Linjie Yu

Hydroxy-safflor yellow A attenuates Aβ1-42-induced inflammation by modulating the JAK2/STAT3/NF-κB pathway

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.

TL-2 attenuates β-amyloid induced neuronal apoptosis through the AKT/GSK-3β/β-catenin pathway.

β-amyloid (Aβ)-mediated neuronal apoptosis contributes to the progression of Alzheimers disease (AD), although the exact mechanism remains unclear. This study aimed to investigate whether Dalesconol B (TL-2), a potent immunosuppressive agent with an unusual carbon skeleton, could inhibit Aβ-induced apoptosis in vitro and in vivo and to explore the underlying mechanisms. Aβ(1-42) was injected to bilateral hippocampus of mice to make the AD models in vivo. TL-2 was able to cross the blood-brain barrier and attenuate memory deficits in the AD mice. TL-2 also inhibited Aβ(1-42)-induced neuronal apoptosis in vitro and in vivo. In addition, TL-2 could activate the AKT/GSK-3β pathway, and inhibition of AKT and activation of GSK-3β partially eliminated the neuroprotective effects of TL-2. Furthermore, TL-2 induced the nuclear translocation of β-catenin and enhanced its transcriptional activity through the AKT/GSK-3β pathway to promote neuronal survival. These results suggest that TL-2 might be a potential drug for AD treatment.

Oridonin Attenuates Aβ1–42-Induced Neuroinflammation and Inhibits NF-κB Pathway

Neuroinflammation induced by beta-amyloid (Aβ) plays a critical role in the pathogenesis of Alzheimer’s disease (AD), and inhibiting Aβ-induced neuroinflammation serves as a potential strategy for the treatment of AD. Oridonin (Ori), a compound of Rabdosia rubescens, has been shown to exert anti-inflammatory effects. In this study, we demonstrated that Ori inhibited glial activation and decreased the release of inflammatory cytokines in the hippocampus of Aβ1–42-induced AD mice. In addition, Ori inhibited the NF-κB pathway and Aβ1–42-induced apoptosis. Furthermore, Ori could attenuate memory deficits in Aβ1–42-induced AD mice. In conclusion, our study demonstrated that Ori inhibited the neuroinflammation and attenuated memory deficits induced by Aβ1–42, suggesting that Ori might be a promising candidate for AD treatment.

Neuronal Soluble Fas Ligand Drives M1-Microglia Polarization after Cerebral Ischemia

This study explored sFasL expression in neurons and the potential role of neuronal sFasL in modulating the microglial phenotypes.

Esculentoside A suppresses Aβ1–42-induced neuroinflammation by down-regulating MAPKs pathways in vivo

Abstract Introduction: Esculentoside A (EsA) is a saponin isolated from the roots of Phytolacca esculenta. Previous studies have demonstrated that EsA exerts strong anti-inflammatory effects in peripheral immune inflammation. This study is to determine whether EsA is effective in inflammation-related neurodegenerative diseases, such as Alzheimers disease (AD). Methods: Male C57BL/6(B6) mice were divided into three groups of six mice as follows: (1) control group; (2) AD model group (Aβ1–42-induced AD mice with saline); (3) EsA group (Aβ1–42-induced AD mice with EsA, 5 mg/kg/day, i.p. for 15 days). Behavioural testing was performed after 15 days of EsA treatment. Real time PCR and Western blot were used to assess the level of inflammation factors and mitogen-activated protein kinases (MAPKs). Immunostaining was used to determine the level of activated microglia and astrocyte. Results: The results showed that EsA attenuated memory deficits in Aβ1–42-induced AD mice. Esculentoside A decreased the pro-inflammatory factors and microglia and astrocyte activation in the hippocampi of Aβ1–42-induced AD mice. Moreover, Aβ1–42 activated phosphorylation of ERK, JNK and p38 MAPKs in the hippocampi of mice in the AD model group, while EsA significantly decreased the phosphorylation levels. Conclusion: These findings indicate that EsA provides protective effects against neuroinflammation triggered by β-amyloid.

