Antagonistic Effects Research Articles

Effects of dopamine receptor antagonists and radiation on mouse neural stem/progenitor cells

BackgroundDopamine receptor antagonists have recently been identified as potential anti-cancer agents in combination with radiation, and a first drug of this class is in clinical trials against pediatric glioma. Radiotherapy causes cognitive impairment primarily by eliminating neural stem/progenitor cells and subsequent loss of neurogenesis, along with inducing inflammation, vascular damage, and synaptic alterations. Here, we tested the combined effects of dopamine receptor antagonists and radiation on neural stem/progenitor cells. MethodsUsing transgenic mice that report the presence of neural stem/progenitor cells through Nestin promoter-driven expression of EGFP, the effects of dopamine receptor antagonists alone or in combination with radiation on neural stem/progenitor cells were assessed in sphere-formation assays, extreme limiting dilution assays, flow cytometry and real-time PCR in vitro and in vivo in both sexes. ResultsWe report that hydroxyzine and trifluoperazine exhibited sex-dependent effects on murine newborn neural stem/progenitor cells in vitro. In contrast, amisulpride, nemonapride, and quetiapine, when combined with radiation, significantly increased the number of neural stem/progenitor cells in both sexes. In vivo, trifluoperazine showed sex-dependent effects on adult neural stem/progenitor cells, while amisulpride demonstrated significant effects in both sexes. Further, amisulpride increased sphere forming capacity and stem cell frequency in both sexes when compared to controls. ConclusionWe conclude that a therapeutic window for dopamine receptor antagonists in combination with radiation potentially exists, making it a novel combination therapy against glioblastoma. Normal tissue toxicity following this treatment scheme likely differs depending on age and sex and should be taken into consideration when designing clinical trials.

Synergistic inhibition effect of thioureido imidazoline and cationic surfactants with different alkyl chain lengths on X80 carbon steel in CO2-satureted NaCl solutions

The corrosion inhibition performance of the thioureido imidazoline (TU-IM) corrosion inhibitor, along with three surfactants, was assessed for X80 carbon steels in a CO2-saturated NaCl solution using weight loss tests, electrochemical and microstructural characterization. Results demonstrate that the corrosion-inhibition efficiency of surfactants improves with increasing alkyl-chain length in the following order: cetyltrimethylammonium bromide (CTAB) > tetradecyltrimethylammonium bromide (TTAB) > dodecyltrimethylammonium bromide (DTAB). A synergistic corrosion inhibition effect between TU-IM and DTAB/TTAB was observed, with the best performance achieved using 10mg/L TU-IM and 10mg/L DTAB/TTAB (inhibition efficiency: 97.68%), which is mainly attributed to the cooperative adsorption of both substances. By contrast, the synergistic inhibition capability of TU-IM with the surfactants decreased as the alkyl-chain length increased, and even an antagonistic effect was noted for the combination of TU-IM + CTAB owing to the competitive adsorption between the surfactant and the corrosion inhibitor.

Acute toxicity of binary and ternary mixtures of La, Ce and Dy on Daphnia magna: Toxicity patterns depend on the ratios of the components and the concentration gradient

Rare earth elements (REEs) have raised significant environmental contamination concerns, yet the combined toxicity of REE mixtures remains inadequately understood. In this study, acute toxicity of individual, binary and ternary mixtures of lanthanum (La), cerium (Ce), and dysprosium (Dy) on neonatal Daphnia magna was investigated. Dy exhibited the greatest toxicity on neonatal Daphnia magna, followed by La and Ce. The concentration addition (CA) model was superior to the independent action (IA) model for predicting the toxicity of binary mixtures. The CA model indicated additive effects for LaCe mixture and antagonistic effects for LaDy and CeDy mixtures. In contrast, IA model suggested synergistic interactions for LaCe and LaDy mixtures, with antagonistic effects for CeDy mixture when considering dissolved concentration and synergistic effects when considering free-ion concentration. The nonadditive interactions and deviation parameters from the prediction of binary mixture toxicity were assessed by using MixTox model. The ternary mixture of LaCeDy exhibited antagonistic effects on Daphnia magna, and IA model slightly outperformed CA model. Overall, the type of combined toxicity in REE mixtures is influenced by constituents in the mixture and concentration levels. These findings provide scientific basis for the toxicological assessment, risk evaluation and pollution control of REE mixtures. Environmental implicationRare earth elements (REEs) level is increasing in water environment due to wide use and exploitation. However, currently, we know little about the difference of REEs toxicity and combined toxicity of mixture to aquatic organism, which limited the assessment of toxicity and hazard risk of REEs in natural water. Here, this study demonstrates the acute toxicity of individual, binary and ternary mixtures of lanthanum, cerium, and dysprosium on neonatal Daphnia magna according to the measured data and predicted model, identifying the influence factors for combined toxicity. This discovery offers new insights for the assessment and prediction of REEs toxicity.

