Antagonistic Effects Research Articles

Pullulan nanoparticles inhibit the pathogenicity of Candida albicans by regulating hypha-related gene expression

ABSTRACT Candida albicans is a prevalent opportunistic pathogenic fungus that resides in the skin and gastrointestinal (GI) tract of humans. Under specific conditions, C. albicans cells transition from a commensal to a pathogenic state, leading to both superficial and invasive infections. Although systemic candidiasis poses a life-threatening risk, a limited number of antifungal drugs are employed for its treatment. Moreover, the emergence of resistant strains to antifungal agents underscores the pressing need for new treatment options. In this study, we propose the use of polysaccharide nanoparticles as a strategy for treating candidiasis. We synthesized phthalic pullulan nanoparticles (PPNPs) and examined their ability to inhibit the pathogenicity of C. albicans . We observed that PPNPs inhibit hyphal growth, adhesion to abiotic surfaces, and biofilm formation of C. albicans in a dose-dependent manner. This inhibitory effect is mediated by transcriptional modulation, particularly the downregulation of hypha-related genes and the upregulation of stress-responsive genes, involving the Ras/cAMP/PKA signaling pathway. Furthermore, we observed that PPNPs inhibit the adhesion of C. albicans to human epithelial cells without inducing toxicity in human cells. In addition, PPNPs inhibited the in vivo pathogenicity of C. albicans in Caenorhabditis elegans , suggesting an antagonistic effect on candidiasis. Our findings suggest that PPNPs exhibit inhibitory effects on C. albicans biofilm formation and in vivo pathogenicity, indicating their potential as a novel therapeutic agent for candidiasis. IMPORTANCE The pathogenic process of Candida albicans , the primary causative species of candidiasis, involves hyphal growth, biofilm formation, and secretion of virulence factors. Of these factors, the biofilm, created by the secretion of extracellular matrix from adherent cells, shields cells from external threats, enabling them to withstand high concentrations of antifungal agents. Therefore, suppressing biofilm formation is a crucial aspect of combating candidiasis. This study developed phthalic pullulan nanoparticles (PPNPs) as a novel material for inhibiting C. albicans ’ pathogenicity. PPNPs were internalized within Candida cells and reduced pathogenicity at the gene expression level, resulting in reduced in vitro biofilm formation, adhesion to human cells, and mortality of infected Caenorhabditis elegans . Moreover, PPNPs exhibited these effects without toxicity to human cells and host animals. These findings not only indicate that PPNPs can be employed to hinder in vitro biofilm formation but also suggest their potential as a novel treatment for candidiasis.

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.

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.

Whole Genome Sequencing and Comparative Genomic Analysis of Pseudomonas aeruginosa SF416, a Potential Broad-Spectrum Biocontrol Agent Against Xanthomonas oryzae pv. oryzae

Rice is one of the most important staple crops worldwide. However, the bacterial blight of rice caused by Xanthomonas oryzae pv. oryzae (Xoo) poses a major threat to the production of rice. In this study, we isolated and identified the strain Pseudomonas aeruginosa SF416, which exhibited significant antagonistic activity against Xoo, from a soil sample collected in a winter wheat field in Shannanzhalang County, Tibet, China. The bacterial solution (BS) and cell-free supernatant (CFS) of SF416 had significant prevention effects for the bacterial blight of rice, with an efficacy of 45.1% and 34.18%, respectively, while they exhibited a slightly lower therapeutic efficiency of 31.64% and 25.09%. The genomic analysis showed that P. aeruginosa SF416 contains genes involved in cell motility, colonization, cold and hot shock proteins, antibiotic resistance, and plant growth promotion. SF416 also harbors two sets of phenazine-1-carboxylic acid (PCA) synthesis gene clusters, phz1 (phzA1-G1) and phz2 (phzA2-G2), and other phenozine product-synthesis--related genes phzS, phzM, and phzH, as well as genes in the SF416 genome that share high similarity with the ones in the genomes of P. aeruginosa M18, suggesting that the two sets of PCA synthesis gene clusters are responsible for the antagonistic effect of SF416 against Xoo. A comparative antiSMASH analysis revealed that P. aeruginosa SF416 contains 17 gene clusters related to secondary metabolite synthesis, 7 of which, encoding for pyochelin, azetidomonamide A/B, L-2-amino-4-methoxy-trans-3-butenoic acid, hydrogen cyanide, pyocyanine, pseudopaline, and bicyclomycin, are conserved in strains of P. aeruginosa. Moreover, SF416 can produce protease and siderophores and display a broad-spectrum antagonistic activity against various major plant pathogenic bacteria and fungi. The results suggest that P. aeruginosa SF416 could be a potential candidate agent for the bacterial blight of rice.

