25 research outputs found
Hepatic Metabolic, Inflammatory, and Stress-Related Gene Expression in Growing Mice Consuming a Low Dose of Trans-10, cis-12-Conjugated Linoleic Acid
Dietary trans-10, cis-12-conjugated linoleic acid (trans-10, cis-12-CLA) fed to obese and nonobese rodents reduces body fat but leads to greater liver mass due to steatosis. The molecular mechanisms accompanying such responses remain largely unknown. Our study investigated the effects of chronic low trans-10, cis-12-CLA supplementation on hepatic expression of 39 genes related to metabolism, inflammation, and stress in growing mice. Feeding a diet supplemented with 0.3% trans-10, cis-12-CLA (wt/wt basis) for 6 weeks increased liver mass and concentration of long-chain fatty acids (LCFAs) in liver, while adipose tissue mass decreased markedly. These changes were accompanied by greater expression of genes involved in LCFA uptake (Cd36), lipogenesis, and triacylglycerol synthesis (Acaca, Gpam, Scd, Pck1, Plin2). Expression of these genes was in line with upregulation of the lipogenic transcription factor Srebf1. Unlike previous studies where higher >0.50% of the diet) doses of trans-10, cis-12-CLA were fed, we found greater expression of genes associated with VLDL assembly/secretion (Mttp, Cideb), ketogenesis (Hmgcs2, Bdh1), and LCFA oxidation (Acox1, Pdk4) in response to trans-10, cis-12-CLA. Dietary CLA, however, did not affect inflammation- and stress-related genes. Results suggested that a chronic low dose of dietary CLA increases liver mass and lipid accumulation due to activation of lipogenesis and insufficient induction of LCFA oxidation and VLDL assembly/secretion
Energy-Based Pharmacophore and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) Modeling Combined with Virtual Screening To Identify Novel Small-Molecule Inhibitors of Silent Mating-Type Information Regulation 2 Homologue 1 (SIRT1)
Silent
mating-type information regulation 2 homologue 1 (SIRT1),
being the homologous enzyme of silent information regulator-2 gene
in yeast, has multifaceted functions. It deacetylates a wide range
of histone and nonhistone proteins; hence, it has good therapeutic
importance. SIRT1 was believed to be overexpressed in many cancers
(prostate, colon) and inflammatory disorders (rheumatoid arthritis).
Hence, designing inhibitors against SIRT1 could be considered valuable.
Both structure-based and ligand-based drug design strategies were
employed to design novel inhibitors utilizing high-throughput virtual
screening of chemical databases. An energy-based pharmacophore was
generated using the crystal structure of SIRT1 bound with a small
molecule inhibitor and compared with a ligand-based pharmacophore
model that showed four similar features. A three-dimensional quantitative
structure–activity relationship (3D-QSAR) model was developed
and validated to be employed in the virtual screening protocol. Among
the designed compounds, <b>Lead 17</b> emerged as a promising
SIRT1 inhibitor with IC<sub>50</sub> of 4.34 μM and, at nanomolar
concentration (360 nM), attenuated the proliferation of prostate cancer
cells (LnCAP). In addition, <b>Lead 17</b> significantly reduced
production of reactive oxygen species, thereby reducing pro inflammatory
cytokines such as IL6 and TNF-α. Furthermore, the anti-inflammatory
potential of the compound was ascertained using an animal paw inflammation
model induced by carrageenan. Thus, the identified SIRT1 inhibitors
could be considered as potent leads to treat both cancer and inflammation
Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure
Therapeutic
options for brain infections caused by pathogens with
a reduced sensitivity to drugs are limited. Recent reports on the
potential use of linezolid in treating brain infections prompted us
to design novel compounds around this scaffold. Herein, we describe
the design and synthesis of various oxazolidinone antibiotics with
the incorporation of silicon. Our findings in preclinical species
suggest that silicon incorporation is highly useful in improving brain
exposures. Interestingly, three compounds from this series demonstrated
up to a 30-fold higher brain/plasma ratio when compared to linezolid
thereby indicating their therapeutic potential in brain associated
disorders