Soybean Oil-Based Lipid Emulsion Increases Intestinal Permeability of Lipopolysaccharide in Caco-2 Cells by Downregulation of P-Glycoprotein via ERK-FOXO 3a Pathway

Yan, Junkai; Zhu, Jie; Gu, Bei-Lin; Yan, Wei; Xiao, Yongtao; Zhou, Ke-Jun; Wen, Jie; Wang, Yan; Cai, Wei

doi:10.1159/000447860

Cited by 11 publications

(7 citation statements)

References 35 publications

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“…P-gp, one of the most extensively studied and important drug transporters [23], has been investigated in clinical studies. In addition, elevated expression and activity of P-gp have been reported to be associated with poor clinical outcomes among cancer patients [24]. Based on these findings, a rationale was formulated for modulation of P-gp activity as a therapeutic approach [25].…”

Section: Discussionmentioning

confidence: 99%

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

Cheng¹,

Liao²,

Hu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: P-glycoprotein (P-gp, i.e., MDR1) is associated with the phenotype of multidrug resistance (MDR) and causes chemotherapy failure in the management of cancers. Searching for effective MDR modulators and combining them with anticancer drugs is a promising strategy against MDR. Asiatic acid (AA), a natural triterpene isolated from the plant Centella asiatica, may have an antitumor activity. The present study assessed the reversing effect of AA on MDR and possible molecular mechanisms of AA action in MDR1-overexpressing cisplatin (DDP)-resistant lung cancer cells, A549/DDP. Methods: Human lung adenocarcinoma A549/DDP cells were either exposed to different concentrations of AA or treated with DDP, and their viability was measured by the MTT assay. A Rhodamine 123 efflux assay, immunofluorescent staining, ATPase assay, reverse-transcription PCR (RT-PCR), and western blot analysis were conducted to elucidate the mechanisms of action of AA on MDR. Results: Our results showed that AA significantly enhanced the cytotoxicity of DDP toward A549/DDP cells but not its parental A549 cells. Furthermore, AA strongly inhibited P-gp expression by blocking MDR1 gene transcription and increased the intracellular accumulation of the P-gp substrate Rhodamine 123 in A549/DDP cells. Nuclear factor (NF)-kB (p65) activity, IkB degradation, and NF-kB/p65 nuclear translocation were markedly inhibited by pretreatment with AA. Additionally, AA inhibited the MAPK–ERK pathway, as indicated by decreased phosphorylation of ERK1 and -2, AKT, p38, and JNK, thus resulting in reduced activity of the Y-box binding protein 1 (YB1) via blockage of its nuclear translocation. Conclusions: AA reversed P-gp-mediated MDR by inhibition of P-gp expression. This effect was likely related to downregulation of YB1, and this effect was mediated by the NF-kB and MAPK–ERK pathways. AA may be useful as an MDR reversal agent for combination therapy in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

Cheng¹,

Liao²,

Hu³

et al. 2018

Cell Physiol Biochem

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“…In an attempt to further understand the underlying mechanism, we examined possible signalling pathways that may mediate the regulation of P-gp upon DEX treatment, including ERK, PI3K/Akt, JNK, p38 and AMPK. These pathways were examined because: i) Previous studies demonstrated that DEX may elicit various non-anesthetic effects via these pathways ( 17 , 30 ) and ii) these pathways have been reported to be involved in the regulation of P-gp expression in response to a variety of extracellular stimuli ( 31 , 32 ). In the present study, though it lacks statistical significance, it seems that the intracellular accumulation of Rhodamine 123 in L02 cells was slightly increased by inhibition of the ERK and PI3K/Akt pathways, suggesting that these pathways may contribute to the activation of P-gp expression under normal conditions.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine impairs P‑glycoprotein‑mediated efflux function in L02 cells via the adenosine 5'‑monophosphate‑activated protein kinase/nuclear factor‑κB pathway

Lin

Wang

et al. 2018

Mol Med Report

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Dexmedetomidine (DEX) a type of the anaesthetic that has been widely used in anaesthesia and intensive care. However, whether DEX affects the pharmacokinetics of drugs remains elusive. As hepatic P-glycoprotein (P-gp) serves a critical role in the disposition of drugs, the present study aimed to address whether P-gp function could be affected by DEX in vitro. In the present study, L02 cells (a normal human liver cell line) were exposed to DEX for 24 h and P-gp function was evaluated by the intracellular accumulation of Rhodamine 123. The results indicated that P-gp function was significantly impaired by DEX treatment and that the mRNA levels and protein levels of P-gp were downregulated in a dose- and time-dependent manner. Importantly, DEX-induced downregulation of P-gp was associated with adenosine 5′-monophosphate-activated protein kinase (AMPK) activation, as it was significantly attenuated by AMPK inhibition using dorsomorphin. Furthermore, the results revealed that changes in the subcellular localisation of nuclear factor (NF)-κB following AMPK activation were involved in the P-gp regulation in response to DEX treatment. Collectively, these results suggested that DEX impairs P-glycoprotein-mediated efflux function in L02 cells via the AMPK/NF-κB pathway, which provided direct evidence that the hepatic disposition of drugs may be affected by DEX through the downregulation of P-gp.

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“…TEER was measured with an epithelial voltmeter under open-circuit conditions (WPI, Sarasota, FL) as described previously. 27…”

Section: Evaluation Of Intestinal Barrier Function In Vitromentioning

confidence: 99%

Lin 28A/Occludin axis: An aberrantly activated pathway in intestinal epithelial cells leading to impaired barrier function under total parenteral nutrition

et al. 2020

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Disassembly of tight junctions is a major cause of intestinal barrier dysfunction under total parenteral nutrition (TPN), but the precise mechanisms have not been fully understood. Normally, RNA binding protein Lin 28A is highly restricted to embryonic stem cells and dramatically decreases as differentiation progresses; however, in our preliminary study it was found aberrantly increased in the intestinal epithelial cells of TPN rats, and thus its mechanism of action needs to be addressed. Herein, we report a pivotal role of Lin 28A in the regulation of tight junctions, which induces a sustained translational repression of Occludin, leading to disruption of intestinal barrier function under TPN. Using a rat model of TPN, we found time-dependent upregulation of Lin 28A, negatively correlated with Occludin. Using mouse intestinal organoids and human gut-derived Caco-2 cells as in vitro models, we found that expression of Occludin could be significantly suppressed by ectopic overexpression of Lin 28A.The underlying mechanisms may be partially attributed to translational repression, as the abundance of Occludin transcripts in polysomes was dramatically reduced by Lin 28A (polysomal profiling). Furthermore, Lin 28A was found to directly bind to Occludin mRNA 3′ untranslated coding region (UTR), thereby repressing the translation of Occludin transcripts through decapping enzyme 1A (DCP1a). Taken together, our findings revealed that Lin 28A/Occludin axis may be a novel mechanism accounting for the development of barrier dysfunction under TPN.

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Soybean Oil-Based Lipid Emulsion Increases Intestinal Permeability of Lipopolysaccharide in Caco-2 Cells by Downregulation of P-Glycoprotein via ERK-FOXO 3a Pathway

Cited by 11 publications

References 35 publications

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets

Dexmedetomidine impairs P‑glycoprotein‑mediated efflux function in L02 cells via the adenosine 5'‑monophosphate‑activated protein kinase/nuclear factor‑κB pathway

Lin 28A/Occludin axis: An aberrantly activated pathway in intestinal epithelial cells leading to impaired barrier function under total parenteral nutrition

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