ABSTRACT
BACKGROUND AND AIMS: Cross talk between tumor cells and immune cells enables tumor cells to escape immune surveillance and dictate responses to immunotherapy. Previous studies have identified that downregulation of the glycolytic enzyme fructose-1,6-bisphosphate aldolase B (ALDOB) in tumor cells orchestrated metabolic programming to favor HCC. However, it remains elusive whether and how ALDOB expression in tumor cells affects the tumor microenvironment in HCC. APPROACH AND RESULTS: We found that ALDOB downregulation was negatively correlated with CD8 + T cell infiltration in human HCC tumor tissues but in a state of exhaustion. Similar observations were made in mice with liver-specific ALDOB knockout or in subcutaneous tumor models with ALDOB knockdown. Moreover, ALDOB deficiency in tumor cells upregulates TGF-ß expression, thereby increasing the number of Treg cells and impairing the activity of CD8 + T cells. Consistently, a combination of low ALDOB and high TGF-ß expression exhibited the worst overall survival for patients with HCC. More importantly, the simultaneous blocking of TGF-ß and programmed cell death (PD) 1 with antibodies additively inhibited tumorigenesis induced by ALDOB deficiency in mice. Further mechanistic experiments demonstrated that ALDOB enters the nucleus and interacts with lysine acetyltransferase 2A, leading to inhibition of H3K9 acetylation and thereby suppressing TGFB1 transcription. Consistently, inhibition of lysine acetyltransferase 2A activity by small molecule inhibitors suppressed TGF-ß and HCC. CONCLUSIONS: Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-ß signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy.
ABSTRACT
As a biothiol, cysteine (Cys) is essential to both physiological and pathological processes and has been associated with many diseases, including neurological disorders, rheumatoid arthritis, and renal dysfunction. Therefore, the development of a high-performance probe for detecting Cys levels can help prevent and diagnose disease. In this study, a ratiometric fluorescent probe based on a novel fluorophore was developed for detecting Cys, and it showed high specificity and a rapid response time toward Cys. This probe demonstrates excellent biocompatibility and has been utilized effectively for the imaging of Cys in living cells.
Subject(s)
Cysteine , Fluorescent Dyes , Fluorescent Dyes/chemistry , Fluorescent Dyes/chemical synthesis , Cysteine/analysis , Cysteine/chemistry , Humans , Optical Imaging , Molecular Structure , HeLa CellsABSTRACT
BACKGROUND: Paediatric feeding disorder (PFD) is a common childhood condition, estimated to impact one in 37 American children under the age of five. Such high prevalence occurs against a backdrop of limited understanding of the community treatment landscape in the United States. METHOD: To better understand the community treatment landscape for PFD in the United States and identify provider and treatment delivery characteristics, we collected primary data through a web-based survey targeting providers from all four PFD domains (i.e., medical, nutritional, feeding skill, and/or psychosocial) between January 2022 and March 2022. The 71-item cross sectional survey focussed on patient, provider and treatment characteristics. We distributed the survey using an electronic survey tool through Feeding Matters listserv followed by solicitation to discipline specific listservs and professional networks. The analytic approach involved descriptive statistics compared across settings and provider types, focussing on respondents within the United States. RESULTS: Eighty-three percent of respondents reported practicing in the United States. Most of the US sample (74.3%) involved providers from the feeding skill domain (speech-language pathologist - SLP, occupational therapist - OT) who reported delivering care through early intervention or outpatient settings using responsive and sensory based approaches. These approaches lack rigorous empirical evaluation. CONCLUSIONS: Survey results suggest a need to support community providers in engagement with research activity to promote a better understanding of treatment approaches and outcomes associated with a large cohort of providers delivering care (i.e. SLPs, OTs) to patients with PFD.
