Phosphodiesterase 8 (PDE8): Distribution and Cellular Expression and Association with Alzheimer's Disease.

Phosphodiesterase 8 (PDE8), as a member of PDE superfamily, specifically promotes the hydrolysis and degradation of intracellular cyclic adenosine monophosphate (cAMP), which may be associated with pathogenesis of Alzheimer's disease (AD). However, little is currently known about potential role in the central nervous system (CNS). Here we investigated the distribution and expression of PDE8 in brain of mouse, which we believe can provide evidence for studying the role of PDE8 in CNS and the relationship between PDE8 and AD. Here, C57BL/6J mice were used to observe the distribution patterns of two subtypes of PDE8, PDE8A and PDE8B, in different sexes in vivo by western blot (WB). Meanwhile, C57BL/6J mice were also used to demonstrate the distribution pattern of PDE8 in selected brain regions and localization in neural cells by WB and multiplex immunofluorescence staining. Furthermore, the triple transgenic (3×Tg-AD) mice and wild type (WT) mice of different ages were used to investigate the changes of PDE8 expression in the hippocampus and cerebral cortex during the progression of AD. PDE8 was found to be widely expressed in multiple tissues and organs including heart, kidney, stomach, brain, and liver, spleen, intestines, and uterus, with differences in expression levels between the two subtypes of PDE8A and PDE8B, as well as two sexes. Meanwhile, PDE8 was widely distributed in the brain, especially in areas closely related to cognitive function such as cerebellum, striatum, amygdala, cerebral cortex, and hippocampus, without differences between sexes. Furthermore, PDE8A was found to be expressed in neuronal cells, microglia and astrocytes, while PDE8B is only expressed in neuronal cells and microglia. PDE8A expression in the hippocampus of both female and male 3×Tg-AD mice was gradually increased with ages and PDE8B expression was upregulated only in cerebral cortex of female 3×Tg-AD mice with ages. However, the expression of PDE8A and PDE8B was apparently increased in both cerebral cortex and hippocampus in both female and male 10-month-old 3×Tg-AD mice compared WT mice. These results suggest that PDE8 may be associated with the progression of AD and is a potential target for its prevention and treatment in the future.

Imbalance of multiple neurotransmitter pathways leading to depression-like behavior and cognitive dysfunction in the triple transgenic mouse model of Alzheimer disease.

Depression is among the most frequent psychiatric comorbid conditions in Alzheimer disease (AD). However, pharmacotherapy for depressive disorders in AD is still a big challenge, and the data on the efffcacy of current antidepressants used clinically for depressive symptoms in patients with AD remain inconclusive. Here we investigated the mechanism of the interactions between depression and AD, which we believe would aid in the development of pharmacological therapeutics for the comorbidity of depression and AD. Female APP/PS1/Tau triple transgenic (3×Tg-AD) mice at 24 months of age and age- and sex-matched wild-type (WT) mice were used. The shuttle-box passive avoidance test (PAT) were implemented to assess the abilities of learning and memory, and the open field test (OFT) and the tail suspension test (TST) were used to assess depression-like behavior. High-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used to detect the level of neurotransmitters related to depression in the hippocampus of mice. The data was identified by orthogonal projections to latent structures discriminant analysis (OPLS-DA). Most neurotransmitters exert their effects by binding to the corresponding receptor, so the expression of relative receptors in the hippocampus of mice was detected using Western blot. Compared to WT mice, 3×Tg-AD mice displayed significant cognitive impairment in the PAT and depression-like behavior in the OFT and TST. They also showed significant decreases in the levels of L-tyrosine, norepinephrine, vanillylmandelic acid, 5-hydroxytryptamine, and acetylcholine, in contrast to significant increases in 5-hydroxyindoleacetic acid, L-histidine, L-glutamine, and L-arginine in the hippocampus. Moreover, the expression of the alpha 1a adrenergic receptor (ADRA1A), serotonin 1 A receptor (5HT1A), and γ-aminobutyric acid A receptor subunit alpha-2 (GABRA2) was significantly downregulated in the hippocampus of 3×Tg-AD mice, while histamine H3 receptor (H3R) expression was significantly upregulated. In addition, the ratio of phosphorylated cAMP-response element-binding protein (pCREB) and CREB was significantly decreased in the hippocampus of 3×Tg-AD mice than WT mice. We demonstrated in the present study that aged female 3×Tg-AD mice showed depression-like behavior accompanied with cognitive dysfunction. The complex and diverse mechanism appears not only relevant to the imbalance of multiple neurotransmitter pathways, including the transmitters and receptors of the monoaminergic, GABAergic, histaminergic, and cholinergic systems, but also related to the changes in L-arginine and CREB signaling molecules.

