An antiviral oligomerized linear thiopeptide with a nitrile group from soil-derived Streptomyces sp. CPCC 203702.

A new linear thiopeptide, bernitrilecin (1), was isolated from Streptomyces sp. CPCC 203702. Compound 1 is the first example of a nitrile-bearing thiopeptide. Its structure and absolute configuration were elucidated by extensive analysis of spectroscopic data and Marfey's method. The biosynthesis of the nitrile unit for 1 was proposed to be through oxidations, decarboxylation, and dehydration. Compound 1 exhibited significant anti-influenza A virus activity with the IC50 value of 16.7 µM.

Exploring the association between rosacea and acne by integrated bioinformatics analysis.

Clinically, rosacea occurs frequently in acne patients, which hints the existence of shared signals. However, the connection between the pathophysiology of rosacea and acne are not yet fully understood. This study aims to unveil molecular mechanism in the pathogenesis of rosacea and acne. We identified differentially expressed genes (DEGs) by limma and weighted gene co-expression network analysis and screened hub genes by constructing a protein-protein interaction network. The hub genes were verified in different datasets. Then, we performed a correlation analysis between the hub genes and the pathways. Finally, we predicted and verified transcription factors of hub genes, performed the immune cell infiltration analysis using CIBERSORT, and calculated the correlation between hub genes and immune cells. A total of 169 common DEGs were identified, which were mainly enriched in immune-related pathways. Finally, hub genes were identified as IL1B, PTPRC, CXCL8, MMP9, CCL4, CXCL10, CD163, CCR5, CXCR4, and TLR8. 9 transcription factors that regulated the expression of hub genes were identified. The infiltration of γδT cells was significantly increased in rosacea and acne lesions and positively linked with almost all hub genes. These identified hub genes and immune cells may play a crucial role in the development of rosacea and acne.

Eleuthemarins A and B, two new isocoumarin derivatives from the Arctic fungus Eleutheromyces sp. CPCC 401592.

Two new isocoumarin derivatives, eleuthemarins A (1) and B (2), were isolated from the Arctic fungus Eleutheromyces sp. CPCC 401592. Their structures and absolute configurations were elucidated through spectroscopic methods, quantum chemical calculations of NMR shifts, and calculated electronic circular dichroism. This is the first report for the chemical investigation of the genus Eleutheromyces. Compounds 1 and 2 showed selective cytotoxic activities against H460, A549, and HCT116 cancer cell lines with IC50 values in the range of 24.1-57.3 µM, respectively. Compound 1 displayed weak antibacterial activities.

Late-stage cascade of oxidation reactions during the biosynthesis of oxalicine B in Penicillium oxalicum.

Oxalicine B (1) is an α-pyrone meroterpenoid with a unique bispirocyclic ring system derived from Penicillium oxalicum. The biosynthetic pathway of 15-deoxyoxalicine B (4) was preliminarily reported in Penicillium canescens, however, the genetic base and biochemical characterization of tailoring reactions for oxalicine B (1) has remained enigmatic. In this study, we characterized three oxygenases from the metabolic pathway of oxalicine B (1), including a cytochrome P450 hydroxylase OxaL, a hydroxylating Fe(II)/α-KG-dependent dioxygenase OxaK, and a multifunctional cytochrome P450 OxaB. Intriguingly, OxaK can catalyze various multicyclic intermediates or shunt products of oxalicines with impressive substrate promiscuity. OxaB was further proven via biochemical assays to have the ability to convert 15-hydroxdecaturin A (3) to 1 with a spiro-lactone core skeleton through oxidative rearrangement. We also solved the mystery of OxaL that controls C-15 hydroxylation. Chemical investigation of the wild-type strain and deletants enabled us to identify 10 metabolites including three new compounds, and the isolated compounds displayed potent anti-influenza A virus bioactivities exhibiting IC50 values in the range of 4.0-19.9 µmol/L. Our studies have allowed us to propose a late-stage biosynthetic pathway for oxalicine B (1) and create downstream derivatizations of oxalicines by employing enzymatic strategies.

TWEAK/Fn14 signaling may function as a reactive compensatory mechanism against extracellular matrix accumulation in keloid fibroblasts.

