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1.
J Clin Neurosci ; 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31477463

RESUMO

Electroacupuncture (EA) is an adjuvant therapy for peripheral nerve injury (PNI). Both peripheral and central alterations contribute to the rehabilitation process. We employed diffusion tensor imaging (DTI) to investigate the diffusion plasticity of afferent and efferent pathways caused by EA in model of peripheral nerve injury and reparation. Twenty-four rats were divided into three groups: normal group, model group and intervention group. Rats of the model group and the intervention group underwent sciatic nerve transection and anastomosis. EA intervention was performed on the intervention group at ST-36 and GB-30 for three months. Gait assessment and DTI were conducted at days post-operative (DPO) 30, 60 and 90. We selected corticospinal tract, spinothalamic tract and internal capsule as regions of interest and analyzed diffusion metrics including fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). FA values and RD values displayed significant differences or obvious tendency while AD values maintained a stable level. RD values displayed better indicative performance than FA in internal capsule. The intervention group presented significant correlation between RD values and Regularity Index (RI) during the intervention period. The effect of EA on peripheral nerve injury repairing rats appeared to be accelerated recovery process of sensory and motor neural pathway. We proposed that RD was a potential in vivo indicator for structural plasticity caused by EA and PNI.

2.
Nanoscale ; 11(34): 15794-15803, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31432854

RESUMO

Biomimetic scaffolds have been extensively studied for guiding osteogenesis through structural cues. Inspired by the natural bone growth process, we have employed a hierarchical outer-inner dual reinforcing strategy, which relies on the interfacial ionic bond interaction between amine/calcium and carboxyl groups, to build a nanofiber/particle dual strengthened hierarchical silk fibroin scaffold. This scaffold can provide an applicable form of osteogenic structural cue and mimic the natural bone forming process. Owing to the active interaction between compositions located in the outer pore space and the inner pore wall, the scaffold has over 4 times improvement in the mechanical properties, followed by a significant alteration of the cell-scaffold interaction pattern, demonstrated by over 2 times elevation in the spreading area and enhanced osteogenic activity potentially involving the activities of integrin, vinculin and Yes-associated protein (YAP). The in vivo performance of the scaffold identified the inherent osteogenic effect of the structural cue, which promotes rapid and uniform regeneration. Overall, the hierarchical scaffold is promising in promoting uniform bone regeneration through its specific structural cue endowed by its micro-nano construction.

3.
HLA ; 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31448562

RESUMO

There is a single nucleotide different in intron 1 between E*01:01:01:01 and E*01:01:01:11. This article is protected by copyright. All rights reserved.

4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 44(7): 805-812, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31413220

RESUMO

OBJECTIVE: To evaluate the white-matter integrity and its correlation with cognitive function in patients with mild cognitive impairment (MCI) complicated with lacunar infarctions (LI) by diffusion tensor imaging (DTI) of magnetic resonance (MR).
 Methods: Twenty-six patients with MCI were selected including 14 patients with combined LI and 12 patients without combined LI, and 16 healthy volunteers were recruited as normal control. All subjects completed cognitive function assessment and DTI sequence of MR. Factional anisotropy (FA) and mean diffusivity (MD) values among the MCI with LI group (MCI-LI), the MCI without LI group (MCI-non LI), and the normal control group (NC) were compared, and the correlation between DTI parameters and cognition was determined by multiple linear stepwise regression.
 Results: Compared with the MCI-non LI group, the FA values were significantly decreased (P<0.05) and MD values were significantly increased (P<0.05) in the white matter fiber bundles (such as the left hippocampus of the cingulate tract, the frontal fascicle of the corpus callosum, the right inferior frontal occipital fascicle, and the right superior longitudinal fascicle) in the MCI-LI group. In the MCI-LI group, the FA value of right cingulate gyrus was significantly correlated with Activity of Daily Living Scale (ADL) score (B=-50.2, 95% CI -77.7 to -22.7, P=0.003); the FA value of left anterior thalamic radiation (B=443.8, 95% CI 222.9 to 664.8, P=0.001) and MD value of left inferior longitudinal tract (B=-318.5, 95% CI -534.7 to -102.3, P=0.009) were significantly correlated with Wechsler digit symbol substitution (WDSS) score; the FA value of left superior temporal lobe longitudinal tract was significantly correlated with Backward Digit Span (BDSP) score (B=12.5, 95% CI 1.5 to 23.4, P=0.030).
 Conclusion: The integrity of white matter is significantly destroyed in MCI patients with LI than that in MCI patients without LI, and there is a correlation between cognitive function and DTI parameters in some white matter tracts in MCI patients with LI.


