Tiantai Zhang

Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis.

BackgroundIt is known that amyloid-β peptide (Aβ) plays a pivotal role in the pathogenesis of Alzheimers disease (AD). Interaction between Aβ and the receptor for advanced glycation end products (RAGE) has been implicated in neuronal degeneration associated with this disease. Pinocembrin, a flavonoid abundant in propolis, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that pinocembrin has neuroprotective effects on ischemic and vascular dementia in animal models. It has been approved by the State Food and Drug Administration of China for clinical use in stroke patients. Against this background, we investigated the effects of pinocembrin on cognitive function and neuronal protection against Aβ-induced toxicity and explored its potential mechanism.MethodsMice received an intracerebroventricular fusion of Aβ25-35. Pinocembrin was administrated orally at 20 mg/kg/day and 40 mg/kg/day for 8 days. Behavioral performance, cerebral cortex neuropil ultrastructure, neuronal degeneration and RAGE expression were assessed. Further, a RAGE-overexpressing cell model and an AD cell model were used for investigating the mechanisms of pinocembrin. The mechanisms underlying the efficacy of pinocembrin were conducted on target action, mitochondrial function and potential signal transduction using fluorescence-based multiparametric technologies on a high-content analysis platform.ResultsOur results showed that oral administration of pinocembrin improved cognitive function, preserved the ultrastructural neuropil and decreased neurodegeneration of the cerebral cortex in Aβ25-35-treated mice. Pinocembrin did not have a significant effect on inhibiting Aβ1-42 production and scavenging intracellular reactive oxygen species (ROS). However, pinocembrin significantly inhibited the upregulation of RAGE transcripts and protein expression both in vivo and in vitro, and also markedly depressed the activation of p38 mitogen-activated protein kinase (MAPK)-MAPKAP kinase-2 (MK2)-heat shock protein 27 (HSP27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun pathways and the downstream nuclear factor κB (NFκB) inflammatory response subsequent to Aβ-RAGE interaction. In addition, pinocembrin significantly alleviated mitochondrial dysfunction through improving mitochondrial membrane potential and inhibiting mitochondrial oxidative stress, and regulated mitochondrion-mediated apoptosis by restoration of B cell lymphoma 2 (Bcl-2) and cytochrome c and inactivation of caspase 3 and caspase 9.ConclusionsPinocembrin was shown to infer cognitive improvement and neuronal protection in AD models. The mechanisms of action of the compound were illustrated on RAGE-dependent transduction inhibition and mitochondrion protection. It appears to be a promising candidate for the prevention and therapy of AD.

The anti-amnesic effects of luteolin against amyloid β25–35 peptide-induced toxicity in mice involve the protection of neurovascular unit

Luteolin (3,4,5,7-tetrahydroxyflavone) is an important member of the flavonoid family. It exhibits strongly anti-inflammatory, antioxidant and phytoestrogen-like activities. In the present study, we examined the anti-amnesic and protective effects of luteolin against Abeta(25-35)-induced toxicity in mice. Mice were given an i.c.v. injection of aggregated Abeta(25-35) peptide. The learning and memory impairments, ultrastructural changes of cerebral cortex, cerebrovascular dysfunction and neuronal changes were detected after oral administration of luteolin continuously for 8 days. Our results demonstrate that oral administration of luteolin for 8 days for those Abeta(25-35)-induced amnesic mice conferred robust neurovascular protection in Abeta(25-35)-induced amnesia, involving the improvement of the spatial learning and memory capabilities, the modulation of microvascular function, the increase of regional cerebral blood flow values, the clearance of reactive oxygen species, the improvement of cholinergic neuronal system, and the increase of brain-derived neurotrophic factor level and its receptor tyrosine kinase B expression in cerebral cortex.

Protection by borneol on cortical neurons against oxygen-glucose deprivation/reperfusion: involvement of anti-oxidation and anti-inflammation through nuclear transcription factor κappaB signaling pathway

