56 research outputs found
Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability
Voltage-gated ion channels (VGICs), extensively distributed in the central nervous system (CNS), are responsible for the generation as well as modulation of neuroexcitability and considered as vital players in the pathogenesis of human epilepsy, with regulating the shape and duration of action potentials (APs). For instance, genetic alterations or abnormal expression of voltage-gated sodium channels (VGSCs), Kv channels, and voltage-gated calcium channels (VGCCs) are proved to be associated with epileptogenesis. This chapter aims to highlight recent discoveries on the mutations in VGIC genes and dysfunction of VGICs in epilepsy, especially focusing on the pathophysiological and pharmacological properties. Understanding the role of epilepsy-associated VGICs might not only contribute to clarify the mechanism of epileptogenesis and genetic modifiers but also provide potential targets for the precise treatment of epilepsy
Scorpion Toxins from <em>Buthus martensii</em> Karsch (BmK) as Potential Therapeutic Agents for Neurological Disorders: State of the Art and Beyond
Scorpions are fascinating creatures which became residents of the planet well before human beings dwelled on Earth. Scorpions are always considered as a figure of fear, causing notable pain or mortality throughout the world. Their venoms are cocktails of bioactive molecules, called toxins, which are responsible for their toxicity. Fortunately, medical researchers have turned the life-threatening toxins into life-saving therapeutics. From Song Dynasty in ancient China, scorpions and their venoms have been applied in traditional medicine for treating neurological disorders, such as pain, stroke, and epilepsy. Neurotoxins purified from Chinese scorpion Buthus Martensii Karsch (BmK) are considered as the main active ingredients, which act on membrane ion channels. Long-chain toxins of BmK, composed of 58–76 amino acids, could specifically recognize voltage-gated sodium channels (VGSCs). Short-chain BmK toxins, containing 28–40 amino acids, are found to modulate the potassium or chloride channels. These components draw attention as useful scaffolds for drug-design in order to tackle the emerging global medical threats. In this chapter, we aim to summarize the most promising candidates that have been isolated from BmK venoms for drug development
Targeting Neuroglial Sodium Channels in Neuroinflammatory Diseases
The Hodgkin-Huxley model, at its 66th anniversary, remains a footing stone of neuroscience, which describes how the action potential (AP) is generated. As the core player of AP initiation, voltage-gated sodium channels (VGSCs) are always considered to be required for electrogenesis in excitable cells. Cells which are not traditionally been considered to be excitable, including glial cells, also express VGSCs in physiological as well as pathological conditions. The dysfunction of glial VGSCs is seemingly not related to abnormal excitation of neurons, but of importance in the astrogliosis and M1 polarization of microglia, which could induce refractory neuroinflammatory diseases, such as multiple sclerosis, stroke, epilepsy, and Alzheimer’s and Parkinson’s diseases. Therefore, in this chapter, we aim to describe the physiological and pathological roles of VGSCs contributing to the activity of glial cells and discuss whether VGSC subtypes could be used as a novel drug target, with an eye toward therapeutic implications for neuroinflammatory diseases
Evaluation of the reporting quality of clinical practice guidelines on gliomas using the RIGHT checklist
Background: The reporting quality of clinical practice guidelines (CPGs) for gliomas has not yet been thoroughly assessed. The International Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement developed in 2016 provides a reporting framework to improve the quality of CPGs. We aimed to estimate the reporting quality of glioma guidelines using the RIGHT checklist and investigate how the reporting quality differs by selected characteristics. Methods: We systematically searched electronic databases, guideline databases, and medical society websites to retrieve CPGs on glioma published between 2018 and 2020. We calculated the compliance of the CPGs to individual items, domains and the RIGHT checklist overall. We performed stratified analyses by publication year, country of development, reporting of funding, and impact factor (IF) of the journal. Results: Our search revealed 20 eligible guidelines. Mean overall adherence to the RIGHT statement was 54.6%. Eight CPGs reported more than 60% of the items, and five reported less than 50%. All guidelines adhered to the items 1a, 3, 7a, 13a, while no guidelines reported the items 17 or 18b (see http://www.rightstatement.org/right-statement/checklist for a description of the items). Two of the seven domains, "Basic information" and "Background", had mean reporting rates above 60%. The "Review and quality assurance" domain had the lowest mean reporting rate, 12.5%. The reporting quality of guidelines published in 2020, guidelines developed in the United States, and guidelines that reported funding tended to be above average. Conclusions: The reporting quality of CPGs on gliomas is low and needs improvement. Particular attention should be paid on reporting the external review and quality assurance process. The use of the RIGHT criteria should be encouraged to guide the development, reporting and evaluation of CPGs
Metabolite Profiling, Pharmacokinetics, and In Vitro Glucuronidation of Icaritin in Rats by Ultra-Performance Liquid Chromatography Coupled with Mass Spectrometry
