Maintaining Drosha expression with Cdk5 inhibitors as a potential therapeutic strategy for early intervention after TBI.

Traumatic brain injury (TBI) is a major cause of death and disability in adults. The pathological process of TBI involves a multifactorial cascade in which kinases have been proven contribute to interactions between relevant factors and amplification of signaling cascades. Cyclin-dependent kinase 5 (Cdk5) is a promising kinase that has been implicated in various brain disorders, including TBI. However, the mechanism by which Cdk5 induces neuronal damage remains unclear. Here, we show for the first time that Drosha, a key enzyme in microRNA biogenesis, is a pivotal substrate of abnormally activated Cdk5. Cdk5-mediated phosphorylation decreases Drosha expression and exacerbates nerve injury in TBI. We proved that maintaining Drosha expression via the administration of repurposed Cdk5 inhibitors that were previously studied in clinical trials is a promising approach for the early treatment of TBI. Together, our work identifies Drosha as a novel target for neuroprotective strategies after TBI and suggests Cdk5-mediated regulation of Drosha expression as a potential therapeutic strategy for early TBI intervention.

Exploring the mechanism of atherosclerosis and the intervention of traditional Chinese medicine combined with mesenchymal stem cells based on inflammatory targets.

Atherosclerosis (AS) is a chronic inflammatory vascular disease, which is the common pathological basis of cardiovascular and cerebrovascular diseases. The immune inflammatory response throughout the course of AS has been evidenced by studies, in which a large number of immune cells and inflammatory factors play a crucial role in the pathogenesis of AS. The inflammation related to AS is mainly mediated by inflammatory cytokines (IL-1ß, IL-6, IL-18, TNF-α, hs-CRP, SAA), inflammatory enzymes (Lp-PLA2, sPLA2-IIA, MMPs), and inflammatory signaling pathways (P38 MAPK signaling pathway, NF-κB signaling pathway, TLR2/4 signaling pathway). It is involved in the pathophysiological process of AS, and the degree of inflammation measured by it can be used to evaluate the risk of progression of AS plaque instability. In recent years, traditional Chinese medicine (TCM) has shown the advantage of minimal side effects in immune regulation and has made some progress in the prevention and treatment of AS. Mesenchymal stem cells (MSCs), as self-renewal, highly differentiated, and pluripotent stem cells with anti-inflammatory properties and immune regulation, have been widely used for AS treatment. They also play an important inflammation-immune regulatory function in AS. Notably, in terms of regulating immune cells and inflammatory factors, compared with TCM and its compound, the combination therapy has obvious anti-inflammatory advantages over the use of MSCs alone. It is an important means to further improve the efficacy of AS and provides a new way for the prevention and treatment of AS.

[Research progress on traditional Chinese medicine in treatment of neurodegenerative diseases by delaying neurovascular unit aging].

Neurodegenerative diseases are a collective term for a large group of diseases caused by degenerative changes in nerve cells. Aging is the main risk factor for neurodegenerative diseases. The neurovascular unit(NVU) is the smallest functional unit of the brain, which regulates brain blood flow and maintains brain homeostasis. Accelerated aging of NVU cells directly impairs NVU function and leads to the occurrence of various neurodegenerative diseases. The intrinsic mechanisms of NVU cell aging are complex and involve oxidative stress damage, loss of protein homeostasis, DNA damage, mitochondrial dysfunction, immune inflammatory response, and impaired cellular autophagy. In recent years, studies have found that traditional Chinese medicine(TCM) can inhibit NVU aging through multiple pathways and targets, exerting a brain-protective effect. Therefore, this article aimed to provide a theoretical basis for further research on TCM inhibition of NVU cell aging and references for new drug development and clinical applications by reviewing its mechanisms of anti-aging, such as regulating relevant proteins, improving mitochondrial dysfunction, reducing DNA damage, lowering inflammatory response, antioxidant stress, and modulating cellular autophagy.

Potential regulatory effects of stem cell exosomes on inflammatory response in ischemic stroke treatment.

The high incidence and disability rates of stroke pose a heavy burden on society. Inflammation is a significant pathological reaction that occurs after an ischemic stroke. Currently, therapeutic methods, except for intravenous thrombolysis and vascular thrombectomy, have limited time windows. Mesenchymal stem cells (MSCs) can migrate, differentiate, and inhibit inflammatory immune responses. Exosomes (Exos), which are secretory vesicles, have the characteristics of the cells from which they are derived, making them attractive targets for research in recent years. MSC-derived exosomes can attenuate the inflammatory response caused by cerebral stroke by modulating damage-associated molecular patterns. In this review, research on the inflammatory response mechanisms associated with Exos therapy after an ischemic injury is discussed to provide a new approach to clinical treatment.

