Excessive fructose intake is closely associated with the development of metabolic disorders, including insulin resistance, dyslipidemia, and hypertension. Plant-derived bioactive compounds have attracted increasing attention as potential nutritional strategies for improving metabolic health. In this study, we investigated the central regulatory effects of swietenolide (SW), a distinct limonoid isolated from Swietenia macrophylla seeds, on fructose-induced metabolic dysfunction.Male Wistar Kyoto rats were provided with 10% fructose in their drinking water for four weeks to induce metabolic impairment, and SW (3 or 10 mg/kg) was administered orally during the final two weeks. Fructose feeding induced significant systemic metabolic alterations, including hyperinsulinemia, elevated HOMA-IR, dyslipidemia, and elevated blood pressure. Within the nucleus tractus solitarius (NTS), an autonomic regulatory center, fructose intake was associated with significantly increased oxidative stress, TLR4-mediated microglial activation, and disrupted AMPK/nNOS and insulin-related signaling.Notably, high-dose SW treatment significantly attenuated systemic insulin resistance and dyslipidemia, while effectively reducing blood pressure. Furthermore, SW treatment robustly reversed NTS-specific pathological alterations by suppressing NADPH oxidase-associated oxidative stress and neuroinflammation, and by restoring central AMPK- and insulin-related signaling networks.These findings quantitatively indicate that SW effectively alleviates fructose-induced metabolic dysfunction, at least in part, through the modulation of central AMPK-, redox-, and insulin-related signaling in the NTS. Overall, this study highlights the potential of SW as a plant-derived bioactive compound with nutraceutical value for managing diet-induced metabolic stress.

Zoanthus sansibaricus is a marine invertebrate native to the Indian and North Pacific Oceans. A chemical investigation of Z. sansibaricus, cultured in an aquafarm, led to the isolation of two new zoanthamine derivatives, named 3β-hydroxyzoanthamine (1) and 3α-hydroxynorzoanthaminone (2), along with five known derivatives (3‒7). Their structures were elucidated through quantum chemical calculations and a detailed analysis of spectroscopic data, including mass, IR, and NMR spectra. New compounds 1 and 2 represent additional examples of the oxidation of zoanthamine derivatives. The potential photoprotective effect of all isolated alkaloids (1‒7) was evaluated against UVA-induced damage in human dermal fibroblasts. Among the tested compounds, only 26-norzoanthamine (4) significantly attenuated UVA-induced oxidative stress. Notably, this antioxidant activity did not translate into sustained cell viability protection at 72 hours post-irradiation, suggesting that the photoprotective mechanism of compound 4 is limited to acute oxidative stress attenuation.

Angiogenesis, regulated by vascular endothelial growth factor (VEGF), is crucial in tumor growth, metastasis, and inflammation. Leonurus japonicus Houtt., a traditional Chinese herb, was investigated for its anti-angiogenic potential. DNA sequencing confirmed its identity, distinguishing it from the common morphological misidentification with Leonurus sibiricus by the public. Using UHPLC-MS/MS and GNPS (Global Natural Products Social) molecular networking on the active methanol partition, over 6000 nodes were grouped into 273 clusters. Diterpenoids and flavonoids were targeted. Six compounds were successfully isolated from L. japonicus, including four labdane-type diterpenoids (1-4) and two flavonoids (5, 6) using column chromatography. Compound 1, (-)-8S-acetoxy-15,16-epoxy-8,9-seco-13(16),14-labdadiene, was a new stereoisomer, while Compound 6, nevadensin, was reported for the first time from this species. Compounds were characterized by NMR, ESI-MS, and ECD. At 50 μM, Compounds 1, 4, and 5 exhibited inhibitory effects in endothelial progenitor cell (EPC) tube formation. Molecular docking and dynamics simulations supported this anti-angiogenic activity. Compound 1 showed the highest VEGFR-2 binding affinity (-9.24 kcal/mol), comparable to sunitinib (-9.52 kcal/mol), further verified by an immunoblotting assay. This study demonstrated the successful integration of GNPS and bioactivity-guided isolation for identifying natural VEGFR-2 inhibitors. Our findings highlight Compounds 1 and 4 as promising lead candidates for anti-angiogenic therapy.

