Genetic inhibition of PDK1 robustly reduces plaque deposition and ameliorates gliosis in the 5×FAD mouse model of Alzheimer's disease.

AIMS: Abundant recent evidence has shown that 3-phosphoinositide-dependent protein kinase 1 (PDK1) is activated in Alzheimer's disease (AD). However, it remains unknown whether inhibition of PDK1 in neurons may affect AD-like pathology in animal models of AD. Here, we aim to examine the effects of specific inactivation of neuronal PDK1 on pathology and behaviour in 5×FAD mice and to identify the underlying molecular mechanisms. METHODS: The Cre-loxP system was employed to generate Pdk1 cKO/5×FAD mice, in which PDK1 is inactivated in excitatory neurons in the adult forebrain. Cellular and behavioural techniques were used to examine plaque burden, inflammatory responses and spatial working memory in mice. Biochemical and molecular analyses were conducted to investigate relevant mechanisms. RESULTS: First, Aß deposition was massively decreased and gliosis was highly attenuated in Pdk1 cKO/5×FAD mice compared with 5×FAD mice. Second, memory deficits were significantly improved in Pdk1 cKO/5×FAD mice. Third, APP levels were notably decreased in Pdk1 cKO/5×FAD mice. Fourth, mammalian target of rapamycin (mTOR) signalling and ribosome biogenesis were reduced in Pdk1 cKO/5×FAD mice. CONCLUSIONS: Neuron-specific deletion of PDK1 robustly ameliorates AD-like pathology and improves spatial working memory in 5×FAD mice. We propose that genetic approach to inhibit PDK1 may be an effective strategy to slow AD.

TiO2 NPs induce the reproductive toxicity in mice with gestational diabetes mellitus through the effects on the endoplasmic reticulum stress signaling pathway.

The effect of one of the most widely studied nanomaterials at present, TiO2 nanoparticles (NPs), on pregnancy-related diseases is not clear. In this study, the adverse effects of TiO2 NPs on mice with gestational diabetes mellitus (GDM) and their possible mechanism were investigated. GDM mice were orally administered 0, 10, 50 and 250 mg/kg TiO2 NPs for 14 days. GDM reduced the weight of pregnant mice, destroyed the placental structure and caused abnormal fetal development. After exposure to increasing doses of TiO2 NPs, blood glucose levels increased significantly and body weight further decreased in GDM mice. The accumulation of the Ti content was detected in the placenta and fetus, which may further damage the placental structure in GDM mice, thereby exacerbating abnormal fetal development. In addition, the MDA and SOD activities were obviously increased, and the expression of genes associated with endoplasmic reticulum stress (ERS) (PERK, eIF2α, AFT4, IRE1α, and XBP1s) and apoptosis (CHOP, JNK, Bax/Bcl-2, Caspase-12, Caspase-9, and Caspase-3) were also obviously increased in the placenta, which reflected the possible activation of apoptosis. It could be speculated that the reproductive toxicity of TiO2 NPs in GDM mice triggered oxidative stress that subsequently activated ERS pathways to induce cell apoptosis.

Toxic effects of TiO2 NPs in the blood-milk barrier of the maternal dams and growth of offspring.

Titanium dioxide nanoparticles (TiO2 NPs) are amongst the most frequently used nanomaterial in everyday consumer products, and their widespread applications have raised concerns of the consequent deleterious effects on human health, particularly to vulnerable populations, such as lactating females remains elusive. Therefore, this study was initiated to investigate the detrimental effects and toxic mechanisms induced by TiO2 NPs in maternal dams and offspring during the lactation period. Dams were randomly divided into three groups. The water (Control; Group I) and TiO2 NPs (100 mg/kg; Group II) were orally administered from postnatal day 1-20, respectively. The results indicated that TiO2 NPs could cause toxicity in the dams, such as pathological damages to mammary gland tissues. The excessive accumulation of TiO2 NPs could induce oxidative stress in the mammary gland, leading to the dysfunctional blood-milk barrier; besides, TiO2 NPs could also be transferred to offspring via breastfeeding, causing abnormal development of infant. We further accessed the possible underlying molecular mechanism; for this, we orally administered TiO2 NPs with vitamin E (100 mg/kg; Group III). The results revealed that toxicity induced by TiO2 NPs was rescued. Collectively, this study presented the deleterious pathological effects of oral exposure to TiO2 NPs in the mammary gland tissues and blood-milk barrier via the production of reactive oxygen species (ROS) in dams and developmental concerns in offspring. However, the administration of VE could mitigate the toxic effects induced by the TiO2 NPs.