Subject(s)
Early Intervention, Educational , Feeding and Eating Disorders , Child , Humans , United States , Cross-Sectional Studies , Surveys and Questionnaires , Allied Health PersonnelABSTRACT
Real-world understanding serves as a medium that bridges the information world and the physical world, enabling the realization of virtual-real mapping and interaction. However, scene understanding based solely on 2D images faces problems such as a lack of geometric information and limited robustness against occlusion. The depth sensor brings new opportunities, but there are still challenges in fusing depth with geometric and semantic priors. To address these concerns, our method considers the repeatability of video stream data and the sparsity of newly generated data. We introduce a sparsely correlated network architecture (SCN) designed explicitly for online RGBD instance segmentation. Additionally, we leverage the power of object-level RGB-D SLAM systems, thereby transcending the limitations of conventional approaches that solely emphasize geometry or semantics. We establish correlation over time and leverage this correlation to develop rules and generate sparse data. We thoroughly evaluate the system's performance on the NYU Depth V2 and ScanNet V2 datasets, demonstrating that incorporating frame-to-frame correlation leads to significantly improved accuracy and consistency in instance segmentation compared to existing state-of-the-art alternatives. Moreover, using sparse data reduces data complexity while ensuring the real-time requirement of 18 fps. Furthermore, by utilizing prior knowledge of object layout understanding, we showcase a promising application of augmented reality, showcasing its potential and practicality.
ABSTRACT
High carbon dioxide (CO2) concentration in the atmosphere urgently requires eco-friendly mitigation strategies. Carbonic anhydrase (CA) is a high-quality enzyme protein, available from a wide range of sources, which has an extremely high catalytic efficiency for the hydration of CO2 compared with other catalytic CO2 conversion systems. While free CA is costly and weakly stable, CA immobilization can significantly improve its stability and allow enzyme recycling. However, gaseous CO2 is significantly different from traditional liquid substrates. Additionally, due to the presence of enzyme carriers, there is limited mass transfer between CO2 and the active center of immobilized CA. Most of the available reviews provide an overview of the improvement in catalytic activity and stability of CA by different immobilization methods and substrates. However, they do not address the limited mass transfer between CO2 and the active center of immobilized CA. Therefore, by focusing on the mass transfer process, this review presents CA immobilization strategies that are more efficient and of greater environmental tolerance by categorizing the methods of enhancing the mass transfer process at each stage of the enzymatic CO2 capture reaction. Such improvements in this green and environmentally friendly biological carbon capture process can increase its efficiency for industrial applications.
Subject(s)
Carbonic Anhydrases , Enzymes, Immobilized , Enzymes, Immobilized/metabolism , Carbon Dioxide/metabolism , Carbonic Anhydrases/metabolism , CatalysisABSTRACT
Butyrylcholinesterase (BuChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD). Development of selective BuChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Recently, we reported the N-isobutyl-N-((2-(p-tolyloxymethyl)thiazol-4-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide (1) as a selective BuChE inhibitor. Subsequently, 33 analogs were synthesized and assessed by AChE/BuChE activities, indicating an optimal compound 23. Further kinetic tests suggested a competitive manner. Molecular docking and Molecular dynamics (MD) simulation showed that it interacted with several residues in active site gorge of BuChE, possibly contributing to its selectivity and competitive pattern. Moreover, it showed low cytotoxicity and high blood brain barrier (BBB) permeability. Taken together, 23 was a promising BuChE inhibitor for the treatment of AD.
Subject(s)
Alzheimer Disease/drug therapy , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Drug Design , Acetylcholinesterase/metabolism , Alzheimer Disease/metabolism , Cell Line , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Immobilizing cellulase for improving its hydrolysis activity and recyclability is critical for a cost-effective and environment-friendly conversion of cellulosic biomass. However, developing a strategy for achieving a high mass-transfer rate and good separation efficiency between an insoluble cellulose substrate and cellulase remains difficult. Instead of the traditional method, a single-enzyme molecular modification method is used in this study. To modify cellulase and provide it with a temperature-pH dual responsive property, systemized poly(acrylic-acrylonitrile) (PAA-PAN) molecular arms are used. The modified cellulase can reversibly transform between liquid and solid phases. In the liquid phase, the modified cellulase can adjust its active center, increasing its hydrolysis efficiency and separation efficiency. Cellulase and glucose products can be easily separated in the solid phase, allowing the reuse of cellulase. The results show that the modified cellulase's hydrolysis efficiency is comparable to that of free cellulase and that the modified enzyme preserves more than 60% of its initial activity after 15 batches of efficient hydrolysis. Thus, the proposed modification route considerably lowers the cost of cellulose enzymatic hydrolysis.