Mitigating Mercury Accumulation and Enhancing Methylmercury Degradation in Rice: Insights from Zinc-Mercury Antagonism at Molecular Levels.

Zn as an essential element has the potential to protect against mercury (Hg) toxicity in rice. However, the antagonistic effects between Zn and Hg in rice and their mechanisms remain unknown. This study proposed a promising strategy for Zn application to mitigate Hg accumulation and toxicity in rice and revealed the underlying molecular mechanisms. The findings revealed that Zn supplementation significantly reduced the uptake and transportation of both IHg and MeHg in rice, thereby alleviating Hg phytotoxicity. In particular, Zn profoundly mitigated Hg-induced oxidative damage to rice, which was attributed to the redistribution of Hg and Zn in the root and Zn competing for binding sites on glutathione. The co-binding of Zn2+ and HgCH3+ within the same active sites of Zn transporters can promote the transfer of regions with a high charge density distribution at the highest occupied molecular orbital (HOMO) level. This process facilitates proton attack on the Hg-C bond, thereby enhancing MeHg demethylation in rice. By elucidating the molecular mechanisms of Zn, IHg, and MeHg interactions in rice, this study offers new insights for developing efficient strategies to mitigate Hg risks while boosting the Zn content in crops, thereby fortifying food safety.

Mineralocorticoid receptor antagonism attenuates arteriovenous fistula stenosis by modulating the phenotype of vascular smooth muscle cells.

Fistula stenosis is a primary contributor to arteriovenous fistula (AVF) failure in maintenance hemodialysis patients. Emerging data indicated excessive fibrotic remodeling was the primarily contributor to fistula stenosis during AVF remodeling. The mineralocorticoid receptor (MR) has been implicated in vascular remodeling across various cardiovascular pathologies. However, its role in AVF remodeling, particularly concerning fibrotic remodeling, remains elusive. MR expression and the phenotypes of vascular smooth muscle cells (VSMCs) were assessed in dysfunctional AVF. The effects of MR on VSMC phenotypic switching were examined in vitro, and the protective effects of MR antagonists on AVF outcome were evaluated in a rat AVF model. Dysfunctional fistula exhibited significant medial fibrosis and extracellular matrix deposition, alongside markedly increased MR activity. In the dysfunctional fistula vessels, VSMC displayed reduced expression of the contractile marker SMMHC and featured characteristic of a synthetic phenotype, including increased osteopontin expression and heightened proliferation. In vitro studies with cultured VSMC revealed that MR overactivity induced by aldosterone led to phenotypic switching from contractile to synthetic state, concomitant with EGFR-ERK1/2 pathway overactivation. These effects were largely abolished by the MR antagonist fineronone. Knockdown of EGFR expression abrogated ERK1/2 phosphorylation and inhibited the VSMC phenotypic switching. Conversely, ectopic overexpression of EGFR in VSMC diminished the protective effect of finerenone. In rat AVF models, pharmacologic targeting of MR with finerenone significantly improved AVF outcomes, characterized by increased luminal diameters and flow volume, reduced medial fibrosis, and inhibited VSMC phenotypic switching. These beneficial outcomes were likely attributable to a restrained activity of EGFR-ERK1/2 pathway in VSMC and elevated NO production in endothelial cells. Our study demonstrated that therapeutic targeting of MR may improve AVF outcome by modulating VSMC phenotypic switching. These findings offer promising avenues for further clinical investigations aimed at optimizing AVF outcomes in the hemodialysis population.

