A Lipid-Sensitive Spider Peptide Toxin Exhibits Selective Anti-Leukemia Efficacy through Multimodal Mechanisms.

Anti-cancer peptides (ACPs) represent a promising potential for cancer treatment, although their mechanisms need to be further elucidated to improve their application in cancer therapy. Lycosin-I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis, shows significant anticancer potential. Herein, it is found that Lycosin-I, which can self-assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin-I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin-I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K-AKT-mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin-I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin-I can provide new insights into the mechanism of ACPs, and Lycosin-I, which is characterized by high potency and specificity, can be a promising lead for the development of anti-leukemia drugs.

Pillar[5]arene-Based Ion-Pair Recognition for Encapsulation of a Stilbazolium-Type Dye with Enhanced Photophysical Properties and Nonlinear Optical Activity.

Constructing organic composite materials through molecular recognition has emerged as an important theme in materials science. Here we report an ion-pair recognition system involving the use of a propoxylated pillar[5]arene (PrP5) to modulate the solid-state photophysical properties of dye trans-4'-(dimethylamino)-N-methyl-4-stilbazolium hexafluorophosphate (DMASP). Single crystal X-ray diffraction analysis reveals that the dye guest DMASP is encapsulated by PrP5 to form a 2:1 host-guest complex 2PrP5⸧DMASP in the crystalline state. The macrocyclic skeleton of PrP5 imposes restrictions on the intramolecular motions of the dye guest, leading to a significant enhancement of its fluorescence emission. Additionally, within the 2PrP5⸧DMASP complex crystal structure, DMASP molecules are found to display two possible opposite orientations in the one-dimensional channels formed by PrP5 molecules. This arrangement is believed to alter the overall solid-state packing structure of DMASP, thereby activating its nonlinear optical activity. This work not only reports a novel ion-pair molecular recognition system based on pillararenes but also provides valuable insights into the modulation of the crystalline state photophysical properties of organic dyes via cocrystal engineering.

Angelicin improves osteoporosis in ovariectomized rats by reducing ROS production in osteoclasts through regulation of the KAT6A/Nrf2 signalling pathway.

BACKGROUND: Angelicin, which is found in Psoralea, can help prevent osteoporosis by stopping osteoclast formation, although the precise mechanism remains unclear. METHODS: We evaluated the effect of angelicin on the oxidative stress level of osteoclasts using ovariectomized osteoporosis model rats and RAW264.7 cells. Changes in the bone mass of the femur were investigated using H&E staining and micro-CT. ROS content was investigated by DHE fluorescence labelling. Osteoclast-related genes and proteins were examined for expression using Western blotting, immunohistochemistry, tartrate-resistant acid phosphatase staining, and real-time quantitative PCR. The influence of angelicin on osteoclast development was also evaluated using the MTT assay, double luciferin assay, chromatin immunoprecipitation, immunoprecipitation and KAT6A siRNA transfection. RESULTS: Rats treated with angelicin had considerably higher bone mineral density and fewer osteoclasts. Angelicin prevented RAW264.7 cells from differentiating into osteoclasts in vitro when stimulated by RANKL. Experiments revealed reduced ROS levels and significantly upregulated intracellular KAT6A, HO-1, and Nrf2 following angelicin treatment. The expression of genes unique to osteoclasts, such as MMP9 and NFATc1, was also downregulated. Finally, KAT6A siRNA transfection increased intracellular ROS levels while decreasing KAT6A, Nrf2, and HO-1 protein expression in osteoclasts. However, in the absence of KAT6A siRNA transfection, angelicin greatly counteracted this effect in osteoclasts. CONCLUSIONS: Angelicin increased the expression of KAT6A. This enhanced KAT6A expression helps to activate the Nrf2/HO-1 antioxidant stress system and decrease ROS levels in osteoclasts, thus inhibiting oxidative stress levels and osteoclast formation.

A potentiation of REM sleep-active neurons in the lateral habenula may be responsible for the sleep disturbance in depression.