An encrusting, algae-associated octocoral, Briareum stechei, afforded three 8,17-epoxybriarane diterpenoids, including the known compound briaexcavatolide B (1) and two previously undescribed analogues, briastecholides Q (2) and R (3). The absolute configuration of 1 was established for the first time by single-crystal X-ray diffraction analysis. The planar structures and relative configurations of 2 and 3 were determined through extensive spectroscopic analyses. In bioactivity evaluation, compound 2 exhibited cytotoxic effects toward the human acute lymphoblastic leukemia cell lines Molt-4 and CCRF-CEM.

The anticancer effects and mechanisms of the main component (CI-A) of methanol extracts of Clavularia inflat have not been reported. This study explores the anti-oral cancer effect and mechanism of (1R*,12R*)-dolabella-4(16),7,10-triene-3,13-dione (CI-A) and compared with normal cells. CI-A shows oxidative-stress-dependent preferential antiproliferation of oral cancer cells without normal cell toxicity. CI-A triggers cell cycle dysregulation, apoptosis/caspase activation, cellular/mitochondrial ROS induction, glutathione depletion, and oxidative DNA damage in oral cancer but not normal cells. After testing with three MAPK (p38, JNK, and ERK) inhibitors, only the ERK inhibitor (PD98059) protects against CI-A-induced antiproliferation in oral cancer cells. CI-A upregulates phosphorylated ERK in oral cancer cells compared to normal cells. Notably, a ROS inhibitor, N-acetylcysteine (NAC), attenuates all CI-A-modulated changes. Moreover, the CI-A-triggered annexin V-detected apoptosis and caspase 3/8/9 activations of oral cancer cells were downregulated by PD98059. In conclusion, CI-A induces the oxidative-stress- and ERK-dependent antiproliferative and apoptotic mechanism in oral cancer cells and shows the benefit of non-cytotoxicity to normal cells.

INTRODUCTION:Callicarpa rubella is a notable folk medicinal plant of the genus Callicarpa. It is extensively ethnobotanically used for its traditional uses to cure rheumatism, inflammation, and pain in traditional Chinese medicinal systems. OBJECTIVES:This study aimed to isolate unreported diterpenoids with anti-inflammatory activities. MATERIAL AND METHODS:The planar structures of unreported compounds were characterized by interpreting 1D and 2D NMR spectra and HREIMS data. The absolute configurations were determined by comparing the experimental ECD spectra with calculated ECD ones. The potential anti-inflammatory activities of all isolated compounds were assessed by testing their in vitro inhibitory effects against superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. RESULTS:Investigation of chemical constituents from the leaves and twigs of C. rubella leads to the isolation of four unreported diterpenoids (1-4) along with 17 known diterpenoids (5-21). The results showed compounds 1, 3, 5-7, 9, 12, 16, 18, and 20 have potent inhibition against FMLP/CB-induced superoxide anion generation with IC50 values range from 1.37 ± 0.09 μM to 6.29 ± 1.14 μM, while compounds 3, 6, 7, 9, 12, 16, 18, and 20 showed potent inhibition of elastase release with IC50 ranging from 1.47 ± 0.15 μM to 5.79 ± 1.16 μM. CONCLUSION:The results obtained from the current study will enhance our understanding of diterpenoids from the Callicarpa genus and support the identification of unreported diterpenoids with potential anti-inflammatory agents.

Two novel alkaloids, zoanides A and B (1 and 2), 12 new zoanthamine-type alkaloids (3-14), together with two known compounds (15 and 16) were obtained from the zoantharian Zoanthus vietnamensis. Their structures and absolute configurations were established by extensive spectroscopic data, DP4+ probability calculation, and X-ray crystallographic analyses. Structurally, compound 1 represents an unusual functionalized skeleton caused by oxidative cleavage; compound 2 possesses an unprecedented 6/6/5/6/7-fused pentacyclic carbon skeleton. Additionally, the plausible biosynthetic pathways of 1 and 2 were proposed. All isolates were evaluated in vitro for neuroprotection. Among them, compounds 2, 3, 8, 9, and 15 exhibited neuroprotection against paclitaxel-induced neurite damage without interfering with the anticancer effects of paclitaxel. Moreover, compounds 2 and 9 demonstrated moderate protective effects against oxaliplatin-induced oxidative stress overload without interfering with the anticancer effects of oxaliplatin.

