The chemical diversity, the attractant, anti-acetylcholinesterase, and antifungal activities of metabolites from biocontrol Trichoderma harzianum uncovered by OSMAC strategy.

Eight new compounds (1-8) were discovered from Trichoderma harzianum associated with edible mushroom by the one strain many compounds (OSMAC) strategy. Triharzianin A (1) is the first naturally scaffold characterized by a C13-prostaglandin skeleton. The configurations of 1-3, and 5 were determined by the Mosher's method, experimental and calculated ECD spectra, and plausible biosynthesis of stereospecific epoxidation. Most compounds indicated obvious feeding attractant activities to silkworm with attraction rates at 30-90%. Compound 7 showed anti-acetylcholinesterase (anti-AChE) activity with a ratio of 29% at a concentration of 50 µM for insecticidal potential. So 2,​3-​dialkylchromone (7) had potential of chemical entrapment and killing of insects. Compounds 2, 3 and 7-11 showed antifungal activities against Aspergillus fumigates, and Trichoderma sp. from mushroom with MICs ≤ 300 µM. The four fermentation extracts also indicated obvious feeding attractant activities to silkworm for the activities brought by active metabolites from T. harzianum. The material base of biocontrol induced by the interaction of host-fungal symbiont can be investigated by the antifungal metabolites against pathogen fungi.

The Cocultured Nigrospora oryzae and Collectotrichum gloeosporioides, Irpex lacteus, and the Plant Host Dendrobium officinale Bidirectionally Regulate the Production of Phytotoxins by Anti-phytopathogenic Metabolites.

The distinctive nature of the endophyte Irpex lacteus, host plant, and the phytopathogen Collectotrichum gloeosporioides resulted in both negative and positive regulation of the production of phytotoxins from Nigrospora oryzae. The coculture of nonhomologous I. lacteus and N. oryzae resulted in a greater number of anti-phytopathogenic metabolites from the dominant endophyte than the coculture of homologous I. lacteus and N. oryzae. The coculture of the phytopathogen N. oryzae and either the nonhomologous (isolation of I. lacteus and N. oryzae from the different plants) or homologous (isolation of I. lacteus and N. oryzae from the same plant) endophyte I. lacteus from different sources indicated that the nonhomologous I. lacteus grew faster than the homologous I. lacteus, and the production of phytotoxic azaphilone from the phytopathogenic N. oryzae decreased due to the inhibition resulting from being cocultured with nonhomologous I. lacteus. On the other hand, the production of phytotoxic azaphilone was promoted by the coculture of two phytopathogens, N. oryzae and C. gloeosporioides. The extract of the host plant, Dendrobium officinale, also increased anti-phytopathogenic metabolite production. Six new phytotoxic azaphilones from N. oryzae, four new tremulane sesquiterpenes from I. lacteus, and a new polyketone were isolated. The endophyte-phytopathogen, phytopathogen-phytopathogen, and endophyte-phytopathogen-host interactions can induce the chemical diversity of novel anti-phytopathogenic metabolites.

Inducing Intermediates in Biotransformation of Natural Polyacetylene and A Novel Spiro-γ-Lactone from Red Ginseng by Solid Co-Culture of Two Gut Chaetomium globosum and The Potential Bioactivity Modification by Oxidative Metabolism.

The ω-hydroxyl-panaxytriol (1) and ω-hydroxyl-dihydropanaxytriol (2)-are rare examples of polyacetylene metabolism by microbial transformation, and these new metabolites (1, 2) from fermented red ginseng (FRG) by solid co-culture induction of two Chaetomium globosum should be the intermediates of biotransformation of panaxylactone (metabolite A). The metabolic pathway of panaxylactone was also exhibited. The ingredients of red ginseng (RG) also induced the production of rare 6/5/5 tricyclic ring spiro-γ-lactone skeleton (3). The ω-hydroxylation of new intermediates (1, 2) decreases cytotoxicity and antifungal activity against C. globosum compared with that of its bioprecursor panaxytriol. Additionally, compounds 1 and 2 indicated obvious inhibition against nitric oxide (NO) production, with ratios of 44.80 ± 1.37 and 23.10 ± 1.00% at 50 µM. 1 has an equivalent inhibition of NO production compared with the positive drug. So, the microbial biotransformation that occurred in FRG fermented by gut C. globosum can change the original bioactivity of polyacetylene, which gave a basis about the metabolic modification of red ginseng by intestinal fungus fermentation.