Looking beyond the surface: Understanding the role of multiple stressors on the eutrophication status of the Albufera Lake (Valencia, Spain)

Aquatic ecosystems face significant impacts from human-related stressors, demanding a deep understanding of their dynamics and interactions for effective management and restoration. The Albufera Lake (Valencia, Spain) presents a complex scenario of multiple interacting stressors affecting its eutrophic status. In this study, we compiled a 50-year dataset and used Generalized Additive Models (GAMs) to analyse the dynamics of the main stressors affecting the ecological status of the Albufera Lake. Then, we assessed their individual and combined effects on eutrophication using chlorophyll-a concentration as a proxy and provided recommendations to enhance water quality. Overall, we found a decrease in annual water inflow and a clear effect of rice cultivation on the seasonal patterns of the Lake's residence time. Our analysis also shows an increase of average water temperature of 2 °C for the last 50 years, and an increase in the frequency and severity of heat waves. In contrast, we found a slightly negative long-term trend in conductivity, despite the occurrence of seasonal peaks in summer. Regarding nutrients, we identified a clear reduction of total phosphorus (from 1.08 mg/L in 1987 to 0.20 mg/L in 2022), while nitrate concentrations have been rather stable. Our results also point at an increase of toxic pressure exerted by organic and inorganic contaminants during the last years, with seasonal toxicity peaks occurring during rice field drainage periods. The main stressors affecting the chlorophyll-a levels were found to be temperature, water scarcity, and nitrate concentration as well as the interactions between temperature and conductivity, conductivity and nitrate, conductivity and water scarcity, and nitrate and total phosphorus. We found that stressor interactions are highly dynamic and result in synergistic and antagonistic effects that vary according to different stressor levels. Finally, our GAM framework points to two potential scenarios: increasing freshwater inflows or deregulating hydrology to allow seawater exchange, which are key for improving the ecological status of the Albufera Lake in the short-term.

Inhibitory Role of L-theanine, a Structural Analogue of Glutamate, Against GluR5 Kainate Receptor and its Prospective Utility Against Excitotoxicity.

Overactivation of receptors that respond to excitatory neurotransmitters can result in various harmful outcomes, such as the inability to properly modulate calcium levels, generation of free radicals, initiation of the mitochondrial permeability transition, and subsequent secondary damage caused by excitotoxicity. A non-proteinogenic amino acid of tea, L-theanine, is structurally related to glutamate, the major stimulatory neurotransmitter in the brain. Previous reports have emphasised its ability to bind with glutamate receptors. An in-depth understanding of the binding compatibility between ionotropic glutamate receptors and L-theanine is a compelling necessity. In this molecular docking study, the antagonistic effect of L-theanine and its possible therapeutic benefit in GluR5 kainate receptor inhibition has been evaluated and compared to the familiar AMPA and kainite receptor antagonists, cyanoquinoxaline (CNQX) and dinitroquinoxaline (DNQX), using Molegro Virtual Docker 7.0.0. The capacity of L-theanine to cohere with the GluR5 receptor was revealed to be higher than that of glutamate, although it could not surpass the high binding tendency of competitive antagonists CNQX and DNQX. Nonetheless, the drug-likeness score and the blood-brain barrier traversing potential of L-theanine were higher than CNQX and DNQX. The study provides an inference to the advantage of L-theanine, which can be a safe and effective alternative natural therapy for rescuing neuronal death due to excitotoxicity.

