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Frontiers in Immunology 2024Hematopoietic stem cell transplantation (HSCT) is associated with immune complications and endothelial dysfunction due to intricate donor-recipient interactions,...
INTRODUCTION
Hematopoietic stem cell transplantation (HSCT) is associated with immune complications and endothelial dysfunction due to intricate donor-recipient interactions, conditioning regimens, and inflammatory responses.
METHODS
This study investigated the role of the complement system during HSCT and its interaction with the cytokine network. Seventeen acute myeloid leukemia patients undergoing HSCT were monitored, including blood sampling from the start of the conditioning regimen until four weeks post-transplant. Clinical follow-up was 200 days.
RESULTS
Total complement functional activity was measured by WIELISA and the degree of complement activation by ELISA measurement of sC5b-9. Cytokine release was measured using a 27-multiplex immuno-assay. At all time-points during HSCT complement functional activity remained comparable to healthy controls. Complement activation was continuously stable except for two patients demonstrating increased activation, consistent with severe endotheliopathy and infections. experiments with post-HSCT whole blood challenged with , revealed a hyperinflammatory cytokine response with increased TNF, IL-1β, IL-6 and IL-8 formation. Complement C3 inhibition markedly reduced the cytokine response induced by , , and cholesterol crystals.
DISCUSSION
In conclusion, HSCT patients generally retained a fully functional complement system, whereas activation occurred in patients with severe complications. The complement-cytokine interaction indicates the potential for new complement-targeting therapeutic strategies in HSCT.
Topics: Humans; Male; Hematopoietic Stem Cell Transplantation; Female; Middle Aged; Complement Activation; Adult; Cytokines; Transplantation, Homologous; Aged; Leukemia, Myeloid, Acute; Complement System Proteins; Transplantation Conditioning; Young Adult
PubMed: 38938578
DOI: 10.3389/fimmu.2024.1422370 -
Organic & Biomolecular Chemistry Jun 2024is a saprophytic fungus and opportunistic pathogen often causing fatal infections in immunocompromised patients. Recently KDNAse, an exoglycosidase hydrolyzing...
is a saprophytic fungus and opportunistic pathogen often causing fatal infections in immunocompromised patients. Recently KDNAse, an exoglycosidase hydrolyzing 3-deoxy-D-galacto-D--nonulosonic acid (KDN), a rare sugar from the sialic acid family, was identified and characterized. The principal function of KDNAse is still unclear, but a study suggests a critical role in fungal cell wall morphology and virulence. Potent KDNAse inhibitors are required to better probe the enzyme's biological role and as potential antivirulence factors. In this work, we developed a set of KDNAse inhibitors based on enzymatically stable thio-KDN motifs. C2, C9-linked heterodi-KDN were designed to fit into unusually close KDN sugar binding pockets in the protein. A polymeric compound with an average of 54 KDN motifs was also designed by click chemistry. Inhibitory assays performed on recombinant KDNAse showed a moderate and strong enzymatic inhibition for the two classes of compounds, respectively. The poly-KDN showed more than a nine hundred fold improved inhibitory activity (IC = 1.52 ± 0.37 μM, 17-fold in a KDN molar basis) compared to a monovalent KDN reference, and is to our knowledge, the best synthetic inhibitor described for a KDNase. Multivalency appears to be a relevant strategy for the design of potent KDNase inhibitors. Importantly, poly-KDN was shown to strongly decrease filamentation when co-cultured with at micromolar concentrations, opening interesting perspectives in the development of antivirulence factors.
PubMed: 38938184
DOI: 10.1039/d4ob00601a -
Emerging Infectious Diseases Jun 2024Azole-resistant Aspergillus fumigatus (ARAf) fungi have been found inconsistently in the environment in Denmark since 2010. During 2018-2020, nationwide surveillance of...
