Ursonic acid attenuates spermatogenesis in oligozoospermia mice through inhibiting ferroptosis.

Ursonic acid (UNA) is a natural pentacyclic triterpene found in some medicinal plants and foods. The reproductive protective effect of UNA was evaluated in a mouse model of oligozoospermia induced by busulfan (BUS) at 30 mg/kg b.w.. The mice were initially divided into groups with UNA concentrations of 10, 30, 50, 100 mg/kg. Subsequently, based on sperm parameters, the optimal concentration of 50 mg/kg was identified. As a control, an additional group was supplemented with ursolic acid at a concentration of 50 mg/kg. The results indicated that BUS caused the loss of spermatogenic cells in testis, the decrease of sperm in epididymis, the disorder of testicular cytoskeleton, the decrease of serum sex hormones such as testosterone which induced an increase in feedback of androgen receptor and other testosterone-related proteins, the increase of malondialdehyde and reactive oxygen species levels and the increase of ferroptosis in testis while UNA successfully reversed these injuries. High-throughput sequencing revealed that UNA administration significantly upregulated the expression of genes associated with spermatogenesis, such as Tnp1, Tnp2, Prm1, among others. These proteins are crucial in the histone to protamine transition during sperm chromatin remodeling. Network pharmacology analysis reveals a close association between UNA and proteins related to the transformation of histones to protamine. Molecular docking studies reveal that UNA can interact with the ferroptosis-inhibiting gene SLC7A11, thereby modulating ferroptosis. Taken together, UNA alleviated BUS-induced oligozoospermia by regulating hormone secretion, mitigating oxidative stress and promoting recovery of spermatogenesis by inhibiting the ferroptosis.

Biotransformation of Ursonic Acid by Aspergillus ochraceus and Aspergillus oryzae to Discover Anti-Neuroinflammatory Derivatives.

Biotransformation of ursonic acid (1) by two fungal strains Aspergillus ochraceus CGMCC 3.5324 and Aspergillus oryzae CGMCC 3.407 yielded thirteen new compounds (4, 5, 7-10, and 13-19), along with five recognized ones. The structural details of new compounds were determined through spectroscopic examination (NMR, IR, and HR-MS) and X-ray crystallography. Various modifications, including hydroxylation, epoxidation, lactonization, oxygen introduction, and transmethylation, were identified on the ursane core. Additionally, the anti-neuroinflammatory efficacy of these derivatives was assessed on BV-2 cells affected by lipopolysaccharides. It was observed that certain methoxylated and epoxylated derivatives (10, 16, and 19) showcased enhanced suppressive capabilities, boasting IC50 values of 8.2, 6.9, and 5.3 µM. Such ursonic acid derivatives might emerge as potential primary molecules in addressing neurodegenerative diseases.

Chemistry and biological activity of resin glycosides from Convolvulaceae species.

Carbohydrate-based drug discovery has gained more and more attention during the last few decades. Resin glycoside is a kind of novel and complex glycolipids mainly distributed in plants of the family Convolvulaceae. Over the last decade, a number of natural resin glycosides and derivatives have been isolated and identified, and exhibited a broad spectrum of biological activities, such as cytotoxic, multidrug-resistant reversal on both microbial pathogens and mammalian cancer cells, antivirus, anticonvulsant, antidepressant, sedative, vasorelaxant, laxative, and α-glucosidase inhibitory effects, indicating their potential as lead compounds for drug discovery. A systematic review of the literature studies was carried out to summarize the chemistry and biological activity of resin glycosides from Convolvulaceae species, based on various data sources such as PubMed, Web of Science, Scopus, and Google scholar. The keyword "Convolvulaceae" was paired with "resin glycoside," "glycosidic acid," "glycolipid," or "oligosaccharide," and the references published between 2009 and June 2021 were covered. In this article, we comprehensively reviewed the structures of 288 natural resin glycoside and derivatives newly reported in the last decade. Moreover, we summarized the biological activities and mechanisms of action of the resin glycosides with pharmaceutical potential. Taken together, great progress has been made on the chemistry and biological activity of resin glycosides from Convolvulaceae species, however, more exploratory research is still needed, especially on the mechanism of action of the biological activities.

