Alpinia oxyphylla Miquel (Zingiberaceae) has been reported to show antioxidant, anti-inflammatory, and neuroprotective effects. In this study, two new eudesmane sesquiterpenes, 7α-hydroperoxy eudesma-3,11-diene-2-one (1) and 7β-hydroperoxy eudesma-3,11-diene-2-one (2), and a new eremophilane sesquiterpene, 3α-hydroxynootkatone (3), were isolated from the MeOH extract of dried fruits of A. oxyphylla along with eleven known sesquiterpenes (4–14). The structures were elucidated by the analysis of 1D/2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and optical rotation data. Compounds (1–3, 5–14) were evaluated for their protective effects against tert-butyl hydroperoxide (tBHP)-induced oxidative stress in adipose-derived mesenchymal stem cells (ADMSCs). As a result, treatment with isolated compounds, especially compounds 11 and 12, effectively reverted the damage of tBHP on ADMSCs in a dose-dependent manner. In particular, 11 and 12 at 50 µM improved the viability of tBHP-toxified ADMSCs by 1.69 ± 0.05-fold and 1.61 ± 0.03-fold, respectively.

Perilla frutescens var. acuta (Lamiaceae) is widely used not only as an oil or a spice, but also as a traditional medicine to treat colds, coughs, fever, and indigestion. As an ongoing effort, luteolin-7-O-diglucuronide (1), apigenin-7-O-diglucuronide (2), and rosmarinic acid (3) isolated from P. frutescens var. acuta were investigated for their anti-adipogenic and thermogenic activities in 3T3-L1 cells. Compound 1 exhibited a strong inhibition against adipocyte differentiation by suppressing the expression of Pparg and Cebpa over 52.0% and 45.0%, respectively. Moreover, 2 inhibited the expression of those genes in a dose-dependent manner [Pparg: 41.7% (5 µM), 62.0% (10 µM), and 81.6% (50 µM); Cebpa: 13.8% (5 µM), 18.4% (10 µM), and 37.2% (50 µM)]. On the other hand, the P. frutescens var. acuta water extract showed moderate thermogenic activities. Compounds 1 and 3 also induced thermogenesis in a dose-dependent manner by stimulating the mRNA expressions of Ucp1, Pgc1a, and Prdm16. Moreover, an LC-MS/MS chromatogram of the extract was acquired using UHPLC-MS² and it was analyzed by feature-based molecular networking (FBMN) and the Progenesis QI software (version 3.0). The chemical profiling of the extract demonstrated that flavonoids and their glycoside derivatives, including those isolated earlier as well as rosmarinic acid, are present in P. frutescens var. acuta.

Dendropanax morbifera Leveille is a traditional medicine used to treat migraine headache and dysmenorrhea. In this study, three polyacetylenes, methyl (10E,9R,16R)-16-acetoxy-9-hydroxyoctadeca-10,17-dien-12,14-diynoate (1), methyl (10E,9R,16S)-9,16-dihydroxyoctadeca-10-en-12,14-diynoate (2), and methyl (10Z,9R,16S)-9,16-dihydroxyoctadeca-10,17-dien-12,14-diynoate (3), were isolated from the aerial parts of D. morbifera, together with seven known compounds (4–10). Importantly, the isolates (6 and 8) were found in the family Araliaceae for the first time in this study. Compounds 1−10 were evaluated for their binding affinity to AMPK and CTSS receptors using in silico docking simulations. Only compound 7 increased the protein expression levels of PPAR-α, Sirt1, and AMPK when administered to HepG2 cells as a PPAR-α agonist. On the other hand, 7 did not produce any significant reduction in CTSS activity. This study could pave the way for the discovery of novel treatments from D. morbifera targeting PPAR-α and AMPK.

Dendropanax morbifera Leveille is a traditional medicine used to treat migraine headache and dysmenorrhea. In this study, a new phenolic glycoside, morbiferoside A (1), and three polyacetylenes, methyl (10E,9R,16R)-16-acetoxy-9-hydroxyoctadeca-10,17-dien-12,14-diynoate (2), methyl (10E,9R,16S)-9,16-dihydroxyoctadeca-10-en-12,14-diynoate (3), and methyl (10Z,9R,16S)-9,16-dihydroxyoctadeca-10,17-dien-12,14-diynoate (4), were isolated from the aerial parts of D. morbifera, together with seven known compounds (5–11). Importantly, the isolates, 7 and 9 were found in the family Araliaceae for the first time in this study. Compounds 1−11 were evaluated for their binding affinity to AMPK and CTSS receptors using in silico docking simulations. Only compound 8 increased the protein expression levels of PPAR-α, Sirt1, and AMPK when administered to HepG2 cells as a PPAR-α agonist. On the other hand, 8 did not produce any significant reduction in CTSS activity. This study could pave the way for the discovery of novel treatments from D. morbifera targeting PPAR-α and AMPK.

Background and Aim: Cordycepin (CDC), an adenosine (ADO) analog from Cordyceps mushrooms, exhibits potent anti-tumor and immunomodulatory activities. However, the precise mechanisms governing its effects on macrophage plasticity remain poorly understood. This study aimed to isolate CDC from a high-yielding Cordyceps cultivar, validate its systemic anti-tumor efficacy, and elucidate the mechanobiological cues regulating CDC-driven macrophage functions under varying cell-density states. Experimental Procedure: CDC (>98% purity) was isolated and structurally characterized via nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). Primary bone marrow-derived macrophages and RAW264.7 cells, cultured under sparse (~30%) or confluent (100%) conditions, were treated with CDC or ADO. We evaluated cell viability, pro-inflammatory cytokine expression, and Nuclear Factor kappa B (NF-κB) p65 signaling, phagocytosis, and migration. The therapeutic potential of CDC-primed macrophages was assessed via in vitro melanoma co-culture and in vivo intratumoral adoptive transfer in B16F10 tumor-bearing mice. Key Results: Systemic administration of CDC significantly inhibited melanoma growth in vivo, promoting apoptosis, enhancing macrophage infiltration. We discovered that CDC regulates macrophage functions via a density-dependent “switch”: while CDC induced cytotoxicity in sparse cultures, it significantly augmented M1-like cytokine production in confluent states without compromising viability. This density-dependent activation was mediated by the A2A adenosine receptor (A2AR), triggering the Akt–NF-κB p65 signaling axis. Furthermore, CDC upregulated migration- and phagocytosis-associated genes, enhancing tumor cell clearance. Notably, intratumoral injection of CDC-primed macrophages markedly reduced tumor volume and size in vivo. Conclusions and Implications: CDC modulates macrophage activation through a unique mechanobiological switch. Under high-density conditions—mimicking the dense tumor microenvironment—CDC enhances A2AR-mediated NF-κB activation, boosting macrophage activation, recruitment, and phagocytosis to facilitate tumor regression. These findings establish CDC as a context-dependent immunomodulator capable of reprogramming macrophages toward a tumoricidal phenotype.