Induction of functional erythropoietin and erythropoietin receptor gene expression by gamma-aminobutyric acid and piperine in kidney epithelial cells

Lee, Yoon-Mi; Choi, Jun-Ha; Min, Wan-Kwon; Han, Jong-Kwon; Oh, Jae-Wook

doi:10.1016/j.lfs.2018.11.024

Cited by 16 publications

(14 citation statements)

References 45 publications

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“…Also, piperine resulted in inhibition of IgM antibody secretion and reduced expression of cluster of differentiation CD86 [10]. A recent study of Lee et al demonstrated that piperine in combination with gamma-aminobutyric acid (GABA) mediated p38 and JNK MAPK activation, which increased EPO and EPO-R expression, resulting in up-regulation of IL-10 and NF-κB [11].…”

Section: Immunomodulatory and Anti-allergic Effectmentioning

confidence: 99%

Piperine-A Major Principle of Black Pepper: A Review of Its Bioactivity and Studies

et al. 2019

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Piperine is the main compound present in black pepper, and is the carrier of its specific pungent taste, which is responsible for centuries of human dietary utilization and worldwide popularity as a food ingredient. Along with the application as a food ingredient and food preservative, it is used in traditional medicine for many purposes, which has in most cases been justified by modern scientific studies on its biological effects. It has been confirmed that piperine has many bioactive effects, such as antimicrobial action, as well as many physiological effects that can contribute to general human health, including immunomodulatory, hepatoprotective, antioxidant, antimetastatic, antitumor, and many other activities. Clinical studies demonstrated remarkable antioxidant, antitumor, and drug availability-enhancing characteristics of this compound, together with immunomodulatory potential. All these facts point to the therapeutic potential of piperine and the need to incorporate this compound into general health-enhancing medical formulations, as well as into those that would be used as adjunctive therapy in order to enhance the bioavailability of various (chemo)therapeutic drugs.

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Section: Immunomodulatory and Anti-allergic Effectmentioning

confidence: 99%

Piperine-A Major Principle of Black Pepper: A Review of Its Bioactivity and Studies

et al. 2019

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“…In our preliminary experiment, we found that GABA increases the absorption of organic iron in mice with iron deficiency anemia. Co-treatment by GABA and piperine induces Epo and Epor genes in kidney cells through p38/c-JUN N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation [29]. Thus, we hypothesized that GABA treatment may improve anemia and increases endogenous EPO levels that stimulates erythropoiesis.…”

Section: Introductionmentioning

confidence: 99%

Gamma-Aminobutyric Acid Increases Erythropoietin by Activation of Citrate Cycle and Stimulation of Hypoxia-Inducible Factors Expression in Rats

Park

Han²,

Kim³

et al. 2020

Biomolecules

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Erythropoietin (EPO) is the primary regulator of erythropoiesis in the mammalian fetus and adult. Deficiency of EPO induces anemia. In this study, we investigated the effect of gamma-aminobutyric acid (GABA) on serum EPO levels and erythropoiesis in rats. Expression levels of Epo-related genes were measured by quantitative real-time PCR (qPCR) and expression of Epo and Epo receptor (Epor) proteins were measured by immunohistochemistry. The gene and protein expression profiles of kidney tissue in GABA-treated rats were evaluated by ribonucleic acid (RNA) sequencing and two-dimensional electrophoresis (2-DE), respectively. GABA significantly increased serum EPO levels and expression levels of Epo and Epor. GABA increased expression levels of hypoxia-inducible factor (Hif)-1 and Hif-2. Seven proteins with expression levels showing >2-fold change were identified by 2-DE followed by MALDI-TOF MS in GABA-treated rat kidney. The top KEGG pathway from the identified proteins was the tricarboxylic acid cycle, and nicotinamide adenine dinucleotide (NADH) dehydrogenase, succinate dehydrogenase, and isocitrate dehydrogenase were identified as key proteins. GABA treatment significantly increased ATP levels and NADH dehydrogenase activity in a dose-dependent manner. In conclusion, GABA shows a new physiological role in EPO production, and it can thus can contribute to the prevention of anemia when used alone or in combination with other anemia treating drugs.

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“…Indeed, to investigate GABA/PIP synergistic effect, when we treated LLC-PK1 cells with 5 μM PIP. It has been reported that PIP has no toxicity at concentration up to 50 μM [11]. Therefore, to investigate the full potential effect of PIP treatment on the kidney, further analysis with higher concentration might be needed.…”

Section: Discussionmentioning

confidence: 99%

“…Validation was performed for inhibin subunit beta A (INHBA), signal transducer and activator of transcription 1 (STAT1), hypoxia-inducible factor 1-alpha (HIF-1alpha), and SPF36 ring finger protein like 1 (ZPF36L1) among GABA upregulated genes. Our previous study has shown that EPO and EPO-R upregulation by GABA/ PIP in combination can be downregulated by inhibitor of JNK (SP600126) and inhibitor of p38 (SB203580) MAPK [11]. Therefore, we investigated if MAPK inhibition could affect GABA upregulated genes ( Figure 4A).…”

Section: Fold Enrichment Analysis Of Differentially Expressed Genesmentioning

confidence: 99%

Effects of gamma-aminobutyric acid and piperine on gene regulation in pig kidney epithelial cell lines

Shin

Lee

et al. 2020

Asian-Australas J Anim Sci

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Objective: Gamma-aminobutyric acid (GABA) and piperine (PIP) are both nutritional supplements with potential use in animal diets. The purpose of this study is to investigate the effect of GABA and/or PIP treatment on the gene expression pattern of a pig kidney epithelial cell line. Methods: LLCPK1 cells were treated with GABA, PIP, or both, and then the gene expression pattern was analyzed using microarray. Gene ontology analysis was done using GeneOntology (Geneontology.org), and validation was performed using quantitative real-time polymerase chain reaction. Results: Gene ontology enrichment analysis was used to identify key pathway(s) of genes whose expression levels were regulated by these treatments. Microarray results showed that GABA had a positive effect on the transcription of genes related to regulation of erythrocyte differentiation and that GABA and PIP in combination had a synergistic effect on genes related to immune systems and processes. Furthermore, we found that effects of GABA and/or PIP on these selected genes were controlled by JNK/p38 MAPK pathway. Conclusion: These results can improve our understanding of mechanisms involved in the effect of GABA and/or PIP treatment on pig kidney epithelial cells. They can also help us evaluate their potential as a clinical diagnosis and treatment.

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Induction of functional erythropoietin and erythropoietin receptor gene expression by gamma-aminobutyric acid and piperine in kidney epithelial cells

Cited by 16 publications

References 45 publications

Piperine-A Major Principle of Black Pepper: A Review of Its Bioactivity and Studies

Piperine-A Major Principle of Black Pepper: A Review of Its Bioactivity and Studies

Gamma-Aminobutyric Acid Increases Erythropoietin by Activation of Citrate Cycle and Stimulation of Hypoxia-Inducible Factors Expression in Rats

Effects of gamma-aminobutyric acid and piperine on gene regulation in pig kidney epithelial cell lines

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