Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 120
Filter
Add more filters

Country/Region as subject
Publication year range
1.
Nature ; 569(7757): 581-585, 2019 05.
Article in English | MEDLINE | ID: mdl-31043749

ABSTRACT

Methylation of cytosine to 5-methylcytosine (5mC) is a prevalent DNA modification found in many organisms. Sequential oxidation of 5mC by ten-eleven translocation (TET) dioxygenases results in a cascade of additional epigenetic marks and promotes demethylation of DNA in mammals1,2. However, the enzymatic activity and function of TET homologues in other eukaryotes remains largely unexplored. Here we show that the green alga Chlamydomonas reinhardtii contains a 5mC-modifying enzyme (CMD1) that is a TET homologue and catalyses the conjugation of a glyceryl moiety to the methyl group of 5mC through a carbon-carbon bond, resulting in two stereoisomeric nucleobase products. The catalytic activity of CMD1 requires Fe(II) and the integrity of its binding motif His-X-Asp, which is conserved in Fe-dependent dioxygenases3. However, unlike previously described TET enzymes, which use 2-oxoglutarate as a co-substrate4, CMD1 uses L-ascorbic acid (vitamin C) as an essential co-substrate. Vitamin C donates the glyceryl moiety to 5mC with concurrent formation of glyoxylic acid and CO2. The vitamin-C-derived DNA modification is present in the genome of wild-type C. reinhardtii but at a substantially lower level in a CMD1 mutant strain. The fitness of CMD1 mutant cells during exposure to high light levels is reduced. LHCSR3, a gene that is critical for the protection of C. reinhardtii from photo-oxidative damage under high light conditions, is hypermethylated and downregulated in CMD1 mutant cells compared to wild-type cells, causing a reduced capacity for photoprotective non-photochemical quenching. Our study thus identifies a eukaryotic DNA base modification that is catalysed by a divergent TET homologue and unexpectedly derived from vitamin C, and describes its role as a potential epigenetic mark that may counteract DNA methylation in the regulation of photosynthesis.


Subject(s)
5-Methylcytosine/metabolism , Algal Proteins/metabolism , Ascorbic Acid/metabolism , Biocatalysis , Chlamydomonas reinhardtii/enzymology , DNA/chemistry , DNA/metabolism , 5-Methylcytosine/chemistry , Carbon Dioxide/metabolism , DNA Methylation , Glyoxylates/metabolism , Nucleosides/chemistry , Nucleosides/metabolism , Photosynthesis
2.
J Am Chem Soc ; 146(18): 12723-12733, 2024 May 08.
Article in English | MEDLINE | ID: mdl-38654452

ABSTRACT

Enfumafungin-type antibiotics, represented by enfumafungin and fuscoatroside, belong to a distinct group of triterpenoids derived from fungi. These compounds exhibit significant antifungal properties with ibrexafungerp, a semisynthetic derivative of enfumafungin, recently gaining FDA's approval as the first oral antifungal drug for treating invasive vulvar candidiasis. Enfumafungin-type antibiotics possess a cleaved E-ring with an oxidized carboxyl group and a reduced methyl group at the break site, suggesting unprecedented C-C bond cleavage chemistry involved in their biosynthesis. Here, we show that a 4-gene (fsoA, fsoD, fsoE, fsoF) biosynthetic gene cluster is sufficient to yield fuscoatroside by heterologous expression in Aspergillus oryzae. Notably, FsoA is an unheard-of terpene cyclase-glycosyltransferase fusion enzyme, affording a triterpene glycoside product that relies on enzymatic fusion. FsoE is a P450 enzyme that catalyzes successive oxidation reactions at C19 to facilitate a C-C bond cleavage, producing an oxidized carboxyl group and a reduced methyl group that have never been observed in known P450 enzymes. Our study thus sets the important foundation for the manufacture of enfumafungin-type antibiotics using biosynthetic approaches.


