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Keywords = antagonism tests

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22 pages, 4669 KiB  
Article
Metabolomic Insights into the Antimicrobial Effects of Metschnikowia Yeast on Phytopathogens
by Zofia Perek, Sumi Krupa, Joanna Nizioł, Dorota Kręgiel, Tomasz Ruman and Beata Gutarowska
Molecules 2025, 30(15), 3268; https://doi.org/10.3390/molecules30153268 - 4 Aug 2025
Abstract
One of the most important features of Metschnikowia pulcherrima is its strong antimicrobial activity against phytopathogens, which makes it a suitable candidate for use in biocontrol during crop cultivation. However, the mechanisms of its antimicrobial activity are not currently well understood. In this [...] Read more.
One of the most important features of Metschnikowia pulcherrima is its strong antimicrobial activity against phytopathogens, which makes it a suitable candidate for use in biocontrol during crop cultivation. However, the mechanisms of its antimicrobial activity are not currently well understood. In this study, we used metabolomic methods to investigate the possible mechanisms of antimicrobial activity by M. pulcherrima against phytopathogenic fungi. First, we tested the antimicrobial activity of five selected isolates against eleven phytopathogenic molds. Based on the results, selected yeast–pathogen co-cultures were cultivated on liquid and solid media. The supernatants from the liquid co-cultures were analyzed using the UHPLC-QToF-UHRMS and MS/MS methods. Co-culture growth on solid agar media was examined using the LARAPPI/CI MSI method. The yeast exhibited strong antagonism toward the mold phytopathogens. The LARAPPI/CI MSI method revealed the presence of various compounds with potential antifungal activity. The complex UHPLC-QToF-UHRMS analysis confirmed that the metabolic response of M. pulcherrima depends on specific yeast–pathogen interactions. Full article
(This article belongs to the Section Natural Products Chemistry)
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17 pages, 1747 KiB  
Article
Rasagiline Inhibits Human Melanoma Cell Viability and Interacts Synergistically with Mitoxantrone and Antagonistically with Cisplatin—In Vitro Isobolographic Studies
by Danuta Krasowska, Paula Wróblewska-Łuczka, Michał Chojnacki, Katarzyna Załuska-Ogryzek, Jacek Kurzepa and Jarogniew J. Łuszczki
Cancers 2025, 17(15), 2563; https://doi.org/10.3390/cancers17152563 - 3 Aug 2025
Viewed by 58
Abstract
Background: The increased incidence of malignant melanoma is observed in patients with Parkinson’s disease. Methods: The anti-proliferative effects of carbidopa and rasagiline on four human malignant melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were determined in MTT assay. The interaction profiles of [...] Read more.
Background: The increased incidence of malignant melanoma is observed in patients with Parkinson’s disease. Methods: The anti-proliferative effects of carbidopa and rasagiline on four human malignant melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were determined in MTT assay. The interaction profiles of rasagiline in combinations with cisplatin (CDDP) and mitoxantrone (MTX) in four human melanoma cell lines (A375, SK-MEL28, FM55P and FM55M2) were assessed by means of the isobolographic analysis in the MTT test; Results: Rasagiline, but not carbidopa, produced clear-cut anti-proliferative effects on various melanoma cell lines. The median inhibitory concentrations (IC50 values) of rasagiline in the MTT were 280.69 µM for A375, 402.89 µM for SK-MEL28, 349.44 µM for FM55P, and 117.45 µM for FM55M2, respectively. The experimentally-derived selectivity index for rasagiline ranged from 8.22 to 28.18. Flow cytometry assay revealed, in two melanoma cell lines (FM55P and A375), a significant increase in the number of cells in the G0/G1 (up to 76.48% and 75.46% for cell lines, respectively), accompanied by a decrease in the percentage of cells in the S phase (decrease to 9.91% and 10.83% for cell lines, respectively), which may indicate potential cytostatic properties of rasagiline. The combinations of rasagiline with CDDP (at the fixed-ratio of 1:1) exerted either antagonistic interactions (p < 0.05) in the A375 and SK-MEL28, or additive interactions, with a tendency toward antagonism in the FM55P and FM55M2 cell lines in the MTT test. In contrast, the combinations of rasagiline with MTX (ratio of 1:1) produced either synergistic interaction (p < 0.05) in the FM55P cell line or additive interactions with a tendency toward synergy in the FM55M2, SK-MEL28, and A375 cell lines in the MTT test. Conclusions: Rasagiline combined with MTX exerted the most desirable synergistic interactions in relation to the anti-proliferative effects in four malignant melanoma cell lines, as assessed isobolographically. In contrast, rasagiline should not be combined with CDDP during the treatment of malignant melanoma due to the antagonistic interactions in the MTT assay. Full article
(This article belongs to the Special Issue Research on New Drugs and Drug Targets in Melanoma)
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16 pages, 3286 KiB  
Article
Poxvirus K3 Orthologs Regulate NF-κB-Dependent Inflammatory Responses by Targeting the PKR–eIF2α Axis in Multiple Species
by Huibin Yu, Mary Eloise L. Fernandez, Chen Peng, Dewi Megawati, Greg Brennan, Loubna Tazi and Stefan Rothenburg
Vaccines 2025, 13(8), 800; https://doi.org/10.3390/vaccines13080800 - 28 Jul 2025
Viewed by 287
Abstract
Background: Protein kinase R (PKR) inhibits general mRNA translation by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). PKR also modulates NF-κB signaling during viral infections, but comparative studies of PKR-mediated NF-κB responses across mammalian species and their regulation by [...] Read more.