Subject(s)
Cellulase , Cellulose , Cellulase/chemistry , Cellulose/chemistry , Glucose/chemistry , Hydrolysis , TemperatureABSTRACT
In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.
Subject(s)
Alzheimer Disease/drug therapy , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Imidazoles/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Isoindoles/pharmacology , Thiophenes/pharmacology , Alzheimer Disease/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Isoindoles/chemical synthesis , Isoindoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistryABSTRACT
Cellular autophagy is an intracellular degradation pathway, which transports damaged, deformed, senescent or non-functional proteins and organelles to lysosome for digestion and degradation. Cellular autophagy is deeply evolutionarily conservedfromyeasttomammaliancells, and many homologous proteins of the autophahgy regulators are found in several species. This physiological process maintains the steady state of cells. Furtheremore, autophagy dysfunction is closely related to various diseases, such as neurodegenerative diseases, inflammation-related diseases, cardiovascular diseases, metabolic diseases, etc. The LC3 and p62 protein protein interaction (PPI) promotes the formation of autophagosomes and delivers polyubiquitinated "cargoes" to autophagic degradation. Therefore, LC3-p62 PPI plays an integral role in the formation of autophagosomes and effectively inhibits autophagy. However, there are still few studies on the LC3-p62 PPI inhibitors for its unclear molecular mechanism. Furthermore, most of these inhibitors are macromolecules with poorly active, and small molecules are particularly scarce. In this article, the computation method was used to identify the hot spot and design peptides as the binder of LC3-p62 PPI. Findings from this work provide a reference for the follow-up research of discovering small molecule inhibitors targeting LC3-p62 PPI.
Subject(s)
Drug Design , Microtubule-Associated Proteins/antagonists & inhibitors , Peptides/pharmacology , RNA-Binding Proteins/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Microtubule-Associated Proteins/chemistry , Microtubule-Associated Proteins/metabolism , Models, Molecular , Molecular Structure , Peptides/chemical synthesis , Peptides/chemistry , Protein Binding , RNA-Binding Proteins/chemistry , RNA-Binding Proteins/metabolism , Structure-Activity RelationshipABSTRACT
High temperature is a major environmental factor that adversely affects plant growth and production. SlBRI1 is a critical receptor in brassinosteroid signalling, and its phosphorylation sites have differential functions in plant growth and development. However, the roles of the phosphorylation sites of SIBRI1 in stress tolerance are unknown. In this study, we investigated the biological functions of the phosphorylation site serine 1040 (Ser-1040) of SlBRI1 in tomato. Phenotype analysis indicated that transgenic tomato harbouring SlBRI1 dephosphorylated at Ser-1040 showed increased tolerance to heat stress, exhibiting better plant growth and plant yield under high temperature than transgenic lines expressing SlBRI1 or SlBRI1 phosphorylated at Ser-1040. Biochemical and physiological analyses further showed that antioxidant activity, cell membrane integrity, osmo-protectant accumulation, photosynthesis and transcript levels of heat stress defence genes were all elevated in tomato plants harbouring SlBRI1 dephosphorylated at Ser-1040, and the autophosphorylation level of SlBRI1 was inhibited when SlBRI1 dephosphorylated at Ser-1040. Taken together, our results demonstrate that the phosphorylation site Ser-1040 of SlBRI1 affects heat tolerance, leading to improved plant growth and yield under high-temperature conditions. Our results also indicate the promise of phosphorylation site modification as an approach for protecting crop yields from high-temperature stress.
Subject(s)
Brassinosteroids/metabolism , Plant Proteins/metabolism , Protein Kinases/metabolism , Protein Processing, Post-Translational , Solanum lycopersicum/metabolism , Thermotolerance , Fruit/growth & development , Fruit/metabolism , Solanum lycopersicum/genetics , Solanum lycopersicum/growth & development , Phosphorylation , Plant Proteins/chemistry , Protein Kinases/chemistry , Serine/metabolismABSTRACT
A series of novel compounds 6a-h, 8i-1, 10s-v, and 16a-d were synthesized and evaluated, together with the known analogs 11a-f, for their inhibitory activities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The inhibitory activities of AChE and BChE were evaluated in vitro by Ellman method. The results show that some compounds have good inhibitory activity against AChE and BChE. Among them, compound 8i showed the strongest inhibitory effect on both AChE (eeAChE IC50 = 0.39 µM) and BChE (eqBChE IC50 = 0.28 µM). Enzyme inhibition kinetics and molecular modeling studies have shown that compound 8i bind simultaneously to the peripheral anionic site (PAS) and the catalytic sites (CAS) of AChE and BChE. In addition, the cytotoxicity of compound 8i is lower than that of Tacrine, indicating its potential safety as anti-Alzheimer's disease (anti-AD) agents. In summary, these data suggest that compound 8i is a promising multipotent agent for the treatment of AD.