Oral exposure of titanium oxide nanoparticles induce ileum physical barrier dysfunction via Th1/Th2 imbalance.

In this work, we aimed to evaluate the adverse effects and the mechanism of intestinal barrier caused by titanium dioxide nanoparticles (TiO2 NPs). Here, the effects of two different dosages (300 and 1200 mg/kg) of TiO2 NPs on female mice (n = 5) were investigated. After 28-day oral exposure, the results of Ti content were significantly increased in the ileum in comparison with the control. The histopathological structure index of the ileum was significantly changed after TiO2 NPs exposure; villi height and crypt depth were decreased and increased, respectively. Meanwhile, TiO2 NPs treatment also significantly altered the transcription levels of genes. First, the GATA-3 and STAT-4 were upregulation and downregulation, respectively. Second, gene expressions of the Zonula Occludens-1, claudin (CLDN)-12, occludin, and myosin light chain kinase were significantly upregulated, while the CLDN-3 was decreased. Finally, the caspase-3, caspase-9, and caspase-12 were upregulated. The results of TUNEL staining indicated apoptosis in the ileum. In general, TiO2 NPs treatment significantly changed the intestine physical barrier in a dose-dependent manner. The toxicity of TiO2 NPs could be through the imbalance in the Th1/Th2.

Properties Analysis of Asphalt Binders Containing Bayer Red Mud.

In this work, related performances of asphalt binders with Bayer red mud powder (RMP) were studied. RMP replaced the traditional limestone powder (LSP) as a filler in asphalt binder. The replacement rates were 0%, 25%, 50%, 75%, and 100%, respectively. In this study, seven F/A (filler-to-asphalt, weight/weight) ratios for each of the fillers were selected: 0.3, 0.6, 0.9, 1.2, 1.5, 1.8, and 2.1. Penetration, softening point, rotational viscosity (RV), dynamic shear rheometry (DSR), and bending beam rheometry (BBR) tests were used to evaluate the properties of the asphalt binder. Penetration into the asphalt binder decreases linearly with increasing F/A ratio. Moreover, penetration of binder with RMP is lower than that of asphalt binder with LSP (RMP0), and among the five fillers tested, RMP100 showed most significant influence on penetration of the asphalt binder. The addition of RMP increases the softening point of the binder. DSR results show that the improvement in the high temperature performance is most significant after replacing 75% of the LSP with Bayer RMP. BBR results show that with increasing substitution of RMP for LSP, the creep stiffness (S) increased while the rate of change of S (m-value) declined. The low temperature performance of every asphalt binder was not enough to meet the Superpave requirements. In order to meet the Superpave requirements for S and m-values, the maximum F/A ratios of the five replacements corresponding to the fillers with 0%, 25%, 50%, 75%, and 100% RMP, were 1.3, 1.2, 1.1, 1.0 and 0.9, respectively. At 135 °C, rotational viscosity showed that RMP75 and RMP100 with a maximum F/A ratio of 1.1 are the best choices for asphalt binders, considering economic and construction requirements.

Low-Temperature Trigger Nitric Oxide Nanogenerators for Enhanced Mild Photothermal Therapy.

Surmounting the restriction issues of nitric oxide (NO) delivery to realize their precious on-demand release is highly beneficial for the widespread deployment of gas therapy for application in biomedicine. Herein, by employing core-shell structure Au@SiO2 nanomaterials with high photothermal performance, a novel strategy was proposed by integrating photothermal conversion nanomaterials and heat-triggered NO donors (RSNO) into a nanoplatform, which achieved photothermal therapy (PTT)-enhanced NO gas therapy under near-infrared (NIR) radiation. Specifically, 2-phenylethynesulfonamide (PES), an inhibitor of heat shock protein 70 (HSP-70), was loaded into the NO nanogenerators to realize effective low-temperature (∼45 °C) PTT. The obtained results showed that the near-infrared radiation (NIR) mediated mild PTT and gas therapy by releasing NO showed a substantially improved synergistic effect based on in vitro and in vivo results in breast cancer (MCF-7) models. Our study points out a strategy to realize mild photothermal therapy by inhibiting the expression of HSP-70 and simultaneously providing an avenue to achieve controllable release of NO. More important, this research highlights the great potential of multifunctional therapeutic agents in the synergistic treatment of cancer.

