Xinbing Wei

University of Jinan (Jinan, China), Chi-nan-shih, Shandong Sheng, China

Are you Xinbing Wei?

Claim your profile

Publications (40)156.02 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Ligustrazine is the most abundant and bioactive ingredient in Rhizoma Chuanxiong, a Chinese medicinal herb commonly used for the treatment of cardiovascular diseases. Chf197 is one of structurally modified Ligustrazine derivatives in a purpose of overcoming the rapid metabolism and short half-life of original. The plasma and urine pharmacokinetics of Chf197 in rats were studied after intravenous or intraperitoneal injection of Chf197 with the validated RP-HPLC method. The pharmacokinetic parameters of Chf197 injected intravenously 20 mg·kg(-1) were as follows, Cmax , 1.44±0.4mg/L, Tmax , 0.08h, t1/2 , 3.03±1.67h, AUC,3.85±3.88h/L, Vd ,31.66±11.79L/kg, CL,9.29±4.92l/h/kg. Dose-dependent pharmacokinetics were observed, and a significantly higher dose-normalized AUC after intravenous administration was obtained than that after intraperitoneal administration. A possible metabolite was detected at about 3.1min, and full scan mass spectrum was adopted to predict its possible structure. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Fundamental and Clinical Pharmacology 07/2015; DOI:10.1111/fcp.12133 · 2.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). Eriodictyol, a flavonoid isolated from the Chinese herb Dracocephalum rupestre, has long been established as an antioxidant. The present study was designed to investigate the effect of eriodictyol on β-amyloid 25-35 peptide (Aβ25-35)-induced oxidative cell death in primary neurons and to explore the role of the nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway in this process. For this purpose, primary cultures of cortical neurons were exposed to 15 μM Aβ25-35 in the absence or presence of eriodictyol (20, 40 and 80 μM). The results revealed that Aβ25-35-induced cytotoxicity and apoptotic characteristics such as activation of JNK/p38 apoptotic signaling pathway were effectively attenuated by eriodictyol pretreatment. Eriodictyol treatment also resulted in an increase in Nrf2 protein levels and subsequent activation of ARE pathway genes in primary cultured neurons. The protective effects of eriodictyol were attenuated by RNA interference-mediated knockdown of Nrf2 expression. Taken together, these results clearly demonstrate that eriodictyol protects neurons against Aβ25-35-induced cell death partially through Nrf2/ARE signaling pathway, which further supports that eriodictyol might be a promising novel therapeutic agent for AD.
    Neurochemical Research 05/2015; DOI:10.1007/s11064-015-1616-z · 2.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although recent studies have highlighted the importance of innate pattern-recognition receptors (PRRs) in the pathogenesis of cardiovascular diseases by mediating inflammatory responses, their molecular mechanisms of PRRs in cardiovascular diseases are still largely unknown. The present study was designed to explore the contribution of NOD2, an intracellular PRR, to the pathogenesis of myocardial ischemia/reperfusion (I/R) injury. We found that NOD2 was upregulated in ischemic myocardium and NOD2 deficiency ameliorated cardiac injury in myocardial I/R mice accompanied by the decreased levels of pro-inflammatory mediators and cardiac inflammatory cell infiltration. We further found that TIPE2, a recently identified immune regulator, was negatively mediated by NOD2. In vitro, we demonstrated that TIPE2 inhibited NOD2-induced activation of MAPK and NF-κB signaling pathways, thereby reducing the production of pro-inflammatory cytokines in macrophages. Finally, in vivo gene silencing of TIPE2 by lentiviral gene delivery counteracted the reduced inflammation and myocardial injury in NOD2-deficient ischemic mice. Collectively, this study for the first time demonstrates that TIPE2 serves as a negative regulator of immunity, at least in part, by NOD2-mediated inflammatory responses in I/R-induced myocardial injury. A better understanding of NOD2-TIPE2 signaling pathways will provide unexpected opportunities for developing new therapies for ischemic cardiovascular disease. NOD2 deficiency ameliorates myocardial ischemia reperfusion injury. NOD2 deficiency reduces the inflammatory response after myocardial I/R. TIPE2 inhibits NOD2-induced activation of MAPK and NF-κB signaling pathways. TIPE2 silencing counteracts the reduced inflammation and myocardial injury in NOD2(-/-) ischemic mice. TIPE2 acts as a negative regulator linking NOD2 and inflammatory responses.
