Antagonistic Effects Research Articles

Therapeutic effect of long-acting muscarinic antagonist for treating uncontrolled asthma assessed using impulse oscillometry

BackgroundIn recent years, the incorporation of LAMAs into asthma therapy has been expected to enhance symptom control. However, a significant number of patients with asthma continue to experience poorly managed symptoms. There have been limited investigations on LAMA-induced airway alterations in asthma treatment employing IOS. In this study, we administered a LAMA to patients with poorly controlled asthma, evaluated clinical responses and respiratory function, and investigated airway changes facilitated by LAMA treatments using the IOS.MethodsOf a total of 1282 consecutive patients with asthma, 118 exhibited uncontrolled symptoms. Among them, 42 switched their treatment to high-dose fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) (ICS/LABA/LAMA). The patients were then assessed using AHQ-33 or LCQ and ACT. Spirometry parameters (such as FEV1 or MMEF) and IOS parameters (such as R20 or AX) were measured and compared before and after exacerbations and the addition of LAMA.ResultsOf the 42 patients, 17 who switched to FF/UMEC/VI caused by dyspnea exhibited decreased pulmonary function between period 1 and baseline, followed by an increase in pulmonary function between baseline and period 2. Significant differences were observed in IOS parameters such as R20, R5-R20, Fres, or AX between period 1 and baseline as well as between baseline and period 2. Among the patients who switched to inhaler due to cough, 25 were classified as responders (n = 17) and nonresponders (n = 8) based on treatment outcomes. Among nonresponders, there were no significant differences in spirometry parameters such as FEV1 or PEF and IOS parameters such as R20 or AX between period 1 and baseline. However, among responders, significant differences were observed in all IOS parameters, though not in most spirometry parameters, between period 1 and baseline. Furthermore, significant differences were noted between baseline and period 2 in terms of FEV1, %MMEF, %PEF, and all IOS parameters.ConclusionICS/LABA/LAMA demonstrates superiority over ICS/LABA in improving symptoms and lung function, which is primarily attributed to the addition of LAMA. Additionally, IOS revealed the effectiveness of LAMA across all airway segments, particularly in the periphery. Hence, LAMA can be effective against various asthma phenotypes characterized by airway inflammation, even in real-world cases.

Acute aerobic exercise modulates cognition and cortical excitability in adults with attention-deficit hyperactivity disorder (ADHD) and healthy controls

Evidence suggests aerobic exercise has beneficial effects on cognitive performance in adults with attention-deficit hyperactivity disorder (ADHD). The underlying mechanisms might depend on mechanisms of exercise-mediated brain physiology. The study aims to investigate the effects of acute aerobic exercise on cortical excitability and cognitive performance, and the correlation between these phenomena in adults with ADHD. Twenty-six drug-naïve ADHD adults, and twenty-six age-, and gender-matched healthy controls were assessed with respect to cortical excitability and cognitive performance before and after acute aerobic exercise (a single session for 30 min) or a control intervention. The results show significantly enhanced intracortical facilitation (ICF) and decreased short intracortical inhibition (SICI) after aerobic exercise in healthy subjects. In contrast, SICI was significantly enhanced following acute aerobic exercise in ADHD. In ADHD, furthermore inhibitory control and motor learning were significantly improved after the acute aerobic exercise intervention. Alterations of SICI induced by aerobic exercise, and inhibitory control and motor learning improvement were significantly positively correlated in the ADHD group. Aerobic exercise had partially antagonistic effects in healthy controls, and ADHD patients. Furthermore, aerobic exercise-induced cognition-enhancing effects in ADHD depend on specific alterations of brain physiology, which differ from healthy humans.

Prairie soil improves wheat establishment and accelerates the developmental transition to flowering compared to agricultural soils.

Less than 1% of native prairie lands remain in the United States. Located in Eastern Washington, the rare habitat called Palouse prairie was largely converted to wheat monocropping. With this conversion came numerous physical, chemical, and biological changes to the soil that may ultimately contribute to reduced wheat yields. Here we explored how wheat (Tritcum aestivum L.) seedling establishment, plant size, and heading, signifying the developmental transition to flowering, were affected by being planted in prairie soil versus agricultural soils. We then sought to understand if the observed effects were the result of changes to the soil microbiota due to agricultural intensification. We found that prairie soil enhanced both the probability of wheat seedling survival and heading compared to agricultural soil, however wheat growth was largely unaffected by soil source. We did not detect effects on wheat developmental transitions or phenotype when inoculated with prairie microbes compared with agricultural microbes, but we did observe general antagonistic effects of microbes on plant size, regardless of soil source. This work indicates that agricultural intensification has affected soils in a way that changes early seedling establishment and the timing of heading for wheat, but these effects may not be caused by microbes, and instead may be caused by soil nutrient conditions.

