Comparing Equil patch versus traditional catheter insulin pump in type 2 diabetes using continuous glucose monitoring metrics and profiles.

AIMS: It is not clear whether there are differences in glycemic control between the Equil patch and the MMT-712 insulin pump. Our objective was to compare two types of insulin pumps in the treatment of type 2 diabetes mellitus (T2DM), using continuous glucose monitoring (CGM) metrics and profiles. METHODS: This was a randomized case-crossover clinical trial. Participants were hospitalized and randomly allocated to two groups and underwent two types of insulin pump treatments (group A: Equil patch-Medtronic MMT-712 insulin pump; group B: Medtronic MMT-712-Equil patch insulin pump) separated by a 1-day washout period. Glycemic control was achieved after 7-8 days of insulin pump therapy. Each patient received CGM for 5 consecutive days (from day 1 to day 5). On day 3 of CGM performance, the Equil patch insulin pump treatment was switched to Medtronic MMT-712 insulin pump treatment at the same basal and bolus insulin doses or vice versa. CGM metrics and profiles including glycemic variability (GV), time in range (TIR, 3.9-10.0 mmol/L), time below range (TBR, <3.9 mmol/L), time above range (TAR, >10.0 mmol/L), and postprandial glucose excursions, as well as incidence of hypoglycemia. RESULTS: Forty-six T2DM patients completed the study. There was no significant difference in parameters of daily GV and postprandial glucose excursions between the Equil patch insulin pump treatment and the Medtronic insulin pump treatment. Similarly, there was no between-treatment difference in TIR, TBR, and TAR, as well as the incidence of hypoglycemia. CONCLUSION: The Equil patch insulin pump was similar to the traditional MMT-712 insulin pump in terms of glycemic control. Equil patch insulin pump is a reliable tool for glycemic management of diabetes mellitus.

Improvement of Learning and Memory by Elevating Brain D-Aspartate in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is an inherited human mental retardation that arises from expansion of a CGG repeat in the Fmr1 gene, causing loss of the fragile X mental retardation protein (FMRP). It is reported that N-methyl-D-aspartate receptor (NMDAR)-mediated facilitation of long-term potentiation (LTP) and fear memory are impaired in Fmr1 knockout (KO) mice. In this study, biological, pharmacological, and electrophysiological techniques were performed to determine the roles of D-aspartate (D-Asp), a modulator of NMDAR, and its metabolizing enzyme D-aspartate oxidase (DDO) in Fmr1 KO mice. Levels of D-Asp were decreased in the medial prefrontal cortex (mPFC ); however, the levels of its metabolizing enzyme DDO were increased. Electrophysiological recordings indicated that oral drinking of D-Asp recovered LTP induction in mPFC from Fmr1 KO mice. Moreover, chronic oral administration of D-Asp reversed behavioral deficits of cognition and locomotor coordination in Fmr1 KO mice. The therapeutic action of D-Asp was partially through regulating functions of NMDARs and mGluR5/mTOR/4E-BP signaling pathways. In conclusion, supplement of D-Asp may benefit for synaptic plasticity and behaviors in Fmr1 KO mice and offer a potential therapeutic strategy for FXS.

Hand grip strength is inversely associated with total daily insulin dose requirement in patients with type 2 diabetes mellitus: a cross-sectional study.