Calcium homeostasis imbalance mediates DEHP induced mitochondrial damage in cerebellum and the antagonistic effect of lycopene

Phthalates (PAEs), especially di (2-ethylhexyl) phthalate (DEHP), are generally considered to have adverse impact on nervous system. The residue of DEHP in the environment has gradually become a widely concerned environmental problem due to its widespread use in plastic items. Lycopene (LYC) as the readily available natural antioxidant is considered to have the potential to alleviate exogenous poisons-induced nerve damage. However, there is currently a lack of strategies to alleviate the neurotoxicity caused by DEHP, and it is also unknown whether LYC can alleviate the neurotoxicity caused by DEHP. The experiment demonstrated that LYC had the potential to mitigate DEHP-induced mitochondrial damage in cerebellum. DEHP induced the disorder of Ca2+ transport in cerebellum, thereby resulting in the imbalance of protein homeostasis. Such disruption in protein homeostasis further results in the overactivation of mitochondrial unfolded protein response (UPRmt) and mitochondrial injury. Mechanistically, LYC could alleviate the imbalance of calcium homeostasis and protein homeostasis induced by DEHP via regulating inositol 1, 4, 5-trisphosphate receptor type1 (IP3R1) and sarco/endoplasmic reticulum Ca (2+)-ATPase 2 (SERCA2), further alleviating mitochondrial damage in cerebellum. Subsequently, the present study suggested the mechanism of cerebellar injury induced by DEHP, and provided a novel approach to treating DEHP-induced neurotoxicity.

Synergistic and Antagonistic Effects of Mixed-Leaf Litter Decomposition on Nutrient Cycling

Understanding decomposition patterns of mixed-leaf litter from agroforestry species is crucial, as leaf litter in ecosystems naturally occurs as mixtures rather than as separate individual species. We hypothesized that litter mixtures with larger trait divergence would lead to faster mass loss and more balanced nutrient release compared to single-species litter. Specifically, we expected mixtures containing nutrient-rich species to exhibit synergistic effects, resulting in faster decay rates and sustained nutrient release, while mixtures with nutrient-poor species would demonstrate antagonistic effects, slowing decomposition. We conducted a mesocosm experiment using a custom wooden setup filled with soil, and the litterbag method was used to test various leaf litter mixtures. The study involved leaf litter from six agroforestry tree species: three species from humid highland regions and three from semi-arid regions. Treatments included three single-species leaf litter mixtures, three two-species mixtures, and one three-species mixture, based on the sampling region. Species included Calliandra calothyrsus (Ca), Croton megalocarpus (Cr), Grevillea robusta (G), Alnus acuminata (A), Markhamia lutea (M), and Eucalyptus globulus (E). Decay rate constants (k) were estimated using non-linear least-squares regression and observed mass loss was compared to predicted values for mixed-species litter treatments to assess synergistic and antagonistic effects. A two-way linear mixed-effects model was employed to explain variation in mass loss. Results indicate positive non-additive effects for leaf litter mixtures including nutrient-rich species and negative non-additive effects for mixtures including nutrient-poor species. The mixture of Ca + Cr + G had positive non-additive or synergistic effects as it decomposed faster than its corresponding single-species litter. Leaf litters with higher lignin content, such as A + M + E and Ca + Cr + G, exhibited less lignin release compared to what would be expected based on individual litter types, demonstrating antagonistic effects. These findings highlight that both litter nutrient constituents and litter diversity play an important role in decomposition processes and therefore in the restoration of the degraded and nutrient-depleted soils of Rwanda.

