HMGB1 promoted P-glycoprotein at the blood-brain barrier in MCAO rats via TLR4/NF-κB signaling pathway

Wang, Fei; Ji, Shenglan; Wang, Muxi; Liu, Lu; Li, Qiaoling; Fu-xia, Jiang; Cen, Juan; Ji, Bian‐Sheng

doi:10.1016/j.ejphar.2020.173189

Cited by 19 publications

(12 citation statements)

References 37 publications

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“…These results may suggest that the MTX effect on P-gp expression is organ-specific. Previous studies also suggested that certain elements of the inflammatory pathway may modulate the expression of P-gp (Ho and Piquette-Miller, 2006), for example, TLR4 and NF-κB (Liu et al, 2015;Xie et al, 2017;Wang et al, 2020). In the current study, MTX upregulated, while paeonol/MTX downregulated the inflammatory markers TLR4 and NF-κB.…”

Section: Discussionsupporting

confidence: 70%

Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway

et al. 2022

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Methotrexate (MTX) is a well-known anticancer drug that causes nephrotoxicity as a side effect. To investigate the mechanisms by which paeonol, a natural phenolic compound, can protect against MTX-induced nephrotoxicity, paeonol (100 mg/kg/day orally) was given to rats for 10 days, with or without MTX (20 mg/kg once i.p. at day 5). Compared to control, MTX caused nephrotoxic effects manifested by increased serum urea and creatinine and distortion in renal histological architecture, with a significant increase in the mean glomerular diameter and upregulation of kidney injury molecule-1. MTX caused oxidative stress manifested by decreasing reduced glutathione and superoxide dismutase while increasing malondialdehyde and nitric oxide. MTX also induced renal inflammation by upregulating TLR4, NF-κB, and IL-1β and caused apoptosis by induction of caspase 3. Administering paeonol with MTX improved kidney functional and structural parameters, as well as all oxidative, inflammatory, and apoptotic markers tested. Interestingly, both MTX and paeonol increased the expression of the renal efflux transporter P-glycoprotein (P-gp) that helps in MTX elimination, and their drug combination further upregulated renal P-gp. In silico, paeonol was neither a substrate nor an inhibitor of P-gp, suggesting that its effect on P-gp is not on functional but on the expression level. In vitro, paeonol and MTX were administered to colon cancer cells and their combination caused a progressive cellular cytotoxic effect, which was dose-dependent with the increase of paeonol concentration. In conclusion, paeonol protects against MTX-induced nephrotoxicity through antioxidant, anti-inflammatory, and antiapoptotic mechanisms and might potentiate MTX chemotherapeutic efficacy.

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Section: Discussionsupporting

confidence: 70%

Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway

et al. 2022

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“…It results in a mortality rate of approximately 30%, 32,33 and its costs account for approximately 3−7% of total national health care expenditures. 34,35 Stroke is a multifactorial and complex pathophysiological process. The specific pathogenesis is not clear, and the available drugs are not ideal.…”

Section: ■ Discussionmentioning

confidence: 99%

UPLC-Q-TOF/MS-Based Serum Metabolomics Reveals the Anti-Ischemic Stroke Mechanism of Nuciferine in MCAO Rats

Chang

et al. 2020

ACS Omega

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Nuciferine is an aporphine alkaloid monomer that is extracted from the leaves of the lotus species Nymphaea caerulea and Nelumbo nucifera Gaertn. Nuciferine was reported to treat cerebrovascular diseases. However, the potential mechanism of the neuroprotective effects of nuciferine at the metabolomics level is still not unclear. The present research used neurological score, infarct volume, cerebral water content, and ultraperformance liquid chromatography to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based serum metabolomics to elucidate the anti-ischemic stroke effect and mechanisms of nuciferine. The results showed that nuciferine significantly improved neurological deficit scores and ameliorated cerebral edema and infarction. Multivariate data analysis methods were used to examine the differences in serum endogenous metabolism between groups, and the biomarkers of nuciferine on ischemic stroke were identified. Approximately 19 metabolites and 7 metabolic pathways associated with nuciferine on treatment of stroke were found, which indicated that nuciferine exerted a positive therapeutic action on cerebral ischemic by regulating metabolism. These results provided some data support for the study of anti-stroke effect of nuciferine from the perspective of metabolomics.

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“…They observed a significant elevation of all these factors and suggested the presence of brain inflammation with BBB disruption even after a single seizure. It is worth mentioning that HMGB1 might be involved in P-glycoprotein expression during status epilepticus, which is related to drug resistance [ 117 , 118 ].…”

Section: Epilepsy and Bbb Disruptionmentioning

confidence: 99%

High Mobility Group Box-1 and Blood–Brain Barrier Disruption

Nishibori

Wang

Ousaka

et al. 2020

Cells

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Increasing evidence suggests that inflammatory responses are involved in the progression of brain injuries induced by a diverse range of insults, including ischemia, hemorrhage, trauma, epilepsy, and degenerative diseases. During the processes of inflammation, disruption of the blood–brain barrier (BBB) may play a critical role in the enhancement of inflammatory responses and may initiate brain damage because the BBB constitutes an interface between the brain parenchyma and the bloodstream containing blood cells and plasma. The BBB has a distinct structure compared with those in peripheral tissues: it is composed of vascular endothelial cells with tight junctions, numerous pericytes surrounding endothelial cells, astrocytic endfeet, and a basement membrane structure. Under physiological conditions, the BBB should function as an important element in the neurovascular unit (NVU). High mobility group box-1 (HMGB1), a nonhistone nuclear protein, is ubiquitously expressed in almost all kinds of cells. HMGB1 plays important roles in the maintenance of chromatin structure, the regulation of transcription activity, and DNA repair in nuclei. On the other hand, HMGB1 is considered to be a representative damage-associated molecular pattern (DAMP) because it is translocated and released extracellularly from different types of brain cells, including neurons and glia, contributing to the pathophysiology of many diseases in the central nervous system (CNS). The regulation of HMGB1 release or the neutralization of extracellular HMGB1 produces beneficial effects on brain injuries induced by ischemia, hemorrhage, trauma, epilepsy, and Alzheimer’s amyloidpathy in animal models and is associated with improvement of the neurological symptoms. In the present review, we focus on the dynamics of HMGB1 translocation in different disease conditions in the CNS and discuss the functional roles of extracellular HMGB1 in BBB disruption and brain inflammation. There might be common as well as distinct inflammatory processes for each CNS disease. This review will provide novel insights toward an improved understanding of a common pathophysiological process of CNS diseases, namely, BBB disruption mediated by HMGB1. It is proposed that HMGB1 might be an excellent target for the treatment of CNS diseases with BBB disruption.

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HMGB1 promoted P-glycoprotein at the blood-brain barrier in MCAO rats via TLR4/NF-κB signaling pathway

Cited by 19 publications

References 37 publications

Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway

Paeonol Protects Against Methotrexate-Induced Nephrotoxicity via Upregulation of P-gp Expression and Inhibition of TLR4/NF-κB Pathway

UPLC-Q-TOF/MS-Based Serum Metabolomics Reveals the Anti-Ischemic Stroke Mechanism of Nuciferine in MCAO Rats

High Mobility Group Box-1 and Blood–Brain Barrier Disruption

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