Structural basis of TRPV1 inhibition by SAF312 and cholesterol

Transient Receptor Potential Vanilloid 1 (TRPV1) plays a central role in pain sensation and is thus an attractive pharmacological drug target. SAF312 is a potent, selective, and non-competitive antagonist of TRPV1 and shows promising potential in treating ocular surface pain. However, the precise mechanism by which SAF312 inhibits TRPV1 remains poorly understood. Here, we present the cryo-EM structure of human TRPV1 in complex with SAF312, elucidating the structural foundation of its antagonistic effects on TRPV1. SAF312 binds to the vanilloid binding pocket, preventing conformational changes in S4 and S5 helices, which are essential for channel gating. Unexpectedly, a putative cholesterol was found to contribute to SAF312’s inhibition. Complemented by mutagenesis experiments and molecular dynamics simulations, our research offers substantial mechanistic insights into the regulation of TRPV1 by SAF312, highlighting the interplay between the antagonist and cholesterol in modulating TRPV1 function. This work not only expands our understanding of TRPV1 inhibition by SAF312 but also lays the groundwork for further developments in the design and optimization of TRPV1-related therapies.

Selective Estrogen Receptor Modulators’ (SERMs) Influence on TET3 Expression in Breast Cancer Cell Lines with Distinct Biological Subtypes

Tamoxifen, a selective estrogen receptor modulator (SERM), exhibits dual agonist or antagonist effects contingent upon its binding to either G-protein-coupled estrogen receptor (GPER) or estrogen nuclear receptor (ESR). Estrogen signaling plays a pivotal role in initiating epigenetic alterations and regulating estrogen-responsive genes in breast cancer. Employing three distinct breast cancer cell lines—MCF-7 (ESR+; GPER+), MDA-MB-231 (ESR−; GPER−), and SkBr3 (ESR−; GPER+)—this study subjected them to treatment with two tamoxifen derivatives: 4-hydroxytamoxifen (4-HT) and endoxifen (Endox). Through 2D high-performance liquid chromatography with tandem mass spectrometry detection (HPLC-MS/MS), varying levels of 5-methylcytosine (5-mC) were found, with MCF-7 displaying the highest levels. Furthermore, TET3 mRNA expression levels varied among the cell lines, with MCF-7 exhibiting the lowest expression. Notably, treatment with 4-HT induced significant changes in TET3 expression across all cell lines, with the most pronounced increase seen in MCF-7 and the least in MDA-MB-231. These findings underscore the influence of tamoxifen derivatives on DNA methylation patterns, particularly through modulating TET3 expression, which appears to be contingent on the presence of estrogen receptors. This study highlights the potential of targeting epigenetic modifications for personalized anti-cancer therapy, offering a novel avenue to improve treatment outcomes.

In Vitro and In Vivo Studies on a Mononuclear Ruthenium Complex Reveals It is a Highly Effective, Fast-Acting, Broad-Spectrum Antimicrobial in Physiologically Relevant Conditions.

The crystal structure of a previously reported antimicrobial RuII complex that targets bacterial DNA is presented. Studies utilizing clinical isolates of Gram-negative bacteria that cause catheter-associated urinary tract infection, (CA)UTI, in media that model urine and plasma reveal that good antimicrobial activity is maintained in all conditions tested. Experiments with a series of Staphylococcus aureus clinical isolates show that, unlike the majority of previously reported RuII-based antimicrobial leads, the compound retains its potent activity even in MRSA strains. Furthermore, experiments using bacteria in early exponential growth and at different pHs reveal that the compound also retains its activity across a range of conditions that are relevant to those encountered in clinical settings. Combinatorial studies involving cotreatment with conventional antibiotics or a previously reported analogous dinuclear RuII complex showed no antagonistic effects. In fact, although all combinations show distinct additive antibacterial activity, in one case, this effect approaches synergy. It was found that the Galleria Mellonella model organism infected with a multidrug resistant strain of the ESKAPE pathogen Acinetobacter baumannii could be successfully treated and totally cleared within 48 h after a single dose of the lead complex with no detectable deleterious effect to the host.

