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1.
Cell Stem Cell ; 24(4): 621-636.e16, 2019 04 04.
Article in English | MEDLINE | ID: mdl-30930145

ABSTRACT

Tafazzin (TAZ) is a mitochondrial transacylase that remodels the mitochondrial cardiolipin into its mature form. Through a CRISPR screen, we identified TAZ as necessary for the growth and viability of acute myeloid leukemia (AML) cells. Genetic inhibition of TAZ reduced stemness and increased differentiation of AML cells both in vitro and in vivo. In contrast, knockdown of TAZ did not impair normal hematopoiesis under basal conditions. Mechanistically, inhibition of TAZ decreased levels of cardiolipin but also altered global levels of intracellular phospholipids, including phosphatidylserine, which controlled AML stemness and differentiation by modulating toll-like receptor (TLR) signaling.


Subject(s)
Leukemia, Myeloid, Acute/metabolism , Mitochondria/enzymology , Phospholipids/metabolism , Transcription Factors/metabolism , Acyltransferases , Animals , Cell Line, Tumor , Doxorubicin/pharmacology , Female , Humans , Leukemia, Myeloid, Acute/pathology , Male , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Signal Transduction/drug effects , Toll-Like Receptors/metabolism , Transcription Factors/antagonists & inhibitors , Transcription Factors/deficiency
2.
Sci Total Environ ; 637-638: 1508-1517, 2018 Oct 01.
Article in English | MEDLINE | ID: mdl-29801244

ABSTRACT

Traditional foods have significant nutritional, sociocultural and economic value in subarctic First Nations communities of the Northwest Territories, and play a crucial role in promoting cultural continuity and sovereignty. Omega-3 polyunsaturated fatty acids (N-3 PUFAs), including eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), carry significant benefits for neurocognitive development and cardiovascular health. However, the health risks posed by methylmercury may serve to undermine the benefits of fish consumption in Northern Indigenous communities. The objective of this study was to characterize profiles for mercury (Hg) and fatty acids in fish species harvested across lakes of the Dehcho Region, in the Mackenzie Valley of the Northwest Territories, to better understand the risks and benefits associated with traditional foods. Hg levels increased with trophic position, with the highest levels found in Burbot, Lake Trout, Walleye, and Northern Pike. Lake Trout, along with planktivorous species including Lake Whitefish, Cisco, and Sucker, demonstrated higher N-3 PUFAs than other species. Negative associations were observed between Hg and N-3 PUFAs in Lake Trout, Northern Pike, Walleye and Burbot. Further stratifying these relationships revealed significant interactions by lake. Significant differences observed in fatty acid and Hg profiles across lakes underscore the importance of considering both species- and lake-specific findings. This growing dataset of freshwater fish of the Dehcho will inform future efforts to characterize human Hg exposure profiles using probabilistic dose reconstruction models.


Subject(s)
Environmental Monitoring , Fatty Acids, Omega-3/metabolism , Fishes/metabolism , Mercury/metabolism , Water Pollutants, Chemical/metabolism , Animals , Mercury/analysis , Northwest Territories , Risk Assessment
3.
J Nat Prod ; 81(4): 818-824, 2018 04 27.
Article in English | MEDLINE | ID: mdl-29565590

ABSTRACT

Avocatin B, an avocado-derived compound mixture, was demonstrated recently to possess potent anticancer activity by selectively targeting and eliminating leukemia stem cells. Avocatin B is a mixture of avocadene and avocadyne, two 17-carbon polyhydroxylated fatty alcohols (PFAs), first discovered in avocado seeds; their quantities in avocado pulp are unknown. Analytical methods to detect avocado seed PFAs have utilized NMR spectroscopy and GC-MS; both of these lack quantitative capacity and accuracy. Herein, we report a sensitive LC-MS method for the quantitation of avocadene and avocadyne in avocado seed and pulp. The method has a reliable and linear response range of 0.1-50 µM (0.03-17.2 ng/µL) for both avocadene and avocadyne ( r2 > 0.990) with a lower limit of quantitation (LLOQ) of 0.1 µM. The intra- and interassay accuracy and precision of the quality control (QC) samples at LLOQ showed ≤18.2% percentage error and ≤14.4% coefficient of variation (CV). The intra- and interassay accuracy and precision for QC samples at low and high concentrations were well below 10% error and CV. This method was successfully applied to quantify avocadene and avocadyne in total lipid extracts of Hass avocado pulp and seed matter.


Subject(s)
Fruit/chemistry , Persea/chemistry , Plant Extracts/chemistry , Seeds/chemistry , Chromatography, Liquid/methods , Tandem Mass Spectrometry/methods
4.
Data Brief ; 7: 452-6, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27014729

ABSTRACT

Data are presented on the fatty acyl composition of phospholipid from retroperitoneal white adipose tissue of female mice that were either given ad libitum access to food or fasted for 16 h overnight prior to sacrifice. Our data show that total adipose phospholipid concentrations were more than 2-fold higher in the fasted animals compared with the fed animals (33.48±7.40 versus 16.57±4.43 µg phospholipid fatty acids/100 mg tissue). Concentrations of several individual phospholipid fatty acyl species, including palmitic acid (16:0), vaccenic acid (18:1n-7), linoleic acid (18:2n-6), dihomo-gamma-linolenic acid (20:3n-6), arachidonic acid (20:4n-6), eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3), as well as total phospholipid saturated fatty acids, n-6 polyunsaturated fatty acids and n-3 polyunsaturated fatty acids, were significantly higher in adipose tissue from the fasted animals compared with the fed animals. However, when the relative abundance of phospholipid fatty acyl species was analyzed, only 20:4n-6 was specifically enriched (by ~2.5-fold) in adipose phospholipid with fasting.

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