Background: Protein kinase R (PKR) inhibits general mRNA translation by phosphorylating the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). PKR also modulates NF-κB signaling during viral infections, but comparative studies of PKR-mediated NF-κB responses across mammalian species and their regulation by viral inhibitors remain largely unexplored. This study aimed to characterize the conserved antiviral and inflammatory roles of mammalian PKR orthologs and investigate their modulation by poxviral inhibitors. Methods: Using reporter gene assays and quantitative RT-PCR, we assessed the impact of 17 mammalian PKR orthologs on general translation inhibition, stress-responsive translation, and NF-κB-dependent induction of target genes. Congenic human and rabbit cell lines infected with a myxoma virus strain lacking PKR inhibitors were used to compare the effects of human and rabbit PKR on viral replication and inflammatory responses. Site-directed mutagenesis was employed to determine key residues responsible for differential sensitivity to the viral inhibitor M156. Results: All 17 mammalian PKR orthologs significantly inhibited general translation, strongly activated stress-responsive ATF4 translation, and robustly induced NF-κB target genes. Inhibition of these responses was specifically mediated by poxviral K3 orthologs that effectively suppressed PKR activation. Comparative analyses showed human and rabbit PKRs similarly inhibited virus replication and induced cytokine transcripts. Amino acid swaps between rabbit PKRs reversed their sensitivity to viral inhibitor M156 and NF-κB activation. Conclusions: Our data show that the tested PKR orthologs exhibit conserved dual antiviral and inflammatory regulatory roles, which can be antagonized by poxviral K3 orthologs that exploit eIF2α mimicry to modulate the PKR-NF-κB axis. Full article
(This article belongs to the Special Issue Antiviral Immunity and Vaccine Development)
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24 pages, 2289 KiB  
Article
Use of Volatile Organic Compounds Produced by Bacillus Bacteria for the Biological Control of Fusarium oxysporum
by Marcin Stocki, Natalia Stocka, Piotr Borowik, Marzenna Dudzińska, Amelia Staszowska, Adam Okorski and Tomasz Oszako
Forests 2025, 16(8), 1220; https://doi.org/10.3390/f16081220 - 24 Jul 2025
Viewed by 314
Abstract
Restricting the use of chemical pesticides in forestry requires the search for alternative solutions. These could be volatile organic compounds produced by three investigated species of bacteria (Bacillus amyloliquefaciens (ex Fukumoto) Priest, B. subtilis (Ehrenberg) Cohn and B. thuringiensis Berliner), which inhibit [...] Read more.
Restricting the use of chemical pesticides in forestry requires the search for alternative solutions. These could be volatile organic compounds produced by three investigated species of bacteria (Bacillus amyloliquefaciens (ex Fukumoto) Priest, B. subtilis (Ehrenberg) Cohn and B. thuringiensis Berliner), which inhibit the growth of the pathogen F. oxysporum Schltdl. emend. Snyder & Hansen in forest nurseries. The highest inhibition of fungal growth (70%) was observed with B. amyloliquefaciens after 24 h of antagonism test, which had a higher content of carbonyl compounds (46.83 ± 8.41%) than B. subtilis (41.50 ± 6.45%) or B. thuringiensis (34.62 ± 4.77%). Only in the volatile emissions of B. amyloliquefaciens were 3-hydroxybutan-2-one, undecan-2-one, dodecan-5-one and tetradecan-5-one found. In contrast, the main components of the volatile emissions of F. oxysporum were chlorinated derivatives of benzaldehyde (e.g., 3,5-dichloro-4-methoxybenzaldehyde) and chlorinated derivatives of benzene (e.g., 1,4-dichloro-2,5-dimethoxybenzene), as well as carbonyl compounds (e.g., benzaldehyde) and alcohols (e.g., benzyl alcohol). Further compounds were found in the interactions between B. amyloliquefaciens and F. oxysporum (e.g., α-cubebene, linalool, undecan-2-ol, decan-2-one and 2,6-dichloroanisole). Specific substances were found for B. amyloliquefaciens (limonene, nonan-2-ol, phenethyl alcohol, heptan-2-one and tridecan-2-one) and for F. oxysporum (propan-1-ol, propan-2-ol, heptan-2-one and tridecan-2-one). The amounts of volatile chemical compounds found in B. amyloliquefaciens or in