CDH13 Genetic Polymorphisms, Adiponectin and Ischemic Stroke: a Chinese Family-based Sib-pair Study.

OBJECTIVE: To understand the relationships between CDH13 (T-cadherin) genetic polymorphisms, adiponectin levels and ischemic stroke, and possible interactions between CDH13 polymorphisms and other risk factors. METHODS: We recruited 342 Chinese ischemic stroke sib pairs. We genotyped rs4783244 and rs7193788 on CDH13 using time-of-flight mass spectrometry genotyping technology and measured total and high-molecular weight (HMW) adiponectin levels. We investigated associations between SNPs and ischemic stroke, and interactions between SNPs and other risk factors using multi-level mixed-effects regression model. RESULTS: In individuals without ischemic stroke, CDH13 rs4783244 was associated with total adiponectin levels (per T: Coef = -0.257, P = 0.001). CDH13 rs7193788 was associated with total adiponectin levels (per A: Coef = -0.221, P = 0.001) and HMW adiponectin levels (per A: Coef = -0.163, P = 0.003). rs7193788 was significantly associated with ischemic stroke (GA/AA vs. GG: OR = 1.55, 95% CI: 1.07 to 2.24, P = 0.020) after Bonferroni correction (α = 0.025). There was an interaction between rs7193788 and diabetes (P = 0.036). Compared to diabetes-free individuals with rs7193788 GG genotype, diabetes patients with rs7193788 GA/AA genotypes had higher risks for ischemic stroke (OR = 2.64, 95% CI: 1.58-4.40, P < 0.001). CONCLUSION: CDH13 genetic polymorphisms are associated with adiponectin levels and ischemic stroke. An interaction is found between CDH13 SNP and diabetes for ischemic stroke.

Enhanced electrochemical performance and thermal stability of LiNi(0.5)Mn(1.5)O4 using an electrolyte with sulfolane.

A sulfide-based SEI layer was formed on the surface of a LiNi0.5Mn1.5O4 cathode by using a sulfolane-carbonate mixed solvent electrolyte, which led to an improvement in the electrochemical performance. Moreover, the thermal stability of the LiNi0.5Mn1.5O4 cathode was also significantly improved in the presence of the SEI layer. ARC (Accelerating Rate Calorimetry) tests showed that the self-heating rate of the delithiated LiNi0.5Mn1.5O4 material in the sulfolane-carbonate electrolyte was suppressed.

[Association study between PDE4D gene polymorphism and ischemic stroke].

OBJECTIVE: To investigate the linkage and association between rs966221 (SNP 83) in PDE4D gene with stroke and related traits in ischemic stroke families. METHODS: Ischemic stroke families including ischemic stroke patients and their siblings and/or parents were recruited. Generalized estimating equation (GEE) was used to adjust for with-in family correlations and other potential confounding factors. Non-parameter linkage analysis and family based association test (FBAT) were applied to explore the relationship between rs966221 polymorphism and ischemic stroke together with its related traits. RESULTS: In the study 276 ischemic stroke families with totally 776 participants were enrolled. Apolipoprotein B (apoB), carotid intima media thickness (cIMT), high-density lipoprotein cholesterol and blood pressure were associated with ischemic stroke. In family based association test, after being adjusted for related chronic diseases, rs966221 C allele was found to be associated with cIMT in the dominant model (P=0.019), TT genotype (P=0.019) and CT genotype (P=0.007) were associated with cIMT significantly. After being adjusted for potential confounding factors, evidence of linkage was observed for rs966221 with apoB (P<0.001), high-sensitivity C-reactive protein (P=0.003) and systolic blood pressure (P=0.036). CONCLUSION: Abnormal serum lipid, blood pressure and increasing cIMT were associated with ischemic stroke, and linkage was observed for with apoB, high-sensitivity C-reactive protein, and systolic blood pressure; rs966221 C allele was probably associated with cIMT.