Psychiatric disorders with dysfunction of the lateral habenula (LHb) show sleep disturbance, especially a disinhibition of rapid eye movement (REM) sleep in major depression. However, the role of LHb in physiological sleep control and how LHb contributes to sleep disturbance in major depression remain elusive. Here, we found that functional manipulations of LHb glutamatergic neurons bidirectionally modulated both non-REM (NREM) sleep and REM sleep. Activity recording revealed heterogeneous activity patterns of LHb neurons across sleep/wakefulness cycles, but LHb neurons were preferentially active during REM sleep. Using an activity-dependent tagging method, we selectively labeled a population of REM sleep-active LHb neurons and demonstrated that these neurons specifically promoted REM sleep. Neural circuit studies showed that LHb neurons regulated REM sleep via projections to the ventral tegmental area but not to the rostromedial tegmental nucleus. Furthermore, we found that the increased REM sleep in a depression mouse model was associated with a potentiation of REM sleep-active LHb neurons, including an increased proportion, elevated spike firing, and altered activity mode. Importantly, inhibition of REM sleep-active LHb neurons not only attenuated the increased REM sleep but also alleviated depressive-like behaviors in a depression mouse model. Thus, our results demonstrated that REM sleep-active LHb neurons selectively promoted REM sleep, and a potentiation of these neurons contributed to depression-associated sleep disturbance.

The role of GmHSP23.9 in regulating soybean nodulation under elevated CO2 condition.

Legume-rhizobia symbiosis offers a unique approach to increase leguminous crop yields. Previous studies have indicated that the number of soybean nodules are increased under elevated CO2 concentration. However, the underlying mechanism behind this phenomenon remains elusive. In this study, transcriptome analysis was applied to identify candidate genes involved in regulating soybean nodulation mediated by elevated CO2 concentration. Among the different expression genes (DEGs), we identified a gene encoding small heat shock protein (sHSP) called GmHSP23.9, which mainly expressed in soybean roots and nodules, and its expression was significantly induced by rhizobium USDA110 infection at 14 days after inoculation (DAI) under elevated CO2 conditions. We further investigated the role of GmHSP23.9 by generating transgenic composite plants carrying GmHSP23.9 overexpression (GmHSP23.9-OE), RNA interference (GmHSP23.9-RNAi), and CRISPR-Cas9 (GmHSP23.9-KO), and these modifications resulted in notable changes in nodule number and the root hairs deformation and suggesting that GmHSP23.9 function as an important positive regulator in soybean. Moreover, we found that altering the expression of GmHSP23.9 influenced the expression of genes involved in the Nod factor signaling pathway and AON signaling pathway to modulate soybean nodulation. Interestingly, we found that knocking down of GmHSP23.9 prevented the increase in the nodule number of soybean in response to elevated CO2 concentration. This research has successfully identified a crucial regulator that influences soybean nodulation under elevated CO2 level and shedding new light on the role of sHSPs in legume nodulation.

The influence of digestive tract protein on cytotoxicity of polyvinyl chloride microplastics.

Microplastics in food and drinking water can enter the human body through oral exposure, posing potential health risks to the human health. Most studies on the toxic effects of microplastics have focused on aquatic organisms, but the effects of the human digestive environment on the physicochemical properties of microplastics and their potential toxicity during gastrointestinal digestion are often limited. In this study, we first studied the influence of interactions between digestive tract protein (α-amylase, pepsin, and trypsin) and microplastics on the activity and conformation of digestive enzymes, and the physicochemical properties of polyvinyl chloride microplastics (PVC-MPs). Subsequently, a simulated digestion assay was performed to determine the biotransformation of PVC-MPs in the digestive tract and the intestinal toxicity of PVC-MPs. The in vitro experiments showed that the protein structure and activity of digestive enzymes were changed after adsorption by microplastics. After digestion, the static contact angle of PVC-MPs was decreased, indicating that the hydrophilicity of the PVC-MPs increased, which will increase its mobility in organisms. Cell experiment showed that the altered physicochemical property of PVC-MPs after digestion process also affect its cytotoxicity, including cellular uptake, cell viability, cell membrane integrity, reactive oxygen species levels, and mitochondrial membrane potential. Transcriptome analyses further confirmed the enhanced biotoxic effect of PVC-MPs after digestion treatment. Therefore, the ecological risk of microplastics may be underestimated owing to the interactions of microplastics and digestive tract protein during biological ingestion.