Biotransformation of Betulonic Acid by the Fungus Rhizopus arrhizus CGMCC 3.868 and Antineuroinflammatory Activity of the Biotransformation Products.

Biotransformation of betulonic acid (1) by Rhizopus arrhizus CGMCC 3.868 resulted in the production of 16 new (3, 5, 6, and 9-21) and five known compounds. Structures of the new compounds were established by analysis of spectroscopic data. Hydroxylation, acetylation, oxygenation, glycosylation, and addition reactions involved the C-20-C-29 double bond. Antineuroinflammatory activities of the obtained compounds in NO production were tested in lipopolysaccharides-induced BV-2 cells. Compared with the substrate betulonic acid, biotransformation products 3, 8, 9, 14, and 21 exhibited an improved inhibitory effect, with IC50 values of 10.26, 11.09, 5.38, 1.55, and 4.69 µM, lower than that of the positive control, NG-monomethyl-l-arginine.

Glycosidic Acids with Unusual Aglycone Units from Convolvulus arvensis.

Six new glycosidic acids, arvensic acids E-J (1-6), were obtained from a glycosidic acid fraction afforded by alkaline hydrolysis of the crude resin glycosides from Convolvulus arvensis whole plants. Their structures were established from the spectroscopic data obtained and by chemical evidence. They were defined as heptasaccharides or hexasaccharides, comprising d-fucose, d-glucose, and l-rhamnose units. Compounds 1, 3, and 5 were assigned the 11 S-hydroxyheptadecanoic acid as the aglycone, while compounds 2, 4, and 6 were found to possess 11 S-hydroxyhexadecanoic acid as the aglycone. Compounds 1, 3, and 5 are the first representatives of resin glycosides with 11 S-hydroxyheptadecanoic acid as the aglycone.

Anti-inflammatory and α-Glucosidase Inhibitory Activities of Labdane and Norlabdane Diterpenoids from the Rhizomes of Amomum villosum.

A new tetranorditerpenoid (1), two new labdane diterpenoids (2, 3), and nine known analogues (4-12) were isolated from the rhizomes of Amomum villosum var. xanthioides. Compound 1 is an unprecedented rearranged tetranorlabdane diterpenoid, featuring a 6/6/5 fused tricarbocyclic skeleton with an α,ß-unsaturated cyclopentenone unit, while 2 is a structurally rare labdane diterpenoid carrying a five-membered cyclic anhydride moiety. Their structures and absolute configurations were established on the basis of spectroscopic data and the experimental and calculated ECD data. Compound 4 showed inhibitory activity against nitric oxide production, with an IC50 value of 2.4 µM, and also inhibited α-glucosidase activity (IC50 = 10.0 µM).

Anti-Inflammatory 18ß-Glycyrrhetinin Acid Derivatives Produced by Biocatalysis.

In this study, the biocatalysis of 18ß-glycyrrhetinic acid by two strains of filamentous fungi, namely Rhizopus arrhizus AS 3.2893 and Circinella muscae AS 3.2695, was investigated. Scaled-up biotransformation reactions yielded 14 metabolites. Their structures were established based on extensive nuclear magnetic resonance and high-resolution electrospray ionization mass spectrometry data analyses, and seven of them are new compounds. The two fungal strains exhibited distinct biocatalytic features. R. arrhizus could catalyze hydroxylation and carbonylation reactions, whereas C. muscae preferred to catalyze hydroxylation and glycosidation reactions. These highly specific reactions are difficult to achieve by chemical synthesis, particularly under mild conditions. Furthermore, we found that most of the metabolites exhibited pronounced inhibitory activities on lipopolysaccharides-induced nitric oxide production in RAW264.7 cells. These biotransformed derivatives of 18ß-glycyrrhetinic acid could be potential anti-inflammatory agents.

