Discovery of Cryptic Natural Products Using High-Throughput Elicitor Screening on Agar Media.

It is now well-established that microbial genomes carry sparingly expressed biosynthetic gene clusters (BGCs) that need to be induced in order to characterize their products. To do so, we herein subjected two well-known producers, and , to high-throughput elicitor screening (HiTES), an emerging approach for accessing the products of these "cryptic" BGCs. Both organisms have previously been examined extensively in liquid cultures.

Discovery of -Aryl-'-[4-(aryloxy)cyclohexyl]squaramide-Based Inhibitors of LXR/SREBP-1c Signaling Pathway Ameliorating Steatotic Liver Disease: Navigating the Role of SIRT6 Activation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is primarily attributed to the abnormal upregulation of hepatic lipogenesis, which is especially caused by the overactivation of the liver X receptor/sterol regulatory element-binding protein-1c (LXR/SREBP-1c) pathway in hepatocytes. In this study, we report the rational design and synthesis of a novel series of squaramides via bioisosteric replacement, which was evaluated for its inhibitory activity on the LXR/SREBP-1c pathway using dual cell-based assays. Compound was found to significantly downregulate LXR, SREBP-1c, and their target genes associated with lipogenesis.

Regulatory role of Echinochrome A in cancer-associated fibroblast-mediated lung cancer cell migration.

Echinochrome A (Ech A), a marine biosubstance isolated from sea urchins, is a strong antioxidant, and its clinical form, histochrome, is being used to treat several diseases, such as ophthalmic, cardiovascular, and metabolic diseases. Cancer-associated fibroblasts (CAFs) are a component of the tumor stroma and induce phenotypes related to tumor malignancy, including epithelial-mesenchymal transition (EMT) and cancer stemness, through reciprocal interactions with cancer cells. Here, we investigated whether Ech A modulates the properties of CAFs and alleviates CAF-induced lung cancer cell migration.

Hirocidins, Cytotoxic Metabolites from Streptomyces hiroshimensis, Induce Mitochondrion-Mediated Apoptosis.

Recent advances in whole genome sequencing have revealed an immense microbial potential for the production of therapeutic small molecules, even from well-known producers. To access this potential, we subjected prominent antimicrobial producers to alternative antiproliferative assays using persistent cancer cell lines. Described herein is our discovery of hirocidins, novel secondary metabolites from Streptomyces hiroshimensis with antiproliferative activities against colon and persistent breast cancer cells.

Molecular networking and computational NMR analyses uncover six polyketide-terpene hybrids from termite-associated Xylaria isolates.

Fungi constitute the Earth's second most diverse kingdom, however only a small percentage of these have been thoroughly examined and categorized for their secondary metabolites, which still limits our understanding of the ecological chemical and pharmacological potential of fungi. In this study, we explored members of the co-evolved termite-associated fungal genus Xylaria and identified a family of highly oxygenated polyketide-terpene hybrid natural products using an MS/MS molecular networking-based dereplication approach. Overall, we isolated six no yet reported xylasporin derivatives, of which xylasporin A (1) features a rare cyclic-carbonate moiety.

AM-18002, a derivative of natural anmindenol A, enhances radiosensitivity in mouse breast cancer cells.

Natural anmindenol A isolated from the marine-derived bacteria Streptomyces sp. caused potent inhibition of inducible nitric oxide synthase without any significant cytotoxicity. This compound consists of a structurally unique 3,10-dialkylbenzofulvene skeleton.

Determination of the Absolute Configuration of Secondary Alcohols in a Compound Mixture via the Application of Competing Enantioselective Acylation Coupled with LC/MS Analysis.

The determination of natural product stereochemistry plays a significant role in drug discovery and development. Understanding the stereochemistry of natural products is essential for predicting and optimizing their interactions with biological targets, which, in turn, influences their therapeutic efficacy, safety, and overall impact on living organisms. Here, we present the first application of competitive enantioselective acylation (CEA) reactions in conjunction with LC/MS analysis for determining the absolute configuration of secondary alcohols in natural products which were purified as a mixture.

Characterization of Chemical Interactions between Clinical Drugs and the Oral Bacterium, , via Bioactivity-HiTES.

