Polysocial and Polygenic Risk Scores and All-Cause Dementia, Alzheimer's Disease, and Vascular Dementia.

BACKGROUND: To establish a polysocial risk score (PsRS) incorporating various social factors for capturing the dementia risk and investigate the benefits of favorable social conditions across different genetic backgrounds. METHODS: This prospective cohort study comprised 345 439 participants initially free of dementia from the UK Biobank. A total of 10 social factors were summed to create a PsRS. A polygenic risk score (PRS) was constructed based on genome-wide significant variants. RESULTS: During a median follow-up of 12.5 years, we documented 4 595 incident all-cause dementia events including 2 067 Alzheimer's disease (AD) events and 1 028 vascular dementia (VD) events. Each additional PsRS was associated with a 19% increased risk of all-cause dementia (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.17 to 1.21), a 13% increased risk of AD (1.13; 1.10 to 1.16), and a 24% increased risk of VD (1.24; 1.19 to 1.29). 29% (24% to 33%) of dementia cases, 22% (14% to 29%) of AD cases, and 39% (28% to 48%) of VD cases were associated with a disadvantageous social environment. In addition, among participants at a high genetic risk, the low social risk was linked to a lower incidence rate of all-cause dementia, AD, and VD compared to those who had a high social risk, with reductions of 67.8%, 64.5%, and 84.2%, respectively. CONCLUSIONS: The PsRS could be effectively used in discriminating individuals at high risk of dementia. Around a quarter of dementia events could have a connection with a disadvantageous social environment, especially for those genetically susceptible to dementia.

An Integrated Approach Fusing CEEMD Energy Entropy and Sparrow Search Algorithm-Based PNN for Fault Diagnosis of Rolling Bearings.

This paper solves the problem of difficulty in achieving satisfactory results with traditional methods of bearing fault diagnosis, which can effectively extract the fault information and improve the fault diagnosis accuracy. This paper proposes a novel artificial intelligence fault diagnosis method by integrating complementary ensemble empirical mode decomposition (CEEMD), energy entropy (EE), and probabilistic neural network (PNN) optimized by a sparrow search algorithm (SSA). The vibration signal of rolling bear was firstly decomposed by CEEMD into a set of intrinsic mode functions (IMFs) at different time scales. Then, the correlation coefficient was used as a selection criterion to determine the effective IMFs, and the signal features were extracted by EE as the input of the diagnosis model to suppress the influence of the redundant information and maximize the retention of the original signal features. Afterwards, SSA was used to optimize the smoothing factor parameter of PNN to reduce the influence of human factors on the neural network and improve the performance of the fault diagnosis model. Finally, the proposed CEEMD-EE-SSA-PNN method was verified and evaluated by experiments. The experimental results indicate that the presented method can accurately identify different fault states of rolling bearings and achieve better classification performance of fault states compared with other methods.

Exosomes from M2-polarized macrophages relieve oxygen/glucose deprivation/normalization-induced neuronal injury by activating the Nrf2/HO-1 signaling.

Stroke is a life-threatening neurological disorder with limited therapeutic efficacy. Previous studies have demonstrated that macrophages play an important role in brain injury after a stroke. However, its underlying mechanism remains unclear and the role of exosomes derived from M2-polarized macrophages (M2-Exo) in ischemic stroke has not yet been reported. In this study, we established an in vitro oxygen/glucose deprivation and re-oxygen/glucose (OGD/R) model to investigate the potential role of M2-Exo in protecting HT22 neurons against ischemia-reperfusion injury. Interleukin-4 was used to induce the M2 phenotype in macrophages, following which the exosomes were isolated from the supernatant of M2-polarized macrophages and identified by western blotting, transmission electron microscopy, and nanoparticle tracking analysis. After co-incubation with M2-Exo, OGD/R-induced neuronal injury in HT22 cells was improved, accompanied by increased cell viability and decreased lactate dehydrogenase release. In addition, the increase in percentage of terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling-positive cells in OGD/R-treated HT22 cells was attenuated after incubation with M2-Exo. M2-Exo treatment also suppressed reactive oxygen species and malondialdehyde production and improved the reduction of superoxide dismutase activity. Moreover, M2-Exo treatment was found to activate the nuclear factor erythroid related factor 2 (Nrf2)/heme-oxygenase-1 (HO-1) signaling pathway in OGD/R-treated HT22 neurons. Importantly, inhibition of Nrf2 by ML385 partially reversed the protective effects of M2-Exo against OGD/R-induced oxidative damage. Taken together, these data demonstrated that M2-Exo exerted protective effects against OGD/R-induced oxidative damage in HT22 neurons, which was mediated by the activation of Nrf2/HO-1 signaling. Hence, our findings provide a promising therapeutic approach for ischemic stroke.