Soft corals of the genus Caementabunda (synonym Cespitularia) were reported to possess terpenoids with various carbon skeletons. In this research, samples of C. hypotentaculata were collected before and after spawning (in May and August) to compare their secondary metabolites. With the aid of LC–MS/MS molecule networking, a series of unknown verticillane-type diterpenoids were targeted. After repeated column chromatography, five new verticillane-type diterpenoids (1‒5) and one new eudesmanolide-type sesquiterpenoid (6), together with twenty-four known compounds (7‒30), were identified from the Formosan soft coral C. hypotentaculata. Their structures were determined by UV, IR, MS, and NMR analyses, together with the biogenetic considerations of terpenoids. Our pharmacological study showed that the ethanol extract of C. hypotentaculata exhibited antiangiogenic potential against human endothelial progenitor cells. Among all isolated compounds, compound 30 demonstrated a moderate antiangiogenic effect with an IC50 value of 29.0 ± 0.6 μM.

Three new scalarane-type sesterterpenoids, lendenfeldaranes W-Y (1-3), along with a known analogue, lendenfeldarane D (4), were isolated from a marine sponge identified as Lendenfeldia species. The structures of all isolates were determined based on spectroscopic methods. Scalarane 1 exhibited significant activity in enhancing alkaline phosphatase (ALP) activity.

INTRODUCTION:The present investigation of Nymphoides hydrophylla is a Taiwan indigenous edible aquatic plant, belongs to the Menyanthaceae family, and has been used as a traditional food with potential medicinal values against fever, insect bites, ulcer, and skin diseases. Interestingly, we found that the plant extract showed a significant anti-inflammatory effect. OBJECTIVES:The aim is isolation, structure elucidation, and anti-inflammatory evaluation of secondary metabolites from N. hydrophylla. MATERIAL AND METHODS:This study involves the bioactive isolation and structural studies of the pure compounds determined by NMR, UV, IR spectroscopies, and HRMS. The anti-inflammatory activity of the pure compounds was evaluated in vitro. In addition, isolates showed remarkable anti-inflammatory activities to regulate superoxide anion generation and elastase release in fMLF/CB-induced human neutrophils. RESULTS:This study conducted 10 oleanane-type saponins with oligoglycoside linkage, including two new (1 and 2) identified from the butanol extract of N. hydrophylla. As a result, Compounds 1 and 2, representing new triterpene saponins, have not been previously reported. In vitro anti-inflammatory tests revealed that Compounds 1, 5-7, 9, and 10 showed significant anti-inflammatory effects by inhibiting superoxide anion generation with IC50 values of 1.62, 0.92, 0.28, 2.69, 0.29, and 0.15 μM, respectively, whereas compounds 1, 5, 6, 9, and 10 showed potential inhibition on elastase release in human neutrophils, with IC50 values of 0.19, 1.12, 0.70, 0.68, and 0.51 μM, respectively. CONCLUSION:Our findings suggested that the components of N. hydrophylla have the potential to develop anti-inflammatory agents.

Integrating genome mining with LC-MS/MS-based molecular networking analysis has revealed that the extract of the endophytic fungus Penicillium sclerotiorum represents a promising source for the discovery of new azaphilone analogues. Two rare polyketide derivatives (1 and 2), along with 11 new sclerotiorin-type azaphilones (3-13) and eight known compounds (14-21), were isolated from the macroalga-associated fungus P. sclerotiorum. The structural elucidation of these compounds was achieved using ECD, HR-ESI-MS, and NMR spectroscopic analyses. The absolute configurations of compounds 1 and 2 were determined through X-ray single-crystal diffraction. The antilymphangiogenic potential of these isolates was assessed in vitro using human lymphatic endothelial cells (LECs). Compounds 4 and 14, both nitrogenated azaphilones, exhibited significant inhibitory activity, displaying IC50 values of 5.7 ± 0.2 and 5.8 ± 0.2 μg/mL, respectively.