Amelioration of prediabetes-induced changes of dendritic structural plasticity.

Accumulating evidence suggests that the diabetes-induced cognitive dysfunction can be alleviated when exposed to the enriched environment. However, the impact of the changes of the hippocampal plasticity on the cognitive decline and the possible effect of an enriched environment in prediabetes are still not clearly documented. To explore the effect of enriched environment for prediabetes-induced changes of dendritic structural plasticity in hippocampus pyramidal and cognitive deficits, the praxiology experiments for evaluating of anxiety, spatial learning and memory of prediabetic Wistar were performed, and then the dendritic spine density was assessed in the hippocampal CA1 pyramidal neuronal region. The prediabetic rats demonstrated a hyper-anxiety like behavior and significantly decreased spatial learning abilities and memory deficits. Exposing prediabetic rats to an enriched environment appeared to significantly mitigate the above changes in a time-dependent manner. The enriched environment also restored the density of the hippocampal dendritic spine which was significantly reduced in prediabetic rats. We found that the enriched environment was beneficial in overcoming the prediabetes-induced cognitive disorders and diminished dendritic plasticity of hippocampus pyramidal.

TGF-beta/TGF-beta RII/CLC-3 axis promotes cognitive disorders in diabetes.

Transforming growth factor beta (TGF-beta) and Chloride channel-3 (CLC-3) are critical for inflammatory response, cellular proliferation and apoptosis in hippocampus neurons. However, the relationship between CLC-3 and TGF-beta/TGF-beta Receptor II (RII) pathway in diabetic encephalopathy (DE) is unknown. In this study, both diabetes rat model and diabetes cell model were employed to elucidate the mechanisms involved. The increased expressions of CLC-3 and TGF- beta RII with cognitive impairment were observed in diabetic rats. The most obvious reduction on the survival of HT22 cells was at 10 ng/ml or 15 ng/ml TGF- beta stimulation, while the expressions of CLC-3 and TGF-beta RII were significantly increased under high glucose condition. Moreover, the study showed that CLC-3 antagonists had no apparent effect on up-regulated TGF- beta RII, but TGF- beta 1 inhibitors could reduce the up-regulated CLC-3 under high glucose. Results from the present study indicated that CLC-3 and TGF- beta signals might be related to cognitive disorders. The CLC-3 might be modulated by TGF- beta /TGF- beta RII signaling pathway during the development of DE.

Catechins and Their Therapeutic Benefits to Inflammatory Bowel Disease.

Catechins are natural polyphenolic phytochemicals that exist in food and medicinal plants, such as tea, legume and rubiaceae. An increasing number of studies have associated the intake of catechins-rich foods with the prevention and treatment of chronic diseases in humans, such as inflammatory bowel disease (IBD). Some studies have demonstrated that catechins could significantly inhibit the excessive oxidative stress through direct or indirect antioxidant effects and promote the activation of the antioxidative substances such as glutathione peroxidases (GPO) and glutathione (GSH), reducing the oxidative damages to the colon. In addition, catechins can also regulate the infiltration and proliferation of immune related-cells, such as neutrophils, colonic epithelial cells, macrophages, and T lymphocytes, helping reduce the inflammatory relations and provide benefits to IBD. Perhaps catechins can further inhibit the deterioration of intestinal lesions through regulating the cell gap junctions. Furthermore, catechins can exert their significant anti-inflammatory properties by regulating the activation or deactivation of inflammation-related oxidative stress-related cell signaling pathways, such as nuclear factor-kappa B (NF-κB), mitogen activated protein kinases (MAPKs), transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), signal transducer and the activator of transcription 1/3 (STAT1/3) pathways. Finally, catechins can also stabilize the structure of the gastrointestinal micro-ecological environment via promoting the proliferation of beneficial intestinal bacteria and regulating the balance of intestinal flora, so as to relieve the IBD. Furthermore, catechins may regulate the tight junctions (TJ) in the epithelium. This paper elaborates the currently known possible molecular mechanisms of catechins in favor of IBD.

ClC-3 Expression and Its Association with Hyperglycemia Induced HT22 Hippocampal Neuronal Cell Apoptosis.

