Search Results (118)

Dermatophytes are highly infectious pathogenic fungi that colonize keratinized tissues like skin, hair, and nails, causing superficial infections such as tinea capitis, onychomycosis, tinea corporis, and tinea pedis in humans and animals. In immunocompromised patients, they may invade deeper tissues and organs, leading to severe or life-threatening conditions if untreated or inadequately managed. While most infections respond to topical antifungals, some require complex treatment and show resistance to standard therapies. Therefore, novel antifungal agents are needed. We investigated the antidermatophytic activity of imidazole-thiosemicarbazides against Microsporum canis, Trichophyton spp., and Chrysosporium spp. using the broth microdilution method, comparing results to ketoconazole and amphotericin B through minimal inhibitory concentration (MIC), half-maximal inhibitory concentration (IC₅₀), and selectivity index (SI). Iodine- and bromine-substituted compounds showed the strongest activity, with MICs of 15.15 (IC₅₀ < 1 μM; SI > 213) and 73.46 μg/mL (IC₅₀ < 1 μM; SI > 846) against T. tonsurans, and 3.87 (IC₅₀ = 7.21 μM; SI > 29.6) and 7.38 μg/mL (IC₅₀ = 11.06 μM; SI = 76.6) against M. canis. In silico analysis revealed interactions with α-keratin and lanosterol-14-α demethylase (the azole target enzyme), suggesting enhanced drug retention and action. These findings support these compounds as promising leads for further antifungal development. Full article

The worldwide increase in antifungal resistance, particularly in Candida sp., requires the exploration of novel therapeutic agents. Natural compounds have been a rich source of antimicrobial molecules, where peptides constitute the class of the most bioactive components. Therefore, this study looks into the target-specific binding efficacy of insect-derived antifungal peptides (n = 37) as possible alternatives to traditional antifungal treatments. Using computational methods, namely the HPEPDOCK and HDOCK platforms, molecular docking was performed to evaluate the interactions between selected key fungal targets, lanosterol 14-demethylase, or LDM (PDB ID: 5V5Z), secreted aspartic proteinase-5, or Sap-5 (PDB ID: 2QZX), N-myristoyl transferase, or NMT (PDB ID: 1NMT), and dihydrofolate reductase, or DHFR, of C. albicans. The three-dimensional peptide structure was modelled through the PEP-FOLD 3.5 tool. Further, we predicted the physicochemical properties of these peptides through the ProtParam and PEPTIDE 2.0 tools to assess their drug-likeness and potential for therapeutic applications. In silico results show that Blap-6 from Blaps rhynchopeter and Gomesin from Acanthoscurria gomesiana have the most antifungal potential against all four targeted proteins in Candida sp. Additionally, a molecular dynamics simulation study of LDM-Blap-6 was carried out at 100 nanoseconds. The overall predictions showed that both have strong binding abilities and are good candidates for drug development. In in vitro studies, Gomesin achieved complete biofilm eradication in three out of four Candida species, while Blap-6 showed moderate but consistent reduction across all species. C. tropicalis demonstrated relative resistance to complete eradication by both peptides. The present study provides evidence to support the antifungal activity of certain insect peptides, with potential to be used as alternative drugs or as a template for a new synthetic or modified peptide in pursuit of effective therapies against Candida spp. Full article

Background: Exposure to per- and polyfluoroalkyl substances (PFAS, including 7H-Perfluoro-4-methyl-3,6-dioxaoctanesulfonic acid (PFESA-BP2), perfluorooctanoic acid (PFOA), and hexafluoropropylene oxide (GenX), has been associated with liver dysfunction. While previous research has characterized PFAS-induced hepatic lipid alterations, their downstream effects on energy metabolism remain unclear. This study investigates metabolic alterations in the liver following PFAS exposure to identify mechanisms leading to hepatoxicity. Methods: We analyzed RNA sequencing datasets of mouse liver tissues exposed to PFAS to identify metabolic pathways influenced by the chemical toxicant. We integrated the transcriptome data with a mouse genome-scale metabolic model to perform in silico flux analysis and investigated reactions and genes associated with lipid and energy metabolism. Results: PFESA-BP2 exposure caused dose- and sex-dependent changes, including upregulation of fatty acid metabolism, β-oxidation, and cholesterol biosynthesis. On the contrary, triglycerides, sphingolipids, and glycerophospholipids metabolism were suppressed. Simulations from the integrated genome-scale metabolic models confirmed increased flux for mevalonate and lanosterol metabolism, supporting potential cholesterol accumulation. GenX and PFOA triggered strong PPARα-dependent responses, especially in β-oxidation and lipolysis, which were attenuated in PPARα^−/− mice. Mitochondrial fatty acid transport and acylcarnitine turnover were also disrupted, suggesting impaired mitochondrial dysfunction. Additional PFAS effects included perturbations in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and blood–brain barrier (BBB) function, pointing to broader systemic toxicity. Conclusions: Our findings highlight key metabolic signatures and suggest PFAS-mediated disruption of hepatic and possibly neurological functions. This study underscores the utility of genome-scale metabolic modeling as a powerful tool to interpret transcriptomic data and predict systemic metabolic outcomes of toxicant exposure. Full article