Background: Short-term (2 weeks to 3 months) insulin intensive therapy using continuous subcutaneous insulin infusion (CSII) can improve islet beta cell function and prolong glycemic remission in patients with newly diagnosed type 2 diabetes mellitus (T2DM). However, the total daily insulin dose (TDD, IU/kg/d) required to achieve near-normoglycemic control with CSII still needs to be frequently adjusted based on blood glucose monitoring. Although real-time continuous glucose monitoring (rtCGM), which measures the interstitial fluid glucose concentration continuously without much difficulty, facilitates the adjustment of insulin dosage, its adoption in the T2DM population is strictly limited by insurance coverage and lack of awareness of rtCGM among clinicians. Thus, it is of clinical significance to identify easy-to-use parameters that may allow a more rapid and accurate prediction of TDD requirement. This study aimed to explore the association between hand grip strength (HGS) and TDD requirement in patients with T2DM receiving CSII therapy. Methods: A total of 180 eligible patients with T2DM were enrolled in the study and divided into three groups based on their HGS: low (L), medium (M), and high (H). The TDD requirement was calculated on day 7 or 8 of CSII treatment. Anthropometric parameters, including HGS, skeletal muscle mass, skeletal muscle index (SMI) and 6-m gait speed, and laboratory data, were collected on the morning of the second day after admission, within the first 24 h of CSII therapy. These parameters were used to identify significant predictors of TDD requirement using Pearson or Spearman correlation test, and stepwise multiple regression analysis. Results: There were no significant differences in age, duration of T2DM, waist-to-hip ratio (WHR), body mass index (BMI), blood pressure, liver function, estimated glomerular filtration rate, triglyceride, total cholesterol, glycosylated hemoglobin A1c (HbA1c), homeostatic model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of beta cell function (HOMA-ß) among the groups. The H group had higher body muscle mass-to-fat ratio (BMFR), skeletal muscle mass-to-fat ratio (SMFR), SMI, 6-m gait speed, and lower TDD requirement than the M and L groups. The HGS negatively correlated with TDD requirement (r = -0.33, p < 0.001) after adjusting for sex, age, BMI, WHR, HbA1c, Ln (HOMA-ß), Ln (HOMA-IR), Ln (BMFR), Ln (SMFR), SMI, and 6-m gait speed. Multivariate stepwise regression analysis indicated that HGS was an independent predictor of TDD requirement in patients with T2DM (ß = -0.45, p < 0 001). Conclusion: Lower HGS is associated with an increased TDD requirement in T2DM patients. HGS may facilitate the prediction of TDD requirement in T2DM patients receiving CSII therapy.

Prognostic nomograms for nasopharyngeal carcinoma with nodal features and potential indication for N staging system: Validation and comparison of seven N stage schemes.

PURPOSE: To identify the prognostic value of the nodal features, propose a nomogram-based N stage system and evaluate the performance of seven N stage schemes of nasopharyngeal carcinoma (NPC) patients. METHODS: Data from 1638 non-distant metastatic NPC patients were used to develop nomograms predicting 3-year and 5-year overall survival (OS) and distant metastasis-free survival (DMFS). Based on nomogram and multivariate analyses, a new N-stage scheme was proposed. The performance of the nomogram-based N staging system was assessed against five newly proposed N staging systems and the current 8th N staging system using a quantitative model to compare hazard consistency, discrimination, outcome prediction, and sample size balance. The Kaplan-Meier method with log-rank tests was used to compare survival differences. RESULTS: Nomograms to predict OS and DMFS were constructed using extranodal extension infiltrating the surrounding structures (ENEmax), maximal axial diameter (MAD), large retropharyngeal lymph nodes (RLN, minimal axial diameter > 1.5 cm), multiple central nodal necrosis (CNN), and total lymph node (LN) number and level. Multivariate analysis showed the independent prognostic value of ENEmax and MAD > 3 cm for all selected survival endpoints (p < 0.05). Large RLN and lower neck involvement were independently associated with OS (p < 0.05). We proposed using a large RLN and MAD > 3 cm as N2 factors, and ENEmax and lower neck involvement as N3 factors. Among the seven N-stage schemes, our nomogram-based N scheme and ENEmax to N3 scheme (ENE3) ranked in the top two in the overall comparison with the elevated outcome predicting value (highest c-index). However, between the N0, N1, N1, and N2 subgroups, the ENE3 scheme showed no difference in OS or DMFS (p > 0.05). CONCLUSION: The predictive model highlighted the independent prognostic value of ENEmax, cervical lymph node, MAD, and large RLN, which can be used as criteria for future N staging.

8-O-acetyl shanzhiside methylester protects against sleep deprivation-induced cognitive deficits and anxiety-like behaviors by regulating NLRP3 and Nrf2 pathways in mice.