Effects of Non-steroidal Anti-inflammatory Drugs (Ibuprofen and Diclofenac) and Their Mixtures on the Growth of Three Green Algae

Ibuprofen (IBU) and diclofenac (DFN) are the most widely consumed non-steroidal anti-inflammatory (NSAIDs) worldwide. Since they are not completely metabolized in the human body, the unaltered active ingredients can reach aquatic ecosystems through domestic effluents. The aim of this study was to analyse the toxic effects of IBU and DFN, individually and in mixtures, on three freshwater green algae strains, the international standard strain Raphidocelis subcapitata and two native strains, Ankistrodesmus fusiformis and Tetradesmus obliquus. Bioassays were carried out according to the 72-h algal growth inhibition test. The concentration-response curve of the mixture was compared to predicted effects based on both the concentration addition (CA) and the independent action (IA) models. The two drugs tested individually were toxic to all three algal strains, with EC50 values <100 mg L-1. According to these values, the most sensitive strain was R. subcapitata (IBU = 20 mg L-1 and DFN = 8 mg L-1). The most resistant strain was T. obliquus (IBU = 74.1 mg L-1 and DFN = 92.7 mg L-1) and the A. fusiformis strain showed intermediate sensitivity (IBU = 26.7 mg L-1 and DFN = 14.6 mg L-1). The mixtures showed a synergistic effect on R. subcapitata, an additive effect on A. fusiformis, and an antagonistic effect on T. obliquus. Neither the CA nor the IA model was appropriate for predicting the toxicity of the mixtures. In conclusion, IBU and DFN showed toxic effects on the algae growth at the concentrations tested. Individual and mixed toxicity was different according to the species. These differences could be species-specific, showing the importance of including native strains in ecotoxicological studies to evaluate the potential effects of pollutants in regional aquatic environments.

The non-enzymatic oxidation of phosphatidylethanolamine and phosphatidylserine and their intriguing roles in inflammation dynamics and diseases.

Phosphatidylethanolamine (PE) and phosphatidylserine (PS), along with phosphatidylcholine (PC), are key phospholipids (PL) in cell membranes and lipoproteins, prone to oxidative modifications. Their oxidized forms, OxPE and OxPS, play significant roles in inflammation and immune response. This review explores their structural oxidative changes under non-enzymatic conditions and their roles in physiological and pathological contexts, influencing inflammation, and immunity. Specific oxidations of PE and PS significantly alter their physicochemical properties, leading to enhanced biological functions, reduced activity, or inactivation. OxPE may show pro-inflammatory actions, similar to well-documented OxPC, while the OxPS pro-inflammatory effects are less noted. However, OxPS and OxPE have also shown an antagonistic effect against lipopolysaccharides (LPS), suggesting a protective role against exacerbated immune responses, similar to OxPC. Further research is needed to deepen our understanding of these less-studied OxPL classes. The role of OxPE and OxPS in disease pathogenesis remains largely unexplored, with limited studies linking them to Alzheimer's disease, diabetes, rheumatoid arthritis, traumatic brain injury, and skin inflammation. These findings highlight the potential of OxPE and OxPS as biomarkers for disease diagnosis, monitoring, and therapeutic targeting.

Protein Kinase A Inhibitor Attenuates the Antinociceptive Effect of NMDA-Receptor Channel Antagonists in the Capsaicin Test in Mice.

Acute nociceptive pain in mice caused by subcutaneous (intraplantar) injection of TRPV1 ion channel agonist capsaicin (1.6 μg/mouse) and the effects of protein kinase A inhibitor H-89 (0.05 mg/mouse, intraplantar injection) and NMDA receptor channel antagonists MK-801 (7.5 and 15 μg/mouse, topical application) and hemantane (0.5 mg/mouse, topical application) on the pain were assessed. MK-801 and hemantane were found to reduce the duration of the pain response. H-89 did not significantly affect the pain in animals, but preliminary administration of this drug abolished the antinociceptive effect of MK-801 (7.5 μg/mouse) and weakens the effect of hemantane (0.5 mg/mouse).

