, 4264 KiB

Open AccessArticle

Cell Proliferation in the Piriform Cortex of Rats with Motor Cortex Ablation Treated with Growth Hormone and Rehabilitation

by Margarita Heredia, Virginia Sánchez-Robledo, Inés Gómez, José María Criado, Antonio de la Fuente, Jesús Devesa, Pablo Devesa and Adelaida Sánchez Riolobos

Int. J. Mol. Sci. 2021, 22(11), 5440; https://doi.org/10.3390/ijms22115440 - 21 May 2021

Cited by 2 | Viewed by 2037

Abstract

Traumatic brain injury represents one of the main health problems in developed countries. Growth hormone (GH) and rehabilitation have been claimed to significantly contribute to the recovery of lost motor function after acquired brain injury, but the mechanisms by which this occurs are not well understood. In this work, we have investigated cell proliferation in the piriform cortex (PC) of adult rats with ablation of the frontal motor cortex treated with GH and rehabilitation, in order to evaluate if this region of the brain, related to the sense of smell, could be involved in benefits of GH treatment. Male rats were either ablated the frontal motor cortex in the dominant hemisphere or sham-operated and treated with GH or vehicle at 35 days post-injury (dpi) for five days. At 36 dpi, all rats received daily injections of bromodeoxyuridine (BrdU) for four days. We assessed motor function through the paw-reaching-for-food task. GH treatment and rehabilitation at 35 dpi significantly improved the motor deficit caused by the injury and promoted an increase of cell proliferation in the PC ipsilateral to the injury, which could be involved in the improvement observed. Cortical ablation promoted a greater number of BrdU+ cells in the piriform cortex that was maintained long-term, which could be involved in the compensatory mechanisms of the brain after injury. Full article

(This article belongs to the Special Issue Growth Hormone (GH): Multiple Therapeutic Possibilities and Molecular Mechanisms of Action 2.0)

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23 pages, 4805 KiB

Open AccessArticle

Neuroprotective Effects of Growth Hormone (GH) and Insulin-Like Growth Factor Type 1 (IGF-1) after Hypoxic-Ischemic Injury in Chicken Cerebellar Cell Cultures

by Rosario Baltazar-Lara, José Ávila-Mendoza, Carlos G. Martínez-Moreno, Martha Carranza, Santiago Pech-Pool, Olivia Vázquez-Martínez, Mauricio Díaz-Muñoz, Maricela Luna and Carlos Arámburo

Int. J. Mol. Sci. 2021, 22(1), 256; https://doi.org/10.3390/ijms22010256 - 29 Dec 2020

Cited by 11 | Viewed by 2583

Abstract

It has been reported that growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert protective and regenerative actions in response to neural damage. It is also known that these peptides are expressed locally in nervous tissues. When the central nervous system (CNS) is exposed to hypoxia-ischemia (HI), both GH and IGF-1 are upregulated in several brain areas. In this study, we explored the neuroprotective effects of GH and IGF-1 administration as well as the involvement of these endogenously expressed hormones in embryonic chicken cerebellar cell cultures exposed to an acute HI injury. To induce neural damage, primary cultures were first incubated under hypoxic-ischemic (<5% O₂, 1g/L glucose) conditions for 12 h (HI), and then incubated under normal oxygenation and glucose conditions (HI + Ox) for another 24 h. GH and IGF-1 were added either during or after HI, and their effect upon cell viability, apoptosis, or necrosis was evaluated. In comparison with normal controls (Nx, 100%), a significant decrease of cell viability (54.1 ± 2.1%) and substantial increases in caspase-3 activity (178.6 ± 8.7%) and LDH release (538.7 ± 87.8%) were observed in the HI + Ox group. On the other hand, both GH and IGF-1 treatments after injury (HI + Ox) significantly increased cell viability (77.2 ± 4.3% and 72.3 ± 3.9%, respectively) and decreased both caspase-3 activity (118.2 ± 3.8% and 127.5 ± 6.6%, respectively) and LDH release (180.3 ± 21.8% and 261.6 ± 33.9%, respectively). Incubation under HI + Ox conditions provoked an important increase in the local expression of GH (3.2-fold) and IGF-1 (2.5-fold) mRNAs. However, GH gene silencing with a specific small-interfering RNAs (siRNAs) decreased both GH and IGF-1 mRNA expression (1.7-fold and 0.9-fold, respectively) in the HI + Ox group, indicating that GH regulates IGF-1 expression under these incubation conditions. In addition, GH knockdown significantly reduced cell viability (35.9 ± 2.1%) and substantially increased necrosis, as determined by LDH release (1011 ± 276.6%). In contrast, treatments with GH and IGF-1 stimulated a partial recovery of cell viability (45.2 ± 3.7% and 53.7 ± 3.2%) and significantly diminished the release of LDH (320.1 ± 25.4% and 421.7 ± 62.2%), respectively. Our results show that GH, either exogenously administered and/or locally expressed, can act as a neuroprotective factor in response to hypoxic-ischemic injury, and that this effect may be mediated, at least partially, through IGF-1 expression. Full article

(This article belongs to the Special Issue Growth Hormone (GH): Multiple Therapeutic Possibilities and Molecular Mechanisms of Action 2.0)

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Review

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14 pages, 1020 KiB

Open AccessReview

Effects of GH on the Aging Process in Several Organs: Mechanisms of Action

by Jesús Á. F. Tresguerres, Isabel Fernández-Tresguerres, José Viña, Lisa Rancan, Sergio D. Paredes, Beatriz Linillos-Pradillo and Elena Vara

