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Tapinarof is a stilbene drug that is used to treat psoriasis and atopic dermatitis, and is thought to function through regulation of the AhR and Nrf2 signaling pathways, which have also been linked to inflammatory bowel diseases. It is produced by the gammaproteobacterial Photorhabdus genus, which thus represents a model to probe tapinarof structural and functional transformations. We show that Photorhabdus transforms tapinarof into novel drug metabolism products that kill inflammatory bacteria, and that a cupin enzyme contributes to the conversion of tapinarof and related dietary stilbenes into novel dimers. One dimer has activity against methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococcus faecalis (VRE), and another undergoes spontaneous cyclizations to a cyclopropane‐bridge‐containing hexacyclic framework that exhibits activity against Mycobacterium. These dimers lack efficacy in a colitis mouse model, whereas the monomer reduces disease symptoms. [ABSTRACT FROM AUTHOR]

Tapinarof is a stilbene drug that is used to treat psoriasis and atopic dermatitis, and is thought to function through regulation of the AhR and Nrf2 signaling pathways, which have also been linked to inflammatory bowel diseases. It is produced by the gammaproteobacterial Photorhabdus genus, which thus represents a model to probe tapinarof structural and functional transformations. We show that Photorhabdus transforms tapinarof into novel drug metabolism products that kill inflammatory bacteria, and that a cupin enzyme contributes to the conversion of tapinarof and related dietary stilbenes into novel dimers. One dimer has activity against methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococcus faecalis (VRE), and another undergoes spontaneous cyclizations to a cyclopropane‐bridge‐containing hexacyclic framework that exhibits activity against Mycobacterium. These dimers lack efficacy in a colitis mouse model, whereas the monomer reduces disease symptoms. [ABSTRACT FROM AUTHOR]

The amicoumacins belong to a class of dihydroisocoumarin natural products and display antibacterial, antifungal, anticancer, and anti-inflammatory activities. Amicoumacins are the pro-drug activation products of a bacterial nonribosomal peptide-polyketide hybrid biosynthetic pathway and have been isolated from Gram-positive Bacillus and Nocardia species. Here, we report the stimulation of a "cryptic" amicoumacin pathway in the entomopathogenic Gram-negative bacterium Xenorhabdus bovienii, a strain not previously known to produce amicoumacins. X. bovienii participates in a multi-lateral symbiosis where it is pathogenic to insects and mutualistic to its Steinernema nematode host. Waxmoth larvae are common prey of the X. bovienii-Steinernema pair. Employing a medium designed to mimic the amino acid content of the waxmoth circulatory fluid led to the detection and characterization of amicoumacins in X. bovienii. The chemical structures of the amicoumacins were supported by 2D-NMR, HR-ESI-QTOF-MS, tandem MS, and polarimeter spectral data. A comparative gene cluster analysis of the identified X. bovienii amicoumacin pathway to that of the Bacillus subtilis amicoumacin pathway and the structurally-related Xenorhabdus nematophila xenocoumacin pathway is presented. The X. bovienii pathway encodes an acetyltransferase not found in the other reported pathways, which leads to a series of N-acetyl-amicoumacins that lack antibacterial activity. N-acetylation of amicoumacin was validated through in vitro protein biochemical studies, and the impact of N-acylation on amicoumacin's mode of action was examined through ribosomal structural analyses. [ABSTRACT FROM AUTHOR]

Abstract: Two new angucyclic quinones, angumycinones A (1) and B (2) and six known angucyclinone analogues (3–8) were isolated from a liquid culture extract of the Streptomyces sp. KMC004 strain from acidic coal mine drainage. The structures of these compounds were established using extensive spectroscopic data analyses, including NMR, HRFABMS, UV, CD, and X-ray crystallography. Compounds 1–8 were tested for antimicrobial activity against ten pathogenic microbial or fungal strains. Angumycinone B (2) exhibited antimicrobial activity against Micrococcus luteus, Enterococcus hirae, and methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentration values of 0.78, 1.56, and 12.5μg/mL, respectively. [Copyright &y& Elsevier]