Borneol, a terpene and bicyclic organic compound found in several species, can easily penetrate the blood-brain barrier (BBB) and helps the absorption of many agents through BBB in the brain, but there has been no study about its direct action on neurons in the CNS. In the present study, we used an in vitro ischemic model of oxygen-glucose deprivation followed by reperfusion (OGD/R) to investigate the neuroprotective effects of borneol and the related mechanisms. We demonstrated that borneol reversed OGD/R-induced neuronal injury, nuclear condensation, intracellular reactive oxygen species (ROS) generation, and mitochondrial membrane potential dissipation. The elevation of nitric oxide (NO), the increase of inducible nitric oxide synthase (iNOS) enzymatic activity and the upregulation of iNOS expression were also attenuated by borneol. The inhibition of caspase-related apoptotic signaling pathway was consistently involved in the neuroprotection afforded by borneol. Meanwhile, borneol inhibited proinflammatory factor release and IκBα degradation, and blocked nuclear transcription factor κappaB (NF-κB) p65 nuclear translocation induced by OGD/R. On the other hand, borneol did not show obvious effect on the inhibition of phospho-IKKα activation. Furthermore, it failed to affect the OGD/R-induced enhanced level of phospho-SAPK/JNK. In conclusion, our study indicated that borneol protects against cerebral ischemia/reperfusion injury through multifunctional cytoprotective pathways. The mechanisms of this reversal from OGD/R may be involved in the alleviation of intracellular ROS and iNOS/NO pathway, inhibition of inflammatory factor release and depression of caspase-related apoptosis. Among these effects, the inhibition of IκBα-NF-κB and translocation signaling pathway might play a significant role in the neuroprotection of borneol.

The Flavonoid Apigenin Protects Brain Neurovascular Coupling against Amyloid-β25-35-Induced Toxicity in Mice

Apigenin, one of the most common flavonoids, has demonstrated anti-inflammatory, anticarcinogenic, and free radical-scavenging activities. Recent studies revealed its protective effects against amyloid-β (Aβ)-induced neurotoxicity, but the mechanism was unclear. In the present study, we aimed to explore the anti-amnesic and protective effects of apigenin against Aβ₂₅₋₃₅-induced toxicity and the underlying mechanisms in the cerebral cortex in mice. The learning and memory impairments, changes in morphology of major components of neurovascular unit, ultrastructural changes and oxidative stress of cerebral cortex, cerebrovascular dysfunction, and neuronal changes were detected after oral administration of apigenin continuously for 8 days. Our results demonstrate that oral administration of apigenin for Aβ₂₅₋₃₅-induced amnesic mice conferred robust neurovascular coupling protection, involving improvement of the learning and memory capabilities, maintenance of neurovascular unit integrity, modulation of microvascular function, reduction of neurovascular oxidative damage, increase of regional cerebral blood flow, improvement of cholinergic system involving the inhibition of AChE activity and elevation of ACh level, and modification of BNDF, TrkB, and phospho-CREB levels.

Quercetin protects against the Aβ25–35-induced amnesic injury: Involvement of inactivation of RAGE-mediated pathway and conservation of the NVU

Quercetin has demonstrated protective effects against Aβ-induced toxicity on both neurons and endothelial cells. However, whether or not quercetin has an effect on the neurovascular coupling is unclear. In the present study, we aim to investigate the anti-amnesic effects of quercetin and to explore the underlying mechanisms. Aβ(25-35) (10xa0nmol) was administrated to mice i.c.v. Quercetin was administrated orally for 8 days after injection. Learning and memory behaviors were evaluated by measuring spontaneous alternation in Morris Water Maze test and the step-through positive avoidance test. The regional cerebral blood flow was monitored before the Aβ(25-35) injection and on seven consecutive days after injection. Mice were sacrificed and cerebral cortices were isolated on the last day. The effects of quercetin on the neurovascular unit (NVU) integrity, microvascular function and cholinergic neuronal changes, and the modification of signaling pathways were tested. Our results demonstrate that quercetin treatment for Aβ(25-35)-induced amnesic mice improved the learning and memory capabilities and conferred robust neurovascular coupling protection, involving maintenance of the NVU integrity, reduction of neurovascular oxidation, modulation of microvascular function, improvement of cholinergic system, andxa0regulation of neurovascular RAGE signaling pathway and ERK/CREB/BDNF pathway. In conclusion, in Aβ(25-35)-induced amnesic mice, optimal doses of quercetin administration were beneficial. Quercetin protected the NVU likely through reduction of oxidative damage, inactivation of RAGE-mediated pathway and preservation of cholinergic neurons, offering an alternative medication for Alzheimers disease.

Effects of stem cell therapy on left ventricular remodeling after acute myocardial infarction: a meta-analysis

The objective was to perform a meta‐analysis of clinical trials that investigated the effects of stem cell therapy on left ventricular remodeling in patients after acute myocardial infarction (AMI).

Association of circulating levels of asymmetric dimethylarginine (ADMA) with carotid intima-media thickness: evidence from 6168 participants.

