Background and Aims: Fish oil and krill oil are primary sources of Omega-3 polyunsaturated fatty acids (PUFAs), differing in their molecular forms and bioavailability. Understanding these differences can optimize their therapeutic use. This study aims to compare the bioavailability of Omega-3 PUFAs in fish oil and krill oil using a network meta-analysis approach. By evaluating various molecular forms and dosages, the study seeks to identify the most effective Omega-3 sources and dosing regimens to maximize health benefits.

Compound 1 is a curcumin di-O-2,2-bis(hydroxymethyl)propionate that shows significant in vitro and in vivo inhibitory activity against MDA-MB-231 cells with eight to ten-fold higher potency than curcumin. Here, we modified the α-position (C-4 position) of the central 1,3-diketone moiety of 1 with polar or nonpolar functional groups to afford a series of 4,4-disubstituted curcuminoid 2,2-bis(hydroxymethyl)propionate derivatives and evaluated their anticancer activities. A clear structure–activity relationship of compound 1 derivatives focusing on the functional groups at the C-4 position was established based on their anti-proliferative effects against the MDA-MB-231 and HCT-116 cell lines. Compounds 2–6 are 4,4-dimethylated, 4,4-diethylated, 4,4-dibenzylated, 4,4-dipropargylated and 4,4-diallylated compound 1, respectively. Compounds 2m–6m, the ester hydrolysis products of compounds 2–6, respectively, were synthesized and assessed for anticancer activity. Among all compound 1 derivatives, compound 2 emerged as a potential chemotherapeutic agent for colon cancer due to the promising in vivo anti-proliferative activities of 2 (IC₅₀ = 3.10 ± 0.29 μM) and its ester hydrolysis product 2m (IC₅₀ = 2.17 ± 0.16 μM) against HCT-116. The preliminary pharmacokinetic evaluation of 2 implied that 2 and 2m are main contributors to the in vivo efficacy. Compound 2 was further evaluated in an animal study using HCT-116 colon tumor xenograft bearing nude mice. The results revealed a dose-dependent efficacy that led to tumor volume reductions of 27%, 45%, and 60% at 50, 100, and 150 mg/kg doses, respectively. The established structure–activity relationship and pharmacokinetic outcomes of 2 is the guidance for future development of 4,4-disubstituted curcuminoid 2,2-bis(hydroxymethyl)- propionate derivatives as anticancer drug candidates.

Constitutive androstane receptor (CAR) activation has found to ameliorate diabetes in animal models. However, no CAR agonists are available clinically. Therefore, a safe and effective CAR activator would be an alternative option. In this study, sixty courmarin derivatives either synthesized or purified from Artemisia capillaris were screened for CAR activation activity. Chemical modifications were on position 5,6,7,8 with mono-, di-, tri-, or tetra-substitutions. Among all the compounds subjected for in vitro CAR activation screening, 6,7-diprenoxycoumarin was the most effective and was selected for further preclinical studies. Chemical modification on the 6 position and unsaturated chains were generally beneficial. Electron-withdrawn groups as well as long unsaturated chains were hazardous to the activity. Mechanism of action studies showed that CAR activation of 6,7-diprenoxycoumarin might be through the inhibition of EGFR signaling and upregulating PP2Ac methylation. To sum up, modification mimicking natural occurring coumarins shed light on CAR studies and the established screening system provides a rapid method for the discovery and development of CAR activators. In addition, one CAR activator, scoparone, did showed anti-diabetes effect in db/db mice without elevation of insulin levels.

A practical Lewis acid-catalyzed Meyer–Schuster rearrangement of fluoroalkylated propargylic alcohols, leading to a series of β-fluoroalkyl-α,β-enones, is developed. The methodology reported herein features moderate to high yields and high stereoselectivity in the synthesis of β-alkyl-β-fluoroalkyl-α,β-enones.

Drug combination therapy is a key approach in cancer treatments, aiming to improve therapeutic efficacy and overcome drug resistance. Evaluation of intracellular response in cancer cells to drug treatment may disclose the underlying mechanism of drug resistance. In this study, we aimed to investigate the effect of osimertinib, a tyrosine kinase inhibitor (TKI), and a curcumin derivative, 35d, on HCC827 cells and tumors by analyzing alterations in metabolome and related regulations. HCC827 tumor-bearing SCID mice and cultured HCC827 cells were separately examined. The treatment comprised four conditions: vehicle-only, 35d-only, osimertinib-only, and a combination of 35d and osimertinib. The treated tumors/cells were subsequently subjected to metabolomics profiling, fatty acyl analysis, mitochondrial potential measurement, and cell viability assay. Osimertinib induced changes in the ratio of short-chain (SC) to long-chain (LC) fatty acyls, particularly acylcarnitines (ACs), in both tumors and cells. Furthermore, 35d enhanced this effect by further lowering the SC/LC ratio of most ACs. Osimertinib and 35d also exerted detrimental effects on mitochondria through distinct mechanisms. Osimertinib upregulated the expression of carnitine palmitoyltransferase I (CPTI), while 35d induced the expression of heat shock protein 60 (HSP60). The alterations in ACs and CPTI were correlated with mitochondrial dysfunction and inhibited cell growth. Our results suggest that osimertinib and 35d disrupted the fatty acyl metabolism and induced mitochondrial stress in cancer cells. This study provides insights into the potential application of fatty acyl metabolism inhibitors, such as osimertinib or other TKIs, and mitochondrial stress inducers, such as curcumin derivatives, as combination therapy for cancer.

Natural phenolic products from herbal medicines and dietary plants constitute the main source of lead compounds for the development of the new drug. 4,4-Dimethylcurcumin (DMCU) is a synthetic curcumin derivative and exhibits anticancer activities against breast, colon, lung, and liver cancers. However, further development of DMCU is limited by unfavorable compound properties such as very low aqueous solubility and moderate stability. To increase its solubility, we installed either or both of the ethylene-carbonate-linked L-valine side chains to DMCU phenolic groups and produced targeted 1-trifluoroacetic acid (1-TFA) and 2-trifluoroacetic acid (2-TFA) derivatives. The terminus L-valine of ethylene-carbonate-linked side chain is known to be a L-type amino acid transporter 1 (LAT1) recognition element and therefore, these two derivatives were expected to readily enter into LAT1-expressing cancer cells. In practice, 1-TFA or 2-TFA were synthesized from DMCU in four steps with 34–48% overall yield. Based on the corresponding LC-MS analysis, water solubility of DMCU, 1-TFA, and 2-TFA at room temperature (25 ± 1 °C) were 0.018, 249.7, and 375.8 mg/mL, respectively, indicating >10,000-fold higher solubility of 1-TFA and 2-TFA than DMCU. Importantly, anti-proliferative assay demonstrated that 2-TFA is a potent anti-cancer agent against LAT1-expressing lung cancer cells NCI-H460, NCI-H358, and A549 cells due to its high intracellular uptake compared to DMCU and 1-TFA. In this study, we logically designed and synthesized the targeted compounds, established the LC-MS analytical methods for evaluations of drug solubility and intracellular uptake levels, and showed improved solubility and anti-cancer activities of 2-TFA. Our results provide a strategical direction for the future development of curcuminoid-like phenolic compounds.