Overabundance of the extracellular matrix resulting from hyperproliferation of keloid fibroblasts (KFs) and dysregulation of apoptosis represents the main pathophysiology underlying keloids. TWEAK is a weak apoptosis inducer, and it plays a critical role in pathological tissue remodeling via its receptor, Fn14. However, the role of TWEAK/Fn14 signaling in the pathogenesis of keloids has not been investigated. In this study, we confirmed the overexpression levels of TWEAK and Fn14 in clinical keloid tissue specimens and primary KFs. The extracellular matrix (ECM)-related genes were also evaluated between primary KFs and their normal counterparts to determine the factors leading to the formation or development of keloids. Unexpectedly, exogenous TWEAK significantly reduced the levels of collagen I and collagen III, as well as alpha-smooth muscle actin (α-SMA). Additionally, TWEAK promoted MMPs expression and apoptosis activity of KFs. Furthermore, we verified that the inhibitory effect of TWEAK on KFs is through down-regulation of Polo-like kinase 5, which modulates cell differentiation and apoptosis. The TWEAK-Fn14 axis seems to be a secondary, although less effective, compensatory mechanism to increase the catabolic functions of fibroblasts in an attempt to further decrease the accumulation of collagen. DATA AVAILABILITY: All data generated or analyzed during this study are included in this published article (and its Supporting Information files).

Four new chromone derivatives from the Arctic fungus Phoma muscivora CPCC 401424 and their antiviral activities.

The crude extract of the Arctic fungus Phoma muscivora CPCC 401424 displayed anti-influenza A virus activities which led us to investigated their secondary metabolites. Four new chromone derivatives, phomarcticones A-D (1-4) and five known chromone analogs (5-9) have been isolated from Arctic fungus Phoma muscivora CPCC 401424. Compounds 3 and 4 possess rare sulfoxide groups in chromone derivatives. Their structures and absolute configurations were elucidated by extensive analysis of spectroscopic data, electronic circular dichroism, and comparison with reported data. Compounds 3, 7, and 9 showed significant anti-influenza A virus activities with the IC50 values of 24.4, 4.2, and 2.7 µM, respectively.

Geninthiocins E and F, two new cyclic thiopeptides with antiviral activities from soil-derived Streptomyces sp. CPCC 200267 using OSMAC strategy.

On the basis of the one strain-many compounds (OSMAC) strategy, two new cyclic thiopeptides, geninthiocins E and F, together with four known geninthiocin derivatives, geninthiocins A, B, C, and val-geninthiocin were isolated from Streptomyces sp. CPCC 200267. Their structures and absolute configurations were elucidated by extensive spectroscopic analyses and Marfey's method. Geninthiocin E (1), val-geninthiocin (3), geninthiocin A (4), and geninthiocin B (5) exhibited significant anti-influenza A virus activities with the IC50 values of 28.7, 15.3, 7.3, and 18.3 µM, respectively. Compounds 3 and 4 showed moderate antibacterial activities against Staphylococcus aureus.

The Efficacy of Combination Therapy Involving Excision Followed by Intralesional 5-Fluorouracil and Betamethasone, and Radiotherapy in the Treatment of Keloids: A Randomized Controlled Trial.

Background: Combined therapy for keloids is currently recommended. Surgery is one of the main options, but the measures to prevent recurrence after excision are still being explored. Objective: The randomized controlled study aimed at evaluating the efficacy of excision followed by intralesional low concentrations of 5-fluorouracil (5-FU)(12.5 mg/mL) and betamethasone. Methods: Sixty patients were randomly assigned to three groups. Patients in group A had excision followed by 5-FU and betamethasone intralesional injections, group B had 5-FU and betamethasone intralesional injections, and group C had excision followed by radiotherapy. Efficacy parameters were assessed from 8 to 12 months, including improvement on the Vancouver Scar Scale (VSS) and the Patient and Observer Scar Scale (POSAS), as well as side effects and recurrence. Trial registration number: ChiCTR2100046025. Results: After 4 months' treatment, the improvement of the VSS and POSAS scores in group A was not different from that in group C (P > 0.05) but was superior to that in group B (P < 0.05); the pain and pruritus of the three groups were relieved more than 50%. After 8 to 12 months' follow-up, there was no statistical difference in the incidence of side effects and recurrence among the groups (P > 0.05). Conclusion: Excision followed by intralesional low concentrations of 5-FU (12.5mg/mL) with betamethasone is a safe and sustainable treatment for keloid, with no significant difference from excision followed by radiotherapy.

New dimeric chromanone derivatives from the mutant strains of Penicillium oxalicum and their bioactivities.

Three new chromanone dimer derivatives, paecilins F-H (1-3) and ten known compounds (4-13), were obtained from the mutant strains of Penicillium oxalicum 114-2. Their structures were elucidated by extensive analysis of spectroscopic data and comparison with reported data, and the configurations of 1-3 were resolved by quantum chemical calculations of NMR shifts and ECD spectra. Compounds 5 and 11 showed significant anti-influenza A virus activities with IC50 values of 5.6 and 6.9 µM, respectively. Compounds 8 and 9 displayed cytotoxic activities against the MIA-PaCa-2 cell line with IC50 values of 2.6 and 2.1 µM, respectively. Compound 10 exhibited antibacterial activities against Bacillus cereus with a MIC value of 4 µg mL-1.

