Search Results (77)

Ionotropic glutamate receptors—including N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate receptors—play a pivotal role in excitatory signaling in the central nervous system (CNS), which is particularly important for learning and memory processes. Among them, AMPA and kainate receptors (known as ‘non-NMDA’ receptors) have gained increasing attention as therapeutic targets for various CNS disorders. Positive allosteric modulators (PAMs) of these receptors enhance their activity without directly activating them, offering a promising strategy to fine-tune glutamatergic signaling with potentially fewer side effects compared to orthosteric agonists. This review presents a comprehensive overview of recent advances in the development of AMPA and kainate receptor PAMs. We classify the most relevant modulators into main chemotype groups and discuss their binding modes, structure–activity relationships, and efficacy as determined through in vitro and in vivo studies. Additionally, we provide an overview of AMPA receptor PAMs that have entered into clinical trials over the past few decades. The increasing interest in kainate receptor PAMs is also mentioned, underlining their emerging role in future neuropharmacological strategies. Full article

A transdermal drug delivery system based on hydrogel patches was explored, leveraging their sustained release properties and biocompatibility. Despite these advantages, conventional hydrogels often lack proper adhesion to the skin, limiting their practical application. To address this issue, we designed a skin-adhesive hydrogel using a polyacrylamide (PAM)/polydopamine (PDA) dual-network structure. The matrix combines the mechanical toughness of PAM with the strong adhesive properties of PDA, derived from mussel foot proteins, enabling firm tissue attachment and robust performance under physiological conditions. To demonstrate its applicability, the hydrogel was integrated with poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating the hydrophobic antioxidant vitamin E as a model compound. The resulting PAM/PDA@VitE hydrogel system exhibited improved swelling behavior, high water retention, and prolonged release of α-tocopherol. These results suggest that the PAM/PDA hydrogel platform is a versatile vehicle not only for vitamin E, but also for the transdermal delivery of various cosmetic and therapeutic agents. Full article

Butyrate and its derivatives may influence inflammatory status and physiology in a variety of organisms and organ systems. Inflammatory conditions of the gastrointestinal tract, such as post-weaning diarrhea, negatively impact swine. Dietary intervention with butyrate-based compounds should be considered a strategy to improve disease resistance in pigs. We aimed to assess the properties of different forms of butyrate treatments using porcine cell culture experiments. This assessment may inform future in vivo feed experiments designed to determine its potential application of the dietary supplements for pigs. An intestinal porcine enterocyte cell line, IPEC-J2, was seeded at 5 × 10³ cells/mL in 96-well plates to confirm cell viability by MTT assay for each dose range used in the current experiments (0, 0.5, 1, 2, 4 mM butyric acid or tributyrin; 0, 1, 2, 4, 8 mM sodium butyrate or monobutyrin). For transepithelial electrical resistance (TEER) analysis, IPEC-J2 was seeded at 5 × 10⁵ cells/mL in 12-well transwell inserts and treated with 5 levels of each butyrate derivative after adherence (n = 5). TEER was measured at 24, 48, and 72 h post-treatment to quantify intestinal barrier integrity of IPEC-J2 monolayers. Butyric acid, sodium butyrate, and monobutyrin significantly increased (p < 0.05) TEER in IPEC-J2 at different time points compared with control. Further, porcine alveolar macrophages (PAMs) were harvested from donor weaned piglets (n = 6) via bronchoalveolar lavage and isolated for primary culture (6 × 10⁵ cells/well, 6-well plates). PAMs were treated with five levels of each butyrate derivative with or without lipopolysaccharide (LPS, 1 μg/mL) challenge. The concentrations of TNF-α and IL-1β in cell culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Butyric acid and sodium butyrate treatments reduced the production of TNF-α in LPS-challenged PAMs (linear; p < 0.05). Different butyrate derivatives exerted anti-inflammatory properties and improved intestinal barrier integrity. Full article