Optimization of immunosuppression strategies for the establishment of chronic hepatitis E virus infection in rabbits.

Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants.

Identification and validation of two major QTL for grain number per spike on chromosomes 2B and 2D in bread wheat (Triticum aestivum L.).

KEY MESSAGE: Major QTL for grain number per spike were identified on chromosomes 2B and 2D. Haplotypes and candidate genes of QGns.cib-2B.1 were analyzed. Grain number per spike (GNS) is one of the main components of wheat yield. Genetic dissection of their regulatory factors is essential to improve the yield potential. In present study, a recombinant inbred line population comprising 180 lines developed from the cross between a high GNS line W7268 and a cultivar Chuanyu12 was employed to identify quantitative trait loci (QTL) associated with GNS across six environments. Two major QTL, QGns.cib-2B.1 and QGns.cib-2D.1, were detected in at least four environments with the phenotypic variations of 12.99-27.07% and 8.50-13.79%, respectively. And significant interactions were observed between the two major QTL. In addition, QGns.cib-2B.1 is a QTL cluster for GNS, grain number per spikelet and fertile tiller number, and they were validated in different genetic backgrounds using Kompetitive Allele Specific PCR (KASP) markers. QGns.cib-2B.1 showed pleotropic effects on other yield-related traits including plant height, spike length, and spikelet number per spike, but did not significantly affect thousand grain weight which suggested that it might be potentially applicable in breeding program. Comparison analysis suggested that QGns.cib-2B.1 might be a novel QTL. Furthermore, haplotype analysis of QGns.cib-2B.1 indicated that it is a hot spot of artificial selection during wheat improvement. Based on the expression patterns, gene annotation, orthologs analysis and sequence variations, the candidate genes of QGns.cib-2B.1 were predicted. Collectively, the major QTL and KASP markers reported here provided a wealth of information for the genetic basis of GNS and grain yield improvement.

Cerebrospinal Fluid Neutrophil Gelatinase-Associated Lipocalin as a Novel Biomarker for Postneurosurgical Bacterial Meningitis: A Prospective Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Postneurosurgical bacterial meningitis (PNBM) was a significant clinical challenge, as early identification remains difficult. This study aimed to explore the potential of neutrophil gelatinase-associated lipocalin (NGAL) as a novel biomarker for the early diagnosis of PNBM in patients who have undergone neurosurgery. METHODS: A total of 436 postneurosurgical adult patients were enrolled in this study. Clinical information, cerebrospinal fluid (CSF), and blood samples were collected. After the screening, the remaining 267 patients were divided into the PNBM and non-PNBM groups, and measured CSF and serum NGAL levels to determine the diagnostic utility of PNBM. Subsequently, patients with PNBM were categorized into gram-positive and gram-negative bacterial infection groups to assess the effectiveness of CSF NGAL in differentiating between these types of infections. We analyzed the changes in CSF NGAL expression before and after anti-infection treatment in PNBM. Finally, an additional 60 patients were included as an independent validation cohort to further validate the diagnostic performance of CSF NGAL. RESULTS: Compared with the non-PNBM group, CSF NGAL was significantly higher in the PNBM group (305.1 [151.6-596.5] vs 58.5 [30.7-105.8] ng/mL; P < .0001). The area under the curve of CSF NGAL for diagnosing PNBM was 0.928 (95% CI: 0.897-0.960), at a threshold of 119.7 ng/mL. However, there was no significant difference in serum NGAL between the 2 groups (142.5 [105.0-248.6] vs 161.9 [126.6-246.6] ng/mL, P = .201). Furthermore, CSF NGAL levels were significantly higher in patients with gram-negative bacterial infections than those with gram-positive bacteria (P = .023). In addition, CSF NGAL levels decrease after treatment compared with the initial stage of infection (P < .0001). Finally, in this validation cohort, the threshold of 119.7 ng/mL CSF NGAL shows good diagnostic performance with a sensitivity and specificity of 90% and 80%, respectively. CONCLUSION: CSF NGAL holds promise as a potential biomarker for the diagnosis, early drug selection, and efficacy monitoring of PNBM.

