Current Pharmaceutical Design - Volume 25, Issue 43, 2019

Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders and are well recognized to be biologically heterogeneous in which various factors are associated, including genetic, metabolic, and environmental ones. Despite its high prevalence, only a few drugs have been approved for the treatment of ASD. Therefore, extensive studies have been conducted to identify ASD risk genes and novel drug targets. Since many genes and many other factors are associated with ASD, various bioinformatics methods have also been developed for the analysis of ASD. In this paper, we review bioinformatics methods for analyzing ASD data with the focus on computational aspects. We classify existing methods into two categories: (i) methods based on genomic variants and gene expression data, and (ii) methods using biological networks, which include gene co-expression networks and protein-protein interaction networks. Next, for each method, we provide an overall flow and elaborate on the computational techniques used. We also briefly review other approaches and discuss possible future directions and strategies for developing bioinformatics approaches to analyze ASD.

Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are neuron-specific cytoskeletal components. Neurofilaments are axonal structural components and integral components of synapses, which are important for neuronal electric signal transmissions along the axons and post-translational modification. Abnormal assembly of neurofilaments is found in several human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and hereditary sensory-motor neuropathy (HSMN). In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson’s disease (PD), Aβ and tau in Alzheimer’s disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS). When axon damage occurs in central nervous disorders, neurofilament proteins are released and delivered into cerebrospinal fluid (CSF), which are then circulated into blood. New quantitative analyses and assay techniques are well-developed for the detection of neurofilament proteins, particularly NF-L and the phosphorylated NF-H (pNF-H) in CSF and serum. This review discusses the potential of using peripheral blood NF quantities and evaluating the severity of damage in the nervous system. Intermediate filaments could be promising biomarkers for evaluating disease progression in different nervous system disorders.

Vaccination is an effective strategy to reduce the burden of preventable illness. However, many clinical reports revealed that various vaccinations may associate with neurological disorders, mainly including autoimmune disease, febrile seizure, and vaccine-associated paralytic poliomyelitis (VAPP). Although more and more reports revealed that part of the above post-vaccine neurological disorders is not directly related to vaccination, it may be merely a coincidence. However, these reports may increase the hesitancy on vaccination for the public population and influence the coverage of vaccination. In this report, we described a child with acute flaccid paralysis possibly caused by a poliovirus vaccine. To provide feasible ways to realize or reduce the risk of neurological adverse events caused by vaccines, we further provide a mini-review of the literature of vaccination associated with neurological adverse events. This revealed that oral poliomyelitis vaccine use exclusively and type 2 serotype poliomyelitis vaccine virus were the risk factors for VAPP. The combination vaccine was associated with an increased risk of ADEM and FS following immunization when compared with the administration of vaccines separately. Even though cases have been reported that vaccination may be a trigger of anti-NMDARe and GBS, there is no direct evidence to prove that vaccination increased the risk of GBS and anti-NMDARe.

Anti-N-methyl-d-aspartate (Anti-NMDA) receptor encephalitis is an acute autoimmune disorder. The symptoms range from psychiatric symptoms, movement disorders, cognitive impairment, and autonomic dysfunction. Previous studies revealed that vaccination might induce this disease. A few cases were reported to be related to H1N1 vaccine, tetanus/diphtheria/pertussis and polio vaccine, and Japanese encephalitis vaccine. Although vaccination is a useful strategy to prevent infectious diseases, in a low risk, it may trigger serious neurological symptoms. In addition to anti-NMDA receptor encephalitis, other neurological diseases were reported to be associated with a number of vaccines. In this paper, the anti-NMDA receptor encephalitis cases related to a number of vaccines and other neurological symptoms that might be induced by these vaccines were reviewed. In addition, anti-NMDA receptor encephalitis cases that were induced by virus infection were also reviewed.

