Chrysomutanin and related meroterpenoids from a DES mutant of the marine-derived fungus Penicillium chrysogenum S-3-25.

A new meroterpene, chrysomutanin (1), two new meroterpenoids (4 and 5) together with nine known ones were isolated from the diethyl sulphate (DES) mutant 3d10-01 of the marine-derived fungus Penicillium chrysogenum S-3-25. The structures of the isolated compounds were determined by their spectroscopic data, and the absolute configuration of 1 was determined by Rh2-induced electrical circular dichroism (ECD) analysis or by comparison of the measured ECD with that of the known compounds. The cytotoxic activity was preliminarily evaluated against five human cancer cell lines. HPLC-UV analysis showed that compounds 1-12 were all newly produced by the mutant, and were not detected from the initial strain S-3-25. Chrysomutanin (1) is a new member with a chain sesquiterpene unit to the family of meroterpenes. Present results confirm that DES mutagenesis strategy is an effective method to exploit the dormant metabolites of fungi.

Effect of glucose metabolism disorders on the short-term prognosis in neonates with asphyxia: a multicenter study in Hubei Province, China. / çª’æ¯æ–°ç”Ÿå„¿ç³–ä»£è°¢ç´Šä¹±å¯¹è¿‘æœŸé¢„åŽçš„å½±å“ï¼šä¸€é¡¹æ¹–åŒ—çœå¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To study the effect of glucose metabolism disorders on the short-term prognosis in neonates with asphyxia. METHODS: A retrospective analysis was performed on the medical data of the neonates with asphyxia who were admitted to 52 hospitals in Hubei Province of China from January to December, 2018 and had blood glucose data within 12 hours after birth. Their blood glucose data at 1, 2, 6, and 12 hours after birth (with an allowable time error of 0.5 hour) were recorded. According to the presence or absence of brain injury and/or death during hospitalization, the neonates were divided into a poor prognosis group with 693 neonates and a good prognosis group with 779 neonates. The two groups were compared in the incidence of glucose metabolism disorders within 12 hours after birth and short-term prognosis. RESULTS: Compared with the good prognosis group, the poor prognosis group had a significantly higher proportion of neonates from secondary hospitals (48.5% vs 42.6%, P<0.05) or with severe asphyxia (19.8% vs 8.1%, P<0.05) or hypothermia therapy (4.8% vs 1.5%, P<0.05), as well as a significantly higher incidence rate of disorder of glucose metabolism (18.8% vs 12.5%, P<0.05). Compared with the good prognosis group, the poor prognosis group had a significantly higher incidence rate of disorder of glucose metabolism at 1, 2, and 6 hours after birth (P<0.05). The multivariate logistic regression analysis showed that recurrent hyperglycemia (adjusted odds ratio=2.380, 95% confidence interval: 1.275-4.442, P<0.05) was an independent risk factor for poor prognosis in neonates with asphyxia. CONCLUSIONS: Recurrent hyperglycemia in neonates with asphyxia may suggest poor short-term prognosis, and it is necessary to strengthen the early monitoring and management of the nervous system in such neonates.

[Effects of Temperature and Stirring on the Changes of Antibiotic Resistance Genes and Microbial Communities in Anaerobic Digestion of Dairy Manure].

To investigate the effects of temperature and stirring on antibiotic resistance genes (ARGs) and microbial communities during the anaerobic digestion of dairy manure, mesophilic and thermophilic anaerobic digestion experiments were performed with and without stirring. Two-way analysis of variance indicated that temperature affected biogas production more strongly than stirring (η2=0.934>0.911), and thermophilic and stirring increased the total biogas yield by 13.93% and 12.63%, respectively. The effect of temperature on the removal of ARGs was also stronger than that of stirring (η2=0.992>0.920), where thermophilic conditions enhanced the reduction of ARGs and MGEs to 0.09-1.53 (logarithm), while stirring had no significant effects. When temperature was altered from mesophilic to thermophilic, the microbial communities shifted, with Firmicutes becoming the dominant phylum after thermophilic anaerobic digestion, with a relative abundance of >86%. Network analysis demonstrated that eight genera including Sedimentibacter, Sphaerochaeta, and Pseudomonas were the hosts of ARGs and MGEs, and the redundancy analysis suggested that physicochemical parameters play important roles in shaping microbial communities, especially TAN and TVFAs, which indirectly affected the ARGs by altering their host bacteria.