Antagonistic effects of endophytic fungi from Camellia reticulata pedicels on yeasts: implications for antimicrobial mechanism of nectar

Endophytic fungi are extensive in plant tissues and involved in the defense against stress from harmful microbes. The interaction between pedicel endophytic fungi and nectar yeasts is critical for maintaining nectar homeostasis. This study used Camellia reticulata as the research subject. High-throughput sequencing revealed that the community composition of endophytic fungi in the pedicel is dominated by Ascomycota and Basidiomycota. Their abundance varies at different taxonomic levels, showing sample variability. In total, 27 endophytic fungal isolates were isolated and screened from the pedicel under laboratory conditions. They exhibited antagonistic effects against three nectar yeasts (Metschnikowia reukaufii, Cryptococcus laurentii, and Rhodotorula glutinis) and displayed morphological and physiological diversity. The isolates were classified into the phylum Ascomycota and further categorized into the genera Alternaria, Trichoderma, Fusarium, and Dactylaria. The endophytic fungus D23, which effectively antagonizes nectar yeasts, was identified as Alternaria alternata. This fungus produces various secondary metabolites, including antibiotics such as penicillin G, grandiomycin, and cephalosporin C. The metabolic pathways involved include the biosynthesis of plant secondary metabolites, phenylpropanoids, amino acids, nucleotides, and antibiotics. The endophytic fungal community in C. reticulata pedicel is rich and diverse, making it a valuable material for screening antagonistic strains. This study provides a theoretical basis for the antagonistic effects of endophytic fungal metabolites from the pedicel of C. reticulata against nectar yeasts, highlighting their significance in maintaining nectar stability and reproductive fitness in cross-pollinated plants.

Effectiveness and safety of mineralocorticoid receptor antagonists in heart failure patients with and without diabetes: a systematic review and meta-analysis.

Mineralocorticoid receptor antagonists (MRAs) have been shown to improve outcomes in various populations of heart failure (HF) patients. However, the impact of concomitant diseases, such as diabetes mellitus (DM), on these outcomes remains unclear. This meta-analysis aimed to evaluate the efficacy and safety of MRAs in heart failure patients with and without diabetes mellitus. A systematic search was conducted on PubMed, Scopus, and Google Scholar databases up to April 30, 2024. Data analysis was performed using a random-effects model to account for variability across studies, and statistical analysis was carried out using Review Manager 5.4. Efficacy and safety parameters were evaluated in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. The meta-analysis included a total of 21,832 subjects from ten studies. The pooled results demonstrated that MRAs, compared to placebo, significantly reduced all-cause mortality in HF patients with and without DM (RR: 0.85; 95%CI 0.75-0.96; p = 0.009). A similar effect was observed in HF patients without DM (RR: 0.83; 95%CI 0.71-0.97; p = 0.02), while no significant effect was detected in the DM subgroup (RR: 0.87; 95%CI 0.69-1.11; p = 0.27). Both treatments had comparable effects on cardiovascular mortality in HF patients with and without DM (RR: 0.88; 95%CI 0.82-0.94; p = 0.0002), in HF patients with DM (RR: 0.90; 95%CI 0.81-1.01; p = 0.08), and in the non-DM subgroup (RR: 0.86; 95%CI 0.79-0.94; p = 0.0009). MRAs significantly reduced the risk of cardiovascular mortality in HF patients with and without DM (RR: 0.82; 95%CI 0.72-0.94; p = 0.005) and in HF patients with DM (RR: 0.79; 95%CI 0.63-0.98; p = 0.03), but no significant effect was observed in the non-DM subgroup (RR: 0.85; 95%CI 0.69-1.05; p = 0.13). Furthermore, compared to placebo, MRAs were associated with an increased risk of hyperkalemia (> 5.5 mEq/L) in HF patients with and without DM (RR: 1.63; 95%CI 1.18-2.24; p = 0.003), particularly in HF patients with DM (RR: 1.44; 95%CI 0.97-2.13; p = 0.07) and in the non-DM subgroup (RR: 1.87; 95%CI 1.34-2.61; p = 0.0002). MRAs are effective in reducing all-cause mortality, cardiovascular death, and cardiovascular mortality in heart failure patients. However, the use of MRAs is associated with an increased risk of hyperkalemia, necessitating careful monitoring, particularly in patients with diabetes mellitus.