Metformin Impairs Linsitinib Anti-Tumor Effect on Ovarian Cancer Cell Lines

Ovarian cancer (OC) remains one of the leading causes of cancer-related mortality among women. Targeting the insulin-like growth factor 1 (IGF-1) signaling pathway has emerged as a promising therapeutic strategy. Linsitinib, an IGF-1 receptor (IGF-1R) inhibitor, has shown potential in disrupting this pathway. Additionally, metformin, commonly used in the treatment of type 2 diabetes, has been studied for its anti-cancer properties due to its ability to inhibit metabolic pathways that intersect with IGF-1 signaling, making it a candidate for combination therapy in cancer treatments. This study explores the anti-cancer effects of linsitinib and metformin on OVCAR3 cells by the suppression of the IGF-1 signaling pathway by siRNA-mediated IGF-1 gene silencing. The goal is to evaluate their efficacy as therapeutic agents and to emphasize the critical role of this pathway in OC cell proliferation. Cellular viability was evaluated by resazurin-based assay, and apoptosis was assessed by flux cytometry. The results of this study indicate that the combination of linsitinib and metformin exhibits an antagonistic effect (obtained by SynergyFinder 2.0 Software), reducing their anti-neoplastic efficacy in OC cell lines. Statistical analyses were performed using ordinary one-way or two-way ANOVA, followed by Tukey’s or Šídák’s multiple comparison tests. While linsitinib shows promise as a therapeutic option for OC, further research is needed to identify agents that could synergize with it to enhance its therapeutic efficacy, like the combination with standard chemotherapy in OC (carboplatin and paclitaxel).

Complementary Treatment of Breast Cancer Cells with Different Metastatic Potential with Iscador Qu in the Presence of Clinically Approved Anticancer Drugs

European mistletoe extract (Iscador Qu) has been studied for decades, but it has not ceased to arouse scientific interest. The purpose was to investigate the impact of Iscador Qu on the antiproliferative potential of 11 standard chemotherapeutic agents on two breast cancer cell lines: MCF-7 low-metastatic and MDA-MB-231 high-metastatic and control cell lines (MCF-10A). MTT-dye reduction assay, FACS analysis, and PI staining were utilized. The most promising combinations acting against the MDA-MB-231 cell line were observed upon the simultaneous application of Iscador Qu (80 µg/mL) and Docetaxel, with 4-fold reduction in IC50. An antagonistic effect was found under treatment with Cisplatin and Iscador Qu (1.5-fold increase in IC50). The response of the low-metastatic breast cancer cell line MCF-7 to the tested combinations was different compared to the high-metastatic one. The most pronounced cytotoxic effect was found for the combination of Oxaliplatin and Iscador Qu (20 µg/mL) (5.2-fold IC50 reduction). An antagonistic effect for MCF-7 line was also observed when combinations with Olaparib and Tamoxifen were applied. This in vitro study offers new combinations between Iscador Qu and standard chemotherapeutic agents that hold great promise in establishing breast cancer therapeutic protocols compared to traditional monotherapies.

MiR-301b-3p promotes breast cancer development through inhibiting the expression of transforming growth factor-beta receptor 2

Background Breast cancer (BC) is a serious health threat to the patients. The present work explored the mechanism of miR-301b-3p and transforming growth factor-beta receptor 2 (TGFBR2 ) in affecting BC progression. Methods The miR-301b-3p-inhibitor and si-TGFBR2 solution were added to the DEME/F12 medium to culture the BC and normal breast epithelial cell lines to prepare negative control, miR-301b-3p-IN and miR-301b-3p-IN+si-TGFBR2 in the two types of cell lines. The relative expression of target genes and the interference effect were analyzed by quantitative real-time PCR (qRT- PCR). Cell viability was detected applying cell counting kit-8 (CCK-8) assay. Transwell and wound healing assay were conducted to evaluate the invasion and migration of BC cells after miR-301b-3p inhibition. Additionally, cell apoptosis and the expression STAT protein were measured by flow cytometry and Western blot, respectively Results The qRT-PCR results showed that miR-301b-3p were high-expressed but the level of TGFBR2 was significantly inhibited in BC cells. The miR-301b-3p-inhibitor significantly downregulated the expression of miR-301b-3p and upregulated that of TGFBR2. Meanwhile, inhibition of miR-301b-3p suppressed the cell viability, invasion, and migration of BC cells, which, however, were restored by the inhibition of TGFBR2. MiR-301b-3p conferred anti-apoptosis ability to BC cells, while TGFBR2 promoted apoptosis of BC cells through producing an antagonistic effect with miR-301b-3p. We found that miR-301b-3p played a crucial role in the phosphorylation of STAT1 and STAT3 to promote BC progression. Conclusion The present findings demonstrated that miR-301b-3p played a crucial role in promoting BC cell growth, invasion and migration and anti-apoptosis, and that targeting TGFBR2 could inhibit the tumor-promoting effect of miR-301b-3p.