Azole-resistant Aspergillus fumigatus (ARAf) fungi have been found inconsistently in the environment in Denmark since 2010. During 2018-2020, nationwide surveillance of clinical A. fumigatus fungi reported environmental TR/L98H or TR/Y121F/T289A resistance mutations in 3.6% of isolates, prompting environmental sampling for ARAf and azole fungicides and investigation of selected ARAf in field and microcosmos experiments. ARAf was ubiquitous (20% of 366 samples; 16% TR/L98H- and 4% TR/Y121F/T289A-related mechanisms), constituting 4.2% of 4,538 A. fumigatus isolates. The highest proportions were in flower- and compost-related samples but were not correlated with azole-fungicide application concentrations. Genotyping showed clustering of tandem repeat-related ARAf and overlaps with clinical isolates in Denmark. A. fumigatus fungi grew poorly in the field experiment with no postapplication change in ARAf proportions. However, in microcosmos experiments, a sustained complete (tebuconazole) or partial (prothioconazole) inhibition against wild-type A. fumigatus but not ARAf indicated that, under some conditions, azole fungicides may favor growth of ARAf in soil.
PubMed: 38935978
DOI: 10.3201/eid3008.240096 -
Medical Mycology Jun 2024Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In...
Recognizing the growing global burden of fungal infections, the World Health Organization established a process to develop a priority list of fungal pathogens (FPPL). In this systematic review, we aimed to evaluate the epidemiology and impact of invasive infections caused by Aspergillus fumigatus to inform the first FPPL. The pre-specified criteria of mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence were used to search for relevant articles between 1 January 2016 and 10 June 2021. Overall, 49 studies were eligible for inclusion. Azole antifungal susceptibility varied according to geographical regions. Voriconazole susceptibility rates of 22.2% were reported from the Netherlands, whereas in Brazil, Korea, India, China, and the UK, voriconazole susceptibility rates were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively. Cross-resistance was common with 85%, 92.8%, and 100% of voriconazole-resistant A. fumigatus isolates also resistant to itraconazole, posaconazole, and isavuconazole, respectively. The incidence of invasive aspergillosis (IA) in patients with acute leukemia was estimated at 5.84/100 patients. Six-week mortality rates in IA cases ranged from 31% to 36%. Azole resistance and hematological malignancy were poor prognostic factors. Twelve-week mortality rates were significantly higher in voriconazole-resistant than in voriconazole-susceptible IA cases (12/22 [54.5%] vs. 27/88 [30.7%]; P = .035), and hematology patients with IA had significantly higher mortality rates compared with solid-malignancy cases who had IA (65/217 [30%] vs. 14/78 [18%]; P = .04). Carefully designed surveillance studies linking laboratory and clinical data are required to better inform future FPPL.
Topics: Humans; Aspergillus fumigatus; Antifungal Agents; Aspergillosis; World Health Organization; Drug Resistance, Fungal; Voriconazole; Incidence; Microbial Sensitivity Tests; Invasive Fungal Infections; Risk Factors
PubMed: 38935907
DOI: 10.1093/mmy/myad129 -
MBio Jun 2024Contemporary antifungal therapies utilized to treat filamentous fungal infections are inhibited by intrinsic and emerging drug resistance. Consequently, there is an...
Contemporary antifungal therapies utilized to treat filamentous fungal infections are inhibited by intrinsic and emerging drug resistance. Consequently, there is an urgent need to develop novel antifungal compounds that are effective against drug-resistant filamentous fungi. Here, we utilized an cell-based high-throughput screen to identify small molecules with antifungal activity that also potentiated triazole activity. The screen identified 16 hits with promising activity against . A nonspirocyclic piperidine, herein named MBX-7591, exhibited synergy with triazole antifungal drugs and activity against pan-azole-resistant isolates. MBX-7591 has additional potent activity against species and CO-dependent activity against . Chemical, genetic, and biochemical mode of action analyses revealed that MBX-7591 increases cell membrane saturation by decreasing oleic acid content. MBX-7591 has low toxicity and shows good efficacy in decreasing fungal burden in a murine model of invasive pulmonary aspergillosis. Taken together, our results suggest MBX-7591 is a promising hit with a novel mode of action for further antifungal drug development to combat the rising incidence of triazole-resistant filamentous fungal infections.IMPORTANCEThe incidence of infections caused by fungi continues to increase with advances in medical therapies. Unfortunately, antifungal drug development has not kept pace with the incidence and importance of fungal infections, with only three major classes of antifungal drugs currently available for use in the clinic. Filamentous fungi, also called molds, are particularly recalcitrant to contemporary antifungal therapies. Here, a recently developed cell reporter strain was utilized to conduct a high-throughput screen to identify small molecules with antifungal activity. An emphasis was placed on small molecules that potentiated the activity of contemporary triazole antifungals and led to the discovery of MBX-7591. MBX-7591 potentiates triazole activity against drug-resistant molds such as and has activity against Mucorales fungi. MBX-7591's mode of action involves inhibiting the conversion of saturated to unsaturated fatty acids, thereby impacting fungal membrane integrity. MBX-7591 is a novel small molecule with antifungal activity poised for lead development.
