Guided isolation of secondary metabolites from Nectria sp. MHHJ-3 by molecular network strategy.

The fungus Nectria sp. MHHJ-3 was isolated from Illigera rhodantha. A molecular networking-guided the secondary metabolites investigation of Nectria sp. MHHJ-3 led to the isolation of ten metabolites (1-10), including two new naphthalenone derivatives, nectrianaphthalenones A (1) and B (2), and two new steroids, nectriasteroids A (3) and B (4). Their structures were elucidated by extensive spectroscopic analysis including the HRESIMS, 1D/2D NMR and electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway for 1-2 was proposed. Compounds 1 and 2 exhibited moderate acetylcholinesterase (AChE) inhibitory activities. Compounds 3 and 4 showed significant cytotoxic activity against selected tumor cells. Particularly, compound 3 exhibited the strongest activity against A549 cells with an IC50 value of 13.73 ± 0.03 µM, which was at the same grade with that of positive control cisplatin.

Cochlioquinone derivatives produced by coculture of endophytes, Clonostachys rosea and Nectria pseudotrichia.

Three new meroterpenoid derivatives, furanocochlioquinol (1) and furanocochlioquinone (2), as well as nectrianolin D (3), together with two known biogenetically related compounds 4 and 5 were isolated from a mixed culture of two mangrove-derived fungi, Clonostachys rosea B5-2 and Nectria pseudotrichia B69-1. The structures of 1-3 were deduced based on the interpretation of HRMS and NMR data. Compounds 1-5 exhibited cytotoxicity against human promyelocytic leukemia (HL60) cells with IC50 values ranging from 0.47 to 10.16 µM.

Bioactive metabolites from the Arctic fungus Nectria sp. B-13.

Two new cyclohexanone derivatives, nectriatones A-B (1-2), and one new natural product, nectriatone C (3), together with three known phenolic sesquiterpene derivatives (4-6), were isolated from the culture of Nectria sp. B-13 obtained from high-latitude soil of the Arctic. The structures of all compounds were unambiguously elucidated by extensive spectroscopic analysis, as well as by comparison with the literature. These compounds were evaluated in cytotoxic and antibacterial activities. Compounds 1-6 showed cytotoxicities against SW1990, HCT-116, MCF-7, and K562 cells, with IC50 values in the range of 0.43 to 42.64 µM. Only compound 4 exhibited antibacterial activity against Escherichisa coli, Bacillus subtilis, and Staphylococcus aureus (MIC 4.0, 2.0, and 4.0 µg/ml, respectively).

Fungal Immunomodulatory Protein from Nectria haematococca Suppresses Growth of Human Lung Adenocarcinoma by Inhibiting the PI3K/Akt Pathway.

Lung cancer is a common disease that is associated with poor prognosis. Fungal immunomodulatory protein from Nectria haematococca (FIP-nha) has potential as a lung cancer therapeutic; as such, illuminating its anti-tumor mechanism is expected to facilitate novel treatment options. Here, we showed that FIP-nha affects lung adenocarcinoma growth ex vivo and in vivo. Comparative quantitative proteomics showed that FIP-nha negatively regulates PI3K/Akt signaling and induces cell cycle arrest, autophagy, and apoptosis. We further demonstrated that FIP-nha suppresses Akt phosphorylation, leading to upregulation of p21 and p27 and downregulation of cyclin B1, cyclin D1, CDK2, and CDK4 expression, ultimately resulting in G1/S and G2/M cell cycle arrest. Meanwhile, FIP-nha-induced PI3K/Akt downregulation promotes A549 apoptosis by increasing the expression ratio of Bax/Bcl-2 and c-PARP and autophagy by decreasing the phosphorylation of mTOR. Thus, we comprehensively revealed the anti-tumor mechanism of FIP-nha, which inhibits tumor growth by modulating PI3K/Akt-regulated cell cycle arrest, autophagy, and apoptosis, and provided the basis for further application of fungal immunomodulatory proteins, especially FIP-nha.

X-ray structure of a calcium-activated TMEM16 lipid scramblase.

The TMEM16 family of proteins, also known as anoctamins, features a remarkable functional diversity. This family contains the long sought-after Ca(2+)-activated chloride channels as well as lipid scramblases and cation channels. Here we present the crystal structure of a TMEM16 family member from the fungus Nectria haematococca that operates as a Ca(2+)-activated lipid scramblase. Each subunit of the homodimeric protein contains ten transmembrane helices and a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbours a conserved Ca(2+)-binding site located within the hydrophobic core of the membrane. Mutations of residues involved in Ca(2+) coordination affect both lipid scrambling in N. haematococca TMEM16 and ion conduction in the Cl(-) channel TMEM16A. The structure reveals the general architecture of the family and its mode of Ca(2+) activation. It also provides insight into potential scrambling mechanisms and serves as a framework to unravel the conduction of ions in certain TMEM16 proteins.