    Journal of Molecular Medicine 04/2015; DOI:10.1007/s00109-015-1288-9 · 4.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Progranulin (PGRN), an autocrine growth factor, has multiple physiological functions and is widely involved in the pathogenesis of many types of diseases. The pivotal anti-inflammatory function of PGRN in rheumatoid arthritis encouraged us to examine the role of PGRN in acute kidney injury (AKI). We found that levels of PGRN were significantly reduced in the kidney in a mouse model of renal ischemia/reperfusion injury. We also observed that PGRN deficiency (Grn(-/-) mice) significantly aggravated renal injury as evidenced by higher serum creatinine, more severe morphological injury, increased tubular epithelial cell death, and tubulointerstitial neutrophil and macrophage infiltration versus wild-type mice. In vitro, we found that recombinant human PGRN attenuated hypoxia-induced inflammatory actions and apoptosis in proximal tubule epithelial cells, at least in part associated with a nucleotide-binding oligomerization domain containing 2 (NOD2)-mediated immune response. Importantly, pretreatment with or delayed administration of recombinant human PGRN protected against or promoted recovery from renal ischemia/reperfusion injury in wild-type and Grn(-/-) mice. Similar protective effects were also found in cisplatin-induced AKI. Thus, our findings provide a better understanding of the biological activities of PGRN in the kidney and suggest that PGRN may be an innovative therapeutic strategy for treating patients with AKI.Kidney International advance online publication, 21 January 2015; doi:10.1038/ki.2014.403.
    Kidney International 01/2015; 87(5). DOI:10.1038/ki.2014.403 · 8.52 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidences suggest that innate immunity is involved in cerebral ischemia-reperfusion (I/R) injury, but the liable innate immune receptors have not been completely elucidated. Here, we explored the role of the nucleotide-binding oligomerization domain (NOD)2, a member of the cytosolic NOD-like receptor family, in acute focal cerebral I/R injury. An in vivo middle cerebral artery occlusion (MCAO) model that in wild type (WT) and NOD2 deficient (NOD2(-/-)) mice and in vitro model of oxygen glucose deprivation and reoxygenation (OGD/R) in cultured primary microglia and astrocytes were used to investigate the expression of NOD2 and explore the roles of NOD2 in ischemic stroke. Our results showed that NOD2 expression was significantly increased in microglia and astrocytes in response to the I/R insult. Pretreatment with muramyl dipeptide, an extrinsic ligand of NOD2, significantly increased the infarct volume and neurological dysfunction in mice subjected to MCAO. Genetic ablation of the NOD2 gene significantly improved stroke outcomes and reduced inflammation, as evidenced by a lower expression of the pro-inflammatory cytokines IL-1β, IL-6 and TNFα in conjunction with attenuated activation of nuclear factor κB (NF-κB), p38 mitogen activated protein kinases (MAPK) and JNK. Moreover, NOD2 deficiency prevented the upregulation of the NADPH oxidase (NOX) 2 and ROS generation induced by I/R. Mechanistically, NOD2-induced production of IL-6 in primary cultured microglia was mediated through activation of NOX2. This study showed the contribution of NOD2 to inflammatory response and provided direct evidence that NOX2-mediated oxidative stress as an important target molecule linked NOD2 to inflammatory damage in ischemic stroke. Pharmacological targeting of NOD2-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.