Subject(s)
Antifungal Agents , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antifungal Agents/metabolism , Aspergillus oryzae/enzymology , Aspergillus oryzae/metabolism , Multigene Family , Triterpenes/chemistry , Triterpenes/metabolism , Cytochrome P-450 Enzyme System/metabolism
3.
J Nat Prod ; 87(5): 1338-1346, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38447084

ABSTRACT

Oxabornyl polyenes represent a unique group of polyketides characterized by a central polyene core flanked by a conserved oxabornyl moiety and a structurally diverse oxygen heterocyclic ring. They are widely distributed in fungi and possess a variety of biological activities. Due to the significant spatial separation between the two stereogenic ring systems, it is difficult to establish their overall relative configurations. Here, we isolated three oxabornyl polyenes, prugosenes A1-A3 (1-3), from Talaromyces sp. JNU18266-01. Although these compounds were first reported from Penicillium rugulosum, their overall relative and absolute configurations remained unassigned. By employing ozonolysis in combination with ECD calculations, we were able to establish their absolute configurations, and additionally obtained seven new chemical derivatives (4-10). Notably, through NMR data analysis and quantum chemical calculations, we achieved the structural revision of prugosene A2. Furthermore, prugosenes A1-A3 exhibited potent antiviral activity against the respiratory syncytial virus, with compound 1 displaying an IC50 value of 6.3 µM. Our study thus provides a valuable reference for absolute configuration assignment of oxabornyl polyene compounds.


Subject(s)
Polyenes , Polyenes/chemistry , Polyenes/pharmacology , Molecular Structure , Talaromyces/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Respiratory Syncytial Viruses/drug effects , Humans
4.
J Asian Nat Prod Res ; 26(2): 214-227, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38353486

ABSTRACT

Five new sesquiterpenoids, including a campherenane-type (1), a bergamotane-type (2), a drimane-type (3), and two bisabolane-type (5-6) sesquiterpenoids have been isolated from Biscogniauxia sp. 71-10-1-1. Their structures were determined by spectroscopic analyses, quantum chemical ECD calculations,13C chemical shifts calculations, and X-ray crystallography. This is the first report of campherenane-type and drimane-type sesquiterpenoids from Biscogniauxia. Furthermore, the anti-inflammatory assays of all compounds are evaluated, and the results showed that compounds 3 and 7 exhibited the effects against the production of the pro-inflammatory cytokine TNF-α.


Subject(s)
Sesquiterpenes , Xylariales , Sesquiterpenes/pharmacology , Sesquiterpenes/chemistry , Polycyclic Sesquiterpenes , Molecular Structure
5.
Angew Chem Int Ed Engl ; : e202407895, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38949843

ABSTRACT

The diterpene synthase AfAS was identified from Aspergillus fumigatiaffinis. Its amino acid sequence and - according to a structural model - active site architecture are highly similar to those of the fusicocca-2,10(14)-diene synthase PaFS, but AfAS produces a structurally much more complex diterpene with a novel 6-5-5-5 tetracyclic skeleton called asperfumene. The cyclisation mechanism of AfAS was elucidated through isotopic labelling experiments and DFT calculations. The reaction cascade proceeds in its initial steps through similar intermediates as for the PaFS cascade, but then diverges through an unusual vicinal deprotonation-reprotonation process that triggers a skeletal rearrangement at the entrance to the steps leading to the unique asperfumene skeleton. The structural model revealed only one major difference between the active sites: The PaFS residue F65 is substituted by I65 in AfAS. Intriguingly, site-directed mutagenesis experiments with both diterpene synthases revealed that position 65 serves as a bidirectional functional switch for the biosynthesis of tetracyclic asperfumene versus structurally less complex diterpenes.