The Phosphodiesterase-4 Inhibitor Roflumilast, a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer's Disease: A Preclinical Study in APP/PS1 Transgenic Mice.

BACKGROUND: Depression is highly related to Alzheimer's disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis. METHODS: Here we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays. RESULTS: In the novel object recognition and Morris water-maze, APPswe/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin-eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice. CONCLUSIONS: Together, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B/PDE4D-mediated cAMP/cAMP response element-binding protein/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.

The WRKY transcription factor WRKY8 promotes resistance to pathogen infection and mediates drought and salt stress tolerance in Solanum lycopersicum.

WRKY transcription factors play a key role in the tolerance of biotic and abiotic stresses across various crop species, but the function of some WRKY genes, particularly in tomato, remains unexplored. Here, we characterize the roles of a previously unstudied WRKY gene, SlWRKY8, in the resistance to pathogen infection and the tolerance to drought and salt stresses. Expression of SlWRKY8 was up-regulated upon Pseudomonas syringae pv. tomato DC3000 (Pst. DC3000), abiotic stresses such as drought, salt and cold, as well as ABA and SA treatments. The SlWRKY8 protein was localized to the nucleus with no transcription activation in yeast, but it could activate W-box-dependent transcription in plants. The overexpression of SlWRKY8 in tomato conferred a greater resistance to the pathogen Pst. DC3000 and resulted in the increased transcription levels of two pathogen-related genes SlPR1a1 and SlPR7. Moreover, transgenic plants displayed the alleviated wilting or chlorosis phenotype under drought and salt stresses, with higher levels of stress-induced osmotic substances like proline and higher transcript levels of the stress-responsive genes SlAREB, SlDREB2A and SlRD29. Stomatal aperature was smaller under drought stress in transgenic plants, maintaining higher water content in leaves compared with wild-type plants. The oxidative pressure, indicated by the concentration of hydrogen peroxide (H2 O2 ) and malondialdehyde (MDA), was also reduced in transgenic plants, where we also observed higher levels of antioxidant enzyme activities under stress. Overall, our results suggest that SlWRKY8 functions as a positive regulator in plant immunity against pathogen infection as well as in plant responses to drought and salt stresses.

Manipulation of pseudo-spin guiding and flat bands for topological edge states.

Topological edge states and pseudo spins are promising paradigms to explore a new phase of matter in condensed matter physics. Here, we reveal the regulatory mechanism for guiding pseudo spin states along the interface between trivial and topological regions with elliptic cylinders made of conventional silicon material. A spin-guiding path introduced by an arrangement of elliptic cylinders exhibits high efficiency, large operation bandwidth and robustness to imperfections with tunable parameters. The pseudo spins of four types of silicon-based unit cells are measured, which may open exciting possibilities for unexpected topological properties such as flat bands. We manipulate a wide flat band with near-zero group velocities, which excites both pseudo spin up and down modes at the interface. The proposed concept might be implemented in photonic fabrication, facilitating potential applications for integrated optical devices.

Therapeutic Effects of 6-Gingerol, 8-Gingerol, and 10-Gingerol on Dextran Sulfate Sodium-Induced Acute Ulcerative Colitis in Rats.

Ulcerative colitis is one of the most common types of inflammatory bowel disease and is multifactorial and relapsing. 6-Gingerol, a component of gingerols extracted from ginger (Zingiber officinale), has been reported to improve ulcerative colitis. The present study aims to investigate the therapeutic efficacy of two analogous forms of 6-gingerol, 8-gingerol, and 10-gingerol, on ulcerative colitis. Colitis was induced in rats through consumption of 5% (w/v) dextran sulfate sodium drinking water for 7 consecutive days. 6-Gingerol, 8-gingerol, and 10-gingerol were then given intraperitoneally at doses of 30 mg kg-1  d-1 for another 7 days, respectively. Body weight change, disease activity index, inflammatory cytokines, and oxidative stress indices were measured, and the colonic tissue injuries were assessed macroscopically and histopathologically. Results showed that all three gingerols attenuated colitic symptoms evoked by dextran sulfate sodium, significantly elevated superoxide dismutase activity, decreased malondialdehyde levels and myeloperoxidase activity in the colon tissue, and markedly reduced the content of tumor necrosis factor alpha and Interleukin 1 beta in the serum. Histological observations showed that all three gingerols obviously accelerated mucosal damage healing. It is concluded that 6-gingerol, 8-gingerol, and 10-gingerol, the three analogues, have a strong and relatively equal efficacy in the treatment of colitis. Copyright © 2017 John Wiley & Sons, Ltd.