Sideroxylon cinereum, an endemic Mauritian fruit, was investigated through comprehensive chemical analyses of solvent extracts from its pulp and seed. Dried fruit materials were subjected to maceration using water and organic solvents including methanol, ethanol, propanol, and acetone to obtain extracts of varying polarity. Preliminary phytochemical screening revealed the presence of several bioactive compounds, with pulp extracts generally richer in phytochemicals than seed extracts. UV-Vis and FTIR analyses confirmed key organic constituents, including sulfoxides in seeds. HPLC quantification showed notable citric acid content in the pulp (15.63 mg/g dry weight). Antioxidant assays indicated that organic solvent extracts of the pulp had superior free radical scavenging activity, while the seed’s aqueous extract exhibited the highest ferric reducing power. GC–MS profiling identified a diverse bioactive profile rich in terpenes, notably lanosterol acetate (>45% in both pulp and seeds). It is important to note that these findings are based on solvent extracts, which may differ from the phytochemical composition of the whole fruit as typically consumed. Among the extracts, aqueous fractions are likely the most relevant to dietary intake. Overall, the extracts of Sideroxylon cinereum pulp and seed show potential as sources of bioactive compounds for functional product development. Full article

Cataract formation remains a significant cause of global visual impairment. Increasing attention has been directed toward antioxidant-based interventions as potential non-surgical strategies to delay or prevent cataractogenesis, particularly in the age-related and diabetic contexts. This review summarizes recent preclinical evidence on nutritional antioxidants for the prevention of age-related and diabetic cataracts. Agents such as trimetazidine, Moringa oleifera stem extract, ginsenoside Rg1, lanosterol nanoparticles, β-casomorphin-7, and cerium oxide-based nanotherapies have been shown to mitigate oxidative damage, modulate redox signaling pathways, and preserve lens clarity. Advances in drug delivery, including topical formulations, nanoparticle carriers, and intravitreal injections, have been proposed to overcome the anatomical and pharmacokinetic barriers associated with the avascular lens. The new data support ongoing translational research to maximize the clinical use of antioxidants and highlight their therapeutic potential in the prevention of age-related and diabetic cataracts. Full article

Smith–Lemli–Opitz syndrome (SLOS) is a developmental disability arising from bi-allelic pathogenic variants in the 7-dehydrocholestrol reductase (DHCR7) enzyme and the accumulation of 7-dehydrocholesterol (7-DHC). 7-DHC spontaneously oxidizes and gives rise to cytotoxic oxysterols. Our recent high-throughput screening on Dhcr7-deficient Neuro2a cells identified hydroxyzine (HYZ) as a medication that could counteract the high levels of 7-DHC. We assessed the effects of HYZ in Dhcr7-deficient Neuro2a cells, neuronal cultures and glial cultures from Dhcr7^T93M/T93M transgenic mice, and human dermal fibroblasts from patients with SLOS. LC-MS/MS biochemical analyses revealed a strong modulatory effect of HYZ on post-lanosterol biosynthesis across all four SLOS models. However, the HYZ-induced biochemical changes were complex, dose-dependent, and variable across the four SLOS models. Dhcr7-deficient Neuro2a cells showed decreased 7-DHC, 8-dehydrocholesterol (8-DHC), and desmosterol (DES) levels (all p < 0.01), while neuronal and glial cultures from Dhcr7^T93M/T93M transgenic mice reported 8 significantly altered analytes (all p < 0.001). Human dermal fibroblast from patients with SLOS reacted to HYZ exposure with significantly decreased 7-DHC, 7-dehydrodesmosterol (7-DHD), and dihydrolanosterol (DHL) levels (p < 0.001), coupled with elevation in zymosterol (ZYM), zymostenol (ZYME), and 8-DHC (p < 0.001). Further evaluations are required to determine if the potentially beneficial effects of decreased 7-DHC, 7-DHD and DHL levels in SLOS models and patient biomaterials are counteracted by the rise in other post-lanosterol intermediates. Full article