the bacterium–fungus interaction can be used for further research to limit the pathogenic fungus. In the future, one should focus on the compounds that were found exclusively in interactions and whose content was higher than in isolated bacteria. In order to conquer an ecological niche, bacteria increase the production of secondary metabolites, including specific chemical compounds. The results presented are a prerequisite for creating an alternative solution or supplementing the currently used methods of plant protection against F. oxysporum. Understanding and applying the volatile organic compounds produced by bacteria can complement chemical plant protection against the pathogen, especially in greenhouses or tunnels where plants grow in conditions that favour fungal growth. Full article
(This article belongs to the Special Issue Advances in Forest Tree Seedling Cultivation Technology—2nd Edition)
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13 pages, 4340 KiB  
Article
Synergistic and Antagonistic Mechanisms of Arctium lappa L. Polyphenols on Human Neutrophil Elastase Inhibition: Insights from Molecular Docking and Enzymatic Kinetics
by Yixun Sun, Mingbo Zhang, Yating Zhang, Yu Zheng, Jing Li, Qian Cai, Anqi Wang and Yang Qu
Molecules 2025, 30(13), 2764; https://doi.org/10.3390/molecules30132764 - 27 Jun 2025
Viewed by 349
Abstract
This study systematically investigated the inhibitory mechanism of Arctium lappa L. polyphenols (ALP) against human neutrophil elastase (HNE). Molecular docking techniques were employed to predict the binding patterns and inhibition types between polyphenolic components and HNE, complemented by in vitro enzymatic tests to [...] Read more.
This study systematically investigated the inhibitory mechanism of Arctium lappa L. polyphenols (ALP) against human neutrophil elastase (HNE). Molecular docking techniques were employed to predict the binding patterns and inhibition types between polyphenolic components and HNE, complemented by in vitro enzymatic tests to validate inhibitory efficacy. Combination index (CI) analysis was applied to evaluate synergistic effects. Through preliminary in vitro screening, chlorogenic acid, quercetin, and isochlorogenic acid A were identified as key bioactive constituents. Experimental results demonstrated that the half-inhibitory concentration (IC50) of individual compounds against HNE ranged from 46.4 to 203.3 μM, while ALP extract exhibited dose-dependent inhibition (IC50 = 0.99 mg/mL). Drug combination ratios based on individual IC50 values revealed synergistic effects (CI < 1) in chlorogenic acid-quercetin and isochlorogenic acid A-quercetin combinations, whereas antagonism (CI > 1) was observed in chlorogenic acid-isochlorogenic acid A pairs. The molecular docking results predicted that chlorogenic acid and isochlorogenic acid A competitively occupy the same binding site of the target protein (HNE) to exert inhibitory effects, thereby explaining the antagonism produced by their combination. In contrast, quercetin may inhibit HNE with a binding site different from that of chlorogenic acid or isochlorogenic acid A, which accounts for the observed synergistic effects. This study provides the first systematic elucidation of synergistic mechanisms of ALP as natural HNE inhibitors, providing theoretical foundations for developing novel natural HNE inhibitors with potential applications in acute lung injury, COVID-19-associated inflammatory conditions, and chronic inflammatory diseases. Full article
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17 pages, 1278 KiB  
Article
Antimalarial Drug Repurposing of Epirubicin and Pelitinib in Combination with Artemether and Lumefantrine
by Douglas O. Ochora, Reagan M. Mogire, Bernard M. Murithi, Farid Abdi, Erick N. Ondari, Rael J. Masai, Edwin Mwakio, Agnes Cheruyiot, Abiy Yenesew and Hoseah M. Akala
Pharmaceuticals 2025, 18(7), 956; https://doi.org/10.3390/ph18070956 - 25 Jun 2025
Viewed by 394
Abstract
Background: Drug therapy remains the principal management strategy for malaria but is increasingly challenged by the emergence of drug-resistant malaria parasites. The need for new antimalarial drugs is urgent, yet drug discovery and development are hindered by high costs, long durations, and safety [...] Read more.