BACKGROUNDnEpidemiologic investigations have linked the circulating levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), to carotid intima-media thickness (IMT). However, these studies result in various extent of relation between ADMA and IMT, the conclusions were inconsistent, and the precise relationship is therefore under debate. The objective of this systematic review and meta-analysis is to provide an overview of the relevant studies evaluating the association of levels of ADMA with carotid IMT and to gain more robust estimate of the relationship.nnnMETHODSnStudies were identified through PubMed, Cochrane Library, Embase, reviews, and reference lists of relevant papers. Weighted means of the correlation coefficient (R) and partial correlation coefficient (PR) were calculated for relations by using random-effect models.nnnRESULTSn22 studies with a total of 6168 subjects were included in our meta-analysis. In an overall pooled estimate of correlation coefficient (R), levels of ADMA were significantly related to carotid IMT (pooled R: 0.29; 95% confidence interval [CI]: 0.20-0.38, P<0.001). Pooled estimate of partial correlation coefficient (PR) also resulted in a significant association of ADMA with carotid IMT (pooled PR: 0.21; 95% CI: 0.14-0.29; P<0.001). Furthermore, subgroup analysis found that the relation between ADMA and IMT was stronger in patients with chronic kidney diseases (CKDs) than that in subject with normal renal function.nnnCONCLUSIONSnCirculating levels of ADMA were positively related to carotid IMT, especially in patients with CKDs. The findings need confirmation in longitudinal and interventional studies.

Methyl salicylate 2-O-β-D-lactoside, a novel salicylic acid analogue, acts as an anti-inflammatory agent on microglia and astrocytes

BackgroundNeuroinflammation has been known to play a critical role in the pathogenesis of Alzheimers disease (AD). Activation of microglia and astrocytes is a characteristic of brain inflammation. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) delays the onset of AD and suppresses its progression. Methyl salicylate-2-O-β-D-lactoside (DL0309) is a new molecule chemically related to salicylic acid. The present study aimed to evaluate the anti-inflammatory effects of DL0309.FindingsOur studies show that DL0309 significantly inhibits lipopolysaccharide (LPS)-induced release of the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the expression of the inflammation-related proteins iNOS, COX-1, and COX-2 by microglia and astrocytes. At a concentration of 10 μM, DL0309 prominently inhibited LPS-induced activation of NF-κB in glial cells by blocking phosphorylation of IKK and p65, and by blocking IκB degradation.ConclusionsWe demonstrate here for the first time that DL0309 exerts anti-inflammatory effects in glial cells by suppressing different pro-inflammatory cytokines and iNOS/NO. Furthermore, it also regulates the NF-κB signaling pathway by blocking IKK and p65 activation and IκB degradation. DL0309 also acts as a non-selective COX inhibitor in glial cells. These studies suggest that DL0309 may be effective in the treatment of neuroinflammatory disorders, including AD.

Targeting the neurovascular unit: Development of a new model and consideration for novel strategy for Alzheimer's disease

Alzheimers disease involves the complex and interconnected cascade of cellular and molecular events. Only a few treatments are available to slow the course of the disease at present. Recent studies suggest that neurovascular unit serves to maintain cerebral homeostasis, and pathological interactions between components of neurovascular unit lead to cerebral dysfunction. In present study, we established a functional unit trying to target major components of the neurovascular unit by the co-culture of rat cortical parenchymal culture and cerebral microvascular endothelial cells. This entity allowed the application of techniques such as immunofluorescent imaging and biological assays under defined conditions. The morphology of cell types, blood-brain barrier function and neuronal activation were investigated. The insight revealed that targeting components of the neurovascular unit, rather than just the neuron, might be a priority in Alzheimers disease and more likely to provide cerebroprotection.

Asymmetric dimethylarginine confers the communication between endothelial and smooth muscle cells and leads to VSMC migration through p38 and ERK1/2 signaling cascade.

Communication between endothelial and smooth muscle cells (SMCs) contributes to atherosclerosis induced by atherogenic factors, such as oxide LDL. Asymmetric dimethylarginine (ADMA), a newly found cardiovascular risk factor, accumulates in the culture medium of oxide LDL (oxLDL)‐treated endothelial cells and positively correlates with atherosclerosis. This study demonstrates that ADMA mediates the communication between endothelial cells and SMCs induced by oxLDL leading to SMC migration. In addition, the present study suggests exogenous ADMA directly induces SMC migration via p38 and ERK1/2 MAPK signaling transduction way. Investigations to identify the factors regulating VSMC migration may provide novel insights into atherosclerosis and its complications.