In this study, a novel calcium phosphate/polyacrylamide copolymer/$\alpha$-type hemihydrate gypsum (CPO/PAM/$\alpha$-HHG) composite material was prepared by polymerising a stable inorganic CPO precursor, end-capped with triethylamine (TEA), with an organic polyacrylamide (PAM) hydrogel to form a CPO/PAM precursor solution. Subsequently, this precursor solution was mixed with inorganic $\alpha$-hemihydrate gypsum. The effects of CPO/PAM precursor addition and CPO addition on the slurry flowability, initial setting time, and mechanical properties of hardened specimens of the CPO/PAM/$\alpha$-HHG composite were investigated. The structural characteristics of the composites were analysed by XRD, FE-SEM, and TGA. The results show that the initial setting time of the CPO/PAM/$\alpha$-HHG composites was 26.7 min, which was 140.5% longer than that of the pure water $\alpha$-HHG system and 3.9% longer than that of the PAM/$\alpha$-HHG system; additionally, the oven-dried specimens had a flexural strength of 27.59 MPa and a compressive strength of 68.48 MPa, which were 77.2% and 102.0% higher than those of the pure water $\alpha$-HHG system and 38.8% and 14.1% higher than those of the PAM/$\alpha$-HHG system, respectively. The wet compressive strength of the CPO/PAM/$\alpha$-HHG composites was improved by 11.8% compared to that of the PAM/$\alpha$-HHG system. A structural analysis showed that CPO promoted the gelation process of PAM and allowed the hydration reaction process of $\alpha$-HHG to be fully carried out by slowing down the gelation process of the organic network, which led to the full development of both organic and inorganic networks, ultimately forming an interspersed inorganic/organic dual-network structure, which enhanced the comprehensive mechanical properties of the composites. This study provides a new idea for the modification of $\alpha$-type hemihydrate gypsum and a new method for the preparation of high-utilisation and high-performance gypsum-based composites. Full article

The α7 nicotinic acetylcholine receptor (α7-nAChR) is a pivotal regulator of neurotransmission, neuroprotection, and immune modulation in the central nervous system. This review explores its structural and functional attributes, highlighting its therapeutic potential in neurodegenerative disorders, particularly Parkinson’s disease (PD). α7-nAChRs mediate synaptic plasticity, modulate inflammatory responses, and influence dopamine release, positioning them as a promising pharmacological target. Positive allosteric modulators (PAMs) enhance α7-nAChR activity mainly by reducing desensitization, offering a superior therapeutic approach compared with direct agonists. Emerging preclinical studies suggest that α7-nAChR activation mitigates dopaminergic neurodegeneration, improves L-dopa-induced dyskinesia, and reduces neuroinflammation. Despite promising findings, clinical trials have yielded mixed results, necessitating further research into optimizing α7-targeted therapies. This review underscores the significance of α7-nAChRs in PD pathophysiology and highlights future directions for their translational potential in neuroprotection and symptomatic relief. Full article

Background: Alterations in the adrenergic system have been associated with the pathophysiology of Alzheimer’s disease (AD). A novel α_1A-adrenergic receptor (AR)-positive allosteric modulator (PAM), CCF219B, has been shown to outperform donepezil with rescue of AD cognition/memory deficits with a reduction in amyloid biomarkers and without cardiovascular side effects. Initial pharmacological analysis in transfected cell lines revealed a signal bias with increased efficacy (but not potency) of cAMP signaling and ligand selectivity for norepinephrine (NE). As most GPCR allosteric modulators change the potency of agonists, we hypothesized and now report that CCF219B induced additional aspects of its allosteric interactions with NE that may provide mechanistic insight. Methods: Using Rat-1 fibroblasts stably transfected with α_1A-AR, we determined the activation profile of pERK and p38 messengers by CCF219B in the presence of NE. Using membranes prepared from the stably transfected fibroblasts or from the brain of WT mice or the AD mouse model, hAPP(lon), equilibrium or kinetic radioligand-binding analyses were performed. Results: We identified p-ERK1/2 but not p38 as an additional signal pathway that is potentiated by CCF219B in the presence of NE. An analysis of binding studies of CCF219B in membranes derived from the brains of WT or hAPP(lon) mice revealed profiles that were time-dependent and resulted in an increase in α_1A-AR expression that was unaltered in the presence of cycloheximide or when performed at 37 °C. hAPP(lon) mice displayed a reduction in α_1A-AR-binding sites that were rescued upon prolonged incubation with CCF219B but also displayed a compensatory increase in α_1B/D-AR subtype expression. Binding kinetics reveal that CCF219B can decrease the association rate of ³H-NE but only in the presence of GTP. The association rate increased for the radiolabeled antagonist, ¹²⁵I-HEAT. There were no changes in the dissociation rate of either radiolabel. Conclusions: CCF219B affects the association but not the dissociation rate of NE and explains its ability to increase the active state of the receptor by promoting a pre-coupled conformation, consistent with increasing efficacy but not potency. Potentiation of pERK may contribute to CCF219B’s ability to confer neuroprotection and be pro-cognitive in AD. CCF219B’s ability to increase the expression of α_1A-AR provides a positive feedback loop and strengthens the hypothesis that α₁-AR subtypes may be involved in AD etiology and/or progression. Full article