The thiazole heterocycle is one of the most common moieties found in various drugs. Using 2-aminothiazole as the core structure, the amino group was functionalized with an amide. As a result, 30 trisubstituted 2-amino-4, 5-diarylthiazole derivatives were synthesized, with different substitutions introduced at the C2, C4, and C5 positions. The anti-Candida albicans biological activities of these synthetic compounds on five kinds of Candida albicans at different concentrations were detected by the microdilution method. In the first round, four derivatives of 2-amino-4, 5-diarylthiazole exhibited moderate anti-Candida albicans activity. Among them, 4a8 was chosen to be subjected to a demethylation process. Thus, 5a8 was synthesized successfully, giving anti-Candida albicans activity (MIC₈₀ = 9 μM) similar to that of a typical antifungal drug, fluconazole. To understand the mechanism of anti-Candida albicans, molecular docking of the most active 5a8 against four target proteins of anti-Candida albicans, such as glutamine-fructose-6-phosphoamidamitransferase (GFAT), protein kinase (Yck2), heat-shock protein 90 (Hsp90), and lanosterol 14a-demethylase (CYP51) was carried out. Our research will provide an experimental basis and theoretical guidance for the further design of a new aminothiazole-leading pharmaceutical molecule. Full article

This publication reports the controlled cultivation of Zanthoxylum chiloperone var. angustifolium Engl. (Rutaceae) in several growth substrates under controlled greenhouse conditions. This plant is well-known for its anti-Chagas (trypanocidal) activity, related to the presence of several β-carboline alkaloids. The metabolomic study of Z. chiloperone seedlings over two years of growth (2018–2020) was performed using comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC × GC-TOFMS). The canthin-6-one alkaloids, canthin-6-one and 5-methoxy-canthin-6-one, were putatively identified in Z. chiloperone extracts. Finally, in vitro and in silico studies of trypanocidal activity were performed, suggesting that canthin-6-one alkaloids could interact with the main pharmacological targets against Trypanosoma cruzi, cruzain protease, dihydroorotate dehydrogenase, lanosterol 14-alpha-demethylase, farnesyl diphosphate, and squalene synthases. Full article

Aspergillus fumigatus is intrinsically resistant to the widely used antifungal fluconazole, and therapeutic failure can result from acquired resistance to voriconazole, the primary treatment for invasive aspergillosis. The molecular basis of substrate specificity and innate and acquired resistance of A. fumigatus to azole drugs were addressed using crystal structures, molecular models, and expression in Saccharomyces cerevisiae of the sterol 14α-demethylase isoforms AfCYP51A and AfCYP51B targeted by azole drugs, together with their cognate reductase AfCPRA2 and AfERG6 (sterol 24-C-methyltransferase). As predicted by molecular modelling, functional expression of CYP51A and B required eburicol and not lanosterol. A crowded conformationally sensitive region involving the BC-loop, helix I, and the heme makes AfCYP51A T289 primarily responsible for resistance to fluconazole, VT-1161, and the agrochemical difenoconazole. The Y121F T289A combination was required for higher level acquired resistance to fluconazole, VT-1161, difenoconazole, and voriconazole, and confirms posaconazole, isavuconazole and possibly ravuconazole as preferred treatments for target-based azole-resistant aspergillosis due to such a combination of mutations. Full article

