factor beneficial for increasing bandgap and LIDT usually tend to decrease the NLO coefficient. [5] MIR NLO crystals are important components for outputting MIR lasers. However, according to these requirements, AGS and ZGP cannot satisfy the increasing market's needs in view of their low LIDTs and harmful doublephoton absorption. [6] Therefore, how to maintain the balance between high LIDT and strong NLO response is the main concern for researchers in this field. After years of exploration, MIR NLO materials with superior comprehensive properties are still scarce. Therefore, the discovery of novel ones with balanced comprehensive properties is urgent while challenging.Hitherto, MIR NLO materials are mainly metal chalcogenides, and also several mixed-anionic materials, such as oxyhalides

Chronic neuroinflammation has been shown to exert adverse influences on the pathology of Alzheimer's disease (AD), associated with the release of abundant proinflammatory mediators by excessively activated microglia, causing synaptic dysfunction, neuronal degeneration, and memory deficits. Thus, the prevention of microglial activation‐associated neuroinflammation is important target for deterring neurodegenerative disorders. Peony seed oil (PSO) is a new food resource, rich in α‐linolenic acid, the precursor of long chain omega‐3 polyunsaturated fatty acids, including docosahexaenoic acid and eicosapentaenoic acid, which exhibit anti‐inflammatory properties by altering cell membrane phospholipid fatty acid compositions, disrupting lipid rafts, and inhibiting the activation of the proinflammatory transcription factor NF‐κB. However, few studies have examined the anti‐neuroinflammatory effects of PSO in AD, and the relevant molecular mechanisms remain unclear. Presenilin1/2 conditional double knockout (PS cDKO) mice display obvious AD‐like phenotypes, such as neuroinflammatory responses, synaptic dysfunction, and cognitive deficits. Here, we assessed the potential neuroprotective effects of PSO against neuroinflammation‐mediated cognitive deficits in PS cDKO using behavioral tests and molecular biologic analyses. Our study demonstrated that PSO suppressed microglial activation and neuroinflammation through the down‐regulation of proinflammatory mediators, such as inducible NOS, COX‐2, IL‐1β, and TNF‐α, in the prefrontal cortex and hippocampus of PS cDKO mice. Further, PSO significantly lessened memory impairment by reversing hyperphosphorylated tau and synaptic proteins deficits in PS cDKO mice. Importantly, PSO's therapeutic effects on cognitive deficits were due to inhibiting neuroinflammatory responses mediated by NF‐κB signaling pathway. Taken together, PSO may represent an effective dietary supplementation to restrain the neurodegenerative processes of AD.

AimThe treatment of Alzheimer’s disease (AD) is still a worldwide problem due to the unclear pathogenesis and lack of effective therapeutic targets. In recent years, metabolomic and gut microbiome changes in patients with AD have received increasing attention, and the microbiome–gut–brain (MGB) axis has been proposed as a new hypothesis for its etiology. Considering that electroacupuncture (EA) efficiently moderates cognitive deficits in AD and its mechanisms remain poorly understood, especially regarding its effects on the gut microbiota, we performed urinary metabolomic and microbial community profiling on EA-treated AD model mice, presenilin 1/2 conditional double knockout (PS cDKO) mice, to observe the effect of EA treatment on the gut microbiota in AD and find the connection between affected gut microbiota and metabolites.Materials and methodsAfter 30 days of EA treatment, the recognition memory ability of PS cDKO mice was evaluated by the Y maze and the novel object recognition task. Urinary metabolomic profiling was conducted with the untargeted GC-MS method, and 16S rRNA sequence analysis was applied to analyze the microbial community. In addition, the association between differential urinary metabolites and gut microbiota was clarified by Spearman’s correlation coefficient analysis.Key findingsIn addition to reversed cognitive deficits, the urinary metabolome and gut microbiota of PS cDKO mice were altered as a result of EA treatment. Notably, the increased level of isovalerylglycine and the decreased levels of glycine and threonic acid in the urine of PS cDKO mice were reversed by EA treatment, which is involved in glyoxylate and dicarboxylate metabolism, as well as glycine, serine, and threonine metabolism. In addition to significantly enhancing the diversity and richness of the microbial community, EA treatment significantly increased the abundance of the genus Mucispirillum, while displaying no remarkable effect on the other major altered gut microbiota in PS cDKO mice, norank_f_Muribaculaceae, Lactobacillus, and Lachnospiraceae_NK4A136 group. There was a significant correlation between differential urinary metabolites and differential gut microbiota.SignificanceElectroacupuncture alleviates cognitive deficits in AD by modulating gut microbiota and metabolites. Mucispirillum might play an important role in the underlying mechanism of EA treatment. Our study provides a reference for future treatment of AD from the MGB axis.