Background: Identifying effective candidate drug compounds in patients with neurological disorders based on gene expression data is of great importance to the neurology field. By identifying effective candidate drugs to a given neurological disorder, neurologists would (1) reduce the time searching for effective treatments; and (2) gain additional useful information that leads to a better treatment outcome. Although there are many strategies to screen drug candidate in pre-clinical stage, it is not easy to check if candidate drug compounds can also be effective to human. Objective: We tried to propose a strategy to screen genes whose expression is altered in model animal experiments to be compared with gene expressed differentially with drug treatment to human cell lines. Methods: Recently proposed tensor decomposition (TD) based unsupervised feature extraction (FE) is applied to single cell (sc) RNA-seq experiments of Alzheimer’s disease model animal mouse brain. Results: Four hundreds and one genes are screened as those differentially expressed during Aβ accumulation as age progresses. These genes are significantly overlapped with those expressed differentially with the known drug treatments for three independent data sets: LINCS, DrugMatrix, and GEO. Conclusion: Our strategy, application of TD based unsupervised FE, is useful one to screen drug candidate compounds using scRNA-seq data set.

Background: Glycemic variability is a risk factor for total death and cardiovascular events. There are no obvious guidelines for the direct treatment of glycemic variability, but it can be improved with the treatment of postprandial hyperglycemia. Objective: We compared the effect of repaglinide versus the combination of mitiglinide and voglibose, used to improve postprandial hyperglycemia, on glycemic variability in Japanese patients with type 2 diabetes. Methods: We performed an open-label randomized cross-over trial between April 2016 and April 2018. Patients with type 2 diabetes who were admitted to our hospital were enrolled in our study (n = 12). Glycemic variability. was assessed using a continuous glucose monitoring system. Results: The average glucose level of the repaglinide phase (146.1 ± 20.7 mg/dl) and the combination of mitiglinide and voglibose phase (132.3 ± 19.8 mg/dl) were similar (P = 0.10). The standard division (P = 0.0005), coefficient of variation (P = 0.006), and mean amplitude of glycemic excursion (P = 0.002) of glucose were lower in the combination of mitiglinide and voglibose phase than in the repaglinide phase. Conclusion: Treatment with the combination of mitiglinide and voglibose might be more effective than repaglinide for the improvement of glycemic variability.

Background: The human ether-a-go-go-related gene (hERG) potassium channel is the rapidly activating component of cardiac delayed rectifier potassium current (IKr), which is a crucial determinant of cardiac repolarization. The reduction of hERG current is commonly believed to cause Long QT Syndrome (LQTs). Probucol, a cholesterol-lowering drug, induces LQTs by inhibiting the expression of the hERG channel. Unfortunately, there is currently no effective therapeutic method to rescue probucol-induced LQTs. Methods: Patch-clamp recording techniques were used to detect the action potential duration (APD) and current of hERG. Western blot was performed to measure the expression levels of proteins. Results: In this study, we demonstrated that 1 μM matrine and oxymatrine could rescue the hERG current and hERG surface expression inhibited by probucol. In addition, matrine and oxymatrine significantly shortened the prolonged action potential duration induced by probucol in neonatal cardiac myocytes. We proposed a novel mechanism underlying the probucol induced decrease in the expression of transcription factor Specificity protein 1 (Sp1), which is an established transactivator of the hERG gene. We also demonstrated that matrine and oxymatrine were able to upregulate Sp1 expression which may be one of the possible mechanisms by which matrine and oxymatrine rescued probucol-induced hERG channel deficiency. Conclusion: Our current results demonstrate that matrine and oxymatrine could rescue probucol-induced hERG deficiency in vitro, which may lead to potentially effective therapeutic drugs for treating acquired LQT2 by probucol in the future.

Background: Osteoarthritis (OA) pertains to a chronic disease of degenerative joints distinguished by articular cartilage destruction, subchondral bone remodeling, osteophyte formation, and inflammatory changes. Chondrocyte apoptosis is inextricably linked to cartilage degeneration. SRY-related high-mobility-group-box 9 (SOX9) is a well-acknowledged transcription factor in the chondrogenesis. Nevertheless, the detailed function of miR-138-5p/SOX9 in OA remains to be fully clarified. Materials and Methods: qRT-PCR was performed to measure the expressions of miR-138-5p and SOX9 mRNA in OA and normal cartilage tissues and cells. Human chondrocyte cell lines, CHON-001 and ATDC5, were treated with different doses of interleukin-1β (IL-1β) to simulate the inflammatory response environment of OA. miR-138-5p mimics, miR-138-5p inhibitors, and SOX9 small interfering RNA (siRNA) were constructed and transfected into CHON-001 and ATDC5 cells. CCK-8 was conducted to determine the cell viability and transwell assay was used to monitor the migration of cells. Western blot was carried out to detect the expressions of apoptosis- related factors. Enzyme-linked immunosorbent assay (ELISA) was adopted to measure the contents of inflammatory factors. TargetScan predicted SOX9 was a target gene of miR-138-5p, which was then verified by luciferase assay. Results: miR-138-5p expression was down-regulated in OA and regulated SOX9 expression. The downregulation of miR-138-5p facilitated the proliferation and migration of CHON-001 and ATDC5 cells, while impeded their apoptosis and inflammatory response. Besides, down-regulated SOX9 can counteract the promoting effect of down-regulated miR-138-5p on the proliferation and migration of chondrocytes. Conclusion: miR-138-5p can arrest the proliferation and migration of CHON-001 and ATDC5 via restraining SOX9, and facilitate the apoptosis and inflammation. This study revealed the protective effect of down-regulated miR-138-5p on the inflammatory injury of chondrocytes caused by IL-1β.