6.
Org Biomol Chem ; 21(35): 7141-7150, 2023 09 13.
Article in English | MEDLINE | ID: mdl-37608696

ABSTRACT

Bisabosqual-type meroterpenoids are fungi-derived polyketide-terpenoid hybrids bearing a 2,3,3a,3a1,9,9a-hexahydro-1H-benzofuro[4,3,2-cde]chromene skeleton (6/6/6/5 ring system) or its seco-C-ring structure, and exhibit diverse bioactivities. Their unique structural architecture and impressive biological activities have led to considerable interest in discovering new analogues. However, to date, only nine analogues have been identified. Herein, we reported the isolation and identification of six new bisabosqual-type meroterpenoids stachybisbins C-H (1-6), together with one known compound bisabosqual C (7), from Stachybotrys bisbyi PYH05-7. Intriguingly, we found that 7, which contains the intact tetracyclic skeleton, can be non-enzymatically converted into its seco derivative stachybisbin I (8), unveiling the biosynthetic relationship between bisabosquals and seco-bisabosquals. Moreover, based on CRISPR/Cas9-mediated gene disruption, we revealed that the three-gene cluster responsible for the formation of LL-Z1272ß is associated with the biosynthesis of bisabosqual-type meroterpenoids, and then proposed a plausible route to 1-8.


Subject(s)
Benzopyrans , Polyketides , Radiopharmaceuticals , Terpenes
7.
Org Biomol Chem ; 21(4): 851-857, 2023 01 25.
Article in English | MEDLINE | ID: mdl-36602159

ABSTRACT

Fernane-type triterpenoids are a small group of natural products mainly found in plants and fungi with a wide range of biological activities. Polytolypin is a representative fernane-type triterpenoid from fungi and possesses potent antifungal activity. So far, biosynthesis of fungal-derived fernane-type triterpenoids has not been characterized, which hinders the expansion of their structural diversity using biosynthetic approaches. Herein, we identified the biosynthetic gene cluster of polytolypin and elucidated its biosynthetic pathway through heterologous expression in Aspergillus oryzae NSAR1, which involves a new triterpene cyclase for the biosynthesis of the hydrocarbon skeleton motiol, followed by multiple oxidations via three P450 enzymes. Moreover, two new triterpene cyclases for the biosynthesis of two other fernane-type skeletons isomotiol and fernenol were identified from fungi, and were individually co-expressed with the three P450 enzymes involved in polytolypin biosynthesis. These studies led to the generation of 13 fernane-type triterpenoids including eight new compounds, and two of them showed stronger antifungal activity towards Candida albicans FIM709 than polytolypin.


Subject(s)
Antifungal Agents , Triterpenes , Antifungal Agents/pharmacology , Triterpenes/pharmacology , Triterpenes/metabolism , Cytochrome P-450 Enzyme System/metabolism , Pentacyclic Triterpenes , Biosynthetic Pathways/genetics
8.
J Asian Nat Prod Res ; 25(10): 957-967, 2023 Oct.
Article in English | MEDLINE | ID: mdl-36729489

ABSTRACT

19-Hydroxybrevianamide M (1) and 6 R-methoxybrevianamide V (2), two new alkaloids, were isolated from an extract of the endophytic fungus Aspergillus sp. JNU18HC0517J, together with six known analogues (3- 8). Their structures were elucidated by extensive spectroscopic analyses, NMR calculations, and ECD calculations. 6 R-methoxybrevianamide V (2) was the first L-proline indole DKP alkaloid with substitution at C-6 on the proline ring. Furthermore, the cytotoxities and antimicrobial activities of these isolated compounds were also evaluated. Compound 8 exhibited moderate antibacterial activity against Staphylococcus aureus 209 P with a minimal inhibitory concentration (MIC) value of 16 µg/ml.[Figure: see text].


Subject(s)
Alkaloids , Aspergillus , Molecular Structure , Aspergillus/chemistry , Alkaloids/chemistry , Fungi , Indole Alkaloids/chemistry , Anti-Bacterial Agents/chemistry , Microbial Sensitivity Tests
9.
BMC Gastroenterol ; 22(1): 155, 2022 Mar 29.
Article in English | MEDLINE | ID: mdl-35350979