Two previously unreported spiro-cyclopentenones, spirobacillenes A (1) and B (2), were isolated from the 24 h broth culture of Lysinibacillus fusiformisKMC003 derived from acidic coal-mine drainage. The structures of 1and 2were elucidated by analyses of the NMR, HRFABMS, single-crystal X-ray diffraction crystallography, and circular dichroism (CD) spectral data. Compound 1possessed moderate inhibitory activity against the production of nitric oxide (NO) and reactive oxygen species (ROS). [ABSTRACT FROM AUTHOR]

Simple Summary: This study addresses the limited understanding of the molecular consequences of low-dose ionizing radiation (LDIR), a relatively unexplored area compared to high-dose radiation methods. The research focuses on profiling RNA species crosslinked to the RNA-binding protein human antigen R (HuR) using LDIR and high throughput RNA sequencing. The developed method involves isolating RNA fragments crosslinked to HuR through LDIR and immunoprecipitation followed by RNA sequencing, revealing rapid degradation of target mRNAs (e.g., PAX6, ZFP91, NR2F6, and CAND2) in human cell lines. Notably, the downregulation of PAX6 and NR2F6 is identified as a protein mediating the beneficial effects of LDIR on cell viability. The findings underscore the significance of investigating post-transcriptional gene regulation under LDIR conditions. Overall, this research introduces a valuable approach for understanding the impact of LDIR on RNA dynamics, shedding light on the molecular consequences and potential therapeutic applications of low-dose ionizing radiation. Although ionizing radiation (IR) is widely used for therapeutic and research purposes, studies on low-dose ionizing radiation (LDIR) are limited compared with those on other IR approaches, such as high-dose gamma irradiation and ultraviolet irradiation. High-dose IR affects DNA damage response and nucleotide–protein crosslinking, among other processes; however, the molecular consequences of LDIR have been poorly investigated. Here, we developed a method to profile RNA species crosslinked to an RNA-binding protein, namely, human antigen R (HuR), using LDIR and high-throughput RNA sequencing. The RNA fragments isolated via LDIR-crosslinking and immunoprecipitation sequencing were crosslinked to HuR and protected from RNase-mediated digestion. Upon crosslinking HuR to target mRNAs such as PAX6, ZFP91, NR2F6, and CAND2, the transcripts degraded rapidly in human cell lines. Additionally, PAX6 and NR2F6 downregulation mediated the beneficial effects of LDIR on cell viability. Thus, our approach provides a method for investigating post-transcriptional gene regulation using LDIR. [ABSTRACT FROM AUTHOR]

Angumycinone B (Ib) exhibits antimicrobial activity against Micrococcus luteus, Enterococcus hirae, and methicillin-resistant Staphylococcus aureus (MRSA). [ABSTRACT FROM AUTHOR]

Background Inhibition of fatty acid synthase (FAS) is regarded as a sensible therapeutic strategy for the development of optimal anti-cancer agents. Flavonoids exhibit potent anti-neoplastic properties. Methods The MeOH extract of Sophora flavescens was subjected to chromatographic analyses such as VLC and HPLC for the purification of active flavonoids. The DP4 chemical-shift analysis protocol was employed to investigate the elusive chirality of the lavandulyl moiety of the purified polyphenols. Induced Fit docking protocols and per-residue analyses were utilized to scrutinize structural prerequisites for hampering FAS activity. The FAS-inhibitory activity of the purified flavonoids was assessed via the incorporation of [ 3 H] acetyl-CoA into palmitate. Results Six flavonoids, including lavandulyl flavanones, were purified and evaluated for FAS inhibition. The lavandulyl flavanone sophoraflavanone G ( 2 ) exhibited the highest potency (IC 50 of 6.7 ± 0.2 μM), which was more potent than the positive controls. Extensive molecular docking studies revealed the structural requirements for blocking FAS. Per-residue interaction analysis demonstrated that the lavandulyl functional group in the active flavonoids ( 1 – 3 and 5 ) significantly contributed to increasing their binding affinity towards the target enzyme. Conclusion This research suggests a basis for the in silico design of a lavandulyl flavonoid-based architecture showing anti-cancer effects via enhancement of the binding potential to FAS. General significance FAS inhibition by flavonoids and their derivatives may offer significant potential as an approach to lower the risk of various cancer diseases and related fatalities. In silico technologies with available FAS crystal structures may be of significant use in optimizing preliminary leads. [ABSTRACT FROM AUTHOR]