Pharmacokinetics and retinal toxicity of various doses of intravitreal triamcinolone acetonide in rabbits.

PURPOSE: To compare the pharmacokinetics and retinal toxicity of various doses of intravitreal triamcinolone acetonide (TA) in rabbits. METHODS: The rabbits received intravitreal injections of 4 mg and 8 mg TA. The drug concentrations were determined with high-performance liquid chromatography after extraction from the vitreous at various time points. The main pharmacokinetics parameters were calculated with 3p97 pharmacokinetics software. The intraocular pressure, electroretinography, and pathological examinations were evaluated before and after intravitreal injection of different doses of TA. RESULTS: The half-life of intravitreal injection of 4 mg and 8 mg TA was 24 days and 34 days, respectively. No significant differences were found in intraocular pressure (p>0.05) and the electroretinography b-wave amplitudes (p>0.05) among the rabbits before and after intravitreal injection of 4 mg and 8 mg TA. Light and electron microscopy did not show any retinal damage in any group. CONCLUSIONS: Intravitreal injection of 4 mg and 8 mg TA are safe for the rabbit retina. The injection of 8 mg TA produced a longer vitreous half-life and had a prolonged effect on the retina. This conclusion may be referenced in the clinical application of TA in retinal diseases.

[Research on several times of abruptly changes in the ultrafast transient reflectivity in Co films].

In the present paper, cobalt films, chromium and cobalt double layer films, and silver and cobalt double layer films were deposited by magnetron sputtering technique. The transient reflectivity response in cobalt thin films and their double layer films was studied by using femtosecond laser pump-probe transient reflection experimental technology. The result shows that, under the condition of the cobalt films of the same thickness, when the pump power increases, the heating time of the electrons in cobalt thin films is independent of the pump power, and is 0. 134 4 ps. And for the cobalt films of different thickness, the electron thermalization time is directly related to the film thickness. In addition, when the laser pulse power is high enough, two or three transient reflectivity decline signals on glass substrate films are found which is different with previous researches, when the cobalt films were thin, there are three times of transient reflectivity abruptly decline signals, and when the cobalt films were thick, there are two times of transient reflectivity abruptly decline signals, so the thickness of the cobalt films determines the times of the changes of the ultrafast dynamics in cobalt films.

[Clinical survey and analysis of persistent submacular fluid on optical coherence tomography after surgery for rhegmatogenous retinal detachment].

OBJECTIVE: To investigate the incidence, duration and consequences of persistent submacular fluid after pars plana vitrectomy (PPV) and scleral buckling surgery (SB) in rhegmatogenous retinal detachment, thus to explore the clinical association between persistent SMF and different surgical methods, and simultaneously, to study the effect of persistent submacular fluid on visual outcome. METHODS: It was a retrospective case-series study. Ninety-two qualified eyes including 54 eyes of males and 38 eyes of females with rhegmatogenous retinal detachment which had been performed PPV or SB were recruited. The average age of the patients was (45.8 ± 15.3) years with a age-range from 15 to 76 years. The inclusion criteria was as follows, the macula-off rhegmatogenous retinal detachments without macular hole and obvious proliferative vitreoretinopathy, the retina was completely reattached 1 month after operation and no redetachment was found by ophthalmoscope and B scan till the last follow-up, the minimal follow-up time was 1 year and the submacular fluid must have been dissolved for at least 6 months. All patients underwent thorough ophthalmologic examinations before and after operation, Those patients in whom a persistent submacular fluid was seen on optical coherence tomography (OCT) at 1 month after operation performed follow-up with repeat of the investigations at 3, 6 and 12 months after surgery, If the abnormality resolved, further observations were continued to undertake for 6 months or more till the last follow-up.Rank-sum test, χ²-test and Fisher exact test were applied respectively to analyze for statistical analysis. RESULTS: The incidence of persistent submacular fluid at 1 month after surgery in the PPV and SB group was 13.9% (5/36) and 48.2% (27/56).Six months later however, the figure expressed as percentage was 2.8% (1/36) and 23.2% (18/28) correspondingly. Persistent submacular fluid was more frequent in eyes with inferior breaks (64.3%) than that with superior ones (13.9%), making a significant differences (χ² = 17.38, P < 0.01) . The persistent submacular fluid group showed worse best-corrected visual acuity than no persistent submacular fluid group 6 and 12 months after surgery (t = 2.525, t = 2.254, both P < 0.05). Comparing the visual acuity (VA) between the eyes with or without persistent submacular fluid 6, 12 months after surgery and the latest followed-up among the ever suffered eyes, a statistically significant differences presented in late stages(average VA: 0.47 ± 0.29, 0.30 ± 0.16; 0.44 ± 0.28, 0.27 ± 0.15;0.42 ± 0.22, 0.27 ± 0.19; t = 2.114, 2.207, 2.068; all P < 0.05), though there were no significant differences in the first three months (average VA: 0.70 ± 0.33, 0.63 ± 0.37; 0.50 ± 0.25,0.45 ± 0.22; t = 0.556, 0.601; both P > 0.05). CONCLUSIONS: Persistent submacular fluid presents in both surgical procedures but it is more frequent after buckling surgery than vitrectomy, the selection of patients, the location of retinal breaks and the duration of detachment may be the potential influencing factors. Persistent submacular fluid after retinal detachment surgery is responsible for delayed recovery, and may affect the final visual outcome. The longer it lasts, the more harm may it do.