In the field of natural product research, the rediscovery of already-known compounds is one of the significant issues hindering new drug development. Recently, an innovative approach called bioactivity-HiTES has been developed to overcome this limitation, and several new bioactive metabolites have been successfully characterized by this method. In this study, we applied bioactivity-HiTES to , the human oral bacterium, with 3120 clinical drugs as potential elicitors.

Targeted Discovery of Cryptic Enediyne Natural Products via FRET-Coupled High-Throughput Elicitor Screening.

Enediyne antibiotics are a striking family of DNA-cleaving natural products with high degrees of cytotoxicity and structural complexity. Microbial genome sequences, which have recently accumulated, point to an untapped trove of "cryptic" enediynes. Most of the cognate biosynthetic gene clusters (BGCs) are sparingly expressed under standard growth conditions, making it difficult to characterize their products.

Estrogenic Activity of 4-Hydroxy-Benzoic Acid from via Estrogen Receptor α-Dependent Signaling Pathways.

, a deciduous tree belonging to Aceraceae, has been used in traditional oriental medicine for treating hepatic disorders, such as hepatitis, cirrhosis, and liver cancer. We evaluated the estrogen-like effects of using an estrogen receptor (ER)-positive breast cancer cell line, namely MCF-7, to identify potential phytoestrogens and found that an aqueous extract of promoted cell proliferation in MCF-7 cells. Five phenolic compounds (-) were separated and identified from the active fraction using bioassay-guided fractionation of crude extract and phytochemical analysis.

Targeted Discovery of Cryptic Metabolites with Antiproliferative Activity.

Microorganisms have provided a rich source of therapeutically valuable natural products. Recent advances in whole genome sequencing and bioinformatics have revealed immense untapped potential for new natural products in the form of silent or "cryptic" biosynthetic genes. We herein conducted high-throughput elicitor screening (HiTES) in conjunction with cytotoxicity assays against selected cancer cell lines with the goal of uncovering otherwise undetectable cryptic metabolites with antiproliferative activity.

Antitumor Potential of Withanolide Glycosides from Ashwagandha () on Apoptosis of Human Hepatocellular Carcinoma Cells and Tube Formation in Human Umbilical Vein Endothelial Cells.

Hepatocellular carcinoma (HCC) is the fastest-growing tumor capable of spreading to other organs via blood vessels formed by endothelial cells. Apoptosis and angiogenesis-targeting therapies are attractive for cancer treatment. In this study, we aimed to study the in vitro cytotoxicity of against human HCC (HepG2) cells, identify potential antitumoral withanolide glycosides from the active fraction, and elucidate cytotoxic molecular mechanisms of identified bioactive compounds.

Momomycin, an Antiproliferative Cryptic Metabolite from the Oxytetracycline Producer Streptomyces rimosus.

Natural products provide an important source of pharmaceuticals and chemical tools. Traditionally, assessment of unexplored microbial phyla has led to new natural products. However, with every new microbe, the number of orphan biosynthetic gene clusters (BGC) grows.

Induction of Diverse Cryptic Fungal Metabolites by Steroids and Channel Blockers.

Fungi offer a deep source of natural products but remain underutilized. Most biosynthetic gene clusters (BGCs) that can be detected are silent or "cryptic" in standard lab cultures and their products are thus not interrogated in routine screens. As genetic alterations are difficult and some strains can only be grown on agar, we have herein applied an agar-based high-throughput chemical genetic screen to identify inducers of fungal BGCs.

GNPS-Guided Discovery of Madurastatin Siderophores from the Termite-Associated Actinomadura sp. RB99.

In this study, we analyzed if Actinomadura sp. RB99 produces siderophores that that could be responsible for the antimicrobial activity observed in co-cultivation studies. Dereplication of high-resolution tandem mass spectrometry (HRMS/MS) and global natural product social molecular networking platform (GNPS) analysis of fungus-bacterium co-cultures resulted in the identification of five madurastatin derivatives (A1, A2, E1, F, and G1), of which were four new derivatives.

Structural Elucidation of Cryptic Algaecides in Marine Algal-Bacterial Symbioses by NMR Spectroscopy and MicroED.

Microbial secondary metabolite discovery is often conducted in pure monocultures. In a natural setting, however, where metabolites are constantly exchanged, biosynthetic precursors are likely provided by symbionts or hosts. In the current work, we report eight novel and architecturally unusual secondary metabolites synthesized by the bacterial symbiont Phaeobacter inhibens from precursors that, in a native context, would be provided by their algal hosts.