Background: Drug therapy remains the principal management strategy for malaria but is increasingly challenged by the emergence of drug-resistant malaria parasites. The need for new antimalarial drugs is urgent, yet drug discovery and development are hindered by high costs, long durations, and safety concerns that prevent approval. The current study aimed to determine antiplasmodial activities of approved drugs in combination with artemether (ART) and lumefantrine (LU). Methods: Using the SYBR Green I assay test, this study investigated the efficacy of epirubicin (EPI) and pelitinib (PEL) combined with ART and LU at fixed drug–drug ratios (4:1, 3:1, 1:1, 1:2, 1:3 and 1:4) and volume/volume. These combinations, as well as single drug treatments, were tested against cultured strains of Plasmodium falciparum (W2, DD2, D6, 3D7 and F32-ART) and fresh and cultured clinical isolates. The fifty percent inhibition concentration (IC50) and a mean sum of fifty percent fractional inhibition concentration (FIC50) were determined. Results: Synergism was observed when EPI was combined with both ART and LU across all fixed ratios with a mean of mean FIC50 values of <0.6. The combination of LU and EPI against the 3D7 strain demonstrated the highest efficacy with a synergism FIC50 value of 0.18. Most combinations of PEL with ART and LU showed antagonism (FIC50 > 1) when tested against strains of P. falciparum and clinical isolates. Conclusions: This study underscores the utility of alternative drug discovery and development strategies to bypass cost, time, and safety barriers, thereby enriching the antimalarial drug pipeline and accelerating the transition from lab to market. Full article
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13 pages, 1966 KiB  
Article
In Vitro Evaluation of Antimicrobial Synergy Against Multidrug-Resistant Gram-Negative Paediatric Bloodstream Pathogens in South Africa
by Prenika Jaglal, Sithembiso Christopher Velaphi, Colin Nigel Menezes and Khine Swe Swe-Han
Antibiotics 2025, 14(7), 630; https://doi.org/10.3390/antibiotics14070630 - 20 Jun 2025
Viewed by 350
Abstract
Background: In vitro synergy testing (ST) is a useful means to gauge the performance ofantibiotic combinations against multidrug-resistant (MDR) Gram-negative bacteria (GNB). This study aimed to determine synergy of antibiotics against paediatric bloodstream (BS) carbapenem-resistant Enterobacterales (CRE) and extremely drug-resistant (XDR) Acinetobacter [...] Read more.
Background: In vitro synergy testing (ST) is a useful means to gauge the performance ofantibiotic combinations against multidrug-resistant (MDR) Gram-negative bacteria (GNB). This study aimed to determine synergy of antibiotics against paediatric bloodstream (BS) carbapenem-resistant Enterobacterales (CRE) and extremely drug-resistant (XDR) Acinetobacter species. Methods: This cross-sectional study was conducted at a public tertiary hospital in South Africa, from January 2023 to December 2023. Sixty-eight isolates from children with bloodstream infections (BSI), comprising 55.9% (38/68) CRE and 44.1% (30/68) XDR Acinetobacter species, were performed ST using the fixed-ratio Epsilometer-test method. Combinations of colistin and meropenem, colistin and fosfomycin, colistin and tigecycline, meropenem and fosfomycin, meropenem and tigecycline, and fosfomycin and tigecycline were tested. Results: In vitro synergy for CRE was best demonstrated with tigecycline and meropenem, at 92.1% (35/38), and fosfomycin and meropenem at 73.7% (28/38). Among the XDR Acinetobacter species, the highest rates of synergy of 76.7% (23/30) were observed with tigecycline and meropenem. The absence of synergy was noted with colistin and meropenem for the CRE, with many displaying indifference and antagonism at rates of 65.8% and 22%. Most XDR Acinetobacter species (56.7%; 17/30) expressed indifference to colistin and meropenem with synergy and antagonism displayed in 23.3% and 10% of isolates. Conclusions: This study highlights tigecycline and meropenem displaying impressive in vitro synergy when compared to the in-use colistin and meropenem for CRE and XDR Acinetobacter species. Tigecycline and meropenem may be a viable salvage therapeutic option for MDR Gram-negative paediatric infections. Future research is warranted to confirm in vivo synergy clinically. Full article
(This article belongs to the Special Issue Combination Therapy against Multidrug-Resistant Pathogens)
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21 pages, 4042 KiB  
Article
Screening, Identification, and Application of Superior Starter Cultures for Fermented Sausage Production from Traditional Meat Products
by Zijie Dong, Longfei Wang, Yanzheng Ge, Yongqiang An, Xiaoxue Sun, Ke Xue, Haoyang Xie, Ran Wang, Junguang Li and Lishui Chen
Fermentation 2025, 11(6), 306; https://doi.org/10.3390/fermentation11060306 - 27 May 2025
Viewed by 677
Abstract
In this study, 43 strains of Staphylococcus spp. and 22 strains of lactic acid bacteria (LAB), isolated from six representative fermented meat products (domestic and international), were subjected to a comprehensive safety evaluation, including hemolytic activity, catalase test, hydrogen sulfide production, and antibiotic [...] Read more.