G Protein-Coupled Receptor 120 Mediates Host Defense against Clostridium perfringens Infection through Regulating NOD-like Receptor Family Pyrin Domain-Containing 3 Inflammasome Activation.

Clostridium perfringens is a major cause of infectious foodborne disease, frequently associated with the consumption of raw and undercooked food. Despite intensive studies on clarifying C. perfringens pathogenesis, the molecular mechanisms of host-pathogen interactions remain poorly understood. In soft tissue and mucosal infection models, Gpr120-/- mice, G protein-coupled receptor 120 (GPR120), are more susceptible to C. perfringens infection. Gpr120 deficiency leads to a low survival rate (30 and 10%, p < 0.01), more bacterial loads in the muscle (2.26 × 108 ± 2.08 × 108 CFUs/g, p < 0.01), duodenum (2.80 × 107 ± 1.61 × 107 CFUs/g, p < 0.01), cecum (2.50 × 108 ± 2.05 × 108 CFUs/g, p < 0.01), and MLN (1.23 × 106 ± 8.06 × 105 CFUs/g, p < 0.01), less IL-18 production in the muscle (8.54 × 103 ± 1.20 × 103 pg/g, p < 0.01), duodenum (3.34 × 103 ± 2.46 × 102 pg/g, p < 0.01), and cecum (3.81 × 103 ± 5.29 × 102 pg/g, p < 0.01), and severe organ injury. Obviously, GPR120 facilitates IL-18 production and pathogen control via potassium efflux-dependent NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling. Mechanistically, GPR120 interaction with NLRP3 potentiates the NLRP3 inflammasome assembly. Thus, this study uncovers a novel role of GPR120 in host protection and reveals that GPR120 may be a potential therapeutic target for limiting pathogen infection.

The pseudokinase MLKL contributes to host defense against Streptococcus pluranimalium infection by mediating NLRP3 inflammasome activation and extracellular trap formation.

Host innate immunity plays a pivotal role in the early detection and neutralization of invading pathogens. Here, we show that pseudokinase mixed lineage kinase-like protein (MLKL) is required for host defence against Streptococcus pluranimalium infection by enhancing NLRP3 inflammasome activation and extracellular trap formation. Notably, Mlkl deficiency leads to increased mortality, increased bacterial colonization, severe destruction of organ architecture, and elevated inflammatory cell infiltration in murine models of S. pluranimalium pulmonary and systemic infection. In vivo and in vitro data provided evidence that potassium efflux-dependent NLRP3 inflammasome signalling downstream of active MLKL confers host protection against S. pluranimalium infection and initiates bacterial killing and clearance. Moreover, Mlkl deficiency results in defects in extracellular trap-mediated bactericidal activity. In summary, this study revealed that MLKL mediates the host defence response to S. pluranimalium, and suggests that MLKL is a potential drug target for preventing and controlling pathogen infection.

Erratum: Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis.

[This corrects the article DOI: 10.1016/j.isci.2022.105121.].

Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis.

Despite intense research in understanding Clostridium perfringens (C. perfringens) pathogenesis, the mechanisms by which it is cleared from the host are largely unclarified. In C. perfringens gas gangrene and enterocolitis model, Mlkl -/- mice, lacking mixed lineage kinase-like protein (MLKL), are more susceptible to C. perfringens infection. Mlkl deficiency results in a defect in inflammasome activation, and IL-18 and IL-1ß releases. Exogenous administration of recombinant IL-18 is able to rescue the susceptibility of Mlkl -/- mice. Notably, K+ efflux-dependent NLRP3 inflammasome signaling downstream of active MLKL promotes bacterial killing and clearance. Interestingly, the defect of bactericidal activity is also mediated by decreased classical extracellular trap formation in the absence of Mlkl. Our results demonstrate that MLKL mediates extracellular trap formation in a NLRP3 inflammasome-dependent manner. These findings highlight the requirement of MLKL for host defense against C. perfringens infection through enhancing NLRP3 inflammasome-extracellular traps axis.