Secondary metabolite profiles and anti-SARS-CoV-2 activity of ethanolic extracts from nine genotypes of Cannabis sativa L.

This study deals with the comprehensive phytochemical composition and antiviral activity against SARS-CoV-2 of acidic (non-decarboxylated) and neutral (decarboxylated) ethanolic extracts from seven high-cannabidiol (CBD) and two high-Δ9-tetrahydrocannabinol (Δ9-THC) Cannabis sativa L. genotypes. Their secondary metabolite profiles, phytocannabinoid, terpenoid, and phenolic, were determined by LC-UV, GC-MS, and LC-MS/MS analyses, respectively. All three secondary metabolite profiles, cannabinoid, terpenoid, and phenolic, varied significantly among cannabinoid extracts of different genotypes. The dose-response analyses of their antiviral activity against SARS-CoV-2 showed that only the single predominant phytocannabinoids (CBD or THC) of the neutral extracts exhibited antiviral activity (all IC50 < 10.0 μM). The correlation matrix between phytoconstituent levels and antiviral activity revealed that the phenolic acids, salicylic acid and its glucoside, chlorogenic acid, and ferulic acid, and two flavonoids, abietin, and luteolin, in different cannabinoid extracts from high-CBD genotypes are implicated in the genotype-distinct antagonistic effects on the predominant phytocannabinoid. On the other hand, these analyses also suggested that the other phytocannabinoids and the flavonoid orientin can enrich the extract's pharmacological profiles. Thus, further preclinical studies on cannabinoid extract formulations with adjusted non-phytocannabinoid compositions are warranted to develop supplementary antiviral treatments.

Growth hormone-releasing hormone and its analogues in health and disease.

Growth hormone-releasing hormone (GHRH) and its ability to stimulate the production and release of growth hormone from the pituitary were discovered more than four decades ago. Since then, this hormone has been studied extensively and research into its functions is still ongoing. GHRH has multifaceted roles beyond the originally identified functions that encompass a variety of direct extrapituitary effects. In this Review, we illustrate the different biological activities of GHRH, covering the effects of GHRH agonists and antagonists in physiological and pathological contexts, along with the underlying mechanisms. GHRH and GHRH analogues have been implicated in cell growth, wound healing, cell death, inflammation, immune functions, mood disorders, feeding behaviour, neuroprotection, diabetes mellitus and obesity, as well as cardiovascular, lung and neurodegenerative diseases and some cancers. The positive effects observed in preclinical models in vitro and in vivo strongly support the potential use of GHRH agonists and antagonists as clinical therapeutics.

Investigating the Antagonistic Effects of Novel Combination Fungicides against Fusarium oxysporum f. sp. ricini under In-vitro Conditions

Aim: The study aimed to assess the efficacy of nine novel fungicide combinations against Fusarium oxysporum f. sp. ricini, the causal agent of wilt disease in castor. Methodology: The efficacy of fungicides was evaluated using the poisoned food technique under in-vitro conditions. Radial mycelial growth of the pathogen was measured across various concentrations (100 to 1000 ppm) of the fungicide combinations to determine their impact on mycelial inhibition. Results: Results indicated a substantial reduction in radial mycelial growth with increased fungicide concentration. Among the tested fungicides, Tebuconazole + Trifloxystrobin and Prochloraz + Tebuconazole recorded complete mycelial inhibition (100 %) at all the tested concentrations, demonstrating significant fungicidal activity followed by Hexaconazole + Captan with a mean mycelial inhibition of 85.2 %, indicating strong potential for disease management. In contrast, the least mean mycelial inhibition (24.7 %) was observed with Thiophanate methyl + Pyraclostrobin. Conclusion: These findings underscored the importance of selecting effective fungicide combinations to manage F. oxysporum f. sp. ricini, thereby enhancing crop protection and agricultural sustainability.