Assuntos
Disfunção Cognitiva , Acidente Vascular Cerebral Lacunar , Substância Branca , Anisotropia , Encéfalo , Disfunção Cognitiva/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Humanos , Testes Neuropsicológicos
5.
J Org Chem ; 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31414808

RESUMO

A Pd(II)-catalyzed mild and highly regioselective 6-endo cyclization/alkylation reaction of o-(alkynyl)styrenes with simple allylic alcohols has been developed. Under mild reaction conditions, the vinyl palladium species generated in situ after cyclization could insert a C-C double bond of allylic alcohol through a cross-coupling reaction and led to the formation of (alkyl)naphthalenes. This cascade cross-coupling reaction represents a direct and atom economic method for the construction of functionalized naphthalene derivatives in moderate to good yields.

6.
Blood ; 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366618

RESUMO

LMO2 (hematopoietic transcription factor LIM domain only 2), a member of the TAL1 transcriptional complex, plays an essential role during early hematopoiesis and is frequently activated in T cell acute lymphoblastic leukemia (T-ALL) patients. Here, we demonstrated that LMO2 is activated by deacetylation on lysine 74 and 78 via the nicotinamide phosphoribosyltransferase (NAMPT)/sirtuin 2 (SIRT2) pathway. LMO2 deacetylation enables LMO2 to interact with LDB1 and activate the TAL1 complex. NAMPT/SIRT2-mediated activation of LMO2 by deacetylation is essential for hematopoietic differentiation of induced pluripotent stem (iPS) cells and blood formation in zebrafish embryos. In T-ALL, deacetylated LMO2 induces expression of TAL1 complex target genes HHEX, NKX3.1 as well as LMO2 autoregulation. Consistent with this, inhibition of NAMPT or SIRT2 suppressed the in vitro growth and in vivo engraftment of T-ALL cells via diminished LMO2 deacetylation. This new molecular mechanism may provide new therapeutic possibilities in T-ALL and may contribute to the development of new methods for in vitro generation of blood cells.

7.
Neurology ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31405905

RESUMO

OBJECTIVE: To study the intrinsic organization of the thalamocortical circuitry in patients with generalized epilepsy with tonic-clonic seizures (GTCS) via resting-state fMRI (rs-fMRI) connectome analysis and to evaluate its relation to drug response. METHODS: In a prospectively followed-up sample of 41 patients and 27 healthy controls, we obtained rs-fMRI and structural MRI. After 1 year of follow-up, 27 patients were classified as seizure-free and 14 as drug-resistant. We examined connectivity within and between resting-state communities in cortical and thalamic subregions. In addition to comparing patients to controls, we examined associations with seizure control. We assessed reproducibility in an independent cohort of 21 patients. RESULTS: Compared to controls, patients showed a more constrained network embedding of the thalamus, while frontocentral neocortical regions expressed increased functional diversity. Findings remained significant after regressing out thalamic volume and cortical thickness, suggesting independence from structural alterations. We observed more marked network imbalances in drug-resistant compared to seizure-free patients. Findings were similar in the reproducibility dataset. CONCLUSIONS: Our findings suggest a pathoconnectomic mechanism of generalized epilepsy centered on diverging changes in cortical and thalamic connectivity. More restricted thalamic connectivity could reflect the tendency to engage in recursive thalamocortical loops, which may contribute to hyperexcitability. Conversely, increased connectional diversity of frontocentral networks may relay abnormal activity to an extended bilateral territory. Network imbalances were observed shortly after diagnosis and related to future drug response, suggesting clinical utility.