Penicacids E-G, three new mycophenolic acid derivatives from the marine-derived fungus Penicillium parvum HDN17-478.

Three new mycophenolic acid derivatives, penicacids E-G (1-3), together with three known analogues, mycophenolic acid (4), 4'-hydroxy-mycophenolic acid (5) and mycophenolic methyl ester (6), were isolated from a marine-derived fungus Penicillium parvum HDN17-478 from a South China Sea marine sediment sample. The structures of compounds 1-3 were elucidated by HRMS, NMR, and Mosher's method. Among them, compounds 1 and 2 were the first examples of mycophenolic acid analogs with a double bond at C-3'/C-4' position. The cytotoxicity of 1-6 was evaluated against the HCT-116, BEL-7402, MGC-803, SH-SY5Y, HO-8910 and HL-60 cell lines, and compounds 4 and 6 showed potent cytotoxicity with IC50 values ranging from 1.69 to 12.98 µmol·L-1.

New metabolites from a Mariana Trench-derived actinomycete Nocardiopsis sp. HDN 17-237.

One new ß,γ-butenoate derivative phenylbutenote (1), and one new α-pyrone nocapyrone T (2) were isolated from the deep-sea derived actinomycete Nocardiopsis sp. HDN 17-237. Their structures were elucidated by extensive HRMS, IR and NMR analyses. Among them, compound 1 is the first microbial natural products bearing a rare ß,γ-butenoate moiety, and compound 2 is the first α-pyrone isolated from strain of Mariana Trench. Compounds 1 and 2 were tested for antioxidant and antibacterial activities, while none of them showed significant activity.

Secondary metabolites from Antarctic marine-derived fungus Penicillium crustosum HDN153086.

A new polyene compound (1) and a new diketopiperazine (2), as well as three known compounds (3-5), were isolated from the Antarctic marine-derived fungus Penicillium crustosum HDN153086. The structures of 1-5 were deduced based on MS, NMR and TD-DFT calculations of specific ECD spectra. These compounds were evaluated for their cytotoxic activities against K562 cell line and only compound 2 exhibited cytotoxicity against K562 cell, with IC50 value of 12.7 µM.

[Association between glutamate receptor 2 polymorphisms and epilepsy in children].

OBJECTIVE: To investigate the association between two single nucleotide polymorphisms (SNPs), rs9390754 and rs4840200, in the glutamate receptor 2 (GRIK2) gene and the genetic susceptibility to epilepsy (EP) in the Han population in Central China. METHODS: A case-control study was performed in 284 EP children (including 132 children with refractory epilepsy) and 315 normal children from Central China. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the genotypes of the two SNPs rs9390754 and rs4840200. The genotype frequency was compared between groups. RESULTS: The frequencies of GG, GA, and AA genotypes of SNP rs9390754 showed a significant difference between the EP and normal control groups (P=0.016). The allele frequency also showed a significant difference between the two groups (P=0.002). The frequencies of CC, CT, and TT genotypes of SNP rs4840200 and allele frequency showed no significant differences between the two groups. The C allele frequency of SNP rs4840200 in the refractory EP subgroup was significantly higher than in the non-refractory EP subgroup (OR=1.435, 95% CI: 1.021-2.016, P=0.037). CONCLUSIONS: In the Han population in Central China, the polymorphisms of SNP rs9390754 in the GRIK2 gene may be associated with EP susceptibility, and the C allele of SNP rs4840200 may be a genetic risk factor for the development of drug resistance in children with EP.

Exopisiod B and farylhydrazone C, two new alkaloids from the Antarctic-derived fungus Penicillium sp. HDN14-431.