Sesquiterpenes from the endophytic fungus Periconia sp. F-31.

One new eremophilane sesquiterpene periconianone L (1), together with four known guaiane-type sesquiterpenes 4,10,11-trihydroxyguaiane (2), (-)-guai-1(10)-ene-4α,11-diolhydroxymecuration (3), guaidiol A (4), and epi-guaidiol A (5) were isolated from the endophytic fungus Periconia sp. F-31. The structure of the new compound was established by spectroscopic methods, including UV, IR, HRESIMS, and extensive NMR techniques. Compound 3 was isolated as natural product for the first time.

Microbial Transformation of neo-Clerodane Diterpenoid, Scutebarbatine F, by Streptomyces sp. CPCC 205437.

Biotransformation of the neo-clerodane diterpene, scutebarbatine F (1), by Streptomyces sp. CPCC 205437 was investigated for the first time, which led to the isolation of nine new metabolites, scutebarbatine F1-F9 (2-10). Their structures were determined by extensive high-resolution electrospray ionization mass spectrometry (HRESIMS) and NMR data analyses. The reactions that occurred included hydroxylation, acetylation, and deacetylation. Compounds 2-4 and 8-10 possess 18-OAc fragment, which were the first examples of 13-spiro neo-clerodanes with 18-OAc group. Compounds 7-10 were the first report of 13-spiro neo-clerodanes with 2-OH. Compounds 1-10 were biologically evaluated for the cytotoxic, antiviral, and antibacterial activities. Compounds 5, 7, and 9 exhibited cytotoxic activities against H460 cancer cell line with inhibitory ratios of 46.0, 42.2, and 51.1%, respectively, at 0.3 µM. Compound 5 displayed a significant anti-influenza A virus activity with inhibitory ratio of 54.8% at 20 µM, close to the positive control, ribavirin.

New phenol and chromone derivatives from the endolichenic fungus Daldinia species and their antiviral activities.

Three new phenolic metabolites, daldispols A-C (1-3), two new chromone derivatives, (5R,7R)-5,7-dihydroxy-2-methyl-5,6,7,8-tetrahydro-4H-chromen-4-one (9) and (5R,7R)-5,7-dihydroxy-2-propyl-5,6,7,8-tetrahydro-4H-chromen-4-one (10), together with five known phenolic compounds (4-8) and two known chromone compounds (11 and 12) were isolated from the endolichenic fungus Daldinia sp. CPCC 400770. Their structures were elucidated on the basis of spectroscopic methods, electronic circular dichroism (ECD), and comparison with reported data. Compounds 1, 3, 4, 9, and 11 exhibited significant anti-influenza A virus (IAV) activities with IC50 values of 12.7, 6.4, 12.5, 16.1, and 9.0 µM, respectively, and compound 8 displayed significant anti-ZIKV activity with inhibitory ratio of 42.7% at 10 µM. The results demonstrated that the fungus Daldinia sp. CPCC 400770 might be a rich source for discovering anti-IAV secondary metabolites as potential novel leading compounds.

Daldispones A and B, two new cyclopentenones from Daldinia sp. CPCC 400770.

Two new cyclopentenone derivatives, daldispones A (1) and B (2) were isolated from the fungus Daldinia sp. CPCC 400770. Their structures and absolute configurations were elucidated by extensive spectroscopic analyses and calculated electronic circular dichroism (ECD). Compounds 1 and 2 exhibited significant anti-influenza A virus activities with IC50 values of 16.0 and 7.4 µM, respectively. Compound 2 showed moderate antibacterial activities against Staphylococcus aureus, Enterococcus faecalis and Bacillus cereus.

Morusalones A-D, Diels-Alder Adducts with 6/7/6/6/6/6 Hexacyclic Ring Systems as Potential PTP1B Inhibitors from Cell Cultures of Morus alba.

Morusalones A-D (1-4), a new class of Diels-Alder adducts featuring unprecedented 6/7/6/6/6/6 hexacyclic core skeletons with a unique bridged cycloheptenone ring, were isolated from Morus alba cell cultures. The biosyntheses for 1-4 were proposed through an unusual Diels-Alder cycloaddition with quinostilbenes as dienophiles and prenyl 2-phenylbenzofuran as a diene to yield the typical methylhexene unit and a rare intramolecular nucleophilic addition to form the cycloheptenone ring. Compounds 1-4 exhibited protein tyrosine phosphatase 1B inhibitory activity.

Knockdown of FOXM1 inhibits activation of keloid fibroblasts and extracellular matrix production via inhibition of TGF-ß1/Smad pathway.