ABSTRACT

PURPOSES: In this study, we aimed to identify the distribution of presenting laboratory and nonenhanced computed tomography (CT) imaging features within 48 h before percutaneous cholecystostomy (PC) and create a model to appropriately guide the diagnosis of acute suppurative cholecystitis (ASC). METHODS: The study population included 204 acute cholecystitis patients who underwent PC. Based on the timing of the last laboratory and CT examinations before PC, the patients were divided into two groups: within 48 h before PC (Group 1, n = 138) and over 48 h before PC (Group 2, n = 63). The clinical features of the ASC patients in the two groups were compared. A multivariable model for the diagnosis of ASC in the patients in Group 1 was developed. RESULTS: Thirty-nine patients in Group 1 had ASC (28.3%). Gallbladder stones, common bile duct stones, gallbladder wall thickness > 2.85 mm, and neutrophil granulocytes > 82.55% were confirmed to be independent risk factors for ASC. The receiver operating characteristic curve of the recurrence prediction model verified its accuracy (area under the curve: 0.803). Compared with the ASC patients in Group 2, the ASC patients in Group 1 had a higher proportion of pericholecystic exudation or fluid (P = 0.013) and thicker gallbladder walls (P = 0.033). CONCLUSIONS: Using nonenhanced CT imaging features and cutoffs for neutrophil granulocytes, we were able to identify a simple algorithm to discriminate ASC. The degree of local inflammation of the gallbladder in ASC patients progressively increases over time, and these changes can be observed on nonenhanced CT images. However, the symptoms of abdominal pain are of little help in estimating the disease duration in elderly patients.


Subject(s)
Cholecystitis, Acute , Cholecystostomy , Gallstones , Aged , Cholecystitis, Acute/diagnostic imaging , Cholecystitis, Acute/surgery , Cholecystostomy/methods , Humans , Retrospective Studies , Tomography, X-Ray Computed/methods
10.
J Nat Prod ; 85(10): 2312-2331, 2022 10 28.
Article in English | MEDLINE | ID: mdl-36137221

ABSTRACT

Twenty new malabaricane triterpenoids, astramalabaricosides A-T (1-20), were isolated from the roots of Astragalus membranaceus var. mongholicus (Astragali Radix). Their structures were determined by spectroscopic analysis, and the use of the circular dichroism exciton chirality method, quantum chemical calculations, and chemical methods. Malabaricane triterpenoids, an unusual group with the 6-6-5-tricyclic core, are distributed in plants (e.g., Simaroubaceae, Polypodiaceae, and Fabaceae), a marine sponge, and fungi, and their number obtained to date is limited. Compounds 1-20 were characterized as glycosides with a highly oxygenated side chain, and 13-20 were the first cyclic carbonate derivatives among the malabaricane triterpenoids. The stereocluster formed from the continuous hydroxylated chiral carbons in each highly oxygenated side chain and the 6-6-5-tricyclic core system were entirely segregated, and the independent identification of their stereoconfigurations required considerable effort. The migratory inhibitory and antiproliferative activities of 1-20 were evaluated by wound-healing and cell-viability assays, respectively. Most compounds showed significant migratory inhibitory activity, and a preliminary structure-activity relationship was developed. Malabaricane triterpenoids are being reported in the genus Astragalus for the first time.


Subject(s)
Astragalus Plant , Triterpenes , Astragalus propinquus/chemistry , Triterpenes/pharmacology , Triterpenes/analysis , Plant Roots/chemistry
11.
Beilstein J Org Chem ; 18: 1396-1402, 2022.
Article in English | MEDLINE | ID: mdl-36262672

ABSTRACT

Fusicoccane-type terpenoids are a subgroup of diterpenoids featured with a unique 5-8-5 ring system. They are widely distributed in nature and possess a variety of biological activities. Up to date, only five fusicoccane-type diterpene synthases have been identified. Here, we identify a two-gene biosynthetic gene cluster containing a new fusicoccane-type diterpene synthase gene tadA and an associated cytochrome P450 gene tadB from Talaromyces wortmannii ATCC 26942. Heterologous expression reveals that TadA catalyzes the formation of a new fusicoccane-type diterpene talaro-7,13-diene. D2O isotope labeling combined with site-directed mutagenesis indicates that TadA might employ a different C2,6 cyclization strategy from the known fusicoccane-type diterpene synthases, in which a neutral intermediate is firstly formed and then protonated by an environmental proton. In addition, we demonstrate that the associated cytochrome P450 enzyme TadB is able to catalyze multiple oxidation of talaro-7,13-diene to yield talaro-6,13-dien-5,8-dione.

