Cytotoxic phenazine and antiallergic phenoxazine alkaloids from an arctic Nocardiopsis dassonvillei SCSIO 502F.

Microbes well-adapted to the Arctic Ocean are promising for producing novel compounds, due to their fancy strategies for adaptation and being under-investigated. Two new phenazine alkaloids (1 and 2) and one new phenoxazine (3) were isolated from Nocardiopsis dassonvillei 502F, a strain originally isolated from Arctic deep-sea sediments. AntiSMASH analysis of the genome of Nocardiopsis dassonvillei 502F revealed the presence of 16 putative biosynthetic gene clusters (BGCs), including a phenazine BGC. Most of the isolated compounds were evaluated for their antibacterial, antiallergic, and cytotoxic activities. Among them, compounds 4 and 5 exhibited potent in vitro cytotoxic activities against osteosarcoma cell line 143B with IC50 values 0.16 and 20.0 µM, respectively. Besides, the results of antiallergic activities of compounds 6-8 exhibited inhibitory activities with IC50 values of 10.88 ± 3.05, 38.88 ± 3.29, and 2.44 ± 0.17 µg/mL, respectively (IC50 91.6 µM for the positive control loratadine).

Indole diketopiperazine alkaloids and aromatic polyketides from the Antarctic fungus Penicillium sp. SCSIO 05705.

A new indole diketopiperazine alkaloid, named penilline D (1), together with five known indole alkaloid analogues (2-5, 11), two meroterpenoids (6 and 12), and four butenolide derivatives (7-10), were isolated from the Antarctic fungus Penicillium sp. SCSIO 05705. Extensive spectroscopic analysis and electronic circular dichroism (ECD) calculation were used to elucidate the structure of penilline D (1), including its absolute configuration. All isolated compounds (1-12) were evaluated for their cytotoxic, antibacterial and enzyme inhibitory activities against acetylcholinesterase (AChE) and pancreatic lipase (PL). Among them, compound 5 exhibited moderate in vitro cytotoxic activity against the 143B cell line with IC50 value of 12.64 ± 0.78 µM. Compound 6 showed strong inhibitory activity against AChE with IC50 value of 0.36 nM (IC50 18.7 nM for Tacrine), while compounds 6 and 11 showed weak PL enzyme inhibitory activity. Furthermore, an in silico molecular docking study was also performed between 6 and AChE.

The marine-derived furanone reduces intracellular lipid accumulation in vitro by targeting LXRα and PPARα.

Recent studies have demonstrated that commercially available lipid-lowering drugs cause various side effects; therefore, searching for anti-hyperlipidaemic compounds with lower toxicity is a research hotspot. This study was designed to investigate whether the marine-derived compound, 5-hydroxy-3-methoxy-5-methyl-4-butylfuran-2(5H)-one, has an anti-hyperlipidaemic activity, and the potential underlying mechanism in vitro. Results showed that the furanone had weaker cytotoxicity compared to positive control drugs. In RAW 264.7 cells, the furanone significantly lowered ox-LDL-induced lipid accumulation (~50%), and its triglyceride (TG)-lowering effect was greater than that of liver X receptor (LXR) agonist T0901317. In addition, it significantly elevated the protein levels of peroxisome proliferator-activated receptors (PPARα) and ATP-binding cassette (ABC) transporters, which could be partially inhibited by LXR antagonists, GSK2033 and SR9243. In HepG2 cells, it significantly decreased oleic acid-induced lipid accumulation, enhanced the protein levels of low-density lipoprotein receptor (LDLR), ABCG5, ABCG8 and PPARα, and reduced the expression of sterol regulatory element-binding protein 2 (~32%). PPARα antagonists, GW6471 and MK886, could significantly inhibit the furanone-induced lipid-lowering effect. Furthermore, the furanone showed a significantly lower activity on the activation of the expression of lipogenic genes compared to T0901317. Taken together, the furanone exhibited a weak cytotoxicity but had powerful TC- and TG-lowering effects most likely through targeting LXRα and PPARα, respectively. These findings indicate that the furanone has a potential application for the treatment of dyslipidaemia.

Sesquiterpenes from the whole plants of Parasenecio roborowskii.

Six eremophilane-type (parasenolide A-F) and an eudesmane-type (parasenin) sesquiterpenoids, along with eight known sesquiterpenes, were isolated from the whole plants of Parasenecio roborowskii. The structures and absolute configurations of new compounds were elucidated using extensive spectroscopic analysis, including HRESIMS, 1D and 2D NMR experiments, the CD exciton chirality methods, and single-crystal X-ray crystallography. All isolated compounds were evaluated for cytotoxicity against five human cancer (HeLa, HepG2, K562, MDA231, and NCI-H460) cell lines and a murine melanoma B16 F10 cell line by MTT assay. Compounds 1-15 showed cytotoxic activities, especially compounds 3, 4, 8, 10, and 12. These five compounds showed broad spectrum activities against all the tested cancer cell lines with IC50 ranging from 9.2 to 35.5µM. The study supports that eremophilenolides and eudesmane-type sesquiterpenes occur mainly in the genus Parasenecio and can be used as a chemosystematic marker of the genus.