Subject(s)
Acetylcholinesterase/chemistry , Alzheimer Disease/enzymology , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Neuroprotective Agents/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Animals , Binding Sites , Butyrylcholinesterase/metabolism , Catalytic Domain , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Donepezil/pharmacology , Kinetics , Molecular Docking Simulation , PC12 Cells , Rats , Structure-Activity Relationship , Tacrine/pharmacologyABSTRACT
BACKGROUND: Appropriate brassinosteroid (BR) signal strength caused by exogenous application or endogenous regulation of BR-related genes can increase crop yield. However, precise control of BR signals is difficult and can cause unstable effects and failure to reach full potential. Phosphorylated BRASSINOSTEROID INSENSITIVE1 (BRI1), the rate-limiting receptor in BR signalling, transduces BR signals, and we recently demonstrated that modifying BRI1 phosphorylation sites alters BR signal strength and botanical characteristics in Arabidopsis. However, the functions of such phosphorylation sites in agronomic characteristics of crops remain unclear. RESULTS: In this work, we investigated the roles of tomato SlBRI1 threonine-1050 (Thr-1050). SlBRI1 mutant cu3-abs1 plants expressing SlBRI1 with a non-phosphorylatable Thr-1050 (T1050A), with a wild-type SlBRI1 transformant used as a control, were examined. The results showed enhanced autophosphorylation of SlBRI1 and BR signal strength for cu3-abs1 harbouring T1050A, which promoted yield through increased plant expansion, leaf area, fruit weight and fruit number per cluster but reduced nutrient contents, including ascorbic acid and soluble sugar levels. Moreover, plant height, stem diameter, and internodal distance were similar between the transgenic plants. CONCLUSION: Our results reveal the biological role of Thr-1050 in tomato and provide a molecular basis for establishing high-yield crops by precisely controlling BR signal strength via phosphorylation site modification.
Subject(s)
Brassinosteroids/metabolism , Fruit/growth & development , Plant Proteins/physiology , Protein Kinases/physiology , Signal Transduction , Solanum lycopersicum/growth & development , Solanum lycopersicum/genetics , Mutation , Phosphorylation , Plant Proteins/genetics , Plant Proteins/metabolism , Plants, Genetically Modified , Protein Kinases/genetics , Protein Kinases/metabolismABSTRACT
Designing small molecule inhibitors targeting cholinesterases (ChEs) is considered as an efficient strategy for the treatment of Alzheimer's disease (AD). In the present study, based on a shaped-based pharmacophore (SBP) model that we reported previously, virtual screening was performed on four commercial compound databases, from which eight small molecules containing new structurally scaffolds were retained and evaluated. In general, six of these potential hits were identified to be selective ChEs inhibitors. Three compounds exhibited IC50 values and Ki values in micromolar range on acetylcholinesterase (AChE), the most active compound 4 showed IC50 value of 6.31⯱â¯2.68⯵M and Ki value of 4.76⯵M. Other three compounds displayed IC50 values and Ki values in micromolar range on butyrylcholinesterase (BChE) with high target selectivity, the most active compound 1 showed IC50 value of 3.87⯱â¯2.48⯵M and Ki value of 1.52⯵M. Multiple biological evaluations were performed to determine their cytotoxicity, cyto-protective effects, antioxidant effect as well as druglike properties. These compounds provide new cores for the further design and optimization, with the aim to discover new ChEs inhibitors for the treatment of AD.