12.
BMC Cancer ; 21(1): 772, 2021 Jul 03.
Article in English | MEDLINE | ID: mdl-34217251

ABSTRACT

BACKGROUND: Epidermal growth factor-like domain 7 (Egfl7), a recently identified secreted protein, was significantly increased in patients with HCC by our previous studies. However, its efficacy in the diagnosis of early HCC remains unknown. In this study, we therefore evaluate the efficacy of serum Egfl7 for early HCC diagnosis and compare it with alpha-fetoprotein (AFP). METHODS: Serum Egfl7 levels in testing cohort (1081 participants) and validation cohort (476 participants) were measured by a sandwich enzyme-linked immunoassay (ELISA). The cut-off value of Egfl7 was determined by Youden's index and the efficacies of Egfl7 and AFP in diagnosing early HCC were estimated by receiver operating characteristic (ROC). RESULTS: Serum Egfl7 was significantly elevated in patients with early HCC than all non-HCC controls in whatever Testing Cohort or Validation Cohort. In the Testing Cohort, ROC curves showed the optimum cut-off value of Egfl7 was 2610 ng/mL and Egfl7 showed a significantly higher sensitivity than AFP in discriminating early HCC from healthy individuals (77.4% vs. 65.3%, P = 0.0013) but the area under ROC (AUROC) and accuracy of Egfl7 and AFP were similar (0.860 vs. 0.868, P = 0.704; 80.2% vs. 83.8%, P = 0.184). In distinguishing patients with early HCC from patients with chronic liver disease (CLD), the AUROC, sensitivity, specificity and accuracy of Egfl7 were 0.800, 75.2, 71.7 and 73.5%, which were all significantly higher than AFP (0.675, 61.8, 62.0 and 61.9% in order). Egfl7 also showed a significant higher sensitivity and accuracy than AFP (76.6% vs. 64.0%, P = 0.0031; 79.9% vs. 66.1%, P < 0.0001) in differentiating early HCC patients from non-HCC individuals. Additionally, 70.8% of early HCC patients with negative AFP could be diagnosed by Egfl7 and the combined use of Egfl7 and AFP increased the sensitivity to 91.0%. These results were confirmed by a validation cohort. CONCLUSION: Egfl7 is a valuable serum marker in the diagnosis of early HCC and could complement the efficacy of AFP, especially in distinguishing early HCC from CLD and identifying patients with AFP-negative early HCC.


Subject(s)
Calcium-Binding Proteins/metabolism , Carcinoma, Hepatocellular/genetics , EGF Family of Proteins/metabolism , Liver Neoplasms/genetics , Adult , Aged , Biomarkers, Tumor/blood , Carcinoma, Hepatocellular/pathology , Female , Humans , Liver Neoplasms/pathology , Male , Middle Aged , Young Adult
13.
J Org Chem ; 86(16): 11177-11188, 2021 08 20.
Article in English | MEDLINE | ID: mdl-34043349

ABSTRACT

A secondary metabolites investigation on Biscogniauxia sp. 71-10-1-1 was carried out, which led to the obtention of nine new diisoprenyl-cyclohexene/ane-type meroterpenoids (1-9) and two new isoprenylbenzoic acid-type meroterpeniods (10-11). The structures of these isolates were established on the basis of multispectroscopic analyses, ECD, and 13C chemical shifts calculations, and single-crystal X-ray diffraction. Among them, biscognin A (1) is the first diisoprenyl-cyclohexene-type meroterpenoid with a unique 2-isopropyl-6'-methyloctahydro-1'H-spiro[cyclopropane-1,2'-naphthalene] skeleton. Biscognienyne F (5) is the first diisoprenyl-cyclohexene-type meroterpenoid with a cyclic carbonate. The anti-inflammatory assays of the majority of compounds were evaluated, which exhibited that compounds 3 and 5 can obviously inhibit pro-inflammatory cytokines TNF-α and IL-6 productions. This is the first report for diisoprenyl-cyclohexene-type meroterpenoids with anti-inflammatory activity. Moreover, the possible biogenetic pathways of the majority of compounds (1-5) are proposed.