Inducing secondary metabolite production from Daldinia eschscholzii JC-15 by red ginseng medium.

Red ginseng (RG) is one of the most popular herbal medicines and used as a dietary supplement in recent years. The bioactive ingredient in RG can induce the production of novel microbial metabolite from fermented RG. Using the one strain-many compounds strategy, the reinvestigation of the metabolites from Daldinia eschscholzii JC-15 cultured in red ginseng medium led to the isolation of an unprecedented benzopyran-naphthalene hybrid, daldinsin (1) and a new lactone (2). In this research, a new lactone, 8-hydroxylhelicascolide A (2) instead of helicascolide A was produced by the D. eschscholzii JC-15 induced by the red ginseng medium. Compound 1 showed anti-acetylcholinesterase activity with the inhibition ratio of 38.8% at 50 µM. Compound 2 indicated antimicrobial activities against Fusarium Solani, F. oxysporum, and Escherichia coli with MICs at 128 µg/mL. RG is therefore a promising activator in production of novel microbial metabolite.

Stable Na Plating and Stripping Electrochemistry Promoted by In Situ Construction of an Alloy-Based Sodiophilic Interphase.

Sodium metal anodes are poor due to the reversibility of Na plating/stripping, which hinders their practical applications. A strategy to form a sodiophilic Au-Na alloy interphase on a Cu current collector, involving a sputtered Au thin layer, is shown to enable efficient Na plating/stripping for a certain period of time. Herein, electrochemical behaviors of Na plating on different substrates are explored, and it is revealed that the sodiophilic interphase can be achieved universally by in situ formation of M-Na (M = Au, Sn, and Sb) alloys during Na plating prior to Na bulk deposition in the initial cycle. Moreover, it is found that repetitive alloying-dealloying leads to falling-off of thin film sodiophilic materials and thus limits the lifespan of efficient Na cycling. Therefore, an approach is further developed by employing particles of sodiophilic materials combined with the control over the cutoff potential, which significantly improves the stability of Na plating/stripping process. Especially, the low-cost Cu@Sn-NPs and Cu@Sb-MPs composite current collectors allow Na plating and stripping to cycle for 2000 and 1700 times with the average efficiency of 99.9% at 2 mA cm-2 .

Linkage and association between interleukin-6 gene polymorphisms and ischemic stroke: a family-based study in the northern Chinese Han population.

BACKGROUND: Numerous genetic risk factors of ischemic stroke (IS) have been reported from both candidate gene and genome-wide strategies with inconsistent results. The objective of this study was to confirm the relationship between 10 previously identified single-nucleotide polymorphisms (SNPs) and IS in the Chinese population. METHODS: A family-based study was conducted in a rural area of Beijing, with a total of 227 IS families with 622 participants recruited. Both linkage and association analyses were performed, with all the sibling pairs derived from the 227 families analyzed using the sib-pair test of model-free linkage to assess linkage between SNPs and IS, with association analyses including a family-based association test (FBAT) and generalized estimating equations (GEE). RESULTS: Nonparametric linkage analysis revealed that the rs1800796 polymorphism in the interleukin-6 (IL-6) gene is significantly linked to the small arterial occlusion (SAO) subtype (p=0.022), while the rs7193343 polymorphism in the ZFHX3 gene is linked to IS (p=0.002) under the dominant model. Significant allelic associations were identified between the G allele of rs1800796 and IS (p=0.042) and the SAO subtype (p=0.025) in the FBAT. The GEE method revealed that the G allele of rs1800796 increased IS risk by 1.55-fold (95% 95% confidence interval [CI]: 1.01, 2.37; p=0.043) and 2.43-fold (95% CI: 1.32, 4.45; p=0.004) in the SAO subtype in the dominant model, which correlated with the significant associations detected in the FBAT. CONCLUSIONS: In this study, we confirmed that the SNP of rs1800796 in the IL-6 gene is related to IS and the SAO subtype using different statistical approaches. These findings could contribute to identifying individuals with a high IS risk.