    International journal of biological sciences 01/2015; 11(5):525-35. DOI:10.7150/ijbs.10927 · 4.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although our recent studies have demonstrated that NOD2 is one of critical components of a signal transduction pathway that links renal injury to inflammation in diabetic nephropathy (DN), the regulatory mechanisms for NOD2 expression under hyperglycemia have not yet been elucidated. Considering that NOD2 mRNA from different species bearing long 3'-UTR with various AU-rich elements (AREs), the present study was designed to investigate the potential contribution of the RNA binding protein human antigen R (HuR) on the posttranscriptional regulation of NOD2 expression. In this study, we firstly found that the up-regulation of HuR in the kidney from DN subjects, which was correlated with proteinuria, indicating the role of HuR in the pathogenesis of DN. In vitro, high glucose (HG) induced a distinct increase in cytoplasmic HuR in rat glomerular mesangial cells (RMCs). By RNA-EMSA analysis, we found that HuR bind to the 3'-UTR NOD2, while HuR silencing reduced HG-induced NOD2 expression and mRNA stability. Mechanistically, we further found that NADPH oxidase-mediated redox signaling contributed to the expression and translocation of HuR and NOD2 mRNA stability. Finally, we evaluated the role of HuR showing that in vivo gene silencing of HuR by intrarenal lentiviral gene delivery ameliorated renal injury as well as reduced NOD2 expression in diabetic rats. Collectively, our studies demonstrate that HuR acts as a key posttranscriptional regulator of NOD2 expression, suggesting that targeting of HuR-NOD2 signaling might be crucial for the treatment of DN. Copyright © 2014. Published by Elsevier Inc.
    Free Radical Biology and Medicine 12/2014; 79. DOI:10.1016/j.freeradbiomed.2014.12.013 · 5.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress is central to the pathology of several neurodegenerative diseases, including Parkinson's disease (PD), and therapeutics designed to enhance antioxidant potential could have clinical value. In this study, we investigated whether dimethyl fumarate (DMF) has therapeutic effects in cellular and animal model of PD, and explore the role of nuclear transcription factor related to NF-E2(Nrf2) in this process. Treatment of animals and dopaminergic SH-SY5Y cells with DMF resulted in increased nuclear levels of active Nrf2, with subsequent upregulation of antioxidant target genes. The cytotoxicity of 6-hydroxydopamine (6-OHDA) was reduced by pre-treatment with DMF in SH-SY5Y cells. The increase in the reactive oxygen species caused by 6-OHDA treatment was also attenuated by DMF in SH-SY5Y cells. The neuroprotective effects of DMF against 6-OHDA neurotoxicity was dependent on Nrf2, since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity and induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells. In vivo, DMF oral administration was shown to upregulate mRNA and protein levels of Nrf2 and Nrf2-regulated cytoprotective genes, attenuate 6-OHDA induced striatal oxidative stress and inflammation. Moreover, DMF ameliorated dopaminergic neurotoxicity in 6-OHDA-induced PD animal models as evidenced by amelioration of locomotor dysfunction, loss in striatal dopamine, and reductions in dopaminergic neurons in substantia nigra and striatum. Taken together, these data strongly suggest that DMF may be beneficial for the treatment of neurodegenerative diseases like PD. Copyright © 2014. Published by Elsevier Ltd.
    Neuroscience 11/2014; 286. DOI:10.1016/j.neuroscience.2014.11.047 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A novel tetramethylpyrazine derivative, CXC195, has been recently shown to protect against cerebral ischemia-reperfusion (I/R) injury. However, the detailed mechanisms underlying the neuroprotection of CXC195 are still unclear. The aim of the present study was to investigate the effects of CXC195 on the phosphorylation of endothelial nitric oxide synthase (eNOS) in response to cerebral I/R and to determine whether phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway might be involved. An in vitro model of oxygen glucose deprivation (OGD) which was performed on primary cultured human aortic endothelial cells (HAECs) and an in vivo middle cerebral artery occlusion (MCAO) model that was performed on Wistar rats were used in this study. CXC195 increased nitric oxide (NO) production and the phosphorylation but not the protein level of eNOS in HAECs subjected to 1 h OGD followed by reperfusion. In addition, CXC195 increased the phosphorylation of Akt; inhibition of PI3K/Akt pathway by a specific inhibitor, wortmannin, suppressed CXC195-induced NO release in HAECs. Consistently, CXC195 treatment significantly restored the phosphorylations of eNOS and Akt in the cortical penumbra of rats subjected to 2 h MCAO followed by reperfusion. Moreover, wortmannin abolished CXC195-induced eNOS phosphorylation and neuroprotection as evidenced by a reversal of the reduction in infarct volume and neurobehavioral outcomes. In conclusion, CXC195 induced phosphorylation of eNOS by activation of PI3K/Akt signaling under pathological cerebral I/R conditions, which provided a novel explanation for the neuroprotective effect of CXC195.
