Inhibition of GHRH aggravated acetaminophen-induced acute mice liver injury through GH/IGF-I axis

Wang, Tao; Hai, Jian; Chen, Xuehui; Peng, Hua; Zhang, He; Li, Lake; Zhang, Qinggui

doi:10.1507/endocrj.ej11-0356

Cited by 4 publications

(7 citation statements)

References 38 publications

(32 reference statements)

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“…Of note, IH and SF are both associated with increased oxidative stress, the magnitude of which is a critical determinant of end-organ injury in general, and CNS dysfunction in particular (Row et al 2003(Row et al , 2007Xu et al 2004;Shan et al 2007;Douglas et al 2010;Nair et al 2011a). GHRH has been postulated to modulate oxidative stress in specific cancer lines, as well as other settings (Barabutis and Schally 2008;Banks et al 2010;Wang et al 2012), such that the beneficial effects of JI-34 in our IH-exposure murine model could be ascribable to the attenuation of free-radical induced neuronal injury. A substantial component of the neuroprotective effect conferred by the administration of the GHRH analog JI-34 may be because of the downstream effects of this compound on GH-IGF-1 dependent cellular pro-survival pathways.…”

Section: Discussionmentioning

confidence: 90%

“…GHRH has been postulated to modulate oxidative stress in specific cancer lines, as well as other settings (Barabutis & Schally 2008, Banks et al 2010, Wang et al 2012), such that the beneficial effects of JI-34 in our IH-exposure murine model could be ascribable to the attenuation of free radical-induced neuronal injury. A substantial component of the neuroprotective effect conferred by the administration of the GHRH analog JI-34 may be due to the downstream effects of this compound on GH-IGF-1 dependent cellular pro-survival pathways.…”

Section: Discussionmentioning

confidence: 99%

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Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia‐induced oxidative stress and cognitive deficits in mouse

Nair

Ramesh

et al. 2013

Journal of Neurochemistry

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Intermittent hypoxia (IH) during sleep, such as occurs in obstructive sleep apnea (OSA), leads to degenerative changes in the hippocampus, and is associated with spatial learning deficits in adult mice. In both patients and murine models of OSA, the disease is associated with suppression of growth hormone (GH) secretion, which is actively involved in the growth, development and function of the central nervous system (CNS). Recent work showed that exogenous GH therapy attenuated neurocognitive deficits elicited by IH during sleep in rats. Here we show that administration of the Growth Hormone Releasing Hormone (GHRH) agonist JI-34 attenuates IH-induced neurocognitive deficits, anxiety, and depression in mice along with reduction in oxidative stress markers such as MDA and 8-OHDG, and increases in HIF-1α DNA binding and up-regulation of IGF-1 and erythropoietin expression. In contrast, treatment with a GHRH antagonist (MIA-602) during intermittent hypoxia did not affect any of the IH-induced deleterious effects in mice. Thus, exogenous GHRH administered as the formulation of a GHRH agonist may provide a viable therapeutic intervention to protect IH-vulnerable brain regions from OSA-associated neurocognitive dysfunction.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia‐induced oxidative stress and cognitive deficits in mouse

Nair

Ramesh

et al. 2013

Journal of Neurochemistry

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“…Recently, Wang et al (2012) showed that the growth hormone (GH)-releasing hormone (GHRH) has a protective role in APAP-induced acute liver injury). It is known that GHRH is synthesized in the hypothalamus and stimulates the release of GH from the pituitary gland.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of GHRH reduces the levels of hepatic and circulating IGF-I (Barabutis and Schally, 2010). The liver protection of GHRH is through GH/IGF-I axis and the Janus kinase 2/signal transducer and activator of transcription 5 pathway (Wang et al, 2012). It is shown that APAP inhibits liver cell in a time-dependent fashion (Hwang et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Effects of administration of subtoxic doses of acetaminophen on liver and blood levels of insulin-like growth factor-1 in rats

et al. 2013

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Acetaminophen (APAP) is widely used in the treatment of pain. Toxic doses of APAP cause acute liver failure, but therapeutic doses are believed to be safe. The purpose of this study is to investigate the effects of administration of subtoxic doses of APAP on liver and blood levels of insulin-like growth factor-1 (IGF-1) in rats. Low dose (100 mg/kg) and high dose (250 mg/kg) of APAP were intraperitoneally injected into Wistar albino rats. Following administration of therapeutic doses of APAP, there were no significant changes in serum transaminases and liver glutathione levels. Both doses of APAP induced a decrease in liver and blood levels of IGF-1 when compared with the controls. There was no significant difference in liver IGF-1 levels between the high-dose and low-dose APAP groups; however, there was a significant difference in blood IGF-1 levels between both the groups. The histological examination showed that low dose of APAP induced mild degree of structural change, while high dose of APAP induced severe structural damage. In conclusion, these results suggest that blood IGF-1 levels may have a value in predicting hepatic damage resulting from therapeutic doses of APAP.

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Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury

Everton

Moreno

Villacorta‐Martin

et al. 2023

Preprint

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Background and Aims: Acetaminophen (APAP) overdose is the leading cause of acute liver failure, with one available treatment, N-acetyl cysteine (NAC). Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. This study addresses this need by deciphering a mechanism of sexual dimorphism in APAP-induced liver injury, and leveraging it to accelerate liver recovery via growth hormone (GH) treatment. GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. Here, we aim to establish GH as a novel therapy to treat APAP hepatotoxicity. Approach and Results: Our results demonstrate sex-dependent APAP toxicity, with females showing reduced liver cell death and faster recovery than males. Single-cell RNA sequencing analyses reveal that female hepatocytes have significantly greater levels of GH receptor expression and GH pathway activation compared to males. In harnessing this female-specific advantage, we demonstrate that a single injection of recombinant human GH protein accelerates liver recovery, promotes survival in males following sub-lethal dose of APAP, and is superior to standard-of-care NAC. Alternatively, slow-release delivery of human GH via the safe non-integrative lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP), a technology validated by widely used COVID-19 vaccines, rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice. Conclusions: Our study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients.

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Inhibition of GHRH aggravated acetaminophen-induced acute mice liver injury through GH/IGF-I axis

Cited by 4 publications

References 38 publications

Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia‐induced oxidative stress and cognitive deficits in mouse

Growth hormone releasing hormone (GHRH) signaling modulates intermittent hypoxia‐induced oxidative stress and cognitive deficits in mouse

Effects of administration of subtoxic doses of acetaminophen on liver and blood levels of insulin-like growth factor-1 in rats

Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury

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