Jeong Ah Kim

Tumor angiogenesis is a critical driver of cancer progression; however, current anti-angiogenic therapies remain limited by resistance and toxicity. Hypoxia within the tumor microenvironment induces hypoxia-inducible factor-1α (HIF-1α), which promotes aberrant angiogenesis by upregulating vascular endothelial growth factor (VEGF) and, subsequently, delta-like ligand 4 (DLL4) in endothelial cells. A systematic screening of flavanone derivatives was performed to identify compounds capable of dual inhibition of HIF-1α and DLL4. Among 16 natural compounds evaluated, isoxanthohumol (IXN), a prenylated flavanone, emerged as the most potent, suppressing both hypoxia-induced HIF-1α accumulation in tumor cells and VEGF-induced DLL4 expression in endothelial cells. IXN markedly inhibited endothelial proliferation, migration, and tube formation in vitro. In a Lewis lung carcinoma (LLC) mouse syngeneic model, IXN monotherapy reduced tumor growth and vessel density. Notably, combination treatment with IXN and anti-PD-1 immunotherapy produced greater anti-tumor effects than either monotherapy. This combination enhanced cytotoxic T cell infiltration into the tumor core, increased granzyme B expression, and induced widespread tumor cell apoptosis, consistent with improved vascular normalization. These findings identify IXN as a promising dual-targeting agent that inhibits both HIF-1α and DLL4 and demonstrate its potential to enhance immune checkpoint blockade. Simultaneous targeting of hypoxia-driven and VEGF-DLL4-mediated angiogenic pathways represents a compelling therapeutic strategy to overcome the limitations of current anti-angiogenic and immunotherapeutic approaches.

A comprehensive phytochemical investigation of the methanol extract from the aerial parts of Lespedeza cuneata resulted in the isolation of 36 compounds, i

This study presents the first comprehensive phytochemical analysis of Hydrangea macrophylla var. acuminata leaves, resulting in the isolation of 41 secondary metabolites, including four new compounds: one phenolic (3) and three bis-iridoid glycosides (30-32). The inhibitory activities of these compounds against PTP1B and α-glucosidase were evaluated. Among them, compound 12 exhibited the most potent dual inhibition, with IC₅₀ values of 8.0 ± 1.1 µM for PTP1B and 3.4 ± 0.2 µM for α-glucosidase. Compounds 8 and 9 showed notable α-glucosidase inhibitory activity, with IC₅₀ values of 21.9 ± 0.4 µM and 43.8 ± 2.1 µM, respectively. Enzyme kinetics and molecular docking studies revealed their inhibition mechanisms and binding interactions. This study is the first detailed phytochemical investigation of H. macrophylla var. acuminata and highlights its potential as a natural source of PTP1B and α-glucosidase inhibitors. These findings underscore the plant's promise for developing antidiabetic agents targeting PTP1B and α-glucosidase.

A phytochemical investigation of Punica granatum L. stems and pericarpium yielded five new polyphenols (punicagranols A-E) and 47 known compounds. Antioxidant activity evaluated by DPPH assay indicated that compounds 13 and 25-33 exhibited strong radical-scavenging activity (IC₅₀ < 5 μM), outperforming ascorbic acid. Structure-activity relationship (SAR) analysis linked this activity to hydroxyl group distribution and the presence of hexahydroxydiphenoyl and galloyl moieties. Compounds were also tested for inhibition of α-glucosidase and PTP1B, enzymes involved in type 2 diabetes. Notably, compounds 25, 29, and 33 exhibited potent dual inhibition, exceeding reference inhibitors. Kinetic and docking studies revealed that compound 25 acts as a competitive inhibitor, while compounds 29 and 33 inhibit PTP1B noncompetitively. SAR analysis further emphasized the importance of glucose core stereochemistry and galloyl substitution. These findings highlight ellagitannins as promising antidiabetic leads and support the use of P. granatum as a valuable source of health-promoting food.

Mangifera indica L., a member of the Anacardiaceae family, is widely cultivated across the globe. The leaves of M. indica are renowned for their medicinal properties, attributed to the abundance of bioactive compounds. This study investigated the effects of mango leaf extract on oxidative stress in HeLa cells. Notably, the n-hexane fraction (MLHx) significantly enhanced antioxidant response element (ARE)-luciferase activity at a concentration of 100 µg/mL, surpassing other fractions. MLHx also promoted the expression of HO-1 mRNA by increasing nuclear NRF2 levels. The molecular mechanism of MLHx involves increased phosphorylation of ERK1/2 and stabilization of NRF2. Bioactivity-guided isolation resulted in the identification of six oxylipins: 13(R)-hydroxy-octadeca-(9Z,11E,15Z)-trienoic acid (C-1), 9(R)-hydroxy-octadeca-(10E,12Z,15Z)-trienoic acid (C-2), 13(R)-hydroxy-(9Z,11E)-octadecadienoic acid (C-3), 9(R)-hydroxy-(10E,12Z)-octadecadienoic acid (C-4), 9-oxo-(10E,12E)-octadecadienoic acid (C-5), and 9-oxo-(10E,12Z)-octadecadienoic acid (C-6). These structures were elucidated using comprehensive spectroscopic techniques, including MS and 1H NMR. Additionally, compounds C-7 (9-oxo-(10E,12Z,15Z)-octadecatrienoic acid) and 8 (13-oxo-(9E,11E)-octadecadienoic acid) were characterized by LC-MS/MS mass fragmentation. This study reports the isolation of compounds 1–6 from M. indica for the first time. When tested for their effect on NRF2 activity in HeLa cells, compounds 3, 5, and 6 showed strong stimulation of ARE-luciferase activity in a dose-dependent manner.