PubMed: 38934618
DOI: 10.1128/mbio.01166-24 -
Pharmaceuticals (Basel, Switzerland) May 2024The importance of natural plant materials in modern medicine is considerable, and raw materials with antiviral, antibacterial, antifungal, and anticancer properties are... (Review)
Review
The importance of natural plant materials in modern medicine is considerable, and raw materials with antiviral, antibacterial, antifungal, and anticancer properties are still sought because of microbe resistance and difficulties in anticancer therapy. This review focuses on the lemongrass (DC.) Stapf. and on the lemongrass oil properties and applications. Multiple applications of this plant were described in different latitudes and cultures, including cases of digestive disorders and anti-inflammatory, antipyretic, diaphoretic, stimulating, and antispasmodic conditions. Data from the literature on the composition of essential oil and extracts from were analyzed, and the results of research on the antifungal, antibacterial, and antiviral effects were quoted. Essential oil inhibits the growth of fungi (, , spp.) and has an antibacterial effect (, , ). It also shows antiviral activity and deters insects. Lemongrass contains active substances with potential anticancer effects. This plant has apoptosis-stimulating properties, mainly through the activity of apigenin, which is the main active flavonoid in this plant. This active substance helps inhibit cell proliferation by stopping the cell cycle and directing cancer cells toward apoptosis.
PubMed: 38931371
DOI: 10.3390/ph17060705 -
Marine Drugs Jun 2024Four new cyclic pentapeptides, avellanins D-G (-), together with four known compounds (-), were isolated from a mangrove-derived GXIMD 03099 fungus from L. Their...
Four new cyclic pentapeptides, avellanins D-G (-), together with four known compounds (-), were isolated from a mangrove-derived GXIMD 03099 fungus from L. Their structures were elucidated by analysis of HRESIMS, NMR, and ESI-MS/MS data. Their absolute configurations were determined by X-ray diffraction analysis and Marfey's method. Compounds - were screened for insecticidal and antibacterial activities. Compound showed insecticidal activity against newly hatched larvae of with an LC value of 86.6 µM; compound had weak activity against with an MIC value of 5.85 µM.
Topics: Aspergillus fumigatus; Peptides, Cyclic; Animals; Anti-Bacterial Agents; Insecticides; Microbial Sensitivity Tests; Vibrio; Culex; Larva; Molecular Structure
PubMed: 38921593
DOI: 10.3390/md22060282 -
Marine Drugs Jun 2024Cyclic pentapeptide compounds have garnered much attention as a drug discovery resource. This study focused on the characterization and anti-benign prostatic hyperplasia...
Cyclic pentapeptide compounds have garnered much attention as a drug discovery resource. This study focused on the characterization and anti-benign prostatic hyperplasia (BPH) properties of avellanin A from fungus in marine sediment samples collected in the Beibu Gulf of Guangxi Province in China. The antiproliferative effect and molecular mechanism of avellanin A were explored in testosterone propionate (TP)-induced RWPE-1 cells. The transcriptome results showed that avellanin A significantly blocked the ECM-receptor interaction and suppressed the downstream PI3K-Akt signalling pathway. Molecular docking revealed that avellanin A has a good affinity for the cathepsin L protein, which is involved in the terminal degradation of extracellular matrix components. Subsequently, qRT-PCR analysis revealed that the expression of the genes , , , , , , , and was significantly downregulated after avellanin A intervention. The Western blot results also confirmed that it not only reduced ITGB3 and FAK/p-FAK protein expression but also inhibited PI3K/p-PI3K and Akt/p-Akt protein expression in the PI3K-Akt signalling pathway. Furthermore, avellanin A downregulated Cyclin D1 protein expression and upregulated Bax, p21, and p53 proapoptotic protein expression in TP-induced RWPE-1 cells, leading to cell cycle arrest and inhibition of cell proliferation. The results of this study support the use of avellanin A as a potential new drug for the treatment of BPH.