Subject(s)
Cyclohexenes , Terpenes , Anti-Inflammatory Agents/pharmacology , Biosynthetic Pathways , Crystallography, X-Ray , Cyclohexenes/pharmacology , Terpenes/pharmacology
14.
BMC Surg ; 21(1): 439, 2021 Dec 27.
Article in English | MEDLINE | ID: mdl-34961498

ABSTRACT

BACKGROUND: In this study, we aimed to investigate risk factors for the relapse of moderate and severe acute acalculous cholecystitis (AAC) patients after initial percutaneous cholecystostomy (PC) and to identify the predictors of patient outcomes when choosing PC as a definitive treatment for AAC. MATERIALS AND METHODS: The study population comprised 44 patients (median age 76 years; range 31-94 years) with moderate or severe AAC who underwent PC without subsequent cholecystectomy. According to the results of follow-up (followed for a median period of 17 months), the data of patients with recurrence versus no recurrence were compared. Patients were divided into the death and non-death groups based on patient status within 60 days after PC. RESULTS: Twenty-one (47.7%) had no recurrence of cholecystitis during the follow-up period after catheter removal (61-1348 days), six (13.6%) experienced recurrence of cholecystitis after PC, and 17 (38.6%) patients died during the indwelling tube period (5-60 days). The multivariate analysis showed that coronary heart disease (CHD) or congestive heart failure (odds ratio [OR] 26.50; 95% confidence interval [CI] 1.21-582.06; P = 0.038) was positively correlated with recurrence. The age-adjusted Charlson comorbidity index (OR 1.53; 95% CI 1.08-2.17; P = 0.018) was independently associated with 60-day mortality after PC. CONCLUSIONS: Our results suggest that CHD or congestive heart failure was an independent risk factor for relapse in moderate and severe AAC patients after initial PC. AAC patients with more comorbidities had worse outcomes.


Subject(s)
Acalculous Cholecystitis , Cholecystitis, Acute , Cholecystitis , Cholecystostomy , Acalculous Cholecystitis/epidemiology , Acalculous Cholecystitis/surgery , Adult , Aged , Aged, 80 and over , Cholecystitis, Acute/surgery , Humans , Middle Aged , Retrospective Studies , Treatment Outcome
15.
J Nat Prod ; 83(11): 3338-3346, 2020 11 25.
Article in English | MEDLINE | ID: mdl-33095987

ABSTRACT

4-Hydroxy pyridones are a class of fungi-derived polyketide-nonribosomal peptide products featuring a core of 4-hydroxy-2-pyridone which have a wide range of biological activities. Genome mining of in-house strains using polyketide synthase-nonribosomal peptide synthase as a query identified an endophyte Tolypocladium sp. 49Y, which possesses a potential 4-hydroxy pyridone biosynthetic gene cluster. Heterologous expression in Aspergillus oryzae NSAR1 revealed that this gene cluster is functional and able to produce a rare type of 4-hydroxy pyridones called tolypyridones (compounds 3 and 4). Tolypocladium sp. 49Y was grown in a variety of media which led to the isolation of six 4-hydroxy pyridones (5-10) and one pyrrolidone (11) from a rice culture, and compounds 3 and 9 showed antifungal activity. These latter compounds are different from those obtained by heterologous expression. This study shows that both heterologous expression and cultivation of the native host are complementary approaches to discover new natural products.