8.
Eur J Pharmacol ; 861: 172610, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31425684

RESUMO

Echinocystic acid (EA) was found to possess antiviral, anti-inflammatory and antioxidation activities. A recent study showed the antiapoptotic effects of EA on acute myocardial infarction. In this study, we demonstrated the potential neuroprotective effects of EA on cerebral ischemia/reperfusion (I/R) injury in mice. Intraperitoneal injection of EA 1 h before ischemia significantly reduced the cerebral infarct volume and neurological deficit after 60 min of ischemia and 24 h of reperfusion. The neuroprotective effects of EA occurred in a dose-dependent manner. Then, we explored the mechanisms of neuroprotection by EA. This compound exerted antiapoptotic activity by upregulating the level of Bcl-2 and simultaneously downregulating the levels of cleaved caspase-3 and Bax. Furthermore, EA also possessed anti-inflammatory activity and prevented the excessive phosphorylation of NF-κB (p-P65) and the increase in IL-1ß and IL-6 levels. Finally, our data indicated that EA treatment decreased the level of phosphorylated JNK in vivo, and the JNK activator anisomycin (AN) reversed the neuroprotective effects of EA, indicating that the JNK pathway is involved in the antiapoptotic and anti-inflammatory mechanisms of EA. In summary, our findings suggest that EA provides neuroprotective effects through its antiapoptotic and anti-inflammatory activities by inhibiting the JNK signaling pathway in cerebral I/R injury. Due to its safety and lack of toxicity, EA is a potential candidate for the treatment of ischemic stroke in future clinical trials.

9.
Metab Eng ; 55: 231-238, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31382013

RESUMO

As an alternative to in vitro lipase dependent biotransformation and to traditional assembly of pathways in cytoplasm, the present study focused on targeting lipase dependent pathways to a subcellular compartment lipid body (LB), in combination with compartmentalization of associated pathways in other lipid relevant organelles including endoplasmic reticulum (ER) and peroxisome for efficient in vivo biosynthesis of fatty acid methyl esters (FAMEs) and hydrocarbons, in the context of improving Yarrowia lipolytica lipid pool. Through knock in and knock out of key genes involved in triacylglycerols (TAGs) biosynthesis and degradation, the TAGs content was increased to 51.5%, from 7.2% in parent strain. Targeting lipase dependent pathway to LB gave a 10-fold higher FAMEs titer (1028.0 mg/L) compared to cytosolic pathway (102.8 mg/L). Furthermore, simultaneously targeting lipase dependent pathway to LB, ER and peroxisome gave rise to the highest FAMEs titer (1644.8 mg/L). The subcellular compartment engineering strategy was extended to other lipase dependent pathways for fatty alkene and alkane biosynthesis, which resulted in a 14-fold titer enhancement compared to traditional cytosolic pathways. We developed yeast subcellular cell factories by directing lipase dependent pathways towards the TAGs storage organelle LB for efficient biosynthesis of TAG derived chemicals for the first time. The successful exploration of targeting metabolic pathways towards LB centered organelles is expected to promote subcellular compartment engineering for other lipid derived product biosynthesis.