Seed extracts as an effective strategy in the control of plant pathogens: scalable industry bioactive compounds for sustainable agriculture

With a growing global population, maintaining sufficient agricultural production is crucial. However, agriculture faces numerous challenges today, particularly due to the undeniable impacts of climate change, which are expected to intensify pest and disease pressures. The traditional approach to combat these phytopathological issues has relied on synthetic chemical pesticides. While their use has indeed increased productivity, it is also evident their detrimental and cumulative effects on the environment, and the current negative perception of the population toward these chemicals. In response, governments are prompting the search for alternatives to synthetic pesticides, through different policies, such as the strategy From Farm to Fork in the European Union, which aims to reduce the use of chemical pesticides by 50% by 2030, among other measures. At this point, seed extracts with biocidal activity are emerging as a viable option for the control and management of various pathogenic agents, such as harmful bacteria, fungal and oomycete pathogens, and plant-parasitic nematodes. Nevertheless, it is worth mentioning that most of the studies have been only conducted under highly controlled conditions. Thus, this line of research should be still more deeply developed, including proofs under field conditions in order to become the extensive and widespread use of these bio-products a reality. In this review, we compile the main studies focused on the use of these compounds for phytosanitary purposes, describing and analysing the key metabolites, their composition, extraction processes and the mechanisms involved in their antagonistic effects. Additionally, we analyse the primary factors contributing to the limited adoption of these extracts in the field, such as the scarcity of studies under real conditions or the possible impact on non-target organisms, and discuss future prospects for their development.

Adrenergic Agonists Activate Transcriptional Activity in Immortalized Neuronal Cells From the Mouse Suprachiasmatic Nucleus.

The suprachiasmatic nucleus of the hypothalamus (SCN) houses the central circadian oscillator of mammals. The main neurotransmitters produced in the SCN are γ-amino-butyric acid, arginine-vasopressin (AVP), vasoactive intestinal peptide (VIP), pituitary-derived adenylate cyclase-activating peptide (PACAP), prokineticin 2, neuromedin S, and gastrin-releasing peptide (GRP). Apart from these, catecholamines and their receptors were detected in the SCN as well. In this study, we confirmed the presence of β-adrenergic receptors in SCN and a mouse SCN-derived immortalized cell line by immunohistochemical, immuno-cytochemical, and pharmacological techniques. We then characterized the effects of β-adrenergic agonists and antagonists on cAMP-regulated element (CRE) signaling. Moreover, we investigated the interaction of β-adrenergic signaling with substances influencing parallel signaling pathways. Our findings have potential implications on the role of stress (elevated adrenaline) on the biological clock and may explain some of the side effects of β-blockers applied as anti-hypertensive drugs.

Caffeine weakens the astringency of epigallocatechin gallate by inhibiting its interaction with salivary proteins

The astringency of green tea is an integrated result of the synergic and antagonistic effects of individual tea components, whose mechanism is highly complex and not completely understood. Herein, we used an epigallocatechin gallate (EGCG)/caffeine (CAF)/saliva model to simulate the oral conditions during tea drinking. The effect of CAF on the interaction between EGCG and salivary proteins was first investigated using molecular docking and isothermal titration calorimetry (ITC). Then, the rheological properties and the micro-network structure of saliva were studied to relate the molecular interactions and perceived astringency. The results revealed that CAF partially occupied the binding sites of EGCG to salivary proteins, inhibiting their interaction and causing changes in the elastic network structure of the salivary film, thereby reducing astringency.

Insights into the antagonistic effects of calcium on cadmium accumulation in peanuts (Arachis hypogaea L.)

Peanut (Arachis hypogaea L.) plant has a high requirement for calcium (Ca) during its growth and development, and possesses the ability to accumulate cadmium (Cd) from soil. However, the precise mechanisms underlying the antagonistic effects between Ca and Cd remain unclear. This study aimed to explore the dynamic changes in Cd accumulation in peanut seedlings by varying the Ca-to-Cd concentration ratio (CRCa/Cd) from 250 to 3500. Additionally, the influence of ion channel competition and cell wall fixation in the root on Cd accumulation in peanuts was explored by analyzing Cd chemical forms, subcellular distribution, pectin content, and Cd2+ fluxes using a non-invasive micro-test technique (NMT). The findings revealed that Cd accumulation in peanut seedlings was significantly lower when the CRCa/Cd was higher than 2000. In the Ca-pretreated seedlings (cell wall fixation treatment), Cd content in the shoots and roots decreased by 18.9% and 25.0%, respectively, compared with the simultaneous exposure to Ca and Cd (ion channel competition treatment). Cd2+ influx in peanut roots decreased by 55.8% in the Ca-pretreated group. However, increasing the competitive strength of Ca2+ and Cd2+ did not affect Cd2+ influx under normal Ca conditions (>2 mM Ca). Meanwhile, Ca pretreatment significantly increased Cd distribution in the root cell wall, pectate, and protein-binding forms, while significantly reducing Cd distribution in root soluble components and inorganic Cd forms. The pectin content in the roots increased by 128% and 226% in the Ca and Cd simultaneous exposure treatment and Ca pretreatment, respectively. These results suggest that Ca pretreatment enhanced Cd retention in the root cell wall. Overall, exogenous Ca effectively mitigated Cd accumulation in peanut plants when the CRCa/Cd was below 2000, and Ca2+ channels partially facilitate the entry of Cd2+ into peanut roots. Under normal Ca supply conditions, exogenous Ca reduced Cd accumulation in peanuts primarily through root cell wall fixation rather than ion channel competition. Our findings provide insights into the mechanism by which Ca alleviates the uptake and transfer of Cd in peanuts.