Sleep deprivation (SD) is prevalent throughout the world, which has negative effects on cognitive abilities, and causing mood alterations. 8-O-acetyl shanzhiside methylester (8-OaS), a chief component in Lamiophlomis rotata (L. rotata) Kudo, possesses potent neuroprotective properties and analgesic effects. Here, we evaluated the alleviative effects of 8-OaS on memory impairment and anxiety in mice subjected to SD (for 72-h). Our results demonstrated that 8-OaS (0.2, 2, 20 mg/kg) administration dose-dependently ameliorated behavioral abnormalities in SD mice, accompanied with restored synaptic plasticity and reduced shrinkage and loss of hippocampal neurons. 8-OaS reduced the inflammatory response and oxidative stress injury in hippocampus caused by SD, which may be related to inhibition of NLRP3 inflammasome-mediated inflammatory process and activation of the Nrf2/HO-1 pathway. SD also led to increases in the expressions of TLR-4/MyD88, active NF-κB, pro-IL-1ß, TNFα and MDA, as well as a decrease in the level of SOD in mice hippocampus, which were reversed by 8-OaS administration. Moreover, our molecular docking analyses showed that 8-OaS also has good affinity for NLRP3 and Nrf2 signaling pathways. These results suggested that 8-OaS could be used as a novel herbal medicine for the treatment of sleep loss and for use as a structural base for developing new drugs.

Dissecting the heterogeneity of the microenvironment in primary and recurrent nasopharyngeal carcinomas using single-cell RNA sequencing.

Nasopharyngeal carcinoma (NPC) has a 10-15% recurrence rate, while no long term or durable treatment options are currently available. Single-cell profiling in recurrent NPC (rNPC) may aid in designing effective anticancer therapies, including immunotherapies. For the first time, we profiled the transcriptomes of ∼60,000 cells from four primary NPC and two rNPC cases to provide deeper insights into the dynamic changes in rNPC within radiation fields. Heterogeneity of both immune cells (T, natural killer, B, and myeloid cells) and tumor cells was characterized. Recurrent samples showed increased infiltration of regulatory T cells in a highly immunosuppressive state and CD8+ T cells in a highly cytotoxic and dysfunctional state. Enrichment of M2-polarized macrophages and LAMP3+ dendritic cells conferred enhanced immune suppression to rNPC. Furthermore, malignant cells showed enhanced immune-related features, such as antigen presentation. Elevated regulatory T cell levels were associated with a worse prognosis, with certain receptor-ligand communication pairs identified in rNPC. Even with relatively limited samples, our study provides important clues to complement the exploitation of rNPC immune environment and will help advance targeted immunotherapy of rNPC.

The effects of endodontic access cavity design on dentine removal and effectiveness of canal instrumentation in maxillary molars.

AIM: To evaluate in a laboratory setting, the impact of three designs of endodontic access cavities on dentine removal and effectiveness of canal instrumentation in extracted maxillary first molars using micro-computed tomography (micro-CT). METHODOLOGY: A total of 30 extracted intact maxillary first molars were selected and scanned by micro-CT with a voxel size of 24 µm and randomly distributed into three groups: the traditional endodontic cavity (TEC) group, the conservative endodontic cavity (CEC) group and the guided endodontic cavity (GEC) group. The pulp chambers of teeth in the groups were accessed accordingly. After root canal preparation, the teeth were rescanned. The volume of dentine removed after canal preparation, the noninstrumented canal areas, canal transportation and centring ratio were analysed. Data were analysed statistically using one-way analysis of variance. Tukey's post hoc test was used for multiple comparisons. The significance level was set at p < .05. RESULTS: The total volume of dentine removed was significantly greater in the TEC group after root canal preparation (p < .05). No significant differences in the volume of dentine removed occurred between the CEC and GEC groups (p > .05). The volume of dentine removed in the crown, pericervical dentine and coronal third of the canal was significantly lower in CEC and GEC groups when compared to that in the TEC group (p < .05), no difference was observed in the middle third of the canal and apical third of the canal amongst the three groups (p > .05). There was no significant difference in noninstrumented canal area, canal transportation and centring ratio amongst the TEC, CEC and GEC groups (p > .05). CONCLUSIONS: In extracted maxillary molars tested in a laboratory setting, CEC and GEC preserved more tooth tissue in the crown, pericervical dentine and coronal third of the canal compared with TEC after root canal preparation. The design of the endodontic access cavity did not impact on the effectiveness of canal instrumentation in terms of noninstrumented canal area, canal transportation and centring ratio.

Scutellarin ameliorates the stress-induced anxiety-like behaviors in mice by regulating neurotransmitters.

