Chloranthus holostegius, a perennial herbaceous plant of the family Chloranthaceae, is predominantly distributed in southern China and exhibits significant value in both horticultural and medicinal applications. In this study, nine previously undescribed lindenane-type sesquiterpenoid homo/heterodimers with diverse skeletons, designated as chlorholidenes A-I (1-9), including two novel naphthalene-fused norlindenane sesquiterpenoid dimers (1-2), two lindenane-type sesquiterpenoid dimers with naphthalene skeleton and 18-membered macrocycle (3-4), a 8,9-seco lindenane-type sesquiterpenoid dimer with an 18-membered macrocycle (5), a 2,3-seco lindenane-type dimer with [6 + 6] cycloaddition-formed 12-membered ring (6), an eudesmane-lindenane heterodimer (7), an lindenane-type sesquiterpenoid dimer with an oxaspiro [4.5]decane skeleton (8), and a classical lindenane dimer (9), together with two known acorane-lindenane heterodimers (10-11), were isolated from C. holostegius. Their structures were elucidated using 1D/2D NMR, HRESIMS, and ECD calculations. In vitro antiinflammatory assays showed compounds 3, 4, and 11 exhibited significant inhibition of LPS-induced NO release in RAW 264.7 cells (IC50: 12.14-16.13 & micro;M), outperforming dexamethasone (IC50 = 18.43 +/- 3.17 & micro;M). Compound 3 also suppressed neutrophil recruitment and ROS accumulation in CuSO4-induced inflammatory zebrafish in vivo. Mechanistically, compound 3 regulated the NF-kappa B/JAK pathways by inhibiting phosphorylation of key proteins (IKK-alpha/beta, I kappa B-alpha, p65, JAK1-3, TYK2) and blocking NF-kappa B p65 nuclear translocation. This study enriches lindenane sesquiterpenoid dimers structural diversity and identifies compound 3 as a promising lead for antiinflammatory drug development.

Mitophagy, the selective autophagic degradation of mitochondria, often acts as a pro-survival mechanism in tumor cells, including Glioblastoma (GBM), by clearing damaged mitochondria and mitigating oxidative stress. GBM is a highly aggressive brain tumor characterized by profound resistance to conventional therapies. Our recent study identified Molephantin (EM-5), a natural small molecule capable of crossing the blood-brain barrier, as a potent anti-GBM agent. Mechanistically, EM-5 triggers severe mitochondrial dysfunction and massive reactive oxygen species (ROS) production in GBM. Crucially, we discovered that EM-5 acts as a novel late-stage mitophagy inhibitor. It specifically blocks the fusion of mitophagosomes with lysosomes without affecting early autophagosome formation or lysosomal acidification. This ROS-driven fusion defect leads to the toxic accumulation of damaged mitochondria, thereby amplifying oxidative stress and driving GBM cells into apoptosis. Collectively, our work establishes that targeting late-stage mitophagy flux via ROS modulation is a valuable paradigm for the discovery and development of therapeutic agents against GBM.

Six undescribed Daphniphyllum alkaloids, daphcalycines E-J (1-6), possessing structurally diverse skeletal frameworks, were isolated from the seeds of Daphniphyllum calycinum. Their structures and relative configurations were elucidated by comprehensive spectroscopic analysis, including extensive 2D NMR techniques and single-crystal X-ray diffraction. Compounds 1-6 were evaluated in vitro for cytotoxicity and for their effects on oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in H9c2 cells. None of the compounds showed detectable cytotoxicity at 10 μM. Under the OGD/R conditions, compound 4 (Daphcalycine H) significantly increased cell viability at 10 μM, indicating a measurable protective effect in this ischemia-reperfusion-like cell model, with an EC50 value of 4.862 μM. Further ROS analysis showed that compound 4 attenuated OGD/R-induced ROS accumulation in H9c2 cells.

Five new sesquiterpenoids, named torijapolides A‒E, including three germacrane-type (1‒3) and two cadinene-type sesquiterpenoids (4‒5), were isolated from the fruits of Torilis japonica. Their structures were elucidated through comprehensive spectroscopic analysis, including MS, UV, IR, and 1D/2D NMR and quantum chemical calculations of electronic circular dichroism (ECD). In bioactivity evaluation, all isolates were evaluated for their inhibition effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells. Among them, compounds 1 and 2 exhibited significant inhibition of NO release, with IC50 values of 8.38 ± 0.06 µM and 10.27 ± 0.68 µM, respectively.