Introduction: The association between obesity and physical activity level is well established in the literature, as well as its consequences that lead to chronic noncommunicable diseases. In addition, it is also possible to obtain the immunometabolic mechanism that explains the pathway of associations between obesity, chronic noncommunicable diseases and the level of physical activity. It also seems clear that treating illnesses has a financial impact on healthcare systems around the world, so it seems important to assess the financial impact on the healthcare system of individuals with immunometabolic dysfunction. Aim: This study aimed to assess whether there is a correlation between metabolic and inflammatory markers and healthcare costs according to body adiposity and habitual physical activity (HPA). Methods: This is a cross-sectional study, where the sample includes men and women aged over 50. Participants underwent evaluations that included the following variables: i) immunometabolic markers, ii) healthcare costs, iii) obesity, iv) habitual physical activity, and v) history of personal illness. Statistical significance was set at values lower than 5% and the software used was BioEstat. Results: The correlation between metabolic and inflammatory markers and healthcare costs demonstrated a positive and significant relationship, adjusted for obesity and HPA, between glucose concentrations and exam costs (r = 0.343, p-value = 0.007) and total cost (r = 261; p-value = 0.043); HOMA index and cost of exams (r = 0.267; pvalue = 0.038); and IL-10 and cost of medical consultation (r = 0.297; p-value = 0.020). Conclusion: Metabolic and inflammatory markers may be related to the costs of consultations and examinations, independent of obesity and HPA.

Background: Hepatocellular carcinoma (HCC) is one of the most deadly cancer types worldwide, and its incidence is high in China. Multiple long non-coding RNAs (lncRNAs) have been recently identified as crucial oncogenic factors or tumor suppressors. In this study, we explored the effects of LncRNA RHPN1 antisense RNA 1 (RHPN1-AS1) on the progression of HCC. Methods: Expression levels of RHPN1-AS1 and miR-596 in HCC samples were measured by qRT-PCR. The association between pathological indexes and the expression level of RHPN1-AS1 was also analyzed. Human HCC cell lines Huh7 and SMMC-7721 were used as cell models. CCK-8 and colony formation assays were performed to assess the effect of RHPN1-AS1 on HCC cell line proliferation. The flow cytometer instrument was used to study the effect of RHPN1-AS1 on apoptosis of HCC cells. The transwell assay was conducted to detect the effect of RHPN1-AS1 on migration and invasion. Furthermore, luciferase reporter assay was used to confirm targeting of miR-596 by RHPN1-AS1. Additionally, the regulatory function of RHPN1-AS1 on insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was detected by western blot. Results: The expression level of RHPN1-AS1 in HCC samples was observed to significantly increase compared with normal tissues and its high expression was correlated with unfavorable pathological indexes. Highly expressed RHPN1-AS1 was associated with shorter overall survival time. RHPN1-AS1 overexpression remarkably accelerated proliferation and metastasis of HCC cells, while reduced apoptosis. Accordingly, RHPN1-AS1 knockdown suppressed the malignant phenotypes of HCC cells. RHPN1-AS1 overexpression significantly reduced miR-596 expression by sponging it, but enhanced IGF2BP2 expression. Conclusion: RHPN1-AS1 acts as a sponge of tumor suppressor miR-596 in HCC that can indirectly enhance the IGF2BP2 expression and function as an oncogenic lncRNA.