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Silymarin, also known as milk thistle extract, inhibits hepatitis C virus (HCV) infection and also displays antioxidant, anti-inflammatory, and immunomodulatory actions that contribute to its hepatoprotective effects. In the current study, we evaluated the hepatoprotective actions of the seven major flavonolignans and one flavonoid that comprise silymarin. Activities tested included inhibition of: HCV cell culture infection, NS5B polymerase activity, TNF-α-induced NF-κB transcription, virus-induced oxidative stress, and T-cell proliferation. All compounds were well tolerated by Huh7 human hepatoma cells up to 80 μM, except for isosilybin B, which was toxic to cells above 10 μM. Select compounds had stronger hepatoprotective functions than silymarin in all assays tested except in T cell proliferation. Pure compounds inhibited JFH-1 NS5B polymerase but only at concentrations above 300 μM. Silymarin suppressed TNF-α activation of NF-κB dependent transcription, which involved partial inhibition of IκB and RelA/p65 serine phosphorylation, and p50 and p65 nuclear translocation, without affecting binding of p50 and p65 to DNA. All compounds blocked JFH-1 virus-induced oxidative stress, including compounds that lacked antiviral activity. The most potent compounds across multiple assays were taxifolin, isosilybin A, silybin A, silybin B, and silibinin, a mixture of silybin A and silybin B. The data suggest that silymarin- and silymarin-derived compounds may influence HCV disease course in some patients. Studies where standardized silymarin is dosed to identify specific clinical endpoints are urgently needed.

Bacterial efflux pumps are active transport proteins responsible for resistance to selected biocides and antibiotics. It has been shown that production of efflux pumps is up-regulated in a number of highly pathogenic bacteria, including methicillin resistant Staphylococcus aureus. Thus, the identification of new bacterial efflux pump inhibitors is a topic of great interest. Existing assays to evaluate efflux pump inhibitory activity rely on fluorescence by an efflux pump substrate. When employing these assays to evaluate efflux pump inhibitory activity of plant extracts and some purified compounds, we observed severe optical interference that gave rise to false negative results. To circumvent this problem, a new mass spectrometry-based method was developed for the quantitative measurement of bacterial efflux pump inhibition. The assay was employed to evaluate efflux pump inhibitory activity of a crude extract of the botanical Hydrastis Canadensis, and to compare the efflux pump inhibitory activity of several pure flavonoids. The flavonoid quercetin, which appeared to be completely inactive with a fluorescence-based method, showed an IC50 value of 75 μg/mL with the new method. The other flavonoids evaluated (apigenin, kaempferol, rhamnetin, luteolin, myricetin), were also active, with IC50 values ranging from 19 μg/mL to 75 μg/mL. The assay described herein could be useful in future screening efforts to identify efflux pump inhibitors, particularly in situations where optical interference precludes the application of methods that rely on fluorescence.

Coagulase-negative staphylococci are dominant human skin colonizers, producing natural products that shape the community and prevent pathogen colonization. The molecular mechanisms by which these natural products mediate interbacterial competition are not fully understood. Here, we identify a plasmid-borne daptide bacteriocin (hominicin) from a human skin isolate of Staphylococcus hominis , which features an unusual N 2 - N 2 -dimethyl-1,2-propanediamine C-terminus. Heterologous expression of the reconstituted biosynthetic loci yields a daptide product of the same molecular mass that exhibits antimicrobial activity against the skin pathogen Staphylococcus aureus , with amino-modified termini being essential for activity. Membrane permeability and voltage-clamp lipid bilayer experiments support a mechanism by which the daptide rapidly dissipates the transmembrane potential by forming peptidic channels. Additionally, we identify a cognate homI gene that confers resistance against membrane damage. Finally, the purified daptide effectively protects mouse skin from S. aureus- induced epicutaneous injury, as evidenced by reduced bacterial burden, inflammation, and transepithelial water loss, highlighting its therapeutic potential for treating bacterial skin infections. Our findings elucidate a mechanism of action, biosynthesis, and resistance for a staphylococcal bacteriocin belonging to a class of natural products called daptides. Coagulase-negative staphylococci secrete natural products that prevent pathogen colonization. Here, the authors identify hominicin, a daptide bacteriocin produced by Staphylococcus hominis that has antimicrobial activity against a skin pathogen.