    Neurochemical Research 11/2014; 40(3). DOI:10.1007/s11064-014-1485-x · 2.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Stroke is a devastating clinical condition for which an effective neuroprotective treatment is currently unavailable. S-allyl cysteine (SAC), the most abundant organosulfur compound in aged garlic extract, has been reported to possess neuroprotective effects against stroke. However, the mechanisms underlying its beneficial effects remain poorly defined. The present study tests the hypothesis that SAC attenuates ischemic neuronal injury by activating the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response in both in vitro and in vivo models. Our findings demonstrate that SAC treatment resulted in an increase in Nrf2 protein levels and subsequent activation of antioxidant response element (ARE) pathway genes in primary cultured neurons and mice. Exposure of primary neurons to SAC provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insults. In wild type (Nrf2(+/+) ) mice, systemic administration of SAC attenuated middle cerebral artery occlusion (MCAO)-induced ischemic damage, a protective effect not observed in Nrf2 knockout (Nrf2(-/-) ) mice. Taken together, these findings provide the first evidence that activation of the Nrf2 antioxidant response by SAC is strongly associated with its neuroprotective effects against experimental stroke and suggest that targeting the Nrf2 pathway may provide therapeutic benefit for the treatment of stroke. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 11/2014; 133(2). DOI:10.1111/jnc.12986 · 4.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Acetylpuerarin (AP), because of its lower water solubility, shows poor absorption that hinders its therapeutic application. Thus, the aim of this study was to prepare nanoemulsions for AP, enhance its oral bioavailability, and thus improve the therapeutic effect. Methods The nanoemulsions stabilized by D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared by high-pressure homogenization and characterized in terms of particle size, drug loading, morphology, and in vitro drug release. A lipid digestion model was used to predict in vivo drug solubilization in the gastrointestinal environment. The pharmacokinetics of AP formulations were performed in rats; meanwhile, a chylomicron flow-blocking rat model was used to evaluate the lymphatic drug transport. Moreover, the therapeutic effects of AP nanoemulsions on the model of focal cerebral ischemia-reperfusion for brain injury were also assessed. Results The nanoemulsions with a droplet size of 150 nm were well stabilized by TPGS and showed a high loading capacity for AP. In the digestion model, the distribution of AP in aqueous phase/pellet phase was about 90%/10% for nanoemulsions and 5%/95% for oil solution, indicating that the drug encapsulated in nanoemulsions would present in solubilized form after transportation into the gastrointestinal tract, whereas drug precipitation would occur as the oil solution was orally administered. The area under the curve value of AP nanoemulsions was 5.76±0.56 μg·hour·mL−1, or was about 2.6 and 1.7 times as great as that of suspension and oil solution, respectively, indicating enhanced drug absorption and thus achieving a better neuroprotection effect on cerebral ischemic reperfusion injury. The values of peak plasma concentration and area under the curve from the blocking model were significantly less than those of the control model, suggesting that the lymphatic transport performed a very important role in absorption enhancement. Conclusion Enhanced oral bioavailability in nanoemulsions was achieved via the mechanism of the maintenance of drug solubilization in the gastrointestinal tract and the enhancement of lymphatic transport, which resulted in therapeutic improvement of cerebral ischemic reperfusion injury.
    International Journal of Nanomedicine 07/2014; 9:3413-23. DOI:10.2147/IJN.S63777 · 4.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Studies have highlighted the importance of histone deacetylase (HDAC)-mediated epigenetic processes in the development of diabetic complications. Inhibitors of HDAC are a novel class of therapeutic agents in diabetic nephropathy, but currently available inhibitors are mostly nonselective inhibit multiple HDACs, and different HDACs serve very distinct functions. Therefore, it is essential to determine the role of individual HDACs in diabetic nephropathy and develop HDAC inhibitors with improved specificity. First, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC2/4/5 were upregulated in the kidney from streptozotocin-induced diabetic rats, diabetic db/db mice, and in kidney biopsies from diabetic patients. Podocytes treated with high glucose, advanced glycation end products, or transforming growth factor-β (common detrimental factors in diabetic nephropathy) selectively increased HDAC4 expression. The role of HDAC4 was evaluated by in vivo gene silencing by intrarenal lentiviral gene delivery and found to reduce renal injury in diabetic rats. Podocyte injury was associated with suppressing autophagy and exacerbating inflammation by HDAC4-STAT1 signaling in vitro. Thus, HDAC4 contributes to podocyte injury and is one of critical components of a signal transduction pathway that links renal injury to autophagy in diabetic nephropathy.Kidney International advance online publication, 9 April 2014; doi:10.1038/ki.2014.111.