Anxiety disorders are a common frequently psychiatric symptom in patients that lead to disruption of daily life. Scutellarin (Scu) is the main component of Erigeron breviscapus, which has been used as a neuroprotective agent against glutamate-induced excitotoxicity. However, the potential effect of Scu on the stress-related neuropsychological disorders has not been clarified. In this study, Anxiety-like behavior was induced by acute restraint stress in mice. Scu were injected intraperitoneally (twice daily, 3 days). Results showed that Scu exhibited good protective activity on mice by decreasing transmitter release levels. Restraint stress caused significant anxiety like behavior in mice. Treatment of Scu could significantly improve the moving time of open arms in Elevated Plus Maze and central time on open field test. Scu treatment suppressed action potential firing frequency, restored excessive presynaptic quantal release, and down-regulated glutamatergic receptor expression levels in the prefrontal cortex (PFC) of stressed mice. GABAA Rα1 and GABAA γ2 expression in the brain PFC tissues of mice were nearly abrogated by Scu treatment. In stress-induced anxiety mice, stress can increase the frequency of mini excitatory postsynaptic currents (mEPSC), which can be reversed by Scu treatment. Therefore, Scu has a potent anxiolytic activity and may be valuable for the treatment of stress-induced anxiety disorders.

The Cognitive-Enhancing Effects of Dendrobium nobile Lindl Extract in Sleep Deprivation-Induced Amnesic Mice.

Chronic sleep deprivation (SD) causes neurological and neurodegenerative dysfunction including learning and memory deficit. The orchid Dendrobium nobile Lindl (DNL), is widely used as a Yin tonic and medicinal food throughout Asia, and has many reported pharmacological effects. This study focused on the cognitive-enhancing effects of DNL in sleep deprivation-induced amnesia in mice and its biochemical mechanisms. Our results showed that the mice displayed significant cognitive deficits after 2-week SD while treatment with the extract of DNL prevented these impairments. In the novel object recognition and object location recognition tasks, a significant increase in the discrimination index was observed in DNL-treated (200 and 400 mg/kg) mice. In the MWM test, DNL (200 and 400 mg/kg) treatment shorten the prolongation of latency and increased the crossing numbers compared with SD mice. The biochemical analysis of brain tissue showed a decrease in NE, dismutase (T-SOD) and catalase (CAT) activity and an increase in 5-HT and malondialdehyde (MDA) concentration after the treatment with DNL in mice. Our findings indicated that DNL exerted a positive effect in preventing and improving cognitive impairment induced by SD, which may be mediated via the regulation of neurotransmitters and alleviation of oxidative stress.

Epigenetic suppression of liver X receptor ß in anterior cingulate cortex by HDAC5 drives CFA-induced chronic inflammatory pain.

BACKGROUND: Liver X receptors (LXRs), including LXRα and LXRß, are key regulators of transcriptional programs for both cholesterol homeostasis and inflammation in the brain. Here, the modes of action of LXRs and the epigenetic mechanisms regulating LXRß expression in anterior cingulate cortex (ACC) of chronic inflammatory pain (CIP) are investigated. METHODS: The deficit of LXR isoform and analgesic effect of LXR activation by GW3965 were evaluated using the mouse model of CIP induced by hindpaw injection of complete Freund's adjuvant (CFA). The mechanisms involved in GW-mediated analgesic effects were analyzed with immunohistochemical methods, ELISA, co-immunoprecipitation (Co-IP), Western blot, and electrophysiological recording. The epigenetic regulation of LXRß expression was investigated by chromatin immunoprecipitation, quantitative real-time PCR, and sequencing. RESULTS: We revealed that CFA insult led to LXRß reduction in ACC, which was associated with upregulated expression of histone deacetylase 5 (HDAC5), and knockdown of LXRß by shRNA led to thermal hyperalgesia. Co-IP showed that LXRß interacted with NF-κB p65 physically. LXRß activation by GW3965 exerted analgesic effects by inhibiting the nuclear translocation of NF-κB, reducing the phosphorylation of mitogen-activated protein kinases (MAPKs) in ACC, and decreasing the promoted input-output and enhanced mEPSC frequency in ACC neurons after CFA exposure. In vitro experiments confirmed that HDAC5 triggered histone deacetylation on the promoter region of Lxrß, resulting in downregulation of Lxrß transcription. CONCLUSION: These findings highlight an epigenetic mechanism underlying LXRß deficits linked to CIP, and LXRß activation may represent a potential novel target for the treatment of CIP with an alteration in inflammation responses and synaptic transmission in ACC.