In this study, 43 strains of Staphylococcus spp. and 22 strains of lactic acid bacteria (LAB), isolated from six representative fermented meat products (domestic and international), were subjected to a comprehensive safety evaluation, including hemolytic activity, catalase test, hydrogen sulfide production, and antibiotic susceptibility screening. Nine strains were selected for secondary screening based on safety criteria, fermentation characteristics, and acid and salt tolerance tests. Two optimal strains were identified—Staphylococcus saprophyticus LH-5 and Latilactobacillus sakei OFN-11—demonstrating excellent compatibility and no mutual antagonism. Both strains were non hemolytic, catalase positive, susceptible to some of the antibiotic tested, and did not produce hydrogen sulfide, mucus, or gas. These favorable fermentation characteristics included lipase/protease production, amino acid decarboxylase negativity, and salt and acid tolerance. Application experiments in fermented sausages were analyzed for 55 volatile compounds, related to meaty, fruity, and fatty aroma profiles compared to commercial starter cultures. The formulation including the selected strains exhibited lower acidity than its commercial unterparts while maintaining superior sensory and physicochemical attributes. These findings suggest that the S. saprophyticus LH-5 and L. sakei OFN-11 consortium holds promising potential as a starter culture for fermented meat products, offering technological advantages to become a fermentation agent that meets the preferences of Chinese consumers. Full article
(This article belongs to the Section Fermentation for Food and Beverages)
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21 pages, 1766 KiB  
Article
MvfR Shapes Pseudomonas aeruginosa Interactions in Polymicrobial Contexts: Implications for Targeted Quorum-Sensing Inhibition
by Kelsey M. Wheeler, Myung Whan Oh, Julianna Fusco, Aishlinn Mershon, Erin Kim, Antonia De Oliveira and Laurence G. Rahme
Cells 2025, 14(10), 744; https://doi.org/10.3390/cells14100744 - 20 May 2025
Viewed by 901
Abstract
Infections often occur in complex niches consisting of multiple bacteria. Despite the increasing awareness, there is a fundamental gap in understanding which interactions govern microbial community composition. Pseudomonas aeruginosa is frequently isolated from monomicrobial and polymicrobial human infections. This pathogen forms polymicrobial infections [...] Read more.
Infections often occur in complex niches consisting of multiple bacteria. Despite the increasing awareness, there is a fundamental gap in understanding which interactions govern microbial community composition. Pseudomonas aeruginosa is frequently isolated from monomicrobial and polymicrobial human infections. This pathogen forms polymicrobial infections with other ESKAPEE pathogens and defies eradication by conventional therapies. By analyzing the competition within co-cultures of P. aeruginosa and representative secondary pathogens that commonly co-infect patients, we demonstrate the antagonism of P. aeruginosa against other ESKAPEE pathogens and the contribution of this pathogen’s multiple quorum-sensing (QS) systems in these interactions. QS is a highly conserved bacterial cell-to-cell communication mechanism that coordinates collective gene expressions at the population level, and it is also involved in P. aeruginosa virulence. Using a collection of P. aeruginosa QS mutants of the three major systems, LasR/LasI, MvfR/PqsABCDE, and RhlR/RhlI, and mutants of several QS-regulated functions, we reveal that MvfR and, to a lesser extent, LasR and RhlR, control competition between P. aeruginosa and other microbes, possibly through their positive impact on pyoverdine, pyochelin, and phenazine genes. We show that MvfR inhibition alters competitive interspecies interactions and preserves the coexistence of P. aeruginosa with the ESKAPEE pathogens tested while disarming the pathogens’ ability to form biofilm and adhere to lung epithelial cells. Our results highlight the role of MvfR inhibition in modulating microbial competitive interactions across multiple species, while simultaneously attenuating virulence traits. These findings reveal the complexity and importance of QS in interspecies interactions and underscore the impact of the anti-virulence approach in microbial ecology and its importance for treating polymicrobial infections. Full article
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15 pages, 885 KiB  
Review
The Role of Complement in the Pathogenesis and Treatment of Myasthenia Gravis
by Armando Martinez Salazar, Sepideh Mokhtari, Edwin Peguero and Muhammad Jaffer
Cells 2025, 14(10), 739; https://doi.org/10.3390/cells14100739 - 19 May 2025
Viewed by 1357
Abstract
Myasthenia gravis is an antibody-mediated autoimmune condition characterized by defects in cholinergic transmission at the neuromuscular junction. In AchR antibody-positive patients, complement activation plays a prominent role in the disease process, which appears to be mediated by the activation of the membrane attack [...] Read more.
Myasthenia gravis is an antibody-mediated autoimmune condition characterized by defects in cholinergic transmission at the neuromuscular junction. In AchR antibody-positive patients, complement activation plays a prominent role in the disease process, which appears to be mediated by the activation of the membrane attack complex. Since IgG4 is not a good complement activator, the role of complement in MuSK antibody-positive myasthenia gravis patients is negligible. Experimental animal models of myasthenia gravis have shown promise with the antagonism of different elements of the complement cascade, with positive clinical outcomes. This has led to the development of the first C5 inhibitors approved for myasthenia gravis with AchR antibodies: eculizumab, ravulizumab, and zilucoplan. Other clinical trials are currently in progress, investigating the potential therapeutic role of other targets, including the Factor B inhibition or hepatic synthesis of the C5 protein. Other proposed potential targets that have not yet been clinically tested are also discussed in this review article. Full article
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19 pages, 532 KiB  
Article
Conventional Antimicrobial and Medicinal Plants from a Traditional Medicine Market in South Africa: An Interactive Antimicrobial and Toxicity Study
by Zelna Booth, Sabiha Essack and Sandy van Vuuren
Antibiotics 2025, 14(5), 512; https://doi.org/10.3390/antibiotics14050512 - 15 May 2025
Viewed by 560
Abstract
Background: The World Health Organization (WHO) has proposed the use of integrative medicine to achieve extended healthcare coverage in developing countries facing high morbidity. Traditional remedies are frequently employed to prevent and treat infections among South Africans; however, the ways in which they [...] Read more.
