Therapeutic potential of CB1R activation by Qingyangshen glycoside M1 for seizure relief.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchum otophyllum C.K.Schneid.PI.Wilson, commonly referred as ''Qingyangshen'' (QYS), is a traditional folk medicine from Yunnan, renowned for its efficacy in neurological and psychiatric disorders. Glycosides isolated from QYS have shown promise in alleviating epilepsy, however, mechanisms of action and specific molecular targets remain to be elucidated. AIM OF THE STUDY: The study aimed to evaluate the anticonvulsant effects of Qingyangshen glycosides M1 (M1), a C21 steroidal glycoside from QYS, on pentylenetetrazol (PTZ)-induced convulsions in zebrafish (Danio rerio), and its neuroprotective effect on Glutamate (Glu)-induced damage to PC12 cells, and importantly to identify its potential molecular targets. MATERIALS AND METHODS: To evaluate anticonvulsant activity of M1, 7 days-post-fertilization (7-dpf) animals were pretreated (by immersion) and then exposed to PTZ (10 mM) solution. Furthermore, Glu-induced PC12 cell damage was employed to investigate the neuroprotective and anti-apoptotic capacity. Cells were pretreated with various concentrations of M1 (0-10 µM) for 12 h and then co-treated with Glu (15 mM) for an additional 24 h. The cell viability, apoptosis rate and apoptosis-related proteins (p-PI3K, PI3K, Akt, p-Akt, CREB, p-CREB, BDNF, Bax and Bcl-2) were measured using CCK-8, annexin V/PI and Western blot assays. To model the expected interaction between M1 and candidate cannabinoid receptor type 1 (CB1R), ERK phosphorylation, molecular docking, and drug affinity responsive target stability (DARTS) techniques were employed. Finally, CB1R antagonist Rimonabant (Rim) was validated by co-administration in both zebrafish and cells to confirm the requirement of CB1R for M1 efficacy. RESULTS: At a concentration of 400 µM, M1 dramatically reversed PTZ-induced convulsive-like behaviors in zebrafish, as evidenced by a significant reduction in locomotor activity. In the context of Glu-induced cytotoxicity, M1 (10 µM) demonstrated a notable increase in cell viability and suppressed apoptosis through modulation of the Bax/Bcl-2 ratio and activation of the PI3K/Akt/CREB/BDNF signaling axis. These effects were facilitated through CB1R activation. In contrast, Rim dampened the beneficial activities of M1 as a cannabinoid agonist. CONCLUSIONS: These results demonstrated that M1 as a potential CB1R activator, exhibiting anticonvulsive effects in a PTZ-induced zebrafish model and neuroprotective properties via the PI3K/Akt/CREB/BDNF signaling axis in a Glu-induced PC12 cell injury model. Notably, the observed seizure relief attenuated by CB1R chemical antagonism.

Virtual Screening-Based Drug Development for the Treatment of Nervous System Diseases.

The incidence rate of nervous system diseases has increased in recent years. Nerve injury or neurodegenerative diseases usually cause neuronal loss and neuronal circuit damage, which seriously affect motor nerve and autonomic nervous function. Therefore, safe and effective treatment is needed. As traditional drug research becomes slower and more expensive, it is vital to enlist the help of cutting- edge technology. Virtual screening (VS) is an attractive option for the identification and development of promising new compounds with high efficiency and low cost. With the assistance of computer- aided drug design (CADD), VS is becoming more and more popular in new drug development and research. In recent years, it has become a reality to transform non-neuronal cells into functional neurons through small molecular compounds, which provides a broader application prospect than transcription factor-mediated neuronal reprogramming. This review mainly summarizes related theory and technology of VS and the drug research and development using VS technology in nervous system diseases in recent years, and focuses more on the potential application of VS technology in neuronal reprogramming, thus facilitating new drug design for both prevention and treatment of nervous system diseases.

A genetic algorithm with two-step rank-based encoding for closed-loop supply chain network design.