Four novel Daphniphyllum alkaloids with highly rearranged skeletons involving a 6/5/7/7/5 pentacyclic scaffold ( 1 ), a 6/5/7/5/6/5/6 heptacyclic scaffold ( 2 and 4 ), and a 6/5/7/5/6/5 hexacyclic scaffold ( 3 ), were isolated from Daphniphyllum calycinum. Particularly, compound 1 contains a unique 13-oxa-17-aza-pentacyclo[7.6.4.112,15.04,8.09,15] eicosane core. Their structures were elucidated by comprehensive spectroscopic analyses, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Putative biosynthetic pathways for compounds 1-4 were discussed with caldaphnidine C ( 5 ) as their biosynthetic precursor. Compound 2 markedly enhanced the survival of H9c2 cardiomyocytes under oxygen glucose deprivation and reoxygenation conditions. Mechanistic study revealed that 2 exerted its cardioprotective effects by activating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) antioxidant pathway, thereby enhancing cellular antioxidant capacity and alleviating oxidative stress induced by hypoxia. (c) 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

C25H38O5, orthorhombic, P212121, a = 8.80210(10) & Aring;, b = 10.91830(10) & Aring;, c = 24.8521(2) & Aring;, V = 2388.39(4) & Aring;3, Z = 4, Rgt(F) = 0.0340, wRref(F2) = 0.0930, T = 170 K.

For colorectal cancer (CRC), treatment outcomes and prognosis remain poor even when using first-line chemotherapeutics and immunotherapeutics. The main reasons include (i) lack of tumor specificity, severe off-target cytotoxicity leading to adverse side effects, and occurrence of chemoresistance, and (ii) the immunosuppressive "cold" tumor microenvironment (TME). Herein, we demonstrate an example of highly efficient targeted CRC chemoimmunotherapy with cisplatin (CDDP)-containing nanomedicine (CDDP@MSN-Anti-CD47) in a patient-derived organoids xenograft model. The CDDP@MSN-Anti-CD47 is composed of CDDP-loaded mesoporous silica nanoparticles with superficially functionalized anti-CD47 antibodies to target cluster of differentiation CD47, a transmembrane integrin-associated protein that is over-expressed in CRC cells and can bind with signal regulatory protein alpha on tumor-associated macrophages (TAMs) to maintain the immunosuppressive TME. Our results demonstrated that CDDP@MSN-Anti-CD47 achieved targeted delivery of CDDP to CRC cells with extended release, and induced reactive oxygen species overproduction to inhibit CRC cells and CRC patient-derived organoids growth via activating caspase-3-related apoptosis and immunogenic cell death. DAMPs released following CDDP@MSN-Anti-CD47 treatment promoted the polarization of TAMs from immunosuppressive M2 to pro-inflammatory M1 phenotype and also synergized with the functionalized anti-CD47 antibodies to restore macrophage phagocytic activity against CRC cells. In both CRC cell and patient-derived organoid xenograft models, CDDP@MSN-Anti-CD47 could specifically target the tumor, showing strong anti-tumor effects, prolonged survival rate, and low systemic cytotoxicity. Overall, CDDP@MSN-Anti augments combination chemotherapy and immunotherapy, and can be developed as a novel and promising strategy for the clinical treatment of CRC.

A phytochemical study on the stems of Tinospora sinensis led to the isolation of ten previously undescribed compounds, including three new clerodane diterpenoids (1-3), three new lignans (10-12), two new phenylpropanoids (17 and 18), and two new amide alkaloids (22 and 23), along with 16 known compounds (4-9, 13-16, 19-21, 24-26). Their structures and absolute configurations were elucidated through extensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction. All isolated compounds were evaluated for their α-glucosidase inhibitory and nitric oxide (NO) production activities. Notably, compounds 11, 14, and 26 exhibited significantly α-glucosidase inhibitory activity, with IC50 values of 13.57 ± 0.12, 11.30 ± 0.21, and 4.41 ± 0.02 μM, respectively. Additionally, compounds 21 and 22 significantly suppressed NO production in LPS-induced RAW 264.7 macrophage cells, with IC50 values of 10.26 ± 1.00, and 8.02 ± 0.92 μM, respectively.