Oridonin Attenuates Synaptic Loss and Cognitive Deficits in an Aβ1–42-Induced Mouse Model of Alzheimer’s Disease

Synaptic loss induced by beta-amyloid (Aβ) plays a critical role in the pathophysiology of Alzheimer’s disease (AD), but the mechanisms underlying this process remain unknown. In this study, we found that oridonin (Ori) rescued synaptic loss induced by Aβ1–42 in vivo and in vitro and attenuated the alterations in dendritic structure and spine density observed in the hippocampus of AD mice. In addition, Ori increased the expression of PSD-95 and synaptophysin and promoted mitochondrial activity in the synaptosomes of AD mice. Ori also activated the BDNF/TrkB/CREB signaling pathway in the hippocampus of AD mice. Furthermore, in the Morris water maze test, Ori reduced latency and searching distance and increased the number of platform crosses in AD mice. These data suggest that Ori might prevent synaptic loss and improve behavioral symptoms in Aβ1–42-induced AD mice.

Panaxatriol saponins promotes angiogenesis and enhances cerebral perfusion after ischemic stroke in rats

BackgroundPanaxatriol saponins (PTS), an extract from the traditional Chinese herb Panax notoginseng, which has been used to treat ischemic stroke for many years in China. However, the mechanism underlying the effects of PTS remains unclear. This study aimed to determine whether PTS can protect against ischemic brain injury by promoting angiogenesis and to explore the possible mechanism by which it promotes angiogenesis.MethodsMiddle cerebral artery occlusion (MCAO) was induced in rats, and neurological deficit scores and brain infarct volumes were assessed. Micro-Positron emission tomography (PET) was adopted to assess cerebral perfusion, and real-time PCR and western blotting were used to evaluate vascular growth factor and Sonic hedgehog (Shh) pathway component levels. Immunofluorescence staining was used to determine capillary densities in ischemic penumbrae.ResultsWe showed that PTS improved neurological function and reduced infarct volumes in MCAO rats. Micro-PET indicated that PTS can significantly increase 18F-fluorodeoxyglucose (18F-PDG) uptake by ischemic brain tissue and enhance cerebral perfusion after MCAO surgery. Moreover, PTS was able to increase capillary densities and enhance angiogenesis in ischemic boundary zones and up-regulate vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1) expression by activating the Shh signaling pathway.ConclusionThese findings indicate that PTS exerts protective effects against cerebral ischemic injury by enhancing angiogenesis and improving microperfusion.

Esculentoside A exerts anti-inflammatory activity in microglial cells

Abstract Esculentoside A (EsA) is a saponin isolated from the roots of Phytolacca esculenta. This study was designed to evaluate the pharmacological effects of EsA on lipopolysaccharide (LPS)‐stimulated BV2 microglia and primary microglia cells. Our results indicated that EsA pretreatment significantly decreased LPS‐induced production of Nitric Oxide (NO) and Prostaglandin E2 (PGE2) and impeded LPS‐mediated upregulation of pro‐inflammatory mediators’ expression such as nitric oxide synthase (iNOS), cyclooxygenase‐2 (COX‐2), interleukin‐1&bgr; (IL‐1&bgr;), interleukin‐6 (IL‐6), interleukin‐12 (IL‐12) and tumor necrosis factor‐a (TNF‐&agr;) in both BV2 microglia and primary microglia cells. Moreover, EsA markedly suppressed nuclear factor‐&kgr;B p65 (NF‐&kgr;B p65) translocation by blocking I&kgr;B‐&agr; phosphorylation and degradation in LPS‐treated BV2 cells. EsA also decreased phosphorylation level of mitogen‐activated protein kinases (MAPKs) and inhibited NOD‐like receptor pyrin domain‐containing protein 3 (NLRP3) inflammasome mediated caspase‐1 activation in LPS‐stimulated BV2 cells. Additionally, EsA decreased &bgr;‐amyloid1–42 (A&bgr;1–42)‐induced production of TNF‐&agr;, IL‐1&bgr; and IL‐6 in primary microglia. Thus, EsA might be a promising therapeutic agent for alleviating neuroinflammatory diseases. HighlightsEsA attenuated LPS‐induced inflammatory mediators’ production in activated microglia.The anti‐inflammatory effects of EsA was associated with the inactivation of NF‐&kgr;B, MAPKs and NLRP3 pathways.EsA suppressed mRNA levels of cytokines in A&bgr;1–42‐induced primary microglia cells.

HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer's disease

The accumulation and deposition of beta‐amyloid (Aβ) is a key neuropathological hallmark of Alzheimers disease (AD). Histone deacetylases (HDACs) are promising therapeutic targets for the treatment of AD, while the specific HDAC isoforms associated with cognitive improvement are poorly understood. In this study, we investigate the role of HDAC3 in the pathogenesis of AD. Nuclear HDAC3 is significantly increased in the hippocampus of 6‐ and 9‐month‐old APPswe/PS1dE9 (APP/PS1) mice compared with that in age‐matched wild‐type C57BL/6 (B6) mice. Lentivirus ‐mediated inhibition or overexpression of HDAC3 was used in the hippocampus of APP/PS1 mice to investigate the role of HDAC3 in spatial memory, amyloid burden, dendritic spine density, glial activation and tau phosphorylation. Inhibition of HDAC3 in the hippocampus attenuates spatial memory deficits, as indicated in the Morris water maze test, and decreases amyloid plaque load and Aβ levels in the brains of APP/PS1 mice. Dendritic spine density is increased, while microglial activation is alleviated after HDAC3 inhibition in the hippocampus of 9‐month‐old APP/PS1 mice. Furthermore, HDAC3 overexpression in the hippocampus increases Aβ levels, activates microglia, and decreases dendritic spine density in 6‐month‐old APP/PS1 mice. In conclusion, our results indicate that HDAC3 negatively regulates spatial memory in APP/PS1 mice and HDAC3 inhibition might represent a potential therapy for the treatment of AD.

CART modulates beta-amyloid metabolism-associated enzymes and attenuates memory deficits in APP/PS1 mice

Abstract Introduction: Cocaine- and amphetamine-regulated transcript (CART) peptide has been demonstrated to exert neuroprotective effects in stroke and some neurodegeneration diseases. In current study, we investigated the protective effects and underlying mechanisms of CART in APP/PS1 mice. Methods: The protein levels of CART, soluble Aβ1–40 and Aβ1–42 were measured in the hippocampus of APP/PS1 mice by enzyme-linked immunosorbent assay. We determined the mRNA and protein levels of Aβ metabolism-associated enzymes including neprilysin (NEP), insulin-degrading enzyme (IDE), receptor for advanced glycation end products (RAGE), and low-density lipoprotein receptor-related protein 1 (LRP-1) in the hippocampus of APP/PS1 mice using real-time PCR and western blotting. Spatial memory was measured in APP/PS1 mice using the Morris water maze. The phosphorylation of AKT, ERK, p38, and JNK was determined using western blotting. Results: The levels of soluble Aβ1–40 and Aβ1–42 were significantly decreased in the hippocampus of APP/PS1 mice after CART treatment. CART modulated the levels of NEP, IDE, RAGE, and LRP-1. In addition, CART inhibited the MAPK pathways and activated the AKT pathway, whereas inhibition of the AKT pathway decreased the levels of IDE and LRP-1. Furthermore, CART attenuated spatial memory deficits in the APP/PS1 mice. Conclusion: CART decreases the levels of soluble Aβ in the hippocampus of APP/PS1 mice by modulating the expression of Aβ metabolism-associated enzymes, which may be associated with the MAPK and AKT pathways.