Background Chronic neuroinflammation has been regarded as an important part of the pathological initiation of Alzheimer’s disease (AD), which is associated with the regulation of microglial activation. Preventing of microglial activation to inhibit neuroinflammation may become a potential target for the treatment of neurodegenerative diseases. Guizhi Fuling capsule (GZFL) has a strong repression on inflammatory responses. The phenotypes of presenilin1/2 conditional double knockout (PS cDKO) mice, which could well simulate a series of pathological characteristics in AD patients aggravated with age, were subject to behavioral tests and molecular biological analyses to evaluate the latent neuroprotective effects of GZFL on neuroinflammation-mediated cognitive deficits. Primary microglia induced by lipopolysaccharide (LPS) were used to explore the possible mechanism of GZFL on the improvement of neuroinflammation via testing the production of pro-inflammatory mediators and activation of Janus kinase 2 (JAK2) / signal transducer and activator of transcription 3 (STAT3) signaling pathway. Materials and methods PS cDKO mice were divided into: WT mice (WT), WT mice+GZFL (WT+GZFL), PS cDKO mice (cDKO), and PS cDKO mice+GZFL (cDKO+GZFL). Mice in the WT+GZFL and cDKO+GZFL group were fed standard chow containing 2000 ppm GZFL for 90 days. After 60 days of GZFL treatment, mice were given to behavioral tests for 30 days in order to explore the effects of GZFL on cognitive and motor function. Then, mice were sacrificed for examining the effects of GZFL on inflammation. Furthermore, primary microglia were obtained from neonatal Sprague-Dawley rats and pretreated with or without GZFL (50 μg/ml) for 1 h in the absence or presence of LPS (100 ng/ml) stimulation to speculate whether the underlying mechanism of GZFL’s anti-inflammatory potential was closely associated with JAK2/STAT3 signaling pathway. Results Our findings indicated that GZFL has the ability to alleviate memory deficits in PS cDKO mice, which attributes to the improvement of neuroinflammation by inhibiting microglial activation and the levels of pro-inflammatory mediators. In addition, GZFL can inverse the tau hyperphosphorylation and the lessened expression of synaptic proteins in hippocampus of PS cDKO mice. Furthermore, GZFL plays a key role in preventing LPS-induced neuroinflammatory responses in primary microglia by decreasing the levels of pro-inflammatory mediators. It is noteworthy that therapeutic effects of GZFL on memory impairment are depended on the inhibition of neuroinflammatory responses by the blockage of JAK2/STAT3 signaling pathway. Conclusions GZFL may be an effective compound Chinese medicine for the improvement and postponement of neurodegenerative progression in AD.

Anxiety, as an early manifestation of Alzheimer’s disease (AD), plays a significant role in the initial stages of cognitive decline and has a negative impact on the progression of the disease. However, the specific pathological mechanisms underlying anxiety in early stage of AD remain largely unknown. In this study, we investigated anxiety-like behaviors in presenilin 1/2 conditional double knockout (PS cDKO) mice, which are commonly used to study AD. To characterize anxiety-like behaviors, we conducted a battery of behavioral tests on young adult PS cDKO mice. Additionally, we performed electrophysiological recordings to examine the balance of excitatory and inhibitory activity in the synapses of pyramidal neurons and the neural network oscillations in the ventral hippocampus (vHPC) CA1 (vCA1) region of PS cDKO mice displaying anxiety-like behaviors. Our findings revealed a shift in the normal excitatory/inhibitory (E/I) balance and neural oscillations in the vCA1 region of PS cDKO mice with anxiety-like behaviors. Furthermore, we observed that parvalbumin-positive (PV+) interneurons, which play a crucial role in regulating the balance of excitatory and inhibitory activity, exhibited hypoexcitability in the vCA1 of PS cDKO mice. Mechanistically, we identified increased levels of Kv1.1, a voltage-gated potassium channel, in the vCA1 PV+ interneurons of PS cDKO mice. Genetically or pharmacologically, when we inhibited Kv1.1 in the vCA1 region, the hypoexcitability of PV+ interneurons was reversed and anxiety-like behaviors in PS cDKO mice were rescued. Therefore, we propose that the increased Kv1.1 levels in vCA1 PV+ interneurons reduce the excitability of PV+ interneurons, ensuing disrupted E/I balance of pyramidal neuron synapses causes anxiety in young adult PS cDKO mice. These findings provide new insights into the mechanisms underlying early AD-related anxiety-like behaviors.

Chronic neuroinflammation has been regarded as an important part of the pathological initiation of Alzheimer’s disease (AD), which is associated with the regulation of microglial activation. Preventing microglial activation to inhibit neuroinflammation may become a potential target for the treatment of neurodegenerative diseases. Guizhi Fuling capsule (GZFL) has a strong repression on inflammatory responses. Here, the presenilin1/2 conditional double knockout (PS cDKO) mice, a well-established mouse model of AD, were divided into: WT mice (WT), WT mice+GZFL (WT+GZFL), PS cDKO mice (cDKO), and PS cDKO mice+GZFL (cDKO+GZFL). Mice in the WT+GZFL and cDKO+GZFL group were fed standard chow containing 2000 ppm GZFL for 90 days. After 60 days of GZFL treatment, mice were given to behavioral tests for 30 days in order to explore the effects of GZFL on cognitive and motor function. Then, mice were sacrificed for examining the effects of GZFL on inflammation. Furthermore, primary microglia were obtained from neonatal Sprague-Dawley rats and pretreated with or without GZFL (50 μg/ml) for 1 h in the absence or presence of lipopolysaccharide (LPS) (100 ng/ml) stimulation to speculate whether the underlying mechanism of GZFL’s anti-inflammatory potential was closely associated with Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Our findings indicated that GZFL has the ability to alleviate memory deficits in PS cDKO mice, which attributes to the improvement of neuroinflammation by inhibiting microglial activation and the levels of pro-inflammatory mediators. In addition, GZFL could inverse the tau hyperphosphorylation and the lessened expression of synaptic proteins in hippocampus of PS cDKO mice. Furthermore, GZFL prevented LPS-induced neuroinflammatory responses in primary microglia by decreasing the levels of pro-inflammatory mediators. It is noteworthy that therapeutic effects of GZFL on memory impairment are depended on the inhibition of neuroinflammatory responses by the blockage of JAK2/STAT3 signaling pathway. Taken together, GZFL may be an effective compound Chinese medicine for the improvement and postponement of neurodegenerative progression in AD.