A phytochemical study of Tripterygium wilfordii root bark was conducted 25 novel dihydro-β-agarofuran sesquiterpenoids (1-25) and 20 known analogues (26-45). Structural analysis elucidated by comprehensive spectroscopic analysis, including X-ray crystallography and electronic circular dichroism (ECD). Anti-neuroinflammatory assessments in BV-2 cells revealed certain compounds effectively suppressed tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). A preliminary structure-activity relationships analysis explored the relationship between compound structure and their inflammatory mediator inhibition. Notably, compound 7 modulated nuclear factor-κB (NF-κB) signaling by inhibiting IκBα and p65 phosphorylation. These findings offer novel perspectives on the bioactivity and anti-neuroinflammatory mechanisms of Tripterygium wilfordii derivatives.

Lung cancer, 85% of which is non-small cell lung cancer (NSCLC), is the cancer with the highest incidence and mortality rate worldwide. Despite recent advancements in therapeutic approaches, the efficacy of conventional radiotherapy and chemotherapy remains suboptimal, highlighting the urgent need for more effective treatment strategies. Dysregulation of kinases MST1 and MST2 (MST1/2) is implicated in the progression of NSCLC, positioning MST1/2 as a potential therapeutic target. However, no high-selectivity and high-efficacy MST1/2 activator is identified to date. In this study, by using computer-aided virtual screening combined with cell experiments, EM2 is identified as a promising MST1/2-binding candidate. Subsequent experimental validation demonstrates that EM2 significantly suppresses the proliferation, migration, and invasion of NSCLC cells by directly targeting MST1/2 and enhancing its kinase activity, thereby activating the Hippo signaling pathway and reducing nuclear translocation of the downstream effector YAP. Both in vivo xenograft models and organoid models demonstrates that EM2 effectively suppresses NSCLC tumor growth. In summary, this study not only reaffirms MST1/2 as a viable therapeutic target for NSCLC but also provides compelling experimental evidence supporting EM2 as a highly effective and promising anti-cancer agent.

Four undescribed 3,4-seco-labdane diterpenoid derivatives (nudifloids O-R) along with 12 known terpenoids were isolated from the aerial part of Callicarpa nudiflora Hook. et Arn. Nudifloids O and P (compounds 1 and 2) represent the first examples of 3,4-seco-labdane diterpenoid coupled with 2-methylene-3-butenal likely via the Diels-Alder reaction, forming a rare cyclohexene moiety. The structures including absolute configurations were elucidated using comprehensive spectral data, calculated 13C NMR-DP4+ probability analysis, and electronic circular dichroism. Putative biosynthetic pathways for nudifloids O and P were proposed. All isolates were evaluated for their inhibitory activities on NO and IL-1β production in the LPS-stimulated RAW 264.7 macrophage cells. Nudifloids P (compound 2) showed potent inhibitory activities against IL-1β and NO production.

Advanced algorithms have significantly improved the efficiency of in vitro screening for protein-interactive compounds. However, target antigen (TAA/TSA)-based drug discovery remains challenging, as predictions of compound-protein interaction (CPI) based solely on molecular structure fail to fully elucidate the underlying mechanisms. In this study, we utilized deep learning, specifically TransformerCPI to screen active molecules from a Chinese herb compound library based on protein sequences. Two natural products, Polyphyllin V and Polyphyllin H, were identified as targeting the pan-cancer marker CD133. Their anti-tumor efficacy and safety were confirmed across validation in cancer cell lines, tumor patient-derived organoids, and animal models. Despite their analogous structures and binding affinity to CD133, Polyphyllin V suppresses the PI3K-AKT pathway, inducing pyroptosis and blockage of mitophagy, whereas Polyphyllin H inhibits the Wnt/β-catenin pathway and triggers apoptosis. These distinct mechanisms underscore the potential of combining AI-driven screening with biological validation. This AI-to-patient pipeline identifies Polyphyllin V and Polyphyllin H as CD133-targeted drugs for pan-cancer therapy, and reveals the limitations of virtual screening alone and emphasizes the necessity of live model evaluation in AI-based therapeutic discovery.

