The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

The small GTPases from the Ras superfamily play crucial roles in basic cellular processes during practically the entire process of neurodevelopment, including neurogenesis, differentiation, gene expression, membrane and protein traffic, vesicular trafficking, and synaptic plasticity. Small GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Different subfamilies of small GTPases have been linked to a number of non-neoplastic cerebral diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), intellectual disability, epilepsy, drug addiction, Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS) and a large number of idiopathic cerebral diseases. Here, we attempted to make a clearer illustration of the relationship between Ras superfamily GTPases and non-neoplastic cerebral diseases, as well as their roles in the neural system. In future studies, potential treatments for non-neoplastic cerebral diseases which are based on small GTPase related signaling pathways should be explored further. In this paper, we review all the available literature in support of this possibility

The New Application of UHPLC-DAD-TOF/MS in Identification of Inhibitors on β-Amyloid Fibrillation From Scutellaria baicalensis

Literary evidence depicts that aggregated β-amyloid (Aβ) leads to the pathogenesis of Alzheimer’s disease (AD). Although many traditional Chinese medicines (TCMs) are effective in treating neurodegenerative diseases, there is no effective way for identifying active compounds from their complicated chemical compositions. Instead of using a traditional herbal separation method with low efficiency, we herein apply UHPLC-DAD-TOF/MS for the accurate identification of the active compounds that inhibit the fibrillation of Aβ (1-42), via an evaluation of the peak area of individual chemical components in chromatogram, after incubation with an Aβ peptide. Using the neuroprotective herbal plant Scutellaria baicalensis (SB) as a study model, the inhibitory effect on Aβ by its individual compounds, were validated using the thioflavin-T (ThT) fluorescence assay, biolayer interferometry analysis, dot immunoblotting and native gel electrophoresis after UHPLC-DAD-TOF/MS analysis. The viability of cells after Aβ (1-42) incubation was further evaluated using both the tetrazolium dye (MTT) assay and flow cytometry analysis. Thirteen major chemical components in SB were identified by UHPLC-DAD-TOF/MS after incubation with Aβ (1–42). The peak areas of two components from SB, baicalein and baicalin, were significantly reduced after incubation with Aβ (1–42), compared to compounds alone, without incubation with Aβ (1–42). Consistently, both compounds inhibited the formation of Aβ (1–42) fibrils and increased the viability of cells after Aβ (1–42) incubation. Based on the hypothesis that active chemical components have to possess binding affinity to Aβ (1–42) to inhibit its fibrillation, a new application using UHPLC-DAD-TOF/MS for accurate identification of inhibitors from herbal plants on Aβ (1–42) fibrillation was developed

Altered Activity of SK Channel Underpins Morphine Withdrawal Relevant Psychiatric Deficiency in Infralimbic to Accumbens Shell Pathway

Drug addiction can be viewed as a chronic psychiatric disorder that is related to dysfunction of neural circuits, including reward deficits, stress surfeits, craving changes, and compromised executive function. The nucleus accumbens (NAc) plays a crucial role in regulating craving and relapse, while the medial prefrontal cortex (mPFC) represents a higher cortex projecting into the NAc that is active in the management of executive function. In this study, we investigated the role of the small conductance calcium-activated potassium channels (SK channels) in NAc and mPFC after morphine withdrawal. Action potential (AP) firing of neurons in the NAc shell was enhanced via the downregulations of the SK channels after morphine withdrawal. Furthermore, the expression of SK2 and SK3 subunits in the NAc was significantly reduced after 3 weeks of morphine withdrawal, but was not altered in the dorsal striatum. In mPFC, the SK channel subunits were differentially expressed. To be specific, the expression of SK3 was upregulated, while the expression of SK2 was unchanged. Furthermore, the AP firing in layer 5 pyramidal neurons of the infralimbic (IL) cortex was decreased via the upregulations of the SK channel-related tail current after 3 weeks of morphine withdrawal. These results suggest that the SK channel plays a specific role in reward circuits following morphine exposure and a period of drug withdrawal, making it a potential target for the prevention of relapse

Insufficient maintenance DNA methylation is associated with abnormal embryonic development

<p>Abstract</p> <p>Background</p> <p>Early pregnancy loss (EPL) is a frustrating clinical problem, whose mechanisms are not completely understood. DNA methylation, which includes maintenance methylation and <it>de novo </it>methylation directed by DNA methyltransferases (DNMTs), is important for embryo development. Abnormal function of these DNMTs may have serious consequences for embryonic development.</p> <p>Methods</p> <p>To evaluate the possible involvement of DNA methylation in human EPL, the expression of DNMT proteins and global methylation of DNA were assessed in villous or decidua from EPL patients. The association of maintenance methylation with embryo implantation and development was also examined.</p> <p>Results</p> <p>We found that DNMT1 and DNMT3A were both expressed in normal human villous and decidua. DNMT1 expression and DNA global methylation levels were significantly down-regulated in villous of EPL. DNMT3A expression was not significantly changed in the EPL group compared to controls in either villous or decidua. We also found that disturbance of maintenance methylation with a DNMT1 inhibitor may result in a decreased global DNA methylation level and impaired embryonic development in the mouse model, and inhibit <it>in vitro </it>embryo attachment to endometrial cells.</p> <p>Conclusions</p> <p>Our results demonstrate that defects in DNA maintenance methylation in the embryo, not in the mother, are associated with abnormal embryonic implantation and development. The findings of the current study provide new insights into the etiology of EPL.</p

Non-coding RNAs in pancreatic ductal adenocarcinoma: New approaches for better diagnosis and therapy

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies with a 5-year survival rate less than 8%, which has remained unchanged over the last 50 years. Early detection is particularly difficult due to the lack of disease-specific symptoms and a reliable biomarker. Multimodality treatment including chemotherapy, radiotherapy (used sparingly) and surgery has become the standard of care for patients with PDAC. Carbohydrate antigen 19–9 (CA 19–9) is the most common diagnostic biomarker; however, it is not specific enough especially for asymptomatic patients. Non-coding RNAs are often deregulated in human malignancies and shown to be involved in cancer-related mechanisms such as cell growth, differentiation, and cell death. Several micro, long non-coding and circular RNAs have been reported to date which are involved in PDAC. Aim of this review is to discuss the roles and functions of non-coding RNAs in diagnosis and treatments of PDAC