3×Tg-AD Mice Overexpressing Phospholipid Transfer Protein Improves Cognition Through Decreasing Amyloid-ß Production and Tau Hyperphosphorylation.

BACKGROUND: Phospholipid transfer protein (PLTP) belongs to the lipid transfer glycoprotein family. Studies have shown that it is closely related to Alzheimer's disease (AD); however, the exact effect and mechanism remain unknown. OBJECTIVE: To observe the effect of PLTP overexpression on behavioral dysfunction and the related mechanisms in APP/PS1/Tau triple transgenic (3×Tg-AD) mice. METHODS: AAV-PLTP-EGFP was injected into the lateral ventricle to induce PLTP overexpression. The memory of 3×Tg-AD mice and wild type (WT) mice aged 10 months were assessed using Morris water maze (MWM) and shuttle-box passive avoidance test (PAT). Western blotting and ELISA assays were used to quantify the protein contents. Hematoxylin and eosin, Nissl, and immunochemistry staining were utilized in observing the pathological changes in the brain. RESULTS: 3×Tg-AD mice displayed cognitive impairment in WMW and PAT, which was ameliorated by PLTP overexpression. The histopathological hallmarks of AD, senile plaques and neurofibrillary tangles, were observed in 3×Tg-AD mice and were improved by PLTP overexpression. Besides, the increase of amyloid-ß42 (Aß42) and Aß40 were found in the cerebral cortex and hippocampus of 3×Tg-AD mice and reversed by PLTP overexpression through inhibiting APP and PS1. PLTP overexpression also reversed tau phosphorylation at the Ser404, Thr231 and Ser199 of the hippocampus in 3×Tg-AD mice. Furthermore, PLTP overexpression induced the glycogen synthase kinase 3ß (GSK3ß) inactivation via upregulating GSK3ß (pSer9). CONCLUSION: These results suggest that PLTP overexpression has neuroprotective effects. These effects are possibly achieved through the inhibition of the Aß production and tau phosphorylation, which is related to GSK3ß inactivation.

Moderate salt treatment alleviates ultraviolet-B radiation caused impairment in poplar plants.

The effects of moderate salinity on the responses of woody plants to UV-B radiation were investigated using two Populus species (Populus alba and Populus russkii). Under UV-B radiation, moderate salinity reduced the oxidation pressure in both species, as indicated by lower levels of cellular H2O2 and membrane peroxidation, and weakened the inhibition of photochemical efficiency expressed by O-J-I-P changes. UV-B-induced DNA lesions in chloroplast and nucleus were alleviated by salinity, which could be explained by the higher expression levels of DNA repair system genes under UV-B&salt condition, such as the PHR, DDB2, and MutSα genes. The salt-induced increase in organic osmolytes proline and glycine betaine, afforded more efficient protection against UV-B radiation. Therefore moderate salinity induced cross-tolerance to UV-B stress in poplar plants. It is thus suggested that woody plants growing in moderate salted condition would be less affected by enhanced UV-B radiation than plants growing in the absence of salt. Our results also showed that UV-B signal genes in poplar plants PaCOP1, PaSTO and PaSTH2 were quickly responding to UV-B radiation, but not to salt. The transcripts of PaHY5 and its downstream pathway genes (PaCHS1, PaCHS4, PaFLS1 and PaFLS2) were differently up-regulated by these treatments, but the flavonoid compounds were not involved in the cross-tolerance since their concentration increased to the same extent in both UV-B and combined stresses.