Formaldehyde as a Chemical Defence Agent of Fruiting Bodies of Mycena rosea and its Role in the Generation of the Alkaloid Mycenarubin†C.

Mycenarubin C, a previously unknown red pyrroloquinoline alkaloid, was isolated from fruiting bodies of the mushroom Mycena rosea and its structure was elucidated mainly by NMR spectroscopy and mass spectrometry. Unlike mycenarubin A, the major pyrroloquinoline alkaloid in fruiting bodies of M. rosea, mycenarubin C, contains an eight-membered ring with an additional C1 unit that is hitherto unprecedented for pyrroloquinoline alkaloids known in nature. Incubation of mycenarubin A with an excess of formaldehyde revealed that mycenarubin C was generated nearly quantitatively from mycenarubin A. An investigation into the formaldehyde content of fresh fruiting bodies of M. rosea showed the presence of considerable amounts of formaldehyde, with values of 5 µg per gram of fresh weight in fresh fruiting bodies. Although mycenarubin C did not show bioactivity against selected bacteria and fungi, formaldehyde inhibits the growth of the mycoparasite Spinellus fusiger at concentrations present in fruiting bodies of M. rosea. Therefore, formaldehyde might play an ecological role in the chemical defence of M. rosea against S. fusiger. In turn, S. fusiger produces gallic acid-presumably to detoxify formaldehyde by reaction of this aldehyde with amino acids and gallic acid to Mannich adducts.

Mycenaflavin†A, B, C, and D: Pyrroloquinoline Alkaloids from the Fruiting Bodies of the Mushroom Mycena haematopus.

Four so far unknown pyrroloquinoline alkaloids, yellow mycenaflavins A, B, and C, and the purple mycenaflavin D, have been isolated from the fruiting bodies of Mycena haematopus. The structures of these new alkaloids were elucidated by NMR spectroscopy and HRMS (ESI+ ). The mycenaflavins are structurally related to mycenarubins and haematopodins, which have been previously identified in M. haematopus. However, compared with other known fungal pyrroloquinoline alkaloids, the mycenaflavins contain an additional double bond within the pyrroloquinoline moiety that accounts for the yellow colour of the monomeric mycenaflavins A, B, and C. The purple mycenaflavin D is the first known dimeric pyrroloquinoline alkaloid with a C-C bridge between the two pyrroloquinoline units. Although the minor pyrroloquinoline alkaloid constituent mycenaflavin A exhibits only moderate bioactivity against the soil bacterium Azoarcus tolulyticus, the major pyrroloquinoline alkaloid constituent haematopodin B is similarly active as the antibiotic gentamicin.

Pelianthinarubins A and B, Red Pyrroloquinoline Alkaloids from the Fruiting Bodies of the Mushroom Mycena pelianthina.

Pelianthinarubin A (1) and pelianthinarubin B (2), two previously unknown pyrroloquinoline alkaloids, have been isolated from fruiting bodies of Mycena pelianthina. The structures of these alkaloids have been deduced from their HR-(+)-ESIMS and 2D NMR data. The absolute configurations of the pelianthinarubins A (1) and B (2) were assigned by analysis of the NOE correlations and coupling constants and by comparison of the CD spectra of 1 and 2 and of hercynine obtained by degradation of 1 with suitable compounds of known absolute configuration. The pelianthinarubins A (1) and B (2), which contain an S-hercynine moiety, differ considerably from the known pyrroloquinoline alkaloids from marine organisms and other Mycena species, such as the mycenarubins, the haematopodins, and the sanguinones.

Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms.

The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.

The pathogenesis of molybdenum cofactor deficiency, its delay by maternal clearance, and its expression pattern in microarray analysis.

Molybdenum cofactor (Moco)-deficiency is a lethal autosomal recessive disease, for which until now no effective therapy is available. The biochemical hallmark of this disorder is the inactivity of the Moco-dependent sulfite oxidase, which results in elevated sulfite and diminished sulfate levels throughout the organism. In humans, Moco-deficiency results in neurological damage, which is apparent in untreatable seizures and various brain dysmorphisms. We have recently described a murine model for Moco-deficiency, which reflects all enzyme and metabolite changes observed in the patients, and an efficient therapy using a biosynthetic precursor of Moco has been established in this animal model. We now analyzed these mice in detail and excluded morphological brain damage, while expression analysis with microarrays indicates a massive cell death program. This neuronal damage appears to be triggered by elevated sulfite levels and is ameliorated in affected embryos by maternal clearance.