Medicinal uses, pharmacology, and phytochemistry of Convolvulaceae plants with central nervous system efficacies: A systematic review.

Central nervous system (CNS) disorders play a major impact on individual lives and place a severe strain on health care resources. Convolvulaceae is a family comprising approximately 1,600-1,700 species grouped in 55-60 genera, and many species are reported to have an effect on CNS functions. A systematic review of the literature studies was carried out to summarize available evidences on Convolvulaceae plants with CNS efficacies. This review is based on various data sources such as Google Scholar, Web of Science, Scopus, PubMed, and Wanfang Data. A total of 200 related articles were included in this review. According to the research result, 54 Convolvulaceae species are suggested to display CNS efficacies historically, and 46 species have been evaluated for their CNS efficacies. In addition, 67 compounds from 16 Convolvulaceae species are recognized to possess CNS efficacies. Despite great progress made through pharmacology and phytochemistry studies on CNS active Convolvulaceae species, more exploratory research is needed to gain a better understanding of the CNS efficacies of this plant family.

Honokiol trimers and dimers via biotransformation catalyzed by Momordica charantia peroxidase: novel and potent α-glucosidase inhibitors.

Ten honokiol oligomers (1-10), including four novel trimers (1-4) and four novel dimers (5-8), were obtained by means of biotransformation of honokiol catalyzed by Momordica charantia peroxidase (MCP) for the first time. Their structures were established on the basis of spectroscopic methods. The biological results demonstrated that most of the oligomers were capable of inhibiting α-glucosidase with significant abilities, which were one to two orders of magnitude more potent than the substrate, honokiol. In particular, compound 2, the honokiol trimer, displayed the greatest inhibitory activity against α-glucosidase with an IC50 value of 1.38µM. Kinetic and CD studies indicated that 2 inhibited α-glucosidase in a reversible, mixed-type manner and caused conformational changes in the secondary structure of the enzyme protein. These findings suggested that 2 might be exploited as a promising drug candidate for the treatment of diabetes.

Cytotoxic resin glycosides from Ipomoea aquatica and their effects on intracellular Ca2+ concentrations.

Eleven new resin glycosides, aquaterins I-XI (1-11), were isolated from the whole plants of Ipomoea aquatica. The structures of 1-11 were elucidated by a combination of spectroscopic and chemical methods. They were found to be partially acylated tetra- or pentasaccharides derived from simonic acid B and operculinic acids A and C. The site of the aglycone macrolactonization was placed at C-2 or C-3 of the second saccharide moiety, while the two acylating residues could be located at C-2 (or C-3) of the second rhamnose unit and at C-4 (or C-3) on the third rhamnose moiety. All compounds were evaluated for cytotoxicity against a small panel of human cancer cell lines. Compound 4 exhibited the most potent activity against HepG2 cells with an IC50 value of 2.4 µM. Cell cycle analysis revealed 4 to inhibit the proliferation of HepG2 cells via G0/G1 arrest and apoptosis induction. In addition, compounds 1-4, 7, 9, and 10 were found to elevate Ca(2+) in HepG2 cells, which might be involved in the regulation of the cytotoxic activities observed.

The Natural Products Discovery Center: Release of the First 8490 Sequenced Strains for Exploring Actinobacteria Biosynthetic Diversity.

Actinobacteria, the bacterial phylum most renowned for natural product discovery, has been established as a valuable source for drug discovery and biotechnology but is underrepresented within accessible genome and strain collections. Herein, we introduce the Natural Products Discovery Center (NPDC), featuring 122,449 strains assembled over eight decades, the genomes of the first 8490 NPDC strains (7142 Actinobacteria), and the online NPDC Portal making both strains and genomes publicly available. A comparative survey of RefSeq and NPDC Actinobacteria highlights the taxonomic and biosynthetic diversity within the NPDC collection, including three new genera, hundreds of new species, and ~7000 new gene cluster families. Selected examples demonstrate how the NPDC Portal's strain metadata, genomes, and biosynthetic gene clusters can be leveraged using genome mining approaches. Our findings underscore the ongoing significance of Actinobacteria in natural product discovery, and the NPDC serves as an unparalleled resource for both Actinobacteria strains and genomes.