Interleukin-35 from Interleukin-4-Stimulated Macrophages Alleviates Oxygen Glucose Deprivation/Re-oxygenation-Induced Neuronal Cell Death via the Wnt/ß-Catenin Signaling Pathway.

Currently, brain stroke is one of the leading causes of death and disabilities. It results in depletion of oxygen and glucose in certain areas of the brain, leading to neuronal death. Re-oxygenation has been proven to attenuate neuronal damage; however, sudden oxygen supply may also cause oxidative stress and subsequent inflammation. Hence, therapies to suppress re-oxygenation-induced oxidative damage are urgently needed. Interleukin (IL)-35, an immunomodulator secreted by regulatory T cells and regulatory B cells, is proven to be a strong immune-repressive cytokine. Here, we investigated the potential role of IL-35 in a disease model of oxygen glucose deprivation/re-oxygenation (OGD/R) and found that M2 macrophage-derived IL-35 significantly alleviated inflammatory response induced by oxidative stress. Our results also showed that IL-35 treatment decreased OGD/R-induced neuronal cell death and inflammatory response. Additionally, we demonstrated that IL-35 suppresses inflammatory response via the Wnt/ß-catenin signaling pathway. Hence, our findings indicate that IL-35 therapy has great potential in the treatment of OGD/R-induced oxidative damage and related inflammatory diseases.

Modulation of autophagy in traumatic brain injury.

Traumatic brain injury (TBI) is defined as a traumatically induced structural injury or physiological disruption of brain function as a result of external forces, leading to adult disability and death. A growing body of evidence reveals that alterations in autophagy-related proteins exist extensively in both experimentally and clinically after TBI. Of note, the autophagy pathway plays an essential role in pathophysiological processes, such as oxidative stress, inflammatory response, and apoptosis, thus contributing to neurological properties of TBI. With this in mind, this review summarizes a comprehensive overview on the beneficial and detrimental effects of autophagy in pathophysiological conditions and how these activities are linked to the pathogenesis of TBI. Moreover, the relationship between oxidative stress, inflammation, apoptosis, and autophagy occur TBI. Ultimately, multiple compounds and various drugs targeting the autophagy pathway are well described in TBI. Therefore, autophagy flux represents a potential clinical therapeutic value for the treatment of TBI and its complications.

Wnt/ß-catenin signaling cascade: A promising target for glioma therapy.

Glioma is one of the most treatment-refractory intracranial tumors, and the aberrant expressed Wnt/ß-catenin pathway is closely associated with glioma malignancy. In this regard, Wnt/ß-catenin signaling has been reported to play an essential role in cellular proliferation, migration, invasion, and angiogenesis, therefore contributing to glioma progression. However, the underlying mechanisms of Wnt/ß-catenin signaling involvement in gliomagenesis remain unknown. Here, we present an overview of the Wnt components and then go on to summarize the current knowledge describing the multitude of roles of Wnt/ß-catenin in glioma, which are mediated by transcription factors, microRNAs, long noncoding RNAs, and so on. In the latter portion of the review, we elaborate the increasing apparent crosstalk of Wnt/ß-catenin pathway with PI3K/AKT signaling involved in these processes. Ultimately, compounds targeting the Wnt/ß-catenin are described in glioma. As better understanding of the regulatory mechanisms to glioma malignancies increases, Wnt/ß-catenin cascade may represent an area of developmental glioma therapeutics focus.

LncRNA NKILA suppresses TGF-ß-induced epithelial-mesenchymal transition by blocking NF-κB signaling in breast cancer.

TGF-ß plays a central role in mediating epithelial-mesenchymal transition (EMT) by activating the Smad pathway. In addition, accumulating evidence suggests that TGF-ß-induced EMT is NF-κB-dependent in various cancer types. However, it is largely unclear if NF-κB mediates TGF-ß-induced EMT in breast cancer, and if this mediation occurs, the regulatory mechanisms are unknown. In our study, we found that TGF-ß activates the NF-κB pathway. Inhibition of NF-κB signaling markedly abrogates TGF-ß-induced EMT. By studying the regulatory mechanism of TGF-ß-induced NF-κB signaling, we found that lncRNA NKILA was upregulated by TGF-ß and was essential for the negative feedback regulation of the NF-κB pathway. Accordingly, overexpression of NKILA significantly reduced TGF-ß-induced tumor metastasis in vivo. Consistent with the results from mice, the expression of NKILA was negatively correlated with EMT phenotypes in clinical breast cancer samples. Collectively, our study indicated that the NKILA-mediated negative feedback affects TGF-ß-induced NF-κB activation and that NKILA may be a therapeutic molecule in breast cancer metastasis via inhibition of EMT.