Seven novel acylphloroglucinol-sesquiterpenoid adducts, designated as dryatraols J-P (1-7), were isolated from the rhizomes of Dryopteris atrata (Wall. ex Kunze) Ching. The structures, including absolute configurations, were elucidated using comprehensive spectroscopic data, calculated 13C Nuclear Magnetic Resonance-Diastereotopic Probability Assignment Plus (13C NMR-DP4+) probability analysis, and ECD calculations. These structures represent a rare subclass of carbon skeleton of acylphloroglucinol-sesquiterpenoid adducts with a furan ring connecting the acylphloroglucinol and sesquiterpenoid moieties. Notably, compounds 1-6 are the first reported examples of acylphloroglucinol-sesquiterpenoid adducts with dimeric acylphloroglucinol incorporated into the aristolane- or rulepidanol-type sesquiterpene, while compound 7 features a hydroxylated monomeric acylphloroglucinol motif. A preliminary evaluation of their antiviral activities revealed that compounds 1-6 exhibited more potent activities against respiratory syncytial virus (RSV) with IC50 values ranging from 0.75 to 3.12 μmol·L-1 compared to the positive control (ribavirin).

Peganum harmala L. (P. harmala) is a significant economic and medicinal plant. The seeds of P. harmala have been extensively utilized in traditional Chinese medicine, Uighur medicine, and Mongolian medicine, as documented in the Drug Standard of the Ministry of Health of China. Twelve novel tryptamine-derived alkaloids (1-12) and eight known compounds (13-20) were isolated from P. harmala seeds. Compounds 1 and 2 represent the first reported instances of tryptamine-derived heteromers, comprising tryptamine and aniline fragments with previously undocumented C-3-N-1' linkage and C-3-C-4' connection, respectively. Compounds 3-5 were identified as indole-quinazoline heteromers, exhibiting a novel C-3 and NH-1' linkage between indole and quinazoline-derived fragments. Compound 6 demonstrates the dimerization pattern of C-C linked tryptamine-quinazoline dimer. Compound 8 represents a tryptamine-derived heterodimer with a distinctive carbon skeleton, featuring an unusual spiro-tricyclic ring (7) and conventional bicyclic tryptamine. Compounds 9-11 constitute novel 6/5/5/5 spiro-tetracyclic tryptamine-derived alkaloids presenting a unique ring system of tryptamine-spiro-pyrrolizine. Compounds 1-3 and 6-11 were identified as racemates. Compounds 2, 7, 9, 10, and 12 were confirmed via X-ray crystallographic analysis. All isolated compounds (1-20) exhibited varying degrees of antiviral efficacy against respiratory syncytial virus (RSV). Notably, the anti-RSV activity of compound 12 (IC50 5.01 ± 0.14 μmol·L-1) surpassed that of the positive control (ribavirin, IC50 6.23 ± 0.95 μmol·L-1), as validated through plaque reduction and immunofluorescence assays. The identification of anti-RSV compounds from P. harmala seeds may enhance the development and application of this plant in antiviral therapeutic products.

The four matrine-derived alkaloids, namely sophflarines B-E (14), with distinct skeleton types, were isolated from Sophora flavescens. Compounds 1 and 2 possess rare 1-aza-11-oxatricyclo[5.3.1.02,6] undecane cores, featuring unprecedented N,O-heterocyclic systems of 5/5/6/6/6 and 6/5/5/6/6, respectively. Compounds 3 and 4 exhibit two novel C 15 units with tetracyclic skeletons of 5/6/6/6 and 6/5/6/6, respectively. The structures were elucidated through spectroscopic analyses, quantum chemical calculations, and X-ray diffraction data. A plausible biosynthetic pathway for these newly discovered compounds was proposed. Furthermore, compounds 1 and 2 showed anti-neuroinflammatory activity against the cytokines NO, TNF-alpha, and IL-6. Compound 2 exhibited a neuroprotective effect potentially mediated by activating the Keap1-Nrf2/HO-1 pathway to reduce inflammation and oxidative stress.