Community-level trophic characteristics and interactions between native and non-native fish: The example of the Lower Pearl River Basin of China

Aquatic ecosystems can harbour more than one non-native fish species and this can represent a threat due to trophic interactions with native fishes. However, research on interactions amongst multiple co-occurring native and non-native fish remains scarce. In this study, 551 organisms from 44 native fish, 11 non-native fish, 35 macroinvertebrates (of which one was non-native), together with 162 samples of basal resources were collected from six rivers of the Lower Pearl River Basin of China. Nitrogen and carbon stable isotope analysis was used to calculate community-wide trophic metrics and the degree of trophic overlap between native and non-native fish at both the community and functional feeding group level, together with diet composition. At the community level, there was a high degree of trophic niche overlap between native and non-native fish as a result of similarities in trophic characteristics. At the functional feeding group level, both native and non-native functional feeding groups demonstrated the capacity to occupy the niche space of each other. A significant trophic niche overlap, exceeding 50%, was found between non-native detritivorous and omnivorous fish, suggesting competition. The difference in diet composition between some native and non-native fish depended on the category of diet source across the rivers, suggesting dietary segregation. Albeit limited, the present findings suggest that trophic interaction between native and non-native fish is likely to reach a dynamic equilibrium status in the community owing to trophic segregation of fish species and the antagonistic effects amongst non-native fish.

Targeting the NLRP3 inflammasome-IL-1β pathway in type 2 diabetes and obesity.

Increased activity of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome-IL-1β pathway is observed in obesity and contributes to the development of type 2 diabetes and its complications. In this review, we describe the pathological activation of IL-1β by metabolic stress, ageing and the microbiome and present data on the role of IL-1β in metabolism. We explore the physiological role of the IL-1β pathway in insulin secretion and the relationship between circulating levels of IL-1β and the development of diabetes and associated diseases. We highlight the paradoxical nature of IL-1β as both a friend and a foe in glucose regulation and provide details on clinical translation, including the glucose-lowering effects of IL-1 antagonism and its impact on disease modification. We also discuss the potential role of IL-1β in obesity, Alzheimer's disease, fatigue, gonadal dysfunction and related disorders such as rheumatoid arthritis and gout. Finally, we address the safety of NLRP3 inhibition and IL-1 antagonists and the prospect of using this therapeutic approach for the treatment of type 2 diabetes and its comorbidities.

Isolation, identification, characterization and in vitro assay of saline tolerant endophytes against groundnut root rot caused by Rhizoctonia bataticola (Taub.) Butler

Groundnut, known as Arachis hypogaea L., is India's significant oil seed crop. Dry root rot, caused by Rhizoctonia bataticola, poses a substantial challenge to cultivating groundnuts. During the roving survey, 60.50% dry root rot disease incidence was recorded in Namakkal district, Tamil Nadu. This study aims to acquire salt-tolerant endophytic bacteria residing in groundnuts with significant antagonistic activity against R. bataticola. A total of 27 bacterial strains were isolated from groundnuts. Among these strains, RMV 3 and RMV 2 are the most effective isolates, exhibiting 60.1% and 50% inhibition zones, respectively. The effective isolates were characterized through morphological, biochemical and phytostimulation activities and 16S rDNA sequencing. Among the isolates, RMV 3 and RMV 2 showed positive results for siderophore, indole acetic acid (IAA) and cellulase test. The strain RMV 3 was identified as Bacillus subtilis through 16S rDNA sequencing. GC-MS analysis identified twenty bioactive compounds produced by B. subtilis RMV 3, such as pyrrolo [12-a] pyrazine-14-dione hexahydro-3 (2-methylpropyl) and hexadecanoic acid methyl ester. The crude metabolite assay demonstrated a 96.6% inhibition of R. bataticola by RMV 3. This study demonstrated that Bacillus subtilis RMV 3, which exhibits a robust antagonistic effect on R. bataticola, can potentially be an effective biocontrol agent for groundnut dry root rot.

Cysteine Leukotriene Receptor Antagonist-Montelukast Effects on Diabetic Retinal Microvascular Endothelial Cells Curtail Autophagy.