[NRH2 induces cell apoptosis of cerebral tissues around hematomas after intracerebral hemorrhage through up-regulating proNGF, sortilin and p75NTR expressions].

OBJECTIVE: To observe the expressions of neurotrophin receptor homolog 2 (NRH2), nerve growth factor precursor (proNGF), sortilin and neurotrophin receptor p75 (p75NTR) in cerebral tissues around hematomas in the different periods after intracerebral hemorrhage, and explore their relationships to cell apoptosis. METHODS: The specimens of cerebral tissues around hematomas were collected from the patients undergoing hematoma removal operation after intracerebral hemorrhage. These specimens were divided into four groups, namely ≤ 6 hours, 6-24 hours(including 24 hours), 24-72 hours (including 72 hours) and over 72 hours according to the time from intracerebral hemorrhage to specimen collection. At the same time, 10 brain tissues distant to hemorrhage that dropped in the operative process were collected as a control group. Apoptosis index (AI) was examined in brain cells by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling (TUNEL). The expressions of NRH2, proNGF, sortilin and p75NTR mRNAs and proteins in brain tissues were detected through real-time quantitative PCR and Western blotting, respectively. Also, the expressions of Bcl-2 and Bax in brain tissues were analyzed using Western blotting. In vitro cultured astrocytes of rat cortex were transfected by NRH2 siRNA or scramble siRNA. The expressions of proNGF, sortilin and p75NTR proteins were detected using Western blotting. RESULTS: AI was higher in all groups of hemorrhage for 6 hours or longer than that in control and ≤ 6 hours groups, and AI in the group of 24-72 hours after intracerebral hemorrhage was the highest. However, there was no significant difference in AI between ≤ 6 hours group and control group. With the extension of intracerebral hemorrhage time, the expression levels of proNGF and p75NTR mRNAs and proteins were gradually elevated, reached the peak in 24-72 hours, and maintained a higher level after 72 hours, whereas there were no significant differences in the above indicators between ≤ 6 hours group and control group. In comparison with control group and ≤ 6 hours group, the expression levels of NRH2 and sortilin mRNAs and proteins and Bax expression started to increase in 6-24 hours, reached the peak in 24-72 hours, and then stayed a higher level after 72 hours, whereas there were no significant differences in the above indicators between ≤ 6 hours group and control group. There was no obvious change in Bcl-2 expression level between ≤ 6 hours group and control group. The level of Bcl-2 decreased in all groups of intracerebral hemorrhage for over 6 hours, and reached the nadir in 24-72 hours. Astrocytes transfected with NRH2 siRNA displayed a significant decrease in proNGF, sortilin and p75NTR protein levels as compared with scramble siRNA or blank control groups. CONCLUSION: The expression of NRH2 would increase in the cerebral tissues around hematomas after intracerebral hemorrhage. NRH2 might enhance the ratio of Bax/Bcl-2 by promoting the expressions of proNGF, sortilin and p75NTR, thereby inducing brain cell apoptosis.

[Inhibitory effect of wogonin on the proliferation and invasion of glioblastoma U87 cells and related mechanism].

OBJECTIVE: To explore the effect of wogonin on the proliferation and invasion of glioblastoma U87 cells and its related mechanism. METHODS: Glioblastoma U87 cells were cultured in vitro in RPMI1640 medium added with 100 mL/L fetal bovine serum. After cell adherence, the cells were inoculated with 20 µL culture solution (control group), 20 µL wogonin solutions (0, 50 and 100) µmol/L for 48 hours, respectively. The 0 µmol/L wogonin group used 20 µL PBS instead. Cell proliferation was analyzed by MTT assay. The cell invasion ability was detected using Transwell™ invasion assay. The expressions of ezrin mRNA was examined through real-time quantitative PCR. The expressions of ezrin, Bcl-2 and Bax proteins as well as phosphorylated ezrin protein level were measured by Western blotting. Apoptosis index (AI) was determined through terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. RESULTS: The inhibitory rate of cell proliferation significantly increased in 50 and 100 µmol/L wogonin groups as compared with 0 µmol/L wogonin group and control group. Moreover, that was higher in 100 µmol/L wogonin group than 50 µmol/L wogonin group. In comparison with control and 0 µmol/L wogonin groups, the mean cell numbers of permeated membrane, levels of ezrin mRNA, ezrin protein and Bcl-2 protein, and phosphorylated ezrin protein level gradually decreased but the level of Bax protein and AI were gradually elevated with the increase of wogonin concentrations; however, there was no significant difference in these indicators between 0 µmol/L wogonin group and control group. CONCLUSION: Wogonin could attenuate the proliferation and invasion of wogonin U87 cells, which may be associated with the inhibition of ezrin protein expression and phosphorylation activity and the induction of cell apoptosis.