Subject(s)
Acetylcholinesterase/metabolism , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/pharmacology , Drug Discovery , Molecular Dynamics Simulation , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Animals , Cell Survival/drug effects , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Electrophorus , Hep G2 Cells , Horses , Humans , Molecular Structure , PC12 Cells , Rats , Structure-Activity RelationshipABSTRACT
A general approach is presented for synthesis of multicolored gold nanoparticles (GNPs) by Au(I)-mediated generation of interlocking rings in proteins and antibiotics. The Au(I) ions are shuttled from proteins to antibiotics, and this causes the formation of interlocking rings. The multicolored GNPs of different sizes were synthesized in the rings by using the rapid nucleation method. To take the unique colors of GNPs, a functional array was designed for the colorimetric determination and discrimination of antibiotics, specifically of amoxicillin, chlortetracycline, erythromycin, spiramycin, neomycin, thiamphenicol, gentamycin and lincomycin. The method is based on the "three color" (RGB) principle. The color response patterns are characteristic for each antibiotic and can be quantitatively differentiated by statistical techniques. The limits of detection (LOD, at S/N = 3) for spiramycin (Sp) have been calculated to be 0.18 µM and 0.10 µM in water and milk, respectively. The good linear range (from 0.3 to 3.5 µM) has been used for the quantitative assay of Sp in a certified reference material. Graphical abstractSchematic presentation of gold nanoparticles (GNPs) synthesis via formation of interlocking rings in protein and antibiotics. The Au(I) ions mediate protein and antibiotics to be interlocking rings, which are quickly fixed via microwave reaction. The GNPs are synthesized and assembled in the rings.
Subject(s)
Anti-Bacterial Agents/analysis , Metal Nanoparticles/chemistry , Animals , Colorimetry/methods , Food Contamination/analysis , Gold/chemistry , Limit of Detection , Milk/chemistry , Particle Size , Water/analysis , Water Pollutants, Chemical/analysisABSTRACT
Developing artificial leaves to address the environmental burden of CO2 is pivotal for advancing our Net Zero Future. In this study, we introduce EcoLeaf, an artificial leaf that closely mimics the characteristics of natural leaves. It harnesses visible light as its sole energy source and orchestrates the controlled expansion and contraction of stomata and the exchange of petiole materials to govern the rate of CO2 sequestration from the atmosphere. Furthermore, EcoLeaf has a cellulose composition and mechanical strength similar to those of natural leaves, allowing it to seamlessly integrate into the ecosystem during use and participate in natural degradation and nutrient cycling processes at the end of its life. We propose that the carbon sequestration pathway within EcoLeaf is adaptable and can serve as a versatile biomimetic platform for diverse biogenic carbon sequestration pathways in the future.
Subject(s)
Carbon Dioxide , Carbon Sequestration , Cellulose , Plant Leaves , Carbon Dioxide/metabolism , Carbon Dioxide/chemistry , Plant Leaves/metabolism , Cellulose/metabolism , Cellulose/chemistry , Ecosystem , Plant Stomata/metabolism , Photosynthesis , LightABSTRACT
For the potential therapy of Alzheimer's disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual screening (VS) approach to identify Z32439948 as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed. Specifically, a subpocket was found and structure-guided design of a series of novel compounds was conducted. Derivatives were evaluated in vitro for cholinesterase inhibition and physicochemical properties (BBB, logâ¯P, and solubility). The investigation involved docking, molecular dynamics, enzyme kinetics, and surface plasmon resonance as well. The study highlighted compounds 27a (hBChE IC50 = 0.078 ± 0.03 µM) and (R)-37a (hBChE IC50 = 0.005 ± 0.001 µM) as the top-ranked BChE inhibitors. These compounds showed anti-inflammatory activity and no apparent cytotoxicity against the human neuroblastoma (SH-SY5Y) and mouse microglia (BV2) cell lines. The most active compounds exhibited the ability to improve cognition in both scopolamine- and Aß1-42 peptide-induced cognitive deficit models. They can be promising lead compounds with potential implications for treating the late stage of AD.