Diabetic macular edema (DME) is the primary cause of vision impairment in diabetic retinopathy (DR) patients. A previous study has shown the efficacy of montelukast, a cysteinyl leukotriene receptor (CysLTR)1 antagonist, in a diabetic mouse model. This study aims to understand the CysLTR1 signaling in retinal endothelial cells and the impact of montelukast. Primary human retinal microvascular endothelial cells (HRECs) challenged with 20 ng/mL TNF-α and 30mM D-glucose (D-glu) for six to 24 hours served as a model of endothelial activation. HRECs were incubated with L-glucose (L-glu) as an osmotic control. CysLTR1 knockdown and montelukast pretreatment assessed CysLTR1 antagonism. Gene expression, protein expression, and cell-permeable dyes were utilized to measure autophagy and inflammation. Transendothelial electrical resistance (TER) and transendothelial migration of mononuclear leukocytes across HRECs monolayer were measured as a functional assessment of vascular permeability. Endothelial activation induced by hyperglycemia and inflammation increased CysLTR1 expression, triggering autophagy within two to six hours, IL-1β production, loss of junction integrity, decreased TER, and increased leukocyte migration within six to 24 hours. Pretreatment with montelukast effectively alleviated these effects, demonstrating its dependence on CysLTR1. Dysfunctional retinal endothelium initiates a self-reinforcing loop of inflammation, autophagy, and compromised integrity associated with heightened CysLTR1 levels. The antagonistic effect of montelukast against CysLTR1 effectively mitigates these detrimental changes. This study reveals CysLTR1 as a potential therapeutic target in treating DME and offers a novel strategy to mitigate detrimental changes in DR.

Hierarchical regulation of functionally antagonistic neuropeptides expressed in a single neuron pair

Neuronal communication involves small-molecule transmitters, gap junctions, and neuropeptides. While neurons often express multiple neuropeptides, our understanding of the coordination of their actions and their mutual interactions remains limited. Here, we demonstrate that two neuropeptides, NLP-10 and FLP-1, released from the same interneuron pair, AVKL/R, exert antagonistic effects on locomotion speed in Caenorhabditis elegans. NLP-10 accelerates locomotion by activating the G protein-coupled receptor NPR-35 on premotor interneurons that promote forward movement. Notably, we establish that NLP-10 is crucial for the aversive response to mechanical and noxious light stimuli. Conversely, AVK-derived FLP-1 slows down locomotion by suppressing the secretion of NLP-10 from AVK, through autocrine feedback via activation of its receptor DMSR-7 in AVK neurons. Our findings suggest that peptidergic autocrine motifs, exemplified by the interaction between NLP-10 and FLP-1, might represent a widespread mechanism in nervous systems across species. These mutual functional interactions among peptidergic co-transmitters could fine-tune brain activity.

Quantitative summary on the human pharmacokinetic properties of cannabidiol to accelerate scientific clinical application of cannabis.

Cannabidiol (CBD) is a non-psychoactive substance that exerts numerous pharmacological benefits, including anti-inflammatory and antioxidant properties. It has received attention as a useful substance for the treatment of intractable pain, seizures, and anxiety, and related clinical trials have continued. However, the CBD pharmacokinetic results between reports are highly variable, making it difficult to clearly identify the pharmacokinetic properties of CBD. The main purpose of this study was to identify CBD clinical pharmacokinetic properties through meta-analysis. In particular, we sought to derive valid, interpretable independent variables and interpret their pharmacokinetic parameter correlations in relation to the large inter-individual and inter-study variability in CBD pharmacokinetics. For this study, CBD-related clinical trial reports were extensively screened and intercomparisons were performed between internal data sets through systematic classification and extraction of pharmacokinetic parameter values. The candidate independent variables associated with interpretation of CBD pharmacokinetic diversity established and explored in this study were as follows: diet, tetrahydrocannabinol (THC) combination, sample matrix type, liver and renal function, exposure route, dosage form, CBD exposure dose, cannabis smoking frequency, multiple exposure. The results of this study showed that CBD pharmacokinetics were influenced (increased plasma exposure by approximately 2-5 times) by diet immediately before or during CBD exposure, and that THC was not expected to have an antagonistic effect on the CBD absorption. The influence of changes in liver function would be significant in CBD pharmacokinetic diversity. Due to decreased liver function, the plasma exposure of CBD increased 2.57-5.15 times compared to healthy adults, and the half-life and clearance showed a 2.58-fold increase and a 5.15-fold decrease, respectively. CBD can be rapidly absorbed into the body (time to reach maximum concentration within 3.18h) by oral, transdermal, and inhalation exposures, and lipid emulsification and nanoformulation of CBD will greatly improve CBD bioavailability (up to approximately 2 times). The pharmacokinetics of CBD generally follow linear kinetic characteristics. The importance of this study is that it suggests key factors that should be considered in terms of pharmacokinetics in further clinical trials and formulations of CBD in the future.