    Kidney International 04/2014; 86(4). DOI:10.1038/ki.2014.111 · 8.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: CXC195 showed strongest protective effects among the ligustrazine derivatives in cells and prevented apoptosis induced by H2O2 injury. We recently demonstrated that CXC195 protected against cerebral ischemia/reperfusion (I/R) injury by its antioxidant activity. However, whether the anti-apoptotic action of CXC195 is involved in cerebral I/R injury is unknown. Here, we investigated the role of CXC195 in apoptotic processes induced by cerebral I/R and the possible signaling pathways. Male Wistar rats were submitted to transient middle cerebral artery occlusion for 2 h, followed by 24 h reperfusion. CXC195 was injected intraperitoneally at 2 h and 12 h after the onset of ischemia. The number of apoptotic cells was measured by TUNEL assay, apoptosis-related protein cleaved caspase-3, Bcl-2, Bax and the phosphorylation levels of Akt and GSK3β in ischemic penumbra were assayed by western blot. The results showed that administration of CXC195 at the doses of 3 mg/kg and 10 mg/kg significantly inhibited the apoptosis by decreasing the number of apoptotic cells, decreasing the level of cleaved caspase-3 and Bax, and increasing the level of Bcl-2 in rats subjected to I/R injury. Simultaneously, CXC195 treatment markedly increased the phosphorylation of Akt and GSK3β. Blockade of PI3K activity by wortmannin, dramatically abolished its anti-apoptotic effect and lowered both Akt and GSK3β phosphorylation levels. Our study firstly demonstrated that CXC195 protected against cerebral I/R injury by reducing apoptosis in vivo and PI3K/Akt/GSK3β pathway involved in the anti-apoptotic effect.
    Neurochemistry International 01/2014; 66(1). DOI:10.1016/j.neuint.2014.01.006 · 2.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3(-/-), NOX2(-/-), or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood-brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1β (IL-1β) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.Journal of Cerebral Blood Flow & Metabolism advance online publication, 15 January 2014; doi:10.1038/jcbfm.2013.242.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2014; 34(4). DOI:10.1038/jcbfm.2013.242 · 5.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background/Aims: Although the pathogenesis of myocardial infarction (MI) is multifactorial, activation of innate immune system to induce inflammation has emerged as a key pathophysiological process in MI. NOD2, one member of the NOD-like receptor (NLR) family, plays an important role in the innate immune response. This study was to examine the role of NOD2 during MI. Methods: MI was induced by permanent ligation of the left coronary artery in wild type and NOD2(-/-) mice and cardiac fibroblasts were isolated. Results: NOD2 expression was significantly increased in myocardium in post-MI mice. NOD2 deficiency improved cardiac dysfunction and remodeling after MI as evidenced by echocardiographic analysis, reduced the levels of cytokines, inflammatory cell infiltration and matrix metalloproteinase-9 (MMP-9) activity. In vitro, we further found that NOD2 activation induced the activation of MAPK signaling pathways, production of proinflammatory mediators and MMP-9 activity in cardiac fibroblasts. Conclusions: Our studies demonstrate that NOD2 is a critical component of a signal transduction pathway that links cardiac injury by exacerbation of inflammation and MMP-9 activity. Pharmacological targeting of NOD2-mediated signaling pathways may provide a novel approach to treatment of cardiovascular diseases. © 2014 S. Karger AG, Basel.