Identification of Renoprotective Phytosterols from Mulberry () Fruit against Cisplatin-Induced Cytotoxicity in LLC-PK1 Kidney Cells.

The aim of this study was to explore the protective effects of bioactive compounds from the fruit of the mulberry tree ( L.) against cisplatin-induced apoptosis in LLC-PK1 pig kidney epithelial cells. fruit is a well-known edible fruit commonly used in traditional folk medicine.

Withasomniferol D, a New Anti-Adipogenic Withanolide from the Roots of Ashwagandha ().

(Solanaceae), well-known as 'Indian ginseng' or 'Ashwagandha', is a medicinal plant that is used in Ayurvedic practice to promote good health and longevity. As part of an ongoing investigation for bioactive natural products with novel structures, we performed a phytochemical examination of the roots of employed with liquid chromatography-mass spectrometry (LC/MS)-based analysis. The chemical analysis of the methanol extract of roots using repeated column chromatography and high-performance liquid chromatography under the guidance of an LC/MS-based analysis resulted in a new withanolide, withasomniferol D ().

Non-peptide secondary metabolites from poisonous mushrooms: overview of chemistry, bioactivity, and biosynthesis.

Covering: up to June 2021A wide variety of mushrooms have traditionally been recognized as edible fungi with high nutritional value and low calories, and abundantly produce structurally diverse and bioactive secondary metabolites. However, accidental ingestion of poisonous mushrooms can result in serious illnesses and even death. Chemically, mushroom poisoning is associated with secondary metabolites produced in poisonous mushrooms, causing specific toxicity.

Bioactive Phytochemicals from Mulberry: Potential Anti-Inflammatory Effects in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages.

The fruits of the mulberry tree ( L.), known as white mulberry, have been consumed in various forms, including tea, beverages, and desserts, worldwide. As part of an ongoing study to discover bioactive compounds from fruits, the anti-inflammatory effect of compounds from were evaluated in lipopolysaccharide (LPS)-stimulated mouse RAW 264.

A community resource for paired genomic and metabolomic data mining.

Genomics and metabolomics are widely used to explore specialized metabolite diversity. The Paired Omics Data Platform is a community initiative to systematically document links between metabolome and (meta)genome data, aiding identification of natural product biosynthetic origins and metabolite structures.

Antioxidant and Anti-Inflammatory Effects of White Mulberry ( L.) Fruits on Lipopolysaccharide-Stimulated RAW 264.7 Macrophages.

In this study, the protective effects of white mulberry () fruits on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages were investigated. The ethanol (EtOH) extract of white mulberry fruits and its derived fractions contained adequate total phenolic and flavonoid contents, with good in vitro antioxidant radical scavenging activity.

Polyhalogenation of Isoflavonoids by the Termite-Associated sp. RB99.

Based on high-resolution tandem mass spectrometry (HR-MS) and global natural products social molecular networking (GNPS), we found that plant-derived daidzein and genistein derivatives are polyhalogenated by termite-associated species RB99. MS-guided purification from extracts of bacteria grown under optimized conditions led to the isolation of eight polychlorinated isoflavones, including six unreported derivatives, and seven novel polybrominated derivatives, two of which showed antimicrobial activity.

Ergostane-Type Steroids from Korean Wild Mushroom that Control Adipocyte and Osteoblast Differentiation.

As part of our current work to discover structurally and/or biologically novel compounds from Korean wild mushrooms, we isolated five ergostane-type steroids (1-5) from the fruiting bodies of via repeated column chromatographic separations and HPLC purification. The chemical structures of the isolated steroids were shown to be (22E,24)-24-methylcholesta-4,22- diene-3,6-dione (1), ergosta-7,22-diene-3,5,6-triol (2), ergosta-7,22-diene-3,5,6,9-tetraol (3), (22E,24)-5,8-epidioxyergosta-6,22-diene-3-ol-3-O--D-glucopyranoside (4), and (22E,24)-5,8-epidioxyergosta-6,9,22-triene-3-ol-3-O--D-glucopyranoside (5) based on comparison of the data regarding their spectroscopic and physical properties with those of previous studies. Notably, this is the first report on the presence of the identified steroids (1-5) in this mushroom.