Keloid is characterized by overactive fibroblasts. Forkhead box M1 (FOXM1) is transcription factor that plays important roles in the progression of fibrosis. However, the role of FOXM1 in keloid has not been elucidated. In the present study, we examined the expression levels of FOXM1 in clinical keloid tissue specimens and primary keloid fibroblasts (KFs). The results showed that FOXM1 levels were significantly increased in both keloid tissues and KFs. To further investigate the biological functions of FOXM1, FOXM1 was knocked down in KFs by transfection with small interfering RNA targeting FOXM1 (si-FOXM1). Knockdown of FOXM1 inhibited transforming growth factor-ß1 (TGF-ß1)-induced cell proliferation and migration of KFs. Besides, the increased expressions of collagen (coll I), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) in TGF-ß1-induced KFs were suppressed by si-FOXM1 transfection. Furthermore, TGF-ß1-induced increase in p-Smad2 and p-Smad3 expressions was attenuated by FOXM1 knockdown. These data indicated that knockdown of FOXM1 inhibited TGF-ß1-induced KFs activation and extracellular matrix (ECM) accumulation, which was attributed to the inhibition of TGF-ß1/Smad pathway.

Biosynthetic Hypothesis-Guided Discovery and Total Syntheses of PKS-NRPS Hybrid Metabolites from Endophytic Fungus Periconia Species.

Guided by our biosynthetic hypothesis, pericoannosins C-F, four new PKS-NRPS hybrid metabolites, were discovered from the endophytic fungus Periconia sp. F-31. Their structures and absolute configurations were elucidated by extensive spectroscopic data and electronic circular dichroism analyses. Preliminary biological evaluation revealed that pericoannosins C-D exhibited anti-HIV activities with IC50 values of 15.5 and 13.5 µM. Furthermore, the bioinspired syntheses of pericoannosins C-E have also been completed with high efficiency.

Roseomonas globiformis sp. nov., an airborne bacteria isolated from an urban area of Beijing.

A novel dark pink pigmented bacterium, designated strain CPCC 100847T (deposited with strain code 0113-15), was isolated from the urban air of Beijing, China. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain CPCC 100847T was related to members of the genus Roseomonas and had the highest 16S rRNA gene sequence similarity to Roseomonas aestuarii JC17T (97.5 %). A low level of DNA-DNA relatedness (18.7 %) with its closest type strain R. aestuarii JC17T (KCTC 22692T) proved that strain CPCC 100847T belonged to a unique genomic species. CPCC 100847T had many common characteristics of the genus Roseomonas, but also had a range of cultural, physiological and biochemical characteristics that separated it from related Roseomonas species. Cells were Gram-negative, cocci- to oval-shaped, non-motile, non-endospore-forming and strictly aerobic. The respiratory ubiquinone was Q-10. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, an unidentified aminolipid and an unidentified phospholipid. The major fatty acids (>5 %) were C18 : 1ω7c, anteiso-C15 : 0, C16 : 0, iso-C15 : 0 and summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c). The combined genotypic and phenotypic data indicated that the isolate represents a novel species of the genus Roseomonas. The name proposed for this species is Roseomonasglobiformis sp. nov., with CPCC 100847T (=KCTC 52094T) as the type strain. The DNA G+C composition is 65.2 mol%.

Peniazaphilin A, a new azaphilone derivative produced by Penicillium sp. CPCC 400786.

A new azaphilone derivative, named peniazaphilin A (1) and one known isocoumarin, (R)-3-methyl-6-hydroxy-8-methoxy-3,4-dihydroisocoumarin (2) were isolated from the fungus Penicillium sp. CPCC 400786. Their structures were elucidated by means of extensive spectroscopic analysis. The absolute configuration of 2 was established by circular dichroism for the first time. Compounds 1 and 2 exhibited weak anti-HIV activities with the IC50 values of 60.4 and 69.3 µM, respectively.

Oxazole-Containing Diterpenoids from Cell Cultures of Salvia miltiorrhiza and Their Anti-HIV-1 Activities.

Four new oxazole-containing diterpenoids, salvianans A-D (1-4), along with three known diterpenoids (5-7), were isolated from Salvia miltiorrhiza cell cultures. The structures of the new compounds were elucidated using spectroscopic methods and single-crystal X-ray diffraction. The evaluation for their anti-HIV-1 activities revealed that 2 and 3 displayed inhibitory activities with IC50 values of 0.03 and 1.2 µM, respectively. The time of addition (TOA) assay and long terminal repeat (LTR) luciferase reporter assay results indicated that compound 2 was an HIV-1 transcription inhibitor and might be a lead compound of antiviral agents acting on HIV-1 transcription.