A N‐Cadherin Nano‐Antagonist Hydrogel Enhances Recovery From Spinal Cord Injury by Impeding Glial Scarring

AbstractThe role of glial scars in the pathophysiology of spinal cord injury (SCI) is widely recognized, as they pose physical barriers against axonal regeneration and persistent chronic inflammation by releasing cytotoxic agents, thereby impeding nerve repair. Consequently, preventing glial scarring has emerged as an important therapeutic objective in SCI management. Following SCI, astrocytes undergo a phenotypic transition into scar‐forming astrocytes, which critically depends on the activation of inflammatory responses and the integrin‐N‐cadherin pathway. To explore improved SCI treatment, a nano‐antagonist hydrogel (Nano‐ant Gel), comprising N‐cadherin nano‐antagonists and a polyphenol hydrogel designed to inhibit glial scarring by mitigating inflammatory response and modulating astrocyte behavior, thereby facilitating spinal cord‐injury repair, is developed and characterized. The hydrogel exhibits notable anti‐inflammatory properties, specific calcium ion‐adsorption capabilities, and antagonistic effects against N‐cadherin, effectively impeding the formation and aggregation of scar‐forming astrocytes. Its efficacy is comprehensively assessed using a model of contusive SCI, with which it effectively inhibits glial scar formation and promotes axonal regeneration. Notably, the Nano‐ant Gel significantly improves the locomotor functions of mice with SCI, suggesting that it represents a promising approach for treating the condition.

Core microbiome-associated proteins associated with ulcerative colitis interact with cytokines for synergistic or antagonistic effects on gut bacteria.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is associated with a loss or an imbalance of host-microorganism interactions. However, such interactions at protein levels remain largely unknown. Here, we applied a depletion-assisted metaproteomics approach to obtain in-depth host-microbiome association networks of IBD, where the core host proteins shifted from those maintaining mucosal homeostasis in controls to those involved in inflammation, proteolysis, and intestinal barrier in IBD. Microbial nodes such as short-chain fatty acid producer-related host-microbial crosstalk were lost or suppressed by inflammatory proteins in IBD. Guided by protein-protein association networks, we employed proteomics and lipidomics to investigate the effects of UC-related core proteins S100A8, S100A9, and cytokines (IL-1β, IL-6, and TNF-α) on gut bacteria. These proteins suppressed purine nucleotide biosynthesis in stool-derived in vitro communities, which was all reduced in IBD stool samples. Single species study revealed that S100A8, S100A9, and cytokines can synergistically or antagonistically alter gut bacteria intracellular and secreted proteome, with combined S100A8 and S100A9 potently inhibiting beneficial Bifidobacterium adolescentis. Furthermore, these inflammatory proteins only altered the extracellular but not intracellular proteins of Ruminococcus gnavus. Generally, S100A8 induced more significant bacterial proteome changes than S100A9, IL-1β, IL-6, and TNF-α. But gut bacteria degrade significantly more S100A8 than S100A9 in the presence of both proteins. Among the investigated species, distinct lipid alterations were only observed in Bacteroides vulgatus treated with combined S100A8, S100A9, and cytokines. These results provided a valuable resource of inflammatory protein centric host-microbial molecular interactions.

Antagonistic Effects and the Underlying Mechanisms of Bacillus velezensis and its Antibacterial Peptide LCI Against Aeromonas hydrophila Infection in Largemouth Bass.