The quantitative determination of conotoxins has great potential in the development of natural marine peptide pharmaceuticals. Considering the time-consuming sample pretreatment and expensive equipment in MS or LC-MS/MS analysis, an electrochemical sensor combined with molecularly imprinted polymer (MIP) is fabricated for the rapid monitoring of conotoxin αB-VxXXIVA to promote its pharmaceutical value and eliminate the risk of human poisoning. Electrochemically reduced graphene oxide–gold composite (rGO-Au) is modified with chitosan (CS) and glutaraldehyde (GA) to immobilize the macromolecular peptide, conotoxin αB-VxXXIVA. Subsequently, acrylamide (AAM) with a cross-linking agent, N,N′-methylene-bisacrylamide (NNMBA), is introduced into the rGO-Au electrode to form MIPs by electro-polymerization. The proposed MIP-based electrochemical sensor, PAM/αB-CTX/CS-GA/rGO-Au/SPE, exhibits satisfactory sensing performance in the detection of αB-VxXXIVA. Based on current change versus logarithm concentration, a wide linear range from 0.1 to 10,000 ng/mL and a low detection limit (LOD) of 0.014 ng/mL for this sensor are obtained. This work provides a promising method in electrochemical determination combined with MIP for the determination of macromolecular peptides. Full article

Selenium reagents are useful for selenoenzyme-mimicking reactions, as well as for organic synthesis. However, the reaction waste containing selenium frequently smells unpleasant and exhibits serious toxicity. Herein, we have developed new-type on-resin selenium reagents, H-UXX···-PAM (5) and Ac-(X)U*XX···-PAM (6), where U and U* represent selenocysteine (U) and p-methoxybenzyl (PMB)-protected U, respectively, as recyclable catalysts, in which U-containing peptide chains are linked to the polystyrene resin PAM. Synthesized on-resin selenopeptides 5a–g with a variable amino acid sequence were evaluated for their glutathione peroxidase (GPx)-like activity using the UV and ¹H NMR methods, using the reaction between dithiothreitol (DTT^red) and H₂O₂ in methanol. It was found that the intramolecular interaction between U and a basic amino acid residue, such as histidine (H) and lysine (K), enhances peroxidase activity through the formation of an NH···Se hydrogen bond. On the other hand, the catalytic activity of 6a–d was evaluated in the oxidative cyclization of β,γ-unsaturated acids (7) into α,β-unsaturated lactones (8). Although the yield of 8 was significantly decreased after second- or third-round reaction, due to detachment of the selenium moiety from the resin, the results demonstrated reusability, as well as a substrate scope of 6 as a catalyst. Since U is a natural amino acid, on-resin selenopeptides are potential targets as novel-type green redox catalysts. Full article

The high amount of starch in fruits is responsible for its post-processing cloudiness. In the current study, α-amylase from porcine pancreases was immobilized onto carboxymethyl cellulose/polyacrylamide (CMC/PAM) hydrogel. This in-house-built CMC/PAM-Amy hydrogel offers a more efficient and sustainable solution for apple juice clarification. To acquire the best immobilization efficiency, the concentration of glutaraldehyde crosslinker was optimized. Biocatalytic characterization studies were brought into consideration for free and immobilized α-amylase. The synthesized native and immobilized CMC/PAM-Amy hydrogels were also characterized using SEM, FTIR and XRD. Under ideal circumstances, the activity of CMC/PAM-Amy was up to 604 μmolmin⁻¹, and its immobilization efficiency was 96.29 ± 1.15%. A kinetic parameters study resulted in a conspicuously lowered Km value for immobilized amylase, signifying its higher affinity for its substrate. CMC/PAM-Amy showed a half-life (t_1/2) 3.5 times higher than free-Amy at 50, 55 and 60 °C. The higher values of the inactivation rate constant (k_d), free energy of inactivation (ΔG*), enthalpy of inactivation (ΔH*) and change in entropy (ΔS*) of CMC/PAM-Amy manifested the enhanced thermal stability of amylase after immobilization. A reusability study revealed that immobilized amylase retained roughly 70% of its initial catalytic activity after six successive repetitions of the process. CMC/PAM-Amy displayed improved recycling ability operational stability and biocatalytic activity, rendering it an auspicious tool in decreasing the starch content of crude apple juice to about 61% of its total starch content before treatment. Moreover, the values of Brix, viscosity, acidity and turbidity were also decreased in CMC/PAM-Amyclarified apple juice. Therefore, immobilized amylases with other industrial enzymes could be an efficient tool for potential industrial application. Full article

