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Background: The oral ingestion of scallop-derived plasmalogen (sPlas) significantly improved cognitive function in Alzheimer's disease (AD) patients.Objective: However, the effects and mechanisms of sPlas on AD with chronic cerebral hypoperfusion (CCH), a class of mixed dementia contributing to 20-30% among the dementia society, were still elusive.Methods: In the present study, we applied a novel mouse model of AD with CCH to investigate the potential effects of sPlas on AD with CCH.Results: The present study demonstrated that sPlas significantly recovered cerebral blood flow, improved motor and cognitive deficits, reduced amyloid-β pathology, regulated neuroinflammation, ameliorated neural oxidative stress, and inhibited neuronal loss in AD with CCH mice at 12 M.Conclusion: These findings suggest that sPlas possesses clinical and pathological benefits for AD with CCH in the novel model mice. Furthermore, sPlas could have promising prevention and therapeutic effects on patients of AD with CCH. [ABSTRACT FROM AUTHOR]

PUMA ( p53 up-regulated mediator of apoptosis) is particularly important in initiating radiation-induced damage and apoptosis. It has been shown that inhibition of PUMA can provide a profound benefit for the long-term survival of the mice, without an increased risk of malignancies after irradiation. It becomes to be a potential target for developing an effective treatment aimed to protect cells from lethal radiation. CLZ-8, a novel small-molecular inhibition targeting PUMA, could have considerable protection against cell apoptosis and DNA damage. The aim of the present study is to evaluate CLZ-8′s radioprotective ability to enhance survival rate of mice exposed to gamma radiation, prevent radiation-induced apoptosis, and repair DNA damage in cultured cells. We have determined the best effective dose in vivo is 200 mg/kg. This dose of CLZ-8 administered at 30 min before radiation can notably enhance mice survival rate. CLZ-8 ameliorates radiation-induced HUVEC cells damage and reduces apoptosis counts compared to vehicle-treated cells. Western blotting analysis indicates that CLZ-8 selectively inhibits overexpressed PUMA induced by radiation. The results demonstrate that CLZ-8 ameliorates radiation-induced cell depletion, promotes DNA recovery, and protects mice from radiation injury. [ABSTRACT FROM AUTHOR]

[Display omitted] • sPlas significantly reduced cerebral ischemic infarction in mice at 5 d after tMCAO. • sPlas significantly alleviated neural oxidative stress in mice at 5 d after tMCAO. • sPlas significantly regulated neural inflammation in mice at 5 d after tMCAO. • sPlas significantly attenuated neurovascular unit damage in mice at 5 d after tMCAO. • sPlas may be a preventive and therapeutic candidate against ischemic stroke. Scallop-derived plasmalogen (sPlas) has both anti-oxidative and anti-inflammation activities, but its efficacy has not been investigated in ischemic stroke models where oxidative stress, inflammation, and neurovascular unit (NVU) damage accelerates pathophysiological progression. Therefore, in the present study, we aimed to assess the neuroprotective effects of sPlas in ischemic stroke by using a transient middle cerebral artery occlusion (tMCAO) mouse model. After the pretreatment of vehicle or sPlas (10 mg/kg/day) for 14 days, adult male mice were subjected to tMCAO for 60 min, then continuously treated with vehicle or sPlas during reperfusion and for an additional 5 days. The administration of sPlas significantly improved motor deficits (corner and rotarod tests, * p < 0.05 vs vehicle), enhanced serum antioxidative activity (OXY-adsorbent and d-ROMs tests, * p < 0.05 vs vehicle), reduced infarction volume (* p < 0.05 vs vehicle), decreased the expression of two oxidative stress markers, 4-HNE (* p < 0.05 vs vehicle) and 8-OHdG (* p < 0.05 vs vehicle), decreased the expression of pro-inflammatory markers Iba-1 (** p < 0.01 vs vehicle), IL-1β (** p < 0.01 vs vehicle), and TNF-α (** p < 0.01 vs vehicle), and alleviated NVU damage (collagen IV, MMP9, and GFAP/collagen IV, * p < 0.05 vs vehicle). Our present findings are the first to demonstrate the neuroprotective effects of sPlas on acute ischemic stroke mice at 5 d after tMCAO via anti-oxidative stress, anti-inflammation, and improvement of NVU damage, suggesting the potential of sPlas in preventing and treating ischemic stroke. [ABSTRACT FROM AUTHOR]