Background: The World Health Organization (WHO) has proposed the use of integrative medicine to achieve extended healthcare coverage in developing countries facing high morbidity. Traditional remedies are frequently employed to prevent and treat infections among South Africans; however, the ways in which they interact with conventional antimicrobials are largely unknown. Therefore, this study aimed to explore the interactions between commonly traded medicinal plants at a traditional medicine market in KwaZulu-Natal (KZN), South Africa, and conventional antibiotics and antifungals. Methods: To determine the interactive antimicrobial profiles for plant/conventional antimicrobial combinations, minimum inhibitory concentration (MIC) assays were performed against ESKAPE pathogens and the yeasts Candida albicans and Candida glabrata. Calculated fractional inhibitory concentration (ΣFIC) values were used to identify synergism or antagonism, with synergistic interactions further tested in vitro for toxicity. Results: A total of 952 combinations were tested, of which 5.8% and 54.6% of the plant/antibiotic combinations were synergistic and antagonistic, respectively; additionally, 1.7% and 58.6% of the plant/antifungal combinations showed synergism or antagonism, respectively. The most toxic plant/antibiotic combination was Artemisia afra with doxycycline (71.1% mortality). The most toxic plant/antifungal combination was Acorus calamus with fluconazole (78.8% mortality). Conclusions: When medicinal plants acquired from a traditional medicine market in South Africa are used in combination with conventional antibiotics and antifungals, more than half of the combinations exhibit antagonism, which is concerning. Full article
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28 pages, 5232 KiB  
Article
Evaluation of the Synergistic Activity of Antimicrobial Peptidomimetics or Colistin Sulphate with Conventional Antifungals Against Yeasts of Medical Importance
by Shyam Kumar Mishra, Rajesh Kuppusamy, Christina Nguyen, Jennifer Doeur, Harleen Atwal, Samuel Attard, Kristian Sørensen, Jennifer S. Lin, Edgar H. H. Wong, Alex Hui, Annelise E. Barron, Naresh Kumar and Mark Willcox
J. Fungi 2025, 11(5), 370; https://doi.org/10.3390/jof11050370 - 12 May 2025
Viewed by 1400
Abstract
With rising multidrug-resistant yeast pathogens, conventional antifungals are becoming less effective, urging the need for adjuvants that enhance their activity at lower doses. This study evaluated the synergistic activity of antimicrobial peptidomimetics (TM8 and RK758) or colistin sulphate in combination with conventional antifungals [...] Read more.
With rising multidrug-resistant yeast pathogens, conventional antifungals are becoming less effective, urging the need for adjuvants that enhance their activity at lower doses. This study evaluated the synergistic activity of antimicrobial peptidomimetics (TM8 and RK758) or colistin sulphate in combination with conventional antifungals against Candida albicans, C. tropicalis, C. parapsilosis, Meyerozyma guilliermondii, Nakaseomyces glabratus, Pichia kudriavzevii and Kluyveromyces marxianus, and Candidozyma auris using the checkerboard microdilution test. RK758 was synergistic with fluconazole in 78% of isolates, with the remaining 22% of isolates still showing partial synergy; it showed synergy with amphotericin B in 56% of isolates, and with caspofungin, 78% of isolates exhibited either synergy or partial synergy. TM8 showed synergy with fluconazole in 44% (with partial synergy in another 44%) of isolates, with amphotericin B in 67% of isolates, and with caspofungin in 44% (with partial synergy in another 44%) of isolates. Colistin with fluconazole or caspofungin exhibited synergy or partial synergy in 56% of the isolates. No antagonism was observed in any of the combinations. Additionally, a time-kill assay further demonstrated synergistic activity between fluconazole and TM8 or RK758. The effects of these peptidomimetics on cell membrane integrity were demonstrated in an ergosterol binding assay, supported by SYTOX Green and cellular leakage assays, both indicating a lytic effect. These results suggest that peptidomimetics can synergise with conventional antifungals, offering a potential strategy for combination therapy against yeast infections. The membrane lytic activity of the peptidomimetics likely plays a role in their synergistic interaction with antifungals, thereby enhancing the antimicrobial activities of both compounds at sub-MIC levels. Full article
(This article belongs to the Special Issue Alternative Therapeutic Approaches of Candida Infections, 4th Edition)
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18 pages, 6031 KiB  
Article
Semaglutide and High-Intensity Interval Exercise Attenuate Cognitive Impairment in Type 2 Diabetic Mice via BDNF Modulation
by Sijie Lai, Zhenghong Kang, Jianting Sun, Ziyu Wang, Yanzi Xu, Sisi Xing, Mengying Feng, Yiyi Wang and Hua Liu
Brain Sci. 2025, 15(5), 480; https://doi.org/10.3390/brainsci15050480 - 1 May 2025
Viewed by 1231
Abstract
Background/Objectives: Diabetes frequently leads to cognitive impairment, encompassing issues with memory and executive function, as well as depression and anxiety. This study examines the impact of high-intensity interval exercise (HIIE) alongside glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide on cognitive dysfunction associated [...] Read more.