Integration of metabolomics and transcriptomics to reveal anti-immunosuppression mechanism of Lycium barbarum polysaccharide

It is well documented that immunosuppression in chickens increases the risk of secondary infections and immunodeficiencies, resulting in significant financial setbacks for the poultry sector. It is crucial to determine if Lycium barbarum polysaccharide (LBP) can counteract immune suppression in young chickens, considering its known ability to modulate immune responses. The aim of this study was to investigate the antagonistic effect and mechanism of LBP on immunosuppression in chicks. A total of 200 seven-day-old Hyland Brown laying hens were used to develop an immunosuppression model and to investigate the optimal time of use and optimal dosage of LBP. A further 120 seven-day-old Hyland Brown laying hens were used to investigate the mechanism of antagonism of LBP against immunosuppression at the optimal time and dosage. The results demonstrated that LBP significantly elevated body weight, spleen index, and peripheral lymphocyte transformation rate, and ameliorated pathological spleen damage in immunosuppressed chickens. A total of 178 differential genes were significantly upregulated following LBP intervention, with a significant enrichment in immune-related pathways, including the chemokine signalling pathway, the C-type lectin receptor signalling pathway, the B-cell receptor signalling pathway, platelet activation, natural killer cell-mediated cytotoxicity, and Th1 and Th2 cell differentiation. A total of 20 different metabolites were identified by metabolomics, which were mainly involved in vitamin metabolism, lipid metabolism, nucleic acid metabolism and amino acid metabolism. The integrated examination of transcriptomic and metabolomic data revealed that the glycerophospholipid metabolic pathway stands out as the most significant among all metabolic pathways. The results demonstrated that LBP regulate the immune system in a multi-pathway and multi-target way.

Influence of sleep on seizures and interictal epileptiform discharges in epilepsy.

Sleep significantly influences seizure occurrence and interictal epileptiform discharges (IEDs) in patients with epilepsy. Sleep-related epilepsy, where seizures occur exclusively or predominantly during sleep, has been observed in various epilepsy syndromes. Understanding the influence of sleep on seizures and IEDs is crucial in the diagnosis, classification, and management of epilepsy. Although there is a bidirectional relationship between sleep and epilepsy, this review focuses on the influence of sleep on seizures and IEDs in epilepsy. Seizures are more common during non-rapid eye movement (NREM) sleep, particularly during stage N2, and are suppressed during rapid eye movement (REM) sleep. Sleep also activates IEDs, increasing the diagnostic yield of EEG recordings. The rate of IEDs increases during NREM sleep, reaches its maximum during stage N3, and decreases during REM sleep. Sleep affects the electrical field of IEDs, with an increase of spiking fields during NREM sleep and a decrease during REM sleep. In the localization of epileptogenic foci, REM sleep is less sensitive but more specific than NREM sleep. Thalamocortical EEG synchronization during NREM sleep and desynchronization during REM sleep underlie their opposing effects on seizures and IEDs. Accumulating evidence has suggested an antiseizure effect of orexinergic antagonism in animal studies. Interventions that promote REM sleep, including orexinergic antagonists, should be studied in the future as novel treatment strategies for epilepsy.

Pseudoalteromonas flavipulchra as a dual-functional probiotic for aquaculture: enhancing microalgae growth and antagonizing Vibrio pathogens

Vibrio disease is a prevalent bacterial infection in aquaculture, and using bacteria with antagonistic properties against Vibrio species as probiotics has emerged as a promising method for disease prevention. Additionally, low biomass productivity of microalgae feed remains a significant bottleneck in bivalve aquaculture. Therefore, it is essential to screen for bacteria that both enhance microalgae growth and inhibit Vibrio pathogens. In this study, seven bacterial strains capable of promoting microalgae growth were screened for their ability to inhibit three Vibrio pathogens, i.e., Vibrio vulnificus, Vibrio parahaemolyticus and Vibrio cholerae, and thus serve as a dual-functional probiotic for aquaculture. The antagonistic mechanism of these bacteria was further investigated by analyzing the inhibitory effects of their extracellular products (ECP) on Vibrio species. Results indicated that Pseudoalteromonas flavipulchra exhibited antagonistic effects against all three Vibrio species tested. The ECP of P. flavipulchra displayed stable antibacterial activity, though this ability was lost after the ECP was treated with heat, alkali, or proteinase K. The proteinaceous fraction isolated from the ECP by precipitation with 90% saturated ammonium sulfate demonstrated concentration-dependent antibacterial activity. These findings suggest that P. flavipulchra could serve as a promising dual-functional probiotic for aquaculture, warranting further research to optimize its application in this field.