Aeromonas hydrophila is one of the most prevalent pathogenic bacteria in largemouth bass. The use of antibiotics to inhibit A. hydrophila poses a significant threat to fish and environmental safety. Bacillus velezensis, a safe bacterium with probiotic and antibacterial characteristics, is an ideal candidate for antagonizing A. hydrophila. This study explored the antagonistic effects of B. velezensis FLU-1 on A. hydrophila in vivo and in vitro. In addition, we explored the antimicrobial peptides (AMPs) produced by strain FLU-1 and clarified the underlying antibacterial mechanisms. The results showed that strain FLU-1 could inhibit a variety of fish pathogens, including A. hydrophila. The challenge test showed that dietary supplementation with B. velezensis FLU-1 significantly improved the survival rate of largemouth bass and reduced the bacterial load in liver. Subsequently, the AMP LCI was isolated from B. velezensis FLU-1 and was found to be effective against A. hydrophila in vitro and in vivo. Transcriptomic analysis revealed that LCI downregulated the genes associated with flagellar assembly and peptidoglycan synthesis in A. hydrophila. Phenotypic test results showed that LCI disrupted the membrane integrity, markedly reduced the biofilm biomass and diminished the swimming motility of A. hydrophila. Furthermore, the results showed that LCI bound to the genomic DNA of A. hydrophila and destroyed the DNA structures. Overall, these findings elucidated the mechanism of action of LCI against A. hydrophila at the phenotypic and physiological levels. This study suggests that B. velezensis FLU-1 and its AMP LCI could serve as antibiotic alternatives for controlling pathogens in aquaculture.

Antidepressant effects of selective adenosine receptor antagonists targeting the A1 and A2A receptors administered jointly with NMDA receptor ligands: behavioral, biochemical and molecular investigations in mice.

The objective of the study was to ascertain the antidepressant potential of the co-administration of NMDA receptor ligands and selective adenosine A1 and A2A receptor antagonists. The forced swim test (FST) and spontaneous locomotor activity test were carried out in adult male naïve mice. Before the behavioral testing, animals received DPCPX (a selective adenosine A1 receptor antagonist, 1mg/kg) or istradefylline (a selective adenosine A2A receptor antagonist, 0.5mg/kg) in combination with L-701,324 (a potent NMDA receptor antagonist, 1mg/kg), D-cycloserine (a partial agonist at the glycine recognition site of NMDA receptor, 2.5mg/kg), CGP 37849 (a competitive NMDA receptor antagonist, 0.3mg/kg) or MK-801 (a non-competitive NMDA receptor antagonist, 0.05mg/kg). Additionally, serum BDNF level and the mRNA level of the Adora1, Comt, and Slc6a15 genes in the murine prefrontal cortex were determined. The obtained results showed that DPCPX and istradefylline administered jointly with NMDA receptor ligands (except for DPCPX + D-cycloserine combination) produced an antidepressant effect in the FST in mice without enhancement in spontaneous motility of animals. An elevation in BDNF concentration was noted in the D-cycloserine-treated group. Adora1 expression increased with L-701,324, DPCPX + D-cycloserine, and DPCPX + CGP 37849, while D-cycloserine, CGP 37849, and MK-801 led to a decrease. Comt mRNA levels dropped with DPCPX + L-701,324, istradefylline + L-701,324/CGP 37849 but increased with D-cycloserine, MK-801, CGP 37849 and DPCPX + MK-801/ CGP 37849. Slc6a15 levels were reduced by D-cycloserine, DPCPX + L-701,324 but rose with DPCPX + CGP 37849/MK-801 and istradefylline + D-cycloserine/MK-801/CGP 37849. Our study suggests that selective antagonists of adenosine receptors may enhance the antidepressant efficacy of NMDA receptor ligands highlighting a potential synergistic interaction between the adenosinergic and glutamatergic systems. Wherein, A2A receptor antagonists are seen as more promising candidates in this context. Given the intricate nature of changes in BDNF levels and the expression of Adora1, Comt, and Slc6a15 seen after drug combinations exerting antidepressant properties, further research and integrative approaches are crucial understand better the mechanisms underlying their antidepressant action.

