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Zhang M.,Nanjing Medical University | Han L.,Nanjing Medical University | Xu Y.,Nanjing Medical University | Xu Y.,Nanjing University | Xu Y.,Jiangsu Key Laboratory for Molecular Medicine
Clinical and Experimental Pharmacology and Physiology | Year: 2012

1. Cocaine- and amphetamine-regulated transcript (CART), first isolated from the ovine hypothalamus, is a potential neurotransmitter widely distributed throughout the central and peripheral nervous systems, as well as in endocrine cells in the pituitary and adrenal glands, pancreatic islets and stomach. 2. Numerous studies have established the role of CART in food intake, maintenance of bodyweight, stress control, reward and pain transmission. Recently, it was demonstrated that CART, as a neurotrophic peptide, had a cerebroprotective against focal ischaemic stroke and inhibited the neurotoxicity of β-amyloid protein, which focused attention on the role of CART in the central nervous system (CNS) and neurological diseases. 3. In fact, little is known about the way in which CART peptide interacts with its receptors, initiates downstream cascades and finally exerts its neuroprotective effect under normal or pathological conditions. The literature indicates that there are many factors, such as regulation of the immunological system and protection against energy failure, that may be involved in the cerebroprotection afforded by CART. 4. The present review provides a brief summary of the current literature on CART synthesis and active fragments, its distribution in the CNS and, in particular, the role of CART peptide (and its receptors and signalling) in neurological diseases. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd. Source

Zhang Z.-H.,Nanjing Medical University | Zhang Z.-H.,Xuzhou Medical College | Yu L.-J.,Nanjing Medical University | Hui X.-C.,Nanjing Medical University | And 9 more authors.
Brain Research | Year: 2014

Beta-amyloid (Aβ)-mediated inflammation plays a critical role in the initiation and progression of Alzheimer's disease (AD). Anti-inflammatory treatment may provide therapeutic benefits. In this study, the effect of hydroxy-safflor yellow A (HSYA) on Aβ1-42-induced inflammation in AD mice was investigated and the underlying mechanisms were explored. Aβ1-42 was injected into bilateral hippocampi of mice to induce AD models in vivo. Spatial learning and memory of mice were investigated by the Morris water maze test. Activated microglia and astrocytes were examined by immunofluorescence staining for ionized calcium-binding adapter molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP). The mRNA of inflammatory cytokines were measured using real-time PCR. NF-κB p65 translocation was analyzed by western blotting and immunostaining. IκB and phosphorylation of JAK2 and STAT3 were tested by western blotting. The results showed that HSYA ameliorated the memory deficits in Aβ1-42-induced AD mice. HSYA suppressed Aβ1-42-induced activation of microglia and astrocytes and reduced the mRNA expression of pro-inflammatory mediators. HSYA up-regulated the JAK2/STAT3 pathway and inhibits the activation of NF-κB signaling pathways. Pharmacological inhibition of STAT3 by AG490 reversed the inactivation of p65 and anti-inflammatory effects of HSYA. In conclusion, these results suggest that HSYA protects Aβ1-42-induced AD model through inhibiting inflammatory response, which may involve the JAK2/STAT3/NF-κB pathway. © 2014 Elsevier B.V. Source

Zhu X.,Nanjing University | Zhu X.,Nanjing Medical University | Chen C.,Nanjing Medical University | Ye D.,Nanjing Medical University | And 11 more authors.
PLoS ONE | Year: 2012