Background/Objectives: Diabetes frequently leads to cognitive impairment, encompassing issues with memory and executive function, as well as depression and anxiety. This study examines the impact of high-intensity interval exercise (HIIE) alongside glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide on cognitive dysfunction associated with diabetes. Methods: Db/db mice were divided into a control group, semaglutide group, HIIE group, and semaglutide combined with HIIE group to study metabolic and neurobehavioral effects. Cognitive and behavioral tests, hippocampal morphology, and molecular analyses (APP, BDNF, Aβ, p-Tau, PKA, AMPK) were performed. HT22 cells under high glucose were treated with semaglutide, L-lactate, PKA inhibitor H89, and AMPK inhibitor Compound C to validate mechanisms. Results: Over 8 weeks, both HIIE and semaglutide improved neuronal morphology and cognitive performance while reducing depression in db/db mice. However, the current study observed no synergistic effects. Both therapies decreased Aβ and p-Tau protein levels and increased BDNF levels in the hippocampus, likely through the AMPK and PKA signaling pathways, respectively. In vitro, HT22 cells under high glucose conditions exhibited elevated APP and p-Tau expression and reduced BDNF levels, which could be altered by L-lactate and semaglutide. The AMPK inhibitor Compound C and the PKA inhibitor H89 attenuated the increase in BDNF levels induced by L-lactate and semaglutide, but their combination mitigated this inhibitory effect. This study suggests that while HIIE and semaglutide improve cognitive function and reduce depression via BDNF, their combined use did not show the anticipated synergistic benefits due to potential antagonism between the AMPK and PKA pathways. Conclusions: This has important implications for designing exercise prescriptions for cognitive impairment in diabetics. Full article
(This article belongs to the Section Cognitive, Social and Affective Neuroscience)
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27 pages, 3238 KiB  
Article
Synthesis and Neurotropic Activity of New 5-Piperazinopyrazolo[3,4-c]-2,7-naphthyridines and Isoxazolo[5,4-c]-2,7-naphthyridines
by Samvel N. Sirakanyan, Elmira K. Hakobyan, Athina Geronikaki, Domenico Spinelli, Anthi Petrou, Victor G. Kartsev, Hasmik A. Yegoryan, Hasmik V. Jughetsyan, Mariam E. Manukyan, Ruzanna G. Paronikyan, Tatevik A. Araqelyan and Anush A. Hovakimyan
Pharmaceuticals 2025, 18(4), 597; https://doi.org/10.3390/ph18040597 - 19 Apr 2025
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Abstract
Background/Objectives: Approximately 1% of people worldwide suffer from epilepsy. The development of safer and more effective antiepileptic medications (AEDs) is still urgently needed because all AEDs have some unwanted side effects and roughly 30% of epileptic patients cannot stop having seizures when [...] Read more.