[Adsorption, Reclaim, and Regeneration of Cd by Magnetic Calcium Dihydrogen Phosphate Nanoparticles].

In order to improve the adsorption-separation of Cd2+ in water treatment, magnetic Fe3O4 coated Ca(H2PO4)2 nanoparticles (NMCDP) were developed by coprecipitation. The properties of these nanoparticles were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and magnetization curves. Experiments were carried out to investigate the effect of adsorption, reclaiming, and regeneration. The results showed that NMCDP was a stable material with a particle size of 60 nm and a saturation magnetization of 30.9 emu·g-1. The adsorption rate of Cd2+ by NMCDP was fast, and adsorption equilibrium could be achieved within 1 hour. The kinetic data were well fitted by a pseudo-second-order model, and the isotherm adsorption data agreed with the Langmuir and Freundlich model, with a maximum adsorption capacity of 142.50 mg·g-1. The adsorption capacity of Cd2+ was affected by the pH and increased when the pH was increased from 2 to 3, while with continued increase of the pH of the solution, the adsorption capacity gradually became stable. The coexisting ions in the solution had an effect on the adsorption of Cd2+, especially the divalent cation Cu2+. The NMCDP could be regenerated by using 0.01 mol·L-1 HCl and EDTA-Na2, and the results indicated that it could be recycled with a desorption rate of 68% by EDTA-Na2 solution.

CB1 agonism prolongs therapeutic window for hormone replacement in ovariectomized mice.

Hormone therapy (HT) is reported to be deficient in improving learning and memory in older postmenopausal women according to recent clinical studies; however, the reason for failure is unknown. A "window of opportunity" for estrogen treatment is proposed to explain this deficiency. Here, we found that facilitation of memory extinction and long-term depression by 17ß-estradiol (E2) was normal in mice 1 week after ovariectomy (OVXST), but it was impaired in mice 3 months after ovariectomy (OVXLT). High-throughput sequencing revealed a decrease of miR-221-5p, which promoted cannabinoid receptor 1 (CB1) ubiquitination by upregulation of Neurl1a/b in E2-treated OVXLT mice. Blood samples from postmenopausal women aged 56-65 indicated decreases of miR-221-5p and 2-arachidonoylglycerol compared with samples from perimenopausal women aged 46-55. Replenishing of miR-221-5p or treatment with a CB1 agonist rescued the impairment of fear extinction in E2-treated OVXLT mice. The present study demonstrates that an HT time window in mice can be prolonged by cotreatment with a CB1 agonist, implying a potential strategy for HT in long-term menopausal women.

SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice.

Intermittent food deprivation (fasting, IF) improves mood and cognition and protects neurons against excitotoxic degeneration in animal models of epilepsy and Alzheimer's disease (AD). The mechanisms by which neuronal networks adapt to IF and how such adaptations impact neuropathological processes are unknown. We show that hippocampal neuronal networks adapt to IF by enhancing GABAergic tone, which is associated with reduced anxiety-like behaviors and improved hippocampus-dependent memory. These neuronal network and behavioral adaptations require the mitochondrial protein deacetylase SIRT3 as they are abolished in SIRT3-deficient mice and wild type mice in which SIRT3 is selectively depleted from hippocampal neurons. In the AppNL-G-F mouse model of AD, IF reduces neuronal network hyperexcitability and ameliorates deficits in hippocampal synaptic plasticity in a SIRT3-dependent manner. These findings demonstrate a role for a mitochondrial protein deacetylase in hippocampal neurons in behavioral and GABAergic synaptic adaptations to IF.

In Vitro Susceptibility of Berberine Combined with Antifungal Agents Against the Yeast Form of Talaromyces marneffei.

Talaromyces (Penicillium) marneffei can cause fatal disseminated infection in immunocompromised hosts. However, therapeutic strategies for the mycosis are limited. Reports of the other fungi suggest that berberine, a component of traditional herb, inhibitors interact with antifungal agents to improve the treatment outcomes. In the study, we evaluated the in vitro efficacy of berberine in combination with conventional antifungal agents against the pathogenic yeast form of T. marneffei. We demonstrate the synergistic effect of combination of berberine with fluconazole (52.38%), itraconazole (66.67%), voriconazole (71.43%), amphotericin B (71.43%) or caspofungin (52.38%) of T. marneffei strains, respectively. Time-kill curves confirmed the synergistic interaction, and no antagonistic was observed in all of the combinations. In conclusion, berberine could enhance the efficacy of conventional antifungal agents against the yeast form of T. marneffei in vitro. The results indicated berberine might have a potential role in combination therapy for talaromycosis.

