Isaridin E Protects against Sepsis by Inhibiting Von Willebrand Factor-Induced Endothelial Hyperpermeability and Platelet-Endothelium Interaction.

Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvß3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE's influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin αvß3 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to αvß3. Activation of the integrin αvß3-FAK/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.

Flagellimonas halotolerans sp. nov., a novel bacterium isolated from the South China Sea.

Two Gram-stain-negative strains, designed SYSU M86414T and SYSU M84420, were isolated from marine sediment samples of the South China Sea (Sansha City, Hainan Province, PR China). These strains were aerobic and could grow at pH 6.0-8.0 (optimum, pH 7.0), 4-37 °C (optimum, 28 °C), and in the presence of 0-10 % NaCl (w/v; optimum 3 %). The predominant respiratory menaquinone of strains SYSU M86414T and SYSU M84420 was MK-6. The primary cellular polar lipid was phosphatidylethanolamine. The major cellular fatty acids (>10 %) in both strains were iso-C15 : 0, iso-C15 : 1 G, and iso-C17 : 0 3-OH. The DNA G+C content of strains SYSU M86414T and SYSU M84420 were both 42.10 mol%. Phylogenetic analyses based on 16S rRNA gene sequences and core genes indicated that these novel strains belonged to the genus Flagellimonas and strain SYSU M86414T showed the highest 16S rRNA gene sequence similarity to Flagellimonas marinaquae JCM 11811T (98.83 %), followed by Flagellimonas aurea BC31-1-A7T (98.62 %), while strain SYSU M84420 had highest 16S rRNA gene sequence similarity to F. marinaquae JCM 11811T (98.76 %) and F. aurea BC31-1-A7T (98.55 %). Based on the results of polyphasic analyses, strains SYSU M86414T and SYSU M84420 should be considered to represent a novel species of the genus Flagellimonas, for which the name Flagellimonas halotolerans sp. nov. is proposed. The type strain of the proposed novel isolate is SYSU M86414T (=GDMCC 1.3806T=KCTC 102040T).

Cereibacter flavus sp. nov., a novel member of the family Rhodobacteraceae isolated from seawater of the South China Sea and reclassification of Rhodobacter alkalitolerans as Cereibacter alkalitolerans comb. nov.

A Gram-stain-negative, aerobic, motile, ovoid-shaped and yellow-coloured strain, designated SYSU M79828T, was isolated from seawater collected from the South China Sea. Growth of this strain was observed at 4-37 °C (optimum, 28 °C), pH 6.0-8.0 (optimum, pH 7.0) and with 0-6% NaCl (optimum, 3.0 %, w/v). The respiratory quinone was found to be Q-10. Major fatty acid constituents were C18 : 1 ω7c/C18 : 1 ω6c, C18 : 1 ω7c11-methyl and C18 : 0 (>5 % of total). The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine, phosphoglycolipid, two unidentified phospholipid, one unidentified lipid and an unidentified glycolipid. The genomic DNA G+C content was 64.5 mol%. Phylogenetic analyses based on 16S rRNA gene sequences and core genes indicated that strain SYSU M79828T belonged to the genus Cereibacter and had the highest sequences similarity to 'Rhodobacter xinxiangensis' TJ48T (98.41 %). Based on 16S rRNA gene phylogeny, physiological and chemotaxonomic characterizations, we consider that strain SYSU M79828T represents a novel species of the genus Cereibacter, for which the name Cereibacter flavus sp. nov. is proposed. The type strain is SYSU M79828T (=GDMCC 1.3803T=KCTC 92893T). In addition, according to the results of phylogenetic analysis and similar taxonomic characteristics, we propose that Rhodobacter alkalitolerans should be reclassified as Cereibacter alkalitolerans comb. nov.

Elucidation of the Complete Biosynthetic Pathway of Phomoxanthone A and Identification of a Para-Para Selective Phenol Coupling Dimerase.

Fungal cytochrome P450 enzymes have been shown to catalyze regio- and stereoselective oxidative intermolecular phenol coupling. However, an enzyme capable of catalyzing undirected para-para (C4-4') coupling has not been reported. Here, we revealed the biosynthetic gene cluster (BGC) of phomoxanthone A from the marine fungus Diaporthe sp. SYSU-MS4722. We heterologously expressed 14 biosynthetic genes in Aspergillus oryzae NSAR1 and found that PhoCDEFGHK is involved in the early stage of phomoxanthone A biosynthesis to give chrysophanol and that chrysophanol is then processed by PhoBJKLMNP to yield penexanthone B. A feeding experiment suggested that PhoO, a cytochrome P450 enzyme, catalyzed the regioselective oxidative para-para coupling of penexanthone B to give phomoxanthone A. The mechanism of PhoO represents a novel enzymatic 4,4'-linkage dimerization method for tetrahydroxanthone formations, which would facilitate biosynthetic engineering of structurally diverse 4,4'-linked dimeric tetrahydroxanthones.

Antiplatelet and Antithrombotic Effects of Isaridin E Isolated from the Marine-Derived Fungus via Downregulating the PI3K/Akt Signaling Pathway.

Isaridin E, a cyclodepsipeptide isolated from the marine-derived fungus Amphichorda felina (syn. Beauveria felina) SYSU-MS7908, has been demonstrated to possess anti-inflammatory and insecticidal activities. Here, we first found that isaridin E concentration-dependently inhibited ADP-induced platelet aggregation, activation, and secretion in vitro, but did not affect collagen- or thrombin-induced platelet aggregation. Furthermore, isaridin E dose-dependently reduced thrombosis formation in an FeCl3-induced mouse carotid model without increasing the bleeding time. Mechanistically, isaridin E significantly decreased the ADP-mediated phosphorylation of PI3K and Akt. In conclusion, these results suggest that isaridin E exerts potent antithrombotic effects in vivo without increasing the risk of bleeding, which may be due to its important role in inhibiting ADP-induced platelet activation, secretion and aggregation via the PI3K/Akt pathways.

A new diphenolic metabolite isolated from the marine-derived fungus Aspergillus niger 102.

A new diphenolic derivative asperdiphenol A (1), along with nine known compounds (2-10), was isolated from the marine-derived fungus Aspergillus niger 102. Their structures were elucidated on the basis of spectroscopic analysis including NMR and MS spectrometry. Compound 1 was suggested to be a chiral mixture by the specific rotation and chiral HPLC. Compound 1 was evaluated for its anti-inflammatory, antibacterial, and cytotoxic activity.