Two new compounds, exopisiod B (1) and farylhydrazone C (2), together with two known compounds (3-4), were isolated from the Antarctic-derived fungus Penicillium sp. HDN14-431. Their structures including absolute configurations were elucidated by spectroscopic methods and TDDFT ECD calculations. The cytotoxicity and antimicrobial activities of all compounds were tested.

[Association of TIAM1 gene polymorphisms with Kawasaki disease and its clinical characteristics].

OBJECTIVE: To investigate the association of single nucleotide polymorphisms (SNP) rs22833188 and rs2833195 in TIAM1 gene with the susceptibility to Kawasaki disease (KD) and its clinical characteristic in children. METHODS: A case-control study was performed in this study. One hundred and eighty-eight children with KD and 197 normal children served as controls were enrolled. The genotypes of two SNPs rs22833188 and rs2833195 in TIAM1 gene were detected using PCR-RFLP. RESULTS: There were no significant differences in the genotype (AA, AG and GG) and allele frequencies of SNP rs2833188 between the KD and control groups. Significant differences in the genotype (CC, GC and GG) frequency of SNP rs2833195 were noted between the KD and control groups (P=0.017). The frequency of C allele in the KD group was higher than in the control group (P=0.015). The polymorphism of SNP rs2833188 was associated with the occurrence of rash (P=0.011), and the polymorphism of SNP rs2833195 was associated with the occurrence of conjunctival hyperemia (P=0.021). CONCLUSIONS: The polymorphism of rs2833195 in TIAM1 gene is associated with the susceptibility to KD. The polymorphisms rs2833188 and rs2833195 in TIAM1 gene may be associated with some clinical characteristics in children with KD.

Cladosins F and G, two new hybrid polyketides from the deep-sea-derived Cladosporium sphaerospermum 2005-01-E3.

Two new fungal hybrid polyketides, cladosins F (1) and G (2), with rare 6(3)-enamino-8,10-dihydroxy-tetraketide system were discovered from the deep-sea-derived fungus Cladosporium sphaerospermum 2005-01-E3 guided by OSMAC approach. Their structures were elucidated on the basis of comprehensive spectroscopic analyses, and cytotoxicity, antitubercular, anti-influenza A H1N1 virus, and NF-κB inhibitory activities were evaluated.

Activation of dormant secondary metabolite production by introducing neomycin resistance into the deep-sea fungus, Aspergillus versicolor ZBY-3.

A new ultrasound-mediated approach has been developed to introduce neomycin-resistance to activate silent pathways for secondary metabolite production in a bio-inactive, deep-sea fungus, Aspergillus versicolor ZBY-3. Upon treatment of the ZBY-3 spores with a high concentration of neomycin by proper ultrasound irradiation, a total of 30 mutants were obtained by single colony isolation. The acquired resistance of the mutants to neomycin was confirmed by a resistance test. In contrast to the ZBY-3 strain, the EtOAc extracts of 22 of the 30 mutants inhibited the human cancer K562 cells, indicating that these mutants acquired a capability to produce antitumor metabolites. HPLC-photodiode array detector (PDAD)-UV and HPLC-electron spray ionization (ESI)-MS analyses of the EtOAc extracts of seven bioactive mutants and the ZBY-3 strain indicated that diverse secondary metabolites have been newly produced in the mutant extracts in contrast to the ZBY-3 extract. The followed isolation and characterization demonstrated that six metabolites, cyclo(D-Pro-D-Phe) (1), cyclo(D-Tyr-D-Pro) (2), phenethyl 5-oxo-L-prolinate (3), cyclo(L-Ile-L-Pro) (4), cyclo(L-Leu-L-Pro) (5) and 3ß,5α,9α-trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one (6), were newly produced by the mutant u2n2h3-3 compared to the parent ZBY-3 strain. Compound 3 was a new compound; 2 was isolated from a natural source for the first time, and all of these compounds were also not yet found in the metabolites of other A. versicolor strains. Compounds 1-6 inhibited the K562 cells, with inhibition rates of 54.6% (1), 72.9% (2), 23.5% (3), 29.6% (4), 30.9% (5) and 51.1% (6) at 100 µg/mL, and inhibited also other human cancer HL-60, BGC-823 and HeLa cells, to some extent. The present study demonstrated the effectiveness of the ultrasound-mediated approach to activate silent metabolite production in fungi by introducing acquired resistance to aminoglycosides and its potential for discovering new compounds from silent fungal metabolic pathways. This approach could be applied to elicit the metabolic potentials of other fungal isolates to discover new compounds from cryptic secondary metabolites.