The closed-loop supply chain (CLSC) plays an important role in sustainable development and can help to increase the economic benefits of enterprises. The optimization for the CLSC network is a complicated problem, since it often has a large problem scale and involves multiple constraints. This paper proposes a general CLSC model to maximize the profits of enterprises by determining the transportation route and delivery volume. Due to the complexity of the multi-constrained and large-scale model, a genetic algorithm with two-step rank-based encoding (GA-TRE) is developed to solve the problem. Firstly, a two-step rank-based encoding is designed to handle the constraints and increase the algorithm efficiency, and the encoding scheme is also used to improve the genetic operators, including crossover and mutation. The first step of encoding is to plan the routes and predict their feasibility according to relevant constraints, and the second step is to set the delivery volume based on the feasible routes using a rank-based method to achieve greedy solutions. Besides, a new mutation operator and an adaptive population disturbance mechanism are designed to increase the diversity of the population. To validate the efficiency of the proposed algorithm, six heuristic algorithms are compared with GA-TRE by using different instances with three problem scales. The results show that GA-TRE can obtain better solutions than the competitors, especially on large-scale instances.

A coevolutionary algorithm based on the auxiliary population for constrained large-scale multi-objective supply chain network.

Supply chain network is important for the enterprise to improve the operation and management, but has become more complicated to optimize in reality. With the consideration of multiple objectives and constraints, this paper proposes a constrained large-scale multi-objective supply chain network (CLMSCN) optimization model. This model is to minimize the total operation cost (including the costs of production, transportation, and inventory) and to maximize the customer satisfaction under the capacity constraints. Besides, a coevolutionary algorithm based on the auxiliary population (CAAP) is proposed, which uses two populations to solve the CLMSCN problem. One population is to solve the original complex problem, and the other population is to solve the problem without any constraints. If the infeasible solutions are generated in the first population, a linear repair operator will be used to improve the feasibility of these solutions. To validate the effectivity of the CAAP algorithm, the experiment is conducted on the randomly generated instances with three different problem scales. The results show that the CAAP algorithm can outperform other compared algorithms, especially on the large-scale instances.

A Novel 5-HT1B Receptor Agonist of Herbal Compounds and One of the Therapeutic Uses for Alzheimer's Disease.

The serotonin receptor 5-HT1B is widely expressed in the central nervous system and has been considered a drug target in a variety of cognitive and psychiatric disorders. The anti-inflammatory effects of 5-HT1B agonists may present a promising approach for Alzheimer's disease (AD) treatment. Herbal antidepressants used in the treatment of AD have shown functional overlap between the active compounds and 5-HT1B receptor stimulation. Therefore, compounds in these medicinal plants that target and stimulate 5-HT1B deserve careful study. Molecular docking, drug affinity responsive target stability, cellular thermal shift assay, fluorescence resonance energy transfer (FRET), and extracellular regulated protein kinases (ERK) 1/2 phosphorylation tests were used to identify emodin-8-O-ß-d-glucopyranoside (EG), a compound from Chinese medicinal plants with cognitive deficit attenuating and antidepressant effects, as an agonist of 5-HT1B. EG selectively targeted 5-HT1B and activated the 5-HT1B-induced signaling pathway. The activated 5-HT1B pathway suppressed tumor necrosis factor (TNF)-α levels, thereby protecting neural cells against beta-amyloid (Aß)-induced death. Moreover, the agonist activity of EG towards 5-HT1B receptor, in FRET and ERK1/2 phosphorylation, was antagonized by SB 224289, a 5-HT1B antagonist. In addition, EG relieved AD symptoms in transgenic worm models. These results suggested that 5-HT1B receptor activation by EG positively affected Aß-related inflammatory process regulation and neural death resistance, which were reversed by antagonist SB 224289. The active compounds such as EG might act as potential therapeutic agents through targeting and stimulating 5-HT1B receptor for AD and other serotonin-related disorders. This study describes methods for identification of 5-HT1B agonists from herbal compounds and for evaluating agonists with biological functions, providing preliminary information on medicinal herbal pharmacology.