    Cellular Physiology and Biochemistry 12/2013; 32(6):1857-1866. DOI:10.1159/000356618 · 3.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Stroke is a complex disease that may involve oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and thus has been considered a potential target for neuroprotection in stroke. The aim of the present study was to determine whether eriodictyol-7-O-glucoside (E7G), a novel Nrf2 activator, can protect against cerebral ischemic injury and to understand the role of the Nrf2/ARE pathway in neuroprotection. In primary cultured astrocytes, E7G increased the nuclear localization of Nrf2 and induced the expression of the Nrf2/ARE-dependent genes. Exposure of astrocytes to E7G provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. The protective effect of E7G was abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo administration of E7G in a rat model of focal cerebral ischemia significantly reduced the amount of brain damage and ameliorated neurological deficits. These data demonstrate that activation of Nrf2/ARE signaling by E7G is directly associated with its neuroprotection against oxidative stress-induced ischemic injury and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in stroke.
    Toxicology and Applied Pharmacology 12/2013; 273(3):672-9. DOI:10.1016/j.taap.2013.10.018 · 3.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: There is increasing evidence that oxidative stress is critically involved in the pathogenesis of Parkinson's disease (PD), suggesting that pharmacological targeting of the antioxidant machinery may have therapeutic value. Naringenin, a natural flavonoid compound, has been reported to possess neuroprotective effect against PD related pathology; however the mechanisms underlying its beneficial effects are poorly defined. Thus, the purpose of the present study was to investigate the potential neuroprotective role of naringenin and to delineate its mechanism of action against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in models of PD both in vitro and in vivo. Naringenin treatment resulted in an increase in nuclear factor E2-related factor 2 (Nrf2) protein levels and subsequent activation of antioxidant response element (ARE) pathway genes in SH-SY5Y cells and in mice. Exposure of SH-SY5Y cells to naringenin provided protection against 6-OHDA-induced oxidative insults that was dependent on Nrf2, since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity or induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells. In mice, oral administration of naringenin resulted in significant protection against 6-OHDA-induced nigrostriatal dopaminergic neurodegeneration and oxidative damage. Our results indicate that activation of Nrf2/ARE signaling by naringenin is strongly associated with its neuroprotective effects against 6-OHDA neurotoxicity and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in PD.
    Neuropharmacology 12/2013; 79. DOI:10.1016/j.neuropharm.2013.11.026 · 4.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammation is involved in various central nervous system (CNS) disorders, including brain infections, ischemia, trauma, stroke, and degenerative CNS diseases. In the CNS inflammation, secretory phospholipase A2-IIA (sPLA2-IIA) acts as a mediator, resulting in the generation of the precursors of pro-inflammatory lipid mediators, such as prostaglandins (PGs) and leukotrienes (LTs). However, the role of sPLA2-IIA in neuroinflammation is more complicated and remains unclear yet. In the present study, we investigated the effect of sPLA2-IIA inhibition by specific inhibitor SC-215 on the inflammation in LPS-induced mice cerebral cortex and primary astrocytes. Our results showed that the inhibition of sPLA2-IIA alleviated the release of PGE2 by suppressing the activation of ERK1/2, cPLA2α, COX-2 and mPGES-1. These findings demonstrated that sPLA2-IIA showed the potential to regulate the neuroinflammation in vivo and in vitro, indicating that sPLA2-IIA might be a novel target for the treatment of acute neuroinflammation.
    PLoS ONE 10/2013; 8(10):e77909. DOI:10.1371/journal.pone.0077909 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims: This study was conducted to investigate the protective effects of CXC195, a tetramethylpyrazine analogue, in acute focal cerebral ischemia/reperfusion (I/R) injury in rats and to elucidate the potential mechanism. Methods: Middle cerebral artery occlusion for 2 h followed by reperfusion for 24 h was conducted in male Wistar rats and different doses of tetramethylpyrazine and CXC195 were intraperitoneally injected at 30 min after reperfusion. Results: Our results demonstrated that CXC195 at the dosage of 3 and 10 mg/kg significantly reduced the neurological deficit score and the infarct volume compared to the vehicle-treated group. In addition, CXC195 exhibited a protective effect against hippocampus neuronal cell death and significantly restored the brain ATP content. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and total antioxidative capability (T-AOC), as well as production of malondialdehyde (MDA) and reactive oxygen species (ROS) were assayed in ipsilateral hemisphere homogenates to evaluate the redox status after I/R injury. Treatment with CXC195 significantly attenuated the decrease of SOD, GPx and T-AOC activities and inhibited the elevation of MDA content and ROS generation. Furthermore, CXC195 prevented the upregulation of the NADPH oxidase (NOX) 2 and NOX4, and reduced inducible nitric oxide synthase (iNOS) induction and production of nitric oxide induced by I/R. Conclusion: These results suggest that CXC195 has a neuroprotective effect in transient focal ischemia, which is most likely due to its antioxidant activity by inhibiting NOX and iNOS expression. © 2013 S. Karger AG, Basel.