Nanotechnological methods for creating multifunctional fabrics are attracting global interest. The incorporation of nanoparticles in the field of textiles enables the creation of multifunctional textiles exhibiting UV irradiation protection, antimicrobial properties, self-cleaning properties and photocatalytic. Nanomaterials-loaded textiles have many innovative applications in pharmaceuticals, sports, military the textile industry etc. This study details the biosynthesis and characterization of silver nanoparticles (AgNPs) using the aqueous mycelial-free filtrate of Aspergillus flavus. The formation of AgNPs was indicated by a brown color in the extracellular filtrate and confirmed by UV-Vis spectroscopy with a peak at 426 nm. The Box-Behnken design (BBD) is used to optimize the physicochemical parameters affecting AgNPs biosynthesis. The desirability function was employed to theoretically predict the optimal conditions for the biosynthesis of AgNPs, which were subsequently experimentally validated. Through the desirability function, the optimal conditions for the maximum predicted value for the biosynthesized AgNPs (235.72 µg/mL) have been identified as follows: incubation time (58.12 h), initial pH (7.99), AgNO₃ concentration (4.84 mM/mL), and temperature (34.84 °C). Under these conditions, the highest experimental value of AgNPs biosynthesis was 247.53 µg/mL. Model validation confirmed the great accuracy of the model predictions. Scanning electron microscopy (SEM) revealed spherical AgNPs measuring 8.93–19.11 nm, which was confirmed by transmission electron microscopy (TEM). Zeta potential analysis indicated a positive surface charge (+1.69 mV), implying good stability. X-ray diffraction (XRD) confirmed the crystalline nature, while energy-dispersive X-ray spectroscopy (EDX) verified elemental silver (49.61%). FTIR findings indicate the presence of phenols, proteins, alkanes, alkenes, aliphatic and aromatic amines, and alkyl groups which play significant roles in the reduction, capping, and stabilization of AgNPs. Cotton fabrics embedded with AgNPs biosynthesized using the aqueous mycelial-free filtrate of Aspergillus flavus showed strong antimicrobial activity. The disc diffusion method revealed inhibition zones of 15, 12, and 17 mm against E. coli (Gram-negative), S. aureus (Gram-positive), and C. albicans (yeast), respectively. These fabrics have potential applications in protective clothing, packaging, and medical care. In silico modeling suggested that the predicted compound derived from AgNPs on cotton fabric could inhibit Penicillin-binding proteins (PBPs) and Lanosterol 14-alpha-demethylase (L-14α-DM), with binding energies of −4.7 and −5.2 Kcal/mol, respectively. Pharmacokinetic analysis and sensitizer prediction indicated that this compound merits further investigation. Full article

Background/Objectives: The increase in fungal infections, both systemic and invasive, is a major source of morbidity and mortality, particularly among immunocompromised people such as cancer patients and organ transplant recipients. Because of their strong therapeutic activity and excellent safety profiles, azole antifungals are currently the most extensively used systemic antifungal drugs. Antibacterial properties of various topical antifungals, such as oxiconazole, which features oxime ether functionality, were discovered, indicating an exciting prospect in antimicrobial chemotherapy. Methods: In this study, eleven new oxime ether derivatives with the azole scaffold (5a–k) were synthesized and tested for their antimicrobial effects using the microdilution method to obtain broad-spectrum hits. Results: Although the title compounds showed limited efficacy against Candida species, they proved highly effective against dermatophytes. Compounds 5c and 5h were the most potent derivatives against Trichophyton mentagrophytes and Arthroderma quadrifidum, with minimum inhibitory concentration (MIC) values lower than those of the reference drug, griseofulvin. The MIC of 5c and 5h were 0.491 μg/mL and 0.619 μg/mL against T. mentagrophytes (MIC of griseofulvin: 2.52 μg/mL). The compounds were also tested against Gram-positive and Gram-negative bacteria. Briefly, 5c was the most active against Escherichia coli and Bacillus subtilis, with MIC values much better than that of ciprofloxacin (MIC of 5c = 1.56 μg/mL and 1.23 μg/mL, MIC of ciprofloxacin = 31.49 and 125.99 μg/mL, respectively). Molecular docking suggested a good fit in the active site of fungal lanosterol 14α-demethylase (CYP51) and bacterial FtsZ (Filamenting temperature-sensitive mutant Z) protein. Conclusions: As a result, the title compounds emerged as promising entities with broad antifungal and antibacterial effects, highlighting the utility of oxime ether function in the azole scaffold. Full article

Phylloporia pulla, a macrofungal species in the Hymenochaetales, Basidiomycota, is known to enhance the nutritional and bioactive properties of rice through co-fermentation; however, its own secondary metabolites are not well understood. In this study, an integrative analysis of transcriptome and metabolome data revealed that the accumulation of steroids, steroid derivatives, and triterpenoids in P. pulla peaks during the mid-growth stage, while the genes associated with these metabolites show higher expression levels from the early to mid-growth stages. Weighted gene co-expression network analysis identified several modules containing candidate genes involved in the synthesis of steroids, steroid derivatives, and triterpenoids. Specifically, six key hub genes were identified, along with their connectivity to other related genes, as potential catalysts in converting the precursor lanosterol to celastrol. This study enhances our understanding of the secondary metabolites of P. pulla and is essential for the selective utilization of these bioactive compounds. Full article