CXCR4 antagonism ameliorates leukocyte abnormalities in a preclinical model of WHIM syndrome

BackgroundWHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is an ultra-rare, combined primary immunodeficiency and chronic neutropenic disorder characterized by a range of clinical presentations, including peripheral neutropenia, lymphopenia, and recurrent infections. WHIM syndrome is most often caused by gain-of-function mutations in the gene encoding C-X-C chemokine receptor 4 (CXCR4). As such, inhibition of CXCR4 with XOLREMDI® (mavorixafor), an orally bioavailable CXCR4 antagonist, demonstrated clinically meaningful increases in absolute neutrophil and lymphocyte counts and concomitant reduction in infections in patients with WHIM syndrome, resulting in its recent U.S. Food and Drug Administration approval. The impact of CXCR4 antagonism on other aspects of the pathobiology in WHIM syndrome, such as lymphopoiesis and leukocyte trafficking between primary and secondary lymphoid organs, is less understood.MethodsIn the current study, the effects of CXCR4 antagonism on leukocyte trafficking and distribution in primary and secondary lymphoid organs were investigated in a mouse model of WHIM syndrome carrying the heterozygous Cxcr41013 mutation. Cxcr4+/1013 and Cxcr4 wild-type mice received the orally bioavailable CXCR4 antagonist X4-185. Blood, spleen and bone marrow samples were collected for numeration, flow cytometry, and functional studies.ResultsCxcr4+/1013 mice exhibited profound peripheral blood leukopenia as seen in patients with WHIM syndrome. CXCR4 antagonism corrected circulating leukopenia and mobilized functional neutrophils without disrupting granulopoiesis in the bone marrow of Cxcr4+/1013 mice. Furthermore, Cxcr4+/1013 displayed aberrant splenic T and B-cell counts and frequency. Treatment with X4-185 normalized splenic T-cell abnormalities, correcting the reduced CD8+ T-cell numbers, restoring the CD4/CD8 T-cell ratio, and ameliorating peripheral blood T-cell lymphopenia. In addition, CXCR4 antagonism was able to correct the abnormal frequencies and numbers of splenic marginal zone and follicular B cells in Cxcr4+/1013 mice, and ultimately normalize B-cell lymphopenia in the peripheral circulation.ConclusionsOur study provides comprehensive evidence that oral dosing with a CXCR4 antagonist can effectively correct WHIM-associated neutrophil and lymphocyte abnormalities in a mouse model of WHIM syndrome. These findings extend our understanding of how targeting the dysregulated CXCR4 signaling pathway can ameliorate the pathogenesis of WHIM syndrome.

Molecular insights into acetyl triethyl citrate (ATEC) induced toxic effect in HepG2 cells based on multi‐omics integrative analysis

AbstractCitrate esters have become the main alternatives to traditional plasticizers in food packaging materials. However, there is a lack of understanding of their toxic effects, particularly the combined effects and inner mechanisms has not been well studied. Our group pioneered the study on combined toxicity of tributyl citrate (TBC) and acetyl triethyl citrate (ATEC), two commonly co‐used citrate esters in food packaging materials. The results showed that exposure to TBC and ATEC can decrease the viability of HepG2 cells in a dose dependent manner. When the mixtures of ATEC and TBC exposed to HepG2 cells, they exhibited antagonism effect. Therefore, ATEC was selected to investigate the molecular mechanisms with multi‐omics techniques at its 1/4 EC50 concentration. A total of 31 metabolites with significant changes were found as potential biomarkers. The LIPG (Lipase G, endothelial type) and GCLM (glutamate‐cysteine ligase modifier subunit) were identified as differentially expressed genes based on transcriptomic analysis. Moreover, downregulated l‐glutamate and l‐glutamine which participate in TCA cycle, resulting in the collapse of energy production and cytotoxicity. These findings on major metabolic pathways will provide insight into the mechanism of cytotoxicity of HepG2 cells after ATEC exposure.