Mitochondrial dysfunction is a hallmark of beta-amyloid (Aβ)-induced neurotoxicity in Alzheimer's disease (AD), and is considered an early event in AD pathology. Diammonium glycyrrhizinate (DG), the salt form of Glycyrrhizin, is known for its anti-inflammatory effects, resistance to biologic oxidation and membranous protection. In the present study, the neuroprotective effects of DG on Aβ 1-42-induced toxicity and its potential mechanisms in primary cortical neurons were investigated. Exposure of neurons to 2 μM Aβ 1-42 resulted in significant viability loss and cell apoptosis. Accumulation of reactive oxygen species (ROS), decreased mitochondrial membrane potential, and activation of caspase-9 and caspase-3 were also observed after Aβ 1-42 exposure. All these effects induced by Aβ 1-42 were markedly reversed by DG treatment. In addition, DG could alleviate lipid peroxidation and partially restore the mitochondrial function in Aβ 1-42-induced AD mice. DG also significantly increased the PGC-1α expression in vivo and in vitro, while knocking down PGC-1α partially blocked the protective effects, which indicated that PGC-1α contributed to the neuroprotective effects of DG. Furthermore, DG significantly decreased the escape latency and search distance and increased the target crossing times of Aβ 1-42-induced AD mice in the Morris water maze test. Therefore, these results demonstrated that DG could attenuate Aβ 1-42-induced neuronal injury by preventing mitochondrial dysfunction and oxidative stress and improved cognitive impairment in Aβ 1-42-induced AD mice, indicating that DG exerted potential beneficial effects on AD. © 2012 Zhu et al. Source

Qian L.,Nanjing University | Ding L.,Peoples Hospital of Jiangyan | Cheng L.,Fourth Peoples Hospital of Wuxi | Zhu X.,Nanjing University | And 7 more authors.
Journal of Neurology | Year: 2012

The aim of this study was to investigate whether some biomarkers could predict cognitive impairment after stroke. One hundred fifty-two first-ever stroke patients were recruited within 6-72 h after the onset of symptoms. Blood was drawn within 1 h after admission for determining biomarkers. Cognitive function was assayed 2 weeks after stroke. The patients were divided into four groups: stroke, vascular cognitive impairment with no dementia (VCIND), vascular dementia (VaD), and mixed dementia (MD). Forty healthy subjects were used as controls. The results indicated that lower soluble receptor levels for advanced glycation end products (sRAGE) and higher β-secretase enzyme (BACE1) and neprilysin (NEP) levels were found in the VCIND, VaD, and MD groups. In addition, the percentages of ε3/ε4 genotypes and ε4 alleles in the VCIND, VaD, and MD groups were higher than in the stroke group. Correlation analysis determined that sRAGE, BACE1, and NEP were significantly related to the results of neuropsychological assessments. Logistic regression analysis, however, suggested that only sRAGE and BACE1 changed ahead of cognitive impairment after stroke. In conclusion, only BACE1 and sRAGE, not NEP or APOE genotypes, may be biomarkers diagnosing poststroke cognitive impairment. © Springer-Verlag 2012. Source

Zhao H.,Nanjing University | Zhao H.,Nanjing Medical University | Wang S.-L.,Nanjing University | Qian L.,Nanjing Medical University | And 7 more authors.
CNS Neuroscience and Therapeutics | Year: 2013

Background and purpose: Beta-amyloid (Aβ)-mediated inflammation contributes to the progression and chronicity of Alzheimer's disease (AD), although the exact mechanism remains unclear. This study aimed to investigate whether diammonium glycyrrhizinate (DG) could inhibit Aβ-induced inflammation in vitro and in vivo and to explore the underlying mechanisms. Methods: Aβ1-42 was injected to bilateral hippocampus of mice to make the AD models in vivo. The levels of mRNA and protein of inflammatory cytokines were measured by real-time PCR and Western blotting, respectively. The viability of SH-SY5Y and HT-22 cells was determined by MTT. NF-κB p65 translocation was analyzed by Western blotting and immunostaining. Phosphorylation of ERK, p38, and JNK was tested by Western blotting. Results: DG suppressed Aβ1-42-induced activation of microglia and inflammation in vitro and in vivo. The media from Aβ1-42-activated microglia decreased the viability of SH-SY5Y and HT-22 cells, but it was rescued when pretreated with DG. DG could inhibit the activation of MAPK and NF-κB signaling pathways and attenuate the memory deficits in Aβ1-42-induced AD mice. Conclusions: DG protects Aβ1-42-induced AD models in vitro and in vivo through reducing activation of microglia and inflammation, which may be involved in MAPK and NF-κB pathways. © 2012 Blackwell Publishing Ltd. Source

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