    Pharmacology 10/2013; 92(3-4):198-206. DOI:10.1159/000354722 · 1.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Astrocytes activation has been implicated in the inflammatory responses underlying brain injury and neurodegenerative diseases including bacterial infections, cerebral ischemia, and Parkinson's diseases. Acetylpuerarin is a newly modified isoflavone based on puerarin that has neuroprotective and antioxidant effects. In this study, we investigated the anti-inflammatory action of acetylpuerarin in regulating the eicosanoids generation and its underlying molecular mechanisms in lipopolysaccharide (LPS)-induced production of arachidonic acid (AA) metabolites in primary rat astrocytes. The results showed that acetylpuerarin concentration dependently inhibited the LPS-induced production of AA metabolites such as prostaglandin E2 (PGE2) and leukotriene C4 (LTC4), and acetylpuerarin significantly attenuated the expression and immunoreactivity of group V secretory phospholipase A2 (sPLA2) protein induced by LPS in astrocytes. Furthermore, in astrocytes pretreated with acetylpuerarin, the time course of phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and of cytosolic PLA2 alpha (cPLA2α) and expression of transcription factors, nuclear factor kappa B (NF-κB), was markedly truncated. Acetylpuerarin concentration dependently abolished the LPS-induced expressions of AA-metabolizing enzymes including cyclooxygenase-2 (COX-2) and lipooxygenase-5 (LOX-5). This study indicates that acetylpuerarin inhibited LPS-induced AA-metabolizing enzymes and AA metabolites in astrocytes via downregulation expression of group V sPLA2 and phosphorylation of ERK1/2, cPLA2α, and NF-κB. These findings reveal, in part, the molecular basis underlying the anti-inflammatory properties of acetylpuerarin.
    Journal of Molecular Neuroscience 09/2013; 52(4). DOI:10.1007/s12031-013-0113-6 · 2.76 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hydroxysafflor yellow A (HSYA) is the major active chemical component of the flower of the safflower plant, Carthamus tinctorius L. Previously, its neuroprotection against cerebral ischemia-reperfusion (I/R) injury was reported by anti-oxidant action and suppression of thrombin generation. Here, we investigate the role of HSYA in cerebral I/R-mediated apoptosis and possible signaling pathways. Male Wistar rats were subjected to transient middle cerebral artery occlusion for 2 h, followed by 24 h reperfusion. HSYA was administered via tail-vein injection just 15 min after occlusion. The number of apoptotic cells was measured by TUNEL assay, apoptosis-related proteins Bcl-2, Bax and the phosphorylation levels of Akt and GSK3β in ischemic penumbra were assayed by western blot. The results showed that administration of HSYA at the doses of 4 and 8 mg/kg significantly inhibited the apoptosis by decreasing the number of apoptotic cells and increasing the Bcl-2/Bax ratio in rats subjected to I/R injury. Simultaneously, HSYA treatment markedly increased the phosphorylations of Akt and GSK3β. Blockade of PI3K activity by wortmannin dramatically abolished its anti-apoptotic effect and lowered both Akt and GSK3β phosphorylation levels. Taken together, these results suggest that HSYA protects against cerebral I/R injury partly by reducing apoptosis via PI3K/Akt/GSK3β signaling pathway.
    Neurochemical Research 08/2013; 38(11). DOI:10.1007/s11064-013-1135-8 · 2.55 Impact Factor

Publication Stats

486 Citations
156.02 Total Impact Points

Institutions

  • 2010–2015
    • University of Jinan (Jinan, China)
      Chi-nan-shih, Shandong Sheng, China
  • 2005–2014
    • Shandong University
      • Department of Pharmacology
      Chi-nan-shih, Shandong Sheng, China