Biotransformation of asiatic acid by Cunninghamella echinulata and Circinella muscae to discover anti-neuroinflammatory derivatives.

In this study, the biotransformation of asiatic acid by Cunninghamella echinulata CGMCC 3.970 and Circinella muscae CGMCC 3.2695 was investigated. Scaled-up biotransformation reactions yielded eight metabolites. Their structures were established based on extensive NMR and HR-ESI-MS data analyses and four of them are new compounds. C. echinulata could catalyze the regioselecitve hydroxylation, carbonylation and lactonization to yield five metabolites. C. muscae could selectively catalyze hydroxylation, acetylation and glycosylation to yield four products. Furthermore, all the identified metabolites were evaluated for their anti-neuroinflammatory activities in LPS-induced BV-2 cells. Most metabolites displayed pronounced inhibitory effect on nitric oxide (NO) production. The results suggested that biotransformed derivatives of asiatic acid might be served as potential neuroinflammatory inhibitors.

Biotransformation of ursolic acid by Circinella muscae and their anti-neuroinflammatory activities of metabolites.

In this study, the biotransformation of ursolic acid by Circinella muscae CGMCC 3.2695 was investigated. Scaled-up biotransformation reactions yielded ten metabolites. Their structures were established based on extensive NMR and HR-ESI-MS data analyses, and four of them are new compounds. C. muscae could selectively catalyze hydroxylation, lactonisation, carbonylation and carboxyl reduction reactions. Furthermore, all the identified metabolites were evaluated for their anti-neuroinflammatory activities in LPS-induced BV-2 cells. Most metabolites displayed pronounced inhibitory effect on nitric oxide (NO) production. The results suggested that biotransformed derivatives of ursolic acid might be served as potential neuroinflammatory inhibitors.

Microbial transformation of betulonic acid by Circinella muscae CGMCC 3.2695 and anti-neuroinflammatory activity of the products.

Microbial transformation of betulonic acid with Circinella muscae CGMCC 3.2695 yielded nine undescribed metabolites and eight known compounds. The structures of the metabolites were established based on extensive NMR and HR-ESI-MS data analyses. It is shown that C. muscae could catalyze the regioselective hydroxylation at C-2, C-7, C-15, C-16, C-21, and C-30 along with carbonylation at C-2 and C-21. Furthermore, potential anti-neuroinflammatory activities of the obtained compounds in NO production were tested in lipopolysaccharides-induced BV-2 cells. Some of the metabolites exhibited pronounced inhibitory activities with IC50 values of 4.27-16.68 µM.

Progress in the total synthesis of resin glycosides.

Resin glycosides, mainly distributed in plants of the family Convolvulaceae, are a class of novel and complex glycolipids. Their structural complexity and significant biological activities have received much attention from synthetic chemists, and a number of interesting resin glycosides have been synthesized. The synthesized resin glycosides and their analogues not only helped in structural verification, structural modification, and further biological activity exploration but also provided enlightenment for the synthesis of glycoside compounds. Herein, the present review summarizes the application of various efforts toward the synthesis of resin glycosides in the last decade.

Arvensic acids K and L, components of resin glycoside fraction from Convolvulus arvensis.

Alkaline hydrolysis of the resin glycoside fraction of the whole plants of Convolvulus arvensis gave two new glycosidic acids, named arvensic acids K and L (1 and 2). Their structures were characterized on the basis of spectroscopic data as well as chemical evidence. They possessed a same pentasaccharide chain, composed of one D-fucose, three D-glucose and one L-rhamnose units. The aglycone of compound 1 was identified to be rarely existing 11S-hydroxyheptadecanoic acid, while compound 2 possessed 11S-hydroxyhexadecanoic acid as the aglycone. Their cytotoxic and anti-migration activities were also evaluated.