10.
Environ Pollut ; 254(Pt B): 113046, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31454587

RESUMO

Parent polycyclic aromatic hydrocarbons (PPAHs) in the ambient air of the coastal cities near the Bohai and Yellow Seas were measured over a full year. The range and geometric average of total PPAH29 (29 species) were 5.16-1.22 × 103 and 118 ng/m3, respectively, with 77 ±â€¯14% in a gaseous phase. The 16 priority components accounted for 90 ±â€¯4% of the total mass concentration. The incremental life cancer risk (ILCR) via inhalation exposure to the PPAHs (3.17 × 10-4) was underestimated by 80%, as only the priority PPAHs were considered. The air concentrations of PPAHs in the Bohai Sea area were generally higher (p < 0.01) than those in the Yellow Sea area. A significant increase (p < 0.01) in the levels of PPAHs and large fractions of high molecular weight (HMW) components were observed in winter. Absorption by particulate organic carbon dominated in gas-particle partitioning of the PPAHs, and the seasonal variations in gas-particle partitioning of the low and moderate molecular weight compounds were more noticeable relative to the HMW species. In summer, significantly higher concentrations of PPAHs were found in the daytime than during nighttime, while the opposite case occurred in winter (p < 0.05). The positive matrix factorization (PMF) results indicated greater contributions of coal and biomass combustion to the PPAH emissions in the coastal cities of the Bohai Sea area compared with the Yellow Sea area. The burning of coal and biomass served as the main source of PPAHs in winter, while traffic exhaust was the dominant source in other seasons. The potential source contribution function (PSCF) revealed the important impacts of the external inputs on the local PPAHs via air mass transport. The contributions of the resolved emission sources to the ILCR were clearly different from those of the mass concentrations, indicating the necessity for source-oriented risk assessments.

11.
Cancer Lett ; 464: 37-55, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31465841

RESUMO

Long noncoding RNAs (lncRNAs) are defined as RNA transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs have been documented to exhibit aberrant expression in various types of cancer, including prostate cancer. Currently, screening for prostate cancer results in overdiagnosis. The consequent overtreatment of patients with indolent disease in the clinic is due to the lack of appropriately sensitive and specific biomarkers. Thus, the identification of lncRNAs as novel biomarkers and therapeutic targets for prostate cancer is promising. In the present review, we attempt to summarize the current knowledge of lncRNA expression patterns and mechanisms in prostate cancer. In particular, we focus on lncRNAs regulated by the androgen receptor and the specific molecular mechanism of lncRNAs in prostate cancer to provide a potential clinical therapeutic strategy for prostate cancer.

12.
Mol Cell ; 75(3): 644-660.e5, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398325

RESUMO

Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.

13.
J Cardiovasc Magn Reson ; 21(1): 36, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262337

RESUMO

BACKGROUND: To determine the usefulness of the size of carotid artery intraplaque hemorrhage (IPH) in discriminating the risk of acute ischemic stroke using cardiovascular magnetic resonance (CMR) vessel wall imaging. METHODS: Symptomatic patients with carotid atherosclerotic plaque who participated in a cross-sectional, multicenter study of CARE-II (NCT02017756) were included. All patients underwent carotid and brain CMR imaging. Carotid plaque burden and the size of plaque compositions including calcification, lipid-rich necrotic core (LRNC), and IPH were measured. Presence of acute cerebral infarct (ACI) in ipsilateral hemisphere of carotid plaque was determined. The relationship between carotid plaque features and presence of ipsilateral ACI was then analyzed. RESULTS: Of 687 recruited patients (62.7 ± 10.1 years; 69.4% males) with carotid plaque, 28.5% had ACI in ipsilateral hemispheres. Logistic regression revealed that carotid plaque burden was significantly associated with the presence of ACI before and after adjusted for clinical confounding factors. The volume of LRNC, %LRNC volume, volume of IPH, and %IPH volume were significantly associated with ACI before (volume of LRNC: OR = 1.297, p = 0.005; %LRNC volume: OR = 1.119, p = 0.018; volume of IPH: OR = 2.514, p = 0.003; %IPH volume: OR = 2.202, p = 0.003) and after (volume of LRNC: OR = 1.312, p = 0.006; %LRNC volume: OR = 1.90, p = 0.034; volume of IPH: OR = 2.907, p = 0.007; % IPH volume: OR = 2.374, p = 0.004) adjusted for clinical confounding factors. The association between volume of IPH and ACI remained statistically significant after further adjusted for plaque volume (OR = 2.813, p = 0.016) or both plaque volume and volume of LRNC (OR = 4.044, p = 0.024). CONCLUSIONS: In symptomatic patients with carotid atherosclerotic plaques, the size of IPH is independently associated with ipsilateral ACI, suggesting the size of IPH might be a useful indicator for the risk of ACI. TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov . Unique Identifier: NCT02017756.