Although apoptosis plays an important role in the development of Diabetic Encephalopathy (DE), the underlying molecular mechanisms remain unclear. With respect to this, the present work aims to study the variation in chloride/proton exchanger ClC-3 expression and its association with HT22 hippocampal neuronal apoptosis under hyperglycemic condition in vitro. The cells were stimulated with added 0, 5, or 25 mM glucose or mannitol for up to 72 hours before assessing the rate of ClC-3 expression, cell viability, and apoptosis. In a consecutive experiment, cells received chloride channel blocker in addition to glucose. The rate of cellular death/apoptosis and viability was measured using Flow Cytometry and MTT assay, respectively. Changes in ClC-3 expression were assessed using immunofluorescence staining and western blot analysis. The results revealed a significant increase in cellular apoptosis and reduction in viability, associated with increased ClC-3 expression in high glucose group. Osmolarity had no role to play. Addition of chloride channel blocker completely abolished this effect. Thus we conclude that, with its increased expression, ClC-3 plays a major role in hyperglycemia induced hippocampal neuronal apoptosis. To strengthen our understanding of this aforesaid association, we conducted an extensive literature search which is presented in this paper.

The coexistence of VGluT2 and neurotensin or leu-enkephalin in the medullary dorsal horn: a confocal and electron microscopic immunohistochemical study in the rat.

Neuropeptides such as neurotensin (NT), and enkephalin (ENK) in the medullary dorsal horn (MDH) are involved in excitatory synaptic transmission to modulate nociceptive information. However, morphological evidence indicating that NT or ENK coexists with glutamate in the MDH is still meager. Using fluorescent immunohistochemistry, the results showed that double labeling of NT or ENK terminals with VGluT2 is mainly concentrated in the lamina II of the MDH, and many axon terminals exhibiting NT or ENK immunoreactivity in the superficial layers of the MDH showed VGluT2 immunoreactivity. Electron microscopy confirmed the coexpression of NT or ENK and VGluT2 in axon terminals within the laminae I and II of the MDH. These axon terminals make asymmetrical synapses with immunonegative neuronal cell bodies and dendrites. The findings suggest that glutamate is coreleased with NT or ENK from axon terminals of interneurons in the superficial layers of the MDH.

Combined detection of Gab1 and Gab2 expression predicts clinical outcome of patients with glioma.

Grb2-associated binder 1 (Gab1) and Gab2 play important roles in cancer cell signaling. In particular, it has been demonstrated that the upregulation of Gab2 may be correlated with the World Health Organization (WHO) grade of gliomas and that patients with high Gab2 expression levels exhibited shorter survival time. However, the prognostic value of combined expression of Gab1 and Gab2 has not been explored. Gab1 and Gab2 expression in human gliomas and non-neoplastic brain tissues was measured by immunohistochemistry. Both the expression levels of Gab1 and Gab2 proteins in glioma tissues were significantly higher than those in non-neoplastic brain tissues (both P < 0.001). In addition, the overexpression of Gab1 and Gab2 proteins were both significantly associated with advanced WHO grades (both P < 0.001) and low KPS (both P = 0.01). Moreover, the overall survival of patients with high Gab1 protein expression or high Gab2 protein expression was obviously lower than those with low expressions (both P < 0.001). Notably, glioma patients with combined overexpression of Gab1 and Gab2 proteins (Gab1-high/Gab2-high) had shortest overall survival (P < 0.001). Furthermore, multivariate analysis showed that Gab1 expression (P = 0.01), Gab2 expression (P = 0.02), and combined expression of Gab1 and Gab2 (Gab1/Gab2, P = 0.006) were all independent prognostic factors for overall survival in glioma patients. Gab1 and Gab2 proteins are differentially expressed in glioma patients and closely correlated with the biological behavior of this malignancy. Combination of Gab1 and Gab2 expression may represent a promising biomarker for prognostication of human gliomas.