Amentoflavone alleviated cartilage injury and inflammatory response of knee osteoarthritis through PTGS2.

The role of amentoflavone on cartilage injury in knee osteoarthritis (KOA) rats and the underlying mechanism were explored. KOA rat and IL-1ß-stimulated chondrocyte models were constructed. MTT, colony formation, and ELISA were performed to determine the cytotoxicity, cell proliferation, and inflammatory factors. The role of PTGS2 in IL-1ß-stimulated chondrocytes was also confirmed through transfecting PTGS2 overexpression and silencing plasmids. Further, we analyzed how amentoflavone regulated PTGS2 to improve IL-1ß-stimulated chondrocytes in vitro. Additionally, we analyzed the expression of PTGS2 after amentoflavone treatment. In vivo, HE and Safranin-O staining were carried out, and the inflammatory response was detected by ELISA and HE staining. In addition, we also analyzed the regulatory effect of amentoflavone on PTGS2 and explored the mechanism effect of PTGS2 in vitro and in vivo. The results indicated that PTGS2 was the downstream molecule of amentoflavone, which was highly expressed in IL-1ß-stimulated chondrocytes and KOA rats, and amentoflavone decreased PTGS2 expression. We also confirmed the potential role of amentoflavone on KOA, which was also characterized by the repair of cartilage injury, reduction of inflammatory infiltration, and improvement of functional disability. Consistent with in vivo results, in vitro experiments gave the same conclusions. Amentoflavone reduced PTGS2 expression in IL-1ß-stimulated chondrocytes and inhibited inflammation of chondrocytes via PTGS2. Collectively, the results confirmed that this drug was the potential targeted drug for KOA, whose repair effect on cartilage injury was partly related to PTGS2.

Adsorption behavior of triazine pesticides on polystyrene microplastics aging with different processes in natural environment.

The presence of microplastics in the ecological environment, serving as carriers for other organic pollutants, has garnered widespread attention. These microplastics exposed in the environment may undergo various aging processes. However, there is still a lack of information regarding how these aged microplastics impact the environmental behavior and ecological toxicity of pollutants. In this study, we modified polystyrene microplastics by simulating the aging behavior that may occur under environmental exposure, and then explored the adsorption behavior and adsorption mechanism of microplastics before and after aging for typical triazine herbicides. It was shown that all aging treatments of polystyrene increased the adsorption of herbicides, the composite aged microplastics had the strongest adsorption capacity and the fastest adsorption rate, and of the three herbicides, metribuzin was adsorbed the most by microplastics. The interactions between microplastics and herbicides involved mechanisms such as hydrophobic interactions, surface adsorption, the effect of π-π interactions, and the formation of hydrogen bonds. Further studies confirmed that microplastics adsorbed with herbicides cause greater biotoxicity to E. coli. These findings elucidate the interactions between microplastics before and after aging and triazine herbicides. Acting as carriers, they alter the environmental behavior and ecological toxicity of organic pollutants, providing theoretical support for assessing the ecological risk of microplastics in water environments.

IPAD-DB: a manually curated database for experimentally verified inhibitors of proteins associated with Alzheimer's disease.