Streptococcus suis is an important bacterial pathogen that affects the global pig industry. The immunosuppressive nature of S. suis infection is recognized, and our previous research has confirmed thymus atrophy with a large number of necrotic cells. In this current work, we aimed to uncover the role of pyroptosis in cellular necrosis in thymic cells of S. suis-infected mice. Confocal microscopy revealed that S. suis activated the M1 phenotype and primed pyroptosis in the macrophages of atrophied thymus. Live cell imaging further confirmed that S. suis could induce porcine alveolar macrophage (PAM) pyroptosis in vitro, displaying cell swelling and forming large bubbles on the plasma membrane. Meanwhile, the levels of p-p38, p-extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) were increased, which indicated the mitogen-activated protein kinase (MAPK) and AKT pathways were also involved in the inflammation of S. suis-infected PAMs. Furthermore, RT-PCR revealed significant mRNA expression of pro-inflammatory mediators, including interleukin (IL)-1β, IL-6, IL-18, tumor necrosis factor (TNF)-α and chemokine CXCL8. The data indicated that the inflammation induced by S. suis was in parallel with pro-inflammatory activities of M1 macrophages, pyroptosis and MAPK and AKT pathways. Pyroptosis contributes to necrotic cells and thymocyte reduction in the atrophied thymus of mice. Full article

The thermal decomposition of the thermodynamic, kinetic and mechanisms of copolymer P(DAC-AM) samples with serial cationicity and intrinsic viscosity ([η]), and the control samples of homopolymer PAM and PDAC, were studied and analyzed using TG, DSC, FTIR. The results of the thermal decomposition thermodynamics confirmed that the thermal decomposition processes of the serial P(DAC-AM) samples and the two control samples could be divided into two stages. It was found that the processes of the copolymer P(DAC-AM) samples were not a simple superposition of those of homopolymers, whose monomers had composed the unit structures of the copolymer, but there were interactions between the two suspension groups. The results of thermal decomposition kinetics showed that the apparent activation energy (E) of the thermal decomposition process of all polymer samples had different varying trends in the terms of weight-loss rate (α). The reaction order (n) of the thermal decomposition of P(DAC-AM) in Stage I and II was close to 1, but in the former and the latter it tended to be 2 and 0.5, respectively. Finally, the thermal decomposition mechanism of copolymer P(DAC-AM) samples was discussed. The above research could not only fill in the knowledge vacancy of the thermal decomposition of the thermodynamic, kinetic and mechanisms of P(DAC-AM), but could also lay a foundation for the study of thermal decomposition mechanisms of the other types of polymers, including cationic polymers. Full article

Graft copolymers have unique application scenarios in the field of high-performance thermoplastic elastomers, resins and rubbers. β-myrcene (My) is a biomass monomer derived from renewable plant resources, and its homopolymer has a low glass transition temperature and high elasticity. In this work, a series of tapered copolymers P(My-co-AMS)_k (k = 1, 2, 3) were first synthesized in cyclohexane by one-pot anionic polymerization of My and α-methyl styrene (AMS) using sec-BuLi as the initiator. PAMS chain would fracture when heated at high temperature and could endow the copolymer with thermal degradation property. The effect of the incorporation of AMS unit on the thermal stability and glass transition temperature of polymyrcene main chain was studied. Subsequently, the double bonds in the linear copolymers were partially epoxidized and hydroxylated into hydroxyl groups to obtain hydroxylated copolymer, which was finally used to initiate the ring-opening polymerization (ROP) of ε-caprolactone (ε-CL) to synthesize the graft copolymer with PCL as the side chain. All these copolymers before and after modifications were characterized by proton nuclear magnetic resonance (¹H NMR), gel permeation chromatography (GPC), thermogravimetry analysis (TGA), and differential scanning calorimeter (DSC). Full article