Subject(s)
Alzheimer Disease , Neuroblastoma , Humans , Mice , Animals , Butyrylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Molecular Structure , Molecular Docking Simulation , Cholinesterase Inhibitors/chemistry , Cell Line, Tumor , Acetylcholinesterase/metabolism , Structure-Activity RelationshipABSTRACT
OBJECTIVES: Characterizing inflammatory syndromes during the coronavirus disease 2019 pandemic was complicated by recognition of multisystem inflammatory syndrome in children (MIS-C), contemporaneous with episodes of Kawasaki disease. We hypothesized a substantial overlap between the 2 and assessed the performance of an MIS-C likelihood score in differentiating inpatients with nonsevere MIS-C from prepandemic incomplete Kawasaki disease (iKD) without coronary involvement. METHODS: A retrospective review of inpatient records was conducted; the nonsevere MIS-C cohort (March 2020-February 2021) met the 2023 definition for MIS-C; the iKD cohort (January 2018-January 2019) met the American Heart Association criteria for iKD without coronary involvement. We applied the likelihood score to both cohorts. We estimated the percent of children with iKD who could have met the clinical criteria of the MIS-C, had they presented in 2023. RESULTS: The 68 children in the nonsevere MIS-C cohort were older (8 vs 4 years, P < .001) than the 28 children in the iKD cohort. Those in the nonsevere MIS-C cohort had higher rates of thrombocytopenia (P < .001) and lymphopenia (P = .021); those in the iKD cohort had higher rates of pyuria (P < .001). Twenty-four (86%) children in the iKD cohort met the 2023 MIS-C definition. The scoring system correctly predicted 71% to 74% children with their respective clinical diagnoses. CONCLUSIONS: Though there was considerable clinical overlap, thrombocytopenia, lymphopenia, and the absence of pyuria were the most helpful parameters to distinguish children with nonsevere MIS-C from those with iKD.
ABSTRACT
Butyrylcholinesterase (BChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD), the development of selective BChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Previously, an aromatic tertiary amine derivative (S17-1001) was screened and validated as a selective BChE inhibitor. Structured-based molecular modification guided the synthesis of 43 analogs. Biological test of cholinesterase inhibition, in vitro blood brain barrier permeation assay, neurotoxicity assay and neuroprotective effects assay indicated two optimal compounds 17c and 19c. Both compounds showed selective BChE inhibitory (hBChE < 20 nM, eeAChE > 10 µM), good BBB permeation and primary cell safety. Besides, 17c can dose-response protect cell from Aß1-42 induced damage. It also demonstrated that 17c and 19c were able to restore cognitive impairment in vivo test. These data suggest that 17c and 19c represent promising candidate for follow-up in the drug-discovery process against AD.
Subject(s)
Alzheimer Disease , Butyrylcholinesterase , Humans , Butyrylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Molecular Structure , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/therapeutic use , Amines/pharmacology , Amines/therapeutic use , Acetylcholinesterase/metabolism , Structure-Activity Relationship , Molecular Docking SimulationABSTRACT
Glioblastoma (GBM) is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable. A variety of treatment options are currently being explored to improve patient survival, including small molecule inhibitors, viral therapies, cancer vaccines, and monoclonal antibodies. Among them, the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma. Currently, the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma, including receptor tyrosine kinase, PI3K/AKT/mTOR pathway, DNA damage response, TP53 and cell cycle inhibitors. This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways. Meanwhile, the recent advances in temozolomide resistance and drug combination are also reviewed. In the last part, due to the constant clinical failure of targeted therapies, this paper reviewed the research progress of other therapeutic methods for glioblastoma, to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma.
ABSTRACT
Herein, we report a series of selective sub-nanomolar inhibitors against butyrylcholinesterase (BChE). These compounds, bearing a novel N-benzyl benzamide scaffold, inhibited BChE with IC50 from picomolar to nanomolar. The inhibitory activity was confirmed by the surface plasmon resonance assay, showing a sub-nanomolar KD value, which revealed that the compounds exert the inhibitory effect through directly binding to BChE. Several compounds showed neuroprotective effects verified by the oxidative damage model. Furthermore, the safety of S11-1014 and S11-1033 was demonstrated by the in vivo acute toxicity test. In the behavior study, 0.5 mg/kg S11-1014 or S11-1033 exhibited a marked therapeutic effect, which was almost equal to the treatment with 1 mg/kg rivastigmine, against the cognitive impairment induced by Aß1-42. The pharmacokinetics studies characterized the metabolic stability of S11-1014. Thus, N-benzyl benzamide inhibitors are promising compounds with drug-like properties for improving cognitive dysfunction, providing a potential strategy for the treatment of Alzheimer's disease.