• Plasmalogen strongly attenuated the activation of pSTAT3/PIM1/NFATc1 axis. • Plasmalogen significantly suppressed NLRP3 inflammasome activation. • Plasmalogen tended to improve cerebral HP-enhanced cerebral vascular dysfunction. A strong relationship between Alzheimer's disease (AD) and vascular dysfunction has been the focus of increasing attention in aging societies. In the present study, we examined the long-term effect of scallop-derived plasmalogen (sPlas) on vascular remodeling-related proteins in the brain of an AD with cerebral hypoperfusion (HP) mouse model. We demonstrated, for the first time, that cerebral HP activated the axis of the receptor for advanced glycation endproducts (RAGE)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/provirus integration site for Moloney murine leukemia virus 1 (PIM1)/nuclear factor of activated T cells 1 (NFATc1), accounting for such cerebral vascular remodeling. Moreover, we also found that cerebral HP accelerated pSTAT3-mediated astrogliosis and activation of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, probably leading to cognitive decline. On the other hand, sPlas treatment attenuated the activation of the pSTAT3/PIM1/NFATc1 axis independent of RAGE and significantly suppressed NLRP3 inflammasome activation, demonstrating the beneficial effect on AD. [ABSTRACT FROM AUTHOR]

Carnosine (β-alanyl-L-histidine) is a natural dipeptide with multiple neuroprotective properties. Previous studies have advertised that carnosine scavenges free radicals and displays anti-inflammatory activity. However, the underlying mechanism and the efficacies of its pleiotropic effect on prevention remained obscure. In this study, we aimed to investigate the anti-oxidative, anti-inflammative, and anti-pyroptotic effects of carnosine in the transient middle cerebral artery occlusion (tMCAO) mouse model. After a daily pre-treatment of saline or carnosine (1000 mg / kg / day) for 14 days, mice (n = 24) were subjected to tMCAO for 60 min and continuously treated with saline or carnosine for additional 1 and 5 days after reperfusion. The administration of carnosine significantly decreased infarct volume 5 days after the tMCAO (* p < 0.05) and effectively suppressed the expression of 4-HNE, 8-OHdG, Nitrotyrosine 5 days, and RAGE 5 days after tMCAO. Moreover, the expression of IL-1 β was also significantly suppressed 5 days after tMCAO. Our present findings demonstrated that carnosine effectively relieves oxidative stress caused by ischemic stroke and significantly attenuates neuroinflammatory responses related to IL-1 β , suggesting that carnosine can be a promising therapeutic strategy for ischemic stroke. [Display omitted] • Carnosine significantly reduced infarct volume 5 days after tMCAO. • Carnosine significantly alleviated neural oxidative stress 1 and 5 days after tMCAO. • Carnosine significantly regulated inflammation marker expression 5 days after tMCAO. [ABSTRACT FROM AUTHOR]

Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients. Compared with wild type (WT), these proteins displayed age-dependent and progressive nuclear precipitations, and cytoplasmic aberrant expressions in motor neurons of lumbar cord in SOD1-Tg mice from 10 to 18 weeks (W). Double immunofluorescent analysis showed abnormal nuclear retention and apparent co-localizations of RanGAPl with NUP205 and NUP205 with NUPl07, meanwhile, GP210 with NUP205 mainly co-localized in the nuclear envelope (NE) of motor neurons. Furthermore, RanGAP1, GP210 and NUP50 showed similarly abnormal nuclear precipitations and cytoplasmic upregulations in SOD1-Tg mice and ALS patients, moreover, aberrant co-localizations of RanGAP1 with TDP-43 and NUP205 with TDP-43 were also observed in motor neurons. The present study indicated that the mislocalization of these proteins of NPCs may underlie the pathogenesis of ALS both in SOD1-Tg mice and human sporadic ALS patients, and these dysfunctions may be a fundamental pathway for ALS that is not specific only in C9-ALS but also in SOD1-ALS, which may be amenable to pharmacotherapeutic intervention. [ABSTRACT FROM AUTHOR]

[Display omitted] • FGA, FGB, and FGG accumulation increased in the CNS in Alzheimer's disease. • Aβ deposition related to FGA, FGB, and FGG accumulated in neural cells and vessels. • FGA, FGB, and FGG are potential targets for AD diagnosis and therapy. Alzheimer's disease (AD) is a common neurodegenerative disease that is characterized by the abnormal accumulation of intracellular and extracellular amyloid-β (Aβ) as well as disruption of the blood brain barrier (BBB). Fibrinogen plays an essential role in regulating thrombosis, wound healing, and other biological functions. In the present study, we investigated the relationship between three polypeptide chains α, β, and γ (FGA, FGB, and FGG) and Aβ deposition in the APP23 plus chronic cerebral hypoperfusion (CCH) mice model as well as the human AD brain. FGA, FGB, and FGG accumulated when Aβ was deposited in neural cells and cerebral vessels. This deposition was significantly higher in AD plus CCH mice models relative to wild-type brains, and in human AD brains compared to control brains. The present study demonstrates that FGA, FGB, and FGG are associated with AD progress, and can thus be potential targets for the diagnosis and therapy of AD. [ABSTRACT FROM AUTHOR]