Subject(s)
Ascomycota/metabolism , Aspergillus oryzae/genetics , Pyridones/isolation & purification , Ascomycota/growth & development , Culture Media , Genes, Fungal , Magnetic Resonance Spectroscopy/methods , Molecular Structure , Multigene Family , Plasmids , Pyridones/chemistry , Pyridones/metabolism , Spectrometry, Mass, Electrospray Ionization/methods
16.
Bioorg Chem ; 101: 104043, 2020 08.
Article in English | MEDLINE | ID: mdl-32629286

ABSTRACT

Nine new N-methoxy-ß-carboline alkaloids (NMCAs) (1a/1b-3a/3b and 4-6) and two known NMCAs (7 and 8) were isolated from the stems of Picrasma quassioides. Their structures were elucidated by spectroscopic data analyses, quantum chemical calculations, and single-crystal X-ray crystallographic data. An analysis of the 13C NMR chemical shifts of the N-methoxy groups in these NMCAs and 41 gathered known compounds reveals the phenomenon that the chemical shifts of all these N-methoxy groups are greater than δC 62, which can be used to recognize the N-methoxy group rapidly. In addition, the acetylcholinesterase (AChE) and Aß42 aggregation inhibitory activities of 1-8 were evaluated. Compounds 1, 2, 7, and 8 displayed AChE inhibitory activity with IC50 values of 14.9, 13.2, 17.6, and 43.9 µM, respectively. Compound 2 showed inhibition activity against Aß42 aggregation with an IC50 value of 10.1 µM.


Subject(s)
Alkaloids/chemistry , Amyloid beta-Peptides/drug effects , Peptide Fragments/drug effects , Picrasma/chemistry , Acetylcholinesterase , Humans , Molecular Structure , Structure-Activity Relationship
17.
Angew Chem Int Ed Engl ; 59(32): 13531-13536, 2020 08 03.
Article in English | MEDLINE | ID: mdl-32364293

ABSTRACT

The alkyne is a biologically significant moiety found in many natural products and a versatile functional group widely used in modern chemistry. Recent studies have revealed the biosynthesis of acetylenic bonds in fatty acids and amino acids. However, the molecular basis for the alkynyl moiety in acetylenic prenyl chains occurring in a number of meroterpenoids remains obscure. Here, we identify the biosynthetic gene cluster and characterize the biosynthetic pathway of an acetylenic meroterpenoid biscognienyne B based on heterologous expression, feeding experiments, and in vitro assay. This work shows that the alkyne moiety is constructed by an unprecedented cytochrome P450 enzyme BisI, which shows promiscuous activity towards C5 and C15 prenyl chains. This finding provides an opportunity for discovery of new compounds, featuring acetylenic prenyl chains, through genome mining, and it also expands the enzyme inventory for de novo biosynthesis of alkynes.


Subject(s)
Alkynes/metabolism , Ascomycota/metabolism , Cytochrome P-450 Enzyme System/metabolism , Fungal Proteins/metabolism , Hemiterpenes/biosynthesis , Ascomycota/enzymology , Ascomycota/genetics , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/genetics , Fungal Proteins/chemistry , Fungal Proteins/genetics , Multigene Family , Oxidation-Reduction , Substrate Specificity
18.
Cell Microbiol ; 20(9): e12860, 2018 09.
Article in English | MEDLINE | ID: mdl-29749709

ABSTRACT

Systemic bacterial infections are prone to secondary Candida albicans super-infection. However, the molecular mechanisms involved remain poorly understood. In this study, a model comprising sublethal cecal ligation and puncture plus C. albicans intravenous injection was applied to mimic the situation in super-infection. Compared with mice without systemic bacterial infection, mice with systemic bacterial infection had lower antifungal gene expression (including Il1b, Tnf, Il6, Ifnb, Ifng, Cxcl1, and Ccr2) in monocytes and less inflammatory monocytes and neutrophils infiltrating into the kidney when challenged with C. albicans. Further, lentivirus-mediated Setdb2-knockout and overexpression experiments verified that Setdb2 levels in monocytes correlated negatively with antifungal gene expression and survival rates. Transcriptional repression was probably achieved by Setdb2 through H3 methylation at lysine 9 in promoter regions of these antifungal genes.