Silibinin exerts antidepressant effects by improving neurogenesis through BDNF/TrkB pathway.

Classic antidepressants benefit depression patients partially by improving neurogenesis and/or brain-derived neurotrophic factor (BDNF)/TrkB pathway which were impaired in depression. In this study, we demonstrated that Silibinin (SLB), a polyphenolic flavanoid from Silybum marianum, ameliorated reserpinized mouse depressant-like behaviors. The antidepressants of SLB administration was associated with increased neural stem cells (NSCs) proliferation and further confirmed in BDNF/TrkB signaling transduction. SLB treatment reversed the decreased expression levels of BDNF and its receptor TrkB, and the reduced activation of downstream target proteins including phosphorylated extracellular-regulated protein kinase (p-ERK) and phosphorylated cAMP-response element binding protein (p-CREB) in depressived hippocampus. Furthermore, intracerebroventricular injection of GNF5837, a TrkB antagonist, abrogated antidepressant-like effects of SLB in mice along with the improved NSC proliferation, as well as enhanced levels of p-ERK and p-CREB in mice hippocampus. Taken together, these results suggest that SLB may exert antidepressant effects through BDNF/TrkB signaling pathway to improve NSC proliferation in acute depression.

Activation of liver X receptor ß-enhancing neurogenesis ameliorates cognitive impairment induced by chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion (CCH), a leading cause of various cerebrovascular diseases, leads to cognitive dysfunction due to neuron loss and impaired neurogenesis. Liver X receptors (LXRs), including LXRα and LXRß isoforms, are crucial for cholesterol metabolism, synaptic plasticity as well as neurogenesis. However, it is not clear the potential roles of LXRs in the pathogenesis of cognitive impairment induced by CCH. In this study, we demonstrated that LXRß expression decreased in hippocampus of CCH mice. GW3965, a synthetic dual agonist for both LXRα and LXRß, ameliorated impairment of learning and memory in CCH mice by promoting neuronal survival and neural stem cells (NSCs) proliferation in dentate gyrus (DG) of CCH mice. The proliferative effects of GW3965 were further confirmed in cultured neural progenitor cells (NPCs) and showed in a concentration-dependent manner. Moreover, GW3965 phosphorylated protein kinase B (Akt) at Ser473 in a time- and concentration-dependent manner in NPCs. Furthermore, both LY294002, an inhibitor for phosphoinositide-3-kinase (PI3K), and short hairpin RNAs for LXRß knockdown, abrogated GW3965-induced Akt phosphorylation, and therefore abolished GW3965-mediated proliferation-promoting of NPCs. All the data suggested that GW3965 ameliorated impaired cognitive functions in CCH by promoting NSC proliferation through PI3K/Akt pathway followed LXRß activation. This study correlates a deficit of LXRß in cognitive dysfunction in CCH with impaired neurogenesis in hippocampus, and LXRs may serve as a potential therapeutic target for chronic cerebral ischemia.

Elevated progranulin contributes to synaptic and learning deficit due to loss of fragile X mental retardation protein.

Fragile X syndrome is an inheritable form of intellectual disability caused by loss of fragile X mental retardation protein (FMRP, encoded by the FMR1 gene). Absence of FMRP caused overexpression of progranulin (PGRN, encoded by GRN), a putative tumour necrosis factor receptor ligand. In the present study, we found that progranulin mRNA and protein were upregulated in the medial prefrontal cortex of Fmr1 knock-out mice. In Fmr1 knock-out mice, elevated progranulin caused insufficient dendritic spine pruning and late-phase long-term potentiation in the medial prefrontal cortex of Fmr1 knock-out mice. Partial progranulin knock-down restored spine morphology and reversed behavioural deficits, including impaired fear memory, hyperactivity, and motor inflexibility in Fmr1 knock-out mice. Progranulin increased levels of phosphorylated glutamate ionotropic receptor GluA1 and nuclear factor kappa B in cultured wild-type neurons. Tumour necrosis factor receptor 2 antibody perfusion blocked the effects of progranulin on GluA1 phosphorylation; this result indicates that tumour necrosis factor receptor 2 is required for progranulin-mediated GluA1 phosphorylation and late-phase long-term potentiation expression. However, high basal level of progranulin in Fmr1 knock-out mice prevented further facilitation of synaptic plasticity by exogenous progranulin. Partial downregulation of progranulin or tumour necrosis factor receptor 2/nuclear factor kappa B signalling restored synaptic plasticity and memory deficits in Fmr1 knock-out mice. These findings suggest that elevated PGRN is linked to cognitive deficits of fragile X syndrome, and the progranulin/tumour necrosis factor receptor 2 signalling pathway may be a putative therapeutic target for improving cognitive deficits in fragile X syndrome.