ZnO Nanoparticles Induced Male Reproductive Toxicity Based on the Effects on the Endoplasmic Reticulum Stress Signaling Pathway.

PURPOSE: The aim of this study was to evaluate the adverse effects of ZnO NPs on male reproductive system and explore the possible mechanism. METHODS: In this study, the effect of oral administration of 50, 150 and 450 mg/kg zinc oxide nanoparticles (ZnO NPs) in adult male mice was studied over a 14-day period. RESULTS: The results showed that the number of sperms in the epididymis and the concentration of testosterone in serum were decreased with an increased dose of ZnO NPs. Testicular histopathological lesions like detachment, atrophy and vacuolization of germ cells were observed. The results showed that increased dosage of ZnO NPs correspondingly up-regulated the IRE1α, XBP1s, BIP, and CHOP (P<0.05) which are genes related to ER stress. These observations indicated that ZnO NPs had adverse effects on the male reproductive system in a dose-dependent manner possibly through ER stress. The expression of caspase-3 was significantly increased in all the treated groups (P<0.001), which reflected the possible activation of apoptosis. Additionally, there was significant down-regulation of the gene StAR (P<0.05), a key player in testosterone synthesis. When an ER-stress inhibitor salubrinal was administered to the 450 mg/kg ZnO NPs treatment group, the damages to the seminiferous tube and vacuolization of Sertoli and Leydig cells were not observed. Furthermore, the testosterone levels in the serum were similar to the control group after the subsequent salubrinal treatment. CONCLUSION: It may be inferred that the ZnO NP's reproductive toxicity in male mice occurred via apoptosis and ER-stress signaling pathway.

An inflammatory memory and angiogenic self-assembling nanofiber hydrogel scaffold seeded with Akkermansia muciniphila to accelerate the healing of diabetic ischemic ulcers.

Refractory ulcers are a major challenge in the treatment of a diabetic foot, because of the immunodeficient, ischemic and high-glucose microenvironment. Inflammatory memory peptides, which were extracted from the immune mediator absent in melanoma 2 (AIM2), could effectively improve the immunodeficient microenvironment and special angiogenic peptides could effectively promote angiogenesis. Moreover, the gut flora Akkermansia muciniphila (A. muciniphila) participates in diabetic metabolism and could decrease high-glucose levels. In this research, a polypeptide skeleton (PPS) was synthesized based on 3,4-dihydroxyphenylalanine (DOPA) and peptides, forming the hydrophilic and hydrophobic parts. Inflammatory memory peptides and angiogenic peptides were synthesized and conjugated with the PPS, which then formed an anisotropic hydrogel through the self-assembling of ß-sheet peptides based on hydrophobicity and DOPA oxidation. A. muciniphila was seeded into the hydrogel and transported into diabetic ischemic ulcers through subcutaneous injection, and the healing of diabetic ischemic ulcers was promoted. The inflammatory memory peptides were released based on the A. muciniphila enzyme response, and they firstly improved the immunity of the local surroundings. Then, the angiogenic peptides were also released through irradiation and they promoted angiogenesis. Additionally, the transported A. muciniphila could decrease the local glucose levels and spontaneously regress once the diabetic ischemic ulcers had healed. A. muciniphila combined with a functional polypeptide hydrogel may be a novel strategy for diabetic ischemic ulcer treatment.

Ranking scientific publications: the effect of nonlinearity.

Ranking the significance of scientific publications is a long-standing challenge. The network-based analysis is a natural and common approach for evaluating the scientific credit of papers. Although the number of citations has been widely used as a metric to rank papers, recently some iterative processes such as the well-known PageRank algorithm have been applied to the citation networks to address this problem. In this paper, we introduce nonlinearity to the PageRank algorithm when aggregating resources from different nodes to further enhance the effect of important papers. The validation of our method is performed on the data of American Physical Society (APS) journals. The results indicate that the nonlinearity improves the performance of the PageRank algorithm in terms of ranking effectiveness, as well as robustness against malicious manipulations. Although the nonlinearity analysis is based on the PageRank algorithm, it can be easily extended to other iterative ranking algorithms and similar improvements are expected.