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.

Citrullus colocynthis (L.) Schrad.: A Promising Pharmaceutical Resource for Multiple Diseases.

Citrullus colocynthis (L.) Schrad. (Cucurbitaceae) is widely distributed in the desert areas of the world. The fruit bodies of C. colocynthis are recognized for their wide range of nutraceutical potential, as well as medicinal and pharmaceutical uses. The plant has been reported for various uses, such as asthma, bronchitis, cancer, colic, common cold, cough, diabetes, dysentery, and jaundice. The fruit has been extensively studied for its biological activities, which include insecticide, antitumor, and antidiabetic effects. Numerous bioactive compounds have been reported in its fruit bodies, such as essential oils, fatty acids, glycosides, alkaloids, and flavonoids. Of these, flavonoids or caffeic acid derivatives are the constituents associated with the inhibition of fungal or bacterial growth, whereas eudesmane sesquiterpenes or sesquiterpene lactones are most active against insects, mites, and nematodes. In this review, the scientific evidence for the biological activity of C. colocynthis against insecticide, cytotoxic, and antidiabetic effects is summarized.

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.

Cardiac Protection of a Novel Lupane-Type Triterpenoid from Injuries Induced by Hypoxia-Reperfusion.

Myocardial ischemia-reperfusion injury (MIRI) leads to cardiac remodeling and heart failure associated with acute myocardial infarction, which is one of the leading causes of death worldwide. Betulinic acid (BA), a widely distributed lupane-type triterpenoid, has been reported to possess antioxidative activity and inhibit apoptosis in MIRI. Due to the low bioavailability and water insolubility of BA, a previous study found a series of BA-derivative compounds by microbial transformation. In this study, we observe whether there are anti-MIRI effects of BTA07, a BA derivative, on cardiac injuries induced by hypoxia/reoxygenation (H/R) in adult rat cardiomyocytes in vitro and in Langendorff-perfused hearts ex vivo, and further explore its mechanism of cardioprotection to find more efficient BA derivatives. The hemodynamic parameters of isolated hearts were monitored and recorded by a Lab Chart system. The markers of oxidative stress and apoptosis in isolated hearts and adult rat cardiomyocytes (ARCMs) were evaluated. The expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X (Bax), protein kinase B (Akt) and phospho-Akt (pAkt, Ser473) induced by H/R were detected via Western blot. The Langendorff experiments showed that BTA07 improves hemodynamic parameters, reduces myocardium damage and infarct size, inhibits levels of myocardial tissue enzymes lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary outflow and reduces oxidative stress and the activation of caspase-3 in the myocardium. In vitro, BTA07 reduced cell death and caspase-3 activation and inhibited reactive oxygen species (ROS) generation. Furthermore, the protective effects of BTA07 were attenuated by inhibition of the PI3K/Akt signaling pathway with LY294002 in ARCMs. BTA07 protects ARCMs and isolated hearts from hypoxia-reperfusion partly by inhibiting oxidative stress and cardiomyocyte apoptosis.

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.

Bioactive Constituents from the Bryophyta Hypnum plumaeforme.

Chemical investigation of the secondary metabolites of the whole plant of bryophyte Hypnum plumaeforme Wilson led to the isolation of a new pimarane-type diterpenoid, momilactone F (1), along with seventeen known compounds. Their chemical structures were elucidated based on massive spectroscopic data. The allelopathic and antifungal properties were evaluated. Among them, momilactone F (1), acrenol (2),[11] momilactones A (3) and B (4) showed significant allelopathic activity against Samolus parviflorus Raf. and Lactuca sativa L. var. angustana Irish, as well as selected antifungal property against crop pathogenic fungi strains. On the other hand, 8(14)-podocarpen-13-on-18-oic acid (8) exhibited strong promoting activity on the growth of L. sativa L. var. angustana Irish. The present investigation provided new insights for developing of H. plumaeforme for further application as a potential agricultural tool.

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 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.

(R)-panaxadiol by whole cells of filamentous fungus Absidia coerulea AS 3.3382.