Quinones and coumarins from Ajania salicifolia and their radical scavenging and cytotoxic activity.

1,4-Naphthoquinone (1) and a new coumarin (3) were isolated from Ajania salicifolia, together with two known compounds (2, 4). The structures and stereochemistry of new compounds were elucidated using spectroscopic methods. Two compounds exhibited potent ABTS cation radical scavenging activities with IC50 values ranging 7.97-8.44 µM. Two quinones (1, 2) exhibited moderate cytotoxic activity against the human cancer cell lines (Hela, HepG2, and K562) with IC50 values of 11.24-35.15 µM in vitro. This is the first report of naphthoquinone in the genus Ajania.

PEComa of the uterus with coexistence of situs inversus totalis, a case report and literature review.

PEComas are a group of very rare mesenchymal neoplasms, which express myogenic and melanocytic markers, such as HMB-45 and actin. Situs inversus totalis represents a complete left to right side transposition of the asymmetrical thoracic and abdominal organs and incorporates dextrocardia. The presence of uterus PEComa in the setting of situs inversus totalis is extremely rare. Here, we report a case of PEComa of uterus with coexistence of situs inversus totalis and review the literatures. To the best of our knowledge this is the fist report of a uterus PEComa patient with situs inversus totalis.

Unfolded protein response mediated JNK/AP-1 signal transduction, a target for ovarian cancer treatment.

Researches have revealed several stressors, which could activate unfolded protein response (UPR) in cells. However, the survival or death pathway was determined by the duration of UPR exposure. Based on the UPR mediated death pathway, our study was aimed to investigate role of UPR on c-Jun N-terminal kinase (JNK)/activator protein-1 (Ap-1) signal transduction in diindolylmethane (DIM) treated ovarian cancer cell lines. Activation of UPR proteins, UPR mediated apoptotic signaling proteins and expression level of EpCAM, JNK, Ap-1, Caspase-3 and Bcl-2 were measured. Protein and gene expression, transcription factor activity, and protein phosphorylation were measured using standard molecular biology techniques. Our results demonstrated DIM treatment had significantly increased the expression of Endoplasmic reticulum (ER) stress regulators such as Bip, IRE1, CHOP and activation of UPR related apoptotic proteins in ovarian cancer cells. Decreased expression of EpCAM and activity of AP-1 transcription factor were observed in DIM treated cells. The pharmacologic inhibitors of the JNK signal transduction pathway, suggest that the impact of EpCAM expression on AP-1 transcription factor activity is mediated through the JNK pathway. Taken together, these results suggest that UPR mediated JNK/Ap-1 signal transduction has a significant role in the regulation of apoptosis in human ovarian cancer cells, and is a potential molecular target to enhance sensitivity of ovarian cancer to chemotherapy.

Structure/function relationships of adipose phospholipase A2 containing a cys-his-his catalytic triad.

Adipose phospholipase A(2) (AdPLA or Group XVI PLA(2)) plays an important role in the onset of obesity by suppressing adipose tissue lipolysis. As a consequence, AdPLA-deficient mice are resistant to obesity induced by a high fat diet or leptin deficiency. It has been proposed that AdPLA mediates its antilipolytic effects by catalyzing the release of arachidonic acid. Based on sequence homology, AdPLA is part of a small family of acyltransferases and phospholipases related to lecithin:retinol acyltransferase (LRAT). To better understand the enzymatic mechanism of AdPLA and LRAT-related proteins, we solved the crystal structure of AdPLA. Our model indicates that AdPLA bears structural similarity to proteins from the NlpC/P60 family of cysteine proteases, having its secondary structure elements configured in a circular permutation of the classic papain fold. Using both structural and biochemical evidence, we demonstrate that the enzymatic activity of AdPLA is mediated by a distinctive Cys-His-His catalytic triad and that the C-terminal transmembrane domain of AdPLA is required for the interfacial catalysis. Analysis of the enzymatic activity of AdPLA toward synthetic and natural substrates indicates that AdPLA displays PLA(1) in addition to PLA(2) activity. Thus, our results provide insight into the enzymatic mechanism and biochemical properties of AdPLA and LRAT-related proteins and lead us to propose an alternate mechanism for AdPLA in promoting adipose tissue lipolysis that is not contingent on the release of arachidonic acid and that is compatible with its combined PLA(1)/A(2) activity.