PtmC Catalyzes the Final Step of Thioplatensimycin, Thioplatencin, and Thioplatensilin Biosynthesis and Expands the Scope of Arylamine N-Acetyltransferases.

The members of the arylamine N-acetyltransferase (NAT) family of enzymes are important for their many roles in xenobiotic detoxification in bacteria and humans. However, very little is known about their roles outside of detoxification or their specificities for acyl donors larger than acetyl-CoA. Herein, we report the detailed study of PtmC, an unusual NAT homologue encoded in the biosynthetic gene cluster for thioplatensimycin, thioplatencin, and a newly reported scaffold, thioplatensilin, thioacid-containing diterpenoids and highly potent inhibitors of bacterial and mammalian fatty acid synthases. As the final enzyme of the pathway, PtmC is responsible for the selection of a thioacid arylamine over its cognate carboxylic acid and coupling to at least three large, 17-carbon ketolide-CoA substrates. Therefore, this study uses a combined approach of enzymology and molecular modeling to reveal how PtmC has evolved from the canonical NAT scaffold into a key part of a natural combinatorial biosynthetic pathway. Additionally, genome mining has revealed the presence of other related NATs located within natural product biosynthetic gene clusters. Thus, findings from this study are expected to expand our knowledge of how enzymes evolve for expanded substrate diversity and enable additional predictions about the activities of NATs involved in natural product biosynthesis and xenobiotic detoxification.

Anti-aging derivatives of cycloastragenol produced by biotransformation.

In this study, the microbial transformation of cycloastragenol (CA) by the fungi Mucor subtilissimus AS 3.2456 and Aspergillus oryzae AS 3.407 yielded 19 metabolites. Their structures were established based on extensive NMR and HR-MS data analyses, and six of them are new compounds. The two fungal strains exhibited distinct biocatalytic features. M. subtilissimus could catalyse hydroxylation and carbonylation reactions meanwhile the fragile 9,19-cyclopropane ring remained intact. A. oryzae preferred to catalyse hydroxylation, acetylation and ring expansion reactions. These highly specific reactions are difficult to achieve by chemical synthesis, particularly under mild conditions. Furthermore, we found that most of the metabolites could significantly extend the lifespan of Caenorhabditis elegans at 50 µM. These biotransformed derivatives of CA could be potential anti-aging agents.

Isolation of evolvulic acids B and C, two new components of crude resin glycoside fraction from Evolvulus alsinoides.

Two new glycosidic acids, evolvulic acids B and C (1 and 2), along with a known one, evolvulic acid A (3), were isolated from the glycosidic acid fraction afforded by alkaline hydrolysis of crude resin glycosides from Evolvulus alsinoides whole plants. Their structures were characterized by the spectroscopic data and chemical evidences. Compounds 1 and 2 are both defined as tetrasaccharides, composed of D-fucose, D-glucose, L-rhamnose or D-galactose units. Their aglycones are identified to be a distinctive 3S,11R,14R-trihydroxyhexadecanoic acid, which is only discovered from E. alsinoides up to now. The cytotoxic and anti-migration activities of compounds 1-3 were also tested.

Biotransformation of betulinic acid by Circinella muscae and Cunninghamella echinulata to discover anti-inflammatory derivatives.

Biotransformation of betulinic acid was carried out with Circinella muscae CGMCC 3.2695 and Cunninghamella echinulata CGMCC 3.970, yielded six previously undescribed hydroxylated metabolites and four known compounds. C. muscae could catalyze the regioselecitve hydroxylation and carbonylation at C-3, C-7, C-15 and C-21 to yield seven products. C. echinulata could catalyze the C-1, C-7 and C-26 regioselecitve hydroxylation and acetylation to yield five metabolites. The structures of the metabolites were established based on extensive NMR and HR-ESI-MS data analyses. Furthermore, most of the metabolites exhibited pronounced inhibitory activities on lipopolysaccharides-induced NO production in RAW264.7 cells.