This study combined inorganic α-hemihydrate gypsum (α-HHG) with organic polyacrylamide (PAM) hydrogel to create a novel α-HHG/PAM composite material. Through this facile composite strategy, this fabricated material exhibited a significantly longer initial setting time and higher mechanical strength compared to α-HHG. The effects of the addition amount and the concentration of PAM precursor solution on the flowability of the α-HHG/PAM composite material slurry, initial setting time, and mechanical properties of the hardened specimens were investigated. The structural characteristics of the composite material were examined using XRD, FE-SEM, and TGA. The results showed that the initial setting time of the α-HHG/PAM composite material was 25.7 min, which is an extension of 127.43% compared to that of α-HHG. The flexural strength and compressive strength of the oven-dried specimens were 23.4 MPa and 58.6 MPa, respectively, representing increases of 34.73% and 84.86% over values for α-HHG. The XRD, FE-SEM, and TGA results all indicated that the hydration of α-HHG in the composite material was incomplete. The incompleteness is caused by the competition between the hydration process of inorganic α-HHG and the gelation process of the acrylamide molecules for water, which hinders some α-HHG from entirely reacting with water. The enhanced mechanical strength of the α-HHG/PAM composite material results from the tight interweaving and integrating of organic and inorganic networks. This study provides a concise and efficient approach to the modification research of hemihydrate gypsum. Full article

African swine fever (ASF) is an acute and severe disease transmitted among domestic pigs and wild boars. This disease is notorious for its high mortality rate and has caused great losses to the world’s pig industry in the past few years. After infection, pigs can develop symptoms such as high fever, inflammation, and acute hemorrhage, finally leading to death. African swine fever virus (ASFV) is the causal agent of ASF; it is a large DNA virus with 150–200 genes. Elucidating the functions of each gene could provide insightful information for developing prevention and control methods. Herein, to investigate the function of I267L, porcine alveolar macrophages (PAMs) infected with an I267L-deleted ASFV strain (named ∆I267L) and wild-type ASFV for 18 h and 36 h were taken for transcriptome sequencing (RNA-seq). The most distinct different gene that appeared at both 18 hpi (hours post-infection) and 36 hpi was F3; it is the key link between inflammation and coagulation cascades. KEGG analysis (Kyoto encyclopedia of genes and genomes analysis) revealed the complement and coagulation cascades were also significantly affected at 18 hpi. Genes associated with the immune response were also highly enriched with the deletion of I267L. RNA-seq results were validated through RT-qPCR. Further experiments confirmed that ASFV infection could suppress the induction of F3 through TNF-α, while I267L deletion partially impaired this suppression. These results suggest that I267L is a pathogenicity-associated gene that modulates the hemorrhages of ASF by suppressing F3 expression. This study provides new insights into the molecular mechanisms of ASFV pathogenicity and potential targets for ASFV prevention and control. Full article

Porcine reproductive and respiratory syndrome viruses (PRRSV-1 and -2) are the causative agents of one of the most important infectious diseases affecting the global pig industry. Previous studies, largely focused on PRRSV-2, have shown that non-structural protein-1α (NSP1α) and NSP1β modulate host cell responses; however, the underlying molecular mechanisms remain to be fully elucidated. Therefore, we aimed to identify novel PRRSV-1 NSP1–host protein interactions to improve our knowledge of NSP1-mediated immunomodulation. NSP1α and NSP1β from a representative western European PRRSV-1 subtype 1 field strain (215-06) were used to screen a cDNA library generated from porcine alveolar macrophages (PAMs), the primary target cell of PRRSV, using the yeast-2-hybrid system. This identified 60 putative binding partners for NSP1α and 115 putative binding partners for NSP1β. Of those taken forward for further investigation, 3 interactions with NSP1α and 27 with NSP1β were confirmed. These proteins are involved in the immune response, ubiquitination, nuclear transport, or protein expression. Increasing the stringency of the system revealed NSP1α interacts more strongly with PIAS1 than PIAS2, whereas NSP1β interacts more weakly with TAB3 and CPSF4. Our study has increased our knowledge of the PRRSV-1 NSP1α and NSP1β interactomes, further investigation of which could provide detailed insight into PRRSV immunomodulation and aid vaccine development. Full article