Background Perylenequinones, such as hypocrellins and hypomycins, are fungal secondary metabolites with potential for pharmaceutical and industrial applications due to both their physical and biological properties. This study focused on their sustainable production. Additionally, stable isotope labeling was used to probe the biosynthesis of these compounds, demonstrating how sugars are likely incorporated into the perylenequinone scaffold. Methods Shiraia sp. (strain MSX60519; Shiraiaceae, Pleosporales) was cultivated under varying nutrient conditions to evaluate the production of perylenequinones, with sugars serving as primary carbon sources. Five metabolites were isolated (from oatmeal cultures) using environmentally friendly solvent-based techniques, and the process was further optimized to maximize yields. High-performance liquid chromatography (HPLC) and liquid chromatography–high-resolution mass spectrometry (LC–HRMS) were employed to detect, characterize, and quantify the major compounds. Furthermore, feeding experiments were performed using 13 C-labeled glucose, with droplet probe mass spectrometry used to monitor stable isotope incorporation in situ. Results This study yielded three key findings. First, the production of perylenequinones was significantly enhanced by supplementing fermentation media with sugars, and disaccharides significantly enhanced the production of perylenequinones compared to monosaccharides. Optimizing sugar concentrations during the fermentation further influenced the profile of secondary metabolites. Second, stable isotope labeling experiments confirmed that sugars are the primary building blocks of perylenequinones, as noted by tracing 13 C-labeling into ent -shiraiachrome A ( 1 ). Finally, a green, scalable, and sustainable strategy for producing these compounds on the gram scale was developed by optimizing fermentation conditions, refining purification methods, and improving extraction efficiency. Conclusion These findings provide critical insights into optimizing fermentation conditions for the scaled and sustainable production of perylenequinones. This approach offers a cost-effective and environmentally friendly pipeline for harnessing these valuable compounds, paving the way for broader pharmaceutical and industrial applications. Graphical abstract

Background The growing consumer preference for natural and sustainable products has heightened interest in biopigments across pharmaceutical, cosmetic, and food industries. In this study, we investigate endophytic fungi as a viable and eco-friendly source for the production of bioactive natural pigments. Methods and results A promising strain, Aspergillus westerdijkiae 17P, was isolated from Betula pendula and assessed for its pigment-producing potential and associated bioactivities. The biomass extract was fractionated, and the resulting components were evaluated for antimicrobial, antioxidant, anticancer, neuroprotective, and peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist activities. Among the fractions, 17P2 exhibited broad-spectrum antimicrobial effects, notable antioxidant activity (83% DPPH radical scavenging at 1000 mg/mL), and cytotoxicity against MCF-7 and HepG2 cancer cell lines, with IC₅₀ values of 250 mg/mL. Isothermal titration calorimetry (ITC) demonstrated strong binding affinities of 17P2 to acetylcholinesterase (Kd = 1.63 µM) and butyrylcholinesterase (Kd = 0.03 µM), indicating potential anti-Alzheimer’s properties. Additionally, significant interactions with monoamine oxidase A and PPAR-γ suggest possible antidepressant and antidiabetic applications. Four major pigment fractions (17P1–17P4) were purified and structurally characterized using UHPLC-MS and NMR, revealing key metabolites such as aluminium and iron aspergillic acid complexes, penicillic acid, and preussin. Notably, gamma irradiation at 2000 Gy significantly enhanced the red, yellow, and orange pigments yield compared to the non-irradiated control cultures. Conclusions Collectively, these findings position A. westerdijkiae 17P as a valuable and versatile biotechnological resource for the sustainable production of multifunctional fungal pigments with potential industrial and therapeutic applications.

Silymarin prevents liver disease in many experimental rodent models, and is the most popular botanical medicine consumed by patients with hepatitis C. Silibinin is a major component of silymarin, consisting of the flavonolignans silybin A and silybin B, which are insoluble in aqueous solution. A chemically modified and soluble version of silibinin, SIL, has been shown to potently reduce hepatitis C virus (HCV) RNA levels in vivo when administered intravenously. Silymarin and silibinin inhibit HCV infection in cell culture by targeting multiple steps in the virus lifecycle. We tested the hepatoprotective profiles of SIL and silibinin in assays that measure antiviral and anti-inflammatory functions. Both mixtures inhibited fusion of HCV pseudoparticles (HCVpp) with fluorescent liposomes in a dose-dependent fashion. SIL inhibited 5 clinical genotype 1b isolates of NS5B RNA dependent RNA polymerase (RdRp) activity better than silibinin, with IC50 values of 40-85 µM. The enhanced activity of SIL may have been in part due to inhibition of NS5B binding to RNA templates. However, inhibition of the RdRps by both mixtures plateaued at 43-73%, suggesting that the products are poor overall inhibitors of RdRp. Silibinin did not inhibit HCV replication in subgenomic genotype 1b or 2a replicon cell lines, but it did inhibit JFH-1 infection. In contrast, SIL inhibited 1b but not 2a subgenomic replicons and also inhibited JFH-1 infection. Both mixtures inhibited production of progeny virus particles. Silibinin but not SIL inhibited NF-κB- and IFN-B-dependent transcription in Huh7 cells. However, both mixtures inhibited T cell proliferation to similar degrees. These data underscore the differences and similarities between the intravenous and oral formulations of silibinin, which could influence the clinical effects of this mixture on patients with chronic liver diseases.