Octocoral of the genus Clavularia is a kind of marine invertebrate possessing abundant cytotoxic secondary metabolites, such as prostanoids and dolabellanes. In our continuous natural product study of C. spp., two previously undescribed prostanoids [clavulone I-15-one (1) and 12-O-deacetylclavulone I (2)] and eleven known analogs (3–13) were identified. The structures of these new compounds were elucidated based on analysis of their 1D and 2D NMR, HRESIMS, and IR data. Additionally, all tested prostanoids (1 and 3–13) showed potent cytotoxic activities against the human oral cancer cell line (Ca9-22). The major compound 3 showed cytotoxic activity against the Ca9-22 cells with the IC50 value of 2.11 ± 0.03 μg/mL, which echoes the cytotoxic effect of the coral extract. In addition, in silico tools were used to predict the possible effects of isolated compounds on human tumor cell lines and nitric oxide production, as well as the pharmacological potentials.

The ancient Chinese medical book “Compendium of Materia Medica” records that pears can relieve symptoms of respiratory-related diseases. Previous research has shown that pear Pyrus Pyrifolia (Burm.f.) Nakai has antioxidant and anti-inflammatory properties. However, the anti-inflammatory, antioxidant, and anti-photoaging protective effects of Pyrus pyrifolia (Burm.f.) Nakai seed components have not been studied. Ultraviolet light (UV) causes skin inflammation, damages the skin barrier, and is an important cause of skin photoaging. Therefore, UV light with a wavelength of 365 nm was used to irradiate HaCaT and mice. Western blot, real-time quantitative polymerase chain reaction, and fluorescence imaging system were used to explore its anti-UVA mechanism. Dialysis membrane and nuclear magnetic resonance were used for the chemical constituent analysis of pear seed water extract (PSWE). We found that PSWE can significantly reduce UVA-induced skin cell death and mitogen-activated protein kinase phosphorylation and can inhibit the mRNA expression of UVA-induced cytokines (including IL-1β, IL-6, and TNF-α). In addition, PSWE can also reduce the generation of oxidative stress within skin cells. In vivo experimental studies found that PSWE pretreatment effectively reduced transepidermal water loss, inflammation, redness, and dryness in hairless mice. The molecular weight of the active part of pear water extract is approximately 384. Based on the above results, we first found that pear seeds can effectively inhibit oxidative stress and damage caused by UVA. It is a natural extract with antioxidant properties and anti-aging activity that protects skin cells and strengthens the skin barrier.

Sixteen azaphilone derivatives, including four new compounds, penicilazaphilones H and I (1 and 2), 11-epi-geumsanol F ( 3), and 11-epi-geumsanol B (4), together with twelve known analogues (5-16), were isolated from the algae-derived fungus Penicillium sclerotiorum purified from fresh marine macroalgae Grateloupia sp. The planar structures of 1-4 were identified by HRESIMS, IR, NMR, and UV spectroscopic analyses. Their absolute configurations were unambiguously determined by comparing the NMR and ECD spectra. These secondary metabolites were evaluated on the anti-angiogenic effect in human endothelial progenitor cells (EPCs). As a result, compounds 12, 14, and 16 exhibited anti-angiogenic activities by blocking cell growth, migration, and tube formation of EPCs. Additionally, the structure-activity relationships (SAR) for anti-angiogenic effects of isolated azaphilones were deduced.

Five new eudensamane-type sesquiterpene lactones, clasamanes A–E (1–5), three new dolabellane-type diterpenes, clabellanes A–C (6–8), and fifteen known compounds (9–23) were isolated from the ethanolic extract of Taiwanese soft coral Clavularia spp. The structures of all undescribed components (1–8) were determined by analysis of IR, mass, NMR, and UV spectroscopic data. The absolute configuration of new compounds was determined by using circular dichroism and DP4+ calculations. The cytotoxic activities of all isolated marine natural products were evaluated. Compound 7 showed a significant cytotoxic effect against oral cancer cell line (Ca9-22) with an IC50 value of 7.26 ± 0.17 μg/mL.