Subject(s)
Bacteremia/complications , Candida albicans/immunology , Candidemia/immunology , Candidemia/physiopathology , Disease Susceptibility , Histone-Lysine N-Methyltransferase/metabolism , Animals , Gene Expression , Gene Expression Profiling , Gene Knockout Techniques , Histone-Lysine N-Methyltransferase/genetics , Kidney/pathology , Mice, Inbred C57BL , Monocytes/immunology , Neutrophils/immunology , Survival Analysis
19.
BMC Nephrol ; 20(1): 446, 2019 12 03.
Article in English | MEDLINE | ID: mdl-31796001

ABSTRACT

BACKGROUND: To investigate predictive factors related to graft failure of IgA nephropathy(IgAN) in renal allografts following living donor transplantation. METHODS: We identified a series of 102 biopsies diagnosed as IgAN in renal allografts following living donor transplantation from July 2004 to January 2017 at our center, and assess the predict value of the Lee's classification and the 2009 Oxford classification in IgAN in renal allografts, clinical, ultrasonic and pathological characteristics at biopsy and the outcomes were retrospectively analyzed. RESULTS: The 5-year graft cumulative survival rate after transplantation was 91.4%. The 4-year graft cumulative survival rate after biopsy diagnosis of IgAN in renal allografts was 59.6%. The mean time ± SD to disease was 4.7 ± 3.5 years. The color doppler ultrasound and blood flow imagine showed the echo enhancement, the reduced blood flow distribution, the reduced peak systolic velocity of main renal artery, and the increased resistance index of arcuate renal artery were valuable in evaluating the graft dysfunction. The Cox multivariate analysis revealed that the 24-h urinary protein level (HR 1.6 for 1-g increase, 95%CI 1.2-2.0), estimated glomerular filtration rate (eGFR) (HR 1.0 for 1-mL/min/1.73 m^2 decline, 95%CI 1.0-1.1), and mesangial C1q deposition (HR 3.0, 95%CI 1.2-7.4) at biopsy were independent predictive factors of graft failure of IgAN in renal allografts. CONCLUSIONS: IgAN in renal allografts occurred frequently within 5 years after transplantation. The risk of graft failure should be taken seriously in patients who exhibit heavy proteinuria and/or a declined eGFR as the initial symptoms; a high lesion grade (grade IV-V of Lee's classification) and/or mesangial C1q deposition may also indicated a poor outcome.


Subject(s)
Allografts , Biopsy , Glomerulonephritis, IGA/diagnosis , Kidney Failure, Chronic/surgery , Kidney Transplantation , Kidney , Proteinuria , Adult , Allografts/diagnostic imaging , Allografts/pathology , Allografts/physiopathology , Biopsy/methods , Biopsy/statistics & numerical data , Echocardiography, Doppler, Color/methods , Female , Glomerular Filtration Rate , Graft Survival , Humans , Kidney/diagnostic imaging , Kidney/pathology , Kidney/physiopathology , Kidney Transplantation/adverse effects , Kidney Transplantation/methods , Living Donors , Male , Prognosis , Proteinuria/diagnosis , Proteinuria/etiology , Renal Circulation
20.
J Asian Nat Prod Res ; 21(5): 494-501, 2019 May.
Article in English | MEDLINE | ID: mdl-29595069

ABSTRACT

A novel valerenane sesquiterpenoid sinulaspirolactam A (1), together with five known compounds, was isolated from the soft coral Sinularia sp. Their structures were determined by spectroscopic analyses. The absolute configuration of 1 was established by ECD calculation. Compound 1 was the first example of valerenane sesquiterpenoid bearing an aza-spiro[4.5] ring moiety, the plausible biogenetic pathway of which was proposed. Cytotoxic activities of these compounds were also evaluated.


Subject(s)
Anthozoa/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacology , Animals , Cell Line, Tumor , Cell Survival/drug effects , Models, Molecular , Molecular Structure
SELECTION OF CITATIONS
SEARCH DETAIL