14.
J Neurosci ; 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311824

RESUMO

Circular RNAs (circRNAs) are expressed at high levels in the brain and are involved in various central nervous system diseases. However, the potential role of circRNAs in ischemic stroke-associated neuronal injury remains largely unknown. Here, we investigated the important functions of circRNA TLK1 (circTLK1) in this process. The levels of circTLK1 were significantly increased in brain tissues in a mouse model of focal cerebral ischemia and reperfusion. Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved neurological deficits. Furthermore, circTLK1 functioned as an endogenous miR-335-3p sponge to inhibit miR-335-3p activity, resulting in the increase of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly (ADP-ribose) polymerase expression and a subsequent exacerbation of neuronal injury. Clinical studies confirmed increased levels of circTLK1 in the plasma of patients with acute ischemic stroke (59 males and 12 females). Our findings reveal a detrimental role of circTLK1 in ischemic brain injury.SIGNIFICANCE STATEMENTThe extent of neuronal injury after brain ischemia is a primary factor determining stroke outcomes. However, the molecular switches that control the death of ischemic neurons are poorly understood. While our previous studies indicated the involvement of circRNAs in ischemic stroke, the potential role of circRNAs in neuronal injury remains largely unknown. The levels of circTLK1 were significantly increased in the brain tissue and plasma isolated from animal models of ischemic stroke and patients. Knockdown of circTLK1 significantly decreased infarct volumes, attenuated neuronal injury, and improved subsequent long-term neurological deficits. To our knowledge, these results provide the first definitive evidence that circTLK1 is detrimental in ischemic stroke.

15.
ACS Appl Mater Interfaces ; 11(33): 29814-29820, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31340645

RESUMO

A large transition dipole moment is usually pursued by strategies of twisted intramolecular charge transfer (TICT) or planar intramolecular charge transfer (PICT) to obtain obvious Stokes shifts and dramatic color changes with tuning of polarities. However, both strategies have their drawbacks and suffer from fluorescence quenching in solid states. Herein, a ladder-type molecule ISOAA-H with an intramolecular hydrogen bond is designed, which undergoes intramolecular charge transfer and proton shift to harvest a large transition dipole moment under light irradiation. Thanks to its out-of-plane side chains, the intermolecular π-π stacking of backbones is prohibited and solid emission is generated. ISOAA-H exhibits outstanding solvatochromic behavior with polarity changes of solvents or polymer matrixes and is successfully used to detect the microphase separation of polymer blends. These results indicate that a strategy combining the advantages of TICT and PICT is established for environment-sensitive dyes used in both solution and solid state.

16.
Life Sci ; 232: 116654, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306657

RESUMO

AIMS: Immuno-inflammation contributes to the pathogenesis of Duchenne muscular dystrophy (DMD), characterized by progressive muscle degeneration and weakness. The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is crucial for initiating innate immunity. Ghrelin is a circulating hormone that exerts anti-inflammatory activity in several inflammatory diseases. However, the role of ghrelin in DMD and underlying mechanism are still unstated. Therefore, we investigated the effect and potential mechanism of ghrelin on muscle morphology and muscular function of mdx mice, a mouse model of DMD. MAIN METHODS: 4-Week-old male mdx mice were injected intraperitoneally with ghrelin (100 µg/kg of body weight/day) or saline for 4 weeks. Then, muscle performance was evaluated by behavioral tests. Skeletal muscles samples were collected and relevant parameters were measured by using histopathological analysis and molecular biology techniques both in mdx muscles and primary myoblasts. KEY FINDINGS: Ghrelin significantly improved motor performance, alleviated muscle pathology and decreased inflammatory cell infiltration in mdx mice. Importantly, ghrelin dramatically inhibited NLRP3 inflammasome activation and reduced the production of mature IL-1ß both in dystrophic muscles and in lipopolysaccharide (LPS)-primed primary myoblasts induced by the NLRP3 inflammasome activator benzylated ATP (BzATP). Furthermore, the inhibition of NLRP3 inflammasome by ghrelin was partly mediated by the suppression of JAK2-STAT3 and p38 MAPK signaling pathway. SIGNIFICANCE: Our findings reveal that ghrelin suppresses muscle inflammation and ameliorates disease phenotype through inhibition of NLRP3 inflammasome activation and the production of IL-1ß in mdx mice, which suggests new therapeutic potential of ghrelin in DMD.

