The Isoxazole Derivative of Usnic Acid Induces an ER Stress Response in Breast Cancer Cells that Leads to Paraptosis-like Cell Death

Derivatives of usnic acid (UA), a secondary metabolite from lichens, were synthesized to improve its anticancer activity and selectivity. Recently we reported the synthesis and activity of an UA isoxazole derivative, named 2b, against cancer cells of different origins. Herein, the molecular mechanisms underlying its activity and efficacy in vivo were tested. The viability of breast cancer or normal cells has been tested using an MTT assay. Cell and organelle morphology was analyzed using light, electron and fluorescence microscopy. Gene expression was evaluated by RNAseq and protein levels were evaluated by Western blotting. In vivo anticancer activity was evaluated in a mice xenograft model. We found that 2b induced massive vacuolization which originated from the endoplasmic reticulum (ER). ER stress markers were upregulated both at the mRNA and protein levels. ER stress was caused by the release of Ca2+ ions from the ER by IP3R channels which was mediated, at least partly, by phospholipase C (PLC)-synthetized 1,4,5-inositol triphosphate (IP3). ER stress led to cell death with features of apoptosis and paraptosis. When applied to nude mice with xenografted breast cancer cells, 2b stopped tumour growth. In mice treated with 2b, vacuoli-zation was observed in tumour cells, but not in other organs. This study shows that the antiprolif-erative activity of 2b relates to the induction of ER stress in cancer, not in healthy, cells and it leads to breast cancer cell death in vitro and in vivo

Erratum: Synthesis of Usnic Acid Derivatives and Evaluation of Their Antiproliferative Activity against Cancer Cells (Journal of Natural Products (2019) 82:7 (1768-1778) DOI: 10.1021/acs.jnatprod.8b00980)

The (+)-enantiomer of compound 1 was incorrectly assigned as the S-configuration where it is in fact the Rconfiguration. As a consequence, compounds 2b, 3b, 3d, 3f, 3h, 3j, 3l, and 3n are also the R-configuration. Page 1769: The table within Scheme 2 should be substituted with the following:. The compound names within the Supporting Information (pp 2-6) need to be altered as follows: • (R)-8-Acetyl-5,7-dihydroxy-3,4a,6-trimethyl-1-phenyl- 1,4a-dihydro-4Hbenzofuro[3,2-f ]indazol-4-one (3d) • (R)-8-Acetyl-5,7-dihydroxy-1-(4-methoxyphenyl)- 3,4a,6-trimethyl-1,4a-dihydro4H-benzofuro[3,2-f ]- indazol-4-one (3f) • (R)-8-Acetyl-1-(4-fluorophenyl)-5,7-dihydroxy-3,4a,6- trimethyl-1,4a-dihydro-4Hbenzofuro[3,2-f ]indazol-4- one (3h). • (R)-8-Acetyl-1-(3,4-dichlorophenyl)-5,7-dihydroxy- 3,4a,6-trimethyl-1,4a-dihydro4H-benzofuro[3,2-f ]- indazol-4-one (3j) (Table Presented). • (R)-8-Acetyl-1-(4-chlorophenyl)-5,7-dihydroxy-3,4a,6- trimethyl-1,4a-dihydro4H-benzofuro[3,2-f ]indazol-4- one (3n) Accordingly, the structures of compounds 2b, 3b, 3d, 3f, 3h, 3j, 3l, and 3n in the Supporting Information have been revised. Additionally, the Abstract is revised as follows: Moreover, they induced massive cytoplasmic vacuolization, which was associated with elevated dynamin-dependent endocytosis, a process that has not been reported for usnic acid and indicates a novel mechanism of action of its synthetic derivatives. The authors sincerely apologize for any inconvenience caused by these errors

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Analysis of intraoperative transfusions of red blood cell concentrates in adults

BACKGROUND: Transfusion of red blood cell (RBC) concentrates is the most common allogeneic transplantation. The aim of the study was to analyse the indications for RBC transfusions, compared to the estimated intraoperative blood loss and the actual requirements for blood transfusion.METHODS: We retrospectively analysed the files of 250 adult patients who were transfused over the year 2006, during various general, oncologic, trauma, vascular, plastic and thoracic surgical procedures. Preoperative screening was done in a hospital laboratory, whereas postoperative haemoglobin concentration and haematocrit were assessed at the bedside using a co-oximeter.RESULTS: The majority of RBC transfusions were started at relatively high haemoglobin concentrations (mean 5.6 mmol L-1), contrary to the current guidelines. A high correlation coefficient (r=0.82) was found between the estimated blood loss and the volume of RBCs transfused; therefore we concluded that the observed blood loss was the main factor in transfusion decisions.CONCLUSIONS: Despite enormous progress in transfusion science, the current practice in our institution is still far from ideal; RBCs are frequently transfused too early and without a real indication.BACKGROUND: Transfusion of red blood cell (RBC) concentrates is the most common allogeneic transplantation. The aim of the study was to analyse the indications for RBC transfusions, compared to the estimated intraoperative blood loss and the actual requirements for blood transfusion.METHODS: We retrospectively analysed the files of 250 adult patients who were transfused over the year 2006, during various general, oncologic, trauma, vascular, plastic and thoracic surgical procedures. Preoperative screening was done in a hospital laboratory, whereas postoperative haemoglobin concentration and haematocrit were assessed at the bedside using a co-oximeter.RESULTS: The majority of RBC transfusions were started at relatively high haemoglobin concentrations (mean 5.6 mmol L-1), contrary to the current guidelines. A high correlation coefficient (r=0.82) was found between the estimated blood loss and the volume of RBCs transfused; therefore we concluded that the observed blood loss was the main factor in transfusion decisions.CONCLUSIONS: Despite enormous progress in transfusion science, the current practice in our institution is still far from ideal; RBCs are frequently transfused too early and without a real indication