Caramel pigment (CP), one of the most widely used food coloring agent in food industry, whose chemical composition as well as safety research has not been deeply clarified yet. Therefore, we systematically separated the chemical components and identified the structures of CP, which is commonly used in the market, in order to explain the specific chemical composition of CP. This study selected type III and IV CPs as the research objects, and the main components were isolated through separation methods such as column chromatography (CC), high performance liquid chromatography (HPLC), and preparative HPLC. Then, their chemical structures were elucidated by nuclear magnetic resonance (NMR), mass spectrometry (MS), and other methods. As a result, twelve fat-soluble constituents were isolated, mainly furan, pyrazine, and pyridine compounds, three of which (compounds 1-3) were new compounds, and eight ones were identified for the first time from CP. After that, the possible formation pathways of the products in the Maillard reaction were inferred. The cytotoxic effects of isolates and their digestion and absorption processes in vitro simulated digestion system were also studied. As a result, these components did not show obvious toxicity at concentrations of 25-100 mu g/mL, which has laid the foundation for chemical profiling of CP and their toxicity, providing scientific research data for further in-depth study of the quality standard and safety of CP.

Three novel β-carboline alkaloid dimers, pecanthines A–C (1−3), featuring unprecedented 6/5/6/6-5/6 and 6/5/6/6/5/6 polycyclic frameworks, were isolated from the seeds of Peganum harmala. Their structures were elucidated by spectroscopic analyses and X-ray diffraction. Notably, compounds 1 and 2 represent the first heterodimeric alkaloids merging canthin-6-one and melatonin-type scaffolds, with 1 additionally displaying neuroprotective activity. In addition, a gram-scale synthesis of 3 was achieved in six steps, leveraging a key acyl-ketene imine condensation and Suzuki coupling. Biological evaluation revealed that 3 acts as a new topoisomerase I (Topo I) inhibitor, exhibiting remarkable antiproliferative activity. Mechanistic studies demonstrated that 3 induces DNA damage, triggering apoptosis and cell cycle arrest in cancer cells. The discovery and gram-scale synthesis of 3 provide a promising lead compound and a novel molecular scaffold for anticancer drug development.

Ethnopharmacological relevance The root of Croton crassifolius Geiseler (C. crassifolius), commonly known as "Jiguxiang" in traditional Chinese medicine, is globally recognized for its ethnomedical applications in treating a spectrum of diseases. Crassifolin A (CA), a diterpenoid compound extracted from the roots of C. crassifolius, exhibits anti- herpes simplex virus (HSV), anti-viral and anti-angiogenic properties. Aim of the review This study aimed to explore the effects of CA on aging and the mechanisms involved. Materials and methods Utilizing Caenorhabditis elegans (C. elegans) as a model organism, we conducted a comprehensive survival analysis and evaluated aging-related phenotypes, including the period of fast body movement and body bending rates. To elucidate the molecular mechanisms of CA’s impact on aging, we employed a multifaceted approach, including reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, and fluorescence quantification of transgenic reporter strains. Results Our findings demonstrated that CA significantly prolonged both the lifespan and healthspan of C. elegans. The survival benefits conferred by CA were found to correlate with the activation of several key aging-related signaling pathways, including insulin/insulin-like signaling pathway (IIS), dietary restriction (DR) pathway, and germline signaling pathway. Engagement of these pathways led to the activation of transcription factors DAF-16/FOXO, SKN-1/NRF2, HSF-1 and HLH-30/TFEB, as well as the nuclear receptor DAF-12. Consequently, this activation cascade prompted an upregulation of autophagy, a cellular process associated with the maintenance of cellular homeostasis and longevity. Conclusion Our study delineates novel mechanisms underlying anti-aging strategies, establishing a conceptual framework for the exploitation and advancement of traditional Chinese medicinal herbs as potential therapeutic agents in the fight against aging and its associated pathologies.

Five new terpenoids, including one isocamphane-type monoterpenoid (1), one labdane-type diterpenoid (2), and three cadinane-type sesquiterpenoids (3‒5), were isolated from the whole plant of Chloranthus holostegius. A combination of spectral analysis (HR-ESI-MS, UV, IR, and 1D/2D NMR), quantum chemical calculations (NMR/ECD), and X-ray crystallography were employed in the structural characterization. In anti-inflammatory assays, all isolates were evaluated by examination of their inhibitory effects on nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells, and compounds 1 and 5 exhibited moderate inhibitory activity against NO release, with IC50 values of 21.16 ± 1.37 and 18.03 ± 1.24 µM, respectively.