17.
Org Lett ; 21(15): 6016-6020, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31318220

RESUMO

A copper-catalyzed highly regio- and stereoselective silaboration of alkynes was developed. In this work, direct cis-difunctionalization of alkynes was realized with silaboronate reagent and copper catalyst in aprotic solvents. The regiodivergent silaborations were controlled by tuning the copper catalysts and phosphine ligands used in reactions. This protocol provides an efficient and practical method to synthesize the multisubstituted functionalized alkenes with specific stereoselectivity.

18.
HLA ; 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31338993

RESUMO

The novel HLA-E*01:03:07 allele, differs from E*01:03:01 by a single synonymous change in exon 3.

19.
CNS Neurosci Ther ; 25(9): 1042-1053, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31334611

RESUMO

AIMS: Effects of dl-3-n-butylphthalide (NBP) on white matter damage and cognitive impairment in vascular cognitive impairment (VCI) have not been well studied. This study aimed to investigate the effects of NBP treatment on chronic cerebral hypoperfusion-induced white matter lesions and cognitive dysfunction in mice. METHODS: Mice were subjected to bilateral common carotid artery stenosis (BCAS) for over 30 days. The cerebral blood flow was detected using a laser Doppler flowmetry. Cognitive functions were assessed by several behavioral tests. We also evaluated the effects of NBP on the blood-brain barrier (BBB) disruption and reactive astrogliosis, using Evans Blue extravasation, Western blot, CBA, and immunofluorescence in BCAS mice and cultured astrocytes. RESULTS: The results indicated that NBP treatment attenuated spatial memory dysfunction while promoted cerebral perfusion and white matter integrity in BCAS mice. Moreover, NBP treatment prevented BBB leakage and damage of endothelial cells, as well as disruption of endothelial tight junctions. Furthermore, NBP administration effectively decreased the number of activated astrocytes and pro-inflammatory cytokines, as well as the production of MMPs, in BCAS-induced mice and LPS-stimulated astrocytes. CONCLUSION: Our results indicated that NBP represents a promising therapy for chronic cerebral hypoperfusion-induced white matter damage and cognitive impairment.

20.
Brain Res Bull ; 152: 85-94, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31301379

RESUMO

Absent in melanoma 2 (AIM2) senses damaged-associated molecular patterns (DAMPs) and recruits apoptosis speck-like protein (ASC) and caspase-1 to form a molecular platform for cerebral inflammation and neuronal pyroptosis. Here, we found that AIM2 was up-regulated in the hippocampus of 6-months-old APP/PS1 mice and further investigated the role of AIM2 in spatial memory, long term potentiation (LTP) and synaptic morphology. Our study demonstrated that AIM2 deletion remarkably promoted spatial memory of mice using Morris Water Maze test and Y-Maze test. In addition, AIM2 was found to be widely expressed in the CA1 neurons in the hippocampus. AIM2 deletion facilitated LTP in hippocampal slices and altered the structure of dendrites, especially increased the dendritic spine densities. Using transcriptional microarray, we found that 41 genes were down-regulated and 16 genes were up-regulated in AIM2-/- mice (fold change>=2.0 and p<0.05) compared to WT mice. We further verificated that AIM2 knockout significantly altered hippocampal Pten, Homer1 and Ppp2r3a levels with Western blotting and qPCR. Additionally, phosphorylation of AKT was profoundly enhanced after AIM2 deletion. Collectivelly, our data indicated that AIM2 deletion promoted spatial memory, synaptic plasticity and dendrite branching, which was probably related to its repressive effects on Pten and Ppp2r3a and stimulative effects on Homer 1 and AKT pathways.

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