Int. J. Mol. Sci. 2022, 23(14), 7848; https://doi.org/10.3390/ijms23147848 - 16 Jul 2022

Cited by 3 | Viewed by 2863

Abstract

In order to investigate the possible beneficial effects of GH administration on the aging process, 24-month-old rats of both sexes and 10-month-old SAMP8 mice were used. Male rats showed increased fat content and decreased lean body mass together with enhanced vasoconstriction and reduced vasodilation of their aortic rings compared to young adult animals. Chronic GH treatment for 10 weeks increased lean body mass and reduced fat weight together with inducing an enhancement of the vasodilatory response by increasing eNOS and a reduction of the constrictory responses. Old SAMP8 male mice also showed insulin resistance together with a decrease in insulin production by the endocrine pancreas and a reduced expression of differentiation parameters. GH treatment decreased plasma levels and increased pancreatic production of insulin and restored differentiation parameters in these animals. Ovariectomy plus low calcium diet in rabbits induced osteoporosis Titanium implants inserted into these rabbit tibiae showed after one month lesser bone to implant (BIC) surface and bone mineral density (BMD). Local application of GH in the surgical opening was able to increase BIC in the osteoporotic group. The hippocampus of old rats showed a reduction in the number of neurons and also in neurogenesis compared to young ones, together with an increase of caspases and a reduction of Bcl-2. GH treatment was able to enhance significantly only the total number of neurons. In conclusion, GH treatment was able to show beneficial effects in old animals on all the different organs and metabolic functions studied. Full article

(This article belongs to the Special Issue Growth Hormone (GH): Multiple Therapeutic Possibilities and Molecular Mechanisms of Action 2.0)

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21 pages, 1915 KiB

Open AccessReview

Contribution of Ghrelin to the Pathogenesis of Growth Hormone Deficiency

by Andrzej Lewiński, Małgorzata Karbownik-Lewińska, Katarzyna Wieczorek-Szukała, Magdalena Stasiak and Renata Stawerska

Int. J. Mol. Sci. 2021, 22(16), 9066; https://doi.org/10.3390/ijms22169066 - 23 Aug 2021

Cited by 11 | Viewed by 4753

Abstract

In this review we described the interactions between ghrelin and the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis in children and adults with growth hormone deficiency (GHD). A possible involvement of these interactions in the pathogenesis of unexplained cases of GHD was suggested. Current research provides more and more details to the knowledge on the circadian rhythm of ghrelin. We gathered reports on the decreasing effect of Helicobacter pylori-related chronic gastritis on the number of ghrelin immunopositive cells and the consequent decrease in ghrelin serum concentration. The gastrointestinal tract microflora modification of the ghrelin action, by the mechanism of molecular mimicry, was also stressed. Moreover, the mutual relationships between ghrelin and the TSH-FT4/FT3 axis in growth and metabolic processes are described. It is to be recalled that FT4 and FT3 exert a permissive impact on IGF-1 action and, in turn, GH, in reaction mediated by IGF-1, enhances the monodeiodination of FT4 to FT3. Finally, we discussed the latest attempts to use the GH secretagogue receptor (GHS-R) analogues for possible diagnostic and therapeutic purposes. Full article

(This article belongs to the Special Issue Growth Hormone (GH): Multiple Therapeutic Possibilities and Molecular Mechanisms of Action 2.0)

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Other

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16 pages, 813 KiB

Open AccessCase Report

Delayed Diagnosis of Congenital Combined Pituitary Hormone Deficiency including Severe Growth Hormone Deficiency in Children with Persistent Neonatal Hypoglycemia—Case Reports and Review

by Joanna Smyczyńska, Natalia Pawelak, Maciej Hilczer and Andrzej Lewiński

Int. J. Mol. Sci. 2022, 23(19), 11069; https://doi.org/10.3390/ijms231911069 - 21 Sep 2022

Cited by 2 | Viewed by 2492

Abstract

Apart from stimulation of human growth and cell proliferation, growth hormone (GH) has pleiotropic metabolic effects in all periods of life. Severe GH deficiency is a common component of combined pituitary hormone deficiency (CPHD). CPHD may be caused by mutations in the genes encoding transcription factors and signaling molecules involved in normal pituitary development; however, often its genetic cause remains unknown. Symptoms depend on which hormone is deficient. The first symptom of GH or adrenocorticotropic hormone (ACTH) deficiency may be persistent hypoglycemia in apparently healthy newborns, which is often neglected. Diagnosing CPHD is based on decreased concentrations of hormones secreted by the anterior pituitary and peripheral endocrine glands. Findings in magnetic resonance imaging vary widely, including anterior pituitary hypoplasia/aplasia or pituitary stalk interruption syndrome (PSIS). Delayed diagnosis and treatment can be life-threatening. GH therapy is necessary to recover hypoglycemia and to improve auxological and psychomotor development. We present two girls, diagnosed and treated in our departments, in whom the diagnosis of CPHD was delayed, despite persistent neonatal hypoglycemia; and a review of similar cases, with attention paid to progress in the genetic assessments of such patients, since the introduction of whole exome sequencing that is especially important for PSIS. Full article

(This article belongs to the Special Issue Growth Hormone (GH): Multiple Therapeutic Possibilities and Molecular Mechanisms of Action 2.0)

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