Topics: Humans; Proto-Oncogene Proteins c-akt; Signal Transduction; Cell Proliferation; Phosphatidylinositol 3-Kinases; Molecular Docking Simulation; Cell Line; Male; Apoptosis
PubMed: 38921586
DOI: 10.3390/md22060275 -
Journal of Fungi (Basel, Switzerland) May 2024The efficacy of different echinocandins is assessed by evaluating the in vitro activity of a novel antifungal, rezafungin, against invasive fungal isolates in comparison...
The efficacy of different echinocandins is assessed by evaluating the in vitro activity of a novel antifungal, rezafungin, against invasive fungal isolates in comparison with anidulafungin and caspofungin. Using the broth microdilution (BMD) method, the susceptibility of 1000 clinical isolates (including 400 , 200 , 200 , 150 and 50 ) and 150 isolates (100 and 50 ) from the Eastern China Invasive Fungi Infection Group (ECIFIG) was tested for the antifungals including anidulafungin, rezafungin, caspofungin and fluconazole. The echinocandins showed strong activity against that was maintained against fluconazole-resistant isolates. The GM MIC (geometric mean minimum inhibitory concentration) value of rezafungin was found to be comparable to that of anidulafungin or caspofungin against the five tested common species. exhibited higher resistance rates (about 8.67-40.67% in different antifungals) than the other four species. Through the sequencing of genes, we searched for mutations in echinocandin-resistant isolates and found that all displayed alterations in S654P. The determined MEC (minimal effective concentration) values against and for rezafungin (0.116 μg/mL, 0.110 μg/mL) are comparable to those of caspofungin (0.122 μg/mL, 0.142 μg/mL) but higher than for anidulafungin (0.064 μg/mL, 0.059 μg/mL). Thus, the in vitro activity of rezafungin appears comparable to anidulafungin and caspofungin against most common and species. Rezafungin showed higher susceptibility rates against . Rezafungin indicates its potent activity for potential clinical application.
PubMed: 38921383
DOI: 10.3390/jof10060397 -
Current Issues in Molecular Biology Jun 2024is commonly found in the airway and is associated with airway inflammatory diseases. Zinc oxide (ZO) is known to be an essential microelement that facilitates fungal...
is commonly found in the airway and is associated with airway inflammatory diseases. Zinc oxide (ZO) is known to be an essential microelement that facilitates fungal survival, growth, and proliferation. This study aimed to investigate the impact of ZO on -induced fungal sinusitis in rabbits. Twenty-eight New Zealand white rabbits were divided into four groups for this study. Group 1 (6 sides) was treated with intramaxillary phosphate buffer saline (PBS) served as the negative control, Group 2 (6 sides) received intramaxillary PBS and ZO, Group 3 (8 sides) was treated with intramaxillary alone, and Group 4 (8 sides) treated with intramaxillary with ZO. After 4 and 12 weeks, sinus mucosal cytokine and transcription factor expressions were determined. A histological analysis was performed to determine inflammatory cell infiltration, number of secretory cells, and mucosal thickness. Fungal biofilm formation was determined using confocal laser microscopy. The intramaxillary instillation of conidia led to an increase in protein and mRNA expression of interleukin (IL)-1β and IL-8 in the maxillary sinus mucosa. They were associated with mitogen-activated protein kinase and activator protein-1. Furthermore, intramaxillary instillation of fungal conidia resulted in significant enhancement of inflammatory cell infiltration, epithelial thickening, and fungal biofilm formation. However, intramaxillary ZO did not have a significant impact on -induced cytokine protein and mRNA expression, and inflammatory cell infiltration and epithelial thickness in sinonasal mucosa. While intramaxillary instillation of increased mucosal inflammation, cytokine production, and biofilm formation, the intramaxillary application of ZO did not have a significant influence on inflammation in the maxillary sinus mucosa.
PubMed: 38921013
DOI: 10.3390/cimb46060342