Increased expression of microRNA-9 predicts an unfavorable prognosis in human glioma.

microRNA-9 (miR-9) has been found to be upregulated along with tumor progression of gliomas by microarray-based expression profiling, and also be strongly linked to glioblastoma subtypes. However, its prognostic value in glioma is still elusive. miR-9 expression in human gliomas and nonneoplastic brain tissues was measured by real-time quantitative RT-PCR assay. miR-9 expression in glioma tissues was significantly higher than that in corresponding nonneoplastic brain tissues (P\0.001). The increased expression of miR-9 was more frequently observed in glioma tissues with high WHO grade than those with low WHO grade tissues (P = 0.001). The expression levels of miR-9 in glioma tissues with low Karnofsky performance score (KPS) were also significantly higher than those with high KPS (P = 0.008). Moreover, the overall survival of glioma patients with high miR-9 expression was obviously lower than that with low miR-9 expression (P\0.001). Multivariate analysis further showed that high miR-9 expression was an independent prognostic factor for overall survival in glioma patients (P = 0.01). More importantly, the subgroup analyses indicated that the overall survival of glioma patients with high WHO grade (III­IV) was significantly worse for high miR-9 expression group than for low miR-9 expression group (P\0.001), but no significant difference was found for patients with low WHO grade (I­II). These findings suggest for the first time that the increased expression of miR-9 may play an important role in tumor progression in human gliomas. miR-9 might be a useful marker for predicting the clinical outcome of glioma patients, especially for advanced subtypes.

Combined aberrant expression of Bmi1 and EZH2 is predictive of poor prognosis in glioma patients.

BACKGROUND AND OBJECTIVES: Bmi1 and EZH2 are involved in tumorigenesis of gliomas. However, clinicopathologic significance of their expression in gliomas is unknown; especially, the prognostic value of combined expression of Bmi1 and EZH2 has not been explored. METHODS: Bmi1 and EZH2 expression in human gliomas and nonneoplastic brain tissues was measured by immunohistochemistry. RESULTS: Both Bmi1 and EZH2 expressions in glioma tissues were significantly higher than those in corresponding nonneoplastic brain tissues (both P<0.001). Additionally, the upregulations of Bmi1 and EZH2 proteins were both significantly associated with advanced WHO grades (both P<0.001) and low KPS (P=0.008 and 0.01, respectively). Moreover, the overall survival of patients with high Bmi1 protein expression (P=0.006) or high EZH2 protein expression (P=0.01) was obviously lower than those with low expressions. More interestingly, glioma patients with combined overexpression of Bmi1 and EZH2 proteins had the shortest overall survival (P<0.001). Furthermore, multivariate analysis showed that Bmi1n expression (P=0.02), EZH2 expression (P=0.03), and combined expression of Bmi1 and EZH2 (P=0.008), were all independent prognostic factors for overall survival in glioma patients. CONCLUSIONS: Our data suggest for the first time that the combination of Bmi1 and EZH2 overexpression may be a highly sensitive marker for the prognosis in glioma patients.

Detecting the determinism of EEG time series using a nonlinear forecasting method.

The determinism of time series is investigated using a nonlinear non-parametric forecasting method. The goodness of prediction was estimated in terms of the prediction error of the predicted time series. A new definition of the prediction effect was made in the present study. Three typical kinds of time series were detected using our new method. In deterministic chaotic time series, good prediction was obtained in the new definition. However, for Gaussian random noise and schizophrenia EEG signal, the predictability could not found. We concluded that EEGs in schizophrenic patients were not deterministic.

Use of ANN and Complexity Measures in Cognitive EEG Discrimination.

The purpose of this paper is to apply BP ANN to the discrimination of three kinds of subjects (clinical diagnosed 62 schizophrenic patients, 48 depressive patients and 26 normal controls) respectively in resting state with eyes closed and three cognitive tasks, with EEG complexity measures used as feature vectors. EEG activity is recorded from 16 scalp electrodes and recordings are digitized for off-line processing. Features vectors based on Lep-Ziv complexity and classification with ANN are implemented in Matlab6.5. The comparison between the results of classifying in four states is illustrated and discussed. The classification accuracies achieved are 60% and over. The results show that ANN is an effective approach for discrimination of these three kinds of objects both in baseline and some cognitive states.

Classification of Schizophrenia and Depression by EEG with ANNs*.

The clinical application shows that it is possible to differentiate between patients suffering from schizophrenia, depression and normal healthy persons on the basis of EEG rhythms. This paper describes the application of two artificial neural networks (ANN) approaches, BP ANN and self-organizing competitive ANN for the discrimination of three kinds of subjects (including 10 normal control, 10 schizophrenic patients and 10 depressive patients), with EEG rhythms used as feature vectors. In addition, the comparison between two ANNs is illustrated in this paper. The results show that ANN is an effective approach for discrimination of these three kinds of objects and BP ANN has better comprehensive performance than self-organizing competitive ANN technique in this study. Therefore, the ANN technique could be used as a new tool for computer-aided diagnosis for some psychosis.