Three new alkaloids, hipporidine A ( 1 ), hipporidine B ( 2 ), and (-)-lobeline N -oxide ( 3 ), were discovered from the whole plant of Hippobroma longiflora together with five known compounds ( 4 - 8 ). Their 2,6-disubstituted piperidine structures were established based on the HRESIMS, NMR (COSY, HMBC, HSQC, NOESY), and UV spectroscopic data. Hipporidines A ( 1 ) and B ( 2 ) possess a rare 1,3-oxazinane moiety. Compound 3 is the N -oxide derivative of (-)-lobeline ( 6 ). Moreover, the absolute configuration of norlobeline ( 5 ) was established by single-crystal X-ray diffraction analysis. Three major secondary metabolites ( 6 - 8 ) were evaluated for their neuroprotective effect against paclitaxel-induced neurotoxicity. Consequently, pretreatment with compound 8 at a concentration of 1.0 mu M displayed significant attenuation on paclitaxel-damaged neurite outgrowth of dorsal root ganglion neurons without interfering with the cytotoxicity of paclitaxel on cervical cancer SiHa cells.

Background: Lung cancer is one of the most common cancers worldwide and is by far the leading cause of cancer death attributed to its rapid metastasis and poor prognosis. Given that hypoxia-inducible factors (HIFs) are associated with cancer metastasis, discovering agents to inhibit HIF-mediated invasive cancer is highly desired. Purpose: This study aimed to investigate the natural acridone compounds isolated from Severinia buxifolia for the potential to delay hypoxia-induced lung cancer invasiveness by HIF inhibition. Methods: Using a hypoxia-responsive element (HRE) luciferase reporter, cell migration and invasion assays, real-time PCR, Western blot, and DNA recombinant clones, compound effect on HIF activity, cancer metastasis, HIF-1 alpha mRNA transcription, HIFs protein stability, and HIF-1 alpha translation were observed under hypoxia conditions. Results: Atalaphyllidine (Sbs-A) and atalaphyllinine (Sbs-B) were found to show the most potent effects on HIF transcriptional activity and HIF-1 alpha protein expression in NSCLC cell line A549, although Sbs-A and Sbs-B might not attribute decreasing HIF-1 alpha mRNA expression to potent inhibition of HIF activity. HIF-1 alpha protein stability was not affected by Sbs-A; also, prolyl hydroxylase and proteasome inhibitors could not reverse the inhibitory effect from compounds. Furthermore, 3 - 10 mu M low concentrations of Sbs-A inhibited HIF target gene expression, gelatin zymography activity, and A549 cancer invasion. Ultimately, Sbs-A inhibited HIF-1 alpha 5 ' UTR-mediated translation independent of oxygen concentration, underlying the mechanism of compounds inhibiting HIF-1 alpha protein expression. Conclusion: Our study proposed Severinia buxifolia-isolated acridone compounds inhibited 5'-mRNA HIFA-mediated translation and provided evidence supporting the ability of acridone compounds in targeting HIF alpha for delayed lung cancer metastasis.

Physalis plants are commonly used traditional medicinal herbs, and most of their extracts containing withanolides show anticancer effects. Physapruin A (PHA), a withanolide isolated from P. peruviana, shows antiproliferative effects on breast cancer cells involving oxidative stress, apoptosis, and autophagy. However, the other oxidative stress-associated response, such as endoplasmic reticulum (ER) stress, and its participation in regulating apoptosis in PHA-treated breast cancer cells remain unclear. This study aims to explore the function of oxidative stress and ER stress in modulating the proliferation and apoptosis of breast cancer cells treated with PHA. PHA induced a more significant ER expansion and aggresome formation of breast cancer cells (MCF7 and MDA-MB-231). The mRNA and protein levels of ER stress-responsive genes (IRE1α and BIP) were upregulated by PHA in breast cancer cells. The co-treatment of PHA with the ER stress-inducer (thapsigargin, TG), i.e., TG/PHA, demonstrated synergistic antiproliferation, reactive oxygen species generation, subG1 accumulation, and apoptosis (annexin V and caspases 3/8 activation) as examined by ATP assay, flow cytometry, and western blotting. These ER stress responses, their associated antiproliferation, and apoptosis changes were partly alleviated by the N-acetylcysteine, an oxidative stress inhibitor. Taken together, PHA exhibits ER stress-inducing function to promote antiproliferation and apoptosis of breast cancer cells involving oxidative stress.