Antagonistic Effects of Actin-Specific Toxins on Salmonella Typhimurium Invasion into Mammalian Cells

Competition between bacterial species is a major factor shaping microbial communities. It is possible but remains largely unexplored that competition between bacterial pathogens can be mediated through antagonistic effects of bacterial effector proteins on host systems, particularly the actin cytoskeleton. Using Salmonella Typhimurium invasion into cells as a model, we demonstrate that invasion is inhibited if the host actin cytoskeleton is disturbed by actin-specific toxins, namely, Vibrio cholerae MARTX actin crosslinking (ACD) and Rho GTPase inactivation (RID) domains, Photorhabdus luminescens TccC3, and Salmonella’s own SpvB. We noticed that ACD, being an effective inhibitor of tandem G-actin-binding assembly factors, is likely to inhibit the activity of another Vibrio effector, VopF. In reconstituted actin polymerization assays and by live-cell microscopy, we confirmed that ACD potently halted the actin nucleation and pointed-end elongation activities of VopF, revealing competition between these two V. cholerae effectors. These results suggest that bacterial effectors from different species that target the same host machinery or proteins may represent an effective but largely overlooked mechanism of indirect bacterial competition in host-associated microbial communities. Whether the proposed inhibition mechanism involves the actin cytoskeleton or other host cell compartments, such inhibition deserves investigation and may contribute to a documented scarcity of human enteric co-infections by different pathogenic bacteria.

Three New Species and Five New Host Records from Chaetomiaceae with Anti-Phytopathogenic Potential from Cover Crops Astragalus sinicus and Vicia villosa

Cover crops, typically planted during off-seasons and requiring less agronomic manipulation, may provide abundant fungal resources. Certain species of Chaetomiaceae could serve as potential agents for controlling plant diseases and developing bioorganic fertilizers. Eight species from five genera of Chaetomiaceae were identified from healthy Astragalus sinicus and Vicia villosa, two major cover crops, through multigene phylogenetic analysis, morphological identification, and pairwise homoplasy index testing. The identified species comprise three new species: Achaetomium astragali, Subramaniula henanensis, and S. sichuanensis, as well as five known but new host record species: Botryotrichum murorum, Chaetomium coarctatum, C. pseudocochliodes, C. pseudoglobosum, and Collariella pachypodioides. Dual culture tests revealed that isolates of all eight Chaetomiaceae species exhibited antagonistic effects on multiple phytopathogens. Among the identified fungi, the NSJA2 isolate, belonging to C. coarctatum, exhibited significant relative inhibition effects on 14 out of 15 phytopathogens tested in this study, indicating its broad-spectrum antagonistic effects. Additionally, NSJA2 exhibited excellent salt tolerance. Overall, our study has identified multiple fungi with anti-phytopathogens potential, among which NSJA2 exhibits high potential for practical application. This finding paves the way for further exploration and exploitation of NSJA2 as a promising biocontrol agent.

Pharmacological modulation of dopamine receptors reveals distinct brain-wide networks associated with learning and motivation in non-human primates.

D1 and D2 receptors are heavily implicated in cognitive and motivational processes, as well as in a number of psychiatric disorders. Despite this, little is known about how selective manipulation of these different receptors impacts cognition through changing activity across brain-wide intrinsic networks. Here, we examined the acute behavioral and brain-wide effects of D1 and D2 receptor-selective antagonists, SCH-23390 and haloperidol, in macaques performing a probabilistic learning task. SCH administration diminished, and haloperidol improved, animals' task performance. Mirroring these effects on behavior, SCH reduced, and haloperidol increased, the resting-state functional connectivity across brain-wide networks, most notably in the cortico-striatal areas. Thus, our results highlight the opposing effects of D1 and D2 receptor modulation on the brain and behavior.