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

Higher Baseline Serum Bilirubin Levels Are Associated With Increased Risk of Early Neurological Deterioration in Women With Acute Ischemic Stroke

BACKGROUND AND OBJECTIVES: Early neurological deterioration (END) occurs in up to one-third of patients with acute ischemic stroke (AIS) and associated with poor outcome. The role of serum bilirubin in END remains controversial. This study aims to investigate the association of total bilirubin (TBIL), direct bilirubin (DBIL) and indirect bilirubin (IBIL) with END. METHODS: This study was a cross-sectional retrospective study with 344 AIS patients enrolled. We retrospectively reviewed consecutive AIS patients with END through a medical record retrieval system and enrolled patients as control randomly from the AIS patients without END at the same period. The bilirubin levels were compared between the END group and No END group. The correlations of bilirubin with END were assessed according to the bilirubin tertiles on the cohort of different genders. RESULTS: In women, as the bilirubin level increased, the occurrence of END showed an increasing trend. The linear association was significant based on the tertiles of all bilirubin types (TBIL DISCUSSION: There were gender differences in the relationship between bilirubin and END, and DBIL level was positively associated with END occurrence in women, not in men. DBIL had greater incremental predictive value for END than TBIL and IBIL

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

Biodistribution in sarcoma 180-bearing mice of N-succinyl-chitosan nanoparticles for tumor targeting

In the present study, we sought to systemically evaluate the biodistribution and the tumor-accumulation of N-succinyl-chitosan nanoparticles (Suc-Chi-NPs, 200 nm in diameter) in model tumor-bearing mice and also the binding of Suc-Chi-NPs to k562 cells was evaluated by flow cytometry. In vitro studies showed that all Suc-Chi-NPs displayed high affinity to k562 cells. After intravenous injection of Suc- Chi-NPs via the tail vein, a small amount of Suc-Chi-NPs was found in liver and spleen for 4 days, whereas a negligible quantity was detected in heart and lung. The distributed amount of Suc-Chi-NPs in blood was as a high level throughout the 4 days. The distributed amount of Suc-Chi-NPs (> 15 % of dose) was accumulated at 1 day and gradually increased in tumor, as blood circulation time increased. This result suggests that Suc-Chi-NPs accumulate passively in the tumor tissue due to the enhanced permeability and retention (EPR) effect, following intravenous administration. These findings revealed the promising potential of Suc-Chi-NPs on the basis of Suc-Chi as a carrier for cancer therapy.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Pushing the Limits of ChatGPT on NLP Tasks

Despite the success of ChatGPT, its performances on most NLP tasks are still well below the supervised baselines. In this work, we looked into the causes, and discovered that its subpar performance was caused by the following factors: (1) token limit in the prompt does not allow for the full utilization of the supervised datasets; (2) mismatch between the generation nature of ChatGPT and NLP tasks; (3) intrinsic pitfalls of LLMs models, e.g., hallucination, overly focus on certain keywords, etc. In this work, we propose a collection of general modules to address these issues, in an attempt to push the limits of ChatGPT on NLP tasks. Our proposed modules include (1) a one-input-multiple-prompts strategy that employs multiple prompts for one input to accommodate more demonstrations; (2) using fine-tuned models for better demonstration retrieval; (3) transforming tasks to formats that are more tailored to the generation nature; (4) employing reasoning strategies that are tailored to addressing the task-specific complexity; (5) the self-verification strategy to address the hallucination issue of LLMs; (6) the paraphrase strategy to improve the robustness of model predictions. We conduct experiments on 21 datasets of 10 representative NLP tasks, including question answering, commonsense reasoning, natural language inference, sentiment analysis, named entity recognition, entity-relation extraction, event extraction, dependency parsing, semantic role labeling, and part-of-speech tagging. Using the proposed assemble of techniques, we are able to significantly boost the performance of ChatGPT on the selected NLP tasks, achieving performances comparable to or better than supervised baselines, or even existing SOTA performances

Genome-wide annotation and comparative analysis of cuticular protein genes in the noctuid pest \u3cem\u3eSpodoptera litura\u3c/em\u3e

Insect cuticle is considered an adaptable and versatile building material with roles in the construction and function of exoskeleton. Its physical properties are varied, as the biological requirements differ among diverse structures and change during the life cycle of the insect. Although the bulk of cuticle consists basically of cuticular proteins (CPs) associated with chitin, the degree of cuticular sclerotization is an important factor in determining its physical properties. Spodoptera litura, the tobacco cutworm, is an important agricultural pest in Asia. Compared to the domestic silkworm, Bombyx mori, another lepidopteran whose CP genes have been well annotated, S. litura has a shorter life cycle, hides in soil during daytime beginning in the 5th instar and is exposed to soil in the pupal stage without the protection of a cocoon. In order to understand how the CP genes may have been adapted to support the characteristic life style of S. litura, we searched its genome and found 287 putative cuticular proteins that can be classified into 9 CP families (CPR with three groups (RR-1, RR-2, RR-3), CPAP1, CPAP3, CPF, CPFL, CPT, CPG, CPCFC and CPLCA), and a collection of unclassified CPs named CPH. There were also 112 cuticular proteins enriched in Histidine residues with content varying from 6% to 30%, comprising many more His-rich cuticular proteins than B. mori. A phylogenetic analysis between S. litura, M. sexta and B. mori uncovered large expansions of RR-1 and RR-2 CPs, forming large gene clusters in different regions of S. liturachromosome 9. We used RNA-seq analysis to document the expression profiles of CPs in different developmental stages and tissues of S. litura. The comparative genomic analysis of CPs between S. litura and B. moriintegrated with the unique behavior and life cycle of the two species offers new insights into their contrasting ecological adaptations

Dictamnine, a novel c-Met inhibitor, suppresses the proliferation of lung cancer cells by downregulating the PI3K/AKT/mTOR and MAPK signaling pathways

Dictamnine (Dic), a naturally occurring small-molecule furoquinoline alkaloid isolated from the root bark of Dictamnus dasycarpus Turcz., is reported to display anticancer properties. However, little is known about the direct target proteins and anticancer mechanisms of Dic. In the current study, Dic was found to suppress the growth of lung cancer cells in vitro and in vivo, and to attenuate the activation of PI3K/AKT/mTOR and mitogen-activated protein kinase (MAPK) signaling pathways by inhibiting the phosphorylation and activation of receptor tyrosine kinase c-Met. Moreover, the binding of Dic to c-Met was confirmed by using cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay. Among all cancer cell lines tested, Dic inhibited the proliferation of c-Met-dependent EBC-1 cells with the greatest potency (IC50 = 2.811 μM). Notably, Dic was shown to synergistically improve the chemo-sensitivity of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant lung cancer cells to gefitinib and osimertinib. These results suggest that Dic is a c-Met inhibitor that can serve as a potential therapeutic agent in the treatment of lung cancer, especially against EGFR TKI-resistant and c-Met-dependent lung cancer