Nine new and five known polyketides derived from a deep sea-sourced Aspergillus sp. 16-02-1.

Nine new C9 polyketides, named aspiketolactonol (1), aspilactonols A-F (2-7), aspyronol (9) and epiaspinonediol (11), were isolated together with five known polyketides, (S)-2-(2'-hydroxyethyl)-4-methyl-γ-butyrolactone (8), dihydroaspyrone (10), aspinotriol A (12), aspinotriol B (13) and chaetoquadrin F (14), from the secondary metabolites of an Aspergillus sp. 16-02-1 that was isolated from a deep-sea sediment sample. Structures of the new compounds, including their absolute configurations, were determined by spectroscopic methods, especially the 2D NMR, circular dichroism (CD), Mo2-induced CD and Mosher's 1H NMR analyses. Compound 8 was isolated from natural sources for the first time, and the possible biosynthetic pathways for 1-14 were also proposed and discussed. Compounds 1-14 inhibited human cancer cell lines, K562, HL-60, HeLa and BGC-823, to varying extents.

Three new polyketides from marine-derived fungus Aspergillus glaucus HB1-19.

Two new benzyl derivatives, aspergentisyl A (1) and aspergentisyl B (2), as well as one new naphthoquinone derivative, aspergiodiquinone (3), together with seven known prenylated benzaldehyde derivatives (4-10) were isolated from the marine-derived fungus Aspergillus glaucus HB1-19. The structures of these compounds were characterized based on 1D and 2D NMR spectra analyses and comparison with those reported in the literature. In addition, each isolate was tested for its 1,1-diphenyl-2-picrylhydrazyl radical-scavenging property and all these compounds except compound 3 exhibited strong radical-scavenging activity.

Unprecedented citrinin trimer tricitinol B functions as a novel topoisomerase IIα inhibitor.

Fifteen citrinin derivatives (1-4, 6-16), including two unprecedented citrinin trimers tricitrinols A (3) and B (4), were isolated from Penicillium citrinum HGY1-5. The six-membered ring A system is essential for the cytotoxicity of active dimers (1, 2, and 5) and trimers (3 and 4). Tricitrinol B (4) showed extensive cytotoxicity in 17 tumor cells with comparable low-micromolar IC(50) values (1-10 µM) and potential antimultidrug resistance capabilities. Tricitrinol B (4) induced cell apoptosis in HL60 and HCT116 cells via mainly extrinsic pathways and G2/M arrest. Further antitumor mechanism study and computational docking analysis indicated that tricitrinol B (4) works as an intercalating topoisomerase IIα (topo IIα) poison, which inhibits the enzyme activity of topo IIα by interfering predominantly with the topo IIα-mediated poststrand-passage cleavage/religation equilibrium over with the prestrand-passage one and induced DNA damage. Tricitrinol B (4) represents a novel class of topo IIα-inhibitory skeletons for developing new chemotherapeutic agents.

Streptomyces fildesensis sp. nov., a novel streptomycete isolated from Antarctic soil.