Background/Objectives: Approximately 1% of people worldwide suffer from epilepsy. The development of safer and more effective antiepileptic medications (AEDs) is still urgently needed because all AEDs have some unwanted side effects and roughly 30% of epileptic patients cannot stop having seizures when taking current AEDs. It should be noted that the derivatives of pyrazolo[3,4-b]pyridine are important core structures in many drug substances. The aim of this study is to synthesize new derivatives of piperazino-substituted pyrazolo[3,4-c]-2,7-naphthyridines and 9,11-dimethylpyrimido[1′,2′:1,5]pyrazolo[3,4-c]-2,7-naphthyridines for the evaluation of their neurotropic activity. Methods: The synthesis of the target compounds was performed starting from 1-amino-3-chloro-2,7-naphthyridines and using well-known methods. The structures of all the synthesized compounds were confirmed by spectroscopic data. Compounds were studied for their potential neurotropic activities (anticonvulsant, sedative, anti-anxiety, and antidepressive), as well as side effects, in 450 white mice of both sexes and 50 male Wistar rats. The anticonvulsant effect of the newly synthesized compounds was investigated by using the following tests: pentylenetetrazole, thiosemicarbazide-induced convulsions, and maximal electroshock. The psychotropic properties of the selected compounds were evaluated by using the following tests: the Open Field test, the Elevated Plus Maze (EPM), the Forced Swimming test, and Rotating Rod Test to study muscle relaxation. For the docking studies, AutoDock 4 (version 4.2.6) was used, as well as the structures of the GABAA receptor (PDB ID: 4COF), the SERT transporter (PDB ID: 3F3A), and the 5-HT1A receptor (PDB ID: 3NYA) obtained from the Protein Data Bank. Results: A series of piperazino-substituted pyrazolo[3,4-c]-2,7-naphthyridines (3aj) and 9,11-dimethylpyrimido[1′,2′:1,5]pyrazolo[3,4-c]-2,7-naphthyridines (4aj), as well as new heterocyclic systems, i.e., isoxazolo[5,4-c]-2,7-naphthyridines 6ad, were synthesized and evaluated for their neurotropic activity. The investigation showed that some of these compounds (3a,b,d,fi and 4a,d,f,i) display high anticonvulsant activity, especially in the test of antagonism with pentylenetetrazol, surpassing the well-known antiepileptic drug ethosuximide. Thus, the most active compounds in the pentylenpotetrazole test are 3h, 3i, and 4i; the ED50 of compound 4i is 23.8, and the therapeutic index is more than 33.6, which is the highest among these three active compounds. On the other hand, they simultaneously exhibit psychotropic (anxiolytic, antidepressant, or sedative) or behavioral depressant) effects. The effective compounds do not cause myorelaxation at the tested doses and have high therapeutic indices. Docking on the most active compounds, i.e., 3h, 3i, and 4i, is in agreement with the experimental results. Conclusions: The studies reveled that some of these compounds (3i, 4a, and 4i) display high anticonvulsant and psychotropic activities. The most active compounds contained methyl and diphenylmethyl groups in the piperazine ring. The docking studies identified compounds 3i, 4i, and 4a as the most potent anticonvulsants, showing strong affinity for GABAA, 5-HT1A receptors, and the SERT transporter. Notably, compound 4i formed two hydrogen bonds with Thr176 and Arg180 on GABAA and exhibited a binding energy (−8.81 kcal/mol) comparable to that of diazepam (−8.90 kcal/mol). It also showed the strongest binding to SERT (−7.28 kcal/mol), stabilized by interactions with Gly439, Ile441, and Arg11. Furthermore, 4i displayed the best docking score with 5-HT1A (−9.10 kcal/mol) due to multiple hydrogen bonds and hydrophobic interactions, supporting its potential as a dual-acting agent targeting both SERT and 5-HT1A. Full article
(This article belongs to the Special Issue Pyrazole and Thiazole Derivatives in Medicinal Chemistry)
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17 pages, 7461 KiB  
Article
Apoptotic Effect of Combinations of T-2, HT-2, and Diacetoxyscirpenol on Human Jurkat T Cells
by Phattarawadee Wattanasuntorn, Saranya Poapolathep, Patchara Phuektes, Imourana Alassane-Kpembi, Johanna Fink-Gremmels, Isabelle P. Oswald and Amnart Poapolathep
Toxins 2025, 17(4), 203; https://doi.org/10.3390/toxins17040203 - 18 Apr 2025
Viewed by 511
Abstract
Trichothecene type A mycotoxins, such as T-2, HT-2, and diacetoxyscirpenol (DAS), are known to induce cytotoxicity and apoptosis in different cell types. As all three Fusarium toxins may occur concomitantly in a given food or feed commodity, there is growing interest in the [...] Read more.
Trichothecene type A mycotoxins, such as T-2, HT-2, and diacetoxyscirpenol (DAS), are known to induce cytotoxicity and apoptosis in different cell types. As all three Fusarium toxins may occur concomitantly in a given food or feed commodity, there is growing interest in the effect of such mycotoxin mixtures. This study aimed to identify the toxic interactions among T-2, HT-2, and DAS in a human Jurkat cell model. As a first step, an MTT assay was used to assess cytotoxicity after 24 h of cell exposure to individual mycotoxins and their mixtures. The results were used to calculate the combination index (CI), which indicates the nature of the mycotoxin interactions. In Jurkat T cells, the toxicity ranking for the individual mycotoxins was T-2 > HT-2 > DAS. The CI values of the dual and triple mycotoxin combinations calculated from the results of the MTT and reactive oxygen species assays showed synergistic effects at low concentrations and an apparent antagonism at very high concentrations for all combinations. The additional cytometric analyses confirmed the synergistic effects, as expected, following co-exposure to the three tested trichothecenes. As the lower toxin concentrations investigated reflect natural contamination levels in food and feeds, the synergistic effects identified should be considered in risk characterization for trichothecene exposure in humans and animals. Full article
(This article belongs to the Special Issue Alleviation of Mycotoxin-Induced Toxicity)
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