Stigma is a critical issue among people with epilepsy (PWE). There is a need to undertake an integrative review of the factors associated with stigma, as it is experienced subjectively, and cannot be fully understood through quantitative research alone. The aims of this study were to explore the factors influencing epilepsy-associated stigma and to extend our understanding of stigma using an integrative review approach. Three databases (i.e., CINAHL, PubMed, and PsycINFO) were searched for articles published from January 2010 through December 2018 on stigma among PWE. Selected articles were assessed for quality using the mixed-method appraisal tool. The matrix method was used for data extraction and analysis. Overall, the process of the review was guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Overall, 26 studies were included in this review: four qualitative studies, twenty-one quantitative studies, and one mixed-method study. Several factors associated with stigma were found, divided into four categories across two main aspects: individual (i.e., disease and social characteristics) and community (i.e., overall impression/beliefs regarding epilepsy and social networks) based on the Framework Integrating Normative Influences on Stigma. The impression of and beliefs about epilepsy among the general population as well as among PWE were the primary factors affecting stigma. Thus, there is a need for the provision of accurate information about epilepsy to both these groups. Additional studies on epilepsy-associated stigma employing various methodological approaches are required. • Stigma is a critical issue among people with epilepsy. • Both individual and community factors affected epilepsy-associated stigma. • Impression of and beliefs about epilepsy primarily affect the stigma. • Accurate information about epilepsy should be provided to reduce stigma. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: This study demonstrates the biological and chemical analysis of the mushroom Armillariella tabescens (Scop.) Sing. (Tricholomataceae). Methods: Chemical structures of the isolates were determined by 1D and 2D NMR, and ESI‐MS, as well as comparison with previously reported data. All isolates were tested for anti‐inflammatory effects based on their ability to inhibit LPS‐stimulated nitric oxide (NO) production in RAW264.7 cells. Key findings: We found that the MeOH extract of the fruiting bodies of A. tabescens showed antigastritis activity against ethanol‐induced gastric damage in rats and notably reduced the gastric damage index compared to control in a concentration‐dependent manner. Chemical investigation of the MeOH extract led to the isolation of four steroids (1–4), three alkaloids (5–7), two nucleic acids (8–9) and four fatty acids (10–13). This is the first study to report the identification of all isolates, except for compound 7, from A. tabescens. Compounds 1, 2, 3, 4 and 10 showed inhibition on LPS‐stimulated NO production. Treatment with compound 10 inhibited expression of iNOS, COX‐2, phospho‐IKKα, IKKα, phospho‐IκBα, IκBα and NF‐kappa B in LPS‐stimulated RAW264.7 cells. Conclusions: Compound 10 likely contributes to the health benefits of A. tabescens as an antigastritis agent through its anti‐inflammatory effects. [ABSTRACT FROM AUTHOR]