Alzheimer's disease (AD) is a universal neurodegenerative disease with the feature of progressive dementia. Currently, there are only seven Food and Drug Administration-approved drugs for the treatment of AD, which merely offer temporary relief from symptom deterioration without reversing the underlying disease process. The identification of inhibitors capable of interacting with proteins associated with AD plays a pivotal role in the development of effective therapeutic interventions. However, a vast number of such inhibitors are dispersed throughout numerous published articles, rendering it inconvenient for researchers to explore potential drug candidates for AD. In light of this, we have manually compiled inhibitors targeting proteins associated with AD and constructed a comprehensive database known as IPAD-DB (Inhibitors of Proteins associated with Alzheimer's Disease Database). The curated inhibitors within this database encompass a diverse range of compounds, including natural compounds, synthetic compounds, drugs, natural extracts and nano-inhibitors. To date, the database has compiled >4800 entries, each representing a correspondent relationship between an inhibitor and its target protein. IPAD-DB offers a user-friendly interface that facilitates browsing, searching and downloading of its records. We firmly believe that IPAD-DB represents a valuable resource for screening potential AD drug candidates and investigating the underlying mechanisms of this debilitating disease. Access to IPAD-DB is freely available at http://www.lamee.cn/ipad-db/ and is compatible with all major web browsers. Database URL: http://www.lamee.cn/ipad-db/.

Design and synthesis of matrine derivatives for anti myocardial ischemia-reperfusion injury by promoting angiogenesis.

Myocardial ischemia/reperfusion (MI/R) is a common cardiovascular disease that seriously affects the quality of life and prognosis of patients. In recent years, matrine has attracted widespread attention in the treatment of cardiovascular diseases. This study designed, synthesized, and characterized 20 new matrine derivatives and studied their protective effects on ischemia-reperfusion injury through in vivo and in vitro experiments. Based on cellular assays, most newly synthesized derivatives have a certain protective effect on Hypoxia/Reoxygenation (H/R) induced H9C2 cell damage, with compound 22 having the best activity and effectively reducing cell apoptosis and necrosis. In vitro experimental data shows that compound 22 can significantly reduce the infarct size of rat myocardium and improve cardiac function after MI/R injury. In summary, compound 22 is a new potential cardioprotective agent that can promote angiogenesis and enhance antioxidant activity by activating ADCY5, CREB3l4, and VEGFA, thereby protecting myocardial cell apoptosis and necrosis induced by MI/R.

Wheat MIXTA-like Transcriptional Activators Positively Regulate Cuticular Wax Accumulation.

MIXTA-like transcription factors AtMYB16 and AtMYB106 play important roles in the regulation of cuticular wax accumulation in dicot model plant Arabidopsis thaliana, but there are very few studies on the MIXTA-like transcription factors in monocot plants. Herein, wheat MIXTA-like transcription factors TaMIXTA1 and TaMIXTA2 were characterized as positive regulators of cuticular wax accumulation. The virus-induced gene silencing experiments showed that knock-down of wheat TaMIXTA1 and TaMIXTA2 expressions resulted in the decreased accumulation of leaf cuticular wax, increased leaf water loss rate, and potentiated chlorophyll leaching. Furthermore, three wheat orthologous genes of ECERIFERUM 5 (TaCER5-1A, 1B, and 1D) and their function in cuticular wax deposition were reported. The silencing of TaCER5 by BSMV-VIGS led to reduced loads of leaf cuticular wax and enhanced rates of leaf water loss and chlorophyll leaching, indicating the essential role of the TaCER5 gene in the deposition of wheat cuticular wax. In addition, we demonstrated that TaMIXTA1 and TaMIXTA2 function as transcriptional activators and could directly stimulate the transcription of wax biosynthesis gene TaKCS1 and wax deposition gene TaCER5. The above results strongly support that wheat MIXTA-Like transcriptional activators TaMIXTA1 and TaMIXTA2 positively regulate cuticular wax accumulation via activating TaKCS1 and TaCER5 gene transcription.

Pathways linking watershed development and riparian quality to stream water quality and fish communities: Insights from 233 subbasins of the Great Lakes region.

