Botanical Drug Puerarin Coordinates with Nerve Growth Factor in the Regulation of Neuronal Survival and Neuritogenesis via Activating <scp>ERK</scp>1/2 and <scp>PI</scp>3K/Akt Signaling Pathways in the Neurite Extension Process

Zhao, Jia; Cheng, Yuan; Fan, Wen; Yang, Chuanbin; Ye, Shui Fen; Cui, Wei; Wei, Wei; Lao, Lixing; Cai, Jing; Han, Yifan; Rong, Jianhui

doi:10.1111/cns.12334

Cited by 55 publications

(54 citation statements)

References 55 publications

(62 reference statements)

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“…Oxidative stressors and some anti-inflammatory electrophilic drugs disrupt Keap1-Nrf2 complex, promote the nuclear translocation of Nrf2 and finally activate the transcription of antioxidant genes including HO-1 [42]. We have previously identified several botanicals (e.g., Z-ligustilide, senkyunolide H, senkyunolide I, puerarin, PACA) for activating the Nrf2-Keap1 pathway and inducing HO-1 expression [18][19][20]43]. In the present study, therefore, we hypothesized that PACA might regulate iNOS induction and macrophage M2 polarization via activating Nrf2/HO-1 pathway.…”

Section: Discussionmentioning

confidence: 99%

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N-Propargyl Caffeamide Skews Macrophages Towards a Resolving M2-Like Phenotype Against Myocardial Ischemic Injury via Activating Nrf2/HO-1 Pathway and Inhibiting NF-ĸB Pathway

Cheng

Yang

Luo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Macrophages exhibit dynamic pro-inflammatory and resolving activities in myocardial infarction. The present study investigated whether caffeic acid derivatives could induce macrophage polarization towards a resolving M2 phenotype against myocardial infarction injury. Methods: Western blotting, RT-PCR and flow cytometry techniques are used to evaluate macrophage biomarkers expression and specific proteins in the related signaling pathways. Ligation of the left anterior descending artery induced rat model of myocardial infarction, TTC staining and immunohistochemical staining are used to examine cardioprotective effect in vivo. Results: We initially evaluated the anti-inflammatory activity of four caffeic acid derivatives including n-propargyl caffeamide (PACA) in RAW264.7 macrophages. As result, PACA selectively suppressed the up-regulation of inducible nitric oxide synthase (iNOS) over cyclooxygenase-2 (COX-2) in lipopolysaccharides (LPS)-stimulated cells. We subsequently examined the effects of PACA on macrophage polarization by determining macrophage biomarkers. PACA down-regulated M1 biomarkers (e.g., iNOS, tumor necrosis factor-α (TNF-α), C-X-C motif chemokine 10 (CXCL10) and CD80) but up-regulated M2 biomarkers (e.g., Ym-1 and arginase-1). On the other hand, PACA suppressed macrophage chemotaxis while enhanced macrophage phagocytosis. We further examined the in vivo cardioprotective activity of PACA in a rat model of myocardial infarction. Following ligation of the left anterior descending artery, PACA treatment effectively reduced myocardial infarct size and promoted macrophage M2 polarization. We finally explored the underlying mechanisms. We found that PACA attenuated LPS-induced NF-ĸB activation while activated Nrf2/HO-1 pathway. HO-1 inhibitor SnPP attenuated the effects of PACA on iNOS expression in LPS-challenged macrophages, possibly by regulating the cross-talk between HO-1 and NF-ĸB pathways. Conclusions: The key finding from the present study was that PACA promoted timely switch of macrophage phenotypes from pro-inflammatory M1 to resolving M2. We anticipate that PACA is a potential drug candidate for the resolution of inflammation and cardiac repair after myocardial infarction.

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Section: Discussionmentioning

confidence: 99%

“…By mimicking HO-1 activation, CO-releasing molecules (CORMs) was recently evaluated for anti-inflammatory potential in different in vitro and in vivo models [17]. Along this line, we attempted to demonstrate the pharmacological activation of HO-1 pathway as a new anti-inflammatory strategy [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

N-Propargyl Caffeamide Skews Macrophages Towards a Resolving M2-Like Phenotype Against Myocardial Ischemic Injury via Activating Nrf2/HO-1 Pathway and Inhibiting NF-ĸB Pathway

Cheng

Yang

Luo

et al. 2018

Cell Physiol Biochem

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“…In SCI model, activation of the PI3K/Akt has also been demonstrated to mediate recovery of motor function [46]. Numerous bioactivities of puerarin were mediated through regulating the PI3K/Akt signaling pathway, including protection of pancreatic β-cell [47], prevention of osteoporosis [48], attenuation of hepatic fibrosis [49], alleviation of cardiac hypertrophy [50], as well as neuroprotection [51][52][53]. Interestingly, the majority of studies demonstrated that puerarin exerted bioactivities via activating the PI3K/Akt pathway, whereas some of the studies reported that the therapeutic effects of puerarin were mediated via blocking PI3K/Akt [49,50].…”