Poria cocos Wolf (Polyporaceae) has been used as a medicinal fungus to treat various diseases since ancient times. This study aimed to investigate the anti-inflammatory chemical constituents of the sclerotia of P. cocos . Based on bioassay-guided fractionation using lipopolysaccharide (LPS)-stimulated Raw264.7 cells, chemical investigation of the EtOH extract of the sclerotia of P. cocos resulted in the isolation and identification of eight compounds including six triterpenoids, namely poricoic acid A ( 1 ), 3- O -acetyl-16α-hydroxydehydrotrametenolic acid ( 2 ), polyporenic acid C ( 3 ), 3β-hydroxylanosta-7,9(11),24-trien-21-oic acid ( 4 ), trametenolic acid ( 5 ), and dehydroeburicoic acid ( 6 ), as well as (−)-pinoresinol ( 7 ) and protocatechualdehyde ( 8 ). The structures of the isolated compounds were determined by spectroscopic analysis, including 1 H and 13 C NMR spectra, and LC/MS analysis. The anti-inflammatory activities of the isolates were evaluated by estimating their effect on the production of nitric oxide (NO) and prostaglandin E 2 (PGE 2 ) in LPS-stimulated Raw264.7 as well as on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Compounds 1 – 5 inhibited NO production and iNOS expression in LPS-stimulated Raw264.7 cells. Among them, compound 1 exerted the highest anti-inhibitory activity and reduced PGE 2 levels via downregulation of COX-2 protein expression. The findings of this study provide experimental evidence that the sclerotia of P. cocos are a potential source of natural anti-inflammatory agents for use in pharmaceuticals and functional foods. Furthermore, the most active compound 1 , seco -lanostane triterpenoid, could be a promising lead compound for the development of novel anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

The bark of Betula platyphylla var. japonica (Betulaceae) has been used to treat pneumonia, choloplania, nephritis, and chronic bronchitis. This study aimed to investigate the bioactive chemical constituents of the bark of B. platyphylla var. japonica . A bioassay-guided fractionation and chemical investigation of the bark of B. platyphylla var. japonica resulted in the isolation and identification of a new lupane-type triterpene, 27-hydroxybetunolic acid ( 1 ), along with 18 known triterpenoids ( 2–19 ). The structure of the new compound ( 1 ) was elucidated on the basis of 1D and 2D NMR spectroscopic data analysis as well as HR-ESIMS. Among the known compounds, chilianthin B ( 17 ), chilianthin C ( 18 ), and chilianthin A ( 19 ) were triterpene-lignan esters, which are rarely found in nature. Compounds 4 , 6 , 7 , 17 , 18 , and 19 showed significant antioxidant activities with IC 50 values in the range 4.48–43.02 μM in a DPPH radical-scavenging assay. However, no compound showed significant inhibition of acetylcholine esterase (AChE). Unfortunately, the new compound ( 1 ) exhibited no significance in both biological activities. This study strongly suggests that B. platyphylla var. japonica bark is a potential source of natural antioxidants for use in pharmaceuticals and functional foods. [ABSTRACT FROM AUTHOR]

Escherichia coli broadly colonize the intestinal tract of humans and produce a variety of small molecule signals. However, many of these small molecules remain unknown. Here, we describe a family of widely distributed bacterial metabolites termed the "indolokines." In E. coli , the indolokines are upregulated in response to a redox stressor via aspC and tyrB transaminases. Although indolokine 1 represents a previously unreported metabolite, four of the indolokines (2–5) were previously shown to be derived from indole-3-carbonyl nitrile (ICN) in the plant pathogen defense response. We show that the indolokines are produced in a convergent evolutionary manner relative to plants, enhance E. coli persister cell formation, outperform ICN protection in an Arabidopsis thaliana-Pseudomonas syringae infection model, trigger a hallmark plant innate immune response, and activate distinct immunological responses in primary human tissues. Our molecular studies link a family of cellular stress-induced metabolites to defensive responses across bacteria, plants, and humans. • Cellular stress-induced indole metabolites termed indolokines in diverse bacteria • Indolokines were identified in fecal samples and enhanced E. coli persister formation • Indolokines outperformed plant defense metabolites in Arabidopsis-Pseudomonas model • Indolokines activated human aryl hydrocarbon receptor and induced IL-6 secretion Kim, Li, et al. describe the characterization of cellular stress-induced, bacterial indole-functionalized metabolites termed "indolokines." The indolokines are found in diverse bacteria, enhance persister formation in E. coli , and activate innate immune responses in both plant and human tissues. [ABSTRACT FROM AUTHOR]