Anthropogenic stressors such as urban development, agricultural runoff, and riparian zone degradation impair stream water quality and biodiversity. However, the intricate pathways that connect these stressors at watershed and riparian scales to stream ecosystems-and their interplay with climate and hydrology-remain understudied. In this study, we used Partial Least Squares (PLS) path modeling to examine these pathways and their collective impacts on stream water quality and fish community structures across 233 watersheds in the Great Lakes region. Our study suggests that moderate levels of watershed development enhance overall fish richness, potentially due to increased water temperature and nutrient availability, but reduces both the percentages and richness of cold water and intolerant taxa. Riparian quality exerts indirect effects on water quality with climate and stream order serving as key mediators. Complementing our SEM analysis, we also used Multiple Linear Regression (MLR) models and identified a significant positive relationship between the proportion of clay and agricultural land with TN concentrations. However, TP concentrations are influenced by a more complex set of interactions involving developed areas, soil, and slope. These findings emphasize the necessity of adopting integrated management strategies to preserve the health and integrity of freshwater ecosystems in the Great Lakes region. These strategies should integrate watershed and riparian protection measures while also taking into account the effects of climate change and specific local conditions.

Gut microbiome-derived hydrolases-an underrated target of natural product metabolism.

In recent years, there has been increasing interest in studying gut microbiome-derived hydrolases in relation to oral drug metabolism, particularly focusing on natural product drugs. Despite the significance of natural product drugs in the field of oral medications, there is a lack of research on the regulatory interplay between gut microbiome-derived hydrolases and these drugs. This review delves into the interaction between intestinal microbiome-derived hydrolases and natural product drugs metabolism from three key perspectives. Firstly, it examines the impact of glycoside hydrolases, amide hydrolases, carboxylesterase, bile salt hydrolases, and epoxide hydrolase on the structure of natural products. Secondly, it explores how natural product drugs influence microbiome-derived hydrolases. Lastly, it analyzes the impact of interactions between hydrolases and natural products on disease development and the challenges in developing microbial-derived enzymes. The overarching goal of this review is to lay a solid theoretical foundation for the advancement of research and development in new natural product drugs and personalized treatment.

Design, synthesis, and biological evaluation of new bis-benzylisoquinoline-based analogues as potential neuromuscular blocking agents.

Neuromuscular blocking agents (NMBAs) are widely used in anesthesia for intubation and surgical muscle relaxation. Novel atracurium and mivacurium derivatives were developed, with compounds 18c, 18d, and 29a showing mivacurium-like relaxation at 27.27 nmol/kg, and 15b, 15c, 15e, and 15h having a shorter duration at 272.7 nmol/kg. The structure-activity and configuration-activity relationships of these derivatives and 29a's binding to nicotinic acetylcholine receptors were analyzed through molecular docking. Rabbit trials showed 29a has a shorter duration compared to mivacurium. This suggests that linker properties, ammonium group substituents, and configuration are crucial for NMBA activity and duration, with compound 29a emerging as a potential ultra-short-acting NMBA.

Utilizing a structure-based virtual screening approach to discover potential LSD1 inhibitors.

BACKGROUND: Lysine-specific demethylase 1 (LSD1) is highly expressed in a variety of malignant tumors, rendering it a crucial epigenetic target for anti-tumor therapy. Therefore, the inhibition of LSD1 activity has emerged as a promising innovative therapeutic approach for targeted cancer treatment. METHODS: In our study, we employed innovative structure-based drug design methods to meticulously select compounds from the ZINC15 database. Utilizing virtual docking, we evaluated docking scores and binding modes to identify potential inhibitors. To further validate our findings, we harnessed molecular dynamic simulations and conducted meticulous biochemical experiments to deeply analyze the binding interactions between the protein and compounds. RESULTS: Our results showcased that ZINC10039815 exhibits an exquisite binding mode with LSD1, fitting perfectly into the active pocket and forming robust interactions with multiple critical residues of the protein. CONCLUSIONS: With its significant inhibitory effect on LSD1 activity, ZINC10039815 emerges as a highly promising candidate for the development of novel LSD1 inhibitors.