The microbial transformation of 20(R)-panaxadiol (PD) by the fungus Absidia coerulea AS 3.3382 afforded three new and three known metabolites. The structures of the metabolites were characterized as 3-oxo-20(R)-panaxadiol (1), 3-oxo-7ß- hydroxyl-20(R)-panaxadiol (2), 3-oxo-22ß-hydroxyl-20(R)-panaxadiol (3), 3-oxo- 7ß,22ß-dihydroxyl-20(R)-panaxadiol (4), 3-oxo-7ß,24ß-dihydroxyl-20(R)-panaxadiol (5), and 3-oxo-7ß,24α-dihydroxyl-20(R)-panaxadiol (6). Among them, 2-4 were new compounds. In addition, compounds 3 and 4 exhibited significant anti-hepatic fibrosis activity.

Microbial transformation of 20(S)-protopanaxatriol by Mucor spinosus.

Microbial transformation of 20(S)-protopanaxatriol (1) by Mucor spinosus afforded two new and eight known metabolites. The structures of the metabolites were identified as 12-oxo-20(S)-protopanaxatriol (2), 23,24-en-25-methoxyl-20(S)-protopanaxatriol (3), 29-hydroxyl-20(S)-protopanaxatriol (4), 20(S),24(S)-epoxy-dammaran-3ß,6α,12ß,25-triol (5), 12-oxo-27-hydroxyl-20(S)-protopanaxatriol (6), 12-oxo-26-hydroxyl-20(S)-protopanaxatriol (7), 12-oxo-23ß-hydroxyl-20(S)-protopanaxatriol (8), 12-oxo-11ß-hydroxyl-20(S)-protopanaxatriol (9), 12-oxo-15α-hydroxyl-20(S)-protopanaxatriol (10), and 12-oxo-25,26-en-15α-hydroxyl-20(S)-protopanaxatriol (11). Among them, 3 and 11 are new compounds. The metabolites 3, 10 and 11 showed the more potent inhibitory effects against seven cell lines than the substrate.

Biotransformation of 20(S)-protopanaxatriol by Mucor racemosus and the anti-cancer activities of some products.

OBJECTIVE: To produce new derivatives of 20(S)-protopanaxatriol by fungal biotransformation. RESULT: Biotransformation of 20(S)-protopanaxatriol (1) by Mucor racemosus AS 3.205 afforded six products. Their structures were elucidated on the basis of extensive spectroscopic analyses. M. racemosus could selectively catalyze dehydrogenation at C-12 and further hydroxylation at C-7, C-11, and C-15, as well as rearrangement of double bond at C-26. Two of these new compounds exhibited potent inhibitory activity against SH-SY5Y and HepG2 cell lines. CONCLUSION: Biotransformation by M. racemosus AS 3.205 was an effective approach to produce new derivatives of 20(S)-protopanaxatriol.

Pongamol Alleviates Neuroinflammation and Promotes Autophagy in Alzheimer's Disease by Regulating the Akt/mTOR Signaling Pathway.

Alzheimer's disease (AD), one of the neurodegenerative disorders, is highly correlated with the abnormal hyperphosphorylation of Tau and aggregation of ß-amyloid (Aß). Oxidative stress, neuroinflammation, and abnormal autophagy are key drivers of AD and how they contribute to neuropathology remains largely unknown. The flavonoid compound pongamol is reported to possess a variety of pharmacological activities, such as antioxidant, antibacterial, and anti-inflammatory. This study investigated the neuroprotective effect and its mechanisms of pongamol in lipopolysaccharide (LPS)-induced BV2 cells, d-galactose/sodium nitrite/aluminum chloride (d-gal/NaNO2/AlCl3)-induced AD mice, and Caenorhabditis elegans models. Our research revealed that pongamol reduced the release of inflammatory factors IL-1ß, TNF-α, COX-2, and iNOS in LPS-induced BV2 cells. Pongamol also protected neurons and significantly restored memory function, inhibited Tau phosphorylation, downregulated Aß aggregation, and increased oxidoreductase activity in the hippocampus of AD mice. In addition, pongamol reversed the nuclear transfer of NF-κB and increased the levels of Beclin 1 and LC3 II/LC3 I. Most importantly, the anti-inflammatory and promoter autophagy effects of pongamol may be related to the regulation of the Akt/mTOR signaling pathway. In summary, these results showed that pongamol has a potential neuroprotective effect, which greatly enriched the research on the pharmacological activity of pongamol for improving AD.