The Analytical Quality by Design (AQbD) concept was adopted to establish a quantitative analysis of multi-components with a single marker (QAMS) method for industrial lanolin alcohol, targeting cholesterol, lanosterol, and 24,25-dihydrolanosterol. The potential critical method parameters (CMPs) were identified as column temperature, flow rate, and gradient. Definitive screening design and statistical modeling were employed to optimize the gradient conditions of the mobile phase, column temperature, and flow rate. The Method Operable Design Region (MODR) was determined using a risk-based quantification approach. The robustness was assessed using a Plackett–Burman experimental design, followed by methodological validation. Optimal analytical conditions were as follows: acetonitrile (B)—water (A) mobile phase system; flow rate of 1.58 mL/min; detection wavelength of 205 nm; injection volume of 10 µL; and column temperature of 37 °C. A gradient elution program was implemented as follows: 0–19.0 min, 90.5% B; 19.0–25.0 min, 90.5–100% B; and 25.0–55.0 min, 100% B. Cholesterol served as an internal standard for quantifying lanosterol and 24,25-dihydrolanosterol, with relative correction factors of 0.4227 and 0.8228, respectively. This analytical method utilized only the cholesterol reference substance as an internal standard to quantify the content of cholesterol, lanosterol, and 24,25-dihydrolanosterol in industrial lanolin alcohol. It reduced the testing costs and enhanced efficiency, making it potentially suitable for widespread adoption in lanolin alcohol processing industries. Full article

Cytochrome P450 (P450) enzymes dominate steroid metabolism. In general, the simple C-hydroxylation reactions are mechanistically straightforward and are generally agreed to involve a perferryl oxygen species (formally FeO³⁺). Several of the steroid transformations are more complex and involve C-C bond scission. We initiated mechanistic studies with several of these (i.e., 11A1, 17A1, 19A1, and 51A1) and have now established that the dominant modes of catalysis for P450s 19A1 and 51A1 involve a ferric peroxide anion (i.e., Fe³⁺O₂¯) instead of a perferryl ion complex (FeO³⁺), as demonstrated with ¹⁸O incorporation studies. P450 17A1 is less clear. The indicated P450 reactions all involve sequential oxidations, and we have explored the processivity of these multi-step reactions. P450 19A1 is distributive, i.e., intermediate products dissociate and reassociate, but P450s 11A1 and 51A1 are highly processive. P450 17A1 shows intermediate processivity, as expected from the release of 17-hydroxysteroids for the biosynthesis of key molecules, and P450 19A1 is very distributive. P450 11B2 catalyzes a processive multi-step oxidation process with the complexity of a chemical closure of an intermediate to a locked lactol form. Full article

Chaga mushroom (Inonotus obliquus) is a pathogenic fungus that grows mostly on birch species (Betula pendula Roth and B. pubescens Ehrh.) and has traditionally been used as an anticancer medicine. This study aimed to compare the chemical composition and cytotoxic activity of chagas growing on both Betula spp. on various cancer cell lines. The freeze-dried extracts contained triterpenes inotodiol, lanosterol betulin, and betulinic acid typical to conks growing on Betula species. The cytotoxic activity of chaga growing on Betula pendula and B. pubescens 80% ethanolic extracts against 31 human cancer cell lines was evaluated by a sulforhodamine B assay. Chaga extract showed moderate activity against all cancer cell lines examined; it did not result in high cytotoxicity (IC₅₀ ≤ 20 µg/mL). The strongest inhibitions were observed with chaga (growing on B. pendula) extract on the HepG2 and CAL-62 cell line and with chaga (from B. pubescens) extract on the HepG2 cell line, with IC₅₀ values of 37.71, 43.30, and 49.99 μg/mL, respectively. The chaga extracts from B. pendula exert somewhat stronger effects on most cancer cell lines studied than B. pubescens extracts, which can be attributed to a higher content of inotodiol in B. pendula extracts. This study highlights the potential of chaga as a source of bioactive compounds with selective anticancer properties. To the best of our knowledge, this study is the first investigation of the chemical composition of I. obliquus parasitizing on B. pubescens. Full article