Echinacea preparations, which are used for the prevention and treatment of upper respiratory infections, account for 10% of the dietary supplement market in the U.S., with sales totaling more than $100 million annually. In an attempt to shed light on Echinacea's mechanism of action, we evaluated the effects of a 75% ethanolic root extract of Echinacea purpurea, prepared in accord with industry methods, on cytokine and chemokine production from RAW 264.7 macrophage-like cells. We found that the extract displayed dual activities; the extract could itself stimulate production of the cytokine TNF-α, and also suppress production of TNF-α in response to stimulation with exogenous LPS. Liquid:liquid partitioning followed by normal-phase flash chromatography resulted in separation of the stimulatory and inhibitory activities into different fractions, confirming the complex nature of this extract. We also studied the role of alkylamides in the suppressive activity of this E. purpurea extract. Our fractionation method concentrated the alkylamides into a single fraction, which suppressed production of TNF-α, CCL3, and CCL5; however fractions that did not contain detectable alkylamides also displayed similar suppressive effects. Alkylamides, therefore, likely contribute to the suppressive activity of the extract but are not solely responsible for that activity. From the fractions without detectable alkylamides, we purified xanthienopyran, a compound not previously known to be a constituent of the Echinacea genus. Xanthienopyran suppressed production of TNF-α suggesting that it may contribute to the suppressive activity of the crude ethanolic extract. Finally, we show that ethanolic extracts prepared from E. purpurea plants grown under sterile conditions and from sterilized seeds, do not contain LPS and do not stimulate macrophage production of TNF-α, supporting the hypothesis that the macrophage-stimulating activity in E. purpurea extracts can originate from endophytic bacteria. Together, our findings indicate that ethanolic E. purpurea extracts contain multiple constituents that differentially regulate cytokine production by macrophages.

Tef (Eragrostis tef) is an orphan crop that is widely grown in East Africa, primarily in Ethiopia as a staple crop. It is becoming popular in the Western world owing to its nutritious and gluten-free grains and the forage quality of its biomass. Tef is also considered to have a high antioxidant capacity based on cell-free studies. However, the antioxidant activity of tef has never been validated using a physiologically relevant cell model. The purpose of this study was to investigate the antioxidant capacity of tef grain extracts using a mammalian cell model. We hypothesized that the tef grain extracts are capable of modulating the cellular antioxidant response via the modulation of glutathione (GSH) biosynthetic pathways. Therefore, we evaluated the antioxidant activity of purified tef grain extracts in the human acute monocytic leukemia (THP-1) cell line. Our findings revealed that the organic fraction of grain extracts increased the cellular GSH level, which was more evident for brown-colored tef than the ivory variety. Moreover, a brown-tef fraction increased the expressions of GSH-pathway genes, including γ-glutamate cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits and glutathione reductase (GR), an enzyme that plays a key role in GSH biosynthesis, suggesting that tef extracts may modulate GSH metabolism. Several compounds were uniquely identified via mass spectrometry (MS) in GSH-modulating brown-tef samples, including 4-oxo-β-apo-13-carotenone, γ-linolenic acid (methyl ester), 4,4′-(2,3-dimethyl-1,4-butanediyl)bis-phenol (also referred to as 8,8′-lignan-4,4′-diol), and (3β)-3-[[2-[4-(Acetylamino)phenoxy]acetyl]oxy]olean-12-en-28-oic acid. Tef possesses antioxidant activity due to the presence of phytochemicals that can act as direct antioxidants, as well as modulators of antioxidant-response genes, indicating its potential role in alleviating diseases triggered by oxidative stresses. To the best of our knowledge, this is the first report revealing the antioxidant ability of tef extracts in a physiologically relevant human cell model.

Bioactivity-directed fractionation of the organic extracts of two filamentous fungi of the Bionectriaceae, strains MSX 64546 and MSX 59553 from the Mycosynthetix library, led to the isolation of a new dimeric epipolythiodioxopiperazine alkaloid, verticillin H ( 1 ), along with six related analogs, Sch 52900 ( 2 ), verticillin A ( 3 ), gliocladicillin C ( 4 ), Sch 52901 ( 5 ), 11′-deoxyverticillin A ( 6 ) and gliocladicillin A ( 7 ). The structures of compounds 1 – 7 were determined by extensive NMR and HRMS analyses, as well as by comparisons to the literature. All compounds ( 1 – 7 ) were evaluated for cytotoxicity against a panel of human cancer cell lines, displaying IC 50 values ranging from 1.2 μ M to 10 n M . Compounds 1 – 5 were examined for activity in the NF-κB assay, where compounds 2 and 3 revealed activity in the sub-micromolar range. Additionally, compounds 1 , 3 and 4 were tested for EGFR inhibition using an enzymatic assay, while compound 3 was examined against an overexpressing EGFR +ve cancer cell line.

Two new xanthone–anthraquinone heterodimers, acremoxanthone C ( 5 ) and acremoxanthone D ( 2 ), have been isolated from an extract of an unidentified fungus of the order Hypocreales (MSX 17022) by bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Two known related compounds, acremonidin A ( 4 ) and acremonidin C ( 3 ) were also isolated, as was a known benzophenone, moniliphenone ( 1 ). The structures of these isolates were determined via extensive use of spectroscopic and spectrometric tools in conjunction with comparisons to the literature. All compounds ( 1–5 ) were evaluated against a suite of biological assays, including those for cytotoxicity, inhibition of the 20S proteasome, mitochondrial transmembrane potential and nuclear factor-κB.