Icaritin is a naturally bioactive flavonoid with several significant effects. This study aimed to clarify the metabolite profiling, pharmacokinetics, and glucuronidation of icaritin in rats. An ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) assay was developed and validated for qualitative and quantitative analysis of icaritin. Glucuronidation rates were determined by incubating icaritin with uridine diphosphate glucuronic acid- (UDPGA-) supplemented microsomes. Kinetic parameters were derived by appropriate model fitting. A total of 30 metabolites were identified or tentatively characterized in rat biosamples based on retention times and characteristic fragmentations, following proposed metabolic pathway which was summarized. Additionally, the pharmacokinetics parameters were investigated after oral administration of icaritin. Moreover, icaritin glucuronidation in rat liver microsomes was efficient with CLint (the intrinsic clearance) values of 1.12 and 1.56 mL/min/mg for icaritin-3-O-glucuronide and icaritin-7-O-glucuronide, respectively. Similarly, the CLint values of icaritin-3-O-glucuronide and icaritin-7-O-glucuronide in rat intestine microsomes (RIM) were 1.45 and 0.86 mL/min/mg, respectively. Taken altogether, dehydrogenation at isopentenyl group and glycosylation and glucuronidation at the aglycone were main biotransformation process in vivo. The general tendency was that icaritin was transformed to glucuronide conjugates to be excreted from rat organism. In conclusion, these results would improve our understanding of metabolic fate of icaritin in vivo
Ganoderma lucidum Polysaccharide Enhanced the Antitumor Effects of 5-Fluorouracil against Gastric Cancer through Its Upregulation of NKG2D/MICA
5-Fluorouracil (5-Fu) is one of the frequently used first-line cytotoxic drugs for chemotherapy against gastric cancer. Chemotherapy and immunotherapy are currently the main methods for treating gastric cancer. Immunotherapy can enhance the antitumor effect of chemotherapy drugs at the same time reducing its toxicity. The combination of these two therapies to treat cancer has become a mainstay and has received increasing attention in clinical practice. Ganoderma lucidum polysaccharide (GLP) is isolated from the Ganoderma lucidum fruiting body. Studies have shown that GLP has antitumor effects, where GLP does not directly kill tumors, rather exerting its antitumor function by stimulating immune cells including natural killer (NK) cells and T cells. In this study, the antitumor effect of GLP combined with 5-Fu was studied in vivo. At the same time, the associated mechanism of GLP combined with 5-Fu in gastric cancer cell lines BGC823 and SGC7901 was investigated in vitro. The results showed that GLP could stimulate the killing effect of NK-92 cells on gastric cancer cell lines BGC823 and SGC7901 and synergistically enhance the toxic effects of NK-92 cells on gastric cancer cell lines BGC823 and SGC7901. Moreover, GLP could further promote the activity of NK-92 cells by activating the NK cell activating receptor NKG2D and its downstream DAP10/PI3K/ERK signaling pathway
Nuclear Protein 1 Expression Is Associated with PPARG in Bladder Transitional Cell Carcinoma
Background. The Nuclear protein 1 gene was first discovered in acute pancreatitis and functions as an oncogene in cancer progression and drug resistance. However, the role of Nuclear protein 1 in bladder transitional cell carcinoma (BTCC) is still unclear. Methods. The Cancer Genome Atlas database and immunohistochemical analysis were adopted to evaluate Nuclear protein 1 expression in BTCC. We applied lentivirus-mediated small-interfering RNA to down-regulate the expression of Nuclear protein 1 in BTCC cell lines. We further performed an Affymetrix microarray and Gene Set Enrichment Analysis (GSEA) to assess the genes and signaling pathways related to Nuclear protein 1. Results. We found that Nuclear protein 1 expression was up-regulated in BTCC and positively related to the degree of BTCC malignancy. Compared with Caucasian patients with BTCC, Nuclear protein 1 expression was attenuated in Asian patients. The Affymetrix microarray showed that lipopolysaccharide was the upstream regulatory factor of Nuclear protein 1 in BTCC. The GSEA indicated that Nuclear protein 1 expression was associated with signaling pathways in cancer, peroxisome proliferator-activated receptor (PPAR) pathways, and RNA degradation. The expression of Nuclear protein 1 was negatively correlated with PPARG (R=−0.290, P<0.001), but not with PPARA (R=0.047, P=0.344) and PPARD (R=−0.055, P=0.260). Conclusions. The study findings indicate that Nuclear protein 1 is positively associated with the malignancy degree of BTCC and that Nuclear protein 1 expression is negatively correlated with PPARG
Anticonvulsant Effects of Dingxian Pill in Pentylenetetrazol-Kindled Rats
Dingxian pill has been used as an antiepilepsy agent in China from ancient to modern times, of which the concrete pharmacological characterization and the underlying molecular mechanism remain unclear. The present study was undertaken to investigate them by animal behavior, electroencephalogram (EEG), Morris water maze, immunohistochemistry, transcriptomics, and real-time PCR. In our results, the treatment of Dingxian pill dose-dependently inhibited PTZ-induced seizure-like behavior and reduced the seizure grades, LFP power spectral density, and brain wave of the epileptiform EEG component induced by PTZ. In Morris water maze tests, the learning and memory ability of kindled epileptic rats could be attenuated more efficiently by Dingxian pill. For the immediate early gene c-fos, the expression was reduced after Dingxian pill treatment, and the difference was significant between the treatment and the model group. Through the transcriptome analysis of the gene expression in hippocampus, Egr3, Nrg, Arc, and Ptgs2, closely related to epilepsy, had been proved to be downregulated by application of Dingxian pill. All of the results not only highlight the antiepileptic effects of Dingxian pill and its molecular mechanism, but also provide a modern validity theory for the clinical application of traditional Chinese medicine (TCM)
Optimization of Nanoparticles for Smart Drug Delivery: A Review
Nanoparticle delivery systems have good application prospects in the treatment of various diseases, especially in cancer treatment. The effect of drug delivery is regulated by the properties of nanoparticles. There have been many studies focusing on optimizing the structure of nanoparticles in recent years, and a series of achievements have been made. This review summarizes the optimization strategies of nanoparticles from three aspects—improving biocompatibility, increasing the targeting efficiency of nanoparticles, and improving the drug loading rate of nanoparticles—aiming to provide some theoretical reference for the subsequent drug delivery of nanoparticles
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