Section: Discussionmentioning

confidence: 99%

The Neuroprotective Effect of Puerarin in Acute Spinal Cord Injury Rats

Zhang

Hou

et al. 2016

Cell Physiol Biochem

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Background: Acute spinal cord injury (SCI) leads to permanent disabilities. This study evaluated the neuroprotective effect of puerarin, a natural extract, in a rat model of SCI. Methods: Acute SCI models were established in rats using a modified Allen's method. Locomotor function was evaluated using the BBB test. The histological changes in the spinal cord were observed by H&E staining. Neuron survival and glial cells activation were evaluated by immunostaining. ELISA and realtime PCR were used to measure secretion and gene expression of cytokines. TUNEL staining was used to examine cell apoptosis and western blot analysis was used to detect protein expression. Results: Puerarin significantly increased BBB score in SCI rats, attenuated histological injury of spinal cord, decreased neuron loss, inhibited glial cells activation, alleviated inflammation, and inhibited cell apoptosis in the injured spinal cords. In addition, the downregulated PI3K and phospho-Akt protein expression were restored by puerarin. Conclusion: Puerarin accelerated locomotor function recovery and tissue repair of SCI rats, which is associated with its neuroprotection, glial cell activation suppression, anti-inflammatory and anti-apoptosis effects. These effects may be associated with the activation of PI3K/Akt signaling pathway.

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“…Rat pheochromocytoma PC12 cell line was purchased from American Type Culture Collection (Manassas, VA, USA) and maintained as described [24,26]. To induce neuronal differentiation, PC12 cells were treated with puerarin (50 μM) or NGF (20 ng/ml) as positive control in the differentiation medium (DMEM+1 % HS+0.5 % FBS) for 3 days, whereas an equal volume of DMSO in the differentiation medium was added to control cultures.…”

Section: Pc12 Cell Culturementioning

confidence: 99%

Botanical Drug Puerarin Attenuates 6-Hydroxydopamine (6-OHDA)-Induced Neurotoxicity via Upregulating Mitochondrial Enzyme Arginase-2

et al. 2015

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Inhibition of nitric oxide synthases (NOSs) shows promise to halt the progression of neurodegenerative diseases. The present study was designed to explore whether botanical isoflavone puerarin could attenuate nitric oxide (NO)-mediated neurotoxicity via modulating the enzymes in the L-arginine-NO pathway. Neurotoxin 6-hydroxydopamine (6-OHDA) is well known to induce neurodegeneration via a NO-dependent mechanism. We first validated that puerarin protected rat dopamingeric PC12 cells against 6-OHDA-induced neurotoxicity in a concentration-dependent manner. We subsequently profiled the cellular responses to puerarin by a proteomic response fingerprinting approach. A total of 16 protein spots with >1.5-fold change of intensity were selected and identified by mass spectrometry. As one of puerarin-upregulated proteins, mitochondrial arginase-2 hydrolyzes L-arginine to L-ornithine, thereby competing with neuronal NOS for substrate L-arginine in mitochondria. Thus, we hypothesize that puerain may attenuate nitric oxide (NO)-mediated mitochondrial injury via increasing arginase-2 expression. Western blot and reverse transcription polymerase chain reaction (RT-PCR) analyses confirmed that puerarin increased arginase-2 expression in a concentration- and time-dependent manner. Accordingly, puerarin suppressed 6-OHDA-induced NO production and neurotoxicity in PC12 cells and primary rat midbrain neurons. Arginase inhibitor BEC diminished the effect of puerarin on 6-OHDA-induced NO production and neurotoxicity. The activation of arginase-2 by puerarin represents an endogenous mechanism for specific control of NO-mediated mitochondrial damage. Thus, puerarin is a useful lead for suppressing NO-mediated neurotoxicity in neurodegenerative diseases. Graphical Abstract Arginase-2 dependent mechanism underlying the neuroprotective activity of puerarin.

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Botanical Drug Puerarin Coordinates with Nerve Growth Factor in the Regulation of Neuronal Survival and Neuritogenesis via Activating ERK1/2 and PI3K/Akt Signaling Pathways in the Neurite Extension Process

Abstract: Puerarin effectively coordinated with NGF to stimulate neuritogenesis via activating ERK1/2 and PI3K/Akt pathways in neurite extension process. These results demonstrated a general mechanism supporting the therapeutic application of puerarin-related compounds in neurodegenerative diseases.

Cited by 55 publications

References 55 publications

N-Propargyl Caffeamide Skews Macrophages Towards a Resolving M2-Like Phenotype Against Myocardial Ischemic Injury via Activating Nrf2/HO-1 Pathway and Inhibiting NF-ĸB Pathway

N-Propargyl Caffeamide Skews Macrophages Towards a Resolving M2-Like Phenotype Against Myocardial Ischemic Injury via Activating Nrf2/HO-1 Pathway and Inhibiting NF-ĸB Pathway

The Neuroprotective Effect of Puerarin in Acute Spinal Cord Injury Rats

Botanical Drug Puerarin Attenuates 6-Hydroxydopamine (6-OHDA)-Induced Neurotoxicity via Upregulating Mitochondrial Enzyme Arginase-2

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