6 research outputs found
Neutral lipids associated with haemozoin mediate efficient and rapid β-haematin formation at physiological pH, temperature and ionic composition
Slc7a8 Deletion Is Protective against Diet-Induced Obesity and Attenuates Lipid Accumulation in Multiple Organs
Adipogenesis, through adipocyte hyperplasia and/or hypertrophy, leads to increased adiposity, giving rise to obesity. A genome-wide transcriptome analysis of in vitro adipogenesis in human adipose-derived stromal/stem cells identified SLC7A8 (Solute Carrier Family 7 Member 8) as a potential novel mediator. The current study has investigated the role of SLC7A8 in adipose tissue biology using a mouse model of diet-induced obesity. slc7a8 knockout (KO) and wildtype (WT) C57BL/6J mice were fed either a control diet (CD) or a high-fat diet (HFD) for 14 weeks. On the HFD, both WT and KO mice (WTHFD and KOHFD) gained significantly more weight than their CD counterparts. However, KOHFD gained significantly less weight than WTHFD. KOHFD had significantly reduced levels of glucose intolerance compared with those observed in WTHFD. KOHFD also had significantly reduced adipocyte mass and hypertrophy in inguinal, mesenteric, perigonadal, and brown adipose depots, with a corresponding decrease in macrophage infiltration. Additionally, KOHFD had decreased lipid accumulation in the liver, heart, gastrocnemius muscle, lung, and kidney. This study demonstrates that targeting slc7a8 protects against diet-induced obesity by reducing lipid accumulation in multiple organs and suggests that if targeted, has the potential to mitigate the development of obesity-associated comorbidities
Barriers to Implementing Clinical Pharmacogenetics Testing in Sub-Saharan Africa. A Critical Review
Synthetic Hemozoin (β-Hematin) Crystals Nucleate at the Surface of Neutral Lipid Droplets that Control Their Sizes
Emulsions
of monopalmitoylglycerol (MPG) and of a neutral lipid
blend (NLB), consisting of MPG, monostearoylglycerol, dipalmitoylglycerol,
dioleoylglycerol, and dilineoylglycerol (4:2:1:1:1), the composition
associated with hemozoin from the malaria parasite Plasmodium falciparum, have been used to mediate
the formation of β-hematin microcrystals. Transmission electron
microscopy (TEM), electron diffraction, and electron spectroscopic
imaging/electron energy loss spectroscopy (ESI/EELS) have been used
to characterize both the lipid emulsion and β-hematin crystals.
The latter have been compared with β-hematin formed at a pentanol/aqueous
interface and with hemozoin both within P. falciparum parasites and extracted from the parasites. When lipid and ferriprotoporphyrin
IX solutions in 1:9 v/v acetone/methanol were thoroughly premixed
either using an extruder or an ultrasound bath, β-hematin crystals
were found formed in intimate association with the lipid droplets.
These crystals resembled hemozoin crystals, with prominent {100} faces.
Lattice fringes in TEM indicated that these faces made contact with
the lipid surface. The average length of these crystals was 0.62 times
the average diameter of NLB droplets, and their size distributions
were statistically equivalent after 10 min incubation, suggesting
that the lipid droplets also controlled the sizes of the crystals.
This most closely resembles hemozoin formation in the helminth worm Schistosoma mansoni, while in P. falciparum, crystal formation appears to be associated with the much more gently
curved digestive vacuole membrane, which apparently leads to formation
of much larger hemozoin crystals, similar to those formed at the flat
pentanol–water interface
Insights into the Role of Heme in the Mechanism of Action of Antimalarials
By using cell fractionation and measurement of Fe(III)heme-pyridine,
the antimalarial chloroquine (CQ) has been shown to cause a dose-dependent
decrease in hemozoin and concomitant increase in toxic free heme in
cultured <i>Plasmodium falciparum</i> that is directly correlated
with parasite survival. Transmission electron microscopy techniques
have further shown that heme is redistributed from the parasite digestive
vacuole to the cytoplasm and that CQ disrupts hemozoin crystal growth,
resulting in mosaic boundaries in the crystals formed in the parasite.
Extension of the cell fractionation study to other drugs has shown
that artesunate, amodiaquine, lumefantrine, mefloquine, and quinine,
all clinically important antimalarials, also inhibit hemozoin formation
in the parasite cell, while the antifolate pyrimethamine and its combination
with sulfadoxine do not. This study finally provides direct evidence
in support of the hemozoin inhibition hypothesis for the mechanism
of action of CQ and shows that other quinoline and related antimalarials
inhibit cellular hemozoin formation