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Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model.

ABSTRACT: Hyperproteinemia is a metabolic disorder associated with increased plasma protein concentration (PPC) and is often clinically complicated by malignant diseases or severe infections. At present, however, research on the molecular mechanism underlying high PPC (HPPC) is scant. Here, an animal model of primary hyperproteinemia was constructed in an invertebrate ( Bombyx mori) to investigate the effects of HPPC on circulating blood cells. Results showed that HPPC affected blood cell homeostasis, leading to increased reactive oxygen species levels, and induced programmed cell death dependent on the endoplasmic reticulum-calcium ion signaling pathway. HPPC induced the proliferation of blood cells, mainly granulocytes, by activating the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. Supplementation with the endocrine hormone active substance 20E significantly reduced the impact of HPPC on blood cell homeostasis. Thus, we identified a novel signaling pathway by which HPPC affects blood cell homeostasis, which differs from hyperglycemia, hyperlipidemia, and hypercholesterolemia. In addition, we showed that down-regulation of gene expression of the hematopoietic factor Gcm could be used as a potential early detection indicator for hyperproteinemia.

SUBMITTER: Wang G

PROVIDER: S-EPMC9113973 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model.

Wang Guang G Wang Yong-Feng YF Li Jiang-Lan JL Peng Ru-Ji RJ Liang Xin-Yin XY Chen Xue-Dong XD Jiang Gui-Hua GH Shi Jin-Fang JF Si-Ma Yang-Hu YH Xu Shi-Qing SQ

Zoological research 20220501 3

Hyperproteinemia is a metabolic disorder associated with increased plasma protein concentration (PPC) and is often clinically complicated by malignant diseases or severe infections. At present, however, research on the molecular mechanism underlying high PPC (HPPC) is scant. Here, an animal model of primary hyperproteinemia was constructed in an invertebrate ( <i>Bombyx mori</i>) to investigate the effects of HPPC on circulating blood cells. Results showed that HPPC affected blood cell homeostas ...[more]

PMID: 35312240

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Project description:Background & Aims Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor. Methods In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration. Results In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals. Conclusions These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE. Lay summary Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore. Graphical abstract Highlights • Using a rat model, we showed that HE is associated with reduced brain tissue oxygen, glucose and lactate content.• Cerebrovascular dilating agents and ammonia-lowering treatment reduced the effect on brain oxygenation.• Ammonia could therefore act by increasing central vascular tone.• Cerebrovascular tone could be a potential therapeutic target alongside ammonia-lowering strategies.

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Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model.

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Mechanism of hyperproteinemia-induced blood cell homeostasis imbalance in an animal model.

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