Large‐Scale Screening of Natural Products Transactivating Peroxisome Proliferator‐Activated Receptor α Identifies 9S‐Hydroxy‐10E,12Z,15Z‐Octadecatrienoic Acid and Cymarin as Potential Compounds Capable of Increasing Apolipoprotein A‐I Transcription in Human Liver Cells

Abstract

Increasing apolipoprotein A‐I (apoA‐I), the predominant protein of high‐density lipoprotein (HDL) particles, has favorable effects on atherogenic risk factors. Here, we investigated the effects of peroxisome proliferator‐activated receptor α (PPARα) transactivating compounds on apoA‐I transcription in HepG2 cells. A transient PPARα agonist transactivation assay was used to screen 2500 natural compounds. To analyze the effects on apoA‐I transcription, human hepatocellular liver carcinoma (HepG2) were exposed to 0.1, 1, and 10 μg/mL of the natural PPARα transactivators. ApoA‐I mRNA expression was determined by quantitative polymerase chain reaction. Extensive dose–response experiments were performed using compounds that increased apoA‐I transcription by minimally 20%. Kelch‐like ECH‐associated protein 1 (KEAP) and carnitine palmitoyltransferase 1 alpha (CPT1α) expression were used respectively to confirm Bromodomain‐containing protein 4 inhibition or PPARα activation. Twenty‐eight natural compounds increased PPARα transactivation by at least twofold. Despite the increased CPT1α expression seen after the addition of most PPARα activating compounds, CPT1α expression and PPARα transactivation did not correlate. Addition of 0.05 μg/mL 9S‐hydroxy‐10E,12Z,15Z‐octadecatrienoic acid (9(S)‐HOTrE) increased apoA‐I mRNA expression by 35%, whereas 10–25 μg/mL of cymarin increased apoA‐I transcription by 37%. However, combining cymarin and 9(S)‐HOTrE did not result in a synergistic effect, in contrast this combination even decreased apoA‐I transcription. ApoA‐I transcription involves multiple regulatory players, and PPARα transactivation alone is not sufficient. A search for natural compounds resembling the molecular structure of 9(S)‐HOTrE or cymarin could aid to find additional components that increase apoA‐I transcription.

Natural and Semisynthetic Chalcones as Dual FLT3 and Microtubule Polymerization Inhibitors

“…Initially, all the chalcones obtained were screened in leukemia cell lines expressing FLT3-ITD (MV-4-11) or BCR-ABL (K562) at 25 and 50 μM concentrations in three-day MTS proliferation assays. The three natural chalcones, viz., 2′-hydroxychalcone ( 1 ), 2′-hydroxy-3,4,4′-trimethoxychalcone ( 2 ), and 4,4′-dimethoxy-2′-hydroxychalcone ( 3 ) , (Scheme ), were found to be differentially more potent toward the MV-4-11 (FLT3-ITD) cell line compared to the K562 (BCR-ABL) cell line at both concentrations [Figure S1, Supporting Information (pink outline)]. It is noteworthy that the new synthesized chalcone 4 , which is the 2′-allyloxy analogue of the natural chalcone 3 , inhibited the growth of both cell lines by >95% at the two concentrations tested (25 and 50 μM; Figure S1, Supporting Information).…”

Evaluation of the plasma oxylipin and endocannabinoid profile and the platelet and plasma proteome in postpartum dairy cows experiencing elevated systemic inflammation

“…Furthermore, the group reported significantly reduced production of inducible nitric oxide synthase (iNOS), TNF-, and IL-1 by inhibiting nuclear factor-B (NF-B) translocation to the nucleus in murine macrophage in vivo samples. 9(S)-HOTrE has been described to exert an anti-inflammatory effect by activating peroxisome proliferator-activated receptor alpha (PPAR), which represses NF-B signaling and thus limits proinflammatory cytokine production [38][39][40] . The noted increase in the circulating plasma concentrations of ALA-derived oxylipins identified in this study (9(S)-HpOTrE, 9(S)-HOTrE, 9-OxoOTrE, and 13(S)-HpOTrE) may indicate that high-inflammation cows were attempting to restore homeostasis as we observed increased concentrations of these anti-inflammatory oxylipins.…”

Search for Natural Compounds That Increase Apolipoprotein A‐I Transcription in HepG2 Cells: Specific Attention for BRD4 Inhibitors

“…In addition, a well-curated database of bioactivities (Gaulton et al, 2017) was used to identify natural compounds and synthetic compounds, which inhibit BRD4. Additionally, we recently identified cymarin and 9 (S)-HOTrE as apoA-I transcriptional elevating compounds (van der Krieken et al, 2018). Therefore, these two compounds were included in our literature review results as well.…”