Microbial transformation of 20(S)-protopanaxatriol by Absidia corymbifera and their cytotoxic activities against two human prostate cancer cell lines.

Seven hydroxylates of 20(S)-protopanaxatriol (1) transformed by Absidia corymbifera AS 3.3387 were isolated and identified by spectral methods including 2D-NMR. Among them, 7ß-hydroxyl-20(S)-protopanaxatriol (2), 7α-hydroxyl-20(S)-protopanaxatriol (3), and 7ß, 15α-dihydroxyl-20(S)-protopanaxatriol (7) are new compounds. The metabolites 2, 6, 7, and 8 showed the more potent inhibitory effects against DU-145 and PC-3 cell lines than the substrate.

Two novel hydroperoxylated products of 20(S)-protopanaxadiol produced by Mucor racemosus and their cytotoxic activities against human prostate cancer cells.

Microbial transformation of 20(S)-protopanaxadiol (1) by Mucor racemosus AS 3.205 yielded two novel hydroperoxylated metabolites and three known hydroxylated metabolites. The structures of the metabolites were identified as 26-hydroxyl-20(S)-protopanaxadiol (2), 23,24-en-25-hydroxyl-20(S)-protopanaxadiol (3), 25,26-en-24(R)-hydroperoxyl-20(S)-protopanaxadiol (4), 23,24-en-25-hydroperoxyl-20(S)-protopanaxadiol (5), and 25-hydroxyl-20(S)-protopanaxadiol (6). 4 and 5 are new compounds. Metabolites 2, 4, and 5 showed the more potent inhibitory effects against DU-145 and PC-3 cell lines than the substrate.

A new flavonoid glycoside from Toxicodendron vernicifluum (Stokes) F.A. Barkley.

Toxicodendron vernicifluum (Stokes) F.A. Barkley, also called 'Qishu', is a shrub belonging to the Anacardiaceae family and producing lacquer. In this work, a new flavonoid glycoside (1), was isolated from the heartwood of T. vernicifluum, together with four known compounds (2-5). The structure of the new compound was determined as 4',7-dihydroxy-3'-methoxy-3-O-ß-D-glucopyranosyl-flavonoid (1), on the basis of acidic hydrolysis, and spectroscopic analyses. Compound 1 showed significantly cytotoxic against A549 cell lines with the values of IC50 at 1.5 µM.

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.

Novel pleuromutilin derivatives as antibacterial agents: synthesis, biological evaluation and molecular docking studies.

Owing to the increasingly serious problems caused by multidrug resistance in community-acquired infection pathogens, it has become an urgent need to develop new classes of antibiotics for overcoming the resistance. In this paper, we describe the design and synthesis of novel pleuromutilin derivatives containing the (2-aminothiazol-4-yl)-4-methyl group, as well as their in vitro antibacterial activities against Gram-positive clinical bacteria. Most of the tested compounds displayed strong antibacterial activities against these methicillin-susceptible and methicillin-resistant bacteria. Particularly noteworthy compound 15 and its derivative 16e, both showed potent antibacterial properties (0.0625-0.5µg/mL) that are superior to amoxicillin and tiamulin. Molecular docking studies suggested that the amino thiazole ring on the side chains of the pleuromutilin derivatives can in general be accommodated near the mutilin core in the binding pocket, and thus play an important role in the activity of the whole molecule. The findings reported herein may provide a new insight into the design of novel pleuromutilin derivatives for human clinical use.

Design, synthesis, and antibacterial activity of novel pleuromutilin derivatives bearing an amino thiazolyl ring.

A series of novel pleuromutilin derivatives containing the amino thiazolyl ring were designed, synthesized, and evaluated for their antibacterial activities in vitro against Gram-positive clinical bacteria. All the target compounds showed better aqueous solubility compared with the lead compound (10). Most compounds displayed strong antibacterial activities against both susceptible and resistant bacteria, particularly for the compound (12f) which showed extraordinary antibacterial properties superior to amoxicillin and tiamulin. Molecular docking studies revealed that the amino thiazolyl ring, the side chains of the pleuromutilin derivatives, can be adopted in the binding pocket of the 50S ribosomal subunit near the mutilin core. Therefore, our novel findings may provide new insights into the design of novel pleuromutilin derivatives and lay the basis for further studies on these promising antibiotics for human clinical use.