The effect of P2X7 antagonism on subcortical spread of optogenetically-triggered cortical spreading depression and neuroinflammation

Migraine is a neurological disorder characterized by episodes of severe headache. Cortical spreading depression (CSD), the electrophysiological equivalent of migraine aura, results in opening of pannexin 1 megachannels that release ATP and triggers parenchymal neuroinflammatory signaling cascade in the cortex. Migraine symptoms suggesting subcortical dysfunction bring subcortical spread of CSD under the light. Here, we investigated the role of purinergic P2X7 receptors on the subcortical spread of CSD and its consequent neuroinflammation using a potent and selective P2X7R antagonist, JNJ-47965567. P2X7R antagonism had no effect on the CSD threshold and characteristics but increased the latency to hypothalamic voltage deflection following CSD suggesting that ATP acts as a mediator in the subcortical spread. P2X7R antagonism also prevented cortical and subcortical neuronal activation following CSD, revealed by bilateral decrease in c-fos positive neuron count, and halted CSD-induced neuroinflammation revealed by decreased neuronal HMGB1 release and decreased nuclear translocation of NF-kappa B-p65 in astrocytes. In conclusion, our data suggest that P2X7R plays a role in CSD-induced neuroinflammation, subcortical spread of CSD and CSD-induced neuronal activation hence can be a potential target.

Epigenetic factors direct synergistic and antagonistic regulation of transposable elements in Arabidopsis.

Arabidopsis (Arabidopsis thaliana) HISTONE DEACETYLASE 6 (HDA6) and HISTONE DEMETHYLASES LSD-LIKE 1 (LDL1) and LDL2 synergistically regulate the expression of long non-coding RNAs associated with H3Ac and H3K4me2. The underlying mechanisms of such highly coordinated interactions among genetic and epigenetic factors contributing to this collaborative regulation remain largely unclear. We analyzed all transposable elements (TEs) across the Arabidopsis genome and the individual and combined roles of HDA6 and LDL1/LDL2 by dissecting multi-layered epigenomes and their association with transcription. Instead of an individual synergistic effect, we observed dual synergistic and antagonistic effects, which are positively associated with H3Ac and H3K4me2 while maintaining a negative but moderate association with DNA methylation. Specifically, two modes of synergistic regulation were discovered in TEs: 74% are primarily regulated by HDA6, with less dependence on LDL1/LDL2, and the remaining 26% are co-regulated by both. Between the two modes, we showed that HDA6 has a strong effect on TE silencing, whereas LDL1/LDL2 plays a weaker yet crucial role in co-regulation with HDA6. Our results led to a model of epigenomic regulation - the differential de-repression between the two modes of synergistic regulation of TEs was determined by H3Ac and H3K4me2 levels, where TEs are in accessible chromatins free of DNA methylation, and this open chromatin environment precedes transcriptional changes and epigenome patterning. Our results discovered unbalanced effects of genetic factors in synergistic regulation through delicately coordinated multi-layered epigenomes and chromatin accessibility.

Evaluating the efficacy of microbial antagonists in inducing resistance, promoting growth, and providing biological control against powdery mildew in wheat.

This study evaluates the biocontrol efficacy of three bacterial strains (Pseudomonas fluorescens DTPF-3, Bacillus amyloliquefaciens DTBA-11, and Bacillus subtilis DTBS-5) and two fungal strains (Trichoderma harzianum Pusa-5SD and Aspergillus niger An-27) antagonists, along with their combinations at varying doses (5.0, 7.5, and 10.0 g/kg of seeds), against wheat powdery mildew. The most effective dose (10 g/kg seeds) was further analyzed for its impact on induced resistance and plant growth promotion under greenhouse conditions. The study measured defense enzyme activities, biochemical changes, and post-infection plant growth metrics. All tested microbial antagonists at 10 g/kg significantly reduced PM severity, with B. subtilis strain DTBS-5 outperforming others in reducing PM severity and achieving the highest biocontrol efficacy. It was followed by B. amyloliquefaciens strain DTBA-11 and P. fluorescens strain DTPF-3, with the fungal antagonists showing no significant effect. Wheat crops treated with B. subtilis strain DTBS-5 exhibited substantial increases in defense-related enzyme activities and biochemicals, suggesting an induced resistance mechanism. The study found a 45% increase in peroxidase (POD) activity, a 50% increase in catalase (CAT) activity, a 30% increase in phenolic content, and a 25% increase in soluble protein content in the wheat plants treated with microbial antagonists. The study highlights the effectiveness of microbial antagonists, particularly B. subtilis strain DTBS-5, in managing wheat PM through biocontrol, induced resistance, and enhanced plant growth, offering a sustainable alternative to chemical treatments.