Picosecond mid-infrared optical parametric amplifier based on LiInSe2 with tenability extending from 3.6 to 4.8 µm.

A picosecond (ps) mid-infrared (MIR) optical parametric amplifier (OPA) with LiInSe2 crystal was demonstrated for the first time. The MIR OPA was pumped by a 30 ps 1064 nm Nd:YAG laser and injected by a barium boron oxide (BBO)-based widely tunable near-infrared seed. A maximum idler pulse energy of 433 µJ at 4 µm has been obtained under a pump energy of 17 mJ, and the corresponding pulse duration was estimated to be ~13 ps. To our knowledge, this is the highest single pulse energy generated by LiInSe2 crystal. Furthermore, an idler spectrum tuning from 3.6 to 4.8 µm was investigated at fixed pump energy of 15 mJ.

Imbalance between TNFα and progranulin contributes to memory impairment and anxiety in sleep-deprived mice.

Sleep disorder is becoming a widespread problem in current society, and is associated with impaired cognition and emotional disorders. Progranulin (PGRN), also known as granulin epithelin precursor, promotes neurite outgrowth and cell survival, and is encoded by the GRN gene. It is a tumor necrosis factor α receptor (TNFR) ligand which is implicated in many central nervous system diseases. However, the role PGRN in sleep disorder remains unclear. In the present study, we found that sleep deprivation (S-DEP) impaired the memory and produced thigmotaxis/anxiety-like behaviors in mice. S-DEP increased the levels of TNFα but decreased PGRN levels in the hippocampus. The intracerebroventricular (ICV) injection of PGRN or intraperitoneal injection of TNFα synthesis blocker thalidomide (25 mg/kg), prevented the memory impairment and anxiety behaviors induced by S-DEP. PGRN treatment also restored dendritic spine density in the hippocampus CA1 region and neurogenesis in hippocampus dentate gyrus (DG). These results indicate that an imbalance between TNFα and PGRN contributes to memory impairment and thigmotaxis/anxiety caused by sleep deprivation.

A novel thiazolidinediones ATZD2 rescues memory deficits in a rat model of type 2 diabetes through antioxidant and antiinflammation.

Type 2 diabetes (T2DM) has been associated with learning and memory impairment; however, drugs for diabetes could not prevent the development of cognitive decline in T2DM patients. In the present study, compounds derived from thiazolidinediones (TZD), a PPAR-γ agonist, were synthesized by conjuncting the alkyl-substituted benzimidazole group to TZD group (ATZDs). Based on the in vitro evaluation, the neuroprotection of ATZD2 was further investigated using a streptozotocin-induced T2DM rat model. Pharmacokinetic study showed that ATZD2 could pass the blood-brain barrier (BBB) while the rosiglitazone (RSG, the precursor compound of ATZD2) not. Administration of ATZD2 significantly promoted the survival rate and attenuated fasting blood glucose (FBG) levels as compared to RSG treatment in T2DM rats. Furthermore, ATZD2 treatment ameliorated the impairment of learning and memory by Morris water maze test. The beneficial effects of ATZD2 were associated with the down-regulation of hypoxia induced factor-1α, aldose reductase, and Bax expression which are related to T2DM pathology. ATZD2 treatment also attenuated the expression of inflammatory cytokines and restored the balance of redox in the diabetic hippocampus. These effects were more potent as compared with that of RSG at the same dose. The data indicate that ATZD2 may be a potent agent for the treatment of cognitive dysfunction in T2DM.