A novel actinomycete strain, GW25-5(T), was isolated from a soil sample collected from the Fildes Peninsula, King George Island, West Antarctica. The strain was characterized by white to grey aerial mycelia, which were differentiated to straight to flexuous spore chains, with rod-shaped smooth spores. The cell wall of strain GW25-5(T) contained LL-diaminopimelic acid (A(2)pm) and traces of meso-A(2)pm. Whole-cell sugars were galactose and minor amounts of mannose and glucose. The predominant menaquinones were MK-9(H(6)) (49%), MK-9(H(8)) (24%) and MK-9(H(4)) (12%). The phospholipids contained DPG, PE, PI, PIM and PL(s). The major cellular fatty acids were iso-C(16:0) and anteiso-C(15:0). Genomic DNA G+C content of strain GW25-5(T) was 70.0 mol%. BLAST result showed that strain GW25-5 has the 16S rRNA gene sequence highest similarity of 97.5% with members of genus Streptomyces and phylogenetic analysis indicated that this strain belongs to the genus Streptomyces. DNA-DNA relatedness values of strain GW25-5(T) with the closest species of Streptomyces purpureus LMG 19368(T) and Streptomyces beijiangensis YIM 6(T) were significantly lower than 70% of the threshold value for the delineation of genomic species. A polyphasic taxonomic investigation based on a judicious combination of genotypic and phenotypic characteristics revealed that the organism represents a novel species of the genus Streptomyces. Thus, we propose strain GW25-5(T) as the type strain of this novel species, Streptomyces fildesensis (=CGMCC 4.5735(T) = YIM 93602(T) = DSM 41987(T) = NRRL B 24828(T)).

Three new cytochalasins from the marine-derived fungus Spicaria elegans KLA03 by supplementing the cultures with L- and D-tryptophan.

Three new cytochalasins Z(21) -Z(23) (1-3, resp.), together with five analogs, 4-8, were isolated from Spicaria elegans KLA03 by the OSMAC (one strain-many compounds) approach with adding L- and D-tryptophan during its cultivation. The structures of new cytochalasins were elucidated on the basis of comprehensive 1D- and 2D-NMR and HR-ESI-MS analyses. Cytochalasins Z(21) and Z(22) (1 and 2, resp.), and compound 5 showed cytotoxic activities against A-549 cell lines with IC(50) values of 8.2, 20.0, and 3.1 µM, respectively.

New cytotoxic metabolites from a deep-sea-derived fungus, Phialocephala sp., strain FL30r.

Two new sorbicillinoids, 1 and 2, together with a novel benzofuranone derivative named phialofurone (3), were isolated from a deep-sea sediment-derived fungus, Phialocephala sp. Their structures were established on the basis of spectroscopic data. All compounds displayed cytotoxic effects against P388 (IC(50) values of 11.5±1.4, 0.1±0.1, and 0.2±0.01 µM, resp.) and K562 (IC(50) values of 22.9±0.8, 4.8±0.3 and 22.4±0.9 µM, resp.) cell lines.

Three new dioxopiperazine metabolites from a marine-derived fungus Aspergillus fumigatus Fres.

Three new dioxopiperazine metabolites (1-3), together with two known compounds, N-acetyltyramine (4) and cyclo-(Ala-Val) (5), were isolated from a marine-derived fungus Aspergillus fumigatus Fres. Their structures were established by spectroscopic methods. Their cytotoxic activities against the K562 cell line were preliminarily evaluated by the sulphorhodamine B (SRB) method.

A new gliotoxin analogue from a marine-derived fungus Aspergillus fumigatus Fres.

A new gliotoxin analogue (1), as well as four known compounds gliotoxin (2), bisdethiobis (methylthio) gliotoxin (3), bis-N-norgliovictin (4) and didehydrobisdethiobis (methylthio) gliotoxin (5), were isolated from a culture of marine-derived fungus Aspergillus fumigatus Fres. The structure of 1 was determined on the basis of spectroscopic methods. All five compounds were evaluated for the cytotoxic effects on tsFT210 cell line by the SRB method.

GPR12 selections of the metabolites from an endophytic Streptomyces sp. associated with Cistanches deserticola.

An endophytic Streptomyces sp. (AC-2) was isolated from the root of Cistanches deserticola Y.C.Ma.. Chemical investigations of the culture broth of AC-2 afforded fifteen compounds including K1115 A (1), tyrosol (2), phenylethylamine derivatives (3, 4), cyclic dipeptides (5-8), nucleosides and their aglycones (9-13), N-acetyltryptamine (14), and pyrrole-2-carboxylic acid (15). Only tyrosol can promote an increase of intracellular cAMP special on GPR12 transfected cells, such as CHO and HEK293, which means it may be a possible ligand for GPR12.